An Update on the Current State of Management and Clinical Trials for IgA Nephropathy.
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ABSTRACT:
SUBMITTER: Cheung CK
PROVIDER: S-EPMC8200196 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia and the Western world. In most patients, it follows an asymptomatic to oligosymptomatic course and GFR loss, if any, is slow. The mainstay of therapy therefore is optimized supportive care, i.e., measures that lower blood pressure, reduce proteinuria, minimize lifestyle risk factors, and otherwise help to reduce non-specific insults to the kidneys. The value of immunosuppression has become controversial and if at all, systemic high-dose corticosteroid therapy should be considered for a few months taking into account patient characteristics that would caution against or preclude such therapy. In addition, adverse events related to corticosteroid therapy markedly increase as GFR declines. Beyond corticosteroids, there is little evidence that any additional immunosuppression is helpful, with the exception of mycophenolate mofetil in patients of Asian descent. A considerable number of clinical trials ranging from enteric coated budesonide to blockade of B-cell function to complement inhibitors are currently ongoing and will hopefully allow a more targeted therapy of high-risk patients with progressive IgAN in the future.
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Project description:In the last 15 years clinical islet transplantation has made the leap from experimental procedure to standard of care for a highly selective group of patients. Due to a risk-benefit calculation involving the required systemic immunosuppression the procedure is only considered in patients with type 1 diabetes, complicated by severe hypoglycemia or end stage renal disease. In this review we summarize current outcomes of the procedure and take a look at ongoing and future improvements and refinements of beta cell therapy.
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Project description:IgA Nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Despite the histopathologic hallmark of mesangial IgA deposition, IgAN is a heterogenous autoimmune disease not only in terms of clinical presentation but also in long-term disease progression. The pathogenesis of the disease is complex and includes the generation of circulating IgA immune complexes with chemical and biological characteristics that favor mesangial deposition and reaction to mesangial under-glycosylated IgA1 accumulation, which leads to tissue injury with glomerulosclerosis and interstitial fibrosis. Patients with proteinuria over 1 g, hypertension, and impaired renal function at diagnosis are considered to be at high risk for disease progression and end-stage kidney disease (ESKD). Glucocorticoids have been the mainstay of treatment for these patients for years, but without long-term benefit for renal function and accompanied by several adverse events. A better understanding of the pathophysiology of IgAN in recent years has led to the development of several new therapeutic agents. In this review, we summarize the current therapeutic approach for patients with IgAN as well as all novel investigational agents.
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Project description:IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end-stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin- angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrated renoprotective effects following the use of oral corticosteroids. However, results have been inconsistent, and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high-profile STOP-IgAN and TESTING clinical trials. Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T-cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signaling pathways of nephritogenic polymeric IgA1 complexes (e.g., signaling of immune receptors via spleen tyrosine kinase) has formed the rationale for the development of novel agents and clinical trials of more targeted therapies. However, translating findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation into future targeted therapies for this complex disease.
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Project description:IntroductionRenin-angiotensin system (RAS) blockade using angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) is first-line therapy for IgA nephropathy (IgAN). There is a paucity of information on the predictors and magnitude of response to this treatment.MethodsIn a prospective study, treatment-naive patients with IgAN with urinary protein ≥ 1 g/d and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2 received supportive treatment including ACEi (ramipril) or ARB (losartan) in patients intolerant to ACEi, and optimal blood pressure (BP) control to ≤130/80 mm Hg, with a follow-up of 6 months. The primary outcome was remission of proteinuria. Complete remission (CR) was defined as proteinuria < 0.5 g/d and partial remission (PR) as proteinuria < 1g/d with at least a 50% decline from the baseline with stable renal function (≤ 25% reduction in eGFR).ResultsA total of 96 patients were analyzed, with a mean age of 33.3 ± 10.2 years, baseline eGFR 74.0 ± 30.9 ml/min per 1.73 m2, and urinary protein 2.6 ± 1.2 g/d. In all, 71.9% patients received ≥ 75% of the maximum approved dose of ACEi/ARB. Remission was observed in 36.5% (CR, 6.3%) patients at 3 months and in 55.2% (CR, 31.3%) at 6 months. Patients who failed to achieve remission had lower baseline eGFR (P = 0.002) and serum albumin levels (P< 0.001), asymptomatic hyperuricemia (P < 0.001), and higher proteinuria (P = 0.076). E1 (P= 0.053) and T1/T2 (P = 0.009) lesions were more frequent on histology. The ACEi/ARB had to be discontinued in 17 (17.7%) patients. These patients were older (P= 0.085) with lower eGFR (P < 0.002) and serum albumin levels (P = 0.001) and more E1 (P = 0.012) and T1/T2 (P = 0.001) lesions on histology.ConclusionMeticulous supportive therapy with optimal use of ACEi/ARB achieved remission in half of IgAN patients in this study. Increasing the treatment duration to 6 months improved remission rates. Patients with severe clinical and histological disease were less likely to tolerate and respond to treatment with RAS blockade.
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Project description:Immunoglobulin (Ig) A nephropathy (IgAN) is the commonest form of primary glomerulonephritis worldwide and is, considered a significant cause of end-stage renal disease in young adults. The precise pathogenesis of IgAN is unclear. The clinical and pathological features vary significantly between individuals and races, which makes treating IgAN difficult. Currently, the therapeutic strategies in IgAN are still optimal blood pressure control and proteinuria remission to improve the renal function in most cases. Immunosuppressive drugs such as corticosteroids can be considered in patients with persistent proteinuria and a high risk of renal function decline; however, they include a high toxicity profile. Therefore, the safety and selectivity of medications are critical concerns in the treatment of IgAN. Various pharmacological therapeutic targets have emerged based on the evolving understanding of the autoimmune pathogenesis of IgAN, which involves the immune response, mucosal immunity, renal inflammation, complement activation, and autophagy; treatments based on these mechanisms have been explored in preclinical and clinical studies. This review summarizes the progress concerning targeted therapeutic strategies and the relevant autoimmune pathogenesis in IgAN.
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