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.
Cytomegalovirus (CMV) infection, either de novo or as reactivation after allotransplantation and chronic immunosuppression, is recognized to cause detrimental alloimmune effects, inclusive of higher ...susceptibility to graft rejection and substantive impact on chronic graft injury and reduced transplant survival. To obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host we evaluated changes in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR).
LC-MS-based proteomics was conducted on 168 serially banked plasma samples, from 62 propensity score-matched kidney transplant recipients. Patients were stratified by CMV replication status into 31 with CMV DNAemia and 31 without CMV DNAemia. Patients had blood samples drawn at protocol times of 3- and 12-months post-transplant. Additionally, blood samples were also drawn before and 1 week and 1 month after detection of CMV DNAemia. Plasma proteins were analyzed using an LCMS 8060 triple quadrupole mass spectrometer. Further, public transcriptomic data on time matched PBMCs samples from the same patients was utilized to evaluate integrative pathways. Data analysis was conducted using R and Limma.
Samples were segregated based on their proteomic profiles with respect to their CMV Dnaemia status. A subset of 17 plasma proteins was observed to predict the onset of CMV at 3 months post-transplant enriching platelet degranulation (FDR, 4.83E-06), acute inflammatory response (FDR, 0.0018), blood coagulation (FDR, 0.0018) pathways. An increase in many immune complex proteins were observed at CMV infection. Prior to DNAemia the plasma proteome showed changes in the anti-inflammatory adipokine vaspin (SERPINA12), copper binding protein ceruloplasmin (CP), complement activation (FDR = 0.03), and proteins enriched in the humoral (FDR = 0.01) and innate immune responses (FDR = 0.01).
Plasma proteomic and transcriptional perturbations impacting humoral and innate immune pathways are observed during CMV infection and provide biomarkers for CMV disease prediction and resolution. Further studies to understand the clinical impact of these pathways can help in the formulation of different types and duration of anti-viral therapies for the management of CMV infection in the immunocompromised host.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed ...unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.
The association between pretransplant body composition and posttransplant outcomes in renal transplant recipients is unclear. It was hypothesized that in hemodialysis patients higher muscle mass ...(represented by higher pretransplant serum creatinine level) and larger body size (represented by higher pretransplant body mass index BMI) are associated with better posttransplant outcomes.
Linking 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, 10,090 hemodialysis patients were identified who underwent kidney transplantation from July 2001 to June 2007. Cox regression hazard ratios and 95% confidence intervals of death and/or graft failure were estimated.
Patients were 49 ± 13 years old and included 49% women, 45% diabetics, and 27% African Americans. In Cox models adjusted for case-mix, nutrition-inflammation complex, and transplant-related covariates, the 3-month-averaged postdialysis weight-based pretransplant BMI of 20 to <22 and < 20 kg/m(2), compared with 22 to <25 kg/m(2), showed a nonsignificant trend toward higher combined posttransplant mortality or graft failure, and even weaker associations existed for BMI ≥ 25 kg/m(2). Compared with pretransplant 3-month- averaged serum creatinine of 8 to <10 mg/dl, there was 2.2-fold higher risk of combined death or graft failure with serum creatinine <4 mg/dl, whereas creatinine ≥14 mg/dl exhibited 22% better graft and patient survival.
Pretransplant obesity does not appear to be associated with poor posttransplant outcomes. Larger pretransplant muscle mass, reflected by higher pretransplant serum creatinine level, is associated with greater posttransplant graft and patient survival.
Type 2 diabetic patients with end-stage renal disease may receive a simultaneous pancreas-kidney (SPK) transplant. However, outcomes are not well described. Risks for death and graft failure were ...examined in SPK type 2 diabetic recipients.
Using the United Network for Organ Sharing database, outcomes of SPK transplants were compared between type 2 and type 1 diabetic recipients. All primary SPK adult recipients transplanted between 2000 and 2007 (n=6756) were stratified according to end-stage pancreas disease diagnosis (type 1: n=6141, type 2: n=582). Posttransplant complications and risks for death and kidney/pancreas graft failure were compared.
Of the 6756 SPK transplants, 8.6% were performed in recipients with a type 2 diabetes diagnosis. Rates of delayed kidney graft function and primary kidney nonfunction were higher in the type 2 diabetics. Five-year overall and death-censored kidney graft survival were inferior in type 2 diabetics. After adjustment for other risk factors, including recipient (age, race, body weight, dialysis time, and cardiovascular comorbidities), donor, and transplant immune characteristics, type 2 diabetes was not associated with increased risk for death or kidney or pancreas failure when compared with type 1 diabetic recipients.
After adjustment for other risk factors, SPK recipients with type 2 diabetes diagnosis were not at increased risk for death, kidney failure, or pancreas failure when compared with recipients with type 1 diabetes.
Background Diabetes and acute rejection are major contributors to morbidity and mortality in kidney transplant recipients. Immunosuppressive medications decrease acute rejection, but increase the ...frequency of new-onset diabetes after transplant. Our objective was to investigate the joint associations of diabetes (pretransplant diabetes and new-onset diabetes after transplant) and acute rejection with transplant outcomes in a recent transplant cohort. Study Design Historical cohort study. Setting & Participants 37,448 recipients (age ≥18 years; 2004-2007) surviving with a functioning transplant for longer than 1 year were identified in the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database as of May 22, 2009. Predictors Recipients were stratified into 6 mutually exclusive groups according to status of diabetes and acute rejection at 1 year: group 1, neither (reference; n = 20,964); group 2, new-onset diabetes alone (n = 2,140); group 3, pretransplant diabetes alone (n = 10,730); group 4, acute rejection alone (n = 2,282); group 5, new-onset diabetes and acute rejection (n = 361); and group 6, pretransplant diabetes and acute rejection (n = 1,061). Analyses were adjusted for other recipient, donor, and transplant characteristics. Outcomes Measurements Multivariate Cox regression analysis of time to transplant failure (overall and death censored) and mortality (all-cause and cardiovascular). Results Median follow-up after 1 year was 548 days (25th-75th percentiles, 334-752 days). During this time, there were 3,047 outcomes of overall transplant failure. New-onset diabetes alone (group 2) was not associated significantly with any study outcomes. Groups 3-6 were associated with higher overall transplant failure risk. However, only groups 4-6 were associated with higher death-censored transplant failure risk. Group 3, 4, and 6 were associated with higher all-cause mortality risk, whereas only groups 3 and 6 were associated with higher cardiovascular mortality risk. Limitations Potential information bias with exposure, covariable, or outcome misclassification; relatively short follow-up. Conclusions Pretransplant diabetes is the major predictor of all-cause and cardiovascular mortality, and acute rejection during the first year is the major predictor of death-censored transplant failure in kidney recipients surviving with a functioning transplant for at least 1 year. The influence of new-onset diabetes on long-term outcomes needs further observation.
OBJECTIVE.: To analyze the risk factors for new-onset diabetes mellitus (NODM) in liver transplant recipients using the Organ Procurement and Transplant Network/United Network for Organ Sharing ...database. METHODS.: Among 20,172 primary liver recipients (age > or =18 years) transplanted between July 2004 and December 2008 in Organ Procurement and Transplant Network/United Network for Organ Sharing databases, 15,463 recipients without pretransplant diabetes were identified. Risk factors for NODM were examined using multivariate Cox regression analysis. RESULTS.: NODM was reported in 26.4% of recipients (median follow-up, 685 days). Independent predictors of NODM development included recipient age (> or = 50 vs. <50 years, hazard ratio HR=1.241), African American race (HR=1.147), body mass index (> or = 25 vs. <25, HR=1.186), hepatitis C (HR=1.155), recipient cirrhosis history (HR=1.107), donor age (> or = 60 vs. <60 year, HR=1.152), diabetic donor (HR=1.151), tacrolimus (tacrolimus vs. cyclosporine, HR=1.236), and steroid at discharge (HR=1.594). Living donor transplant (HR=0.628) and induction therapy (HR=0.816) were associated with a decreased risk of NODM. CONCLUSION.: The incidence of NODM was 26.4% in liver recipients with a median follow-up time of 685 days. Identified risk factors for NODM in liver transplantation were similar to that in kidney transplantation. Some of the identified factors are potentially modifiable, including obesity and the choice of immunosuppressive regimens.
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.
BACKGROUNDPosttransplant malignancy is a major cause of death in orthotopic heart transplant recipients. Our study objective is to identify whether pretransplant malignancy increases the risk for ...posttransplant malignancy.
METHODSUsing the Organ Procurement and Transplantation Network/United Network for Organ Sharing database, adult (≥18 years old) recipients of a primary orthotopic heart transplant performed between 2000 and 2012 were included. The cohort was stratified according to the presence and type of pretransplant malignancy. Outcomes were posttransplant overall, skin, solid malignancies, and posttransplant lymphoproliferative disorder. Incidence of and time to first posttransplant malignancy, accounting for death as a competing event, were calculated. Fine and Gray competing risks regression was performed to examine risk factors associated with posttransplant malignancy.
RESULTSOf 23,171 recipients, overall posttransplant malignancy was diagnosed in 2673 recipients (11.5%).The median time to overall, skin, solid posttransplant malignancies, and posttransplant lymphoproliferative disorder were 3.2 (1.6-5.7), 3.2 (1.7-5.6), 3.5 (1.7-5.9), and 2.5 years(0.8-5.2), respectively. Pretransplant malignancy increased the risk of posttransplant overall (subhazard ratio SHR, 1.51; 95% confidence interval 95% CI, 1.27-1.81), skin (SHR, 1.55, 95% CI, 1.23-1.93), and solid organ malignancies (SHR, 1.54; 95% CI, 1.13-2.11). Pretransplant skin malignancy increased the risk of posttransplant skin malignancy (SHR, 2.79; 95% CI, 1.82-4.28). Pretransplant solid malignancy also increased the risk of posttransplant skin malignancy (SHR, 1.55; 95% CI, 1.07-2.25) but not of posttransplant solid tumors (SHR, 1.23; 95% CI, 0.69-2.19). Older, male, and white were also risk factors for posttransplant malignancy.
CONCLUSIONSA history of any pretransplant malignancy was associated with increased risks of skin and solid malignancies after transplantation. The specific type of posttransplant malignancy risk differed according to the type of pretransplant malignancy.
Renal dysfunction is a frequent complication in patients with end-stage liver disease awaiting orthotopic liver transplantation and in the post-liver transplant period. Although the stereotypical ...form of renal dysfunction is the hepatorenal syndrome, other causes of acute kidney injury in this population include prerenal azotemia and acute tubular necrosis. Renal injury in a patient with cirrhosis is associated with a poor prognosis.
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