Paul F. Gores

Risk factors for chronic rejection in renal allograft recipients.

Chronic rejection is a major barrier to long-term renal allograft survival. Cyclosporine, though effective at reducing graft loss to acute rejection, has had little impact on the incidence of chronic rejection. Between June 2, 1986 and January 22, 1991, 587 kidney-alone transplants (566 patients) were performed, and had been entered into our renal transplant database and had at least 1 year of follow-up: 103 with biopsy-proven chronic rejection (37 living-related donor, 66 cadaver) and 484 without chronic rejection (236 LRD 248 CAD). The 5-year patient survival was 84% for recipients with biopsy-proven chronic rejection vs. 89% without (P = .08). The 5-year graft survival was 31% for recipients with biopsy-proven chronic rejection vs. 81% without (P < .0001). Using multivariate analysis, we determined the impact on the incidence of chronic rejection of these variables: transplant number, age at transplant (< 18 years, 18 to 50 years, > 50 years), gender, human leukocyte antigen matching, peak and transplant panel-reactive antibody, acute rejection episodes, infections (including cytomegalovirus, viral, and bacterial), donor age, and CsA dosage at 1 year (< 5 mg/kg vs. > or = 5 mg/kg). Logistic regression models were fit to the data using a forward stepwise selection procedure. In this analysis, risk factors included an acute rejection episode (P < .001), CsA dosage < 5 mg/kg/day at 1 year (P = .007), infection (P = .023), female gender (P = .042), and retransplant (P = .103). Individual analyses were done for CAD and LRD recipients. For both groups, important variables were acute rejection, infection, CsA dosage at 1 year, and age at transplant. In conclusion, acute rejection, CsA dosage < 5 mg/kg/day at 1 year, and infection are the major risk factors for the development of chronic rejection, suggesting that chronic rejection may be the result of inadequate immunosuppression (acute rejection episodes and low CsA dosage) or the production of inflammatory cytokines (infections).

Early versus late acute renal allograft rejection : impact on chronic rejection

We studied the effect of acute renal allograft rejection and its timing on the development of chronic rejection and subsequent graft loss. Between January 1, 1987 and April 30, 1991, 424 patients at the University of Minnesota received a primary kidney transplant (minimum follow-up, 1 year). Patients were subdivided by donor source, presence or absence of acute rejection, and the timing of acute rejection onset (early, ≤ 60 days vs. late, > 60 days post-transplant). For living donor (LD) transplant recipients (n=219), the incidence of chronic rejection is 0.8% in those who had no acute rejection (n=130), 20% in those with acute rejection ≤60 days (n=59) (P<0.001 vs. no acute rejection), and 43% in those with acute rejection > 60 days (n=30) (P<0.001 vs. no acute rejection, P=0.04 vs. early acute rejection). For cadaver (CAD) transplant recipients (n=205), the incidence of chronic rejection is 0% in those who had no acute rejection (n=109), 36% in those with acute rejection ≤ 60 days (n=69) (P<0.001 vs. no acute rejection), and 63% in those with acute rejection > 60 days (n=27) (P<0.001 vs. no acute rejection, P=0.03 vs. early acute rejection). For both LD and CAD recipients, no grafts have been lost to chronic rejection among those who did not first have at least 1 acute rejection episode. In contrast, 23 patients with acute rejection have had graft loss to chronic rejection. For both LD and CAD recipients, those with > 1 acute rejection episode had significantly more chronic rejection than those with only 1 rejection (P<0.05). There was no significant difference in the incidence of chronic rejection based on whether the first acute rejection episode was steroid resistant or steroid responsive. We conclude that acute rejection is strongly related to the development of biopsy-proven chronic rejection and subsequent graft loss. Patients undergoing their first acute rejection episode > 60 days (vs. ≤ 60 days) have an increased incidence of chronic rejection.

Causes of renal allograft loss. Progress in the 1980s, challenges for the 1990s.

A variety of refinements in the care of kidney transplant recipients have been instituted over the past decade. The authors studied the overall impact of these refinements on kidney allograft losses at a single institution. To do this they compared the causes and rates of graft loss for primary kidney transplants in the 1970s (January 1,1970 to December 31,1979; n = 1012; 657 nondi-abetics, 355 diabetics; 617 living donors, 395 cadaver donors) versus the 1980s (January 1, 1980 to December 31, 1989; n = 1,384; 756 nondiabetics, 628 diabetics; 740 living donors, 644 cadaver donors). Overall patient survival improved significantly, with rates at 1, 5, and 10 years of 94%, 84%, and 68% for the 1980s, compared with 86%, 69%, and 57% for the 1970s (p < 0.001). Actuarial graft survival also improved significantly, with rates at 1, 5, and 10 years of 86%, 71%, and 52% for the 1980s, compared with 73%, 58%, and 43% for the 1970s (p < 0.001). This improvement occurred even though there were proportionately more cadaver donors and diabetic recipients in the 1980s. For both decades combined, 24% of the lost grafts were due to chronic rejection, 18% to cardiovascular causes of death with function, 13% to infectious causes of death with function, and 11% to acute rejection. The overall gain in graft survival rates in the 1980s was principally due to fewer cases of acute rejection and fewer infectious deaths. Improvement in graft survival due to the two leading causes–chronic rejection and cardiovascular causes of death–was relatively small, if any. These data indicate that future kidney transplantation research should emphasize prevention of chronic rejection and cardiovascular death.

Insulin independence in type I diabetes after transplantation of unpurified islets from single donor with 15-deoxyspergualin

Islet transplantation has been slow to develop as a therapy for type I diabetes mellitus. Conventional immunosuppression does not protect islet allografts from early failure and by current techniques the yield of purified islets from a single pancreas is inadequate or only marginally in excess of the number needed to sustain normoglycaemia. We transplanted unpurified islets from a single pancreas concomitantly with a kidney to two uraemic diabetic patients. The novel agent 15-deoxyspergualin, along with antilymphocyte globulin, was used for induction immunosuppression, and azathioprine, prednisone, and cyclosporin for maintenance. Islet function has been sustained in both, and the second patient is insulin-independent and euglycaemic more than 6 months after transplantation.

Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota

Transplantation began at the University of Minnesota in 1963. Treatment of diabetes and its complications has been emphasized since 1966, when the first pancreas-kidney transplant was done. Of 3,640 kidneys transplanted by 1992, 1,373 were for diabetic recipients, including 658 from living donors and 715 from cadaver donors. The results progressively improved; since 1984, survival rates of kidney grafts have been similar for diabetic and nondiabetic recipients, with three fourths of the grafts functioning at 4 years. As of 1992, 501 pancreas transplants had been done, including 170 simultaneous with a kidney, 142 after a kidney, and 188 alone for nonuremic diabetic patients; again, the results have improved: by the 1990s, graft survival rates were similar in the 3 recipient categories. Successful pancreas transplants have been shown by our coworkers to stabilize or improve neuropathy and prevent recurrence of diabetic nephropathy in kidney grafts. In an attempt to simplify endocrine replacement therapy, we have done 63 human islet transplants, 34 as allografts for patients with type I diabetes and 29 as autografts after total pancreatectomy to treat chronic pancreatitis. Insulin independence occurs for about 50% of islet autograft recipients. Two recent islet allograft recipients treated with 15-deoxyspergualin have had sustained insulin independence. We anticipate that endocrine replacement therapy by transplantation will become routine for diabetic patients as methods to prevent rejection are refined.

A prospective randomized study of acyclovir versus ganciclovir plus human immune globulin prophylaxis of cytomegalovirus infection after solid organ transplantation

Cytomegalovirus disease occurs frequently after solid organ transplantation and has been associated with decreased patient and allograft survival. We hypothesized that CMV transmission or reactivation begins immediately or soon after transplantation, and that a short-duration ganciclovir (GCV)-based regimen would obviate the need for long-term antiviral agent administration, perhaps serving to interdict CMV infection and disease as well as, or perhaps even more effectively than, a more prolonged, oral acyclovir (ACV)-based form of prophylaxis. A total of 311 patients were stratified according to allograft type, age, and presence or absence or diabetes mellitus, and were then randomized to receive either long-duration ACV prophylaxis (800 mg orally or 400 mg i.v. q.i.d. for 12 weeks after transplantation or 6 weeks after any antirejection therapy) versus short-duration GCV (5 mg/kg/12 hr i.v. for 7 days after transplant or after any antirejection therapy) plus human immune globulin (HIg; Sandoglobulin or Minnesota CMV immune globulin) 100 mg/kg i.v. administered on days 1, 4, and 7 after transplant or after any antirejection therapy. A total of 266 patients (ACV, n = 133; GCV+HIg, n = 133) completed the protocol and were available for follow-up. CMV disease occurred in fewer patients (n = 28, 21.0%) in the ACV group, while significantly more patients (n = 42, 31.6%) in the GCV + HIg group developed group developed CMV disease slightly later (2.83 +/- 0.70 months) than those who received GCV/HIg (2.15 +/- 0.21 months, P > 0.01). Multivariate analysis demonstrated (2.15 +/- 0.21 months, P > 0.1). Multivariate analysis demonstrated that receiving antirejection therapy, a liver transplant, or a donor organ from a CMV-seropositive individual if the recipient was CMV seronegative were major risk factors for the development of CMV disease (P < 0.001), while the difference between ACV versus GCV + HIg prophylaxis was also significant (P = 0.054). No differences in actuarial patient or allograft survival, however, were noted between the 2 prophylaxis groups. Overall, ACV prophylaxis appeared to be more effective in reducing the incidence of posttransplant CMV disease, although this effect was diminished in high-risk groups of patients. Our findings indicate that CMV transmission or reactivation may best be prevented by long-term antiviral agent administration, and that the primary morbidity of CMV disease is the need for rehospitalization when either prolonged ACV or short-duration GCV + HIg prophylaxis is used in this patient population.

Hyperuricemia after renal transplantation

Hyperuricemia is common in cyclosporine-treated renal allograft recipients. An increased incidence of gout in patients receiving both diuretics and cyclosporine has been reported, but the effect of hyperuricemia on renal allograft function has not been studied. In a prospective, randomized trial of cyclosporine and prednisone versus azathioprine, prednisone, and antilymphocyte globulin for immunosuppression in renal allograft recipients, 105 of 131 cyclosporine and prednisone-treated patients (80 percent) experienced hyperuricemia (serum uric acid level above 8 mg/dl) and 13 of 131 (10 percent) were severely hyperuricemic (serum uric acid level above 14 mg/dl). In contrast, hyperuricemia developed in 63 of 115 patients (55 percent) treated with azathioprine, prednisone, and antilymphocyte globulin (p less than 0.002). Despite the frequent occurrence of hyperuricemia, gout was rare. Clinical gout developed in six patients in the cyclosporine and prednisone group and in 0 patients in the azathioprine, prednisone, and antilymphocyte globulin group between 1 and 43 months (median 22.5 months) after transplantation. Neither severe hyperuricemia nor diuretic therapy were associated with a significantly increased incidence of gout. The mean serum creatinine concentration of severely hyperuricemic patients (all on cyclosporine and prednisone) was similar to that of normouricemic cyclosporine and prednisone patients (1.8 mg/dl versus 1.6 mg/dl, p greater than 0.2), and the severely hyperuricemic patients had a 4-year graft survival rate of 90 percent. Asymptomatic hyperuricemia after renal transplantation does not adversely affect allograft function, requires no specific therapy, and is not a contraindication to use of diuretics.

Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: Three-year results

Background. Historically, antibody induction has been used because of the higher immunologic risk of graft loss or rejection observed in simultaneous pancreas and kidney (SPK) transplantation compared with kidney transplantation alone. This trial was designed to assess the effect of antibody induction in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids. Induction agents included T-cell–depleting and interleukin-2 receptor antibodies. Methods. A total of 174 SPK transplant recipients were enrolled in a prospective, open-label, multi-center study. They were randomized to induction (n=87) or non-induction (n=87) groups and followed for 3 years. Results. At 3 years, actual patient (94.3% and 89.7%) and pancreas (75.9% and 75.9%) survivals were similar between the induction and non-induction groups, respectively. Actual kidney survival was similar at 1 and 2 years, but at 3 years, it was significantly better in the induction group compared with the non-induction group (92% vs. 81.6%; P =0.04). At 3 years, median serum creatinine and hemoglobin A1C were similar between the induction and non-induction groups (1.35 mg/dL and 1.20 mg/dL, 5.4% and 5.5%, respectively). Three-year cumulative incidence of biopsy-confirmed, treated acute kidney rejection in the induction and non-induction groups was 19.5% and 27.5% (P =0.14), respectively, with odds 4.6 times greater in African Americans regardless of treatment (P =0.004). Significantly higher rates of cytomegalovirus (CMV) viremia and CMV syndrome occurred in those receiving T-cell–depleting antibody induction (36.1%) when compared with those receiving anti–interleukin-2 receptor antibodies (2%) and non-induction (8.1%) (P <0.0001). Conclusions. Tacrolimus, mycophenolate mofetil, and corticosteroids resulted in excellent safety and efficacy in SPK transplant recipients. Actual 3-year kidney survival was significantly better in the induction group; however, CMV viremia and CMV syndrome rates were significantly higher in the T-cell–depleting antibody group. African Americans demonstrated a significantly greater risk of acute rejection despite antibody induction. Decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.

Recurrence of disease in patients retransplanted for focal segmental glomerulosclerosis

The natural history of focal segmental glomerulosclerosis in patients retransplanted after loss of a primary allograft is not well established. We studied 14 patients with FSGS who were retransplanted between April 1964 and September 1990 to determine if recurrence in a second or subsequent allograft could be predicted. In this group, 8 of the primary allografts were lost to recurrent disease and 6 to rejection. None of the 6 patients who lost their primary allograft to rejection without evidence of recurrent FSGS suffered recurrent disease after retransplantation. In contrast, 3 of the 8 patients who lost their primary allograft rapidly to FSGS suffered recurrent disease and loss of function in all subsequent allografts. The remaining 5 patients had prolonged function of the primary allograft ranging between 4 and 10.5 years, despite recurrence of FSGS. Of these 5 patients, 2 have excellent renal function after retransplantation without recurrence of FSGS in the secondary allograft at 9 and 10.5 years posttransplant; 2 have lost their secondary allograft to recurrent FSGS, but are free of recurrence in the third allograft at 0.5 and 5.8 years postoperatively; 1 maintains a serum creatinine level of 1.9 mg% despite recurrence of FSGS in the secondary allograft at 1 year postoperatively. Our data show that, without recurrence of FSGS in the primary allograft, further renal transplants will be free of recurrent disease. Based on this finding, we advocate use of living-related donors for second transplants in these patients. With rapid recurrence of FSGS and subsequent accelerated loss of the primary allograft, further renal transplants carry a high likelihood of recurrent FSGS and graft loss. A substantial proportion of patients with recurrent FSGS in the primary allograft will have prolonged renal function, and are likely to have excellent results with subsequent allografts.

Pancreatic islet transplantation: is purification necessary?

Successful islet allotransplantation in diabetic patients has been slow to develop. In the past, it has been assumed that the low success rates are, in part, due to difficulty in obtaining high-quality human islet preparations. The assumption has been that purified islets are essential because exocrine contamination hampers engraftment and makes islets more vulnerable to rejection by increasing graft immunogenicity. We reviewed the existing experimental data on the consequences of exocrine contamination and concluded that most clinical trials of islet allotransplantation have involved efforts to over-purify the allograft. Until antigen-specific tolerance or the biohybrid artificial pancreas is a reality, the best strategy for clinical trials is to test new immunosuppressive protocols in a search for a more effective way of modifying the hosts immune response while maximizing islet yield by using less pure preparations.