Metabolic Acidosis and Risk for Cardiovascular Events Following Transplantation

Of the 135,436 kidneys transplanted between 2008 and 2015, an estimated 20% will be lost within 5 years. An additional 35,000 kidney transplants will be lost by 2025, which will result in significant morbidity, mortality, and public health costs. Patient death, primarily due to cardiovascular disease, accounts for nearly half of the failed transplanted kidneys. The other 50% are lost to rejection, disease recurrence, and tubulointerstitial fibrosis.

Kidney transplant recipients often experience metabolic acidosis. The high prevalence of metabolic acidosis in the transplant population compared with other patients with chronic kidney disease (CKD) is associated with distinct immunologic and drug-induced effects that regulate its pathogenesis following kidney transplantation.

There is no evidence that treatment of metabolic acidosis prevents cardiovascular events in patients with CKD or kidney transplant recipients. There is concern regarding sodium loading with bicarbonate. Results of the CRIC (Chronic Renal Insufficiency Cohort) study demonstrated that the risk for developing a renal end point was 3% lower per 1-mEq/L higher serum bicarbonate level (P=.01), while the risk for congestive heart failure increased by 14% for every 1-mEq/L higher serum bicarbonate level in those with bicarbonate >24 mEq/L (P=.02).

Researchers, led by Arjang Djamali, MD, conducted a single-center observational cohort study designed to assess whether metabolic acidosis is a risk factor for cardiovascular events after kidney transplantation. The study examined the association between mean serum bicarbonate (measured as total carbon dioxide [tCO2] in serum) concentration at 1 year following transplantation and the incidence of de novo ischemic, arrhythmic, or heart failure events in 2018 kidney transplant recipients. Results of the study were reported in the American Journal of Kidney Diseases [2019;73(4):476-485].

Included participants were recipients of a kidney transplant at the University of Wisconsin from January 1, 2000, to November 15, 2013, who survived at least 13.5 months without a cardiovascular event and had at least one measurement of tCO2, serum creatinine, systolic and diastolic blood pressures, and lipids during the 3-month baseline window centered at 1 year (10.5-13.5 months post-transplantation). Patients with a mean estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 during the baseline window were excluded. Patients were divided into five groups based on mean tCO2 concentration: <20.0, 20.0 to 21.9, 22.0 to 23.9 mEq/L, 24.0 to 25.9 (reference group), and ≥26 mEq/L.

A total of 3266 kidney transplant recipients survived without a cardiovascular event until the end of the 3-month baseline window (13.5 months post-transplantation). Of those, 2128 recipients had complete data available during the baseline window and had a mean eGFR ≥15 mL/min/1.73 m2 and were included in the study. Compared with excluded recipients, those included in the study were older (50.9 vs 48.5 years at the time of transplantation) and less likely to have received a prior transplant (20.0% vs 25.0%; P=.001). There  were no significant differences between the two groups in age, race, sex, living/deceased donor, presence of diabetes at the time of transplantation, or delayed graft function.

Mean recipient age was 50.9 years, 40% were women, and 83% were white. Metabolic acidosis was defined as tCO2 level <24 mEq/L; 826 patients met that criterion (38.9%). Patients in the lowest category of tCO2 concentration were significantly younger and had worse kidney function and higher diastolic blood pressures. They were also more likely to have received a deceased donor kidney transplant or thymoglobulin induction and have delayed graft function. There was no difference in maintenance therapy with calcineurin inhibitors.

Diabetes was the primary cause of end-stage renal disease in 24.3% of participants and 7.1% developed new-onset diabetes following transplantation prior to the end of the baseline window. Also, before the end of the baseline window, 20.7% of recipients had an acute rejection event, and 44.9% had a history of infection other than urinary tract infection. A total of 23% of patients were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers during the baseline window.

During a median follow-up of 3.75 years, 384 recipients had at least one cardiovascular event. A total of 241 had an ischemic event, 137 had an arrhythmic event, and 150 had a heart failure event. There were 610 deaths; 82 were considered due to a cardiovascular event.

There was no statistically significant difference found for patients with mild acidosis (tCO2 of 22-23.9 mEq/L)l; however, the adjusted hazard ratio (aHR) for all cardiovascular events in patients with tCO2 levels <20 mEq/L was significantly greater than for the reference group with tCO2 levels of 24.0 to 25.9 mEq/L (aHR, 2.00; 95% confidence interval [CI], 1.29-3.10).

The risk for cardiovascular events was driven primarily by ischemic events (aHR, 2.28; 95% CI, 1.34-3.90). For every 1 mEq/L lower tCO2 level for those with tCO2 <24 mEq/L, risks for all cardiovascular events and ischemic cardiovascular events were 17% and 15% higher, respectively (aHR for all cardiovascular events, 0.83; 95% CI, 0.74-0.94 and aHR for ischemic cardiovascular events, 0.85; 95% CI, 0.74-0.99). There were no associations between metabolic acidosis and arrhythmic or heart failure events.

There was an independent association between tCO2 level <20 mEq/L, compared with tCO2 level of 24.0 to 25.9 mEq/L, and all-cause mortality (aHR, 1.43; 95% CI, 1.02-2.02). For every 1-mEq/L lower tCO2 level for those with tCO2 <24 mEq/L, there was a 17% higher risk for death (aHR, 0.83; 95% CI, 0.75-0.92).

There were some limitations to the study, including the retrospective, single-center design, lack of measurement of pH values, and lack of repeated tCO2 and covariate data.

The researchers said, “In summary, our findings indicate that metabolic acidosis is a predictor of ischemic cardiovascular events in kidney transplant recipients, independent of traditional and transplant-specific risk factors, and suggest that alkali therapy, provided as either sodium ion-based alkali and/or base producing fruits and vegetables, should be considered to correct tCO2 levels to the normal range. However, this indication should be tempered because the safety and efficacy of bicarbonate therapy in kidney transplant recipients is yet to be demonstrated.”

Takeaway Points

  1. A single-center observational cohort study examined whether metabolic acidosis is a risk factor for cardiovascular events following kidney transplantation.
  2. There was an association between total carbon dioxide (tCO2) in serum concentration level and increased risk for cardiovascular events.
  3. The risk was driven primarily by ischemic cardiovascular events (adjusted hazard ratio, 2.28; 95% confidence interval, 1.34-3.90).