Association between hemoglobin and chronic kidney disease progression: a secondary analysis of a prospective cohort study in Japanese patients
Authors: Pan Wushan , Han Yong , Hu Haofei , He Yongcheng 
Published: August 2022

Abstract
Objective
Anemia has been reported as a risk factor for chronic kidney disease (CKD) progression. However, there are still few studies examining the relationship between specific hemoglobin (Hb) levels and renal prognosis and renal function decline simultaneously. Meanwhile, the possible non-linear relationship between Hb and CKD progression also deserves further exploration. On that account, our primary goal is to explore the link of Hb on renal prognosis and renal function decline in patients with CKD.

Methods
This study was a secondary analysis of a prospective cohort study, which consecutively and non-selectively collected 962 participants from the research of CKD-ROUTE in Japan from November 2010 to December 2011. We used the Cox proportional-hazards and linear regression models to evaluate the independent association between baseline Hb and renal prognosis (renal composite endpoint, initiation of dialysis during follow-up or 50% decline in eGFR from baseline) and renal function decline(annual eGFR decline), respectively. A multivariate Cox proportional hazards regression analysis with cubic spline functions model and smooth curve fitting (penalized spline method) were conducted to address Hb and CKD prognosis's non-linearity. At the same time, a generalized additive model (GAM) and smooth curve fitting (penalized spline method) was conducted to explore the exact shape of the curve between Hb and renal function decline. Additionally, we did a series of sensitivity analyses to ensure the robustness of the results. Moreover, we conducted subgroup analyses.

Results
The mean age of the included patients was 67.35 ± 13.56 years old, and 69.65% were male. The mean baseline Hb and estimated glomerular filtration rate (eGFR) was 12.06 ± 2.21 g/dL and 33.04 ± 18.01 ml/min per 1.73 m2. The annual decline in eGFR was 2.09 mL/min/1.73 m2/year. During a median follow-up time of 33.5 months, 252(26.2%) people experienced renal composite endpoint. After adjusting covariates, the results showed that Hb was negatively associated with renal composite endpoint (HR = 0.836, 95%CI: 0.770, 0.907) and renal function decline (β = -0.436, 95%CI: -0.778, -0.093). There was also a non-linear relationship between Hb and renal composite endpoint, and the inflection point of Hb was 8.6 g/dL. The effect sizes(HR) on the left and right sides of the inflection point were 1.257 (0.841, 1.878) and 0.789 (0.715, 0.870), respectively. And the sensitive analysis demonstrated the robustness of the results. Subgroup analysis showed that Hb was more strongly associated with the renal composite endpoint in non-hypertensive, SBP < 140 mmHg, urine protein-to-creatinine ratio (UPCR) < 0.5 g/gCr, and diuretic use patients. In contrast, the weaker association was probed in hypertensive and non-diuretic use patients and the patients with SBP ≥ 140 mmHg, and UPCR ≥ 0.5 g/gCr.

Conclusion
This study demonstrates a negative and non-linear relationship between Hb and renal prognosis and renal function decline in Japanese CKD patients. Hb is strongly related to renal prognosis when Hb is above 8.6 g/dL.