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Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10–15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment. Methods: ASCEND-D (NCT02879305) recruited 2964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA Units/kg/week/hemoglobin g/l) ≥2 or IV standardized ESA dose ≥450 Units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored. Results: Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (P < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (P = 0.010), history of heart failure (P = 0.035), longer dialysis vintage (P = 0.077), smoking status (P = 0.247), aspirin use (P = 0.121), and angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker use (P = 0.214). Conclusion: This is the first global HIF-PHI study to report pre-specified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.

The burden of chronic kidney disease is increasing worldwide, largely due to the increasing global prevalence of diabetes mellitus and hypertension. While renin angiotensin system inhibitors and sodium-glucose cotransporter two inhibitors are the management cornerstone for reducing kidney and cardiovascular complications in patients with diabetic and non-diabetic kidney disease (DKD), they are partially effective and further treatments are needed to prevent the progression to kidney failure. Endothelin receptor antagonism represent a potential additional therapeutic option due to its beneficial effect on pathophysiological processes involved in progressive kidney disease including proteinuria, which are independently associated with progression of kidney disease. This review discusses the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential future use in both diabetic and non-DKDs.

Chronic kidney disease (CKD) is characterised by progressive loss of kidney function leading to kidney failure. Significant kidney damage can occur before symptoms are detected. Currently, kidney tissue biopsy is the gold standard for evaluation of renal damage and CKD severity. This study explores how to precisely quantify morphology characteristics of kidney cells exfoliated into urine, with a view to establish a future urine-based non-invasive diagnostic for CKD. We report the development of a novel deep learning method, which was able to discover a RELIC (moRphology dEep Learning Imaging Cells) signature that can differentiate between kidney cells exfoliated in human urine of and CKD patients with varying degree of kidney damage and non-CKD controls. Exfoliated proximal tubule cells (PTCs) originating from kidneys were isolated from the urine of patients with different levels of kidney damage using previously published methods. An advanced combination of artificial intelligence techniques, deep learning, swarm intelligence, and discriminative analysis was used to discover a RELIC signature in brightfield microscopy images of exfoliated PTCs. Kidney damage in the study subjects was characterised by assessing kidney tissues obtained through a nephrectomy or kidney biopsy. A special deep learning algorithm was developed and trained to create a predictive tool. The algorithm was then used to analyse data from patients with normal and fibrotic kidneys. Data were then classified according to different groups (healthy or fibrosis) and clustering of the training and validation cells was determined for model validation. We developed a novel deep learning method, to obtain RELIC signatures and identify specific deep morphological features which can be used to differentiate urinary PTC cells shed by people with CKD (confirmed by tissue histology obtained from an invasive kidney biopsy) from those without CKD, with a discriminatory accuracy of 82%. We identified a RELIC signature which can be used on a collection of bright field images of exfoliated urinary PTCs to create a predictive tool and differentiate between normal and pathological kidney cells. This study, for the first time, provides a proof of concept that urinary exfoliated tubule cells in patients with kidney fibrosis and healthy controls differ in appearance (morphology) as observed under a basic brightfield microscope. The results suggest that morphological signatures of exfoliated PTCs have the potential to serve as a non-invasive marker of kidney fibrosis.

Background: SGLT2 inhibition decreases albuminuria and reduces the risk of kidney disease progression in patients with type 2 diabetes. These benefits are unlikely to be mediated by improvements in glycaemic control alone. Therefore, we aimed to examine the kidney effects of the SGLT2 inhibitor dapagliflozin in patients with proteinuric kidney disease without diabetes. Methods: DIAMOND was a randomised, double-blind, placebo-controlled crossover trial done at six hospitals in Canada, Malaysia, and the Netherlands. Eligible participants were adult patients (aged 18–75 years) with chronic kidney disease, without a diagnosis of diabetes, with a 24-h urinary protein excretion greater than 500 mg and less than or equal to 3500 mg and an estimated glomerular filtration rate (eGFR) of at least 25 mL/min per 1·73 m2, and who were on stable renin–angiotensin system blockade. Participants were randomly assigned (1:1) to receive placebo and then dapagliflozin 10 mg per day or vice versa. Each treatment period lasted 6 weeks with a 6-week washout period in between. Participants, investigators, and study personnel were masked to assignment throughout the trial and analysis. The primary outcome was percentage change from baseline in 24-h proteinuria during dapagliflozin treatment relative to placebo. Secondary outcomes were changes in measured GFR (mGFR; via iohexol clearance), bodyweight, blood pressure, and concentrations of neurohormonal biomarkers. Analyses were done in accordance with the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03190694. Findings: Between Nov 22, 2017, and April 5, 2019, 58 patients were screened, of whom 53 (mean age 51 years [SD 13]; 32% women) were randomly assigned (27 received dapagliflozin then placebo and 26 received placebo then dapagliflozin). One patient discontinued during the first treatment period. All patients were included in the analysis. Mean baseline mGFR was 58·3 mL/min per 1·73 m2 (SD 23), median proteinuria was 1110 mg per 24 h (IQR 730–1560), and mean HbA1c was 5·6% (SD 0·4). The difference in mean proteinuria change from baseline between dapagliflozin and placebo was 0·9% (95% CI −16·6 to 22·1; p=0·93). Compared with placebo, mGFR was changed with dapagliflozin treatment by −6·6 mL/min per 1·73 m2 (–9·0 to −4·2; p

American journal of nephrology 52(10/11), 827-836 (2021). doi:10.1159/000519812, Published by Karger, Basel [u.a.]

The TESTING (Therapeutic Evaluation of STeroids in IgA Nephropathy Global) study is a multicenter, double-blinded, randomised, placebo-controlled trial designed to evaluate the long-term efficacy and safety of oral methylprednisolone, on a background of routine renin angiotensin system (RAS) inhibitor therapy, in preventing kidney events in patients with IgA nephropathy with features suggestive of a high risk of disease progression. This statistical analysis plan (SAP) provides the details of all pre-specified analyses to be conducted at the end of the trial. The SAP was written by the trial statistician, chief investigator, study director and project manager and approved by the management committee.

AIM: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library to August 7, 2018, as well as the websites of the United States, European, and Japanese regulatory authorities to July 27, 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal, or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals.RESULTS: Data were obtained from 27 studies with up to 7,363 participants contributing. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated hemoglobin (-0.29%, 95% CI -0.39 to -0.19), as well as blood pressure, body weight, and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR 0.81, 95% CI 0.70-0.94) and heart failure (RR 0.61, 95% CI 0.48-0.78), without a clear effect on all-cause mortality (HR 0.86, 95% CI 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73m2 /year, 95% CI 0.78-1.93) and reduced the risk of the composite renal outcome (HR 0.71, 95% CI 0.53-0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes.CONCLUSION: Currently available data suggest that despite only modest reductions in glycated hemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns. This article is protected by copyright. All rights reserved.

Optimally preserved urinary exfoliated renal proximal tubule cells were assessed by multispectral imaging of cell autofluorescence. We demonstrated different multispectral autofluorescence signals in such cells extracted from the urine of patients with healthy or diseased kidneys. Using up to 10 features, we were able to differentiate cells from individuals with heathy kidneys and impaired renal function (indicated by estimated glomerular filtration rate (eGFR) values) with the receiver operating characteristic area under the curve (AUC) of 0.99. Using the same method, we were also able to discriminate such urine cells from patients with and without renal fibrosis on biopsy, where significant differences in multispectral autofluorescence signals (AUC = 0.90) were demonstrated between healthy and diseased patients (p

Oceania and South East Asia (OSEA) is a socioeconomically, culturally, and ethnically diverse region facing a rising epidemic of noncommunicable diseases, including chronic kidney disease (CKD). The second iteration of the International Society of Nephrology Global Kidney Health Atlas aimed to provide a comprehensive evaluation of kidney care in OSEA. Of the 30 countries/territories in OSEA, 15 participated in the survey, representing 98.5% of the region's population. The median prevalence of treated kidney failure in OSEA was 1352 per million population (interquartile range, 966-1673 per million population), higher than the global median of 787 per million population. Although the general availability, access, and quality of kidney replacement therapy (i.e., dialysis and transplantation) was high in OSEA, inequalities in accessibility and affordability of kidney replacement therapy across the region resulted in variability between countries. According to the survey results, in a third of the participating countries (mostly lower-income countries), less than half the patients with kidney failure were able to access dialysis, whereas it was readily available to all with minimal out-of-pocket costs in high-income countries; similar variability in access to transplantation was also recorded. Limitations in workforce and resources vary across the region and were disproportionately worse in lower-income countries. There was little advocacy for kidney disease, moderate use of registries, restricted CKD detection programs, and limited availability of routine CKD testing in some high-risk groups across the region. International collaborations, as seen in OSEA, are important initiatives to help close the gaps in CKD care provision across the region and should continue receiving support from the global nephrology community.

Introduction: Hemodialysis (HD) with medium cut-off (MCO) dialyzers may expand molecular clearance, predominantly larger middle molecules (molecular weight 25–60 kDa). However, the impact of MCO dialyzers on long-term clearance of various other components of the uremic milieu is unknown. The tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) provided an opportunity to assess the effect of MCO dialyzers on protein-bound uremic toxins and novel markers of mineral metabolism. Methods: This exploratory sub-study of REMOVAL-HD evaluated changes in protein-bound solutes (total and free indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) and mineral metabolism markers (intact fibroblast growth factor-23 [iFGF23], fetuin-A and endogenous calciprotein particles [CPP-1 and CPP-2]). Mid-week, pre-HD serum samples were collected at baseline and after 12 and 24 weeks of MCO use in stable adult patients. Change from baseline to Week 12 and 24 was estimated using linear mixed effects models. Findings: Eighty-nine participants were studied (mean age 67 ± 15 years, 38% female, 51% diabetic, median urine output 200 ml/24 h). Serum iFGF23 was reduced at Week 12 compared to baseline (−26.8% [95%CI −39.7, −11.1], p = 0.001), which was sustained at Week 24 (−21.7% [95%CI -35.7, −4.5], p = 0.012). There was no significant change in serum IS, PCS, fetuin-A, CPP-1, or CPP-2. Discussion: The use of a MCO dialyzer over 24 weeks was associated with a sustained reduction in FGF23, while other measured components of the uremic milieu were not significantly altered. Further studies are required to determine whether FGF23 reduction is associated with improved patient outcomes.

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.

Introduction Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts. Methods In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes. Results Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit, P < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers. Conclusion Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus., Graphical abstract

It is increasingly recognized that maternal obesity is implicated in developmental programming, contributing to the future risk of chronic disease development in offspring. The exact mechanisms of the role of maternal obesity in the development of chronic kidney disease in offspring remain unclear and animal models used are not without limitation. Human studies are limited by the effects of postnatal environmental conditions, which may have a direct impact on disease phenotype; and animal models are limited by use of species that differ significantly. This review will examine the most recent evidence from animal models on the impact of maternal factors during pregnancy/lactation on the future risk of chronic kidney disease development in offspring, emphasising the role of maternal obesity in exacerbating the deleterious effects of diet-induced obesity and/or diabetes on renal health.

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme with a unique dual function in controlling inflammation as well as reactive oxygen species (ROS) generation. We have demonstrated benefit of SSAO inhibition in acute kidney fibrosis. However the function of SSAO in chronic kidney disease (CKD) and diabetic kidney disease (DKD) is yet to be determined. We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator. Extracellular matrix markers, fibronectin and oxidative stress, were downregulated in diabetic mice treated with SSAOi compared with untreated diabetic mice. Expression of the pan-leukocyte marker CD45 was also supressed by SSAOi. SSAO inhibition in diabetic mice resulted in a significant reduction in glomerulosclerosis and associated albuminuria compared to untreated diabetic mice. However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis.

Aim There is no national consensus on infection control in haemodialysis units in Australia and New Zealand. The primary aim of this guideline was to provide recommendations on screening for blood-borne viruses and multi-resistant organisms for dialysis units based on the available evidence. Methods The Kidney Health Australia Caring for Australasians with Renal Impairment guidelines, overall approach to guideline development follows the GRADE framework. A facilitated workshop was conducted to ensure that patient and caregiver concerns were considered. The evidence from relevant medical databases on the impact of screening on detection and transmission rates, hospitalization, mortality and psychosocial care, was reviewed and critically appraised. The guideline group made recommendations from the evidence available. Results The main guideline recommendations are: Dialysis units adopt a comprehensive approach that encompasses standard infection control precautions. Conduct routine surveillance for key blood-borne viruses and methicillin-resistant Staphylococcus aureus. Conduct routine surveillance of individual levels of protection against hepatitis B for patients on haemodialysis. Use dedicated dialysis machines for HBV-infected patients. The evidence in totality was not found to support routine surveillance of vancomycin-resistant Enterococci . Enhanced surveillance in light of the local risk of transmittable infectious agents should be considered by dialysis units. Very few studies have reported on the potential adverse effects of screening and associated practices. Conclusions Future research should focus on the potential benefits and adverse effects of screening and associated practices on clinical outcomes including infections prevented and health service delivery, and psychosocial domains for patients. Given the results of trials in the critical setting, the effectiveness of methicillin-resistant Staphylococcus aureus decolonization in people receiving dialysis therapy warrants further research.

Maternal obesity has been associated with kidney disorders in male offspring. Our previous studies have demonstrated that Sirtuin (SIRT)1, an essential regulator of metabolic stress responses, is suppressed in the offspring as the result of maternal high-fat diet (HFD) consumption, which is likely to underpin the adverse metabolic and renal outcomes. To examine if SIRT1 overexpression or activation early in life can protect the offspring kidney, wild-type (WT) and transgenic (Tg) offspring were born to the same diet-induced obese female C57BL/6 mice through breeding with hemizygous SIRT1-transgenic (Tg) male mice and examined for renal pathological changes. In separate experiments, SIRT1 activator SRT1720 (25 mg/kg/2 days i.p) was administrated in WT offspring over 6 weeks of postnatal high-fat diet exposure. The results show that offspring born to obese dams have increased kidney weight, higher levels of renal triglycerides, and increased expression of oxidative stress, inflammatory, and fibrotic markers, as well as increased albuminuria compared to offspring of control dams. Both SIRT1 overexpression and SRT1720 treatment attenuated renal lipid contents and expression of lipogenesis, oxidative stress, and inflammatory markers, however, fibrosis was modestly reduced and albuminuria was not affected. The findings suggest that SIRT1 therapy can ameliorate some pathological mechanisms of kidney programming due to maternal obesity but may not be sufficient to prevent the resulting chronic kidney injury.

A 66-year-old Asian woman presented with severe kidney injury, microscopic haematuria and subnephrotic range proteinuria with elevated serum anti-glomerular basement membrane (anti-GBM) titre. She had a history of renal cell carcinoma. Renal biopsy revealed dual pathology with immunofluorescence showing 3+ linear glomerular IgG staining and 3+ IgA mesangial staining. Cellular crescents were present on light microscopy and electron microscopy revealed increased mesangial matrix. She was treated with plasma exchange and immunosuppression and remained in stage 4 chronic kidney disease. This case describes the coexistence of anti-GBM disease and IgA nephropathy, a phenomenon not well described in the literature. The report also explores the association of malignancy and glomerulonephritis as well as the role of genetics and the utility of human leukocyte antigen (HLA) typing in risk stratification.

Introduction: The integration of patient and caregiver input into guideline development can help to ensure that clinical care addresses patient expectations, priorities, and needs. We aimed to identify topics and outcomes salient to patients and caregivers for inclusion in the Kidney Health Australia Caring for Australasians with Renal Impairment (KHA-CARI) clinical practice guideline on the screening and management of infectious microorganisms in hemodialysis units. Methods: A facilitated workshop was conducted with 11 participants (patients [n = 8], caregivers [n = 3]). Participants identified and discussed potential topics for inclusion in the guidelines, which were compared to those developed by the guideline working group. The workshop transcript was thematically analyzed to identify and describe the reasons underpinning their priorities. Findings: Patients and caregivers identified a range of topics already covered by the scope of the proposed guidelines and also suggested additional topics: privacy and confidentiality, psychosocial care during/after disease notification, quality of transportation, psychosocial treatment of patients in isolation, patient/caregiver education and engagement, and patient advocacy. Five themes characterized discussion and underpinned their choices: shock and vulnerability, burden of isolation, fear of infection, respect for privacy and confidentiality, and confusion over procedural inconsistencies. Discussion: Patients and caregivers emphasized the need for guidelines to address patient education and engagement, and the psychosocial implications of communication and provision of care in the context of infectious microorganisms in hemodialysis units. Integrating patient and caregiver perspectives can help to improve the relevance of guidelines to enhance quality of care, patient experiences, and health and psychosocial outcomes.

BackgroundResidual kidney function (RKF) is associated with improved survival and quality of life in dialysis patients. Previous studies have suggested that initiation of peritoneal dialysis (PD) may slow RKF decline compared to the pre-dialysis period. We sought to evaluate the association between PD initiation and RKF decline in the Initiating Dialysis Early And Late (IDEAL) trial.MethodsIn thispost hocanalysis of the IDEAL randomized controlled trial, PD participants were included if results from 24-hour urine collections had been recorded within 30 days of dialysis initiation, and at least one value pre- and one value post-dialysis commencement were available. The primary outcome was slope of RKF decline, calculated as mean of urinary creatinine and urea clearances. Secondary outcomes included slope of urine volume decline and time from PD initiation to anuria.ResultsThe study included 151 participants (79 early start, 72 late start). The slope of RKF decline was slower after PD initiation (-2.69±0.18mL/min/1.73m2/yr) compared to before PD (-4.09±0.33mL/min/1.73m2/yr; change in slope +1.19 mL/min/1.73m2/yr, 95%CI 0.48–1.90, pConclusionsInitiation of PD was associated with a slower decline of RKF compared to the pre-dialysis period.