Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 in the complicated pathophysiology of diabetic nephropathy is not understood. In ...this study, we report elevated expression of TLR4, its endogenous ligands and downstream cytokines, chemokines and fibrogenic genes in diabetic nephropathy in WT mice with streptozotocin (STZ) diabetes. Subsequently, we demonstrated that TLR4-/- mice were protected against the development of diabetic nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic wild-type controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR4 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR4 activation in podocytes and tubular epithelial cells in vitro, resulting in NF-κB activation and consequent inflammatory and fibrogenic responses. Our data indicate that TLR4 activation may promote inflammation, podocyte and tubular epithelial cell injury and interstitial fibrosis, suggesting TLR4 is a potential therapeutic target for diabetic nephropathy.
The 2020 Kidney DiseaseImproving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care ...professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual’s suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate’s profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.
Studies have reported "dysbiotic" changes to gut microbiota, such as depletion of gut bacteria that produce short-chain fatty acids (SCFAs) through gut fermentation of fiber, in CKD and diabetes. ...Dietary fiber is associated with decreased inflammation and mortality in CKD, and SCFAs have been proposed to mediate this effect.
To explore dietary fiber's effect on development of experimental diabetic nephropathy, we used streptozotocin to induce diabetes in wild-type C57BL/6 and knockout mice lacking the genes encoding G protein-coupled receptors GPR43 or GPR109A. Diabetic mice were randomized to high-fiber, normal chow, or zero-fiber diets, or SCFAs in drinking water. We used proton nuclear magnetic resonance spectroscopy for metabolic profiling and 16S ribosomal RNA sequencing to assess the gut microbiome.
Diabetic mice fed a high-fiber diet were significantly less likely to develop diabetic nephropathy, exhibiting less albuminuria, glomerular hypertrophy, podocyte injury, and interstitial fibrosis compared with diabetic controls fed normal chow or a zero-fiber diet. Fiber beneficially reshaped gut microbial ecology and improved dysbiosis, promoting expansion of SCFA-producing bacteria of the genera
and
, which increased fecal and systemic SCFA concentrations. Fiber reduced expression of genes encoding inflammatory cytokines, chemokines, and fibrosis-promoting proteins in diabetic kidneys. SCFA-treated diabetic mice were protected from nephropathy, but not in the absence of GPR43 or GPR109A.
, SCFAs modulated inflammation in renal tubular cells and podocytes under hyperglycemic conditions.
Dietary fiber protects against diabetic nephropathy through modulation of the gut microbiota, enrichment of SCFA-producing bacteria, and increased SCFA production. GPR43 and GPR109A are critical to SCFA-mediated protection against this condition. Interventions targeting the gut microbiota warrant further investigation as a novel renoprotective therapy in diabetic nephropathy.
Kidney transplantation offers improved survival and quality of life compared to dialysis for most recipients; however, benefits for elderly patients (>70 years) remain uncertain. Using the Australia ...and New Zealand Dialysis and Transplant Registry (2009-2019), elderly transplant recipients were matched to a waitlisted dialysis patient by age, cause of end-stage kidney disease, and dialysis duration (paired controls). We censored dialysis patients at the time of transplant. Survival was compared using stratified Cox regression. Elderly transplant recipients (KTRs) (n = 465) were matched to waitlisted pairs. Transplant group mortality initially exceeded dialysis due to excess infection-related deaths (1.9 transplant versus 0.3 dialysis/100 patient-years, P = .03). Beyond month 9, a progressive survival benefit in favor of transplantation was apparent. Over a median follow-up of 1.7 years, mortality was 38% lower for KTRs (95% confidence interval 0.41-0.94, P = .02), and 5-year survival was 80% KTRs vs 53% dialysis (P < .001). Recipients of living and standard criteria donor kidneys acquired immediate survival advantage compared with dialysis, while recipients of expanded criteria donor's kidneys experienced elevated risk of death for the first 17 months. Compared with remaining on dialysis, elderly KTRs incur an increased risk of early posttransplant mortality but thereafter may anticipate progressively superior survival rates.
Mortality risk after kidney transplantation can vary significantly during the post-transplant course. A contemporary assessment of trends in all-cause and cause-specific mortality at different ...periods post-transplant is required to better inform patients, clinicians, researchers, and policy makers.
We included all first kidney-only transplant recipients from 1980 through 2018 from the Australia and New Zealand Dialysis and Transplant Registry. We compared adjusted death rates per 5-year intervals, using a piecewise exponential survival model, stratified by time post-transplant or time post-graft failure.
Of 23,210 recipients, 4765 died with a functioning graft. Risk of death declined over successive eras, at all periods post-transplant. Reductions in early deaths were most marked; however, recipients ≥10 years post-transplant were 20% less likely to die in the current era compared with preceding eras (2015-2018 versus 2005-2009, adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.90). In 2015-2018, cardiovascular disease was the most common cause of death, particularly in months 0-3 post-transplant (1.18 per 100 patient-years). Cancer deaths were rare early post-transplant, but frequent at later time points (0.93 per 100 patient-years ≥10 years post-transplant). Among 3657 patients with first graft loss, 2472 died and were not retransplanted. Death was common in the first year after graft failure, and the cause was most commonly cardiovascular (50%).
Reductions in death early and late post-transplant over the past 40 years represent a major achievement. Reductions in cause-specific mortality at all time points post-transplant are also apparent. However, relatively greater reductions in cardiovascular death have increased the prominence of late cancer deaths.
Antibody-mediated rejection (AMR) is a recognized cause of allograft loss in kidney transplant recipients. A range of therapies targeting removal of circulating donor-specific antibodies (DSAs), ...blocking their effect or reducing production have been reported.
We conducted a systematic review to determine the efficacy of treatments for acute AMR in renal allografts. Electronic databases, reference lists, and conference proceedings were searched for controlled trials. Nonrandomized publications were reviewed for the purpose of discussion.
We identified 10,388 citations, including five randomized and seven nonrandomized controlled trials. The randomized studies were small (median, 13 patients/arm; range, 5-23), of which, four examined plasmapheresis (one suggested benefit) and one for immunoadsorption (also suggesting benefit). Marked heterogeneity was evident, including the definition and severity of AMR and the treatment regimen. The end point of graft survival was common to all studies. Small, nonrandomized controlled studies suggested benefit from rituximab or bortezomib. The effects of dose and regimen on the clinical response to any of the current treatments were not apparent from the available data.
Data describing the efficacy of treatments for AMR in renal allografts are of low or very low quality. Larger randomized controlled trials and dose-response studies are required.
The role of the pro-inflammatory cytokine IL-17 in the pathogenesis of numerous inflammatory disorders is well-documented, but conflicting results are reported for its role in diabetic nephropathy. ...Here we examined the role of IL-17 signalling in a model of streptozotocin-induced diabetic nephropathy through IL-17 knockout mice, administration of neutralising monoclonal anti-IL-17 antibody and in vitro examination of gene expression of renal tubular cells and podocytes under high glucose conditions with or without recombinant IL-17. IL-17 deficient mice were protected against progression of diabetic nephropathy, exhibiting reduced albuminuria, glomerular damage, macrophage accumulation and renal fibrosis at 12 weeks and 24 weeks. Administration of anti-IL-17 monoclonal antibody to diabetic wild-type mice was similarly protective. IL-17 deficiency also attenuated up-regulation of pro-inflammatory and pro-fibrotic genes including IL-6, TNF-α, CCL2, CXCL10 and TGF-β in diabetic kidneys. In vitro co-stimulation with recombinant IL-17 and high glucose were synergistic in increasing the expression of pro-inflammatory genes in both cultured renal tubular cells and podocytes. We conclude that absence of IL-17 signalling is protective against streptozotocin-induced diabetic nephropathy, thus implying a pro-inflammatory role of IL-17 in its pathogenesis. Targeting the IL-17 axis may represent a novel therapeutic approach in the treatment of this disorder.
IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in ...estimated glomerular filtration rate GFR of −57% or greater) is a late event. OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12 344 ESRD events and 223 944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% 95% CI, 6.4%-7.4% of the entire consortium) were more common than changes of −57% (0.79% 95% CI, 0.52%-1.06%). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.
Trials designed to assess the effect of interventions on death and graft failure in kidney transplant recipients are not feasible, because these are predominantly late events. Here, we examined the ...potential of percentage decline in eGFR as a surrogate for hard outcomes. We obtained deidentified data from the Australia and New Zealand Dialysis and Transplant Registry and studied 7949 transplants performed from 1995 to 2009, including 71,845 patient-years of follow-up, 1121 graft losses, and 1192 deaths. We used adjusted Cox proportional hazards models to determine risks of death or death-censored graft failure related to percentage change in eGFR between years 1 and 3 after transplant. Percentage change in eGFR was modeled as a restricted cubic spline. Rate of eGFR decline associated with exponentially increased risks of graft failure and death. Compared with stable eGFR, a ≥30% decline in eGFR, detected in 10% of patients, strongly associated with subsequent death (hazard ratio, 2.20; 95% confidence interval, 1.87 to 2.60) and death-censored graft failure (hazard ratio, 5.14; 95% confidence interval, 4.44 to 5.95). Decline in eGFR was superior to other surrogates, including acute rejection, doubling of serum creatinine level, and eGFR at year 1 or year 2. We conclude that 30% decline in eGFR between years 1 and 3 after kidney transplant is common and strongly associated with risks of subsequent death and death-censored graft failure, which mirrors findings in CKD. Percentage decline in eGFR should be considered for use as a surrogate outcome in kidney transplant trials.
BACKGROUNDCurrent treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B cells, ...plasma cells, and the complement system have featured in recent studies of AMR.
METHODSWe conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE, and CENTRAL from inception to February 2017.
RESULTSOf 14 380 citations, we identified 21 studies, including 10 randomized controlled trials, involving 751 participants. Since the last systematic review conducted in 2011, we found nine additional studies evaluating plasmapheresis + intravenous immunoglobulin (IVIG) (two), rituximab (two), bortezomib (two), C1 inhibitor (two), and eculizumab (one). Risk of bias was serious or unclear overall and evidence quality was low for the majority of treatment strategies. Sufficient RCTs for pooled analysis were available only for antibody removal, and here there was no significant difference between groups for graft survival (HR 0.76; 95% CI 0.35-1.63; P = 0.475). Studies showed important heterogeneity in treatments, definition of AMR, quality, and follow-up. Plasmapheresis and IVIG were used as standard-of-care in recent studies, and to this combination, rituximab seemed to add little or no benefit. Insufficient data are available to assess the efficacy of bortezomib and complement inhibitors.
CONCLUSIONNewer studies evaluating rituximab showed little or no difference to early graft survival, and the efficacy of bortezomib and complement inhibitors for the treatment of AMR remains unclear. Despite the evidence uncertainty, plasmapheresis and IVIG have become standard-of-care for the treatment of acute AMR.
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