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Epoetin Therapy and Hemoglobin Level Variability in Nondialysis Patients with Chronic Kidney Disease

Roberto Minutolo^*, Paolo Chiodini, Bruno Cianciaruso, Andrea Pota, Vincenzo Bellizzi, Deborah Avino^*, Sara Mascia^*, Simona Laurino^*, Valerio Bertino^*, Giuseppe Conte^*, and Luca De Nicola^*

^* Nephrology Division, Second University of Naples-Santa Maria del Popolo degli Incurabili Hospital-Azienda Sanitaria Locale NA1, Department of Biostatistics, Second University of Naples, and Nephrology Division, University Federico II, Naples, and Nephrology Division, County Hospital, Solofra, Italy

Correspondence: Prof. Luca De Nicola, Cattedra di Nefrologia, Dip. Gerontologia, Geriatria, Mal. Metabolismo, Seconda Università di Napoli, Piazza Miraglia, 80131 Napoli, Italia. Phone/Fax: +39-081-2549409; E-mail: luca.denicola{at}unina2.it

Background and objectives: Intrapatient variability of hemoglobin (Hb) is a newly proposed determinant of adverse outcome in chronic kidney disease (CKD). We evaluated whether intensity of epoetin therapy affects Hb variability and renal survival in nondialysis CKD.

Design, setting, participants, & measurements: We calculated the individual therapeutic index (TI) for epoetin (EPO; difference between rates of visits that required EPO dosage change and those with effective EPO change) from 1198 visits during the first year of EPO in 137 patients. Renal death was registered in the subsequent 18.1 mo. Analysis was made by TI tertile (lower, middle, and higher; i.e., from more to less intensive therapy).

Results: Main features and visit number were similar in tertiles. Lower Hb response to first EPO dosage was an independent predictor of higher TI (P = 0.002). The area under the curve for Hb (11.56 ± 0.87, 11.46 ± 1.20, and 10.95 ± 1.48 g/dl per yr; P = 0.040) decreased from lower to higher tertile. Hb variability increased in parallel, as shown by the reduction of time with Hb at target (time in target, from 9.2 ± 2.0 to 3.0 ± 2.2 mo; P < 0.0001) and the wider values of within-patient Hb standard deviation (from 0.70 to 0.96; P = 0.005) and Hb fluctuations across target (P < 0.0001). In Cox analyses (hazard ratio [95% confidence interval]), risk for renal death was increased in the middle and higher tertiles (2.79 [1.36 to 5.73] and 2.94 [1.40 to 6.20]) and reduced by longer time in target (0.90 [0.83 to 0.98]).

Conclusions: Lack of adjustment of EPO worsens Hb variability in CKD. Hb variability may be associated with renal survival, but further studies are needed to explore the association versus causal relationship.