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Preview: Nephrology Dialysis Transplantation - current issue

Nephrology Dialysis Transplantation Current Issue





Published: Fri, 01 Dec 2017 00:00:00 GMT

Last Build Date: Fri, 08 Dec 2017 15:00:49 GMT

 



Announcements

Fri, 01 Dec 2017 00:00:00 GMT

News from ERA-EDTA:



Investigation and management of renal stone disease

Mon, 13 Nov 2017 00:00:00 GMT

Management of nephrolithiasis constitutes a small fraction of the training of most nephrologists, but when done well it can be highly satisfying and—even though the randomized controlled trial (RCT) evidence base is small—intellectually rewarding. The majority of patients who pass a kidney stone are not referred for metabolic evaluation, and that is the way it should be: although up to 75% of stone formers will have a recurrence within 25 years, 25 years is a long time to be restricting diet or taking tablets. So the patients who merit evaluation are those with early-onset or recurrent disease [1–3].



Composing a new song for trials: the Standardized Outcomes in Nephrology (SONG) initiative

Fri, 03 Nov 2017 00:00:00 GMT

Randomized trials provide the most reliable evidence about the safety and effectiveness of interventions to improve health care and patient outcomes. Unfortunately, the potential for trials to inform treatment decisions remains limited because the outcomes reported often do not resonate with what is directly meaningful and relevant to patients and their clinicians [1–3]. Further, inconsistent reporting of outcomes across trials prevents assessment of the comparative effect of interventions [4]. Outcome reporting bias, whereby authors cherry-pick the outcomes they report on the basis of favourable results, may also occur when there is not a standardized list of outcomes measured and reported [5, 6]. Collectively these problems may undermine the reliability of published trials, leading to inefficient use of scarce research and health care resources and unintended harm to patients [6].






Targeting new cellular disease pathways in autosomal dominant polycystic kidney disease

Wed, 25 Oct 2017 00:00:00 GMT

Nephrol Dial Transplant 2017 gfx262. doi: 10.1093/ndt/gfx262



Are there any relations among transplant centre volume, surgical technique and anatomy for donor graft selection? Ten-year multicentric Italian experience on mini-invasive living donor nephrectomy

Wed, 25 Oct 2017 00:00:00 GMT

Abstract
Background
Selection of the right or left living donor kidney for transplantation is influenced by many variables. In the present multi centric study including 21 Italian transplant centres, we evaluated whether centre volume or surgical technique may influence the selection process.
Methods
Intra- and perioperative donor data, donor kidney function, and recipient and graft survival were collected among 693 mini-invasive living donor nephrectomies performed from 2002 to 2014. Centre volume (LOW, 1–50 cases; HIGH, >50 cases) and surgical technique (FULL-LAP, full laparoscopic and robotic; HA-LAP, hand-assisted laparoscopy; MINI-OPEN, mini-lumbotomy) were correlated with selection of right or left donor kidney and with donor and recipient outcome.
Results
HIGH-volume centres retrieved a higher rate of donor right kidneys (29.3% versus 17.6%, P < 0.01) with single artery (83.1% versus 76.4%, P < 0.05) compared with LOW-volume centres. Surgical technique correlated significantly with rate of donor right kidney and presence of multiple arteries: MINI-OPEN (53% and 13%) versus HA-LAP (29% and 22%) versus FULL-LAP (11% and 23%), P < 0.001 and P < 0.05, respectively. All donors had an uneventful outcome; donor bleeding was more frequent in LOW-volume centres (4% versus 0.9%, P < 0.05).
Conclusions
Centre volume and surgical technique influenced donor kidney side selection. Donor nephrectomy in LOW-volume centres was associated with higher risk of donor bleeding.



White blood cell fractions correlate with lesions of diabetic kidney disease and predict loss of kidney function in Type 2 diabetes

Mon, 23 Oct 2017 00:00:00 GMT

Kevin M. Wheelock, Pierre-Jean Saulnier, Stephanie K. Tanamas, Pavithra Vijayakumar, E. Jennifer Weil, Helen C. Looker, Robert L. Hanson, Kevin V. Lemley, Berne Yee, William C. Knowler, Samy Hadjadj, Behzad Najafian, Michael Mauer and Robert G. Nelson; White blood cell fractions correlate with lesions of diabetic kidney disease and predict loss of kidney function in Type 2 diabetes. Nephrol Dial Transplant 2017 gfx231. doi: 10.1093/ndt/gfx231



T-cadherin gene variants are associated with nephropathy in subjects with type 1 diabetes

Wed, 18 Oct 2017 00:00:00 GMT

Nephrol Dialy Transplant, gfx071. doi: 10.1093/ndt/gfx071



Kidney injury molecule-1 staining in renal allograft biopsies 10 days after transplantation is inversely correlated with functioning proximal tubular epithelial cells

Mon, 16 Oct 2017 00:00:00 GMT

Abstract
Background
Kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are promising biomarkers for monitoring delayed graft function (DGF) after kidney transplantation. Here we investigated localization and distribution of KIM-1 and NGAL staining in renal allograft biopsies and studied their association with histological features, functional DGF (fDGF) and the tubular function slope (TFS), a functioning proximal tubular epithelial cell (PTEC) marker.
Methods
Day 10 protocol biopsies of 64 donation after circulatory death recipients were stained for KIM-1 and NGAL and the positive area was quantified using ImageJ software. Biopsies were scored according to Banff and acute tubular necrosis (ATN) criteria. A 99mtechnetium-mercaptoacetyltriglycine (99mTc-MAG3)-renography was performed to calculate TFS.
Results
KIM-1 staining was located on the brush border of tubular epithelial cells (TECs) and correlated with denudation, while NGAL was present more focally in a cytoplasmic distribution. KIM-1 and NGAL staining were not correlated and no co-localization was observed. Quantitative stainings were not associated with fDGF, but KIM-1 tended to be higher in patients with prolonged fDGF (≥21 days; P = 0.062). No correlation was observed between the quantitative tissue stainings and urinary KIM-1 or NGAL. Quantitative KIM-1 staining was inversely correlated with the TFS (Spearman’s ρ = −0.53; P < 0.001), whereas NGAL was not. The latter finding might be because cortical NGAL staining is dependent on filtration and subsequent reabsorption by functioning PTECs. Staining of NGAL was indeed restricted to PTECs, as shown by co-localization with a PTEC-specific lectin.
Conclusions
KIM-1 and NGAL staining showed different localization and distribution. Quantitative KIM-1 staining was inversely correlated with functioning PTECs.



p-Cresyl glucuronide is a major metabolite of p-cresol in mouse: in contrast to p-cresyl sulphate, p-cresyl glucuronide fails to promote insulin resistance

Thu, 03 Aug 2017 00:00:00 GMT

Abstract
Background
The role of uraemic toxins in insulin resistance associated with chronic kidney disease (CKD) is gaining interest. p-Cresol has been defined as the intestinally generated precursor of the prototype protein-bound uraemic toxins p-cresyl sulphate (p-CS) as the main metabolite and, at a markedly lower concentration in humans, p-cresyl glucuronide (p-CG). The objective of the present study was to evaluate the metabolism of p-cresol in mice and to decipher the potential role of both conjugates of p-cresol on glucose metabolism.
Methods
p-CS and p-CG were measured by high performance liquid chromatography-fluorescence in serum from control, 5/6 nephrectomized mice and mice injected intraperitoneously with either p-cresol or p-CG. The insulin sensitivity in vivo was estimated by insulin tolerance test. The insulin pathway in the presence of p-cresol, p-CG and/or p-CS was further evaluated in vitro on C2C12 muscle cells by measuring insulin-stimulated glucose uptake and the insulin signalling pathway (protein kinase B, PKB/Akt) by western blot.
Results
In contrast to in humans, where p-CS is the main metabolite of p-cresol, in CKD mice both conjugates accumulated, and after chronic p-cresol administration with equivalent concentrations but a substantial difference in protein binding (96% for p-CS and <6% for p-CG). p-CG exhibited no effect on insulin sensitivity in vivo or in vitro and no synergistic inhibiting effect in combination with p-CS.
Conclusions
The relative proportion of the two p-cresol conjugates, i.e. p-CS and p-CG, is similar in mouse, in contrast to humans, pinpointing major inter-species differences in endogenous metabolism. Biologically, the sulpho- (i.e. p-CS) but not the glucuro- (i.e. p-CG) conjugate promotes insulin resistance in CKD.



Heterozygosity of mitogen-activated protein kinase organizer 1 ameliorates diabetic nephropathy and suppresses epithelial-to-mesenchymal transition-like changes in db/db mice

Wed, 12 Jul 2017 00:00:00 GMT

Abstract
Background
Progressive diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis that is caused by accumulation of extracellular matrix. Induced by several factors, matrix-producing myofibroblasts may to some extent originate from tubular cells by epithelial-to-mesenchymal transition (EMT). Although previous data document that activation of hypoxia-inducible factor (HIF) signalling can be renoprotective in acute kidney disease, this issue remains controversial in chronic kidney injury. Here, we studied whether DN and EMT-like changes are ameliorated in a mouse model of type 2 diabetes mellitus with increased stability and activity of the HIF.
Methods
We used db/db mice that were crossed with transgenic mice expressing reduced levels of mitogen-activated protein kinase organizer 1 (MORG1), a scaffold protein interacting with prolyl hydroxylase domain 3 (PHD3), because of deletion of one MORG1 allele.
Results
We found significantly reduced nephropathy in diabetic MORG1+/− heterozygous mice compared with the diabetic wild-types (db/dbXMORG1+/+). Furthermore, we demonstrated that EMT-like changes in the tubulointerstitium of diabetic wild-type MORG1+/+ mice are present, whereas diabetic mice with reduced expression of MORG1 showed significantly fewer EMT-like changes.
Conclusions
These findings reveal that a deletion of one MORG1 allele inhibits the development of DN in db/db mice. The data suggest that the diminished interstitial fibrosis in these mice is a likely consequence of suppressed EMT-like changes.



A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion

Sat, 10 Jun 2017 00:00:00 GMT

Abstract
Heterozygous mutations in UMOD encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous UMOD mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low levels of uromodulin and aberrant uromodulin fragments in the urine of the homozygote proband. Despite an amplified biological effect of the homozygote mutation, the proband did not show a strikingly more severe clinical evolution nor was the near absence of urinary uromodulin associated with urinary tract infections or kidney stones.



Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein

Thu, 01 Jun 2017 00:00:00 GMT

Abstract
Background
Medullary cystic kidney disease Type 1 is an autosomal dominant tubulointerstitial kidney disease (ADTKD). Recently, mucin 1 (MUC1) was identified as a causal gene of medullary cystic kidney disease (ADTKD-MUC1). However, the MUC1 mutation was found to be a single cytosine insertion in a single copy of the GC-rich variable number of tandem repeats (VNTRs), which are very difficult to analyze by next-generation sequencing. To date, other mutations have not been detected in ADTKD-MUC1, and the mutant MUC1 protein has not been analyzed because of the difficulty of genetically modifying the VNTR sequence.
Methods
We conducted whole-exome analyses of an ADTKD family by next-generation sequencing. We also performed histopathological analyses of a renal biopsy from a pedigree family member. We constructed a mutant protein expression vector based on the patient genome sequence and characterized the nature of the mutant protein.
Results
We found a novel frameshift mutation before the VNTR in the MUC1 gene. The resulting mutant MUC1 protein had a very similar amino acid sequence and predicted 3D structure to the previously reported mutant protein. Notably, the recombinant mutant MUC1 protein was trapped in the cytoplasm and appeared to self-aggregate. The patient native mutant protein was also found in urine exosomes.
Conclusions
This novel frameshift mutation in the MUC1 gene and consequent mutant protein may contribute to the future discovery of the pathophysiology of ADTKD-MUC1. The mutant MUC1 protein in urine exosomes may be used for non-DNA-related diagnosis.



Chronic respiratory disease: an unrecognized risk factor in dialysis

Tue, 30 May 2017 00:00:00 GMT

Abstract
Background
Few studies have analysed the impact of chronic respiratory disease (CRD) on outcomes in dialysis. We therefore sought to describe patients with CRD and end-stage renal disease and their outcomes after dialysis start, compared with patients without CRD, focusing especially on causes of death, access to renal transplantation and causes of hospital admissions.
Methods
The study included 52 797 adults aged 18 years and older who began dialysis from 2008 to 2013 and are recorded in the French national REIN registry. Survival, specific mortality and access to the waiting list and to renal transplantation were analysed, with adjustment for various comorbidities and consideration of competitive risks. The numbers of hospitalizations and hospital days, together with their causes, were analysed through an indirect link between the REIN database and the national French hospital discharge database.
Results
The frequency of CRD at dialysis start was 12% and was associated with various other comorbidities, including obesity and tobacco use. After adjustment for those comorbidities, CRD remained associated with a higher risk of death [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.16–1.25]. Patients with CRD were 30% less likely to undergo transplantation (HR 0.67, 95% CI 0.6–0.7) than patients without CRD. Their risk of dying from a respiratory disease was 8.8 times higher; their risk of dying from infection was also higher. Patients with CRD had a higher rate of admissions and more hospital days, for all causes and for every cause, except cancer.
Conclusions
CRD was associated with higher risks of death and hospital admissions and with lower likelihoods of being wait-listed for and undergoing renal transplantation. Increasing clinical awareness by patients and doctors and encouragement of spirometry use should promote more accurate clinical diagnosis and better preventive care for CRD.



T-cadherin gene variants are associated with nephropathy in subjects with type 1 diabetes

Fri, 12 May 2017 00:00:00 GMT

Abstract
Background
High plasma adiponectin levels are associated with diabetic nephropathy (DN). T-cadherin gene (CDH13) variants have been shown to be associated with adiponectin levels. We investigated associations between allelic variations of CDH13 and DN in subjects with type 1 diabetes.
Methods
Two CDH13 polymorphisms were analysed in 1297 Caucasian subjects with type 1 diabetes from the ‘Survival Genetic Nephropathy’ (SURGENE) (n = 340, 10-year follow-up), ‘Genesis France–Belgium’ (GENESIS) (n = 501, 5-year follow-up for n = 462) and ‘Génétique de la Néphropathie Diabétique’ (GENEDIAB) (n = 456, 9-year follow-up for n = 283) cohorts. Adiponectin levels were measured in plasma samples from GENESIS and GENEDIAB cohorts.
Results
Pooled analysis of GENEDIAB and GENESIS studies showed that baseline plasma adiponectin levels were higher in subjects with established/advanced DN at inclusion (P < 0.0001) and in subjects who developed end-stage renal disease (ESRD) at follow-up (P < 0.0001). The minor allele of rs3865188 was associated with lower adiponectin levels (P = 0.006). rs11646213 [odds ratio (OR) 1.47; 95% confidence interval (CI) 1.18–1.85; P = 0.0009] and rs3865188 (OR 0.71; 95% CI 0.57–0.90; P = 0.004) were associated with baseline prevalence of established/advanced DN. These polymorphisms were also associated with the risk of ESRD (0.006 < P < 0.03). The association between rs11646213 (but not rs3865188) and renal function remained significant after adjustment for plasma adiponectin. In SURGENE, rs11646213 [hazard ratio (HR) 1.69; 95% CI 1.01–2.71; P = 0.04] and rs3865188 (HR 0.74; 95% CI 0.55–0.99; P = 0.04) were associated with risk of renal events (defined as progression to more severe DN stages).
Conclusions
Plasma adiponectin levels are associated with the prevalence of DN and the incidence of ESRD in patients with type 1 diabetes. CDH13 polymorphisms are also associated with the prevalence and incidence of DN, and with the incidence of ESRD in these patients. The association between CDH13 and DN may be due to pleiotropic effects, both dependent and independent of plasma adiponectin levels.



Hyperkalaemia prevalence, recurrence and management in chronic haemodialysis: a prospective multicentre French regional registry 2-year survey

Fri, 28 Apr 2017 00:00:00 GMT

Abstract
Background
Observational studies have reported increased mortality rates in hyperkalaemic or hypokalaemic chronic haemodialysis patients. This study assessed the prevalence and recurrence of hyperkalaemia (HK) along with the concomitant prescription of low-potassium (K) dialysis baths and of K-binding agents in a registry within a French regional disease management programme.
Methods
This was a prospective multicentre (14 chronic haemodialysis centres, Lorraine Region) study encompassing 527 chronic haemodialysis patients followed from 2 January 2014 to 31 December 2015. Predialysis serum K (14 734) measurements, dialysis bath K concentrations and concomitant K binder prescriptions were collected with an electronic health record system.
Results
At baseline, 26.4%, 13.8% and 4.9% of patients were hyperkalaemic (i.e. K >5.1, 5.5 or 6 mmol/L, respectively) and 12.5%, 1.9% and 0.4% were hypokalaemic (i.e. K<4, 3.5 or 3 mmol/L, respectively). A total of 61% of patients were prescribed a K-binding resin [essentially sodium polystyrene sulfonate (SPS)], while 2 mmol/L and 3 mmol/L K concentration baths were used relatively equally. Over time, the proportion of patients being prescribed any K-binding agent increased up to 78%. The percentage of patients experiencing HK at any time was 73.8% (HK >5.1 mmol/L), 57.9% (HK >5.5 mmol/L) and 34.5% (HK >6 mmol/L). Only 6.3% of patients became normokalaemic within 3 months after an HK >5.5 mmol/L despite dynamic management of K baths and K binders (i.e. increased prescription of 2 mmol/L K baths and increased SPS doses).
Conclusions
HK was found to be highly prevalent and recurrent in this regional registry despite the widespread and dynamic prescription of low-K dialysis baths and K binders. More effective potassium mitigating strategies are eagerly warranted.



The quest for equilibrium: exploring the thin red line between bleeding and ischaemic risks in the management of acute coronary syndromes in chronic kidney disease patients

Mon, 27 Mar 2017 00:00:00 GMT

Abstract
Coronary artery disease and acute coronary syndrome (ACS) are both common in patients with chronic kidney disease (CKD). CKD patients have higher risks of bleeding and thrombosis. However, they remain under-represented in major randomized clinical trials (RCTs), and there is no medical evidence-based foundation on which to issue specific recommendations about the management of ACS in CKD. CKD patients with ACS frequently are diagnosed later, receive fewer acute interventions and are at increased risk of over-dosage of medications and under-prescription/under-performance of interventional treatments than CKD patients without ACS. The lack of RCTs should not discourage reliance on clinical common sense, while clearer decisional algorithms with better outcomes are a priority for urgent development. Future guidelines should further refine the assessment of CKD with ACS while placing much greater emphasis on the correct dosing of medications based on contemporaneous renal function. Until a strategy is designed with specific measures translated into the actual decrease of bleeding risk, providers will be forced to balance the equilibrium on a thin red line that is not clearly established.



Urinary tract infection: recent insight into the evolutionary arms race between uropathogenic Escherichia coli and our immune system

Wed, 15 Mar 2017 00:00:00 GMT

Abstract
Urinary tract infections (UTIs) are among the most common bacterial infections worldwide. Humans evolved various immune-dependent and independent defense mechanisms, while pathogens evolved multiple virulence factors to fight back. This article summarizes recent findings regarding the arms race between hosts and pathogens in UTIs. It was recently reported that macrophage subsets regulate neutrophil-mediated defense in primary UTIs but seem to subvert adaptive immunity upon re-infection. Moreover, some bacterial strains can survive inside macrophages, leading to recurrent infections. Inflammasome activation results in infected host cell death and pathogen release, facilitating the removal of intracellular bacteria. As a counteraction, some bacteria evolved mechanisms to disrupt inflammasome activation. Mucosal-associated invariant T cells are further effectors that can lyse infected epithelial cells and release intracellular bacteria. Once released, the bacteria are phagocytosed by neutrophils. However, some bacteria can inhibit neutrophil migration and deprive neutrophils of nutrients. Furthermore, the complement system, considered generally bactericidal, is exploited by the bacteria for cellular invasion. Another weapon against UTI is antimicrobial peptides, e.g. ribonuclease 7, but its production is inhibited by certain bacterial strains. Thus the arms race in UTI is ongoing, and knowing the enemy’s methods can help in developing new drugs to win the race.



Sofosbuvir-based antiviral therapy in hepatitis C virus patients with severe renal failure

Wed, 19 Oct 2016 00:00:00 GMT

Abstract
Background
Chronic hepatitis C virus (HCV) infection is the most common chronic liver disease in patients with end-stage renal disease (ESRD). Over the last few years, second-generation direct-acting antivirals have been revolutionary in the treatment of hepatitis C, and sofosbuvir (SOF) is the backbone of most modern treatment strategies. Since SOF is eliminated through the kidney, the aim of this multicentre retrospective study was to assess its antiviral efficacy and safety in HCV-infected patients with severe renal failure [including haemodialysis (HD) patients].
Methods
Fifty patients (36 males, mean age ± standard deviation 60.5 ± 7.5 years) with chronic HCV infection (G1: 28/56%, cirrhosis: 27/54%) and severe renal failure [i.e. MDRD estimated glomerular filtration rate (eGFR) <35 mL/min], including 35 on HD, were enrolled. Antiviral treatment consisted of SOF/ribavirin (RBV) (n = 7), SOF/RBV/pegylated interferon (n = 2), SOF/daclatasvir ± RBV (n = 30) or SOF/simeprevir ± RBV (n = 11) for 12 or 24 weeks. A reduced dose of SOF (400 mg three times a week or 400 mg every other day) was given to all HD patients. Initial dose of RBV (n = 12) ranged from 400 to 4200 mg/week.
Results
On an intent-to-treat-based analysis, sustained virological response rate was 86% at 12 weeks. During therapy, haemoglobin levels were not significantly modified, but recombinant erythropoietin (rEPO) dose significantly increased in patients treated with RBV. Two patients (4%) required blood transfusion. No patient had treatment discontinuation due to side effects. Dose of RBV was reduced in two patients (16.7%) during antiviral therapy. Dose of SOF was reduced in two non-HD patients because of side effects. In non-HD patients, median eGFR was not significantly modified during treatment.
Conclusions
Our results strongly suggest that SOF-based antiviral therapy, with a reduced dose of SOF, is safe and effective for the treatment of HCV patients with ESRD, including HD patients.



Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging

Mon, 17 Oct 2016 00:00:00 GMT

Abstract
Background
Determinations of renal oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in chronic kidney disease (CKD) patients have given heterogeneous results, possibly due to the lack of a reproducible method to analyse BOLD-MRI. It therefore remains uncertain whether patients with CKD have a reduced renal tissue oxygenation. We developed a new method to analyse BOLD-MRI signals and applied it to CKD patients and controls.
Methods
MRI was performed under standardized conditions before and 15 min after IV furosemide in 104 CKD patients, 61 hypertensives and 42 controls. MR images were analysed with the new twelve-layer concentric objects method (TLCO) that divides renal parenchyma in 12 layers of equal thickness. The mean R2* value of each layer was reported, along with the change in R2* between successive layers, as measured by the slope steepness of the relevant curve.
Results
Inter-observer variability was 2.3 ± 0.9%, 1.9 ± 0.8% and 3.0 ± 2.3% in, respectively, controls, moderate and severe CKD. The mean R2* of the outer (more cortical) layers was significantly higher in CKD, suggesting lower cortical oxygenation as compared with controls. In CKD patients, the response to furosemide was blunted in the inner (more medullary) layers, and the R2* slope was flatter. In multivariable regression analysis, the R2* slope correlated positively with estimated glomerular filtration rate (eGFR) in patients with an eGFR <90 mL/min/1.73 m2 (P < 0.001).
Conclusions
Using the new TLCO method, we confirm the hypothesis that renal cortical oxygenation is reduced in CKD in humans, and that the level of cortical oxygenation correlates with CKD severity.



Noninvasive diagnosis of chronic kidney diseases using urinary proteome analysis

Thu, 06 Oct 2016 00:00:00 GMT

Abstract
Background
In spite of its invasive nature and risks, kidney biopsy is currently required for precise diagnosis of many chronic kidney diseases (CKDs). Here, we explored the hypothesis that analysis of the urinary proteome can discriminate different types of CKD irrespective of the underlying mechanism of disease.
Methods
We used data from the proteome analyses of 1180 urine samples from patients with different types of CKD, generated by capillary electrophoresis coupled to mass spectrometry. A set of 706 samples served as the discovery cohort, and 474 samples were used for independent validation. For each CKD type, peptide biomarkers were defined using statistical analysis adjusted for multiple testing. Potential biomarkers of statistical significance were combined in support vector machine (SVM)-based classifiers.
Results
For seven different types of CKD, several potential urinary biomarker peptides (ranging from 116 to 619 peptides) were defined and combined into SVM-based classifiers specific for each CKD. These classifiers were validated in an independent cohort and showed good to excellent accuracy for discrimination of one CKD type from the others (area under the receiver operating characteristic curve ranged from 0.77 to 0.95). Sequence analysis of the biomarkers provided further information that may clarify the underlying pathophysiology.
Conclusions
Our data indicate that urinary proteome analysis has the potential to identify various types of CKD defined by pathological assessment of renal biopsies and current clinical practice in general. Moreover, these approaches may provide information to model molecular changes per CKD.



Comprehensive microbiome analysis of tonsillar crypts in IgA nephropathy

Wed, 28 Sep 2016 00:00:00 GMT

Abstract
Background
Immunoglobulin A nephropathy (IgAN) is the most prevalent primary chronic glomerular disease, in which the mucosal immune response elicited particularly in the tonsils or intestine has been estimated to be involved in the development of the disease. To explore the relationship between IgAN and bacterial flora in the tonsils, we conducted a comprehensive microbiome analysis.
Methods
We enrolled 48 IgAN patients, 21 recurrent tonsillitis (RT) patients without urine abnormalities and 30 children with tonsillar hyperplasia (TH) who had undergone tonsillectomy previously. Genomic DNA from tonsillar crypts of each patient was extracted, and V4 regions of the 16S ribosomal RNA gene were amplified and analysed using a high-throughput multiplexed sequencing approach. Differences in genus composition among the three study groups were statistically analysed by permutational multivariate analysis of variance and visualized by principal component analysis (PCA).
Results
Substantial diversity in bacterial composition was detected in each sample. Prevotella spp., Fusobacterium spp., Sphingomonas spp. and Treponema spp. were predominant in IgAN patients. The percentage of abundance of Prevotella spp., Haemophilus spp., Porphyromonas spp. and Treponema spp. in IgAN patients was significantly different from that in TH patients. However, there was no significant difference in the percentage of abundance of any bacterial genus between IgAN and RT patients. PCA did not distinguish IgAN from RT, although it discriminated TH. No significant differences in microbiome composition among the groups of IgAN patients according to clinicopathological parameters were observed.
Conclusions
Similar patterns of bacteria are present in tonsillar crypts of both IgAN and RT patients, suggesting that the host response to these bacteria might be important in the development of IgAN.



Renal function predicts long-term outcome on enzyme replacement therapy in patients with Fabry disease

Tue, 27 Sep 2016 00:00:00 GMT

Abstract
Background
Renal and cardiac involvement is responsible for substantial morbidity and mortality in Fabry disease (FD). We analysed the incidence of FD-related renal, cardiac and neurologic end points in patients with FD on long-term enzyme replacement therapy (ERT).
Methods
A retrospective analysis of prospectively collected data from two German FD centres was performed. The impact of renal and cardiac function at ERT-naïve baseline on end point development despite ERT was analysed.
Results
Fifty-four patients (28 females) receiving ERT (mean 81 ± 21 months) were investigated. Forty per cent of patients were diagnosed with clinical end points before ERT initiation and 50% of patients on ERT developed new clinical end points. In patients initially diagnosed with an end point before ERT initiation, the risk for an additional end point on ERT was increased {hazard ratio [HR] 3.83 [95% confidence interval (CI) 1.61–9.08]; P = 0.0023}. A decreased glomerular filtration rate (eGFR) ≤75 mL/min/1.73 m2 in ERT-naïve patients at baseline was associated with an increased risk for cardiovascular end points [HR 3.59 (95% CI 1.15–11.18); P = 0.0273] as well as for combined renal, cardiac and neurologic end points on ERT [HR 4.77 (95% CI 1.93–11.81); P = 0.0007]. In patients with normal kidney function, left ventricular hypertrophy at baseline predicted a decreased end point–free survival [HR 6.90 (95% CI 2.04–23.27); P = 0.0018]. The risk to develop an end point was independent of sex.
Conclusions
In addition to age, even moderately impaired renal function determines FD progression on ERT. In patients with FD, renal and cardiac protection is warranted to prevent patients from deleterious manifestations of the disease.



Health-related quality of life across all stages of autosomal dominant polycystic kidney disease

Fri, 23 Sep 2016 00:00:00 GMT

Abstract
Background
A limited number of studies have assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease (ADPKD). Results to date have been conflicting and studies have generally focused on patients with later stages of the disease. This study aimed to assess HRQoL in ADPKD across all stages of the disease, from patients with early chronic kidney disease (CKD) to patients with end-stage renal disease.
Methods
A study involving cross-sectional patient-reported outcomes and retrospective clinical data was undertaken April–December 2014 in Denmark, Finland, Norway and Sweden. Patients were enrolled into four mutually exclusive stages of the disease: CKD stages 1–3; CKD stages 4–5; transplant recipients; and dialysis patients.
Results
Overall HRQoL was generally highest in patients with CKD stages 1–3, followed by transplant recipients, patients with CKD stages 4–5 and patients on dialysis. Progressive disease predominately had an impact on physical health, whereas mental health showed less variation between stages of the disease. A substantial loss in quality of life was observed as patients progressed to CKD stages 4–5.
Conclusions
Later stages of ADPKD are associated with reduced physical health. The value of early treatment interventions that can delay progression of the disease should be considered.



Albuminuria and masked uncontrolled hypertension in chronic kidney disease

Tue, 20 Sep 2016 00:00:00 GMT

Abstract
Background
Masked uncontrolled hypertension (MUCH) is associated with greater target organ damage such as left ventricular hypertrophy, increased arterial stiffness and albuminuria. Whether MUCH independently associates with greater cardiovascular end-organ damage or kidney damage is unclear. The objective of this study was to assess the strength of the relationship of MUCH (awake ambulatory blood pressure ≥135/85 mmHg and clinic blood pressure <140/90 mmHg) with target organ damage.
Methods
In a cross-sectional study at a veterans' administration medical center, clinically normotensive veterans without chronic kidney disease (CKD) (n = 29) and 287 patients with CKD and controlled hypertension (CH, n = 193), MUCH (n = 67) and uncontrolled hypertension (UCH, n = 27) had evaluation of target organ damage. Target organ damage was measured by echocardiography [left ventricular mass index (LVMI)], arterial ultrasonography [aortic pulse wave velocity (PWV)] and 24-h urine collection [albuminuria (urine albumin to creatinine ratio)] in all participants.
Results
Compared to that of controls, LVMI was higher by 21.8 g/m2 (CI, 4.0–39.7 g/m2) in CH, 27.9 (CI, 8–47.8) in MUCH and 39.5 (CI, 15.7–63.2) in UCH (P < 0.01 for group differences, P < 0.01 for linear trend). Although differences persisted after adjustment for age, sex and race, they lost significance after adjustments for cardiovascular risk factors and their treatment. Compared to that of controls, PWV was different among CH, MUCH and UCH (P = 0.04 for group differences, P = 0.02 for linear trend). However, differences lost significance after adjustments for age, sex and race. Compared to that of controls, log2 UACR was higher by 2.40 mg/mg (CI, 1.28–3.52) in CH, 4.94 (CI, 3.70–6.18) in MUCH and 6.01 (CI, 4.49–7.53) in UCH (P < 0.0001 for group difference, P < 0.0001 for linear trend). Differences persisted after adjustment for age, sex and race, cardiovascular risk factors and their treatment and cardiovascular disease (P < 0.0001 for group difference, P < 0.0001 for linear trend).
Conclusions
MUCH is more strongly related to albuminuria compared with cardiovascular damage as assessed by left ventricular mass and PWV. A graded and an independent relationship of blood pressure classification status with albuminuria is consistent with the hypothesis that renal mechanisms may be more important than cardiovascular disease in mediating the pathogenesis of MUCH.



Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III—rationale, trial design and baseline data

Sat, 17 Sep 2016 00:00:00 GMT

Abstract
Background
Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis.
Methods
UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin–angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD.
Results
Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol.
Conclusions
UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD.



Prevalence, incidence and prognosis of chronic kidney disease classified according to current guidelines: a large retrospective cohort study of rheumatoid arthritis patients

Fri, 16 Sep 2016 00:00:00 GMT

Abstract
Background
The prevalence, incidence and prognosis of chronic kidney disease (CKD) have not been fully understood in rheumatoid arthritis (RA) patients.
Methods
A retrospective cohort study was performed in 1077 RA patients from July 2004 to June 2014. CKD was defined as either proteinuria ≥1+ or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or both, according to the current CKD classification with risk categories for future death, end-stage renal disease and cardiovascular disease. The cumulative incidence of mortality and CKD was analyzed using the Kaplan–Meier method. The association of each outcome with known risk factors was analyzed using multivariate Cox proportional hazards regression models. Hazard ratios (HRs) with 95% confidence intervals (CIs) for mortality and incidence of CKD were calculated for estimation.
Results
The mean follow-up period was 51.5 ± 39.6 months, and the cumulative mortality was 20.6% over 10 years. The prevalence of any CKD was 24.5% at enrollment. Preexisting CKD was significantly associated with future death [HR 1.64 (95% CI 1.05–2.57)]. This association was the most robust in very-high-risk CKD [HR 4.76 (95% CI 2.24–9.51)]. The cumulative incidence of CKD over time was 59.5% in 813 patients who did not have prior CKD. Aside from the commonly known risk factors, the use of prednisolone and nonsteroidal anti-inflammatory drugs increased the likelihood of death [HR 1.75 (95% CI 1.11–2.79)] and incident CKD [HR 1.44 (95% CI 1.13–1.86)].
Conclusions
The incidence of CKD increases over time among RA patients and prevalent CKD may be an insidious risk factor linked to increased mortality in RA patients.



An investigation of APOL1 risk genotypes and preterm birth in African American population cohorts

Fri, 16 Sep 2016 00:00:00 GMT

Abstract
Background
Two genetic variants in apolipoprotein L1 (APOL1) are associated with increased risk of focal segmental glomerulosclerosis as well as other glomerular phenotypes. These risk variants are common in individuals of African ancestry but absent in other racial groups. Yet, the majority of individuals with two APOL1 risk alleles [high-risk (HR) genotype] do not have renal disease. It is critical to identify environmental and secondary genetic influences that, when combined with these alleles, lead to kidney disease. In a recent study of black children with glomerular disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) and Chronic Kidney Disease in Children Study (n = 104), we found that subjects with an HR genotype had a 4.6-fold increase in the odds of preterm birth as compared to those with a low risk (LR) genotype [odds ratio 4.6 (CI 1.4–15.5)]. There are known racial disparities in preterm birth, which itself is a known risk factor for chronic kidney disease and focal segmental glomerulosclerosis. Thus, we questioned whether an HR APOL1 genotype is associated with prematurity in the general African American population.
Methods
We analyzed two publically available genetic datasets of preterm birth in African Americans, including 867 infants and 519 mothers from the Gene Environment Association Studies (GENEVA) study of preterm delivery and 960 mothers from the Boston Medical Center genome-wide association study of preterm birth. We performed multivariable analyses testing for association between HR APOL1 and birth outcomes.
Results
In both studies, there was no association between HR APOL1 in mothers and prematurity, gestational age or birthweight. Additionally, in the GENEVA study, we saw no association between infant HR APOL1 and prematurity, gestational age or birthweight.
Conclusion
From these data, we conclude that the previously observed association between HR APOL1 and prematurity is specific to those with glomerular disease, suggesting prematurity may act as an additional risk factor in APOL1-associated renal disease.