Metabolic Acidosis and Long-Term Clinical Outcomes in Kidney Transplant Recipients

Abstract

Metabolic acidosis (MA), indicated by low serum total CO₂ (TCO₂) concentration, is a risk factor for mortality and progressive renal dysfunction in CKD. However, the long-term effects of MA on kidney transplant recipients (KTRs) are unclear. We conducted a multicenter retrospective cohort study of 2318 adult KTRs, from January 1, 1997 to March 31, 2015, to evaluate the prevalence of MA and the relationships between TCO₂ concentration and clinical outcomes. The prevalence of low TCO₂ concentration (<22 mmol/L) began to increase in KTRs with eGFR<60 ml/min per 1.73 m² and ranged from approximately 30% to 70% in KTRs with eGFR<30 ml/min per 1.73 m² Multivariable Cox proportional hazards models revealed that low TCO₂ concentration 3 months after transplant associated with increased risk of graft loss (hazard ratio [HR], 1.74%; 95% confidence interval [95% CI], 1.26 to 2.42) and death-censored graft failure (DCGF) (HR, 1.66; 95% CI, 1.14 to 2.42). Cox regression models using time-varying TCO₂ concentration additionally demonstrated significant associations between low TCO₂ concentration and graft loss (HR, 3.48; 95% CI, 2.47 to 4.90), mortality (HR, 3.16; 95% CI, 1.77 to 5.62), and DCGF (HR, 3.17; 95% CI, 2.12 to 4.73). Marginal structural Cox models adjusted for time-varying eGFR further verified significant hazards of low TCO₂ concentration for graft loss, mortality, and DCGF. In conclusion, MA was frequent in KTRs despite relatively preserved renal function and may be a significant risk factor for graft failure and patient mortality, even after adjusting for eGFR.

Keywords: acidosis; chronic graft deterioration; glomerular filtration rate; kidney transplantation; mortality; transplant recipients.

Figure 1.

Distribution of serum TCO₂ and eGFR among KTRs with follow-up from 1 month to 60 months post-transplant. (A) Bar plots for the prevalence of TCO₂ groups. Low, <22 mmol/L; normal, 22–29.9 mmol/L; high, ≥30 mmol/L. (B) Bar plots for the prevalence of eGFR categories stratified as follows: stage 1, ≥90 ml/min per 1.73 m²; stage 2, ≥60 and <90 ml/min per 1.73 m²; stage 3, ≥30 and <60 ml/min per 1.73 m²; stage 4, ≥15 and <30 ml/min per 1.73 m²; stage 5, <15 ml/min per 1.73 m². (C) Box-and-whisker plots for TCO₂. (D) Box-and-whisker plots for eGFR. The numbers of subjects at each month were as follows: 1 month, 2318; 3 months, 2318; 6 months, 2299; 9 months, 2285; 12 months, 2262; 18 months, 2180; 24 months, 2082; 36 months, 1801; 48 months, 1518; and 60 months, 1304.

Figure 2.

TCO2 <22 mmol/L was associated with higher probabilities of graft loss, mortality and DCGF. Participants were grouped into three categories according to serum TCO₂ (low, <22 mmol/L; normal, 22–29.9 mmol/L; high, ≥30 mmol/L). Cumulative probabilities of (A) graft loss, (C) mortality, and (E) DCGF were plotted according to TCO₂ groups using single TCO₂ values at 3 months post-transplant. Cumulative probabilities of (B) graft loss, (D) mortality, and (F) DCGF were plotted according to TCO₂ groups using time-varying TCO₂ values.

Figure 3.

Lower than normal serum TCO2 levels were associated with higher relative hazards for clinical outcomes. HRs with 95% CIs for (A) graft loss, (B) mortality, and (C) DCGF according to serum TCO₂ in time-varying Cox models adjusted for the following covariates: age, sex, body mass index, cause of ESRD, smoking, diabetes, systolic blood pressure category, eGFR, pre-emptive transplantation, donor age, donor sex, donor status (deceased versus living), ABO incompatibility, HLA mismatch, cross-match, donor-specific antibody, delayed graft function, acute rejection, and calcineurin inhibitor. Restricted cubic spline regression models were applied.