Search

Bodyweight-based tacrolimus dosing followed by therapeutic drug monitoring is standard clinical care after renal transplantation. However, after transplantation, a meager 38% of patients are on target at first steady-state and it can take up to 3 weeks to reach the target tacrolimus predose concentration (C0). Tacrolimus underexposure and overexposure is associated with an increased risk of rejection and drug-related toxicity, respectively. To minimize subtherapeutic and supratherapeutic tacrolimus exposure in the immediate post-transplant phase, a previously developed dosing algorithm to predict an individual’s tacrolimus starting dose was tested prospectively. In this single-arm, prospective, therapeutic intervention trial, 60 de novo kidney transplant recipients received a tacrolimus starting dose based on a dosing algorithm instead of a standard, bodyweight-based dose. The algorithm included cytochrome P450 (CYP)3A4 and CYP3A5 genotype, body surface area, and age as covariates. The target tacrolimus C0, measured for the first time at day 3, was 7.5–12.5 ng/mL. Between February 23, 2019, and July 7, 2020, 60 patients were included. One patient was excluded because of a protocol violation. On day 3 post-transplantation, 34 of 59 patients (58%, 90% CI 47–68%) had a tacrolimus C0 within the therapeutic range. Markedly subtherapeutic ( 20 ng/mL) tacrolimus concentrations were observed in 7% and 3% of the patients, respectively. Biopsy-proven acute rejection occurred in three patients (5%). In conclusion, algorithm-based tacrolimus dosing leads to the achievement of the tacrolimus target C0 in as many as 58% of the patients on day 3 after kidney transplantation.

Aims: Tacrolimus is a critical dose drug and to avoid under- and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug-related toxicity occur despite whole-blood tacrolimus pre-dose concentrations ([Tac]blood) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac]cells) may better correlate with drug-efficacy. The aim of this study was to (1) investigate the relationship between [Tac]blood and [Tac]cells, (2) identify factors affecting the tacrolimus distribution in cells and whole-blood, and (3) study the relationship between [Tac]cells and clinical outcomes after kidney transplantation. Methods: A total of 175 renal transplant recipients were prospectively followed. [Tac]blood and [Tac]cells were determined at Months 3, 6 and 12 post-transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus-related nephrotoxicity and post-transplant diabetes mellitus were collected. Results: Correlations between [Tac]blood and [Tac]cells were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac]cells/[Tac]blood ratio was stable over time in most patients (median intra-patient variability 39.0%; range 3.5%–173.2%). Age, albumin and haematocrit correlated with the [Tac]cells/[Tac]blood ratio. CYP3A5 and CYP3A4 genotype combined affected both dose-corrected [Tac]blood and [Tac]cells. ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes. Conclusions: The correlation between [Tac]blood and [Tac]cells is poor. Age, albumin and haematocrit correlate with the [Tac]cells/[Tac]blood ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes.

Iron deficiency (ID) is highly prevalent in kidney transplant recipients (KTRs) and has been independently associated with an excess mortality risk in this population. Several causes lead to ID in KTRs, including inflammation, medication and an increased iron need after transplantation. Although many studies in other populations indicate a pivotal role for iron as a regulator of the immune system, little is known about the impact of ID on the immune system in KTRs. Moreover, clinical trials in patients with chronic kidney disease or heart failure have shown that correction of ID, with or without anaemia, improves exercise capacity and quality of life, and may improve survival. ID could therefore be a modifiable risk factor to improve graft and patient outcomes in KTRs; prospective studies are warranted to substantiate this hypothesis.

Immunosuppressive drugs have been key to the success of liver transplantation and are essential components of the treatment of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). For many but not all immunosuppressants, therapeutic drug monitoring (TDM) is recommended to guide therapy. In this article, the rationale and evidence for TDM of tacrolimus, mycophenolic acid, the mammalian target of rapamycin inhibitors, and azathioprine in liver transplantation, IBD, and AIH is reviewed. New developments, including algorithm-based/computer-assisted immunosuppressant dosing, measurement of immunosuppressants in alternative matrices for whole blood, and pharmacodynamic monitoring of these agents is discussed. It is expected that these novel techniques will be incorporate into the standard TDM in the next few years.

Supplemental Digital Content is available in the text., Background. Cholesterol embolization syndrome (CES) is an uncommon but well-known cause of renal failure in native kidneys, but little is known about CES in kidney transplant recipients. The aim of this study was to determine the incidence, clinical characteristics, histopathology, and prognosis of CES after kidney transplantation. Methods. CES cases in both transplanted and native kidneys (control group) were identified by searching the databases of the divisions of Nephrology and Pathology of our institution. Clinical data were retrospectively collected. Biopsies were classified according to the latest Banff 2019 Update. Second, a systematic literature search was performed (December 01, 2020) of Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science. Results. CES was observed in for-cause biopsies of 11 out of 2350 (0.47%) kidney transplant recipients transplanted between January 1, 2006, and December 31, 2018 (0.0009 cases per person-year). All patients had ≥1 cardiovascular risk factor, and 9 donors were expanded criteria donors. Graft loss occurred in 27.3% of the patients diagnosed with CES. Eight transplant biopsies with CES were also classified as biopsy-proven acute rejection. Transplant biopsies showed signs of inflammation (arteritis, n = 7; interstitial inflammation, n = 5; tubulitis, n = 7). One patient with CES in a native kidney was identified. The biopsy of the native kidney only showed arteritis and classified as an isolated “v” lesion. The literature search resulted in 188 unique articles of which 20 were included. A total of 47 cases of CES after kidney transplantation was reported. Cholesterol emboli were found in

BK virus (BKV) infection after kidney transplantation can cause BKV nephropathy (BKVAN) resulting in graft dysfunction and allograft loss. The treatment for BKVAN is reduction of the immunosuppressive load which increases the risk of kidney transplant rejection. There is no biomarker to monitor BKV activity besides BK viral load. The value of the Enzyme-Linked Immunosorbent Spot (ELISPOT) assay as a tool to monitor the recipient's anti-BKV immune response after transplantation was investigated systematically. Electronic databases, including MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials were searched for studies of ELISPOT evaluating the immune response against BKV. BKV status was categorized as "active BKV infection" and as "resolving BKV infection". Random-effects model meta-analysis was performed to determine the diagnostic performance of the ELISPOT assay, after stratifying patients into groups based on positive and negative ELISPOT results. One-hundred twenty-seven articles were identified of which nine were included. Patients with negative ELISPOT had an increased risk of having active BKV replication (odds ratio of 71.9 (95%-CI 31.0–167.1). Pooled sensitivity was 0.95 (95%-CI 0.89–0.98) and specificity was 0.88 (95%-CI 0.78–0.94). The standardized mean difference of the number of IFN-γ producing cells between patients with active BKV infection compared with patients who had resolving BKV infection was -2.09 (95%-CI -2.50, -1.68). The ELISPOT assay is a useful tool for BKV risk assessment and in combination with BKV load may support clinicians in guiding immunosuppressive therapy in patients with BKV replication.

Twenty-five years after its approval by the FDA and EMA, tacrolimus remains the cornerstone of immunosuppressive treatment following solid organ transplantation [1,2]. The drug is highly effective ...

Background: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. Methods: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. Results: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Conclusions: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.