Very Early Cytomegalovirus Infection After Renal Transplantation: A Single-Center 20-Year Perspective.

BACKGROUND: Cytomegalovirus (CMV) infection risk in the first month after transplantation is felt to be minimal; however, the epidemiology has not been specifically investigated, particularly in the modern era of potent immunosuppressive regimens and universal CMV prophylaxis. OBJECTIVE: The aim of this study was to describe the incidence of and risk factors associated with CMV occurring less than 30 days after transplant and evaluate the effect of very early CMV on outcomes. METHODS: Retrospective, single-center study of adult renal transplant (RTX) recipients between January 1, 1994 and December 31, 2014. RESULTS: A total of 5225 patients who received a renal transplant in the study time period were reviewed for the presence of CMV infection occurring less than 30 days after transplant. Of these, only 14 patients demonstrated this finding for an overall incidence of 0.27%. Half of these patients were considered to be at heightened risk due to being a recipient of a non-primary transplant or on chronic immunosuppression. This left seven patients without known risk factors for very early CMV to evaluate. In this group, time from transplant to CMV infection was 13.5 ± 7 days. The majority (57.1%, n = 4) were high-risk serostatus (CMV D+/R-) and occurred in the valganciclovir era (71.4%, n = 5). Lymphocyte-depleting induction predominated (57.1%, n = 4). Average cold ischemic time (CIT) was 19.7 ± 7.7 hours. Three patients had post-operative complications, two required exploratory-laparotomy for hemorrhage. When evaluating outcomes, 43% (n = 3) had subsequent episodes of CMV infection, 28.6% (n = 2) developed rejection, and 28.6% (n = 2) died. Outcomes between patients with CMV infection less than 30 days and those with CMV infection more than 30 days after transplant were not significantly different. CONCLUSIONS: In our review of over 5000 kidney transplants, the incidence of CMV infection in the first 30 days after renal transplant is 0.2%. Notable common patient characteristics include hemorrhage requiring re-operation and prolonged CIT. Outcomes were similar to CMV occurring more than 30 days after transplant. This study should provide the clinician with some reassurance; despite potent immunosuppressive therapy, CMV infection in the first 30 days is unlikely.

Mood, body image, fear of kidney failure, life satisfaction, and decisional stability following living kidney donation: Findings from the KDOC study.

Prior studies demonstrate that most living kidney donors (LKDs) report no adverse psychosocial outcomes; however, changes in psychosocial functioning at the individual donor level have not been routinely captured. We studied psychosocial outcomes predonation and at 1, 6, 12, and 24 months postdonation in 193 LKDs and 20 healthy controls (HCs). There was minimal to no mood disturbance, body image concerns, fear of kidney failure, or life dissatisfaction, indicating no incremental changes in these outcomes over time and no significant differences between LKDs and HCs. The incidence of any new-onset adverse outcomes postdonation was as follows: mood disturbance (16%), fear of kidney failure (21%), body image concerns (13%), and life dissatisfaction (10%). Multivariable analyses demonstrated that LKDs with more mood disturbance symptoms, higher anxiety about future kidney health, low body image, and low life satisfaction prior to surgery were at highest risk of these same outcomes postdonation. It is important to note that some LKDs showed improvement in psychosocial functioning from pre- to postdonation. Findings support the balanced presentation of psychosocial risks to potential donors as well as the development of a donor registry to capture psychosocial outcomes beyond the mandatory 2-year follow-up period in the United States.

Direct and Indirect Costs Following Living Kidney Donation: Findings From the KDOC Study.

Some living kidney donors (LKDs) incur costs associated with donation, although these costs are not well characterized in the United States. We collected cost data in the 12 mo following donation from 182 LKDs participating in the multicenter prospective Kidney Donor Outcomes Cohort (KDOC) Study. Most LKDs (n = 167, 92%) had one direct cost or more following donation, including ground transportation (86%), health care (41%), meals (53%), medications (36%), lodging (23%), and air transportation (12%). LKDs missed 33 072 total work hours, 40% of which were unpaid and led to $302 175 in lost wages (mean $1660). Caregivers lost $68 655 in wages (mean $377). Although some donors received financial assistance, 89% had a net financial loss in the 12-mo period, with one-third (33%) reporting a loss exceeding $2500. Financial burden was higher for those with greater travel distance to the transplant center (Spearman's ρ = 0.26, p < 0.001), lower household income (Spearman's ρ = -0.25, p < 0.001), and more unpaid work hours missed (Spearman's ρ = 0.52, p < 0.001). Achieving financial neutrality for LKDs must be an immediate priority for the transplant community, governmental agencies, insurance companies, nonprofit organizations, and society at large.

Outpatient Management of Delayed Graft Function Is Associated With Reduced Length of Stay Without an Increase in Adverse Events.

Delayed graft function (DGF) is a common and costly complication of kidney transplantation. In July 2011, we established a multidisciplinary DGF clinic managed by nurse practitioners to facilitate early discharge and intensive management of DGF in the outpatient setting. We compared length of stay, 30-day readmission, acute rejection, and patient/graft survival in 697 consecutive deceased donor kidney transplantations performed between July 2009 and July 2014. Patients were divided into three groups: no DGF (n = 487), DGF before implementation of the DGF clinic (n = 118), and DGF clinic (n = 92). Baseline characteristics including age, gender, panel reactive antibody, retransplantation rates, HLA mismatches, induction, and maintenance immunosuppression were not significantly different between pre- and post-DGF clinic groups. Length of stay was significantly longer in pre-DGF clinic (10.9 ± 6.2 vs. 6.1 ± 2.1 days, p < 0.001). Thirty-day readmission (21% vs. 16%), graft loss (7% vs. 20%), and patient death (2% vs. 11%) did not differ significantly between pre- and post-DGF clinic. Patients in the DGF clinic were less likely to develop acute rejection (21% vs. 40%, p = 0.006). Outpatient management of DGF in a specialized clinic is associated with substantially shorter hospitalization and lower incidence of acute rejection without significant difference in 30-day readmission or patient and graft survival.

Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus.

This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

Predonation Direct and Indirect Costs Incurred by Adults Who Donated a Kidney: Findings From the KDOC Study.

Limited information exists on the predonation costs incurred by eventual living kidney donors (LKDs). Expenses related to completion of the donation evaluation were collected from 194 LKDs participating in the multi-center, prospective Kidney Donor Outcomes Cohort (KDOC) Study. Most LKDs (n = 187, 96%) reported one or more direct costs, including ground transportation (80%), healthcare (24%), lodging (17%) and air transportation (14%), totaling $101 484 (USD; mean = $523 ± 942). Excluding paid vacation or sick leave, donor and companion lost wages totaled $35 918 (mean = $187 ± 556) and $14 378 (mean = $76 ± 311), respectively. One-third of LKDs used paid vacation or sick leave to avoid incurring lost wages. Few LKDs reported receiving financial support from the transplant candidate (6%), transplant candidate's family (3%), a nonprofit organization (3%), the National Living Donor Assistance Center (7%), or transplant center (3%). Higher total costs were significantly associated with longer distance traveled to the transplant center (p < 0.001); however, total costs were not associated with age, sex, race/ethnicity, household income, marital status, insurance status, or transplant center. Moderate predonation direct and indirect costs are common for adults who complete the donation evaluation. Potential LKDs should be advised of these possible costs, and the transplant community should examine additional strategies to reimburse donors for them.

Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care.

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.

The independent living donor advocate: a guidance document from the American Society of Transplantation's Living Donor Community of Practice (AST LDCOP).

The independent living donor advocate (ILDA) serves a mandated and supportive role in the care of the living organ donor, yet qualifications and role requirements are not clearly defined. Guidance comes from Centers for Medicare and Medicaid Services (CMS) Conditions for Transplant Center Participation and interpretive guidelines, Organ Procurement and Transplantation Network (OPTN) Policy and CMS and OPTN site surveys, yet interpretation of regulations varies. Herein, the AST Living Donor Community of Practice (LDCOP) offers seven recommendations to clarify and optimize the ILDA role: (a) the ILDA must have a certain skill set rather than a specific profession, (b) the ILDA must be educated and demonstrate competence in core knowledge components, (c) the ILDA's primary role is to assess components of informed consent, (d) centers must develop a transparent system to define ILDA independence, (e) the ILDA should have a reporting structure outside the transplant center, (f) the ILDA's role should be integrated throughout the donor care continuum, (g) the ILDA role should include a narrow "veto power." We address controversies in ILDA implementation, and offer pathways to maximize benefits and minimize limitations of approaches that may each meet regulatory requirements but confer different practice benefits. We propose a research agenda to explore the impact of the ILDA.

Disclosing recipient information to potential living donors: preferences of donors and recipients, before and after surgery.

Consensus guidelines, while recommending that potential living donors should be given information that could impact their donation decision, are nonspecific about the types of information that should be disclosed. We surveyed potential (n = 36) and past (n = 45) living donors and transplant candidates (n = 45) and recipients (n = 45) about their preferences for sharing or knowing specific information about the recipient, how this information would impact decision-making, and who should be responsible for disclosing information. Potential donors were less likely than all others to feel that recipient information should be disclosed to potential donors. Donors and recipients felt most strongly about disclosing if the recipient lost a previously transplanted kidney due to medication nonadherence as well as the likelihood of 1- and 5-year graft survival. Most donors would be less likely to pursue donation if the recipient lost a previously transplanted kidney due to medication nonadherence or generally had problems with taking medications as prescribed. Transplant programs should consider how to best balance the potential donor's right to receive information that could reasonably be expected to affect their decision-making process with the recipient's right to privacy and confidentiality.

Evaluating living kidney donors: relationship types, psychosocial criteria, and consent processes at US transplant programs.

We conducted a survey of 132 US kidney transplant programs to examine how they evaluate and select potential living kidney donors, focusing on donor-recipient relationships, psychosocial criteria, and consent processes. There is heterogeneity in donor-recipient relationships that are considered acceptable, although most programs (70%) will not consider publicly solicited donors. Most programs (75%) require a psychosocial evaluation for all potential living donors. Most programs agree that knowledge of financial reward (90%), active substance abuse (86%), and active mental health problems (76%) are absolute contraindications to donation. However, there is greater variability in how other psychosocial issues are considered in the selection process. Consent processes are highly variable across programs: donor and recipient consent for the donor evaluation is presumed in 57% and 76% of programs, respectively. The use of 13 different informed consent elements varied from 65% (alternative donation procedures) to 86% (description of evaluation, surgery and recuperative period) of programs. Forty-three percent use a 'cooling off' period. Findings demonstrate high variability in current practice regarding acceptable donor-recipient relationships, psychosocial criteria, and consent processes. Whether greater consensus should be reached on these donor evaluation practices, especially in the context of more expansive use of living donor kidney transplantation, is discussed.

The medical evaluation of living kidney donors: a survey of US transplant centers.

The use of living donors for kidney transplantation in the United States is common, and long-term studies have demonstrated the safety of donation by young, healthy individuals. However, transplant programs have little data to guide them in deciding which donors are unacceptable, and which characteristics are associated with kidney disease or poor psychosocial outcomes after donation. To document current practices in evaluating potential donors, we surveyed all US kidney transplant programs. Compared to a survey 12 years ago, medical criteria for donation are more inclusive in several areas. All responding programs now accept living unrelated donors. Most programs no longer have an upper age limit to be eligible. Programs are now more likely to accept donors with treated hypertension, or a history of kidney stones, provided that certain additional criteria are met. In contrast, medical criteria for donation are more restrictive in other areas, such as younger donor age and low creatinine clearance. Overall, significant variability remains among transplant programs in the criteria used to evaluate donors. These findings highlight the need for more data on long-term outcomes in various types of donors with potential morbidities related to donation.

Efficacy of anti-IL-2 receptor antibodies compared to no induction and to antilymphocyte antibodies in renal transplantation.

The relative efficacy of anti-IL-2 receptor antibodies (IL2R Abs) and antilymphocyte antibodies in preventing acute rejection and improving graft survival after renal transplantation is poorly defined. In particular, the benefits of these agents in specific subgroups, such as recipients with different degrees of HLA mismatch, are unknown. Using the SRTR database, we compared IL2R Abs to no induction and to antilymphocyte antibody induction in 48 948 first renal transplant recipients in the United States between 1998 and 2003 with respect to acute rejection and graft failure. IL2R Abs decreased acute rejection at 6 months (OR: 0.81(0.75-0.87)), and reduced graft failure (HR: 0.90(0.84-0.95)), compared to no induction over a follow-up of 1059 days. Compared to IL2R Abs, antilymphocyte Abs were associated with decreased acute rejection (OR: 0.90(0.83-0.99)) at 1 year, but were not associated with improved graft survival (OR: 1.08(1.00-1.18)) over a follow-up of 732 days. The benefit of IL2R Abs in reducing acute rejection increased significantly with greater HLA mismatch (p = 0.007). IL2R Abs remain an important option in the management of renal transplant patients, and may be particularly useful in specific patient subsets.

Rejection of mouse cardiac allografts by costimulation in trans.

The activation of T cells by B7 costimulation in trans has been demonstrated in vitro, but the in vivo relevance is unknown. To study costimulation in trans of CD4(+) T cells in vivo, we performed cardiac transplants from B7-1/B7-2-deficient mice to recipients that do not express MHC class II molecules on peripheral APCs, but do have functional CD4(+) T cells (II(-)/4(+) mice). This model restricts the B7-dependent activation of CD4(+) T cells to costimulation in trans and excludes any contribution from indirect Ag presentation. We find that II(-)/4(+) recipients reject B7-deficient grafts as rapidly as wild-type grafts, suggesting that costimulation in trans can mediate rejection as potently as costimulation in cis. Treatment of II(-)/4(+) recipients of B7-deficient grafts with depleting Abs to CD4 or CD8 demonstrates that indirect Ag presentation to CD8(+) cells does not significantly contribute to rejection. This is the first demonstration that costimulation in trans can mediate an immune response in vivo and has important therapeutic implications.

CD28-independent costimulation of T cells in alloimmune responses.

T cell costimulation by B7 molecules plays an important role in the regulation of alloimmune responses. Although both B7-1 and B7-2 bind CD28 and CTLA-4 on T cells, the role of B7-1 and B7-2 signaling through CTLA-4 in regulating alloimmune responses is incompletely understood. To address this question, we transplanted CD28-deficient mice with fully allogeneic vascularized cardiac allografts and studied the effect of selective blockade of B7-1 or B7-2. These mice reject their grafts by a mechanism that involves both CD4(+) and CD8(+) T cells. Blockade of CTLA-4 or B7-1 significantly accelerated graft rejection. In contrast, B7-2 blockade significantly prolonged allograft survival and, unexpectedly, reversed the acceleration of graft rejection caused by CTLA-4 blockade. Furthermore, B7-2 blockade prolonged graft survival in recipients that were both CD28 and CTLA-4 deficient. Our data indicate that B7-1 is the dominant ligand for CTLA-4-mediated down-regulation of alloimmune responses in vivo and suggest that B7-2 has an additional receptor other than CD28 and CTLA-4 to provide a positive costimulatory signal for T cells.

B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4.

To examine whether B7 costimulation can be mediated by a molecule on T cells that is neither CD28 nor CTLA4, we generated mice lacking both of these receptors. CD28/CTLA4(-/-) mice resemble CD28(-/-) mice in having decreased expression of T-cell activation markers in vivo and decreased T-cell proliferation in vitro, as compared with wild-type mice. Using multiple approaches, we find B7-dependent costimulation in CD28/CTLA4(-/-) mice. The proliferation of CD28/CTLA4(-/-) T cells is inhibited by CTLA4-Ig and by the use of antigen-presenting cells lacking both B7-1 and B7-2. CD28/CTLA4(-/-) T-cell proliferation is increased by exposure to Chinese hamster ovary cells transfected with B7-1 or B7-2. Finally, administration of CTLA4-Ig to CD28/CTLA4(-/-) cardiac allograft recipients significantly prolongs graft survival. These data support the existence of an additional receptor for B7 molecules that is neither CD28 nor CTLA4.

Association of B7-1 co-stimulation with the development of graft arterial disease. Studies using mice lacking B7-1, B7-2, or B7-1/B7-2.

To investigate the roles of B7-1 and/or B7-2 co-stimulatory molecule in the development of graft arterial disease (GAD), major histocompatibility complex (MHC) class II-mismatched allograft hearts were transplanted into wild-type, B7-1(-/-), B7-2(-/-), or B7-1/B7-2(-/-) recipient mice. Grafts were explanted at 4 or 8 weeks and used for histological and immunohistochemical analyses, RNase protection assay, and flow cytometry of graft infiltrating cells. Grafts in wild-type recipients showed macrophage, recipient MHC class II, and B7 molecule co-localization by immunohistochemistry to GAD lesions. Flow cytometry revealed that CD11b(+) and MHC class II(+) graft infiltrating cells expressed B7-1 more than B7-2, whereas B7-2 expression was predominant in CD11b(-) cells at 4 and 8 weeks. GAD was significantly attenuated in the allografts in B7-1(-/-) and B7-1/B7-2(-/-) but not in B7-2(-/-) recipients compared to wild-type hosts. Interferon-gamma mRNA levels were comparable in all graft combinations, whereas interleukin-4 mRNA levels decreased in grafts in B7-2 deficient hosts, but did not correlate with GAD attenuation. The findings indicate distinct roles for B7-1 and B7-2 co-stimulatory molecules in the development of GAD, potentially because of differential expression of B7-1 and B7-2 molecules on distinct stimulator and/or effector cell populations.

Molecular basis for leukocyte integrin alpha(E)beta(7) adhesion to epithelial (E)-cadherin.

Cadherins are expressed in tissue-restricted patterns and typically mediate homophilic adhesion. Cadherins also mediate lymphocyte adhesion, providing the opportunity for lymphocyte attachment to parenchymal cells. The best characterized example of lymphocyte adhesion to a tissue-specific cell adhesion molecule, as opposed to a vascular endothelial adhesion molecule, is the interaction between integrin alpha(E)beta(7) on intraepithelial lymphocytes and E-cadherin on epithelial cells. However, the molecular basis for an integrin-cadherin interaction is not well defined. Realization that the cadherin domain adopts a topology similar to the immunoglobulin (Ig) fold suggested that integrin recognition of E-cadherin might be similar to recognition of Ig superfamily ligands. Thus, we modeled domain 1 of human E-cadherin and studied the role of solvent-exposed loops that connect Ig-like core-forming beta strands. Mutational analyses localized the integrin alpha(E)beta(7) recognition site to the top of domain 1 at the face formed by the BC and FG loops, a site distinct from the region recognized in intercellular adhesion molecule (ICAM)-1, -2, and -3, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), vascular cell adhesion molecule 1 (VCAM-1), and fibronectin by their integrin ligands. Moreover, the integrin alpha(E)beta(7) binding site is distinct from the homophilic binding site on E-cadherin. These studies provide a conceptual basis for integrin-cadherin binding and extend the model that an Ig-like fold can serve as a scaffold for recognition.