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Increased albuminuria indicates underlying glomerular pathology and is associated with worse renal disease outcomes, especially in diabetic kidney disease. Many single nucleotide polymorphisms (SNPs), associated with albuminuria, could be potentially useful to construct polygenic risk scores (PRSs) for kidney disease. We investigated the diagnostic accuracy of SNPs, previously associated with albuminuria-related traits, on albuminuria and renal injury in the UK Biobank population, with a particular interest in diabetes. Multivariable logistic regression was used to evaluate the influence of 91 SNPs on urine albumin-to-creatinine ratio (UACR)-related traits and kidney damage (any pathology indicating renal injury), stratifying by diabetes. Weighted PRSs for microalbuminuria and UACR from previous studies were used to calculate the area under the receiver operating characteristic curve (AUROC). CUBN-rs1801239 and DDR1-rs116772905 were associated with all the UACR-derived phenotypes, in both the overall and non-diabetic cohorts, but not with kidney damage. Several SNPs demonstrated different effects in individuals with diabetes compared to those without. SNPs did not improve the AUROC over currently used clinical variables. Many SNPs are associated with UACR or renal injury, suggesting a role in kidney dysfunction, dependent on the presence of diabetes in some cases. However, individual SNPs or PRSs did not improve the diagnostic accuracy for albuminuria or renal injury compared to standard clinical variables.

Aims/hypothesis Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. Methods We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. Results The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR2) and DKD (microalbuminuria or worse) phenotype (p=9.8×10−9; although not withstanding correction for multiple testing, p>9.3×10−9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN–RESP18, GPR158, INIP–SNX30, LSM14A and MFF; p−6). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10−6). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p−11). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10−8] and negatively with tubulointerstitial fibrosis [p=2.0×10−9], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10−16], and SNX30 expression correlated positively with eGFR [p=5.8×10−14] and negatively with fibrosis [p−16]). Conclusions/interpretation Altogether, the results point to novel genes contributing to the pathogenesis of DKD. Data availability The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages (https://t1d.hugeamp.org/downloads.html; https://t2d.hugeamp.org/downloads.html; https://hugeamp.org/downloads.html). Graphical abstract

BackgroundDiabetes is the leading cause of kidney disease, and heritability studies demonstrate a substantial, yet poorly understood, contribution of genetics to kidney complications in people with diabetes.MethodsWe performed genome-wide association study (GWAS) meta-analyses using ten different phenotypic definitions of diabetic kidney disease (DKD), including nearly 27,000 individuals with diabetes, and integrated the results with various kidney omics datasets.ResultsThe meta-analysis identified a novel low frequency intronic variant (rs72831309) in the TENM2 gene encoding teneurin transmembrane protein 2 associated with a lower risk of the combined chronic kidney disease (CKD; eGFR2) and DKD (microalbuminuria or worse) phenotype (“CKD-DKD”, odds ratio 2.08, p=9.8×10−9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A, and MFF, p−6). Integration of GWAS data with human glomerular and tubular expression data in a transcriptome-wide association study demonstrated higher tubular AKIRIN2 gene expression in DKD versus non-DKD controls (p=1.1×10−6). The lead SNPs within the DCLK1, AKIRIN2, SNX30 and three other gene regions significantly alterated the methylation at this region in kidneys (p−11). Expression of target genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes. For example, tubular TENM2 expression positively correlated with eGFR (p=2.3×10−9) and negatively with tubulointerstitial fibrosis (p=4.7×10−9), tubular DCLK1 expression positively correlated with fibrosis (p=1.6×10−12), and SNX30 level positively correlated with eGFR (p=7.6×10−13) and negatively with fibrosis (p−16).ConclusionsGWAS meta-analysis and integration with renal omics data points to novel genes contributing to pathogenesis of DKD.

Inflammation is an essential response to injury and its timely and adequate resolution permits tissue repair and avoidance of chronic inflammation. Ageing is associated with increased inflammation, sub-optimal resolution and these act as drivers for a number of ageing-associated pathologies. We describe the role played by specialised proresolving lipid mediators (SPMs) in the resolution of inflammation and how insufficient levels of these mediators, or compromised responsiveness may play a role in the pathogenesis of many ageing-associated pathologies, e.g. Alzheimer's Disease, atherosclerosis, obesity, diabetes and kidney disease. Detailed examination of the resolution phase of inflammation highlights the potential to harness these lipid mediators and or mimetics of their bioactions, in particular, their synthetic analogues to promote effective resolution of inflammation, without compromising the host immune system.

High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ∼4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease.

Purpose of review Nephrology lacks effective therapeutics for many of the presentations and diseases seen in clinical practice. In recent decades, we have come to understand the central place of inflammation in initiating and propagating kidney disease, and, research in more recent years has established that the resolution of inflammation is a highly regulated and active process. With this, has evolved an appreciation that this aspect of the host inflammatory response is defective in kidney disease and led to consideration of a therapeutic paradigm aiming to harness the activity of the molecular drivers of the resolution phase of inflammation. Fatty-acid-derived Specialized pro-resolving mediators (SPMs), partly responsible for resolution of inflammation have gained traction as potential therapeutics. Recent findings We describe our current understanding of SPMs for this purpose in acute and chronic kidney disease. These studies cement the place of inflammation and its defective resolution in the pathogenesis of kidney disease, and highlight new avenues for therapy. Summary Targeting resolution of inflammation is a viable approach to treating kidney disease. We optimistically look forward to translating these experimental advances into tractable therapeutics to treat kidney disease.

Objective Vitamin D insufficiency is highly prevalent among renal transplant recipients and in observational studies is associated with adverse outcomes. Hypercalcemia, usually due to persistent hyperparathyroidism, also commonly occurs in this population and often coexists with vitamin D insufficiency. However, concern that vitamin D supplementation might exacerbate the pre-existing hypercalcemia often leads clinicians to avoid vitamin D supplementation in such patients. This feasibility study aimed to quantify the effect on serum calcium of short-term low-dose cholecalciferol supplementation in a group of renal transplant recipients with a recent history of serum calcium levels >10 mg/dL. Design A 2-week, single arm, open-label trial. Setting Renal transplant follow-up clinic in an Irish University Hospital. Subjects Eighteen vitamin D–insufficient adult patients with a functioning renal allograft (estimated glomerular filtration rate > 30 mL/minute/1.73 m2) and a recent history of serum calcium >10 mg/dL. Intervention Two weeks of treatment with 1,000 IU cholecalciferol/day. Main Outcome Measure Change in ionized calcium and urine calcium:creatinine ratio at follow-up compared with baseline. Results Mean (standard deviation [SD]) baseline 25 (OH) vitamin D (25 (OH) D) concentration was 15.9 (5.97) ng/mL and mean (SD) baseline serum calcium was 10.50 (0.6) mg/dL. Following the 2-week intervention, median (interquartile range [IQR]) change in serum calcium from baseline was −0.08 (−3.6 to 0.08) mg/dL, P = .3. Mean (SD) ionized calcium decreased from 5.24 (0.32) mg/dL at baseline to 5.16 (0.28) mg/dL, P = .05. Median (IQR) change in the urinary calcium:creatinine ratio was 0.001 (−0.026 to 0.299) mg/mg, P = .88. Median (IQR) change in 25 (OH) D was 3.6 (2.9-6.2) ng/mL, P Conclusions In vitamin D–insufficient renal transplant recipients at risk of hypercalcemia, low-dose short-term oral cholecalciferol supplementation improves 25 (OH) D concentrations without exacerbating hypercalcemia or increasing the urinary calcium:creatinine ratio.

BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain(COL4A3)gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD(BMP7)or renal biology (COLEC11andDDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

Background and objectives An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003–2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. Design, setting, participants, & measurements We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. Results Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster ( n =10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster ( n =7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. Conclusions To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.

Genetic factors have been implicated in the pathogenesis of certain cases of MPGN. Familial cases of all three histological subtypes have been described. Genetic defects in the control of complement pathways appear to be at the root of many hereditary forms of MPGN. Here we describe a series of three families with familial MPGN. We have identified 3 individuals with a diagnosis of idiopathic MPGN, each with a sibling with the same diagnosis. Data collected included age at presentation, histological findings and age at commencement of renal replacement therapy. A family pedigree was generated for each family as well as a description of the long-term clinical course and transplant outcomes of affected individuals. We have identified male and female affected individuals in this series of three families. The progression to end-stage kidney disease was universal amongst affected individuals. The majority of cases were successfully transplanted. Recurrence in a transplanted kidney occurred in only one individual. This series of familial MPGN provides further evidence for a genetic basis for the disease. Additional studies on these three families will further our knowledge of the underlying mutations in hereditary MPGN and contribute to the understanding of complement-mediated renal disease.

INTRODUCTION AND AIMS: Vitamin D insufficiency is highly prevalent amongst renal transplant recipients and in observational studies is associated with adverse outcomes. Hypercalcaemia, usually due to persistent hyperparathyroidism, also commonly occurs in this population and often coexists with vitamin D insufficiency. However, concern that Vitamin D supplementation might exacerbate the pre-existing hypercalcemia often leads clinicians to avoid Vitamin D supplementation in such patients. This feasibility study aimed to quantify the effect on serum calcium of short-term low dose cholecalciferol supplementation in a group of hypercalcemic renal transplant recipients. METHODS: We conducted a two-week, single arm, open-label, trial of 1000iu cholecalciferol supplementation daily in 18 hypercalcaemic, vitamin D insufficient adult patients with a functioning renal allograft (eGFR >30 30 ml/min/1.73m2). At baseline and following 2 weeks of treatment serum creatinine, eGFR, calcium, phosphorous, iPTH, albumin, 25- and 1,25-dihydroxycholecalciferol, fibroblast growth factor-23 (FGF23) and urinary calcium and creatinine were measured. Subjects were counseled to maintain their usual diet. Variables are summarized using their mean (sd) or median (Intra-Quartile Range [IQR]). Change over follow-up are examined using Wilcoxin signed ranks tests with a 2-sided type 1 error rate of 0.05. RESULTS: The mean age was 53(13) years and mean duration of transplantation was 7.6(4.8) years; 13(72%) of subjects were male. Baseline eGFR was 56(12) ml/min/1.73m2. All subjects were vitamin D insufficient (mean baseline 25-hydroxycholecalciferol level was 40.1(14.3) nmol/L); all had a baseline serum albumin >42 mmol/L and the mean (sd) serum calcium was 2.63(0.15) mmol/L. Mean (sd) iPTH was 127(72). PTH correlated with ionized calcium r=0.69, p=0.03. With supplementation the median rise in 25- and 1,25-hydroxycholecalciferol were 9.0 nmol/L, p

Hypertension is the most common medical disorder encountered during pregnancy, occurring in about 6-8 % of pregnancies. Preeclampsia is a pregnancy-specific disorder that occurs after 20 weeks' gestation, characterized by hypertension and proteinuria. Preeclampsia can also occur superimposed upon chronic hypertension. Eclampsia is the convulsive form of preeclampsia, and affects 0.1 % of all pregnancies. In low-income and middle-income countries, preeclampsia and eclampsia are associated with 10-15 % of direct maternal deaths. Women who develop preeclampsia in pregnancy are at greater risk of cardiovascular and cerebrovascular events even years after their pregnancies. There is significant progress in the elucidation of the underlying mechanisms and pathophysiology of preeclampsia, although its therapeutics remains challenging; delivery of the fetus is still the definitive treatment. Different international societies have produced recommendations and guidelines for clinicians treating preeclampsia, with an overall goal of improving maternal and fetal outcomes. In this review, we focus on the level of blood pressure at which to commence treatment and the current clinical management strategies available to treat and possibly prevent preeclampsia. We also briefly outline some newer perspectives on management of the disorder.

The role of local interactions in protein folding has recently been the subject of some controversy. Here we investigate an extension of Zwanzig's simple and general model of folding in which local and nonlocal interactions are represented by functions of single and multiple conformational degrees of freedom, respectively. The kinetics and thermodynamics of folding are studied for a series of energy functions in which the energy of the native structure is fixed, but the relative contributions of local and nonlocal interactions to this energy are varied over a broad range. For funnel shaped energy landscapes, we find that 1) the rate of folding increases, but the stability of the folded state decreases, as the contribution of local interactions to the energy of the native structure increases, and 2) the amount of native structure in the unfolded state and the transition state vary considerably with the local interaction strength. Simple exponential kinetics and a well-defined free energy barrier separating folded and unfolded states are observed when nonlocal interactions make an appreciable contribution to the energy of the native structure; in such cases a transition state theory type approximation yields reasonably accurate estimates of the folding rate. Bumps in the folding funnel near the native state, which could result from desolvation effects, side chain freezing, or the breaking of nonnative contacts, significantly alter the dependence of the folding rate on the local interaction strength: the rate of folding decreases when the local interaction strength is increased beyond a certain point. A survey of the distribution of strong contacts in the protein structure database suggests that evolutionary optimization has involved both kinetics and thermodynamics: strong contacts are enriched at both very short and very long sequence separations.