title: Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease in which lysis of PNH red blood cells frequently manifests with chronic hemolysis, anemia, and thrombosis. Renal damage in PNH is associated with chronic hemosiderosis and/or microvascular thrombosis. We determined the incidence of renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients and evaluated the safety and efficacy of the complement inhibitor eculizumab in altering its progression. Renal dysfunction or damage was observed in 65% of the study population at baseline with 21% of patients with later stage CKD or kidney failure (glomerular filtration rate [GFR] <or=60 ml/min/1.73 m(2); Stage 3, 4, or 5). Eculizumab treatment was safe and well-tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P < 0.001) compared with baseline and to placebo (P = 0.04). Improvement in renal function was more commonly seen in patients with baseline CKD Stages 1-2 (67.1% improvement, P < 0.001) although improvement was also observed in patients with CKD Stages 3-4 (P = 0.05). Improvements occurred quickly and were sustained for at least 18 months of treatment. Patients categorized at CKD Stages 3-5 did not worsen during treatment with eculizumab. Overall, 40 (21%) of 195 patients who demonstrated renal dysfunction or damage at baseline were no longer classified as such after 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement.
authors.affiliation: Department of Hematology, St. James's Institute of Oncology, Leeds, United Kingdom. peter.hillmen@nhs.net
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.forename: Modupe
authors.initials: M
authors.lastname: Elebute
authors.forename: Richard
authors.initials: R
authors.lastname: Kelly
authors.forename: Alvaro
authors.initials: A
authors.lastname: Urbano-Ispizua
authors.forename: Anita
authors.initials: A
authors.lastname: Hill
authors.forename: Russell P
authors.initials: RP
authors.lastname: Rother
authors.forename: Gus
authors.initials: G
authors.lastname: Khursigara
authors.forename: Chieh-Lin
authors.initials: CL
authors.lastname: Fu
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Omine
authors.forename: Paul
authors.initials: P
authors.lastname: Browne
authors.forename: Wendell
authors.initials: W
authors.lastname: Rosse
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D003167:Complement Activation / Q000187:drug effects; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006457:Hemoglobinuria, Paroxysmal / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D010865:Pilot Projects; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; D051056:Complement Inactivating Agents; C481642:eculizumab