A quick algorithmic review on management of viral infectious diseases in pediatric solid organ transplant recipients.

Pediatric solid organ transplant is a life-saving procedure for children with end-stage organ failure. Viral infections are a common complication following pediatric solid organ transplantation (SOT), which can lead to increased morbidity and mortality. Pediatric solid organ transplant recipients are at an increased risk of viral infections due to their immunosuppressed state. The most commonly encountered viruses include cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), adenoviruses, and BK polyomavirus. Prevention strategies include vaccination prior to transplantation, post-transplant prophylaxis with antiviral agents, and preemptive therapy. Treatment options vary depending on the virus and may include antiviral therapy and sometimes immunosuppression modification. This review provides a Quick Algorithmic overview of prevention and treatment strategies for viral infectious diseases in pediatric solid organ transplant recipient.

Additive Manufacturing of an Extended-Release Tablet of Tacrolimus.

An extended-release tablet of tacrolimus as once-daily dosing was fabricated using 3D printing technology. It was developed by combining two 3D-printing methods in parallel. Indeed, an optimized mixture of PVA, sorbitol, and magnesium stearate as a shell compartment was printed through a hot-melt extrusion (HME) nozzle while an HPMC gel mixture of the drug in the core compartment was printed by a pressure-assisted micro-syringe (PAM). A 3D-printed tablet with an infill of 90% was selected as an optimized formula upon the desired dissolution profile, releasing 86% of the drug at 12 h, similar to the commercial one. The weight variation, friability, hardness, assay, and content uniformity determination met USP requirements. A microbial evaluation showed that the 3D-printed tablet does not support microbial growth. SEM analysis showed smooth surfaces with multiple deposited layers. No peak interference appeared based on FTIR analysis. No decomposition of the polymer and drug was observed in the printing temperature, and no change in tacrolimus crystallinity was detected based on TGA and DSC analyses, respectively. The novel, sTable 3D-printed tablet, fabricated using controllable additive manufacturing, can quickly provide tailored dosing with specific kinetic release for personalized medicine at the point-of-care.

Management of drug-induced neutropenia, thrombocytopenia, and anaemia after solid organ transplantation: A comprehensive review.

WHAT IS KNOWN AND OBJECTIVE: Advances in the development of more effective immunosuppressive drugs have increased graft survival and drug induced adverse effects. Haematological complications including neutropenia, thrombocytopenia, and anaemia are common side effects that affect the grafts' and patients' outcomes. Several studies have stated the important role of various medications in haematological complications after transplantation. They have reported the incidence and different mechanisms of drug induced cytopenia, as well as an overview of possible treatment modalities. However, there is no comprehensive protocol for the management of these complications following transplantation. This narrative review was performed to develop a comprehensive practical approach for management of drug induced haematological complications following solid organ transplantation. METHOD: PubMed, Embase, Cochrane library, Web of Science, and Google scholar databases were searched without time limitations until March, 2021. In addition, some valid drug information data bases (Uptodate and Micromedex) were searched for detailed information until October, 2021. RESULTS AND DISCUSSION: Several immunosuppressive and antimicrobial medications may induce neutropenia, thrombocytopenia or anaemia following transplantation. Most of these agents cause dose-related cytopenia, which resolves with dose reduction or drug withdrawal. However, any change in medications may result in negative consequences such as severe infections, bleeding, cardiovascular complications, acute allograft rejection, and graft or patient loss. Thus, cautious evaluation of the patient's condition and the pharmacological properties of the culprit medication are required. WHAT IS NEW AND CONCLUSION: Three algorithms are presented to guide healthcare providers in the stepwise management of drug-induced neutropenia, thrombocytopenia, and anaemia after solid organ transplantation.

Antibody-Mediated Rejection in Adult Liver Transplant Recipients: A Case Series and Literature Review.

Antibody-mediated rejection is a rare complication following liver transplantation, and there is a lack of a comprehensive treatment strategy to provide detailed information about the dose and duration of antibody-mediated rejection treatment. This study describes 8 adult liver transplantation recipients who developed antibody-mediated rejection between 2002 and 2021 in our center, as well as a review of the literature on the reported cases of antibody-mediated rejection in liver transplantation recipients. Our center's medical records were reviewed retrospectively to extract the necessary data on patients' characteristics, management, and outcomes. Then, a comprehensive search using Embase, PubMed, Web of Science, Cochrane Library, and Google Scholar databases was conducted without time limitation until June 2021. Finally, a stepwise protocol was developed for managing acute, chronic, and recurrent antibody-mediated rejection in patients undergoing liver transplantation, based on our own experience, reported cases in the literature, and data from kidney transplantation. By review of the literature, 24 case studies containing 64 patients were identified, and their management strategies and outcomes were evaluated. Although various combinations of corticosteroids, plasma exchange, intravenous immunoglobulin, and biological agents are used in the treatment of acute antibody-mediated rejection in liver transplantation, treatment strategies should be classified according to the type, severity, and the timing of its onset. Given the importance of early treatment, rituximab and/or bortezomib should be started as soon as possible if no improvement in liver enzymes/bilirubin is observed during the initial treatment strategy using corticosteroids, plasma exchange, and intravenous immunoglobulin.

Comparing safety of proton-pump inhibitors versus H2-receptor antagonists in kidney transplant recipients: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Multiple studies have been conducted to compare the safety of proton-pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) as acid-suppressive treatment in kidney transplant recipients with conflicting results. This systematic review and meta-analysis aimed to evaluate the risk of adverse effects in kidney transplant patients receiving PPIs compared to those treated with H2RAs. METHODS: A systematic search was performed on the databases from inception to June 2021. The treatment effects were expressed as odds ratio (OR), weighted mean differences (WMD) and their 95% confidence intervals (CI) and pooled by a random-effects model. RESULTS AND DISCUSSIONS: Eight studies, consisting 4,844 patients, were included. Patients were followed for a mean duration of 23.57 months after transplantation. Compared with H2RAs, PPIs exposure was associated with similar rate of biopsy-proven acute rejection (BPAR) (OR = 1.05, 95% CI 0.83-1.34, p = 0.67), mortality (OR = 1.31, 95% CI 0.56-3.07, p = 0.533), graft loss (OR = 1.06, 95% CI 0.59-1.93, p = 0.842), Clostridioides difficile infection (OR = 1.37, 95% CI 0.49-3.85, p = 0.545) and pneumonia (OR = 1.83, 95% CI 0.95-3.52, p = 0.072). The estimated glomerular filtration rate (eGFR) at 12 months was lower in patients who received PPIs than those treated with H2RAs (WMD = -1.01, 95% CI -1.89 to -0.12 ml/min/1.73m2 , p = 0.02). The PPI-treated kidney transplant patients experienced higher rate of antibody-mediated rejection (AMR) (OR = 1.87, 95% CI 1.03-3.04, p = 0.039) and hypomagnesemia (OR = 2.16, 95% CI 1.46-3.20, p Ë‚ 0.001). WHAT IS NEW AND CONCLUSIONS: Compared with H2RAs, PPIs were not associated with higher risks of BPAR, mortality, graft loss or infection-related outcomes. However, taking PPIs was associated with higher rates of AMR and hypomagnesemia, and lower eGFR at one year after transplantation. Further well-controlled studies are needed to assess the impact of acid-suppressive strategy on long-term outcomes in KTRs.

Current status of glucocorticoid usage in solid organ transplantation.

Glucocorticoids (GCs) have been the mainstay of immunosuppressive therapy in solid organ transplantation (SOT) for decades, due to their potent effects on innate immunity and tissue protective effects. However, some SOT centers are reluctant to administer GCs long-term because of the various related side effects. This review summarizes the advantages and disadvantages of GCs in SOT. PubMed and Scopus databases were searched from 2011 to April 2021 using search syntaxes covering "transplantation" and "glucocorticoids". GCs are used in transplant recipients, transplant donors, and organ perfusate solution to improve transplant outcomes. In SOT recipients, GCs are administered as induction and maintenance immunosuppressive therapy. GCs are also the cornerstone to treat acute antibody- and T-cell-mediated rejections. Addition of GCs to organ perfusate solution and pretreatment of transplant donors with GCs are recommended by some guidelines and protocols, to reduce ischemia-reperfusion injury peri-transplant. GCs with low bioavailability and high potency for GC receptors, such as budesonide, nanoparticle-mediated targeted delivery of GCs to specific organs, and combination use of dexamethasone with inducers of immune-regulatory cells, are new methods of GC application in SOT patients to reduce side effects or induce immune-tolerance instead of immunosuppression. Various side effects involving different non-targeted organs/tissues, such as bone, cardiovascular, neuromuscular, skin and gastrointestinal tract, have been noted for GCs. There are also potential drug-drug interactions for GCs in SOT patients.

A Pilot Study on Controlling Coronavirus Disease 2019 (COVID-19) Inflammation Using Melatonin Supplement.

No effective antiviral drugs and vaccines are available for the treatment of patients with severe coronavirus 2019 (COVID-19). Therefore, available, safe, and inexpensive drugs and supplements such as melatonin are among the proposed options for controlling inflammation. We did a randomized, single-blind study in Imam Khomeini Hospital between June 30, 2020, and August 5, 2020. Mild to moderate COVID-19 patients aged 25-65 years were eligible to enter the study based on chest CT scan, clinical symptoms, and physician diagnosis. The intervention group was prescribed 6 mg of oral melatonin for 2 weeks, which consumed half an hour before bedtime every night in low light conditions. Clinical symptoms and C-reactive protein (CRP) were measured before and after treatment in the melatonin received and control (regular medications) groups. Among screened patients with COVID-19, 14 patients were assigned to receive melatonin, and 17 patients were considered as controls. A significant difference (p=0.005) between CRP 1 and CRP 2 levels (before and after using melatonin) was found in the melatonin group while this difference (p=0.069) was not significant in the control group. Also, the percentage of recovery (based on symptoms) in patients who took melatonin was higher than that of patients in the control group (85.7% VS 47.1%). The result of this study confirmed the effectiveness of melatonin in mild to moderate outpatients with COVID-19. More clinical trials on elderly, diabetic, obese patients and severe cases are suggested in future studies.

Thrombotic Microangiopathy, Antibody-Mediated Rejection, and Posterior Reversible Leukoencephalopathy Syndrome in a Liver Transplant Recipient: Interplay Between COVID-19 and Its Treatment Modalities.

The present COVID-19 pandemic is a cause for concern among solid-organ transplant recipients, who are generally at high risk for infection and for whom infection with COVID-19 carries additional risks for complications and mortality that are higher than the COVID-19-associated risks for the general population. We report the case of a liver transplant recipient who presented with COVID-19 and multiple complications. A 39-year-old woman with a liver transplant was diagnosed with COVID-19 within the first week after transplant surgery. Mycophenolate was withheld, and interferon ß was administered for management of COVID-19. She developed thrombotic thrombocytopenic purpura, acute antibody-mediated rejection, and posterior reversible leukoencephalopathy syndrome during hospitalization. All of these complications may be related to COVID-19 or its management modalities. We considered 3 possible causes for thrombotic thrombocytopenic purpura in this patient: the COVID-19 infection itself, immunosuppression treatment with cyclosporine, and treatment with interferon ß. Immunosuppression reduction and interferon treatment may result in antibody-mediated rejection. COVID-19, thrombotic thrombocytopenic purpura, and cyclosporine may play a combined role in the development of posterior reversible leukoencephalopathy syndrome. In conclusion, thrombotic thrombocytopenic purpura, antibody-mediated rejection, and posterior reversible leukoencephalopathy syndrome may represent a continuum of 3 thrombotic microangiopathy conditions fostered by interplay between the COVID-19 infection and the treatment modalities for COVID-19 management in this patient.

Association between cumulative rATG induction doses and kidney graft outcomes and adverse effects in kidney transplant patients: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis were performed to explore the association between rabbit thymoglobulin (rATG) doses and transplant-related efficacy and safety outcomes. METHODS: We searched PubMed and Scopus databases from inception up to June 2020. The primary efficacy and safety endpoints in kidney transplant recipients were evaluated. RESULTS: Data of 23 cohort studies (3457 patients) and three RCTs (154 patients) were extracted and analyzed. rATG doses of ≤4.5 m/kg was associated with lower rates of biopsy proven acute rejection, cytomegalovirus infection, BK virus infection, and malignancy with a comparable rate of delayed graft function, patients' mortality, and death-censored graft loss compared to rATG total doses of 4.5-6 mg/kg or more than 6 mg/kg. The rATG doses of 3-4.5 mg/kg was associated with better outcomes in dose-response analysis. EXPERT OPINION: Cumulative rATG induction doses as much as 3-4.5 mg/kg is as effective as higher doses regarding to allograft and patient outcomes while minimizing potential adverse effects in kidney transplant recipients.

Discordance Between Using Estimated and Measured Glomerular Filtration Rate for Drug Dosing in Kidney Transplant Recipients.

INTRODUCTION: Estimating glomerular filtration rate (eGFR) using different formulas is common clinical practice for evaluating kidney function and drug dosing. But, the performance of available eGFR equations is questionable during early days after kidney transplantation. METHODS: This study compared the performance of three common eGFR equations (Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) in relation with measured GFR (mGFR) using clearance of Tc-99m-diethylenetriaminepentaacetic acid, 7 to 10 days post kidney transplantation. Agreement of mGFR and different eGFR equations in the staging of kidney function and dosing of 8 common antimicrobials were assessed. RESULT: Thirty kidney and 5 simultaneous pancreas-kidney transplant recipients were included. CG applying total body weight (CGTBW) had the lowest bias (-12 mL/min/ 1.73 m2) and the highest percentage of estimation within 30% of mGFR (71.4%). MDRD showed the best precision (13.14 mL/min/ 1.73m2) and linear correlation with mGFR. CKD-EPI and MDRD acted better than CG for staging the level of kidney function. CGTBW had the lowest discordance rate with mGFR for antimicrobials dosing (33.6%). Discordance rates of drug dosing between mGFR and eGFR formulas were greater for drugs that have higher dosing levels such as (val)-ganciclovir (≥ 54.3%). CONCLUSION: Until developing more accurate methods for estimating kidney function during first 1 to 2 weeks after kidney transplantation, CGTBW method is suggested for drug dose adjustment and MDRD or CKD-EPI equation for the staging of kidney function in these patients, keeping in mind that these formulas underestimate the level of kidney function in new transplant recipients.

The need for an integrated pharmacological response to the treatment of HIV/AIDS and depression.

Introduction: The coexistence of depression and HIV infection affects more than 9 million people worldwide. A literature review revealed a large gap regarding the pharmacotherapy of depression among patients dually diagnosed with HIV and depression.Areas covered:In this review, the authors covered the various dimensions of deploying integrated pharmacological treatment of HIV/AIDS and depression. This topic was addressed in two ways; first, the direct results of integrated pharmacotherapy in syndemic patients; second, the indirect effects of the integrated model on other outcomes of HIV care.Expert opinion: An integrated pharmacological response to the treatment of HIV and depression can bring substantial benefits to HIV outcomes and reduce the burden of both diseases. The direct advantages regarding pharmacological response to the treatment of depression along with HIV care are improving adherence to antiretroviral therapy, optimizing pharmacotherapy, minimizing drug interaction, and prevention of additive adverse drug reactions. Furthermore, in some cases, medication can target both depression and other neuropsychiatric or somatic comorbidities among people living with HIV/AIDS. The integrated pharmacotherapy also has some potential indirect advantages on HIV care outcomes like minimizing loss of care, reducing ongoing HIV transmission, and improving the outcomes of both diseases.

Vitamin C and kidney transplantation: Nutritional status, potential efficacy, safety, and interactions.

BACKGROUND AND AIM: There are several observational and interventional studies regarding the advantages of sufficient serum levels of vitamin C and the evaluation of the effects of vitamin C supplementation post kidney transplantation. These studies have been put together to investigate the role of vitamin C post-kidney transplantation and make suggestions for designing future studies based on the use of vitamin C supplements or nutritional interventions among these patients. METHODS: This narrative review was done by searching in the Embase, PubMed, and SCOPUS databases. RESULTS: The results are presented in several sections as follows; nutritional status, potential protective effects, safety concerns, and medications/laboratory tests interactions of vitamin C. CONCLUSIONS: Kidney transplant recipients are prone to vitamin C deficiency, which is related to higher mortality based on several long-term observational studies. Vitamin C supplementation improves endothelial function and creatinine clearance. Vitamin C is considered as a safe supplement, however, side effects such as kidney stones, pro-oxidant effect, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, impact on lymphocytic activity, acid-base disturbance, and increased sodium load following its administration have been reported. Interaction of vitamin C and cyclosporine is the most important interaction with post-renal transplant medications. Vitamin C also interferes with creatinine assay using Jaffe and enzymatic methods.

Orthotopic Liver Transplantation for Etanercept-induced Acute Hepatic Failure: A Case Report.

Occurrence of hepatotoxicity following prescription of etanercept, a tumor necrosis factor-alpha (TNF-α) antagonist, is a relatively well-known issue. On the other hand, acute hepatic failure which could lead to liver transplantation is extremely rare to the best of our knowledge, and there is no previously published case in the literature. In this article, we presented a case of acute liver failure followed by liver transplantaion, in a 32- year old man with a previous history of ankylosing spondylitis after etanercept usage. On pathologic examination of the explanted liver of the patient, extensive confluent necrosis in all liver segments with prominent infiltration of a mixed population of inflammatory cells in portal tracts was noticed. In conclusion, close follow-up of patients who are receiving etanercept is crucial, since its liver complications could be severe enough to subject the patients for liver transplantation.

Clinical characteristics and outcome of COVID-19 pneumonia in kidney transplant recipients in Razi hospital, Rasht, Iran.

BACKGROUND: In late December 2019, a novel coronavirus SARS-CoV-2 started to spread around the world in different populations. Its clinical and laboratory characteristics and outcome in kidney transplant recipients are little known. Therefore, we describe 22 kidney transplant recipients with SARS-CoV-2-induced pneumonia. METHODS: All kidney transplant recipients who referred to the Razi Hospital of Rasht with a diagnosis of SARS-CoV-2 infection from February 20 to 19th of April 2020 have been included in this observational study. RESULTS: We present 22 cases of COVID-19 in kidney transplant recipients (median age 52 years [interquartile range 40.75-62.75 years]) and baseline eGFR 60 (mL/min/1.73 m2 ) (44.75-86.75). Patients complained of cough (72.7%), dyspnea (63.6%), fever (68.2%), and chill (72.7%) with greater prevalence. We decreased the dose of immunosuppression and started stress dose of intravenous hydrocortisone or equivalent oral prednisolone. Each patient received antiviral therapy based on the latest updated version of local protocol at the time of admission. CT scan findings in 90.9% of patients showed bilateral multifocal lesions. Acute kidney injury (AKI) was observed in 12 patients during hospitalization. Six patients died after a median of 12 days from admission (IQR, 1-21). CONCLUSIONS: In this small observational study, we observed high AKI occurrence and mortality rate in kidney transplant recipients with COVID-19.

Dose discordance of direct acting oral anticoagulants using different equations for estimating GFR: a literature review.

INTRODUCTION: Direct oral anticoagulants (DOACs) are widely prescribed nowadays. Available DOACs are renally eliminated to some extent and need dose adjustment in patients with kidney dysfunction. Cockcroft-Gault (CG) formula has been used to estimate creatinine clearance in DOACs trials. Nowadays, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are preferred equations for estimating glomerular filtration rate (GFR). We reviewed studies that simulated DOACs dosing in patients with atrial fibrillation by MDRD, CKD-EPI, and CG. AREAS COVERED: DOACs dose discordance varies from 28.8% underdosing to 59.2% overdosing when MDRD or CKD-EPI equations are substituted for CG. MDRD and CKD-EPI overestimate the GFR in lower thresholds of kidney function especially in elderly and females and result in overestimation of DOACs dosing or misclassifying the patients to be eligible for receiving DOACs when they are contraindicated. Compared with CG, MDRD and CKD-EPI underestimate the level of kidney function in higher GFR extremes and in these patients suggest DOACs when they are not recommended or suggest lower doses. EXPERT OPINION: Until running large clinical studies on efficacy/safety of DOACs dosing using MDRD or CKD-EPI equations, use of CG method for DOACs dosing is recommended in real practice.

Pharmacotherapeutic considerations in solid organ transplant patients with COVID-19.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide. While there are presently a few case reports/series on COVID-19 amongst solid organ transplant (SOT) patients, there is no official guideline for the management of SOT patients. AREAS COVERED: The authors discuss the pharmacotherapeutic management of SOT patients during the COVID-19 outbreak and provide their expert perspectives. EXPERT OPINION: Prophylactic reduction of immunosuppression because of fear of COVID-19 is not suggested in SOT patients. With maintenance immunosuppressive regimens, corticosteroids can be continued during COVID-19. Continuing other immunosuppressive drugs with lowest effective dose/blood concentration is suggested for patients with mild to moderate COVID-19. Discontinuation of antimetabolites and perhaps inhibitors of mammalian target of rapamycin (mTOR) is suggested in moderate to severe COVID-19. Calcineurin inhibitors (CNIs) may be continued or substituted for mTOR inhibitors with lowest therapeutic concentrations in moderate to severe COVID-19. If continued in patients with COVID-19, therapeutic drug monitoring of CNIs/mTOR inhibitors and appropriate dose reduction is recommended in co-administration with protease inhibitors, hydroxychloroquine/chloroquine, or interleukin (IL)-1/IL-6 receptor antagonists. Complete blood count monitoring is recommended in patients who continue taking antimetabolites or mTOR inhibitors. Dose modification/avoidance should be considered for chloroquine, atazanavir, oseltamivir, ribavirin, anakinra, and Janus associated kinase inhibitors in patients with organ function impairment.

Pharmacotherapy Considerations in CKD Patients With COVID-19, A Narrative Review.

Treatment of coronavirus disease 2019 (COVID-19) among patients with CKD requires special pharmacotherapy considerations that are reviewed here. Literature review was done for several pharmacotherapy aspects in CKD patients including selection and modification of COVID-19 treatment, drug interactions, nephrotoxicity of drugs that are used for treatment of COVID-19 and potential risks/benefits of routine medications of CKD patients during COVID-19 pandemic. CKD patients should be treated according to local or national COVID-19 protocols as other patients. But, there is no data on using remdesivir in patients with severe CKD. Oseltamivir and ribavirin require dose modification in patients with moderate to severe CKD. Nephrolithiasis, CKD, and acute interstitial nephritis have been reported with protease inhibitors. Acute kidney injury has been reported with remdesivir in patients with severe COVID-19. Pharmacokinetic-enhanced protease inhibitors increase the concentration of some drugs such as statins, cinacalcet, steroids, calcineurin inhibitors (CNIs). Some hypothetical benefits and harms have been suggested for statins and renin-angiotensinaldosterone system inhibitors in COVID-19 patients. Continuing guideline-directed administration of these drugs is recommended. Among different immunomodulating/immunosuppressive drugs, hydroxychloroquine and CNIs are the safest ones during COVID-19. Antimetabolites are suggested to be withheld during moderate to severe COVID-19. Fluid therapy and anticoagulant prophylaxis/ treatment need special attention in CKD patients with COVID-19. CKD patients with COVID-19 are treated as other patients, with some dose modifications if needed. Be mindful for management of drug interactions as well as modification of immunosuppressive drugs in patients with moderate to severe COVID-19.

Association Between Pre-Transplant Magnesemia and Post-Transplant Dysglycemia in Kidney Transplant Recipients.

BACKGROUND: Serum magnesium (Mg) status in kidney transplant recipients has been a center of attention in the past few years. Current evidence suggests an association between pre-transplant hypomagnesemia and post-transplant hyperglycemia. OBJECTIVE: The purpose of this study was to assess the associations of pre-transplant magnesemia with blood glucose disturbances within 6 months post-kidney transplantation. METHODS: In this retrospective cohort, 89 first-time kidney transplant recipients with 6 months of follow-up were included. None of the participants had a positive history of rejection, pre-transplant history of diabetes mellitus or fasting plasma glucose ≥ 100 mg/dL. RESULTS: Post-transplant diabetes mellitus (PTDM) and impaired fasting glucose (IFG) 6 months post-transplant was found in 7.9% and 41.6% of the study group, respectively. The mean pre-transplant serum Mg level was 1.92 ± 0.30 mg/dL in the study population (n = 89), and it was significantly lower in IFG (n = 37) and IFG/PTDM (n = 44) groups compared to normoglycemic (n = 45) recipients (1.83 ± 0.31 mg/dL vs. 2.00 ± 0.27 mg/dL, P = 0.008, and 1.84 ± 0.31 mg/dL vs. 2.00 ± 0.27 mg/dL, P = 0.012, respectively). Patients with serum Mg less than 1.9 mg/dL were nearly 2.6 times more likely to develop IFG or IFG/PTDM within 6 months post-transplant (P = 0.044 and P = 0.040, respectively). CONCLUSIONS: Pre-transplant hypomagnesemia may be considered a risk factor for developing post-transplant glycemic disturbances, and patients with lower pre-transplant Mg concentration could be at a higher risk for developing IFG.

Association Between CYP3A5 Genetic Polymorphisms with Tacrolimus Dose Requirement and Allograft Outcomes in Iranian Kidney Transplant Recipients.

INTRODUCTION: Tacrolimus is the cornerstone of immunosuppressive therapy in organ transplantation with variable inter-individual pharmacokinetics. This study assessed the relationship between CYP3A5/3A4 polymorphisms and tacrolimus dose requirement as well as 6-month transplant outcomes in Iranian kidney transplant recipients. METHODS: In this prospective study, 110 adult kidney transplant recipients treated with tacrolimus were genotyped for the presence of common SNPs: rs776746: A > G (CYP3A5*3). Patients who carried at least one CYP3A5*1 allele were known as CYP3A5 expressers while those who were CYP3A5*3/*3 homozygotes were classified as CYP3A5 non-expressers. RESULTS: The daily tacrolimus dose was significantly higher and tacrolimus dose adjusted trough levels (C/D ratio) was significantly lower in CYP3A5 expressers compared with non-expressers (P < .05). Although the incidence of clinically suggested acute allograft rejection was significantly higher (OR = 0.365 [95% CI: 0.14 - 0.93]; P < .05) and median time to first acute rejection was sooner among CYP3A5 expressers compared with non-expressers (12.17 vs. 26.83 days, P < .05); however, estimated glomerular filtration rate, incidence of biopsy proven acute rejection and delayed graft function and 6-month patients' and grafts' survival did not differ between the two groups. CONCLUSION: CYP3A5 genetic polymorphism is significantly associated with required tacrolimus dose. After achieving desired tacrolimus blood level, although some transplant outcomes such as the incidence of clinically suggested acute rejection and time to first rejection were different between CYP3A5 expressers and non-expressers, however, other clinical outcomes did not differ between groups. Therefore, it is not the time to routinely assess kidney transplant recipients for CYP3A5 genetic polymorphism before transplantation.