Eculizumab in Pediatric Dense Deposit Disease

Abstract

Background and objectives: Dense deposit disease (DDD), a subtype of C3 glomerulopathy, is a rare disease affecting mostly children. Treatment options are limited. Debate exists whether eculizumab, a monoclonal antibody against complement factor C5, is effective in DDD. Reported data are scarce, especially in children.

Design, setting, participants, & measurements: The authors analyzed clinical and histologic data of five pediatric patients with a native kidney biopsy diagnosis of DDD. Patients received eculizumab as therapy of last resort for severe nephritic or nephrotic syndrome with alternative pathway complement activation; this therapy was given only when the patients had not or only marginally responded to immunosuppressive therapy. Outcome measures were kidney function, proteinuria, and urine analysis.

Results: In all, seven disease episodes were treated with eculizumab (six episodes of severe nephritic syndrome [two of which required dialysis] and one nephrotic syndrome episode). Median age at treatment start was 8.4 (range, 5.9-13) years. For three treatment episodes, eculizumab was the sole immunosuppressive treatment. In all patients, both proteinuria and renal function improved significantly within 12 weeks of treatment (median urinary protein-to-creatinine ratio of 8.5 [range, 2.2-17] versus 1.1 [range, 0.2-2.0] g/g, P<0.005, and eGFR of 58 [range, 17-114] versus 77 [range, 50-129] ml/min per 1.73 m(2), P<0.01). A striking finding was the disappearance of leukocyturia within 1 week after the first eculizumab dose in all five episodes with leukocyturia at treatment initiation.

Conclusions: In this case series of pediatric patients with DDD, eculizumab treatment was associated with reduction in proteinuria and increase in eGFR. Leukocyturia resolved within 1 week of initiation of eculizumab treatment. These results underscore the need for a randomized trial of eculizumab in DDD.

Keywords: C3 glomerulopathy; C3 nephritic factor; complement; dense deposit disease; glomerulonephritis; membranoproliferative.

Figure 1.

Improvement in serum creatinine levels and urinary protein-to-creatinine ratios (UPCRs) during the first 12 weeks of eculizumab therapy. Initiation of eculizumab treatment is indicated by the vertical dotted line. Serum creatinine is indicated by closed circles, urinary protein-to-creatinine levels by open squares, plasma exchange (PLEX) treatments by vertical arrows, courses of intravenous methylprednisolone by black rectangles, eculizumab doses by capital Es, and oral prednisone dosage (mg/kg per day) as shaded rectangles. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; MMF, mycophenolate mofetil; CyA, cyclosporine.

Figure 2.

Fast and almost complete resolution of leukocyturia (upper panel) compared with delayed and partial response in hematuria (lower panel) following initiation of eculizumab therapy. Squares represent urinary counts (expressed as cells/μl) of leukocytes or erythrocytes with lines interconnecting individual subject's values. Initiation of eculizumab treatment is indicated by the vertical dotted line.