Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond?

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.

Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment.

Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidney-limited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.

Predictive Models for Recurrent Membranous Nephropathy After Kidney Transplantation.

Recurrent membranous nephropathy (MN) posttransplantation affects 35% to 50% of kidney transplant recipients (KTRs) and accounts for 50% allograft loss 5 y after diagnosis. Predictive factors for recurrent MN may include HLA-D risk alleles, but other factors have not been explored with certainty. Methods: The Australian and New Zealand Dialysis and Transplant registry was used to develop 3 prediction models for recurrent MN (Group Least Absolute Shrinkage and Selection Operator [LASSO], penalized Cox regression, and random forest), which were tuned using tenfold cross-validation in a derivation cohort with complete HLA data. KTRs with MN but incomplete HLA data formed the validation cohort. Model performance was evaluated using area under the receiver operating characteristic curve (AUC-ROC). Results: One hundred ninety-nine KTRs with MN were included, and 25 (13%) had recurrent MN (median follow-up 5.9 y). The AUC-ROCs for Group LASSO, penalized Cox regression, and random forest models were 0.85 (95% confidence interval, 0.76-0.94), 0.91 (0.85-0.96), and 0.62 (0.57-0.69), respectively, in the derivation cohort, with moderate agreement in selected variables between the models (55%-70%). In their validation cohorts, the AUC-ROCs for Group LASSO and penalized Cox regression were 0.60 (0.49-0.70) and 0.73 (0.59-0.86), respectively. Variables of importance chosen by all models included recipient HLA-A2, donor HLA-DR12, donor-recipient HLA-B65, and HLA-DR12 match. Conclusions: A penalized Cox regression performed reasonably for predicting recurrent MN and was superior to Group LASSO and random forest models. These models highlighted the importance of donor-recipient HLA characteristics to recurrent MN, although validation in larger datasets is required.

Biomarkers in Cardiorenal Syndrome and Potential Insights Into Novel Therapeutics.

Heart and kidney failure often co-exist and confer high morbidity and mortality. The complex bi-directional nature of heart and kidney dysfunction is referred to as cardiorenal syndrome, and can be induced by acute or chronic dysfunction of either organ or secondary to systemic diseases. The five clinical subtypes of cardiorenal syndrome are categorized by the perceived primary precipitant of organ injury but lack precision. Traditional biomarkers such as serum creatinine are also limited in their ability to provide an early and accurate diagnosis of cardiorenal syndrome. Novel biomarkers have the potential to assist in the diagnosis of cardiorenal syndrome and guide treatment by evaluating the relative roles of implicated pathophysiological pathways such as hemodynamic dysfunction, neurohormonal activation, endothelial dysfunction, inflammation and oxidative stress, and fibrosis. In this review, we assess the utility of biomarkers that correlate with kidney and cardiac (dys)function, inflammation/oxidative stress, fibrosis, and cell cycle arrest, as well as emerging novel biomarkers (thrombospondin-1/CD47, glycocalyx and interleukin-1ß) that may provide prediction and prognostication of cardiorenal syndrome, and guide potential development of targeted therapeutics.

Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor.

BACKGROUND: The cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy. METHODS: We administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice. RESULTS: BAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33-treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33-stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)-depleted splenocytes. Wild-type mice infused with IL-33-treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution. CONCLUSIONS: IL-33-expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.

Immunosuppression therapy for idiopathic membranous nephropathy: systematic review with network meta-analysis.

BACKGROUND: Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adults. The Kidney Disease Improving Global Outcomes guidelines recommend rituximab or cyclophosphamide and steroids, or calcineurin inhibitor-based therapy. However, there have been few or no head-to-head comparisons of the relative efficacy and safety of different immunosuppression regimens. We conducted a network meta-analysis to evaluate the comparative efficacy and safety of available immunosuppression strategies compared to cyclophosphamide in adults with idiopathic membranous nephropathy. METHODS: We performed a systematic search of MEDLINE, Embase and CENTRAL for randomized controlled trials in the treatment of adults with idiopathic membranous nephropathy. The primary outcome was complete remission. Secondary outcomes were kidney failure, partial remission, estimated glomerular filtration rate, doubling of serum creatinine, proteinuria, serious adverse events, discontinuation of treatment, serious infection and bone marrow suppression. RESULTS: Cyclophosphamide had uncertain effects on inducing complete remission when compared to rituximab (OR 0.35, CI 0.10-1.24, low certainty evidence), mycophenolate mofetil (OR 1.81, CI 0.69-4.71, low certainty), calcineurin inhibitor (OR 1.26, CI 0.61-2.63, low certainty) or steroid monotherapy (OR 2.31, CI 0.62-8.52, low certainty). Cyclophosphamide had a higher probability of inducing complete remission when compared to calcineurin inhibitor plus rituximab (OR 4.45, CI 1.04-19.10, low certainty). Compared to other immunosuppression strategies, there was limited evidence that cyclophosphamide had different effects on other pre-specified outcomes. CONCLUSIONS: The comparative effectiveness and safety of immunosuppression strategies compared to cyclophosphamide is uncertain in adults with idiopathic membranous nephropathy.

Retrospective study on the epidemiology of antineutrophil cytoplasmic autoantibodies-associated vasculitis in two Australian health districts.

BACKGROUND: Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV) is more prevalent in rural Australia compared with metropolitan areas, suggesting a role of environment in disease pathogenesis. However, the prevalence of environmental risk factors in Australian AAV patients has not been described. AIMS: To compare the incidence of AAV between two health districts (Illawarra Shoalhaven Local Health District (ISLHD), a mixed rural/metropolitan region, and South Eastern Sydney Local Health District (SESLHD), a metropolitan region) in Australia and its relationship to environmental exposures. METHODS: Cases of AAV from 2002 to 2017 were retrospectively identified from ISLHD and SESLHD using electronic medical records. Eligible participants were invited to complete a standardised questionnaire examining their exposure to silica, solvents, metal, dust, farming, gardening and sunlight. RESULTS: One hundred and fifty-six cases of AAV were identified from 2002 to 2017. A higher cumulative incidence of AAV was observed in the ISLHD (184.2 (95% confidence interval (CI) 143.6-232.7) per million) compared with SESLHD (102.6 (95% CI 82.1-126.8) per million). Over 50% of the cohort had high levels of silica and solvents exposure, based on self-reported questionnaires. There was no significant relationship between region and exposure to silica (P = 0.96), solvents (P = 0.44), metal (P = 0.33), dust (P = 0.25), farming (P = 0.90), gardening (P = 0.93) or sunlight (P = 0.55). CONCLUSIONS: We found a higher incidence of AAV in ISLHD compared with SESLHD with high levels of exposure to silica and solvents in both regions based on self-reported questionnaires. Prospective systematic collection of data, such as a registry of AAV, is warranted to further explore the relationship between environmental exposures and AAV.

Incidence and Outcomes of COVID-19 in People With CKD: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: Coronavirus disease 2019 (COVID-19) disproportionately affects people with chronic diseases such as chronic kidney disease (CKD). We assessed the incidence and outcomes of COVID-19 in people with CKD. STUDY DESIGN: Systematic review and meta-analysis by searching MEDLINE, EMBASE, and PubMed through February 2021. SETTING & STUDY POPULATIONS: People with CKD with or without COVID-19. SELECTION CRITERIA FOR STUDIES: Cohort and case-control studies. DATA EXTRACTION: Incidences of COVID-19, death, respiratory failure, dyspnea, recovery, intensive care admission, hospital admission, need for supplemental oxygen, hospital discharge, sepsis, short-term dialysis, acute kidney injury, and fatigue. ANALYTICAL APPROACH: Random-effects meta-analysis and evidence certainty adjudicated using an adapted version of GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: 348 studies (382,407 participants with COVID-19 and CKD; 1,139,979 total participants with CKD) were included. Based on low-certainty evidence, the incidence of COVID-19 was higher in people with CKD treated with dialysis (105 per 10,000 person-weeks; 95% CI, 91-120; 95% prediction interval [PrI], 25-235; 59 studies; 468,233 participants) than in those with CKD not requiring kidney replacement therapy (16 per 10,000 person-weeks; 95% CI, 4-33; 95% PrI, 0-92; 5 studies; 70,683 participants) or in kidney or pancreas/kidney transplant recipients (23 per 10,000 person-weeks; 95% CI, 18-30; 95% PrI, 2-67; 29 studies; 120,281 participants). Based on low-certainty evidence, the incidence of death in people with CKD and COVID-19 was 32 per 1,000 person-weeks (95% CI, 30-35; 95% PrI, 4-81; 229 studies; 70,922 participants), which may be higher than in people with CKD without COVID-19 (incidence rate ratio, 10.26; 95% CI, 6.78-15.53; 95% PrI, 2.62-40.15; 4 studies; 18,347 participants). LIMITATIONS: Analyses were generally based on low-certainty evidence. Few studies reported outcomes in people with CKD without COVID-19 to calculate the excess risk attributable to COVID-19, and potential confounders were not adjusted for in most studies. CONCLUSIONS: The incidence of COVID-19 may be higher in people receiving maintenance dialysis than in those with CKD not requiring kidney replacement therapy or those who are kidney or pancreas/kidney transplant recipients. People with CKD and COVID-19 may have a higher incidence of death than people with CKD without COVID-19.

The global incidence and mortality of contrast-associated acute kidney injury following coronary angiography: a meta-analysis of 1.2 million patients.

BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) is a common complication after coronary angiography (CAG), which brings a poor prognosis. But up to now, there were fewer studies to discuss the incidence of CA-AKI comprehensively. We comprehensively explore the incidence of CA-AKI after coronary angiography. METHODS: We searched Medline, Embase, and Cochrane Database of Systematic Reviews (to 30th June 2019). We evaluated the world's incidence of the CA-AKI, and associated mortality, and to described geographic variations according to countries, regions, and economies. CA-AKI was defined as an increase in serum creatinine ≥ 0.5 mg/dl or ≥ 25% within 72 h. Random effects model meta-analyses and meta-regressions was performed to derive the sources of heterogeneity. RESULTS: A total of 134 articles (1,211,106 participants) were included in our meta-analysis. Most studies originated from China, Japan, Turkey and United States, from upper middle income and high income countries. The pooled incidence of CA-AKI after coronary angiography was 12.8% (95% CI 11.7-13.9%), and the CA-AKI associated mortality was 20.2% (95% CI 10.7-29.7%). The incidence of CA-AKI and the CA-AKI associated mortality were not declined over time (Incidence rate change: 0.23% 95% CI - 0.050 to 0.510 p = 0.617; Mortality rate change: - 1.05% 95% CI - 3.070 to 0.970 p = 0.308, respectively). CONCLUSION: CA-AKI was a universal complication in many regions, and the burden of CA-AKI remains severe. In clinical practice, physicians should pay more attention to the occurrence and active prevention and treatment of CA-AKI.

Glomerular, Mesangial, and Tubular Cytoplasmic Fibrillary Inclusions in a Patient with Light-Chain Proximal Tubulopathy.

Monoclonal immunoglobulin or free light chains, produced in the setting of plasma cell dyscrasias, are a common cause of kidney injury with a wide variety of disease patterns. Light-chain proximal tubulopathy is a rare form of this disease that is often difficult to diagnose due to its relatively indolent presentation, subtle light microscopic findings, and often negative immunofluorescence using routine laboratory techniques. We report a case of light-chain proximal tubulopathy with cytoplasmic fibrillary inclusions in tubular cells, glomerular endothelial cells, and mesangial cells, which were positive for κ light chains on immunostaining after pronase digestion. Cytoplasmic fibrillary inclusions, composed of monoclonal protein, are strongly suggestive of underlying plasma cell dyscrasias, and such cases warrant further hematological investigations.

Interventions to Prevent Nonmelanoma Skin Cancers in Recipients of a Solid Organ Transplant: Systematic Review of Randomized Controlled Trials.

BACKGROUND: Organ transplant recipients are at high risk of developing skin cancer. The benefits and harms of interventions to prevent nonmelanoma skin cancer in solid organ transplant recipients have not been summarized. METHODS: We searched MEDLINE, Embase, and CENTRAL through April 2018. Risk of bias was assessed using the Cochrane tool, and evidence certainty was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation process. Prespecified outcomes were nonmelanoma skin cancer, clearance and prevention of keratotic skin lesions, and intervention-specific adverse events. RESULTS: Ninety-two trials (20 012 participants) were included. The evaluated treatments were cancer-specific interventions (acitretin, imiquimod, photodynamic therapy, nicotinamide, topical diclofenac, and selenium) and immunosuppression regimes (azathioprine, mycophenolate mofetil, calcineurin inhibitors, mammalian target of rapamycin [mTOR] inhibitors, belatacept, induction agents, and withdrawal of calcineurin inhibitors or corticosteroids). Effects on nonmelanoma skin cancer were uncertain for photodynamic therapy (3 trials, 93 participants, risk ratio [RR] 1.42 [95% confidence interval (CI), 0.65-3.11]; low certainty evidence), nicotinamide (2 trials, 60 participants), acitretin (2 trials, 61 participants), and imiquimod (1 trial, 20 participants) compared to control. mTOR inhibitors probably reduced skin cancer compared to calcineurin inhibitors (12 trials, 2225 participants, RR 0.62 [95% CI, 0.45-0.85]; moderate certainty evidence). Photodynamic therapy may cause pain at the treatment site (4 trials, 95 patients, RR 17.09 [95% CI, 4.22-69.26]; low certainty evidence). CONCLUSIONS: There is limited evidence for the efficacy and safety of specific treatments to prevent nonmelanoma skin cancers among solid organ transplant recipients.