December 05, 2017
3 min read

Calcineurin inhibitors increase risk for cognitive dysfunction

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Calcineurin inhibitor therapy for orthotopic liver transplantation — at both low and standard doses — increased the risk for cognitive dysfunction, especially among patients with preexisting nephrotoxic side effects, according to recently published data.

“Our results suggest that long-term [calcineurin inhibitor (CNI)] therapy may induce neurotoxic effects especially in subjects who present with nephrotoxicity with tacrolimus seeming to be more neurotoxic than ciclosporine A,” Henning Pflugrad, MD, from the Hannover Medical School, Germany, and colleagues wrote. “After the occurrence of nephrotoxic side effects, continuation of CNI therapy — even in a low dose — might carry the risk for cognitive alterations in the long-term, indicating an increased susceptibility against toxic CNI effects in this subgroup of patients.”

The researchers enrolled 85 adult patients who had undergone orthotopic liver transplantation more than 2 years prior. Those selected had no prior organ transplants other than incident liver transplantation, no neurological or psychiatric diseases, and no regular intake of drugs that may affect brain function.

Mean patient age was 58.2 years, 56 were men, and the median time from liver transplantation was 10 years (range, 8-13.5 years). Additionally, the researchers included 33 age- and sex-matched controls.

Patients achieved immunosuppression without CNI (n = 20); received low dose CNI therapy with either less than 5 µg/L tacrolimus or less than 50 g/L ciclosporine A (n = 35); or received standard dose CNI therapy with more than 5 µg/L tacrolimus or more than 50 µg/L ciclosporine A (n = 30).

The CNI-free group had been treated with CNI therapy for a mean of 4.2 years after liver transplant and were CNI-free for a mean of 8 years at study baseline. Fifty-seven patients treated with CNI therapy also received at least one other immunosuppressant. The main reason for termination of CNI therapy was CNI-induced kidney damage.

Compared with controls, patients who received standard does CNI therapy (P = .04) and those on low dose CNI therapy (P = .01) had significantly worse visuospatial and constructional ability.

Patients on low does CNI therapy also had worse results in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) sum score (P = .02), total scale (P = .01) and percentile (P = .03) vs. controls.

Years on standard dose CNI therapy correlated negatively with RBANS sum score (P = .04). Tacrolimus total dose also correlated negatively with RBANS sum score, total scale and percentile (P = .04).


All patients had significantly more white matter hyperintensities (WMH) in the parietal (2 vs. 1.2; P = .02) and temporal regions (0.4 vs. 0.1; P = .04) compared with controls. WMH in the temporal region occurred more frequently in patients on standard dose CNI therapy compared with those in the CNI-free group (0.5 vs. 0.1; P = .02) and controls (0.5 vs. 0.1; P = .01).

Mean ciclosporine A trough level correlated significantly with WMH in the frontal (r = 0.4; P = .01), parietal (r = 0.3; P = .02), occipital (r = 0.4; P = .006) and temporal regions (r = 0.3; P = .03). Mean tacrolimus trough level also showed a significant correlation with WMH in the frontal region (r = 0.5; P = .004) and the total WMH (r = 0.4; P = .03).

Final analysis

During multivariate regression analysis, the researchers observed that education in years (regression coefficient = 10.7; 95% CI, 4.6-16.9), ventricular width at the level of the caudate nucleus (RC = –2.8; 95% CI, –5.3 to –0.4) and years of standard dose CNI therapy (RC = –2; 95% CI, –3.8 to –0.1) were independent prognostic factors for the RBANS sum score.

Additionally, ventricular width at the level of the caudate was a significant negative prognostic factor for the RBANS sum score (RC = –4.3; 95% CI, –7.1 to –1.4) and total scale (RC = –1.1; 95% CI, –1.9 to –0.4) among patients treated with ciclosporine A.

Among those treated with tacrolimus, total dose was a significant negative prognostic factor for the RBANS sum score (RC = –0.002; 95% CI, –0.003 to –0.001).

“The correlation analysis between CNI total dosage and mean trough level and RBANS results suggests an increased neurotoxicity of tacrolimus than of ciclosporine A. However, we found as well that both, ciclosporine A and tacrolimus mean trough levels, correlated with WMH indicating a similar effect on brain structure for both drugs,” the researchers concluded. “As long as transplant function is preserved patients showing CNI toxicity early after [orthotopic liver transplantation] might benefit from a change to CNI free immunosuppression in the long-term because cognitive dysfunction might impair patients’ everyday life, job-related performance and health related quality of life.” – by Talitha Bennett

Disclosure: The authors report no relevant financial disclosures.