Abdolreza Haririan

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.

Positive Cross-Match Living Donor Kidney Transplantation: Longer-Term Outcomes

The long‐term graft outcomes after positive cross‐match (PXM) living donor kidney transplantation (LDKT) are unknown and the descriptive published data present short‐medium term results. We conducted a retrospective cohort study of LDKT with PXM by flow cytometry performed at our center during February 1999 to October 2006, compared to a control group, matched 1:1 for age, sex, race, retransplantation and transplant year. The PXM group was treated with a course of plasmapheresis/low‐dose intravenous immunoglobulin (IVIg) preoperatively, and OKT3 or thymoglobulin induction.

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.

Polyomavirus nephropathy in native kidneys of a solitary pancreas transplant recipient.

Background. Latent polyomavirus (PV) infection of the urinary tract can be reactivated by immunosuppression. When this occurs in the renal allograft, permanent loss of allograft function can occur. Polyomavirus reactivation could potentially affect the native kidneys of nonrenal transplant recipients and cause renal dysfunction. Methods. This article describes a case of PV nephropathy in the native kidneys of a solitary-pancreas transplant recipient. This patient had a progressive increase in serum creatinine. Screening urine cytology showed numerous cells with cytopathic changes suggestive of polyomavirus infection. Results. Biopsy of the native kidneys of this patient showed renal tubular cells with intranuclear inclusions characteristic of PV infection, which was confirmed by immunohistochemistry. Electron microscopy showed intranuclear viral particles. Patchy inflammation and fibrosis also were noted. Conclusion. Polyomavirus reactivation can occur in the native kidneys of nonrenal solid organ transplant recipients. This should be considered in the differential diagnosis of renal impairment in these patients. The effects of PV reactivation on long-term native kidney function are not known.

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.

The Impact of C4d Pattern and Donor-Specific Antibody on Graft Survival in Recipients Requiring Indication Renal Allograft Biopsy

We examined the pattern of PTC C4d by immunohistochemistry and DSA in 297 kidney recipients with indication biopsies, and evaluated their predictive value for graft survival. Median biopsy time was 5.1 months posttransplant. Patients were followed for 17.9 ± 9.4 months postbiopsy. An 18.5% had focal and 15.2% had diffuse C4d, with comparable graft survival (adjusted graft failure HR: 2.3, p = 0.001; HR:1.9, p < 0.02, respectively). 31.3% were DSA+, 19.5% class I and 22.9% class II DSA. Only those with class II DSA had worse outcome (adjusted HR:2.5, p = 0.001 for class II only; HR:2.7, p < 0.001 for class I/II DSA). Among patients with <10%C4d, 23.9% had DSA, compared to 68.9% with diffuse staining. For patients biopsied in first‐year posttransplant presence of DSA, regardless of C4d positivity in biopsy, was a poor prognostic factor (adjusted graft failure HR: 4.2, p < 0.02 for C4d−/DSA+; HR:4.9, p = 0.001 for C4d+/DSA+), unlike those biopsied later. We have shown that focal C4d had similar impact on graft survival as diffuse pattern. During the first‐year posttransplant either class I or II DSA, and afterward only class II DSA were associated with worse graft survival. DSA was predictive of worse outcome regardless of C4d for patients biopsied in first year and only with C4d positivity afterward, supporting the importance of assessment of both DSA and C4d pattern in biopsy.

The Detrimental Effect of Poor Early Graft Function After Laparoscopic Live Donor Nephrectomy on Graft Outcomes

We undertook this study to assess the rate of poor early graft function (EGF) after laparoscopic live donor nephrectomy (lapNx) and to determine whether poor EGF is associated with diminished long‐term graft survival. The study population consisted of 946 consecutive lapNx donors/recipient pairs at our center. Poor EGF was defined as receiving hemodialysis on postoperative day (POD) 1 through POD 7 (delayed graft function [DGF]) or serum creatinine ≥ 3.0 mg/dL at POD 5 without need for hemodialysis (slow graft function [SGF]). The incidence of poor EGF was 16.3% (DGF 5.8%, SGF 10.5%), and it was stable in chronologic tertiles. Poor EGF was independently associated with worse death‐censored graft survival (adjusted hazard ratio (HR) 2.15, 95% confidence interval (CI) 1.34–3.47, p = 0.001), worse overall graft survival (HR 1.62, 95% CI 1.10–2.37, p = 0.014), worse acute rejection‐free survival (HR 2.75, 95% CI 1.92–3.94, p < 0.001) and worse 1‐year renal function (p = 0.002). Even SGF independently predicted worse renal allograft survival (HR 2.54, 95% CI 1.44–4.44, p = 0.001). Risk factors for poor DGF included advanced donor age, high recipient BMI, sirolimus use and prolonged warm ischemia time. In conclusion, poor EGF following lapNx has a deleterious effect on long‐term graft function and survival.

The independent association between serum uric acid and graft outcomes after kidney transplantation.

Background. Improving long-term outcomes of kidney transplantation depends on identifying novel risk factors that lead to poor outcomes. We sought to evaluate the predictive value of mean uric acid (UA) level during the first 6 months posttransplant for graft survival and function. Methods. Two hundred twelve recipients of living donor kidneys transplanted during January 2000 to December 2001 were included. The study outcome included graft and patient survival and graft function at 1 year posttransplant. Regression models were used to adjust for the confounding variables including graft function during first 6 months. Results. During 68.3±27.2 months follow-up, UA level (mg/dL) and hyperuricemia (n=45) were associated with graft loss (hazard ratio [HR]=1.26, P=0.026, 95% confidence interval [CI]=1.03–1.53, and HR=1.92, P=0.029, 95% CI=1.1–3.4, respectively) independent of graft function and other confounders. UA also seemed to be associated with risk of death with borderline significance (HR=1.2, P=0.096, 95% CI=0.97–1.46). Examining the predictive value for graft function, UA level and hyperuricemia were independent predictors of 1-year serum creatinine (&bgr;=0.10, P=0.013, 95% CI=0.02–0.18, and &bgr;=0.25, P<0.04, 95% CI=0.01–0.49, respectively). Similarly, both were associated with 1-year estimated glomerular filtration rate (&bgr;=−3.9, P<0.001, 95% CI=−5.7 to −1.5 for UA, and &bgr;=−7.6, P<0.02, 95% CI=−13.6 to −1.5 for hyperuricemia). Notably, these associations were all independent of renal function during first 6 months. Conclusion. The results of this study suggest that mean UA level during the first 6 months posttransplant is an independent predictor of long-term graft survival and short-term graft function. Further investigations are needed to evaluate its causal association with chronic allograft injury and cardiovascular disease.