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WORLD HOSPITAL DIRECTORY has the World's largest online database of general, multispeciality, eye, dental, children, maternity, cardiac care, orthopedic, nephrology, neurology, diabetic, psychiatric, cancer, ENT, hospice, Rehabilitation, alternate medicine, veterinary hospitals across globe. Discover the complete list of hospitals available in North America, South America, Europe, Asia, Australia, New Zealand, rest of the world and online.

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CEMIC
Category: General Hospitals

Argentina
South America, America

Croydon Hospital (Tablelands HSD)
Category: Mulispeciality Hospitals

Australia
Australia and New Zealand, Oceanic

Regionaal Hospital Sint-Maria
Category: Mulispeciality Hospitals

Belgium
Western Europe, Europe

Bairro Passo D'areia Farmaconte Dist. Produtos Hospitalares Ltda.
Category: Mulispeciality Hospitals

Brazil
South America, America

BCIT - Technology Centre, Health Technology Research Group
Category: General Hospitals

Canada
North America, America

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8.	Physicians, Chiropractors and Physical Therapist Agree on a New Treatment for Low Back Pain One of the most prevalent and difficult health conditions to treat in the physical medicine is low back pain. The difficulty in tre More >>
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15.	Contact Lenses and Eye Glasses How is Your Vision? Notice friends getting contact lenses and pulling out eye glasses? "What do you recommend?" More >>
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18.	New Surgical Treatment Options for Hernias Hernia repair is one of the most commonly performed surgical procedures worldwide. In fact, there are over 600,000 hernia repa More >>
19.	Arthritis Pain Relief : FAQ A great place to begin taking charge of you arthritis pain relief and prevention planning is by making an appointment with your healthc More >>
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21.	Root Canal Therapy:FAQ Overview A diseased or injured nerve use to mean that you were likely to lose a tooth. This is no longer the case thanks to root More >>
22.	ADHD - Are there Treatment Options? As an ADD coach I am often asked about the treatment options available for Attention Deficit Disorder. Generally when someone says "ADD" the f More >>
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The renal archaeologist: digging for clues in archived tissues to understand diabetic kidney disease

Opening a treasure chest: glomerular proteome analyses of formalin-fixed paraffin-embedded kidney tissue in the investigation of diabetic nephropathy

Can inhibition of proteasomes or NF-kappaB help control idiopathic nephrotic syndrome?

Measurement of serum soluble Klotho levels in CKD 5D patients: useful tool or dispensable biomarker?

Role of vitamin D in vascular calcification: bad guy or good guy?

Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension

FGF23 and PTH--double agents at the heart of CKD

Cellular adaptive changes in AKI: mitigating renal hypoxic injury

Hypoxia plays a role in ischemic, toxic and sepsis-induced acute kidney injury. Evolving hypoxia triggers renal adaptive responses that may mitigate the insult, leading to sublethal forms of cell injury. The unique capability of the kidney to downregulate oxygen consumption for tubular transport could represent one such adaptive response which promotes maintenance of renal oxygenation, thereby preserving cellular integrity. Tran et al. recently explored a novel mechanism that might prevent tubular damage by downregulation of mitochondrial biogenesis and oxygen consumption. Using expression profiling of kidney RNA in endotoxemic rodents and complementary studies in vitro and in PGC-1α knockout mice, they found a sepsis-related decline in PPAR coactivator-1α (PGC-1α) expression and of PGC-1α-dependent genes involved in oxidative phosphorylation. This response may explain their observation of a paradoxical preservation of kidney oxygenation and structural integrity in sepsis, despite reduced renal blood flow and oxygen delivery. Thus, resetting of mitochondrial respiration and oxygen consumption during sepsis might be added to the growing list of adaptive responses that occur during hypoxic stress. This review will focus on these mechanisms that mitigate evolving hypoxic injury, even at the expense of transient renal dysfunction.

Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment

Primary hyperoxaluria Type 1 is a rare autosomal recessive inborn error of glyoxylate metabolism, caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. The disorder results in overproduction and excessive urinary excretion of oxalate, causing recurrent urolithiasis and nephrocalcinosis. As glomerular filtration rate declines due to progressive renal involvement, oxalate accumulates leading to systemic oxalosis. The diagnosis is based on clinical and sonographic findings, urine oxalate assessment, enzymology and/or DNA analysis. Early initiation of conservative treatment (high fluid intake, pyridoxine, inhibitors of calcium oxalate crystallization) aims at maintaining renal function. In chronic kidney disease Stages 4 and 5, the best outcomes to date were achieved with combined liver–kidney transplantation.

Transcription of nephrin-Neph3 gene pair is synergistically activated by WT1 and NF-{kappa}B and silenced by DNA methylation

<sec><st>Background.</st> Nephrin and Neph3 are homologous molecules expressed in the podocyte slit diaphragms that are essential for normal glomerular ultrafiltration. Nephrin and Neph3 genes form a bidirectional gene pair suggesting that they may share key features in their regulation. We investigated if nephrin and Neph3 genes have similar mechanisms in their transcriptional regulation focussing on transcription factor Wilms’ tumour 1 (WT1) and nuclear factor-B (NF-B) and DNA methylation. </sec> <sec><st>Methods.</st> Transcriptional regulation of nephrin and Neph3 by WT1 and NF-B was analysed by overexpression studies, reporter gene assay and chromatin immunoprecipitation using A293 cells and cultured podocytes. The interaction between WT1 and NF-B was studied by co-immunoprecipitation. The effect of NF-B activator tumour necrosis factor-α (TNF-α) with or without NF-B pathway inhibitor (BAY 11-7082) on nephrin and Neph3 messenger RNA (mRNA) expression and on cellular distribution of NF-B was determined by quantitative polymerase chain reaction (PCR) and immunostaining, respectively. The role of DNA methylation in regulating nephrin and Neph3 genes was studied by demethylating agent (5-aza-2'-deoxycytidine) treatment and quantitative PCR. </sec> <sec><st>Results.</st> WT1 and NF-B interact with nephrin and Neph3 promoter and cooperatively regulate nephrin and Neph3. The cooperation was further supported by the physical interaction between WT1 and NF-B. TNF-α increased nephrin and Neph3 mRNA expression and this effect was mediated by NF-B. Furthermore, DNA methylation played a role in silencing nephrin and Neph3 expression in a cell-type and differentiation stage-dependent manner. </sec> <sec><st>Conclusion.</st> These results provide novel insights into the transcriptional regulation of nephrin and Neph3 genes and indicate that nephrin and Neph3 share the same mechanisms in their regulation. </sec>

Amiloride off-target effect inhibits podocyte urokinase receptor expression and reduces proteinuria

The urokinase receptor (uPAR) and its soluble form play a key role in the pathogenesis of focal segmental glomerulosclerosis (FSGS). The modification of uPAR pathological actions on podocytes will become an important task for the development of improved nephroprotective therapeutics. Here we show that podocyte uPAR expression can be reduced using amiloride. Amiloride has a significant role in the reduction of podocyte cell motility in vitro and proteinuria in mice. Amiloride inhibited the induction of uPAR protein and PLAUR messenger RNA (encoding uPAR) and with that it reduced uPAR-mediated β3 integrin activation in lipopolysaccharide (LPS)-treated podocytes. Transwell migration assay and wound healing assay showed that directed and random podocyte motility of LPS-treated podocytes were increased and substantially reduced by amiloride. The off-target effect of amiloride was independent of its function as epithelial sodium channel blocker and different from triamterene. Amiloride was also effective in the LPS mouse model of transient proteinuria (LPS mice) and in the 5/6 nephrectomy rat FSGS model (NTX) by significantly inhibiting podocyte uPAR induction, reducing proteinuria. In addition, amiloride attenuated glomerulosclerosis, as determined by glomerulosclerotic index. Thus, our observations show that amiloride inhibits podocyte uPAR induction and reduces proteinuria in NTX rats and LPS mice. Given the pathological relevance of the uPAR-β3 integrin signaling axis in FSGS, amiloride may be utilized in patients with FSGS.

Beneficial effects of integrin {alpha}v{beta}3-blocking RGD peptides in early but not late phase of experimental glomerulonephritis

<sec><st>Background.</st> Integrin αvβ3 plays an important role in the regulation of cell proliferation and neoangiogenesis. We found mesangial de novo expression of integrin αvβ3 in mesangioproliferative glomerulonephritis (MesGN). The aim of the study was to clarify if blockade of αvβ3 integrin with the specific αvβ3-blocking cyclic peptide RGDdFV (cRGD) has beneficial effects on the course of this disease. </sec> <sec><st>Methods.</st> Habu snake venom (Habu) GN was induced in male C57BL/6 mice 1 week after uninephrectomy (6 mg Habu toxin/kg body weight intravenously). After 24 h, nephritic animals received αvβ3-inhibitory cRGD or cRAD control peptides for 3 or 7 days, respectively. The kidneys were investigated using morphometry, immunohistochemistry and TaqMan polymerase chain reaction. </sec> <sec><st>Results.</st> At Day 3, serum creatinine and albuminuria were lower after cRGD compared to cRAD treatment. At Day 3, glomerulosclerosis index, percentage of glomerular injury, mesangial cell (MC) number and volume density of mesangial matrix were significantly lower (P < 0.05) in cRGD-treated mice than in cRAD-treated controls. At Day 7, only a mild effect of cRGD on mesangial matrix expansion and fibronectin messenger RNA was still detectable (P < 0.05). Complementary in vitro studies in MCs revealed that inhibition of αvβ3 by cRGD-blocked adhesion, reduced proliferation and increased apoptosis of MCs. </sec> <sec><st>Conclusion.</st> Habu GN inhibition of integrin αvβ3 by cRGD partly ameliorates early injury but has no or only mild effects on late glomerular lesions. </sec>

Are ex vivo mesothelial cells representative of the in vivo transition from epithelial-to-mesenchymal cells in peritoneal membrane?

<sec><st>Background.</st> We investigated whether ex vivo mesothelial cells found in peritoneal dialysis (PD) effluents were representative of the in vivo epithelial-to-mesenchymal transition (EMT) in peritoneal membrane. </sec> <sec><st>Methods.</st> Thirty-six male Sprague–Dawley rats were equally divided into three groups: Group C (control), no PD; Group D, infused with 4.25% Dianeal and Group P, infused with 4.25% Physioneal. PD infusions (25 mL) were given twice daily for 8 weeks. The in vivo study included morphometric analyses performed on the peritoneal membranes of tissue specimens obtained at the end of the study. The ex vivo study included peritoneal mesothelial cells collected from PD effluent and cultured to confluence. Cells were scored with light microscopy. </sec> <sec><st>Results.</st> PD for 8 weeks induced significant EMT. The in vivo expression of EMT markers (α-smooth muscle actin:E-cadherin ratio, matrix metalloproteinase-2 and Snail) was higher in Group D than in Group P. However, ex vivo EMT marker expression was similar in cells derived from Groups D and P. A significant correlation was observed among in vivo EMT markers. Moreover, the ex vivo cell score increased with time on PD. However, changes in the ex vivo cell score did not correlated with changes in the in vivo EMT marker expression. Furthermore, we found no correlation between ex vivo and in vivo cells in the expression of EMT markers. </sec> <sec><st>Conclusions.</st> In this animal study, ex vivo findings did not reflect the in vivo EMT changes in the peritoneum. It may be necessary to improve the current methodology for ex vivo studies. </sec>

Stem cells from foreign body granulation tissue accelerate recovery from acute kidney injury

<sec><st>Background.</st> In previous studies, we obtained mesenchymal stem cells called granulation tissue stem cells (GTSC) from a regenerating granulation tissue created by placing a foreign body in the subcutaneous tissue of rats. Here, we used GTSC to ameliorate ischemia/reperfusion-induced acute kidney injury (AKI) in rats. </sec> <sec><st>Methods.</st> In two groups of Fischer rats, we induced ischemia/reperfusion injury. Group 1 (treated rats) received one intravenous injection of GTSC 3 h after injury; Group 2 (control rats) received vehicle. Both groups were subsequently studied by renal function tests, kidney histology and immunohistochemistry. </sec> <sec><st>Results.</st> At 24 and 48 h after injury, plasma creatinine and blood urea nitrogen were significantly lower in the treated rats as compared to control rats. The levels remained low and declined to near baseline levels by Day 4 in the treated group. At the cortico-medullary region, the treated rats showed significantly higher renal tubular cell proliferation and less tubular cell apoptosis. Histological analysis of the kidney for tubular dilatation, necrosis, congestion and casts was not significantly different in the two groups. To understand the mechanism of the GTSC effect, messenger RNA levels of several growth and immune modulatory factors were quantified in cultured GTSC and compared with those in cultured glomerular epithelial cell (GEC; a non-stem cell line). GTSC had 2- to 8-fold higher expression of FGF2, HGF, IGF-1, vascular endothelial growth factor (growth factors) and IL-4, IL-6 (anti-inflammatory factors) than GEC. </sec> <sec><st>Conclusions.</st> Administration of GTSC accelerates recovery in rats with ischemia/reperfusion-induced AKI. This effect may be mediated by the paracrine action of growth and immune-suppressive factors secreted by these cells. </sec>

Development of features of glomerulopathy in tumor-bearing rats: a potential model for paraneoplastic glomerulopathy

<sec><st>Background.</st> It has been well-recognized that cancer patients occasionally develop renal disorders independently of direct tumor invasion. However, the clinical entity of paraneoplastic glomerulopathy remains poorly understood, in part due to the lack of an animal model for basic research. In the present study, we investigated whether cancer-bearing rats develop features of glomerulopathy. </sec> <sec><st>Methods.</st> RCN-9 rat colon cancer cells (1 x 107) were injected into F344 rats (n = 13) and T cell-deficient F344 rats (nude rats; n = 7) via the portal system. Urinalysis and histological examinations were performed in comparison with control rats (n = 6) that received a vehicle injection. </sec> <sec><st>Results.</st> Metastatic growth of RCN-9 cells exclusively in the liver was observed in the cancer-injected F344 rats, whereas direct invasion into the kidney was not evident even microscopically. Two of the cancer-injected F344 rats died within 2 days, but 9 of the 11 that avoided early death showed elevation of urinary protein (up to 158.0 mg/day) compared to controls (mean values: 60.8 ± 12.9 versus 17.8 ± 2.1 mg/day, P = 0.0291). Although morphological changes were not evident in light microscopy, abundant IgG in the glomerular tufts of the proteinuric rats was shown immunohistochemically. Ultrastructure analysis revealed electron-dense deposits in the glomerular basement membrane zone and effacement of the podocytic foot process. Interestingly, none of the nude rats showed proteinuria despite of cancer growth, suggesting that a specific immune response was involved. </sec> <sec><st>Conclusions.</st> The tumor-bearing rats developed features of glomerulopathy, as expected from the clinical perspective, and this animal model may provide new insights into the development of paraneoplastic glomerulopathies. </sec>

High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage

<sec><st>Background.</st> Angiotensin II (AngII) contributes to salt-driven kidney damage. In this study, we aimed at investigating whether and how the renal damage associated with a high-salt diet could result from changes in the ratio between angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). </sec> <sec><st>Methods.</st> Forty-eight rats randomly allocated to three different dietary contents of salt were studied for 4 weeks after undergoing a left uninephrectomy. We focussed on kidney functional, structural and molecular changes. At the same time, we studied kidney molecular changes in 20 weeks old Ace2-knockout mice (Ace2KO), with and without ACE inhibition. </sec> <sec><st>Results.</st> A high salt content diet significantly increased the glomerular ACE/ACE2 ratio. This was associated with increased oxidative stress. To assess whether these events were related, we measured renal oxidative stress in Ace2KO, and found that the absence of ACE2 promoted oxidative stress, which could be prevented by ACE inhibition. </sec> <sec><st>Conclusion.</st> One of the mechanisms by which a high-salt diet leads to renal damage seems to be the modulation of the ACE/ACE2 ratio which in turn is critical for the cause of oxidative stress, through AngII. </sec>

Vitamin D receptor activators inhibit vascular smooth muscle cell mineralization induced by phosphate and TNF-{alpha}

<sec><st>Background.</st> Vascular calcification is a highly regulated process. Tumor necrosis factor-α (TNF-α) has been shown to accelerate the highly regulated osteogenic process in vascular smooth muscle cells (VSMCs). Vitamin D receptor activators (VDRAs) have been associated with beneficial cardiovascular outcomes in patients with chronic kidney disease. We examined whether maxacalcitol, a vitamin D3 analog, exhibits a suppressive effect on VSMC mineralization induced by phosphate and TNF-α. </sec> <sec><st>Methods.</st> Human VSMCs were treated with either vehicle, maxacalcitol (10–9 to 10–7 M), or calcitriol (10–9 to 10–7 M) in 2.5 mM of phosphate media with TNF-α (1 ng/mL) for 9 days. VSMC mineralization was determined and expression of genes associated with the osteogenic process was examined by real-time reverse transcription–polymerase chain reaction. Expression of matrix metalloproteinase-2 (MMP-2) messenger RNA (mRNA) in VSMCs and MMP-2 protein in media was also analyzed. </sec> <sec><st>Results.</st> Vehicle-treated VSMCs exhibited massive mineralization, which was inhibited by maxacalcitol in a concentration-dependent manner. Calcitriol also inhibited the mineralization. While vehicle-treated VSMCs exhibited increased mRNA expression of genes associated with the osteogenic process (Cbfa1/Runx2 and osteocalcin) compared with VSMCs grown in normal media without TNF-α (control), maxacalcitol and calcitriol suppressed the increase in mRNA species. Furthermore, vehicle-treated VSMCs exhibited increased MMP-2 mRNA and protein in the media that were suppressed notably by maxacalcitol. </sec> <sec><st>Conclusions.</st> Both the VDRAs abrogated the acceleration of the osteogenic process induced by phosphate and TNF-α in VSMCs, which was linked to inhibition of mineralization in VSMCs. MMP-2 blockade by VDRAs may contribute to an inhibitory effect on vascular calcification. </sec>

Teaching and training acute renal replacement therapy in children

<sec><st>Background.</st> The objective of this study is to describe and analyse the initial experience in paediatric acute renal replacement therapy (ARRT) education by means of specific courses. </sec> <sec><st>Methods.</st> Three paediatric ARRT courses were run. The course programme included initial and final multiple-choice question (MCQ) exams, short lectures, practical workshops [in vitro peritoneal dialysis (PD) and continuous renal replacement therapy (CRRT) machines skill stations, real-time PD and CRRT in paediatric animal models and paediatric CRRT advanced simulation scenarios based on real cases) and an anonymous survey on the perceived value of the course (score from 0: very bad to 10: perfect). Number of students per workshop was six to eight. Continuous assessment of participants’ performance was done. </sec> <sec><st>Results.</st> In the initial MCQ, only 11% of students answered correctly at least 70% of questions, while in the final test, 90.5% hit this target (P < 0.001). In the performance assessments, all of the students demonstrated sufficient acquisition of practical skills. In the perceived value survey, the course methodology was rated at 9.3, organization 9.9, teaching staff 9.6, lectures 9 and practical sessions 9.1. </sec> <sec><st>Conclusions.</st> Specifically designed CRRT and PD courses are adequate for teaching the theoretical aspects and training these procedures. The combination of laboratory, training with animals and advanced simulation scenarios might have a synergistic effect on learning. </sec>

Measuring the population burden of chronic kidney disease: a systematic literature review of the estimated prevalence of impaired kidney function

<sec><st>Background.</st> Internationally, there have been substantial efforts to improve the early identification of chronic kidney disease (CKD), with a view to improving survival, reducing progression and minimizing cardiovascular morbidity and mortality. In 2002, a new and globally adopted definition of CKD was introduced. The burden of kidney function impairment in the population is unclear and widely ranging prevalence estimates have been reported. </sec> <sec><st>Methods.</st> We conducted a systematic literature review, searching databases to June 2009. We included all adult population screening studies and studies based on laboratory or clinical datasets where the denominator was clear. Studies reporting prevalence estimates based on at least one eGFR <60 mL/min/1.73m2 or elevated creatinine above a stated threshold were included. Study design and quality were explored as potential factors leading to heterogeneity. </sec> <sec><st>Results.</st> We identified 43 eligible studies (57 published reports) for inclusion. Substantial heterogeneity was observed with estimated prevalence (0.6–42.6%). The included studies demonstrated significant variation in methodology and quality that impacted on the comparability of their findings. From the higher quality studies, the six studies measuring impaired kidney function (iKF) using estimated glomerular filtration rate in community screening samples reported a prevalence ranging from 1.7% in a Chinese study to 8.1% in a US study, with four reporting an estimated prevalence of 3.2–5.6%. Heterogeneity was driven by the measure used, study design and study population. </sec> <sec><st>Conclusion.</st> In the general population, estimated iKF, particularly eGFR 30–59 mL/min/1.73m2 was common with prevalence similar to diabetes mellitus. Appropriate care of patients poses a substantial global health care challenge. </sec>

Glomerular hyperfiltration in prediabetes and prehypertension

<sec><st>Background.</st> This study aimed to investigate the associations of hyperfiltration and hypofiltration with prediabetes and prehypertension. </sec> <sec><st>Methods.</st> The study subjects included 99 140 people aged 20–89 years who underwent health checkups in Aichi Prefecture, Japan. The prevalence of hyperfiltration [estimated glomerular filtration rate (eGFR) above the age-/sex-specific 95th percentile] and hypofiltration (eGFR below the age-/sex-specific 5th percentile) was compared among stages of prediabetes (fasting plasma glucose <100, 100–109, 110–125 and ≥126 mg/dL for no prediabetes, Stage 1 prediabetes, Stage 2 prediabetes and diabetes, respectively) and prehypertension [blood pressure (BP) <120/80, 120–129/80–84, 130–139/85–89 and ≥140/90 mmHg for no prehypertension, Stage 1 prehypertension, Stage 2 prehypertension and hypertension, respectively). </sec> <sec><st>Results.</st> The prevalence of hyperfiltration increased with increasing stage of prediabetes [odds ratios (ORs): 1.29, 1.58 and 2.47 for Stage 1 prediabetes, Stage 2 prediabetes and diabetes, respectively] and prehypertension (ORs: 1.10, 1.33 and 1.52 for Stage 1 prehypertension, Stage 2 prehypertension and hypertension, respectively). Hypofiltration was not associated with prediabetes or prehypertension. </sec> <sec><st>Conclusions.</st> The prevalence of glomerular hyperfiltration increased with increasing stages of prediabetes and prehypertension. Therefore, kidney function should be monitored in subjects with prediabetes or prehypertension. In subjects with hyperfiltration, earlier treatment of hyperglycemia and high BP may be necessary to prevent the development of kidney damage. </sec>

Validating a case definition for chronic kidney disease using administrative data

<sec><st>Background.</st> Administrative data are commonly used for surveillance of chronic medical conditions. The purpose of this study was to determine the validity of an algorithm derived from administrative data for identifying chronic kidney disease (CKD) compared to the reference standard of estimated glomerular filtration rate (eGFR). </sec> <sec><st>Methods.</st> We identified adults from the province of Alberta with at least two outpatient serum creatinine measurements within a 1-year time period. Validity indices were estimated for CKD using up to 3 years of administrative data (physician billing claims and hospital discharge abstracts) for various case–definition combinations. For each algorithm, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated against two reference standard definitions of CKD (two eGFR measurements <60 mL/min/1.73m2 or mean eGFR < 30 mL/min/1.73m2). </sec> <sec><st>Results.</st> A total of 321 293 eligible subjects were identified. Irrespective of the algorithm, sensitivities for defining CKD (eGFR < 60 mL/min/1.73m2) using administrative codes were low. A case–definition algorithm employing two physician claims or one hospitalization within a 2-year period had sensitivity of 19.4%, specificity of 97.2%, PPV of 60.1% and NPV of 84.8% for detecting CKD. Estimates of sensitivity were higher when <30 mL/min/1.73m2 was used as the reference standard, although PPVs were lower and consistently less than 50%. </sec> <sec><st>Conclusion.</st> These results, using eGFR as a reference standard, suggest that administrative data have insufficient sensitivity and PPV for CKD surveillance, although they may be useful when highly specific algorithms are required for research purposes. </sec>

Serum uric acid and chronic kidney disease: the Severance cohort study

<sec><st>Background.</st> Both serum uric acid (SUA) and chronic kidney disease (CKD) are associated with the risk of cardiovascular disease; however, it is unclear whether SUA independently increases the risk of CKD based on longitudinal data. </sec> <sec><st>Methods.</st> To investigate the relationship between SUA levels and CKD development, we initiated a 10.2-year prospective cohort study. Data from 14 939 Koreans, 20–84 years of age, who completed a questionnaire and medical examination at the Severance Health Promotion Center were evaluated. The outcome of interest, CKD, was defined as an estimated glomerular filtration rate (GFR) of <60 mL/min/1.73m2 via the simplified Modification of Diet in Renal Disease equation. </sec> <sec><st>Results.</st> A multivariate Cox proportional hazard model, controlling for age, life style and other cardiovascular risk factors, showed an increased risk of developing CKD for men [hazard ratio (HR) 2.1; 95% confidence interval (CI) 1.6–2.9] and women (HR = 1.3; 95% CI = 1.0–1.8) in the highest quartiles of SUA compared to their counterparts in the lowest quartiles. The relationship between SUA and CKD was linear and stepwise in men. The HRs for renal function Grade 2 (75–89.9 mL/min/1.73m2), Grade 3 (60–74.9 mL/min/1.73m2) and Grade 4 (<60 mL/min/1.73m2) increased with an increase in SUA quartiles as compared to the baseline GFR group (Grade 1, ≥90 mL/min/1.73m2). </sec> <sec><st>Conclusions.</st> Higher SUA levels increased the risk of CKD, suggesting that at least part of the reported association between SUA and cardiovascular disease may be connected to CKD. </sec>

The association between plasma uric acid and renal function decline in a Chinese population-based cohort

<sec><st>Background.</st> Uric acid may be associated with kidney damage through multiple pathways. Previous cohort studies revealed inconsistent results, and research among the non-hypertensive and non-diabetic population are extremely limited. </sec> <sec><st>Methods.</st> This prospective cohort study included 1410 residents aged 59.1 ± 9.4 years from an urban district of Beijing, China. All participants had an estimated glomerular filtration rate >60 mL/min/1.73m2. Plasma uric acid was assessed at baseline; and its relation with renal function decline after 4 years’ follow-up was analyzed. </sec> <sec><st>Results.</st> During 4 years (5630 person-years) of follow-up, 168 patients (11.9%) developed renal function decline. After adjusting for potential confounders including baseline renal function, plasma uric acid levels were independently associated with an increased risk of renal function decline, with a fully adjusted odds ratio (OR) of 1.19 [per 1 mg/dL increase; 95% confidence interval (CI) 1.04–1.38]. Analysis among 615 hypertension-free and diabetes-free participants yielded similar results, with an adjusted OR of 1.50 (per 1 mg/dL increase; 95% CI 1.13–1.98). </sec> <sec><st>Conclusion.</st> Our prospective cohort study revealed that plasma uric acid level is independently associated with an increasing likelihood of renal function decline. </sec>

Increased prevalence of albuminuria among non-European peoples with type 2 diabetes

<sec><st>Background.</st> A high incidence of albuminuria, varying by ethnicity, has been found in a number of populations worldwide. There have been few opportunities to explore the prevalence of albuminuria as a marker of chronic kidney disease while adjusting for other risk factors in the different ethnic groups in New Zealand. </sec> <sec><st>Methods.</st> We examined the association between albuminuria and ethnicity using cross-sectional data from a large cohort study of type 2 diabetes conducted in New Zealand. </sec> <sec><st>Results.</st> The study population was 65 171 adults in primary care with type 2 diabetes, not on renal replacement therapy; median age was 64.7 years, median diabetes duration 5.1 years and 48.5% were non-European. Microalbuminuria or greater was present in 50% of Maori, 49% of Pacific people, 31% of Indo- and East-Asians and 28% of Europeans. Regression analyses were used to examine the association between ethnicity and albuminuria—measured as albumin:creatinine ratio—after controlling for study site and other known risk variables: age, sex, duration of diabetes, smoking status, socioeconomic status, body mass index, systolic and diastolic blood pressure, triglyceride levels, HbA1C and being on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. After controlling for these risk factors and compared with Europeans, odds ratios for ‘advanced’ albuminuria (≥100 mg/mmol) were 3.9 (95% confidence interval: 3.2–4.6) in Maori, 4.7 (3.6–6.3) in Pacific people, 2.0 (1.5–2.7) in Indo-Asians and 4.1 (3.2–5.1) in East-Asians. </sec> <sec><st>Conclusion.</st> Non-European ethnicities appear to carry significantly higher risks of albuminuria in type 2 diabetes. </sec>

A study of the natural history of diabetic kidney disease (DKD)

<sec><st>Background.</st> In view of the alarming increase in the number of people with diabetes mellitus (DM), a rising number of patients with diabetic kidney disease (DKD), end-stage renal disease (ESRD) and cardiovascular disease (CVD) is forecasted. It is therefore imperative to re-visit the natural history of DKD and to identify potential risk factors, which may enhance the progression of the disease and its complications. </sec> <sec><st>Methods.</st> The medical records of 270 Type 2 diabetic chronic kidney disease patients followed up at the Sheffield Kidney Institute between 2000 and 2008 were reviewed. Various socio-demographic, clinical and biochemical parameters (baseline and follow-up parameters) were retrospectively collected from the patients’ database. Progression of DKD was evaluated by evaluation of the rate of decline of estimated glomerular filtration rate (eGFR) as calculated from the simplified Modification of Diet in Renal Disease formula [progressors: loss of glomerular filtration rate (GFR) >2 mL/min/1.73m2/year] as well as by the progression pattern based on the slope of GFR changes. Variables associated with progression in univariate analysis were examined by multivariate analysis to determine the factors independently associated with DKD progression. </sec> <sec><st>Results.</st> The majority of the study populations were males (66.7%) and Caucasians (88%). Ninety-four patients (34.8%) had progressive, whereas 176 (65.2%) had non-progressive DKD. The rate of eGFR decline in progressors was –3.57 ± 1.45 mL/min/1.73m2/year compared to –1.31 ± 0.23 mL/min/1.73m2/year in non-progressors. The following parameters discriminated progressors from non-progressors by univariate analysis: baseline—blood pressure (BP) parameters, eGFR and proteinuria as well as serum uric acid. We also observed that area under the curve for follow-up systolic blood pressure (SBP), glycosylated haemoglobin (HbA1c) and proteinuria were significantly higher among the progressors (P = 0.043, P = 0.02 and P = 0.001, respectively). Independent determinants of DKD progression in this study in an adjusted logistic regression model were baseline HbA1c [odds ratio (OR), 2.27; 95% confidence interval (CI), 1.14–4.54], baseline SBP (OR, 1.23; 95% CI, 1.06–1.41), baseline proteinuria (OR, 3.24; 95% CI, 2.1–5.38), baseline serum uric acid (OR, 1.16; 95% CI, 1.09–1.39) and vascular co-morbidities (OR, 1.61; 95% CI, 1.02–2.54). Percentage changes in the key parameters (BP, HbA1c and proteinuria) during the first year of the study did not affect the rate of eGFR decline. </sec> <sec><st>Conclusions.</st> Baseline HbA1c, SBP, proteinuria and serum uric acid together with the presence of vascular co-morbidities are strongly and independently associated with faster DKD progression. A further prospective observational study is currently undertaken to evaluate these findings and to determine the predictive value of other biochemical peptides and cellular markers on DKD outcome. </sec>

Effects of chronotherapy on blood pressure control in non-dipper patients with refractory hypertension

<sec><st>Background.</st> Refractory arterial hypertension (RAH) is frequently associated to a non-dipping blood pressure (BP) pattern; this profile has been shown to have a worse clinical prognosis. It is a common clinical practice that patients receive anti-hypertensive medication preferentially in the morning. Non-dipping could be related to the timing of anti-hypertensive drug administration. We analysed whether switching anti-hypertensive medication to bedtime could improve BP control in non-dipper patients with RAH. </sec> <sec><st>Methods.</st> Twenty-seven consecutive patients with RAH and non-dipper or riser BP pattern on ambulatory blood pressure (ABP) monitoring were studied before and after 6 weeks of a change in the timing of anti-hypertensive medications. The intervention consisted of shifting all non-diuretic anti-hypertensive drugs from morning to evening, maintaining the same drugs at the same doses. A parallel group of 12 consecutive patients with similar characteristics and no changes in the therapeutic regimen formed the control group. </sec> <sec><st>Results.</st> There were 59% women, mean age 65.7 ± 8.4 years. They were treated with 4 ± 0.7 anti-hypertensive drugs, 90% administered in the morning. At baseline, diurnal and nocturnal ABP averaged 141.6 ± 10.6/81.5 ± 9.3 and 141.7 ± 11/78 ± 8.8, respectively. After the drug shift, mean diurnal and nocturnal ABP was 140.5 ± 10.4/80.5 ± 9.6 and 135.7 ± 12.5/73.8 ± 9.3 (P = 0.005 and 0.04 for systolic and diastolic ABP), 15% of the patients restored a normal ABP circadian rhythm. No changes were observed in the control group. </sec> <sec><st>Conclusion.</st> In non-dipper or riser patients with RAH, changing the timing of anti-hypertensive medication to the evening could improve BP control. </sec>

Association of anthropometric obesity measures with chronic kidney disease risk in a non-diabetic patient population

<sec><st>Background.</st> Obesity is a risk factor for both chronic kidney disease (CKD) and cardiovascular disease. The association of simple indices of obesity with CKD remains poorly understood. Evidence suggests that measures of central obesity such as waist circumference (WC) and waist-to-hip ratio (WHR) are more accurate predictors of morbidity and cardiovascular risk than body mass index (BMI). This study aimed to investigate the association of BMI, WC and WHR with CKD risk in a population screened for type 2 diabetes. </sec> <sec><st>Methods.</st> Data were drawn from a population-based screening programme of 6475 volunteers without pre-existing diabetes. A number of investigations and cardiovascular health-related assessments were performed. Participants were categorized into two groups: those with an estimated glomerular filtration rate (eGFR) ≥60 and <60 mL/min/1.73m2. Participants were also categorized as low, medium and high risk according to each anthropometric variable. </sec> <sec><st>Results.</st> CKD was independently associated with higher WC and BMI (P < 0.01) but not WHR (P = 0.47). Increasing obesity measured by BMI and WC was associated with a reduction in eGFR for both men and women (P < 0.001). Increasing risk categories for BMI and WC were also associated with lower eGFR in men and women (P < 0.001). Combining anthropometric measures provided no additional measure of risk for underlying CKD. </sec> <sec><st>Conclusions.</st> WC may be a simple and reliable clinical tool for the detection of underlying CKD within primary care. Given the complex interaction between adiposity and uraemia, a combined screening tool using BMI and WC or WHR is unlikely to provide any additional benefit to risk analysis. </sec>

Angiopoietin-2 levels predict mortality in CKD patients

<sec><st>Background.</st> The pathophysiology of aggravated atherosclerosis in chronic kidney disease (CKD) is still incompletely understood. However, there is an increasing focus on non-traditional risk factors, including endothelial dysfunction. Angiopoietin-2 (Ang-2) impairs endothelial function by inhibiting the binding of Angiopoietin-1 (Ang-1) to their shared receptor Tie2 and is increased in diabetes, hypertension, coronary heart disease and CKD. Furthermore, Ang-2 levels are associated with the prevalent vascular burden of CKD patients. Thus, we aimed to investigate its impact on outcome in CKD, the population most likely to die of cardiovascular events. </sec> <sec><st>Methods.</st> We prospectively studied 128 CKD patients [43 CKD Stage 4, 85 CKD Stage 5 (57 haemodialysis, 28 peritoneal dialysis)] over a follow-up period of 4 years. Biochemical and clinical parameters, including objective scoring of vascular calcification (VC) by computed tomography (CT) and arterial stiffness by applanation tonometry (including radial-dorsalis pedis pulse wave velocity (PWVrd)) were recorded. Baseline Ang-1 [enzyme-linked immunosorbent assay (ELISA)], Ang-2 [immunoluminometric assay (ILMA)] and soluble Tie2 (sTie2) (ELISA) levels were measured in this group as well as in 20 healthy controls. </sec> <sec><st>Results.</st> Ang-2 values were significantly higher in CKD patients than in controls (2.01 ± 0.94 versus 1.00 ± 0.47 ng/mL, P < 0.0001). Furthermore, Ang-2 was significantly higher in dialysis than in Stage 4 CKD patients and correlated with markers of vascular disease [cholesterol, hsCRP, osteoprotegerin (OPG)]. However, elevated Ang-2 was not associated with the degree of VC or with arterial stiffness. Cox-regression analysis detected Ang-2 as an independent predictor of mortality in both unadjusted [hazard ratio (HR) 1.15; P = 0.002] and models adjusted for age and VC (HR 1.14; P = 0.003). </sec> <sec><st>Conclusions.</st> Ang-2 levels are associated with systemic markers/mediators of micro-inflammation in CKD patients. Furthermore, elevated Ang-2 levels are strong predictors of long-term mortality, independent of conduit arterial stiffness or VC. </sec>

Predictive value of circulating endothelial microparticles for cardiovascular mortality in end-stage renal failure: a pilot study

<sec><st>Background.</st> Endothelial dysfunction in cardiovascular (CV) diseases is closely associated with increases in plasma level of shed membrane microparticles (MPs) of endothelial origin. As arterial damage is a major contributor to CV mortality, we examined whether or not increases in endothelial microparticles (EMPs) circulating levels could predict outcome in patients with end-stage renal disease (ESRD). </sec> <sec><st>Methods.</st> This prospective pilot study conducted in a community hospital (median follow-up: 50.5 months), included 81 stable haemodialysed ESRD patients (59 ± 14 years; 63% male). Platelet-free plasma obtained 72 h after last dialysis was analysed by flow cytometry, and MPs cellular origin identified as endothelial (CD31+CD41–MPs; EMPs), platelets (CD31+CD41+MPs) or erythrocyte (CD235a+MPs). The main outcome measures were global and CV mortality (fatal myocardial infarction, stroke, acute pulmonary oedema and sudden cardiac death). </sec> <sec><st>Results.</st> Non-survivors (n = 24) were older (P < 0.001) and characterized by higher levels of EMPs (P < 0.01) and high-sensitivity C-reactive protein (P < 0.05) and lower diastolic blood pressure (P < 0.001). Kaplan–Meier analysis demonstrated significantly higher probability of all-cause (P < 0.001) and CV mortality (P < 0.0001) between the lower and upper EMPs tertiles. Multivariate Cox regression analysis demonstrated that baseline EMP levels independently predicted all-cause [hazard ratio (HR) = 21.7, 95% confidence interval (CI): 4.23–111.18 per log EMPs/μL; P = 0.0002] and CV mortality (HR = 20.0, 95% CI: 3.86–103.5) per log EMPs/μL; P < 0.0004) after adjustment for confounding factors. EMPs baseline level was a stronger predictor of poor outcome than classical risk factors. </sec> <sec><st>Conclusion.</st> This study demonstrates that increased plasma levels of EMPs is a robust independent predictor of severe CV outcome in end-stage renal failure patients. </sec>

Estimating individual glomerular volume in the human kidney: clinical perspectives

<sec><st>Background.</st> Measurement of individual glomerular volumes (IGV) has allowed the identification of drivers of glomerular hypertrophy in subjects without overt renal pathology. This study aims to highlight the relevance of IGV measurements with possible clinical implications and determine how many profiles must be measured in order to achieve stable size distribution estimates. </sec> <sec><st>Methods.</st> We re-analysed 2250 IGV estimates obtained using the disector/Cavalieri method in 41 African and 34 Caucasian Americans. Pooled IGV analysis of mean and variance was conducted. Monte-Carlo (Jackknife) simulations determined the effect of the number of sampled glomeruli on mean IGV. Lin’s concordance coefficient (RC), coefficient of variation (CV) and coefficient of error (CE) measured reliability. </sec> <sec><st>Results.</st> IGV mean and variance increased with overweight and hypertensive status. Superficial glomeruli were significantly smaller than juxtamedullary glomeruli in all subjects (P < 0.01), by race (P < 0.05) and in obese individuals (P < 0.01). Subjects with multiple chronic kidney disease (CKD) comorbidities showed significant increases in IGV mean and variability. Overall, mean IGV was particularly reliable with nine or more sampled glomeruli (RC > 0.95, <5% difference in CV and CE). These observations were not affected by a reduced sample size and did not disrupt the inverse linear correlation between mean IGV and estimated total glomerular number. </sec> <sec><st>Conclusions.</st> Multiple comorbidities for CKD are associated with increased IGV mean and variance within subjects, including overweight, obesity and hypertension. Zonal selection and the number of sampled glomeruli do not represent drawbacks for future longitudinal biopsy-based studies of glomerular size and distribution. </sec>

Proteome analysis of laser microdissected glomeruli from formalin-fixed paraffin-embedded kidneys of autopsies of diabetic patients: nephronectin is associated with the development of diabetic glomerulosclerosis

<sec><st>Background.</st> To date, little proteomic information has been available from the glomeruli of diabetic patients, possibly due to the clinical limitations of renal biopsy in diabetic patients and insufficient quantities of such specimens for proteome analysis. The purpose of the present study was to identify altered protein expression profiles in diabetic glomeruli using formalin-fixed paraffin-embedded (FFPE) kidney tissues from diabetic patients. </sec> <sec><st>Methods.</st> Glomeruli were laser microdissected from FFPE autopsy kidney tissues from 10 patients with diabetic nephropathy and 10 non-diabetic control patients and underwent proteome analysis using QSTAR Elite liquid chromatography with tandem mass spectrometry and iTRAQ technology. Immunohistochemical analysis was performed on 93 autopsy samples from diabetic patients with and without nephropathy (n = 45 and n = 48, respectively). </sec> <sec><st>Results.</st> Thirty-one renal and urological disease-related proteins displayed a differential abundance in glomerular samples from patients with diabetic nephropathy compared with non-diabetic control patients. Among them, we found that nephronectin, which functions in the assembly of extracellular matrix, showed clearly positive immunoreactivity in diabetic glomeruli. The numerical fraction of nephronectin-positive glomerular cross sections was increased significantly in diabetic patients with nephropathy compared to those without nephropathy (32.1 ± 31.5 versus 4.14 ± 5.65%, P < 0.0001). Furthermore, there was a significant positive correlation between this numerical fraction of nephronectin-positive glomerular cross sections and the glomerular sclerosis index ( = 0.881, P < 0.0001, n = 93). </sec> <sec><st>Conclusion.</st> The present study demonstrated, for the first time, that nephronectin may be associated with the development of diabetic glomerulosclerosis and that proteome analysis with FFPE kidney tissues from diabetic patients with nephropathy is useful in understanding diabetic nephropathy. </sec>

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure

<sec><st>Background.</st> Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure. </sec> <sec><st>Methods.</st> We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed. </sec> <sec><st>Results.</st> We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings. </sec> <sec><st>Conclusions.</st> Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients. </sec>

Saquinavir in steroid-dependent and -resistant nephrotic syndrome: a pilot study

<sec><st>Background.</st> Some difficult cases of idiopathic nephrotic syndrome (NS) have been treated with a HIV protease inhibitor provided with proteasome-inhibiting activity. The objective of this study was to limit nuclear factor B (NF-B) activation which is up-regulated in these patients, aiming at decreasing proteinuria and prednisone need. </sec> <sec><st>Methods.</st> Ten cases with long-lasting (up to 15 years) history of NS with steroid dependence (six cases, of which three with secondary steroid resistance) or resistance to steroids (four cases) unsuccessfully treated with multiple immunosuppressive drugs, accepted a treatment with the protease inhibitor saquinavir. p50/p65 NF-B nuclear localization and immunoproteasome/proteasome messenger RNA (mRNA) were monitored in peripheral blood mononuclear cells (PBMCs). The effects of saquinavir on NF-B nuclear localization in cultured PBMCs and in immortalized human podocytes were assessed. </sec> <sec><st>Results.</st> After a median follow-up of 14.7 months (6–68.7), 1/4 primary steroid-resistant NS (SRNS) and 5/6 steroid-dependent NS or secondary SRNS became infrequent (5) or frequent (1) relapsers, with 63% prednisone reduction (from 25.3 to 8.4 mg/kg/month, P = 0.015). Saquinavir was effective in association with low doses of calcineurin inhibitors (cyclosporine 2 mg/kg/day or tacrolimus 0.01–0.06 mg/kg/day). No side effects were observed apart from transitory mild diarrhoea. In PBMCs, NF-B was down-regulated, while MECL-1 immunoproteasome/beta2 proteasome mRNA ratio was reversed to normal values. In culture, saquinavir blunted NF-B activation in human podocytes and in PBMCs. </sec> <sec><st>Conclusions.</st> In this pilot study, a HIV antiprotease drug reduced proteinuria and had a steroid-sparing effect in some multidrug-resistant/-dependent NS. This observation warrants further investigation. </sec>

Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome

<sec><st>Background.</st> In patients with refractory steroid-sensitive nephrotic syndrome (SSNS), treatment with rituximab has shown encouraging results; however, long-term follow-up data are not available. </sec> <sec><st>Methods.</st> We performed a retrospective analysis of 37 patients (25 boys) with steroid-dependent nephrotic syndrome who were treated with rituximab (375 mg/m2 given weekly for one to four courses). Long-term follow-up data (>2 years, median 36, range 24–92.8 months) are available for 29 patients (12 boys). </sec> <sec><st>Results.</st> Twenty-six of 37 (70.3%) patients remained in remission after 12 months. Relapses occurred in 24 (64.8%) patients after a median of 9.6 (range 5.2–64.1) months. Time to first relapse was significantly shorter in patients receiving one or two compared to three or four initial infusions. In the 29 patients with long-term follow-up for >2 years, 12 (41%) patients remained in remission after the initial rituximab course for >24 months, 7 (24.1%) patients without further maintenance immunosuppression. Nineteen children received two to four repeated courses of rituximab increasing the total number of patients with long-term remission to 20 (69%), remission including 14 (48%) patients off immunosuppression. The proportion of patients with long-term remission was not related to the number of initial rituximab applications. No serious side effects were noted. </sec> <sec><st>Conclusion.</st> Rituximab is an effective treatment option in the short- and long-term control of treatment refractory SSNS. Further controlled studies are needed to address optimal patient selection, dose and safety of rituximab infusions. </sec>

Soluble interleukin-2 receptor alfa predicts renal outcome in IgA nephropathy

<sec><st>Background.</st> Both systemic and mucosal IgA production are controlled by T lymphocytes and infiltrating T lymphocytes are involved in the progression of interstitial fibrosis in chronic kidney disease (CKD). Since the concentration of soluble interleukin-2 receptor alfa (sIL-2Ra) reflects the degree of T cell activation over time, we studied the impact of interleukin-2 receptor alfa levels on disease progression in patients with biopsy-proven IgA nephropathy (IgAN), a disease in which 20–30% of the patients progress to end-stage renal failure. </sec> <sec><st>Methods.</st> sIL-2Ra plasma levels were measured in 194 patients (median age 39 years, 70% men) and 84 matched controls. One hundred and seventy-nine of the patients, with an estimated glomerular filtration rate (GFR) of ≥15 mL/min/1.73m2 at baseline (CKD Stages 1–4), were followed for up to 15 years (median 52 months; range 12–188). sIL-2Ra was evaluated as a risk marker for severe renal progression, here defined by the development of CKD Stage 5 (GFR <15 mL/min/1.73m2), a 50% decline in GFR during the follow-up period or a 30% GFR decline within 5 years of follow-up. In 51 patients, upon whom a renal biopsy had been performed within 2 years of IL2-Ra measurement, the biopsies were scored according to the Oxford classification. The correlations between the histopathological findings and the sIL-2Ra levels were examined. </sec> <sec><st>Results.</st> sIL2-Ra levels were significantly higher in patients than in controls (P < 0.001). sIL-2Ra levels in the upper third tertile predicted a severe renal outcome, even after adjustment for the main clinical risk factors: time average albuminuria and GFR at baseline (Relative risk 5.35, P < 0.001). sIL-2Ra levels also correlated significantly to the yearly GFR slope (β = –0.24, P = 0.01). According to the Oxford classification, the presence of >25% tubular atrophy/interstitial fibrosis (T1–2) was associated with higher sIL-2Ra levels, after adjustment for serum creatinine levels, if analysed within 4 months [n = 24, odds ratio (OR) 1.0, P = 0.044] or within 2 years from the kidney biopsy (n = 51, OR 1.0, P = 0.017). </sec> <sec><st>Conclusions.</st> The plasma levels of sIL-2Ra were predictive of long-term renal disease progression in a large cohort of patients with biopsy-proven IgAN. Further studies are warranted to evaluate if sIL-2Ra levels can feasibly contribute in the monitoring of effects of treatment, aimed to prevent the progression of interstitial fibrosis and progressive glomerulosclerosis in IgAN. </sec>

Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial

<sec><st>Background.</st> In the MAINTAIN Nephritis Trial, azathioprine (AZA) and mycophenolate mofetil (MMF) were compared as maintenance immunosuppressive treatment of proliferative lupus nephritis (LN) after a short-course of intravenous cyclophosphamide. Here, we compare the pathological findings on repeat kidney biopsies between the two groups. </sec> <sec><st>Methods.</st> Per protocol, repeat renal biopsies were obtained in 30 patients (16 AZA and 14 MMF) at 2 years (±6 months). Baseline and follow-up biopsies were graded according to the International Society of Nephrology/Renal Pathological Society (ISN/RPS) classification. The activity and chronicity indices (AI, CI) were calculated using two different semiquantitative scoring systems (Morel-Maroger and National Institutes of Health). Statistics were performed by non-parametric tests. </sec> <sec><st>Results.</st> The clinical characteristics of the 30 re-biopsied patients only marginally differ from the entire MAINTAIN cohort (105 patients). Clinical baseline and follow-up characteristics of AZA- and MMF-treated re-biopsied patients did not differ. Time (SD) to repeat renal biopsy was 25.0 (2.0) and 26.5 (3.3) months in AZA and MMF patients, respectively. More patients had normal renal biopsies or Classes I/II/V LN at follow-up compared to baseline and conversely, less patients had Class IV LN at follow-up. In both groups, the AI statistically decreased at follow-up compared to baseline, while the CI slightly, but significantly, increased. No differences could be detected between the groups. </sec> <sec><st>Conclusion.</st> Centralized pathological analyses, including ISN/RPS classification and comparisons of AI/CI, failed to find differences between MMF and AZA at 2 years, a result well in line with the absence of difference in long-term clinical outcome reported elsewhere. </sec>

Absence of glomerular IgG4 deposition in patients with membranous nephropathy may indicate malignancy

<sec><st>Background.</st> The renal pathological manifestations of malignancy-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) are similar. It has been suggested that glomerular IgG4 deposition may play an important role in the pathogenesis of I-MN. In the present study, we compared the IgG subclass of immune complex deposition, clinical data and pathological data of patients with M-MN and I-MN. </sec> <sec><st>Methods.</st> Eight patients with M-MN and 42 patients with I-MN diagnosed between 1997 and 2009 in our hospital were enrolled. The clinical and pathological data were retrospectively collected, and glomerular IgG subclass deposition was detected by immunohistochemistry. </sec> <sec><st>Results.</st> Patients with M-MN were older (P = 0.003), with lower serum albumin (P = 0.034) and higher serum C-reactive protein (CRP) level (P = 0.003) than patients with I-MN. The majority of patients with M-MN had earlier pathological stages (P = 0.003) and less IgG deposition in glomeruli (P = 0.029). Absence of IgG4 deposition in glomeruli was notably observed in patients with M-MN (7/8 in M-MN versus 6/42 in I-MN, P < 0.001) and it was an independent predictor for occurrence of malignancy (hazard ratio 0.065, 95% confidence intervals 0.007–0.571, P = 0.014). </sec> <sec><st>Conclusion.</st> Absence of glomerular IgG4 deposition, together with older age, severe hypoalbuminemia and high serum CRP level could be useful clues to differentiate M-MN from I-MN. </sec>

Distribution of glomerular IgG subclass deposits in patients with membranous nephropathy and anti-U1 ribonucleoprotein antibody

<sec><st>Background.</st> It is known that a predominant glomerular deposition of IgG4 is characteristic of idiopathic membranous nephropathy (MN) and that significant deposition of other IgG subclasses is also observed in lupus MN. However, there is no report focusing on the distribution of glomerular IgG subclass deposits in MN patients with anti-U1 ribonucleoprotein (RNP) antibody. </sec> <sec><st>Methods.</st> We evaluated clinicopathological features and the distribution patterns of glomerular IgG subclass deposits in seven MN patients with positive anti-RNP antibody and negative antibodies to double-stranded DNA (dsDNA) and Smith antigen (Sm) (RNP-MN group) and in seven age- and sex-matched lupus MN patients with positive anti-dsDNA antibody and negative antibodies to RNP and Sm (L-MN group). </sec> <sec><st>Results.</st> Mixed connective tissue disease was diagnosed in four patients in the RNP-MN group. Two patients in the RNP-MN group and three patients in the L-MN group developed nephrotic syndrome. Renal insufficiency was not present in all patients in both groups. Hypocomplementemia was found in two patients in the RNP-MN group and six patients in the L-MN group. In the RNP-MN group, positive stainings for glomerular IgG1, IgG2, IgG3 and IgG4 were observed in one, seven, zero and five patients, respectively. On the contrary, in the L-MN group, positive stainings for glomerular IgG1, IgG2, IgG3 and IgG4 were observed in seven, seven, seven, and six patients, respectively. </sec> <sec><st>Conclusions.</st> This is the first study showing striking differences in the distribution of glomerular IgG subclass deposits between RNP-MN and L-MN groups. RNP-MN and L-MN may result from different immunological mechanisms. </sec>

Paricalcitol versus cinacalcet plus low-dose vitamin D for the treatment of secondary hyperparathyroidism in patients receiving haemodialysis: study design and baseline characteristics of the IMPACT SHPT study

Background. Paricalcitol and cinacalcet are common therapies for patients on haemodialysis with secondary hyperparathyroidism (SHPT). We conducted a multi-centre study in 12 countries to compare the safety and efficacy of paricalcitol and cinacalcet for the treatment of SHPT. Methods. Patients aged ≥18 years with Stage 5 chronic kidney disease receiving maintenance haemodialysis and with intact parathyroid hormone (iPTH) 300–800 pg/mL, calcium 8.4–10.0 mg/dL (2.09–2.49 mmol/L) and phosphorus ≤6.5 mg/dL (2.09 mmol/L) were randomized within two strata defined by the mode of paricalcitol administration to treatment with paricalcitol- (intra-venous, US and Russian sites, IV stratum; oral, non-US and non-Russian sites, oral stratum) or cinacalcet-centred therapy. The primary endpoint is the proportion of patients in each treatment group who achieve a mean iPTH value of 150–300 pg/mL during Weeks 21–28 of treatment. Assuming efficacy response rates of 36 and 66% for cinacalcet and paricalcitol, respectively, and a 20% discontinuation rate, 124 subjects in each stratum were estimated to provide 81% power to detect a 30% absolute difference in the primary endpoint. Results. Of 746 patients screened, 272 (mean age, 63 years; mean iPTH, 509 pg/mL) were randomized. Mean duration of haemodialysis at baseline was 3.7 years. Comorbidities included hypertension (90.4%), Type 2 diabetes (40.4%), congestive heart failure (17.3%), coronary artery disease (34.6%) and gastrointestinal disorders (75%). Conclusions. The study participants are representative of a multinational cohort of patients on haemodialysis with elevated iPTH. The study results will provide valuable information on the best available treatment of SHPT in patients on haemodialysis.

Interpretation of serum PTH concentrations with different kits in dialysis patients according to the KDIGO guidelines: importance of the reference (normal) values

<sec><st>Background.</st> The recommended target range for serum parathyroid hormone (PTH) in dialysis patients has changed from 150 to 300 pg/mL in the KDOQI guidelines to two to nine times the upper normal limit in the KDIGO ones. Although inclusion/exclusion criteria for the reference population are highly important, they are usually not mentioned in the commercial kits. In this study, we used the same reference population of vitamin D-replete normal subjects to establish reference values for 10 commercial PTH kits. We evaluated whether this may improve the classification of dialysis patients according to the KDIGO compared to the use of reference values proposed by the manufacturers. </sec> <sec><st>Methods.</st> We measured serum PTH with 10 different kits in 149 haemodialysis patients, and 240 25-OH-vitamin D-replete (>75 nmol/L) individuals with an estimated glomerular filtration rate >60 mL/min/1.73 m2. </sec> <sec><st>Results.</st> For the 10 kits, our upper normal limit was lower than those of the manufacturers. The difference was, however, variable from one kit to another. The two kits that yielded the lowest and the highest absolute concentrations classified differently 84/149 patients (56.4%) according to the KDOQI and 53/149 (36.2%) according to the KDIGO using the manufacturers’ normal values. Using our normal values significantly decreased the discrepancies with 24/149 patients (16.1%) being still classified differently. Taking the measurement uncertainty into consideration, 8% of the patients only remained differently classified by these two kits. </sec> <sec><st>Conclusions.</st> Using the same vitamin-D-replete population to establish the reference range for 10 commercial PTH kits significantly improved the classification of haemodialysis patients according to the KDIGO target range. </sec>

Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD

<sec><st>Background.</st> Vascular stiffening occurs in normal ageing and is accelerated in chronic kidney disease (CKD). Vascular calcification contributes to this stiffening and to the high incidence of vascular morbidity and mortality in this population. A network of inhibitors work in concert to reduce mineralization risk in extra-osseous tissue. Fetuin-A is an important systemic inhibitor of ectopic calcification. A fraction of the total circulating fetuin-A interacts with mineral ions to form stable colloidal complexes, calciprotein particles (CPP), preventing deposition. We sought to assess whether CPP fetuin-A levels were associated with procalcific factors and aortic stiffness in a cohort of patients with Stages 3 and 4 CKD. </sec> <sec><st>Methods.</st> We measured fetuin-A CPP levels, serum inflammatory markers [C-reactive protein (CRP), interleukin-6, tumour necrosis factor-α], oxidized low-density lipoprotein (oxLDL), bone morphogenetic protein-2 (BMP-2) and -7 (BMP-7) and aortic pulse wave velocity (APWV) in a cohort of 200 CKD patients. Serum measurements were also made in 78 healthy controls. CPP fetuin-A phosphorylation was characterized by phosphate-affinity gel chromatography. </sec> <sec><st>Results.</st> Fetuin-A-containing CPPs were only detectable in the serum of CKD patients. Inflammatory markers, oxLDL and BMP-2 levels were all significantly higher in the CKD than control subjects. CPP fetuin-A levels were independently associated with serum phosphate, high-sensitivity C-reactive protein, oxLDL, BMP-2/7 ratio and inversely with estimated glomerular filtration rate (model R2 = 0.51). After adjusting for confounders, CPP fetuin-A levels were independently associated with APWV. Only phosphorylated fetuin-A was present in serum CPP. </sec> <sec><st>Conclusion.</st> Increased CPP fetuin-A levels reflect an increasingly procalcific milieu and are associated with increased aortic stiffness in patients with pre-dialysis CKD. </sec>

Effects of cinacalcet treatment on serum soluble Klotho levels in haemodialysis patients with secondary hyperparathyroidism

<sec><st>Background.</st> Klotho is a transmembrane protein that acts as a cofactor for fibroblast growth factor 23 (FGF23). Klotho also exists as a soluble circulating protein, but its role in secondary hyperparathyroidism (SHPT) is largely unknown. </sec> <sec><st>Methods.</st> We measured serum soluble Klotho levels in 51 haemodialysis patients, who participated and completed a 52-week, multicentre, open-label single-arm trial that examined the effectiveness of cinacalcet for treating SHPT. </sec> <sec><st>Results.</st> After 12 weeks of cinacalcet treatment, serum soluble Klotho decreased significantly (P = 0.03) but only marginally from 398 pg/mL [interquartile range (IQR), 268–588 pg/mL] to 378 pg/mL (IQR, 266–568 pg/mL) and returned to baseline levels. There were no significant associations between the changes in soluble Klotho levels and changes in any other parameters of mineral metabolism, including serum calcium, phosphorus, intact parathyroid hormone and FGF23. </sec> <sec><st>Conclusion.</st> Despite significant alterations in mineral and bone metabolism during treatment with cinacalcet, this resulted in only small and transient reductions in serum levels of soluble Klotho. </sec>

Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome

<sec><st>Background.</st> There is currently no established standard for maintenance therapy of steroid-resistant nephrotic syndrome (SRNS). We report the long-term clinical course, medication, pharmacokinetic data, and renal function of 23 children with primary, non-familial SRNS with focal segmental glomerulosclerosis (FSGS). </sec> <sec><st>Methods.</st> To achieve initial remission, patients were treated with high-dose intravenous (i. v.) methylprednisolone and oral cyclosporin A (CsA). Maintenance therapy included transient alternate day oral prednisolone, CsA and angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers. In 18 patients, mycophenolate mofetil (MMF) (adjusted to achieve blood mycophenolic acid trough concentrations > 2 μg/mL) was sequentially added, and 16 patients were converted to MMF monotherapy. </sec> <sec><st>Results.</st> During a mean follow-up time of 7.0 years (1.7–16.5 years; cumulative observation time 161 patient-years), sustained remission could be achieved in all patients. Five of 23 patients (21%) experienced 10 relapses; all responded to relapse therapy. Maintenance therapy could be permanently discontinued in seven patients (30%). After conversion from CsA to MMF, renal function improved significantly; the eGFR at last follow-up was 137 (range 106–198) mL/min x 1.73 m2. The mean number of anti-hypertensive drugs decreased from 1.86 per patient after initial remission to 0.57 on MMF monotherapy (P < 0.002). </sec> <sec><st>Conclusions.</st> The data of this uncontrolled retrospective study indicate that in children with SRNS/FSGS achieving initial remission, a sequential steroid-free therapy consisting of a combination of CsA and MMF followed by MMF alone (with the addition of ACE inhibitors and angiotensin receptor blockers), can provide sustained long-term remission, preservation of renal function and better control of blood pressure. </sec>

Epidemiology of chronic kidney disease in children in Serbia

<sec><st>Background.</st> The epidemiological information from well-defined populations regarding childhood chronic kidney disease (CKD), particularly those concerning non-terminal stages, are scanty. The epidemiology of CKD in children is often based on renal replacement therapy (RRT) data, which means that a considerable number of children in earlier stages of CKD are missed as they will reach end-stage renal disease (ESRD) in adulthood. Here, we report the basic epidemiological data on childhood CKD in Serbia, gathered over the 10-year period of activity of the Serbian Pediatric Registry of Chronic Kidney Disease. </sec> <sec><st>Methods.</st> Since 2000–09, data on incidence, prevalence, aetiology, treatment modalities and outcome of children aged 0–18 years, with CKD Stages 2–4 and CKD Stage 5, were collected by reporting index cases from paediatric centres. </sec> <sec><st>Results.</st> Three hundred and thirty-six children were registered (211 boys, 125 girls, male/female ratio 1.7). The median age at registration was 9.0 years [interquartile range (IQR) 3–13]. Median follow-up was 4.0 years (IQR, 1–9). The median glomerular filtration rate (GFR) at the time of the registration was 39.6 mL/min/1.73m2 (IQR, 13.8–65.4). Median annual incidence of CKD 2–5 stages was 14.3 per million age-related population (p.m.a.r.p.), while those of CKD 2–4 or CKD 5 were 9.1 and 5.7 p.m.a.r.p., respectively. The median prevalence of CKD 2–5 was 96.1 p.m.a.r.p., 52.8 p.m.a.r.p. in CKD 2–4 and 62.2 p.m.a.r.p. in CKD 5. The main causes of CKD were congenital anomalies of kidney and urinary tract and hereditary nephropathies. Kidney survival was the worst in children with glomerular diseases and in those with advanced CKD. Haemodialysis was the most common first modality of RRT. Mortality rate was 4.5%, mainly due to cardiovascular and infectious complications. </sec> <sec><st>Conclusions.</st> Epidemiology of paediatric CKD in Serbia is similar to that reported from developed European countries. The knowledge of the epidemiology of earlier stages of CKD is essential for both institution of renoprotective therapy and planning of RRT, a fact of paramount importance in countries with limited resources. </sec>

Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study

<sec><st>Background.</st> The low prevalence of childhood end-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence-based guidelines for chronic renal replacement therapy (cRRT) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in nine centres that deliver cRRT for children. </sec> <sec><st>Methods.</st> We surveyed treatment policies in all nine centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to 2010. </sec> <sec><st>Results.</st> Data on policies and actual patient care were obtained from all nine centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated glomerular filtration rate threshold as an indication for initiation of cRRT, preferred initial mode of cRRT, peritoneal dialysis catheter care, haemodialysis frequency and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies, no evidence-based guidelines are available. </sec> <sec><st>Conclusions.</st> Health care disparities exist due to large and unwanted variation in treatment policies between hospitals providing cRRT for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking. </sec>

Physical examination of dysfunctional arteriovenous fistulae by non-interventionalists: a skill worth teaching

<sec><st>Background.</st> Physical examination (PE) of arteriovenous fistulae (AVF) has recently emerged as an important element in the detection of stenotic lesions. This study examines the accuracy of PE in the assessment of AVF dysfunction by non-interventionalists in comparison with angiography. </sec> <sec><st>Methods.</st> A total of 177 consecutive patients who had AVF dysfunction and were referred to our centre by general nephrologists for angioplasty between November 2009 and July 2010 were included in this analysis. Eleven referring general nephrologists completed a form reporting the PE findings regarding their patients’ AVFs. Before angiography examination was carried out, a trained nephrology resident performed a PE in all the cases. Angiography of the AVFs was then performed by an interventionalist. Cohen’s value was used as the measurement of the level of agreement beyond chance between the diagnosis made on PE and angiography. </sec> <sec><st>Results.</st> There was a moderate agreement beyond chance between the general nephrologists’ PE and angiography in the detection of AVF inflow stenosis ( = 0.49), outflow stenosis ( = 0.58) and thrombosis ( = 0.52). On the other hand, PE performed by the trained nephrology resident strongly agreed with angiography in the detection of AVF inflow stenosis ( = 0.84), outflow stenosis ( = 0.92) and thrombosis ( = 0.98). The agreement between PE and angiography in the detection of co-existing AVF inflow–outflow stenosis was poor for the general nephrologists and moderate for the trained nephrology resident ( = 0.14 versus = 0.55, respectively). </sec> <sec><st>Conclusion.</st> PE may provide an accurate means of diagnosis of AVF dysfunction. Theoretical and hands-on training in PE of dysfunctional AVFs should be provided for nephrologists in-training and for the dialysis staff. </sec>

Suppression of neointimal hyperplasia by sirolimus-eluting expanded polytetrafluoroethylene (ePTFE) haemodialysis grafts in comparison with paclitaxel-coated grafts

<sec><st>Background.</st> Haemodialysis vascular access dysfunction caused by aggressive venous neointimal hyperplasia is a major problem for haemodialysis patients with synthetic arteriovenous (AV) grafts. Several different strategies to prevent venous stenosis by inhibiting smooth muscle cell proliferation and migration using local delivery of potent antiproliferative agents are currently under investigation. We performed this study to evaluate the efficacy of sirolimus-eluting vascular grafts in preventing stenosis and to compare the effectiveness of sirolimus-coated grafts with that of paclitaxel-coated vascular grafts that we characterized in a previous study. </sec> <sec><st>Methods.</st> AV grafts were implanted laterally between the common carotid artery and external jugular vein of 14 female Landrace pigs. Three types of grafts were implanted: grafts coated with 1.08 μg/mm2 sirolimus (low dose, n = 6), grafts coated with 2.41 μg/mm2 sirolimus (high dose, n = 2) and uncoated control grafts (n = 6). Animals were sacrificed 6 weeks after surgery. Cross-sections of the venous anastomoses were analysed to determine the percentage of luminal stenosis in each group, and immunohistochemistry was performed to identify the cellular phenotypes of the neointimal hyperplasia and tissues adjacent to the implanted grafts. </sec> <sec><st>Results.</st> Compared with the control group, neointimal hyperplasia in the venous anastomoses of the groups implanted with sirolimus-coated vascular grafts was significantly suppressed without infection. The mean ± standard error values for the percentage of luminal stenosis were 75.7 ± 12.7% in the control group and 22.2 ± 1.41% in the low-dose sirolimus-coated group. Myofibroblasts and fibroblasts were the major cell types found in the neointimal hyperplasia. </sec> <sec><st>Conclusions.</st> Neointimal hyperplasia was effectively suppressed by sirolimus-eluting grafts. However, the inhibitory effects of sirolimus-eluting grafts were weaker than those observed for paclitaxel-coated grafts in our previous study. </sec>

Pharmacotherapy to improve outcomes in vascular access surgery: a review of current treatment strategies

<sec><st>Background.</st> Renal failure is a major cause of morbidity in western Europe, with rising prevalence. Vascular access complications are the leading cause of morbidity among patients on haemodialysis. Considering the health care burden of vascular access failure, there is limited research dedicated to the topic. </sec> <sec><st>Methods.</st> Randomised control trials of medications aimed at improving vascular access patency were identified using a medline search between January 1950 and January 2011. </sec> <sec><st>Results.</st> Thirteen randomised trials were identified, investigating antiplatelets, anticoagulants and fish oil in preserving vascular access patency. Outcomes are presented and reviewed in conjunction with the underlying pathophysiological mechanisms of failure of vascular access. </sec> <sec><st>Discussion.</st> Vascular access failure is a complex process. Most clinical trials so far have involved medications primarily aimed at preventing thrombosis. Other contributing pathways such as neointimal hyperplasia have not been investigated clinically. Improved outcomes may be seen by linking future therapies to these pathways. </sec>

Residual renal function is an independent determinant of serum FGF-23 levels in dialysis patients

<sec><st>Background.</st> Both poor residual renal function (RRF) and high fibroblast growth factor 23 (FGF-23) levels are associated with arterial stiffness, left ventricular hypertrophy and increased (cardiovascular) mortality. Whether FGF-23 and RRF are interrelated is unknown. </sec> <sec><st>Methods.</st> We performed a prospective observational cohort study in 35 peritoneal dialysis (PD) patients with evaluation at 1, 6, 12 and 24 months after start of PD. In addition, the role of RRF was assessed in a cross-sectional observational cohort study including 68 prevalent haemodialysis patients. </sec> <sec><st>Results.</st> RRF significantly declined over time in PD patients. This decline was parallelled by a significant increase of both serum phosphorus and FGF-23 levels. In the prevalent dialysis cohort, RRF was found to be inversely associated with serum FGF-23 levels, independent of dialysis vintage, dialytic creatinine clearance, estimates of dietary phosphate intake (i.e. normalized protein nitrogen appearance), active vitamin D therapy and serum phosphorus and calcium levels. RRF, serum phosphorus and calcium levels and active vitamin D therapy explain 69% of the variation in FGF-23. The 38 anuric patients had higher FGF-23 levels but similar serum phosphorus levels. </sec> <sec><st>Conclusions.</st> We demonstrate an important association between RRF and FGF-23, independent of classical determinants. This favours the hypothesis that the ailing kidney directly contributes to the raised FGF-23 levels. Whether FGF-23 is associated with poor outcomes independent of RRF, or vice versa, remains to be clarified. </sec>

Pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial

<sec><st>Aim.</st> The aim of this study was to compare the effect of pentoxifylline versus placebo on serum concentrations of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and C-reactive protein (CRP) of hemodialysis (HD) patients. </sec> <sec><st>Methods.</st> This is a randomized double-blind, controlled clinical trial. HD patients without infection or drugs with anti-inflammatory effect were randomly allocated to a study (n = 18, pentoxifylline 400 mg/day) or control (n = 18, placebo) group; all patients had arteriovenous fistula. Besides clinical and laboratory monthly assessments, serum TNF-α and IL-6 (ELISA) and CRP (nephelometry) were measured at 0, 2 and 4 months. </sec> <sec><st>Results.</st> All the inflammation markers significantly (P < 0.05) decreased in the pentoxifylline group: TNF-α [baseline 0.4 (0–2) versus final 0 (0–0) pg/mL], IL-6 [baseline 9.4 (5–14) versus final 2.9 (2–5) pg/mL] and CRP [baseline 7.1 (3–20) versus final 2.6 (1–8) mg/L], whereas no significant changes were observed in the placebo group: TNF-α [baseline 0 (0–0) versus final 1.2 (0–4) pg/mL], IL-6 [baseline 8.0 (5–11) versus final 8.7 (4–11) pg/mL] and CRP [baseline 4.5 (2–9) versus final 3.8 (3–23) mg/L]. </sec> <sec><st>Conclusions.</st> Pentoxifylline significantly decreased serum concentrations of TNF-α, IL-6 and CRP compared to placebo. Pentoxifylline could be a promising and useful strategy to reduce the systemic inflammation frequently observed in patients on HD. </sec>

Seasonal variation in peritoneal dialysis-associated peritonitis: a multi-centre registry study

<sec><st>Background.</st> The role of seasonal variation in peritoneal dialysis (PD)-related peritonitis has been limited to a few small single-centre studies. </sec> <sec><st>Methods.</st> Using all 6610 Australian patients receiving PD between 1 October 2003 and 31 December 2008, we evaluated the influence of seasons on peritonitis rates (Poisson regression) and outcomes (multivariable logistic regression). </sec> <sec><st>Results.</st> The overall rate of peritonitis was 0.59 episodes per patient-year of treatment. Using winter as the reference season, the peritonitis incidence rate ratios (95% confidence interval) for summer, autumn and spring were 1.02 (0.95–1.09), 1.01 (0.94–1.08) and 0.99 (0.92–1.06), respectively. Significant seasonal variations were observed in the rates of peritonitis caused by coagulase-negative Staphylococci (spring and summer peaks), corynebacteria (winter peak) and Gram-negative organisms (summer and autumn peaks). There were trends to seasonal variations in fungal peritonitis (summer and autumn peaks) and pseudomonas peritonitis (summer peak). No significant seasonal variations were observed for other organisms. Peritonitis outcomes did not significantly vary according to season. </sec> <sec><st>Conclusions.</st> Seasonal variation has no appreciable influence on overall PD peritonitis rates or clinical outcomes. Nevertheless, significant seasonal variations were observed in the rates of peritonitis due to specific microorganisms, which may allow institutions to more precisely target infection control strategies prior to higher risk seasons. </sec>

Impaired exercise performance and muscle Na+,K+-pump activity in renal transplantation and haemodialysis patients

<sec><st>Background.</st> We examined whether abnormal skeletal muscle Na+,K+-pumps underlie impaired exercise performance in haemodialysis patients (HDP) and whether these are improved in renal transplant recipients (RTx). </sec> <sec><st>Methods.</st> Peak oxygen consumption (<f><inline-fig> <link locator="ndtjgfr586fx1_ht"></inline-fig></f>O2peak) and plasma [K+] were measured during incremental exercise in 9RTx, 10 HDP and 10 healthy controls (CON). Quadriceps peak torque (PT), fatigability (decline in strength during thirty contractions), thigh muscle cross-sectional area (TMCSA) and vastus lateralis Na+,K+-pump maximal activity, content and isoform (α1–α3, β1–β3) abundance were measured. </sec> <sec><st>Results.</st> <f><inline-fig> <link locator="ndtjgfr586fx1_ht"></inline-fig></f>O2peak was 32 and 35% lower in RTx and HDP than CON, respectively (P < 0.05). PT was less in RTx and HDP than CON (P < 0.05) but did not differ when expressed relative to TMCSA. Fatigability was ~1.6-fold higher in RTx (24 ± 11%) and HDP (25 ± 4%) than CON (15 ± 5%, P < 0.05). Na+,K+-pump activity was 28 and 31% lower in RTx and HDP, respectively than CON (P < 0.02), whereas content and isoform abundance did not differ. Pooled (n = 28) <f><inline-fig> <link locator="ndtjgfr586fx1_ht"></inline-fig></f>O2peak correlated with Na+,K+-pump activity (r = 0.45, P = 0.02). </sec> <sec><st>Conclusions.</st> <f><inline-fig> <link locator="ndtjgfr586fx1_ht"></inline-fig></f>O2peak and muscle Na+,K+-pump activity were depressed and muscle fatigability increased in HDP, with no difference observed in RTx. These findings are consistent with the possibility that impaired exercise performance in HDP and RTx may be partially due to depressed muscle Na+,K+-pump activity and relative TMCSA. </sec>

Effects of icodextrin on patient survival and technique success in patients undergoing peritoneal dialysis

Background. Many studies have suggested clinical benefits of icodextrin in peritoneal dialysis (PD) patients regarding fluid management, glycaemic control and metabolic improvement. However, reports on whether icodextrin can improve patient and technique survival is sparse. Methods. A total of 2163 patients from 54 centres in Korea who initiated PD from July 2003 to December 2006 were enrolled. Outcomes data were retrieved retrospectively from the Baxter Korea database. Among these patients, 641 patients who had been prescribed icodextrin for >50% of their PD duration were defined as the ‘icodextrin’ group and the remaining 1522 patients as the ‘non-icodextrin’ group. Propensity score matching yielded 640 matched pairs of patients. We compared all-cause mortality and technique failure rates between the two groups. Results. There were no significant differences in age, gender, diabetes, cardiovascular comorbidity, socioeconomic status, biocompatible solution use in short dwells or centre experience between the two groups. Death occurred in 92 (14.4%) patients in the icodextrin group compared with 128 (20.0%) in the non-icodextrin group [hazard ratio (HR), 0.69; 95% confidence interval (CI), 0.53–0.90; P = 0.006]. In addition, icodextrin use was associated with a significantly lower risk of technique failure (HR, 0.60; 95% CI, 0.40–0.92; P = 0.018). The icodextrin group had fewer technique failures due to non-compliance compared with the non-icodextrin group whereas peritonitis- or ultrafiltration failure-related technique failure was not different between the two groups. Conclusion. This study further supports previous findings of long-term utilization of icodextrin solution improving patient and technique survival in PD patients. To confirm these results, a large randomized prospective study is warranted.

Effect of self-administered intraperitoneal bemiparin on peritoneal transport and ultrafiltration capacity in peritoneal dialysis patients with membrane dysfunction. A randomized, multi-centre open clinical trial

<sec><st>Background.</st> Progressive peritoneal membrane injury and dysfunction are feared repercussions of peritoneal dialysis (PD), and may compromise the long-term feasibility of this therapy. Different strategies have been attempted to prevent or reverse this complication with limited success. </sec> <sec><st>Methods.</st> We performed a randomized, open multi-centre trial, aimed at scrutinizing the efficacy of self-administered intraperitoneal (i.p.) bemiparin (BM) to modulate peritoneal membrane dysfunction. The main outcome variables were peritoneal creatinine transport and the ultrafiltration (UF) capacity, estimated during consecutive peritoneal equilibration tests. The trial included a control group who did not undergo intervention. The treatment phase lasted 16 weeks with a post-study follow-up of 8 weeks. </sec> <sec><st>Results.</st> Intraperitoneal BM did not significantly improve creatinine transport or the UF capacity, when the whole group was considered. However, we observed a time-limited improvement in the UF capacity for the subgroup of patients with overt UF failure, which was not observed in the control group. Intraperitoneal injection of BM did not carry an increased risk of peritoneal infection or major haemorrhagic complications. </sec> <sec><st>Conclusions.</st> Our data do not support the systematic use of BM for management of peritoneal membrane dysfunction in PD patients. Further studies on the usefulness of this approach in patients with overt UF failure are warranted. Intraperitoneal administration of BM is safe in PD patients, provided regulated procedures are respected. </sec>

On-pump beating-heart coronary artery bypass provides efficacious short- and long-term outcomes in hemodialysis patients

<sec><st>Background.</st> On-pump beating-heart coronary artery bypass grafting surgery (CABG) is beneficial due to the elimination of cardioplegic arrest. However, there are few reports regarding its efficacy in chronic hemodialysis patients. This study investigated the potential benefits of on-pump beating-heart CABG in chronic hemodialysis patients. </sec> <sec><st>Methods.</st> From January 2002 to January 2010, 186 patients with chronic hemodialysis underwent CABG in our institution. In total, 82 patients underwent conventional CABG with cardioplegic arrest, 56 underwent off-pump CABG and 48 underwent on-pump beating-heart CABG. The early results and long-term outcomes were compared among these three groups. </sec> <sec><st>Results.</st> On-pump beating-heart CABG significantly reduced the duration of cardiopulmonary bypass (CPB) compared with conventional CABG. The post-operative pericardial drainage amount (P < 0.01), length of hospital stay (P < 0.001) and length of post-operative intensive care unit stay (P < 0.001) were significantly lower in the on-pump beating-heart and off-pump CABG groups than in the conventional CABG group. No significant difference was found regarding 30-day mortality and morbidity rates including stroke, pneumonia, arrhythmia, intestinal complication and low cardiac output syndrome. There were no statistical differences in the freedom from cardiac events (P = 0.323), but on-pump beating-heart CABG provided better long-term survival than conventional CABG (P = 0.009). </sec> <sec><st>Conclusions.</st> On-pump beating-heart CABG is a safe procedure that provides optimal operative exposure in chronic hemodialysis patients. The use of CPB and the elimination of cardioplegic arrest may be beneficial for the short- and long-term survival of chronic hemodialysis patients. </sec>

Transcutaneous oxymetry as predictive test of peripheral vascular revascularization in haemodialysis population

<sec><st>Background.</st> Peripheral arterial disease (PAD) occurs frequently among haemodialysis patients but it is underestimated. Vascular treatment and amputations are more frequent in end stage renal disease (ESRD) population compared to the general population possibly because of a diagnosis of PAD delayed. Transcutaneous oxymetry (TcPO2) is commonly used in vascular medicine to reflect local arterial blood flow and skin oxygenation.The aim of this study was to assess the accuracy of the TcPO2 measurements to screen PAD and to predict vascular outcomes in haemodialysis population. </sec> <sec><st>Methods.</st> In a 1-year prospective study, the value of TcPO2 was assessed in a cohort of 48 patients when starting haemodialysis. </sec> <sec><st>Results.</st> Twenty one patients had at least one vascular stenosis (42%) on Doppler examination and were considered as affected by PAD. At inclusion a pathologic resting TcPO2 (<40mmHg) was found in 13 patients (29%). A severe ischemia (TcPO2 <30mmHg) was noted in 8 patients (16.7%) and a critical limb ischemia (TcPO2 <10mmHg) in 3 patients.(6%). Eleven (25.5%) and 6 patients (15%) had a TcPO2 <40mmHg at 6 and 12 months respectively. During the follow-up, death was seven times more frequent in patients with abnormal TcPO2 at T0 compared to patients with normal TcPO2 (38% vs 5.7%; p = 0.04). Revascularization (n = 6) or amputation (n = 5) were required for 5 patients. TcPO2 was pathologic in all patients and legs requiring a vascular treatment. The sensitivity, specificity, positive predictive value and negative predictive value were 100%, 85.2%, 38% and 100% respectively. </sec> <sec><st>Conclusions.</st> This study confirms the underestimated PAD diagnosis and the severity of PAD in haemodialysis population. A TcPO2 less than 40mmHg at the onset of the haemodialysis could identify patients at high risk of death and patients requiring vascular treatment. Moreover, since haemodialysis seems to be an accelerating factor of atherosclerosis, TcPO2 might be perform as a complement to traditional vascular explorations to assess the distal vascular conditions of limbs of haemodialysis patients. </sec>

Renal replacement therapy in rural and urban Australia

<sec><st>Background.</st> Australians living in rural regions have poorer health outcomes than city residents. This study compares rural and city patient access to and outcomes of renal replacement therapy (RRT) in Australia. </sec> <sec><st>Methods.</st> Non-indigenous Australians aged ≥16 years who commenced dialysis or underwent renal transplantation between 1996 and 2009 and were registered with the Australia and New Zealand Dialysis and Transplant Registry were included. Each patient’s location was classified according to a remote area index as major city (MC), inner regional (IR), outer regional (OR) or remote/very remote (REM). </sec> <sec><st>Results.</st> A total of 24 068 commenced dialysis and 5399 received a renal transplant during the study period. Patient distribution by remote area index was 71.3 and 70.8% MC, 19.1 and 18.6% IR, 8.4 and 9.1% OR and 1.1 and 1.5% REM for dialysis and transplant patients, respectively. RRT incidence per million population after adjusting for age and gender was 124 [95% confidence interval (CI): 122–126] MC, 106 (95% CI: 103–110) IR, 100 (95% CI: 96–105) OR and 96 (95% CI: 84–109) REM. After controlling for demographic variables, comorbidities and other covariates, hazard ratios for dialysis survival compared to MC were 1.08 (95% CI: 1.03–1.14) IR, 1.19 (95% CI: 1.11–1.28) OR and 1.03 (95% CI: 0.84–1.25) REM. Transplant patient survival was not statistically different by remoteness. </sec> <sec><st>Conclusions.</st> Rural Australians have lower incidence of RRT. Whether the causes of the lower RRT reflect lower disease rates or differential treatment access is not known. Differences in outcomes were seen for dialysis but not transplantation. </sec>

Effect of steroid-free low concentration calcineurin inhibitor maintenance immunosuppression regimen on renal allograft histopathology and function

<sec><st>Background.</st> The most common cause of late kidney transplant failure is insidiously progressive renal dysfunction associated with organ scarring and fibrosis. Advanced donor age, delayed graft function, calcineurin toxicity and repeated acute rejection episodes are risk factors for this pathophysiology. </sec> <sec><st>Methods.</st> We employed 3, 12 and 24 months surveillance renal biopsies, scored using the Chronic Allograft Damage Index (CADI), with periodic estimates of glomerular filtration rate (eGFR) to assess the effect of a steroid-free maintenance immunosuppression regimen on allograft histology and function. Ninety-one patients were induced with Alemtuzumab and then treated with mycophenolate sodium and low trough concentrations of tacrolimus. </sec> <sec><st>Results.</st> Fifty-six of 91 patients followed for 24 months showed no clinical rejection and in 16 more only minimal histological or borderline changes as defined by Banff criteria were observed. Histologically acute rejection was observed in 14 patients including two detected on surveillance biopsy. Five patients refused biopsies but showed stable eGFR for 24 months. Graft histopathology in the group with no rejection did not worsen. In contrast, nearly half the patients with acute rejection showed progression of CADI scores and a total of four grafts were lost over the 2 years. The 16 patients with borderline rejection changes exhibited stable glomerular filtration rate throughout, but 12.5% showed progression of CADI scores in the 12- to 24-month period. </sec> <sec><st>Conclusions.</st> Following Alemtuzumab induction and in conjunction with low-dose tacrolimus and mycophenolate, continuous steroid therapy was not required to prevent progressive injury or preservation of graft function in patients without biopsy-proven acute rejection. Scored surveillance renal biopsies provide a useful tool to monitor transplanted kidneys. </sec>

Kidney and liver transplantation in patients with autosomal recessive polycystic kidney disease: a multicentric study

<sec><st>Background and objectives.</st> In contrast to the improvement in our understanding of the pathogenesis and presentation of autosomal recessive polycystic kidney disease (ARPKD), data regarding the issue of kidney and liver transplantation in patients with ARPKD remain particularly scarce. Here, we report the results and outcome of renal and/or liver transplantation in a series of patients with ARPKD. </sec> <sec><st>Methods.</st> Fourteen ARPKD patients (age: 3–25 years) who underwent renal transplantation with or without liver transplantation were retrospectively identified in five French nephrology departments. The patients’ medical charts were reviewed and relevant data were collected. </sec> <sec><st>Results.</st> The clinical and radiological presentation of the 14 patients was highly variable illustrating the heterogeneity of ARPKD. Six patients underwent kidney and/or liver transplantation in adulthood. First renal graft survival was 92, 78 and 14% at 1, 5 and 10 years after renal transplantation, respectively. Mortality rate was relatively high (3/14; 21%) in these young patients and was directly related to infectious complications (recurrent angiocholitis) of severe Caroli’s disease (dilatation of intra- and/or extra-hepatic bile ducts), a typical feature of ARPKD. </sec> <sec><st>Conclusions.</st> Our data suggest that ARPKD patients evaluated for renal transplantation should be carefully screened for severe Caroli’s disease. Even though the limited number of patients included in our study precludes any definite recommendation, pre-emptive liver transplantation may be a therapeutic option in ARPKD patients with severe Caroli’s disease evaluated for renal transplantation. </sec>

Reverse dipper pattern of blood pressure at 3 months is associated with inflammation and outcome after renal transplantation

<sec><st>Background.</st> Cardiovascular disease is the major cause of morbidity and mortality after renal transplantation. It has been shown that both traditional and transplant-specific risk factors contribute to the high cardiovascular burden after renal transplantation The aim is to evaluate the association among ambulatory blood pressure monitoring (ABPM) at 3 months, inflammation and graft outcome. </sec> <sec><st>Methods.</st> ABPM at 3 months was performed in 126 consecutive renal transplants. According to the nocturnal reduction of systolic blood pressure (SBP), dipper (SBP ≥ 10%), non-dipper (0 < SBP < 10%) and reverse dipper (SBP nocturnal rise) pattern were defined. The outcome variable was the combination of any cardiovascular event and graft failure for any reason. </sec> <sec><st>Results.</st> Circadian blood pressure pattern was dipper (n = 22), non-dipper (n = 65) and reverse dipper (n = 39). Reverse dipper pattern was associated with pre-transplant diabetes (18 versus 2%, P = 0.004), body mass index (26.9 ± 5.0 versus 24.8 ± 3.8 kg/m2, P = 0.001), calcineurin inhibitor treatment (74 versus 54%, P = 0.001) and serum soluble tumour necrosis factor receptor 2 levels (18 ± 15 versus 11 ± 6 ng/mL, P = 0.010). During 45 ± 11 months of follow-up, 22 patients reached the combined outcome variable. Multivariate Cox regression analysis showed that reverse dipper pattern [relative risk (RR): 3.50 and 95% confidence interval (CI): 1.36–8.93; P = 0.009] and creatinine clearance (RR: 0.94 and 95% CI: 0.91–0.98, P = 0.003) were independently associated with outcome. </sec> <sec><st>Conclusion.</st> The reverse dipper circadian pattern is associated with inflammation and constitutes an independent predictor of graft outcome. </sec>

Cardiovascular and renal outcome in recipients of kidney grafts from living donors: role of aortic stiffness

<sec><st>Background.</st> Cardiovascular (CV) risk remains high in renal transplant patients despite a clear improvement conferred by transplantation. This risk is attributed mostly to recipient-related risk factors. Donor vascular characteristics, such as arterial stiffness, have been poorly investigated in this regard. </sec> <sec><st>Methods.</st> Recipients of living-related (n = 75) and living-unrelated (n = 20) kidney grafts were recruited at a mean time of 107 ± 41 months after transplantation for baseline evaluation and follow-up for the occurrence of the following composite outcome: myocardial infarction, stroke, CV death, doubling of serum creatinine or development of end-stage renal disease (ESRD). At inclusion, recipients and their corresponding donors underwent complete history, physical examination, laboratory tests and non-invasive measurement of aortic pulse wave velocity (PWV). </sec> <sec><st>Results.</st> During a mean follow-up of 56 ± 18 months, 20 recipients doubled their serum creatinine, of whom 16 reached ESRD, and 9 suffered of a new CV event (5 of which were fatal). Cox proportional hazards regression analysis showed that, in addition to recipient-related parameters, such as the presence of CV event and the estimated glomerular filtration rate at inclusion, donor aortic PWV was a strong and independent predictor of the composite recipient outcome. </sec> <sec><st>Conclusions.</st> Donor large artery stiffness may predict recipient CV and graft outcome. This finding demonstrates the tight link that exists between the vascular system and the kidneys and suggests that donor contribution to recipient outcome goes beyond simple parameters like age, gender and even familial or non-familial donor type. </sec>

Progression of coronary artery calcification in renal transplant recipients

Background. Cardiovascular disease is the leading cause of mortality among renal transplant recipients. In the general population, coronary artery calcification (CAC) and progression of CAC are predictors of future cardiac risk. We conducted a study to determine the progression of CAC in renal transplant recipients; we also examined the factors associated with progression and the impact of the analytic methods used to determine CAC progression. Methods. We used multi-detector computed tomography to examine CAC in 150 prevalent renal transplant recipients, who did not have a documented cardiovascular disease. A baseline and a follow-up scan were performed and changes in CAC scores were evaluated in each patient individually, to calculate the incidence of CAC progression. Multivariate logistic regression analysis was used to evaluate the determinants of CAC progression. Results. Baseline CAC prevalence was 35.3% and the mean CAC score was 60.0 ± 174.8. At follow-up scan that was performed after an average of 2.8 ± 0.4 years, CAC prevalence increased to 64.6% and the mean CAC score to 94.9 ± 245.7. Progression of individual CAC score was found between 28.0 and 38.0%, depending on the method used to define progression. In patients with baseline CAC, median annualized rate of CAC progression was 11.1. Baseline CAC, high triglyceride and bisphosphonate use were the independent determinants of CAC progression. Conclusions. Renal transplantation does not stop or reverse CAC. Progression of CAC is the usual evolution pattern of CAC in renal transplant recipients. Beside baseline CAC, high triglyceride level and bisphosphonate use were associated with progression of CAC.

Psychosocial variables are associated with being wait-listed, but not with receiving a kidney transplant in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Background. Psychosocial factors are associated with clinical outcomes in patients with end-stage renal disease. It is not known if self-reported depression and quality of life influence the likelihood of being wait-listed and receiving a transplant. Methods. Prevalent cross section of 18- to 65-year-old hemodialysis (HD) patients in the USA (N = 2033) and seven European countries (N = 4350) from the Dialysis Outcomes and Practice Patterns Study phase II and III was analyzed. Wait-listed patients (N = 1838) were followed until kidney transplantation. Self-reported depressive symptoms were assessed by the Center for Epidemiologic Studies-Depression scale, 10-item version (CES-D) and health-related quality of life (HR-QoL) by the Kidney Disease Quality of Life Short Form 12 scale Physical Component Score (PCS). Results. At study entry, 27% (USA) to 53% (UK) of patients were wait-listed in participating countries. Variables associated with lower odds of being on the waiting list included worse HR-QoL, more severe depressive symptoms, older age, fewer years of education, lower serum albumin, lower hemoglobin, shorter time on dialysis and presence of multiple comorbid conditions. Among wait-listed patients, significantly lower transplantation rates were seen for females, blacks, patients having prior transplantation and multiple comorbid conditions but not PCS or CES-D. Conclusions. Fewer depressive symptoms and better HR-QoL are associated with being on the waiting list in prevalent HD patients but not with receiving a kidney transplant among wait-listed dialysis patients. Regular assessment of subjective well-being may help identify patients with reduced access to wait-listing and kidney transplantation.

ADAM17 up-regulation in renal transplant dysfunction and non-transplant-related renal fibrosis

Background. Interstitial fibrosis and tubular atrophy (IF/TA) is an important cause of renal function loss and ischaemia–reperfusion (I/R) injury is considered to play an important role in its pathophysiology. The aim of the present study was to investigate the role of a disintegrin and metalloproteinase 17 (ADAM17) in human renal allograft disease and in experimental I/R injury of the kidney. Methods. We studied the expression of ADAM17 messenger RNA (mRNA) in IF/TA and control kidneys by reverse transcription–polymerase chain reaction and in situ hybridization. Moreover, we assessed ADAM17-mediated heparin-binding epidermal growth factor (HB-EGF) shedding in immortalized human cells. Finally, we studied the effect of pharmacological ADAM17 inhibition in a model of renal I/R injury in rats. Results. ADAM17 mRNA was up-regulated in IF/TA when compared to control kidneys. In normal kidneys, ADAM17 mRNA was weakly expressed in proximal tubules, peritubular capillaries, glomerular endothelium and parietal epithelium. In IF/TA, tubular, capillary and glomerular ADAM17 expression was strongly enhanced with de novo expression in the mesangium. In interstitial fibrotic lesions, we observed co-localization of ADAM17 with HB-EGF protein. In vitro, inhibition of ADAM17 with TNF484 resulted in a dose-dependent reduction of HB-EGF shedding in phorbol 12-myrisate 13-acetate-stimulated cells and non-stimulated cells. In vivo, ADAM17 inhibition significantly reduced the number of glomerular and interstitial macrophages at Day 4 of reperfusion. Conclusions. In conclusion, HB-EGF co-expresses with ADAM17 in renal interstitial fibrosis, suggesting a potential interaction in IF/TA. Targeting ADAM17 to reduce epidermal growth factor receptor phosphorylation could be a promising way of intervention in human renal disease.

Anti-A/B antibody depletion by semiselective versus ABO blood group-specific immunoadsorption

Background. Recipient desensitization using blood group (BG)-specific immunoadsorption (ABO-IA) has proven to enable successful kidney transplantation across major ABO barriers. In this context, the efficiency of non-antigen-specific (semiselective) IA adsorbers has not yet been established. The objective of our study was to quantify anti-A/B antibody depletion by protein A-, peptide ligand- and anti-human immunoglobulin-based semiselective IA in comparison to ABO-IA. Methods. Eight ABO-IA-treated transplant candidates and 39 patients subjected to semiselective IA for a variety of different indications outside the context of ABO-incompatible transplantation were included. Antibody patterns (IgG, IgG1-4 subclasses, IgM, C4d-fixing reactivities) were analysed applying conventional agglutination testing and flow cytometry. Results. As assessed by sensitive flow cytometric antibody detection, ABO-IA-based desensitization led to a profound even though often incomplete reduction of anti-A/B reactivities. Persistent complement- or non-complement-fixing reactivities, however, were not associated with transplant rejection or capillary C4d deposition. Single sessions of semiselective IA turned out to be more effective than ABO-IA in decreasing levels of anti-A/B IgG [median reduction to 28 versus 59% (ABO-IA) of baseline values, P < 0.001). In contrast, BG-specific IgM (74 versus 30%, P < 0.001) and IgG3 (72 versus 42%, P < 0.05) were reduced to a lesser extent, without differences between tested adsorber types. Analysis of four consecutive IA sessions revealed that inferior efficiency could not be overcome by serial treatment. Conclusion. Our observation of limited adsorption capacities regarding distinct BG-specific Ig (sub)classes suggests caution in applying semiselective IA techniques in ABO-incompatible kidney transplantation.

Pre-dialysis creatinine and interdialytic change in creatinine as nutritional markers in haemodialysis patients

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Glomerular density and progression

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Renoprotective antioxidant effect of alagebrium in experimental diabetes

Announcements

Recommendations for the Management of Crush Victims in Mass Disasters: Short Field Version

Abstract

Recommendations for the Management of Crush Victims in Mass Disasters

Preface

Abbreviations

Section I: Definitions and Basic Concepts

Section II. Interventions at the Disaster Field

Section III: Interventions on Admission to Hospital

Section IV: Fasciotomies and Amputations in Crush Syndrome Victims

Section V: Prevention and treatment of AKI in crush syndrome victims

Section VI: Diagnosis, prevention and treatment of medical complications during the clinical course of crush-related AKI

Section VII: Logistic Issues in the Treatment of Crush Syndrome Victims

Section VIII: Implementation of a Renal Disaster Relief Response Program

APPENDIX

Acknowledgements:

References

Tony Wing (1933-2012)

Crush recommendations: a step forward in disaster nephrology

Ongoing gaps in CKD and CVD care: re-evaluating strategies for knowledge dissemination

Kt/V urea does not tell it all

The new era of APOL1-associated glomerulosclerosis

Volume overload as a mechanism for obstructive sleep apnea in CKD?

Urinary albumin to protein ratio: more of the same or making a difference?

Epidermal growth factor: a new therapeutic target in glomerular disease

Glomerular kidney diseases are of major public health importance because of their strong impact on the quality of life of patients and of their costly management. A relatively neglected area of study is the local factors that influence development of glomerular demolition. The involvement of a glomerular factor has been now demonstrated in glomerulonephritis with cell proliferation such as crescentic rapidly progressive glomerulonephritis (RPGN). Various unrelated immune disorders promote RPGN, such as antibodies directed against the glomerular basement membrane, deposition of immune complexes or antibodies directed against neutrophils. Despite the heterogeneity of these causing diseases, RPGNs share similar histopathological features, which suggest involvement of common final pathways. De novo expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in glomerular epithelial cells is found specifically in human glomerulonephritis with proliferation of these cells and dedifferentiation of podocytes. A receptor for HB-EGF, the EGF receptor (EGFR), is expressed by parietal epithelial cells and podocytes. Furthermore, in a mouse model of RPGN, HB-EGF deficiency or conditional targeting of the Egfr alleles in podocytes markedly alleviated RPGN, renal failure and death. This indicates that the HB-EGF/EGFR pathway plays a pivotal role in RPGN and opens therapeutic perspectives as EGFR inhibitors are clinically available.

Cystatin C in HIV-infected patients: promising but not yet ready for prime time

With the development of highly active antiretroviral therapy, chronic kidney disease has become a prominent cause of morbidity in individuals infected by HIV. Because serum creatinine has significant limitations in this specific population, cystatin C is emerging as a promising biomarker for both the evaluation of glomerular filtration rate (GFR) and the detection of drug-induced kidney injury. Along with renal function, serum cystatin C concentration is associated with several biological parameters such as C-reactive protein, HIV viral load and CD4+ cells count. All these determinants of cystatin C are, however, more or less independent of GFR. Studies evaluating the accuracy of cystatin C for estimating GFR in the setting of HIV infection are scarce and methodology is often questionable (lack of reference method or inadequate statistical analyses). Thus far, data are insufficient to encourage the use of cystatin C or cystatin C-based equations to estimate GFR in the HIV-infected population. Further research is needed to explore the clinical utility of cystatin C in this setting. Beyond the use of cystatin C as a GFR marker, future studies will have to evaluate its role as a predictor of patient outcome, particularly in regard to cardiovascular morbi-mortality.

Calciphylaxis in CKD and beyond

Calciphylaxis is still an incompletely understood rare disease, which most often affects people on haemodialysis. For the majority of patients, calciphylaxis means a massive reduction in quality of life and is associated with high morbidity and mortality. We still know little about the concert of local and systemic risk factors and underlying causes that finally lead to the development of calciphylaxis. Recent work from Asia points towards persistent uncertainties in the diagnosis and management of the disease which the nephrology community has to address by establishing standards in both diagnosis as well as treatment strategies. Hayashi et al. have published results from a Japanese survey in which the authors collected data from calciphylaxis patients and compared clinical and laboratory data with those of control subjects. This innovative approach allowed the authors to calculate relative risks for various parameters in terms of calciphylaxis development. While uncontrolled hyperparathyroidism seemingly plays a secondary role, vitamin K antagonist usage proved to be of particular importance. Survey as well as registry data may help to close the gap in our knowledge about calciphylaxis which may ultimately result in improved prevention, patient care and outcome.

Current status of transplantation and organ donation in the Balkans--could it be improved through the South-eastern Europe Health Network (SEEHN) initiative?

Organ donation and transplantation activity in the majority of Balkan countries (Albania, Bosnia and Herzegovina, Croatia, Macedonia, Moldova, Montenegro, Serbia, Romania and Bulgaria) are lagging far behind international averages. Inadequate financial resources, unclear regional data and lack of government infrastructure are some of the issues which should be recognized to draw attention and lead to problem-solving decisions. The Regional Health Development Centre (RHDC) Croatia, a technical body of the South-eastern Europe Health Network (SEEHN), was created in 2011 after Croatia's great success in the field over the last 10 years. The aim of the RHDC is to network the region and provide individualized country support to increase donation and transplantation activity in collaboration with professional societies (European Society of Organ Transplantation, European Transplant Coordinators Organization, The Transplantation Society and International Society of Organ Donation and Procurement). Such an improvement would in turn likely prevent transplant tourism. The regional data from 2010 show large discrepancies in donation and transplantation activities within geographically neighbouring countries. Thus, proposed actions to improve regional donation and transplantation rates include advancing living and deceased donation through regular public education, creating current and accurate waiting lists and increasing the number of educated transplant nephrologists and hospital coordinators. In addition to the effort from the professionals, government support with allocated funds per deceased donation, updated legislation and an established national coordinating body is ultimately recognized as essential for the successful donation and transplantation programmes. By continuous RHDC communication and support asked from the health authorities and motivated professionals from the SEEHN initiative, an increased number of deceased as well as living donor kidney transplantations in the future should be more realistic.

Dynamics of absolute amount of nephrin in a single podocyte in puromycin aminonucleoside nephrosis rats calculated by quantitative glomerular proteomics approach with selected reaction monitoring mode

Background. The slit diaphragm (SD) is a complex of podocyte-specific proteins and plays a significant role in glomerular filtration. To understand podocyte biology, it is important to determine the expression amount of the SD complex proteins. This study aimed to quantify the absolute amount of nephrin, which is believed to be a major component of SD, in podocytes and to apply that method to normal and puromycin aminonucleoside (PAN) nephrosis rats. Methods. The counting method for podocyte number in a glomerulus was developed by three-dimensional reconstruction imaging of Wilms tumor (WT-1) immunofluorescence on isolated glomeruli. Absolute amount of nephrin was quantified by mass spectrometry using the selected reaction monitoring (SRM) mode with a stable isotope-labeled peptide. Results. The number of podocytes per glomerulus was 95.5 ± 17.6 in the control rats, 90.7 ± 19.2 on Day 4 and 90.7 ± 26.2 on Day 7 in PAN nephrosis rats. The amount of nephrin per glomerulus in control rats was 1.02 ± 0.11 fmol and those in PAN nephrosis rats were reduced to 0.46 ± 0.06 fmol and 0.35 ± 0.04 fmol on Day 4 and Day 7. The nephrin amount per podocyte was significantly decreased association with the development of proteinuria in PAN nephrosis rats. Conclusions. This study established the absolute quantification of nephrin and determined the amount of nephrin in a podocyte of normal and PAN nephrosis rat kidneys. This highly sensitive and selective quantification method for protein is a useful tool for the analysis of SD protein in a podocyte.

Albumin-induced apoptosis of glomerular parietal epithelial cells is modulated by extracellular signal-regulated kinase 1/2

Background. The biological role(s) of glomerular parietal epithelial cells (PECs) is not fully understood in health or disease. Given its location, PECs are constantly exposed to low levels of filtered albumin, which is increased in nephrotic states. We tested the hypothesis that PECs internalize albumin and increased uptake results in apoptosis. Methods. Confocal microscopy of immunofluorescent staining and immunohistochemistry were used to demonstrate albumin internalization in PECs and to quantitate albumin uptake in normal mice and rats as well as experimental models of membranous nephropathy, minimal change disease/focal segmental glomerulosclerosis and protein overload nephropathy. Fluorescence-activated cell sorting analysis was performed on immortalized cultured PECs exposed to fluorescein isothiocyanate (FITC)-labeled albumin in the presence of an endosomal inhibitor or vehicle. Apoptosis was measured by Hoechst staining in cultured PECs exposed to bovine serum albumin. Levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) were restored by retroviral infection of mitogen-activated protein kinase (MEK) 1/2 and reduced by U0126 in PECs exposed to high albumin levels in culture and apoptosis measured by Hoechst staining. Results. PECs internalized albumin normally, and this was markedly increased in all of the experimental disease models (P < 0.05 versus controls). Cultured immortalized PECs also internalize FITC-labeled albumin, which was reduced by endosomal inhibition. A consequence of increased albumin internalization was PEC apoptosis in vitro and in vivo. Candidate signaling pathways underlying these events were examined. Data showed markedly reduced levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (ERK1/2) in PECs exposed to high albumin levels in nephropathy and in culture. A role for ERK1/2 in limiting albumin-induced apoptosis was shown by restoring p-ERK1/2 by retroviral infection, which reduced apoptosis in cultured PECs, while a forced decrease of p-ERK1/2 through inhibition of MEK 1/2 significantly increased albumin-induced PEC apoptosis. Conclusions. A normal role of PECs is to take up filtered albumin. However, this is increased in proteinuric glomerular diseases, leading to apoptosis through changes in ERK1/2.

Stimulation of the PD-1/PDL-1 T-cell co-inhibitory pathway is effective in treatment of experimental autoimmune glomerulonephritis

<sec><st>Background.</st> Experimental autoimmune glomerulonephritis (EAG) can be induced in Wistar–Kyoto (WKY) rats by immunization with the recombinant NC1 domain of the alpha 3 chain of type IV collagen [α3(IV)NC1]. EAG is characterized by circulating and deposited anti-α3(IV)NC1 antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. Programmed death-1 (PD-1) receptor is preferentially expressed on activated T cells and binds two known ligands present on antigen presenting cells, PDL-1 and PDL-2. Engagement of PD-1 by its ligands results in a negative regulatory effect, with inhibition of downstream cellular signalling events and diminished cellular proliferation. </sec> <sec><st>Methods.</st> In order to investigate the role of the PD-1/PDL-1 co-inhibitory pathway in development of EAG, the in vivo effects of a stimulating PDL-1/Fc fusion protein were examined after the onset of disease. </sec> <sec><st>Results.</st> Stimulation of PD-1 led to a significant reduction in albuminuria, serum urea, serum creatinine, crescent formation and tubular damage compared with controls. There was also a reduction in numbers of glomerular macrophages, CD4+ T cells, CD8+ T cells and PD1+ cells compared with controls. No reduction was observed in levels of circulating or deposited antibodies. </sec> <sec><st>Conclusions.</st> These results demonstrate that PDL-1/Fc fusion protein is effective in treatment of glomerulonephritis and confirm the importance of the PD-1/PDL-1 T-cell co-inhibitory pathway in development of EAG. Strategies designed to stimulate this pathway may provide a novel approach to treatment of human glomerulonephritis. </sec>

Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model

<sec><st>Background.</st> Nephronophthisis (NPHP), the most frequent genetic cause of end-stage kidney disease in children and young adults, is characterized by a variable number of renal cysts associated with cortical tubular atrophy and interstitial fibrosis. The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling pathway involved in the production of profibrotic mediators. The relationship between p38 MAPK and renal fibrosis in NPHP2 is unknown. </sec> <sec><st>Methods.</st> We administered a selective p38 MAPK inhibitor, FR167653, in a NPHP2 mouse model (inv/inv, invC mice) from 3 to 6 weeks old, and the kidneys were examined at 6 weeks of age. Phosphorylation of p38 MAPK (p-p38 MAPK) protein levels, the degree of renal fibrosis, messenger RNA (mRNA) levels for extracellular matrix genes and mRNA levels for transforming growth factor in the kidneys were studied. Effect of an extracellular signal-regulated protein kinase (ERK) kinase (MEK) inhibitor on renal fibrosis was also evaluated. </sec> <sec><st>Results.</st> Expression of extracellular matrix genes and p-p38 MAPK were increased in the NPHP2 mouse model kidney. FR167653 successfully decreased p-p38 MAPK levels, the degree of fibrosis and extracellular matrix gene expressions. However, the FR167653 did not prevent cyst expansion, abnormal cell proliferation and acceleration of apoptosis and did not influence ERK activation. In contrast, MEK inhibition reduced both cyst expansion and fibrosis without affecting p38 MAPK activation. </sec> <sec><st>Conclusions.</st> These results suggest that inhibition of p38 MAPK reduced renal fibrosis but not cyst expansion, cell proliferation and apoptosis in NPHP2 model mice. Our results suggest that p38 MAPK and ERK signaling pathways independently affect renal fibrosis in inv mutant mice. </sec>

Recombinant chaperonin 10 suppresses cutaneous lupus and lupus nephritis in MRL-(Fas)lpr mice

<sec><st>Background.</st> Systemic lupus erythematosus (SLE) is still treated with global immunosuppressants with serious toxicities. We hypothesized that endogenous immunosuppressive molecules might be able to control SLE manifestations more specifically. Heat shock protein 10, or chaperonin 10 (Cpn10), is a secretory molecule that can suppress innate and adaptive immunity. </sec> <sec><st>Methods.</st> Recombinant human Cpn10 (100 μg per mouse) was given intraperitoneally to healthy-appearing female MRL-(Fas)lpr mice from 12 to 22 weeks of age. At the age of 22 weeks, mice were analysed for treatment outcome by harvesting organs, plasma and urine. </sec> <sec><st>Results.</st> Cpn10 entirely prevented cutaneous lupus lesions as compared to vehicle-treated mice. Cpn10 also suppressed lupus nephritis as evident from serum creatinine levels, albuminuria and the scores of disease activity and chronicity. Autoimmune lung disease was unaffected by Cpn10 treatment while overall survival of mice was prolonged. Cpn10 did not have any major effects on either dendritic cell or B-cell counts except T cells in spleen, plasma interferon-gamma, tumour necrosis factor-alpha, interleukin-10, anti-nuclear autoantibody levels or markers of lymphoproliferation. </sec> <sec><st>Conclusions.</st> In summary, recombinant Cpn10 selectively prevents cutaneous lupus and suppresses nephritis in MRL-(Fas)lpr mice without affecting the underlying systemic autoimmune process. Hence, Cpn10 might be useful for the treatment of skin and kidney manifestations of SLE. </sec>

Deletion of the Cl-/HCO3- exchanger pendrin downregulates calcium-absorbing proteins in the kidney and causes calcium wasting

<sec><st>Background.</st> The epithelial calcium channel (ECaC) (TRPV5) and the Cl–/HCO3– exchanger pendrin (SLC26A4) are expressed on the apical membrane of tubular cells in the distal nephron and play essential roles in calcium re-absorption and bicarbonate secretion, respectively, in the kidney. </sec> <sec><st>Methods.</st> A combination of functional and molecular biology techniques were employed to examine the role of pendrin deletion in calcium excretion. </sec> <sec><st>Results.</st> Here, we demonstrate that deletion of pendrin causes acidic urine [urine pH 4.9 in knockout (KO) versus 5.9 in wild-type (WT) mice, P < 0.03)] and downregulates the calcium-absorbing molecules ECaC and Na/Ca exchanger in the kidney, as shown by northern hybridization, immunoblot analysis and/or immunofluorescent labeling. These changes were associated with a ~100% increase in 24-h urine calcium excretion in pendrin null mice. Subjecting the pendrin WT and KO mice to oral bicarbonate loading for 12 days increased the urine pH to ~8 in both genotypes, normalized the expression of ECaC and Na/Ca exchanger and reduced the urine calcium excretion in pendrin-null mice to levels comparable to WT mice. </sec> <sec><st>Conclusions.</st> We suggest that pendrin dysfunction should be suspected and investigated in humans with an otherwise unexplained acidic urine and hypercalciuria. </sec>

Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms

<sec><st>Background.</st> Renal failure as a consequence of eating mushrooms has been reported repeatedly after ingestion of webcaps of the Cortinarius orellanus group. But mushrooms of the genus Amanita can also cause renal failure: Amanita smithiana (North America) and Amanita proxima (Mediterranean area). Here, we discuss poisonings caused by other white amanitas. A German and—independently—two Portuguese patients reported the ingestion of completely white mushrooms with ring. Similar to intoxications with A. smithiana or A. proxima, the clinical picture was characterized by nausea and vomiting 10–12 h after ingestion, severe acute renal failure and mild hepatitis. Renal biopsy showed acute interstitial nephritis and tubular necrosis. Two patients were given temporary haemodialysis. All have fully recovered their renal function. Poisonings caused by mushrooms containing the toxin of A. smithiana were suspected. We tested 20 Amanita species for the presence of this toxin. </sec> <sec><st>Methods.</st> Thin layer chromatography was applied to detect A. smithiana nephrotoxin in herbarium specimens using authentic material of A. smithiana as reference. </sec> <sec><st>Results.</st> A. smithiana toxin could be detected in Amanita boudieri, Amanita gracilior and in Amanita echinocephala. A. boudieri was collected by the Portuguese patients. A. echinocephala is the only nephrotoxic Amanita growing North of the Alps and is suspected to be the cause of renal failure in the German patient. No A. smithiana toxin was detectable in the nephrotoxic A. proxima. </sec> <sec><st>Conclusions.</st> A. boudieri, A. gracilior and A. echinocephala are nephrotoxic. These intoxications are clinically similar to that of A. smithiana, with acute reversible renal failure and mild hepatitis but are different in their clinical picture from Orellanus syndrome characterized by a delayed onset of severe and often irreversible renal failure. </sec>

Urinary organic anion transporter protein profiles in AKI

<sec><st>Background.</st> Organic anion transporters (OATs) are located on either the basolateral or the apical membrane of the proximal tubule cell and mediate the absorption and secretion of various drugs and endogenous metabolites. It has been shown that cellular damage in acute kidney injury (AKI) involves three forms of injury: sublethal damage resulting in loss of cell polarity, cell death through apoptosis and necrosis. We hypothesize that cellular mistargeting of OAT proteins in AKI will change the profile of OAT proteins in urine. </sec> <sec><st>Methods.</st> Thirty AKI patients were included in the study. AKI was defined by clinical course, daily urine output, response to fluid repletion, urinary sediment, fractional excretion of sodium (FeNa) and urine osmolality. Urinary OAT1, OAT3 and OAT4 protein abundance was measured from semiquantitative immunoblots of urine membrane fraction samples (exosome) collected from patients with AKI and from control subjects. </sec> <sec><st>Results.</st> Although all patients studied reached a similar severity of renal failure measured by serum creatinine, some of them recovered from AKI with supportive care only, while others required renal replacement therapy (RRT). OAT1 and OAT3, which are normally localized in the basolateral membrane of the proximal tubule cell, were detected at low levels in urine from control subjects and were increased significantly in all patients with AKI. OAT4 protein, which is normally localized in the luminal membrane of proximal tubule cells, was present in abundance in urine of control subjects. Interestingly, in patients with AKI who eventually recovered, urinary OAT4 was found to be significantly lower than in controls, while in patients who needed RRT, it was higher than in controls. </sec> <sec><st>Conclusions.</st> We have shown that OATs are mistargeted in AKI. The urinary OAT protein profile can help us to learn about the pathophysiology of the disease and might be a marker of AKI severity. AKI patients with early reversible proximal tubular damage will have high urine OAT1 and OAT3 and low OAT4, while patients with severe AKI will have high urine OAT1, OAT3 and OAT4. </sec>

Cardiovascular risk management in chronic kidney disease in general practice (the AusHEART study)

<sec><st>Background.</st> Chronic kidney disease (CKD) is common and increasing in prevalence. Adverse outcomes of CKD can be prevented through early detection and treatment. There is limited data on the awareness of CKD and the quality of care offered to patients with CKD in the primary care setting. The objectives of this study were to assess the prevalence, general practitioner (GP) awareness and extent of current evidence–practice gaps in the management of CKD in Australian primary care. </sec> <sec><st>Methods.</st> The Australian Hypertension and Absolute Risk Study (AusHEART) was a nationally representative, cluster stratified, cross-sectional survey among 322 GPs. Each GP was asked to provide data for 15–20 consecutive patients (age ≥ 55 years) who presented between April and June, 2008. The main outcome measures were CKD prevalence based on proteinuria and decreased estimated glomerular filtration rate. Evidence–practice gaps in management of patients with CKD were identified. </sec> <sec><st>Results.</st> Among a total of 4966 patients with kidney function test data, 1845 (37%) had abnormal kidney function. Of the 1312 patients with abnormal kidney function known to the GP at the time of visit, only 235 were correctly identified as having CKD. GPs under-estimated cardiovascular (CV) risks in patients with CKD when compared with the prevailing guidelines at the time of survey and the recent national guidelines, particularly in later stages of CKD. Among CKD patients not prescribed blood pressure-lowering agents or lipid-lowering agents, treatment was indicated as per relevant guidelines in 51 and 46%, respectively. For CKD patients who were already prescribed blood pressure-lowering and lipid-lowering agents, 61 and 50%, respectively, did not meet the treatment targets recommended by the relevant guidelines. </sec> <sec><st>Conclusions.</st> CKD is common, significantly under-recognized and under-treated in primary care. Effort to increase awareness and provide opportunities for improved screening and assessment should improve the management and outcome of these patients at high risk of CV disease. </sec>

Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease

<sec><st>Background.</st> Many physicians retain reservations regarding the routine prescription of renin–angiotensin blockade (RAB) in patients with atheromatous renovascular disease (ARVD). Conversely, these patients are in most need of the cardio- and renal protection offered by RAB. This reservation is mostly because of fear of precipitating acute renal deterioration. We aimed to study whether RAB can be used safely in ARVD patients and whether it altered their outcome. </sec> <sec><st>Methods.</st> Prospective observational study of all ARVD patients presenting to our tertiary referral centre from 1999–2009. Data capture included usage and tolerability of RAB, and correlation with endpoints of cardiovascular events, dialysis or death. </sec> <sec><st>Results.</st> Six hundred and twenty-one subjects were available for analysis. Mean age (SD) of the cohort was 71.3 (8.8) years, median (interquartile range) follow-up 3.1 (2.1, 4.8), range 0.2–10.61 years. Seventy-four patients had an intolerance to RAB at study entry. When utilized prospectively, RAB was tolerated in 357 of 378 patients (92%), and this was even seen in 54/69 (78.3%) patients with bilateral >60% renal artery stenosis (RAS) or occlusion. Patients (4/21) who were intolerant of RAB during follow-up (and 12 retrospectively intolerant), underwent renal revascularization which facilitated safe use of these medications post-procedure. On multivariate time-adjusted analysis, patients receiving RAB were significantly less likely to die (P = 0.02). </sec> <sec><st>Conclusion.</st> RAB is well tolerated even in patients with bilateral severe RAS and reduced mortality in a large group of ARVD patients. We recommend all ARVD patients be considered for RAB therapy unless an absolute contra-indication exists. Intolerance of these agents due to renal dysfunction should be considered an emerging indication for renal revascularization to facilitate their re-introduction. </sec>

Metabolic syndrome, insulin resistance and kidney function in non-diabetic individuals

<sec><st>Background.</st> Metabolic syndrome has been recently identified as a risk factor for chronic kidney disease (CKD). Since the five individual components of the metabolic syndrome have also been identified as risk factors for CKD, the metabolic syndrome diagnosis may represent an aggregate of CKD risk factors. On the other hand, the components of the metabolic syndrome are also associated with insulin resistance, which may directly mediate the increased CKD risk. </sec> <sec><st>Methods.</st> This study was a cross-sectional evaluation of the relationship between metabolic syndrome, insulin resistance and estimated glomerular filtration rate (eGFR) in 574 non-diabetic individuals. Insulin resistance was directly quantified using the insulin suppression test, and the metabolic syndrome components were measured. eGFR was calculated using the three validated estimation equations: the Chronic Kidney Disease Epidemiology Collaboration equation, the Mayo quadratic equation and the Modification of Diet in Renal Disease study equation. </sec> <sec><st>Results.</st> While CKD prevalence was higher and mean eGFR was lower in individuals who met the metabolic syndrome criteria compared with those who did not, we did not observe a significant relationship between insulin resistance and eGFR. Of all of the components of the metabolic syndrome, only hypertension was significantly associated with CKD prevalence [odds ratio (95% confidence interval), 3.5 (1.2–10.1), P = 0.02]. </sec> <sec><st>Conclusion.</st> Although CKD is more common among individuals with the metabolic syndrome, insulin resistance is not a common factor. </sec>

High levels of oxidized LDL in circulating immune complexes are associated with increased odds of developing abnormal albuminuria in Type 1 diabetes

<sec><st>Background.</st> Modified low-density lipoprotein (LDL) immune complexes (IC) have proinflammatory properties and play a role in albuminuria development. </sec> <sec><st>Methods.</st> We measured oxidized LDL (oxLDL) and advanced glycation end-product (AGE)–LDL in IC isolated from sera of Type 1 diabetic subjects followed for 14–20 years and studied their association with abnormal albuminuria. Patients with albumin excretion rates (AER) <40 mg/24 h at baseline and follow-up (n = 302) were deemed resistant to developing abnormal albuminuria. Patients with AER <40 mg/24 h at baseline whose AER levels progressed to >40 mg/24 h were considered prone to abnormal albuminuria (n = 185), those who progress to AER >299 mg/24 h were considered as having macroalbuminuria (n = 57). The odds of developing abnormal albuminuria were estimated by logistic regression based on natural log-transformed levels of oxLDL and AGE–LDL in IC and stratified by baseline AER decile. </sec> <sec><st>Results.</st> OxLDL and AGE–LDL were significantly higher in IC isolated from patients progressing to abnormal albuminuria. In unadjusted conditional logistic analysis, an increase of 1 SD in oxLDL and AGE–LDL levels in IC significantly increased the odds ratio (OR) for development of macroalbuminuria, respectively, by a factor of 2.5 and 1.8 (P < 0.001, P = 0.008). The increased odds of developing macroalbuminuria remained significant when adjusted for treatment group, diabetes duration, retinopathy, baseline hemoglobin A1c and LDL (OR = 2.5 and 1.8, respectively, P < 0.01). </sec> <sec><st>Conclusion.</st> Higher levels of oxLDL and AGE–LDL in circulating IC were associated with increased odds to develop abnormal albuminuria. </sec>

Annual variation in body fat is associated with systemic inflammation in chronic kidney disease patients Stages 3 and 4: a longitudinal study

<sec><st>Background.</st> In dialysis patients, cross-sectional studies show that total and abdominal body fat associate with inflammatory markers. Whether this is true in earlier disease stages is unknown. We evaluated the cross-sectional and longitudinal (12-month interval) association between body fat markers and C-reactive protein (CRP) in pre-dialysis chronic kidney disease (CKD) patients. </sec> <sec><st>Methods.</st> We studied, over a period of 1 year, clinically stable CKD patients at Stages 3–4 who were under treatment in a single outpatient clinic. Fifty-seven patients were included and 44 concluded the observational period [males: 66%; age: 62.9 ± 13.9 years; body mass index (BMI): 25.5 ± 5.1 kg/m2; estimated glomerular filtration rate (eGFR): 34 ± 12.3 mL/min/1.73m2]. Total body fat (skinfold thicknesses), waist circumference (WC), laboratory measurements (serum creatinine, total cholesterol, albumin, high-sensitivity CRP and leptin) and food intake (24-h food recall) were assessed at baseline and after 12 ± 2 months. </sec> <sec><st>Results.</st> Most patients had anthropometric parameters in the range of overweight/obesity and none had signs of protein-energy wasting. In univariate analysis, changes (delta: end—baseline) in CRP were associated (P < 0.05) with changes in BMI (r = 0.39) and WC (r = 0.33). In multiple regression analysis, these associations remained significant (P < 0.05) even after adjusted by potential confounders (sex, diabetes, baseline age and eGFR). </sec> <sec><st>Conclusions.</st> During a follow-up of 12 months, changes in BMI and WC were directly associated with changes in CRP. Our results support the concept that interventions aimed at reducing weight and/or abdominal adiposity in pre-dialysis CKD patients may also translate into reduced systemic inflammation. </sec>

Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling

<sec><st>Aim.</st> The aim of this study was to investigate the influence of age, gender, obesity and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects. </sec> <sec><st>Methods.</st> This is a retrospective multi-centre study of 1878 healthy prospective kidney transplant donors (819 men) from 15 centres. Age and body mass index (BMI) were not significantly different between men and women. Slope-intercept GFR was measured (using Cr-51-EDTA in 14 centres; Tc-99m-DTPA in one) and scaled to body surface area (BSA) and lean body mass (LBM), both estimated from height and weight. GFR was also expressed as the slope rate constant, with one-compartment correction (GFR/ECV). ECV was measured as the ratio, GFR to GFR/ECV. </sec> <sec><st>Results.</st> ECV was age independent but GFR declined with age, at a significantly faster rate in women than men. GFR/BSA was higher in men but GFR/ECV and GFR/LBM were higher in women. Young women (<30 years) had higher GFR than young men but the reverse was recorded in the elderly (>65 years). There was no difference in GFR between obese (BMI > 30 kg/m2) and non-obese men. Obese women, however, had lower GFR than non-obese women and negative correlations were observed between GFR and both BMI and %fat. The decline in GFR with age was no faster in obese versus non-obese subjects. ECV/BSA was higher in men but ECV/LBM was higher in women. ECV/weight was almost gender independent, suggesting that fat-free mass in women contains more extracellular water. BSA is therefore a misleading scaling variable. </sec> <sec><st>Conclusion.</st> There are several significant differences in GFR and ECV between healthy men and women. </sec>

Parathyroid hormone and phosphorus overload in uremia: impact on cardiovascular system

<sec><st>Background.</st> Cardiac remodeling in uremia is characterized by left ventricular hypertrophy, interstitial fibrosis and microvascular disease. Cardiovascular disease is the leading cause of death in uremic patients, but coronary events alone are not the prevalent cause, sudden death and heart failure are. We studied the cardiac remodeling in experimental uremia, evaluating the isolated effect of parathyroid hormone (PTH) and phosphorus. </sec> <sec><st>Methods.</st> Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx); they also received vehicle (V) and PTH at normal (nPTH) or high (hPTH) doses. They were fed with a poor-phosphorus (pP) or rich-phosphorus (rP) diet and were divided into the following groups: ‘Sham’: G1 (V + normal-phosphorus diet (np)) and ‘Nx + PTx’: G2 (nPTH + pP), G3 (nPTH + rP), G4 (hPTH + pP) and G5 (hPTH + rP). After 8 weeks, biochemical analysis, myocardium morphometry and arteriolar morphological analysis were performed. In addition, using immunohistochemical analysis, we evaluated angiotensin II, α-actin, transforming growth factor-beta (TGF-β) and nitrotyrosine, as well as fibroblast growth factor-23 (FGF-23), fibroblast growth factor receptor-1 (FGFR-1) and runt-related transcription factor-2 (Runx-2) expression. </sec> <sec><st>Results.</st> Nx animals presented higher serum creatinine levels as well as arterial hypertension. Higher PTH levels were associated with myocardial hypertrophy and fibrosis as well as a higher coronary lesion score. High PTH animals also presented a higher myocardial expression of TGF-β, angiotensin II, FGF-23 and nitrotyrosine and a lower expression of α-actin. Phosphorus overload was associated with higher serum FGF-23 levels and Runx-2, as well as myocardial hypertrophy. FGFR-1 was positive in the cardiomyocytes of all groups as well as in calcified coronaries of G4 and G5 whereas Runx-2 was positive in G3, G4 and G5. </sec> <sec><st>Conclusion.</st> In uremia, PTH and phosphorus overload are both independently associated with major changes related to the cardiac remodeling process, emphasizing the need for a better control of these factors in chronic kidney disease. </sec>

Chronic renal failure is accompanied by endothelial activation and a large increase in microparticle numbers with reduced procoagulant capacity

<sec><st>Background.</st> In patients with chronic renal failure (CRF), cardiovascular disease is the leading cause of increased morbidity and mortality. We hypothesized a role for endothelial activation and microparticle (MP) numbers and procoagulant activity in the pre-thrombotic state of these patients. </sec> <sec><st>Methods.</st> We analysed blood samples of 27 patients with CRF [8 chronic kidney disease Stage 4 (CKD4), 9 peritoneal dialysis (PD) and 10 haemodialysis (HD), samples taken before and after HD] and 10 controls. Degree and nature of endothelial activation were assessed by measuring mature von Willebrand factor (vWF) and vWF propeptide levels. Cellular MPs were characterized by flow cytometry and MP-specific thrombin generation (TG) measurements. </sec> <sec><st>Results.</st> CRF was accompanied by chronic (CKD4 and PD) or acute (HD) endothelial activation. Patients with CRF had substantially higher MP numbers than controls (median 9400 versus 4350 x 106/L, P = 0.001), without significant differences between the treatment subgroups or between pre- and post-HD. The vast majority of MPs were platelet derived. Of the minor populations, endothelial MPs and tissue factor-bearing MPs were more abundant in CRF. MPs were procoagulant, but the increase in numbers was not reflected in a proportional increase in MP-specific TG. </sec> <sec><st>Conclusion.</st> Renal failure is accompanied by endothelial activation of a different nature in CKD4 and PD patients compared to HD patients, and results in all subgroups in an increase of mainly platelet-derived MPs that appear to be less procoagulant than in other disease states, possibly because of the uraemic functional defect of their cellular source. </sec>

The German Chronic Kidney Disease (GCKD) study: design and methods

<sec><st>Background.</st> Chronic kidney disease (CKD) is increasingly recognized as a global health problem. The conditions leading to CKD, the health impact of CKD and the prognosis differ markedly between affected individuals. In particular, renal failure and cardiovascular mortality are competing risks for CKD patients. Opportunities for targeted intervention are very limited so far and require an improved understanding of the natural course of CKD, of the risk factors associated with various clinical end points and co-morbidities as well as of the underlying pathogenic mechanisms. </sec> <sec><st>Methods.</st> The German Chronic Kidney Disease (GCKD) study is a prospective observational national cohort study. It aims to enrol a total of 5000 patients with CKD of various aetiologies, who are under nephrological care, and to follow them for up to 10 years. At the time of enrolment, male and female patients have an estimated glomerular filtration rate (eGFR) of 30–60 mL/min x 1.73m2 or overt proteinuria in the presence of an eGFR >60 mL/min x 1.73m2. Standardized collection of biomaterials, including DNA, serum, plasma and urine will allow identification and validation of biomarkers associated with CKD, CKD progression and related complications using hypothesis-driven and hypothesis-free approaches. Patient recruitment and follow-up is organized through a network of academic nephrology centres collaborating with practising nephrologists throughout the country. </sec> <sec><st>Conclusions.</st> The GCKD study will establish one of the largest cohorts to date of CKD patients not requiring renal replacement therapy. Similarities in its design with other observational CKD studies, including cohorts that have already been established in the USA and Japan, will allow comparative and joint analyses to identify important ethnic and geographic differences and to enhance opportunities for identification of relevant risk factors and markers. </sec>

High frequency of aspirin resistance in patients with nephrotic syndrome

<sec><st>Background.</st> Aspirin has a beneficial role in prevention of cardiovascular and thromboembolic events. Patients may experience thromboembolic events despite aspirin treatment, a phenomenon called aspirin resistance. We evaluated the frequency of aspirin resistance and its correlation with clinical and biochemical parameters among patients with nephrotic syndrome (NS). </sec> <sec><st>Methods.</st> A total of 83 patients (50 males, 33 females, age range 18–79 years) with NS using aspirin 100 mg/day were included in the study. Demographic information and aetiology of NS based on the histology of a renal biopsy were recorded for each patient. Blood samples were drawn to investigate the association of aspirin resistance with inflammation and thrombotic risk factors. Aspirin resistance was defined as a normal collagen/epinephrine closure time <159 s using a platelet function analyzer (PFA-100). </sec> <sec><st>Results.</st> Aspirin resistance was determined in 51 patients (61.4%). The number of patients exposed to azathioprine therapy was significantly higher in the aspirin-sensitive group (P = 0.043), whereas patients exposed to cyclosporine therapy were significantly higher in the aspirin-resistant group (P = 0.017). More patients in the aspirin-resistant group were on angiotensin-converting enzyme inhibitor therapy compared with the aspirin-sensitive group (P = 0.024). The aspirin-resistant group showed significantly higher serum low-density lipoprotein cholesterol (LDL-C) (151 ± 47 versus 104 ± 21 mg/dL; P < 0.001), triglyceride levels (192 ± 116 versus 134 ± 82 mg/dL; P = 0.015) and glomerular filtration rates (91.8 ± 43.0 versus 74.0 ± 35.6 mL/min/1.73m2; P = 0.044) compared with the aspirin-sensitive group. In multivariate analysis, LDL-C was the only parameter associated independently with aspirin resistance [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.02–1.06; P = 0.004]. </sec> <sec><st>Conclusions.</st> A significant number of patients with NS are resistant to aspirin therapy. Serum LDL-C level is closely associated with aspirin resistance in NS. </sec>

Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis

<sec><st>Background.</st> Although the use of aggressive immunosuppression has improved both patient and renal survival of patients with lupus nephritis (LN), the optimal treatment of LN remains challenging. The objective of this study is to assess the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus compared with intravenous cyclophosphamide (IVC) as induction therapies for active lupus nephritis (ALN). </sec> <sec><st>Methods.</st> In this open-label, 24-week prospective study, 60 patients with biopsy-proven ALN (Classes III, IV, V or combination) were randomly assigned to receive MMF, tacrolimus or IVC in combination with corticosteroids. The remission of proteinuria, systemic lupus erythematosus disease active index and adverse events were compared. </sec> <sec><st>Results.</st> The response rates at 24 weeks were 70% (14/20) in the MMF group, 75% (15/20) in the tacrolimus group and 60% (12/20) in the IVC group (P > 0.05). The complete remission rates were also similar in the three groups (40, 45 and 30%, respectively; P > 0.05). There were more cases of infection in the IVC group (8/20) and the MMF group (8/20) than the tacrolimus group (3/20) and more hyperglycemia in the tacrolimus group (5/20) than the other two groups (2 or 3/20), but the results were not statistically significant among the three groups. Proteinuria decreased and serum albumin increased more quickly in the patients treated with tacrolimus (P = 0.0051 and P = 0.048). </sec> <sec><st>Conclusions.</st> This pilot study suggests that both MMF and tacrolimus are possible alternatives to IVC as induction therapies for ALN in Chinese patients. Tacrolimus possibly results in a faster resolution of proteinuria and hypoalbuminemia. Further studies are necessary to determine the optimal dosage and duration of the therapies. </sec>

Strategy for second kidney biopsy in patients with lupus nephritis

<sec><st>Background.</st> Standard clinical and laboratory parameters have limited predictive values for discriminating between active lupus nephritis and chronic disease. The objective of this study was to examine the predictive utility of a second kidney biopsy in patients with lupus nephritis. </sec> <sec><st>Methods.</st> Patients with lupus nephritis were advised to have second kidney biopsies at the end of the maintenance phase of their therapies. Baseline and second renal biopsies were re-classified by pathologists blinded to the clinical data. The relationships between remission status and histological parameters were examined. </sec> <sec><st>Results.</st> Included in this study were 77 patients followed up for a median duration of 8.7 years (interquartile range, 5.3–10.1 years). Their renal survival rates were 93% for those in complete remission (CR), 69% for partial remission (PR) and 41% for no remission (NR). One-third of the patients with PR and 14% of patients with NR had no histological evidence of active disease on second biopsy. At the second biopsy, but not at the baseline biopsy, activity index was predictive of survival. The 10-year renal survival rate was 100% for those with an activity index of 0, 80% for those with an activity index of 1 or 2 on the second biopsy and 44% for those with an index of >2, regardless of remission status. </sec> <sec><st>Conclusion.</st> Second kidney biopsy at the end of maintenance phase of therapy is an important diagnostic and prognostic tool that could guide physicians to safer practices with better outcomes. </sec>

Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population

<sec><st>Background.</st> We sought to identify the long-term renal survival rate and related risk factors of progression to renal failure in Chinese adult patients with IgA nephropathy (IgAN) and to quantify the effects of proteinuria during the follow-up on outcome in patients with IgAN. </sec> <sec><st>Methods.</st> Patients with biopsy-proven primary IgAN in the Nanjing Glomerulonephritis Registry were studied. Renal survival and the relationships between clinical parameters and renal outcomes were assessed. </sec> <sec><st>Results.</st> One thousand one hundred and fifty-five patients were enrolled in this study. The 10-, 15- and 20-year cumulative renal survival rates, calculated by Kaplan–Meier method, were 83, 74 and 64%, respectively. At the time of biopsy, proteinuria >1.0 g/day [hazard ratio (HR) 3.2, P < 0.001], estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 (HR 2.6, P < 0.001), hypertension (HR 1.9, P < 0.001), hypoproteinemia (HR 2.0, P < 0.001) and hyperuricemia (HR 2.1, P < 0.001) were the independent risk factors. Multivariate Cox analysis showed the time-average proteinuria (TA-P) during follow-up was the most important risk factor of renal failure. Patients with TA-P >1.0 g/day were associated with a 9.4-fold risk than patients with TA-P <1.0 g/day (P < 0.001) and 46.5-fold risk than those with TA-P <0.5 g/day (P < 0.001). Moreover, patients who achieved TA-P <0.5 g/day benefit much more than those with TA-P between 0.5 and 1.0 g/day (HR 13.1, P < 0.001). </sec> <sec><st>Conclusions.</st> Thirty-six percent of Chinese adult patients with IgAN progress to end stage renal disease within 20 years. Five clinical features—higher proteinuria, hypertension, impaired renal function, hypoproteinemia and hyperuricemia—are independent predictors of an unfavorable renal outcome. The basic goal of anti-proteinuric therapy for Chinese patients is to lower proteinuria <1.0 g/day and the optimal goal is to lower proteinuria to <0.5 g/day. </sec>

Long-term risk of ESRD in IgAN; validation of Japanese prognostic model in a Norwegian cohort

<sec><st>Background.</st> Recently, a Japanese model used to predict 10-year risk of end-stage renal disease (ESRD) in IgA nephropathy (IgAN) patients was published. We tested the applicability of the Japanese model in predicting 10- to 20-year risk of ESRD and all-cause mortality in a cohort of Norwegian IgAN patients. </sec> <sec><st>Methods.</st> A cohort of IgAN patients (1988–2004) were identified in the Norwegian Kidney Biopsy Registry (NKBR) and ESRD or death during follow-up through 2008 was identified through record linkage with the Norwegian Renal Registry (ESRD) and the Norwegian Population Registry (deaths). Data from the NKBR were used to classify patients into nine different prognostic groups (0–1, 1–5, 5–10, 10–20, 20–30, 30–50, 50–70, 70–90 and >90% risk of ESRD) according to the Japanese prognostic model. The predicted risk was compared to the measured risk of ESRD in the different prognostic groups. </sec> <sec><st>Results.</st> In eight of the nine risk groups, representing 597/633 (94%) of the patients in our cohort, the observed 10-year risk was within or close to the expected 10-year risk of ESRD. ESRD occurring after >10 years of observation was most frequent in the groups with 5–30% expected risk at 10 years of follow-up. A close association between risk of ESRD and risk of death prior to ESRD was observed. </sec> <sec><st>Conclusions.</st> The Japanese prognostic model is applicable to predict 10-year risk of ESRD in Norwegian IgAN patients. A new finding in the present study is that the model can also be used to predict which patients have the highest risk of developing ESRD after 10–20 years of follow-up as well as all-cause mortality risk. </sec>

The retrospective analysis of 343 Czech patients with IgA nephropathy--one centre experience

<sec><st>Background.</st> The aim of our study was to retrospectively analyse the clinical data and the histological findings of 343 patients (pts) followed up with IgA nephropathy (IgAN) in our department of nephrology. We have assessed the main demographic, clinical and histological data, and the medical treatment of IgAN pts. </sec> <sec><st>Methods.</st> Multivariate analysis was used to evaluate the effect of different variables on ≥ 50% increase of plasma creatinine level from baseline during a median follow-up of 4 years. </sec> <sec><st>Results.</st> In our group of IgAN pts, the male gender (68%) predominated over female gender (32%). At the time of renal biopsy, the median age of IgAN pts was 32.3 (18–90) years, the median level of serum creatinine was 119 μmol/L and the median level of proteinuria was 1.8 g/day. Most of the pts were found to have arterial hypertension (56.7%). The majority of the pts with arterial hypertension were treated with inhibitors of angiotensin-converting enzyme (80.4%) and the remaining pts (42.6%) were treated with angiotensin II receptor blockers. Fifty per cent of the pts (170 pts) were treated of corticosteroids, 21% of the pts (71 pts) used a combined immunosuppressive treatment of corticosteroids and cyclophosphamide, 8% of the pts (27 pts) took azathioprine, 1.5% of the pts (5 pts) took cyclosporine and 1.5% of the pts (5 pts) were given mycophenolate mofetil. Hypertension at presentation, fibrointimal proliferation of arterial vessels, interstitial fibrosis and interstitial inflammation were shown to be associated with ≥50% increase of plasma creatinine level from baseline in univariate analysis (P < 0.05 for hypertension and fibrointimal proliferation; P < 0.01 for interstitial fibrosis and inflammation). Using stepwise logistic regression presenting proteinuria >2 g/day [odds ratio (OR) = 2.24, P < 0.01], tubular atrophy (OR = 4.97, P < 0.01) and damage of tubular epithelium (OR = 1.78, P < 0.05) were found as risk factors for ≥50% increase of plasma creatinine level from baseline. </sec> <sec><st>Conclusion.</st> Our retrospective analysis found valuable information not only about the clinical, laboratory and histological findings in IgAN pts but also information about the risk factors influencing the progression of renal insufficiency. </sec>

APOL1 allelic variants are associated with lower age of dialysis initiation and thereby increased dialysis vintage in African and Hispanic Americans with non-diabetic end-stage kidney disease

<sec><st>Background.</st> The APOL1 G1 and G2 genetic variants make a major contribution to the African ancestry risk for a number of common forms of non-diabetic end-stage kidney disease (ESKD). We sought to clarify the relationship of APOL1 variants with age of dialysis initiation and dialysis vintage (defined by the time between dialysis initiation and sample collection) in African and Hispanic Americans, diabetic and non-diabetic ESKD. </sec> <sec><st>Methods.</st> We examined APOL1 genotypes in 995 African and Hispanic American dialysis patients with diabetic and non-diabetic ESKD. </sec> <sec><st>Results.</st> The mean age of dialysis initiation for non-diabetic African-American patients with two APOL1 risk alleles was 48.1 years, >9 years earlier than those without APOL1 risk alleles (t-test, P = 0.0003). Similar results were found in the non-diabetic Hispanic American cohort, but not in the diabetic cohorts. G1 heterozygotes showed a 5.3-year lower mean age of dialysis initiation (t-test, P = 0.0452), but G2 heterozygotes did not show such an effect. At the age of 70, 92% of individuals with two APOL1 risk alleles had already initiated dialysis, compared with 76% of the patients without APOL1 risk alleles. Although two APOL1 risk alleles are also associated with ~2 years increased in dialysis vintage, further analysis showed that this increase is fully explained by earlier age of dialysis initiation. </sec> <sec><st>Conclusions.</st> Two APOL1 risk alleles significantly predict lower age of dialysis initiation and thereby increased dialysis vintage in non-diabetic ESKD African and Hispanic Americans, but not in diabetic ESKD. A single APOL1 G1, but not G2, risk allele also lowers the age of dialysis initiation, apparently consistent with gain of injury or loss of function mechanisms. Hence, APOL1 mutations produce a distinct category of kidney disease that manifests at younger ages in African ancestry populations. </sec>

Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans

<sec><st>Background.</st> Polymorphisms in the non-muscle myosin IIA gene (MYH9) are associated with focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease (ESRD) in African Americans and FSGS in European Americans. We tested for association of single nucleotide polymorphisms (SNPs) in MYH9 with T2DM–ESRD in European Americans; additionally, three APOL1 gene variants were evaluated. </sec> <sec><st>Methods.</st> Fifteen MYH9 SNPs and two APOL1 SNPs plus a 6-bp deletion were genotyped in 1963 European Americans, 536 cases with T2DM–ESRD and 1427 non-nephropathy controls (467 with T2DM and 960 without diabetes). </sec> <sec><st>Results.</st> Comparing T2DM–ESRD cases with the 467 T2DM non-nephropathy controls, single variant associations trending toward significance were detected with SNPs rs4821480, rs2032487 and rs4281481 comprising part of the major MYH9 E1 risk haplotype [P-values 0.053–0.055 recessive, odds ratio (OR) 6.08–6.14]. Comparing T2DM–ESRD cases to all 1427 non-nephropathy controls, we confirmed evidence of association in these three SNPs as well as in the fourth E1 SNP (rs3752462) (P-values 0.017–0.035, OR 1.41–3.72). APOL1 G1/G2 nephropathy risk variants were rare in individuals of European American heritage, present in 0.28% of chromosomes in T2DM–ESRD cases and 0.32% of controls. </sec> <sec><st>Conclusions.</st> MYH9 SNPs rs4821480, rs2032487, rs4281481 and rs3752462 are associated with T2DM–ESRD susceptibility in European Americans. The APOL1 risk variants are not present at appreciable frequency in this cohort with T2DM–ESRD. Therefore, polymorphisms in MYH9 appear to influence nephropathy risk in this sample. </sec>

Estimated glomerular filtration rate and its association with the retinol-binding protein 4 (RBP4) locus on human chromosome 10q23

Background. We tested for associations between estimated glomerular filtration rate (eGFR) and retinol-binding protein 4 (RBP4) haplotypes found on human chromosome 10q23. This locus had been linked to eGFR in a previous linkage scan in patients with Type 2 diabetes mellitus. Methods. We analysed 469 patients with Type 2 diabetes and 174 normoalbuminuric controls for associations between RBP4 haplotypes and eGFR. For comparison with controls, 295 cases with proteinuria/end-stage renal disease were tested for associations with advanced diabetic nephropathy. Genotyping was performed using high-resolution DNA melting assays. Data analysis was performed using the haplo.stats package. Results. Genetic variations in RBP4 were not associated with advanced diabetic nephropathy. Compared with the common A/G/G/C haplotype, C/A/A/C carriers among the normoalbuminuric controls had higher eGFR values among younger patients but lower eGFRs among the older patients (effect size = 2.2, P = 3.3 x 10–7). Furthermore, while eGFR values were fairly consistent over the range of systolic blood pressure (SBP) values for the common haplotype, eGFR in C/A/A/C carriers increased with SBP (effect size = 3.6, P = 1.5 x 10–2). There was a significant interaction between the C/A/A/C haplotype and HbA1c as they affect eGFR compared to the common haplotype (effect size = 2.1, P = 2.1 x 10–3). Power calculations demonstrated that our study had >90% power to detect the observed interactions even while performing multiple hypotheses testing. The interaction between SBP and the C/A/A/C haplotype remained significant (P = 2.8 x 10–2) even when these three haplotype–environment interactions were simultaneously estimated. Conclusion. RBP4 haplotypes may be important in genetically modulating renal function in response to environmental challenges among patients with Type 2 diabetes.

Genetic basis of Bartter syndrome in Korea

<sec><st>Background.</st> Bartter syndrome (BS) is clinically classified into antenatal or neonatal BS (aBS) and classic BS (cBS) as well as five subtypes based on the underlying mutant gene; SLC12A1 (BS I), KCNJ1 (BS II), CLCNKB (BS III), BSND (BS IV) and CASR (BS V). </sec> <sec><st>Methods.</st> Clinico-genetic features of a nationwide cohort of 26 Korean children with BS were investigated. </sec> <sec><st>Results.</st> The clinical diagnosis was aBS in 8 (30.8%), cBS in 15 (57.7%) and mixed Bartter–Gitelman phenotype in 3 cases (11.5%). Five of eight patients with aBS and all 18 patients with either cBS or mixed Bartter–Gitelman phenotype had CLCNKB mutations. Among the 23 patients (46 alleles) with CLCNKB mutations, p.W610X and large deletions were detected in 25 (54.3%) and 10 (21.7%) alleles, respectively. There was no genotype–phenotype correlation in patients with CLCNKB mutations. </sec> <sec><st>Conclusions.</st> Twenty-three (88.5%) of the 26 BS patients involved in this study had CLCNKB mutations. The p.W610X mutation and large deletion were two common types of mutations in CLCNKB. The clinical manifestations of BS III were heterogeneous without a genotype–phenotype correlation, typically manifesting cBS phenotype but also aBS or mixed Bartter–Gitelman phenotypes. The molecular diagnostic steps for patients with BS in our population should be designed taking these peculiar genotype distributions into consideration, and a new more clinically relevant classification including BS and Gitelman syndrome is required. </sec>

Functional characterization of novel loss-of-function mutations in the vasopressin type 2 receptor gene causing nephrogenic diabetes insipidus

Background. X-linked nephrogenic diabetes insipidus (NDI) is a rare polyuric disorder caused by inactivating mutations in the arginine vasopressin receptor Type 2 (AVPR2) gene. Methods. NDI patients from six unrelated families were subjected to mutational analysis of the AVPR2 gene. In-depth in vitro characterization of novel AVPR2 mutants by a combination of functional and immunological techniques provided further insight into molecular mechanisms causing receptor dysfunction. Results. Mutational analysis revealed four novel (A89P, G107R, Q174R, W208X) and three recurrent (V277A, R337X, R247-G250) mutations within the AVPR2 gene. One family carried the missense mutation R337X and a 12-bp deletion (R247-G250), corresponding to a fragment in the third intracellular loop (ICL3), which was not genetically linked to R337X. The functionally tested missense mutations A89P, G107R and Q174R led to reduced receptor cell surface expression in transfected COS-7 cells, most probably due to misfolding and intracellular retention, and consequently to reduction or loss of agonist-mediated cyclic adenosine monophosphate formation. Deletion of R247-G250 had no effect on receptor function in vitro. Comparison with other mammalian AVPR2 orthologs showed that this part of the ICL3 is structurally not conserved and, therefore, less relevant for receptor function. In contrast, all missense mutations (A89P, G107R, Q174R, V277A) affect receptor positions that were fully preserved during mammalian evolution. Conclusion. Our results provide valuable information about residues critical for AVPR2 folding, trafficking and function and proof that these mutations are responsible for causing NDI in the affected subjects.

Papillary stones with Randall's plaques in children: clinicobiological features and outcome

The value of simultaneous measurements of urinary albumin and total protein in proteinuric patients

Background. Proteinuria is a common pathological finding in renal disease. Examining the urinary protein electrophoretic pattern gives clues to the site of origin of the protein. We hypothesized that the type of proteinuria, classified by urine protein electrophoresis and immunofixation (uPEI), may be predicted by simply examining the proportion of higher molecular weight protein (e.g. albumin) in urine total protein content. Methods. One thousand and eleven patients, whose urine had been sent to the pathology department for uPEI, were analysed for total protein and albumin to creatinine ratio (uPCR and uACR) and the ratio reported as the albumin to total protein ratio (uAPR). In a group of renal outpatients (n = 248), we also specifically measured tubular proteins (N-acetyl-β-<scp>D</scp>-glucosaminidase, NAG, and β2-microglobulin) and expressed these as ratios to creatinine (uNCR and uβ2CR). To validate these findings, we correlated these measurements with 68 patients in whom we also had renal biopsy data. Results. In receiver operating characteristic (ROC) curve analysis, the AUC for uAPR was 0.84 for predicting tubular proteinuria pattern on uPEI. In the renal outpatient subgroup, uAPR predicted a tubular pattern of urinary protein equally as well as testing for specific tubular protein markers (uNCR and uβ2CR). In the validation cohort, a uAPR cut-off of <0.40 was 88% sensitive and 99% specific for the diagnosis of primary tubulointerstitial disorders on renal biopsy. Conclusions. Useful information about the origins of urinary protein may be inferred by measuring uAPR, the measurement of which is both simple and inexpensive.

What influences patient choice of treatment modality at the pre-dialysis stage?

Background. There is little information on factors influencing patient choice of renal replacement modality (RRM) in the UK. Pre-dialysis education programmes have been associated with increased uptake of peritoneal dialysis (PD) in other countries but their relevance in informing patient choice within UK centres has not been extensively studied. In this study, we examined how patient choice of different treatment modalities [haemodialysis (HD), PD and conservative management (CM)] is influenced by personal and demographic parameters. Methods. Questionnaires were sent to 242 pre-dialysis patients from a single centre. Patients were asked to rate factors affecting their treatment choice. Demographics, functional status, educational day attendance and Charlson index (CI) scores were also collected. Results. One hundred and eighteen replies were received. Seventy per cent of patients had chosen HD, 20% PD and 10% had opted for CM. There was a clear association between age and modality choice. Mean age of patients choosing PD was 55 years compared to 68 years for HD and 84 years for CM (P < 0.001). Similarly, the degree of co-morbidity was linked with treatment choice, with patients choosing PD having a mean CI score of 4.1 compared to 5.8 among HD patients and 7.7 for CM (P < 0.001). Factors rated as important by all three groups were: the ability to cope, fitting modality with lifestyle, distance to centre and verbal and written information about modality. Conversely, factors rated as not important by all groups were: use of internet, religious beliefs and friends’ views. Using analysis of variance, there was a statistically significant variance between the HD and the PD group responses in the following factors: provision of written information (P = 0.048), fitting modality with lifestyle (P = 0.025), family/home/work circumstances (P = 0.003) and past medical history (P = 0.018). Fifty per cent of patients who chose PD attended a formal education day compared to 32.9% that chose HD and 0% that chose CM (P = 0.011). The following demographic factors were crucial in predicting RRM choice: being married (PD 95.7%, HD 53.8%, CM 41.7%; P < 0.001), being employed (PD 33.3%, HD 11.5%, CM 0%; P = 0.015) and having another person living at home (PD 100%, HD 69.5%, CM 50%; P = 0.003). Patients who have had a social services assessment in the last 12 months or received private care services or disability allowance were more likely to choose CM. Conclusions. This study highlights important factors influencing patient choice of end-stage renal disease treatment modality including CM. While some of these are non-modifiable, such as age and degree of co-morbidity, others draw attention to the importance of good information provision and pre-dialysis education in empowering socially able patients to choose self-care therapies. Furthermore, the overwhelming association of having a strong social support network and being functionally able with choosing PD emphasizes the need for assisted PD.

Measuring the quality of end of life management in patients with advanced kidney disease: results from the pan-Thames renal audit group

Background. Despite a recent increased awareness of the need for quality End of Life (EOL) care for patients with advanced kidney disease, there is no established method for measuring or auditing outcomes relating to EOL care in this population. Methods. We designed a one-page proforma, which was used to collect data on various aspects of EOL care relating to all deaths of patients on dialysis and patients dying on specialist renal wards, over a predefined 8-week period in 10 hospitals in London and South–East England. Results. One hundred and thirty-eight deaths were recorded over the 8-week study period. The majority of patients (83%) were receiving maintenance haemodialysis prior to their terminal presentation. About 69% of deaths occurred during an in-patient hospital admission—of these, 36% were considered ‘unexpected’ and most quality markers of good EOL management were significantly less likely to be achieved in these patients, including use of palliative care strategies, good symptom control and overall quality of death. Thirty-six per cent of patients were from various ethnic minorities, and in this group, there was a trend towards lower use of palliative care pathways and lower rates of withdrawal from dialysis. Conclusions. This study confirms that it is possible to measure many important outcomes relating to quality of EOL care using a proforma completed at the time of death. Our findings suggest that many aspects of good EOL care are under-achieved in our region. This, in part, is due to a failure to recognize the worsening trajectory of the deteriorating patient, resulting in missed opportunities for EOL care planning and appropriate symptom control. Our observations suggest that there is a need for improved education and training in this area, particularly in detection of the dying patient, the value of advance care planning and the utility of tools such as the Liverpool Care Pathway.

Acute and chronic nephropathy induced by fluindione must be addressed

Background. Among the vitamin K antagonists (VKA), indanedione-derived VKA is suspected to induce an immunoallergic risk. One indanedione-derived VKA, fluindione, is still being used in France. The aim of this study was to evaluate the contribution of VKA to acute and chronic nephritis. Methods. Twenty-four cases of biopsy proven acute interstitial nephritis (AIN) were retrospectively selected, based on a first intake of VKA within the previous 12 months as well as an increase of at least 50% of the basal level of serum creatinine. The 24 cases were all treated with fluindione VKA and not with coumarinic VKA. Results. The subjects studied included 20 men and 4 women, with a mean age of 73.0 ± 9.3 years (range: 44–84). The delay between fluindione introduction and the appearance of an AIN, proven by biopsy when available, was 11.9 ± 6.9 weeks (range: 3–28). Creatinine increased from 123.0 ± 56.4 μmol/L (range: 56–335) at fluindione introduction to 460.7 ± 265.3 μmol/L (range: 109–1200) at the time of AIN discovery. The treatment then consisted of stopping the fluindione and introducing steroids for 21 patients. If a VKA was necessary, fluindione was replaced by a coumarinic VKA. After 6 months, 1 patient died and 15 patients presented severe chronic kidney disease (CKD Stages 4–5). Two patients still required chronic dialysis after 6 months and five patients after 3 years. Patients with pre-existing kidney disease were more prone to develop severe CKD with fluindione. Conclusion. In this large study, arguments are presented to incriminate fluindione in the induction of acute and chronic nephritis.

Metabolic effects of dialyzate glucose in chronic hemodialysis: results from a prospective, randomized crossover trial

Background. There is no agreement concerning dialyzate glucose concentration in hemodialysis (HD) and 100 and 200 mg/dL (G100 and G200) are frequently used. G200 may result in diffusive glucose flux into the patient, with consequent hyperglycemia and hyperinsulinism, and electrolyte alterations, in particular potassium (K) and phosphorus (P). This trial compared metabolic effects of G100 versus G200. Methods. Chronic HD patients participated in this randomized, single masked, controlled crossover trial (<A HREF="www.clinicaltrials.gov">www.clinicaltrials.gov</A>: #NCT00618033) consisting of two consecutive 3-week segments with G100 and G200, respectively. Intradialytic serum glucose (SG) and insulin concentrations (SI) were measured at 0, 30, 60, 120, 180, 240 min and immediately post-HD; P and K were measured at 0, 120, 180 min and post-HD. Hypoglycemia was defined as an SG <70 mg/dL. Mean SG and SI were computed as area under the curve divided by treatment time. Results. Fourteen diabetic and 15 non-diabetic subjects were studied. SG was significantly higher with G200 as compared to G100, both in diabetic {G200: 192.8 ± 48.1 mg/dL; G100: 154.0 ± 27.3 mg/dL; difference 38.8 [95% confidence interval (CI): 21.2–56.4] mg/dL; P < 0.001} and non-diabetic subjects [G200: 127.0 ± 11.2 mg/dL; G100 106.5 ± 10.8 mg/dL; difference 20.6 (95% CI: 15.3–25.9) mg/dL; P < 0.001]. SI was significantly higher with G200 in non-diabetic subjects. Frequency of hypoglycemia, P and K serum levels, interdialytic weight gain and adverse intradialytic events did not differ significantly between G100 and G200. Conclusion. G200 may exert unfavorable metabolic effects in chronic HD patients, in particular hyperglycemia and hyperinsulinism, the latter in non-diabetic subjects.

Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea

Background. In both healthy male subjects and men with heart failure, the severity of obstructive sleep apnea (OSA) is related to the amount of fluid displaced from their legs into the neck overnight. Whether overnight rostral fluid shift contributes to the pathogenesis of OSA in patients with end-stage renal disease (ESRD) is unknown. We hypothesized that the change in neck circumference (NC) and severity of OSA are related to the extent of overnight change in leg fluid volume (LFV) in patients with ESRD. Methods. We studied 26 patients with ESRD (14 men) on conventional hemodialysis. All subjects underwent polysomnography. LFV was measured by bioelectric impedance at bedtime and repeated in the next morning on awakening. Results. Our cohort’s overall apnea–hypopnea index was 22.8 ± 26.8 episodes/h of sleep. Their overnight change in LFV was –243 ± 278 mL. The change in LFV correlated with apnea–hypopnea time (AHT) (P = 0.001) and NC (P = 0.0016). Other independent factors associated with AHT included age (P = 0.005), baseline neck (P = 0.0002), sitting time (P = 0.008) and male gender. Stepwise multiple regression analysis revealed that age, change in LFV and male gender remained independent related to AHT. Conclusions. Nocturnal rostral fluid shift is associated with the severity of OSA in ESRD. Prospective evaluation of the effect of reducing fluid overload and severity of OSA in ESRD patients warrants further examination.

Selectively increasing the clearance of protein-bound uremic solutes

Background. The toxicity of bound solutes could be better evaluated if we could adjust the clearance of such solutes independent of unbound solutes. This study assessed whether bound solute clearances can be increased while maintaining urea clearance constant during the extended hours of nocturnal dialysis. Methods. Nine patients on thrice-weekly nocturnal dialysis underwent two experimental dialysis treatments 1 week apart. The experimental treatments were designed to provide the same urea clearance while providing widely different bound solute clearance. One treatment employed a large dialyzer and high dialyzate flow rate (Qd) of 800 mL/min while blood flow (Qb) was 270 mL/min. The other treatment employed a smaller dialyzer and Qd of 300 mL/min while Qb was 350 mL/min. Results. Treatment with the large dialyzer and higher Qd greatly increased the clearances of the bound solutes p-cresol sulfate (PCS: 27 ± 9 versus 14 ± 6 mL/min) and indoxyl sulfate (IS: 26 ± 8 versus 14 ± 5 mL/min) without altering the clearance of urea (204 ± 20 versus 193 ± 16 mL/min). Increasing PCS and IS clearances increased the removal of these solutes (PCS: 375 ± 200 versus 207 ± 86 mg/session; IS: 201 ± 137 versus 153 ± 74 mg/session), while urea removal was not different. Conclusions. The removal of bound solutes can thus be increased by raising the dialyzate flow and dialyzer size above the low levels sufficient to achieve target Kt/Vurea during extended treatment. Selectively increasing the clearance of bound solutes provides a potential means to test their toxicity.

A case-control study of calciphylaxis in Japanese end-stage renal disease patients

Background. Calciphylaxis, also called calcific uremic arteriolopathy, is a rare and often fatal complication of end-stage renal disease and is characterized by painful skin ulceration, necrosis, medial calcification and intimal proliferation of small arteries. Studies in western countries have reported incidences ranging from 1 to 4% in chronic hemodialysis patients. Since no systematic studies of calciphylaxis have ever been performed in Japan, we conducted a nationwide survey and a case–control study to identify the characteristics of calciphylaxis in the Japanese dialysis population. Methods. Firstly, we sent a questionnaire to 3760 hemodialysis centers in Japan, asking whether calciphylaxis cases had been encountered in the past, and detailed clinical data regarding each case were then collected from the centers. In addition, two control dialysis patients matched for age and duration of hemodialysis to each calciphylaxis case were identified at the participating centers, and their data were analyzed to identify risk factors for calciphylaxis. Results. Responses to the questionnaire were obtained from 1838 centers (48.3%), and 151 centers reported that a total of 249 cases had been encountered. Sixty-four centers agreed to participate in the case–control study, and detailed clinical data in regard to 67 cases were obtained. In 28 of the 67 cases, a definite diagnosis of calciphylaxis was made by our study group based on the clinical characteristics and skin biopsy findings. A univariate logistic regression model comparing them with 56-matched controls identified warfarin therapy [odds ratio (OR) 11.4, 95% confidence interval (CI)] 2.7–48.1, P = 0.0009], each 1 g/dL decline in serum albumin level (OR 19.8, 95% CI 4.4–89.5, P = 0.0001), each 100 mg/dL increment in plasma glucose level (OR 3.74, 95% CI 1.08–12.9, P = 0.037) and each 1 mg/dL increment in adjusted serum calcium level (OR 3.2, 95% CI 1.63–6.30, P = 0.0008) at the time of diagnosis as significantly associated with calciphylaxis, but no significant associations were found with female gender, vitamin D analog therapy, serum phosphate level, adjusted calcium–phosphate products or serum alkaline–phosphatase level. Warfarin therapy and lower serum albumin levels were still significant risk factors after a multivariate logistic regression model analysis. Conclusion. The results of this study showed that warfarin therapy and lower serum albumin levels are significant and strong risk factors for the development of calciphylaxis in chronic hemodialysis patients in Japan.

Increased risk of cancer in chronic dialysis patients: a population-based cohort study in Taiwan

Background. An increased incidence of cancer in chronic dialysis patients has not been confirmed in the Chinese population. The aim of this population-based study was to examine the risk of various types of cancers in chronic dialysis patients in Taiwan. Methods. Data of 92 348 chronic dialysis patients extracted from the National Health Institutes Research Database during 1997–2008 were analyzed. Patients newly diagnosed with end-stage renal disease, free of cancer and receiving dialysis for >3 months were eligible for inclusion in the study. Results. After a mean follow-up of 4.4 years, a new cancer was diagnosed in 4328 chronic dialysis patients. The standardized incidence ratio (SIR) of chronic dialysis patients was 1.4 [95% confidence interval (CI): 1.3–1.4] and annual incidence of cancer was 1.1%. A trend of an increased SIR of cancer was observed in young patients and within the first year of dialysis. Bladder cancer carried the highest SIR (SIR: 8.2, 95% CI: 6.7–9.9) and had the highest frequency (21.2%). Importantly, the frequency (15.3%) of liver cancer was the second highest and the SIR (SIR: 1.4, 95% CI: 1.2–1.5) of liver cancer in chronic dialysis patients was higher than that of their healthy counterparts. Unexpectedly, chronic dialysis patients had a significantly reduced risk of developing lung cancer. Conclusion. Increased risk of cancer in chronic dialysis patients is confirmed in the Taiwanese population and it is necessary to develop different strategies for cancer screening in chronic dialysis patients among different ethnicities.

Beta-blockers and cardiovascular outcomes in dialysis patients: a cohort study in Ontario, Canada

Background. Beta-blockers may be cardioprotective in patients receiving chronic dialysis. We examined cardiovascular outcomes among incident dialysis patients receiving beta-blocker therapy. Methods. We conducted a retrospective cohort study employing linked healthcare databases in Ontario, Canada. We studied all consecutive chronic dialysis patients aged ≥66 years who initiated dialysis between 1 July 1991 and 31 July 2007. Patients were divided into three groups according to new medication use after the initiation of chronic dialysis. The three groups were patients initiated on beta-blockers, calcium channel blockers and statins only. Patients in the beta-blocker and calcium channel blocker groups could also be concurrently receiving a statin. The primary outcome was time to a composite endpoint of death, myocardial infarction, stroke or coronary revascularization. Results. There were a total of 1836 patients (504 beta-blocker, 570 calcium channel blocker and 762 statin-only users). Compared to statin-only use, beta-blocker use was not associated with improved cardiovascular outcomes [adjusted hazard ratio (aHR) 1.07, 95% confidence interval (CI) 0.92–1.23]. As expected, calcium channel blocker use was also not associated with improved cardiovascular outcomes (aHR 0.91, 95% CI 0.79–1.06). Among all subgroup analyses by beta-blocker attributes, only high-dose beta-blocker therapy was associated with better cardiovascular outcomes as compared to low-dose beta-blockers (aHR 0.50, 95% CI 0.29–0.88). Conclusions. We observed no beneficial effect of beta-blocker use among patients receiving chronic dialysis relative to our comparator groups. Given current uncertainty around the cardioprotective benefits of beta-blockers in patients receiving dialysis, a large randomized clinical trial is warranted.

Inequalities in rates of renal replacement therapy in England: does it matter who you are or where you live?

Introduction. This study explores the geographical variation in renal replacement therapy (RRT) incidence and prevalence after adjusting for general population socio-demographics, renal unit treatment patterns and travel times. Methods. The UK Renal Registry provided data on all patients in England commencing RRT in 2007 and receiving RRT on 31 December 2007. Multilevel Poisson regression models were constructed separately for incidence and prevalence. Geographical Information Systems software enabled estimation of road travel times and renal unit catchment areas. Small area estimates of RRT prevalence were produced for all 354 local authority districts. Results. Adjusted RRT incidence rates were 1.4 (95% confidence interval 1.2–1.6) times higher in the most deprived areas and 1.7 (1.5–2.0) and 1.5 (1.3–1.7) times higher in areas with most Black and South Asian inhabitants (10+%), respectively. The proportion of a centre’s patients on haemodialysis or transplanted were positively associated with RRT incidence (not prevalence); numbers of satellite units were negatively associated with RRT incidence (not prevalence). While only 3% of patients lived >30 min from a dialysis unit, there was an effect of travel time on RRT rates; individuals living 45+ min from a dialysis unit were 20% less likely to commence or receive RRT than those living within 15 min (Ptrend = 0.36 and Ptrend < 0.001, respectively). A 4-fold variation in adjusted local authority district RRT prevalence rates could not be explained. Conclusion. Expansion of renal unit facilities in England has reduced travel times in most areas though the possibility of inequitable geographic access to RRT persists.

Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney disease and end-stage renal disease

Background. With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31 December 2008. Methods. Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular, cerebrovascular, infection, other and unknown. Results. Cardiovascular disease was the major cause of death. A multivariate competing risk model comparing the two 8-year periods, adjusted for age at ESRD, gender and treatment modality, showed that deaths from cardiovascular disease decreased by 35% [hazard ratios (HR) 0.65, P = 0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P = 0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval, the prevalence of cancer increased by 35% (P = 0.0002) while the cancer incidence was stable. Conclusions. In Danish patients with ADPKD and ESRD, there was a significant reduction in cardiovascular and cerebrovascular deaths from 1993 to 2008. The prevalence of cancer increased without significant change in cancer incidence or deaths from cancer.

Dialysate sodium, serum sodium and mortality in maintenance hemodialysis

Background. Individuals with end-stage kidney disease appear to have stable pre-dialysis serum sodium concentrations over time, with lower values associating with increased mortality. Dialysate sodium concentrations have increased over many years in response to shorter treatments, but the relationship between serum sodium, dialysate sodium and outcomes in chronic hemodialysis patients has not yet been systematically examined. Methods. We studied a cohort of 2272 individuals receiving thrice-weekly hemodialysis treatment. Available data included demographics, laboratory and clinical measures, details of the dialysis prescription and 30-month follow-up. We examined the distribution of serum and dialysate sodium among subjects and compared mortality according to dialysate and serum sodium concentrations using Cox regression models. Results. Dialysate sodium concentration varied within and among dialysis centers. The pre-dialysis serum sodium concentration (mean 136.1 mmol/L) did not differ across dialysate sodium concentrations. There was evidence for effect modification for mortality according to differing serum sodium and dialysate sodium concentrations (P = 0.05). For each 4 mmol/L increment in serum sodium, the hazard ratio for death was 0.72 [95% confidence interval (CI) 0.63–0.81] with lower dialysate sodium compared to 0.86 (95% CI 0.75–0.99) for higher dialysate sodium. Higher dialysate sodium concentration was associated with mortality at higher, but not lower, pre-dialysis serum sodium concentrations. Conclusions. The pre-dialysis serum sodium concentration appears to be unaffected by the dialysate sodium concentration. The relationship between serum and dialysate sodium and mortality appears to be variable. Further research is warranted to determine the biological mechanisms of these associations and to re-examine total body sodium handling in hemodialysis.

Nocturnal, every-other-day, online haemodiafiltration: an effective therapeutic alternative

Background. Longer and more frequent dialysis sessions have demonstrated excellent survival and clinical advantages, while online haemodiafiltration (OL-HDF) provides the most efficient form of dialysis treatment. The aim of this study was to evaluate the beneficial effects of a longer (nocturnal) and more frequent (every-other-day) dialysis schedule with OL-HDF at the same or the highest convective volume. Methods. This prospective, in-centre crossover study was carried out in 26 patients, 18 males and 8 females, 49.2 ± 14 years old, on 4–5 h thrice-weekly post-dilution OL-HDF, switched to nocturnal every-other-day OL-HDF. Patient inclusion criteria consisted of stable patients with good vascular access and with good prospects for improved occupational, psychological and social rehabilitation. Patients were randomly assigned into two groups: Group A received the same convective volume as previously for 6 months followed by a higher convective volume for a further 6 months, while Group B received the same schedule in reverse order. Results. Nocturnal every-other-day OL-HDF was well tolerated and 56% of patients who were working during the baseline period continued to work throughout the study with practically no absenteeism. The convective volume was 26.7 ± 2 L at baseline, 27.5 ± 2 with the unchanged volume and 42.9 ± 4 L with the higher volume. eKt/V increased from 1.75 ± 0.4 to 3.37 ± 0.9. Bicarbonate, blood urea nitrogen (BUN) and creatinine values decreased, while phosphate levels fell markedly with a 90% reduction in phosphate binders. Blood pressure and left ventricular hypertrophy (LVH) improved and the use of anti-hypertensive drugs decreased. In both groups, BUN, creatinine and β2-microglobulin reduction ratios improved. Different removal patterns were observed for myoglobin, prolactin and α1-acid glycoprotein. Conclusions. Nocturnal every-other-day OL-HDF could be an excellent therapeutic alternative since good tolerance and occupational rehabilitation, marked improvement in dialysis dose, nutritional status, LVH, phosphate and hypertension control and a substantial reduction in drug requirements were observed. In this crossover study, different removal patterns of large solutes were identified.

Comparative outcomes of treated symptomatic versus non-treated asymptomatic high-grade central vein stenoses in the outflow of predominantly dialysis fistulas

Background. Witholding treatment in asymptomatic/pauci-symptomatic high-grade central vein stenosis (CVS), i.e. those not causing debilitating painful extremity oedema, the benefits of which have been shown in only one study in grafts, is debatable. The aim of our study was to assess the short- and long-term benefits of such a strategy in mainly autogenous fistulas. Methods. We retrospectively compared the outcomes of 53 untreated asymptomatic/pauci-symptomatic and 50 symptomatic high-grade CVS treated by dilation with or without stenting between January 1998 and August 2010 at a single center. Central vein and access patency was estimated by Kaplan–Meier analysis. Results. Mean age, central catheter use and location of stenosis (brachiocephalic vein) in asymptomatic/pauci-symptomatic and symptomatic CVS were significantly different at 69 versus 75 years, 28 versus 48% and 74 versus 56%, respectively. Ninety percent of the cases had an autogenous fistula. The mean degree of stenosis was >80%. Fourty percent of asymptomatic/pauci-symptomatic CVS became severely symptomatic after 4 years. Primary central vein patency at 3, 12, 24 and 36 months in asymptomatic/pauci-symptomatic and symptomatic CVS were 87 ± 5 versus 82 ± 6, 77 ± 6 versus 55 ± 9, 71 ± 7 versus 35 ± 9 and 67 ± 7 versus 18 ± 9%, respectively (P = 0.002). Primary access circuit patency rate was not significantly different between the two groups with 66 ± 5 versus 50 ± 4% at 1 year. Secondary central vein and access circuit patency rates at 1 and 3 years were 100 and 93 ± 7 versus 89 ± 5 and 84 ± 7% (P = 0.014). Conclusions. Withholding treatment in asymptomatic/pauci-symptomatic CVS in dialysis fistulas yielded significantly better short- and long-term central vein patency than treatment of symptomatic cases without detrimental effects on overall dialysis circuit.

Peritoneal dialysis-associated nontuberculous mycobacterium peritonitis: a systematic review of reported cases

Background. Peritonitis caused by nontuberculous mycobacterium (NTM) is an important complication in peritoneal dialysis (PD) patients. Methods. Cases of PD complicated by NTM peritonitis reported in the English language literature were identified in the PubMed database. The characteristics of these cases were reviewed. Results. In 41 articles, we identified 57 cases of PD-associated NTM peritonitis in patients ranging from 5 to 82 years. The prevalent clinical findings of these cases were fever, abdominal pain, cloudy fluid and an elevated leukocyte count in peritoneal fluid. These findings were non-specific and could not be differentiated from symptoms caused by Mycobacterium tuberculosis or other bacteria. The majority of these cases received empirical antibacterial therapy before diagnosis of NTM peritonitis. Isolates in more than half of the peritonitis cases were the rapidly growing Mycobacterium, Mycobacterium fortuitum (38.6%) and Mycobacterium chelonae (14.0%). In most cases, PD catheters were removed and experience with non-removal was limited. Conclusion. Diagnosis of NTM infection should be considered in PD patients with peritonitis that are culture negative or refractory to empirical antibiotic therapy.

Diagnosing latent tuberculosis infection in haemodialysis patients: T-cell based assay (T-SPOT.TB) or tuberculin skin test?

Background. The international guidelines recommend screening haemodialysis (HD) patients for latent tuberculosis infection (LTBI). The aim of this study is to compare the diagnostic utility of tuberculin skin test (TST) with an interferon--based assay (T-SPOT.TB) for the diagnosis of LTBI in HD patients. Methods. A total of 411 patients [233 male (57%), mean age 56 ± 16 years] in five HD centres were prospectively tested by TST and T-SPOT.TB assays. A total of 302 patients (75%) had Bacillus Calmette-Guerin vaccination scar. Results. LTBI was detected in 39 and 61% of patients by one-step TST and T-SPOT.TB, respectively. The booster phenomenon determined additional 60 (25%) LTBI among 243 patients. Overall, 218 (53%) patients showed a positive reaction to TST after performing the two-step TST. Among 250 one-step TST negative patients T-SPOT.TB assay was positive in 118 (47%). Of 158 patients with a positive one-step TST, T-SPOT.TB was negative in 34 (22%). On the other hand, T-SPOT.TB was negative in 16 (27%) of boosted patients. T-SPOT.TB was negative in 50 (23%) of overall TST-positive patients and positive in 71 (39%) of TST negative ones. Multivariate logistic regression analysis revealed that male gender was independently associated with positive T-SPOT.TB, and positive T-SPOT.TB was inversely associated with the presence of BCG vaccine scar, serum albumin level and HD duration. Annual conversion rates were 12 and 32% for TST and T-SPOT.TB tests, respectively. Conclusion. Usage of T-SPOT.TB in HD patients with negative TST may enhance diagnosis of LTBI.

Efficacy and safety of regional citrate anticoagulation in liver transplant patients requiring post-operative renal replacement therapy

Background. Liver transplant patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) early post-operatively are at high risk for bleeding. Using heparin for anticoagulation during CRRT may contribute to the increased bleeding risk. Regional anticoagulation with citrate may decrease the risk of bleeding. However, citrate anticoagulation may be associated with metabolic complications in patients with liver impairment. The aim of the study was to evaluate the safety and efficacy of citrate anticoagulation in liver transplant patients. Methods. All liver transplant recipients transplanted between November 2004 and August 2007, requiring CRRT and using citrate as the anticoagulant were included in this retrospective study. Demographic data, CRRT specific and metabolic data were collected and analysed. Results. Sixty-eight patients (40 male/28 female) with a mean age of 47.1 ± 11.8 years and a Model of End-stage Liver Disease score of 23 ± 9 developed post-operative AKI requiring CRRT using citrate as the anticoagulant. The median duration on CRRT was 8 days (range 1–39 days) with a mean circuit life of 22.7 ± 14.6 h. There was no relevant time trend of serum sodium, potassium, calcium, bicarbonate and pH values during CRRT. Bleeding occurred in 8 of 68 (11.7%) patients during CRRT. Conclusion. Regional citrate anticoagulation for CRRT in the early post-operative period after liver transplantation is effective and safe. Therefore, the general exclusion of citrate anticoagulation during CRRT in patients after liver transplantation is not justified.

Outcome of surgical complications following simultaneous pancreas-kidney transplantation

Background. Simultaneous pancreas–kidney (SPK) transplantation carries a higher risk of surgical complications than kidney transplantation alone. We aimed to establish the incidence of surgical complications after SPK transplantation and determine the effect on graft and patient survival. Methods. Outcomes of all SPK transplants performed at our centre were compared between patients who experienced a surgical complication (SC group) and those who did not (NSC group). Results. Our centre performed 193 SPK transplants in a 15-year period; 44 patients (23%) experienced a surgical complication. One-year and 5-year pancreatic graft survival was 89 and 80%, respectively; this was lower in the SC group. There was no significant difference in patient or kidney graft survival between the SC and NSC groups at 5 years (92 and 83%, respectively.) Conclusion. Surgical complications following SPK transplantation can cause significant morbidity and adversely affect pancreas graft survival, but do not affect long-term kidney or patient survival.

Age is an important predictor of kidney transplantation outcome

Background. Donor and recipient age may have an impact on the renal transplant outcome. Kidney transplantation from older donors may result in a worse outcome, and the survival benefit of kidney transplantation compared with dialysis may be reduced. The aim of this study was to evaluate the impact of donor and recipient age on kidney transplant outcome. Materials and methods. Two hundred and twenty-three recipients of kidney transplants performed at our institution between 2002 and 2007 were analysed. The role of donor and recipient age matching on survival rate were investigated performing the Kaplan–Meier survival time analysis by decades, considering the donor’s age of 60 and 70 years. The Cox proportional hazard uni- and multivariate regressions were also performed. Finally, Kaplan–Meier survival time analysis was performed to assess survival rates of patients transplanted stratified by donor age compared with wait-listed renal transplant candidates. Results. Elderly recipients had a significant lower graft and patient survival as well as a significantly higher risk of graft loss and patient death. Recipients younger and older than 65 years of age were at higher risk of graft loss if they received grafts from donors >65 years [hazard ratio (HR) = 2.59, 95% confidence interval (CI): 1.12–6 and HR = 5.65, 95% CI: 2.31–13.79, respectively]. Elderly recipients displayed a worse survival compared with transplant candidates on the waiting list. Conclusions. Age is an important predictor of kidney transplantation outcome. Kidney transplantation does not offer a significant survival benefit in the intermediate term, compared to the waiting list, to elderly recipients transplanted with grafts from older donors. However, it cannot be excluded that it is still possible that there is a long-term benefit of transplantation over dialysis in this group of patients.

The influence of low donor age, living related donation and pre-emptive transplantation on end-organ damage based on arterial hypertension after paediatric kidney transplantation

Background. To date, no study has described the pre-transplant and transplant risk factors for end-organ damage based on arterial hypertension in children after kidney transplantation (KTX). Methods. A retrospective chart review was performed of 206 children with KTX between 1991 and 2007. Patients <120 cm were excluded as no validated percentiles for 24-h ambulant blood pressure monitoring (ABPM) exist. Complete data sets were available for 116 patients. Data were recorded at 12, 24 and 36 months post- KTX. We analysed the influence of donor age, age at transplantation, pre-emptive transplantation, living or deceased transplantation and glomerular filtration rate (GFR) on the presence of end-organ damage, ABPM, ABPM standard deviation score and the numbers of anti-hypertensives used. Results. Lower donor age and the decade of transplantation were associated with less detection of end-organ damage (P = 0.001). A lower need for anti-hypertensive medication (P = 0.001) was detected in children who received organs from living donors and from deceased donors with a donor age <35 years and who were transplanted pre-emptively. Low recipient age was the only factor associated with lower ABPM (P = 0.001). In our study, the type of immunosuppressive regimen and the GFR had no influence on the blood pressure. Conclusions. It may be speculated that the risk of arterial hypertension and associated end-organ damage in children after KTX could be reduced by using organs from young donors with an advantage for living related and pre-emptive donation.

Influence of physical activity on cardiorespiratory fitness in children after renal transplantation

Background. Cardiorespiratory fitness is significantly reduced in children with end-stage renal disease. The role of renal transplantation in improving cardiorespiratory fitness has not been thoroughly investigated. Methods. In this work, we wanted to assess whether, in children after a successful renal transplant, the amount of weekly physical exercise affects cardiorespiratory fitness and left ventricular mass (LVM). The study was conducted on 16 children after renal transplantation and 36 matching healthy controls. Four groups were formed according to the weekly amount of physical exercise; all children received an echocardiogram and underwent a treadmill exercise test according to the Bruce protocol. Results. Cardiorespiratory fitness is worst in renal transplant children with a weekly physical exercise <3 h; renal transplant children with a physical exercise of 3–5 h per week attain a cardiorespiratory fitness comparable to controls with a sedentary lifestyle (<3-h exercise per week); healthy controls with a weekly physical exercise of 3–5 h per week show the highest levels of cardiorespiratory fitness; the LVM assessed via echocardiography follows the same pattern. Conclusions. In children with a successful renal transplant, a weekly physical exercise of 3–5 h significantly improves the cardiorespiratory fitness and the LVM, up to the level of matching healthy controls with a sedentary lifestyle (<3 h exercise per week).

Does allograft failure impact school attendance in children? A NAPRTCS study

Background. Studies show that adult dialysis patients with allograft failure have increased mortality and morbidity on dialysis compared to transplant naïve patients. We previously showed comparable mortality risk in pediatric dialysis patients after allograft failure compared to transplant naïve patients; the impact on morbidity is less clear. Specifically, the effect of allograft failure on school attendance in pediatric patients has not previously been studied. Methods. Using the North American Pediatric Renal Trials and Collaborative Studies database, we compared school attendance between transplant naïve and allograft failure patients from 1 January 1992 to 31 December 2007. School attendance was compared between the two groups at 6 and 12 months after dialysis initiation using a chi-square test. Factors which can potentially impact on school attendance data were evaluated using a multivariate logistic regression analysis. Results. There were 2783 patients who had a follow-up at least 6 months after dialysis initiation and were capable of attending school during the study period. Patients were categorized by transplant history: previous allograft failure (n = 576) and transplant naïve (n = 2207). At 6 months, full-time school attendance was 67.2% in the allograft failure group and 72.3% in the transplant naïve group (P = 0.0164). At 12 months, attendance was 68.6% in the allograft failure group and 72.5% in the transplant naïve group (P = 0.103). After covariate adjustment, transplant failure did not impact school attendance at either 6 or 12 months follow-up [hazard ratio (HR) 1.12, confidence interval (CI) 0.91–1.39; HR 0.99, CI 0.78–1.27, respectively]. Conclusions. Children with failed allografts who return to dialysis have comparable school attendance compared to their transplant naïve dialysis counterparts. These results suggest that transplant failure is not an adverse prognostic factor for quality of life as measured by full-time school attendance.

Vitamin D and nephrology

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Light chain cast nephropathy in Waldenstrom's macroglobulinaemia

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Renal sympathetic nerve ablation for the treatment of difficult-to-control or refractory hypertension in a haemodialysis patient

Haemodialysis patients show sympathetic hyperactivity. Hyperactivation of the sympathetic nervous system aggravates hypertension and it is related to left ventricular hypertrophy, heart failure, arrhythmias and atherogenesis. We report the first use of renal sympathetic nerve ablation for correction of uncontrolled hypertension in an end-stage renal disease patient on maintenance dialysis. We observed a progressive and sustained reduction of systemic blood pressure. Our case demonstrates the safety, the feasibility and the efficacy of this procedure. These findings suggest, however, that further clinical trials are needed into renal nerve radiofrequency ablation therapy for the treatment of hypertension and for the improvement of cardiovascular prognosis in this high-risk patient group.

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