Publications by authors named "Suphamai Bunnapradist"

153 Publications

Extremely High Cell-free DNA Levels Observed in Renal Allograft Patient With SARS-CoV-2 Infection.

Transplant Direct 2021 May 23;7(5):e691. Epub 2021 Apr 23.

David Geffen School of Medicine at UCLA, Department of Nephrology, Los Angeles, CA.

Beyond its widely recognized morbidity and mortality, coronavirus disease 2019 poses an additional health risk to renal allograft recipients. Detection and measurement of donor-derived cell-free DNA (dd-cfDNA), expressed as a fraction of the total cell-free DNA (cfDNA), has emerged as a noninvasive biomarker for allograft rejection. Here, we present a case report of a patient who was infected with severe acute respiratory syndrome coronavirus 2, 11 mo post-kidney transplant. The patient was serially monitored using an analytically and clinically validated massively multiplex PCR-based dd-cfDNA assay to assess allograft injury and risk for rejection. Over the course of infection, low dd-cfDNA fractions were observed (below the 1% cutoff) and were accompanied by unusually highly elevated levels of total cfDNA, which gradually declined as the infection resolved. The case study highlights the variability in total cfDNA levels during and after viral infection, and the need to consider both total and dd-cfDNA levels when clinically interpreting the results for allograft rejection. Furthermore, the study highlights the importance of serial testing, wherein an interplay between total cfDNA and dd-cfDNA can inform the optimization of a patient's immunosuppressive treatment regimen in response to infection.
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http://dx.doi.org/10.1097/TXD.0000000000001145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078311PMC
May 2021

Efficacy and Safety of Once-Daily LCP-Tacrolimus Versus Twice-Daily Immediate-Release Tacrolimus in Adult Hispanic Stable Kidney Transplant Recipients: Sub-Group Analysis from a Phase 3 Trial.

Ann Transplant 2021 Apr 16;26:e929535. Epub 2021 Apr 16.

Department of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA.

BACKGROUND The pharmacokinetics and metabolism of tacrolimus, an immunosuppressant commonly used to prevent transplant rejection, can differ in specific subpopulations. This analysis examined treatment outcomes and safety of immediate-release tacrolimus (IR-Tac) and LCP-tacrolimus (LCPT) in stable Hispanic kidney transplant recipients. MATERIAL AND METHODS This was a post hoc analysis of clinical trial data from Hispanic adult stable kidney transplant recipients randomized to remain on IR-Tac or convert from IR-Tac to a reduced dose of LCPT (NCT00817206). Composite treatment failure was evaluated at 12 months. Estimated glomerular filtration rate and tacrolimus trough concentrations were evaluated over 12 months. RESULTS Fifty-five stable (LCPT n=26, IR-Tac n=29) kidney transplant recipients who self-identified as Hispanic or Latino were included in this analysis. Composite treatment failure occurred in 1 patient (4%) who converted to LCPT and 1 (3%) who remained on IR-Tac. The estimated glomerular filtration rate was stable over time and similar in the 2 treatment groups (P=0.08). Tacrolimus trough levels for both groups were similar over time in the 2 treatment groups (P=0.98). Treatment-emergent adverse events were similar in patients who converted to LCPT and in those who remained on IR-Tac. CONCLUSIONS Efficacy and safety were similar in Hispanic kidney transplant recipients who converted from IR-Tac to LCPT and in those remaining on IR-Tac.
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http://dx.doi.org/10.12659/AOT.929535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056872PMC
April 2021

Leukocyte transcriptome indicators of development of infection in kidney transplant recipients.

Clin Transplant 2021 Apr 5;35(4):e14252. Epub 2021 Mar 5.

Department of Medicine, Division of Hematology-Oncology, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

After kidney transplantation, infection and death are important clinical complications, especially for the growing numbers of older patients with limited resilience to withstand adverse events. Evaluation of changes in gene expression in immune cells can reveal the underlying mechanisms behind vulnerability to infection. A cohort of 60 kidney transplant recipients was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between patients with infection and those who were infection-free in the first-year post-transplant. Pro-inflammatory genes such as IL1B, CCL4, and TNF were found to be downregulated in post-transplant PBMC from patients who developed infection. In contrast, genes involved in metabolism, HLA genes, and transcripts involved in type I interferon innate antiviral responses were found to be upregulated. Promoter-based bioinformatic analyses implicated increased activity of interferon regulatory factors, erythroid nuclear factor (E2), and CCAAT-enhancer-binding protein (C/EBP) in patients who developed infections. Differential patterns of gene expression were observed in patients who developed infection after kidney transplantation, with patterns distinct from changes associated with patient age, suggesting possible mechanisms behind vulnerability to infection. Assessment of gene expression in blood may offer an approach for patient risk stratification and monitoring after transplantation.
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http://dx.doi.org/10.1111/ctr.14252DOI Listing
April 2021

Impact of donor obesity on allograft outcomes after kidney transplantation adjusted for kidney donor profile index - a national cohort study.

Transpl Int 2021 Apr 7;34(4):681-688. Epub 2021 Mar 7.

Division of Nephrology, Department of Medicine, Kidney and Pancreas Transplant Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Obesity in deceased kidney donors is a known risk factor for poor allograft outcomes. The Kidney Donor Profile Index (KDPI) has been introduced to predict graft survival in deceased donor kidney transplantation (DDKT). Obesity, however, is not included in KDPI. We study the impact of donor obesity on DDKT outcomes after adjusting for organ quality by KDPI. The Organ Procurement Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data of DDKT from 2005 to 2017, with donor BMI ≥ 18.5 kg/m and weight >80 kg were included. There was a total of 66 382 DDKTs with 10 917 death-censored graft failures. For KDPI ≤ 30%, the 10-year death-censored graft survival (DCGS) rates among donor BMI < 30, 30-35, 35-40, 40-45 and ≥45 kg/m groups were 75.9%, 75.4%, 76.1%, 74.9% and 79.6%, respectively. For KDPI > 30%, 10-year DCGS rates were 67.5%, 66.1%, 65.9%, 62.6% and 63.2%, respectively. After adjusting for known confounding factors including KDPI, donor obesity was not independently associated with an increased risk for graft failure. In DDKT with donor weight >80 kg, donor obesity was not associated with a lower long term DCGS compared to non-obesity when KDPI ≤ 30%.
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http://dx.doi.org/10.1111/tri.13826DOI Listing
April 2021

DNA Methylation Age Is More Closely Associated With Infection Risk Than Chronological Age in Kidney Transplant Recipients.

Transplant Direct 2020 Aug 15;6(8):e576. Epub 2020 Jul 15.

Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age.

Methods: DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30-59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age.

Results: Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection.

Conclusions: Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000001020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581059PMC
August 2020

Spectrum of Coronavirus Disease 2019 Outcomes in Kidney Transplant Recipients: A Single-Center Experience.

Transplant Proc 2020 Nov 10;52(9):2654-2658. Epub 2020 Sep 10.

Division of Infectious Diseases, UCLA David Geffen School of Medicine, University of California, Los Angeles, California. Electronic address:

Purpose: We reviewed the clinical experience of kidney transplant recipients diagnosed with severe acute respiratory syndrome coronavirus 2 infection in order to understand the impact of the current coronavirus disease 2019 (COVID-19) pandemic infection on transplant recipients. Given that early reports from heavily affected areas demonstrated a very high mortality rate amongst kidney transplant recipients, ranging between 30% and 40%, we sought to evaluate outcomes at a center with a high burden of cases but not experiencing acute crisis due to COVID-19.

Procedures: In this single center retrospective observational study, medical records of all kidney transplant recipients at the UCLA Medical Center were reviewed for a diagnosis of COVID-19 by polymerase chain reaction, followed by chart review to determine kidney transplant characteristics and clinical course.

Main Findings: A total of 41 kidney transplant recipients were identified with COVID-19 positive polymerase chain reaction. Recipients had been transplanted for a median of 47 months before diagnosis. The large proportion of infected individuals were minorities (Hispanic 65.9%, black 14.6%), on prednisone, tacrolimus, and mycophenolate mofetil (95.1%, 87.8%, and 87.8%, respectively), and had excellent allograft function (median 1.25 mg/dL). The most common presenting symptoms were fever, dyspnea, or cough. Most patients were hospitalized (63.4%); mortality was 9.8% and occurred only in patients in the intensive care unit. The most common treatment was reduction or removal of antimetabolite (77.8%). Approximately 26.9% presented with AKI.

Conclusions: COVID-19 infection in kidney transplant recipients results in a higher rate of hospitalization and mortality than in the general population. In an area with a high number of infections, the mortality rate was lower compared with earlier reports from areas experiencing early surge and strain on the medical system. Minorities were disproportionately affected. Future studies are needed to determine optimal approach to treatment and management of immunosuppression in kidney transplant recipients with COVID-19 infection.
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http://dx.doi.org/10.1016/j.transproceed.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832798PMC
November 2020

Early cytomegalovirus DNAemia and antiviral dose adjustment in high vs intermediate risk kidney transplant recipients.

Transpl Infect Dis 2021 Feb 22;23(1):e13457. Epub 2020 Sep 22.

Division of Nephrology, David Geffen School of Medicine, Los Angeles, CA, USA.

Background: Cytomegalovirus (CMV) infection continues to negatively affect outcomes for solid organ transplant recipients, despite the advent of strategies for preemptive surveillance and prophylaxis. The impact is especially great for CMV seronegative recipients of donor seropositive organs, who typically lack the ability to control CMV infection at the time of transplantation.

Methods: We reviewed episodes of CMV DNAemia in a modern cohort of kidney transplant recipients over a 3-year period at a high-volume transplant center to investigate the frequency of DNAemia during antiviral prophylaxis.

Results: Despite receipt of antiviral prophylaxis per current guidelines, 75 cases of CMV DNAemia were observed in the first 100 days after transplantation. For high risk patients, median time to DNAemia was 75 days after transplantation, and the majority of patients had experienced dose-reduction of valganciclovir due to renal insufficiency. Review of CMV seropositive intermediate risk patients demonstrated DNAemia occurring earlier after transplantation compared with high risk patients with a median time of 64 days (P = .029). The impact of valganciclovir dose adjustment was less notable in the intermediate risk group.

Conclusions: Guidelines recommend beginning routine surveillance for CMV after the completion of antiviral prophylaxis. Our findings suggest that closer monitoring may be beneficial, especially for high risk patients at risk for DNAemia. Patients requiring dose adjustment of valganciclovir due to renal insufficiency may be at increased risk for CMV DNAemia. Improved methods for CMV prophylaxis and evaluation of immunologic risk for CMV DNAemia and disease are needed to improve patient outcomes after kidney transplantation.
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http://dx.doi.org/10.1111/tid.13457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962879PMC
February 2021

Time to second kidney transplantation in young adults after failed pediatric kidney transplant.

Pediatr Transplant 2020 11 28;24(7):e13800. Epub 2020 Jul 28.

Division of Nephrology, Department of Medicine, Kidney and Pancreas Transplant Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Background: Under the current kidney allocation system, pediatric candidates listed prior to age 18 receive priority for high-quality deceased donor organs. This has resulted in a decline in living donor transplantation in pediatrics, despite superior outcomes of living donor transplantation. Due to a young age at transplantation, most pediatric kidney transplant recipients require re-transplantation. The effects of a previously failed deceased donor vs a previously failed living donor on re-transplant candidates are unknown.

Methods: Using the United Network for Organ Sharing database, we examined 2772 re-transplant recipients aged 18-30 years at time of relisting for second KT from 2000 to 2018 with history of prior pediatric KT (age ≤ 18 years).

Results: PFLDKT recipients compared to those with PFDDKT had shorter median waiting times and dialysis time regardless of their second donor type (14.0 vs 20.3 months, and 19.1 vs 34.5 months, respectively). PFLDKT recipients had higher re-transplant rates (adjusted HR 1.17, 95% CI 1.09-1.27, and adjusted HR 1.05, 95% CI 0.95-1.15 when calculating from time of relisting and time of returning to dialysis, respectively). PFDDKT recipients were more likely to have higher median PRA levels (90% vs 73%).

Conclusions: Re-transplant candidates who received a previous deceased donor as a child had a higher level of sensitization, longer waiting time, and dialysis exposure compared to those with PFLDKT. Among primary pediatric kidney transplant candidates, consideration should be considered for living donor transplantation, despite the priority for deceased donor organs, to avoid increased sensitization and longer waiting times for with re-transplantation.
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http://dx.doi.org/10.1111/petr.13800DOI Listing
November 2020

Effect of Concentration/Dose Ratio in De Novo Kidney Transplant Recipients Receiving LCP-Tacrolimus or Immediate-Release Tacrolimus: Post Hoc Analysis of a Phase 3 Clinical Trial.

Ann Transplant 2020 Jul 28;25:e923278. Epub 2020 Jul 28.

Department of Nephrology and Medical Intensive Care, Charité - University Medicine Berlin, Berlin, Germany.

BACKGROUND A previous phase 3 clinical trial in de novo adult kidney transplant recipients (NCT01187953) compared the efficacy and safety of once-daily LCP-tacrolimus (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). However, whether the rate of tacrolimus metabolism affects outcomes between LCPT and IR-Tac was not examined. MATERIAL AND METHODS Patients were initiated on 0.17 mg/kg/day LCPT or 0.1 mg/kg/day IR-Tac, with doses adjusted over time to maintain target therapeutic trough concentrations. This post hoc analysis examined dosing trends, relative efficacy, and safety of LCPT (n=247) and IR-Tac (n=249) in slow, intermediate, and rapid metabolizers as defined by concentration/dose ratios at day 30. RESULTS For all metabolizer subgroups, minimum target tacrolimus trough concentrations were obtained more rapidly with LCPT than with IR-Tac. Slow metabolizers were more likely to exceed target trough concentrations with LCPT, while rapid metabolizers were more likely to fall below target trough concentrations with IR-Tac. Regardless of metabolizer status, significant differences were not detected between LCPT and IR-Tac for treatment failure, death, graft failure, biopsy-proven acute rejection, estimated glomerular filtration rate, or other clinical outcomes. CONCLUSIONS Although within metabolizer subgroups, attainment of target trough concentrations in the first week differed between LCPT and IR-Tac, these results suggest that, regardless of metabolizer phenotype, clinical outcomes do not differ between these formulations when dose adjustments are made.
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http://dx.doi.org/10.12659/AOT.923278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412936PMC
July 2020

Listing Malignant Melanoma Patients for Renal Transplantation.

Transplant Proc 2020 Dec 9;52(10):3033-3037. Epub 2020 Jul 9.

Department of Medicine, Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, California.

Background: Melanoma is an immune responsive malignancy and the need for immunosuppression for successful transplantation may lead to recurrent disease. The recommended waiting time is unknown with various groups recommending anywhere from no wait to 5 years.

Methods: In this single-center, retrospective observational study all kidney transplant recipients' charts from 1991 to 2015 were reviewed for a diagnosis of melanoma before transplantation. The charts were reviewed for the clinical characteristics of melanoma pre transplantation, induction immunosuppression, maintenance immunosuppression, graft function, death, and recurrence of melanoma.

Results: Thirteen patients with a history of melanoma underwent kidney transplantation during this period. Recipients had been in remission for an average of 7.0 years (range, 10 months to 20 years, median 6 years). Approximately 61.5% received a living donor transplant, antithymocyte globulin was administered in 23.1% of recipients, and the remaining 76.9% received basiliximab. Melanoma recurred in 1 patient (7.7%). Maintenance immunosuppression varied, but only 2 patients remained on standard triple therapy with prednisone, calcineurin inhibitor, and antimetabolite therapy. Average follow-up time since transplant was 7.5 years, with 1 patient death 9 years post transplant from sepsis.

Conclusion: In conclusion, with our center demonstrates safety of kidney transplantation in patients with a prior history of localized melanoma and shorter waiting time. In malignant melanoma stage 0 and 1, waiting the recommended 5 years from the time of remission to kidney transplantation should be reconsidered.
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http://dx.doi.org/10.1016/j.transproceed.2020.04.1823DOI Listing
December 2020

BK Viremia Exacerbation With Adalimumab Coadministration.

Transplant Direct 2020 Jun 22;6(6):e557. Epub 2020 May 22.

Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

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http://dx.doi.org/10.1097/TXD.0000000000001000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266362PMC
June 2020

Evaluation of Renal Disease in Patients With Cirrhosis.

J Clin Gastroenterol 2020 04;54(4):314-321

Department of Medicine, Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Renal dysfunction in cirrhosis is common and is associated with increased mortality. Identifying and treating reversible causes of renal disease can significantly improve outcomes. The etiology, approach, and evaluation of renal disease in this group of patients is similar to the noncirrhosis patient, with a few specific caveats. Renal disease may be unrelated to the cause of cirrhosis (eg, prerenal acute kidney injury, acute tubular necrosis), occur as a manifestation of the same systemic disease responsible for the liver disease (eg, chronic viral hepatitis B and C infection) or as a consequence of cirrhosis (hepatorenal syndrome). Kidney impairment may be underrecognized in patients with cirrhosis due to over-reliance on creatinine-based glomerular filtration rate equations used in clinical practice. The first steps of evaluation for the renal disease include a thorough medical history to identify the underlying cause of cirrhosis and any potential trigger for renal dysfunction, physical examination, and review of prior laboratory records for baseline renal function. Renal imaging and urinalysis should be performed on all cirrhotic patients with renal dysfunction to establish the presence of urinary obstruction, chronicity and intrinsic renal disease.
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http://dx.doi.org/10.1097/MCG.0000000000001325DOI Listing
April 2020

Cutaneous Fungal Masses From Prior Environmental Injury Following Kidney Transplant: A Case Report.

Transplant Proc 2019 Nov 11;51(9):3087-3091. Epub 2019 Oct 11.

Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.

Fungus account for ∼ 5% of all cases infections following solid organ transplant. Fungal infections in the setting of immunosuppression may progress rapidly and present in an atypical pattern. Herein we describe 4 cases of environmental fungal infections acquired decades prior to transplant that developed into localized atypical cutaneous masses following kidney transplant.
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http://dx.doi.org/10.1016/j.transproceed.2019.07.011DOI Listing
November 2019

Current opinions in nephrology and hypertension: kidney transplantation in patients with plasma cell dyscrasias.

Curr Opin Nephrol Hypertens 2019 11;28(6):573-580

Division of Nephrology, David Geffen School of Medicine, Los Angeles, California, USA.

Purpose Of Review: Plasma cell dyscrasias encompass a group of hematological disorders characterized by increased production of immunoglobulins by clonal B cells. Kidney involvement is common. Significant advances in the treatment of plasma cell dyscrasias have resulted in improved survival and may permit kidney transplantation in candidates previously denied transplantation. Treatments may also have effects on kidney transplant recipients who develop plasma cell dyscrasias post transplantation.

Recent Finding: The available evidence suggests that transplantation of candidates with nonmultiple myeloma plasma cell dyscrasias provides good outcome with low recurrence rates, so long as the disease has been treated with a complete or good partial response prior to transplantation. Candidates with a history untreated MGRS or a history of multiple myeloma have a high rate of recurrence posttransplant. Kidney transplant recipients who develop plasma cell dyscrasias post transplantation have an increased risk of death and thalidomide-based regimens may increase the risk of rejection.

Summary: Transplant candidates with a history of plasma cell dyscrasia who are in remission should not be excluded from transplantation. Individuals with multiple myeloma have a high rate of recurrence and myeloma post kidney transplant must be managed carefully.
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http://dx.doi.org/10.1097/MNH.0000000000000544DOI Listing
November 2019

Factors predicting kidney delayed graft function among recipients of simultaneous liver-kidney transplantation: A single-center experience.

Clin Transplant 2019 06 7;33(6):e13569. Epub 2019 May 7.

Division of Transplantation and Hepatobiliary Surgery, University of Florida, Gainesville, Florida.

Background: Kidney delayed graft function (kDGF) remains a challenging problem following simultaneous liver and kidney transplantation (SLKT) with a reported incidence up to 40%. Given the scarcity of renal allografts, it is crucial to minimize the development of kDGF among SLKT recipients to improve patient and graft outcomes. We sought to assess the role of preoperative recipient and donor/graft factors on developing kDGF among recipients of SLKT.

Methods: A retrospective review of 194 patients who received SLKT in the period from January 2004 to March 2017 in a single center was performed to assess the effect of preoperative factors on the development of kDGF.

Results: Kidney delayed graft function was observed in 95 patients (49%). Multivariate analysis revealed that donor history of hypertension, cold static preservation of kidney grafts [versus using hypothermic pulsatile machine perfusion (HPMP)], donor final creatinine, physiologic MELD, and duration of delay of kidney transplantation after liver transplantation were significant independent predictors for kDGF. kDGF is associated with worse graft function and patient and graft survival.

Conclusions: Kidney delayed graft function has detrimental effects on graft function and graft survival. Understanding the risks and combining careful perioperative patient management, proper recipient selection and donor matching, and graft preservation using HPMP would decrease kDGF among SLKT recipients.
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http://dx.doi.org/10.1111/ctr.13569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653637PMC
June 2019

Differences in Gene Expression in Older Compared With Younger Kidney Transplant Recipients.

Transplant Direct 2019 Apr 4;5(4):e436. Epub 2019 Mar 4.

Division of Hematology-Oncology, Department of Medicine, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Background: For the growing numbers of older transplant patients, increased incidence of infection and death compared with younger patients may limit the many benefits provided by transplantation. However, little is known about age-associated immune dysfunction in the older transplant recipient.

Methods: A cohort of 60 kidney transplant recipients, 23 older (≥ 60y) and 37 younger (30-59y), matched on antithymocyte induction and donor type (living vs deceased) was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between older and younger patients.

Results: Proinflammatory genes were upregulated in older kidney transplant patients, including cytokines IL1-β and IL-6. Downregulated genes were associated with B-cell and T-cell function, including CCR7 and CD27. Analysis of predicted transcription factor binding suggested an increase in proinflammatory transcription factor CCAAT/enhancer binding protein β-binding sites in older patients, whereas interferon regulatory factor 2 transcription factor binding sites were less prevalent.

Conclusions: Older kidney transplant recipients exhibited multiple differences in gene expression compared with younger patients, with upregulation of proinflammatory genes and downregulation of adaptive immune response genes. These findings may explain the mechanism of increased vulnerability to infection and malignancy observed in older transplant patients.
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http://dx.doi.org/10.1097/TXD.0000000000000870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445656PMC
April 2019

Allocation of the Highest Quality Kidneys and Transplant Outcomes Under the New Kidney Allocation System.

Am J Kidney Dis 2019 05 28;73(5):605-614. Epub 2019 Mar 28.

Division of Nephrology, Department of Medicine, Comprehensive Transplant Center, Cedars Sinai Medical Center, West Hollywood. Electronic address:

Rationale & Objective: Increased access to transplantation for highly sensitized candidates following implementation of the kidney allocation system (KAS) has been mostly due to higher use of organs with a lower kidney donor profile index (KDPI; a quality metric for donated kidneys), although changes in allocation of these organs was not intended. It is unclear whether clinical outcomes have changed in association with these changes. We investigated the use of kidneys with low and high KDPI scores over time and whether KDPI score affects patient and graft survival differently across varying levels of allosensitization.

Study Design: Observational cohort study.

Setting & Participants: Adult (aged ≥18 years) recipients of a deceased donor kidney transplant between October 1, 2009, and September 30, 2017 (Organ Procurement and Transplantation Network/United Network for Organ Sharing database; n = 84,451).

Predictors: Calculated panel-reactive antibody (cPRA) level (0%, 1%-79%, 80%-89%, 90%-98%, and 99%-100%) and KDPI score (≤20%, 21%-85%, and >85%).

Outcomes: Death, graft loss.

Analytical Approach: Time to event.

Results: Allocation of kidneys with KDPI scores ≤ 20% and KDPI scores of 21% to 85% to recipients with cPRA levels ≥ 99% increased 4-fold following implementation of the KAS with little change in allocation of kidneys with KDPI scores > 85%. Patient survival and graft loss were strongly associated with KDPI score, whereas the association with cPRA level was minimal. There was no evidence of a differential effect of KDPI scores across the range of cPRA levels on patient survival (P for interaction=0.06-0.9) or graft loss (P for interaction=0.5-0.9). Patient survival at 5 years among the 5 cPRA groups ranged from 87.2% to 89.8% for recipients of kidneys with KDPI scores ≤ 20% (P=0.2), 82.8% to 85.5% for KDPI scores of 21% to 85% (P=0.04), and 70.2% to 79.2% for KDPI scores > 85% (P=0.2). Cumulative incidence of graft loss by cPRA level ranged from 7.7% to 10.6% for recipients of kidneys with KDPI scores ≤ 20% (P=0.2), 11.8% to 15.0% for KDPI scores of 21% to 85% (P < 0.001), and 19.8% to 29.7% for KDPI scores > 85% (P = 0.4).

Limitations: Lack of data for crossmatches, donor-specific antibodies, and immunomodulation.

Conclusions: Highly sensitized recipients received kidneys with lower KDPI scores following implementation of the KAS, reducing access to these kidneys by less-sensitized candidates. KDPI score has a stronger association with patient survival and graft loss than cPRA level. The association of KDPI score with these outcomes was not modified by the recipient's level of sensitization. The impact of the redistribution of kidneys with low KDPI scores on outcomes among less-sensitized recipients needs further evaluation.
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http://dx.doi.org/10.1053/j.ajkd.2018.12.036DOI Listing
May 2019

Current Status of Simultaneous Liver-Kidney Transplantation in the United States.

Liver Transpl 2019 05 3;25(5):797-806. Epub 2019 Apr 3.

Division of Nephrology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA.

On August 10, 2017, a formal policy was enacted in the United States that defined listing criteria for simultaneous liver-kidney transplantation and priority for patients who received a liver transplantation (LT) and subsequently developed significant kidney disease after LT. This article reviews and summarizes the rationale for such policies, the policies themselves, and the potential impact on LT candidates.
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http://dx.doi.org/10.1002/lt.25444DOI Listing
May 2019

Three patients with injection of intravitreal vascular endothelial growth factor inhibitors and subsequent exacerbation of chronic proteinuria and hypertension.

Clin Kidney J 2019 Feb 27;12(1):92-100. Epub 2018 Jul 27.

Retinal Disorders and Ophthalmic Genetics, Department of Ophthalmology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.

Vascular endothelial growth factor (VEGF) receptor inhibition is a commonly used tool to prevent vascular proliferation in tumors and retinal diseases. The antiangiogenic effects of these drugs have made them potent adjunct therapies when given systemically for malignancies. They are also useful tools to ameliorate diminishing eyesight in retinopathy. Hypertension and proteinuria have been observed in systemic VEGF inhibitor therapy, with rarer presentations involving nephrotic-range proteinuria due to glomerulopathies. Pharmacokinetic studies have shown detectable blood levels of anti-VEGF inhibitors up to 30 days postintravitreal injection. Animal studies have also demonstrated binding of VEGF inhibitors in simian glomeruli 1 week after a single intravitreal injection. We report three patients who received intravitreal bevacizumab and/or aflibercept with worsening hypertension, proteinuria and renal injury. Data regarding emerging evidence of VEGF inhibitor nephrotoxicity after intravitreal injections are also presented. The clinical data and the existing literature are reviewed to support the hypothesis that intravitreal anti-VEGF agents may be unrecognized nephrotoxins. These agents are given to vulnerable patients with diabetes, hypertension and preexisting nephropathy and proteinuria. This case series is reported to spur further study of the systemic effects of intravitreal VEGF inhibitors.
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http://dx.doi.org/10.1093/ckj/sfy060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366143PMC
February 2019

Donor-derived Cell-free DNA Identifies Antibody-mediated Rejection in Donor Specific Antibody Positive Kidney Transplant Recipients.

Transplant Direct 2018 Sep 20;4(9):e379. Epub 2018 Aug 20.

Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN.

Background: Elevated levels of donor-derived cell-free DNA (dd-cfDNA) in the plasma of renal allograft recipients indicates organ injury and an increased probability of active rejection. Donor-specific antibodies (DSA) to HLA antigens are associated with risk of antibody-mediated rejection (ABMR). This study assessed the combined use of dd-cfDNA and DSA testing to diagnose active ABMR.

Methods: Donor-derived cell-free DNA was assayed in 90 blood samples with paired DSA and clinically indicated biopsies from 87 kidney transplant patients. Sixteen cases met criteria for active ABMR. Performance characteristics of dd-cfDNA for diagnosis of active ABMR were determined for samples with prior or current positive DSA (DSA+, n = 33).

Results: The median level of dd-cfDNA (2.9%) in DSA+ patients with active ABMR was significantly higher than the median level (0.34%) in DSA+ patients without ABMR ( < 0.001). The median level of dd-cfDNA in DSA- patients was 0.29%. The positive predictive value of dd-cfDNA (at 1%) to detect active ABMR in DSA+ patients was 81%, whereas the negative predictive value was 83%. The positive predictive value for DSA+ alone was 48%.

Conclusions: The combined use of dd-cfDNA and DSA testing may improve the noninvasive diagnosis of active ABMR in kidney transplant patients. Patients with dd-cfDNA+/ DSA+ results have a high probability of active ABMR.
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http://dx.doi.org/10.1097/TXD.0000000000000821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133406PMC
September 2018

The Reply.

Am J Med 2018 08 19;131(8):e349-e351. Epub 2018 Jun 19.

Departments of Medicine andSurgery,Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass; Division of Nephrology, New EnglandMedical Center, Tufts UniversitySchool of Medicine, Boston,Mass.

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http://dx.doi.org/10.1016/j.amjmed.2018.04.003DOI Listing
August 2018

Screening Coccidioides serology in kidney transplant recipients: A 10-year cross-sectional analysis.

Transpl Infect Dis 2018 Oct 26;20(5):e12932. Epub 2018 Jul 26.

Department of Medicine, Division of Nephrology, Kidney and Pancreas Transplant Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Background: Kidney transplant recipients (KTRs) are at risk for reactivation and complicated infection due to Coccidioides. Pre-transplant serological screening should provide benefit for patients from endemic areas. We evaluated Coccidioides seroprevalence by area of residence in KTRs at a major transplant program in Los Angeles.

Methods: We performed cross-sectional analyses of adult KTRs who underwent transplantation at UCLA between 2007-2016. Patients with Coccidioides serology by enzyme immunoassay (EIA) before or within 14 days from transplantation were included. Patients were classified as living in highly, established, suspected, or not endemic areas by their residential zip code.

Results: Overall prevalence of Coccidioides IgG and IgM were 1.4% and 2.8%, respectively. Of patients with positive serology, 31.4% had isolated IgG and 66.3% isolated IgM. Patients from established and highly endemic areas had IgG seropositivity of 3.7% versus 1.3% for patients living in suspected endemic areas(P < .01). Rates of IgM seropositivity were 3.7% compared to 2.8% respectively (P = .28). No patients from non-endemic areas had positive screening serology.

Conclusions: Pre-transplant serological screening for Coccidioides is recommended in kidney transplant candidates from endemic areas. We observed high seroprevalence among patients from highly and established endemic areas, for whom universal prophylaxis is recommended. For residents from less well-established areas of endemicity, serological screening showed benefit in identifying patients at risk. In patients with isolated EIA IgM, performing repeat and confirmatory tests is recommended. Patients from non-endemic areas had low risk of infection, however, a thorough social history is necessary to evaluate risk.
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http://dx.doi.org/10.1111/tid.12932DOI Listing
October 2018

Differences in Proinflammatory Cytokines and Monocyte Subtypes in Older as Compared With Younger Kidney Transplant Recipients.

Transplant Direct 2018 Mar 14;4(3):e348. Epub 2018 Feb 14.

Division of Infectious Diseases, Department of Medicine, University of California Los Angeles Immunogenetics Center, Los Angeles, CA.

Background: The number of elderly patients with end-stage kidney disease requiring kidney transplantation continues to grow. Evaluation of healthy older adults has revealed proinflammatory changes in the immune system, which are posited to contribute to age-associated illnesses via "inflamm-aging." Immunologic dysfunction is also associated with impaired control of infections. Whether these immunologic changes are found in older kidney transplant recipients is not currently known, but may have important implications for risk for adverse clinical outcomes.

Methods: Three months after transplant, innate immune phenotype was evaluated by flow cytometry from 60 kidney transplant recipients (22 older [≥60 years] and 38 younger [<60 years old]). Multiplex cytokine testing was used to evaluate plasma cytokine levels. Younger patients were matched to older patients based on transplant type and induction immune suppression.

Results: Older kidney transplant recipients demonstrated decreased frequency of intermediate monocytes (CD14++CD16+) compared with younger patients (1.2% vs 3.3%, = 0.007), and a trend toward increased frequency of proinflammatory classical monocytes (CD14++CD16-) (94.5% vs 92.1%) ( = 0.065). Increased levels of interferon-gamma (IFN-γ) were seen in older patients.

Conclusions: In this pilot study of kidney transplant recipients, we identified differences in the innate immune system in older as compared with younger patients, including increased levels of IFN-γ. This suggests that age-associated nonspecific inflammation persists despite immune suppression. The ability to apply noninvasive testing to transplant recipients will provide tools for patient risk stratification and individualization of immune suppression regimens to improve outcomes after transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000000762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912018PMC
March 2018

Combined Dual-Kidney Liver Transplantation in the United States: A Review of United Network for Organ Sharing/Organ Procurement and Transplantation Network Data Between 2002 and 2012.

Liver Transpl 2018 11;24(11):1570-1577

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.

In kidney-alone recipients, dual-kidney transplantation using "higher-risk" donor organs has shown outcomes comparable to those of single-kidney transplantation using extended criteria donor (ECD) organs. To investigate the feasibility of a similar approach with combined kidney-liver transplantation, we identified 22 dual-kidney liver transplantations (DKLTs) and 3044 single-kidney liver transplantations (SKLTs) performed in the United States between 2002 and 2012 using United Network for Organ Sharing/Organ Procurement and Transplantation Network registry data. We compared donor/recipient characteristics as well as graft/recipient survival between DKLT recipients and SKLT recipients of "higher-risk" kidneys (ECD and high kidney donor profile index [KDPI; >85%] donors). Despite having overall similar donor and recipient characteristics compared with both "higher-risk" donor groups, recipient survival in the DKLT group at 36 months was markedly inferior at 40.9% (compared with 67.5% for ECD SKLT recipients and 64.5% for high-KDPI SKLT recipients); nondeath-censored graft survival did not differ. Death was the most common cause of graft loss in all groups. Contrary to dual-kidney transplantation data in kidney-alone recipients, DKLT recipients in our study had inferior survival when compared with SKLT recipients of "higher-risk" donor kidneys. These findings would suggest that dual kidney-liver transplantation has an uncertain role as a strategy to expand the existing kidney donor pool in combined transplantation.
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http://dx.doi.org/10.1002/lt.25045DOI Listing
November 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

Infection and Malignancy Outweigh Cardiovascular Mortality in Kidney Transplant Recipients: Post Hoc Analysis of the FAVORIT Trial.

Am J Med 2018 02 21;131(2):165-172. Epub 2017 Sep 21.

Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass; Division of Nephrology, New England Medical Center, Tufts University School of Medicine, Boston, Mass.

Objective: Now that long-term survival after successful renal transplantation is no longer limited by excessive cardiovascular risk, the primary care physician should consider that infection and malignancy are leading noncardiovascular causes of death even in the recipient with diabetes.

Methods: We accessed the National Institutes of Health-sponsored Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) study population (4010 renal transplant recipients with elevated homocysteine levels) studied to determine whether folate and B12 supplementation would reduce cardiovascular end points. This trial had a null result. Patients were classified as being nondiabetic or having type 1 or type 2 diabetes.

Results: We report an excess (cardiovascular and noncardiovascular) 6-year mortality risk associated with the presence of diabetes mellitus. Two thirds of fatal events in our renal transplant recipients were centrally adjudicated as noncardiovascular. The incidence of noncardiovascular death was 70% higher in the diabetic patient cohort than in the nondiabetic cohort.

Conclusions: These results demonstrate that infection (but not malignancy) risks are far higher in diabetic than nondiabetic immunosuppressed individuals (although noncardiovascular death rate in nondiabetic individuals also exceeded cardiovascular deaths) and may play a larger role in the excess mortality populations than previously thought. Given that follow-up in this study was 4 to 10 years after allograft surgery, there was a lesser degree of acute rejection requiring high-dose immunosuppression than in the initial postallograft years. This unique perspective allows transplant recipients to return to primary physicians when taking low doses of immunosuppressive agents and provides focus for follow-up care.
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http://dx.doi.org/10.1016/j.amjmed.2017.08.038DOI Listing
February 2018

Does diabetes impact therapeutic immunomodulation therapy decisions for kidney transplant recipients? Data from the Folic Acid for Vascular Outcome Reduction in Transplant (FAVORIT) trial.

Int J Nephrol Renovasc Dis 2017 18;10:233-242. Epub 2017 Aug 18.

Medicine and Surgery, Beth Israel Deaconess Medical Center, Boston MA.

Although survival has improved for kidney transplant recipients over the past several decades, long-term survival in diabetic cohorts still is significantly less than that of non-diabetic cohorts. We hypothesized that among stable kidney transplant recipients, there might be differences between subgroups with and without diabetes with respect to prevalence of prior cardiovascular events and post-transplant antihypertensive and immunosuppressive therapy. We performed a post hoc analysis of participants in the Folic Acid for Vascular Outcome Reduction in Transplant (FAVORIT) trial, a multicenter international trial of 4110 prevalent kidney transplant recipients enrolled from 2002 to 2007 evaluating the effect of homocysteine-lowering vitamin therapy on cardiovascular outcomes. There were 2447 participants without diabetes, 166 with type 1 diabetes, and 1447 with type 2 diabetes at study entry, which occurred on average 4 years post-transplant. Recipients with diabetes had a greater prevalence of prior cardiovascular events, were more likely to have required multiple medications to control hypertension, and were more likely to have received tacrolimus as opposed to cyclosporine than the non-diabetic transplant recipients (all <0.001). The effect of differences in treatment of non-diabetic vs diabetic cohorts after stable renal transplantation upon outcomes has not yet been studied and could provide additional information that might lead to improved care.
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http://dx.doi.org/10.2147/IJNRD.S139901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571849PMC
August 2017

Kidney Transplantation in Patients With Active Multiple Myeloma: Case Reports.

Transplant Direct 2017 Aug 21;3(8):e200. Epub 2017 Jul 21.

Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Kidney disease is a common complication in patients with multiple myeloma. Traditionally, patients with active multiple myeloma and end-stage renal disease have been excluded from kidney transplantation due to the risk of malignancy progression. The introduction of bortezomib-based therapy for patients with multiple myeloma and renal impairment has significantly improved survival in this population. In this report, we present 2 cases of patients with active and controlled multiple myeloma who underwent successful kidney transplantation without progression of their underlying malignancy. In patients with active multiple myeloma controlled with bortezomib, kidney transplantation should be considered a valid option for patients with end-stage kidney disease.
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http://dx.doi.org/10.1097/TXD.0000000000000716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540638PMC
August 2017

Cell-Free DNA and Active Rejection in Kidney Allografts.

J Am Soc Nephrol 2017 Jul 9;28(7):2221-2232. Epub 2017 Mar 9.

Washington University School of Medicine, St. Louis, Missouri

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), <0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.
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http://dx.doi.org/10.1681/ASN.2016091034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491290PMC
July 2017

Acute Kidney Allograft Rejection Precipitated by Lenalidomide Treatment for Multiple Myeloma.

Am J Kidney Dis 2017 May 9;69(5):701-704. Epub 2017 Feb 9.

Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.
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http://dx.doi.org/10.1053/j.ajkd.2016.11.024DOI Listing
May 2017