The most common GN globally is IgA nephropathy (IgAN). Prevalence varies geographically, and estimates of disease burden vary according to whether ascertained using biopsy registry data versus dialysis registries.


Biopsy registry data underestimate disease burden as patients with mild disease may not undergo biopsy, and in countries lacking screening programs disease may not be detected.


Pooled cohorts from the European Validation Study of the Oxford Classification of IgA Nephropathy (VALIGA) and North American cohorts indicate rates ESRD or halving of eGFR of 27% at 10 years (7). There are regional differences in the progression of disease, however these are difficult to ascertain given lead-time biases introduced by variation in biopsy practice. In our cohort of 669 patients, multivariable analysis demonstrated that individuals of Pacific Asian origin have an increased risk of ERSD.


DISEASE PATHOGENESIS


Susceptibility to IgAN and risk of disease progression are influenced by a confluence of genetic and environmental factors.A central finding in patients with IgAN is the presence of circulating and glomerular immune complexes comprised of galactose-deficient IgA1, an IgG autoantibody directed against the hinge region O-glycans, and C3. The presence of aberrantly glycosylated IgA1 is an heritable trait.These immune complexes are nephritogenic, contributing directly to glomerular inflammation and mesangial proliferation. Activation of the local and systemic renin angiotensin system and complement activation also ultimately contribute to glomerulosclerosis and tubulo-interstitial fibrosis, leading to loss of renal function.


These findings suggest that, at least in mice, exposure to commensal or pathogenic bacteria is necessary for excess IgA production, and this is facilitated by the presence of mediators of B cell differentiation and proliferation BAFF and/or APRIL.


TREATMENT STRATEGIES


1) Conservative Therapy


The importance of conservative therapy to reduce proteinuria and slow the rate of renal function decline in IgAN cannot be overemphasized. In the recent Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) trial, nearly one third of patients who completed a 6-month run-in phase of intensive optimization of conservative therapy no longer qualified for randomization to immunosuppressive therapy.


2) CORTICOSTEROIDS


There are several clinical trials supporting that corticosteroids reduce proteinuria in IgAN. Although earlier studies supported that this was associated with an improvement in clinical outcome, more recent large trials question the sustained benefits of a brief period of immunosuppression.


One of the first randomized trials suggesting a benefit of corticosteroids was a study of 86 patients with biopsy-proven IgAN with proteinuria 1–3.5 g/d for at least 3 months and a serum creatinine ≤1.5 g/dl (52). Patients received steroid therapy (1 g intravenously for 3 days at months 1, 3, and 5, and oral prednisone at 0.5 mg/kg per day on alternate days for 6 months) or supportive therapy alone.


3) MYCOPHENOLATE


Data regarding the efficacy of mycophenolate are mixed, such that current clinical guidelines recommend against use of this agent in IgAN.


4) RITUXIMAB


Although evidence for rituximab in other glomerular diseases is promising, early results in IgAN are not encouraging. A pilot trial evaluated the outcome of 34 patients with proteinuria>1 g/d and eGFR<90 ml/min per 1.73 m2 randomized to rituximab versus conservative management. No effects on proteinuria or renal function were seen


5) COMBINATION THERAPY


Combination therapy with corticosteroid plus an additional agent is generally reserved for patients with progressive disease. A single-center, prospective, randomized, controlled trial of 38 patients with “high-risk” IgAN (hypertension, >15% rise in creatinine in prior year) demonstrated improved renal survival after 2 years in patients receiving prednisone and cyclosphosphamide/azathioprine as compared with no immunotherapy.


None of the information regarding the pathogenesis of this disease suggests a curable time-limited event. Perhaps there is a role for treatment to be divided into induction and maintenance phases, with use of steroid-sparing maintenance therapy to achieve sustained reductions in time-averaged proteinuria that ultimately affect renal survival. Furthermore, studies of immunotherapy in IgAN consistently demonstrate significant risk of toxicity. Ultimately, it is anticipated that improved understanding of the immunopathogenesis of this disease will lead to development of more targeted and less toxic treatment options.