Robert S. Gaston

Interleukin-2–Receptor Blockade with Daclizumab to Prevent Acute Rejection in Renal Transplantation

Background Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen-reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the α chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation. Methods We administered daclizumab (1.0 mg per kilogram of body weight) or placebo intravenously before transplantation and once every other week afterward, for a total of five doses, to 260 patients receiving first cadaveric kidney grafts and immunosuppressive therapy with cyclosporine, azathioprine, and prednisone. The patients were followed at regular intervals for 12 months. The primary end point was the incidence of biopsy-confirmed acute rejection within six months after transplantation. Results Of the 126 patients given daclizumab, 28 (22 percent) had biopsy-confirmed episodes of acute rejection, as compared with 47 of the ...

Report of a National Conference on Donation after cardiac death.

A national conference on organ donation after cardiac death (DCD) was convened to expand the practice of DCD in the continuum of quality end‐of‐life care.

Evidence for antibody-mediated injury as a Major determinant of late kidney allograft failure

Background. Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF. Methods. One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3±6.0 years) had a baseline serum creatinine level of 1.4±0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7±1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations. Results. Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF. Conclusions. Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

Results of the double-blind, randomized, multicenter, phase III clinical trial of thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation

BACKGROUND Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Evaluation of living renal donors: The current practice of US transplant centers

To examine practice patterns regarding how living donors are evaluated and selected in the U.S., a survey was sent to all 231 United Network of Organ Sharing (UNOS)-approved transplant centers. Respondents from 75% of centers completed the questionnaire, all of whom utilize living donors for renal transplantation. Although the use of living-unrelated donors is also widely accepted (in 92% of centers), only 31% of responding centers performed such transplants in 1992, indicating a discrepancy between acceptance and actual practice. Morbidity (0.23%) and mortality (0.03%) of kidney donation continue to be low. The long-term risk of renal insufficiency in kidney donors appears to be similar to, or lower than, that in the general population. There is substantial variability in how potential donors are evaluated and what they are told regarding the risk involved in renal donation. There is also variability in exclusion criteria such as the acceptance of older donors (>55 years old); those with borderline-to-mild hypertension, and those with borderline low glomerular filtration rate. Larger centers tended to be less rigid in their exclusion criteria compared with smaller centers. While our results indicate widespread acceptance and use of living donors, they also highlight the need for future studies to examine the efficacy of tests used in the evaluation process and to determine the long-term risks of renal donation.

Kidney Transplantation as Primary Therapy for End-Stage Renal Disease: A National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQI™) Conference

BACKGROUND AND OBJECTIVES Kidney transplantation is the most desired and cost-effective modality of renal replacement therapy for patients with irreversible chronic kidney failure (end-stage renal disease, stage 5 chronic kidney disease). Despite emerging evidence that the best outcomes accrue to patients who receive a transplant early in the course of renal replacement therapy, only 2.5% of incident patients with end-stage renal disease undergo transplantation as their initial modality of treatment, a figure largely unchanged for at least a decade. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The National Kidney Foundation convened a Kidney Disease Outcomes Quality Initiative (KDOQI) conference in Washington, DC, March 19 through 20, 2007, to examine the issue. Fifty-two participants representing transplant centers, dialysis providers, and payers were divided into three work groups to address the impact of early transplantation on the chronic kidney disease paradigm, educational needs of patients and professionals, and finances of renal replacement therapy. RESULTS Participants explored the benefits of early transplantation on costs and outcomes, identified current barriers (at multiple levels) that impede access to early transplantation, and recommended specific interventions to overcome those barriers. CONCLUSIONS With implementation of early education, referral to a transplant center coincident with creation of vascular access, timely transplant evaluation, and identification of potential living donors, early transplantation can be an option for substantially more patients with chronic kidney disease.

Prevention of cardiovascular disease in adult recipients of kidney transplants

Although advances in immunosuppression, tissue typing, surgery, and medical management have made transplantation a routine and preferred treatment for patients with irreversible renal failure, successful transplant recipients have a greatly increased risk of premature mortality because of cardiovascular disease and malignancy compared with the general population. Conventional cardiovascular risk factors such as hyperlipidaemia, hypertension, and diabetes are common in transplant recipients, partly because of the effects of immunosuppressive drugs, and are associated with adverse outcomes. However, the natural history of cardiovascular disease in such recipients differs from that in the general population, and only statin therapy has been studied in a large-scale interventional trial. Thus, the management of this disease and the balance between management of conventional risk factors and modification of immunosuppression is complex.

The Report of a National Conference on the Wait List for Kidney Transplantation

In March, 2002, over 100 members of the transplant community assembled in Philadelphia for a meeting designed to address problems associated with the growing number of patients seeking kidney transplantation and added to the waiting list each year. The meeting included representatives of nine US organizations with interests in these issues. Participants divided into work groups addressing access to the waiting list, assigning priority on the list, list management, and identifying appropriate candidates for expanded criteria donor kidneys. Each work group outlined problems and potential remedies within each area. This report summarized the issues and recommendations regarding the waiting list for kidney transplantation addressed in the Philadelphia meeting.

Association of CD20+ Infiltrates with Poorer Clinical Outcomes in Acute Cellular Rejection of Renal Allografts

We undertook a study to ascertain the relationship between the presence of CD20‐positive B‐lymphocytes in renal allografts undergoing acute cellular rejection and graft survival. We identified 27 patients transplanted between January 1, 1998 and December 31, 2001, with biopsy‐proven Banff 1‐A or Banff 1‐B rejection in the first year after transplantation, and stained the specimens for CD20 and C4d. At least 4 years of follow‐up data were available for each patient studied. Six patients had CD20‐positive B‐cell clusters in the interstitium, and 21 patients were negative for CD20 infiltrates. The CD20‐positive group was significantly more likely to have steroid‐resistant rejection and reduced graft survival compared to CD20‐negative controls. This study supports prospective identification of CD20‐positive B‐cell clusters in biopsy‐proven rejection and offers a therapeutic rationale for a trial of monoclonal anti‐CD20 antibody in such patients.

Inflammation in Areas of Tubular Atrophy in Kidney Allograft Biopsies: A Potent Predictor of Allograft Failure

The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new‐onset late graft dysfunction (N = 337). We found inflammation (‘iatr’) and tubulitis (‘tatr’) in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death‐censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10–4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16–5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.