• Calcineurin inhibitor
• Minor glomerular abnormality
• Splice donor site
• Steroid-resistant nephrotic syndrome
• TRPC6

• Humans
• Female
• Nephrotic Syndrome/drug therapy
• Nephrotic Syndrome/genetics
• Nephrotic Syndrome/diagnosis
• TRPC6 Cation Channel/genetics
• Adult
• Calcineurin Inhibitors/therapeutic use
• Calcineurin Inhibitors/administration & dosage
• Cyclosporine/therapeutic use
• Cyclosporine/administration & dosage
• Tacrolimus/therapeutic use
• Tacrolimus/administration & dosage
• Drug Resistance
• RNA Splice Sites/genetics
• Treatment Outcome
• Kidney/pathology

• JP24ek0109672 Japan Agency for Medical Research and Development
• JP24ek0109760 Japan Agency for Medical Research and Development

• Acute nephrotoxicity
• calcineurin inhibitors
• cardiovascular toxicity
• chronic nephrotoxicity
• dyslipidemia
• graft rejection

• Humans
• Calcineurin Inhibitors/therapeutic use
• Calcineurin Inhibitors/adverse effects
• Graft Rejection/prevention & control
• Kidney Transplantation/adverse effects
• Cardiovascular Diseases/prevention & control
• Cardiovascular Diseases/chemically induced
• Immunosuppressive Agents/therapeutic use
• Immunosuppressive Agents/adverse effects
• Animals

• haematological cancer
• predictive markers
• prognostic markers
• genetics research
• translational research
• pharmacogenetics

• Humans
• Male
• Methotrexate/adverse effects
• Methotrexate/administration & dosage
• Female
• Middle Aged
• Thailand/epidemiology
• Aged
• Adult
• Hematologic Neoplasms/drug therapy
• Hematologic Neoplasms/genetics
• Acute Kidney Injury/chemically induced
• Acute Kidney Injury/genetics
• Antimetabolites, Antineoplastic/adverse effects
• Antimetabolites, Antineoplastic/administration & dosage
• Polymorphism, Single Nucleotide
• Young Adult
• Southeast Asian People

• RA-MF-14/64 Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University
• RA65/18 Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University

• concentration/ dose ratio
• cyp3a5 genotype
• nephrotoxicity
• post-renal transplant
• tacrolimus

• medical research
• risk factors
• adverse effects
• drug therapy
• health care
• therapeutics
• comorbidities

Non-adherence to immunosuppressant therapy reduces long-term graft and patient survival after solid organ transplantation. The objective of this 24-month prospective study was to determine adherence, efficacy and safety after conversion of stable liver transplant (LT) recipients from a standard twice-daily immediate release Tacrolimus (IR-Tac) to a novel once-daily life cycle pharma Tacrolimus (LCP-Tac) formulation. We converted a total of 161 LT patients at baseline, collecting Tacrolimus trough levels, laboratories, physical examination data and the BAASIS^© questionnaire for self-reported adherence to immunosuppression at regular intervals. With 134 participants completing the study period (17% dropouts), the overall adherence to the BAASIS^© increased by 57% until month 24 compared to baseline (51% vs. 80%). Patients who required only a morning dose of their concomitant medications reported the largest improvement in adherence after conversion. The intra-patient variability (IPV) of consecutive Tacrolimus trough levels after conversion did not change significantly compared to pre-conversion levels. Despite reducing the daily dose by 30% at baseline as recommended by the manufacturer, Tac-trough levels remained stable, reflected by an increase in the concentration-dose (C/D) ratio. No episodes of graft rejection or loss occurred. Our data suggest that the use of LCP-Tac in liver transplant patients is safe and can increase adherence to immunosuppression compared to conventional IR-Tac.

• conversion ratio
• formulation
• solid-organ transplant
• tacrolimus
• therapeutic drug monitoring

• graft survival
• kidney disease
• regeneration
• review
• transplantation

• Graft survival
• immunosuppressant
• immunosuppression
• immunosuppressive agents
• kidney transplantation
• pediatric
• pharmacokinetics
• renal transplant

• Age Factors
• Child
• Drug Interactions
• Graft Survival/drug effects
• Humans
• Immunosuppressive Agents/administration & dosage
• Immunosuppressive Agents/adverse effects
• Immunosuppressive Agents/pharmacokinetics
• Kidney Transplantation/methods
• Polymorphism, Genetic

• U01 FD005191 FDA HHS

• calcineurin inhibitor
• estimated glomerular filtration rate
• heart transplant
• pharmacogenetics
• pharmacogenomics
• renal dysfunction
• single nucleotide variant

• TL1 TR002533 NCATS NIH HHS
• UL1 TR002535 NCATS NIH HHS

• Wuzhi capsule
• clinical efficacy
• myasthenia gravis
• tacrolimus

• Allografts
• Capsules
• Graft Rejection
• Humans
• Lymph Nodes
• Tacrolimus
• beta-Glucans

A previous phase 3 clinical trial in de novo adult kidney transplant recipients (NCT01187953) compared the efficacy and safety of once-daily LCP-tacrolimus (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). However, whether the rate of tacrolimus metabolism affects outcomes between LCPT and IR-Tac was not examined.

Patients were initiated on 0.17 mg/kg/day LCPT or 0.1 mg/kg/day IR-Tac, with doses adjusted over time to maintain target therapeutic trough concentrations. This post hoc analysis examined dosing trends, relative efficacy, and safety of LCPT (n=247) and IR-Tac (n=249) in slow, intermediate, and rapid metabolizers as defined by concentration/dose ratios at day 30.

For all metabolizer subgroups, minimum target tacrolimus trough concentrations were obtained more rapidly with LCPT than with IR-Tac. Slow metabolizers were more likely to exceed target trough concentrations with LCPT, while rapid metabolizers were more likely to fall below target trough concentrations with IR-Tac. Regardless of metabolizer status, significant differences were not detected between LCPT and IR-Tac for treatment failure, death, graft failure, biopsy-proven acute rejection, estimated glomerular filtration rate, or other clinical outcomes.

Although within metabolizer subgroups, attainment of target trough concentrations in the first week differed between LCPT and IR-Tac, these results suggest that, regardless of metabolizer phenotype, clinical outcomes do not differ between these formulations when dose adjustments are made.

https://clinicaltrials.gov/ct2/show/NCT01187953

Recently, proton pump inhibitor (PPI) intake has been linked to acute kidney injury and chronic kidney disease. The objective of this study was to assess the effect of PPIs on renal function and rejection rate in kidney transplant patients. We performed a single center, retrospective analysis of 455 patients who received a kidney transplant between May 2010 and July 2015. Median follow-up time was 3.3 years. PPI prescription was assessed in half-year intervals. Primary outcome parameters were the estimated glomerular filtration rate (eGFR), change in the eGFR, and >30% and >50% eGFR decline for different time periods (up to four years post-transplantation). Our secondary outcome parameter was occurrence of biopsy proven acute rejection (BPAR) in the first two years after transplantation. Except for >30% eGFR decline from half a year to two years post-transplantation (p = 0.044) and change in the eGFR, >30% and >50% eGFR decline showed no association with PPI intake in our patient cohort (p > 0.05). Similarly, by analyzing 158 rejection episodes, BPAR showed no correspondence with mean daily PPI intake. We conclude that prolonged PPI intake has no relevant adverse effect on kidney transplant function or rejection rates. Polypharmacy, however, remains a problem in renal transplant recipients and it is thus advisable to question the necessity of PPI prescriptions when clear indications are missing.

• GFR
• kidney transplantation
• proton pump inhibitor
• transplant rejection

• Graft Rejection
• Immunosuppressive Agents
• Kidney Transplantation
• Tacrolimus

• Corticosteroid
• Immunosuppression
• Intravenous immunoglobulin
• Myasthenia gravis
• Non-steroid immunosuppressive agent
• Plasmapheresis
• Thymectomy

Drug response variations amongst different individuals/populations are influenced by several factors including allele frequency differences of single nucleotide polymorphisms (SNPs) that functionally affect drug-response genes. Here, we aim to identify drugs that potentially exhibit population differences in response using SNP data mining and analytics. Ninety-one pairwise-comparisons of >22,000,000 SNPs from the 1000 Genomes Project, across 14 different populations, were performed to identify ‘population-differentiated’ SNPs (pdSNPs). Potentially-functional pdSNPs (pf-pdSNPs) were then selected, mapped into genes, and integrated with drug–gene databases to identify ‘population-differentiated’ drugs enriched with genes carrying pf-pdSNPs. 1191 clinically-approved drugs were found to be significantly enriched (Z > 2.58) with genes carrying SNPs that were differentiated in one or more population-pair comparisons. Thirteen drugs were found to be enriched with such differentiated genes across all 91 population-pairs. Notably, 82% of drugs, which were previously reported in the literature to exhibit population differences in response were also found by this method to contain a significant enrichment of population specific differentiated SNPs. Furthermore, drugs with genetic testing labels, or those suspected to cause adverse reactions, contained a significantly larger number (P < 0.01) of population-pairs with enriched pf-pdSNPs compared with those without these labels. This pioneering effort at harnessing big-data pharmacogenomics to identify ‘population differentiated’ drugs could help to facilitate data-driven decision-making for a more personalized medicine.

• Estimated glomerular filtration rate
• Kidney transplantation
• Outcome
• Renal transplantation
• Tacrolimus

• CYP3A5
• immunosuppression
• kidney
• tacrolimus
• therapeutic drug monitoring
• transplantation

Prolonged-release tacrolimus (PR-TAC) was associated with improved renal function after transplantation when compared to immediate-release tacrolimus (IR-TAC) although evidence is still scarce. This study aimed to compare clinical outcomes and treatment costs in patients who converted from IR-TAC to PR-TAC during the first year after renal transplantation (RT) (early converters [EC]) or after that period (late converters [LC]).

We performed a retrospective study including 79 patients (EC, 39; LC, 41) which were followed up over 60 months. A mixed-effects approach was used to investigate the differences between both groups regarding renal and metabolic outcomes as well as treatment costs.

The median time from RT to conversion was 3 months for EC and 25 months for LC. For both EC and LC, a significant increase in estimated glomerular filtration rate was observed after conversion (5.2 and 4.9 mL/min per 1.73 m², respectively). During the first year after RT, EC presented a higher estimated glomerular filtration rate and inferior tacrolimus trough levels when compared to LC, with higher mean treatment costs associated. However, thereafter, these outcomes were similar between groups over the remaining time. At the end of follow-up, no significant differences were found regarding allograft acute rejection (2.6% and 2.4%), new-onset diabetes (15.7% vs 12.2%) or cardiovascular events (5.2% vs 7.3%).

There was a significant benefit on renal function after conversion from IR-TAC to PR-TAC. During the first year after RT, EC presented improved renal function, but higher treatment costs. None of these differences persisted at the end of follow-up.

Conversion from tacrolimus to belatacept has been shown to be beneficial for an increasing number of kidney transplant (KT) patients. Predicting factors for favorable outcomes are still unknown. We aimed to investigate whether histological vascular lesions at the time of conversion might correlate with greater improvement in renal function post-conversion.

The study was conducted on a retrospective cohort of 34 KT patients converted from tacrolimus to belatacept. All patients underwent an allograft biopsy prior to conversion. We analyzed the evolution of the estimated glomerular filtration rate (eGFR) at 3 and 12 months after conversion.

Median time to conversion was 6 (2–37.2) months post-transplant. About 52.9% of patients had moderate-to-severe chronic vascular lesions (cv2–3). We observed an increase in eGFR in the whole cohort from 35.4 to 41 mL/min/1.73 m² at 3 months (P = 0.032) and 43.7 at 12 months (P = 0.013). Nine patients experienced acute rejection post-conversion, with one graft loss observed beyond the first year after conversion. Patients with cv2–3 had significant improvement in eGFR at 12 months (+8.6 mL/min/1.73 m²; 31.6 to 40.2 mL/min/1.73 m²; P = 0.047) compared with those without these lesions (+6.8 mL/min/1.73 m²; 40.9 to 47.7 mL/min/1.73 m²; P = 0.148).

Conversion from tacrolimus to belatacept has a beneficial effect in terms of renal function in KT patients. This benefit might be more significant in patients with cv in the biopsy.

• creatinine clearance
• immunosuppression
• kidney transplantation
• renal biopsy
• tacrolimus

Prolonged immunosuppressive therapy is a risk factor for invasive pulmonary aspergillosis. We report a case of a 79-yearold man who underwent immunosuppressive therapy with methylprednisolone and cyclosporine for an acute exacerbation of interstitial lung disease. Ten days after initiation of immunosuppressive therapy, the patient reported night sweats and purulent sputum, and chest computed tomography scan revealed consolidation. He was diagnosed with invasive pulmonary aspergillosis, and required vasopressor support with oxygen therapy. After the administration of voriconazole and the modulation of immunosuppressive therapy, his condition improved. Short-term immunosuppressive therapy can also induce invasive pulmonary aspergillosis.

• Immunosuppressive therapy
• Interstitial lung disease
• Invasive pulmonary aspergillosis

• CYP3A4
• CYP3A5
• Transplant
• kidney
• pharmacogenetics
• single nucleotide polymorphisms
• tacrolimus

• calcineurin inhibitor
• meta-analysis
• nephrotoxicity
• risk factor
• systematic review
• transplantation

• Antibody
• Immunotherapy
• Myasthenia gravis
• Tacrolimus

• kidney transplantation
• nephrotoxicity
• pharmacist
• pharmacy
• tacrolimus

• Pathophysiology of Renal Disease and Progression
• cell activation
• cyclosporine nephrotoxicity
• gene expression
• renal proximal tubule cell

• clinical research/practice
• delayed graft function (DGF)
• donors and donation: extended criteria
• drug toxicity
• fusion proteins and monoclonal antibodies: adhesion molecule specific
• immunosuppressant
• immunosuppression/immune modulation
• kidney (allograft) function/dysfunction
• kidney transplantation/nephrology

• MODY
• Minigene assay
• PAX4
• Splice site mutation
• mRNA splicing defect
• β-Cell survival

• Adult
• Alternative Splicing/genetics
• Animals
• Apoptosis/drug effects
• Cell Survival/drug effects
• Diabetes Mellitus, Type 2/genetics
• Female
• Gene Deletion
• Glucose/pharmacology
• Homeodomain Proteins/genetics
• Humans
• Insulin-Secreting Cells/drug effects
• Insulin-Secreting Cells/metabolism
• Mice
• Mutation/genetics
• Paired Box Transcription Factors/genetics
• Repressor Proteins/drug effects
• Translocation, Genetic

Genetic association studies of transplantation outcomes have been hampered by small samples and highly complex multifactorial phenotypes, hindering investigations of the genetic architecture of a range of comorbidities which significantly impact graft and recipient life expectancy. We describe here the rationale and design of the International Genetics & Translational Research in Transplantation Network. The network comprises 22 studies to date, including 16494 transplant recipients and 11669 donors, of whom more than 5000 are of non-European ancestry, all of whom have existing genomewide genotype data sets.

iGeneTRAiN is a consortium that has genome-wide genotype datasets. These genomic data allows robust statistically analysis of genetic associations that impact graft and patients variables such as, such as: graft survival, acute rejection, new onset of diabetes after transplantation, and delayed graft kidney function. Supplemental digital content is available in the text.

• Graft Rejection
• Graft Survival
• Humans
• Kidney
• Kidney Transplantation
• Survival Rate
• Treatment Outcome
• United States

In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation.

We describe here the design and implementation of a customized genome-wide genotyping array, the ‘TxArray’, comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios.

We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.

We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.

The online version of this article (doi:10.1186/s13073-015-0211-x) contains supplementary material, which is available to authorized users.

Transplant recipients receive potent immunosuppressive drugs in order to prevent graft rejection. Therapeutic drug monitoring is the current approach to guide the dosing of calcineurin inhibitors, mammalian target of rapamycin inhibitors (mTORi) and mofetil mycophenolate. Target concentrations used in pediatric patients are extrapolated from adult studies. Gene polymorphisms in metabolizing enzymes and drug transporters such as cytochromes CYP3A4 and CYP3A5, UDP-glucuronosyl transferase, and P-glycoprotein are known to influence the pharmacokinetics and dose requirements of immunosuppressants. The implications of pharmacogenomics in this patient population is discussed. Genetic information can help with achieving target concentrations in the early post-transplant period, avoiding adverse drug reactions and drug-drug interactions. Evidence about genetic studies and transplant outcomes is revised.

• GWAS
• acute rejection
• adverse reactions
• drug metabolism
• genotype
• graft survival
• immunosuppression
• pharmacogenomics

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.

Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.

• Kidney transplantation
• Calcineurin inhibitor
• Withdrawal
• Sparing
• Cyclosporine
• Tacrolimus
• Renal function
• Graft survival

• Biomarkers
• calcineurin inhibitors
• kidney transplant
• toxicity

• Adult
• Allografts
• Area Under Curve
• Biomarkers/blood
• Calcineurin Inhibitors/adverse effects
• Cross-Sectional Studies
• Disease Progression
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Graft Rejection/blood
• Graft Rejection/classification
• Graft Rejection/drug therapy
• Graft Rejection/genetics
• Humans
• Kidney Failure, Chronic/complications
• Kidney Failure, Chronic/surgery
• Kidney Transplantation
• Longitudinal Studies
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Postoperative Complications
• Prognosis
• Prospective Studies

• R01 DK080074 NIDDK NIH HHS
• R21 DK100678 NIDDK NIH HHS
• R01DK080074 NIDDK NIH HHS