What's the score? A comparison of deceased donor kidney scoring systems and correlation with graft outcome.

BACKGROUND: A number of deceased donor kidney scoring systems have been developed to predict post-transplant graft failure. However, studies comparing the predictive ability of these scoring systems to each other are lacking. METHODS: We used single-center histopathologic and UNOS data from 140 marginal deceased donor kidneys and transplant recipients to compare the predictive accuracy of the Maryland Aggregate Pathology Index (MAPI), Kidney Donor Risk Index (KDRI), Remuzzi, and Nyberg scoring systems for 2-year graft survival using time-dependent receiver operating curves and Kaplan-Meier analysis. RESULTS: MAPI had the highest predictive accuracy (area under curve [AUC] = 0.81) compared to KDRI (AUC = 0.45), Remuzzi (AUC = 0.59), and Nyberg (AUC = 0.63) for 2-year graft survival. Furthermore, when analyzing each score according to its pre-defined risk strata, MAPI was the only scoring system for which 2-year graft survival was significantly different across strata (84.3% for low risk, 56.5% for intermediate risk, and 50% for high risk, P < .001). Additionally, MAPI was the only risk score significantly associated with 2-year graft survival (hazard ratio per point: 1.12, 95% confidence interval [CI]: 1.01-1.23, P = .03). CONCLUSIONS: In a single-center cohort of biopsied marginal kidneys used for transplantation, MAPI had the best predictive ability of these four scoring systems. When biopsy data are available for kidneys considered for transplantation, the MAPI score may provide additional information that could be used to better identify kidneys likely to have longer graft survival.

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice.

Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19), a STAT3-inhibitory protein, was isolated as a growth-suppressive gene product using a genome-wide expression knockdown screen. We and others have shown a loss of expression and occurrence of mutations in the GRIM-19 gene in a variety of primary human cancers, indicating its potential role as tumor suppressor. To help investigate its role in tumor development in vivo, we generated a genetically modified mouse in which Grim-19 can be conditionally inactivated. Deletion of Grim-19 in the skin significantly increased the susceptibility of mice to chemical carcinogenesis, resulting in development of squamous cell carcinomas. These tumors had high Stat3 activity and an increased expression of Stat3-responsive genes. Loss of Grim-19 also caused mitochondrial electron transport dysfunction resulting from failure to assemble electron transport chain complexes and altered the expression of several cellular genes involved in glycolysis. Surprisingly, the deletion of a single copy of the Grim-19 gene was sufficient to promote carcinogenesis and formation of invasive squamous cell carcinomas. These observations highlight the critical role of GRIM-19 as a tumor suppressor.

Pig-to-baboon liver xenoperfusion utilizing GalTKO.hCD46 pigs and glycoprotein Ib blockade.

BACKGROUND: Although transplantation of genetically modified porcine livers into baboons has yielded recipient survival for up to 7 days, survival is limited by profound thrombocytopenia, which becomes manifest almost immediately after revascularization, and by subsequent coagulopathy. Porcine von Willebrand's factor (VWF), a glycoprotein that adheres to activated platelets to initiate thrombus formation, has been shown to constitutively activate human platelets via their glycoprotein Ib (GPIb) receptors. Here, we report our pig-to-primate liver xenoperfusion model and evaluate whether targeting the GPIb-VWF axis prevents platelet sequestration. METHODS: Twelve baboons underwent cross-circulation with the following extracorporeal livers: one allogeneic control with a baboon liver, 4 xenogeneic controls with a GalTKO.hCD46 pig liver, 3 GalTKO.hCD46 pig livers in recipients treated with αGPIb antibody during perfusion, and 4 GalTKO.hCD46 pig livers pre-treated with D-arginine vasopressin (DDAVP) in recipients treated with αGPIb antibody during perfusion. RESULTS: All perfused livers appeared grossly and macroscopically normal and produced bile. Xenograft liver perfusion experiments treated with αGPIb antibody may show less platelet sequestration during the initial 2 h of perfusion. Portal venous resistance remained constant in all perfusion experiments. Platelet activation studies demonstrated platelet activation in all xenoperfusions, but not in the allogeneic perfusion. CONCLUSION: These observations suggest that primate platelet sequestration by porcine liver and the associated thrombocytopenia are multifactorial and perhaps partially mediated by a constitutive interaction between porcine VWF and the primate GPIb receptor. Control of platelet sequestration and consumptive coagulopathy in liver xenotransplantation will likely require a multifaceted approach in our clinically relevant perfusion model.

Validation of the Maryland Aggregate Pathology Index (MAPI), a pre-implantation scoring system that predicts graft outcome.

Predicting graft outcome after renal transplantation based on donor histological features has remained elusive and is subject to institutional variability. We have shown in a retrospective study that the Maryland Aggregate Pathology Index score reliably predicts graft outcome. We sought to validate the scoring system in our center and a second transplant center. We analyzed 140 deceased donor kidneys pre-implantation biopsies from center 1 and 65 from center 2. The patients had a mean follow-up of 695 ± 424 and 656 ± 305 d respectively. Although MAPI scores were similar, there were significant differences in donor and recipient parameters between both centers. Despite this, MAPI was predictive of graft outcome for both centers by Cox univariate, multivariate and time dependent ROC analysis. For center 1 and 2, three yr graft survival within each MAPI group was statistically equivalent. The three-yr graft survival at center 1 for low, intermediate, and high MAPI groups were 84.3%, 56.5%, and 50.0%, respectively, p ≤ 0.0001, and at center 2 were 83.3%, 33.3%, and 33.3%, p = 0.006. MAPI, which is based on a pre-implantation biopsy, demonstrated similar predictive and outcome results from both centers. As expanded criteria donors (ECD) criteria have redefined marginal kidneys, MAPI has the potential to further define ECD kidneys, increase utilization, and ultimately improve outcomes.

Single-port donor nephrectomy provides improved patient satisfaction and equivalent outcomes.

OBJECTIVE: Minimally invasive techniques have expanded the donor pool for living kidney donation. We changed our approach to single-port donor nephrectomy in 2009 and have compared outcomes with traditional multiple-port laparoscopic donor nephrectomy. BACKGROUND: The development of minimally invasive surgical techniques to procure kidneys from living donors has allowed expansion of living donor renal transplantation to account for one third of all renal transplants. Recent technical advancement allows for the entire surgical procedure to be done through a single incision contained within the umbilicus. METHODS: We compared outcomes from 135 single-port donor nephrectomies with an immediately preceding cohort of 100 multiple-port laparoscopic donor nephrectomies. Survey data were collected from both groups to compare outcomes. Additional comparisons were made to total center experience with 1300 laparoscopic donor nephrectomies. RESULTS: A total of 135 patients completed successful single-port donor nephrectomy without major complication or open conversion. Another 16 patients required additional port placement because of excessive intra-abdominal fat or limited abdominal domain. Compared with multiple-port donor nephrectomy, single-port patients had similar operative times to cross clamp (2.8 vs 2.6 hours; P = 0.11) that normalized after a learning curve of approximately 50 cases. Recipient creatinine levels were similar at 1 week and 1 month posttransplant. Although 36-Item Short Form Health Surveys demonstrated no significant differences, additional survey data revealed that single-port patients were more satisfied with cosmetic outcomes (P < 0.01) and the overall donation process (P = 0.01). Single-port approach had similar outcomes compared with all previous laparoscopic donor nephrectomies. CONCLUSIONS: Single-port donor nephrectomy can be integrated as a standardized approach for renal donation without additional donor risk, and with benefits of improved patient satisfaction with cosmetic and overall outcomes. Although the primary benefit is cosmetic, (a single incision predominantly contained within the umbilicus) outcomes justify application for kidney donors in experienced centers and may motivate additional living kidney donation.

Valganciclovir is an effective prophylaxis for cytomegalovirus disease in liver transplant recipients.

OBJECTIVES: Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality among solid organ transplant recipients. Prophylaxis using valganciclovir (VGCV) in orthotopic liver transplant (OLT) recipients is not approved by the Food and Drug Administration and its use is controversial. This study aimed to evaluate the effectiveness of VGCV in CMV prophylaxis in OLT recipients. METHODS: We carried out a retrospective, single-centre study including all OLT procedures performed during 2005-2008. Patients with early death (at ≤ 30 days), without CMV serology or prophylaxis, or with follow-up of <1 year were excluded. RESULTS: The overall incidence of CMV disease was 6% (n= 9). The ganciclovir (GCV) and VGCV groups had similar incidences of CMV disease (4.6% vs. 7.0%; P= 0.4) and similar distributions of disease presentation (CMV syndrome vs. tissue-invasive CMV; P= 0.4). Incidences of CMV infection, as well as disease presentation, were similar between the high-risk (CMV D+/R-) and non-high-risk groups (P= 0.16). Although acute cellular rejection occurred more frequently in patients who developed CMV disease (P= 0.005), overall survival in these patients did not differ from that in patients who did not develop CMV infection (P= 0.5). CONCLUSIONS: Valganciclovir is an effective antiviral for the prevention of CMV disease in liver transplant recipients. Our data support its use in high-risk OLT patients.

Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation.

BACKGROUND: JC virus (JCV) viruria is more common than BK virus (BKV) viruria in healthy individuals but in kidney transplants (KT), polyomavirus nephropathy (PVAN) is primarily caused by BKV. Few cases of PVAN have been attributed to JCV. Systematic studies on JCV replication in KT are lacking. METHODS: Out of a cohort of KT patients screened with urine cytology, patients shedding decoy cells were studied (n=103). Molecular studies demonstrated BKV, JCV, or BKV+JCV shedding in 58 (56.3%), 28 (27.2%), and 17 (16.5%), respectively. Biopsy was performed when decoy cells persisted 2 months or serum creatinine increased >20%. RESULTS: BKV viruria was strongly associated with BKV viremia (93%), PVAN (48%, P=0.01) and graft loss (P=0.03). Higher BKV viremia correlated with graft dysfunction (P=0.01), more advanced histological pattern of PVAN (P<0.0001), and more infected cells in biopsy (P=0.0001). BKV viremia of > or =10,000 copies/mL was significantly associated with histologically confirmed PVAN (P=0.0001). Reduction of immunosuppression lead to disappearance of decoy cells in patients shedding BK (>93%). JCV viruria, was more often asymptomatic (P=0.002) and affected older patients (P=0.02). JCV PVAN was less common (21.4%) and was characterized by sparse cytopathic changes but significant inflammation and fibrosis. JCV viremia was rare (14.2%), transient, and low (mean 2.0E+03/mL). After reduction of immunosuppression decoy cells persisted in >50% of patients with JCV (P=0.0001), but no graft loss occurred. During the period of the current study, the incidence of BKV-PVAN was 5.5% and the incidence of JCV-PVAN was 0.9%. CONCLUSIONS: The data point to significant differences of BKV and JCV biology regarding replication and disease in KT patients, with important implications for screening and management.

Shorter waitlist times and improved graft survivals are observed in patients who accept hepatitis C virus+ renal allografts.

BACKGROUND: There is a paucity of data regarding long-term renal graft survival in hepatitis C virus positive (HCV+) patients. We analyzed our institution's experience with HCV+ renal transplantation and factors contributing to subsequent renal graft failure. METHODS: We analyzed 1,679 adult, deceased donor, single-organ renal transplants occurring between 2000 and 2012. Recipient and donor demographics, HCV serostatus, and graft outcome and function were evaluated. RESULTS: Of 1,679 patients, 195 HCV+ recipients (R+) received renal transplants from HCV+ donors (D+), in contrast to 1,418 HCV negative (HCV-) recipients (R-) who received grafts from HCV- donors (D-), and 66 R+ patients who received D- kidneys. Death-censored graft survival in the R+/D+ population was better than graft survival for R+/D- patients, despite R+/D+ patients having higher rates of hypertension and African Americans. Waitlist times for patients accepting HCV+ grafts was 318 days (for R+/D+ patients) versus 613 days (R-/D-) or 570 days (R+/D-). On multivariate analysis, waitlist times were independently predictive of graft failure. CONCLUSION: R+/D+ patients spent less time on the transplant waitlist, which contributed to improved death censored graft survival when compared with R+/D- patients.

Histopathology of chronic rejection in a nonhuman primate model of vascularized composite allotransplantation.

BACKGROUND: Chronic rejection of vascularized composite allografts (VCA) is an emerging phenomenon that may decrease long-term allograft survival and impair allograft function. Although intimal hyperplasia has been reported in human hand transplants, chronic changes in VCAs remain poorly described. METHODS: We developed a nonhuman primate model of face transplantation to evaluate the effect of various immunosuppressive regimens on allograft survival that we have previously reported. Nineteen grafts were successfully transplanted and serially biopsied to assess for rejection. Five VCA grafts with long-term survival (>200 days) were weaned off immunosuppression. We performed additional histologic and immunohistochemical studies on previously collected samples. RESULTS: All five grafts developed features consistent with chronic rejection, including neointimal proliferation, transplant vasculopathy, vessel wall fibrosis, progressive luminal occlusion, and tertiary lymphoid follicles. Review of 186 serial allograft skin and subcutaneous tissue biopsies revealed that tertiary follicles and vascular changes developed in the absence of acute skin rejection. No relationship was found between alloantibody production and these changes. CONCLUSIONS: Recognition of these characteristics of VCA chronic rejection is important for diagnosis in clinical hand and face transplantation. Studies directed towards minimizing VCA chronic rejection responses may be required to improve long-term outcomes.

Regulatory T cells are not predictive of outcomes in a nonhuman primate model of vascularized composite allotransplantation.

BACKGROUND: T regulatory cells (Tregs) have been associated with prolonged allograft survival and tolerance across a wide variety of species and organ types. We used our nonhuman primate model of facial vascularized composite allotransplantation (VCA) to study the association of Tregs with graft outcomes. METHODS: We quantified Tregs in peripheral blood and allograft biopsies from nonhuman primates after heterotopic partial facial segment allotransplantation from major histocompatibility complex class I-mismatched donors using flow cytometry and immunohistochemistry. Immunosuppression consisted of tacrolimus and mycophenolate mofetil without induction or depletional therapies. Circulating and graft skin Treg values were compared with graft outcomes and with histologic grade from concurrent biopsies. RESULTS: Treg proportion in peripheral blood ranged from 0.156% to 9.00% with a mean of 3.34%±0.22%. FoxP3 staining was observed in 3 of 29 graft biopsies. Median circulating Treg value did not predict time to Banff grade II rejection (hazard ratio, 0.9; confidence interval, 0.4-2.2) or graft loss (hazard ratio, 0.5; confidence interval, 0.01-5.3). Animals that experienced rejection did not have significantly different peripheral blood or graft skin Treg values from those that did not. Biopsy specimens with grade I or II rejection were more likely to contain Tregs (25% vs. 0%; P=0.044) despite no difference in concurrent circulating Tregs (3.56% vs. 3.36%; P=0.704). CONCLUSIONS: These findings in a clinically relevant model suggest that Tregs may have limited prognostic value with standard immunosuppressive protocols used in VCA. Further studies are necessary to determine the specific role of Tregs in VCA and any role of Treg monitoring in clinical practice.

Endothelitis in cardiac allograft biopsy specimens: possible relationship to antibody-mediated rejection.

BACKGROUND: The incidence of endothelitis in cardiac transplants, and the relationship to clinical symptoms and humoral rejection, is unclear. Recently, the finding of intravascular macrophages has been found to represent antibody-mediated rejection. This study investigated the role of intravascular T lymphocytes in antibody-mediated rejection. METHODS: A total of 819 sequential biopsy specimens from 93 cardiac allograft recipients were prospectively studied. Rejection was graded according to International Society for Heart and Lung Transplantation (ISHLT) criteria and inflammatory infiltrates characterized by immunohistochemical staining for CD3, CD4, CD8, CD68, and CD20. Endothelitis was defined as lymphocyte and macrophage infiltrates within arteriolar, capillary, or venular walls, with endothelial swelling, in contrast to perivascular inflammation of cellular rejection. Complement C4d was identified in capillary walls by immunofluorescent staining and immunohistochemical staining on paraffin sections. RESULTS: Endothelitis was identified in 27 specimens (3%) from 14 patients (15%). ISHLT rejection grades were 0 in 6 specimens, 1R in 20 (1A in 8; 1B in 12), and 2R (3A) in 1. In all cases, there were admixtures of macrophages and T lymphocytes. Inflammation was most prominent in venules. C4d was localized in 12 of the 27 specimens (44%). C4d was localized in 31 of 796 specimens without endothelitis (p < 0.001). The endothelial infiltrates were CD3, CD4, CD8, and CD68+. Twelve of 14 patients had > 0 panel reactive antibodies (PRA), 9 were above 10%, and 8 were above 25%; 5 patients were treated for clinical antibody-mediated rejection, and 4 had possible cardiac allograft vasculopathy by ultrasound imaging (mean follow-up, 40 months). CONCLUSION: Endothelitis is present in more than 10% of heart transplant recipients and is associated with complement deposition on biopsy samples. Approximately 33% of patients have clinical evidence of humoral rejection. The eventual risk for developing graft vascular disease remains undetermined.

Glomerular inflammation in renal allografts biopsies after the first year: cell types and relationship with antibody-mediated rejection and graft outcome.

BACKGROUND: Antibody-mediated rejection manifests with glomerular and peritubular capillary inflammation and transplant glomerulopathy (TG). The role of glomerular inflammation (GI) components in the development of TG and their impact on outcome are incompletely understood. METHODS: GI was quantified on hematoxylin-eosin, CD3, CD20, and CD68 stains on biopsies from 240 patients with grafts functioning more than or equal to 1 year. RESULTS: A predominance of CD68+ cells followed by less numerous CD3+ cells was found in TG and glomerulitis. CD68+ cells more than 12 in the most inflamed glomerulus were strongly associated with TG, donor-specific antibody (DSA), and C4d staining. Glomerular CD68+ cells correlated with peritubular capillary multilamellation, and similarly, the Banff g score correlated with light and electron microscopic indexes of chronic microvascular damage. Overall, GI components correlated with the g score, DSA, and peritubular capillary C4d+. The Banff cg 1, 2, and 3 scores showed high levels of GI composed mostly of CD68+ cells, similar to but not higher than cases of g2 and g3 glomerulitis. Glomerular T cells and neutrophils followed similar trends as the predominant macrophages. T-cell-mediated rejection in this cohort did not significantly affect the composition of GI. Prognostically, all types of pronounced GI, g scores, DSA+, C4d+, and capillaropathy were associated with worse prognosis; however, only high level of macrophages was an independent predictor of graft failure. CONCLUSIONS: GI in more than or equal to 1 year grafts is mostly antibody-mediated rejection related, correlates with chronic microvascular damage, and consists predominantly of macrophages. The latter seem to represent a pivotal pathogenetic, diagnostic, and prognostic factor in this setting.

Deceased-donor renal transplantation in the geriatric population demonstrates equal graft survival compared with younger recipients.

BACKGROUND: Renal transplantation (RTx) in the geriatric population (age >65 years) accounts for 14% of all RTx performed nationally in 2007. METHODS: We reviewed 3297 RTx recipients from our database over a 15-year period to evaluate recipient and donor age, date of transplant and graft loss, cause of graft loss, and cold ischemic time in the geriatric population. RESULTS: Since 1991, we have performed 468 living donor RTx (LDRTx) and deceased donor RTx (DDRTx) in patients more than 65 years: 280 (65-69 years), 128 (70-74 years), and 60 (>75 years). Geriatric recipients of DDRTx demonstrated 83.0%, 74.1%, and 64.1% uncensored graft survival at 1, 3, and 5 years, respectively. Interestingly, these rates were similar compared with DDRTx in adults (18-64 years, P=0.49). Geriatric recipients of LDRTx demonstrated 1-year, 3-year, and 5-year graft survival rates of 94.3%, 88.8%, and 72.3%, respectively. Although better than geriatric DDRTx recipients, these results were not equal to the success of adult LDRTx recipients, potentially because of poorer graft survival in LDRTx recipients more than 75 years (P=0.004). Death-censored graft survivals were similar between adult and geriatric recipients of LDRTx (P=0.28). Graft loss secondary to death was twice as great in geriatric versus adult recipients (P<0.01). CONCLUSIONS: DDRTx geriatric recipients of each group showed similar uncensored graft survivals to adult DDRTx recipients. LDRTx had better outcomes than DDRTx in geriatric recipients. Death-censored outcomes were similar between adult and geriatric LDRTx recipients. These data support the equivalent outcomes of RTx in appropriately selected geriatric recipients.

Maintenance immunosuppressive agents as risk factors for BK virus nephropathy: a case-control study.

BACKGROUND: The specific role of different immunosuppressive agents as risk factors for BK virus nephropathy (BKN) has not been well studied. METHODS: In this case-control study, we examined the association of tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone with BKN in renal allograft recipients transplanted between 1997 and 2004 at our center who underwent biopsies for allograft dysfunction. Drug levels or doses were recorded during the 3 months before the index biopsy. Random effects logistic modeling was used for data analysis. RESULTS: There were 33 cases with BKN, biopsied at 16.4+/-2.8 months and 66 matched controls with biopsies at 21.5+/-2.1 months posttransplant (P=0.16). After adjusting for sex, race, retransplant status, diabetes, donor source, and induction agent, TAC blood level was associated with increased risk of BKN (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.02-1.7, P=0.03), whereas MMF dose was not (OR 1.0, 95% CI 0.99-1.0, P=0.2). Moreover, prednisone dose was also found to be a significant risk factor for BKN (OR 1.22, 95% CI 1.04-1.4, P=0.02). CONCLUSIONS: The results of this study show that BKN is associated with TAC level and prednisone dose and not with MMF dose. This suggests that reducing TAC and prednisone dose and maintaining MMF may be a more appropriate initial approach for the treatment of BKN. Further studies are needed to compare the efficacy and safety of this approach with the currently recommended one.

Pancreas transplant alone as an independent risk factor for the development of renal failure: a retrospective study.

BACKGROUND: Pancreas transplant alone (PTA) is a controversial procedure. Without clearly demonstrated patient survival, recipients report improved quality of life. Nephrotoxic immunosuppression (IS) may exacerbate diabetic renal injury post-PTA. METHODS: A single institution retrospective review of patients receiving PTA over a 14-year period was completed. Patient and donor demographics, surgical outcomes, rejection, and patient or graft survival were analyzed. Pre- and Postoperative estimated glomerular filtration rates (eGFR) were calculated based on the modification of diet and renal disease. Multivariate analysis was performed. RESULTS: One hundred twenty-three patients undergoing 131 PTAs had an average age of 40.0 years. Seven patients were retransplanted and one received a third pancreas. Mean graft survival was 3.26 years (0-11.3 years) with 21 patients (17%) lost to follow-up. One- and 5-year patient survivals were 96.6% and 91.5%, respectively (mean, 7.15 year). Seventeen patients had an eGFR less than 50 mL/min/1.73 m preoperatively, whereas 64 patients did so post-PTA and 24 had an eGFR less than 30 mL/min. Mean eGFR pretransplantation was 88.9 vs. 55.6 posttransplantation (P<0.0001) with mean follow-up of 3.68 years. All but 16 (12%) patients showed a decrease in eGFR. Mean decrement was 32.1 mg/min/1.73 m. Thirteen developed end-stage renal disease chronic kidney disease (CKD 5) requiring kidney transplantation (KT) at a mean of 4.36 years. Eighty-three patients had an episode of rejection. In post-PTA RF, graft survival was 3.2 vs. 2.4 years (P=0.13). In those requiring KT, graft survival was 7.9 vs. 2.9 years (P<0.0001). Cold ischemia times, donor age, and preoperative eGFR for those with and without RF-requiring KT were not significant. Body mass index was statistically significant. Leukocyte-depleting agents was evaluated, but was not significant. All patients received calcineurin inhibitor IS. CONCLUSIONS: Patients who undergo PTA may be at increased risk for RF. After comparing patient and donor demographics, IS, and human leukocyte antigen mismatch, it seems that PTA is an independent risk factor for the development of renal failure. Patients with more successful pancreatic grafts demonstrated lower eGFR. Patients should be made aware of the risks of long-term IS. Only the most appropriate patients should be chosen for PTA.