Setting Of Renal Transplantation Research Articles

#2251 Long-term systolic blood pressure variability as an independent risk factor for cardiovascular events in kidney transplant recipients

Abstract Background and Aims Cardiovascular (CV) events represent the main cause of death in patients undergoing renal transplantation. Several studies have described the role of blood pressure variability (BPV) in predicting all-cause mortality and fatal and non-fatal CV events in the general population and in diabetic patients. Systolic blood pressure variability (SBPV) has recently been proposed as a predictor of clinical outcomes in patients with chronic kidney disease. However, evidence is still scarce about the prognostic role of BPV in the setting of renal transplantation. The aim of the study was to evaluate the role of long-term SBPV in the development of fatal and non-fatal CV events (myocardial infarction, unstable angina or revascularization, stroke and hospitalization for heart failure) in subjects undergoing kidney transplantation. Method We performed a single-center retrospective observational analysis in a cohort of 272 kidney transplant patients (mean age 64 ± 13 years, 66% men), with a transplant duration ≥12 months and with at least 6 blood pressure measurements at defined intervals (3 months ±15 days) over an assessment period of 18 months. BPV was expressed as standard deviation of ambulatory systolic blood pressure (SBP) and patients were accordingly classified in tertiles (low <9.3 mmHg, medium 9.3-13 mmHg, high >13 mmHg). The role of SBPV was analyzed by Kaplan-Meier (logrank) and its independent effect by Cox Regression. Results Over a mean follow-up of 58.7 ± 17.2 months, 27 subjects (9.9%) developed CV events. For each increase of 2.7 mmHg in SBP standard deviation, the risk for fatal or non-fatal CV events increased almost 3-folds (P = 0.02) and patients in the highest tertile of SBP standard deviation showed a 4-fold increased risk (P = 0.01) (Fig. 1). This relationship was maintained even after incremental adjustment for time-averaged pulse pressure, age, diabetes, prior CV event, and dialysis vintage (HR 3.2, 95% CI 1.1–10.0, p 0.04) (Table 1). Conclusion Long-term BPV represents an independent risk factor for CV events in kidney transplant patients. It is therefore essential to seek for stable long-term blood pressure levels in this population in order to minimize the residual CV risk.

LONG-TERM SYSTOLIC BLOOD PRESSURE VARIABILITY AS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR EVENTS IN KIDNEY TRANSPLANT RECIPIENTS

Objective: Cardiovascular (CV) events represent the main cause of death in patients undergoing renal transplantation. Several studies have described the role of blood pressure variability (BPV) in predicting all-cause mortality and fatal and non-fatal CV events in the general population and in diabetic patients. Systolic blood pressure variability (SBPV) has recently been proposed as a predictor of clinical outcomes in patients with chronic kidney disease. However, evidence is still scarce about the prognostic role of BPV in the setting of renal transplantation. The aim of our study was to evaluate the role of long-term SBPV in the development of fatal and non-fatal CV events (myocardial infarction, unstable angina or revascularization, stroke and hospitalization for heart failure) in subjects undergoing kidney transplantation. Design and method: We performed a single-center retrospective observational analysis in a cohort of 272 kidney transplant patients (mean age 64±13 years, 66% men), with a transplant duration beyond 12 months and with at least 6 blood pressure measurements at defined intervals (3 months ± 15 days) over an assessment period of 18 months. BPV was expressed as standard deviation of ambulatory systolic blood pressure (SBP) and patients were accordingly classified in tertiles (low <9.3 mmHg, medium 9.3-13 mmHg, high >13 mmHg). The role of SBPV was analyzed by Kaplan-Meier (logrank) and its independent effect by Cox Regression. Results: Over a mean follow-up of 58.7±17.2 months, 27 subjects (9.9%) developed CV events. For each increase of 2.7 mmHg in SBP standard deviation, the risk for fatal or non-fatal CV events increased almost 3-folds (P=0.02) and patients in the highest tertile of SBP standard deviation showed a 4-fold increased risk (P= 0.01) (Figure 1). This relationship was maintained even after incremental adjustment for time-averaged pulse pressure, age, diabetes, prior CV event, and dialysis vintage (HR 3.2, 95% CI 1.1–10.0, p 0.04) (Table 1). Conclusions: Long-term BPV represents an independent risk factor for CV events in kidney transplant patients. It is therefore essential to seek for stable long-term blood pressure levels in this population in order to minimize the residual CV risk.

Biomarker-Development Proteomics in Kidney Transplantation: An Updated Review.

Kidney transplantation (KT) is the optimal therapeutic strategy for patients with end-stage renal disease. The key to post-transplantation management is careful surveillance of allograft function. Kidney injury may occur from several different causes that require different patient management approaches. However, routine clinical monitoring has several limitations and detects alterations only at a later stage of graft damage. Accurate new noninvasive biomarker molecules are clearly needed for continuous monitoring after KT in the hope that early diagnosis of allograft dysfunction will lead to an improvement in the clinical outcome. The advent of "omics sciences", and in particular of proteomic technologies, has revolutionized medical research. Proteomic technologies allow us to achieve the identification, quantification, and functional characterization of proteins/peptides in biological samples such as urine or blood through supervised or targeted analysis. Many studies have investigated proteomic techniques as potential molecular markers discriminating among or predicting allograft outcomes. Proteomic studies in KT have explored the whole transplant process: donor, organ procurement, preservation, and posttransplant surgery. The current article reviews the most recent findings on proteomic studies in the setting of renal transplantation in order to better understand the effective potential of this new diagnostic approach.

Clinical and economic burden of benign and malignant skin lesions in renal transplant recipients.

Studies evaluating the economic burden of dermatological care in the transplant setting are currently not available in Australia. To evaluate the clinical and economic burden of benign and malignant skin lesions in renal transplant recipients in Central Queensland. A bottom-up approach was used to determine the clinical burden and direct costs from patient-level Medicare data obtained from Service Australia for skin lesions. Seventy-six percent of the renal transplant population in Central Queensland participated in this study. The median age was 57.0 years (standard deviation ± 13.6) and the majority (61.8%) of participants were men. The mean duration after transplant surgery was 99.9 months (interquartile range, 73.2-126.6months). During a 2-year follow-up, 22 (40%) patients were diagnosed with benign skin lesions, 21 (38%) with nonmelanoma skin carcinoma(NMSC) and one (2%) with melanoma. There was a total of 231 visits to clinicians for diagnostic and therapeutic skin procedures and thedirect costs to Medicare was $48 806 Australian Dollars (AUD) or $30 427 US Dollars (USD). Approximately 86% of the total direct costs was spent for nonNMSC and mean direct costs for NMSC was $763 AUD (or $476 USD). This Medicare data-based study provides further insight into the burgeoning clinical and economic burden of the care for benign and malignant skin lesions in the renal transplantation setting in Australia.

Surgical Management of Second Trimester Cesarean Scar Ectopic Pregnancy with Laparoscopic Wedge Resection

<h3>Study Objective</h3> To review the case of a second trimester cesarean scar ectopic pregnancy managed with laparoscopic resection in a patient with a history of renal transplant. <h3>Design</h3> Video demonstration of surgical technique with narrated description. <h3>Setting</h3> Academic tertiary care site. <h3>Patients or Participants</h3> 36yo G5P0221 found to have a 14-week cesarean scar ectopic pregnancy, desiring fertility sparing intervention. <h3>Interventions</h3> In this video, we demonstrate the case of a second trimester cesarean scar ectopic pregnancy resected laparoscopically. We illustrate several key points including: - Safe port placement in the setting of prior renal transplant - Preemptive hemostasis management with temporary uterine artery ligation - Intraoperative strategies for reducing blood loss - Considerations for management of gestational sac rupture and abdominal spill of fetal contents <h3>Measurements and Main Results</h3> A 14-week cesarean scar ectopic pregnancy was successfully resected with minimal blood loss and excellent recovery. <h3>Conclusion</h3> Laparoscopic resection can be safely and effectively utilized even for cesarean scar ectopic pregnancies of more advanced gestational ages.

Vancomycin Nephrotoxicity Causing Renal Transplant Acute Kidney Injury

Nephrotoxicity is a rather frequent side effect of vancomycin treatment. Attributes of vancomycin nephrotoxicity (VN) are well documented, including its clinical manifestations and renal morphologic changes. However, VN has not been emphasized as the cause of acute kidney injury (AKI) in the renal transplant setting. We report the first 3 such cases. In each of these cases, AKI developed concurrently with vancomycin treatment and resolved after its cessation. As compared with the general population, VN in the renal transplant setting displayed some unusual clinical behaviors. Its development was rather capricious, being noted in some but not every episode of vancomycin treatment, even in the same individual. AKI developed gradually in conjunction with protracted vancomycin treatment, in contrast to a precipitous course in the nontransplant setting. However, renal transplant biopsies showed typical features of VN in each case. VN is an unusual but now well-documented cause of AKI in renal transplant recipients. VN in this setting may display some atypical features, setting it apart from that in the general population. However, renal transplant biopsy changes are characteristic and are amenable to a definitive diagnosis.

Evolution of Monoclonal Gammopathy of Undetermined Significance in Kidney Transplant Recipients at the CHUM (Centre Hospitalier de l'Université de Montréal) — a Single-Institution Retrospective Study

IntroductionRecommendations guiding the care of patients with monoclonal gammopathy of undetermined significance (MGUS) in the setting of kidney transplant are scarce. Nevertheless, monoclonal gammopathies carry a risk of neoplastic progression to hematologic malignancies and may induce renal injury from their deposition in the kidney (monoclonal gammopathy of renal significance - MGRS). However, it remains largely uncertain if these considerations translate into adverse outcomes in the setting of transplantation, as immunosuppression might favor malignant evolution of MGUS or, alternatively, a nephrotoxic paraprotein could lead to graft loss.MethodsWe conducted a retrospective review of the medical records of patients who received a kidney transplant at our institution between Jan 1, 2000 and Jan 1, 2016. We included patients with at least one available serum protein electrophoresis at any time before or after transplantation. Exclusion criteria consisted of age < 18 years at the time of transplant, no follow-up at our center, multiorgan transplant (liver, lung, pancreas, heart), as well as first transplant prior to study period or presence of any plasma cell malignancy before transplant. Outcomes of interest included paraprotein evolution, appearance of hematologic malignancy, graft rejection and loss. Chi-square tests and Fischer's exact probability test for categorical data and Student's t test for continuous variables were used to assess statistical significance.ResultsOut of 1009 eligible transplant recipients, 755 patients were included in our study based on our inclusion and exclusion criteria. Thirteen patients were found to have MGUS prior to transplant and a monoclonal gammopathy appeared in 43 patients after transplant corresponding to a 5-year incidence rate of 2.7%. Median patient follow-up was 7.5 years. Of the patients with MGUS prior to transplant, 2 developed light chain deposition disease (LCDD) after a follow-up of 1 and 2 years and 2 evolved to smoldering multiple myeloma (SMM) at 1 month and 4 years post-transplant. Of the 43 patients who developed MGUS after transplant, 1 transformed into multiple myeloma (MM) 8 years later and 1 progressed to LCDD 2 months after transplant. None of the 6 patients who evolved to malignancy after transplantation had a systematic hematologic workup prior to allograft implantation questioning whether SMM or MGRS may have already been present before transplant. Figure 1 summarizes the evolution of monoclonal gammopathies in our study population. Of monoclonal gammopathies appearing after transplantation, most remained stable (n=26, 60%) and 9 (21%) were found to be transient. Median size was 0.76 g/L (range 0.1 - 21.6 g/L). Twenty-two (74%) were of IgG isotype and an abnormal kappa/lambda ratio was present in 6 cases (14%). We conducted a univariate analysis to compare allograft outcomes between patients who developed post-transplant MGUS (n=43) and patients who did not (n=699). No differences in induction immunosuppression, occurrence of graft loss (18% and 11%, p=0.14) and acute rejection rates (26% and 27%, p=0.866) were observed between these two groups, respectively. However, the former were found to have an increased risk of CMV (26% and 12%, p=0.01) and polyoma BK virus (26% and 14%, p=0.04). Of note, 7 cases of post-transplant lymphoproliferative disorder (PTLD) were identified in our study population and none was preceded by MGUS.ConclusionOur study suggests a reassuring evolution of true MGUS in the setting of renal transplantation. Indeed, the cases of plasma cell malignancies diagnosed in transplant recipients may have already been present before transplant, yet undetected from lack of systematic investigation. We therefore highlight the importance of identifying and diligently investigating monoclonal immunoglobulins in transplant candidates. If a paraprotein is found before transplant, further investigations with bone marrow biopsy and review of native kidney biopsy appear warranted in order to identify cases of plasma cell dyscrasias (such as SMM) and MGRS prior to transplant. Additionally, MGUS arising after transplant appear to carry a favorable evolution. They also tend to be transient and their appearance may be related to prior CMV and BK virus infections. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Monomorphic Cutaneous T-Cell Lymphoma in a Patient with Cadaveric Renal Transplant on Immunosuppressive Drugs and Renal Impairment Treated Successfully with Single Agent Brentuximab Vedotin

BACKGROUND:Patients with renal transplants on immunosuppressive drugs are more likely to develop skin malignancies secondary to T-cell dysfunction and are at increased risk of viral reactivation. Cutaneous lymphomas are the second most common form of malignancy after skin cancer. B-cell lymphoma accounts for majority of the cases, with T-cell lymphoma accounting for 30% of the cases. T cell post-transplant lymphoproliferative disorder is usually an aggressive lymphoma. Skin lesions may be either erythematous, infiltrative plaque, nodular or ulcerative tumor. Cutaneous T-cell lymphoma expressing CD 30 generally have a good prognosis and can be treated with targeted antibody against CD30 avoiding systemic toxicity of chemotherapy. Brentuximab vedotin CD30 antibody is an antibody-drug conjugate (ADC) consisting of CD30-directed antibody, cAC10, conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). ADC binds to CD30-expressing cells, followed by internalization of the ADC-CD30 complex and the release of MMAE via proteolytic cleavage. MMAE then binds to tubulin to disrupt the microtubule network within the cell causing cell cycle arrest and apoptotic cell deathOBSERVATION:A 46 year old male received a Cadaveric Renal transplant in 1999 for presumed renal failure after Streptococcal Nephritis. Patient experienced couple of rejections and has Chronic Kidney Disease, stage III. He is maintained on immunosuppressive medication which included prednisone, Mycophenolate Mofetil and cyclosporine. Patient noticed progressive lumps in his neck, back and arms which gradually increased in size and number to occupy his front and back of neck, chest and abdomen as well as axilla. The patient did not have any constitutional symptoms. PET/CT prior to treatment revealed widespread hypermetabolic soft tissue nodules involving skin, subcutaneous fat and muscle throughout the neck, chest, abdomen and pelvis as well as anterior mediastinal lymph node consistent with malignancy. Excisional biopsy from right axillary mass showed High Grade Lymphoma in setting of post -transplant. The immunopheno type of tumor cells were positive for CD2, CD4, MUM1 and CD138 (focal, especially the larger cells). CD3 was positive mostly in apparent background lymphocytes. CD30 was strongly and diffusely positive. The malignant cells were negative for EBV, CD79A, ALK-1 and CD20. The complex immunophenotype was consistent with the diagnosis of monomorphic post-transplant lymphoproliferative disorder of T lymphocytes. The dose of immunosuppressive drug was reduced and the patient was treated with Brentuximab vedotin CD30 antibody - drug conjugate 1.2 mg/kg every 3 week (Dose adjusted for renal impairment). The patient tolerated the treatment very well with mild grade 1 peripheral sensory neuropathy localized to bilateral finger tips treated with Pregabalin. Repeat PET/CT after six cycles of treatment with Brentuximab vedotin showed interval resolution of previously described hypermetabolic soft tissue nodules and anterior mediastinal lymph node. No evidence of residual/recurrent hyper-metabolic foci. The patient continues to be on Brentuximab vedotin every three week now after 6 months of treatment.CONCLUSION:CD30+ Monomorphic cutaneous T-cell lymphoma occurring in post renal transplant patients with renal impairment and on immunosuppressive medication can be successively treated with targeted drug Brentuximab vedotin with dose adjustment with excellent response as in this case. Brentuximab Vedotin should be avoided in severe renal failure (Creatinine Clearance< 30 mlL/min) due to higher risk of Grade 3 adverse reactions. Brentuximab vedotincan be safely use with dose modification and close observation for toxicity in patients with moderate renal impairment and post renal transplant setting. [Display omitted] DisclosuresD'Cunha:Seattle Genetics Inc.: Honoraria.

Model-Based Estimation of Iohexol Plasma Clearance for Pragmatic Renal Function Determination in the Renal Transplantation Setting

BackgroundIohexol plasma clearance-based glomerular filtration rate (GFR) determination provides an accurate method for renal function evaluation. This technique is increasingly advocated for clinical situations that dictate highly accurate renal function assessment, as an alternative to conventional serum creatinine-based methods with limited accuracy or poor feasibility. In the renal transplantation setting, this particularly applies to living renal transplant donor eligibility screening, renal transplant function monitoring and research purposes. The dependency of current iohexol GFR estimation techniques on extensive sampling, however, has limited its clinical application. We developed a population pharmacokinetic model and limited sampling schedules, implemented in the online InsightRX precision dosing platform, to facilitate pragmatic iohexol GFR assessment.MethodsIohexol concentrations (n = 587) drawn 5 min to 4 h after administration were available from 67 renal transplant recipients and 41 living renal transplant donor candidates with measured iohexol GFRs of 27–117 mL/min/1.73 m2. These were split into a model development (n = 72) cohort and an internal validation (n = 36) cohort. External validation was performed with 1040 iohexol concentrations from 268 renal transplant recipients drawn between 5 min and 4 h after administration, and extended iohexol curves up to 24 h from 11 random patients with impaired renal function. Limited sampling schedules based on one to four blood draws within 4 h after iohexol administration were evaluated in terms of bias and imprecision, using the mean relative prediction error and mean absolute relative prediction error. The total deviation index and percentage of limited sampling schedule-based GFR predictions within ± 10% of those of the full model (P10) were assessed to aid interpretation.ResultsIohexol pharmacokinetics was best described with a two-compartmental first-order elimination model, allometrically scaled to fat-free mass, with patient type as a covariate on clearance and the central distribution volume. Model validity was confirmed during the internal and external validation. Various limited sampling schedules based on three to four blood draws within 4 h showed excellent predictive performance (mean relative prediction error < ± 0.5%, mean absolute relative prediction error < 3.5%, total deviation index < 5.5%, P10 > 97%). The best limited sampling schedules based on three to four blood draws within 3 h showed reduced predictive performance (mean relative prediction error < ± 0.75%, mean absolute relative prediction error < 5.5%, total deviation index < 9.5%, P10 ≥ 85%), but may be considered for their enhanced clinical feasibility when deemed justified.ConclusionsOur online pharmacometric tool provides an accurate, pragmatic, and ready-to-use technique for measured GFR-based renal function evaluation for clinical situations where conventional methods lack accuracy or show limited feasibility. Additional adaptation and validation of our model and limited sampling schedules for renal transplant recipients with GFRs below 30 mL/min is warranted before considering this technique in these patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-00998-z.

Plasma neutrophil gelatinase-associated lipocalin and Interleukin-18 as predictors of acute kidney injury in renal transplant recipients: A pilot study.

Urine neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL- 18) have shown promise for predicting renal graft recovery. However, urinary flow rate variations may cause variable biomarker dilution. Plasma NGAL and IL-18 may form a biomarker panel that may help predict delayed graft function and slow graft function (SGF) in renal transplant recipients within the first two postoperative days earlier than serum creatinine. There are only a few studies in the literature using plasma NGAL for predicting renal graft recovery. Hence, we planned this study. This observational single-center, prospective cohort study was conducted in renal transplant recipients above 18 years of age. In 22 consecutive renal transplant recipients, we collected ethylenediaminetetraacetic acid-plasma samples 1 h before surgery and subsequently at 6 h, 24 h, and 48 h after surgery for NGAL and IL-18 by sandwich enzyme-linked immuno-sorbent assay technique. Serum creatinine was measured as a part of routine transplant protocol. In renal transplant recipients, neither serum levels of NGAL and IL-18 nor their trends could reliably predict SGF. The only significant correlation existed between serum creatinine at day 2 and IL-18 at day 2 with P = 0.023. Serum NGAL did not correlate with serum creatinine in this setting of renal transplantation. Patients with immediate graft function had a greater percentage decrease of creatinine at day 1 and day 2 (P = 0.002 and 0.001) The percentage change in IL-18 at 24 h and 48 h after transplant from baseline could predict the occurrence of early graft loss (EGL) (P = 0.05, 0.04). The cutoffs were -4.12% at day 1 and +3.39% at day 2 with area under receiver operator characteristics of 0.82 and 0.83, respectively. The percentage change in IL-18 may be a useful marker of EGL in renal transplant recipients. Serum NGAL and creatinine were not able to predict EGL.

Outcomes of a Clinician-Directed Protocol for Discontinuation of Complement Inhibition Therapy in Atypical Hemolytic Uremic Syndrome

Introduction : Terminal complement inhibition with a C5 inhibitor (eculizumab or ravulizumab) is the standard of care for treatment of atypical hemolytic uremic syndrome (aHUS) and leads to rapid resolution of thrombotic microangiopathy and improvement in renal function. The ideal duration of complement inhibition in aHUS is not established. Indefinite therapy is standard, though recent studies suggest that many patients with aHUS may safely discontinue therapy. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 32 patients with aHUS. Methods: Consecutive patients with aHUS enrolled in the Hopkins Complement Associated Disease Registry between January 2014 and December 2019 who initiated eculizumab therapy during an acute episode of aHUS were included in the study. Patients starting eculizumab in the setting of renal transplant were excluded from the analysis. Physician directed discontinuation and monitoring was done according to the protocol outlined in Figure 1. We also evaluated relapse rate and renal outcomes and examined clinical and genetic risk factors for relapse. Results: Thirty-two consecutive patients who initiated eculizumab therapy for acute aHUS. Median age at initial diagnosis of aHUS was 44 (IQR 25, 53.5) years, 78.1% were female, and complement gene variants were present in 59.0% (13 of 22 patients with sequencing data available). Of these 32 patients, 25 (78%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (IQR 1.06, 9.70) months. Six (18%) patients continued receiving it and 1 patient died during the first episode of aHUS. Of the 25 patients that discontinued eculizumab, 18 (72%) discontinued under physician direction (17 per protocol due to TMA remission including two with no renal recovery and end stage renal disease, and 1 due to non-response and a metabolic TMA thought more likely). Seven (28%) patients interrupted or discontinued therapy due to non-adherence. Overall relapse rate after eculizumab discontinuation was 20.0% (5 of 25); however, the relapse rate was higher in the case of non-adherence versus a physician directed cessation protocol (42.8% versus 11.1%, P=0.074) (Figure 2). Of the five patients who relapsed, four were re-treated and achieved remission without a decline in renal function with eculizumab; one patient died due to recurrent TMA and hypertensive emergency in the setting of non-adherence. On univariate analysis, non-adherence with therapy [OR 8.25 (95% CI 1.02 - 66.19) P=0.047] was associated with relapse while underlying complement gene variant [OR 1.39 (95% CI 0.39-4.87), P=0.598] and presence/absence of a trigger for aHUS [OR 0.66 (95% CI 0.09-4.79), P=0.687] were not significantly associated with relapse. We examined relapse rates in patients with CFH or MCP variants (40%, 2 of 5), other variants (33.3%, 2 of 6), no variants (0%, 0 of 6), and sequencing not completed (11.1%, 1 of 9) (P=0.217). These analyses are limited by the small sample size and limited number of events (5 relapses), which precluded multivariable regression analysis. Among patients that discontinued eculizumab, there was no significant decline in mean estimated glomerular filtration rate (eGFR) from the date of stopping eculizumab (47.09 + 28.28 ml/min/1.73 m2) until the most recent follow-up (56.95 + 28.02 ml/min/1.73 m2, one sided t-test P = 0.987). As seen in figure 3, improvement in eGFR (changed to a less severe eGFR category between stopping eculizumab and end of follow up) was seen in 9 of 25 patients (36%) and stable eGFR (no change in eGFR category) was seen in 15 of 25 patients (60%). Conclusion: Eculizumab discontinuation with close monitoring is safe in the majority of patients with aHUS (with native kidneys), with low rates of TMA recurrence and nearly complete salvage with eculizumab retreatment in the event of a recurrence. CFH and MCP variants may be associated with higher risk of relapse, which needs to be evaluated in larger, multicenter studies. Disclosures Moliterno: Pharmessentia: Consultancy; MPNRF: Research Funding. Chaturvedi:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Human BK Polyomavirus Nephropathy (BKVN) In Non- Kidney-Transplant Patients

Abstract Introduction/Objective Human BK polyomavirus nephropathy (BKVN) occurs in up to 10% of renal transplant recipients, and can result in graft loss. Transplant biopsy is the gold standard to diagnose BKVN, and SV40 immunohistochemical (IHC) staining is helpful in confirming the diagnosis. BKVN is uncommon outside the setting of renal transplantation. To understand more about its occurrence in other contexts, we reviewed our renal biopsies files for cases of BKVN. Methods Our renal biopsy files for the past 20 years were reviewed for all cases with a diagnosis of BKVN or polyoma virus infection, and the clinical characteristics of the affected patients noted. Results Evidence of BKVN was found in 44 renal biopsies, of which 39 (86%) were renal transplant patients. Of the remaining five patients (14%), two had undergone heart transplantation, one lung transplantation, one was undergoing chemotherapy for acute lymphoblastic leukemia, and one patient had active HIV infection. All patients had elevated serum creatinine, and four out of five patients had documented BK viremia. Four of the five biopsies showed typical tubular injury with viral nuclear cytopathic changes (inclusions). In the lung transplant patient, the biopsy showed advanced chronic tubulointerstitial injury without distinct viral inclusions, but SV40 staining confirmed the presence of BK virus antigen. Conclusion The BKVN is distinctly uncommon outside the context of kidney transplantation. In our series, 14% of patients with BKVN were not kidney transplant recipients, but all were immune compromised in some fashion. The pathologic features of BKVN appear similar, regardless of whether the host is a renal transplant recipient or not. Although uncommon, it is important to consider the possibility of BKVN in non-renal transplant patients with persistent or progressive renal dysfunction.

Everolimus, an mTORC1/2 inhibitor, in ART-suppressed individuals who received solid organ transplantation: A prospective study.

Pharmacologic inhibition of the mammalian target of rapamycin (mTOR) in the setting of renal transplantation has previously been associated with lower human immunodeficiency virus 1 (HIV-1) DNA burden, and in vitro studies suggest that mTOR inhibition may lead to HIV transcriptional silencing. Because prospective clinical trials are lacking, we conducted an open-label, single-arm study to determine the impact of the broad mTOR inhibitor, everolimus, on residual HIV burden, transcriptional gene expression profiles, and immune responses in HIV-infected adult solid organ transplant (SOT) recipients on antiretroviral therapy. Whereas everolimus therapy did not have an overall effect on cell-associated HIV-1 DNA and RNA levels in the entire cohort, participants who maintained everolimus time-averaged trough levels >5ng/mL during the first 2months of therapy had significantly lower RNA levels up to 6months after the cessation of study drug. Time-averaged everolimus trough levels significantly correlated with greater inhibition of mTOR gene pathway transcriptional activity. Everolimus treatment also led to decreased PD-1 expression on certain T cell subsets. These data support the rationale for further study of the effects of mTOR inhibition on HIV transcriptional silencing in non-SOT populations, either alone or in combination with other strategies. Trial Registration: ClinicalTrials.gov NCT02429869.

Imaging spectrum of pulmonary infections in renal transplant patients.

In the post renal transplant setting, pulmonary infections comprise an important set of complications. Microbiological diagnosis although specific is often delayed and insensitive. Radiography is the most common and first imaging test for which patient is referred, however it is relatively insensitive. HRCT is a very useful imaging tool in the scenario where radiography is negative or inconclusive and high clinical suspicion for infection is present. HRCT features vary among the various pathogens and also depend on the level of immunocompromise. Certain HRCT findings are characteristic for specific pathogens and may help narrow diagnosis. In this review article, we will summarize the imaging findings of various pulmonary infections encountered in post renal transplant patients.

Pulmonary Artery Migration of a Peripheral Endovascular Stent Discovered Prior to Renal Transplantation: A Case Report

Background: Arteriovenous fistulas and grafts are preferred access for hemodialysis. Outflow stenosis is a common complication that can be managed with angioplasty and stenting. Stent placement can be complicated by thrombosis, limited area of cannulation, fracture, and migration. Objective: This case reports a rare complication of endovascular stents, namely stent migration to the pulmonary artery in the setting of renal transplantation. Methods: A 55-year-old woman with end stage renal disease secondary to diabetes mellitus on hemodialysis via a left arm basilic vein transposition. She subsequently developed outflow stenosis that was treated with a stent placement. She was admitted for deceased donor kidney transplantation and preoperative x-ray showed migration of the stent into a segmental pulmonary artery. After a pre-operative, multidisciplinary discussion between interventional radiology, cardiothoracic surgery, transplant nephrology and transplant surgery, the decision was made to proceed with rental transplantation followed by stent removal. Interventional radiology removed the stent on postoperative day two without complication. She has not experienced any complications in the year following her transplantation. Conclusion: Postoperative stent removal by interventional radiology is a feasible management option in lieu of lifelong anticoagulation.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Metastatic Cancer Post Solid Organ Transplantation: A Case Report and Review of the Literature

Immunotherapy is expanding its role in cancer therapy, and in various tumor types it has now become the frontline treatment. Though generally better tolerated than traditional chemotherapy, its mechanism of activating the immune system results in a unique set of adverse reactions that maybe disastrous in the setting of post solid organ transplantation. We herein describe a case report of a patient who was post–renal transplant, developed metastatic, relapsed, refractory renal cell carcinoma, and was successfully treated with nivolumab for 6 cycles while maintaining renal graft function. We also reviewed the published case reports of immunotherapy administered in the post–renal transplantation setting.

Complement in the Pathophysiology of the Antiphospholipid Syndrome.

The antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Complement is a system of enzymes and regulatory proteins of the innate immune system that plays a key role in the inflammatory response to pathogenic stimuli. The complement and coagulation pathways are closely linked, and expanding data indicate that complement may be activated in patients with aPL and function as a cofactor in the pathogenesis of aPL-associated clinical events. Complement activation by aPL generates C5a, which induces neutrophil tissue factor-dependent procoagulant activity. Beta-2-glycoprotein I, the primary antigen for pathogenic aPL, has complement regulatory effects in vitro. Moreover, aPL induce fetal loss in wild-type mice but not in mice deficient in specific complement components (C3, C5). Antiphospholipid antibodies also induce thrombosis in wild type mice and this effect is attenuated in C3 or C6 deficient mice, or in the presence of a C5 inhibitor. Increased levels of complement activation products have been demonstrated in sera of patients with aPL, though the association with clinical events remains unclear. Eculizumab, a terminal complement inhibitor, has successfully been used to treat catastrophic APS and prevent APS-related thrombotic microangiopathy in the setting of renal transplant. However, the mechanisms of complement activation in APS, its role in the pathogenesis of aPL related complications in humans, and the potential of complement inhibition as a therapeutic target in APS require further study.

External Iliac Artery Dissection During Renal Transplantation: A Case Report and Literature Review

Iliac artery dissection in the setting of renal transplant is a rare but potentially catastrophic event that may result in loss of kidney and lower extremity perfusion. We report a right external iliac artery dissection in a 45-year-old man with end-stage renal disease, diabetes, and hypertension who underwent a renal transplant at our institution. An external iliac artery dissection was diagnosed intraoperatively after completion of the arterial anastomosis given the mottled appearance of the kidney and loss of Doppler signal. The dissection was repaired via open endarterectomy, intimal tacking, bovine patching, and re-anastomosis of the kidney to a proximal site on the external iliac artery. To date, 23 cases of transplant-related iliac artery dissection have been described in the literature. Predisposing risk factors include atherosclerosis and hypertension combined with trauma from vascular clamps or suturing. There is a slight male predominance. Only one group utilized an open endarterectomy approach similar to ours, whereas others used synthetic vascular grafts (12 of 23), endovascular stents (4 of 23), donor iliac artery grafts (4 of 23), or saphenous vein grafts (2 of 23). In the absence of long-term outcomes data, the optimal repair mechanism is yet to be established.

P030How do different testing platforms influence novel allele characterization? A case study of a novel DPB1 allele

A renal transplant patient sample was submitted in order to characterize an unresolved HLA-DPB1 allele. Sanger sequence-based typing (SBT) resulted in DPB1*04:02:01 and a number of equally possible candidates for the second allele, each with a single nucleotide mismatch. Removing all exons except exon 2 from analysis resulted in a perfect match with homozygous DPB1*04:02:01G. However, several heterozygous positions leading to non-synonymous mutations were present in the excluded exons, contradicting this apparent homozygosity. One next-generation sequencing (NGS) platform then typed the sample as DPB1*04:02:01 for the first allele and various ambiguous alleles for the second. However, this was due to low coverage in a 19-nucleotide region of exon 2 rather than a mismatch. The low coverage pattern was replicated on a repeat run. DPB1*414:01 with one mismatch in exon 2 was called as the second allele when the minimum read depth was lowered. Interestingly, none of the possible second alleles were part of DPB1*04:02:01G. Upon testing on a second NGS platform, DPB1*04:02:01, DPB1*463:01:01 was obtained with novel mutations in exon 4 and introns. Comparing this result to the Sanger SBT data revealed the same heterozygous mismatch in exon 4. A third NGS platform verified this typing and associated mismatches. Therefore, if potential intronic mutations are ignored, the typing may be reported in two ways: as DPB1*04:02:01, DPB1*463:01 with a mutation in exon 4, or as DPB1*04:02:01, DPB1*414:01 with a mutation in exon 2. The first combination may lead to the assumption of homozygosity for treatment purposes, since DPB1*463:01 is part of DPB1*04:02:01G. This is currently the practice in the HLA field when exons 3 and 4 are not included in analysis. Ignoring heterozygous positions in exons that make up regions outside the antigen binding groove could lead to development of antibodies. This may be an important consideration in the renal transplant setting, depending on patient-donor matching and determination of immunogenicity.

Renal function outcomes in pediatric patients with symptomatic reflux into the transplanted kidney treated with redo ureteroneocystostomy

Asymptomatic post-renal transplant reflux is common but only 5-10% patients are diagnosed with vesico-ureteral reflux in the setting of post-transplant febrile urinary tract infections, requiring redo ureteroneocystostomy (redo-UNC). Here wereport the renal function outcomes of 37 such patients, stratified by lower urinary tract (LUT) status. We hypothesized that those with pre-transplant LUT dysfunction would have lower glomerular filtration rate (GFR) on follow-up. Using procedure codes, 37 patients who underwent renal transplant followed by redo-UNC for transplant reflux at our institution between 1991 and 2014 were identified. Patient characteristics and GFR levels from four different time points were recorded. Comparisons were made between those with andwithout LUT dysfunction, using Fisher's exact, Wilcoxon rank sum, or signed-rank tests. Generalized estimating equations were constructed to accountfor the clustered nature of GFR within eachLUT group and to assess their change over time. Twelve patients (32%) had pre-transplant LUT dysfunction. The proportion of males in this group was significantly higher (75% vs. 32%, p=0.032), and there was no statistical difference towards presenting earlier with post-transplant reflux (1.4 vs. 2.3 years, p=0.087). After an average of 4.9 years, the median GFRs were similar between the two groups (53mg/dL vs. 58mg/dL, p=0.936). There was no significant difference in GFR at this last follow-up time point in patients with and without LUT dysfunction. Vesicoureteral reflux in the setting of renal transplantation is common and doesn't often require repair. In our series, we found that those with LUT dysfunction did not present statistically sooner with symptomatic transplant reflux. Longer-term follow-up did show a decline in GFR but did not reveal a difference in GFR in patients' with and without LUT dysfunction. Pediatric post-transplant GFR after open redo ureteral reimplant decreases over time in similar fashion in patients with symptomatic reflux regardless of whether they have LUT dysfunction or normal anatomy. Vigilance should apply to the recognition, treatment, and follow-up of all symptomatic transplant reflux regardless of LUT status.