Effect of Treatment With Tabalumab, a B Cell-Activating Factor Inhibitor, on Highly Sensitized Patients With End-Stage Renal Disease Awaiting Transplantation.

B cell-activation factor (BAFF) is critical for B cell maturation. Inhibition of BAFF represents an appealing target for desensitization of sensitized end-stage renal disease (ESRD) patients. We conducted a Phase 2a, single-arm, open-label exploratory study investigating the effect of tabalumab (BAFF inhibitor) in patients with ESRD and calculated panel reactive antibodies (cPRAs) >50%. The treatment period duration was 24 weeks. Eighteen patients received tabalumab, at doses of 240-mg subcutaneous (SC) at Week 0 followed by 120-mg SC monthly for 5 additional months. Patients were followed for an additional 52 weeks. Immunopharmacologic effects were characterized through analysis of blood for HLA antibodies, BAFF concentrations, immunoglobulins, T and B cell subsets, as well as pre- and posttreatment tonsil and bone marrow biopsies. Significant reductions in cPRAs were observed at Weeks 16 (p = 0.043) and 36 (p = 0.004); however, absolute reductions were small (<5%). Expected pharmacologic changes in B cell subsets and immunoglobulin reductions were observed. Two tabalumab-related serious adverse events occurred (pneumonia, worsening of peripheral neuropathy), while the most common other adverse events were injection-site pain and hypotension. Three patients received matched deceased donor transplants during follow-up. Treatment with a BAFF inhibitor resulted in statistically significant, but not clinically meaningful reduction in the cPRA from baseline (NCT01200290, Clinicaltrials.gov).

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.

Donor horseshoe kidneys for transplantation.

BACKGROUND: Experience with donor horseshoe kidneys for transplantation is very limited. Currently, horseshoe kidneys may be underutilized for transplantation because of the greater incidence of vascular anomalies, associated renal anomalies, and predisposition to renal disease. METHODS: In this report, we review five transplantations using horseshoe kidneys: the largest reported institutional experience. In addition, a review of all published cases in the English literature is performed. RESULTS: All five patients underwent successful renal transplantations with a median follow-up of 35 months. One patient lost his kidney from recurrent disease soon after transplantation. CONCLUSION: With appropriate reconstruction of the vessels, careful division of the isthmus, and avoidance of ureteral obstruction, long-term data revealed good graft survival of donor horseshoe kidneys in renal transplantation.

Suppression of lymphocyte interleukin-2 receptor expression by glucocorticoids, cyclosporine, or both.

Although glucocorticoids and cyclosporine are frequently used to treat patients with various types of glomerulopathy, clinical responses to treatment vary considerably. Considerable interindividual heterogeneity in the suppressive effects of glucocorticoids on lymphocyte proliferation in vitro has been previously reported, suggesting that differences in the pharmacodynamic responsiveness of the immune system to these agents might be an important determinant of how well an individual patient responds to treatment. It also has been shown that methylprednisolone is significantly more suppressive than prednisolone. To identify cellular mechanisms by which these drugs act, a study of the suppressive effects of prednisolone, methylprednisolone, and cyclosporine on lymphocyte proliferation and the expression of the cell surface receptor for interleukin-2 (IL-2R) was conducted using phytohemagglutin-stimulated peripheral blood mononuclear cells (PBMCs) from 13 patients with glomerulopathy and 12 control subjects. Heterogeneity among individuals in both parameters of lymphocyte responsiveness to these drugs was again found, and the significantly greater suppressive effect of methylprednisolone was confirmed for both proliferation and IL-2R expression in patients and control subjects. Cyclosporine alone was moderately suppressive. For most individuals, the greatest degree of suppression occurred when cells were exposed to both cyclosporine and glucocorticoid. Further studies are being conducted to determine whether pretreatment assessment of in vitro lymphocyte responsiveness has any predictive value regarding therapeutic efficacy of each drug in individual patients and to identify of those patients likely to require a more intensive or multidrug immunosuppressive regimen.

Suppression of dialysis patients' lymphocyte IL-2R expression by glucocorticoids and cyclosporine.

Previous studies have shown interindividual heterogeneity in the suppressive effects of glucocorticoids and cyclosporine (CsA) on the proliferation responses of dialysis patients' peripheral blood mononuclear cells (PBMC). In addition, methylprednisolone (MP) was shown to be significantly more suppressive than prednisolone (P), and PBMC from patients on peritoneal dialysis (PD) were found to be more sensitive to both glucocorticoids than those from patients on haemodialysis (HD). In order to begin to explore the cellular mechanism(s) underlying these observations, the differential suppressive effects of these drugs on lymphocyte interleukin 2 receptor (IL-2R) expression by mitogen-stimulated PBMC from 23 PD and 30 HD were determined. The mean+/-SD concentrations (ng/ml) of steroid causing 50% inhibition (IC50) of cell proliferation was significantly lower for PD than HD PBMC with both P (94+/-93 vs 148+/-105, P<0.05) and MP (21+/-25 vs 35+/-31, P<0.05). MP was significantly (P<0.001) more suppressive than P of IL-2R expression in both PD and HD. PD IL-2R expression was significantly (P<0.05) more suppressed by CsA alone and by 400 ng/ml CsA+10(-7) MP than was HD IL-2R expression. CsA+10(-7) M MP was significantly (P<0.001) more suppressive of IL-2R expression than the other drugs, alone or in combination, in both groups of patients. In conclusion, these results support the notion that at least one mechanism underlying the significantly greater efficacy of MP compared to P in suppressing PBMC proliferation is its significantly greater suppression of lymphocyte IL-2R expression, either alone or in combination with CsA. Thus, use of MP following allograft transplantation may result in more effective immunosuppression for many recipients.