Efficacy and safety of ketoconazole combined with calmodulin inhibitor in solid organ transplantation: A systematic review and meta-analysis
Journal of Clinical Pharmacy & Therapeutics. 2020;45(1):29-34
WHAT IS KNOWN AND OBJECTIVE Calcineurin inhibitors (CNIs) can significantly improve the results of solid organ transplantation regarding graft and patient survival. However, the high cost, chronic nephrotoxicity and other side effects are major challenges for the long-term use of these drugs. Ketoconazole can significantly increase the plasma concentration of CNIs by inhibiting the activity of the cytochrome P450 enzyme. The combination of ketoconazole-CNIs can reduce the cost of medication for patients by reducing the dosage of CNIs, but its safety is still controversial. Therefore, this study was designed to assess the safety and efficacy of this combination. METHODS We performed a systematic literature search in PubMed, Embase, Cochrane Library and clinicaltrials.gov for randomized controlled trials on ketoconazole and CNI (cyclosporin or tacrolimus) co-administration in solid organ transplantation. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. PROSPERO registration number: CRD42019118796. RESULTS AND DISCUSSION Five relevant trials with 326 patients were included. Compared with the controls, ketoconazole combined with CNIs can significantly reduce the dose of CNIs in patients receiving solid organ transplantation (WMD = -203.04 mg/day; 95% CI: -310.51 to -95.57, P = .0002). There was no significant difference in serum creatinine between the experimental group and the control group (WMD = -0.19 mg/mL; 95% CI: -0.52 to 0.14, P = .26). In addition, there was no significant difference in the number of rejections between the two groups (OR = 0.58; 95% CI: 0.27 to 1.22, P = .15). WHAT'S NEW AND CONCLUSION The co-administration of ketoconazole and CNIs can significantly reduce the dose of CNIs. This combination may be safely used as a CNI-sparing agent from the time of solid organ transplantation with low-dose ketoconazole, based on the findings of this review.
Public knowledge and attitudes towards consent policies for organ donation in Europe. A systematic review
Transplant Rev (Philadelphia). 2019;33(1):1-8
Grafts from selected deceased donors over 80years old can safely expand the number of liver transplants: A systematic review and meta-analysis
Transplant Rev (Philadelphia). 2019;02:02
AIM: The aim of this systematic review and meta-analysis was to present the outcome of deceased adult liver transplantation from octogenarian (>=80years old) donors compared to younger grafts. METHODS A systematic search was performed on six databases to identify all available original papers that report the outcome of adult recipients who underwent liver transplantation from a deceased octogenarian donor. RESULTS Overall, 39,034 liver transplantations from 12 studies were reported with 789 (2.02%) cases receiving grafts from octogenarian donors. Eight studies were included in the meta-analysis. There was no difference regarding the one, three, and five-year graft and patient survival between the recipients of livers <80years old and octogenarian grafts. There were significantly more episodes of biliary complications in the recipients of octogenarian grafts (34/459; 7.4%) in comparison to the recipients of livers <80years old (372/37074; 1.0%) (OR 0.53; 95% CI=0.35-0.81; P 0.004; I2=0%). The incidence of primary non-function, vascular complications and re-transplantation did not differ between groups. CONCLUSIONS The short- and medium-term graft and patient survival of octogenarian liver transplantation is not inferior compared to the liver transplantation with younger grafts, however with a higher rate of biliary complications.
Nimesulide-induced hepatotoxicity: A systematic review and meta-analysis
PLoS ONE [Electronic Resource]. 2019;14(1):e0209264
OBJECTIVE This study aimed to evaluate the risk for hepatotoxicity with nimesulide, a non-steroidal anti-inflammatory drug (NSAID) available in Republic of Korea but withdrawn from the market in several countries. METHODS A systematic review and meta-analysis were conducted of studies retrieved from PubMed, EMBASE, Cochrane, the Research Information Sharing Service and ClinicalTrials.gov up to September 2017. All studies reporting nimesulide-associated hepatotoxicity in patients as compared with the unexposed or the exposed to other NSAIDs were included. Studies using spontaneous reporting databases were included to estimate reporting odds ratio (ROR) of hepatotoxicity associated with nimesulide exposure. The association between nimesulide use and hepatotoxicity was estimated using relative risk (RR) and ROR with 95% confidence interval (CI). RESULTS A total of 25 observational studies were eligible for review. In a meta-analysis of five observational studies, nimesulide was significantly associated with hepatotoxicity [RR 2.21, 95% CI 1.72-2.83]. From studies using spontaneous reporting databases (n = 6), rates of reported hepatotoxicity were significantly higher in patients using nimesulide, compared with those treated with other NSAIDs [pooled ROR 3.99, 95% CI 2.86-5.57]. Of a total of 33 patients from case studies and series, the majority (n = 28, 84.8%) were female, and the mean age (+/- standard deviation) was 56.8 (+/- 15.6) years. Almost half of the patients on nimesulide (45.5%) either required liver transplantation or died due to fulminant hepatic failure, of whom a third developed hepatotoxicity within less than 15 days of nimesulide administration. CONCLUSIONS Our study findings support previous reports of an increased risk for hepatotoxicity with nimesulide use and add to existing literature by providing risk estimates for nimesulide-associated hepatotoxicity. As the limited number of studies with primarily observational study designs were included in the analysis, more studies are needed to further describe the effects of dose and length of treatment on the risk for hepatotoxicity.
Once-Daily versus Twice-Daily Tacrolimus in Kidney Transplantation: A Systematic Review and Meta-analysis of Observational Studies
BACKGROUND Tacrolimus is the most commonly prescribed medication in initial immunosuppressive regimens to prevent acute rejection in kidney transplant recipients (KTRs). Tacrolimus was originally available as an immediate-release formulation (IR-Tac) given twice daily. Extended-release tacrolimus (ER-Tac) given once daily was later developed with the expectation of improved medication adherence. Data from observational studies, which compared outcomes between ER-Tac and IR-Tac in different populations of KTRs including those who are unlikely to be enrolled in randomized clinical trials, have been reported. PURPOSE To evaluate the incidence of biopsy-proven acute rejection (BPAR) at 12 months together with other outcomes reported in observational studies among adult KTRs who received ER-Tac compared to IR-Tac. METHODS In accordance with the recommendations of the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology, we systematically reviewed all observational studies that compared clinical outcomes between ER-Tac and IR-Tac in KTRs. The systematic searches were conducted on PubMed, EMBASE, Scopus, and Web of Science without language restriction. Reference lists were also searched and reviewed. Data were extracted for BPAR, graft survival, patient survival, estimated glomerular filtration rate (eGFR), serum creatinine (Scr), creatinine clearance (CrCl), at different times after kidney transplantation (KT). A meta-analysis was performed to integrate the results from the eligible studies. This study is registered with PROSPERO, number CRD42019135705. RESULTS From the 1401 articles screened, 10 observational studies in KTRs who received tacrolimus were included. The pooled results showed significantly lower BPAR with ER-Tac than with IR-Tac at 12 months post-KT (5 studies, n = 659; RR, 0.69; 95% CI 0.51-0.95; p = 0.02; I2 = 0%). No significant differences in BPAR at other time points after KT were found. Graft survival, patient survival, Scr, and eGFR were comparable between groups at different times over approximately 1 year after transplantation. CONCLUSIONS Based upon currently available evidence in observational studies, 30% lower risk of BPAR was observed in ER-Tac group compared with IR-Tac group at 12 months post-KT, while there was no significant difference in BPAR risk at any other studied time points. No differences in graft- and patient-survival rates and kidney function were found. Given the limitations of observational studies to make causal inference, as well as quality limitations among the included studies, caution should be exercised in interpreting these findings.
Order of liver graft revascularization in deceased liver transplantation: A systematic review and meta-analysis
BACKGROUND The ideal order for liver graft revascularization during liver transplantation remains unknown. The majority of liver transplant centers prefer portal venous reperfusion followed by arterial reperfusion to shorten the warm ischemia time. The aim of this study was to review the different revascularization techniques used in clinical liver transplantation to identify any potential clinical benefits. METHODS A systematic search of 5 databases was performed to identify all available original articles that reported liver transplantation and compared different techniques of reperfusion. The primary outcomes were patient and graft survival. Secondary outcomes were defined by postreperfusion syndrome, primary nonfunction, vascular complications, biliary complications, and retransplantation. RESULTS A total of 1,160 patients undergoing liver transplantation from 15 studies were included in this review and meta-analysis. There were no differences regarding the 1-year patient and graft survival for the revascularization techniques. The incidence of primary nonfunction, vascular complications, and retransplantation did not differ between the groups. Although there were no differences regarding biliary complications between the different groups, there were more nonanastomotic strictures in patients with initial portal revascularization (9%) compared with those with simultaneous revascularization (2%; risk ratio 1.07; 95% confidence interval, 1.00-1.14; P = .05; I2 = 51%). CONCLUSION The order of liver graft revascularization does not influence patient and graft survival. Each revascularization technique offers potential benefits that can be used under specific clinical situations.
Predictability of Capillary Blood Spot Toward Venous Whole Blood Sampling for Therapeutic Drug Monitoring of Tacrolimus in Solid Organ Transplant Recipients
European Journal of Drug Metabolism & Pharmacokinetics. 2019;[record in progress]
The aim of this review was to critically evaluate if dried blood spotting (DBS) can replace venepuncture for the purpose of tacrolimus therapeutic drug monitoring (TDM).
Several databases were searched, including: PubMed, Scopus, EMBASE, and Google Scholar. Combinations of the following terms and phrases was conducted—tacrolimus, FK 506, drug monitoring, alternative methods, capillary blood, dried blood spotting.
11 articles, comprising 525 transplant patients.
Outcomes being assessed included bias and precision data reported in the identified papers. Narrative syntyesis is presented.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
This systematic review aimed to assess the evidence for accuracy and precision of use of dried blood spot sampling as an alternative to venous whole blood sampling for tacrolimus trough monitoring. The authors identified 11 studies which they subjected to a narrative analysis. The underlying literature was found to be of limited quality with small sample sizes, poor description and inadequate reporting of precision. The authors conclude that further, adequately powered studies are required. The methodology used in the review is not well reported. Whilst multiple databases were searched using a variety of terms, non-English data were excluded and
there is no mention of trial registry searches to identify unpublished studies. Details of screening and data extraction protocols are not provided, and there is no mention of a published protocol or detailed inclusion/exclusion criteria.
Therapeutic drug monitoring (TDM) of tacrolimus in whole blood obtained from venipuncture is routinely practiced. Dried blood spotting (DBS) may act as a suitable alternative for tacrolimus TDM due to relative ease of sampling and processing. The objective of this literature review was to provide a critical evaluation on the feasibility (i.e., accuracy and precision) of DBS for predicting tacrolimus whole blood concentrations in solid organ transplant recipients. A comprehensive systematic literature search using PubMed, Scopus, EMBASE, and Google Scholar was conducted. The primary objective was to extract the bias and precision data from the identified papers. In addition, the collection, storage, and analysis protocols were also summarized. Both adult and pediatric data were included. The reported bias data (primarily based on individual concentrations) in the majority of studies were within acceptable limits (< 15%). However, the precision data were not consistently reported. The area under the concentration-time curve of tacrolimus derived from DBS appeared to be a better predictor of whole blood compared to single concentrations based on a limited number of studies. No apparent differences in prediction were observed between pediatric and adult patients. Small sample sizes and the lack of complete description of the study population were common limitations. DBS is a promising approach for tacrolimus TDM. However, in order for DBS to become a useful substitute for tacrolimus whole blood monitoring in solid organ transplant patients, further systematic studies with sufficient power and comprehensive prediction error analyses are required.
Effect of donor hypertension on renal transplant recipients' blood pressure, allograft outcomes and survival: a systematic review and meta-analysis
American Journal of Cardiovascular Disease. 2019;9(4):49-58
BACKGROUND The effect of donor hypertension on the blood pressure of renal transplant recipients and the allograft outcomes are unclear. The aim of this study was to summarize the evidence about the effects of donor hypertension on renal transplant recipients' blood pressure, renal allograft outcomes and mortality. METHODS Studies published from January 1960 to 31 January 2019 in English were identified through a systematic search of six databases; PubMed, Embase, SCOPUS, Web of Science, Cochrane Database of Systematic Reviews, and CINAHL. Eligible observational studies with at least 1 year of follow-up were selected. Pooled estimates were obtained using random effects model. RESULTS We identified 15 papers from eight countries containing data on donor hypertension and renal transplantation carried out between 1963 and 2014. The median (range) follow-up period of the studies was 3.8 (1-11.9) years. The prevalence of post-transplant hypertension among recipients of a renal allograft from a normotensive donor range from 8 to 17.6%, while the prevalence of post-transplant hypertension among recipients of a renal allograft from a hypertensive donor range from 2.9 to 25%. Overall, pooled risk ratios (RR) indicated that donor hypertension was a risk factor for allograft failure or loss among renal transplant recipients (RR 1.31; 95% CI 1.06-1.63: P = 0.014). However, donor hypertension was not a risk factor for mortality among renal transplant recipients (RR 0.996; 95% CI 0.652-1.519: P = 0.984). CONCLUSIONS Donor hypertension increases the risk of post-transplant hypertension among renal transplant recipients and increases the risk of allograft failure, However, donor hypertension was not a risk factor for mortality among renal transplant recipients, Closer monitoring should be given to renal allograft recipients from hypertensive donors, and further well-designed studies are needed to expand our knowledge of the impact of donor hypertension on the survival of renal allograft recipients.
Right posterior segment graft for living donor liver transplantation: A systematic review
Transplant Rev (Philadelphia). 2019;[record in progress]
The clinical significance of the right posterior segment (RPS) graft in living donor liver transplantation (LDLT) is unknown because of its limited use and technical concerns. This study aimed to review published studies investigating outcomes of RPS grafts. The systematic literature search was conducted to retrieve data from Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar. Among the 388 articles, six retrospective studies from Asian countries were included. The overall incidences of major and minor complications after RPS graft procurement were 5.6% and 34.6%, respectively and no donor deaths were reported. RPS graft recipients had the following postoperative complications: overall mortality rate, 14.5%; bile leakage, 8.7%, biliary stenosis, 18.8%, hepatic artery thrombosis, 8.7%, and liver re-transplantation, 2.9%. The RPS graft can be considered as an option for a living liver graft respecting donor safety under strict selection criteria and surgical strategy. The precise evaluation and understanding of anatomical variations and volumetric analyses is critical for selecting donors and planning the surgical strategy in the RPS grafts procurement. The RPS grafts procurement requires carefully dissection of the hepatic artery and portal vein, safely confirmation of the bile duct, and precisely parenchymal transection. However, further experience is needed to clarify the significance of the RPS graft in LDLT. The special technical requirements should limit this donor procedure to centers with a high level of experience in LDLT.
Proton pump inhibitors and adverse effects in kidney transplant recipients: A meta-analysis
World Journal of Transplantation. 2019;9(2):35-47
BACKGROUND The adverse renal effects of proton pump inhibitors (PPIs) are increasingly recognized in both the general population and patients with chronic kidney disease. Several pharmacokinetic studies have also raised concerns regarding the interaction between PPIs and immunosuppressive drugs in transplant patients. Whether the adverse effects of PPIs have a clinical significance in kidney transplant recipients remains unclear. We performed this meta-analysis to assess the risk of adverse effects in kidney transplant recipients on PPI compared with those without PPI exposure. AIM: To investigate the risk of acute rejection, graft loss, hypomagnesemia, renal dysfunction, and overall mortality in kidney transplant recipients on PPI compared with those without PPI exposure. METHODS A systematic review was conducted in MEDLINE, EMBASE, and Cochrane databases from inception through October 2018 to identify studies that evaluated the adverse effects of PPIs in kidney transplant recipients, including biopsy-proven acute rejection, graft loss, hypomagnesemia, renal function, and overall mortality. Effect estimates from the individual studies were extracted and combined using random-effect, generic inverse variance method of DerSimonian and Laird. The protocol for this meta-analysis is registered with PROSPERO, No. CRD42018115676. RESULTS Fourteen observational studies with 6786 kidney transplant recipients were enrolled. No significant association was found between PPI exposure and the risk of biopsy-proven acute rejection at >= 1 year [pooled odds ratio (OR), 1.25; 95% confidence interval (CI), 0.82-1.91, I 2 = 55%], graft loss at 1 year (pooled OR = 1.30, 95%CI: 0.75-2.24, I 2 = 0%) or 1-year mortality (pooled OR = 1.53, 95%CI: 0.90-2.58, I 2 = 34%). However, PPI exposure was significantly associated with hypomagnesemia (pooled OR = 1.56, 95%CI: 1.19-2.05, I 2 = 27%). Funnel plots and Egger regression asymmetry test were performed and showed no publication bias. CONCLUSION PPI use was not associated with significant risks of higher acute rejection, graft loss, or 1-year mortality. However, the risk of hypomagnesemia was significantly increased with PPI use. Thus, future studies are needed to assess the impact of PPIs on long-term outcomes.