Publications by authors named "Jennifer Trofe-Clark"

31 Publications

Use of Dietary Supplements in Living Kidney Donors: A Critical Review.

Am J Kidney Dis 2020 12 10;76(6):851-860. Epub 2020 Jul 10.

Renal-Electrolyte & Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Penn Medicine Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, PA. Electronic address:

Dietary supplement use is high among US adults, with the intention by users to promote overall health and wellness. Kidney donors, who are selected based on their overall good health and wellness, can have high utilization rates of dietary supplements. We provide a framework for the evaluation of living kidney donors and use of dietary supplements. In this review, dietary supplements will include any orally administered dietary or complementary nutritional products, but excluding micronutrients (vitamins and minerals), food, and cannabis. Use of dietary supplements can influence metabolic parameters that mask future risk for chronic illness such as diabetes and hypertension. Dietary supplements can also alter bleeding risk, anesthesia and analgesic efficacy, and safety in a perioperative period. Finally, postdonation monitoring of kidney function and risk for supplement-related nephrotoxicity should be part of a kidney donor educational process. For practitioners evaluating a potential kidney donor, we provide a list of the most commonly used herbal supplements and the effects on evaluation in a predonation, perioperative donation, and postoperative donation phase. Finally, we provide recommendations for best practices for integration into a comprehensive care plan for kidney donors during all stages of evaluation. We recommend avoidance of dietary supplements in a kidney donor population, although there is a paucity of data that identifies true harm. Rather, associations, known mechanisms of action, and common sense suggest that we avoid use in this population.
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http://dx.doi.org/10.1053/j.ajkd.2020.03.030DOI Listing
December 2020

Chronopharmacokinetics and Food Effects of Single-Dose LCP-Tacrolimus in Healthy Volunteers.

Ther Drug Monit 2020 10;42(5):679-685

Division of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, California.

Background: A modified-release version of tacrolimus, LCP-tacrolimus (LCPT; Envarsus XR, Veloxis Pharmaceuticals, Cary, NC), has been licensed in the United States for prophylaxis of organ rejection in de novo kidney transplant patients. As tacrolimus has a narrow therapeutic window, the impact of circadian patterns on LCPT drug exposure, including food and chronopharmacokinetic effects, needs to be elucidated to optimize dosing.

Methods: Two randomized, crossover, phase 1 studies were conducted in healthy volunteers. The first assessed the effect of morning versus evening dosing on the pharmacokinetic profile of LCPT 2 mg; the second assessed the effect of food on the pharmacokinetic profile of LCPT 5 mg. In both, blood samples were drawn from participants for up to 144 hours after administration of a single LCPT dose.

Results: No significant differences were observed between evening and morning dosing in peak blood concentration (4.4 versus 4.0 ng/mL; P = 0.27), area under the time-concentration curve (AUC) from time 0 to time of the last concentration (89.1 versus 102.6 ng/mL; P = 0.20), AUC from time 0 to infinity (99.7 versus 114.3 ng·h/mL; P = 0.18), AUC from 0 to 24 hours post-dose (AUC0-24; 49.4 versus 51.6 ng·h/mL; P = 0.56), time to reach maximum blood concentration (median, 6.0 versus 6.0 hours; P = 0.91), total clearance (arithmetic mean = 21.5 versus 19.5 L/h; P = 0.50), or terminal half-life (arithmetic mean = 26.8 versus 28.1 hours; P = 0.26). After a high-calorie meal in the morning, the AUC0-24 reduced by 54% (ratio of geometric means = 45.6%; P < 0.0001) and peak blood concentration reduced by 22% (ratio of geometric means = 78.4%; P = 0.0006). However, the terminal half-life did not differ between fasted and fed states (33.3 versus 34.8 hours; P = 0.16), implying that these differences occurred because of altered bioavailability rather than modified clearance.

Conclusions: For LCPT, no chronopharmacokinetic effects were observed, whereas food significantly reduced the 24-h exposure and the peak blood concentration.
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http://dx.doi.org/10.1097/FTD.0000000000000773DOI Listing
October 2020

Kidney transplantation and donation in the transgender population: A single-institution case series.

Am J Transplant 2020 10 27;20(10):2899-2904. Epub 2020 May 27.

Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The medical needs of the transgender population are increasingly recognized within the US health care system. Hormone therapy and gender-affirming surgery present distinct anatomic, hormonal, infectious, and psychosocial issues among transgender kidney transplant donors and recipients. We present the first reported experience with kidney transplantation and donation in transgender patients. A single-center case series (January 2014-December 2018) comprising 4 transgender kidney transplant recipients and 2 transgender living donors was constructed and analyzed. Experts in transplant surgery, transplant psychiatry, transplant infectious disease, pharmacy, and endocrinology were consulted to discuss aspects of care for these patients. Four transgender patients identified as male-to-female and 2 as female-to-male. Three of 6 had gender-affirming surgeries prior to transplant surgery, 1 of whom had further procedures posttransplant. Additionally, 4 patients were on hormone therapy. All 6 had psychiatric comorbidities. The 4 grafts have done well, with an average serum creatinine of 1.45 mg/dL at 2 years (range 1.01-1.85 mg/dL). However, patients encountered various postoperative complications, 1 of which was attributable to modified anatomy. Thus, transgender kidney transplant patients can present novel challenges in regard to surgical considerations as well as pre- and posttransplant care. Dedicated expertise is needed to optimize outcomes for this population.
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http://dx.doi.org/10.1111/ajt.15963DOI Listing
October 2020

Class and Kinetics of Weakly Reactive Pretransplant Donor-specific HLA Antibodies Predict Rejection in Kidney Transplant Recipients.

Transplant Direct 2019 Aug 25;5(8):e478. Epub 2019 Jul 25.

Department of Surgery, University of Pennsylvania, Philadelphia, PA.

Background: The clinical impact of weakly reactive pretransplant donor-specific antibody (DSA) in kidney transplantation is controversial. While some evidence suggests that weakly reactive DSA can lead to rejection, it is unclear which patients are at risk for rejection and whether posttransplant changes in weakly reactive DSA are clinically meaningful.

Methods: We retrospectively studied 80 kidney transplant recipients with weakly reactive pretransplant DSA between 2007 and 2014. We performed a multivariate Cox regression analysis to identify immunologic factors most associated with risk of biopsy-proven rejection.

Results: Biopsy-proven rejection occurred in 13 of 80 (16%) patients. The presence of both class I and II DSA before transplant (hazards ratio 17.4, < 0.01) and any posttransplant increase in DSA reactivity above a mean fluorescence intensity of 3000 (hazards ratio 7.8, < 0.01) were each significantly associated with an increased risk of rejection, which primarily occurred within the first 18 months.

Conclusions: Pretransplant DSA class and DSA kinetics after transplantation are useful prognostic indicators in patients with weak DSA reactivity. These results identify a small, high-risk patient group that warrants aggressive posttransplant DSA monitoring and may benefit from alternative donor selection.
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http://dx.doi.org/10.1097/TXD.0000000000000926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708635PMC
August 2019

Bariatric surgery before and after kidney transplantation: long-term weight loss and allograft outcomes.

Surg Obes Relat Dis 2019 Jun;15(6):935-941

Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Severe obesity is frequently a barrier to kidney transplantation, and kidney transplant recipients often have significant weight gain following transplantation.

Objectives: The goals of this study were to evaluate the long-term risks and benefits of bariatric surgery before and after kidney transplantation.

Setting: University Hospital, United States.

Methods: We performed a retrospective cohort study of 43 patients who had pretransplantation bariatric surgery and 21 patients who had posttransplantation bariatric surgery from 1994 to 2017 with propensity-score matching to identify matched controls using national registry data.

Results: Body mass index at the time of transplantation was similar in patients who underwent bariatric surgery before versus after transplantation (32 versus 34 kg/m, P = .172). There was no significant difference in body mass index in the 5 years after bariatric surgery among patients who underwent bariatric surgery before versus after kidney transplantation (36 versus 32 kg/m, P = 0.814). Compared with matched controls, bariatric surgery before (n = 38) and after (n = 18) kidney transplantation was associated with a decreased risk of allograft failure (hazard ratio .31 [95% confidence interval .29-0.33] and .85 [95% confidence interval .85-.86] for pre- and posttransplant, respectively) and mortality (hazard ratio .57 [95% confidence interval .53-.61] and .80 [95% confidence interval .79-.82] for pre- and posttransplant, respectively).

Conclusions: Bariatric surgery before and after kidney transplantation results in similar maintenance of weight loss and improved long-term allograft survival compared with matched controls. Bariatric surgery appears to be a safe and reasonable approach to weight loss both before and after transplantation.
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http://dx.doi.org/10.1016/j.soard.2019.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690384PMC
June 2019

Safety, Effectiveness, and Tolerability of Patiromer in Kidney Transplant Recipients.

Transplantation 2019 09;103(9):e281-e282

Renal, Electrolyte, Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1097/TP.0000000000002829DOI Listing
September 2019

Native kidney BK virus nephropathy, a systematic review.

Transpl Infect Dis 2019 Aug 11;21(4):e13083. Epub 2019 May 11.

Division of Nephrology, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: There is a growing base of literature describing BK nephropathy (BKVN) in patients outside of the setting of kidney transplant. Previous systematic reviews of the literature have been limited by methodology or by the scope of patients included.

Study Design And Methods: Systematic Review (Prospero # CRD42018088524).

Setting & Population: Patients without kidney transplant who had biopsy-proven BKVN.

Selection Criteria For Studies: Full-text articles that describe native BKVN patient cases.

Analytical Approach: Descriptive synthesis.

Results: The search identified 630 unique articles of which 51 were included in the final review. Sixty-five cases (including two new cases presented in this review) were identified, all but one occurred in the setting of known immunosuppression.

Limitations: The primary limitation was the exclusion of studies that did not fulfill the stringent review criteria. We excluded reports with only a clinical diagnosis of BKVN, such as those with viruria and/or viremia without biopsy.

Conclusions: As of May 2018, there are 65 reported cases of BKVN in native kidneys. This represents the most comprehensive description of biopsy-proven BKVN in native kidneys to date. Evaluation for BK nephropathy should be considered in immunocompromised patients who exhibit unexplained renal failure.
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http://dx.doi.org/10.1111/tid.13083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197190PMC
August 2019

Single-center, real-world experience with granulocyte colony-stimulating factor for management of leukopenia following kidney transplantation.

Clin Transplant 2019 06 11;33(6):e13541. Epub 2019 Apr 11.

Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Leukopenia is a frequent complication following kidney transplantation. Granulocyte colony-stimulating factor (G-CSF) has been used to accelerate white blood cell (WBC) count recovery; however, published experience in kidney transplantation is limited.

Methods: We retrospectively reviewed our kidney transplant recipients from January 2012 to September 2016 with a G-CSF order to evaluate leukopenia management (defined as WBC <3000 cells/μL).

Results: Thirty-six recipients were included. On average, G-CSF treatment began at 98 ± 38 days. At G-CSF initiation, mean WBC count was 1240 ± 420 cells/μL and absolute neutrophil count (ANC) was 653 ± 368 cells/μL. Mean G-CSF dose was 4.6 ± 1.2 mcg/kg/dose (total 11.8 ± 9.0 mcg/kg), 77.8% of recipients were prescribed G-CSF as outpatients, and overall, median time to WBC count recovery was 9 (IQR 4-14) days. Changes in immunosuppression and prophylaxis regimens for leukopenia were also common. Within 1 month following leukopenia onset, no patients experienced acute rejection and 5 (14%) developed infection requiring hospitalization or opportunistic infection.

Conclusion: In kidney recipients with leukopenia, G-CSF may be helpful to achieve WBC count recovery in addition to changes in immunosuppression and prophylaxis medications. Prospective, randomized data are still needed to determine optimal G-CSF dosing in this population.
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http://dx.doi.org/10.1111/ctr.13541DOI Listing
June 2019

BK Virus Nephropathy.

Clin J Am Soc Nephrol 2018 12 21;13(12):1893-1896. Epub 2018 Sep 21.

Department of Medicine, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.

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http://dx.doi.org/10.2215/CJN.04080318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302319PMC
December 2018

Twelve-Month Outcomes After Transplant of Hepatitis C-Infected Kidneys Into Uninfected Recipients: A Single-Group Trial.

Ann Intern Med 2018 09 7;169(5):273-281. Epub 2018 Aug 7.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.P.R., P.L.A., E.A.B., V.M.V., R.D.B., V.S.P., M.L., P.P., D.S., S.M.N., A.N., A.S., M.M., M.B., K.R.R., D.S.G.).

Background: Organs from hepatitis C virus (HCV)-infected deceased donors are often discarded. Preliminary data from 2 small trials, including THINKER-1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), suggested that HCV-infected kidneys could be safely transplanted into HCV-negative patients. However, intermediate-term data on quality of life and renal function are needed to counsel patients about risk.

Objective: To describe 12-month HCV treatment outcomes, estimated glomerular filtration rate (eGFR), and quality of life for the 10 kidney recipients in THINKER-1 and 6-month data on 10 additional recipients.

Design: Open-label, nonrandomized trial. (ClinicalTrials.gov: NCT02743897).

Setting: Single center.

Participants: 20 HCV-negative transplant candidates.

Intervention: Participants underwent transplant with kidneys infected with genotype 1 HCV and received elbasvir-grazoprevir on posttransplant day 3.

Measurements: The primary outcome was HCV cure. Exploratory outcomes included 1) RAND-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) quality-of-life scores at enrollment and after transplant, and 2) posttransplant renal function, which was compared in a 1:5 matched sample with recipients of HCV-negative kidneys.

Results: The mean age of THINKER participants was 56.3 years (SD, 6.7), 70% were male, and 40% were black. All 20 participants achieved HCV cure. Hepatic and renal complications were transient or were successfully managed. Mean PCS and MCS quality-of-life scores decreased at 4 weeks; PCS scores then increased above pretransplant values, whereas MCS scores returned to baseline values. Estimated GFRs were similar between THINKER participants and matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs. 66.2 mL/min/1.73 m2; 95% CI for between-group difference, -4.2 to 7.5 mL/min/1.73 m2) and 12 months (median, 72.8 vs. 67.2 mL/min/1.73 m2; CI for between-group difference, -7.2 to 9.8 mL/min/1.73 m2).

Limitation: Small trial.

Conclusion: Twenty HCV-negative recipients of HCV-infected kidneys experienced HCV cure, good quality of life, and excellent renal function. Kidneys from HCV-infected donors may be a valuable transplant resource.

Primary Funding Source: Merck.
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http://dx.doi.org/10.7326/M18-0749DOI Listing
September 2018

Safety and Feasibility of Outpatient Rabbit Antithymocyte Globulin Induction Therapy Administration in Kidney Transplant Recipients.

Pharmacotherapy 2018 06;38(6):620-627

Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Kidney transplant induction therapy often includes inpatient administration of rabbit antithymocyte globulin (rATG) over multiple days. To reduce hospital length of stay (LOS) and drug expenditures, the rATG induction course was completed in the outpatient setting via peripheral intravenous administration. The present study assesses early readmission trends ascribable to an outpatient rATG administration protocol to ensure initial reduction in hospital LOS is sustained early after discharge.

Methods: This was a retrospective study of kidney recipient outcomes for patients transplanted between January 1, 2008, and February 29, 2016, immediately following implementation of an outpatient rATG protocol. Readmission data within 7 days of outpatient rATG administration were collected. The relatedness of rATG administration to an adverse drug reaction resulting in readmission was determined by the World Health Organization-Uppsala Monitoring Centre Causality Assessment Scale and the Naranjo Adverse Drug Reaction Probability Scale.

Results: A total of 1104 patients received outpatient doses of rATG and were included. An upward trend in kidney transplant volume and outpatient rATG administrations per year was found from 2008-2015. Following protocol implementation, the percentage of overall readmissions ranged from 9% to just over 12% from 2008-2014 and remained less than 10% for 2014 through 2016. The percentage of outpatient rATG infusions that potentially led to rATG-related readmissions was less than 4% per year over the study period. A total of 1124 hospital days were saved, 125 days per year on average.

Conclusions: Outpatient administration of rATG is feasible, safe, and did not increase readmissions in the period directly following administration. The findings of this analysis support our continued use of the outpatient rATG protocol at our institution.
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http://dx.doi.org/10.1002/phar.2116DOI Listing
June 2018

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients.

Am J Kidney Dis 2018 03 20;71(3):315-326. Epub 2017 Nov 20.

Renal Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

Background: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile.

Study Design: Randomized prospective crossover study.

Setting & Participants: 50 African American maintenance kidney recipients on stable IR-Tac dosing.

Intervention: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose.

Outcomes: Tacrolimus 24-hour AUC (AUC), peak and trough concentrations (C and C), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype.

Measurements: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles.

Results: ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC or C between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus C was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4).

Limitations: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes.

Conclusions: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT.

Trial Registration: Registered at ClinicalTrials.gov, with study number NCT01962922.
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http://dx.doi.org/10.1053/j.ajkd.2017.07.018DOI Listing
March 2018

Barriers to vaccination in renal transplant recipients.

Transpl Infect Dis 2017 Oct 4;19(5). Epub 2017 Sep 4.

Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Vaccine-preventable diseases remain at the forefront of challenges in the long-term care of renal transplant recipients (RTR). Although global vaccination campaigns targeting patients with end-stage renal disease or RTR are standard, rates of vaccination among renal transplant candidates and RTRs remain suboptimal. We highlight the multifactorial barriers leading to low vaccination rates in this vulnerable population.
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http://dx.doi.org/10.1111/tid.12749DOI Listing
October 2017

Comparing Outcomes between Antibody Induction Therapies in Kidney Transplantation.

J Am Soc Nephrol 2017 Jul 20;28(7):2188-2200. Epub 2017 Mar 20.

Renal Electrolyte and Hypertension Division, Department of Medicine, and

Kidney transplant recipients often receive antibody induction. Previous studies of induction therapy were often limited by short follow-up and/or absence of information about complications. After linking Organ Procurement and Transplantation Network data with Medicare claims, we compared outcomes between three induction therapies for kidney recipients. Using novel matching techniques developed on the basis of 15 clinical and demographic characteristics, we generated 1:1 pairs of alemtuzumab-rabbit antithymocyte globulin (rATG) (5330 pairs) and basiliximab-rATG (9378 pairs) recipients. We used paired Cox regression to analyze the primary outcomes of death and death or allograft failure. Secondary outcomes included death or sepsis, death or lymphoma, death or melanoma, and healthcare resource utilization within 1 year. Compared with rATG recipients, alemtuzumab recipients had higher risk of death (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 1.03 to 1.26; <0.01) and death or allograft failure (HR, 1.18; 95% CI, 1.09 to 1.28; <0.001). Results for death as well as death or allograft failure were generally consistent among elderly and nonelderly subgroups and among pairs receiving oral prednisone. Compared with rATG recipients, basiliximab recipients had higher risk of death (HR, 1.08; 95% CI, 1.01 to 1.16; =0.03) and death or lymphoma (HR, 1.12; 95% CI, 1.01 to 1.23; =0.03), although these differences were not confirmed in subgroup analyses. One-year resource utilization was slightly lower among alemtuzumab recipients than among rATG recipients, but did not differ between basiliximab and rATG recipients. This observational evidence indicates that, compared with alemtuzumab and basiliximab, rATG associates with lower risk of adverse outcomes, including mortality.
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http://dx.doi.org/10.1681/ASN.2016070768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491281PMC
July 2017

Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue.

J Clin Invest 2017 Apr 20;127(4):1375-1391. Epub 2017 Mar 20.

In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have tested this hypothesis in a human-into-mouse xenogeneic islet transplant model and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody-conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue.
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http://dx.doi.org/10.1172/JCI87993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373894PMC
April 2017

Histopathologic changes in anti-angiotensin II type 1 receptor antibody-positive kidney transplant recipients with acute rejection and no donor specific HLA antibodies.

Hum Immunol 2017 Apr 8;78(4):350-356. Epub 2017 Mar 8.

Clinical Immunology and Histocompatibility Laboratory, Perelman School of Medicine, Philadelphia, PA, United States.

Objective: To determine the association of antibodies against angiotensin II type 1 receptor (AT1R Ab) and histopathologic changes seen in patients with kidney allograft rejection and negative donor specific HLA antibodies (DSA).

Methods: Stored sera from 27 patients who had biopsy-proven rejection in the absence of DSA were tested for AT1R Ab. Biopsy slides of all patients were re-examined and classified according to Banff 2013 criteria. Histopathologic changes were compared between AT1R positive and negative patients.

Results: 75% of patients with positive pre-transplant AT1R Ab had antibody mediated rejection (AMR) compared to 37% of AT1R Ab-negative patients. A trend towards increased interstitial inflammation was observed in the AT1R Ab positive group (p=0.08). More patients in the AT1R Ab positive group had microcirculation inflammation (88% vs 58% with glomerulitis scores ≥1; 75% vs 58% with peritubular capillaritis scores ≥1).

Conclusion: In kidney transplant recipients with rejection and no DSA, a higher incidence of AMR and worse inflammation scores are observed in the presence of positive pre-transplant AT1R antibodies.
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http://dx.doi.org/10.1016/j.humimm.2017.03.004DOI Listing
April 2017

Automated Reminders and Physician Notification to Promote Immunosuppression Adherence Among Kidney Transplant Recipients: A Randomized Trial.

Am J Kidney Dis 2017 Mar 7;69(3):400-409. Epub 2016 Dec 7.

Leonard Davis Institute Center for Health Incentives and Behavioral Economics, University of Pennsylvania, Philadelphia, PA; Department of Medicine and Medical Ethics and Health Policy, Perelman School of Medicine, Philadelphia, PA; Department of Health Care Management, Wharton School, University of Pennsylvania, Philadelphia, PA; Center for Health Equity Research and Promotion, Cresencz Philadelphia Veterans Affairs Medical Center, Philadelphia, PA.

Background: Immunosuppression nonadherence increases the risk for kidney transplant loss after transplantation. Wireless-enabled pill bottles have created the opportunity to monitor medication adherence in real time. Reminders may help patients with poor memory or organization. Provision of adherence data to providers may motivate patients to improve adherence and help providers identify adherence barriers.

Study Design: Randomized controlled trial.

Setting & Participants: Kidney transplant recipients (n=120) at a single center.

Intervention: Participants were provided wireless pill bottles to store tacrolimus and record bottle openings. Participants were randomly assigned 1:1:1 to adherence monitoring with customized reminders (including alarms, texts, telephone calls, and/or e-mails), monitoring with customized reminders plus provider notification (every 2 weeks, providers received notification if adherence decreased to <90% during that period), or wireless pill bottle use alone (control).

Outcomes: The main outcome was bottle-measured tacrolimus adherence during the last 90 days of the 180-day trial. A secondary outcome was tacrolimus whole-blood concentrations at routine clinical visits.

Measurements: Adherence for the primary outcome was assessed via wireless pill bottle openings.

Results: Mean participant age was 50 years; 60% were men, and 40% were black. Mean adherence was 78%, 88%, and 55% in the reminders, reminders-plus-notification, and control arms (P<0.001 for comparison of each intervention to control). Mean tacrolimus levels were not significantly different between groups.

Limitations: The study did not assess clinical end points. Participants and study coordinators were not blinded to intervention arm.

Conclusions: Provider notification and customized reminders appear promising in helping patients achieve better medication adherence, but these strategies require evaluation in trials powered to detect differences in clinical outcomes.
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http://dx.doi.org/10.1053/j.ajkd.2016.10.017DOI Listing
March 2017

BK and Other Polyomaviruses in Kidney Transplantation.

Semin Nephrol 2016 09;36(5):372-385

Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

For more than 40 years, polyomaviruses (BK virus and JC virus) have been known to cause disease in human beings. Recently, 11 new polyomaviruses were discovered. However, the majority of these viruses are rare in renal transplant recipients and BK and JC viruses remain the most important polyomaviruses to impact this population. BK virus presents as BK virus nephropathy and has, in rare instances, been associated with hemorrhagic cystitis or ureteral strictures. JC virus can cause progressive multifocal leukoencephalopathy or nephropathy in this population as well, but is uncommon. Antiviral prophylactic and therapeutic interventions for these diseases are lacking to date, although reduction of immunosuppression has been associated with success in treating both BK virus nephropathy and JC virus-induced disease. Risk factors are not well defined and vary across studies. However, the cumulative degree of immunosuppression is regarded universally as an important contributor to BK virus replication. For these reasons, it is recommended to screen all renal transplant recipients prospectively for BK virus infection. Multicenter trials using standardized BK and JC virus screening methods are necessary to define risk factors better, and to determine the effect of prophylaxis and treatments for these polyomaviruses affecting renal transplant recipients.
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http://dx.doi.org/10.1016/j.semnephrol.2016.05.014DOI Listing
September 2016

Systematic Review of Calcineurin Inhibitor Monitoring and Dosing Strategies in Renal Transplantation: Notice of a New Report Funded by the Agency for Healthcare Research and Quality.

Clin Chem 2016 06;62(6):900-1

Department of Medicine and Center for Evidence-based Practice, University of Pennsylvania Health System, Philadelphia, PA; Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;

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http://dx.doi.org/10.1373/clinchem.2016.256479DOI Listing
June 2016

Nonadherence to therapy after adult solid organ transplantation: A focus on risks and mitigation strategies.

Am J Health Syst Pharm 2016 Jun 17;73(12):909-20. Epub 2016 May 17.

Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, PARenal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.2146/ajhp150650DOI Listing
June 2016

Assessing pharmacologic and nonpharmacologic risks in candidates for kidney transplantation.

Am J Health Syst Pharm 2015 May;72(10):781-93

Angela Q. Maldonado, Pharm.D., BCPS, CPP, is Clinical Pharmacy Specialist, Department of Transplant Surgery, Vidant Medical Center, Greenville, NC. Eric M. Tichy, Pharm.D., FCCP, BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, Yale-New Haven Hospital, New Haven, CT. Christin C. Rogers, Pharm.D., FCCP, BCPS, is Clinical Pharmacy Coordinator, Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA. MayaCampara, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, University of Illinois at Chicago. ChristopherEnsor, Pharm.D., BCPS, is Clinical Pharmacy Specialist, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. ChristinaT. Doligalski, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, Tampa General Hospital, Tampa, FL. Steven Gabardi, Pharm.D., FCCP, BCPS, is Clinical Pharmacy Specialist, Departments of Transplant Surgery and Pharmacy and Renal Division, Brigham and Women's Hospital, Boston, MA. JillianL. Descourouez, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison. Ian C. Doyle, Pharm.D., BCPS, is Assistant Professor, School of Pharmacy, Pacific University, Hillsboro, OR. JenniferTrofe-Clark, Pharm.D., FCCP, BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, and Adjunct Associate Professor, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania.

Purpose: Pharmacotherapy concerns and other factors with a bearing on patient selection for kidney transplantation are discussed.

Summary: The process of selecting appropriate candidates for kidney transplantation involves multidisciplinary assessment to evaluate a patient's mental, social, physical, financial, and medical readiness for successful surgery and good posttransplantation outcomes. Transplantation pharmacists can play important roles in the recognition and stratification of pharmacologic and nonpharmacologic risks in prospective kidney transplant recipients and the identification of issues that require a mitigation strategy. Key pharmacotherapy-related issues and considerations during the risk assessment process include (1) anticoagulation concerns, (2) cytochrome P-450 isoenzyme-mediated drug interactions, (3) mental health-related medication use, (4) chronic pain-related medication use, (5) medication allergies, (6) use of hormonal contraception and replacement therapy, (7) prior or current use of immunosuppressants, (8) issues with drug absorption, (9) alcohol use, (10) tobacco use, (11) active use of illicit substances, and (12) use of herbal supplements. Important areas of nonpharmacologic risk include vaccine delivery, infection prophylaxis and treatment, and socially related factors such as nonadherent behavior, communication barriers, and financial, insurance, or transportation challenges that can compromise posttransplantation outcomes.

Conclusion: Consensus opinions of practitioners in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented.
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http://dx.doi.org/10.2146/ajhp140476DOI Listing
May 2015

Value of solid organ transplant-trained pharmacists in transplant infectious diseases.

Curr Infect Dis Rep 2015 Apr;17(4):475

Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA, 19104, USA,

Advances in organ transplantation have led to improved graft and patient survival. Transplant pharmacist's education and training uniquely position them to contribute knowledge and skills to the management of these highly complex patients. In 2004, the United Network for Organ Sharing bylaws added requirements that all transplant programs identify one or more pharmacists with experience in transplant pharmacotherapy to be responsible for providing pharmaceutical care to solid organ transplant recipients. These bylaws also delineated the transplant pharmacist's roles and responsibilities. To further support these efforts, in 2007 the Centers for Medicare and Medicaid Services accreditation standards for transplant centers also mandated that a center have a designated, qualified expert in transplant pharmacology as a multidisciplinary team member. The transplant pharmacist is a consistent member of the transplant team that can add value to the multidisciplinary approach of prevention and treatment of transplant infectious diseases through all phases of transplant care.
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http://dx.doi.org/10.1007/s11908-015-0475-8DOI Listing
April 2015

BKV Viremia and Development of De Novo DSA in Renal Transplant Recipients.

Clin Transpl 2015 ;31:249-256

Department of Medicine, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

BK virus (BKV) viremia is a common complication of kidney transplantation. In 2008, we enacted a screening protocol to detect BKV infection at our institution. The cumulative incidence of BKV viremia at our center is 24%, with most cases being detected in the first year post-transplant. We have previously identified the development of de novo donor specific antibody as a consequence of BKV infection treated with immunosuppression reduction; in this report, we confirm our prior findings and extend them to include an association of both Class I and Class II antibodies with BKV viremia. While with a median time of 4 years follow up there was no difference in patient or allograft survival on the basis of BKV viremia. Identification of treatment strategies for BKV that will prevent complications such as donor specific antibodies should be a research priority in this area.
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January 2015

Persistent BK viremia does not increase intermediate-term graft loss but is associated with de novo donor-specific antibodies.

J Am Soc Nephrol 2015 Apr 25;26(4):966-75. Epub 2014 Sep 25.

Department of Medicine, Renal Electrolyte and Hypertension Division.

There are limited data regarding intermediate-term outcomes in patients with persistent BK viremia. Other viral infections have been implicated in the development of allosensitization through heterologous immunity, but the relationship between BK viremia and donor-specific antibodies (DSAs) is unexplored. In 2008, we initiated routine post-transplant BK viremia and DSA screening at our center; 785 kidney or kidney-pancreas transplant recipients were included in our study. Of these recipients, 132 (17%) recipients developed BK viremia during the study period. The median duration of BK viremia was 140 days (interquartile range=40-393 days), and persistent BK viremia was defined as lasting ≥140 days. Kaplan-Meier curves were generated to assess differences in patient and allograft survival on the basis of BK viremia status; survival was modeled using Cox proportional hazard regression. After a median follow-up of 3 years, there was no significant difference in terms of patient (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.28 to 2.49) or allograft survival (HR, 0.80; 95% CI, 0.37 to 1.73) between patients with and without BK viremia, which was confirmed in a time-varying analysis. In our logistic regression model, persistent BK viremia was strongly associated with the development of class II (HR, 2.55; 95% CI, 1.30 to 4.98) but not class I (HR, 1.13; 95% CI, 0.46 to 2.77) DSAs. These data suggest that persistent BK viremia does not negatively affect intermediate-term patient or allograft survival but is associated with increased risk for de novo DSA, although the exact mechanism is unclear.
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http://dx.doi.org/10.1681/ASN.2014010119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378106PMC
April 2015

Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review.

AIDS Patient Care STDS 2012 Oct;26(10):568-81

Department of Clinical Pharmacy, University Medical Center Utrecht, The Netherlands.

Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.
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http://dx.doi.org/10.1089/apc.2012.0169DOI Listing
October 2012

Efficacy and safety of extended-duration inpatient-to-outpatient rabbit antithymocyte globulin induction in de novo kidney transplant recipients: 6-month outcomes.

Transplantation 2012 Sep;94(5):506-12

Department of Pharmacy Services, Hospital of University of Pennsylvania, Philadelphia, PA 19104-4322, USA.

Background: In an effort to reduce length of stay (LOS) in kidney transplant recipients otherwise ready for discharge, we developed a protocol to extend rabbit antithymocyte globulin (rATG) induction therapy into the outpatient setting through peripheral dose administration.

Methods: A retrospective review of outpatient rATG group (n=185) that received the first two rATG doses inpatient and subsequent doses outpatient was used, compared with concurrently transplanted patients who received all doses of rATG as an inpatient (n=99).

Results: The outpatient group received more rATG (cumulative mg/kg induction) than the inpatient-only group (median [range], 4.8 mg/kg [3.2-10.0] vs. 4.4 mg/kg [2.8-8.6]; P<0.01). Outpatient usage avoided 246 hospital days that would have been required had rATG been administered in the inpatient setting. The incidences of perioperative leukopenia and thrombocytopenia were lower in the outpatient rATG group versus inpatient-only group (5% vs. 21%, P<0.01, and 2% vs. 9%, P<0.01, respectively) but were similar by 3 months. The outpatient rATG group experienced shorter hospitalization LOS compared with the inpatient-only group (median LOS [range], 4 [2-11] vs. 5 [3-20] days; P<0.01) and lower 30-day readmission rates (30% vs. 42%, P=0.03). At 6 months, there were no differences in incidences of biopsy-proven rejection episodes.

Conclusions: When implemented selectively among less complicated kidney transplant recipients, delayed extension of rATG into the outpatient setting was associated with LOS reduction and attendant cost saving without either increasing readmission rate or compromising short-term safety and efficacy.
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http://dx.doi.org/10.1097/TP.0b013e31825c58c0DOI Listing
September 2012

Generic maintenance immunosuppression in solid organ transplant recipients.

Pharmacotherapy 2011 Nov;31(11):1111-29

Comprehensive Transplant Center, The Johns Hopkins Hospital, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.

Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immunosuppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.
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http://dx.doi.org/10.1592/phco.31.11.1111DOI Listing
November 2011