Ronald H. Kerman

Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection.

Antibody‐mediated rejection (AbAR) is increasingly recognized in the renal allograft population, and successful therapeutic regimens have been developed to prevent and treat AbAR, enabling excellent outcomes even in patients highly sensitized to the donor prior to transplant. It has become critical to develop standardized criteria for the pathological diagnosis of AbAR. This article presents international consensus criteria for and classification of AbAR developed based on discussions held at the Sixth Banff Conference on Allograft Pathology in 2001. This classification represents a working formulation, to be revisited as additional data accumulate in this important area of renal transplantation.

POSSIBLE CONTRIBUTION OF PRETRANSPLANT IMMUNE RESPONDER STATUS TO RENAL ALLOGRAFT SURVIVAL DIFFERENCES OF BLACK VERSUS WHITE RECIPIENTS

Black end-stage renal disease patients may present as an immunologically higher-risk group for renal allograft transplantation than white ESRD patients. To test this hypothesis, we correlated graft survivals in 124 black and 241 white cyclosporine-prednisone-treated primary cadaveric renal allograft recipients with pre-Tx nonspecific immune responder status (strong vs. weak immune responders), donor-recipient-specific MLC responsiveness, HLA match, and blood transfusion (BT) history. One-, 2- and 3-year patient survival rates of 95%, 94%, and 94% were identical for both groups. However, the 1-, 2-, 3-year graft survival rates for white recipients of 82%, 79%, and 75% were significantly higher than the 70%, 62%, and 55% rates for black recipients (P less than 0.01 for each, respectively). Pre-Tx nonspecific immune response values for blacks were significantly (P less than 0.01) higher than for whites (38% vs. 28% for active T cell; 1.8 vs. 1.3 for TH:TS ratio; 28,581 c.p.m. vs. 14,870 c.p.m. for spontaneous blastogenesis; and a stimulation index (SI) of 34 vs. 20 for panel mixed lymphocyte culture). Additionally, the specific recipient-donor MLC (SI) for black recipients was significantly greater than the specific recipient-donor MLC for white recipients (MLC SI of 40 vs. 18, P less than 0.01). Blacks present as pre-Tx strong immune responders with a greater frequency than whites (90% vs. 66%, P less than 0.01). Moreover, black strong responders experience a poorer 1-year graft survival than white strong responders (67% vs. 80%, P less than 0.01). Even though the pre-Tx BT histories of white and black ESRD patients studied herein were comparable, the immunoregulatory effect of pre-Tx BT was different in white vs. black patients. A significant reduction in TH:TS ratio was observed when comparing 0 vs. 1-4 pre-Tx white patient BT groups, whereas significant changes in TH:TS ratios were not observed until after comparing 0 vs. greater than or equal to 5 pre-Tx black patient BT groups. HLA matching and pre-Tx BT had no impact on improving the graft survivals of these CsA-Pred-treated white or black recipients. These data, therefore, support the hypothesis that black recipients present as an immunologically higher-risk group than white recipients.

Report from a consensus conference on the sensitized patient awaiting heart transplantation.

A consensus conference took place on April 8, 2008 to assess the current status of sensitization in the pre–heart transplant patient, the use and efficacy of desensitization therapies, and the outcome of desensitized patients after heart transplantation. The conference had 71 participants (transplant cardiologists, surgeons, immunologists and pathologists; see Appendix) representing 51 heart transplant centers from North America, Europe, Asia and Australia. Prior to the conference, survey data (regarding the sensitized patient) were submitted by 23 of the 51 centers participating in the conference (Table 1).

Impact of rituximab therapy for treatment of acute humoral rejection

Abstract:  Introduction:  Antibody mediated rejection (AMR) is associated with a greater incidence of allograft loss because traditional approaches ‐ pulse steroid or anti‐lymphocyte antibodies are usually ineffective. This retrospective analysis documented the benefit of rituximab administration in addition to plasmapheresis (PP).

Evolution of HLA antibody detection: technology emulating biology.

New technological advances in the field of histocompatibility have provided an approach to system atically address the specificity of positive lymphocyte crossmatches. These approaches can now confirm whether a positive crossmatch is (or is not) due to class I and/or class II antibodies directed against donor HLA antigens. The information gained from the application of these sensitive and specific technologies can be used to predict crossmatch results for highly sensitized patients. In summary, these emerging technologies have provided the tools to reliably determine the clinical relevance of a positive lymphocyte crossmatch.

Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience.

ON APRIL 13, 1993, a phase I trial was initiated to assess the safety and pharmacokinetic behavior of ascending doses of a new immunosuppressant discovered by Sehgal and applied in animal transplant models by Calne et al and Morris et al. Forty stable renal transplant patients who received either the oral liquid formulation of sirolimus (SRL) or placebo, displayed only modest adverse reactions. Drug development proceeded rapidly through a subsequent phase I/II study of de novo drug administration which confirmed the safety and documented the efficacy of a sirolimus-cyclosporine (CsA) combination to reduce the incidence of acute rejection episodes. The first multicenter phase II trial showed that reduced doses of CsA were efficacious in non–African Americans when administered in combination with sirolimus. The pivotal phase III trials performed in the United States (US) and across the world (Global) demonstrated the benefit of a sirolimus-CsAPrednisone (Pred) regimen for acute rejection prophylaxis, leading to approval by the US Food and Drug Administration (FDA). This contribution reviews not only the milestones up to FDA approval, but also our present strategies, as utilized in 1008 renal transplant recipients, to deliver the maximal benefit of sirolimus with minimal CsA exposure, thereby reducing the hazards of chronic immunosuppression.

Production of synergistic but nonidentical mechanisms of immunosuppression by rapamycin and cyclosporine.

We report that the mechanism of rapamycin (RAP) inhibition is synergistic, but nonidentical, to the mechanism of CsA inhibition. Like CsA, RAP inhibits T cell proliferation following mitogen (PHA) and/or alloantigen (MLR) stimulation. RAP levels of 100, 33, 11, 3.6, 1.2, and less than 1 ng/ml reduced PHA stimulation by 81%, 84%, 81%, 83%, 62%, and 33%, respectively, without cytotoxicity. The RAP concentration required to achieve 50% proliferative inhibition of either mitogen (PHA) or MLR assays revealed an interindividual variability of 5 pg/ml RAP (2 individuals), 1 ng/ml (3 individuals), and 100 ng/ml (2 individuals). Unlike CsA, RAP proliferative inhibition was not restricted to the G0 phase of the cell cycle. Addition of 100, 10, or 1 ng/ml RAP at the onset (G0), or 24 hr following cultivation (G1) similarly inhibited DNA synthesis by 42%, 42%, and 41% compared with 44%, 48%, and 47%, respectively. PWM-stimulated B cell proliferation was primarily RAP-sensitive during the G0 phase of the cell cycle. RAP at 100, 10, and 1 ng/ml inhibited B cell proliferation 46%, 51%, and 50% when added during G0 but only 15%, 20%, and 20% when added during G1. Generation of a cyclosporine-sensitive cytoplasmic activation signal, activator of DNA replication (ADR), was reduced by RAP. RAP reduction did not correlate directly with T cell proliferative inhibition (as does CsA). RAP-induced proliferative inhibition of 40% and 80% resulted in ADR inhibition of 16% and 33%. Proliferative inhibition was synergistically increased when CsA and RAP were used in combination, whereas ADR inhibition was only additively enhanced. Mechanistic disparity between RAP and CsA may potentiate clinical immunosuppression when RAP and CsA are used together.

Immunopharmacological monitoring of cyclosporin A-treated recipients of cadaveric kidney allografts

Twelve cadaveric kidney allograft recipients, who were established preoperatively to be strong responders, were treated with cyclosporin A (Cy A) and subjected to postoperative monitoring of drug levels and immune performances. The Cy A-treated recipients were compared with 72 historical (36 strong and 36 weak immune responders) and 18 current, strong responder, azathioprine-treated control patients. Estimation of Cy A levels in plasma and whole blood revealed that 75% of the drug at trough and 44% at peak was cell bound. Concomitant radioimmunoassay (RIA) and high performance liquid chromatography (HPLC) determinations on whole blood yielded concordant values. Trough levels above 200 ng/ ml in plasma and 600 ng/ml in whole blood were associated with toxic manifestations. Although absolute peak levels were not helpful, calculation of peak to trough ratios yielded values which when less than 3.0 predicted toxicity. Post-transplant immune monitoring showed administration of Cy A to be associated with fewer (1) rejection episodes; (2) nonspecific immune events; and (3) donor-specific in vitro reactions than were observed after treatment with azathioprine. Although the activity of peripheral blood mononuclear cells as natural killers of K562 target cells was not affected by Cy A treatment, their capacity to suppress the generation of a third-party mixed lymphocyte culture was enhanced to the same degree as cells from azathioprine-treated patients. Enumeration of peripheral blood lymphocyte T cell subpopulations using monoclonal xeonoantisera revealed (1) the total number of T cells to be unaffected by administration of either Cy A or azathioprine and (2) a reduction in the ratio of helper-inducer to suppressor-cytotoxic cells specificially in Cy A-treated recipients compared with normal individuals, hemodialysis patients, or azathioprine-treated recipients. Although pharmacological monitoring of blood levels may be useful to discern patients at high risk for toxic complications, the achievement of maximal therapeutic efficacy may depend upon identifying and quantitating the cellular target responsible for the disruption of immune homeostasis observed during Cy A administration.

Improved graft survival for flow cytometry and antihuman globulin crossmatch-negative retransplant recipients.

We compared our standard NIH (extended incubation) crossmatch (XM) with antihuman globulin (AHG) and flow cytometry XMs and correlated the results with rejection episodes and graft survivals. For 89 CsA-Pred, primary renal allograft recipients, AHG and/or FCXM results did not improve on the NIH-XM-negative (NEG) graft survival results, whether testing pretransplant or historical (Hx) sera. Similarly, there was no association of a positive (POS) AHG or FCXM with increased rejection episodes in these primary recipients. However, for retransplant (Re-Tx) recipients a neg AHG or FCXM did discriminate fewer rejections and an improved graft survival compared with the NIH-XM-neg. results. The overall one-year graft survival for the 47 Re-Tx recipients studied herein was 66% (based on a neg pre-Tx NIH-XM). Pre-Tx AHG-NEG, Re-Tx recipients displayed an improved graft survival compared with NIH-XM NEG recipients (77% vs. 66%, P less than 0.05) and with AHG-POS recipients (77% vs. 47%, P less than 0.05). Similarly, pre-Tx, FCXM-NEG, Re-Tx recipients displayed improved graft survivals compared with NIH-XM-NEG recipients (83% vs. 66%, P less than 0.05) and FCXM-POS recipients (83% vs. 48%, P less than 0.05). Re-Tx recipients displaying a POS AHG and/or FCXM experienced a significantly greater number of rejections than NEG-XM recipients (P less than 0.05, respectively). The AHG and FCXM results correlated with rejections and graft survivals whether testing pre-Tx or Hx high-PRA sera. Re-Tx recipients who were AHG-XM-NEG but FCXM-POS, experienced more rejection episodes than recipients who displayed a negative XM reactivity for both AHG and FCXM (P less than 0.02), but with no resulting differences in graft survival. HLA matching, pre-Tx blood transfusions and PRA did not impact on these crossmatch and graft survival results. Use of AHG and/or FCXMs for Re-Tx, but not primary, recipients should help to improve graft survival for these high-risk recipients.

Risk factors for impaired wound healing in sirolimus‐treated renal transplant recipients

Abstract:  Aim:  As sirolimus has been implicated in impaired wound healing, the aim of this study was to evaluate risk factors for wound complications after renal transplantation in patients treated with this drug de novo.