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] 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 5 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 5 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. Am. J. Hematol. 85:553-559, 2010. V

Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

“…CKD was observed in 64% of patients with paroxysmal nocturnal hemoglobinuria at baseline, with 43% having proteinuria with preserved eGFR and 21% having more advanced stages of CKD characterized by eGFR <60 mL/min/1.73 m 2 . 61 Increased hemosiderin deposits in the tubules are almost universally observed and tubular dysfunction occurs in 67% of patients with paroxysmal nocturnal hemoglobinuria. 62 Similarly, in animal studies with induced hemolysis, hemosiderin deposits are found primarily in the proximal tubular cells and the deposition and oxidative damage to the tubular cells are exacerbated in mice deficient in haptoglobin 20,56 or hemopexin.…”

A Prospective Multicenter Study of Paroxysmal Nocturnal Hemoglobinuria Cells in Patients with Bone Marrow Failure

“…Patients with PNH are at an elevated risk of life-threatening complications such as thrombosis, chronic kidney disease, and end-organ damage as well as disease-related morbidities including pulmonary hypertension, abdominal pain, dyspnea, and debilitating fatigue (5)(6)(7)(8)(9)(10). PNH is associated with early mortality; up to 35% of PNH patients die within 5 years of diagnosis (10), and up to 50% of patients die within 10-15 years of diagnosis (11,12).…”

Nowe spojrzenie na nocną napadową hemoglobinurię

“…Około 64% chorych na PNH cierpi na przewlekłą chorobę nerek (CKD, chronic kidney disease), która odpowiada za 8-18% zgonów [18,25]. Czynnikami prowadzącymi do uszkodzenia nerek są hemosyderyna odkładająca się w kanalikach, przewlekła hemosyderynuria, hemoglobinuria oraz zaburzenia przepływu krwi przez nerki w wyniku zmniejszenia dostępności NO oraz mikrozakrzepicy naczyń nerkowych.…”

“…wody, aminokwasów, glukozy, niektórych jonów) [14]. Jedynie zastosowanie ekulizumabu daje szansę na stabilizację, a nawet poprawę funkcji nerek, szczególnie we wcześniejszych stadiach CKD [25].…”

“…TRIUMPH, SHEPHERD) udowodniono wysoką skuteczność przeciwciała w ograniczaniu procesu hemolizy i stabilizacji stężenia hemoglobiny, co doprowadziło do rejestracji leku w Stanach Zjednoczonych (FDA, Food and Drug Administration) w marcu 2007 roku, a w Europie w czerwcu 2007 toku (EMA, European Medicines Agency). U chorych, u których stosowano ekulizumab, wykazano zmniejszenie zapotrzebowania na transfuzje kkcz, a także ochronę przed skutkami hemolizy wewnątrznaczyniowej (powikłaniami zakrzepowo-zatorowymi, nadciś-nieniem płucnym, pogorszeniem funkcji nerek) oraz istotną poprawę jakości życia [15,25,[60][61][62][63][64]. Ponadto opublikowano dane wskazujące na brak różnic w przeżyciu chorych na PNH leczonych ekulizumabem w porównaniu z grupą zdrowych osób, równoważną pod względem wieku i płci [64,65].…”