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Preview: Nephrology Dialysis Transplantation - current issue

Nephrology Dialysis Transplantation Current Issue

Published: Sat, 10 Jun 2017 00:00:00 GMT

Last Build Date: Mon, 12 Jun 2017 08:49:00 GMT




News from ERA-EDTA:

Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial


Background. Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain.Methods. In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m2 [95% confidence interval (CI) 2.8–8.3 mL/min/1.73 m2, P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m2, 95% CI 2.8–8.2 mL/min/1.73 m2, P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively.Conclusions. Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

Uremia induces adipose tissue inflammation and muscle mitochondrial dysfunction


Background. End-stage renal disease (ESRD) is associated with inflammation and increased reactive oxygen species (ROS). Inflammation and oxidative stress are associated with several complications of ESRD. The aim of this study was to determine histological characteristics of adipose tissue and muscle mitochondrial function in uremia and its relationship with inflammation.Methods. ESRD patients (n = 18) and controls (n = 6) were enrolled for studies of adipose and muscle tissue by immunohistochemistry and western blot. In a uremic muscle cell model, C2C12 cells were exposed to uremic serum and inflammatory cytokines. Mitochondrial function was studied by MitoTracker Orange, translocase of the mitochondrial outer membrane 20 (TOMM20) and mitochondrial oxidative phosphorylation complex subunit expression.Results. ESRD patients had increased macrophage infiltration in subcutaneous and visceral adipose tissue compared with controls, even in nonobese ESRD patients (P < 0.05). Compared with controls, TOMM20 expression in muscle tissue was lower in ESRD, consistent with reduced mitochondrial function (P < 0.05). C2C12 exposed to uremia had decreased mitotracker intensity (P < 0.05) and the reduced mitochondrial function was rescued by N-acetyl cysteine (P < 0.01). Similarly, C2C12 cells exposed to tumor necrosis factor α (TNF-α)/interleukin-6 (IL-6) have decreased mitotracker intensity (P < 0.01) that was rescued with adiponectin (P < 0.05). C2C12 exposed to TNF-α, IL-6 and buthionine sulfoximine had decreased TOMM20 expression and cells exposed to TNF-α showed a decrease in subunits of mitochondrial complexes I and III.Conclusion. Our data indicate that uremia is associated with increased adipose tissue macrophage infiltration and concurrent muscle tissue mitochondrial dysfunction induced by inflammation/ROS. Adipose tissue is a potential source of inflammation in ESRD that is not due to increased adiposity and may contribute to mitochondrial dysfunction in uremia.

Centre effects and peritoneal dialysis-related peritonitis


Peritonitis is a major cause of morbidity, mortality and excess health care costs in peritoneal dialysis (PD) [1–4] and is the predominant factor limiting the uptake and retention of patients on PD [1, 5]. Following a single episode of peritonitis, the risks of further peritonitis episodes, haemodialysis transfer and death (due to infection, cardiovascular disease or dialysis withdrawal) are greatly increased for the first month and continue to remain significantly elevated for up to 6 months thereafter [6–8]. Peritonitis can also lead to accelerated loss of residual renal function, peritoneal membrane damage and failure and, in rare instances, encapsulating peritoneal sclerosis [1, 9]. From a patient’s perspective, fear of peritonitis has been identified as one of the most significant barriers to selection of PD as a dialysis modality [5, 10]. From a health funder’s perspective, the average cost of a peritonitis-related hospitalization is on the order of US $3100 [11]. Consequently, mitigating peritonitis risk is a high priority.

Hypertension in kidney transplantation is associated with an early renal nerve sprouting


Background. Normalization of arterial pressure occurs in just a few patients with hypertensive chronic kidney disease undergoing kidney transplantation. Hypertension in kidney transplant recipients may be related to multiple factors. We aimed to assess whether hypertension in kidney-transplanted patients may be linked to reinnervation of renal arteries of the transplanted kidney.Methods. We investigated renal arteries innervation from native and transplanted kidneys in three patients 5 months, 2 years and 11 years after transplantation, respectively. Four transplanted kidneys from non-hypertensive patients on immunosuppressive treatment without evidence of hypertensive arteriolar damage were used as controls.Results. Evidence of nerve sprouting was observed as early as 5 months following transplantation, probably originated from ganglions of recipient patient located near the arterial anastomosis and was associated with mild hypertensive arteriolar damage. Regeneration of periadventitial nerves was already complete 2 years after transplantation. Nerve density tended to reach values observed in native kidney arteries and was associated with hypertension-related arteriolar lesions in transplanted kidneys. Control kidneys, albeit on an immunosuppressive regimen, presented only a modest regeneration of sympathetic nerves.Conclusions. Our results suggest that the considerable increase in sympathetic nerves, as found in patients with severe arterial damage, may be correlated to hypertension rather than to immunosuppressive therapy, thus providing a morphological basis for hypertension recurrence despite renal denervation.

Centre characteristics associated with the risk of peritonitis in peritoneal dialysis: a hierarchical modelling approach based on the data of the French Language Peritoneal Dialysis Registry


Background. This study investigated the centre effect on the risk of peritonitis in peritoneal dialysis (PD) patients.Methods. This was a retrospective cohort study based on data from the French Language Peritoneal Dialysis Registry. We analysed 5017 incident patients starting PD between January 2008 and December 2012 in 127 PD centres. The end of the observation period was 1 January 2014. The event of interest was the first peritonitis episode. The analysis was performed with a multilevel Cox model and a Fine and Gray model.Results. Among the 5017 patients, 3190 peritonitis episodes occurred in 1796 patients. There was significant heterogeneity between centres (variance of the random effect: 0.11). The variance of the centre effect was reduced by 9% after adjusting for patient characteristics and by 35% after adjusting on centre covariate. In the multivariate analysis with a multilevel Cox model, centre with a nurse specialized in PD or centre providing home visits before dialysis initiation decreased the centre effect on peritonitis. Patients treated in centres with a nurse specialized in PD or in centres providing home visits before dialysis initiation had a lower risk of peritonitis [cause-specific hazard ratio (cs-HR): 0.75 (95% confidence interval, CI, 0.67–0.83) and cs-HR: 0.87 (95% CI 0.76–0.97), respectively]. The data show that neither centre type nor centre volume influenced peritonitis risk. In the competing risk analysis, centre with a nurse specialized in PD and centre with home visits had a protective effect on peritonitis [sub-distribution HR (sd-HR): 0.77 (95% CI 0.70–0.85) and sd-HR: 0.85 (95% CI 0.77–0.94), respectively].Conclusion. There is a significant centre effect on the risk of peritonitis that can be decreased by home visits before dialysis initiation and by the presence of a nurse specialized in PD.

Inflamed fat and mitochondrial dysfunction in end-stage renal disease links to hypoxia—could curcumin be of benefit?


In this issue of Nephrology Dialysis Transplatation, Martinez Cantarin et al. [1] demonstrate increased macrophage infiltration (CD163+) in subcutaneous and visceral adipose tissue from 16 non-diabetic, overweight (median body mass index of 28.5 kg/m2), end-stage renal disease (ESRD) patients undergoing renal transplantation. The control group consisted of nine kidney donors. In addition to inflamed fat, the authors report reduced muscular mitochondrial function (TOMM20 expression) in ESRD. The authors expose a cell model of uraemic muscle (C2C12) to tumour necrosis factor (TNF)/interleukin-6 (IL-6) and find reduced mitotracker orange intensity, an index of reduced mitochondrial function. They report that the reduction in mitochondrial function was rescued by acetylcysteine and adiponectin. Their study implies that increased adipose tissue macrophage infiltration (not linked to increased adiposity) associates to muscle tissue mitochondrial dysfuntion in ESRD.

Renal effects of immune checkpoint inhibitors


Recent advances in immune checkpoint inhibitor (ICPI) development have led to major improvements in oncology patient outcomes. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are two essential immune checkpoint receptors. Ipilimumab and tremelimumab (anti-CTLA-4-blocking antibodies) and pembrolizumab and nivolumab (antibodies targeting PD-1 receptors) have already been approved by US Food and Drug Administration in several malignancies. Two different forms of ICPI-induced renal damage have been identified, including acute (granulomatous) tubulointerstitial nephritis and immune complex glomerulonephritis. The observed acute renal damage can be reversed upon ICPI drug discontinuation and renal function can recover back to normal following the introduction of systemic corticosteroid treatment. Any delay in treating this complication could result in definitive and irreversible renal injury.

Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation


Background: Circulating levels of fibroblast growth factor 23 (FGF23) increase progressively and correlate with systemic inflammation in chronic kidney disease (CKD). The aim of this study was to identify and characterize the causal relationship between FGF23 and inflammation in CKD.Methods: Circulating FGF23 and inflammatory cytokines were correlated in healthy subjects and patients with varying levels of CKD. In addition, FGF23 expression in blood and solid organs was measured in normal mice that were exposed acutely (one time) or chronically (2-week) to low-dose lipopolysaccharide (LPS); chronic exposure being either sustained (subcutaneous pellets), intermittent (daily injections) or combined sustained plus acute (subcutaneous pellets plus acute injection on the day of sacrifice). Blood was analyzed for both terminal (cFGF23) and intact (iFGF23) FGF23 levels. Solid tissues were investigated with immunohistochemistry, enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction.Results: FGF23 levels correlated significantly with neutrophil gelatinase–associated lipocalin (r = 0.72, P < 0.001), C-reactive protein (r = 0.38, P < 0.001), tumor necrosis factor-α (r = 0.32, P = 0.001) and interleukin-6 (r = 0.48, P < 0.001). Acute LPS administration increased tissue FGF23 mRNA and plasma levels of cFGF23 but not iFGF23. Neither chronic sustained nor chronic pulsatile LPS increased the tissue or circulating levels of FGF23. However, acute on chronic LPS raised tissue FGF23 mRNA and both circulating cFG23 and iFGF23. Interestingly, the spleen was the major source of FGF23.Conclusion: Acute on chronic exposure to LPS stimulates FGF23 production in a normal mouse model of inflammation. We provide the first evidence that the spleen, under these conditions, contributes substantially to elevated circulating FGF23 levels.

Nephrotoxicity of anticancer treatment


Severe adverse systemic drug events occur commonly as a result of treatment of cancer patients. Nephrotoxicity of chemotherapeutic agents remains a significant complication limiting the efficacy of the treatment. A variety of renal disease and electrolyte disorders can result from the drugs that are used to treat malignant disease. The kidneys are a major elimination pathway for many antineoplastic drugs and their metabolites. Tumour lysis syndrome, an emergency in haematooncology, occurs most often after the initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukaemia. Chemotherapeutic agents can affect the glomerulus, tubules, interstitium and renal microvasculature, with clinical manifestations that range from asymptomatic elevation of serum creatinine to acute renal failure requiring dialysis. Some factors such as intravascular volume depletion, as well as concomitant use of other drugs or radiographic ionic contrast media, can potentiate or contribute to the nephrotoxicity. Cytotoxic agents can cause nephrotoxicity by a variety of mechanisms. The most nephrotoxic chemotherapeutic drug is cisplatin, which is often associated with acute kidney injury. Many other drugs such as alkylating agents, antimetabolites, vascular endothelial growth factor pathway inhibitors and epidermal growth factor receptor pathway inhibitors may have toxic effects on the kidneys. The aim of this review is to discuss the issue of nephrotoxicity associated with chemotherapy. In routine clinical practice, monitoring of kidney function is mandatory in order to identify nephrotoxicity early, allowing dosage adjustments or withdrawal of the offending drug.

Association of erythropoiesis-stimulating agents and the incidence risk of cancer diagnosis among chronic dialysis patients: a nested case–control study


Background: Erythropoiesis-stimulating agents (ESAs) are the cornerstone of the treatment for anemia in end-stage renal disease (ESRD) patients. Although a correlation has been established between ESAs and increased tumor growth among patients with cancer-related anemia, an association with a higher incidence of cancer among chronic dialysis patients remains relatively unclear.Methods: We completed a nested case–control study in a cohort of 4574 patients who began chronic dialysis treatment between 1 January 2001 and 31 December 2007 in Quebec, Canada, utilizing dialysis registry and administrative databases exclusively to extract our data. We excluded patients with a prior diagnosis of cancer. Eligible cases were identified by the time of initial cancer diagnosis obtained from either the hospital's discharge or physician billing form. We then randomly selected up to 10 controls for each case. ESA exposure was evaluated between 6 and 9 months prior to the initial cancer diagnosis. The mean weekly exposure was used to categorize ESA usage as either a low dose (<30 µg/week), moderate dose (30–70 µg/week) or high dose (>70 µg/week). We estimated the association between ESAs and the risk of developing cancer using a multivariable conditional logistic regression.Results: We identified 419 cases of cancer and 3895 matched controls during the study period. The use of ESAs was associated with a higher risk of cancer {odds ratio [OR] 1.04 [95% confidence interval (CI) 1.02–1.07]}. Specifically, patients in the high exposure group (>70 µg/week) had an increased risk of developing cancer [OR 1.77 (95% CI 1.18–2.66)] compared with patients in the unexposed group.Conclusion: High-dose ESA was associated with an increased incidence risk of new cancer diagnosis among chronic dialysis patients.

Effect of renal artery revascularization upon cardiac structure and function in atherosclerotic renal artery stenosis: cardiac magnetic resonance sub-study of the ASTRAL trial


Background: Cardiac abnormalities are frequent in patients with atherosclerotic renovascular disease (ARVD). The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial studied the effect of percutaneous renal revascularization combined with medical therapy compared with medical therapy alone in 806 patients with ARVD.Methods: This was a pre-specified sub-study of ASTRAL (clinical trials registration, current controlled trials number: ISRCTN59586944), designed to consider the effect of percutaneous renal artery angioplasty and stenting on change in cardiac structure and function, measured using cardiac magnetic resonance (CMR) imaging. Fifty-one patients were recruited from six selected ASTRAL centres. Forty-four completed the study (medical therapy n = 21; revascularization n = 23). Full analysis of CMR was possible in 40 patients (18 medical therapy and 22 revascularization). CMR measurements of left and right ventricular end systolic (LV and RVESV) and diastolic volume (LV and RVEDV), ejection fraction (LVEF) and mass (LVM) were made shortly after recruitment and before revascularization in the interventional group, and again after 12 months. Reporting was performed by CMR analysts blinded to randomization arm.Results: Groups were well matched for mean age (70 versus 72 years), blood pressure (148/71 versus 143/74 mmHg), degree of renal artery stenosis (75 versus 75%) and comorbid conditions. In both randomized groups, improvements in cardiac structural parameters were seen at 12 months, but there were no significant differences between treatment groups. Median left ventricular changes between baseline and 12 months (medical versus revascularization) were LVEDV −1.9 versus −5.8 mL, P = 0.4; LVESV −2.1 versus 0.3 mL, P = 0.7; LVM −5.4 versus −6.3 g, P = 0.8; and LVEF −1.5 versus −0.8%, P = 0.7. Multivariate regression also found that randomized treatment assignment was not associated with degree of change in any of the CMR measurements.Conclusions: In this sub-study of the ASTRAL trial, renal revascularization did not offer additional benefit to cardiac structure or function in unselected patients with ARVD.

The role of tryptophan degradation in the association between inflammatory markers and depressive symptoms in chronic dialysis patients


Background: Among chronic dialysis patients, associations have been found between inflammatory markers and depressive symptoms. In this population, no studies have examined the mechanism linking the association between inflammatory markers and depressive symptoms. We examined whether the association between inflammatory markers and depressive symptoms is mediated by tryptophan (TRP) degradation along the kynurenine (KYN) pathway.Methods: The data are part of an observational, prospective cohort study in five urban dialysis centres in The Netherlands. Depressive symptoms were determined with the Beck Depression Inventory. Peripheral blood was collected before dialysis to measure inflammatory markers [high sensitivity C-reactive protein (HsCRP), interleukin (IL)-1β, IL-6, IL-10 and tumour necrosis factor-α (TNF-α)], TRP, KYN and 3-hydroxykynurenine. The KYN/TRP ratio was used as a measure of TRP degradation. The association between inflammatory markers and depressive symptoms was determined using linear regression analysis and adjusted for the KYN/TRP ratio.Results: In total, 490 chronic dialysis patients were included. HsCRP [β= 3.8; confidence interval (CI): 1.0–6.6], IL-6 (β= 9.1; CI: 4.0–14.1) and TNF-α (β= 1.3; CI: 0.9–1.7) were associated with the KYN/TRP ratio. We found significant associations between HsCRP (β= 0.8; CI: 0.3–1.3) and IL-6 (β= 1.2; CI: 0.3–2.2) levels and depressive symptoms. However, this association was not attenuated after adjustment for the KYN/TRP ratio. Also, no significant associations were found between the KYN/TRP ratio and depressive symptoms.Conclusion: The association between inflammatory markers and depressive symptoms in chronic dialysis patients was not mediated by TRP degradation along the KYN pathway.

A regenerable potassium and phosphate sorbent system to enhance dialysis efficacy and device portability: a study in awake goats


Background: Patients on standard intermittent haemodialysis suffer from strong fluctuations in plasma potassium and phosphate. Prolonged dialysis with a wearable device, based on continuous regeneration of a small volume of dialysate using ion exchangers, could moderate these fluctuations and offer increased clearance of these electrolytes. We report in vivo results on the efficacy of potassium and phosphate adsorption from a wearable dialysis device. We explore whether equilibration of ion exchangers at physiological Ca2+, Mg2+ and hypotonic NaCl can prevent calcium/magnesium adsorption and net sodium release, respectively. Effects on pH and HCO3− were studied.Methods: Healthy goats were instrumented with a central venous catheter and dialysed. Potassium and phosphate were infused to achieve plasma concentrations commonly observed in dialysis patients. An adsorption cartridge containing 80 g sodium poly(styrene-divinylbenzene) sulphonate and 40 g iron oxide hydroxide beads for potassium and phosphate removal, respectively, was incorporated in a dialysate circuit. Sorbents were equilibrated and regenerated with a solution containing NaCl, CaCl2 and MgCl2. Blood was pumped over a dialyser and dialysate was recirculated over the adsorption cartridge in a countercurrent direction.Results: Potassium and phosphate adsorption was 7.7 ± 2.7 and 4.9 ± 1.3 mmol in 3 h, respectively. Adsorption capacity remained constant during consecutive dialysis sessions and increased with increasing K+ and PO43−. Equilibration at physiological Ca2+ and Mg2+ prevented net adsorption, eliminating the need for post-cartridge calcium and magnesium infusion. Equilibration at hypotonic NaCl prevented net sodium release Fe2+ and arterial pH did not change. Bicarbonate was adsorbed, which could be prevented by equilibrating at HCO3− 15 mM.Conclusion: We demonstrate clinically relevant, concentration-dependent, pH-neutral potassium and phosphate removal in vivo with small volumes of regenerable ion exchangers in our prototype wearable dialysis device. Application of the selected ion exchangers for potassium and phosphate removal in a wearable dialysis device appears to be effective with a low-risk profile.

NUP107 mutations in children with steroid-resistant nephrotic syndrome


Background:NUP107 is a novel gene associated with autosomal recessive steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis (FSGS) in children. The frequency of NUP107 mutations in children with SR-FSGS remains unknown.Methods: Nine families with two siblings affected by childhood-onset SRNS or proteinuria were recruited. FSGS was confirmed by a kidney biopsy in at least one affected sibling in all families. Additionally, 69 sporadic pediatric cases with biopsy-proven SR-FSGS who had not responded to any treatment were included. All coding exons with flanking introns of the NUP107 gene were amplified using polymerase chain reaction and directly sequenced.Results: Biallelic NUP107 mutations were detected in four pairs (44.4%) of siblings from the familial cases and three (4.3%) sporadic cases. All affected patients harbored the p.Asp831Ala mutation in one allele and a truncating or abnormal splicing mutation in the other allele. NUP107 mutation-positive patients showed an earlier onset age (39.4 ± 13.1 versus 76.8 ± 50.0 months, P= 0.027) and more rapid progression to end-stage renal disease (at the ages of 58.9 ± 23.4 versus 123.1 ± 62.7 months, P<0.001) compared with mutation-negative patients. None of the eight mutation-positive cases, who underwent kidney transplantation, showed recurrence of FSGS in the graft kidney, while 35.3% of mutation-negative cases showed recurrence of FSGS.Conclusions: An unexpectedly high incidence of NUP107 mutations was observed in Korean children with SR-FSGS. Initial genetic screening of children with SR-FSGS should include the NUP107 gene, at least in Korea. Further studies are necessary to determine the incidences of NUP107 mutations in other countries.

Validation of cystatin C-based equations for evaluating residual renal function in patients on continuous ambulatory peritoneal dialysis


Background: Residual renal function needs to be assessed frequently in patients on continuous ambulatory peritoneal dialysis (CAPD). A commonly used method is to measure creatinine (Cr) and urea clearance in urine collected over 24 h, but collection can be cumbersome and difficult to manage. A faster, simpler alternative is to measure levels of cystatin C (CysC) in serum, but the accuracy and reliability of this method is controversial. Our study aims to validate published CysC-based equations for estimating residual renal function in patients on CAPD.Methods: Residual renal function was measured by calculating average clearance of urea and Cr in 24-h urine as well as by applying CysC- or Cr-based equations published by Hoek and Yang. We then compared the performance of the equations against the 24-h urine results.Results: In our sample of 255 patients ages 47.9 ± 15.6 years, the serum CysC level was 6.43 ± 1.13 mg/L. Serum CysC level was not significantly associated with age, gender, height, weight, body mass index, hemoglobin, intact parathyroid hormone, normalized protein catabolic rate or the presence of diabetes. In contrast, serum CysC levels did correlate with peritoneal clearance of CysC and with levels of prealbumin and high-sensitivity C-reactive protein. Residual renal function was 2.56 ± 2.07 mL/min/1.73 m2 based on 24-h urine sampling, compared with estimates (mL/min/1.73 m2) of 2.98 ± 0.66 for Hoek's equation, 2.03 ± 0.97 for Yang's CysC-based equation and 2.70 ± 1.30 for Yang's Cr-based equation. Accuracies within 30%/50% of measured residual renal function for the three equations were 29.02/48.24, 34.90/56.86 and 31.37/54.90.Conclusion: The three equations for estimating residual renal function showed similar limits of agreement and differed significantly from the measured value. Published CysC-based equations do not appear to be particularly reliable for patients on CAPD. Further development and validation of CysC-based equations should take into account peritoneal clearance of CysC and other relevant factors.

Association of serum vitamin B12 and folate with mortality in incident hemodialysis patients


Background: Vitamin B12 (B12) and folate are essential vitamins that play important roles in physiological processes. In the general population, many studies have evaluated the association of these vitamins with clinical outcomes, yet this association in hemodialysis (HD) patients remains unclear.Methods: We examined the association of serum folate and B12 with mortality in a 5-year cohort of 9517 (folate) and 12 968 (B12) HD patients using Cox models with hierarchical adjustment for sociodemographics, comorbidities, and laboratory variables associated with the malnutrition and inflammation complex syndrome. The associations of baseline B12 and folate (separately) with all-cause mortality were evaluated across five categories of B12 [<400 (reference), 400–<550, 550–<650, 650–<750 and ≥750 pg/mL] and folate [<6.2, 6.2–<8.4, 8.4–<11 (reference), 11–<14.3 and ≥14.3 ng/mL].Results: The study cohort with B12 measurements had a mean ± standard deviation age of 63 ± 15 years, among whom 43% were female, 33% were African-American, and 57% were diabetic. Higher B12 concentrations ≥550 pg/mL were associated with a higher risk of mortality after adjusting for sociodemographic and laboratory variables. However, only lower serum folate concentrations <6.2 ng/mL were associated with a higher risk of all-cause mortality when adjusted for sociodemographic variables [adjusted hazard ratio (95% confidence-interval): 1.18 (1.03–1.35)].Conclusions: Higher B12 concentrations are associated with higher all-cause mortality in HD patients independent of sociodemographics and laboratory variables, whereas lower folate concentrations were associated with higher all-cause mortality after accounting for sociodemographic variables. Further studies are warranted to determine the optimal B12 and folate level targets in this population.

Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome


Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including ‘repurposing’) therapies on an international basis.

Prevalence of reduced kidney function and albuminuria in older adults: the Berlin Initiative Study


Background: Although CKD is said to increase among older adults, epidemiologic data on kidney function in people ≥70 years of age are scarce. The Berlin Initiative Study (BIS) aims to fill this gap by evaluating the CKD burden in older adults.Methods: The BIS is a prospective population-based cohort study whose participants are members of Germany's biggest insurance company. This cross-sectional analysis (i) gives a detailed baseline characterization of the participants, (ii) analyses the representativeness of the cohort's disease profile, (iii) assesses GFR and albuminuria levels across age categories, (iv) associates cardiovascular risk factors with GFR as well as albuminuria and (v) compares means of GFR values according to different estimating equations with measured GFR.Results: A total of 2069 participants (52.6% female, mean age 80.4 years) were enrolled: 26.1% were diabetic, 78.8% were on antihypertensive medication, 8.7% had experienced a stroke, 14% a myocardial infarction, 22.6% had cancer, 17.8% were anaemic and 26.5% were obese. The distribution of comorbidities in the BIS cohort was very similar to that in the insurance ‘source population’. Creatinine and cystatin C as well as the albumin:creatinine ratio (ACR) increased with increasing age. After multivariate adjustments, reduced GFR and elevated ACR were associated with most cardiovascular risk factors. The prevalence of a GFR <60 mL/min/1.73 m2 ranged from 38 to 62% depending on the estimation equation used.Conclusions: The BIS is a very well-characterized, representative cohort of older adults. Participants with an ACR ≥30 had significantly higher odds for most cardiovascular risk factors compared with an ACR <30 mg/g. Kidney function declined and ACR rose with increasing age.

APOL1 -associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts


Background: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 (APOL1) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known.Methods: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE).Results: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m2; NEPTUNE: 74 versus 94 mL/min/1.73 m2). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: −18 versus −8% per year; NEPTUNE: −13 versus −3% per year).Conclusions: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1-associated glomerular disease. Further study is needed to determine the generalizability of these findings.

The effects of short sleep duration on proteinuria and chronic kidney disease: a systematic review and meta-analysis


Background: The risks of proteinuria and chronic kidney disease (CKD) in adults who regularly have short sleep duration (short sleepers) are controversial. The aim of this meta-analysis was to assess the effects of short sleep duration on proteinuria and CKD.Methods: A literature search was conducted using MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews from the inception of the databases through November 2015. Studies that reported relative risks, odd ratios or hazard ratios comparing the risks of proteinuria and CKD in short sleepers were included. Pooled risk ratios (RR) and 95% confidence intervals (CI) were computed utilizing a random-effect, generic inverse variance method.Results: Six observational studies with 252 075 individuals and three observational studies with 37 197 individuals were included in the analyses to assess the risks of CKD and proteinuria in short sleepers, respectively. The pooled RR of CKD in short sleepers was 1.51 (95% CI, 0.99–2.55). When meta-analysis was restricted only to studies with adjusted analysis for confounders assessing the risk of CKD in short sleepers, the pooled RR of CKD was 1.54 (95% CI, 0.80–2.95). The pooled RR of proteinuria in short sleepers was 1.47 (95% CI, 1.26–1.72).Conclusions: Despite the lack of significant association between short sleep duration and CKD, our meta-analysis suggests a potential association between short sleep duration and proteinuria, a surrogate marker for kidney disease progression. Future study is required to investigate if reversal of short sleep helps reduce proteinuria.

Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease


Background: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by multitudes of expanding renal cysts associated with mononuclear interstitial infiltrates. Monocyte chemotactic protein-1 is produced in the kidneys and excreted in the urine (uMCP1) of these patients in increased amounts. In the TEMPO 3:4 trial, tolvaptan slowed the rate of increase in total kidney volume (TKV) and the rate of decline in estimated glomerular filtration rate (eGFR). In a sub-analysis, we determined whether tolvaptan administration for up to 3 years changed the urinary excretion of MCP-1 referenced to creatinine in 869 treated subjects compared with 438 placebo subjects.Methods: Treatment group differences of uMCP1 at 0.75, 12, 24 and 36 months were evaluated by ANCOVA with factor of treatment and covariate baseline.Results: At baseline, mean uMCP1 was 429 ± 224 pg/mg in the tolvaptan and 434 ± 233 pg/mg in the placebo groups, ∼4-fold greater than normal. Log uMCP1 associated positively with log TKV (r = 0.2645, P < 0.0001) and negatively with eGFR (r = −0.1555 P < 0.0001) and fasting urine osmolality (r = −0.1933, P < 0.0001). Tolvaptan reduced uMCP1 13.8 ± 4.4% (P < 0.0001) below placebo-treated subjects at 24 months and 14.4 ± 3.7% (P < 0.0001) at 36 months, and to the same extent in females and males. The effect of tolvaptan on uMCP1 excretion at 36 months extended across CKD Stage 1 (11.1 ± 6.4%, P = 0.0595), CKD 2 (13.9 ± 5.4%, P = 0.0050) and CKD 3 (21.4 ± 8.0%, P = 0.0020).Conclusion: Tolvaptan, administered for 3 years to patients with ADPKD, caused a sustained reduction in the urinary excretion of MCP-1 relative to placebo.

Central blood pressures in early chronic kidney disease: an analysis of CARTaGENE


Background: Vascular stiffness and advanced chronic kidney disease (CKD) are strong determinants of higher central blood pressure (BP) and are associated with high cardiovascular morbidity and mortality. Whether mild-to-moderate CKD is associated with higher central BP independently of other comorbid conditions remains uncertain.Methods: We evaluated the central hemodynamic profile [central systolic BP, central pulse pressure (PP), augmentation index, PP amplification, augmented pressure] of Stage 3 CKD patients and compared it with participants with estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 in the CARTaGENE populational cohort through propensity score matching and multivariate regression analyses.Results: Of the 20 004 participants, 13 114 had valid pulse wave analysis and eGFRs >30 mL/min/1.73 m2, of which 515 had Stage 3 CKD. These 515 patients had significantly higher peripheral systolic BP (127 ± 16 versus 125 ± 15 mmHg, P = 0.01) and central PP (43.0 ± 11.4 versus 39.7 ± 10.0 mmHg, P <0.001) than the control group (eGFR >60 mL/min/1.73 m2). Propensity score matching allowed the creation of 500 pairs with similar clinical characteristics. In this matched cohort, central BPs were similar in Stage 3 CKD patients compared with controls (central PP 42.9 ± 11.3 versus 43.7 ± 11.3 mmHg, P = 0.3). Multivariate analysis using data from all patients also found that the higher central hemodynamic readings found in Stage 3 CKD patients disappeared after adjusting for comorbid conditions. In a subset of 609 participants in whom albuminuria levels were measured, urine albumin excretion was not independently associated with higher central hemodynamic indices.Conclusion: In this large cohort from the general population, early CKD and albuminuria was not independently associated with detrimental central hemodynamic parameters.