A Review of Focal Segmental Glomerulosclerosis Classification With a Focus on Genetic Associations.

Focal segmental glomerulosclerosis (FSGS) defines a distinct histologic pattern observed in kidney tissue that is linked to several distinct underlying causes, all converging on the common factor of podocyte injury. It presents a considerable challenge in terms of classification because of its varied underlying causes and the limited correlation between histopathology and clinical outcomes. Critically, precise nomenclature is key to describe and delineate the pathogenesis, subsequently guiding the selection of suitable and precision therapies. A proposed pathomechanism-based approach has been suggested for FSGS classification. This approach differentiates among primary, secondary, genetic, and undetermined causes, aiming to provide clarity. Genetic FSGS from monogenic mutations can emerge during childhood or adulthood, and it is advisable to conduct genetic testing in cases in which there is a family history of chronic kidney disease, nephrotic syndrome, or resistance to treatment. Genome-wide association studies have identified several genetic risk variants, such as those in apolipoprotein L1 (APOL1), that play a role in the development of FSGS. Currently, no specific treatments have been approved to treat genetic FSGS; however, interventions targeting underlying cofactor deficiencies have shown potential in some cases. Furthermore, encouraging results have emerged from a phase 2 trial investigating inaxaplin, a novel small molecule APOL1 channel inhibitor, in APOL1-associated FSGS.

Charting new frontiers in IgA nephropathy: a paradigm shift toward precision medicine and early intervention?

Advancements in glomerular transcriptomics offer a promising avenue toward precision medicine in IgA nephropathy. Traditional prognostic biomarkers, including proteinuria, blood pressure, and histomorphometry, fall short at capturing the complexity of IgA nephropathy and can only crudely guide therapeutic decisions. This issue needs to be addressed urgently as pathway-specific treatments become available. Glomerular transcriptomics, although technically challenging, offers an opportunity to refine prognostic precision and identify therapeutic targets, even when apparent risk of disease progression is low.

Examining the association between serum galactose-deficient IgA1 and primary IgA nephropathy: a systematic review and meta-analysis.

BACKGROUND: IgA nephropathy (IgAN) is a common primary glomerular disease. The O-glycosylation status of IgA1 plays a crucial role in disease pathophysiology. The level of poorly-O-galactosylated IgA1, or galactose-deficient IgA1 (Gd-IgA1), has also been identified as a potential biomarker in IgAN. We sought to examine the value of serum Gd-IgA1 as a biomarker in IgAN, by investigating its association with clinical, laboratory, and histopathological features of IgAN. METHODS: The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and was registered in PROSPERO (CRD42021287423). The literature search was conducted in PubMed, Web of Science, Cochrane, and Scopus, and the selected articles were evaluated for eligibility based on predefined criteria. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Statistical analysis was performed to calculate effect sizes and assess heterogeneity among the studies. RESULTS: This review analyzed 29 out of 1,986 studies, conducted between 2005 and 2022, with participants from multiple countries. Gd-IgA1 levels were not associated with age and gender, while associations with hypertension, hematuria, and proteinuria were inconsistent. In the meta-analyses, a correlation between serum Gd-IgA1 and estimated glomerular filtration rate was identified, however, the relationships between Gd-IgA1 levels and chronic kidney disease (CKD) stage and progression to kidney failure were inconsistent. CONCLUSIONS: Serum Gd-IgA1 levels were not associated with validated prognostic risk factors, but were negatively correlated with kidney function. Further research in larger studies using standardized assays are needed to establish the value of Gd-IgA1 as a prognostic risk factor in IgAN.

Technological Innovations to Improve Patient Engagement in Nephrology.

Technological innovation has accelerated exponentially over the last 2 decades. From the rise of smartphones and social media in the early 2000s to the mainstream accessibility of artificial intelligence (AI) in 2023, digital advancements have transformed the way we live and work. These innovations have permeated health care, covering a spectrum of applications from virtual reality training platforms to AI-powered clinical decision support tools. In this review, we explore fascinating recent innovations that have and can facilitate patient engagement in nephrology. These include integrated care mobile applications, wearable health monitoring tools, virtual/augmented reality consultation and education platforms, AI-powered appointment booking systems, and patient information tools. We also discuss potential pitfalls in implementation and paradigms to adopt that may protect patients from unintended consequences of being cared for in a digitalized health care system.

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.

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 (miRNAs), regulate gene transcription and post-transcriptional processing of messenger RNA (mRNA). A single miRNA can modulate several genes within a cell, and several miRNAs can regulate expression of the same gene, adding tiers of complexity to the regulation of gene expression. miRNAs 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 focuses on miRNAs and their potential as biomarkers and novel therapeutics for glomerular disease.

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.

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.

Acute respiratory distress syndrome driven by severe hypercalcemia and acute kidney injury: A case report and literature review of a rare, life-threatening complication.

Acute respiratory distress syndrome (ARDS) is a rare and under-reported complication of hypercalcemia, which often presents in conjunction with acute kidney injury (AKI). Unfamiliarity with the condition inevitably leads to management uncertainty, resulting in fatal outcomes. Early identification, however, confers a good prognosis. We report a case of a 40-year-old male who presented with severe hypercalcemia and AKI and rapidly deteriorated due to ARDS, with no evidence of cardiogenic pulmonary edema or fluid overload. Infection screens were negative. He died despite invasive ventilation and continuous venous-venous hemofiltration. His autopsy revealed extensive metastatic pulmonary calcifications and alveolar edema. We found only 10 other cases of hypercalcemia-induced ARDS in the literature, with only 2 patients surviving. We provide the first literature review on the subject to guide the management of this rare but fatal complication, which can be managed with good outcomes if considered early.

Burnout and long COVID among the UK nephrology workforce: results from a national survey investigating the impact of COVID-19 on working lives.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is placing a significant strain on healthcare. We conducted a national survey of the UK nephrology workforce to understand its impacts on their working lives. METHODS: An online questionnaire incorporating the Maslach Burnout Inventory score was distributed between 31 March and 1 May 2021, with a focus on COVID-19 and long COVID incidence, vaccine uptake, burnout and working patterns. Data were analysed qualitatively and quantitatively; multivariable logistic regression was used to identify associations. RESULTS: A total of 423 responses were received. Of them, 29% had contracted COVID-19, which was more common among doctors and nurses {odds ratio [OR] 2.18 [95% confidence interval (CI) 1.13-4.22]} and those <55 years of age [OR 2.60 (95% CI 1.38-4.90)]. Of those who contracted COVID-19, 36% had symptoms of long COVID, which was more common among ethnicities other than White British [OR 2.57 (95% CI 1.09-6.05)]. A total of 57% had evidence of burnout, which was more common among younger respondents [OR 1.92 (95% CI 1.10-3.35)] and those with long COVID [OR 10.31 (95% CI 1.32-80.70)], and 59% with reconfigured job plans continued to work more hours. More of those working full-time wished to retire early. A total of 59% experienced remote working, with a majority preference for continuing this in the future. In terms of vaccination, 95% had received one dose of a COVID-19 vaccine and 86% had received two doses by May 2021. CONCLUSIONS: Burnout and long COVID is prevalent with impacts on working lives. Some groups are more at risk. Vaccination uptake is high and remote and flexible working were well received. Institutional interventions are needed to prevent workforce attrition.

Immunological drivers of IgA nephropathy: Exploring the mucosa-kidney link.

IgA nephropathy (IgAN) is the most common pattern of primary glomerular disease reported worldwide. Up to 40% of those with IgAN progress to end-stage kidney disease within 20 years of diagnosis, with no currently available disease-specific treatment. This is likely to change rapidly, with evolving insights into the mechanisms driving this disease. IgAN is an immune-complex-mediated disease, and its pathophysiology has been framed by the 'four-hit hypothesis', which necessitates four events to occur for clinically significant disease to develop. However, this hypothesis does not explain the wide variability observed in its presentation or clinical progression. Recently, there has been great interest in exploring the role of the mucosal immune system in IgAN, especially given the well-established link between mucosal infections and disease flares. Knowledge of antigen-mucosal interactions is now being successfully leveraged for therapeutic purposes; the gut-directed drug Nefecon (targeted release formulation-budesonide) is on track to become the first medication to be approved specifically for the treatment of IgAN. In this review, we examine established immunological paradigms in IgAN, explore how antigen-mucosal immune responses drive disease, and discuss how this knowledge is being used to develop new treatments.

New Insights into the Pathogenesis and Treatment Strategies in IgA Nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. It is defined by mesangial IgA deposition, with consequent mesangial cell proliferation, inflammation, and tubulointerstitial fibrosis. Summary: Approximately 30% of affected patients will progress to end-stage kidney disease within 20 years of diagnosis. Currently, there is no disease-specific treatment available and management recommendations are, in general, limited to optimization of lifestyle measures and use of renin-angiotensin-aldosterone system blockers. More recently, advances in the understanding of the pathogenesis of IgAN have informed the development of novel therapeutic strategies that are now being tested in clinical trials. These have focused on different areas that include modulating the production of poorly galactosylated IgA1, which is central to the development of IgAN, and inhibiting the downstream signaling pathways and complement activation that are triggered following mesangial IgA1 deposition. In this review, we will summarize important pathogenic mechanisms in IgAN and highlight important areas of interest where treatment strategies are being developed. Key messages: IgAN is a common form of primary glomerulonephritis for which there is no current approved specific therapy. Recent advances in the understanding of its pathogenesis have led to the development of novel therapies, with the hope that new treatment options will be available soon to treat this condition.

IgA nephropathy: an overview of drug treatments in clinical trials.

INTRODUCTION: IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide and may progress to end-stage kidney disease (ESKD) within a 10-20 year period. Its slowly progressive course has made clinical trials challenging to perform, however the acceptance of proteinuria reduction as a surrogate end point has significantly improved the feasibility of conducting clinical trials in IgAN, with several novel and repurposed therapies currently undergoing assessment. Already, interim results are demonstrating value to some of these, offering great hope to those with IgAN. AREAS COVERED: This review explores the rationale, candidates, clinical precedents, and trial status of therapies that are currently or have recently been evaluated for efficacy in IgAN. All IgAN trials registered with the U.S. National Library of Medicine; ClinicalTrials.gov were reviewed. EXPERT OPINION: For the first time, effective treatment options beyond supportive care are becoming available for those with IgAN. This is the culmination of commendable international efforts and signifies a new era for those with IgAN. As more therapies become available, future challenges will revolve around deciding which treatments are most appropriate for individual patients, which is likely to push IgAN into the realm of precision medicine.

A Pilot Study to Predict Risk of IgA Nephropathy Progression Based on miR-204 Expression.

INTRODUCTION: Immunoglobulin (Ig)A nephropathy (IgAN) is the most frequently diagnosed primary glomerulonephritis worldwide. Despite the common diagnostic feature of mesangial IgA-containing immune complex deposition, the clinical course of the disease is extremely variable, with 30% of patients developing end-stage kidney disease within 20 years of diagnosis. Therefore, identifying which patients are likely to progress is paramount. RESULTS: In this pilot study, we found that urinary exosomal miR-204 expression was significantly reduced in IgAN compared with healthy subjects. However, there was no difference in miR-204 expression between IgAN and non-IgAN chronic kidney disease controls. Analysis of miR-204 expression in kidney biopsy cores by next-generation sequencing followed by quantitative polymerase chain reaction validation in independent cohorts demonstrated that expression of miR-204 was significantly lower in IgAN compared with thin-membrane nephropathy but not compared with membranous nephropathy. Patients with IgAN at high risk of future progression had significantly lower expression of miR-204 than those at low risk of progression. Cortical localization indicated that miR-204 was preferentially expressed in the interstitium compared with glomeruli in IgAN nonprogressors and that this distribution was lost in IgAN progressors. Receiver operating characteristic curve analysis between the 2 IgAN cohorts revealed an area under the curve of 0.82. In addition, miR-204 expression correlated with known clinicopathological prognostic risk factors. Importantly, incorporating miR-204 into the International IgAN risk prediction tool improved the diagnostic power of the algorithm to predict risk of progression. CONCLUSION: Additional large-scale studies are now needed to validate the additive value of miR-204 in improving risk prediction in IgAN and more broadly in chronic kidney disease.

An Ethnic Variation in the Acceptance of Biological Disease-Modifying Therapies: A University Hospital Experience.

Ethnic variations in the outcomes of rheumatological diseases are well documented. While physiological differences may account for these disparities, attitude to treatment is also likely to be a significant modifiable contributor. We sought to determine if an ethnic variation exists in the uptake of biological disease-modifying anti-rheumatic drugs (DMARD) among a multi-ethnic cohort when offered in-person through a healthcare system free at the point of access. We conducted a retrospective cross-sectional study of patients seen in a biologic therapy counselling clinic between December 2016 and April 2017. Clinic letters from consultations were reviewed, and data including ethnicity, language spoken, and decision to accept or reject the therapy were extracted. We chose to measure uptake over adherence, as we believe it is an earlier, more direct marker of attitudes to joint saving medications. Ninety-one cases were included in the analysis. Over 13.2% (12/91) of the cohort declined a biologic treatment when it was offered as the standard of care for joint disease. Non-Caucasian patients accepted treatment less often than Caucasian (White British) patients (OR 0.265, CI 0.73-0.959, p = 0.043), as did those who did not speak English as a first language (OR 0.094, CI 0.18-0.497, p = 0.005). Age, sex, and diagnosis were well matched between those who accepted and declined therapy. We demonstrate a disparity in the uptake of biologic therapies between the White British population and patients from other ethnicities. The reasons for this are likely multifactorial and could be related to socio-economic factors, language barriers, and cultural differences. Addressing this discrepancy is a crucial first step to tackling preventable disparities in the outcomes of rheumatological disease between different ethnicities.

The Non-Coding RNA Landscape in IgA Nephropathy-Where Are We in 2021?

IgA nephropathy (IgAN) is the most commonly diagnosed primary glomerulonephritis worldwide. It is a slow progressing disease with approximately 30% of cases reaching end-stage kidney disease within 20 years of diagnosis. It is currently only diagnosed by an invasive biopsy and treatment options are limited. However, the current surge in interest in RNA interference is opening up new horizons for the use of this new technology in the field of IgAN management. A greater understanding of the fundamentals of RNA interference offers exciting possibilities both for biomarker discovery and, more importantly, for novel therapeutic approaches to target key pathogenic pathways in IgAN. This review aims to summarise the RNA interference literature in the context of microRNAs and their association with the multifaceted aspects of IgA nephropathy.

Monitoring Immune Responses in IgA Nephropathy: Biomarkers to Guide Management.

IgA nephropathy (IgAN) is the commonest biopsy-reported primary glomerulonephritis worldwide. It has an incidence which peaks among young adults, and 30 to 40% of patients' progress to end stage kidney disease within twenty years of diagnosis. Ten-year kidney survival rates have been reported to be as low as 35% in some parts of the world. The successful management of IgAN is limited by an incomplete understanding of the pathophysiology of IgAN and a poor understanding of how pathophysiology may vary both from patient to patient and between patient groups, particularly across races. This is compounded by a lack of rigorously designed and delivered clinical trials in IgAN. This is slowly changing, with a number of Phase 2 and 3 clinical trials of novel therapies targeting a number of different putative pathogenic pathways in IgAN due to report in the next 5 years. From our current, albeit limited, understanding of the pathophysiology of IgAN it is unlikely a single therapy will be effective in all patients with IgAN. The successful management of IgAN in the future is, therefore, likely to be reliant on targeted therapies, carefully selected based on an individualized understanding of a patient's risk of progression and underlying pathophysiology. The potential role of biomarkers to facilitate personalization of prognostication and treatment of IgAN is immense. Here we review the progress made over the past decade in identifying and validating new biomarkers, with a particular focus on those that reflect immunological responses in IgAN.