Written by Jasna Trbojevic-Stankovic
Reviewed by Jürgen Floege
Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis worldwide. However, in spite of such high prevalence, there is still much ambiguity in the therapeutic approach to this disease.
The disease typically presents at young age with painless microhaematuria, minimal or no proteinuria and preserved renal function. The patients are often referred to urologist and cease further contacts with nephrologists. The disease usually has benign course and only 5% of these very early patients progress to end-stage renal disease (ESRD), while up to 80% either spontaneously enter into clinical remission or remain with preserved glomerular filtration rate. Unfortunately, there is currently no reliable tool to predict which of these patients will progress thus requiring prolonged follow-up for all diagnosed subjects [1, 2].
IgA nephropathy prediction tools
A recently published study by Barbour et al. presented a new risk-prediction tool in IgA nephropathy which is freely available at the https://qxmd.com/calculate/calculator_499/international-igan-prediction-tool. This tool predicts the risk of 50% decline in eGFR or ESRD in the upcoming 6.7 years . It takes into account a number of factors, including age, blood pressure, estimated eGFR and proteinuria at biopsy, race, use of ACE inhibitors, ARBs or immunosuppression, and MEST scores (M – mesangial hypercellularity, E – endocapillary hypercellularity, S – segmental glomerulosclerosis, T – tubular atrophy/interstitial fibrosis, C – cellular of fibrocellular crescents). The key limitation of this tool is that it’s only valid at the time of the biopsy and further research is needed to define elements necessary for validation at a certain time point following the biopsy and after certain therapeutic measures have been introduced.
Pathohistological evaluation of renal biopsy findings in patients with IgA nephropathy is of undisputable value. In patients of the STOP-IgAN trial, higher mesangial hypercellularity was a predictor of higher annual eGFR decline, while chronic tubulointerstitial changes forecasted higher rate of ESRD . The presence of crescents, endocapillary lesions and glomerular sclerosis presented no predictive value.
Current and new therapeutic approaches to IgA nephropathy
Supportive care is absolutely central in the treatment of IgA nephropathy and encompasses, besides the use of ACE inhibitors or ARBS, controlled protein intake, avoidance of dihydropyridine calcium-channel blockers as first-line antihypertensive medication, also normalizing body weight, cessation of smoking, restriction in sodium and fluid intake, along with use of diuretics, and possibly aldosterone antagonists if there is suspected aldosterone breakthrough [8, 9]. Intensive supportive care actually may even hinder the benefit of added immunosuppression [10, 11, 12]. Furthermore, the use of steroid mono-therapy was associated with a 50% higher rate of infectious complications, glucose intolerance or diabetes and weight gain . The TESTING trial was supposed to shed definitive light into this matter, but although its results were consistent with potential renal benefit from methylprednisolone, it failed to provide definitive conclusions about treatment benefit as it was terminated early for safety reasons following several fatal infections in the steroid-arm .
Sparsentan is a promising new combined angiotensin-endothelin receptor blocker which appears to reduce proteinuria more efficiently than irbesartan and thus might contribute to better preservation of renal function in these patients . It is currently tested in a phase III trial in patients with IgA nephropathy (PROTECT trial). Hydroxychloroquine also seems to decrease proteinuria in IgA nephropathy patients better than placebo with acceptable safety [6, 7]. A six months trial therapy with hydroxychloroquine followed by evaluation of its therapeutic effect and possible side effects might be considered a pragmatic approach.
Studies have shown that azathioprine added to corticosteroid therapy does not carry significant benefit to the patients with IgA nephropathy, but in turn brings more side effects . Furthermore, proteinuria in IgA nephropathy does not respond to rituximab and although this drug effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 in these patients . There were controversial results reported on the effect of mycophenolate-mofetil therapy in IgA nephropathy, as it reduced proteinuria and stabilized eGFR in Asian populations, but not in Caucasians .
A novel targeted-release formulation of budesonide, designed to deliver the drug to the distal ileum, was assessed for safety and efficacy in the NEFIGAN study and at daily dose of 16 mg it efficiently reduced proteinuria and stabilized eGFR in patients with IgA nephropathy . A phase III trial (NEFIGARD trial) is ongoing.
Taken all these data into consideration, the contemporary therapeutic approach to a patient with IgA nephropathy would depend on the level of proteinuria and the rate of progression of eGFR decline [5, 9]. The typical patients with persistent proteinuria above 0.5-1 g/day, with or without reduced eGFR and hypertension should be administered optimized supportive therapy for six months, and then consider corticosteroid therapy depending on the presence of proteinuria and eGFR level, patient preferences and co-morbidities (Figure 1).