Approach

Current treatment strategies are aimed at delaying IgAN disease progression and the subsequent need for dialysis and kidney transplantation; however, not all patients with IgAN require treatment to prevent progressive kidney damage.[50][51] An assessment of the risk of developing progressive kidney disease should be undertaken when deciding whether treatment should be offered. Predictors of progressive kidney disease include:

  • Clinical parameters (degree of proteinuria, hypertension, and existing impaired glomerular filtration rate [GFR])

  • Histological lesions (mesangial hypercellularity [M1], endocapillary hypercellularity [E1], segmental hypercellularity [S1], tubular atrophy/interstitial fibrosis [T2]).[2] In the updated Oxford Classification, published in 2017, crescents were added to the four original lesions: C0 (no crescents), C1 (crescents in less than 25% of glomeruli), and C2 (crescents in 25% or more of glomeruli), forming a new MEST-C score.[6]

A combination of glomerular features or glomerular and tubulointerstitial features will have an impact on deterioration in kidney function. Although the combined presence of glomerular and tubulointerstitial features represents increased risk of kidney disease progression, the rate of decline of kidney function cannot be directly quantified by simply adding the individual scores together.[2]

There is some evidence to suggest that certain histopathological lesions may be more responsive to immunosuppressive therapy than others, but these findings have not been confirmed in prospective studies. Treatment recommendations should not, therefore, be based on histological lesions alone.

There are two main treatment strategies:

  • Goal-directed supportive (non-immunosuppressive) care (e.g., ACE inhibitors, angiotensin-II receptor antagonists, additional blood pressure control, and cardiovascular risk reduction), which should be considered in all patients with IgAN, and

  • Immunomodulatory therapy for select patients who remain at increased risk of progressive kidney disease after optimisation of goal-directed supportive care.

Supportive therapy

Patients with isolated haematuria or proteinuria <0.5 g/day, normal blood pressure, and a normal GFR do not require any specific treatment. All other patients with IgAN should be offered supportive therapy.

Renin-angiotensin system inhibitors (ACE inhibitors, angiotensin-II receptor antagonists) decrease intraglomerular pressure, reducing glomerular injury. Once hypertension (>140/90 mmHg) and/or proteinuria (>0.5 g/day) develops, all patients should receive a renin-angiotensin system inhibitor as first-line treatment, unless there is a contraindication (e.g., pregnancy planning).[52][53][54][55] Angiotensin-II receptor antagonists are generally reserved for patients intolerant of ACE inhibitors.[56] Combination therapy with an angiotensin-II receptor antagonist and an ACE inhibitor should be avoided.[57]

As part of pregnancy planning, women with IgAN should receive pre-conception counselling on cessation of renin-angiotensin system inhibitors and the optimisation of blood pressure control with alternative agents.[40]

Provide all patients with advice on a low-salt diet, smoking cessation, weight control, and exercise.[40]

The goal of supportive therapy is to reduce urine protein excretion to <1 g/day.[40][57]

Immunomodulatory therapy

In patients with persistent proteinuria >1 g/day despite optimised supportive care, immunosuppression may be considered.

KDIGO guidelines suggest a 6-month course of corticosteroids in patients with persistent proteinuria >1 g/day, after at least 3 months of optimisation of blood pressure control and ACE inhibitor/angiotensin-II receptor antagonist therapy.[40] This is based on several small studies investigating the use of corticosteroids in IgAN.[58][59] Similarly, systematic reviews indicate that corticosteroids probably reduce the risk of kidney function decline, but may increase the risk of adverse effects.[60][61] [ Cochrane Clinical Answers logo ] It is difficult to draw any firm conclusions from these studies because ACE inhibitors/angiotensin-II receptor antagonists were used in only a minority of patients, or were stopped prior to recruitment into the studies. In addition, blood pressure control was suboptimal. 

In a multicentre, double-blind, randomised controlled study, the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) trial, IgAN patients receiving oral methylprednisolone, when compared to placebo, had an increased risk of serious adverse events, mostly due to excess serious infections, leading to the early termination of the trial.[62] Although primary composite outcomes (end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR) were lower in the oral methylprednisolone group, no conclusions can be made about the potential kidney benefits as they must be weighed against the serious adverse events observed and the early termination of the study for patient safety reasons.

Corticosteroids should be avoided or administered with great caution in specific situations where the risks of adverse effects may outweigh the benefits or where benefits are unclear, including in patients with: eGFR <30 mL/min/1.73 m², diabetes, obesity (BMI >30 kg/m²), latent infections (e.g., viral hepatitis, tuberculosis), secondary disease (e.g., cirrhosis), active peptic ulceration, uncontrolled psychiatric illness, and severe osteoporosis.[40]

Patients presenting with sudden-onset nephrotic syndrome and histological features of mesangial IgA deposition with minimal glomerular changes and widespread podocyte effacement should be treated as if they have concomitant minimal change disease. The majority of patients treated with a high-dose corticosteroid, such as prednisolone, will experience complete remission of proteinuria.

There is little evidence to support the use of other immunosuppressive agents (such as cyclophosphamide, azathioprine, or mycophenolate) in IgAN, except in patients with a rapidly progressive glomerulonephritis (RPGN).[61] One randomised controlled trial suggests that mycophenolate may be effective as a corticosteroid-sparing agent in Chinese patients.[40][63] 

Tonsillectomy and pulsed dosing of corticosteroids is a favoured treatment regimen in Japan, although there remains a paucity of robust prospective clinical trial data to support this approach.[40] There is no evidence for benefit of tonsillectomy in white populations.[64][65][66][67]

In the STOP IgAN trial, there was no difference in kidney disease progression for patients who received immunosuppression in addition to optimised intensive supportive therapy, compared with patients receiving optimised intensive supportive therapy alone.[68] Nonetheless, as the first published randomised controlled trial that included a 6-month run-in period of optimised intensive supportive therapy, the study highlights the importance of ensuring that intensive supportive therapy is optimised in all patients diagnosed with IgAN before considering immunosuppression.

Randomised controlled trials have shown conflicting results in regard to nephroprotective effects of fish oil in patients with IgAN and declining kidney function.[57] One 2012 meta-analysis found that there are insufficient data to confirm the efficacy of omega-3 fish oils in the treatment of IgAN.[69] As there is no clear evidence of benefit, Kidney Disease: Improving Global Outcomes (KDIGO) guidelines do not recommend the use of fish oil. Provide patients who wish to take fish oil with advice on dose and formulation based on published trials.[40]

Acute kidney injury

Acute kidney injury may occur during episodes of visible haematuria due to tubular obstruction by erythrocytes and acute tubular necrosis.

Recovery is usual with simple supportive measures including avoidance of nephrotoxins and close fluid management, and no specific therapies are required. If there are no signs of recovery within 48 hours of presentation, a kidney biopsy is required.

Rarely, IgAN can either present as a rapidly progressive glomerulonephritis (RPGN), or RPGN can develop on a background of established IgAN. Kidney biopsy in this setting usually shows focal necrotising glomerulonephritis and crescent formation and should be treated in the same way as an anti-neutrophil cytoplasmic antibody (ANCA)-associated RPGN. Patients are typically treated with cyclophosphamide and corticosteroids for an initial six months, followed by azathioprine. Consider combined immunosuppressive therapy in patients presenting with an RPGN characterised by rapid progressive deterioration in kidney function (e.g., rising creatinine, haematoproteinuria); although there are few data, some studies show this improves kidney survival.[57][70][71][72]

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