Successful renal transplantation is the optimal treatment for chronic kidney failure, but this was not always so for children. Beginning with the first kidney transplants in the 1950s, children experienced poorer patient and graft survival rates than adult patients. But over the last 6 decades, an improved understanding of the immune system which has steered pediatric multi-center clinical/pharmacokinetic and mechanistic studies that have sculpted our immunosuppression with markedly better patient and graft survivals. In addition, uniquely pediatric issues related to growth, development, neurocognitive maturation, increased complications from primary viral infections, and comorbid congenital/inherited disorders, are now diagnosed and effectively managed in these children. Refined pretransplant preparation (vaccinations for preventable diseases, attention to cognitive delays, effective dialysis and nutrition) improved donor selection, and more potent immunosuppression have all contributed to enhanced outcomes. Similarly, improvements in pediatric surgical techniques, postoperative care and better antiviral prophylaxis have all shortened hospitalizations and reduced morbidity. Today pediatric kidney transplant outcomes are markedly improved and younger children today experience better long-term graft survival than adults! While difficult problems remain, we have made tremendous progress and anticipate even more advances in the future of pediatric kidney transplantation.

We retrospectively evaluated the long-term results of 53 (3.5%) recipients who received second allograft among 1486 kidney transplants between November 3, 1975 and June 30, 2004. Two study groups were patients in Group 1 (n = 21) who underwent allograft nephrectomy and those in Group 2 (n = 32) who did not. We assessed demographic features, rejection rates throughout the follow-up period, and serum creatinine levels at 12 months as well as graft and patient survival rates, postoperative complications, time interval between transplantations, and HLA matches. Forty-three patients who underwent retransplantation received kidneys from living-related donors and the remaining 10 from cadaveric donors. Mean serum creatinine levels of Group 1 versus Group 2 were 1.8 mg/dL (range, 0.8 to 6.6 mg/dL) versus 2.1 +/- 1.1 mg/dL (range, 1.1 to 7.1 mg/dL). HLA-AB and HLA-DR mismatches were 1.9 +/- 1.1 versus 1 +/- 0.6, respectively (P = .01). Acute rejection rates were not significantly different between Groups 1 (9/21, 43%) and 2 (12/32, 38%) (P < .05). The average intervals between the first and the second transplantations were 62 +/- 26 months in Group 1 (P = .02) and 32 +/- 11 months in Group 2. One-, 3-, and 5-year graft survival rates in Group 1 versus Group 2 were 83% versus 89% (P > .05); 64% versus 79% (P > .05), and 45% versus 68% (P = .04), respectively. In conclusion, we did not observe any advantage of graft nephrectomy before retransplantation. The length of the interval between the first and the second transplantations may have a negative correlation with second graft survival.

The safety of conversion from cyclosporine to azathioprine following renal transplantation in patients generally considered to be at immunologic risk for allograft loss has not been established. We examined a group of 59 patients who underwent cadaveric renal transplantation and elective conversion from cyclosporine to azathioprine 8.3 +/- 3.8 months following transplantation. Forty-three of these patients received a first transplant and had panel-reactive antibodies (PRA) less than 40% (unsensitized). Sixteen patients received at least their second allograft or had PRA of 40% or more (sensitized). Average follow-up was 17.9 +/- 8.2 months. Nine patients (15%) failed conversion as manifested by the need to restart cyclosporine 1 to 10 months following conversion. All were in the unsensitized group. Of those successfully converted, there were six allograft failures, two from patient death, one from acute rejection, one from recurrent diabetic nephropathy, and two from patient noncompliance. All were in the unsensitized group, although the difference from the sensitized group was not statistically significant (P = 0.051). There were three rejection episodes, all successfully reversed, in the sensitized group and six rejection episodes in the unsensitized group, five of which were reversed. Overall renal function improved in both groups as shown by a significant decrease in serum creatinine. Neither group required increased doses of steroid to compensate for lack of cyclosporine. From these data we can recommend conversion from cyclosporine to azathioprine in patients with cytotoxic antibodies or those undergoing retransplantation.

The results of secondary cadaver renal transplantation in 42 patients treated from 1980 to 1986 have been reviewed. The initial graft was from a cadaver donor in all cases. All patients were managed with a maintenance immunosuppressive regimen, including either antilymphoblast globulin and/or cyclosporine. The over-all 1 and 2-year patient survival rates were 97 and 94 per cent, respectively. The over-all 1 and 2-year graft survival rates were 69 and 63 per cent, respectively. Graft success was not influenced by patient age greater than 50 years, diabetes, initial graft removal, interval between initial graft removal and retransplantation, duration of initial graft function, level of presensitization or HLA-Dr antigen matching. Currently, cadaver renal retransplantation can be performed safely and with an improved opportunity for graft success. Patients who return to dialysis after losing an allograft should be encouraged to consider another transplant for the same reasons that prompted initial transplantation.

Fourteen out of 301 patients who underwent allogeneic kidney transplantations, between April, 1970 and December, 1987, received second kidney allografts, including 4 living and 10 cadaveric grafts. The survival of the second grafts transplanted in those 14 recipients was superior to that of the first grafts transplanted in the other 287 recipients. Furthermore, the survival of the second grafts from 4 years onwards was significantly higher than that of the first grafts, in spite of a higher population of cadaveric grafts used in the second transplantation than in the first. Although it was impossible to determine the main factor which induced the improved survival of the second grafts when compared with that of the first, a combination of beneficial factors, such as a high rate of living related transplantation resulting in long-term graft survival of the first transplantation, the administration of immunosuppressive drugs during the period of re-hemodialysis and blood transfusion prior to the second transplantation, was considered to be the reason why successful second graft survival was achieved.

The results of cadaveric retransplantation in 55 recipients immunosuppressed with cyclosporine and prednisone were compared to 156 recipients of primary renal allografts. By 3 yr posttransplant, there is no significant difference in patient survival, but the yearly graft survival for primary (79%, 72%, 72%) as compared to retransplant (69%, 58%, 58%) recipients was significantly (p less than 0.05) better. There was no significant difference in rejection episodes or mean +/- SD serum creatinine (mg/dl) at 2 yr between primary (32%, 2.14 +/- 1.1) and retransplant (33%, 2.08 +/- 1.4) patients, respectively. Donor source, third kidneys, human leukocyte antigen AB and Dr matching, percent reactive antibody levels, and cause of first graft loss do not have significant impact on cyclosporine-treated retransplant outcome. However, retransplant patients who have lost a previous graft in less than 3 months continue to be at high risk for subsequent early graft loss. These results suggest that the combination of cyclosporine and prednisone is the preferred regimen for cadaveric retransplantation.

We report the selective and therapeutic factors affecting multiple kidney transplant success from a prospective multicenter study of the South-Eastern Organ Procurement Foundation. From June 1977 to March 1982, 3,215 cadaver kidney transplants were performed at 39 institutions. There were 2,535 first, 564 second, 103 third and 13 fourth grafts. The actuarial graft survival rates at 1 and 2 years were 52 plus or minus 1 and 45 plus or minus 1 per cent, respectively, for first grafts, 44 plus or minus 2 and 40 plus or minus 3 per cent for second grafts, and 42 plus or minus 5 and 31 plus or minus 6 per cent for third grafts. Graft survival rates were significantly lower for second and third than for first transplants (p less than 0.003). There was no difference in patient survival rates. The data were analyzed to determine which selective and therapeutic variables governed success of primary and secondary grafts. Pre-transplant blood transfusions were associated with a significant increase in graft survival rates in primary (p less than 0.00005) and secondary transplants (p less than 0.01), and did not affect patient survival rates. The administration of antilymphocyte serum also improved graft survival rates significantly in primary (p less than 0.00005) and secondary grafts (p less than 0.00002), without alteration of patient survival rates. HLA compatibility improved primary graft survival rates (p less than or equal to 0.022) but this did not reach statistical significance in secondary graft survival rates. Second transplant graft survival rates were best when the primary graft functioned for more than 12 months (Breslow p less than or equal to 0.02) but were not related to the reason for loss of the first graft. Pre-transplant bilateral nephrectomy improved graft survival rates significantly but this phenomenon was linked to other treatment factors. No beneficial effect on graft survival rate could be shown after pre-transplant splenectomy in patients with primary or secondary grafts and this procedure was associated with reduced patient survival rates in both groups.

Twenty-two patients at high risk to reject renal allografts have been treated with fractionated total lymphoid irradiation (FTLI) prior to transplantation of primary (2), secondary (16) or teritary (4) renal allografts. All patients undergoing retransplantation had rapidly rejected previous grafts. At 24 months following transplantation, 72% of grafts were functioning in the TLI group compared with a 38% graft function in an historical control group of recipients receiving secondary or tertiary grafts and treated with conventional immunosuppression. Important variables in determining success of transplantation following fractionated TLI include the dose of TLI, the interval from radiation to transplantation, and maintenance, post-transplant immunosuppressive therapy. Optimal results were achieved with 2500 rads delivered in 100 rad fractions followed by transplantation within two weeks, and a tapering prednisone schedule and maintenance azathioprine post-transplantation. Seventeen patients had significant complications of the radiation treatment and there was one death, prior to transplantation, associated with pneumonitis. In vitro assessment of immune function demonstrated marked peripheral T cell depletion and loss of in vitro responsiveness to mitogen and allogeneic stimulation following FTLI. The administration of donor bone marrow at the time of transplantation did not produce chimerism. The results suggest that when properly utilized FTLI can produce effective adjunctive immunosuppression for clinical transplantation.

Evaluation of 75 cadaver donor retransplants revealed that the primary factor influencing allograft survival is patient responsiveness as reflected by sensitization with preformed cytotoxic antibodies. Actuarial allograft survival rates for nonpresensitized (less than 5%) and moderately presensitized (5 to 50%) recipients were significantly (P less than 0.01) better than those of highly presensitized (greater than 50%) recipients. Although HLA A&B antigen histocompatibility did not have a statistically significant effect on retransplant outcome, it appeared to influence allograft survival in the highly presensitized recipient. An approach to the management of children who lose an initial or subsequent allograft is indicated by these data.

Recent reports cite better survival when repeatedly rejecting renal allografts are removed and patients returned to hemodialysis. However, the criteria for graft removal remain undefined; although some reports recommend removing all kidneys undergoing a third rejection. In our series (1968-1973) of 316 patients with technically successful first grafts followed 2(1/2)-8 years, graft survival was inversely related to the number of rejection episodes. One hundred per cent of kidneys without rejection are currently functioning or functioned at the time of death compared to 90% with one rejection, 67.4% with two and 21% with three. However, 40% of kidneys having three rejection episodes functioned longer than one year after treatment of the third rejection episode. In an attempt to determine the predictability of one year graft survival or failure following treatment of the third rejection, a formula was developed that correctly predicted in 33 of 38 (87%) patients. The formula was based on information available prior to treatment of the third rejection episode, and represents an index of baseline renal function (serum creatinine after second rejection episode) and two indices of the severity of rejection episodes (serum creatinine change between the first and second rejection episodes; rapidity of sequential rejection).Following its derivation, the formula was applied to a second group (1974) of 19 patients having had three rejection episodes. The formula correctly predicted one year allograft survival or failure following treatment of the third rejection episode in 68% of these patients. A striking finding of our review was a significant difference in current patient survival between those having no rejection episodes (89%) and those having one or more rejection episodes (65%) (p < .00001). There was no significantly greater long-term curtailment in survival if more than one rejection eipsode was treated. Patients having one rejection eipsode seemed to die from varying causes and at varying time periods. Patients dying after two or more rejection episodes had an increased incidence of deaths due to bacterial infection.