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      Tacrolimus-induced Ascites after Liver Transplant

      case-report

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          Abstract

          Massive post-transplantation ascites is a rare but serious condition following liver transplantation. Although, many etiologies are suggested as the cause of this complication, in some cases the definitive etiology remains unknown. Drug-induced post-transplantation ascites is one of the possible etiologies. In this study we present a case of ascites caused by tacrolimus in the post-liver transplantation period. A 49-year-old man with hepatitis B virus cirrhosis underwent liver transplantation and received tacrolimus, mycophenolate and prednisolone, as the immunosuppressive regimen. Progressive ascites developed after 10 days, in spite of a normal liver function. Various studies, including liver biopsy, were performed but we could not find any etiology for this complication. The tacrolimus was switched to rapamune. Ascites was completely disappeared and up to the last follow-up visit, the patient remained asymptomatic for more than two years. We concluded that after ruling out other etiologies, tacrolimus as a rare cause of post-transplantation ascites should be taken into account. The treatment is discontinuation of the drug.

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          The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension

          Ewout J. Hoorn, Stephen B. Walsh, James A McCormick … (2011)
          Calcineurin inhibitors (CNIs) are immunosuppressive drugs, which are used widely to prevent rejection of transplanted organs and treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria, and acidosis often complicate their use 1,2 . These side effects resemble familial hyperkalemic hypertension (FHHt), a genetic disease characterized by overactivity of the renal sodium chloride co-transporter (NCC), and caused by mutations in WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC, and the NCC regulatory kinases WNK3, WNK4, and SPAK. The functional importance of NCC in this response was demonstrated by showing that tacrolimus did not affect blood pressure in NCC knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice over-expressing NCC. Moreover, hydrochlorothiazide reversed tacrolimus-induced hypertension. In kidney transplant recipients treated with tacrolimus, fractional chloride excretion in response to bendroflumethiazide was greater than in controls, and renal NCC abundance was also greater, extending these observations to humans. Together, these findings indicate that tacrolimus-induced hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.
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            Mechanism of action of the immunosuppressant rapamycin.

            F Dumont, Q Su (1995)
            Rapamycin has potent immunosuppressive properties reflecting its ability to disrupt cytokine signaling that promotes lymphocyte growth and differentiation. In IL-2-stimulated T cells, rapamycin impedes progression through the G1/S transition of the proliferation cycle, resulting in a mid-to-late G1 arrest. Two major biochemical alterations underlie this mode of action. The first one affects the phosphorylation/activation of the p70 S6 kinase (p70s6k), an early event of cytokine-induced mitogenic response. By inhibiting this enzyme, whose major substrate is the 40S ribosomal subunit S6 protein, rapamycin reduces the translation of certain mRNA encoding for ribosomal proteins and elongation factors, thereby decreasing protein synthesis. A second, later effect of rapamycin in IL-2-stimulated T cells is an inhibition of the enzymatic activity of the cyclin-dependent kinase cdk2-cyclin E complex, which functions as a crucial regulator of G1/S transition. This inhibition results from a prevention of the decline of the p27 cdk inhibitor, that normally follows IL-2 stimulation. To mediate these biochemical alterations, rapamycin needs to bind to intracellular proteins, termed FKBP, thereby forming a unique effector molecular complex. However, neither(p70s6k) inhibition, nor p27-induced cdk2-cyclin E inhibition are directly caused by the FKBP-rapamycin complex. Instead, this complex physically interacts with a novel protein, designated "mammalian target of rapamycin" (mTOR), which has sequence homology with the catalytic domain of phosphatidylinositol kinases and may therefore be itself a kinase. mTOR may act upstream of (p70s6K) and cdk2-cyclin E in a linear or bifurcated pathway of growth regulation. Molecular dissection of this pathway should further unravel cytokine-mediated signaling processes and help devise new immunosuppressants.
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              AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients.

              R. Scholten, Ajda Rowshani, Piet W J de Groot … (2005)
              Tacrolimus has a narrow therapeutic window, and bioavailability is known to vary considerably between renal transplant recipients. Most centers still rely on measurement of trough levels, but there are conflicting reports on the correlation between tacrolimus trough levels and systemic exposure, as measured by the area-under-the-concentration-over-time curve (AUC((0-12h))). We developed and validated a two-compartmental population-based pharmacokinetic model with Bayesian estimation of tacrolimus systemic exposure. Subsequently, we used this model to apply prospectively AUC-guided dosing of tacrolimus in 15 consecutive renal transplant recipients. The main objective was to study intrapatient variability in the course of time. Bayesian forecasting with a two-point sampling strategy, a trough level, and a second sample obtained between two and four hours post-dose significantly improved the squared correlation with the AUC((0-12h)) (r(2)= 0.94). Compared with trough level monitoring only, this approach reduced the 95%-prediction interval by 50%. The Bayesian approach proved to be feasible in clinical practice, and provided accurate information about systemic tacrolimus exposure in individual patients. In the AUC-guided dosing cohort the apparent clearance of tacrolimus decreased gradually over time, which was not reflected in corresponding trough levels. This simple, flexible method provides the opportunity to tailor immunosuppression, and should help minimize tacrolimus-related toxicity, such as nephrotoxicity and post-transplant diabetes mellitus.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Organ Transplant Med
                Journal ID (iso-abbrev): Int J Organ Transplant Med
                Journal ID (publisher-id): Ijotm
                Title: International Journal of Organ Transplantation Medicine
                Publisher: Avicenna Organ Transplantation Institute (Shiraz, Iran )
                ISSN (Print): 2008-6482
                ISSN (Electronic): 2008-6490
                Publication date (Print): 2018
                Publication date (Electronic): 1 May 2018
                Volume: 9
                Issue: 2
                Pages: 102-104
                Affiliations
                [1 ]Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
                [2 ]Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
                Author notes
                [* ]Correspondence: Mohsen Aliakbarian, MD, Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, E-mail: aliakbarianm@mums.ac.ir
                Article
                Publisher ID: ijotm-7-102
                PMC ID: 6390981
                SO-VID: b52ea0b5-deb0-4757-b04b-dfcb431eba02
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Subject: Case Report

                Keywords: ascites,tacrolimus,liver transplantation,immunosuppressive agents
                Data availability:
                Keywords: ascites, tacrolimus, liver transplantation, immunosuppressive agents

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