Study Design and Methods: 337 patients aged 18-70 were enrolled into this multicentre, prospective, open-label, randomised controlled trial. Key inclusion criteria included biopsy proven IgA Nephropathy, 0.75g/day proteinuria, together with hypertension (defined as ≥140/90), impaired renal function (eGFR<90ml/min) or both.
All patients underwent an initial six month period of supportive care which included maximal recommended or tolerated RAAS blockade, cholesterol lowering with statins and smoking cessation advice. At the end of this period those with proteinuria between 0.75 and 3.5g per litre were eligible for randomisation into immunosuppression or continuation of supportive care groups. This is important as previous studies have discontinued RAAS inhibition before recruitment.
Allowing for dropout and exclusion, 162 patients were randomised with 80 for supportive care and 82 for immunosuppression. Demographics of the two arms were not significantly different and enrolment was for three years. In the immunosupression arm, those with an eGFR of ≥60 received 1g IV methylprednisolone on the first three days of months 1,3 and 5 and otherwise 0.5mg/kg prednisolone on all other days for the duration of the study. Those with an eGFR of ≤30 received cyclophosphamide 1.5mg/kg/day for three months, then azathioprine 1.5mg/kg/day for months 4 to 36 together with prednisolone daily at a dose of 40mg daily tapered to 7.5mg from month 7.
1) Remission of IgA nephropathy defined as urine protein: creatinine ration <0.2g/24hours and stable renal function defined as a fall in eGFR of <5ml per minute per 1.73m² from baseline.
2) Fall in eGFR >15ml per minute per 1.73m² from baseline.
Take home messages: Importantly, 34% of patients had <0.75g proteinuria per day at six months, with supportive care alone, further underlining the importance of this treatment strategy.
At three years, 5% of patients in the supportive care as compared with 17% in the immunosuppression arm had achieved a complete remission (p=0.001). However between the same groups there was no significant difference in the number with a stable eGFR.
At the end of three years there was also no significant difference in those having a decrease in eGFR ≥15ml per minute per 1.73m², 22 of 80 in supportive care versus 21 of 82 in the immunosuppression group. .
While there was no difference in overall adverse events between the groups, predictably there was a significantly increased rate of impaired glucose tolerance in the immunosuppression arm, together with higher trends for infection, malignant neoplasm and indeed there was one sepsis related death in the immunosuppression group.
Discussion: The authors should be commended for the good design, adherence to and implementation of KDIGO guidance. I think what this trial demonstrates best is that aggressive conservative therapy may lead to good outcomes in proteinuric IgA Nephropathy. The benefit of immunosuppression has not been demonstrated, particularly when the toxicity of the regimes are considered. Our practice will therefore be unlikely to change based on these results.
Post by Andrew McClarey,
Royal Infirmary of Edinburgh