Michael R. Leone

The Use of OKT3 in Cadaveric Renal Transplantation for Rejection That Is Unresponsive to Conventional Anti-Rejection Therapy

Thirty-one recipients of cadaver kidney transplants were given OKT3 monoclonal anti-T cell antibody for rejection treatment after conventional therapy had failed. Seventy-four percent of steroid or steroid and antithymocyte globulin (ATG) resistant rejections reversed with a standard course of OKT3. Rejections reversed in 85% of 26 patients treated within 90 days of transplantation. Late rejections treated more than 90 days after transplantation were poorly responsive to OKT3 and graft survival for this group of five patients was poor (20%). However, for those patients treated with OKT3 for early resistant rejection, actuarial 4-year graft survival was 66%. Actuarial 4-year patient survival was 97%, and the incidence of serious infection was low. Acute rejections in cadaver transplantation are common and a small percentage of rejections are resistant to steroids and ATG. OKT3 has proven to be useful for reversing these resistant rejections without causing significant morbidity from infection or death.

Early experience with continuous arteriovenous hemofiltration in critically ill pediatric patients

The applicability of continuous arteriovenous hemofiltration (CAVH) for renal replacement therapy was evaluated in three infants and two young children with catastrophic medical and surgical illnesses. In the first four patients, CAVH was used in conjunction with either peritoneal or hemodialysis. In the fifth patient, CAVH was the sole renal replacement therapy employed; in this critically ill anuric infant, we were best able to evaluate the ability of CAVH to continuously control fluid, electrolyte, and acid-base balance, and allow the administration of adequate parenteral nutrition. The difficulties encountered were related to anticoagulation, establishment of adequate vascular access, and selection of an appropriate hemofilter for the performance of the technique. Despite the application of suction-assistance, we were unable to effectively employ a prototype pediatric hemofilter to attain a level of plasma ultrafiltration consistent with the objectives of therapy. However, we were able to effectively and safely employ an adult hemofilter for these purposes; modifications were made in the adult hemofilter system before its application in the smallest pediatric patients. Our experience suggests that, even in critically ill infants, CAVH can be successfully applied as an effective renal replacement therapy. However, further experience is required before its potential impact on patient survival can be assessed.

Effectiveness of a second course of OKT3 monoclonal anti-T cell antibody for treatment of renal allograft rejection.

A second course of OKT3 monoclonal anti-T cell antibody was given to 21 recipients of kidney transplants. Rejections reversed in 43% of patients in whom 95% of rejections had reversed with their initial OKT3 course. Reversal was highly dependent upon the timing of rejection, anti-OKT3 antibody production, and T cell CD3 modulation. Rejections treated greater than 90 days after transplantation were resistant to OKT3 reversal. High-titer anti-OKT3 antibodies prevented OKT3 reversal of rejection, and effective CD3 (the cell surface target of OKT3) modulation was necessary for successful OKT3 reversal of rejection. Reexposure to OKT3 further stimulated anti-OKT3 antibody production and broadened the specificity of the antibodies produced. OKT3 can effectively and safely be used a second time for treatment of early T cell-mediated renal allograft rejections if high-titer anti-OKT3 antibodies have not been made.

Transmembrane pressures generated by filtrate line suction maneuvers and predilution fluid replacement during in vitro continuous arteriovenous hemofiltration.

A recirculating in vitro CAVH system was designed which generated pulsatile blood and filtrate flows. Monitors recorded hydrostatic pressures simultaneously in the arterial, venous and filtrate lines during varying plasma or blood flow rates and predilution (vs postdilution) replacement fluid flow rates. Similar hydrostatic pressure monitoring was carried out during multiple maneuvers to generate suction on the filtrate side of the hemofilter (Amicon® D-20s and Renaflo®‘s). With a plasma flow (Qp) of 100 cc/min and predilution replacement fluid infusion rate of 500 cc/hr, the arterial pressure was 5% greater than during postdilution (p < 0.05). With a blood flow (Qb) of 50 cc/min, predilution fluid replacement rates of 500 and 1000 cc/hr, and vacuum suction applied to the filtrate compartment, the arterial pressure was 33% lower than during postdilution fluid replacement (p < 0.03). Nonetheless, the ultrafiltration rate (UFR) was 10 to 30% higher (p < 0.03). At many other combinations of Qp, Qb and replacement rates and modes, there were no significant changes in arterial pressure. Despite these arterial pressure changes, > 70% of the transmembrane hydrostatic pressure (TMP) was due to the negative pressure induced by filtrate suction (gravity, Gomco®, wall suction, IMED®). The actual pressure in the filtrate compartment measured during Gomco® or wall suction was 3/4 of that stated by their gauges, presumably due to leakage. Maximum wall suction never generated TMPs > 150 mmHg. Using an IMED® 960 as the suction device (bypassing the air alarm), for a Qp of 50, IMED® settings of 300, 600 and 900 cc/hr generated TMPs of 67 ± 3, 77 ± 3, and 97 ± 3 mmHg, respectively. When Qp was 20 cc/min, an IMED® setting of 999 cc/hr generated TMPs consistently < 136 mmHg but UFR was only 668 ± 246 cc/hr. With the IMED® set at 999 cc/hr and Qp of 30 cc/min, the TMP was < 132 mmHg and the UFR was 944 ± 10 cc/hr. No filters ruptured. These suction maneuvers do not generate enough pressure to rupture filters. When Qp is low the IMED® may not generate the UFR one expects. Predilution will probably alleviate this concern.

THE ROLE OF OKT3 IN CLINICAL TRANSPLANTATION

OKT3 is a murine monoclonal anti-T cell antibody that is directed to CD3, a five-chain molecular complex found in association with the T cell receptor for antigen. OKT3 was the first monoclonal antibody to be used in organ transplantation and during the past 10 years there has been extensive experience of its use both for preventing and treating rejection in organ transplantation. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface. A reaction to OKT3 results from cytokines released when OKT# first reacts with T cells. This reaction is generally mild but can be severe. First rejections following kidney transplantation are reversed in approximately 95% of cases. Steroid-resistant rejections are also susceptible to OKT3 but in only approximately 75% of cases. When used for prophylaxis, OKT3 completely blocks rejection in 95% of patients and significantly delays the onset of rejection in those who do reject. Antibodies to OKT3 are produced in approximately 75% of patients receiving it. However, seldom are the antibodies to OKT3 present in high titer and only in those cases is successful re-use of OKT3 prevented. As is the case with all potent immunosuppressive drugs, the use of OKT3 is associated with increased viral, specifically cytomegalovirus, infections. However, it appears that reduction of concomitant immunosuppression decreases the incidence of severe infections. Unquestionably, OKT3 has been a useful addition to the immunosuppression used for organ transplantation. In addition, its use has stimulated research on other monoclonal antibodies for use in organ transplantation.

Monoclonal antibody OKT3 therapy in pediatric kidney transplant recipients

Thirty-one pediatric patients with acute renal allograft rejection were treated with the monoclonal antibody OKT3. In 24 cases, increased doses of steroids followed by a polyclonal antithymocyte globulin were ineffective in reversing the rejection episode. Twenty-eight patients completed the prescribed minimum 10-day treatment course, with effective rejection reversal in 22. Three patients failed to complete the course of therapy: one because of leukopenia that developed after the first dose, one because of a clotted graft, and another because of symptomatic cytomegalovirus infection. The overall success rate of OKT3 for rejection reversal was 74%; however, 55% of recipients had rebound rejection, and 85% of patients had detectable anti-OKT3 antibodies after completion of the course of therapy. Ten patients were treated with a second course of OKT3, and in eight of these patients, rejection was at least temporarily reversed. The starting dose of OKT3 for second-course therapy was the same as that used during first-course therapy, but in five cases the dose was increased during the course because of inadequate therapeutic response. Seven of these patients lost their grafts a mean of 6.5 months after completion of second-course therapy. We looked for anti-OKT3 antibody in nine recipients after completion of a second treatment course and found it in all nine. Our observations regarding a second treatment course with this monoclonal antibody preparation suggest that although rejection reversal may be observed, ultimate graft survival is poor and anti-OKT3 antibody formation is enhanced.

Backtransport of Dialysate Solutes during in vitro Continuous Arteriovenous Hemodialysis

Simulated continuous arteriovenous hemodialysis (CAVHD) was performed with Renaflo anisotropic polysulfone capillary hemofilters and Biospal homogeneous PAN parallel-plate hemofilters. Inulin and glucose were present in the dialysis solution. Plasma and dialysis solution flow rates were varied as was the delivery of dialysis solution by gravity or pump. The presence of dialysis solution did not affect the components of transmembrane pressure and did not alter ultrafiltration rate. Inulin and glucose backtransported into the plasma perfusate during CAVHD with the Biospal but not with the Renaflo filters. Dialysis solution will need to be sterile and pyrogen-free even in the low-flow, low-pressure system of CAVHD.

OKT3 monoclonal antibody in pediatric kidney transplant recipients with recurrent and resistant allograft rejection.

Twelve pediatric patients, aged 28 months to 17 years, received OKT3 to reverse renal allograft rejection. In 11 patients, the rejection crisis was resistant to conventional antirejection therapy with high doses of prednisone or polyclonal antithymocyte globulin. Reversal of rejection was successful in 10 patients who completed a treatment course. Because of recurring resistant rejection, five patients received a second course of OKT3, which was successful in reversing the rejection crisis in two. Among these patients, the persistence or the appearance of high levels of circulating T3 lymphocytes after initiating the second treatment course correlated with treatment failure. The immediate side effects associated with OKT3 therapy were transient and medically manageable. We conclude that this monoclonal antibody preparation is a safe and effective treatment for pediatric renal allograft in recipients experiencing rejection crisis resistant to conventional therapy. However, the potential impact of this immunosuppressive medication on long-term renal allograft survival in this patient population remains to be determined.

A Comparison of 2 Protocols for Living-Related Renal Transplantation in Children: Donor-Specific Transfusions Versus Cyclosporine

We analyzed the results obtained with protocols for immunosuppression of pediatric recipients of haploidentical living-related renal transplants. In the donor-specific transfusion group transfusion of blood products obtained from the prospective organ donor was performed before transplantation, and at transplantation maintenance immunosuppression of azathioprine and prednisone was begun. In the cyclosporine group donor-specific transfusion was not used, and maintenance immuno-suppression of cyclosporine and azathioprine was begun 1 week before transplantation, with the addition of prednisone at transplantation. Of 24 donor-specific transfusion recipients 3 had circulating cytotoxic antibodies to the prospective donor for an incidence of 12%. There was no significant difference between groups with respect to 1-year actual patient and graft survival (100 and 89 versus 100 and 86%, respectively), 1-year mean serum creatinine level (1.1 versus 1.2 mg./dl.), rejection treatments per patient (2.5 versus 2.6) and total days hospitalized during year 1 after transplantation (27 versus 18), with donor-specific transfusion data presented first. Initial hospitalization was significantly shorter (10 versus 16 days, p less than 0.05) and the incidence of rejection crises within 3 months was significantly less (68 versus 94%, p less than 0.05) in the cyclosporine group. We believe that cyclosporine and azathioprine pre-treatment of pediatric recipients of haploidentical living-related renal transplants with the addition of prednisone at transplantation is preferable to a donor-specific transfusion protocol because there is no risk of recipient sensitization to the prospective donor, and patient and graft survival is not adversely affected.