IgA nephropathy in adults-treatment standard

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary form of glomerular disease worldwide and carries a high lifetime risk of kidney failure. The underlying pathogenesis of IgAN has been characterized to a sub-molecular level; immune complexes containing specific O-glycoforms of IgA1 are central. Kidney biopsy remains the gold-standard diagnostic test for IgAN and histological features (i.e. MEST-C score) have also been shown to independently predict outcome. Proteinuria and blood pressure are the main modifiable risk factors for disease progression. No IgAN-specific biomarker has yet been validated for diagnosis, prognosis or tracking response to therapy. There has been a recent resurgence of investigation into IgAN treatments. Optimized supportive care with lifestyle interventions and non-immunomodulatory drugs remains the backbone of IgAN management. The menu of available reno-protective medications is rapidly expanding beyond blockade of the renin-angiotensin-aldosterone system to include sodium-glucose cotransporter 2 and endothelin type A receptor antagonism. Systemic immunosuppression can further improve kidney outcomes, although recent randomized controlled trials have raised concerns regarding infectious and metabolic toxicity from systemic corticosteroids. Studies evaluating more refined approaches to immunomodulation in IgAN are ongoing: drugs targeting the mucosal immune compartment, B-cell promoting cytokines and the complement cascade are particularly promising. We review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of IgAN.

Keywords: IgA nephropathy; diagnosis; pathophysiology; prognosis; treatment.

Figure 1:

The four pathogenic hits of IgAN targeted by current and new drugs. Hit 1: excessive generation of galactose-deficient IgA1 (gd-IgA1), which enters the circulation from mucosal or possibly systemic sources. Hit 2: generation of auto-reactive IgG autoantibodies that recognise specific O-glycoforms of IgA1 (anti-gd-IgA1 IgG). Hit 3: formation of IgA-containing immune complexes in the circulation. Hit 4: deposition of these circulating immune complexes in the glomerular mesangium, triggering an inflammatory cascade that results in mesangial cell proliferation, activation of the alternative and lectin complement pathways, recruitment of monocyte/macrophages and recruitment of T cells from the circulation. Drugs that have been approved by regulatory authorities specifically for the treatment of IgAN are indicated on a green background; drugs currently available in clinical practice but not approved specifically for treatment of IgAN are indicated on an orange background; drugs currently being evaluated in clinical trials for the treatment of IgAN are indicated on a blue background. Hits targeted by specific drugs are indicated by red bars. Reno-protective non-immunomodulatory drugs used to treat IgAN are listed in a box beside the kidney.

Figure 2:

Proposed algorithm for the management of patients with primary IgAN. Lifestyle interventions should include advice on dietary sodium restriction (<2 g sodium/day), smoking cessation, weight control and exercise, as appropriate. Assess cardiovascular risk and commence appropriate interventions. Patients should be reviewed regularly (every 4–8 weeks) during optimization of supportive care. For patients with secondary causes of IgAN, treatment should be targeted at the primary disease. Increasing relative risk of treatment-related toxicity for interventions beyond supportive care is indicated by increasing intensity of the background orange colour in the text box. For risk assessment, see also Box ‘Strategies for personalizing treatment in IgAN’. *The safety of co-administrating SGLT2i with immunosuppression is currently unknown.