Short-chain fatty acids directly exert anti-inflammatory responses in podocytes and tubular epithelial cells exposed to high glucose

Aims: Gut-microbiome derived short-chain fatty acids exert anti-inflammatory effects and delay progression of kidney disease in diabetic nephropathy. The aim of this study was to examine the impact in vivo and in vitro of short-chain fatty acid treatment on cellular pathways involved in the development of experimental diabetic nephropathy.Methods: To determine the effect of short-chain fatty acids in diabetic nephropathy, we compared wildtype, GPR43−/− and GPR109A−/− mice diabetic mice treated with acetate or butyrate and assessed variables of kidney damage. We also examined the impact of short-chain fatty acid treatment on gene expression in renal tubular cells and podocytes under high glucose conditions.Results: Short-chain fatty acid treatment with acetate or butyrate protected wild-type mice against development of diabetic nephropathy, exhibiting less glomerular hypertrophy, hypercellularity and interstitial fibrosis compared to diabetic controls. Acetate and butyrate treatment did not provide the same degree of protection in diabetic GPR43−/− and GPR109A−/− diabetic mice respectively. Consistent with our in vivo results, expression of pro-inflammatory genes in tubular epithelial cells exposed to high glucose were attenuated by acetate and butyrate treatment. Acetate did not reduce inflammatory or fibrotic responses in glucose stimulated GPR43−/− TECs. Butyrate mediated inhibition of pro-fibrotic gene expression in TECs through GPR109A, and in podocytes via GPR43.Conclusion: SCFAs protect against progression of diabetic nephropathy and diminish podocyte and tubular epithelial injury and interstitial fibrosis via direct, GPR-pathway dependent effects on intrinsic kidney cells. GPR43 and GPR109A are critical to short-chain fatty acid mediated reno-protection and have potential to be harnessed as a therapeutic target in diabetic nephropathy

Survival in Living Kidney Donors: An Australian and New Zealand Cohort Study Using Data Linkage

Background. Living kidney donors are a highly selected healthy population expected to have high survival postdonation, but mortality studies are limited. Our study aimed to compare mortality in living kidney donors with the general population in Australia and New Zealand, hypothesizing that donor survival would exceed average survival. Methods. All living kidney donors in Australia, 2004–2013, and New Zealand, 2004–2012, from the Australian and New Zealand Living Kidney Donor Registry were included. We ascertained primary cause of death from data linkage with national death registers. Standardized mortality ratios and relative survival were estimated, matching on age, sex, calendar year, and country. Results. Among 3253 living kidney donors, there were 32 deaths over 20331 person-years, with median follow-up 6.2 years [interquartile range: 3.9–8.4]. Only 25 donors had diabetes-fasting blood sugar level predonation, of which 3 had impaired glucose toler- ance. At discharge, the median creatinine was 108 μmol/L and estimated glomerular filtration rate was 58 mL/min/1.72 m2. Four deaths occurred in the first year: 2 from immediate complications of donation, and 2 from unrelated accidental causes. The leading cause of death was cancer (n = 16). The crude mortality rate was 157 (95% confidence interval [CI], 111- 222)/100000 person-y, and the standardized mortality ratio was 0.33 (95% CI, 0.24-0.47). The 5-year cumulative relative survival was 1.019 (95% CI, 1.014-1.021), confirming that the survival probability in living kidney donors was 2% higher rela- tive to the general population. Conclusions. As expected, mortality in living kidney donors was substantially lower than the general population and is reassuring for potential donor counseling. The Living Donor Registry only captured a third of the deaths, highlighting the benefit of data linkage to national death registries in the long-term follow-up of living kidney donors.This study received financial support from Kidney Health Australia (2015

Community Preferences for the Allocation &Donation of Organs - The PAraDOx Study

<p>Abstract</p> <p>Background</p> <p>Transplantation is the treatment of choice for people with severe organ failure. However, demand substantially exceeds supply of suitable organs; consequently many people wait months, or years to receive an organ. Reasons for the chronic shortage of deceased organ donations are unclear; there appears to be no lack of 'in principle' public support for organ donation.</p> <p>Methods/Design</p> <p>The PAraDOx Study examines community preferences for organ donation policy in Australia. The aims are to 1) determine which factors influence decisions by individuals to offer their organs for donation and 2) determine the criteria by which the community deems the allocation of donor organs to be fair and equitable. Qualitative and quantitative methods will be used to assess community preferences for organ donation and allocation.</p> <p>Focus group participants from the general community, aged between 18-80, will be purposively sampled to ensure a variety of cultural backgrounds and views on organ donation. Each focus group will include a ranking exercise using a modified nominal group technique. Focus groups of organ recipients, their families, and individuals on a transplant waiting list will also be conducted.</p> <p>Using the qualitative work, a discrete choice study will be designed to quantitatively assess community preferences. Discrete choice methods are based on the premise that goods and services can be described in terms of a number of separate attributes. Respondents are presented with a series of choices where levels of attributes are varied, and a mathematical function is estimated to describe numerically the value respondents attach to different options. Two community surveys will be conducted in approximately 1000 respondents each to assess community preferences for organ donation and allocation. A mixed logit model will be used; model results will be expressed as parameter estimates (β) and the odds of choosing one option over an alternative. Trade-offs between attributes will also be calculated.</p> <p>Discussion</p> <p>By providing a better understanding of current community preferences in relation to organ donation and allocation, the PAraDOx study will highlight options for firstly, increasing the rate of organ donation and secondly, allow for more transparent and equitable policies in relation to organ allocation.</p

Development of Risk Prediction Equations for Incident Chronic Kidney Disease

IMPORTANCE Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.OBJECTIVE To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).DESIGN, SETTING, AND PARTICIPANTS Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).EXPOSURES Demographic and clinical factors.MAIN OUTCOMES AND MEASURES Incident eGFR of less than 60 mL/min/1.73 m(2).RESULTS Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A(1c), and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.CONCLUSIONS AND RELEVANCE Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.</p

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation : The 2019 Expert Consensus From the Transplantion Society Working Group

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes

Decline in Estimated Glomerular Filtration Rate and Subsequent Risk of End-Stage Renal Disease and Mortality

Peer reviewedPostprin

Conversion of Urine Protein-Creatinine Ratio or Urine Dipstick Protein to Urine Albumin-Creatinine Ratio for Use in Chronic Kidney Disease Screening and Prognosis : An Individual Participant–Based Meta-analysis

Financial Support: The CKD-PC Data Coordinating Center is funded in part by a program grant from the U.S. National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100446). Various sources have supported enrollment and data collection, including laboratory measurements and follow-up, in the collaborating cohorts of the CKD-PC. These funding sources include government agencies, such as national institutes of health and medical research councils, as well as the foundations and industry sponsors listed in Supplemental Appendix 3 (available at Annals.org).Peer reviewedPostprin

25-Hydroxyvitamin D levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study

<p>Abstract</p> <p>Background</p> <p>Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).</p> <p>Methods</p> <p>10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m². Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.</p> <p>Results</p> <p>30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).</p> <p>Conclusions</p> <p>Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.</p

Test performance of faecal occult blood testing for the detection of bowel cancer in people with chronic kidney disease (DETECT) protocol

<p>Abstract</p> <p>Background</p> <p>Cancer is a major cause of mortality and morbidity in patients with chronic kidney disease (CKD). In patients without kidney disease, screening is a major strategy for reducing the risk of cancer and improving the health outcomes for those who developed cancers by detecting treatable cancers at an early stage. Among those with CKD, the effectiveness, the efficacy and patients' preferences for cancer screening are unknown.</p> <p>Methods/Design</p> <p>This work describes the protocol for the DETECT study examining the effectiveness, efficiency and patient's perspectives of colorectal cancer screening using immunochemical faecal occult blood testing (iFOBT) for people with CKD. The aims of the DETECT study are 1) to determine the test performance characteristics of iFOBT screening in individuals with CKD, 2) to estimate the incremental costs and health benefits of iFOBT screening in CKD compared to no screening and 3) to elicit patients' perspective for colorectal cancer screening in the CKD population. Three different study designs will be used to explore the uncertainties surrounding colorectal cancer screening in CKD. A diagnostic test accuracy study of iFOBT screening will be conducted across all stages of CKD in patients ages 35-70. Using individually collected direct healthcare costs and outcomes from the diagnostic test accuracy study, cost-utility and cost-effective analyses will be performed to estimate the costs and health benefits of iFOBT screening in CKD. Qualitative in-depth interviews will be undertaken in a subset of participants from the diagnostic test accuracy study to investigate the perspectives, experiences, attitudes and beliefs about colorectal cancer screening among individuals with CKD.</p> <p>Discussion</p> <p>The DETECT study will target the three major unknowns about early cancer detection in CKD. Findings from our study will provide accurate and definitive estimates of screening efficacy and efficiency for colorectal cancer, and will allow better service planning and budgeting for early cancer detection in this at-risk population.</p> <p>The DETECT study is also registered with the Australia New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ACTRN12611000538943.aspx">ACTRN12611000538943</a></p