Variables Associated With Hyperkalemic RTA

Organ transplant recipients require immunosuppressive and anti-infective medications to prevent transplant rejection and opportunistic infections. Two such drugs are calcineurin inhibitors (CNI) and trimethoprim-sulfamethoxazole (TMP-SMX), both of which can lead to hyperkalemic renal tubular acidosis (RTA). Characteristics of hyperkalemic RTA include plasmatic nongap metabolic acidosis (which develops because the renal tubules cannot maintain an acid-base balance), hyperkalemia, and a positive urine anion gap.

The incidence of post-transplant hyperkalemic RTA is unknown and likely underestimated, but transplant recipients often present with clinical and biological characteristics that may be associated with hyperkalemic RTA. Since such characteristics have not been studied, Othmane Mohib, MD, et al attempted to identify patients with a biological profile consistent with hyperkalemic RTA. They conducted a single-center, retrospective, comparative study from January 1, 2017, to January 1, 2022, of kidney, heart, and lung transplant recipients. Results appeared in the journal Cureus.

After analyzing 384 patient records, 168 patients were ultimately selected for the study. The incidence of hyperkalemic RTA was 6.5% among the included records. Participants comprised two groups, one with hyperkalemic RTA (n=11) and a control group (n=157). The mean age was 51.55 years for patients with hyperkalemic RTA and 51.85 years for the control group (P=.96). Hyperkalemic RTA was defined as bicarbonatemia <23 mmol/L, kalemia >4.5 mmol/L, serum anion gap ≤20 mmol/L, and urinary anion gap >0.

The researchers analyzed the following qualitative variables: type of organ transplanted; sex; type of CNI; prophylaxis by TMP-SMX; receipt of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or potassium-sparing diuretics; and diabetes mellitus. They also analyzed the following quantitative variables: age, residual serum tacrolimus level, serum creatinine, estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration formula, kalemia, chloremia, and bicarbonatemia. They attained all quantitative variables except age at 12 days (±1 day) post-transplantation in the control group, correlating with the median time to diagnosis of hyperkalemic RTA.

Due to the small sample size, the research team used Fisher’s exact test (rather than a Chi-square test) to determine whether there was a significant association between the occurrence of hyperkalemic RTA and each qualitative variable; the significance threshold was α=.05 with 95% CI. They used the Mann-Whitney test for quantitative variables, with the same significance threshold and confidence interval. Finally, they applied a logistic regression, selecting the logistic model according to the Akaike Information Criterion and using a significance threshold of α=.05 and 95% CI. The results were also interpreted based on odds ratios (ORs).

The analyses found that kidney and heart transplant recipients were at greater risk of developing hyperkalemic RTA than lung transplant recipients (P=.016). In fact, no instances of RTA occurred in lung transplant recipients (n=59). Although some case reports have associated hyperkalemic RTA with cyclosporine and tacrolimus treatment, this study found no association between type of CNI and RTA. After evaluating all qualitative variables, the type of transplanted organ was the only variable significantly associated with the occurrence of RTA.

Regarding quantitative variables, residual serum tacrolimus levels (P=.13) and creatinine levels (P=.17) of kidney transplant patients were not significantly associated with hyperkalemic RTA. However, researchers identified a significant association between RTA and kalemia (P<.01), chloremia (P<.01), and bicarbonatemia (P<.01), as they had suspected. The multivariate logistic regression results confirmed the impact of these three variables on RTA prevalence. The OR analysis of the final multivariate logistic regression model determined that a one-unit increase in kalemia increased the risk of hyperkalemic RTA by 300 times.

The authors identified two main limitations of their study. First, the sample size was small. Second, the study design was monocentric.

“In this study, the type of transplanted organ and the presence of kalemia, chloremia, or bicarbonatemia were significantly associated with the occurrence of hyperkalemic RTA,” the authors concluded. “It is essential to identify this complication and treat hyperkalemia first before proposing additional treatments. This study calls into question certain approaches to managing this complication proposed in a number of case reports, such as reducing the target serum residual of tacrolimus or discontinuing TMP-SMX in favor of another antibiotic prophylactic agent, potentially exposing patients to the risk of graft rejection and opportunistic infections.” In addition, they said, larger studies are required to more precisely identify transplanted patients at risk for hyperkalemic RTA.

Source: Cureus