C5 Convertase Blockade in Membranoproliferative Glomerulonephritis: A Single-Arm Clinical Trial

Rationale & Objective Primary membranoproliferative glomerulonephritis(MPGN) is a rare glomerulopathycharacterized by complement dysregulation. MPGN progresses rapidly to kidney failure when it is associated with nephrotic syndrome. We assessed the effects of C5 convertaseblockade in patients with MPGN and terminal complement activation. Study Design Prospective off-on-off-on open-label clinical trial. Setting & Participants Consenting patients with immune complex–mediated MPGN (n=6) or C3 glomerulonephritis(n=4) with sC5b-9 (serum complement membrane attack complex) plasma levels>1,000ng/mL and 24-hour proteinuriawith protein excretion>3.5g identified from the Italian Registry of MPGN and followed up at the Istituto di Ricerche Farmacologiche Mario Negri IRCCS (Bergamo, Italy) between March 4, 2014, and January 7, 2015. Intervention Anti-C5 monoclonal antibody eculizumabadministered during 2 sequential 48-week treatment periods separated by one 12-week washoutperiod. Outcomes Primary outcome was change in 24-hour proteinuria(median of 3 consecutive measurements) at 24 and 48 weeks. Results Median proteinuriadecreased from protein excretion of 6.03 (interquartile range [IQR], 4.8-12.4) g/d at baseline to 3.74 (IQR, 3.2-4.4) g/d at 24 weeks ( P =0.01) and to 5.06 (IQR, 3.1-5.8) g/d ( P =0.006) at 48 weeks of treatment, recovered toward baseline during the washoutperiod, and did not significantly decrease thereafter. Hypoalbuminemia, dyslipidemia, and glomerular sieving function improved during the first treatment period. 3 patients achieved partial remission of nephrotic syndromeand all had undetectable C3 nephritic factors before treatment. Mean measured glomerular filtration rate was 69.7±35.2 versus 87.4±55.1 and 75.8±42.7 versus 76.6±44.1mL/min/1.73m 2 at the start versus the end of the first and second treatment periods, respectively, among all 10 study participants. Unlike C3, sC5b-9 plasma levels normalized during both treatment periods and recovered toward baseline during the washoutin all patients. Limitations Single-arm design, small sample size. Conclusions Eculizumabblunted terminal complement activation in all patients with immune complex–mediated MPGN or C3 glomerulonephritisand nephrotic syndrome, but persistently reduced proteinuriain just a subgroup. Trial Registration Registered in the EU Clinical Trials Register with study no. 2013-003826-10.