Primary IgA nephropathy: current challenges and future prospects

Abstract

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.

Elevated Numbers of Circulating Very Small Embryonic-Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy

“…Diagnosis is established exclusively by kidney biopsy where the pathognomonic finding on immunofluorescence microscopy is the presence of mesangial deposits of IgA antibodies. Exact mechanisms leading to development of IgAN are unclear and despite available treatment options, slow progression to end stage renal disease occurs in up to 50% of affected patients [ 1 ]. Therefore, there is still a substantial need for better understanding of mechanisms involved in IgAN pathogenesis and renal regeneration processes.…”

The Role of Wnt Signalling in Chronic Kidney Disease (CKD)

“…IgA nephropathy (IgAN) is one of the most common forms of glomerulonephritis and another leading cause of CKD and ESRD, with an incidence rate of 2.5/100,000 [24]. Clinical manifestations of the disease are variable with common presentations including microscopic/macroscopic haematuria, together with the presentation of proteinuria [25]. Another common characteristic is synpharyngitic macroscopic haematuria, where episodic haematuria follows an upper respiratory tract infection [25].…”

“…Clinical manifestations of the disease are variable with common presentations including microscopic/macroscopic haematuria, together with the presentation of proteinuria [25]. Another common characteristic is synpharyngitic macroscopic haematuria, where episodic haematuria follows an upper respiratory tract infection [25]. The diagnosis of IgAN is dependent on immunofluorescent analysis on kidney biopsy samples, where granular deposition of IgA in mesangium is usually observed [25].…”

<p>The Supportive Treatment of IgA Nephropathy and Idiopathic Nephrotic Syndrome: How Useful are Omega-3 Polyunsaturated Fatty Acids?</p>

“…Although IgAN was traditionally regarded as a single disease entity characterized by IgA deposition in the glomerular mesangium, it is now seen as a "converging point" for a diverse spectrum of endophenotypes and diseases given the heterogeneity in clinical presentation, histopathological response to IgA mesangial deposition and genetic links of the disease. 13 IgAN may present with episodic macroscopic hematuria, acute kidney injury, nephrotic syndrome and a mixed nephrotic and nephritic picture. It runs a variable course which may progress and terminate in ESKD.…”