PURPOSE:

Incisional hernia (IH) post renal transplant (RT) is relatively uncommon and can be challenging to manage clinically due to the presence of the kidney graft and patient immunosuppression. This systematic review and meta-analysis synthesises the current literature in relation to IH rates, risk factors and outcomes post RT.

METHODS:

PubMed, EMBASE, and Cochrane Central Registry of Controlled Trials (CENTRAL) were searched up to July 2023. The most up to date Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines were followed. Pertinent clinical information was synthesised. A meta-analysis of the pooled proportions of IH rates, the rates of patients requiring surgical repair and the rates of recurrence post RT are reported.

RESULTS:

Twenty studies comprising 16,018 patients were included in this analysis. The pooled rate of IH occurrence post RT was 4% (CI 3-5%). The pooled rate of IH repair post RT was 61% (CI 14-100%). The pooled rate of IH recurrence after repair was 16% (CI 9-23%). Risk factors identified for IH development post RT are BMI, immunosuppression, age, smoking, incision type, reoperation, concurrent abdominal wall hernia, lymphocele formation and pulmonary disease.

CONCLUSIONS:

IH post RT is uncommon and the majority of IH post RT are repaired surgically on an elective basis.

OBJECTIVE:

The purpose of this scoping review is to evaluate the oral manifestations (OM) of heart transplant (HT) patients undergoing immunosuppressive therapy (IT).

MATERIAL AND METHODS:

A literature search was performed using keywords and MeSH terms related to OM and HT in the Medline/PubMed, Web of Science, Cochrane Library, Scopus, LILACS/BBO databases and in gray literature without language or date restrictions until June 2023. Studies that evaluated HT individuals who used any IT and who reported the occurrence of OM were considered eligible. The results from the search were imported to EndNote Web, and duplicates were removed followed by title/abstract and full-text analysis.

RESULTS:

A total of 402 nonduplicated studies were found and 13 fulfilled the criteria and were included in the present review: 10 cross-sectional, 2 cohorts, and 1 clinical trial. The most reported OM were periodontal diseases, including drug-induced gingival enlargement (DIGE), gingival bleeding, gingivitis, and periodontitis. Reported in a minority of studies are oral cancer, opportunistic infections (oral hairy leukoplakia and erythematous candidiasis), enamel defects, and burning mouth.

CONCLUSION:

Considering the methodological heterogeneity of the studies analyzed, DIGE is the most commonly observed oral manifestation in HT individuals.

AIMS:

Post-transplant diabetes is a prevalent and consequential complication following kidney transplantation, which significantly augments the risk of cardiovascular disease, graft loss, infection, and mortality, thereby profoundly impacting both graft and patient survival. However, the early stages of post-transplant diabetes often go unnoticed or receive inadequate management. Consequently, this study systematically assesses the incidence of new-onset diabetes after kidney transplantation with the aim to enhance medical staff awareness regarding post-transplantation diabetes and provide clinical management guidance.

METHODS:

We conducted a comprehensive search across multiple databases including PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang, VIP, and SinoMed until September 21, 2023. Data extraction was performed using standardized tables and meta-analysis was conducted using Stata 16.0 software. A random effects model was employed to estimate the combined prevalence along with its corresponding 95% confidence interval. The source of heterogeneity was explored using subgroup analysis and sensitivity analysis, while publication bias was assessed through funnel plot and Egger's test. This study has been registered with PROSPERO under the registration number CRD42023465768.

RESULTS:

This meta-analysis comprised 39 studies with a total sample size of 16,584 patients. The prevalence of new-onset diabetes after transplantation was found to be 20% [95% CI (18.0, 22.0)]. Subgroup analyses were conducted based on age, gender, body mass index, family history of diabetes, type of kidney donor, immunosuppressive regimen, acute rejection episodes, hepatitis C infection status and cytomegalovirus infection.

CONCLUSIONS:

The incidence of post-kidney transplantation diabetes is substantial, necessitating early implementation of preventive and control measures to mitigate its occurrence, enhance prognosis, and optimize patients' quality of life.

CLINICAL TRIAL REGISTRATION:

PROSPERO: CRD42023465768.

OBJECTIVE:

This systematic review and meta-analysis aims to investigate the prevalence of cervical high-risk human papillomavirus (hrHPV) among kidney transplant recipients (KTRs) and, furthermore to compare it to that in immunocompetent controls.

METHODS:

A systematic literature search was conducted in PubMed, EMBASE, and Cochrane Library databases from January 2000 to February 2023, to identify studies investigating the prevalence of cervical hrHPV in KTRs. Pooled cervical hrHPV prevalences, odds ratios (ORs) comparing KTRs to controls and corresponding confidence intervals (CIs) were estimated using random effects logistic regression models. Heterogeneity between studies was assessed through the I2 statistic, and the significance was evaluated by the Cochrane's Q test.

RESULTS:

Altogether, 16 studies covering >1200 KTRs were included. The prevalence of cervical hrHPV in KTRs was 27.7% (95% CI 21.3-35.1) with substantial interstudy heterogeneity. Stratification indicated a higher prevalence in recent years (2019-2023) and in Asia (39% (95% CI 11.2-61.4)). The prevalence of HPV16 and HPV18 in KTRs was 8.0% (95% CI 3.9-15.9) and 1.7% (95% CI 0.8-3.7), respectively. Comparing hrHPV prevalence in KTRs and controls based on six studies including >500 KTRs and 1000 controls, the OR for hrHPV was 2.0 (95% CI 1.1-3.6).

CONCLUSIONS:

This meta-analysis establishes an increased cervical hrHPV prevalence in KTRs compared to controls. The increased risk may be associated with immunosuppressive therapy post-transplantation. Further research is needed to explore the potential benefits of HPV vaccination, including potential revaccination strategies in KTRs.

Tacrolimus is widely reported to display diurnal variation in pharmacokinetic parameters with twice-daily dosing. However, the contribution of chronopharmacokinetics versus food intake is unclear, with even less evidence in the pediatric population. The objectives of this study were to summarize the existing literature by meta-analysis and evaluate the impact of food composition on 24-hour pharmacokinetics in pediatric kidney transplant recipients. For the meta-analysis, 10 studies involving 253 individuals were included. The pooled effect sizes demonstrated significant differences in area under the concentration-time curve from time 0 to 12 hours (standardized mean difference [SMD], 0.27; 95% confidence interval [CI], 0.03-0.52) and maximum concentration (SMD, 0.75; 95% CI, 0.35-1.15) between morning and evening dose administration. However, there was significant between-study heterogeneity that was explained by food exposure. The effect size for minimum concentration was not significantly different overall (SMD, -0.09; 95% CI, -0.27 to 0.09) or across the food exposure subgroups. A 2-compartment model with a lag time, linear clearance, and first-order absorption best characterized the tacrolimus pharmacokinetics in pediatric participants. As expected, adding the time of administration and food composition covariates reduced the unexplained within-subject variability for the first-order absorption rate constant, but only caloric composition significantly reduced variability for lag time. The available data suggest food intake is the major driver of diurnal variation in tacrolimus exposure, but the associated changes are not reflected by trough concentrations alone.

PURPOSE:

This study aimed to investigate the association between cytochrome P450 (CYP) 3A4*22 and cytochrome P450 oxidoreductase (POR)*28 variations and the pharmacokinetics of tacrolimus.

METHODS:

Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (SCI), MEDLINE, and Embase were systematically searched from inception to August 2022. The outcomes were weight-adjusted daily dose and dose-adjusted trough concentration (C0/Dose).

RESULTS:

The study included 2931 renal transplant recipients from 18 publications. Weight-adjusted daily dose of CYP3A4*1/*1 carriers was 0.04 (WMD = 0.04, 95% CI: 0.02 to 0.06), 0.03 (WMD = 0.03, 95% CI: 0.02 to 0.05), 0.02 (WMD = 0.02, 95% CI: 0.01 to 0.03), or 0.02 mg/kg/day (WMD = 0.02, 95% CI: 0.00 to 0.04) higher than CYP3A4*22 carriers in Caucasians at 1 month, 3 months, 6 months, or 12 months post-transplantation. Conversely, C0/Dose was lower for CYP3A4*1/*1 carriers at 3 days (SMD = -0.35, 95% CI: -0.65 to -0.06), 1 month (SMD = -0.67, 95% CI: -1.16 to -0.18), 3 months (SMD = -0.60, 95% CI: -0.89 to -0.31), 6 months (SMD = -0.76, 95% CI: -1.49 to -0.04), or 12 months post-transplantation (SMD = -0.69, 95% CI: -1.37 to 0.00). Furthermore, C0/Dose of POR*1/*1 carriers was 22.64 (WMD = 22.64, 95% CI: 2.54 to 42.74) or 19.41 (ng/ml)/(mg/kg/day) (WMD = 19.41, 95% CI: 9.58 to 29.24) higher than POR*28 carriers in CYP3A5 expressers at 3 days or 7 days post-transplantation, and higher in Asians at 6 months post-transplantation (SMD = 0.96, 95% CI: 0.50 to 1.43).

CONCLUSIONS:

CYP3A4*22 variant in Caucasians restrains the metabolism of tacrolimus, while POR*28 variant in CYP3A5 expressers enhances the metabolism of tacrolimus for renal transplant recipients. However, further well-designed prospective studies are necessary to substantiate these conclusions given some limitations.

BACKGROUND:

Whether trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis prevents nocardiosis in solid organ transplant (SOT) recipients is controversial.

OBJECTIVES:

To assess the effect of TMP-SMX in the prevention of nocardiosis after SOT, its dose-response relationship, its effect on preventing disseminated nocardiosis, and the risk of TMP-SMX resistance in case of breakthrough infection.

METHODS:

A systematic review and individual patient data meta-analysis.

DATA SOURCES:

MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection, and Scopus up to 19 September 2023.

STUDY ELIGIBILITY CRITERIA:

(a) Risk of nocardiosis between SOT recipients with and without TMP-SMX prophylaxis, or (b) sufficient details to determine the rate of TMP-SMX resistance in breakthrough nocardiosis.

PARTICIPANTS:

SOT recipients.

INTERVENTION:

TMP-SMX prophylaxis versus no prophylaxis.

ASSESSMENT OF RISK OF BIAS:

Risk Of Bias In Non-randomized Studies-of Exposure (ROBINS-E) for comparative studies; dedicated tool for non-comparative studies.

METHODS OF DATA SYNTHESIS:

For our primary outcome (i.e. to determine the effect of TMP-SMX on the risk of nocardiosis), a one-step mixed-effects regression model was used to estimate the association between the outcome and the exposure. Univariate and multivariable unconditional regression models were used to adjust for the potential confounding effects. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

RESULTS:

Individual data from three case-control studies were obtained (260 SOT recipients with nocardiosis and 519 uninfected controls). TMP-SMX prophylaxis was independently associated with a significantly decreased risk of nocardiosis (adjusted OR = 0.3, 95% CI 0.18-0.52, moderate certainty of evidence). Variables independently associated with an increased risk of nocardiosis were older age, current use of corticosteroids, high calcineurin inhibitor concentration, recent acute rejection, lower lymphocyte count, and heart transplant. Breakthrough infections (66/260, 25%) were generally susceptible to TMP-SMX (pooled proportion 98%, 95% CI 92-100).

CONCLUSIONS:

In SOT recipients, TMP-SMX prophylaxis likely reduces the risk of nocardiosis. Resistance appears uncommon in case of breakthrough infection.

AIMS:

This study aimed to provide up-to-date information on paediatric population pharmacokinetic models of tacrolimus and to identify factors influencing tacrolimus pharmacokinetic variability.

METHODS:

Systematic searches in the Web of Science, PubMed, Scopus, Science Direct, Cochrane, EMBASE databases and reference lists of articles were conducted from inception to March 2023. All population pharmacokinetic studies of tacrolimus using nonlinear mixed-effect modelling in paediatric solid organ transplant patients were included.

RESULTS:

Of the 21 studies reviewed, 62% developed from liver transplant recipients and 33% from kidney transplant recipients. Most studies used a 1-compartment model to describe tacrolimus pharmacokinetics. Body weight was a significant predictor for tacrolimus volume of distribution (Vd/F). The estimated Vd/F for 1-compartment models ranged from 20 to 1890 L, whereas the peripheral volume of distribution (Vp/F) for 2-compartment models was between 290 and 1520 L. Body weight, days post-transplant, CYP3A5 genotype or haematocrit were frequently reported as significant predictors of tacrolimus clearance. The estimated apparent clearance values range between 0.12 and 2.18 L/h/kg, with inter-individual variability from 13.5 to 110.0%. Only 29% of the studies assessed the generalizability of the models with external validation.

CONCLUSION:

This review highlights the potential factors, modelling approaches and validation methods that impact tacrolimus pharmacokinetics in a paediatric population. The clinician could predict tacrolimus clearance based on body weight, CYP3A5 genotype, days post-transplant or haematocrit. Further research is required to determine the relationship between pharmacogenetics and tacrolimus pharmacodynamics in paediatric patients and confirm the applicability of nonlinear kinetics in this population.

PURPOSE:

Tremor, headache and insomnia have been linked to the immunosuppressant, tacrolimus. The aim of this systematic review was to determine if there is a correlation between tacrolimus exposure and new-onset tremor, headache and insomnia experienced by adult kidney transplant recipients.

METHODS:

PubMed, Embase, Cochrane Library and CINAHL databases were searched up to 11 April 2023 for published studies which reported on tacrolimus exposure in adult kidney transplant recipients, alongside information on treatment-emergent neurologic manifestations, including tremor, headache and insomnia. Review articles, case studies, conference abstracts and articles not published in English in peer-reviewed journals were excluded. The Physiotherapy Evidence Database and Newcastle-Ottawa Quality Assessment Scales were used to assess risk of bias. Extracted data was analysed via a narrative synthesis.

RESULTS:

Eighteen studies involving 4030 patients in total were included in the final analysis. These comprised five randomised control trials and thirteen observational studies. Studies failed to find significant association between tacrolimus trough concentrations in whole blood and the incidence of neurologic side effects such as tremor, headache and insomnia; however, in one study the incidence of toxicity requiring a dose reduction increased with increasing, supratherapeutic targeted levels. Females, especially Black females, and older age were positively associated with the prevalence of neurologic adverse effects. Results were conflicting regarding whether extended-release formulations were associated with fewer neurologic complications than immediate-release formulations.

CONCLUSION:

The varied study designs and criteria for reporting tremor, headache and insomnia impacted on the quality of the data for exploring the relationship between tacrolimus exposure and the onset of neurologic manifestations experienced after kidney transplantation. Studies that examine defined neurologic complications as the primary outcome, and that consider novel markers of tacrolimus exposure while assessing the potential contribution of multiple covariate factors, are required.