Clinical application of microRNAs in glomerular diseases.

RNA interference (RNAi) occurs in all organisms and modulates most, if not all, biological pathways. It is the process by which non-coding RNAs, including microRNAs (miRs), regulate gene transcription and post-transcriptional processing of messenger RNA (mRNA). A single miR can modulate several genes within a cell, and several miRs can regulate expression of the same gene, adding tiers of complexity to regulation of gene expression. MicroRNAs and other RNAi approaches have been successfully used in vitro and in vivo to selectively manipulate gene transcription, making them pivotal agents for basic science research and candidates for targeted therapeutics. This review will focus on miRs and their potential as biomarkers and novel therapeutics for glomerular disease

Diabetic myonecrosis: A case series of two dialysis-dependent patients.

Diabetic myonecrosis (DMN) is a rare microangiopathic disorder that can present as an acutely painful and swollen limb in patients with established diabetes mellitus. The condition can be diagnosed noninvasively with magnetic resonance imaging and resolves with analgesia, bed rest, and glycemic control. Due to a relative lack of awareness regarding the condition, avoidable interventions such as muscle biopsies and even surgery are sometimes pursued, which have been associated with prolonged recovery times. The majority of patients with DMN have diabetic nephropathy, yet this condition is not widely recognized in the nephrology community, resulting in delayed diagnosis and patients undergoing unnecessary and potentially harmful investigations. There is therefore a need for increased awareness of the condition among renal physicians. Here, we report the cases of two patients on hemodialysis who were ultimately diagnosed with DMN, along with a review of the literature

MicroRNAs: a new avenue to understand, investigate and treat immunoglobulin A nephropathy?

IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Up to 30% of cases develop the progressive form of the disease, eventually requiring renal replacement therapy. Diagnosis and risk stratification relies on an invasive kidney biopsy and management options are limited, with recurrence following renal transplantation being common. Thus the quest to understand the pathophysiology of IgAN has been one of great importance. MicroRNAs (miRs) are short nucleotides that suppress gene expression by hybridizing to the 3' untranslated region of messenger RNA (mRNAs), promoting mRNA degradation or disrupting translation. First discovered in 1993, miRs have since been implicated in a number of chronic conditions, including cancer, heart disease and kidney disease. The mounting interest in the field of miRs has led to fascinating developments in the field of nephrology, ranging from their roles as biomarkers for disease to the development of miR antagonists as avenues for treatment. The translational potential for miRs in IgAN is thus well grounded and may represent a paradigm shift in current approaches to the disease. This review aims to summarize the literature with regard to miRs and their roles in IgAN

Novel Treatment Paradigms: Primary IgA Nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Approximately 30% to 45% of patients progress to kidney failure (KF) within 20 to 25 years of diagnosis, and there has long been a lack of effective treatments. The therapeutic landscape in IgAN is rapidly evolving, driven in large part by the acceptance of the surrogate clinical trial end point of proteinuria reduction by regulatory authorities for the accelerated approval of new therapies. Two drugs, targeted release formulation (TRF)-budesonide (nefecon) and sparsentan, have recently been approved under this scheme. Advancing insights into the pathophysiology of IgAN, including the roles of the mucosal immune system, B-cells, the complement system, and the endothelin system have driven development of therapies that target these factors. This review outlines current, recently approved, and emerging therapies for IgAN

New strategies and perspectives on managing IgA nephropathy.

IgA nephropathy is an inflammatory renal disease characterised by the deposition of IgA in the glomerular mesangium and is the most commonly reported primary glomerulonephritis worldwide. Thirty to forty percent of patients with the disease develop progressive renal function decline, requiring renal replacement therapy within two decades of diagnosis. Despite this, accurate individual risk stratification at diagnosis and predicting treatment response remains a challenge. Furthermore, there are currently no disease specific treatments currently licensed to treat the condition due to long standing challenges in the nature and prevalence of the disease. Despite this, there have been exciting recent advances in the field that may represent paradigm shifts in the way IgA nephropathy is managed in the near future. In this review, we explore the evidence base informing current approaches to management and explore new strategies and future directions in the diagnosis and management of IgA nephropathy

The Exclusion of Patients with CKD in Prospectively Registered Interventional Trials for COVID-19-a Rapid Review of International Registry Data.

The exclusion of patients with CKD from clinical trials has been a barrier to therapeutic advancement in CKD for the last two decades.1 These inequities were highlighted by the Kidney Disease Improving Global Outcomes Controversies Conference, with the ambition of ensuring that individuals with CKD are included in relevant clinical trials.2 The coronavirus disease 2019 (COVID-19) pandemic’s global effect has led to rapid clinical trial registration and commencement in search of effective treatments. Individuals with CKD are at higher risk of COVID-19–related mortality.3 It is unclear, however, if these individuals have equitable access to clinical trial recruitment. Therefore, we aimed to assess the CKD-related inclusion and exclusion criteria for COVID-19 trials

Seroprevalence of antibody to S1 spike protein following vaccination against COVID-19 in patients receiving hemodialysis: a call to arms

Letter to the Editor

Risk factors associated with COVID-19 severity among patients on maintenance haemodialysis: a retrospective multicentre cross-sectional study in the UK

Objectives: To assess the applicability of risk factors for severe COVID-19 defined in the general population for patients on haemodialysis.  Setting: A retrospective cross-sectional study performed across thirty four haemodialysis units in midlands of the UK.  Participants: All 274 patients on maintenance haemodialysis who tested positive for SARS-CoV-2 on PCR testing between March and August 2020, in participating haemodialysis centres. Exposure: The utility of obesity, diabetes status, ethnicity, Charlson Comorbidity Index (CCI) and socioeconomic deprivation scores were investigated as risk factors for severe COVID-19.  Main outcomes and measures: Severe COVID-19, defined as requiring supplemental oxygen or respiratory support, or a C reactive protein of ≥75 mg/dL (RECOVERY trial definitions), and its association with obesity, diabetes status, ethnicity, CCI, and socioeconomic deprivation.  Results: 63.5% (174/274 patients) developed severe disease. Socioeconomic deprivation associated with severity, being most pronounced between the most and least deprived quartiles (OR 2.81, 95% CI 1.22 to 6.47, p=0.015), after adjusting for age, sex and ethnicity. There was no association between obesity, diabetes status, ethnicity or CCI with COVID-19 severity. We found no evidence of temporal evolution of cases (p=0.209) or clustering that would impact our findings.  Conclusion: The incidence of severe COVID-19 is high among patients on haemodialysis; this cohort should be considered high risk. There was strong evidence of an association between socioeconomic deprivation and COVID-19 severity. Other risk factors that apply to the general population may not apply to this cohort.</p

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window).Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p Background Methods Findings Interpretation Funding</p

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.</p