Publications by authors named "Roy D Bloom"

97 Publications

Survey of Clinician Opinions on Kidney Transplantation from Hepatitis C Virus Positive Donors: Identifying and Overcoming Barriers.

Kidney360 2020 Nov 25;1(11):1291-1299. Epub 2020 Nov 25.

University of Iowa, Iowa City, IA.

Background: Transplant practices related to use of organs from Hepatitis C virus infected donors (DHCV+) is evolving rapidly.

Methods: We surveyed U.S. kidney transplant programs by email and professional society listserv postings between 7/19-1/20 to assess attitudes, management strategies, and barriers related to use of viremic (nucleic acid testing (NAT)+) donor organs in HCV uninfected recipients.

Results: Staff at 112 unique programs responded, representing 54% of U.S. adult kidney transplant programs and 69% of adult deceased donor kidney transplant volume in 2019. Most survey respondents were transplant nephrologists (46%) or surgeons (43%). Among responding programs, 67% currently transplant DHCV antibody+/NAT- organs under a clinical protocol or as standard of care. By comparison, only 58% offer DHCV NAT+ kidney transplant to HCV- recipients, including 35% under clinical protocols, 14% as standard of care, and 9% under research protocols. Following transplant of DHCV NAT+ organs to uninfected recipients, 53% start direct acting antiviral agent (DAA) therapy after discharge and documented viremia. Viral monitoring protocols after DHCV NAT+ to HCV uninfected recipient kidney transplantation varied substantially. 56% of programs performing these transplants report having an institutional plan to provide DAA treatment if declined by the recipient's insurance. Respondents felt a mean decrease in waiting time of ≥18 months (range 0-60) justifies the practice. Program concerns related to use of DHCV NAT+ kidneys include insurance coverage concerns (72%), cost (60%), and perceived risk of transmitting resistant infection (44%).

Conclusions: Addressing knowledge about safety and logistical/financial barriers related to use of DHCV NAT+ kidney transplantation for HCV uninfected recipients may help reduced discards and expand the organ supply.
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http://dx.doi.org/10.34067/KID.0004592020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695231PMC
November 2020

Financial Evaluation of Kidney Transplant With Hepatitis C Viremic Donors to Uninfected Recipients.

Transplant Direct 2020 Dec 10;6(12):e627. Epub 2020 Nov 10.

Department of Medicine, Saint Louis University, St. Louis, MO.

Kidney transplantation with hepatitis C viremic (dHCV+) donors appears safe for recipients without HCV when accompanied by direct acting antiviral (DAA) treatment. However, US programs have been reluctant to embrace this approach due to concern about insurance coverage. While the cost of DAA treatment is currently offset by the reduction in waiting time, increased competition for dHCV+ organs may reduce this advantage. This analysis sought to demonstrate the financial benefit of dHCV+ transplant for third-party health insurers to expand coverage availability.

Methods: An economic analysis was developed using a Markov model for 2 decisions: first, to accept a dHCV+ organ versus wait for a dHCV uninfected organ; or second, accept a high kidney donor profile index (KDPI) (>85) organ versus wait for a better quality dHCV+ organ. The analysis used Medicare payments, historical survival data, cost report data, and an estimated cost of DAA of $29 874.

Results: In the first analysis, using dHCV+ kidneys reduced the cost of end-stage kidney disease care if the wait for a dHCV uninfected organ exceeded 11.5 months. The financial breakeven point differed according to the cost of DAA treatment. In the second analysis, declining a high-KDPI organ in favor of a waiting dHCV+ organ was marginally clinically beneficial if waiting times were <12 months but not cost effective.

Conclusions: dHCV+ transplant appears to be economically and clinically advantageous compared with waiting for dHCV-uninfected transplant but should not replace high-KDPI transplant when appropriate. Despite the high cost of DAA therapy, health insurers benefit financially from dHCV+ transplant within 1 year.
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http://dx.doi.org/10.1097/TXD.0000000000001056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665247PMC
December 2020

In Reply to 'Response to the KDOQI US Commentary on the 2018 KDIGO Hepatitis C Guideline'.

Am J Kidney Dis 2021 01 3;77(1):152-153. Epub 2020 Sep 3.

Katz Family Division of Nephrology and Hypertension, University of Miami Miller School of Medicine and the Miami Transplant Institute, Miami, FL.

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http://dx.doi.org/10.1053/j.ajkd.2020.08.001DOI Listing
January 2021

KDOQI US Commentary on the 2018 KDIGO Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C.

Am J Kidney Dis 2020 05 9;75(5):665-683. Epub 2020 Apr 9.

Keck School of Medicine, University of Southern California, Los Angeles, CA.

The first KDIGO (Kidney Disease: Improving Global Outcomes) guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection was published in 2008. The ensuing decade bore witness to remarkable advances in the treatment of HCV infection following the approval of direct-acting antiviral (DAA) agents that deliver cure rates routinely >95%. In this context, the KDIGO organization correctly recognized the need for an updated HCV guideline that would be relevant to the treatment of HCV-infected patients with kidney disease in the DAA era. The current NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) commentary provides an in-depth review and perspective on the 2018 KDIGO guideline. Of note, the KDIGO work group made significant updates to guideline chapters 2 and 4 as a direct result of the availability of DAAs. The intent of this commentary is to provide useful interpretation for nephrologists and other practitioners caring for HCV-infected patients with chronic kidney disease, including dialysis patients and kidney transplant recipients. The availability of DAA agents that are safe and highly effective has created new opportunities, such as the transplantation of kidneys from HCV-infected kidney donors. The ability to treat HCV infection in patients with kidney disease will have a significant impact on the care of our patients and should favorably influence long-term outcomes as well.
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http://dx.doi.org/10.1053/j.ajkd.2019.12.016DOI Listing
May 2020

Phenome-wide association analysis suggests the APOL1 linked disease spectrum primarily drives kidney-specific pathways.

Kidney Int 2020 05 17;97(5):1032-1041. Epub 2020 Feb 17.

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

The relationship between commonly occurring genetic variants (G1 and G2) in the APOL1 gene in African Americans and different disease traits, such as kidney disease, cardiovascular disease, and pre-eclampsia, remains the subject of controversy. Here we took a genotype-first approach, a phenome-wide association study, to define the spectrum of phenotypes associated with APOL1 high-risk variants in 1,837 African American participants of Penn Medicine Biobank and 4,742 African American participants of Vanderbilt BioVU. In the Penn Medicine Biobank, outpatient creatinine measurement-based estimated glomerular filtration rate and multivariable regression models were used to evaluate the association between high-risk APOL1 status and renal outcomes. In meta-analysis of both cohorts, the strongest phenome-wide association study associations were for the high-risk APOL1 variants and diagnoses codes were highly significant for "kidney dialysis" (odds ratio 3.75) and "end stage kidney disease" (odds ratio 3.42). A number of phenotypes were associated with APOL1 high-risk genotypes in an analysis adjusted only for demographic variables. However, no associations were detected with non-renal phenotypes after controlling for chronic/end stage kidney disease status. Using calculated estimated glomerular filtration rate -based phenotype analysis in the Penn Medicine Biobank, APOL1 high-risk status was associated with prevalent chronic/end stage kidney disease /kidney transplant (odds ratio 2.27, 95% confidence interval 1.67-3.08). In high-risk participants, the estimated glomerular filtration rate was 15.4 mL/min/1.73m; significantly lower than in low-risk participants. Thus, although APOL1 high-risk variants are associated with a range of phenotypes, the risks for other associated phenotypes appear much lower and in our dataset are driven by a primary effect on renal disease.
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http://dx.doi.org/10.1016/j.kint.2020.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265573PMC
May 2020

Medical Therapies to Reduce Delayed Graft Function and Improve Long-Term Graft Survival: Are We Making Progress?

Clin J Am Soc Nephrol 2020 01 16;15(1):13-15. Epub 2019 Dec 16.

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

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http://dx.doi.org/10.2215/CJN.13961119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946075PMC
January 2020

Liver and Kidney Recipient Selection of Hepatitis C Virus Viremic Donors: Meeting Consensus Report From the 2019 Controversies in Transplantation.

Transplantation 2020 03;104(3):476-481

Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO.

The development of multiple highly effective and safe direct-acting antivirals to treat hepatitis C virus (HCV) has resulted in greater ease and confidence in managing HCV infection in transplant recipients that in turn has impacted the solid organ transplant community as well. In the United States, the opioid epidemic has increased the number of overdose deaths with a concomitant increase in younger HCV viremic donors after brain death being identified. At the same time, a decrease in HCV viremic transplant candidates has led to a growing interest in exploring the use of HCV viremic liver and kidney donor allografts in HCV-negative recipients. To date, experience with the use of HCV viremic liver and kidney allografts in HCV-negative recipients is limited to a few small prospective research trials, case series, and case reports. There are also limited data on recipient and donor selection for HCV viremic liver and kidney allografts. In response to this rapidly changing landscape in the United States, experts in the field of viral hepatitis and liver and kidney transplantation convened a meeting to review current data on liver and kidney recipient selection and developed consensus opinions related specifically to recipient and donor selection of HCV viremic liver and kidney allografts.
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http://dx.doi.org/10.1097/TP.0000000000003014DOI Listing
March 2020

National Trends in Utilization and 1-Year Outcomes with Transplantation of HCV-Viremic Kidneys.

J Am Soc Nephrol 2019 10 12;30(10):1939-1951. Epub 2019 Sep 12.

Renal-Electrolyte and Hypertension Division, Department of Medicine,

Background: Recent pilot trials have demonstrated the safety of transplanting HCV-viremic kidneys into HCV-seronegative recipients. However, it remains unclear if allograft function is impacted by donor HCV-viremia or recipient HCV-serostatus.

Methods: We used national United States registry data to examine trends in HCV-viremic kidney use between 4/1/2015 and 3/31/2019. We applied advanced matching methods to compare eGFR for similar kidneys transplanted into highly similar recipients of kidney transplants.

Results: Over time, HCV-seronegative recipients received a rising proportion of HCV-viremic kidneys. During the first quarter of 2019, 200 HCV-viremic kidneys were transplanted into HCV-seronegative recipients, versus 69 into HCV-seropositive recipients, while 105 HCV-viremic kidneys were discarded. The probability of HCV-viremic kidney discard has declined over time. Kidney transplant candidates willing to accept a HCV-seropositive kidney increased from 2936 to 16,809 from during this time period. When transplanted into HCV-seronegative recipients, HCV-viremic kidneys matched to HCV-non-viremic kidneys on predictors of organ quality, except HCV, had similar 1-year eGFR (66.3 versus 67.1 ml/min per 1.73 m, =0.86). This was despite the much worse kidney donor profile index scores assigned to the HCV-viremic kidneys. Recipient HCV-serostatus was not associated with a clinically meaningful difference in 1-year eGFR (66.5 versus 71.1 ml/min per 1.73 m, =0.056) after transplantation of HCV-viremic kidneys.

Conclusions: By 2019, HCV-seronegative patients received the majority of kidneys transplanted from HCV-viremic donors. Widely used organ quality scores underestimated the quality of HCV-viremic kidneys based on 1-year allograft function. Recipient HCV-serostatus was also not associated with worse short-term allograft function using HCV-viremic kidneys.
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http://dx.doi.org/10.1681/ASN.2019050462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779360PMC
October 2019

Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials.

Am J Transplant 2020 02 8;20(2):564-572. Epub 2019 Oct 8.

Nephrology Division, Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.

Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.
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http://dx.doi.org/10.1111/ajt.15580DOI Listing
February 2020

The effect of transfer to adult transplant care on kidney function and immunosuppressant drug level variability in pediatric kidney transplant recipients.

Pediatr Transplant 2019 09 17;23(6):e13527. Epub 2019 Jun 17.

Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, Pennsylvania.

Adolescent age at time of transplant has been recognized as a risk factor for renal allograft loss. Increased risk for graft failure may persist from adolescence to young adulthood. Transfer of care is hypothesized as a risk factor for non-adherence and graft loss. We explored whether kidney allograft function declined at an accelerated rate after transfer of care to adult transplant centers and whether coefficient of variation of tacrolimus (CV TAC) trough levels predicted allograft loss. Single-center, retrospective chart review was performed for pediatric kidney transplant recipients who received transplants between 1999 and 2011. Change in eGFR pre- and post-transfer was performed via a linear mixed-effects model. CV TAC was calculated in transplant recipients with TAC data pre- and post-transfer. t test was performed to determine the difference between means of CV TAC in subjects with and without allograft loss following transfer of care. Of the 138 subjects who transferred to adult care, 47 subjects with data pre- and post-transfer demonstrated a decrease in the rate of eGFR decline post-transfer from 8.0 mL/min/1.73 m per year to 2.1 mL/min/1.73 m per year, an ~80% decrease in eGFR decline post-transfer (P = 0.01). Twenty-four subjects had CV TAC data pre- and post-transfer of care. Pretransfer CV TAC for subjects with allograft loss post-transfer was significantly higher than in subjects without allograft loss (49% vs 26%, P < 0.05). Transfer of care was not independently associated with acceleration in eGFR decline. CV TAC may aid in identifying patients at risk for allograft loss post-transfer.
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http://dx.doi.org/10.1111/petr.13527DOI Listing
September 2019

Early emergence of anti-HCV antibody implicates donor origin in recipients of an HCV-infected organ.

Am J Transplant 2019 09 28;19(9):2525-2532. Epub 2019 May 28.

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Hepatitis C virus (HCV) seroconversion among HCV-uninfected transplant recipients from HCV-infected (NAT+/Antibody+) or HCV-exposed (NAT-/Antibody+) donors has been reported. However, the origin of anti-HCV antibody and the implications of seroconversion remain unknown. We longitudinally tested plasma from HCV-uninfected kidney (n = 31) or heart transplant recipients (n = 9) of an HCV NAT+ organ for anti-HCV antibody (both IgG and IgM isotypes). Almost half of all participants had detectable anti-HCV antibody at any point during follow-up. The majority of antibody-positive individuals became positive within 1-3 days of transplantation, and 6 recipients had detectable antibody on the first day posttransplant. Notably, all anti-HCV antibody was IgG, even in samples collected posttransplant day 1. Late seroconversion was uncommon (≈20%-25% of antibody+ recipients). Early antibody persisted over 30 days in kidney recipients, whereas early antibody dropped below detection in 50% of heart recipients within 2 weeks after transplant. Anti-HCV antibody is common in HCV-uninfected recipients of an HCV NAT+ organ. The IgG isotype of this antibody and the kinetics of its appearance and durability suggest that anti-HCV antibody is donor derived and is likely produced by a cellular source. Our data suggest that transfer of donor humoral immunity to a recipient may be much more common than previously appreciated.
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http://dx.doi.org/10.1111/ajt.15415DOI Listing
September 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

Using (cell-free) DNA to incriminate rejection as the cause of kidney allograft dysfunction: Do we have a verdict?

Authors:
Roy D Bloom

Am J Transplant 2019 06 26;19(6):1609-1610. Epub 2019 Mar 26.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1111/ajt.15338DOI Listing
June 2019

Introduction to hepatitis C virus infection in patients with kidney disease: A roadmap for nephrologists.

Semin Dial 2019 03;32(2):91-92

Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

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http://dx.doi.org/10.1111/sdi.12775DOI Listing
March 2019

Characterization of early hepatic injury in HCV-negative recipients of HCV-infected kidneys.

Clin Transplant 2019 04 6;33(4):e13494. Epub 2019 Mar 6.

Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1111/ctr.13494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503837PMC
April 2019

Transplanting hepatitis C virus-infected hearts into uninfected recipients: A single-arm trial.

Am J Transplant 2019 09 20;19(9):2533-2542. Epub 2019 Mar 20.

Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

The advent of direct-acting antiviral therapy for hepatitis C virus (HCV) has generated tremendous interest in transplanting organs from HCV-infected donors. We conducted a single-arm trial of orthotopic heart transplantation (OHT) from HCV-infected donors into uninfected recipients, followed by elbasvir/grazoprevir treatment after recipient HCV was first detected (NCT03146741; sponsor: Merck). We enrolled OHT candidates aged 40-65 years; left ventricular assist device (LVAD) support and liver disease were exclusions. We accepted hearts from HCV-genotype 1 donors. From May 16, 2017 to May 10, 2018, 20 patients consented for screening and enrolled, and 10 (median age 52.5 years; 80% male) underwent OHT. The median wait from UNOS opt-in for HCV nucleic-acid-test (NAT)+ donor offers to OHT was 39 days (interquartile range [IQR] 17-57). The median donor age was 34 years (IQR 31-37). Initial recipient HCV RNA levels ranged from 25 IU/mL to 40 million IU/mL, but all 10 patients had rapid decline in HCV NAT after elbasvir/grazoprevir treatment. Nine recipients achieved sustained virologic response at 12 weeks (SVR-12). The 10th recipient had a positive cross-match, experienced antibody-mediated rejection and multi-organ failure, and died on day 79. No serious adverse events occurred from HCV transmission or treatment. These short-term results suggest that HCV-negative candidates transplanted with HCV-infected hearts have acceptable outcomes.
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http://dx.doi.org/10.1111/ajt.15311DOI Listing
September 2019

Mortality and Kidney Transplantation Outcomes Among Hepatitis C Virus-Seropositive Maintenance Dialysis Patients: A Retrospective Cohort Study.

Am J Kidney Dis 2019 06 29;73(6):815-826. Epub 2019 Jan 29.

Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

Rationale & Objective: Hepatitis C virus (HCV) infection is common among maintenance dialysis patients. Few studies have examined both dialysis survival and transplantation outcomes for HCV-seropositive patients because registry data sets lack information for HCV serostatus.

Study Design: Retrospective cohort study.

Setting & Participants: Adult long-term dialysis patients treated by a US national dialysis provider between January 1, 2004, and December 31, 2014.

Exposure: HCV antibody serostatus obtained as part of clinical data from a national dialysis provider.

Outcomes: Mortality on dialysis therapy, entry onto the kidney transplant waiting list, kidney transplantation, and estimated survival benefit from kidney transplantation versus remaining on the waitlist.

Analytical Approach: After linking clinical data with data from the Organ Procurement and Transplantation Network, Cox and cause-specific hazards regression were implemented to estimate the associations between HCV seropositivity and mortality, as well as entry onto the kidney transplant waitlist. Cox regression was also used to estimate the survival benefit from transplantation versus dialysis among HCV-seropositive individuals.

Results: Among 442,171 dialysis patients, 31,624 (7.2%) were HCV seropositive. HCV seropositivity was associated with a small elevation in the rate of death (adjusted HR [aHR], 1.09; 95% CI, 1.07-1.11) and a substantially lower rate of entry onto the kidney transplant waitlist (subdistribution HR [sHR], 0.67; 95% CI, 0.61-0.74). Once wait-listed, the kidney transplantation rate was not different for HCV-seropositive (sHR 1.10; 95% CI, 0.96-1.27) versus HCV-seronegative patients. HCV-seropositive patients lived longer with transplantation (aHR at 3 years, 0.42; 95% CI, 0.27-0.63). Receiving an HCV-seropositive donor kidney provided a survival advantage at the 2-year posttransplantation time point compared to remaining on dialysis therapy waiting for an HCV-negative kidney.

Limitations: No data for HCV viral load or liver biopsy.

Conclusions: HCV-seropositive patients experience reduced access to the kidney transplantation waitlist despite deriving a substantial survival benefit from transplantation. HCV-seropositive patients should consider foregoing HCV treatment while accepting kidneys from HCV-infected donors to facilitate transplantation and prolong survival.
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http://dx.doi.org/10.1053/j.ajkd.2018.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535135PMC
June 2019

Management and treatment of the HCV-infected kidney transplant patient.

Semin Dial 2019 Mar 9;32(2):169-178. Epub 2018 Dec 9.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

The prevalence of hepatitis C virus infection is increased in patients with end stage kidney disease compared to the general population and is an adverse outcome determinant. Direct-acting antiviral therapy for hepatitis C virus is changing the management paradigm of infected kidney transplant candidates and recipients, with potential to reduce patient morbidity and mortality. This review describes the hepatic and nonhepatic manifestations of hepatitis C virus in kidney transplant patients as well as management and treatment strategies to optimize transplant outcomes, highlighting the importance of direct-acting antivirals in this population.
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http://dx.doi.org/10.1111/sdi.12766DOI Listing
March 2019

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

Treating hepatitis C infection in patients with advanced CKD in the real world: time to refocus on what our real treatment goals should be.

Kidney Int 2018 07;94(1):18-21

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

In this issue, Alric and colleagues demonstrate through real-world experience that grazoprevir-elbasvir is safe and effective for treating hepatitis C in advanced kidney disease patients with higher comorbidity burdens. This commentary highlights that this and similar studies have primarily focused on treatment safety and efficacy, rather than the clinical impact of viral eradication. Critical knowledge gaps including which patients to treat, and when, as well as potential management strategies that may improve outcomes, are discussed.
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http://dx.doi.org/10.1016/j.kint.2018.03.018DOI Listing
July 2018

A clone-directed approach may improve diagnosis and treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits.

Kidney Int 2018 07 11;94(1):199-205. Epub 2018 May 11.

Division of Nephrology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

The optimal treatment for the monoclonal gammopathies of renal significance is not known, but there is consensus among experts that treatment should be specific for the underlying clone. The majority of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) do not have an identifiable clone, and prior studies have found poor renal outcomes for patients with PGNMID treated with a variety of regimens. Here we present a retrospective case series of 19 patients with PGNMID with a more uniform, clone-directed approach. A circulating paraprotein was detected in 37% of patients, and the overall clone detection rate was 32%. Treatment was directed at the underlying clone or, for patients without a detectable clone, empirically prescribed to target the hypothesized underlying clone. Of the 16 patients who underwent treatment, the overall renal response rate was 88%, and 38% of patients experienced complete renal response (proteinuria reduction to under 0.5 gm/24 hours) with initial treatment. All patients were End Stage Renal Disease-free at last follow-up (median 693 days after diagnosis), and treatment was well tolerated. Thus, a clone-directed approach may lead to novel, targeted treatment strategies that could significantly improve outcomes for patients with PGNMID.
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http://dx.doi.org/10.1016/j.kint.2018.02.020DOI Listing
July 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

The changing face of adult posttransplant lymphoproliferative disorder: Changes in histology between 1999 and 2013.

Am J Hematol 2018 07 6;93(7):874-881. Epub 2018 May 6.

Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.

Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different with different prognoses and responsiveness to therapy, resulting in 2 different malignancies. We attempted to confirm reports suggesting that the relative frequency of these 2 histologies is shifting over time. We analyzed 3040 adult PTLD cases in the UNOS OPTN database from 1999 to 2013. Changes in PTLD cases over time were analyzed for histology, time from transplant to diagnosis, and patient EBV serostatus. We found that the relative proportion of polymorphic versus monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; P = <.001). The change is driven by a gradual increase in the number of monomorphic PTLD with a steady number of polymorphic PTLD. The change is most strongly seen in transplant recipients who were EBV serostatus positive at the time of transplant. Potential causes are changes in immunosuppressive regimens with increased tacrolimus use (P = .009) and increased survival among transplant patients leading to later occurrence of PTLD (P = .001) that have occurred during the time frame analyzed. As organ transplantation has evolved over time, PTLD has coevolved. These changes in histology have important implications regarding the origin and clinical management of PTLD.
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http://dx.doi.org/10.1002/ajh.25116DOI Listing
July 2018

Impact of prolonged dialysis prior to renal transplantation.

Clin Transplant 2018 06 25;32(6):e13260. Epub 2018 Jun 25.

Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Introduction: The new kidney allocation system (KAS) prioritizes patients based on date of dialysis initiation or waitlisting, whichever is earlier. We hypothesized that this change would increase transplant rates for patients with prolonged pretransplant dialysis times (DT) and aimed to assess the impact of prolonged DT on post-transplant outcomes.

Methods: We used United Network for Organ Sharing registry data to assess outcomes for patients added to the renal transplant waitlist from January 1, 1998 to December 31, 2010 and patients transplanted from January 1, 1998 to December 3, 2012.

Results: Compared with patients transplanted pre-emptively, patients with <5 years, 5-9 years, and ≥10 years DT had progressively decreased graft and patient survival (P < .001). The rates of short-term complications including delayed graft function, graft loss within 30 days, and patient death within 30 days were significantly higher in cohorts with ≥10 years DT than in cohorts with less DT (P < .001).

Conclusions: Patients with pretransplant DT of ≥10 years had worse outcomes than patients pre-emptively transplanted or transplanted with shorter DT. Durations of dialysis dependence beyond 10 years were associated with further deterioration in short-term but not long-term post-transplant outcomes.
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http://dx.doi.org/10.1111/ctr.13260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023748PMC
June 2018

Hepatitis E Virus Infection in Kidney Transplant Patients: A Single-Center Study.

Transplantation 2018 04;102(4):e126-e127

Division of Nephrology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1097/TP.0000000000002071DOI Listing
April 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

Biological Variation of Donor-Derived Cell-Free DNA in Renal Transplant Recipients: Clinical Implications.

J Appl Lab Med 2017 Nov;2(3):309-321

Department of Medicine, University of Pennsylvania, Perelman School of Medicine and Penn Kidney Pancreas Transplant Program, Pennsylvania, PA.

Background: Previous studies have demonstrated that donor-derived cell-free DNA (dd-cfDNA) found in circulating blood of transplant recipients may serve as a noninvasive biomarker of allograft rejection. To better interpret the clinical meaning of dd-cfDNA, it is essential to understand the biological variation of this biomarker in stable healthy recipients. This report establishes the biological variation and clinical reference intervals of dd-cfDNA in renal transplant recipients by using an analytically validated assay that has a CV of 6.8%.

Methods: We sampled venous blood at patient surveillance visits (typically at posttransplant months 1-4, 6, 9, and 12) in a 14-center observational study. Patients with stable renal allograft function spanning ≥3 serial visits were selected. We used AlloSure®, a targeted next-generation sequencing-based approach, to measure dd-cfDNA in the plasma and computed the intraindividual CV (CVI) and interindividual CV (CVG), the index of individuality (II), and reference change value (RCV).

Results: Of 93 patients, 61% were men, 56% were Caucasian, mean age was 49 years, and 63% were deceased donor kidney recipients. Of 380 blood samples, the dd-cfDNA median value was 0.21% (interquartile range 0.12%-0.39%) and the 97.5th percentile was 1.20%. In 18 patients with an average of 4.1 tests, the CVI was 21%, CVG was 37%, II was 0.57, and RCV was 61%.

Conclusions: In a renal transplant recipient, a dd-cfDNA level above 1.2% is out of range and potentially abnormal. A serial increase of up to 61% in level of dd-cfDNA in a patient may be attributable to biological variation.Clinicaltrials.gov Identifier: NCT02424227.
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http://dx.doi.org/10.1373/jalm.2016.022731DOI Listing
November 2017

Recurrent glomerular disease after kidney transplantation.

Curr Opin Nephrol Hypertens 2017 11;26(6):501-508

aDepartment of Medicine, Division of Nephrology, University of Washington, Washington bDepartment of Medicine, Renal Division, University of Pennsylvania cDepartment of Medicine, Penn Transplant Institute, Pennsylvania, USA.

Purpose Of Review: With improving short-term kidney transplant outcomes, recurrent glomerular disease is being increasingly recognized as an important cause of chronic allograft failure. Further understanding of the risks and pathogenesis of recurrent glomerular disease enable informed transplant decisions, along with the development of preventive and treatment strategies.

Recent Findings: Multiple observational studies have highlighted differences in rates and outcomes for various recurrent glomerular diseases, although these rates have not markedly improved over the last decade. Emerging evidence supports use of rituximab to treat recurrent primary membranous nephropathy and possibly focal segmental glomerulosclerosis (FSGS), whereas eculizumab is effective in glomerular diseases associated with complement dysregulation [C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS)].

Summary: Despite the potential for recurrence in the allograft, transplant remains the optimal therapy for patients with advanced chronic kidney disease (CKD) secondary to primary glomerular disease. Biomarkers and therapeutic options necessitate accurate pretransplant diagnoses with opportunities for improved surveillance and treatment of recurrent glomerular disease posttransplant.
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http://dx.doi.org/10.1097/MNH.0000000000000358DOI Listing
November 2017

Immunosuppression for kidney transplantation: Where are we now and where are we going?

Transplant Rev (Orlando) 2017 01 11;31(1):10-17. Epub 2016 Oct 11.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Advances in immunosuppression have propelled kidney transplantation from a scientific curiosity to the optimal treatment for patients with end stage kidney disease. Declining rates of acute rejection have led to improvements in short term kidney transplant survival, culminating in incrementally better long term patient and allograft outcomes. Contextualized around established immune-suppressing drug targets, this review summarizes the history of the clinical science and highlights the pivotal trials that have led to present-day treatment standards at the level of both individual agents and multidrug regimens for kidney recipients. Finally, recently approved and emerging therapies are discussed, with an emphasis on challenges faced by clinicians managing this increasingly complex patient population.
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http://dx.doi.org/10.1016/j.trre.2016.10.006DOI Listing
January 2017