John D. Pirsch

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.

Risk factors for primary dysfunction after liver transplantation - A multivariate analysis

In a retrospective analysis on 323 orthotopic liver transplant procedures performed between July 1984 and October 1991 the incidence of two forms of primary dysfunction (PDF) of the liver: primary nonfunction (PNF), and initial poor function (IPF) were studied. The incidence of PDF was 22% (73/323) with 6% PNF (20/323) and 16% IPF (53/323), while 78% (250/323) had immediate function (IF). Occurrence of both IPF and PNF resulted in a higher graft failure rate (P < 0.001), retransplantation rate (P < 0.001), and patient mortality (P < 0.003) within the first three months after OLTx. Univariate analyses of donor and recipient factors and their influence on PDF demonstrated that longer donor hospitalization (> 3 days), older donor age (> 49 years), extended preservation times (> 18 hr), and fatty changes in the donor liver biopsy, as well as reduced-size livers, younger recipient age, and renal insufficiency prior to OLTx, significantly affected the incidence of IPF and PNF. Multivariate analysis of potential risk factors showed that reduced-size liver (P = 0.0001), fatty changes on donor liver biopsy (P = 0.001), older donor age (P = 0.009), retransplantation (P = 0.01), renal insufficiency (P = 0.02), and prolonged cold ischemia times (P = 0.02) were independently associated with a higher incidence of IPF and PNF. No statistical correlation was found between PDF and etiology of ESLD, nutritional status of the recipient, UNOS status, and Child-Pugh classification in this study. We conclude that PNF and IPF are both separate clinical entities that have a significant effect on outcome after OLTx. Routine donor liver biopsies are recommended to decrease the rate of IPF and PNF. The combination of risk factors shown to be significant for PDF should be avoided--and, if that is not possible, the only variable that can be controlled, the preservation time, should be kept as short as possible.

The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation

Methods of accurately assessing the suitability of donor livers prior to transplantation are required if the incidence of primary nonfunction (PNF) is to be reduced. This study evaluated the ability of donor liver biopsies to predict the development of primary nonfunction after transplantation. From June 1987 until May 1990, 170 liver transplants were performed in 147 patients. A total of 124 donor liver biopsies were obtained and divided into three groups. Group 1 biopsies (n = 77) were obtained after revascularization of the liver, group 2 biopsies (n = 19) were obtained prior to donor hepatectomy but examined only after implantation, and group 3 biopsies (n = 28) were obtained as in group 2, but were examined prior to implantation. Three of 89 (3.4%) livers interpreted as having normal histology developed primary nonfunction, while one of 26 (3.8%) biopsies interpreted as having a minimal or moderate amount of fatty infiltration developed primary nonfunction. PNF occurred in 7 of 8 livers with severe fatty infiltration (3), hydropic degeneration (3), and centrilobular necrosis (1). A fourth liver with hydropic degeneration and poor function ultimately failed requiring retransplantation 8 weeks later. Analysis of liver function revealed progressive elevation in aspartate-aminotransferase, alanine-aminotransferase, lactate dehydrogenase, and serum ammonia (NH3) with increasing degrees of fatty infiltration. Donor age and weight was also found to be significantly higher in livers with fatty infiltration. This study suggests that donor liver biopsies demonstrating normal histology or minimal-to-moderate fatty infiltration function adequately, but that donor livers with severe fatty infiltration or hydropic degeneration function poorly and should not be transplanted.

Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study.

Campath‐1H, an anti‐CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8–15 ng/mL) post‐transplant. Campath‐1H profoundly depletes lymphocytes long‐term and more transiently depletes B cells and monocytes. All patients are alive and well at 3–29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound‐healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid‐lowering agent. Flow crossmatch testing post‐transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath‐1H induction in combination with rapamycin maintenance monotherapy.

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.

A Prospective, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial Comparing Early (7 Day) Corticosteroid Cessation Versus Long-Term, Low-Dose Corticosteroid Therapy

Objective:To compare outcomes with early corticosteroid withdrawal (CSWD) and chronic low dose corticosteroid therapy (CCS). Summary Background Data:Final, 5-year results from the first randomized, double-blind, placebo-controlled trial of early CSWD (at 7 days posttransplant) are presented. Methods:Adult recipients of deceased and living donor kidney transplants without delayed graft function were randomized to receive prednisone (5 mg/d after 6 months posttransplant) or CSWD. Blinding was maintained for 5 years. This clinical trial is registered at www.clinicaltrials.gov (NCT00650468). Results:Results in 386 patients CSWD (n = 191), CCS (n = 195) are presented (CSWD; CCS). No differences were observed at 5 years in the proportion of patients experiencing: primary end point (composite of death, graft loss, or moderate/severe acute rejection) (30/191 (15.7%); 28/195 (14.4%)), patient death (11/191(5.8%);13/195 (6.7%)), death-censored graft loss (11/191 (5.8%); 7/195(3.6%)), biopsy confirmed acute rejection (BCAR) (34/191 (17.8%); 21/195 (10.8%), P = 0.058), moderate/severe acute rejection (15/191 (7.9%); 12/195 (6.2%)). Kaplan Meier analyses of the primary end point and its components also showed no differences; but BCAR was higher with CSWD (P = 0.04). Increased BCAR episodes were primarily corticosteroid-sensitive Banff 1A rejections: the incidence of antibody-treated BCAR was similar between groups (11/191 (5.8%); 13/195 (6.7%)). No differences in renal function were observed at 5 years: mean serum creatinine (1.5 ± 0.6; 1.5 ± 0.7 mg/dL), or Cockroft Gault calculated creatinine clearance (58.6 ± 19.7; 59.8 ± 20.5 mL/min). CSWD was associated with improved serum triglycerides (evaluated by mean and median change from baseline) at all time points (except at 5 years measured by mean change). Weight change also demonstrated changes favoring CSWD (median change from baseline at 5 years: 5.1 vs. 7.7 kg, P = 0.05). New onset diabetes after transplant (NODAT) was similar with respect to proportions who required treatment (23/107 (21.5%)); 18/86 (20.9%); however, fewer CSWD patients required insulin for NODAT at 5 years (4/107 (3.7%)); 10/86 (11.6%), P = 0.049). Changes in HgA1c values (from baseline) were lower in CSWD patients at all time points except 4 years. Conclusions:Early CSWD, compared with CCS, is associated with an increase in BCAR primarily because of mild, Banff 1A, steroid-sensitive rejection, yet provides similar long-term renal allograft survival and function. CSWD provides improvements in cardiovascular risk factors (triglycerides, NODAT requiring insulin, weight gain). Tacrolimus/MMF/antibody induction therapy allows early CSWD with results comparable to long-term low dose (5 mg/d) prednisone therapy.

Rituximab as Treatment for Refractory Kidney Transplant Rejection

Recent studies have shown that a high density of CD 20+ cells are seen in patients who have steroid‐resistant rejection episodes. Rituximab is a high‐affinity CD‐20 specific antibody that inhibits B‐cell proliferation while inducing cellular apoptosis. Thus, it is a rational choice for therapy in transplantation to abrogate B‐cell‐mediated events.

Long-Term Efficacy and Safety of Cyclosporine in Renal-Transplant Recipients

BACKGROUND AND METHODS The safety of long-term immunosuppression with cyclosporine in renal-transplant recipients is not well understood. This drug may cause a progressive toxic nephropathy, but it also preserves renal function because it prevents rejection. To determine the effect of cyclosporine on renal function and graft rejection, we conducted a retrospective analysis of data on 1663 renal-transplant recipients at six centers. RESULTS The rate of graft survival was 78 percent (median follow-up, 36 months). Grafts were was lost in 279 patients (17 percent), mostly because of acute rejection (68 patients) or chronic graft dysfunction that was unresponsive to a reduction in the dose of cyclosporine (125 patients); 92 patients died with functioning grafts. The median change in the serum creatinine concentration in all patients after transplantation was less than 0.001 mg per deciliter per month (< 0.09 mumol per liter per month). Patients who had episodes of rejection had decreased rates of long-term graft function and survival. Eight percent of patients with functioning grafts at one year had first episodes of rejection more than one year after transplantation. These late first rejections were associated with noncompliance with therapy (in 34 percent), blood cyclosporine concentrations that were marginally lower than those of patients who had no episodes of rejection, and a low rate of successful reversal of rejection (77 percent, vs. 97 percent in patients with rejection during the first year; P < 0.001). CONCLUSIONS The majority of renal-transplant patients tolerate long-term cyclosporine therapy without evidence of progressive toxic nephropathy. Graft failure is most often due to rejection.

The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors

Background During pregnancy and nursing, a babys developing immune system is intimately exposed to the mothers antigens. To determine whether this exposure is of clinical benefit to patients who later receive an allograft as an adult, we analyzed the outcome of primary renal transplantations from sibling donors. Methods We retrospectively studied graft survival and rejection episodes in 205 patients who had received renal transplants at nine centers between 1966 and 1996 from sibling donors bearing maternal or paternal HLA antigens not inherited by the recipient. The sibling donors were categorized by analysis of family HLA-typing data. Results In the multicenter analysis, graft survival was higher 5 years and 10 years after transplantation in recipients of kidneys from siblings expressing maternal HLA antigens not inherited by the recipient than in recipients of kidneys from siblings expressing paternal HLA antigens not inherited by the recipient (86 percent vs. 67 percent at 5 years and 77 percent vs....

Experience with 500 simultaneous pancreas-kidney transplants.

METHODS From December 1985 to October 1997, 500 simultaneous pancreas-kidney transplants (SPKs) were performed at the University of Wisconsin. Bladder drainage (BD) was used in 388 and enteric drainage (ED) in 112. All pancreas transplants were preserved in UW solution. RESULTS Patient survival at 1, 5, and 10 years was 96.4%, 88.6%, and 76.3%; kidney function, 88.6%, 80.3%, and 66.6%; and pancreas function, 87.5%, 78.1%, and 67.2%. Thrombosis of the pancreas occurred in three to four (0.6% to 0.8%) and primary nonfunction in one (0.2%). There was a 4.2% acute tubular necrosis rate for the kidney. Conversion from BD to ED was required in 24% of cases. Primary indications for enteric conversion (EC) were leak (14%), urethritis and extravasation (7%), and chronic hematuria (3%). No graft was lost as a result of EC. There was no difference in 1-year graft survival between ED and BD. Leading causes of pancreas loss were rejection in 45 patients and death with a functioning graft in 27 patients. Since June 1995, mycophenolate mofetil was used for immunosuppression (n = 109). One-year survival rates with mycophenolate mofetil are patient, 98.1 %; kidney, 94.2%; and pancreas, 93.1%. Steroid-resistant rejections decreased from 48% to 15%. CONCLUSIONS This series represents the worlds largest experience with SPK, including the longest follow-up for BD pancreatic transplants. Ten-year graft survival rates exceed those of all other transplants, with the exception of HLA-identical living-related grafts. This series confirms that SPK is a highly successful procedure for selected diabetic patients with renal failure.