The Role of Filtered IgA in the Progression of IgA Nephropathy

IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide, with 20-40% of patients developing progressive kidney disease. The most accurate predictors of prognosis are the presence of proteinuria and tubulointerstitial fibrosis, while the degree of mesangial IgA deposition is not a prognostic factor. These findings imply that tubular-specific factors play a key role in progressive IgAN. The aim of this thesis was to explore whether filtered IgA has a direct effect on proximal tubular epithelial cell (PTEC) activation and generation of pro-inflammatory and pro-fibrotic cytokines. The interaction between IgA and PTEC was initially investigated in vivo in Munich Wistar Frömter rats by multiphoton microscopy. These studies demonstrated that IgA, that crossed the glomerular filtration barrier, interacted with PTEC and underwent endocytosis via their apical surface. This process was greatly upregulated in a model of podocyte injury, resulting in increased amounts of filtered IgA. In vitro, human IgA1, and especially galactose-deficient polymeric IgA1, stimulated release of pro-inflammatory and pro-fibrotic cytokines from cultured human HK-2 PTEC. A mouse model of IgAN was optimised that developed both glomerular and tubulointerstitial inflammatory cell infiltration. Although glomerular deposition of complement component C3 was increased in the model, mice genetically deficient in key initiators of the lectin pathway, Collectin-11 (CL-11) or Mannose-binding lectin-associated serine protease-2 (MASP-2), were not protected from interstitial macrophage infiltration, while reductions in glomerular cell number and T cell infiltration were observed. These studies provide evidence for the first time that filtered IgA is able to interact with the proximal tubule and undergo endocytosis. IgA1, and especially galactosedeficient polymeric IgA1, stimulated a pro-inflammatory and pro-fibrotic response from PTEC that may contribute towards progressive IgAN. Understanding this interaction further may reveal novel targets for therapy in this condition. Deficiencies in CL-11 and MASP-2 did not protect against tubulointerstitial inflammation in a mouse model of IgAN, and further studies should concentrate on whether the alternative pathway is activated in this model

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 insights into the pathogenesis of IgA nephropathy

IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic "hits". An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression

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 role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies

Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose-deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary glomerulonephritis worldwide. Recently, an improved understanding of its underlying pathogenesis and the substantial risk of progression to kidney failure has emerged. The “four-hit hypothesis” of IgAN pathogenesis outlines a process that begins with elevated circulating levels of Gd-IgA1 that trigger autoantibody production. This results in the formation and deposition of immune complexes in the mesangium, leading to inflammation and kidney injury. Key mediators of the production of Gd-IgA1 and its corresponding autoantibodies are B-cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL), each playing essential roles in the survival and maintenance of B cells and humoral immunity. Elevated serum levels of both BAFF and APRIL are observed in patients with IgAN and correlate with disease severity. This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease. Finally, the potential therapeutic benefits of inhibiting BAFF and APRIL in IgAN, and a summary of recent clinical trial data, will be discussed

Toscana virus meningo-encephalitis: an important differential diagnosis for elderly travellers returning from Mediterranean countries

BACKGROUND: Elderly patients have a long list of differentials for causes of acute confusion and altered consciousness levels, including infectious agents. In addition, elderly, retired patients often have more time to travel for tourism, particularly to exotic, warmer locations. Mediterranean countries such as Spain and Italy are popular holiday destinations for British and other tourists, especially during the winter months. However, these warm climates allow insect vectors to proliferate, increasing the risk of exposure to endemic vectorborne viral infections whilst on vacation. Such infections may not be routinely considered by geriatric medical teams. CASE PRESENTATION: An 87-year old gentleman presented with a three-day history of worsening confusion, lethargy, ataxia, and fevers following a trip to Spain, where he may have sustained a sandfly bite. By the time of admission, he had a reduced GCS, was hallucinating, and was incontinent of urine and faeces, though blood pressure and heart rate were normal. He also appeared hyperaesthetic, and found even capillary blood sugar testing extremely painful. He had no history of cognitive defect or other neurological conditions. He had been previously independently active, with frequent trips to Spain where he maintained a holiday home. He probably sustained a sandfly bite during this most recent trip, whilst cleaning out a shed. Acute and convalescent sera demonstrated IgG antibodies to Toscana virus at extremely high titres of ≥1:10,000 by immunofluorescence assay, though no Toscana virus RNA was detectable in these sera by the time of presentation. CONCLUSIONS: Toscana virus should be included in the differential diagnosis of any patients presenting with meningo-encephalitis who have recently returned from a Mediterranean country. Testing for Toscana virus infection is performed by serological testing on acute/convalescent paired sera, and/or a polymerase chain reaction (PCR) assay on blood or cerebrospinal fluid (CSF) if presenting within 5 days of illness onset. Making a diagnosis of Toscana virus meningitis/encephalitis (where no other pathogen is detected) has additional clinical utility in reducing or preventing unnecessary use of antibiotics, as well as reassuring the patient and family that generally, this illness is generally self-limiting and full recovery within a few weeks is expected, as in the case reported here

Use of Eculizumab During Pregnancy in Kidney Transplant Recipients With Atypical HUS

To the Editor: Duvaletal. 1 recently described a kidney transplant recipient who developed atypical hemolytic uremic syndrome, and was treated with eculizumab during pregnancy with a successful outcome. We described a similar case recently (Cheung CK, Evans K, Williams M, et al. A successful pregnancy in a patient following renal transplantation for atypical HUS managed with eculizumab. UK Kidney Week; June 2018. Available at: https://britishrenal.org/ukkw2018-2/abstracts-2/. Accessed September 29, 2019)</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