Baseline characteristics of participants
Table 1 provided the baseline demographic and clinical characteristics of the 2336 participants categorized by Hb quartiles: <10(Q1), 10-11(Q2), 11-12(Q3), 12-13(Q4), >13(Q5) g/dL. At baseline, 69.60% of the participants were male, with an average age of 64.91±10.61 years. The average Hb and eGFR were 11.76±2.42 g/dL and 39.84±12.86 ml/min/per 1.73 m2. Patients with lower Hb level were more likely to be thinner, had a lower diastolic blood pressure, and they were at a higher risk of thromboembolic events. In addition, these patients had a lower albumin, serum iron, serum uric acid levels and less inflamed than those with higher Hb level. Kidney function was more preserved and the amount of urinary protein excretion was lower in patients with higher Hb levels. No significant differences in age, comorbid conditions, systolic blood pressure, high-density lipoprotein cholesterol, parathyroid hormone, glycosylated hemoglobin, and medications like β-Blocker and CCB were observed across the hemoglobin quartile groups (P > 0.05, see Table 1 for details). Figure 2 contrasts Hb levels between participants who experienced renal composite endpoints and those who did not. Results suggested a lower distribution of Hb levels in the renal composite endpoint group, while the non-renal composite endpoint group exhibited relatively higher Hb levels.
The incidence rate of the composite renal outcome
The Kaplan Meier survival curves were employed to visualize the cumulative incidence of study outcomes in relation to Hb levels. These curves unveiled distinct differences in the risks of composite renal outcomes across Hb levels. Notably, the risks were markedly elevated in the Q1 and Q2 groups in contrast to the Q3, Q4, and Q5 cohorts (p<0.001 by Log-rank test, as depicted in Figure 3). For the entire study population, the cumulative incidence rate was set at 0.29 per 100 person-years. Breaking this down further, the Hb groups Q1 through Q5 had cumulative incidence rates of 0.09, 0.03, 0.06, 0.07, and 0.04 per 100 person-years, respectively. Intriguingly, as Hb levels ascended, there was a noticeable decline in the incidence of renal composite endpoints. This downward trend in incidence with rising Hb levels was statistically significant (P for trend<0.001), as illustrated in Figure 3.
The results of univariate and multivariate analyses using Cox proportional-hazards regression model and Cox time-varying model.
Univariate analysis revealed a few variables that did not have a significant association with the composite renal outcome. On the other hand, several factors exhibited a negative association with the composite renal outcome: hemoglobin, age, serum iron, serum albumin (HR=0.979, 0.986, 0.980, 0.994, 0.914, respectively, all p<0.05). Conversely, some variables demonstrated a positive correlation with the composite renal outcome: male gender, phosphorus, the use of iron and ESAs (HR=1.245, 1.737, 1.881, 2.179, respectively, all p<0.05).
The multivariate analysis was conducted on the baseline data, validating that hemoglobin, age, serum Albumin (HR=0.507, 0.992, 0.959, respectively, all p<0.05) were negatively linked to the renal composite outcome, history of diabetes mellitus and hypertension (HR=1.237, 1.309, respectively, all p<0.05) has the positive correlation with the outcome (See details for Table 2).
Further exploration with a Cox Time-Varying model for univariate and multivariate analysis supported these findings. The multi-variates time-varying hemoglobin (HR=0.969, 95% CI 0.966-0.972, p<0.05) continued to exhibit a negative association with the study outcomes, as detailed in Table 3.
The effects of Hb level on the composite renal outcomes
We constructed three different analytical models using the Cox proportional hazards regression model and Cox time-varying model to explore the relationship between hemoglobin levels and composite renal outcomes. In the unadjusted model (model 1), participants in the baseline Hb groups Q3(HR=0.59, 95% CI 0.48-0.71, p<0.05), Q4(HR=0.37, 95% CI 0.29-0.47, p<0.05), and Q5(HR=0.29, 95% CI 0.23-0.35, p<0.05) demonstrated a significant reduction in the risk of encountering the composite renal outcome when compared to the Q1 group. Specifically, an increase of 1g/dL of Hb was associated with a 41%, 63%, and 71% decrease in the risk of the study outcome for Q3, Q4, and Q5, respectively. This association was not changed in the minimally adjusted model, after adjustment for demographic factors, body mass index, and comorbidities (model 2). However, in a fully adjusted Cox model in which laboratory parameters and medications were additionally included (model 3), the risk of the composite renal outcome was significantly reduced in the Hb group only Q4 (HR=0.57, 95% CI 0.43-0.76, p<0.05) and Q5(HR=0.50, 95% CI 0.38-0.66, p<0.05), with Q3 losing its previous statistical significance (Table 4).
The time-varying Cox model analysis consistently solidified the observation that throughout all three modeling approaches, it was evident that individuals with Hb levels above 10g/dL (Q3, Q4, and Q5) generally had a decreased risk of the composite renal outcome. Specifically, an increase of 1g/dL of Hb was associated with a 53%, 75%, and 86% decrease in the risk of the composite renal outcome for Q3 (HR=0.47, 95% CI 0.37-0.59, p<0.05), Q4 (HR=0.25, 95% CI 0.17-0.34, p<0.05), and Q5 (HR=0.14, 95% CI 0.10-0.20, p<0.05), compare with the Hb group Q1. This pattern of reduced risk with increasing Hb was depicted in the presented tables and figures (Table 4, Figure 4).