Genetic variants affecting mitochondrial function provide further insights for kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. METHODS: We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. RESULTS: Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. CONCLUSIONS: We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM).

SIGNIFICANCE STATEMENT: Mesenchymal stromal cells (MSCs) may offer a novel therapy for diabetic kidney disease (DKD), although clinical translation of this approach has been limited. The authors present findings from the first, lowest dose cohort of 16 adults with type 2 diabetes and progressive DKD participating in a randomized, placebo-controlled, dose-escalation phase 1b/2a trial of next-generation bone marrow-derived, anti-CD362 antibody-selected allogeneic MSCs (ORBCEL-M). A single intravenous (iv) infusion of 80×10 6 cells was safe and well-tolerated, with one quickly resolved infusion reaction in the placebo group and no subsequent treatment-related serious adverse events (SAEs). Compared with placebo, the median annual rate of decline in eGFR was significantly lower with ORBCEL-M, although mGFR did not differ. The results support further investigation of ORBCEL-M in this patient population in an appropriately sized phase 2b study. BACKGROUND: Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited. METHODS: The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months. RESULTS: At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo. CONCLUSIONS: Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrial.gov NCT02585622 .

Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank.

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.

Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease.

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 (eGFR<60 ml/min per 1.73 m2) 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<2.7×10-6). 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<1.5×10-11). 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<2.0×10-16]). 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 ).

Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection.

BACKGROUND: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection. METHODS: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses. RESULTS: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses. CONCLUSIONS: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).

Clinical features and predictive biomarkers for bladder cancer in patients with type 2 diabetes presenting with haematuria.

AIMS: To identify clinical features and protein biomarkers associated with bladder cancer (BC) in individuals with type 2 diabetes mellitus presenting with haematuria. MATERIALS AND METHODS: Data collected from the Haematuria Biomarker (HaBio) study was used in this analysis. A matched sub-cohort of patients with type 2 diabetes and patients without diabetes was created based on age, sex, and BC diagnosis, using approximately a 1:2 fixed ratio. Randox Biochip Array Technology and ELISA were applied for measurement of 66 candidate serum and urine protein biomarkers. Hazard ratios and 95% confidence intervals were estimated by chi-squared and Wilcoxon rank sum test for clinical features and candidate protein biomarkers. Diagnostic protein biomarker models were identified using Lasso-based binominal regression analysis. RESULTS: There was no difference in BC grade, stage, and severity between individuals with type 2 diabetes and matched controls. Incidence of chronic kidney disease (CKD) was significantly higher in patients with type 2 diabetes (p = 0.008), and CKD was significantly associated with BC in patients with type 2 diabetes (p = 0.032). A biomarker model, incorporating two serum (monocyte chemoattractant protein 1 and vascular endothelial growth factor) and three urine (interleukin 6, cytokeratin 18, and cytokeratin 8) proteins, predicted incidence of BC with an Area Under the Curve (AUC) of 0.84 in individuals with type 2 diabetes. In people without diabetes, the AUC was 0.66. CONCLUSIONS: We demonstrate the potential clinical utility of a biomarker panel, which includes proteins related to BC pathogenesis and type 2 diabetes, for monitoring risk of BC in patients with type 2 diabetes. Earlier urology referral of patients with type 2 diabetes will improve outcomes for these patients. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN25823942.

A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber with reduced kidney function.

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m2. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 µm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2% of 33,222 and 11.3% of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95-1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.

Association of renal impairment with cognitive dysfunction in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA).

INTRODUCTION: Chronic kidney disease (CKD) is a recognized risk factor for cognitive impairment. Identification of those at greatest risk of cognitive impairment may facilitate earlier therapeutic intervention. This study evaluated associations between estimated glomerular filtration rate (eGFR) and cognitive function in the Northern Ireland Cohort for the Longitudinal Study of Ageing. METHODS: Data were available for 3412 participants ≥50 years of age living in non-institutionalized settings who attended a health assessment between February 2014 and March 2016. Measures of serum creatinine (SCr) and cystatin C (cys-C) were used for eGFR. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). RESULTS: Following adjustment for potential confounders, a single unit decrease in eGFR was significantly associated with reduced cognitive function defined by an MMSE ≤24/30 {eGFR calculated using serum cys-C [eGFRcys]: ß = -0.01 [95% confidence interval (CI) -0.001 to -0.01], P = 0.01} and MoCA <26/30 [ß = -0.01 (95% CI -0.002 to -0.02), P = 0.02]. Similarly, CKD Stages 3-5 were also associated with a moderate increase in the odds of cognitive impairment (MMSE ≤24) following adjustment for confounders [eGFRcys: odds ratio 2.73 (95% CI 1.38-5.42), P = 0.004]. CONCLUSIONS: Decreased eGFRcys was associated with a significantly increased risk of cognitive impairment in a population-based cohort of older adults. However, there was no evidence of an association between cognitive impairment and the more commonly used eGFR calculated using SCr. eGFRcys may offer improved sensitivity over eGFRcr in the determination of renal function and associated risk of cognitive impairment.

Using a generic definition of cachexia in patients with kidney disease receiving haemodialysis: a longitudinal (pilot) study.

BACKGROUND: Research indicates that cachexia is common among persons with chronic illnesses and is associated with increased morbidity and mortality. However, there continues to be an absence of a uniformed disease-specific definition for cachexia in chronic kidney disease (CKD) patient populations. OBJECTIVE: The primary objective was to identify cachexia in patients receiving haemodialysis (HD) using a generic definition and then follow up on these patients for 12 months. METHOD: This was a longitudinal study of adult chronic HD patients attending two hospital HD units in the UK. Multiple measures relevant to cachexia, including body mass index (BMI), muscle mass [mid-upper arm muscle circumference (MUAMC)], handgrip strength (HGS), fatigue [Functional Assessment of Chronic Illness Therapy (FACIT)], appetite [Functional Assessment of Anorexia/Cachexia Therapy (FAACT)] and biomarkers [C-reactive protein (CRP), serum albumin, haemoglobin and erythropoietin resistance index (ERI)] were recorded. Baseline analysis included group differences analysed using an independent t-test, dichotomized values using the χ2 test and prevalence were reported using the Statistical Package for the Social Sciences 24 (IBM, Armonk, NY, USA). Longitudinal analysis was conducted using repeated measures analysis. RESULTS: A total of 106 patients (30 females and 76 males) were recruited with a mean age of 67.6 years [standard deviation (SD) 13.18] and dialysis vintage of 4.92 years (SD 6.12). At baseline, 17 patients were identified as cachectic, having had reported weight loss (e.g. >5% for >6 months) or BMI <20 kg/m2 and three or more clinical characteristics of cachexia. Seventy patients were available for analysis at 12 months (11 cachectic versus 59 not cachectic). FAACT and urea reduction ratio statistically distinguished cachectic patients (P = 0.001). However, measures of weight, BMI, MUAMC, HGS, CRP, ERI and FACIT tended to worsen in cachectic patients. CONCLUSION: Globally, cachexia is a severe but frequently underrecognized problem. This is the first study to apply the defined characteristics of cachexia to a representative sample of patients receiving HD. Further, more extensive studies are required to establish a phenotype of cachexia in advanced CKD.

The Potential of Albuminuria as a Biomarker of Diabetic Complications.

Diabetes mellitus is a disease of dysregulated blood glucose homeostasis. The current pandemic of diabetes is a significant driver of patient morbidity and mortality, as well as a major challenge to healthcare systems worldwide. The global increase in the incidence of diabetes has prompted researchers to focus on the different pathogenic processes responsible for type 1 and type 2 diabetes. Similarly, increased morbidity due to diabetic complications has accelerated research to uncover pathological changes causing these secondary complications. Albuminuria, or protein in the urine, is a well-recognised biomarker and risk factor for renal and cardiovascular disease. Albuminuria is a mediator of pathological abnormalities in diabetes-associated conditions such as nephropathy and atherosclerosis. Clinical screening and diagnosis of diabetic nephropathy is chiefly based on the presence of albuminuria. Given the ease in measuring albuminuria, the potential of using albuminuria as a biomarker of cardiovascular diseases is gaining widespread interest. To assess the benefits of albuminuria as a biomarker, it is important to understand the association between albuminuria and cardiovascular disease. This review examines our current understanding of the pathophysiological mechanisms involved in both forms of diabetes, with specific focus on the link between albuminuria and specific vascular complications of diabetes.

Dietary patterns associated with renal impairment in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA).

BACKGROUND: Dietary-based primary prevention guidelines for chronic kidney disease (CKD) treatment are lacking due to limited evidence. Single nutrient intake studies do not account for complex dietary interactions. We assessed associations between dietary patterns and renal function in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). DESIGN: A cross-sectional observational study used NICOLA baseline dietary data collected between February 2014 and March 2016 via a food frequency questionnaire for 2590 participants aged ≥ 50 years. Principal component analysis identified a posteriori dietary patterns. Renal function was characterised by estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin-C. Associations were assessed according to quintiles of dietary pattern adherence and multivariable regression analysis examined associations with eGFR. RESULTS: Variation in three dietary patterns was significantly associated with eGFR. After adjustment for potential confounders, participants with least adherence to the 'healthy' dietary pattern 1 had a mean eGFR 3.4 ml/min/1.73m2 (95% confidence interval, [CI] - 5.0, - 1.7, p < 0.001) lower than the most adherent. Those with lowest adherence to the 'unhealthy' dietary pattern 2 had a mean eGFR 1.9 ml/min/1.73m2 (CI 0.2, 3.5, p = 0.03) higher than those with highest adherence. Participants with lowest adherence to dietary pattern 3, characterised by a high consumption of alcohol and coffee, had a mean eGFR 1.8 ml/min/1.73m2 (- 3.5, - 0.01, p = 0.05) lower than those with greatest adherence. CONCLUSIONS: Our findings identify independent associations between dietary patterns and eGFR. These findings can inform the development of diet-related primary prevention advice for CKD.

The effects of vitamin E supplementation on malondialdehyde as a biomarker of oxidative stress in haemodialysis patients: a systematic review and meta-analysis.

BACKGROUND: Haemodialysis (HD) patients tend to have higher levels of oxidative stress (OS), associated with increased morbidity and premature mortality, compared to the general population. Levels of malondialdehyde (MDA), a biomarker of OS, are reduced by the antioxidant properties of vitamin E (VE) but outcomes from randomised control trials of VE supplementation on MDA in HD patients have been inconsistent. METHODS: We undertook a systematic review and meta-analysis of adult HD patients from VE supplementation studies with measures of MDA. The following search criteria of MEDLINE and EMBASE were considered from inception to January 2020: 'dialysis' AND 'Vitamin E OR tocopherol' AND 'malondialdehyde OR MDA'. Two reviewers independently extracted study data and assessed risk of bias. Mean MDA levels and standard deviation were determined before and after VE supplementation. Standardised mean difference (SMD) and standard error were calculated as the within person difference and units of measure were not consistently recorded across all studies. The SMD were pooled using random effects meta-analysis. RESULTS: The SMD of MDA levels from 18 comparisons was significantly lower in HD patients following VE supplementation (- 1.55; confidence interval: - 2.17 to - 0.94, P < 0.00001). There were significant levels of heterogeneity between studies (I2 value = 91%; P < 0.00001) with evidence of potential publication bias toward smaller studies. CONCLUSIONS: Our findings support the use of VE to reduce the effects of OS in HD patients although high levels of heterogeneity and variation in the methodological approaches used by some studies highlight the need for further investigation.

Investigation of associations between retinal microvascular parameters and albuminuria in UK Biobank: a cross-sectional case-control study.

BACKGROUND: Associations between microvascular variation and chronic kidney disease (CKD) have been reported previously. Non-invasive retinal fundus imaging enables evaluation of the microvascular network and may offer insight to systemic risk associated with CKD. METHODS: Retinal microvascular parameters (fractal dimension [FD] - a measure of the complexity of the vascular network, tortuosity, and retinal arteriolar and venular calibre) were quantified from macula-centred fundus images using the Vessel Assessment and Measurement Platform for Images of the REtina (VAMPIRE) version 3.1 (VAMPIRE group, Universities of Dundee and Edinburgh, Scotland) and assessed for associations with renal damage in a case-control study nested within the multi-centre UK Biobank cohort study. Participants were designated cases or controls based on urinary albumin to creatinine ratio (ACR) thresholds. Participants with ACR ≥ 3 mg/mmol (ACR stages A2-A3) were characterised as cases, and those with an ACR < 3 mg/mmol (ACR stage A1) were categorised as controls. Participants were matched on age, sex and ethnic background. RESULTS: Lower FD (less extensive microvascular branching) was associated with a small increase in odds of albuminuria independent of blood pressure, diabetes and other potential confounding variables (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03-1.34 for arterioles and OR 1.24, CI 1.05-1.47 for venules). Measures of tortuosity or retinal arteriolar and venular calibre were not significantly associated with ACR. CONCLUSIONS: This study supports previously reported associations between retinal microvascular FD and other metabolic disturbances affecting the systemic vasculature. The association between retinal microvascular FD and albuminuria, independent of diabetes and blood pressure, may represent a useful indicator of systemic vascular damage associated with albuminuria.

Experiences of renal healthcare practitioners during the COVID-19 pandemic: a multi-methods approach.

BACKGROUND: Globally, renal healthcare practitioners provide intensive and protracted support to a highly complex multi-morbid patient population however knowledge about the impact of COVID-19 on these practitioners is extremely limited. OBJECTIVE: This study aimed to explore the experiences of COVID-19 with renal healthcare practitioners during the first global lockdown between June 2020 and September 2020. METHODS: A multi-methods approach was carried out including a quantitative survey and qualitative interviews. This was a multinational study of renal healthcare practitioners from 29 countries. Quantitative: A self-designed survey on COVID-19 experiences and standardised questionnaires (General Health Questionnaire-12; Maslach Burnout Inventory). Descriptive statistics were generated for numerical data. Qualitative: Online semi-structured interviews were conducted. Data was subjected to thematic analysis. Renal healthcare practitioners (n = 251) completed an online survey. Thirteen renal healthcare practitioners took part in semi-structured interviews (12 nurses and 1 dietician). RESULTS: The majority of participants surveyed were female (86.9 %; n = 218), nurses (86.9 %; n = 218) with an average 21.5 (SD = 11.1) years' experience since professional qualification, and 16.3 years (SD = 9.3) working in renal healthcare. Survey responses indicated a level of preparedness, training and satisfactory personal protective equipment during the pandemic however approximately 40.3 % experienced fear about attending work, and 49.8 % experienced mental health distress. The highest prevalence of burnout was emotional exhaustion (35.9 %). Three themes emerged from the qualitative analysis highlighting the holistic complexities in managing renal healthcare, a neglected specialist workforce, and the need for appropriate support at work during a pandemic. CONCLUSIONS: Results have highlighted the psychological impact, in terms of emotional exhaustion and mental health distress in our sample of renal healthcare practitioners. As the pandemic has continued, it is important to consider the long-term impact on an already stretched workforce including the risk of developing mental health disorders. Future research and interventions are required to understand and improve the provision of psychological support for specialist medical and nursing personnel.

The role of motivational and legal contexts in understanding support for tissue donation across 27 European countries.

BACKGROUND: There is a mismatch between attitudinal support for tissue donation and its translation into behavioural action (i.e. become registered donor). The legal and motivational context around tissue donation may contribute to better understanding of this mismatch. METHODS: Data were extracted from the Eurobarometer 82.2 survey (2014). Data included socio-demographic characteristics, motivations underlying attitudes to tissue donation and the legal context within which donation was considered (opt-in and opt-out consent). The sample was partitioned based on contextual information and seemingly unrelated bivariate probit regressions were used to explore the relationship between passive and active support for tissue donation. RESULTS: Approximately 56% of 25 879 respondents stated a willingness to donate tissue after death (passive support) and 9.1% reported that they were a registered donor (active support). We found evidence of unobserved heterogeneity between active and passive support across contexts. Our findings suggest that contexts in which altruistic motives can be supported by self-interest may increase the probability of converting passive to active support. Factors associated with increased support for tissue donation included: higher levels of education; good knowledge of the healthcare system; confidence in the safety of tissue donation; readiness to be a tissue recipient and knowing a recipient of donated tissue. CONCLUSIONS: Our findings demonstrate the value of examining active and passive support for tissue donation together within specific contexts. This more nuanced approach affords clearer insights that may help to guide policy makers confronted with apparently conflicting evidence around strategies intended to promote organ and tissue donation.

Prospective payment system and racial/ethnic disparities: a national retrospective observational study in anaemia complication among end-stage renal disease patients in the US.

BACKGROUND: A series of policy changes in 2011 altered reimbursement arrangements and guidance on use of erythropoiesis-stimulating agents for end-stage renal disease (ESRD) patients with anaemia in the US. While the policy changes were principally directed at care delivered in an outpatient setting, these had the potential to affect inpatient care also. This study used HCUP-NIS data (2008-2016) to examine trends in recorded anaemia among ESRD hospitalizations and analyse disparities in inpatient outcomes among ethnic groups following policy changes. METHODS: The International Classification of Diseases codes were used to identify ESRD admissions, recorded anaemia due to chronic kidney disease (CKD), and to generate an age-adjusted Deyo-Charlson comorbidity index. Linear splines with a knot placed at the time point of policy changes and multivariable logistic regression were used to examine the likelihood of recorded anaemia, adjusted for a range of socio-demographic and clinical covariates. Difference-in-difference analyses investigated the impact of policies on recorded anaemia. Other outcomes included hospital cost, mortality and place of discharge. RESULTS: The percentage of inpatient episodes with recorded anaemia arising from CKD increased from 26.2% in 2008 to 50.0% in 2016. Anaemia was more likely to be recorded as a complication of ESRD among minority ethnic groups and Native American admissions, in particular, (OR 1.20, 95%CI 1.15-1.25) relative to White American admissions; and these disparities widened following changes to reimbursement. Minorities were less likely to die in hospital and to be discharged to another healthcare facility, and (with the exception of Black American admissions) they were more expensive to treat. CONCLUSIONS: Our findings provide evidence of an increase in recorded anaemia consistent with a shift of patients from outpatient to inpatient settings in the wake of changes to reimbursement enacted in 2011. In addition, the study highlights the existence of ethnic disparities that widened after the policy initiated reimbursement changes.

Association of soluble ST2 with all-cause and cardiovascular mortality in renal transplant recipients: a single-centre cohort study.

BACKGROUND: Soluble ST2 is a novel biomarker of myocardial fibrosis with an established role in prognostication of patients with heart failure. Its role in cardiovascular risk prediction for renal transplant recipients has not been investigated despite promising results for ST2 in other populations with renal disease. METHODS: In this prospective cohort study, 367 renal transplant recipients were followed up for a median of 16.2 years to investigate the association of soluble ST2 concentration with all-cause mortality. Cardiovascular mortality and major adverse cardiovascular events were secondary outcomes. Cox regression models were used to calculate hazard ratios and 95% confidence intervals for ST2 before and after adjustments. ST2 concentration was analysed both as a continuous variable and following categorisation according to the recommended cut-point of 35 ng/ml. RESULTS: A twofold higher ST2 concentration was associated with a 36% increased risk of all-cause mortality after adjustment for conventional cardiovascular risk factors and high-sensitivity C-reactive protein (adjusted hazard ratio 1.36; 95% confidence interval 1.06-1.75; p = 0.016). Associations with ST2 concentration were similar for cardiovascular events (adjusted hazard ratio 1.31; 95% confidence interval 1.00-1.73; p = 0.054), but were stronger for cardiovascular mortality (adjusted hazard ratio 1.61; 95% confidence interval 1.07-2.41; p = 0.022). Addition of ST2 to risk prediction models for mortality and cardiovascular events failed to improve their predictive accuracy. CONCLUSIONS: ST2 is associated with, but does not improve prediction of, adverse outcomes in renal transplant recipients.

Association of reduced inner retinal thicknesses with chronic kidney disease.

BACKGROUND: Tissue derived biomarkers may offer utility as indicators of accumulated damage. Reduced thickness of retinal neuronal tissue and the vascular choroid have previously been associated with vascular damage and diabetes. We evaluated associations between retinal thickness, retinal microvascular and choroidal measures, and renal function in a population with a high burden of comorbidity. METHODS: Participants were recruited from nuclear cardiology or renal medicine clinics. Retinal and choroidal thickness were measured from spectral-domain optical coherence tomograms. Retinal microvascular parameters were assessed from digital fundus photographs using a semi-automated software package. MAIN OUTCOME MEASURE: Chronic kidney disease (CKD) categorised as: CKD stages 1-2, eGFR ≥60 ml/min/1.73m2; CKD stage 3, eGFR 30-59 ml/min/1.73m2, and CKD stages 4-5, eGFR ≤29 ml/min/1.73m2. RESULTS: Participants (n = 241) had a mean age of 65 years and a mean eGFR of 66.9 ml/min/1.73m2. Thirty-nine % of the cohort had diabetes and 27% were using diuretics. Thinning of the inner retina and changes to its microvascular blood supply were associated with lower eGFR and CKD stages 4 and 5, while no associations were found between the outer retinal layers or their choroidal blood supply and CKD of any stage. These associations remained following adjustment for age, mean arterial blood pressure, diabetes status, low-density lipoprotein, body mass index, and sex. CONCLUSIONS: Inner retinal thinning and retinal microvascular variation is associated with advanced CKD (stages 4 & 5) independent of important confounding factors, but not with earlier stage CKD (stage 3) and, therefore, its utility as a biomarker for early CKD is not supported in this study.

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort.

Renal transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P-value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P-value threshold 1 × 10-5 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P = .0022; AUC [full model adjusted for clinical predictors and PRS] = 0.81). SCC PRS at P-value threshold 1 × 10-5 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10-7 ; HR = 1.41, concordance [full model] = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens.

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population.

Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.