Abstract
Aims: Chronic limb-threatening ischemia (CLTI) is a serious complication in patients with kidney failure. We aimed to investigate the frequency and clinical burden of CLTI in patients undergoing hemodialysis.
Methods: We analyzed a historical cohort of 2,292 maintenance hemodialysis patients to examine the prevalence, risk factors, and clinical outcomes of CLTI, defined as prior surgical or endovascular arterial revascularization and/or lower limb amputation. We also evaluated the incidence of new-onset CLTI during follow-up and its association with the subsequent risk of mortality.
Results: At baseline, 198 patients (8.6%) had prevalent CLTI. These individuals had longer dialysis duration, poorer nutritional status, and higher serum calcium and phosphorus levels, in addition to traditional risk factors. During a median follow-up of 5.8 years, 436 patients experienced cardiovascular events, 77 underwent interventions for CLTI, and 712 died. Prevalent CLTI at baseline was associated with 2.2-, 3.2-, and 9.3-fold higher risks of all-cause mortality, cardiovascular events, and CLTI-related interventions, respectively. These associations were attenuated but remained significant after comprehensive adjustment for potential confounders. Among the 2,094 patients without CLTI at baseline, 49 developed new-onset CLTI. New-onset CLTI was also associated with an increased risk of subsequent mortality, particularly in the early phase following its onset.
Conclusions: CLTI is common and associated with poor clinical outcomes in patients undergoing hemodialysis. Our findings highlight the substantial and persistent burden of CLTI in this population and underscore the urgent need for effective strategies to prevent or delay the progression of lower extremity arterial disease.
Keywords: Amputation, Chronic limb-threatening ischemia, Hemodialysis, Lower extremity arterial disease, Peripheral artery disease
See editorial vol. 33: 252-253
Introduction
Chronic limb-threatening ischemia (CLTI) is a critical complication in patients with an impaired kidney function 1) , particularly in those with kidney failure undergoing dialysis 2 - 7) . It represents the most advanced stage of lower extremity artery disease (LEAD), a form of peripheral artery disease (PAD), and is characterized by persistent and severe impairment of blood flow, often leading to rest pain, non-healing ulcers, gangrene, and ultimately, limb amputation 8 - 10) . According to the Dialysis Outcomes and Practice Patterns Study (DOPPS) 2) , the global prevalence of PAD is 25.3% in the hemodialysis population, with the majority likely representing LEAD. In this report, Japan exhibited the lowest prevalence at 11.5%, although this remains a substantial proportion. If patients with LEAD develop CLTI, it not only severely compromises quality of life but also contributes to increased morbidity and mortality 2 - 7) .
The pathophysiology of CLTI involves both atherosclerosis, which results in intimal plaque formation and intravascular occlusion, and Mönckeberg-type arteriosclerosis, characterized by medial calcification leading to decreased vascular elasticity and impaired diastolic blood flow 11 , 12) . Patients with kidney failure are particularly susceptible to both atherosclerosis and Mönckeberg-type arteriosclerosis, with the latter being especially pronounced due to vascular calcification 13 , 14) . Risk factors for cardiovascular disease in dialysis patients include not only traditional factors (e.g., aging, smoking, diabetes, hypertension, and dyslipidemia) but also kidney failure-specific factors (e.g., dialysis duration, malnutrition, anemia, and hyperphosphatemia) 15 , 16) . However, data on risk factors specifically associated with CLTI in this population remain scarce 2 - 6) . Furthermore, despite the high prevalence of CLTI in dialysis patients, data on its long-term clinical outcomes remain limited, particularly regarding the relative risk of mortality following the development of new-onset CLTI during dialysis.
Aim
To investigate the clinical burden of CLTI in the dialysis population, we analyzed the prevalence and risk factors for CLTI in a historical cohort of 2,292 maintenance hemodialysis patients and examined the impact of prevalent CLTI on all-cause mortality, cardiovascular events, and CLTI-related interventions. Furthermore, we assessed the incidence of new-onset CLTI and its association with subsequent mortality risk.
Methods
Study Design
The design of this historical cohort study has been described previously 17) . Briefly, the study population included 2,292 patients from 22 facilities who had been receiving maintenance hemodialysis for more than three months as of December 31, 2008. Demographic, dialysis information, and comorbidity data were retrospectively collected from medical records, while laboratory and medication data were prospectively collected and uniformly entered into a central database. Patients were followed until death, loss to follow-up, or December 31, 2015, whichever occurred first. Clinical outcomes, including cause-specific mortality and cardiovascular events, were retrospectively collected from medical records. This study was approved by the Institutional Review Board of Tokai University School of Medicine, which waived the requirement for written informed consent.
Baseline Covariates
The following information was obtained from the database: age, sex, dialysis duration, body mass index (BMI), mean blood pressure, pulse pressure, Kt/V (dialysis adequacy), normalized protein catabolic rate (nPCR), catheter use, comorbidities (diabetes, coronary artery disease [CAD], stroke), laboratory values (hemoglobin, albumin, creatinine, potassium, calcium, phosphorus, intact parathyroid hormone [PTH], total cholesterol, C-reactive protein [CRP]), and medications (renin-angiotensin system inhibitors, calcium channel blockers, statin, antiplatelet agents, warfarin). Serum calcium levels were corrected for albumin concentration using Payne’s formula 18) . PTH levels were measured using the Elecsys intact PTH assay (Roche Diagnostics) at 21 facilities, and the whole PTH assay (Scantibodies Laboratories) at one facility. Whole PTH levels were converted to intact PTH levels using the following equation: intact PTH = whole PTH × 1.7 19) .
Definition of CLTI and Other Cardiovascular Events
CLTI was defined as severe PAD requiring surgical revascularization, endovascular arterial revascularization, or lower limb amputation. New-onset CLTI was defined as the first occurrence of any of these interventions during the follow-up period among patients who did not have CLTI at baseline. Cardiovascular events included CAD (acute myocardial infarction or unstable angina) and stroke (symptomatic cerebral infarction or hemorrhage), each requiring hospitalization, as well as CLTI requiring intervention.
Statistical Analysis
Baseline characteristics were compared between patients with and without prevalent CLTI using standard descriptive statistics. A multivariable logistic regression analysis was performed to identify factors independently associated with prevalent CLTI. To assess the specificity of the risk factors for CLTI, factors associated with prevalent CAD were also explored.
We used the Kaplan-Meier method to compare all-cause mortality, cardiovascular events, and interventions for CLTI between patients with and without prevalent CLTI at baseline. To account for potential confounders, Cox proportional hazards models were used to assess the association between prevalent CLTI and these outcomes, adjusting for incremental sets of covariates: Model 1 adjusted for age, sex, dialysis duration, BMI, mean blood pressure, pulse pressure, Kt/V, nPCR, catheter use, diabetes, CAD, and stroke; Model 2 further adjusted for hemoglobin, albumin, creatinine, potassium, calcium, phosphorus, intact PTH, total cholesterol, and CRP; and Model 3 further adjusted for use of renin-angiotensin system inhibitors, calcium channel blockers, statin, antiplatelet agents, and warfarin.
We also examined the incidence of new-onset CLTI during follow-up in participants who were free of CLTI at baseline and its association with subsequent mortality. For this analysis, we used a delayed-entry approach, where time 0 was defined as the date of CLTI onset for individuals who developed CLTI, and as the date of cohort entry (i.e., December 31, 2008) for those who did not. Covariates were adjusted using the same approach as in the analysis of prevalent CLTI. To address the potential for immortal time bias in this analytical approach, we performed a sensitivity analysis in which the CLTI status was modeled as a time-dependent exposure.
The proportion of missing data was ＜10% for all baseline variables except for CRP (29.0%). Missing data were addressed using multiple imputation to create 10 imputed datasets. Statistical analyses were performed for each dataset, and results were pooled to obtain final parameter estimates. Two-sided P values of ＜0.05 were considered statistically significant. Statistical analyses were performed using SPSS Statistics (ver. 24, IBM) and R (ver. 4.0.5, R Foundation for Statistical Computing).
Results
Baseline Characteristics
At baseline, 198 patients (8.6%) had prevalent CLTI. The baseline characteristics of patients with and without prevalent CLTI are shown in Table 1 . Patients with prevalent CLTI were older, more likely to be male, had higher pulse pressure, lower Kt/V, poorer nutritional status, as indicated by lower levels of nPCR, albumin, and creatinine, as well as higher CRP levels. They also had a markedly higher prevalence of diabetes, CAD, and stroke, and were more likely to be prescribed antihypertensive agents, antiplatelet agents, and warfarin.
Table 1. Baseline characteristics in patients with and without prevalent CLTI.
| Characteristic | No prevalent CLTI (n = 2,094) | Prevalent CLTI (n = 198) | P Value |
|---|---|---|---|
| Age, yr | 64.6±12.9 | 67.9±8.8 | <0.001 |
| Male, % | 63.1 | 70.7 | 0.04 |
| Dialysis duration, mo | 68 (29–134) | 64 (35–135) | 0.86 |
| BMI, kg/m2 | 21.4±3.5 | 20.9±3.0 | 0.08 |
| Mean blood pressure, mmHg | 102±16 | 100±16 | 0.09 |
| Pulse pressure, mmHg | 72±19 | 78±20 | <0.001 |
| Kt/V | 1.30±0.25 | 1.25±0.23 | 0.007 |
| nPCR, g/kg/day | 0.86±0.20 | 0.81±0.16 | 0.004 |
| Catheter use, % | 0.5 | 1.5 | 0.10 |
| Comorbidities, % | |||
| Diabetes | 42.7 | 72.2 | <0.001 |
| CAD | 15.0 | 41.4 | <0.001 |
| Stroke | 12.8 | 19.7 | 0.008 |
| Laboratory values | |||
| Hemoglobin, g/dL | 10.4±1.0 | 10.5±1.1 | 0.15 |
| Albumin, g/dL | 3.7±0.3 | 3.7±0.3 | <0.001 |
| Creatinine, mg/dL | 11.8±3.1 | 10.5±2.6 | <0.001 |
| Potassium, mEq/L | 5.2±0.8 | 5.1±0.7 | 0.11 |
| Calcium, mg/dL | 9.4±0.8 | 9.4±0.7 | 0.50 |
| Phosphorus, mg/dL | 5.4±1.4 | 5.5±1.5 | 0.49 |
| Intact PTH, pg/mL | 140 (79–228) | 139 (69–197) | 0.29 |
| Total cholesterol, mg/dL | 160±34 | 162±36 | 0.42 |
| CRP, mg/dL | 0.10 (0.02–0.35) | 0.23 (0.09–1.05) | <0.001 |
| Medication, % | |||
| Renin-angiotensin system inhibitors | 47.0 | 50.5 | 0.37 |
| Calcium channel blockers | 43.9 | 51.0 | 0.06 |
| Statin | 10.3 | 13.1 | 0.22 |
| Antiplatelet agents | 37.1 | 62.1 | <0.001 |
| Warfarin | 5.6 | 17.7 | <0.001 |
Data represent the percentage, mean±SD, or median (interquartile range).
BMI, body mass index; CAD, coronary artery disease; CLTI, chronic limb-threatening ischemia; CRP, C-reactive protein; Kt/V, dialysis adequacy; nPCR, normalized protein catabolic rate; PTH, parathyroid hormone.
Factors Associated with Prevalent CLTI
The factors associated with prevalent CLTI in the multivariable analysis are shown in Table 2 . In addition to traditional risk factors such as male sex, diabetes, and the presence of CAD, dialysis-related clinical parameters, including longer dialysis duration, lower BMI, lower mean blood pressure, higher pulse pressure, lower nPCR, lower serum creatinine, and elevated serum calcium and phosphorus levels, were independently associated with higher odds of CLTI. The use of antiplatelet agents and warfarin, both commonly prescribed in patients with CLTI, was also associated with prevalent CLTI. To assess the specificity of these associations, we also conducted a parallel analysis for prevalent CAD. While the overall pattern of associations was broadly similar, the strength of the association with diabetes was notably stronger for CLTI than for CAD.
Table 2. Baseline characteristics associated with prevalent CLTI or CAD.
| Parameter | CLTI | CAD | ||
|---|---|---|---|---|
| Adjusted OR (95% CI) | P Value | Adjusted OR (95% CI) | P Value | |
| Age, per 10-year increase | 1.00 (0.84–1.20) | 0.96 | 1.18 (1.03–1.35) | 0.02 |
| Sex, male vs. female | 1.80 (1.19–2.74) | 0.006 | 1.72 (1.25–2.37) | <0.001 |
| Dialysis duration, per 1 year increase | 1.04 (1.01–1.06) | 0.01 | 1.02 (1.00–1.04) | 0.03 |
| BMI, per 1 kg/m2 increase | 0.90 (0.85–0.96) | 0.002 | 1.02 (0.98–1.07) | 0.36 |
| Mean blood pressure, per 10 mmHg increase | 0.88 (0.78–0.99) | 0.03 | 0.91 (0.83–1.00) | 0.05 |
| Pulse pressure, per 10 mmHg increase | 1.14 (1.03–1.26) | 0.01 | 1.12 (1.04–1.21) | 0.004 |
| Kt/V, per 0.1 increase | 0.98 (0.90–1.08) | 0.71 | 0.93 (0.86–0.99) | 0.03 |
| nPCR, per 0.1 g/kg/day increase | 0.88 (0.77–1.00) | 0.06 | 1.05 (0.95–1.16) | 0.39 |
| Catheter use, yes vs. no | 1.34 (0.28–6.39) | 0.71 | 0.24 (0.02–2.33) | 0.22 |
| Comorbidities, yes vs. no | ||||
| Diabetes | 2.82 (1.89–4.20) | <0.001 | 1.25 (0.94–1.66) | 0.12 |
| CAD | 2.60 (1.83–3.71) | <0.001 | – | – |
| Stroke | 0.92 (0.61–1.41) | 0.71 | 2.66 (1.88–3.77) | <0.001 |
| CLTI | – | – | 1.73 (1.27–2.36) | <0.001 |
| Laboratory values | ||||
| Hemoglobin, per 1 g/dL increase | 1.14 (0.97–1.33) | 0.11 | 1.04 (0.92–1.18) | 0.51 |
| Albumin, per 0.1 g/dL increase | 0.99 (0.93–1.06) | 0.76 | 1.04 (0.99–1.10) | 0.11 |
| Creatinine, per 1 mg/dL increase | 0.87 (0.81–0.94) | <0.001 | 0.98 (0.93–1.04) | 0.53 |
| Potassium, per 1 mEq/L increase | 1.02 (0.81–1.29) | 0.89 | 1.11 (0.92–1.33) | 0.28 |
| Calcium, per 1 mg/dL increase | 1.30 (1.02–1.67) | 0.04 | 1.09 (0.91–1.30) | 0.34 |
| Phosphorus, per 1 mg/dL increase | 1.29 (1.13–1.47) | <0.001 | 0.93 (0.84–1.03) | 0.17 |
| Intact PTH, per doubling | 1.00 (0.88–1.15) | 0.96 | 0.88 (0.80–0.98) | 0.02 |
| Total cholesterol, per 10 mg/dL increase | 1.04 (0.99–1.09) | 0.12 | 0.99 (0.95–1.03) | 0.53 |
| CRP, per 1 mg/dL increase | 1.06 (0.96–1.17) | 0.25 | 1.04 (0.96–1.12) | 0.35 |
| Medication, yes vs. no | ||||
| Renin-angiotensin system inhibitors | 1.04 (0.71–1.50) | 0.86 | 0.76 (0.58–1.01) | 0.05 |
| Calcium channel blockers | 1.22 (0.85–1.74) | 0.28 | 0.88 (0.67–1.16) | 0.36 |
| Statin | 0.95 (0.58–1.55) | 0.82 | 2.01 (1.43–2.82) | <0.001 |
| Antiplatelet agents | 1.92 (1.37–2.71) | <0.001 | 3.37 (2.62–4.33) | <0.001 |
| Warfarin | 2.85 (1.76–4.61) | <0.001 | 2.07 (1.36–3.15) | <0.001 |
BMI, body mass index; CAD, coronary artery disease; CI, confidence interval; CLTI, chronic limb-threatening ischemia; CRP, C-reactive protein; Kt/V, dialysis adequacy; nPCR, normalized protein catabolic rate; OR, odds ratio; PTH, parathyroid hormone.
Prevalent CLTI and Clinical Outcomes
During a median follow-up period of 5.8 years (interquartile range, 2.8–7.0 years), 436 patients experienced cardiovascular events, 77 received interventions for CLTI, and 712 died. The Kaplan-Meier curves for all-cause mortality, cardiovascular events, and CLTI-related interventions according to the baseline prevalence of CLTI are shown in Fig.1 . Patients with prevalent CLTI at baseline had higher incidences of all-cause mortality (13.2 vs. 5.9 deaths per 100 patient-years), cardiovascular events (9.3 vs. 3.5 events per 100 patient-years), and CLTI-related interventions (3.7 vs. 0.5 events per 100 patient-years) in comparison to those without CLTI. The causes of death in each group are summarized in Supplementary Table 1 , with cardiovascular disease and infection being more common in patients with prevalent CLTI. In univariate Cox regression analyses, the baseline prevalence of CLTI was significantly associated with increased risks of these clinical outcomes ( Table 3 ) . Notably, the relative risk for CLTI interventions was particularly higher, underscoring the frequent need for repeat interventions and the persistent clinical burden of CLTI. These associations tended to attenuate with progressively increasing adjustment for potential confounders yet remained statistically significant, even in the fully adjusted model. The results of the subgroup analysis for the association between prevalent CLTI and clinical outcomes are shown in Fig.2 . Across most patient subgroups, prevalent CLTI appeared to be associated with an increased risk of clinical outcomes.
Fig.1. Kaplan–Meier curves for mortality, cardiovascular events, and interventions for chronic limb-threatening ischemia (CLTI) in patients with and without prevalent CLTI.
Shaded areas represent 95% confidence intervals.
Supplementary Table 1. Causes of death in patients with and without prevalent CLTI.
| Cause of death | No. of deaths (n) | Incidence rate (per 100 person-years) | ||
|---|---|---|---|---|
| No prevalent CLTI | Prevalent CLTI | No prevalent CLTI | Prevalent CLTI | |
| All causes | 612 | 100 | 5.9 | 13.2 |
| Heart failure | 30 | 4 | 0.3 | 0.5 |
| Acute myocardial infarction | 23 | 3 | 0.2 | 0.4 |
| Stroke | 38 | 7 | 0.4 | 0.9 |
| Other cardiovascular disease | 16 | 5 | 0.2 | 0.7 |
| Sudden death | 34 | 3 | 0.3 | 0.4 |
| Infection | 53 | 11 | 0.5 | 1.4 |
| Neoplasm | 60 | 4 | 0.6 | 0.5 |
| Others | 109 | 22 | 1.0 | 2.9 |
| Unknown | 249 | 41 | 2.4 | 5.4 |
CLTI, chronic limb-threatening ischemia.
Table 3. Adjusted HRs (95% CIs) for clinical outcomes associated with prevalent CLTI.
| Model | Mortality | Cardiovascular events | CLTI interventions | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P Value | HR (95% CI) | P Value | |
| Unadjusted | 2.19 (1.76–2.71) | <0.001 | 3.20 (2.47–4.14) | <0.001 | 9.33 (5.82–14.96) | <0.001 |
| Model 1 a | 1.55 (1.24–1.95) | <0.001 | 1.97 (1.50–2.60) | <0.001 | 5.48 (3.28–9.16) | <0.001 |
| Model 2 b | 1.37 (1.09–1.73) | 0.007 | 1.82 (1.37–2.40) | <0.001 | 5.03 (2.96–8.56) | <0.001 |
| Model 3 c | 1.30 (1.03–1.64) | 0.03 | 1.77 (1.33–2.35) | <0.001 | 4.99 (2.89–8.64) | <0.001 |
a Model 1 adjusted for age, sex, dialysis duration, BMI, mean blood pressure, pulse pressure, Kt/V, nPCR, catheter use, diabetes, CAD, and stroke.
b Model 2 adjusted for Model 1 covariates plus hemoglobin, albumin, creatinine, potassium, calcium, phosphorus, intact PTH, total cholesterol, and CRP.
c Model 3 adjusted for Model 2 covariates plus use of renin-angiotensin system inhibitors, calcium channel blockers, statin, antiplatelet agents, and warfarin.
BMI, body mass index; CAD, coronary artery disease; CI, confidence interval; CRP, C-reactive protein; CLTI, chronic limb-threatening ischemia; HR, hazard ratio; Kt/V, dialysis adequacy; nPCR, normalized protein catabolic rate; PTH, parathyroid hormone.
Fig.2. Subgroup analysis of adjusted hazard ratios (HRs) for clinical outcomes associated with prevalent chronic limb-threatening ischemia (CLTI).
Models were adjusted for age, sex, dialysis duration, body mass index (BMI), mean blood pressure, pulse pressure, Kt/V (dialysis adequacy), normalized protein catabolic rate, catheter use, diabetes, coronary artery disease (CAD), stroke, hemoglobin, albumin, creatinine, potassium, calcium, phosphorus, intact parathyroid hormone, total cholesterol, C-reactive protein, use of renin-angiotensin system inhibitors, calcium channel blockers, statin, antiplatelet agents, and warfarin. Squares represent point estimates of the HRs, and horizontal lines indicate 95% confidence intervals (CIs).
Incidence of New-Onset CLTI
Among 2,094 patients without prevalent CLTI at baseline, 49 developed new-onset CLTI during the follow-up period (0.5 events per 100 person-years). The baseline characteristics of patients with and without incident CLTI are shown in Table 4 . Patients who developed new-onset CLTI shared several characteristics with those who had prevalent CLTI, including older age, higher prevalence of diabetes and CAD, and more frequent use of antiplatelet agents.
Table 4. Baseline characteristics in patients with and without incident CLTI during follow-up.
| Characteristic | No incident CLTI (n = 2,045) | Incident CLTI (n = 49) | P Value |
|---|---|---|---|
| Age, years | 64.5±13.0 | 67.7±9.3 | 0.02 |
| Male, % | 63.0 | 67.3 | 0.65 |
| Dialysis duration, months | 71 (31–142) | 55 (34–75) | 0.006 |
| BMI, kg/m2 | 21.4±3.5 | 22.2±3.2 | 0.12 |
| Mean blood pressure, mmHg | 102±16 | 102±15 | 0.95 |
| Pulse pressure, mmHg | 72±19 | 77±19 | 0.08 |
| Kt/V | 1.30±0.25 | 1.19±0.24 | 0.003 |
| nPCR, g/kg/day | 0.86±0.20 | 0.79±0.19 | 0.03 |
| Catheter use, % | 0.5 | 0.0 | 0.99 |
| Comorbidities, % | |||
| Diabetes | 42.1 | 71.4 | <0.001 |
| CAD | 14.7 | 28.6 | 0.01 |
| Stroke | 12.6 | 20.4 | 0.12 |
| Laboratory values | |||
| Hemoglobin, g/dL | 10.4±1.0 | 10.3±1.0 | 0.50 |
| Albumin, g/dL | 3.7±0.3 | 3.7±0.3 | 0.82 |
| Creatinine, mg/dL | 11.8±3.1 | 11.1±3.2 | 0.13 |
| Potassium, mEq/L | 5.2±0.8 | 5.2±0.9 | 0.75 |
| Calcium, mg/dL | 9.4±0.8 | 9.3±0.7 | 0.30 |
| Phosphorus, mg/dL | 5.4±1.4 | 5.3±1.5 | 0.46 |
| Intact PTH, pg/mL | 141 (80–232) | 101 (61–172) | 0.03 |
| Total cholesterol, mg/dL | 160±34 | 165±27 | 0.17 |
| CRP, mg/dL | 0.10 (0.02–0.35) | 0.25 (0.07–0.71) | 0.01 |
| Medication, % | |||
| Renin-angiotensin system inhibitors | 46.9 | 50.0 | 0.77 |
| Calcium channel blockers | 43.7 | 50.0 | 0.46 |
| Statin | 10.3 | 10.4 | 0.99 |
| Antiplatelet agents | 36.8 | 50.0 | 0.07 |
| Warfarin | 5.5 | 8.3 | 0.34 |
Data are percentage, mean±SD, or median (interquartile range).
BMI, body mass index; CAD, coronary artery disease; CLTI, chronic limb-threatening ischemia; CRP, C-reactive protein; Kt/V, dialysis adequacy; nPCR, normalized protein catabolic rate; PTH, parathyroid hormone.
New-Onset CLTI and Mortality
Survival curves for patients who developed new-onset CLTI and those who did not are shown in Fig.3 . Patients who developed CLTI experienced a substantially higher mortality rate in comparison to those who did not (15.2 vs. 5.8 deaths per 100 patient-years). Among patients with new-onset CLTI, the mortality rate was particularly elevated during the first 6 months following onset (31.9 deaths per 100 patient-years) and declined thereafter (11.8 deaths per 100 patient-years). In univariate Cox regression analysis, new-onset CLTI was significantly associated with an increased risk of mortality ( Table 5 ) . This increased mortality risk remained significant even after adjustment for potential confounders. The results were similar when CLTI status was treated as a time-varying exposure.
Fig.3. Kaplan–Meier curves for mortality in patients with and without new-onset chronic limb-threatening ischemia (CLTI).
Time 0 was defined as the date of cohort entry for the non-CLTI group and the date of CLTI onset for the CLTI group. Shaded areas represent 95% confidence intervals.
Table 5. Adjusted HRs (95% CIs) for subsequent mortality associated with new-onset CLTI.
| Model | Cox regression with delayed entrya | Time-dependent Cox regressionb | ||
|---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P Value | |
| Unadjusted | 2.76 (1.96–3.88) | <0.001 | 2.55 (1.63–3.99) | <0.001 |
| Model 1 c | 2.27 (1.59–3.24) | <0.001 | 1.67 (1.06–2.63) | 0.03 |
| Model 2 d | 2.00 (1.39–2.89) | <0.001 | 1.77 (1.12–2.81) | 0.01 |
| Model 3 e | 1.98 (1.37–2.87) | <0.001 | 1.78 (1.12–2.81) | 0.01 |
a Time 0 was defined as the date of cohort entry for the non-CLTI group and the date of CLTI onset for the CLTI group.
b CLTI status was modeled as a time-dependent exposure.
c Model 1 adjusted for age, sex, dialysis duration, BMI, mean blood pressure, pulse pressure, Kt/V, nPCR, catheter use, diabetes, CAD, and stroke.
d Model 2 adjusted for Model 1 covariates plus hemoglobin, albumin, creatinine, potassium, calcium, phosphorus, intact PTH, total cholesterol, and CRP.
e Model 3 adjusted for Model 2 covariates plus use of renin-angiotensin system inhibitors, calcium channel blockers, statin, antiplatelet agents, and warfarin.
BMI, body mass index; CAD, coronary artery disease; CI, confidence interval; CRP, C-reactive protein; CLTI, chronic limb-threatening ischemia; HR, hazard ratio; Kt/V, dialysis adequacy; nPCR, normalized protein catabolic rate; PTH, parathyroid hormone.
Discussion
In this historical cohort study of maintenance hemodialysis patients, we demonstrated that prevalent CLTI was associated with significantly higher risks of all-cause mortality, cardiovascular events, and CLTI-related interventions. We also confirmed an increased risk of subsequent mortality in patients who developed new-onset CLTI during follow-up. These findings reinforce previous results from limited cohort studies of the hemodialysis population 2 - 7) and underscore the persistent and unresolved burden of CLTI.
In this study, we observed that the relationship between CLTI and mortality risk was notably strong in the unadjusted model, but it was progressively attenuated with increasing adjustment for various covariates. This finding, however, is not surprising, as patients with CLTI often have multiple mortality risk factors, such as diabetes and other cardiovascular diseases, which may confound or mediate the association between CLTI and mortality. Nonetheless, the association between CLTI and mortality persisted even after comprehensive adjustment for these factors, suggesting that CLTI may directly contribute to the risk of mortality. Possible mechanisms include infections and sepsis associated with non-healing ulcers and gangrene 20) , local or systemic inflammation leading to increased vascular permeability 21) , and unstable hemodynamics that can become particularly accentuated during ultrafiltration in hemodialysis 22) .
Importantly, our study also demonstrated the substantial impact of new-onset CLTI on subsequent mortality. Although several previous studies have reported poor post-intervention survival in hemodialysis patients with CLTI compared to non-dialysis patients 23 , 24) , to the best of our knowledge, this is the first study to directly compare survival outcomes between hemodialysis patients who developed new-onset CLTI and those who did not. Notably, we observed a markedly increased risk of death in the early phase following CLTI onset. This may reflect the consequences of unsuccessful arterial revascularization or postoperative complications after limb amputation. These findings underscore the even greater impact of CLTI on early mortality and highlight the urgent need for more effective strategies in managing this high-risk condition.
In this study, we also identified several risk factors for prevalent CLTI, including traditional cardiovascular risk factors and dialysis-related factors. Among these, we found that elevated phosphorus and calcium levels were independently associated with CLTI. It is well known that elevated serum phosphorus and calcium contribute to vascular calcification, which not only promotes the deposition of calcium phosphate in vascular walls but also induces the transformation of vascular smooth muscle cells into osteoblast-like cells 11 , 12) . The resultant calcification of arterial walls leads to increased arterial stiffness and hemodynamic instability, potentially contributing to the development of CLTI as well as other cardiovascular diseases 13 , 14) . Consistent with our findings, a previous report from the DOPPS demonstrated an association between higher serum calcium and phosphorus levels and an increased risk of amputation, possibly attributable to LEAD 4) . Analyses from the US Renal Data System 2) and the Q-Cohort Study 5) also revealed a link between elevated serum phosphorus levels and a greater risk of amputation and major adverse limb events, respectively. Together, these findings underscore the importance of controlling disturbances in mineral metabolism to slow the progression of LEAD and reduce the risk of CLTI.
As a unique analytical approach, this study compared the risk factor profiles associated with CLTI and those associated with CAD, a prevalent form of cardiovascular disease. As expected, both outcomes shared similar associations with a range of traditional and dialysis-related risk factors. Interestingly, however, we observed that diabetes showed a substantially stronger association with CLTI than with CAD. These findings further support previous studies reporting a strong association between diabetes and LEAD-related outcomes 2 - 6) . While diabetes contributes to both LEAD and CAD through a shared atherosclerotic mechanism, it may have an additional impact on the risk of CLTI through diabetes-specific complications—such as peripheral neuropathy and immune dysfunction—that increase vulnerability to cellulitis 25) , thereby accelerating both the onset and progression of LEAD.
A high risk of recurrence is a well-recognized feature of cardiovascular disease, and this may be particularly critical in patients with LEAD. In the present study, we found that patients with prevalent CLTI had a more than five-fold increased risk of subsequent CLTI-related interventions in comparison to those without prior CLTI. This underscores the substantial clinical burden of LEAD, where even after successful revascularization of the initial CLTI episode, recurrent CLTI often follows, either in the same region or in other areas. Such recurrences not only severely compromise quality of life but also impose a substantial economic burden on healthcare systems 3 , 26) . These findings emphasize the urgent need to enhance preventive strategies to halt the progression of LEAD and to develop more fundamental therapeutic approaches for CLTI.
This study has several limitations. First, this was an observational study, which does not allow for causal inference. In particular, the associations observed with prevalent CLTI may be subject to reverse causality—for example, nutritional parameters may reflect the consequences rather than the causes of prior CLTI. Second, the definition of CLTI in our study does not fully align with that proposed by the Global Vascular Guidelines 9) . Our study focused specifically on CLTI requiring intervention, which may have excluded less symptomatic patients as well as symptomatic patients who did not undergo intervention. This limits the generalizability of the findings to the full spectrum of the disease. Third, the number of patients who developed new-onset CLTI during follow-up was limited, warranting caution in the interpretation of these results. Furthermore, only the first episode of new-onset CLTI was collected, which restricted our ability to assess amputation-free survival. Fourth, several other potential confounders, including smoking status, were not available. Finally, our database did not differentiate between types of interventions for CLTI and lacked detailed clinical information, such as the anatomical location and severity of the disease.
In conclusion, this study demonstrated that both prevalent and newly developed CLTI were common and strongly associated with poor clinical outcomes in patients undergoing hemodialysis, highlighting the substantial and persistent clinical burden of CLTI. Further research is needed to develop more effective therapeutic approaches to mitigate the serious impact of CLTI on quality of life and survival in this high-risk population.
Conflict of Interest
HK has received personal fees from Kissei Pharmaceutical, Kyowa Kirin, Ono Pharmaceutical, and Sanwa Kagaku Kenkyusho; and grants from Kyowa Kirin. TK has received personal fees from Kissei Pharmaceutical, Kyowa Kirin, Ono Pharmaceutical, and Sanwa Kagaku Kenkyusho. The remaining authors have declared that no conflict of interest exists.
Funding
This work was in part supported by grants from the Japan Society for the Promotion of Science.
Acknowledgments
The authors thank the following investigators who participated in the study: Hajime Suzuki (Bousei Hiratsuka Clinic), Mitsunori Yagame (Bousei Oone Clinic), Kayoko Watanabe (Bousei Fujisawa Clinic), Nobuyoshi Takagi (Bousei Kannai Clinic), Hiroshi Kida (Bousei Akabane Clinic), Mitsumine Fukui (Bousei Tanashi Clinic), Ken-ichi Oguchi (Bousei Hospital), Tetsuo Shirai (Bousei Clinic), Mikako Nagaoka (Honatsugi Medical Clinic), Tsuneyoshi Oh (Tsurumi Nishiguchi Hospital), Eiji Nakano (Motomachi Medical Clinic), Takayuki Hashiguchi (Fujisawa Medical Clinic), Hirofumi Ishii (Shonan Seiwa Clinic), Yoshihide Tanaka (Higasiyamato Nangai Clinic), Yasuji Sugano (Kitahachioji Clinic), Toru Furuya (Higashikurume Clinic), Naoto Ishida (Seichi Clinic), Hiroyuki Ogura (Hadano Minamiguchi Clinic), Yoko Omori (Kitasenju Higashiguchi Jin Clinic), Miho Enomoto (Ayase Ekimae Jin Clinic) and Yuichiro Yamaguchi (Adachi Iriya Toneri Clinic).
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