Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial
Authors: Maruyama Shoichi , Kurasawa Shimon , Hayashi Terumasa , Nangaku Masaomi , Narita Ichiei , Hirakata Hideki , Tanabe Kenichiro , Morita Satoshi , Tsubakihara Yoshiharu , Imai Enyu , Akizawa Tadao ,   PREDICT Investigators, Hiramatsu Takeyuki , Tamai Hirofumi , Iida Yoshiyasu , Naruse Tomohiro , Oishi Hideto , Uchida Shunya , Shimizu Hideaki , Morozumi Kunio , Kurata Hisashi , Hirawa Nobuhito , Nishio Saori , Yuzawa Yukio , Mizutani Makoto , Aoyama Isao , Yoshida Hideaki , Kaneda Kouji , Suzuki Satoshi , Adachi Hiroki , Kinugasa Eriko , Kurata Kei , Morinaga Hiroshi , Tsukamoto Yusuke , Tsuruya Kazuhiro , Ando Ryoichi , Ichida Shizunori , Tamura Teiichi , Masaki Takao , Wada Takashi , Honda Hirokazu , Yamamoto Junichiro , Isaka Yoshitaka , Muso Eri , Komatsu Yasuhiro , Ohashi Norimi , Hara Taiga , Ikeda Kiyoshi , Okada Kazuyoshi , Yoshida Tetsuhiko , Okuda Seiya , Suzuki Hiromichi , Nakanishi Takeshi , Higashi Harumichi , Shirasaki Arimasa , Endo Shuichiro , Osawa Yutaka , Aoyagi Ryuji , Tomino Yasuhiko , Akimoto Tetsu , Watanabe Tsuyoshi , Toyonaga Jiro , Tanaka Motoko , Ishibashi Yoshitaka , Uezono Shigehiro , Sakakibara Masako , Yamazaki Hajime , Takano Hideki , Ikeda Hirofumi , Takata Takuma , Yamashita Hiroshi , Yamagata Kunihiro , Sato Toshinobu , Yoshimura Ashio , Tamagaki Keiichi , Sonomura Kazuhiro , Iguchi Akira , Tamura Masahito , Yasukawa Ryota , Oku Manei 
Published: June 2023

Abstract
Background
In the primary analysis of the PREDICT trial, a higher hemoglobin target (11–13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9–11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes.

Methods
Patients with an estimated glomerular filtration rate (eGFR) 8–20 ml/min/1.73 m2 without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model.

Results
In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43–0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m2/year; 95% confidence interval: 0.38–1.63), while the proteinuria slope did not differ between the groups.

Conclusions
In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes.

Clinical trial registration
Clinicaltrials.gov (identifier: NCT01581073).