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Preview: Nephrology Dialysis Transplantation - current issue

Nephrology Dialysis Transplantation Current Issue





Published: Thu, 01 Feb 2018 00:00:00 GMT

Last Build Date: Thu, 01 Feb 2018 10:49:55 GMT

 



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Thu, 01 Feb 2018 00:00:00 GMT

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Women and kidney disease: reflections on World Kidney Day 2018Kidney Health and Women’s Health: a case for optimizing outcomes for present and future generations

Thu, 01 Feb 2018 00:00:00 GMT

Abstract
Chronic kidney disease (CKD) affects ∼10% of the world’s adult population: it is one of the top 20 causes of death worldwide and its impact on patients and their families can be devastating. World Kidney Day and International Women’s Day coincide in 2018, thus offering an opportunity to reflect on the importance of women’s health, and specifically their kidney health, on the community and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply these learnings more broadly. Girls and women, who make up ∼50% of the world’s population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for the diagnosis of kidney disease, and also a state where acute and chronic kidney diseases may manifest and that may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for childbearing and on the fetus. Women have different complications on dialysis than men and are more likely to be donors than recipients of kidney transplants. In this editorial we focus on what we do and do not know about women, kidney health and kidney disease and what we might learn in the future to improve outcomes worldwide.



Anti-phospholipase A2 receptor antibodies in primary membranous nephropathy—10 key points

Thu, 01 Feb 2018 00:00:00 GMT

Membranous nephropathy (MN) remains the most common primary cause of nephrotic syndrome in Europe and a common cause of end-stage renal failure. The reporting of anti-phospholipase A2 receptor antibody (PLA2RAb) positivity in 70% of patients with primary MN (PMN) in 2009 was a significant advance in the understanding of the disease pathogenicity. What is the antigen? The M-type phospholipase A2 receptor (PLA2R) on the cell surface of podocytes is the target antigen for PLA2RAb. The receptor under normal circumstances binds PLA2, but its exact physiological role is unclear [1]. The trigger for antibody (Ab) production is not known but leads to subepithelial antigen–antibody complexes being deposited, with subsequent complement activation, podocyte damage and proteinuria.Is the value of antibody testing limited in any populations? Detection of the antibody has been confirmed at similar prevalences in different ethnic cohorts, with the exception of the Japanese, where it is nearer 50%. Retrospective testing of serum from cohorts produces some variability in prevalence, as the sample tested may not have been taken when the patient first presented. PLA2RAb is also detected in 70% of children with PMN [2].When should the kidney biopsy be stained for PLA2R? Immunofluorescence uses an antibody to test for the antigen (PLA2R) on renal biopsy specimens. Under normal circumstances, there is weak positive staining. In PMN with PLA2RAb positivity, staining for PLA2R is detected along the capillary walls and noted to be intense and granular [3]. PLA2RAb is predominantly an immunoglobulin G4 (IgG4) subclass, supporting the opinion that positive IgG staining of biopsies for other subclasses (IgG1–3) should prompt a search for secondary causes. In patients with a historical diagnosis of idiopathic MN who are in remission and PLA2RAb is negative, the only way to establish if they have PLA2RAb-positive disease (and therefore would benefit from PLA2RAb monitoring) is to stain their initial renal biopsy for PLA2R. Alternatively, some patients with negative PLA2RAb serology at presentation will have PLA2R-positive biopsy staining (10–15%), consistent with PMN, and the patient may or may not become serologically positive in time. The theory behind this is that the kidney initially acts as an antibody stump and serological testing may lag behind disease activity in the kidney.What is the relevance of different antigenic epitopes? Type 1 PLA2R has nine different domains, of which the cysteine-rich extracellular region (CysR) is the dominant epitope. Blocking a single epitope would be attractive, however, it has been recognized that the epitope profile can change over time, with antibodies to other domains developing that may have a worse prognosis [4]. In time, it may be possible to detect epitope-specific PLA2RAb levels, but at present it is an overall antibody titre that is reported.What is the specificity and sensitivity of the test? PLA2RAb levels are commonly measured using an enzyme-linked immunosorbent assay, which provides a quantitative value for antibody positivity. It is > 90% specific and 70% sensitive, although it is important to note that around two-thirds of patients with hepatitis B- hepatitis C- or sarcoidosis-associated MN exhibit PLA2RAb positivity [1] and staining on biopsy. Positive PLA2RAb should not inhibit symptom-based screening for secondary causes of MN in relevant populations, although secondary causes including malignancy may be a coincidental finding.Can PLA2RAb positivity replace native renal biopsy in diagnosing PMN in a patient with nephrotic syndrome? Given that PLA2RAb is not detected in other proteinuric renal diseases, it is logical that a biopsy is not essential to make the diagnosis. At present however, biopsy remains the gold standard unless the patient is particularly high risk for the procedure. Biopsy will also provide information on any disease chronicity and chronic damage.Can PLA2RAb be used for monitoring disease activity? PLA2RAb tit[...]



Uric acid in chronic kidney disease: the quest for causality continues

Fri, 22 Dec 2017 00:00:00 GMT

Chronic kidney disease (CKD) is now recognized as a major contributor to the global burden of disease and ranks as the 10th cause of death worldwide [1]. Cardiovascular disease is the main driver of the high death risk of CKD and over 2 million cardiovascular deaths could be attributed to CKD per se in 2013 [2]. The introduction of angiotensin-converting enzyme inhibitors and angiotensin II inhibitors has been a major advancement in CKD prevention and the incidence rate of end-stage renal disease (ESRD) has started to decline in the USA [3] and in Europe [4]. However, with the recent exception of glucose-transporter-2 inhibitors, no new nephroprotective drugs have been introduced into the clinical scenario. Knowledge about causal risk factors for CKD progression remains largely incomplete. In an analysis made 20 years ago by Hunsicker et al. in the Modification of Diet in Renal Disease study database [5], known risk factors explained just about one-third of the risk of progression to ESRD. No substantial progress had been made since then in our understanding of the problem at clinical level. Given the public health implications of CKD, extending knowledge on risk factors that can be leveraged to halt progression to ESRD was set as a scientific priority by the International Society Of Nephrology (ISN) Global Kidney Health Summit [6].



Uric acid predicts adverse outcomes in chronic kidney disease: a novel insight from trajectory analyses

Fri, 10 Nov 2017 00:00:00 GMT

Abstract
Background
Very little is known about longitudinal trajectories of serum uric acid (SUA) over the course of chronic kidney disease (CKD). We aimed to determine whether longitudinal SUA trajectories are associated with the risk of end-stage renal disease (ESRD) and all-cause mortality among CKD patients.
Methods
We conducted a prospective cohort study from a 13-year multidisciplinary pre-ESRD care registry. The final study population consisted of 5090 CKD patients aged 20–90 years between 2003 and 2015. An individual’s SUA trajectory was defined by group-based trajectory modeling in four distinct patterns: high, moderate-high, moderate and low. Time to ESRD and death was analyzed by multiple Cox regression.
Results
A total of 948 ESRD events and 472 deaths occurred with incidence rates of 57.9 and 28.7 per 1000 person-years, respectively. Compared with those with a low SUA trajectory, the adjusted hazard ratio of patients for incident ESRD was in a dose–response manner as follows: moderate, 1.89 [95% confidence interval (CI), 1.37–2.60]; moderate-high, 2.49 (1.75–3.55); and high, 2.84 (1.81–4.47); after considering the competing risk of death. For all-cause mortality, the corresponding risk estimate of the same SUA trajectory was 1.38 (95% CI, 0.89–2.12), 1.95 (1.22–3.10) and 4.52 (2.48–8.26), respectively. The unfavorable effect of elevated SUA trajectories on progression to ESRD was differentially higher among CKD patients without using urate-lowering agents at baseline (P for interaction = 0.018).
Conclusions
Elevated SUA trajectories are associated with accelerated kidney failure and all-cause mortality in CKD patients. Adequate experimental evidence is urgently needed to inform when and how to optimize SUA in this population.



Metabolic imaging of fatty kidney in diabesity: validation and dietary intervention

Fri, 15 Sep 2017 00:00:00 GMT

Abstract
Background
Obesity and type 2 diabetes have not only been linked to fatty liver, but also to fatty kidney and chronic kidney disease. Since non-invasive tools are lacking to study fatty kidney in clinical studies, we explored agreement between proton magnetic resonance spectroscopy (1H-MRS) and enzymatic assessment of renal triglyceride content (without and with dietary intervention). We further studied the correlation between fatty kidney and fatty liver.
Methods
Triglyceride content in the renal cortex was measured by 1H-MRS on a 7-Tesla scanner in 27 pigs, among which 15 minipigs had been randomized to a 7-month control diet, cafeteria diet (CAF) or CAF with low-dose streptozocin (CAF-S) to induce insulin-independent diabetes. Renal biopsies were taken from corresponding MRS-voxel locations. Additionally, liver biopsies were taken and triglyceride content in all biopsies was measured by enzymatic assay.
Results
Renal triglyceride content measured by 1H-MRS and enzymatic assay correlated positively (r = 0.86, P < 0.0001). Compared with control diet-fed minipigs, renal triglyceride content was higher in CAF-S-fed minipigs (137 ± 51 nmol/mg protein, mean ± standard error of the mean, P < 0.05), but not in CAF-fed minipigs (60 ± 10 nmol/mg protein) compared with controls (40 ± 6 nmol/mg protein). Triglyceride contents in liver and kidney biopsies were strongly correlated (r = 0.97, P < 0.001).
Conclusions
Non-invasive measurement of renal triglyceride content by 1H-MRS closely predicts triglyceride content as measured enzymatically in biopsies, and fatty kidney appears to develop parallel to fatty liver. 1H-MRS may be a valuable tool to explore the role of fatty kidney in obesity and type 2 diabetic nephropathy in humans in vivo.



STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model

Thu, 17 Aug 2017 00:00:00 GMT

Abstract
Background
Alport syndrome (AS) is a hereditary, progressive nephritis caused by mutation of type IV collagen. Previous studies have shown that activation of signal transducer and activator of transcription 3 (STAT3) exacerbates other renal diseases, but whether STAT3 activation exacerbates AS pathology is still unknown. Here we aim to investigate the involvement of STAT3 in the progression of AS.
Method
Phosphorylated STAT3 expression was assessed by immunoblotting analysis of kidneys and glomeruli of an AS mouse model (Col4a5 G5X mutant). To determine the effect of blocking STAT3 signaling, we treated AS mice with the STAT3 inhibitor stattic (10 mg/kg i.p., three times per week for 10 weeks; n = 10). We assessed the renal function [proteinuria, blood urea nitrogen (BUN), serum creatinine] and analyzed the glomerular injury score, fibrosis and inflammatory cell invasion by histological staining. Moreover, we analyzed the gene expression of nephritis-associated molecules.
Results
Phosphorylated STAT3 was upregulated in AS kidneys and glomeruli. Treatment with stattic ameliorated the progressive renal dysfunction, such as increased levels of proteinuria, BUN and serum creatinine. Stattic also significantly suppressed the gene expression levels of renal injury markers (Lcn2, Kim-1), pro-inflammatory cytokines (Il-6, KC), pro-fibrotic genes (Tgf-β, Col1a1, α-Sma) and Mmp9. Stattic treatment decreased the renal fibrosis congruently with the decrease of transforming growth factor beta (TGF-β) protein and increase of antifibrosis-associated markers p-Smad1, 5 and 8, which are negative regulators of TGF-β signaling.
Conclusion
STAT3 inhibition significantly ameliorated the renal dysfunction in AS mice. Our finding identifies STAT3 as an important regulator in AS progression and provides a promising therapeutic target for AS.



Endothelial glycocalyx—the battleground for complications of sepsis and kidney injury

Tue, 23 May 2017 00:00:00 GMT

Abstract
After briefly discussing endothelial glycocalyx and its role in vascular physiology and renal disease, this overview focuses on its degradation very early in the course of microbial sepsis. We describe our recently proposed mechanism for glycocalyx degradation induced by exocytosis of lysosome-related organelles and release of their cargo. Notably, an intermediate in nitric oxide synthesis, NG-hydroxy-l-arginine, shows efficacy in curtailing exocytosis of these organelles and improvement in animal survival. These data not only depict a novel mechanism responsible for very early glycocalyx degradation, but may also outline a potential preventive therapy. The second issue discussed in this article is related to the therapeutic acceleration of restoration of already degraded endothelial glycocalyx. Here, using as an example our recent findings obtained with sulodexide, we illustrate the importance of the expedited repair of degraded endothelial glycocalyx for the survival of animals with severe sepsis. These two focal points of the review on glycocalyx may not only have broader disease applicability, but they may also provide additional evidence to buttress the idea of the importance of endothelial glycocalyx and its maintenance and repair in the prevention and treatment of an array of renal and nonrenal diseases.



Diagnostic and management challenges in Goodpasture’s (anti-glomerular basement membrane) disease

Fri, 28 Apr 2017 00:00:00 GMT

Abstract
Goodpasture’s or anti-glomerular basement membrane (GBM) disease is classically characterized by the presence of circulating autoantibodies directed against the non-collagenous domain of the α3 chain of type IV collagen, targeting glomerular and alveolar basement membranes, and associated with rapidly progressive crescentic glomerulonephritis, with alveolar haemorrhage in over half the patients. However, there are increasing examples of variants or atypical presentations of this disease, and novel therapeutic options have been proposed, which nephrologists should be aware of. The pathophysiology of this condition has been understood through molecular analysis of the antibody–antigen interactions and the use of human leucocyte antigen-transgenic animals, while the association of anti-GBM antibodies with anti-neutrophil cytoplasm antibodies and their combined impact on disease phenotype is increasingly recognized, providing some insights into the basis of glomerular damage and autoimmunity.



Parapelvic cysts, a distinguishing feature of renal Fabry disease

Tue, 28 Mar 2017 00:00:00 GMT

Abstract
Background
Fabry’s disease (FD) is a rare, multi-organ lysosomal disease, caused by the deficiency of the enzyme α-galactosidase A, and is difficult to diagnose. Although parapelvic cysts (PC) were previously associated with FD, their prevalence and significance are unclear.
Methods
The present study aimed to: (i) evaluate, by renal ultrasound, the real prevalence of PC and of their determinants in a multicentre, nationwide cohort of FD patients (n = 173, Study 1) and (ii) ascertain whether a greater accuracy of PC detection improved their identification, in FD patients from a single centre (n = 67, Study 2). In both studies, for each FD patient, an age- and renal function-matched subject was selected for comparison (1:1).
Results
In Study 1, PC were detected in 28.9% of FD subjects and in only 1.1% of control subjects (P < 0.001). The presence of other renal abnormalities did not differ between the groups, nor differences exist in the main demographic and laboratory parameters between the groups. In Study 2, the greater accuracy of ultrasound increased PC prevalence from 29.8% to 43.3% in the same subjects (P < 0.05). In both studies, no correlation was detected between PC and the main demographic, clinical and biochemical parameters, including use of enzyme replacement therapy (P < 0.1, minimum value). Finally, no difference existed between FD patients with and without PC.
Conclusions
The present study suggests that the presence of PC in renal patients should alert physicians to consider the diagnosis of FD, primarily in subjects with an unclear family history of renal disease and in the presence of other stigmata of the disease.



IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy

Wed, 01 Mar 2017 00:00:00 GMT

Abstract
Background
Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN.
Methods
The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis.
Results
CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL-17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-β1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-β1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-β1, but increased the viability of cultured podocytes.
Conclusions
IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.



Sarcopenia and relationships between muscle mass, measured glomerular filtration rate and physical function in patients with chronic kidney disease stages 3–5

Wed, 01 Mar 2017 00:00:00 GMT

Abstract
Background
Sarcopenia and poor physical function are common in patients with chronic kidney disease (CKD). Our aim was to investigate the relationships between muscle mass and measured glomerular filtration rate (GFR) and between muscle mass and strength and balance, respectively, in patients with CKD stages 3–5.
Methods
This is a baseline data analysis of a randomized controlled clinical trial. A total of 148 adult patients with an estimated GFR <30 mL/min/1.72 m2, not on renal replacement therapy, irrespective of the number of comorbidities were included from the Department of Nephrology, Skåne University Hospital, Lund, from 2011 to 2016. Body composition was measured by dual-energy X-ray absorptiometry (DEXA). GFR was measured by iohexol clearance. Balance was measured by functional reach and the Berg balance test and strength by handgrip strength and isometric quadriceps strength.
Results
Measured GFR ranged from 8 to 55 mL/min/1.73 m2. Lean mass (P < 0.05), fat mass (P < 0.05), appendicular skeletal muscle (P < 0.001) and appendicular skeletal muscle index (P < 0.05) were associated with GFR. Functional reach was associated with leg lean mass (P < 0.05) and the Berg balance test score was associated with trunk lean mass (P < 0.05). Handgrip strength was associated with arm lean mass (P < 0.001). Isometric quadriceps strength was associated with leg lean mass (P < 0.001). More men (44%) suffered from low muscle mass than women (22%), whereas more women (36%) suffered from low muscle strength than men (26%). However, when combining both, men (16%) suffered from sarcopenia to a greater extent than women (8%).
Conclusions
Among patients with CKD stages 3–5, loss of lean body mass, especially appendicular skeletal muscle, was significantly related to GFR decline. Two important markers of physical function, balance and strength, were significantly related to muscle mass. Moreover, men were more prone to sarcopenia than women during kidney function decline.



Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies

Mon, 27 Feb 2017 00:00:00 GMT

Abstract
Background
Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies.
Methods
We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria.
Results
IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis.
Conclusions
The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression.



The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis

Thu, 23 Feb 2017 00:00:00 GMT

Abstract
Background
Existing epidemiological studies illustrate that proton pump inhibitors (PPIs) may be related to adverse kidney outcomes. To date, no comprehensive meta-analysis has been conducted to evaluate and quantify this association.
Methods
We performed a systematic review and meta-analysis of studies to assess the association between PPI use and the risk of adverse kidney outcomes. We searched MEDLINE, Embase, SCOPUS, Web of Science, CINAHL, Cochrane Library and grey literature with no language restrictions (through 31 October 2016). Adverse kidney outcomes were acute interstitial nephritis (AIN), acute kidney injury (AKI), chronic kidney disease (CKD) and end-stage renal disease (ESRD). The risk ratios (RRs) and confidence intervals (CIs) were pooled using a random effects model. The strength of evidence (SOE) for each outcome was assessed using the Grading of Recommended Assessment, Development and Evaluation system.
Results
Of 2037 identified studies, four cohort and five case–control studies with ∼2.6 million patients were included. Of these, 534 003 (20.2%) were PPI users. Compared with non-PPI users, PPI users experienced a significantly higher risk of AKI [RR 1.44 (95% CI 1.08–1.91); P=0.013; SOE, low] and CKD [RR 1.36 (95% CI 1.07–1.72); P=0.012; SOE, low]. Moreover, PPIs increased the risk of AIN [RR 3.61 (95% CI 2.37–5.51); P<0.001; SOE, insufficient] and ESRD [RR 1.42 (95% CI 1.28–1.58); P<0.001; SOE, insufficient].
Conclusion
PPI usage was associated with adverse kidney outcomes; however, these findings were based on observational studies and low-quality evidence. Additional rigorous studies are needed for further clarification.



The clinical epidemiology of young adults starting renal replacement therapy in the UK: presentation, management and survival using 15 years of UK Renal Registry data

Thu, 23 Feb 2017 00:00:00 GMT

Abstract
Background
Clinical epidemiology data for young adults on renal replacement therapy (RRT) are lacking. While mostly transplanted, they have an increased risk of graft loss during young adulthood.
Methods
We combined the UK Renal Registry paediatric and adult databases to describe patient characteristics, transplantation and survival for young adults. We grouped patients 11–30 years of age starting RRT from 1999 to 2008 by age band and examined their course during 5 years of follow-up.
Results
The cohort (n = 3370) was 58% male, 79% white and 29% had glomerulonephritis. Half (52%) started RRT on haemodialysis (HD). Most (78%) were transplanted (18% pre-emptive, 61% as second modality); 11% were not listed for transplant. Transplant timing varied by age group. The deceased:living donor kidney transplant ratio was 2:1 for 11–<16 year olds and 1:1 otherwise. Median deceased donor transplant waiting times ranged from 6 months if <16 years of age to 17 months if ≥21 years. Overall 8% died, with being on dialysis and not transplant listed versus transplanted {hazard ratio [HR] 16.6 [95% confidence interval (CI) 10.8–25.4], P < 0.0001} and diabetes versus glomerulonephritis [HR 4.03 (95% CI 2.71–6.01), P < 0.0001] increasing mortality risk.
Conclusions
This study highlights the frequent use of HD and the importance of transplant listing and diabetes for young adults. More than half the young adults in our cohort started renal replacement therapy on HD. One in 10 young adults were not listed for transplant by 5 years and were ∼20 times more likely to die than those who were transplanted. Diabetes as a primary renal disease was common among young adults and associated with increased mortality. Overall, almost 1 in 10 young adults had died by 5 years from the start of RRT.



A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy

Mon, 20 Feb 2017 00:00:00 GMT

Abstract
Background
Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans.
Methods
We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed.
Results
Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-analysis [meta-analysis P  =  0.0070; odds ratio (OR) = 1.29]; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein.
Conclusions
Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.



Serum uromodulin—a marker of kidney function and renal parenchymal integrity

Thu, 16 Feb 2017 00:00:00 GMT

Abstract
Background
An ELISA to analyse uromodulin in human serum (sUmod) was developed, validated and tested for clinical applications.
Methods
We assessed sUmod, a very stable antigen, in controls, patients with chronic kidney disease (CKD) stages 1–5, persons with autoimmune kidney diseases and recipients of a renal allograft by ELISA.
Results
Median sUmod in 190 blood donors was 207 ng/mL (women: men, median 230 versus 188 ng/mL, P = 0.006). sUmod levels in 443 children were 193 ng/mL (median). sUmod was correlated with cystatin C (rs = −0.862), creatinine (rs = −0.802), blood urea nitrogen (BUN) (rs = −0.645) and estimated glomerular filtration rate (eGFR)–cystatin C (rs  = 0.862). sUmod was lower in systemic lupus erythematosus-nephritis (median 101 ng/mL), phospholipase-A2 receptor- positive glomerulonephritis (median 83 ng/mL) and anti-glomerular basement membrane positive pulmorenal syndromes (median 37 ng/mL). Declining sUmod concentrations paralleled the loss of kidney function in 165 patients with CKD stages 1–5 with prominent changes in sUmod within the ‘creatinine blind range’ (71–106 µmol/L). Receiver-operating characteristic analysis between non-CKD and CKD-1 was superior for sUmod (AUC 0.90) compared with eGFR (AUC 0.39), cystatin C (AUC 0.39) and creatinine (AUC 0.27). sUmod rapidly recovered from 0 to 62 ng/mL (median) after renal transplantation in cases with immediate graft function and remained low in delayed graft function (21 ng/mL, median; day 5–9: relative risk 1.5–2.9, odds ratio 1.5–6.4). Immunogold labelling disclosed that Umod is transferred within cytoplasmic vesicles to both the apical and basolateral plasma membrane. Umod revealed a disturbed intracellular location in kidney injury.
Conclusions
We conclude that sUmod is a novel sensitive kidney-specific biomarker linked to the structural integrity of the distal nephron and to renal function.



Osmotic indices and kidney concentrating activity: population-based data on correlates and prognostic power

Sat, 04 Feb 2017 00:00:00 GMT

Abstract
Background
Research data are limited on indices of osmotic equilibrium and of kidney concentrating activity (KCA). This study investigated correlates and prognostic power of these indices in a sample of the general population.
Methods
Urine osmolality (U-osm), plasma osmolality (P-osm), plasma creatinine and other variables were measured by the Gubbio Study for the 1988–92 exam (baseline). Plasma creatinine and other variables were re-measured in the 2001–07 exam (follow-up). KCA was assessed as the U-osm/P-osm ratio and kidney function as estimated glomerular filtration rate (eGFR).
Results
Baseline data were complete in 4220 adults, of whom 852 died before follow-up and 2795 participated in the follow-up. At baseline, the following independent cross-sectional associations were identified: female sex and higher urine flow with lower values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); obesity with higher values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); older age and lower eGFR with lower U-osm, lower U-osm/P-osm ratio and higher P-osm (P < 0.05); hypertension and smoking with lower U-osm and lower U-osm/P-osm ratio (P < 0.05) but not with P-osm. From baseline to follow-up, the annualized rate was 1.26% for mortality and −0.74 ± 0.76 mL/min × 1.73 m2 for eGFR change. Mortality was independently predicted by baseline U-osm and baseline U-osm/P-osm ratio (hazard ratio for one higher standard deviation was ≤0.91, 95% confidence interval was ≤0.97, P < 0.01), but not by baseline P-osm. The eGFR change was not independently predicted by baseline values of U-osm, P-osm and U-osm/P-osm ratio (P ≥ 0.4).
Conclusions
Sex, age, obesity, eGFR, urine flow, hypertension and smoking independently associated with U-osm and KCA. U-osm and KCA independently predicted mortality, but not kidney function change over time.



Measuring trade-offs in nephrology: a systematic review of discrete choice experiments and conjoint analysis studies

Wed, 01 Feb 2017 00:00:00 GMT

Abstract
Background
Discrete choice experiment (DCE), conjoint analysis or adaptive conjoint analysis methods are increasingly applied to obtain patient, clinician or community preferences in nephrology. This study systematically reviews the above-mentioned published choice studies providing an overview of the issues addressed, methods and findings.
Methods
Choice studies relating to nephrology were identified using electronic databases, including Medline, Embase, PsychINFO and Econlit from 1990 to 2015. For inclusion in the review, studies had to primarily relate to kidney disease and include results from statistical (econometric) analyses of respondents’ choice or preference. Studies meeting the inclusion criteria were assessed against a range of systematic review criteria, and methods and results summarized.
Results
We identified 14 eligible studies from Europe, Australasia, North America and Asia, reporting preferences for treatment or screening, patient experiences, quality of life (QOL), health outcomes and priority-setting frameworks. Specific contexts included medical interventions in kidney transplantation and renal cell carcinoma, health policies for organ donation and allocation, dialysis modalities and end-of-life care, using a variety of statistical models. The characteristics of ‘time’ (i.e. transplant waiting time, dialysis hours, transport time) and QOL (pre- and post-transplant, or pre- and post-dialysis) consistently influenced patient and clinician preferences across the choice studies.
Conclusions
DCE are increasingly used to obtain information about key preferences in kidney transplantation and dialysis. These study methods provide quantitative information about respondents’ trade-offs between conflicting clinical and policy objectives, and can establish how preferences vary among stakeholder groups.



Temporal trends in renal function and birthweight in Japanese adolescent males (1998–2015)

Tue, 17 Jan 2017 00:00:00 GMT

Abstract
Background
Low birthweight (LBW) is a worldwide public health problem, demonstrating an increasing incidence in developed countries, including Japan. LBW is also a risk factor for later development of chronic kidney disease (CKD). To date, studies have not evaluated the population impacts of increasing LBW rates on renal function.
Methods
Estimated glomerular filtration rate (eGFR) was evaluated in 3737 Japanese adolescent males (15–16 years old) using annual cross-sectional data over an 18-year period (1998–2015).
Results
Between the initial (1998–2003) and final (2010–15) periods of the study, the mean birthweight decreased from 3213.4 ± 383.8 to 3116.2 ± 382.3 g and the LBW rate increased from 2.5 to 5.5% (both P ≤ 0.01). Additionally, the mean eGFR decreased from 105.1 ± 15.9 to 97.4 ± 13.8 mL/min/1.73 m2 and the prevalence of mildly reduced renal function (eGFR ≤ 60– <90 mL/min/1.73 m2) increased from 16.4 to 30.0% (both P ≤ 0.01), most evident in the LBW group (from 10.3 to 41.7%, P ≤0.01). The prevalence of proteinuria also increased significantly. Mildly reduced renal function was significantly associated with LBW [odds ratio (LBW 3000–3999 g) 1.51; 95% confidence interval 1.00–2.55; P = 0.047].
Conclusions
In this population of Japanese adolescents, the frequency of mildly reduced renal function increased as the LBW frequency increased. Our findings may have implications for the broader Japanese population as well as for other populations in which the prevalence of LBW is increasing.



Prognostic utility of estimated albumin excretion rate in chronic kidney disease: results from the Study of Heart and Renal Protection

Sat, 14 Jan 2017 00:00:00 GMT

Abstract
Background
Estimated albumin excretion rate (eAER) provides a better estimate of 24-h albuminuria than albumin:creatinine ratio (ACR). However, whether eAER is superior to ACR in predicting end-stage renal disease (ESRD), vascular events (VEs) or death is uncertain.
Methods
The prognostic utility of ACR and eAER (estimated from ACR, sex, age and race) to predict mortality, ESRD and VEs was compared using Cox proportional hazards regression among 5552 participants with chronic kidney disease in the Study of Heart and Renal Protection, who were not on dialysis at baseline.
Results
During a median follow-up of 4.8 years, 1959 participants developed ESRD, 1204 had a VE and 1130 died (641 from a non-vascular, 369 from a vascular and 120 from an unknown cause). After adjustment for age, sex and eGFR, both ACR and eAER were strongly and similarly associated with ESRD risk. The average relative risk (RR) per 10-fold higher level was 2.70 (95% confidence interval 2.45–2.98) for ACR and 2.67 (2.43–2.94) for eAER. Neither ACR nor eAER provided any additional prognostic information for ESRD risk over and above the other. For VEs, there were modest positive associations between both ACR and eAER and risk [adjusted RR per 10-fold higher level 1.37 (1.22–1.53) for ACR and 1.36 (1.22–1.52) for eAER]. Again, neither measure added prognostic information over and above the other. Similar results were observed when ACR and eAER were related to vascular mortality [RR per 10-fold higher level: 1.64 (1.33–2.03) and 1.62 (1.32–2.00), respectively] or to non-vascular mortality [1.53 (1.31–1.79) and 1.50 (1.29–1.76), respectively].
Conclusions
In this study, eAER did not improve risk prediction of ESRD, VEs or mortality.



Prognostic significance of pre-end-stage renal disease serum alkaline phosphatase for post-end-stage renal disease mortality in late-stage chronic kidney disease patients transitioning to dialysis

Sat, 07 Jan 2017 00:00:00 GMT

Abstract
Background
Higher serum alkaline phosphatase (ALP) levels have been associated with excess mortality in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) and end-stage renal disease (ESRD). However, little is known about the impact of late-stage NDD-CKD ALP levels on outcomes after dialysis initiation.
Methods
Among 17 732 US veterans who transitioned to dialysis between October 2007 and September 2011, we examined the association of serum ALP levels averaged over the last 6 months of the pre-ESRD transition period (‘prelude period’) with all-cause, cardiovascular and infection-related mortality following dialysis initiation, using Cox (for all-cause mortality) and competing risk (for cause-specific mortality) regressions adjusted for demographics, comorbidities, medications, estimated glomerular filtration rate and serum albumin levels over the 6-month prelude period, and vascular access type at dialysis initiation.
Results
During a median follow-up of 2.0 (interquartile range, 1.1–3.2) years following dialysis initiation, a total of 9196 all-cause deaths occurred. Higher ALP levels were incrementally associated with higher all-cause, cardiovascular and infection-related mortality. Compared with patients in the lowest ALP quartile (<66.0 U/L), those in the highest quartile (≥111.1 U/L) had multivariable-adjusted hazard/subhazard ratios (95% confidence interval) of 1.42 (1.34–1.51), 1.43 (1.09–1.88) and 1.39 (1.09–1.78) for all-cause, cardiovascular and infection-related mortality, respectively. The associations remained consistent in various subgroups and after further adjustment for liver enzymes, serum phosphorus and intact parathyroid hormone levels.
Conclusions
Higher pre-ESRD serum ALP levels are independently associated with higher post-ESRD mortality risk. Further studies are warranted to determine if interventions that lower pre-ESRD ALP levels reduce mortality in incident dialysis patients.



Predicting albuminuria response to spironolactone treatment with urinary proteomics in patients with type 2 diabetes and hypertension

Sat, 07 Jan 2017 00:00:00 GMT

Abstract
Background
The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in patients with diabetes. Prior studies have shown large between-patient variability in albuminuria treatment response. We previously developed and validated a urinary proteomic classifier that predicts onset and progression of chronic kidney disease. Here, we tested whether the proteomic classifier based on 273 urinary peptides (CKD273) predicts albuminuria response to spironolactone treatment.
Methods
We performed a post hoc analysis in a double-blind randomized clinical trial with allocation to either spironolactone 12.5–50 mg/day (n = 57) or placebo (n = 54) for 16 weeks. Patients were diagnosed with type 2 diabetes and resistant hypertension. Treatment was an adjunct to renin–angiotensin system inhibition. Primary endpoint was the percentage change in urine albumin to creatinine ratio (UACR). Capillary electrophoresis mass spectrometry was used to quantify urinary peptides at baseline. The previously validated combination of 273 known urinary peptides was used as proteomic classifier.
Results
Spironolactone reduced UACR relative to placebo by 50%, although with a large between-patient variability in UACR response (5th to 95th percentile, 7 to 312%). An interaction was detected between CKD273 and treatment assignment (β = −1.09, P = 0.026). Higher values of CKD273 at baseline were associated with a larger reduction in UACR in the spironolactone group (β = −0.70, P = 0.049), but not in the placebo group (β = 0.39, P = 0.25). Stratified in tertiles of baseline CKD273, reduction in UACR was greater in the highest tertile, 63% (95% confidence interval: 35–79%), as compared with the two other tertiles combined, 16% (−17 to 40%) (P = 0.011).
Conclusions
A urinary proteomics classifier can be used to identify individuals with type 2 diabetes who are more likely to show an albuminuria-lowering response to spironolactone treatment. These results suggest that urinary proteomics may be a valuable tool to tailor therapy, but confirmation in a larger clinical trial is required.



Diagnosis, pathogenesis and outcome in leucocyte chemotactic factor 2 (ALECT2) amyloidosis

Thu, 10 Nov 2016 00:00:00 GMT

Abstract
Introduction
Renal biopsy series from North America suggest that leucocyte chemotactic factor 2 (ALECT2) amyloid is the third most common type of renal amyloid. We report the first case series from a European Centre of prevalence, clinical presentation and diagnostic findings in ALECT2 amyloidosis and report long-term patient and renal outcomes for the first time.
Methods
We studied the clinical features, diagnostic investigations and the outcome of all patients with ALECT2 amyloidosis followed systematically at the UK National Amyloidosis Centre (NAC) between 1994 and 2015.
Results
Twenty-four patients, all non-Caucasian, were diagnosed with ALECT2 amyloidosis representing 1.3% of all patients referred to the NAC with biopsy-proved renal amyloid. Diagnosis was made at median age of 62 years, usually from renal histology; immunohistochemical staining was definitive for ALECT2 fibril type. Median estimated glomerular filtration rate (GFR) at diagnosis was 33 mL/min/1.73 m2 and median proteinuria was 0.5 g/24 h. Hepatic amyloid was evident on serum amyloid P component (SAP) scintigraphy in 11/24 cases but was not associated with significant derangement of liver function. No patient had evidence of cardiac amyloidosis or amyloid neuropathy. Median follow-up was 4.8 (range 0.5–15.2) years, during which four patients died and four progressed to end-stage renal disease. The mean rate of GFR loss was 4.2 (range 0.5–9.6) mL/min/year and median estimated renal survival from diagnosis was 8.2 years. Serial SAP scans revealed little or no change in total body amyloid burden.
Conclusions
ALECT2 amyloidosis is a relatively benign type of renal amyloid, associated with a slow GFR decline, which is reliably diagnosed on renal histology. Neither the molecular basis nor the factors underlying the apparent restriction of ALECT2 amyloidosis to non-Caucasian populations have been determined.