Hippuric Acid Levels Predict Death Risk in Hemodialysis Patients Beyond Immune Aging Markers
In 54 hemodialysis patients followed for 2 years, higher total and free hippuric acid independently predicted death, regardless of age, vintage, or lymphocyte profile.
Summary
Hemodialysis removes protein-bound uremic toxins (PBUTs) poorly, and patients also show premature immune aging. This Greek-Belgian prospective study measured six PBUTs and lymphocyte subsets in 54 hemodialysis patients and 31 age-matched controls, then followed the patients for two years. Patients had higher PBUT levels and markedly lower CD4+ T cells and B-cell subsets than controls. Six patients died, all in year two. Higher total and free hippuric acid (HA) was linked to death, and the link held after adjusting for age, dialysis vintage, CD4+CD45RA+CD31+ T cells and naïve B cells. Free indoxyl sulfate was also associated with death, but not after adjustment. Higher CMPF was seen in patients with cardiovascular events. Because only six deaths occurred, the findings are hypothesis-generating.
Detailed Summary
Patients on hemodialysis face high rates of cardiovascular disease, serious infection and death. Two contributors are of growing interest. One is protein-bound uremic toxins (PBUTs), gut- and diet-derived compounds that bind tightly to albumin and are cleared poorly by dialysis. The other is premature immune aging (immunosenescence), marked by loss of naïve lymphocytes. This study asked whether either one, or both, track with clinical outcomes.
The researchers enrolled 54 hemodialysis patients and 31 healthy controls matched for age (mean about 51 years). Patients were relatively young, with a median dialysis vintage of 67 months, and 44% were treated with online hemodiafiltration. Patients with high comorbidity, such as diabetes, were excluded. Lymphocyte subsets were measured by flow cytometry. Six PBUTs (hippuric acid, indoxyl sulfate, p-cresyl sulfate, p-cresyl glucuronide, indole-3-acetic acid and CMPF) were measured by ultra-performance liquid chromatography. Patients were followed for two years for cardiovascular events, infection-related hospitalization and all-cause mortality.
Patients had higher PBUT levels than controls. They also had lower CD4+ T-cell counts and lower counts of total B cells and of every B-cell subset, including naïve, IgM-memory, switched-memory and double-negative cells. Six patients (11%) died, all in the second year. Those who died had fewer naïve B cells (median 23.5 vs 58.5 cells/µL, p = 0.032). Baseline lymphocyte profiles did not differ between patients with and without cardiovascular events or severe infections.
Higher free indoxyl sulfate and higher total and free hippuric acid were associated with death in Kaplan–Meier and logistic analyses. A logistic model of the PBUTs explained about 44% of the variance in death. In Cox regression, total and free HA stayed significant, alone and after adjustment for age, dialysis vintage, CD4+CD45RA+CD31+ T cells and naïve B cells. The association for free indoxyl sulfate disappeared after adjustment. HA levels rose with dialysis vintage (r ≈ 0.38–0.39). Patients with cardiovascular events had higher CMPF (p = 0.015). The two toxins linked to outcomes were not the p-cresyl or IAA compounds.
These results suggest that hippuric acid could be a prognostic marker in hemodialysis, and a possible target for therapies that lower toxin generation or improve removal. They also suggest the toxin signal is not simply a stand-in for immune aging. The caveats are substantial: very few events (six deaths), a single cohort, and an observational design that cannot show causation. Because diabetic and high-comorbidity patients were excluded, the results may not apply to typical dialysis populations. The text available for this summary ended partway through the results, so some analyses are not covered.
Key Findings
- Higher total and free hippuric acid were associated with 2-year all-cause mortality in hemodialysis patients (Cox p = 0.023 and 0.008).
- The hippuric acid–mortality link held after adjusting for age, dialysis vintage, CD4+CD45RA+CD31+ T cells and naïve B cells.
- Free indoxyl sulfate was linked to death in unadjusted analyses, but the association vanished after adjustment.
- Patients who died had fewer naïve B cells (23.5 vs 58.5 cells/µL, p = 0.032); only 6 of 54 died.
- Higher CMPF was observed in patients who had cardiovascular events (p = 0.015).
Methodology
Prospective observational study of 54 hemodialysis patients and 31 age-matched healthy controls. Lymphocyte phenotypes were measured by flow cytometry and six PBUTs by ultra-performance liquid chromatography. Patients were followed for 2 years and analyzed with Kaplan–Meier, logistic and Cox regression.
Study Limitations
Only six deaths occurred, so regression estimates are unstable and prone to overfitting. Diabetic and high-comorbidity patients were excluded and the cohort was relatively young, which limits generalizability. The study is single-cohort and observational, so causality cannot be inferred, and multiple PBUTs were tested without clear correction for multiplicity.
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