Kidney transplant electrolyte disorders do not track NCC activation

About one in four kidney transplant recipients receiving calcineurin inhibitors had the clinical combination of hypertension, hyperkalemia and metabolic acidosis that resembles pseudohypoaldosteronism type II, according to a two-cohort human study. Yet the molecular pattern differed markedly from the genetic disorder: the sodium chloride cotransporter, or NCC, was less abundant and less phosphorylated in urinary extracellular vesicles from transplant recipients than in healthy volunteers, and its abundance did not distinguish recipients with the three-part phenotype from those without it. Kidney-biopsy staining produced the same result, challenging a long-standing explanation for these common complications of transplantation.

The research combined a retrospective cross-sectional cohort of 172 kidney transplant recipients at a three-month post-transplant visit in Bordeaux with a prospective multicenter cohort of 58 recipients in Bordeaux and La Réunion. Most participants in the prospective cohort were taking tacrolimus. The two cohorts had similar prevalences of the full phenotype: 26.2% in the retrospective group and 24.1% in the prospective group, or approximately 24% across 230 recipients. This clinical clustering is important because inherited pseudohypoaldosteronism type II, also called Gordon syndrome, is driven by excessive NCC activity, which promotes sodium and chloride reabsorption in the distal convoluted tubule, reduces distal sodium delivery and impairs potassium and acid-base handling.

Each component of the phenotype was common. In the retrospective cohort, hypertension was present in 84.3% of recipients, metabolic acidosis in 73.8% and hyperkalemia in 38.4%. The corresponding proportions in the prospective cohort were 82.8%, 74.1% and 37.9%. Hypertension accompanied by acidosis without hyperkalemia was also frequent, affecting 36.6% of the retrospective cohort and 34.4% of the prospective cohort. The definition of acidosis was a blood bicarbonate concentration below 22 mM without hypocapnia or a need for alkali supplementation; hyperkalemia meant plasma potassium above 4.5 mM or use of a potassium-chelating agent. Acidosis and hyperkalemia were confirmed with repeated measurements from independent samples, and recipients with an estimated glomerular filtration rate below 15 mL/min per 1.73 m² were excluded from the retrospective analysis.

NCC normally helps the distal convoluted tubule reabsorb sodium chloride. If it is overactive, as in inherited pseudohypoaldosteronism type II, increased electroneutral sodium chloride absorption leaves less sodium available for reabsorption in the collecting system, weakens the electrical gradient that supports potassium secretion and reduces the sodium delivery needed for hydrogen-ion secretion by intercalated cells. Rodent experiments have previously suggested that calcineurin inhibitors could reproduce this molecular pattern by activating WNK and SPAK kinases, increasing NCC phosphorylation and disturbing the WNK–KLHL3–CUL3 regulatory pathway. The human study tested whether that proposed mechanism applied to people receiving the drugs chronically after kidney transplantation.

To investigate NCC without requiring a kidney biopsy from every participant, the prospective investigators isolated extracellular vesicles from morning urine and measured total NCC, phosphorylated NCC at threonine 53 and TSG101, a marker used to estimate vesicle abundance. Because transplant recipients have one kidney rather than two, they might excrete fewer urinary vesicles, and TSG101 abundance was indeed about half as high in recipients as in healthy volunteers. Even after normalization to TSG101, however, both total NCC and phosphorylated NCC were markedly lower in transplant recipients. The reduction persisted when women and men were analyzed separately and was also evident in the small subgroup receiving cyclosporine rather than tacrolimus. The investigators therefore did not interpret the lower readings simply as a consequence of reduced extracellular-vesicle output.

The central comparison was not merely between transplant recipients and healthy volunteers, but between recipients whose electrolyte and blood-pressure findings resembled inherited pseudohypoaldosteronism type II and those whose results did not. There was no significant difference in urinary NCC or phosphorylated NCC between the two groups. The same absence of an association held when hyperkalemia was defined more strictly as serum potassium above 5.0 mmol/L, when recipients were divided by hypertension, and when they were grouped by metabolic acidosis or hyperkalemia alone. Even among seven recipients with potassium above 5 mmol/L, NCC abundance and phosphorylation remained lower than in healthy controls rather than showing the increase expected from activation of the inherited-disease pathway.

The biopsy analysis reinforced the urinary findings. Investigators stained kidney sections from 15 calcineurin-inhibitor-treated recipients: five had the complete hypertension–acidosis–hyperkalemia triad, four had hypertension and acidosis, and six had hypertension without acidosis or hyperkalemia. Because renal tissue from healthy controls was unavailable, the comparison involved four archived biopsies from patients with minimal change disease who were not receiving calcineurin inhibitors. Mean staining intensity for phosphorylated NCC did not differ between the transplant recipients and those controls. The sample was small and the comparator differed in both treatment and diagnosis, so this analysis was supportive rather than definitive, but it provided no evidence for increased NCC activation in the graft.

Clinical differences between phenotype groups did not reveal a clear molecular explanation. Recipients with the full triad in the retrospective cohort had more severe hypertension and lower bicarbonate concentrations, and multivariate analysis associated the phenotype with use of beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and diuretics other than thiazides. In the prospective cohort, recipients with the triad were older, more likely to have received a graft from an older donor and had a lower estimated glomerular filtration rate than those without it. When candidate factors were considered together, age remained independently associated with the phenotype, with an odds ratio of 1.9 per decade and a 95% confidence interval of 1.2 to 3.0. The investigators said declining renal function could be relevant, but noted that the cohort was not large enough to rule out an independent effect of estimated filtration rate.

The study has important limitations. It did not directly measure NCC transport function, for example through the change in renal sodium excretion produced by a thiazide. It examined recipients at approximately three months after transplantation, so it cannot establish whether different periods of exposure produce different molecular effects. The healthy-volunteer and biopsy comparators also do not perfectly match a transplant population, and the study does not exclude a functional increase in NCC without an increase in its measured abundance or phosphorylation, as well as the possibility that a small subset has a true acquired form of the disorder. Previous human studies have reported conflicting results, including increased biopsy staining in some calcineurin-inhibitor-treated recipients and similar urinary NCC excretion in others. The current authors also used a broader definition of the clinical phenotype than some prior work, meaning that only a small number of the 230 recipients would have met stricter criteria.

Animal findings may help explain the discrepancy. Short calcineurin-inhibitor exposure in rodents has activated NCC and WNK-related kinases, whereas three to four weeks of treatment has been associated in some models with reduced NCC and KS-WNK1 abundance. The investigators described this as evidence for a possible biphasic response: early activation followed by downregulation during chronic exposure. Their results argue that, in people receiving the usual chronic regimen after kidney transplantation, the common cluster of hypertension, hyperkalemia and acidosis should not automatically be labeled NCC overactivation or assumed to have the molecular mechanism of inherited pseudohypoaldosteronism type II. The study identifies a frequent clinical reality but rejects its straightforward molecular explanation, leaving renal function, other sodium-transport pathways and potential drug-specific effects as alternatives that require further investigation.

Subject of Research: Molecular testing of electrolyte and blood-pressure disorders in calcineurin-inhibitor-treated kidney transplant recipients

Article Title: Calcineurin inhibitors treatment in kidney transplant recipients is frequently associated with hyperkalemia, acidosis and hypertension but not with increased expression or phosphorylation of the sodium chloride cotransporter

Article References: Di Ascia, L., Baraka-Vidot, J., Ferdynus, C., Duong, J.-P., Bairras Martin, C., Merville, P., Couzi, L., Eladari, D., & Chambrey, R. (2026). Calcineurin inhibitors treatment in kidney transplant recipients is frequently associated with hyperkalemia, acidosis and hypertension but not with increased expression or phosphorylation of the sodium chloride cotransporter. Frontiers in Nephrology, 6, Article 1917605. https://doi.org/10.3389/fneph.2026.1917605

Image Credits: AI Generated

DOI: 10.3389/fneph.2026.1917605

Keywords: kidney transplantation, calcineurin inhibitors, hypertension, hyperkalemia, metabolic acidosis, NCC regulation, extracellular vesicles, pseudohypoaldosteronism type II, tacrolimus, Calcineurin, inhibitors, treatment