Jerry McCauley

INTERFERON-α-INDUCED ACUTE RENAL ALLOGRAFT REJECTION

The immunomodulating effects of interferons have led to their use in the treatment of a variety of illnesses, including cancer (1), and virally mediated infections, such as hepatitis (2). In addition, IFN has been given to immunosuppressed patients in an attempt to reconstitute the immune response to prevent viral infections such as CMV and herpes Simplex (3). Since CMV and viral hepatitis are potentially serious complications of renal transplantation (3, 4), the use of IFN for prophylaxis or treatment has been advocated in this setting. However, the potential effects of giving an immuno-modulator such as IFN to immunosuppressed transplant patients raises theoretical concerns about activation of immune responses and an increased risk of allograft rejection. Current immunosuppressive regimes for renal transplantation include CsA or FK506 in combination with steroids and sometimes AZA. While the mechanisms of action of CsA and FK506 are not completely understood, these agents appear to inhibit T cell activation through binding to specific binding cellular proteins (immunophilins), thereby altering intracellular signaling pathways and ultimately inhibiting expression of IL-2 and other cytokines (5). Both CsA (6) and FK506 (7) may inhibit IFN production, and low levels of circulating IFN-α have been described in renal transplant recipients (8). Although IFN modulate the immune response-both at the level of T cell activation (9) and antigen expression (10), the exact roles of these compounds in the immunosuppressive action of CsA and FK506 are not known. A number of studies have claimed efficacy of IFN-α preparations in the treatment of chronic persistent hepatitis (2) and trials of IFN preparations for viral prophylaxis in renal transplant recipients have been reported (3, 11, 12). The results of such trials suggested a benefit of prophylaxis for viral infections (3, 11), but, at times, at the expense of increased rejection (12). The complex issues involved in using IFN to treat hepatitis in a transplanted, immunosuppressed population prompted us to review our experience with IFN-α treatment in renal transplant patients.

Acute and Chronic Renal Failure in Liver Transplantation

We have performed a retrospective review of the incidence and etiologies of acute renal failure (ARF) in 105 adult patients receiving liver transplants. The prevalence of chronic renal failure was also determined. ARF occurred in 94.2% of these patients. Acute tubular necrosis was the leading cause of ARF and was associated with the highest mortality. Factors associated with increased mortality included: (1) peak serum creatinine greater than 3 mg/dl, (2) multiple liver transplants and (3) the need for dialysis. Pretransplant renal failure did not increase mortality. Chronic renal failure developed in 83% of patients at latest follow-up (mean: 30.5 +/- 7.9 months).

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS IN ADULT AND PEDIATRIC RENAL TRANSPLANT PATIENTS RECEIVING TACROLIMUS-BASED IMMUNOSUPPRESSION

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0+/-22.5 months after transplantation, 25.0+/-24.7 months in adults and 14.4+/-18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor --> seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.

FK506 Rescue for resistant rejection of renal allografts under primary cyclosporine immunosuppression

Seventy-seven patients with ongoing acute rejection on initial CsA therapy were converted to FK506 to attempt graft salvage. Fifty-nine patients had undergone primary transplantation and 18 had been retransplanted; there were 52 cadaveric and 25 living-donor transplants. The indications for conversion to FK506 were ongoing, biopsy-confirmed rejection in all patients, including vascular rejection in 20. The median interval to rescue was 2 months (range 2 weeks to 36 months) after transplantation. Sixty-one of the 77 patients (79%) had already received one or more courses of an antilymphocyte preparation (OKT3: n=33; ALG or ATG: n=1; OKT3+ALG/ATG: n=27). Of the 77 patients, 57 (74%) have been successfully rescued and still have functioning grafts with a mean follow-up of 14 months, with a mean serum creatinine of 2.35±0.97 mg/dl. Eighteen patients were already dialysis-dependent at the time of conversion to FK506; of these, 9 (50%) were successfully salvaged and have a mean serum creatinine of 2.3 mg/dl. Of the 61 patients previously treated with antilymphocyte preparations, 48 (79%) were rescued. In those salvaged, prednisone doses have been lowered from 22.2±7.2 mg/day preconversion to 7.5±5.6 mg/day postconversion, and 12 patients are on FK506 monotherapy. In nondiabetics, mean serum glucose was 101.4±20.5 mg/dl preconversion and 93.2±22 postconversion (P=0.07), uric acid 7.3±2.3 and 7.1±1.5 mg/dl (P=0.53), and triglycerides 199.2±101.6 and 167.2±106.4 mg/dl (P=0.06). Cholesterol levels were significantly lower following FK conversion (207.7±46.5 mg/dl pre. vs. 188.3±39.7 post, P=0.007). FK506 is capable of salvaging renal allografts with ongoing acute rejection on CsA therapy, even when antilymphocyte preparations have been ineffective.

Renal Transplantation In Recipients Over The Age Of 60: The Impact of Donor Age

BACKGROUND Kidneys from older donors exhibit a series of changes characterized by glomerular, vascular, and tubular senescence. These changes may be aggravated by atherosclerosis, hypertension, or diabetes, which are highly prevalent in older individuals. METHODS We analyzed the outcome after transplantation in 230 recipients over the age of 60, who received transplants between February 1990 and December 1996. We assessed the 1- and 5-year patient and graft survival, the quality of renal function, tacrolimus levels, the incidence of rejection, and the incidence of delayed graft function, and compared the outcomes in recipients of kidneys from donors over the age of 60 (group 1, n = 40) with those in recipients of kidneys from donors under the age of 60 (group 2, n = 190). There were no differences between the two groups in terms of recipient sex, race, age, and cold ischemia time. Immunosuppression was with tacrolimus and steroids in 61% of cases; in the remainder of the patients, a third agent, either azathioprine, cyclophosphamide (for 1 week), or mycophenolate mofetil was administered as well. The median follow-up was 31.5 months (range: 1-86). RESULTS In recipients over the age of 60 receiving tacrolimus-based immunosuppression, overall patient survival at 1 and 5 years was 90% and 76%, and was not significantly compromised in recipients receiving a kidney from a donor over the age of 60. The overall 1-and 5-year actuarial graft survival was 84% and 64%; in recipients from donors over the age of 60, it was 73% and 52%, whereas in recipients of kidneys from donors under the age of 60, it was 87% and 66% (P<0.05). Most of the effect on graft survival was seen by 1 year. The mean serum creatinine was 2.6+/-2.7 mg/dl, without any difference between the two groups. Although the incidence of delayed graft function was higher in recipients of kidneys from donors over the age of 60, this difference did not reach statistical significance. CONCLUSIONS Although the overall outcomes of transplantation in older recipients remain reasonable, the inferior outcomes with older donor kidneys call into question proposals to utilize older donor kidneys preferentially in older recipients.

A prospective randomized trial of FK506-based immunosuppression after renal transplantation

A group of 204 adult patients was entered into a prospective, randomized trial comparing FK506/prednisone with FK506/azathioprine/prednisone after renal transplantation between August 1, 1991 and October 11, 1992. The purpose of the study was to see if the addition of azathioprine would reduce the incidence of rejection and improve graft survival. The recipient population was unselected, with 61 (30%) patients undergoing retransplantation, 37 (18%) having a panel-reactive antibody greater than 40%, and 33 (16%) over 60 years of age. The mean recipient age was 43.8 +/- 13.7 years (range 17.6-78). The mean donor age was 34.0 +/- 20.1 years (range 0.3-75); 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4 +/- 8.4 hr. Living donors were the source of 13% of the kidneys. The mean follow-up was 22 +/- 4 months (range 12-29). Overall one-year actual patient survival was 94%. Overall one-year actual graft survival was 87%. Patients starting on double therapy had a one-year actual patient survival of 96% and a one-year actual graft survival of 92%. Patients starting on triple therapy had a one-year actual patient survival of 91% (P = ns compared with double therapy), and a one-year actual graft survival of 82% (P < 0.02, compared with double therapy). Overall results with first cadaver transplants included a one-year actual patient survival of 94% and one-year actual graft survival of 88%, with no differences between double and triple therapy. The overall incidence of rejection was 48%, with 54% in the double therapy group and 41% in the triple therapy group (P < .07). The incidence of steroid-resistant rejection requiring antilymphocyte therapy (OKT3 or ATGAM) was 13%, and was not different between the double and triple therapy groups. The mean serum creatinine was 1.8 +/- 0.8 mg/dl. The mean BUN was 33 +/- 21 mg/dl, with no significant difference between the therapy groups. The mean serum cholesterol was 192 +/- 49 mg/dl. A total of 56% of the patients are off prednisone, and 35% of the patients are not taking any antihypertensive medications. Other complications included cytomegalovirus--14%; new-onset diabetes--16% (half of which was reversible); and posttransplant lymphoproliferative disorder--1%.(ABSTRACT TRUNCATED AT 400 WORDS)

A PROSPECTIVE, RANDOMIZED TRIAL OF TACROLIMUS/PREDNISONE VERSUS TACROLIMUS/PREDNISONE/MYCOPHENOLATE MOFETIL IN RENAL TRANSPLANT RECIPIENTS

BACKGROUND Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection. METHODS The mean recipient age was 50.7+/-13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5+/-21.7 years. The mean cold ischemia time was 30.5+/-9.2 hr. The mean follow-up is 15+/-7 months. RESULTS The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6+/-0.8 mg/dl. A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups. CONCLUSIONS This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids.

Tacrolimus rescue therapy for renal allograft rejection - Five-year experience

Over the 5 year period from 7/14/1989 until 5/24/1994, we have attempted graft salvage with tacrolimus conversion in a total of 169 patients (median age 33 years, range 2-75 years) with ongoing rejection on baseline CsA immunosuppression after failure of high dose corticosteroids and/or antilymphocyte preparations to reverse rejection. The indications for conversion to tacrolimus were ongoing, biopsy confirmed rejection in all patients. The median interval to tacrolimus conversion was 2 months (range 2 days to 55 months; mean 4.3+/-2.6 months) after transplantation. All patients had failed high dose corticosteroid therapy and 144 (85%) of the 169 patients had received at least one course of an antilymphocyte preparation plus high dose corticosteroid therapy prior to conversion. Twenty-eight patients (17%) were dialysis-dependent at the time of conversion owing to the severity of rejection. With a mean follow-up of 30.0+/-2.4 months (median 36.5 months, range 12-62 months), 125 of 169 patients (74%) have been successfully rescued and still have functioning grafts with a mean serum creatinine (SCR) of 2.3+/-1.1 mg/dl. Of the 144 patients previously treated with antilymphocyte preparations, 117 (81%) were salvaged. Of the 28 patients on dialysis at the time of conversion to tacrolimus, 13 (46%) continue to have functioning grafts (mean SCR 2.15+/-0.37 mg/dl) at a mean follow-up of 37.3+/-16.7 months. In the 125 patients salvaged, prednisone doses have been lowered from 28.0+/-9.0 mg/d (median 32, range 4-60 mg/d) preconversion to 8.5+/-4.1 mg/d (median 12 mg/d, range 2.5-20 mg/d) postconversion. Twenty-eight patients (22.4%) are currently receiving no steroids. This 5 year experience demonstrates that tacrolimus has sustained efficacy as a rescue agent for ongoing renal allograft rejection. Based on these data, we recommend that tacrolimus be used as an alternative to the conventional drugs used for antirejection therapy in renal transplantation.

Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy : a clinicopathologic study of 96 patients

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.

An Analysis of Early Renal Transplant Protocol Biopsies - the High Incidence of Subclinical Tubulitis

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one‐week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2 ± 2.6 d (range 3–18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one‐week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.