Anuja Mittalhenkle

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.

African American living-kidney donors should be screened for apol1 risk alleles

The adjusted rate of end-stage kidney disease (ESKD) among African Americans is markedly increased relative to European Americans. African Americans are overrepresented on the kidney transplantation waiting list and experience longer wait times. In aggregate, these pressures drive recommendations for living donor transplantation. Genovese et al. recently implicated the APOL1 gene in ESKD risk among African Americans (Genovese et al. Science 2010; 329: 841). The presence of two APOL1 risk alleles doubles the relative risk for ESKD; moreover, the alleles are prevalent among African Americans. We propose a strategy for screening for the presence of APOL1 risk alleles among African American living kidney donors and for living-related donors for African American recipients.

Pancreas Allograft Rejection: Analysis of Concurrent Renal Allograft Biopsies and Posttherapy Follow-Up Biopsies

Background. Pancreas and kidney allograft function is routinely monitored with serum studies (amylase, lipase, and creatinine). Increased levels commonly prompt tissue biopsy, to diagnose cause of graft dysfunction. Historically, pancreas allografts were infrequently biopsied, although serum enzymes and renal rejection may be poor surrogates for pancreas status. Methods. Pancreas allograft biopsies at our center were reviewed and reclassified according to University of Maryland (UMD) and Banff criteria; C4d immunostaining was performed. Findings were correlated with clinical data and renal allograft biopsies. Results. Fifty-six pancreas allograft biopsies from 27 patients were evaluated. UMD and Banff grading were similar, although two UMD “indeterminate” biopsies were Banff grade 1 rejection. There were 21 concurrent pancreas and renal biopsies, all from simultaneous pancreas-kidney allograft recipients. Thirteen pairs were concordant for rejection; eight pairs were discordant for rejection (38%); six pairs showed pancreas rejection without kidney rejection, and two pairs showed the converse. Fourteen patients had a total of 21 follow-up pancreas allograft biopsies. Seven biopsies showed a lower grade of rejection on follow-up biopsy, 4 biopsies showed more severe rejection, and 10 had unchanged grade. In only 9 of these 21 (43%) cases, did the interval serum amylase or lipase trend parallel the subsequent biopsy diagnosis. Conclusions. With a high biopsy discordance rate, our data suggest that renal allograft rejection is a poor surrogate for pancreas allograft status. Likewise, serum amylase and lipase levels do not predict response to rejection therapy. Surveillance or posttherapy pancreas allograft biopsies may be a useful means to monitor pancreas allograft status.

Cardiovascular Risk Factors and Incident Acute Renal Failure in Older Adults: The Cardiovascular Health Study

BACKGROUND AND OBJECTIVES Although the elderly are at increased risk for acute renal failure, few prospective studies have identified risk factors for acute renal failure in the elderly. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The associations of cardiovascular disease risk factors, subclinical cardiovascular disease, and clinical coronary heart disease with the risk for development of acute renal failure were examined in older adults in the Cardiovascular Health Study, a prospective cohort study of community-dwelling older adults. Incident hospitalized cases of acute renal failure were identified through hospital discharge International Classification of Diseases, Ninth Revision codes and confirmed through physician diagnoses of acute renal failure in discharge summaries. RESULTS Acute renal failure developed in 225 (3.9%) of the 5731 patients during a median follow-up period of 10.2 yr. In multivariate analyses, diabetes, current smoking, hypertension, C-reactive protein, and fibrinogen were associated with acute renal failure. Prevalent coronary heart disease was associated with incident acute renal failure, and among patients without prevalent coronary heart disease, subclinical vascular disease measures were also associated with acute renal failure: Low ankle-arm index (< or =0.9), common carotid intima-media thickness, and internal carotid intima-media thickness. CONCLUSIONS In this large, population-based, prospective cohort study, cardiovascular risk factors and both subclinical and clinical vascular disease were associated with incident acute renal failure in the elderly.

Late Steroid Withdrawal and Cardiovascular Events in Kidney Transplant Recipients

Introduction. Cardiovascular events (CVE) are the leading cause of mortality in kidney transplant recipients. The adverse effects of long-term therapy with steroids on cardiovascular risk have motivated increasing interest in steroid withdrawal (SW). The objective of this study was to compare the incidences of CVE and all-cause mortality between patients who had undergone SW at 1 year posttransplant and control patients who continued on steroids. Methods. A cohort of 400 consecutive adult recipients of a kidney transplant between 1993 and 1998 who qualified for late SW was studied. At 1 year posttransplant 188 patients underwent SW, whereas 212 patients continued on steroids. Cox proportional-hazards analysis was used to estimate CVE (cardiac and cerebrovascular events) and all-cause mortality hazard ratios (HR) for patients who had undergone SW versus controls who continued on steroids beyond 1 year. Results. The average follow-up was 61 months. There were 44 (11%) cardiac events, 18 (4.5%) cerebrovascular events, and 41 deaths (10.3%). The composite outcome of CVE and all-cause mortality was reached in 26 (13.8%) subjects who had undergone SW and 50 (23.6%) controls (P=0.013). In adjusted analyses, SW was associated with decreased risk for the composite outcome (HR 0.46, 95% confidence interval [CI] 0.28–0.76), cardiac events (HR 0.48, 95% CI 0.28–0.84), and all-cause mortality (HR 0.27, 95% CI 0.12–0.59). There was no association of SW with the risk for cerebrovascular events (HR 1.76, 95% CI 0.45–7.01). Conclusion. In this retrospective analysis, SW at 1 year posttransplant was associated with decreased risk for future CVE and all-cause mortality.

Long-Term Kidney Regraft Survival From Deceased Donors : Risk Factors and Outcomes in a Single Center

Background. Although survival of kidney regrafts is similar to that of primary grafts, risk factors associated with regraft survival have not been defined clearly. The aim of this study was to investigate risk factors for regraft outcome, including characteristics of the previous and current transplant, and time to retransplant. Methods. In a historical cohort study, 966 primary and 176 repeat deceased donor kidney graft recipients transplanted between January 1, 1990 and December 31, 2004 were studied. Cox regression analysis was used to estimate graft loss hazard ratios (HR) for regrafts versus primary grafts. Adjustments were made for recipient and donor demographics, transplant-related factors (transplant era, panel reactive antibodies, human leukocyte antigens mismatches, immunosuppression, delayed graft function, acute rejection [AR]), previous transplant characteristics (graft survival, graft loss because of AR), and time to retransplant. Results. A total of 508 kidney grafts were lost in the period between January 1990 and May 2007: 427 primary grafts and 81 regrafts. Regraft recipients had a covariate-adjusted 6% increase in graft loss (HR=1.06; P=0.69). Regraft loss was significantly associated with previous graft survival less than or equal to 1 year (HR=2.01; P=0.004), previous graft loss because of AR (HR=2.26; P=0.017) and time to retransplant more than 1 year (HR=2.42; P=0.002). Other significant predictors of regraft loss were diabetes (HR=1.81), donor age more than 50 years (HR=1.86) and delayed graft function after retransplant (HR=1.95). Conclusions. Kidney regrafts seem to have similar long-term outcome as primary grafts. However, additional risk factors significantly associated with regraft survival are previous graft survival, graft loss because of rejection, and time to retransplant.

Preserved Endocrine Function in a Pancreas Transplant Recipient with Pancreatic Panniculitis and Antibody-Mediated Rejection

Pancreas transplantation is an effective treatment option for patients with complicated diabetes mellitus. Pancreas allograft recipients are followed with laboratory markers such as serum amylase, lipase and glucose levels. Hyperglycemia may indicate severe acute rejection and has recently been associated with antibody‐mediated (humoral) rejection. In this report, we describe a unique case of a pancreas‐after‐kidney (PAK) transplant recipient with the rare presentation of pancreatic panniculitis, biopsy‐proven severe acute cellular and antibody‐mediated pancreas allograft rejection and surprisingly well‐preserved endocrine function despite treatment with high dose steroids. We discuss the clinicopathologic features of antibody‐mediated pancreas rejection, including the importance of correlating pancreas allograft biopsy, C4d staining and donor specific antibodies, to diagnose antibody‐mediated rejection and initiate the correct treatment.

Glomerular fibrin thrombi in ABO and crossmatch compatible renal allograft biopsies

Glomerular fibrin thrombi may be an early indication of antibody-mediated rejection in renal allograft biopsies. However, fibrin thrombi have a broad differential; thus, we sought to evaluate the etiology and implications of glomerular fibrin thrombi in allograft biopsies of blood group and cytotoxic crossmatch compatible renal allografts. Biopsies were identified from the pathology files of Oregon Health & Science University. Detailed histopathologic findings were retrospectively correlated with clinical data, treatment, and outcome. Sixteen early posttransplant biopsies had glomerular fibrin thrombi, including three surveillance biopsies. Six of 16 biopsies had no other histopathologic findings; 5/16 had glomerulitis and peritubular capillaritis; 4/16 had concomitant cellular vascular rejection; one had parenchymal infarction. C4d staining was positive in 4/16 cases. Most patients were treated with IVIg and plasmapheresis, others with rapamycin, thymoglobulin, or rituximab. At an average follow-up of 62 months, 8 patients with functioning grafts had a mean serum creatinine of 1.4 mg/dL (122 μmol/L). Antibody-mediated rejection is an important consideration in blood group compatible allograft biopsies with glomerular fibrin thrombi, even with C4d-negative biopsies. However, multidisciplinary evaluation is necessary, given other etiologies, including drug toxicity, hemolytic-uremia syndrome, and large vessel thrombosis. Despite aggressive treatment, both short and long-term graft survival may be compromised.

Acute Kidney Injury

Renal complications including acute kidney injury (AKI) and chronic kidney disease (CKD) are important complications following hematopoietic stem cell transplantation (HSCT). AKI requiring renal replacement therapy (RRT) in critically ill HSCT patients is associated with a poor prognosis. Mortality for patients receiving myeloablative allogeneic HSCTs who require dialysis exceeds 80%.