Blog entry by Arif Khwaja
The evidence base for managing IgA Nephropathy has been poor based on small studies with variable control groups and standard of care. Until now KDIGO recommends aggressive ACEi/ARB therapy with a blood pressure target of 125/75mmHg. Immunosuppression with corticosteroids is recommended in patients with an eGFR >50mls/min who still have greater than 1g/24 hours of proteinuria - This is a 2C recommendation based on RCTs by Pozzi, Praga, Manno and Lv. However one criticism of these studies is that RAS inhibitors were either not part of standard care in the study or they were stopped and then restarted at baseline.
This week finally sees the publication of the STOP-IgA Nephropathy Study from Germany in the NEJM which is a game changer in clarifying the role of immunosuppression in IgA nephropathy.
In essence patients with proteinuric IgA nephropathy were enrolled into 6 months of best medical care – ACEi/ARBs (aiming for a BP target of 125/75mmHg), statins and low salt diet. Interestingly the protocol dictated that ACEi/ARBs were titrated upto the maximum tolerable dose in patients with significant proteinuria even if BP well controlled. After 6 months those with greater than 0.75g/24 hours of proteinuria (but less than 3.5gm/24hrs) were randomised to continuing supportive care or immunosuppressive therapy - this consisted of:
i) steroids (pulsed methylprednisolone 1g for 3 days on months 1,3,5 and 0.5mg/kg every 48 hours on all other days) for 6 months for those with a GFR>60mls/min/1.73m2 or
ii) cyclophosphamide (1.5mg/kg) and steroids (40mg/day tapered to 7.5mg at month 7) for patients with an eGFR between with 30-59mls/min. After 3 months cyclophosphamide was switched to Azathioprine with prednisolone and azathioprine continued for 3 years).
The two primary endpoints were:
i) clinical remission (defined as a PCR<0.2 and a decline in eGFR <5mls/min/1.73m2 from baseline to the end of 3 years) and
ii) a decrease in eGFR <15mls/min/1.73m2. There were a range of secondary endpoints including eGFR decline >30mls/min, proteinuria, reciprocal creatinine slopes, proteinuria and onset of ESRD.
309 patients completed the run-in phase with 109 responding to supportive care whilst 165 still had >0.75g/24 hours of proteinuria and these patients were randomized to continue best supportive care or start immunosuppression. The groups were well matched at baseline with respect to eGFR (around 57-61mls/min/1.73m2), proteinuria (around 1.6-1.8g/24 hours) and BP (around 125/75) and virtually all patients were on ACEi and ARBs. 80 patients were randomized to supportive care whilst 82 to immunosuppression – of these 55 patients had an eGFR>60mls/min/1.73m2 and so received steroids only whilst 27 received steroids+Cyclophosphamide/Azathioprine as their eGFR was between 30-59mls/min/1.73m2.
5% of patients in the immunosuppression group achieved clinical remission versus 17% of those in standard care group (p<0.01). However this difference was driven by differences in complete remission of proteinuria and importantly there were NO differences in eGFR at 3 years. Furthermore whilst the immunosuppression arm had lower mean proteinuria at 1 year there was no significant difference at 3 years. As regards the other primary endpoint of eGFR decline >15mls/min/1.73m2 there was no difference between the two groups. Importantly 25% of patients had this degree of significant decline in kidney function. Similarly other endpoints such as eGFR/reciprocal creatinine change were not affected by immunosuppression – i.e. immunosuppression had no impact on any measure of progression or proteinuria at 3 years. Microhaematuria was more likely to resolve in the immunosuppression group.
Importantly immunosuppression was associated with a much higher rate of sepsis and glucose intolerance
My immediate thoughts:
i) A really important, excellent, well designed study – Professor Floege and the rest of his co-investigators in Germany must be rightly proud to be actually able to deliver such a study.
ii) The 6 month run-in period that allowed all patients to have that standard care optimized was crucial part of the study design in ensuring patients were well matched at baseline – a problem which has blighted earlier studies in IgA nephropathy. In fact the positive results of steroids in earlier studies could almost be completely explained by this failure in standardizing care. The eGFR decline in this study was 1.6mls/min/year in the supportive arm group – which was much lower than that seen in earlier studies. Furthermore the fact that nearly 1/3 of patients went into remission in this period highlights the importance of basic care – ACEi/ARB, aggressive BP control, salt restriction, lipid management and smoking control.
iii) There is clearly NO role for immunosuppression in patients with IgA nephropathy with proteinuria less than 3.5g/day. I assume KDIGO will change its recommendation about steroids in IgA nephropathy soon. …
iv) Although proteinuria is a very powerful predictor of progression this study is an important reminder that it’s a surrogate endpoint…the higher proteinuria remission rate in the immunosuppression group did not translate into any differences in progression at 3 years…
v) Limitations – (these are well described by the authors though I personally don’t think these are significant to change the take-home message of the study) – 3 year follow up, open label study and failure to measure GFR – however the latter is probably not significant as if anything steroids will lower muscle mass - and therefore lower creatinine and increase eGFR) - finally it may not be applicable to the non-caucasian population given the difference patterns of IgA in different ethnicities