Thursday, December 17, 2015

Stop-IgA: Immunosuppression for proteinuric IgA Nephropathy

Despite being the world’s most common form of glomerulonephritis, IgA Nephropathy treatment strategies have hereto been controversial, particularly surrounding the use of immnosuppression on top of traditional RAAS blockade. The long awaited, Intensive Supportive Care plus Immunosuppression in IgA Nephropathy (STOP-IgAN) in this month’s New England Journal of Medicine set out to clarify this issue.
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. 
Endpoints were:
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


sampath said...

The study used cyclophosphamide in those with CKD stage 4 which is associated with extensive interstitial fibrosis . At this advanced stage it is likely to be countreproductive by increasing the chances of infection.

dodoIgAN said...

We have not population characteristic to interpret roughly the result of this trial. Inclusion criteria excluded all the inflammatory form fo the disease. Proteinuria end point (0,75 g) is not clear. This threshold is very uncommon. I'm surprised by the NEJM to publish this article.

Mohammed A Kaballo said...

At the first glance, this trial looks very well conducted and its findings sounds convincing. Unfortunately, an in-depth review of the STOP IgAN reveals a considerable number of limitations that may render results inconclusive.

1- Histology:
Although the inclusion criteria required a biopsy-proven IgAN, it has completely ignored the histological classification of the disease and hence the trial comprised a mixed bag of IgAN patients with a possible wide variation in histological findings that could predict disease progression. Previous studies showed that widespread glomerulosclerosis and marked tubulointerstitial lesions were strong predictors of disease progression.

2- Haematuria:
It was shown previously that gross haematuria in IgAN is associated with slow disease progression. In STOP IgAN, even though the number of patients without haematuria was small, authors did not tell us if any of the patients without haematuria develop the primary outcome.

3- Follow up:
IgAN is characterized by an extreme variability in clinical course and sometimes by the unpredictability of the ultimate outcome. Approximately, 15 to 40 percent of patients with a progressive disease, excluding the crescentic subtype, will progress to end-stage renal disease over 10 to 20 years period. Therefore, drawing conclusions will be premature if the follow-up period is shorter than 10 years, as in this trial. Moreover, most of the immunosuppression group (67%, n=55) received only a 6-month corticosteroids course, which is quite arbitrary. This regime is of extremely short duration and is unlikely to have any impact on the outcome of a disease that progresses over a decade or two.

In conclusion, the STOP IgAN trial emphasized the dilemmas and potential complications of treating patients with a clinical and pathologic phenotype of IgA nephropathy. It also demonstrated that proper supportive care is helpful, at least in the short run. Definitely we need to improve our basic understanding of IgA nephropathy before we can design better trials that will allow us to draw definitive conclusions about treatment strategies.