Ronald S. Filo

A Comparison Of Tacrolimus (fk506) And Cyclosporine For Immunosuppression After Cadaveric Renal Transplantation1

Background. Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. Methods. A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. Results. One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. Conclusions. Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.

HISTOPATHOLOGIC FINDINGS FROM 2-YEAR PROTOCOL BIOPSIES FROM A U.S. MULTICENTER KIDNEY TRANSPLANT TRIAL COMPARING TACROLIMUS VERSUS CYCLOSPORINE

Background. This paper reports the histopathologic results of 2-year protocol biopsies from patients who were enrolled in the U.S. FK506 kidney transplant study . Methods. Recipients of cadaveric kidney transplants were randomized to tacrolimus or cyclosporine therapy. Patients active in the trial at 2 years after transplantation were approached for a protocol biopsy. Biopsies were scored by the Banff classification in a blinded fashion by one pathologist. Results. A total of 144 patients (41.3% of those active at 2 years) had a 2-year protocol biopsy performed; 79 patients were treated with tacrolimus and 65 patients were treated with cyclosporine. Evidence of acute rejection was found in seven (8.9%) of the 2-year biopsies in tacrolimus-treated patients and six (9.2%) cyclosporine-treated patients. Chronic allograft nephropathy was found in 49 (62.0%) tacrolimus biopsies and 47 (72.3%) cyclosporine biopsies (P=0.155). There were no apparent histopathologic differences between the tacrolimus and cyclosporine biopsies. The occurrence of chronic allograft nephropathy was significantly higher in patients who received a graft from an older donor (P<0.01), who experienced presumed cyclosporine or tacrolimus nephrotoxicity (P<0.001), who developed a cytomegalovirus infection (P=0.038), or who experienced acute rejection in the first year after transplantation (P=0.045). A multivariate analysis showed that nephrotoxicity and acute rejection were the most significant predictors for chronic allograft nephropathy. Conclusions. The occurrence of histologic acute rejection was rare at 2 years, confirming the absence of subclinical acute rejection in these late biopsies. A majority of the biopsies showed features consistent with chronic allograft nephropathy that was associated with acute rejection (particularly in cyclosporine-treated patients), nephrotoxicity, and cytomegalovirus infection in the first year. This suggests that nonimmunologic factors, such as drug-induced toxicity, may play an important role in chronic allograft nephropathy.

A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years.

BACKGROUND The 1-year results of the Phase III U.S. Multicenter Trial comparing tacrolimus (FK506)- and cyclosporine (CsA)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. The present report at 5 years of follow-up focuses on the long-term impact of tacrolimus treatment on kidney allograft outcome. METHODS The study protocol permitted crossover of patients to the alternate treatment arm under stringent conditions. The effect of crossover on graft survival was analyzed. Cardiovascular risk factors and serious adverse events were also monitored over 5 years. RESULTS Intent-to-treat analysis revealed equivalent patient and graft survival between treatment arms at 5 years of follow-up (79.1% vs. 81.4%; P=0.472 and 64.3% vs. 61.6%; P=0.558 among tacrolimus and CsA-treated patients, respectively). However, the rate of crossover was significantly higher among patients randomized to receive CsA-based therapy (27.5% vs. 9.3%; P<0.001). The incidence of treatment failure (43.8% vs. 56.3%; P=0.008) was significantly lower among tacrolimus-treated patients. Graft survival was significantly improved in the tacrolimus treatment arm when crossover due to rejection was counted as graft failure (63.8% vs. 53.8%; P=0.014). Tacrolimus therapy was also associated with a significantly reduced requirement for medications to control hypertension and hyperlipidemia. There was a substantial rate of reversal of tacrolimus-associated insulin dependence. CONCLUSION Tacrolimus-based therapy resulted in significantly reduced risk of graft failure, without an increase in the incidence of adverse events associated with long-term immunosuppression.

Renal transplantation into the reconstructed bladder.

In our experience with 821 renal transplants performed between 1974 and October 1987 we used the native or reconstructed bladder of the patient in all but 2 instances. Seven patients have undergone enterocystoplasty and subsequent renal transplantation, while 1 underwent bladder augmentation after transplantation. Of these 8 patients 4 have functioning grafts 6 months to 7 years after transplant or reconstruction. Renal transplantation coupled with enterocystoplasty in properly selected patients has acceptable morbidity and should be considered as an alternative to other forms of urinary diversion in allograft recipients.

Abdominal wall and inguinal hernias in continuous ambulatory peritoneal dialysis patients

This retrospective analysis of 140 continuous ambulatory peritoneal dialysis patients followed during a 4 year period revealed a 5 percent incidence of abdominal wall hernias. Inguinal hernias were frequently manifested as unilateral scrotal swelling. Hernias too small to be appreciated by physical examination were easily demonstrable with intraperitoneal instillation of technetium 99m sulfur colloid through the continuous ambulatory peritoneal dialysis catheter. This procedure was also useful when differentiating dialysate leaks from inguinal hernia in the early and late postoperative periods. Recurrences developed in 27 percent of the herniorrhaphies. Factors contributing to the development of abdominal wall hernias in continuous ambulatory peritoneal dialysis patients include uremia, obesity, anemia, and chronically elevated intraperitoneal pressures.

Therapy of acute cadaveric renal allograft rejection with adjunctive antithymocyte globulin.

A randomized and controlled study was conducted to evaluate the efficacy of adjunctive antithymocyte globulin (ATG) therapy for the treatment of the initial rejection episode in first cadaveric transplants. When compared to the control group (29), which received only standard antirejection treatment (SAT) of steroid pulsing and local irradiation, the adjunctive ATG treatment group (23) demonstrated significantly faster recovery rates (8.9 ± 4.1 versus 6.9 ± 3.7 days, P = 0.05, respectively) and better graft survival rates (62 ± 9% versus 91 ± 7%, respectively) after the first rejection. ATG treatment did not result in fewer subsequent rejection episodes than SAT but long-term allograft survival rates remained superior to controls for the entire 3-year study period. By avoiding ATG treatment in those patients who never experienced clinical rejection on maintenance immunosuppressive therapy, i.e., nonresponders (23 of 90), complications associated with excessive immunosuppression were minimized. The combined results of the non-responder group of patients and ATG-treated patients resulted in a 1-year patient survival of 97% and graft survival of 86%. These results suggest that the most efficacious use of ATG is therapeutic and not prophylactic in renal transplant patients.

The Manifestation and Management of Late Urological Complications in Renal Transplant Recipients: Use of the Urological Armamentarium

The incidence of urological complications in renal transplant patients is well documented. The majority of these complications occur in the early postoperative period; late occurrences (more than 3 months) are much less common. We have had experience with 7 patients who presented with late complications 3 months to 7 years after transplantation: ureteral obstruction occurred in 4 patients, ureteral disruption or laceration in 2 and neurogenic bladder with hydronephrosis in 1. Management of these patients has been varied and has included cystoscopic stent placement, Boari flap, ureteropyelostomy, ureteroneocystostomy, bladder augmentation and urinary undiversion. Grafts have been salvaged in 6 of 7 patients. Transplant patients who present with late urological complications can be challenging. However, the potential for intervention and graft salvage is excellent.

Preclinical in Vivo Testing of a Rotational Mechanical Thrombolytic Device

PURPOSE To establish the safety and efficacy of the Arrow Trerotola mechanical percutaneous thrombolytic device (PTD) for restoring patency of thrombosed hemodialysis grafts. MATERIALS AND METHODS The hindlimb model of dialysis grafts was created in six dogs. Animals had either unilateral (n = 4) or bilateral (n = 2) polytetrafluoroethylene grafts, totaling eight grafts. Grafts were deliberately clotted 48 hours before thrombolysis. Thrombolysis was performed with five different versions of the PTD constructed of stainless steel (n = 12) or nitinol (n = 26) and rotated with use of a hand-held motor drive. After thrombolysis, fistulography was performed. RESULTS Thirty-eight procedures were performed with the PTD, with 100% success. Thirty-day patency, evaluated in a subset of 15 procedures, was 100%. Complications included a single arterial embolus (2.6%) and eight device breakages (21%, all but two with the stainless steel version); none had any clinical consequences. A final modification of the nitinol device yielded 11 consecutive procedures without further breakage. No residual thrombus occurred in any procedure. Pathologic examination showed no significant injury to the vessels or neointima. CONCLUSION The PTD is highly effective for mechanical thrombolysis in an animal model of clotted dialysis grafts. Based on this animal model, the device appears safe in its final modified form.

Incidence and Management of Arterial Emboli from Hemodialysis Graft Surgical Thrombectomy

PURPOSE To determine the incidence and significance of arterial emboli resulting from surgical thrombectomy/revision of hemodialysis grafts. This information may help in determining the significance and management of similar emboli resulting from percutaneous hemodialysis graft thrombolysis. PATIENTS AND METHODS Patients undergoing surgical thrombectomy/revision of clotted hemodialysis grafts are studied with postoperative fistulography per institutional protocol whenever possible. For this retrospective study, all postoperative fistulograms from a 1-year period were reviewed for the presence of arterial emboli. Patients with documented arterial emboli were examined for evidence of hand/digital ischemia; only those patients with signs or symptoms of ischemia were treated. At clinical follow-up, repeated evaluation for hand/digital ischemia was performed. RESULTS Ninety-one thrombectomy/revision procedures were performed during the study period. Postoperative fistulograms were obtained after 67 of these procedures in 32 patients. One patient complained of hand pain during dialysis prior to acquisition of the postoperative fistulogram. Arterial emboli were documented in eight patients (12%; brachial, n = 3; radial, n = 2; ulnar, n = 2; radial/ulnar, n = 1). The single symptomatic brachial embolus was percutaneously removed; no intervention was undertaken in the remainder. At mean follow-up of 14 months, no patient had developed hand or digital ischemia. Subsequent fistulograms demonstrated partial (n = 2) or complete (n = 2) resolution of the untreated emboli. CONCLUSION Arterial emboli are a relatively common occurrence with surgical thrombectomy/revision. Conservative management appears to be indicated in asymptomatic patients.

In Vitro Effects Of Cyclosporin A On Lymphocyte Subpopulations: 1. Suppressor Cell Sparing By Cyclosporin A

The fungal metabolite, cyclosporin A, is a potent immunosuppressive compound. Experiments were performed in vitro with both human and nonhuman primate peripheral blood lymphocytes to study the effect of this agent on suppressor cell activity. Cyclosporin A did not affect the generation or function of concanavalin A-induced suppressor lymphocytes as measured by their ability to suppress thymidine uptake of lymphocytes in secondary cultures. No evidence of suppressor cell induction was noted by incubation of lymphocytes with only cyclosporin A. We conclude that, although cyclosporin A does not generate or induce suppressor cell lymphocytes, it does spare them, while inhibiting other subpopulations. This effect may create an imbalance in the immune system which results in profound suppression.