, Introduction
Kidney transplantation (KT) is widely regarded as the gold-standard treatment for end-stage kidney disease, offering superior outcomes in survival and quality of life compared to dialysis [1,2]. Despite these advantages, kidney transplant recipients (KTRs) face a heightened risk of mortality and cardiovascular disease relative to the general population [3–5]. Among the complications of KT, posttransplant anemia is a notable concern. Defined as a reduction in hemoglobin (Hb) levels, posttransplant anemia is a prevalent issue during the early posttransplant period [5,6] and has been associated with adverse clinical outcomes, including cardiovascular complications, mortality, and graft function decline [5,7,8].
The optimal management of posttransplant anemia, including the determination of target Hb levels, remains unclear. This uncertainty is particularly apparent in the early posttransplant period, when Hb levels exhibit significant variability. While previous studies have investigated the impact of posttransplant anemia on KTR outcomes, several limitations hinder the generalizability of their findings. Some studies did not stratify Hb levels with sufficient granularity [9,10], whereas others, conducted in earlier eras, may not reflect the contemporary KTR population [11,12]. Additionally, many studies were constrained by small sample sizes, raising concerns about the influence of confounding factors on their conclusions [13,14].
In light of these uncertainties and limitations, the present study aims to clarify the relationship between early posttransplant Hb levels and long-term outcomes in a comprehensive, nationwide cohort of KTRs. Specifically, we hypothesized that lower Hb levels during the early posttransplant period could adversely affect clinical outcomes, including cardiovascular events, mortality, and graft function. Additionally, we evaluated whether elevated Hb levels in this critical period are safe and associated with a favorable long-term prognosis for KTRs.
Methods
Study population and design
This study was a retrospective analysis based on prospective Korean Organ Transplantation Registry (KOTRY), a comprehensive database that records information on organ transplant recipients in Korea. From this registry, we identified 9,199 adults aged 19 years and older who underwent KT between May 2014 and December 2021. After excluding 1,649 KTRs with missing Hb values at 6 months post-KT and 49 patients who experienced composite events within 6 months after KT. A total of 7,501 participants were included in the final analysis. Data extracted from the KOTRY database included demographic characteristics, comorbid conditions, baseline and follow-up laboratory findings, immunosuppressant use, and posttransplant events such as mortality, cardiovascular events, graft loss, and donor information. The tumor variable in the baseline characteristics was defined as a history of malignant neoplasm (including in situ neoplasm) diagnosed prior to KT. Participants were categorized into five groups based on Hb levels at 6 months post-KT: <10, 10 to <11, 11 to <12, 12 to <13 (reference group), and ≥13 g/dL (Fig. 1). The Hb range of 12 to <13 g/dL was selected as the reference group in alignment with the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, which define anemia as Hb levels below 13 g/dL for men and below 12 g/dL for women [15].
Study outcomes
The primary outcome of this study was a composite endpoint comprising cardiovascular events, graft loss, and all-cause mortality. Cardiovascular events were defined as the occurrence of new-onset acute myocardial infarction, angina pectoris, congestive heart failure, valvular heart disease, arrhythmias, or aortic dissection during the follow-up period. Graft loss was defined as the initiation of dialysis lasting more than 3 months, the need for re-transplantation, or death while the graft remained functional.
Statistical analyses
Patient characteristics and the incidence of study outcomes were stratified by Hb levels at 6 months post-KT. Continuous variables were summarized as mean ± standard deviation, while categorical variables were presented as frequencies and percentages. The chi-square test was applied to assess differences in categorical variables, and analysis of variance was used for continuous variables. Crude event proportions across Hb groups were compared using the chi-square test. Restricted cubic spline regression models were employed to explore the association between Hb levels (as a continuous variable) and study outcomes. The Kaplan-Meier method was used to estimate the cumulative incidence of study outcomes, with group differences evaluated using the log-rank test. To minimize survivor bias, both the Cox regression analyses and the Fine-Gray competing risk analyses were performed using a landmark design, in which the 6-month posttransplant Hb measurement served as the baseline, and follow-up for all outcomes began at this time point. Variables demonstrating significant differences between groups in baseline characteristics (p < 0.05) and those of clinical relevance were incorporated into a multivariate Cox proportional hazards model to determine their independent associations with study outcomes. All covariates included in the Cox regression models were tested for the proportional hazards assumption using Schoenfeld residuals, and no violations were detected. For the components of the composite endpoint, such as cardiovascular events, graft loss, and all-cause mortality, we additionally applied the Fine-Gray competing risk regression model to account for competing events, estimating subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs). Linear regression analyses were performed to identify factors associated with Hb levels, with variables significant in univariate analyses subsequently included in multivariate models. Subgroup analyses were conducted based on baseline characteristics, including age, sex, body mass index (BMI), diabetes status, donor subtype, and estimated glomerular filtration rate (eGFR). Statistical significance was defined as a p-value <0.05. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute Inc.) and R version 4.0 (R Foundation for Statistical Computing).
Ethics statement
This study was approved by the Institutional Review Board of the Kyungpook National University Hospital (No. 2020-11-056). All patients provided written informed consent before participation. This study was conducted in accordance with the guidelines of the 2013 Declaration of Helsinki and the Declaration of Istanbul 2008.
Results
Baseline characteristics
The baseline characteristics of the patient population are detailed in Table 1. The mean age of the cohort was 49.6 ± 11.6 years, with 60.4% (n = 4,530) being male. Patients in the group with higher Hb levels were younger and had a higher proportion of males. This group also exhibited a higher mean BMI but a shorter duration of pre-transplant dialysis. Among immunosuppressive therapies, the rate of antithymocyte globulin induction was highest in the group with the lowest Hb levels, whereas the type of maintenance immunosuppressant did not significantly differ between groups. The prevalence of hypertension was greatest among patients with Hb levels ≥13 g/dL, while the prevalence of diabetes and cardiovascular disease was highest in the Hb <10 g/dL group. Furthermore, the proportion of living donor KT was highest in the Hb ≥13 g/dL group, whereas deceased donor KT was most common in the Hb <10 g/dL group.
Association between hemoglobin levels and outcomes
The entire study cohort was followed for a mean of 3.02 ± 1.99 years. The relationship between Hb levels and clinical outcomes was assessed using Cox regression analyses with restricted cubic splines (Fig. 2). Lower Hb levels were associated with a significantly increased risk of composite events, graft loss, and all-cause mortality.
The occurrence of these outcomes, stratified by Hb groups, is summarized in Table 2. Patients with Hb <10 g/dL exhibited the highest rates of graft loss and all-cause mortality, whereas those with Hb ≥13 g/dL demonstrated the lowest rates for these outcomes. Similarly, the composite outcome was significantly more prevalent in the Hb <10 g/dL group. Kaplan-Meier survival curves (Fig. 3) revealed that patients in the lowest Hb group had markedly reduced survival across all endpoints, including composite events, cardiovascular outcomes, graft loss, and all-cause mortality (log-rank p < 0.05 for all).
In multivariate Cox regression models, the Hb <10 g/dL group exhibited a consistently elevated risk for the composite outcome compared with the reference group (model 4: adjusted hazard ratio [aHR], 3.16; 95% CI, 2.05–4.87; p < 0.001) (Table 3, Fig. 4A). This group also displayed significantly higher risks for individual components of the composite outcome, including cardiovascular events, graft loss, and all-cause mortality, even after adjustment for multiple confounders (all p < 0.05) (Fig. 4B–D; Supplementary Tables 1–3, available online). Cumulative incidence curves derived from the Fine-Gray competing risk analysis are presented in Supplementary Fig. 1 (available online). Patients with Hb <10 g/dL showed the highest cumulative incidence of cardiovascular events, graft loss, and all-cause mortality throughout follow-up. Notably, in Fine-Gray competing risk regression, patients with Hb ≥13 g/dL had a significantly reduced risk of all-cause mortality compared with the reference group (adjusted sHR, 0.44; 95% CI, 0.22–0.90; p = 0.02) (Fig. 4D; Supplementary Table 3 and Supplementary Fig. 1C, available online).
Factors associated with hemoglobin
The factors associated with Hb levels are summarized in Table 4. In the multivariate linear regression analysis, BMI, hypertension, and serum albumin were positively correlated with Hb levels (all p < 0.05). In contrast, Hb levels were negatively associated with age, female sex, mismatched human leukocyte antigen number, serum creatinine, and deceased donor KT (all p < 0.05). Additionally, antithymocyte globulin induction demonstrated a borderline negative correlation with Hb levels (p = 0.05).
Subgroup analysis of composite outcomes
The risks of composite outcomes were evaluated across different Hb groups, stratified by age, sex, BMI, diabetes status, donor type, and eGFR. A consistent relationship was observed between Hb levels and composite outcomes in all subgroups. Specifically, an Hb level <10 g/dL was identified as an independent risk factor for adverse outcomes (Fig. 5). Conversely, Hb levels ≥13 g/dL were not associated with an increased risk of composite outcomes compared with the reference group.
Discussion
This nationwide prospective cohort study demonstrated that early posttransplant Hb levels independently predict long-term clinical outcomes in KTRs. Specifically, Hb levels below 10 g/dL were significantly associated with adverse outcomes, including increased mortality, cardiovascular events, and graft failure. Conversely, higher Hb levels exceeding 13 g/dL showed an association with lower mortality, suggesting a potentially favorable survival outcome. These findings underscore the critical role of early posttransplant Hb levels in determining the long-term prognosis of KTRs and highlight the necessity of careful monitoring during the early posttransplant period.
Prior investigations into the relationship between posttransplant Hb levels and clinical outcomes have yielded inconsistent results. While anemia is widely acknowledged as a detrimental factor, the specific prognostic implications of varying Hb levels remain inconclusive. For instance, Moore et al. [16] identified an association between lower Hb levels and graft loss in a large UK cohort; however, this study did not observe a significant relationship between Hb levels and mortality, contrasting with the findings of the present study. Similarly, a large French cohort study reported that posttransplant anemia was independently associated with increased mortality but not graft survival [10]. These discrepancies may reflect differences in patient demographics, such as race and donor type, as well as variations in immunosuppressive regimens and other potential confounders. Compared to these studies, our analysis, which included a large and well-characterized cohort of recently transplanted KTRs, demonstrated that Hb levels <10 g/dL were consistently associated with impaired patient and graft survival, even after adjusting for multiple confounders.
However, low Hb levels may also reflect underlying graft dysfunction, malnutrition, or chronic inflammation rather than representing a purely modifiable predictor. Although serum creatinine and albumin were included in our models, residual confounding from unmeasured biological factors may persist. Therefore, the observed association between low Hb levels and adverse outcomes should be interpreted with caution, recognizing that Hb may serve as an integrated marker of overall systemic and graft health.
Cardiovascular disease remains the leading cause of death among KTRs, with anemia recognized as a major contributor to cardiovascular complications [17]. Although the detrimental effects of anemia in chronic kidney disease are well established, and therapeutic targets are defined, the relationship between anemia and cardiovascular outcomes in KTRs remains insufficiently understood. In this study, multivariate analysis of a large cohort revealed that mild anemia (Hb 10–12 g/dL) was not associated with an elevated risk of cardiovascular events. In contrast, severe anemia (Hb <10 g/dL) emerged as an independent risk factor for such events. This finding aligns with the work of Rigatto et al. [18], who identified anemia as an independent risk factor for congestive heart failure in KTRs. Anemia imposes chronic hemodynamic stress, contributing to ventricular hypertrophy and cardiac cavity enlargement [18]. Given the high prevalence of cardiovascular complications in this population and the modifiable nature of Hb levels, regular monitoring and comprehensive management of anemia in KTRs are essential to mitigate associated risks.
Studies examining the relationship between posttransplant anemia and mortality have yielded inconsistent results. A prospective cohort study reported that anemia was associated with an increased risk of mortality during a 4-year follow-up period following KT [19]. Similarly, a retrospective study demonstrated that each 1 g/dL increase in Hb level was associated with an 18% reduction in mortality risk [20]. In contrast, other prospective and retrospective studies failed to establish a significant association between posttransplant anemia and mortality [14,21,22]. The pathophysiological mechanisms underlying the potential association between anemia and mortality may involve increased cardiovascular risk due to heightened cardiac workload, leading to left ventricular hypertrophy and congestive heart failure—both of which are linked to elevated mortality [23,24]. Moreover, reduced oxygen-carrying capacity in anemic patients may result in tissue hypoxia, potentially triggering fatal events such as myocardial infarction or stroke. These mechanisms underscore the plausibility of anemia as a contributing factor to mortality. In the present study, mortality was consistently higher among patients with Hb levels <10 g/dL. The variability in findings across studies may be explained by differences in anemia severity [25,26]. Specifically, this study observed increased mortality in patients with severe anemia (Hb levels <10 g/dL), while mild anemia (Hb levels between 10 and 12 g/dL) did not demonstrate a significant association with mortality.
The consistent association between Hb <10 g/dL and adverse outcomes across subgroups suggests that the prognostic significance of early posttransplant anemia is robust and not limited to demographic or clinical profiles. Although differences in age, sex, BMI, or donor type influence baseline Hb levels, these factors did not appear to modify the relationship between severe anemia and long-term outcomes. This underscores the importance of early anemia surveillance and intervention in all KTRs, regardless of individual characteristics or donor-related factors.
The implications of elevated Hb levels in KTRs have not been extensively investigated. A cohort study reported that increasing Hb levels beyond 12.5 g/dL through erythropoietin treatment was associated with higher mortality rates in KTRs [27]. However, two randomized controlled trials assessing the use of erythropoietin-stimulating agents to manage Hb levels indicated beneficial effects on allograft function. One trial found that maintaining Hb levels of 13–15 g/dL with erythropoietin significantly reduced the progression of chronic allograft nephropathy and improved allograft survival compared to Hb levels of 10.5–11.5 g/dL [7]. Another trial showed that targeting Hb levels of 12.5–13.5 g/dL slowed renal function decline over a 3-year period, suggesting that moderate Hb control may confer long-term benefits for graft function [28]. Our study contributes additional evidence, indicating that elevated Hb levels may improve patient survival. Specifically, patients with Hb levels above 13 g/dL consistently exhibited reduced mortality across all analytical models. These findings align with a recent study on anemia correction in KTRs, which reported improvements in cardiac index, further supporting the potential benefits of optimized Hb levels for both renal function and patient survival [29]. Whether these outcomes reflect a protective effect of high Hb levels or are influenced by factors such as nutritional status or unmeasured variables warrants further investigation.
Decreased Hb levels in the early posttransplant period can adversely affect graft function due to decreased oxygen delivery to the transplanted kidney. Anemia compromises the oxygen-carrying capacity of the blood, thereby diminishing the efficiency of oxygen transport to tissues, including the graft. Given the kidneys’ high sensitivity to hypoxia, insufficient oxygenation can result in ischemic damage to kidney tissue [30]. This ischemic injury may lead to tubular necrosis, interstitial fibrosis, and, over time, chronic allograft dysfunction [30–32]. Furthermore, anemia during the early posttransplant period is associated with an increased risk of graft dysfunction, including posttransplant hypertension and calcineurin inhibitor toxicity. These factors may create a self-perpetuating cycle of reduced tissue oxygenation and impaired graft recovery, which accelerates graft deterioration [33–35]. Therefore, the observed association between low posttransplant Hb levels and an increased risk of graft loss in this study underscores the critical role of maintaining adequate oxygenation for graft function. Further studies are warranted to elucidate the precise pathophysiological mechanisms by which Hb levels influence graft outcomes.
The key strength of this study lies in its identification of the relationship between Hb levels and various clinical outcomes within a large, prospective KT cohort. However, several limitations should be acknowledged. Given the observational nature of this study, the associations identified between posttransplant Hb levels and subsequent clinical outcomes should not be interpreted as a causal relationship. Despite extensive multivariable adjustment, the possibility of unmeasured confounding cannot be excluded. Therefore, the observed associations should be interpreted with caution, and future prospective or interventional studies are warranted to validate these findings. Second, although the reference range for normal Hb levels varies by sex, a uniform threshold was applied in this study for outcome comparisons. This approach was taken because the study aimed to explore the relationship between Hb levels and clinical prognosis rather than solely differentiate between anemic and non-anemic patients. Importantly, subgroup analyses revealed that Hb levels below 10 g/dL were associated with adverse outcomes in both sexes, with no significant sex-based differences observed. Third, due to data limitations, we were unable to account for erythropoiesis-stimulating agent use, iron replacement therapy, or detailed iron indices. The absence of these parameters may have limited our ability to fully adjust for differences in iron status and anemia management. In addition, the analysis relied on a single Hb measurement obtained 6 months after KT, without considering longitudinal Hb variability. While this time point was selected to reflect the early posttransplant stabilization phase, it remains possible that changes in Hb over time could have influenced the outcomes. Lastly, the KOTRY dataset anonymized the center identifier, which prevented us from assessing inter-center variability. This limitation may have reduced our ability to account for center-level effects in the analysis.
In conclusion, early posttransplant Hb levels were significantly associated with clinical outcomes in KTRs. Severe anemia, defined as Hb levels below 10 g/dL, was significantly associated with increased risks of all-cause mortality, cardiovascular events, and graft loss. Conversely, higher Hb levels, particularly those above 13 g/dL, were associated with more favorable patient survival. Further prospective and randomized controlled trials are warranted to determine whether interventions targeting posttransplant anemia can improve long-term outcomes in KTRs.
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