Millie Samaniego

Diagnosis and management of antibody-mediated rejection: Current status and novel approaches

Advances in multimodal immunotherapy have significantly reduced acute rejection rates and substantially improved 1‐year graft survival following renal transplantation. However, long‐term (10‐year) survival rates have stagnated over the past decade. Recent studies indicate that antibody‐mediated rejection (ABMR) is among the most important barriers to improving long‐term outcomes. Improved understanding of the roles of acute and chronic ABMR has evolved in recent years following major progress in the technical ability to detect and quantify recipient anti‐HLA antibody production. Additionally, new knowledge of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. Still, questions regarding the classification of ABMR, the precision of diagnostic approaches, and the efficacy of various strategies for managing affected patients abound. This review article provides an overview of current thinking and research surrounding the pathophysiology and diagnosis of ABMR, ABMR‐related outcomes, ABMR prevention and treatment, as well as possible future directions in treatment.

Solid-organ transplantation in older adults: Current status and future research

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short‐term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long‐term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans‐disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

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.

Choice of induction regimens on the risk of cytomegalovirus infection in donor‐positive and recipient‐negative kidney transplant recipients

F.L. Luan, M. Samaniego, M. Kommareddi, J.M. Park, A.O. Ojo. Choice of induction regimens on the risk of cytomegalovirus infection in donor‐positive and recipient‐negative kidney transplant recipients.
Transpl Infect Dis 2010: 12: 473–479. All rights reserved

Current outcomes of chronic active antibody mediated rejection – A large single center retrospective review using the updated BANFF 2013 criteria

BACKGROUND The updated BANFF 2013 criteria has enabled a more standardized and complete serologic and histopathologic diagnosis of chronic active antibody mediated rejection (cAMR). Little data exists on the outcomes of cAMR since the initiation of this updated criteria. METHODS 123 consecutive patients with biopsy proven cAMR (BANFF 2013) between 2006 and 2012 were identified. RESULTS Patients identified with cAMR were followed for a median of 9.5 (2.7-20.3) years after transplant and 4.3 (0-8.8) years after cAMR. Ninety-four (76%) recipients lost their grafts with a median survival of 1.9 years after diagnosis with cAMR. Mean C4d and allograft glomerulopathy scores were 2.6 ± 0.7 and 2.2 ± 0.8, respectively. 53.2% had class II DSA, 32.2% had both class I and II, and 14.5% had class I DSA only. Chronicity score >8 (HR 2.9, 95% CI 1-8.4, p=0.05), DSA >2500 MFI (HR 2.8, 95% CI 1.1-6.8, p=0.03), Scr >3mg/dL (HR 3.2, 95% CI 1.6-6.3, p=0.001) and UPC >1g/g (HR 2.5, 95% CI 1.4-4.5, p=0.003) were associated with a higher risk of graft loss. CONCLUSIONS cAMR was associated with poor graft survival after diagnosis. Improved therapies and earlier detection strategies are likely needed to improve outcomes of cAMR in kidney transplant recipients.

Preemptive kidney transplantation: Has it come of age?

The benefits of preemptive kidney transplantation are manifold. By avoiding complications associated with dialysis, preemptive kidney transplantation offers significant benefits in terms of patient welfare and societal cost-saving. Patients transplanted preemptively also tend to enjoy better patient and graft survival, especially when done with a living-donor organ. While dialysis exposure limited to 6 to 12 months may not significantly impact post-transplant outcomes, longer period of dialysis has been shown to increase the risk of mortality, delayed graft function, acute rejection, and death-censored graft loss. The benefits of preemptive transplantation also extend to different age groups and end-stage kidney disease (ESKD) diagnoses. However, multiple barriers have prevented wider adoption of preemptive transplantation as the primary treatment of ESKD around the world. Timely preparation for ESKD and identification of living donors should be encouraged in all patients with advanced chronic kidney disease to increase the chance of preemptive transplantation.

Transplantation in Diabetic Kidney Failure Patients: Modalities, Outcomes, and Clinical Management

Diabetes mellitus (DM) is a common and devastating disease, affecting up to 19.3 million Americans. It is the leading cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD) in the United States. Diabetic patients with ESRD have a high incidence of cardiovascular disease and death. For those kidney transplant patients with no history of DM prior to transplantation, the development of new onset diabetes after transplantation (NODAT) also poses a serious threat to both graft and patient survival. Kidney transplantation is the best renal replacement option for diabetic ESRD and has the potential to halt the progression of cardiovascular diseases. Early referral for transplant evaluation is essential for pre‐emptive or early kidney transplantation in this cohort of patients. In type 1 DM patients with ESRD, simultaneous pancreas and kidney transplantation (SPK) should be encouraged; and in patients facing prolonged waiting time for SPK transplantation but with an available living donor, living donor kidney transplantation followed by pancreas after kidney transplantation (PAK) is a suitable alternative. Islet transplantation in type 1 diabetics is deemed experimental by Medicare, and easy access to this modality remains restricted to qualified patients enrolled in clinical trials or with private insurance. The optimal management of kidney transplant patients with pre‐existent DM or NODAT involves a multi‐pronged approach consisting of pharmacological and nonpharmacological intervention to address all potential cardiovascular risk factors such as glycemic and lipid control, blood pressure control, weight loss, and smoking cessation. Finally, re‐transplantation should be recommended in suitable kidney transplant patients when the kidney allograft demonstrates continuous and progressive decline in function.

A history of chronic opioid usage prior to kidney transplantation may be associated with increased mortality risk.

Chronic opioid usage (COU) for analgesia is common among patients with end-stage renal disease. In order to test whether a prior history of COU negatively affects post-kidney transplant outcomes, we retrospectively examined clinical outcomes in adult kidney transplant patients. Among 1064 adult kidney transplant patients, 452 (42.5%) reported the presence of various body pains and 108 (10.2%) reported a prior history of COU. While the overall death or kidney graft loss was not statistically different between patients with and without a history of COU, the cumulative mortality rate at 1, 3, and 5 years after transplantation, and during the entire study period, appeared significantly higher for patients with than without a history of COU (6.5, 18.5, and 20.4 vs. 3.2, 7.5, and 12.7%, respectively). Multivariate Cox regression analysis adjusted for potential confounding factors in entire cohorts and Cox regression analysis in 1:3 propensity-score matched cohorts suggest that a positive history of COU was significantly associated with nearly a 1.6- to 2-fold increase in the risk of death (hazard ratio 1.65, 95% confidence interval 1.04-2.60, and hazard ratio 1.92, 95% confidence interval 1.08-3.42, respectively). Thus, a history of chronic opioid usage prior to transplantation appears to be associated with increased mortality risk. Additional studies are warranted to confirm the observed association and to understand the mechanisms.

Influence of Recipient Race on the Outcome of Simultaneous Pancreas and Kidney Transplantation

Racial differences on the outcome of simultaneous pancreas and kidney (SPK) transplantation have not been well studied. We compared mortality and graft survival of African Americans (AA) recipients to other racial/ethnic groups (non‐AA) using the national data. We studied a total of 6585 adult SPK transplants performed in the United States between January 1, 2000 and December 31, 2007. We performed multivariate logistic regression analyses to determine risk factors associated with early graft failure and immune‐mediated late graft loss. We used conditional Kaplan–Meier survival and multivariate Cox regression analyses to estimate late death‐censored kidney and pancreas graft failure and death between the groups. Although there was no racial disparity in the first 90 days, AA patients had 38% and 47% higher risk for late death‐censored kidney and pancreas graft failure, respectively (p = 0.006 and 0.001). AA patients were twice more likely to lose the kidney and pancreas graft due to rejection (OR 2.31 and 1.86, p = 0.002 and 0.008, respectively). Bladder pancreas drainage was associated with inferior patient survival (HR 1.42, 95% CI 1.15, 1.75, p = 0.001). In the era of modern immunosuppresion, AA SPK transplant patients continue to have inferior graft outcome. Additional studies to explore the mechanisms of such racial disparity are warranted.

Early hospital readmissions post-kidney transplantation are associated with inferior clinical outcomes.

Unplanned hospital readmissions are common early post‐kidney transplantation. We investigated the relationship between early hospital readmissions and clinical outcomes in a single‐center retrospective study that included all adult kidney transplant patients between 2004 and 2008 with follow‐up to December 2012. The early hospital readmissions within the first 30 d were numbered and the diagnosis ascertained. Patients were grouped as none, once, and twice or more readmissions. Predictors of early readmissions were assessed, and clinical outcomes and patient and death‐censored kidney survival were compared. Among 1064 patients, 203 (19.1%) patients had once and 83 (7.8%) patients had twice or more readmissions within 30 d. Surgical complications, infections, and acute kidney injuries/acute rejection were three most common diagnoses. The length of initial hospital stay and African American race were among the variables associated significantly with readmissions. Patients with early readmissions had lower baseline renal function (p < 0.01) and more early acute rejection (p < 0.01). During follow‐up, only frequent readmissions, twice or more, within 30 d were associated with increased risk of death (AHR 1.75, p = 0.01) and death‐censored kidney failure (AHR 2.20, p < 0.01). Frequent early hospital readmissions post‐transplantation identify patients at risk for poor long‐term outcomes, and more studies are needed to understand the mechanisms.