Immunosuppressive drugs and the gastrointestinal tract in renal transplant patients.

Gastrointestinal (GI) discomfort is common after renal transplantation and can be caused by the use of various immunosuppressive drugs. GI symptoms affect the quality of life, lead to an impaired graft survival and an increased mortality. Moreover, diseases and disturbances of the GI tract also affect the pharmacokinetics of immunosuppressive drugs. This review addresses the interaction between immunosuppressive agents and GI disorders. The GI tract is involved in the metabolism of several immunosuppressive drugs. Calcineurin inhibitors, mTor inhibitors, and corticosteroids are subjected to metabolism by the intestinal cytochrome P450 (CYP3A) and by the drug efflux pump ABCB1. Mycophenolate is partly metabolized in the stomach and intestine and undergoes enterohepatic recirculation. Gastrointestinal disturbances can lead to a modified exposure to immunosuppressive drugs. In the first and second part of this review, we focus on the role of the GI tract in the pharmacokinetics of the immunosuppressive drugs and how to adjust immunosuppressive therapy in patients with vomiting, need for tube feeding, delayed gastric emptying, intestinal resection, and diarrhea. In the third part, we review the GI adverse effects of the various immunosuppressive drugs, with special attention for diarrhea and dyspepsia. Finally, we discuss the effects of drugs used for relief of GI complaints on the exposure to immunosuppressive agents.

Delayed trough level measurement with the use of prolonged-release tacrolimus.

Trough concentrations of prolonged-release tacrolimus are usually measured at 24 h after taking the drug in the morning. It is impractical to measure these trough concentrations in patients who visit the outpatient clinic in the afternoon. Trough concentrations obtained in the afternoon may also be suitable for estimating the 24-h exposure. We therefore aimed to assess the usefulness of tacrolimus concentrations measured at 32 h postdose for therapeutic drug monitoring in renal transplant patients who take prolonged-release tacrolimus. We measured tacrolimus pharmacokinetics in 26 patients using prolonged-release tacrolimus. Eleven blood samples were taken during a period of 32 h after ingestion by use of a validated dried blood spot method. Tacrolimus concentrations were measured with HPLC-tandem mass spectrometry. The mean concentrations at 24 and 32 h postdose were 8.3 µg/l (7.5-9.1) and 6.7 µg/l (6.1-7.4), respectively (P < 0.0001). The Spearman correlation coefficients between these concentrations and 24-h exposure were 0.83 and 0.82, respectively (both P < 0.01). In conclusion, delayed trough level measurement provides lower values and therefore requires adjustment of the target range. However, levels measured until 32 h after ingestion remain strongly correlated with 24-h exposure. This warrants the use of delayed trough level measurement to improve patient convenience.

Treatment satisfaction in renal transplant patients taking tacrolimus once daily.

BACKGROUND: Adherence to immunosuppressive therapy, which is important to prevent rejection after organ transplantation, is influenced by satisfaction of patients with their medication regimen. OBJECTIVE: We investigated the effect of introducing a simplified medication regimen for renal transplant patients on treatment satisfaction, in particular, convenience. METHODS: In a prospective cohort study, treatment was switched from tacrolimus twice daily to tacrolimus once daily with a simultaneous change to a once-daily formulation of other drugs when applicable. Treatment satisfaction was measured in 75 participants with the validated Treatment Satisfaction Questionnaire for Medication version II. RESULTS: The treatment convenience score increased from a mean (SD) of 66.0 (14.5) to 78.5 (14.5) (P < 0.001). The mean (SD) daily number of medication ingestion time points diminished from 2.4 (0.7) to 1.6 (0.7) (P < 0.001), and the mean (SD) daily number of tablets decreased from 12.4 (3.3) to 9.1 (2.6) (P < 0.001). The self-reported adherence to the medication regimen increased from 79.7% to 94.6% (P < 0.001). CONCLUSIONS: The introduction of a simplified medication regimen enabled by the use of a once-daily formulation of tacrolimus increases treatment convenience after renal transplantation. This regimen had a beneficial effect on self-reported adherence.

Early development of hyperparathyroidism due to loss of PTH transcriptional repression in patients with HNF1ß mutations?

CONTEXT: Heterozygous mutations or deletions of the transcription factor hepatocyte nuclear factor 1ß (HNF1ß) result in a heterogeneous syndrome characterized by renal cysts and diabetes, together with a variety of other extrarenal and renal manifestations. Interestingly, in several patients with HNF1ß abnormalities, we observed early hyperparathyroidism and PTH levels that we judged inappropriately high compared with the degree of renal function decline. OBJECTIVE: Based on the above clinical observations, we tested the hypothesis of a direct role of HNF1ß in the transcriptional regulation of the human PTH gene in the parathyroid gland. DESIGN, SETTING, AND PATIENTS: Immunostaining of human parathyroid sections, RT-PCR, chromatin immunoprecipitation (ChIP), and luciferase reporter assays in human embryonic kidney cells (HEK293) were performed. We eventually report clinical data from all 11 HNF1ß patients known at our institute, 9 with heterozygous HNF1ß whole-gene deletions and 2 with heterozygous HNF1ß mutations. RESULTS: PTH levels were high in 8 patients. In 2 of these patients, the hyperparathyroidism was clearly appropriate for the level of kidney function, whereas PTH might be discrepant in the others. We demonstrated HNF1ß expression in PTH-positive cells of human parathyroid gland. Chromatin immunoprecipitation analysis showed that HNF1ß directly binds responsive elements within the human PTH promoter. Cotransfection of a PTH promoter- luciferase construct with a wild-type HNF1ß construct resulted in a maximal reduction of 30% of PTH promoter activity. Importantly, HNF1ß mutants lacked this inhibitory property. Serial deletions in the PTH promoter construct revealed that the inhibitory effect of HNF1ß resides between -200 and -70 bp from the transcription initiation site. CONCLUSIONS: Our data demonstrate that HNF1ß is a novel repressor of human PTH gene transcription, which could contribute to the development of hyperparathyroidism in patients with HNF1ß mutations or deletions.

Effect of mild diarrhea on tacrolimus exposure.

BACKGROUND: Diarrhea is a frequent adverse event in patients treated with the combination of tacrolimus and mycophenolate mofetil (MMF). In case of severe diarrhea, the total exposure to tacrolimus can substantially increase, which is reflected in a rise of the predose trough level (C0). In mild diarrhea (two to three stools per day), an increased exposure might occur without trough levels exceeding the target range, resulting in "silent" chronic tacrolimus overexposure. The aim was to assess the degree of unnoticed tacrolimus overexposure in renal transplant patients with mild diarrhea while on treatment with tacrolimus and MMF. METHODS: A prospective pharmacokinetic study was performed in 12 recipients of a renal allograft using a combination of tacrolimus and MMF with mild diarrhea and in 12 controls. Tacrolimus levels were assessed by a validated dried blood spot method for sampling and measurement. RESULTS: The C0 did not differ between patients with mild diarrhea and controls (mean [95% confidence interval], 9.6 µg/L [8.6-10.9 µg/L] and 8.3 µg/L [6.9-9.9 µg/L]). In addition, there was no significant difference in the 12-hr area under the curve between patients with mild diarrhea and controls (185.6 µg· h/L [153.6-224.2 µg·h/L] vs. 170.5 µg·h/L [137.2-221.8 µg·h/L]). As a result, the ratio between the 12-hr area under the curve and C0 was similar in both groups (19.2 [17.5-21.1] vs. 20.6 [19.0-22.4]). The intraindividual variability in tacrolimus exposure was limited and not affected by the presence of mild diarrhea. CONCLUSIONS: We found no evidence for the presence of hidden tacrolimus overexposure in patients with mild diarrhea while on treatment with tacrolimus and MMF.

Introduction of the CKD-EPI equation to estimate glomerular filtration rate in a Caucasian population.

BACKGROUND: Chronic kidney disease (CKD) is defined as the presence of kidney damage, albuminuria or a reduction in glomerular filtration rate (GFR). A GFR <60 mL/min/1.73 m(2) alone is sufficient to diagnose CKD Stages III-V. Recently, the new chronic kidney disease epidemiology collaboration (CKD-EPI) equation was introduced. It has been suggested to result in higher estimated glomerular filtration rates (eGFRs) than the Modification of Diet in Renal Disease (MDRD(4)) formula. Here, we assess consequences of introducing the CKD-EPI equation in a West European Caucasian population. METHODS: Data were obtained from 6097 Caucasian participants of the Nijmegen Biomedical Study (2823 males and 3274 females). Serum creatinine values were determined using the Jaffe method, calibrated against mass spectrometry and were used to calculate eGFR(MDRD4) and eGFR(CKD-EPI). Demographic data, health status and information on medication use for all participants was obtained with a postal questionnaire. RESULTS: The introduction of the CKD-EPI equation changed the curve of eGFR by age, with higher values in the younger age groups and a steeper decline of eGFR with ageing. As a consequence, younger people were more often classified to a higher GFR stage and older people, especially males, to a lower GFR stage. CONCLUSIONS: In comparison with the MDRD(4) formula, the CKD-EPI equation leads to higher estimates of GFR in young people and lower estimates in the elderly. On a population level, this may lead to higher estimates of kidney function. However, in routine clinical practice where the population is predominantly elderly, the opposite may be true. The introduction of eGFR(CKD-EPI) necessitates reconsidering the definition of CKD. We suggest introducing age-dependent threshold values and/or the use of urinary albumin excretion to improve risk stratification.