Intensive supportive care plus immunosuppression in IgA Nephropathy
Thomas Rauen, M.D., Frank Eitner, M.D., Christina Fitzner, M.Sc., Claudia Sommerer, M.D., Martin Zeier, M.D., Britta Otte, M.D., Ulf Panzer, M.D., Harm Peters, M.D., Urs Benck, M.D., Peter R. Mertens, M.D., Uwe Kuhlmann, M.D., Oliver Witzke, M.D., Oliver Gross, M.D., Volker Vielhauer, M.D., Johannes F.E. Mann, M.D., Ralf-Dieter Hilgers, Ph.D., and Jürgen Floege, M.D. for the STOP-IgAN Investigators
IgA nephropathy is the most common primary glomerulonephritis in the world. It is caused by mesangial deposition of IgA (mostly polymeric IgA of the IgA1 subclass), however this finding does not always cause disease. Treatment has been controversial for years and is typically divided in two approaches: supportive care and immunosuppressive therapy. For another review about this article, please visit the Renal Fellow Network
Here is what the KDIGO guidelines recommend in regards to IgA nephropathy treatment:
In STOP-IgAN, the investigators tested the hypothesis that immunosuppressive therapy combined with supportive care would be superior to supportive care alone.
Setting: 32 Nephrology centers in Germany from February 2008 through October 2011
Design: prospective, open-label, randomized, controlled trial with a two-group, parallel, group sequential design.
- Primary IgA Nephropathy confirmed on biopsy
- Age 18-70
- Proteinuria level above 0.75 grams per day plus hypertension.
- Impaired renal function (eGFR <90ml per min/1.73m2)
- eGFR <30 ml per min/1.73m2
- Secondary and rapidly progressive, crescentic IgA nephropathy.
- Other chronic renal diseases.
- Prior use of immunosuppression
- Full clinical remission defined as: Protein-to-creatinine ratio of <0.2 and stable renal function with a decrease in the eGFR of <5 ml per min/1.73m2 from baseline at the end of the 3-year trial
- Clinical progression: Decrease in eGFR of at least 15 ml per min/1.73m2 from baseline eGFR
- Absolute decrease in eGFR
- Decrease in the eGFR of at least 30 ml per min/1.73m2
- Need for renal replacement therapy
- Mean annual change in the slope of the reciprocal of serum creatinine concentration
- Proteinuria at 12 and 36 months.
- Disappearance of microalbuminuria by dipstick or urinary sediment test
There was initially a 6 month run-in phase where all patients received comprehensive supportive care with optimization of hypertension and proteinuria (with the use of RAAS blockade). At the end of the run-in phase, patients who did not respond to treatment (0.75 - 3.5 grams of proteinuria per day), were randomized to:
- Continued supportive care alone or
- Supportive care with the addition of immunosupression.
The immunosuppression group with eGFR >59 received one gram of IV methylprednisolone daily for 3 days at the start of months 1, 3 and 5; and oral prednisolone at a dose of 0.5 mg/kg every other day.
The immunosuppression group with eGFR between 30-59 ml per min/1.73m2 received cyclophosphamide 1.5 mg/kg/day for 3 months, followed by azathioprine at a dose of 1.5 mg/kg per day during months 4-36, plus oral prednisolone 40 mg/day, tapered to 10 mg/day, over the first 3 months of the study, 10 mg/day during months 4-6 and 7.5 mg per day during months 7-36.
337 patients entered the run-in phase. 309 patients completed the run-in phase and 106 had a response to supportive care although 12 developed proteinuria in follow up after the run-in phase and were re-included. The investigators included a total of 177 participants for randomization (15 declined randomization) and 80 were assigned to supportive care group and 82 to the immunosuppression group.
76 in the supportive care and 78 in the immunosuppression group completed the three year trial. Four patients with supportive care achieved complete remission compared to 14 with immunosuppression. 38 patients in both groups maintained their GFR within 5 ml/min of baseline. With respect to the second primary endpoint, a loss of at least 15 ml/min of eGFR, it occurred in 22 with supportive care and 21 with immunosuppression.
17% of patients in the immunosuppressive group achieved the first primary endpoint of full clinical remission at the end of the 3 years. it’s important to mention that 34% of the patients had a response to supportive care prior to randomization.
The authors added that these findings should not be applied to patients with proteinuria above 3.5 g per day in whom probably, immunosuppressive therapy should be considered; it is also indicated for patients with active disease and rapid progression. For mild and moderate IgA nephropathy, optimization and aggressive conventional therapy should be implemented. More aggressive management is with immunosuppression was not supported in this trial.
For an additional perspective take a look at this post at Renal Fellow Network.
Summary by Hector Madariaga