PNH is a debilitating and life-threatening clonal hematopoietic disease in which lysis of PNH RBCs manifests with chronic hemolysis, anemia and thrombosis. Incidence of progression to chronic renal insufficiency (CRI; GFR < 60 ml/min/1.73 m2) has not been previously examined in a controlled trial. Renal damage in PNH has been associated with chronic hemolysis and subsequent hemosiderosis and/or microvascular thrombosis. A previous study showed that 9/9 hemolytic PNH patients had renal hemosiderin by MRI [Hill et al., 48th Annual ASH meeting, Dec. 9, 2006]. All patients entering into the recently completed eculizumab multinational studies in hemolytic PNH patients (Phase 2, TRIUMPH, SHEPHERD; n=195) were screened for CRI and for a previous clinical diagnosis of CRI and acute renal failure (ARF). The median GFR was 81 ml/min/1.73 m2 (63–97). The incidence of CRI at screening was 21% (40/195) with 10/40 patients having severe CRI (GFR ≤30ml/min). Of 195 patients, 7% (14/195) had previously experienced episodes of ARF which showed at least partial recovery and 21% (3/14) of these patients subsequently developed CRI. Only 25% (10/40) of patients with pre-study CRI had been clinically diagnosed with CRI. Most patients (68%, 27/40) who developed CRI had not previously been clinically diagnosed with either ARF or CRI. Median disease duration and median time from first thrombosis to study entry were increased in CRI patients vs non-CRI patients (8.8 yrs vs 5.1 yrs and 4.6 yrs vs 3.2 yrs, respectively). Proportions of patients with PNH for 10 or more years and 10 or more years since first thrombosis were increased in CRI patients vs non-CRI patients (48%, 19/40 vs 28%, 43/155, P=.02; and 13%, 5/40 vs 3%, 5/155, P=.03, respectively). Eculizumab was safe and well-tolerated in patients with CRI including 1 patient receiving dialysis, with AEs similar to those in patients without CRI. Eculizumab was associated with a reduction in median LDH from 1783 to 331 U/L (P<.0001) and reduction in thrombosis from 5.34 to 0.00 thrombotic events/100 pt-years (P<.0001) in patients with CRI. For patients with baseline CRI, GFR remained stable (median increase 0.47 ml/min/1.73m2) and 10% of patients were no longer classified as CRI, with eculizumab treatment. For the 14 patients with ARF pre-eculizumab, only one patient was reported with ARF during eculizumab (P<.001). CRI is a common finding in PNH as the observed prevalence in hemolytic PNH patients is increased 5-fold compared to the prevalence in the overall U.S. population [

]. ARF is a specific risk factor for development of CRI, although it is not a sensitive risk indicator as most patients with CRI did not previously have ARF. These data suggest that all PNH patients should be closely monitored for CRI and that hemolysis and/or microvascular thrombosis are risk factors for CRI. In the current studies of hemolytic PNH patients, CRI was associated with both increased duration of PNH and duration of exposure to thrombotic events. Eculizumab is safe and effectively reduces hemolysis and thrombosis in PNH patients with ARF and CRI. Moreover, as eculizumab controls hemolysis, reduces thrombosis, and reduces re-occurrence of ARF, the long-term impact of eculizumab on the prevention of renal pathology and CRI in patients with PNH will continue to be evaluated.

Author notes

Disclosure:Employment: Dr. Rother is an employee of Alexion Pharmaceuticals, Inc. Consultancy: Dr. Hillmen has served as a consultant to Alexion Pharmaceuticals, Inc. Ownership Interests:; Dr. Rother has stock in Alexion Pharmaceuticals, Inc. Research Funding: Dr Hillmen has received research funding from Alexion Pharmaceuticals, Inc. Honoraria Information: Dr Hillmen has received lecture fees from Alexion Pharmaceuticals, Inc. Membership Information: Drs. Hillmen, Urbano-Ispizua, and Fu have served on Advisory Boards for Alexion Pharmaceuticals, Inc.