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Fulltext Clinical and genetic risk factors for new-onset diabetes mellitus after transplantation (NODAT) in major transplant centres in Malaysia

Guad RM, Taylor-Robinson AW, Wu YS, Gan SH, Zaharan NL, Basu RC, et al.

BMC Nephrol, 2020 09 07;21(1):388.
PMID: 32894076 DOI: 10.1186/s12882-020-02052-9

BACKGROUND: New-onset diabetes after transplantation (NODAT) is associated with reduced patient and graft survival. This study examined the clinical and selected genetic factors associated with NODAT among renal-transplanted Malaysian patients.
METHODS: This study included 168 non-diabetic patients (58% males, 69% of Chinese ethnicity) who received renal transplantation between 1st January 1994 to 31st December 2014, and were followed up in two major renal transplant centres in Malaysia. Fasting blood glucose levels were used to diagnose NODAT in patients who received renal transplantation within 1 year. Two single nucleotide polymorphisms (SNPs), namely; rs1494558 (interleukin-7 receptor, IL-7R) and rs2232365 (mannose-binding leptin-2, MBL2) were selected and genotyped using Sequenom MassArray platform. Cox proportional hazard regression analyses were used to examine the risk of developing NODAT according to the different demographics and clinical covariates, utilizing four time-points (one-month, three-months, six-months, one-year) post-transplant.
RESULTS: Seventeen per cent of patients (n = 29, 55% males, 69% Chinese) were found to have developed NODAT within one-year of renal transplantation based on their fasting blood glucose levels. NODAT patients had renal transplantation at an older age compared to non-NODAT (39.3 ± 13.4 vs 33.9 ± 11.8 years, p = 0.03). In multivariate analysis, renal-transplanted patients who received a higher daily dose of cyclosporine (mg) were associated with increased risk of NODAT (Hazard ratio (HR) =1.01 per mg increase in dose, 95% confidence interval (CI) 1.00-1.01, p = 0.002). Other demographic (gender, ethnicities, age at transplant) and clinical factors (primary kidney disease, type of donor, place of transplant, type of calcineurin inhibitors, duration of dialysis pre-transplant, BMI, creatinine levels, and daily doses of tacrolimus and prednisolone) were not found to be significantly associated with risk of NODAT. GA genotype of rs1494558 (HR = 3.15 95% CI 1.26, 7.86) and AG genotype of rs2232365 (HR = 2.57 95% CI 1.07, 6.18) were associated with increased risk of NODAT as compared to AA genotypes.
CONCLUSION: The daily dose of cyclosporine and SNPs of IL-7R (rs1494558) and MBL2 (rs2232365) genes are significantly associated with the development of NODAT in the Malaysian renal transplant population.

Matched MeSH terms: Kidney Transplantation
Population Pharmacokinetic Modeling of Cyclosporine Among Malaysian Renal Transplant Patients: An Evaluation of Methods to Handle Missing Doses in Conventional Drug-Monitoring Data

Albitar O, Ballouze R, Harun SN, Mohamed Noor DA, Sheikh Ghadzi SM

J Clin Pharmacol, 2020 11;60(11):1474-1482.
PMID: 32557653 DOI: 10.1002/jcph.1670

Cyclosporine is a primary drug in transplant immunosuppression regimens. It has a narrow therapeutic index and variable pharmacokinetic behavior. This study aimed to develop a population pharmacokinetic model of cyclosporine in Malaysian renal transplant recipients as well as to evaluate the performances of different methodsfor handling missing doses. A total of 2804 concentrationts predose and 2 hours after doses were collected retrospectively from 113 renal transplant patients on cyclosporine in Penang General Hospital. Model structure and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling software. Missing doses were handled using different methods to evaluate their performance. Covariate analysis was performed using stepwise forward addition (P < .05) followed by backward elimination (P < .001). Prediction-corrected visual predictive check and sampling-importance resampling methods were used to validate the final model. A 1-compartment model with first-order absorption and elimination best fitted the data. All methods to handle missing doses performed well with the missing dose method being superior to other methods and thus was applied in the final model. Cyclosporine clearance (CL/F) was estimated as 15.1 L/h, and volume of distribution (V/F) was 108 L. Postoperative time, sex, and calcium channel blockers were identified as significant covariates on CL/F, whereas sex and cholesterol level were identified as significant covariates on V/F. This is the first population pharmacokinetic model developed in Malaysian renal transplant patients using a large sample with an evaluation of different methods to handle missing doses in less informative conventional therapeutic drug-monitoring data.

Matched MeSH terms: Kidney Transplantation
Fulltext Steroid withdrawal or avoidance in renal transplant recipients

Chang, S.H., Tan, S.Y.

JUMMEC, 2006;9(1):2-6.
MyJurnal

Steroids remain an important component of maintenance immunosuppression after renal transplantation. Their anti-inflammatory action is partly due to the sequestration of CD4+ lymphocytes in the reticuloendothelial system. Steroids bind to intracellular receptors and the resulting steroid-receptor complex alters the transcription of cytokines by binding to glucocorticoid response elements on DNA. Transcription factors whose actions are altered by glucocorticoids include activating protein-1 (AP-1) and nuclear factor-B (NF-B). The main cytokines whose production by antigen-presenting cells is inhibited by steroids are interleukin-1 (IL-1), required for helper T-cell activation, and IL-6, required for B-cell activation. Other pro-inflammatory cytokines such as interferon gamma and tumour necrosis factor are also inhibited. This multiplicity of immunosuppressive actions is not fully replicated by other immunosuppressants. However, there are concerns about the long-term side effects of steroids. This review will examine the attempts at steroid withdrawal or steroid avoidance in renal transplant patients.

Matched MeSH terms: Kidney Transplantation

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