R. Munivenkatappa

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 ≥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.

The Maryland aggregate pathology index: a deceased donor kidney biopsy scoring system for predicting graft failure.

Despite the common use of diagnostic pretransplant deceased donor kidney biopsy, there is no consensus on the prognostic significance of the pathologic findings. In order to assist clinicians with interpretation we analyzed 371 pretransplant biopsies and correlated the findings with graft failure. Glomerular pathology was assessed with percent glomerulosclerosis (GS), glomerular size and periglomerular fibrosis (PGF); vascular pathology with arterial wall‐to‐lumen ratio (WLR) and arteriolar hyalinosis and interstitial pathology with measurement of cumulative fibrosis and presence of scar. Using two‐thirds of the study population as a model‐development cohort, we found that biopsy features independently associated with an increased risk of graft failure were GS ≥15%, interlobular arterial WLR ≥0.5 and the presence of PGF, arteriolar hyalinosis or scar. The Maryland Aggregate Pathology Index (MAPI), was developed from these parameters and validated on the remaining one‐third of the population. Five‐year actuarial graft survival was 90% for kidneys with MAPI scores between 0 and 7, 63% for scores from 8 to 11 and 53% for scores from 12 to 15 (p < 0.001). We conclude MAPI may help transplant physicians estimate graft survival from the preimplantation biopsy findings, in clinical situations similar to this study population (cold ischemia over 24 h, GS < 25%).

Guidelines for the Diagnosis of Antibody‐Mediated Rejection in Pancreas Allografts—Updated Banff Grading Schema

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T‐cell‐mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody‐mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad‐based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor‐specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

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.

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.

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.

Pancreas allograft biopsies with positive c4d staining and anti-donor antibodies related to worse outcome for patients.

C4d+ antibody‐mediated rejection following pancreas transplantation has not been well characterized. Therefore, we assessed the outcomes of 27 pancreas transplantation patients (28 biopsies), with both C4d staining and donor‐specific antibodies (DSA) determined, from a cohort of 257 patients. The median follow‐up was 50 (interquartile range [IQR] 8–118) months. Patients were categorized into 3 groups: group 1, patients with minimal or no C4d staining and no DSA (n = 13); group 2, patients with either DSA present but no C4d, diffuse C4d+ and no DSA or focal C4d+ and DSA (n = 6); group 3, patients with diffuse C4d+ staining and DSA (n = 9). Active septal inflammation, acinar inflammation and acinar cell injury/necrosis were significantly more abundant in group 3 than in group 2 (respective p‐values: 0.009; 0.033; 0.025) and in group 1 (respective p‐values: 0.034; 0.009; 0.002). The overall uncensored pancreas graft survival rate for groups 1, 2 and 3 were 53.3%, 66.7% and 34.6%, respectively (p = 0.044). In conclusion, recipients of pancreas transplants with no C4d or DSA had excellent long‐term graft survival in comparison with patients with both C4d+ and DSA present. Hence, C4d should be used as an additional marker in combination with DSA in the evaluation of pancreas transplant biopsies.

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 m2 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 m2. 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.

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.

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.