Acoustic trauma slows AMPAR-mediated EPSCs in the auditory brainstem, reducing GluA4 subunit expression as a mechanism to rescue binaural function

Damaging levels of sound (acoustic trauma, AT) diminish peripheral synapses, but what is the impact on the central auditory pathway? Developmental maturation of synaptic function and hearing were characterized in the mouse lateral superior olive (LSO) from postnatal day 7 (P7) to P96 using voltage-clamp and auditory brainstem responses. IPSCs and EPSCs show rapid acceleration during development, so that decay kinetics converge to similar sub-millisecond time-constants (τ, 0.87 ± 0.11 and 0.77 ± 0.08 ms, respectively) in adult mice. This correlated with LSO mRNA levels for glycinergic and glutamatergic ionotropic receptor subunits, confirming a switch from Glyα2 to Glyα1 for IPSCs and increased expression of GluA3 and GluA4 subunits for EPSCs. The NMDA receptor (NMDAR)-EPSC decay τ accelerated from >40 ms in prehearing animals to 2.6 ± 0.4 ms in adults, as GluN2C expression increased. In vivo induction of AT at around P20 disrupted IPSC and EPSC integration in the LSO, so that 1 week later the AMPA receptor (AMPAR)-EPSC decay was slowed and mRNA for GluA1 increased while GluA4 decreased. In contrast, GlyR IPSC and NMDAR-EPSC decay times were unchanged. Computational modelling confirmed that matched IPSC and EPSC kinetics are required to generate mature interaural level difference functions, and that longer-lasting EPSCs compensate to maintain binaural function with raised auditory thresholds after AT. We conclude that LSO excitatory and inhibitory synaptic drive matures to identical time-courses, that AT changes synaptic AMPARs by expression of subunits with slow kinetics (which recover over 2 months) and that loud sounds reversibly modify excitatory synapses in the brain, changing synaptic function for several weeks after exposure

Regional variations in nephrology trainee confidence with clinical skills may relate to the availability of local training opportunities in the UK: results from a national survey.

BACKGROUND The United Kingdom offers a standardised training program for nephrology fellows. However, local training opportunities vary resulting in mismatches between trainee interests and accessible opportunities. This may impact trainee confidence, satisfaction, and future service provision. METHODS A survey assessing confidence with key procedures and sub-specialities was disseminated. Associations with region of training were probed using Chi square tests, with significance set at p < 0.0008 following a Bonferroni correction. Results were compared to trainee views on available opportunities for development. RESULTS 139 responses were received (32% response rate, demographics representative of the UK nephrology trainee cohort). Procedural independence varied from 98% for temporary femoral vascular catheters to 5% for peritoneal dialysis catheters (PDIs). Independence with inserting tunnelled vascular catheters varied with region (p < 0.0001). Trainees expressed a desire for formal training in kidney ultrasound scanning and PDIs, corresponding with procedures they had least opportunity to become independent with. Trainees felt least confident managing kidney disease in pregnancy. Suggestions for improving training included protected time for garnering sub-speciality knowledge, developing procedural skills and for experiencing practice in other nephrology units. CONCLUSIONS A mismatch between trainee interests and professional development opportunities exists, which may threaten trainee autonomy and impact patient care particularly with regards to peritoneal dialysis. Provisions to facilitate trainee directed development need to be made while balancing the rigors of service provision. Such measures could prove critical to promoting trainee well-being and preventing attrition within the nephrology workforce

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