Publications by authors named "Reginald Gohh"

56 Publications

Coronavirus Disease 2019 in Kidney Transplant Recipients: Single-Center Experience and Case-Control Study.

Transplant Proc 2021 Jan 13. Epub 2021 Jan 13.

Division of Infectious Diseases, Warren Alpert Medical School of Brown University, Providence, Rhode Island. Electronic address:

Background: Kidney transplant recipients (KTR) are considered high-risk for morbidity and mortality from coronavirus disease 2019 (COVID-19). However, some studies did not show worse outcomes compared to non-transplant patients and there is little data about immunosuppressant drug levels and secondary infections in KTR with COVID-19. Herein, we describe our single-center experience with COVID-19 in KTR.

Methods: We captured KTR diagnosed with COVID-19 between March 1, 2020 and May 18, 2020. After exclusion of KTR on hemodialysis and off immunosuppression, we compared the clinical course of COVID-19 between hospitalized KTR and non-transplant patients, matched by age and sex (controls).

Results: Eleven KTR were hospitalized and matched with 44 controls. One KTR and 4 controls died (case fatality rate: 9.1%). There were no significant differences in length of stay or clinical outcomes between KTR and controls. Tacrolimus or sirolimus levels were >10 ng/mL in 6 out of 9 KTR (67%). Bacterial infections were more frequent in KTR (36.3%), compared with controls (6.8%, P = .02).

Conclusions: In our small case series, unlike earlier reports from the pandemic epicenters, the clinical outcomes of KTR with COVID-19 were comparable to those of non-transplant patients. Calcineurin or mammalian target of rapamycin inhibitor (mTOR) levels were high. Bacterial infections were more common in KTR, compared with controls.
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http://dx.doi.org/10.1016/j.transproceed.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836220PMC
January 2021

Management of Cardiovascular Risk Factors in Dialysis-Dependent End Stage Kidney Disease.

R I Med J (2013) 2021 Feb 1;104(1):20-24. Epub 2021 Feb 1.

Brown Medicine, Division of Nephrology and Hypertension, Professor of Medicine, Alpert Medical School of Brown University, Division of Kidney Transplantation, Rhode Island Hospital, Providence, RI.

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February 2021

Clinicians' Update: Kidney Transplantation in End-Stage Renal Disease (ESRD).

Authors:
Reginald Gohh

R I Med J (2013) 2021 Feb 1;104(1):14. Epub 2021 Feb 1.

Brown Medicine, Division of Nephrology and Hypertension; Medical Director, Division of Kidney Transplantation, Rhode Island Hospital; Professor of Medicine, Alpert Medical School of Brown University, Providence, RI.

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February 2021

Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury.

Nephrol Dial Transplant 2021 01;36(2):257-266

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA.

Background: Renal ischemia-reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo.

Methods: Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1-168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18-24 h before ischemia.

Results: Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil.

Conclusions: This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.
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http://dx.doi.org/10.1093/ndt/gfaa236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834597PMC
January 2021

Undiagnosed fibromuscular dysplasia in a deceased donor kidney transplant successfully treated with angioplasty.

BMJ Case Rep 2020 Oct 22;13(10). Epub 2020 Oct 22.

Brown Medicine, Division of Nephrology and Hypertension, Division of Renal Transplantation, Brown University Warren Alpert Medical School, Providence, Rhode Island, USA.

A 41-year-old man with end-stage renal disease received a deceased donor kidney transplant without complication. Maintenance immunosuppression consisted of tacrolimus, mycophenolate and prednisone. Two months after transplantation, his creatinine did not improve beyond 2-2.3 mg/dL, which prompted allograft biopsy. His biopsy showed tubular epithelial injury without rejection, and given concern for possible calcineurin-inhibitor toxicity, his tacrolimus was changed to sirolimus. Renal function improved, but 1 month later he presented to the hospital with seizure activity, severe hypertension, acute kidney injury and MRI findings suggestive of posterior reversible encephalopathy syndrome. Blood pressure was difficult to control, which had not been the case in the immediate posttransplant period, and addition of lisinopril worsened his renal function. Transplant renal artery stenosis was suspected, and allograft ultrasound with doppler confirmed our suspicion. The patient underwent an angiogram, showing 60% stenosis of the mid-distal transplanted renal artery. Interventional radiology successfully stented this lesion, with subsequent improvement in allograft function and blood pressure control. He did not require further intervention in follow-up.
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http://dx.doi.org/10.1136/bcr-2020-237380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583073PMC
October 2020

Kidney Transplantation and COVID-19.

R I Med J (2013) 2020 09 4;103(8):34-37. Epub 2020 Sep 4.

Division of Kidney Transplantation, Department of Medicine, Alpert Medical School of Brown University, Providence, RI.

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September 2020

Successful recovery from COVID-19 in three kidney transplant recipients who received convalescent plasma therapy.

Transpl Infect Dis 2021 Feb 3;23(1):e13451. Epub 2020 Sep 3.

Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.

Novel coronavirus disease 2019 (COVID-19) is a highly infectious, rapidly spreading viral disease that typically presents with greater severity in patients with underlying medical conditions or those who are immunosuppressed. We present a novel case series of three kidney transplant recipients with COVID-19 who recovered after receiving COVID-19 convalescent plasma (CCP) therapy. Physicians should be aware of this potentially useful treatment option. Larger clinical registries and randomized clinical trials should be conducted to further explore the clinical and allograft outcomes associated with CCP use in this population.
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http://dx.doi.org/10.1111/tid.13451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460867PMC
February 2021

Physical activity and risk of cardiovascular events and all-cause mortality among kidney transplant recipients.

Nephrol Dial Transplant 2020 08;35(8):1436-1443

Teachers' College, Columbia University, New York, NY, USA.

Background: Insufficient physical activity (PA) may increase the risk of all-cause mortality and cardiovascular disease (CVD) morbidity and mortality among kidney transplant recipients (KTRs), but limited research is available. We examine the relationship between PA and the development of CVD events, CVD death and all-cause mortality among KTRs.

Methods: A total of 3050 KTRs enrolled in an international homocysteine-lowering randomized controlled trial were examined (38% female; mean age 51.8 ± 9.4 years; 75% white; 20% with prevalent CVD). PA was measured at baseline using a modified Yale Physical Activity Survey, divided into tertiles (T1, T2 and T3) from lowest to highest PA. Kaplan-Meier survival curves were used to graph the risk of events; Cox proportional hazards regression models examined the association of baseline PA levels with CVD events (e.g. stroke, myocardial infarction), CVD mortality and all-cause mortality over time.

Results: Participants were followed up to 2500 days (mean 3.7 ± 1.6 years). The cohort experienced 426 CVD events and 357 deaths. Fully adjusted models revealed that, compared to the lowest tertile of PA, the highest tertile experienced a significantly lower risk of CVD events {hazard ratio [HR] 0.76 [95% confidence interval (CI) 0.59-0.98]}, CVD mortality [HR 0.58 (95% CI 0.35-0.96)] and all-cause mortality [HR 0.76 (95% CI 0.59-0.98)]. Results were similar in unadjusted models.

Conclusions: PA was associated with a reduced risk of CVD events and all-cause mortality among KTRs. These observed associations in a large, international sample, even when controlling for traditional CVD risk factors, indicate the potential importance of PA in reducing CVD and death among KTRs.
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http://dx.doi.org/10.1093/ndt/gfaa038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828582PMC
August 2020

Hyperammonemia syndrome due to Ureaplasma urealyticum in a kidney transplant recipient: A case of disseminated disease from a fluoroquinolone-resistant isolate.

Transpl Infect Dis 2020 Oct 2;22(5):e13328. Epub 2020 Jun 2.

Division of Infectious Diseases, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Ureaplasma species (spp.) are common colonizers of the urogenital tract but may cause systemic infection in immunocompromised patients. They release significant amounts of ammonia via urea hydrolysis and have been recently implicated in the pathogenesis of hyperammonemia syndrome after organ transplantation. We describe a unique case of hyperammonemia syndrome after kidney transplant caused by U urealyticum infection, and the first, to our knowledge, case of a fluoroquinolone-resistant Ureaplasma strain causing hyperammonemia syndrome. A 17-year-old female developed intermittent fevers, rising creatinine, sterile pyuria and debilitating polyarthritis approximately 1 year after kidney transplant. Serum ammonia level was elevated, and urine PCR was positive for U urealyticum. Near the end of treatment with levofloxacin, she had rebound hyperammonemia, which preceded clinical relapse of polyarthritis and encephalopathy. Blood and urine PCR and synovial fluid culture were positive for U urealyticum. Susceptibility testing showed fluoroquinolone resistance, but she responded well to azithromycin and doxycycline. The frequency of Ureaplasma spp. infection in immunocompromised patients is probably underestimated due to diagnostic challenges. Ammonia levels were helpful biomarkers of response to antimicrobial therapy in our case. Susceptibility testing of clinical isolates should be pursued. In serious Ureaplasma spp. infections, particularly in immunocompromised patients, two empiric antibiotics may be indicated given the potential for antimicrobial resistance.
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http://dx.doi.org/10.1111/tid.13328DOI Listing
October 2020

Successful Kidney Transplantation in a Recipient Coinfected with Hepatitis C Genotype 2 and HIV from a Donor Infected with Hepatitis C Genotype 1 in the Direct-Acting Antiviral Era.

Case Reports Hepatol 2020 29;2020:7679147. Epub 2020 Jan 29.

Division of Infectious Diseases, Department of Internal Medicine, Brown Alpert Medical School, Providence, RI, USA.

Despite significant advances in transplantation of HIV-infected individuals, little is known about HIV coinfected patients with hepatitis C virus (HCV) genotypes other than genotype 1, especially when receiving HCV-infected organs with a different genotype. We describe the first case of kidney transplantation in a man coinfected with hepatitis C and HIV in our state. To our knowledge, this is also the first report of an HIV/HCV/HBV tri-infected patient with non-1 (2a) HCV genotype who received an HCV-infected kidney graft with the discordant genotype (1a), to which he converted after transplant. Our case study highlights the following: (1) transplant centers need to monitor wait times for an HCV-infected organ and regularly assess the risk of delaying HCV antiviral treatment for HCV-infected transplant candidates in anticipation of the transplant from an HCV-infected donor; (2) closer monitoring of tacrolimus levels during the early phases of anti-HCV protease inhibitor introduction and discontinuation may be indicated; (3) donor genotype transmission can occur; (4) HIV/HCV coinfected transplant candidates require a holistic approach with emphasis on the cardiovascular risk profile and low threshold for cardiac catheterization as part of their pretransplant evaluation.
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http://dx.doi.org/10.1155/2020/7679147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011348PMC
January 2020

A single-center analysis of early readmission after renal transplantation.

Clin Transplant 2019 05 27;33(5):e13520. Epub 2019 Mar 27.

Division of Organ Transplantation, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.

Background: Thirty-day readmission rates (early hospital readmission, EHR) are an important benchmark for quality improvement. Nationally, patients undergoing renal transplantation incur a 31% EHR rate. While national databases provide useful data, the impact of EHR on individual centers has received little attention. We proposed that an institutional review of EHR after renal transplantation may provide a benchmark for individual transplant programs and identify modifiable program-specific issues to reduce EHR.

Methods: We reviewed 269 consecutive kidney transplant recipients over a five-year period (2012-2016). Early hospital readmission was modeled using generalized linear modeling assuming a binary distribution.

Results: About 21% of patients were readmitted within 30 days. Deceased kidney donation (DD), delayed graft functioning (DGF), anti-thymocyte globulin (ATG) induction, diabetes, public insurance, weekend discharge, and low glomerular filtration rate (eGFR) at discharge were all identified as risk factors for readmission. Early hospital readmission was not correlated with risk of death (5.4% at 44 months: HR 2.2 (95% CI [0.7, 6.6]; P = 0.1473) or graft loss.

Conclusions: EHR after renal transplantation is common. Certain factors may predict an increased risk for EHR. A multi-disciplinary approach to discharge planning may limit some EHR, but most complications and adverse events are unpredictable and require hospital-level of care.
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http://dx.doi.org/10.1111/ctr.13520DOI Listing
May 2019

Targeting Regulatory T Cells for Transplant Tolerance: New Insights and Future Perspectives.

Kidney Dis (Basel) 2018 Nov 31;4(4):205-213. Epub 2018 Jul 31.

Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, USA.

Background: Organ transplantation is considered the ultimate therapy for end-stage organ disease. While pharmacologic immunosuppression is the mainstay of therapeutic strategies to prolong the survival of the graft, long-term use of immunosuppressive medications carries the risk of organ toxicity, malignancies, serious opportunistic infections, and diabetes. Therapies that promote recipient tolerance in solid organ transplantation are able to improve patient outcomes by eliminating the need for long-term immunosuppression.

Summary: Establishing tolerance to an allograft has become an area of intense study and would be the ideal therapy in clinical practice. The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation. Evidence suggests that regulatory T cells (Tregs) are fundamentally involved in promoting allograft tolerance. Efforts to characterize specific markers for Tregs, while challenging, have identified Foxp3 gene expression as a crucial step in promoting the tolerance-inducing features of Tregs. A number of approaches, including those based on targeting the glycogen synthase kinase 3β signaling pathway or activating the melanocortinergic pathway, have been tested as a way to promote Treg lineage commitment and maintenance as well as to facilitate immune tolerance. In order to be effective in clinical practice, Tregs must be allospecific and possess a specific phenotype to avoid suppression of other aspects of the immune system or increasing the risk of malignancy or infections. Multiple experimental and clinical studies have demonstrated the impact of currently used immunosuppressants on the immunoregulatory activities of Tregs and their Foxp3 expression status. Pharmacological induction of tolerogenic Tregs for inducing transplant tolerance, including epigenetic therapies, is in the ascendant.

Key Messages: Therapies that promote Treg function and survival may represent a novel strategy for achieving immune tolerance in transplant patients.
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http://dx.doi.org/10.1159/000490703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276757PMC
November 2018

New England BK consortium: Regional survey of BK screening and management protocols in comparison to published consensus guidelines.

Transpl Infect Dis 2018 Dec 19;20(6):e12985. Epub 2018 Sep 19.

Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Introduction: BK polyomavirus (BKPyV) continues to impact renal transplant recipients (RTR). The New England BK Consortium aims to jointly optimize screening and management of BKPyV.

Methods: Our first project was to survey centers' BKPyV screening protocols and compare them to consensus guidelines.

Results: Thirteen of 15 centers (86.7%) returned the survey. Only two center reported using monitoring parameters that were in line with consensus guidelines for BKPyV screening, while the majority of centers reported less intensive methods and shorter duration. One center reported performing renal biopsies in all patients with plasma viral loads >10 000 copies/mL, while all other centers only perform for-cause biopsies. For presumptive nephropathy, 11 centers recommend a biopsy for confirmation. For management of documented BKPyV-associated nephropathy, 12 centers propose further immunosuppression reduction. Nine centers report CNI dose reduction as their primary treatment. More than half of centers surveyed reported use of leflunomide, cidofovir or intravenous immunoglobulin.

Conclusions: There was a large variance in BKPyV screening and management strategies among centers. Due to these results, all participating centers agreed to implement uniform screening and aim to optimize management protocols.
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http://dx.doi.org/10.1111/tid.12985DOI Listing
December 2018

Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients.

Am J Nephrol 2018 11;48(1):21-31. Epub 2018 Jul 11.

Center For Primary Care and Prevention, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island, USA.

Background: "T50," shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant.

Methods: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization.

Results: During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20-2.89); fetuin-A, (HR 2.25; 95% CI 1.38-3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations.

Conclusions: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.
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http://dx.doi.org/10.1159/000491025DOI Listing
December 2019

Serum Uromodulin: A Biomarker of Long-Term Kidney Allograft Failure.

Am J Nephrol 2018 26;47(4):275-282. Epub 2018 Apr 26.

Department of Family Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

Background: Uromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center -European study involving 91 kidney transplant recipients (KTRs).

Methods: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome.

Results: The 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05-5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06-3.77).

Conclusions: Lower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs.
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http://dx.doi.org/10.1159/000489095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754623PMC
September 2019

Tacrolimus Concentration in Saliva of Kidney Transplant Recipients: Factors Influencing the Relationship with Whole Blood Concentrations.

Clin Pharmacokinet 2018 09;57(9):1199-1210

Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 495A College of Pharmacy, 7 Greenhouse Road, Kingston, RI, 02881, USA.

Objective: The objective of this study was to examine the association between tacrolimus concentration in oral fluids and in whole blood and to investigate the various factors that influence this relationship.

Patients And Methods: Forty-six adult kidney transplant recipients were included in the study. Study A (ten patients) included the collection of several paired oral fluid samples by passive drool over a 12-h post-dose period. Study B (36 patients) included the collection of oral fluids pre-dose and at 2 h after the tacrolimus dose under three conditions: un-stimulated, after stimulation with a tart candy, and after mouth rinsing. The tacrolimus concentration in oral fluids was measured by a specially developed sensitive and specific liquid chromatography mass spectrometry method. A salivary transferrin concentration of >1 mg/dL was used as a cut-off value for oral fluid blood contamination.

Results: Rinsing the oral cavity before sampling proved to provide the most suitable sampling strategy giving a correlation coefficient value of 0.71 (p = 0.001) between the tacrolimus concentration in oral fluids and the tacrolimus concentration in whole blood at trough. Mean and 95% confidence interval of tacrolimus concentration in oral fluids at the pre-dose concentration for samples collected after mouth rinsing was 584 (436, 782) pg/mL. The ratio of the tacrolimus concentration in oral fluids to the tacrolimus concentration in whole blood (*100) was 11% (95% confidence interval 9-13) for all sampling times. Oral fluid pH or weight of a saliva sample did not influence the tacrolimus concentration in oral fluids. Tacrolimus distribution into oral fluids exhibited a delay with a pronounced counter-clockwise hysteresis with respect to the time after dose. A multivariate analysis of variance revealed that the tacrolimus concentration in oral fluids is related to the tacrolimus concentration in whole blood and tacrolimus plasma-binding proteins including albumin and cholesterol.

Conclusion: An optimal sampling strategy for the determination of the tacrolimus concentration in oral fluids was established. Measuring the tacrolimus concentration in oral fluids appears to be a feasible and non-invasive method for predicting the concentration of tacrolimus in whole blood.
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http://dx.doi.org/10.1007/s40262-017-0626-1DOI Listing
September 2018

Urothelial cell carcinoma after BK polyomavirus infection in kidney transplant recipients: A cohort study of veterans.

Transpl Infect Dis 2017 Oct 16;19(5). Epub 2017 Sep 16.

Department of Medicine, Providence VA Medical Center, Providence, RI, USA.

Background: BK polyomavirus (BKPyV) reactivation is a common clinical occurrence in kidney transplant recipients (KTR). Several other polyomaviruses have been implicated as pathogens with a direct role in the development of malignancies, raising the question of whether BKPyV might also be oncogenic.

Methods: This study is the first retrospective, multicenter cohort study evaluating the relative risk for urothelial cell carcinoma (UCC) associated with BKPyV infection among KTR, and was conducted among veterans who underwent transplantation between 2000 and 2009. BKPyV cases were defined as those veterans with any clinical evidence of BKPyV infection, including positive polymerase chain reaction testing of urine and/or serum for BKPyV or kidney biopsy showing BKPyV-associated nephropathy.

Results: Among the 646 veterans who met inclusion criteria for the study, 103 had clinical evidence of BKPyV infection (16%). The overall relative risk for developing any malignancy after BKPyV infection was 1.13 (95% confidence interval [CI] 0.89-1.44). The adjusted relative risk for malignancy after BKPyV infection was greatest with UCC (8.21, 95% CI 0.75-89.7) and with metastatic disease of unknown etiology (8.21, 95% CI 0.75-89.7). The screening prevalence for BKPyV infection increased from 18% for those veterans who underwent transplantation in 2000 to 86% for those veterans who underwent transplantation in 2009, during which time the measured prevalence of BKPyV infection increased from 7% to 24%.

Conclusion: In this cohort of KTR veterans, no overall increased or decreased relative risk for malignancy was associated with evidence of prior BKPyV infection. A >8-fold increased risk of developing UCC after BKPyV infection was seen, although this risk was not found to be statistically significant.
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http://dx.doi.org/10.1111/tid.12752DOI Listing
October 2017

Does size matter? Kidney transplant donor size determines kidney function among living donors.

Clin Kidney J 2017 Feb 4;10(1):116-123. Epub 2016 Oct 4.

Division of Kidney Disease and Hypertension, Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, USA.

Background: Kidney donor outcomes are gaining attention, particularly as donor eligibility criteria continue to expand. Kidney size, a useful predictor of recipient kidney function, also likely correlates with donor outcomes. Although donor evaluation includes donor kidney size measurements, the association between kidney size and outcomes are poorly defined.

Methods: We examined the relationship between kidney size (body surface area-adjusted total volume, cortical volume and length) and renal outcomes (post-operative recovery and longer-term kidney function) among 85 kidney donors using general linear models and time-to-chronic kidney disease data.

Results: Donors with the largest adjusted cortical volume were more likely to achieve an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m over a median 24-month follow-up than those with smaller cortical volumes (P <0.001), had a shorter duration of renal recovery (1.3-2.2 versus 32.5 days) and started with a higher eGFR at pre-donation (107-110 versus 91 mL/min/1.73 m) and immediately post-nephrectomy (∼63 versus 50-51 mL/min/1.73 m). Similar findings were seen with adjusted total volume and length.

Conclusions: Larger kidney donors were more likely to achieve an eGFR ≥60 mL/min/1.73 m with renal recovery over a shorter duration due to higher pre-donation and initial post-nephrectomy eGFRs.
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http://dx.doi.org/10.1093/ckj/sfw097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469570PMC
February 2017

Proliferative glomerulonephritis with monoclonal IgG deposits in two kidney allografts successfully treated with rituximab.

Clin Kidney J 2017 Jun 22;10(3):405-410. Epub 2017 Mar 22.

Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Providence, RI, USA.

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposit (PGNMID), a recently described pathologic entity in native kidneys, has been recognized in kidney transplant patients, where it can present as either recurrent or disease. There is no definitive treatment to date, in either population. Here, we present two cases of PGNMID in kidney allografts that illustrate the challenges of diagnostic approach and highlight the allograft outcome after treatment with rituximab as a potential treatment of this condition.
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http://dx.doi.org/10.1093/ckj/sfx001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466084PMC
June 2017

Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort.

Am J Kidney Dis 2017 Sep 2;70(3):377-385. Epub 2017 Jun 2.

Division of Hypertension and Kidney Diseases, Department of Medicine, Rhode Island Hospital, Providence, RI. Electronic address:

Background: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality.

Study Design: Cohort study.

Setting & Participants: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs.

Predictor: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization.

Results: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54).

Limitations: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites.

Conclusions: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.
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http://dx.doi.org/10.1053/j.ajkd.2017.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704919PMC
September 2017

Acute hypocalcemia following kidney transplantation may depend on the type of remote parathyroidectomy: a retrospective cohort study
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Clin Nephrol 2017 Jun;87(6):287-292

Background: Secondary hyperparathyroidism is a common complication of chronic kidney disease. When medical management fails, parathyroidectomy (PTX) is a treatment option. The two most common types are subtotal PTX and total PTX with autotransplantation (AT). To date, there is no consensus as to which procedure is preferable, especially in patients who are candidates for future kidney transplantation. The aim of this study was to identify if the type of PTX is a risk factor for acute postrenal transplant (postRTX) hypocalcemia and a concern for problems with long-term calcium homeostasis.

Methods: Renal transplant recipients at Rhode Island Hospital from 2005 to 2014 were screened for prior PTX. Out of 297 participants, 11 patients met the criteria. They were further divided into subtotal PTX (n = 5) vs. total PTX+AT (n = 6). Immediate postoperative (14 days) and long-term (1 year) calcium levels were followed and analyzed. Linear growth models were used to determine the effects of type of parathyroidectomy (subtotal PTX, total PTX+AT) alone on hypocalcemia over time. In these models, pretransplant levels of calcium and PTH were included as covariates.

Results: Baseline characteristics showed that prerenal transplant (preRTX) parathyroid hormone (PTH) levels were lower in total PTX+AT vs. subtotal PTX (3.5 vs. 247.2 mg/dL, p < 0.005). PreRTX calcium levels were slightly lower in subtotal PTX (9.5 vs. 8.25 mg/dL, p < 0.01), but were within normal limits for both groups. No significant differences were noted between total vitamin D levels and time between PTX and RTX. Within 14 days postRTX, the total PTX+AT group had lower average calcium levels (5.8 vs 8.8 mg/dL, p < 0.001); however, both groups had normal and stable calcium levels from 1 month to 1 year after transplant. This was further supported after adjusting for preRTX levels of calcium and PTH, showing a significant interaction between treatment and time such that patients had lower calcium levels if they underwent total PTX+AT vs. subtotal PTX within 14 days postRTX (β = -0.204, SE = 0.039, p < 0.001) (Figure 1) but not at 1 year postRTX (β = 0.035, SE = 0.075, p = 0.640).

Conclusion: This study suggests that total PTX+AT increases the risk for acute postRTX hypocalcemia but has no effect on long-term calcium homeostasis. We speculate that the acuity of the hypocalcemia may be compounded by high-dose glucocorticoids required for induction, in addition to the preoperative undetectable PTH. Thus, prior to RTX, physicians should take into account the type of remote PTX. If a patient had a total PTX+AT, then postRTX hypocalcemia is likely to occur.
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http://dx.doi.org/10.5414/CN109001DOI Listing
June 2017

Role for urinary biomarkers in diagnosis of acute rejection in the transplanted kidney.

World J Transplant 2015 Dec;5(4):251-60

Basma Merhi, George Bayliss, Department of Medicine, Division of Kidney Disease and Hypertension, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, United States.

Despite the introduction of potent immunosuppressive medications within recent decades, acute rejection still accounts for up to 12% of all graft losses, and is generally associated with an increased risk of late graft failure. Current detection of acute rejection relies on frequent monitoring of the serum creatinine followed by a diagnostic renal biopsy. This strategy is flawed since an alteration in the serum creatinine is a late clinical event and significant irreversible histologic damage has often already occurred. Furthermore, biopsies are invasive procedures that carry their own inherent risk. The discovery of non-invasive urinary biomarkers to help diagnose acute rejection has been the subject of a significant amount of investigation. We review the literature on urinary biomarkers here, focusing on specific markers perforin and granzyme B mRNAs, FOXP3 mRNA, CXCL9/CXCL10 and miRNAs. These and other biomarkers are not yet widely used in clinical settings, but our review of the literature suggests that biomarkers may correlate with biopsy findings and provide an important early indicator of rejection, allowing more rapid treatment and better graft survival.
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http://dx.doi.org/10.5500/wjt.v5.i4.251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689935PMC
December 2015

Immunosuppression in the failing and failed transplant kidney: optimizing outcomes.

Nephrol Dial Transplant 2016 08 30;31(8):1261-9. Epub 2015 Jun 30.

Department of Medicine, Rhode Island Hospital, Providence, RI, USA Alpert Medical School, Brown University, Providence, RI, USA Transplant Center, Rhode Island Hospital, Providence, RI, USA.

There is little data to guide clinicians on the optimal management of immunosuppression in patients whose kidney transplant has failed and who have returned to dialysis. Nor is there robust data on whether to perform a transplant nephrectomy. Finally, management of late stage chronic kidney disease, including deciding on dialysis initiation, modality and access planning, must occur simultaneously with efforts aimed at preserving the failing kidney and residual renal function for as long as possible. In this article, we will review the evidence on these topics and suggest areas for improvement.
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http://dx.doi.org/10.1093/ndt/gfv256DOI Listing
August 2016

Heroin crystal nephropathy.

Clin Kidney J 2015 Jun 31;8(3):339-42. Epub 2015 Mar 31.

Division of Kidney Disease and Hypertension, Department of Medicine , Rhode Island Hospital, Brown University School of Medicine , Providence, RI , USA.

In this paper we present an interesting case of acute kidney injury and severe metabolic alkalosis in a patient with a history of heavy heroin abuse. Urine microscopy showed numerous broomstick-like crystals. These crystals are also identified in light and electron microscopy. We hypothesize that heroin crystalizes in an alkaline pH, resulting in tubular obstruction and acute kidney injury. Management is mainly supportive as there is no known specific therapy for this condition. This paper highlights the utility of urine microscopy in diagnosing the etiology of acute kidney injury and proposes a novel disease called heroin crystal nephropathy.
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http://dx.doi.org/10.1093/ckj/sfv018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440465PMC
June 2015

Pharmacokinetics of total and unbound prednisone and prednisolone in stable kidney transplant recipients with diabetes mellitus.

Ther Drug Monit 2014 Aug;36(4):448-55

*Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island; †Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut; and ‡Division of Organ Transplantation, Alpert Medical School of Brown University, Providence, Rhode Island.

Background: The corticosteroid prednisone is an important component of posttransplantation immunosuppressive therapy. Pharmacokinetic parameters of prednisone or its pharmacologically active metabolite, prednisolone, are not well characterized in transplant recipients. The objective of this study was to compare the pharmacokinetics of total and unbound prednisone and prednisolone in diabetic and nondiabetic stable kidney transplant recipients and to evaluate the factors influencing plasma protein binding of prednisolone.

Methods: Prednisone and prednisolone concentration-time profiles were obtained in 20 diabetic and 18 nondiabetic stable kidney transplant recipients receiving an oral dose of 5-10 mg prednisone per day. In addition to drug and metabolite exposures, factors influencing prednisolone protein binding were evaluated using a nonlinear mixed-effects modeling approach. This model takes into account the binding of prednisolone and cortisol to corticosteroid-binding globulin (CBG) in a saturable fashion and binding of prednisolone to albumin in a nonsaturable fashion. Finally, we have investigated the influence of several covariates including diabetes, glucose concentration, hemoglobin A1c, creatinine clearance, body mass index, gender, age, and time after transplantation on the affinity constant (K) between corticosteroids and their binding proteins.

Results: In patients with diabetes, the values of dose-normalized area under the concentration-time curves were 27% and 23% higher for total and unbound prednisolone, respectively. Moreover, the ratio of total prednisolone to prednisone concentrations (active/inactive forms) was higher in diabetic subjects (P < 0.001). Modeling protein binding results revealed that the affinity constant of corticosteroid-binding globulin-prednisolone (KCBG,PL) was related to the patient's gender and diabetes status.

Conclusions: Higher prednisolone exposure could potentially lead to the increased risk of corticosteroid-related complications in diabetic kidney transplant recipients.
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http://dx.doi.org/10.1097/FTD.0000000000000045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109138PMC
August 2014

Rapamycin treatment of healthy pigs subjected to acute myocardial ischemia-reperfusion injury attenuates cardiac functions and increases myocardial necrosis.

Ann Thorac Surg 2014 Mar 20;97(3):901-7. Epub 2013 Nov 20.

Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island. Electronic address:

Background: The mammalian target of rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplantation. However, it has other nonimmune functions: in the cardiovascular system, it is a regulator of heart hypertrophy and locally, in coated vascular stents, it inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism, and survival, we hypothesized that inhibiting it with rapamycin before an acute myocardial ischemia-reperfusion injury (IRI) would confer cardioprotection by virtue of slowing down cardiac function and metabolism.

Methods: Yorkshire pigs received either placebo or 4 mg/d rapamycin orally for 7 days before the IRI. All animals underwent median sternotomy, and the mid-left anterior descending coronary artery was occluded for 60 minutes followed by 120 minutes of reperfusion. Left ventricular pressure-volume data were collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively, and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by Western blotting with specific antibodies against mTOR substrates phosphorylating sites.

Results: Rapamycin before treatment impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities.

Conclusions: Acute myocardial IRI, in healthy pigs treated with rapamycin, is associated with decreased cardiac function and higher myocardial necrosis.
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http://dx.doi.org/10.1016/j.athoracsur.2013.09.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943541PMC
March 2014

Immunosuppression after renal allograft failure: a survey of US practices.

Clin Transplant 2013 Nov-Dec;27(6):895-900. Epub 2013 Oct 11.

Department of Medicine, Rhode Island Hospital, Providence, RI, USA.

Background: Little data exist to guide the management of immunosuppression after renal graft failure. More aggressive tapering of immunosuppressive medications may reduce the risk of infection, but may increase the risk of rejection and sensitization.

Methods: To document current practices in the US, we emailed a questionnaire to medical and surgical transplant directors as identified by the United Network for Organ Sharing (UNOS).

Results: Emails were sent to 221 programs, of which 93 (42.1%) responded. About 24.7% of respondents reported adjusting immunosuppression according to a standard protocol; 75.3% said practices are physician dependent. The majority said that 80 or 100% of patients are off all immunosuppression one yr after returning to dialysis. The most important factors cited in deciding whether to stop immunosuppression were plans to retransplant (40.2%) and signs and symptoms of rejection (37.0%). When asked which immunosuppressive medications are continued indefinitely, 21.5% responded prednisone and 71.0% said none. Respondents most commonly said they performed graft nephrectomy only if there are signs and symptoms of rejection (47.3%) or if signs and symptoms of rejection fail to respond to steroids (34.4%).

Conclusions: In the absence of good data to guide decisions on immunosuppression in patients with failed allografts, practices in the US vary greatly. More data are needed to determine which policies lead to the best outcomes.
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http://dx.doi.org/10.1111/ctr.12254DOI Listing
August 2014

Inosine monophosphate dehydrogenase expression and activity are significantly lower in kidney transplant recipients with diabetes mellitus.

Ther Drug Monit 2013 Jun;35(3):374-83

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.

Background: Inosine 5'-monophosphate dehydrogenase (IMPDH) is a target of the immunosuppressive drug, mycophenolic acid (MPA). A 12-hour clinical pharmacokinetic and pharmacodynamic study was conducted to compare IMPDH1 and IMPDH2 gene expression, IMPDHI and IMPDHII protein levels, and enzyme activity between kidney transplant recipients with respect to diabetes status.

Methods: Nondiabetic (ND, n = 11) and diabetic (D, n = 9) kidney transplant recipients and on nontransplant nondiabetic (n = 10) and diabetic (n = 10) volunteers were included in the study.

Results: Area under the effect curve values for gene expression: IMPDH1 [ND: 22.1 (13.8-31.3) versus D: 4.5 (2.3-6.5), P < 0.001] and IMPDH2 [ND: 15.3 (11.0-21.7) versus D: 6.1 (4.6-8.6), P < 0.001], protein level: IMPDHI [ND: 1.0 (0.5-1.3) versus 0.5 (0.4-0.7), P = 0.002] and IMPDHII [ND: 1.0 (0.6-1.6) versus D: 0.7 (0.6-0.8) P < 0.001] and enzyme activity [ND: 180 (105-245) versus D: 29.9 (15.3-35.6) µmole·s(-1)·mole(-1) adenosine monophosphate, P < 0.001] was significantly lower in transplant recipients with diabetes. Similar results were observed in nontransplanted volunteers. Kinetic studies of MPA-mediated suppression of IMPDH activity in nontransplanted individuals revealed an approximately 2.5-fold lower half-maximum effective concentration (EC50) for diabetic as compared with nondiabetic [ND: 50.2 (49.8-50.7) versus D: 15.8 (15.6-16.3) nmole/L, P = 0.004] volunteers. This difference was not related to several IMPDH gene variants.

Conclusions: This study indicates a significantly lower IMPDH gene expression, protein level, and enzyme activity in diabetic patients. Further clinical studies in a larger number of patients are warranted to verify whether MPA dosing must be optimized for kidney transplant recipients with diabetes mellitus.
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http://dx.doi.org/10.1097/FTD.0b013e3182852697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109137PMC
June 2013

Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients.

Clin Pharmacokinet 2013 Sep;52(9):751-62

Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 02881, USA.

Background And Objective: Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus.

Subjects And Methods: A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes were determined. In addition, the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (-24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling.

Results: Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose-normalized trough concentration of tacrolimus by 2.3-fold (p < 0.001) and 1.5-fold (p = 0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7 × (age/50)(-0.78) × 2.03 (CYP3A5 expressers) × 1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus.

Conclusions: This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.
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http://dx.doi.org/10.1007/s40262-013-0069-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755037PMC
September 2013

Concentration of tacrolimus and major metabolites in kidney transplant recipients as a function of diabetes mellitus and cytochrome P450 3A gene polymorphism.

Xenobiotica 2013 Jul 2;43(7):641-9. Epub 2013 Jan 2.

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.

1. Disposition of tacrolimus and its major metabolites, 13-O-desmethyl tacrolimus and 15-O-desmethyl tacrolimus, was evaluated in stable kidney transplant recipients in relation to diabetes mellitus and genetic polymorphism of cytochrome P450 (CYP) 3A. 2. Steady-state concentration-time profiles were obtained for 12-hour or 2-hour post-dose, in 20 (11 with diabetes) and 32 (24 with diabetes) patients, respectively. In addition, single nucleotide polymorphisms of the following genes: CYP3A4 (CYP3A4: CYP3A4*1B, -392A > G), 3A5 (CYP3A5: CYP3A5*3, 6986A > G) and P-glycoprotein (ABCB1: 3435C > T) were characterized. 3. Dose-normalized concentrations of tacrolimus or metabolites were higher in diabetic patients. CYP3A4*1B carriers and CYP3A5 expressers, independently or when assessed as a combined CYP3A4-3A5 genotype, had significantly lower dose-normalized pre-dose (C0/dose) and 2-hour post-dose (C2/dose) concentrations of tacrolimus and metabolites. Non-diabetic patients with at least one CYP3A4*1B and CYP3A5*1 allele had lower C0/dose as compared to the rest of the population. 4. Genetic polymorphism of CYP3A5 or CYP3A4 influence tacrolimus or metabolites dose-normalized concentrations but not metabolite to parent concentration ratios. The effect of diabetes on tacrolimus metabolism is subject to debate and requires a larger sample size of genetically stratified subjects.
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http://dx.doi.org/10.3109/00498254.2012.752118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116556PMC
July 2013