Overview of new immunosuppressive therapies.

This review covers the new immunosuppressive drugs that have appeared in the past 5 years. It begins with the newest formulation (Neoral, Sandoz Pharmaceuticals, East Hanover, NJ, USA) of the clinically "mature" drug cyclosporin A and then reviews the literature on tacrolimus, sirolimus, and mycophenolate mofetil. In each case, the emphasis is on the evolution of experience with the drug and on the questions that the drug poses for pediatricians considering the risk-benefit ratio of the drug in children.

Kidney transplantation in children younger than 1 year using cyclosporine immunosuppression.

OBJECTIVE: The optimal age for transplantation in children with end-stage renal disease remains controversial. Supported by national data, many centers recommend dialysis until the child reaches a certain minimum age. The authors' policy, however, has been to encourage living donor (LD) transplants for young children, with no minimum age restriction. METHODS: Between January 1, 1984, and December 31, 1996, the authors performed 248 kidney transplants in children younger than age 13 years, using cyclosporine as the primary immunosuppressive agent. Recipients were analyzed in three age groups: group 1, younger than age 1 year (n = 26); group 2, age 1 through 4 (n = 92); and group 3, age 5 through 13 (n = 130). Almost all recipients in group 1 underwent a primary LD transplant. Therefore, to compare results more meaningfully among the three age groups, only primary LD transplants were analyzed (group 1, n = 25; group 2, n = 59; group 3, n = 58). RESULTS: In primary LD transplants, no significant difference was noted among the age groups in 1-and 5-year patient or graft survival rates. To date, all 25 recipients from group 1 are alive and well; 19 still have a functional original graft. Causes of graft loss in the remaining six recipients were chronic rejection (n = 3), vascular thrombosis (n = 2), and recurrent disease (n = 1). The incidence of acute rejection in group 1 recipients was lower than in the two older groups. However, the incidence of delayed graft function was slightly higher in the youngest group than in the two older groups. For recipients in group 1, growth (as measured by weight) improved significantly posttransplant: the mean standard deviation score rose from -2.8 pretransplant to -0.2 by age 5 and to +1.8 by age 10. The improvement in height was not as dramatic: the mean standard deviation score rose from -3.2 pretransplant to -1.6 by age 5 and to -1.4 by age 10. CONCLUSIONS: Kidney transplantation in young children, including those younger than 1 year old, can achieve results comparable to those in older children. As long as an adult LD is available, the timing of the transplant should be based on renal function rather than age.

Chronic renal allograft rejection in the first 6 months posttransplant.

Between May 1, 1986 and May 31, 1992 at the University of Minnesota, we interpreted 129 renal allograft biopsy specimens (done in 48 grafts during the first 6 months posttransplant) as showing changes consistent with chronic rejection. For this retrospective analysis, we reexamined these biopsies together with clinical information to determine: (a) whether a diagnosis other than chronic rejection would have been more appropriate, (b) how early posttransplant any chronic rejection changes occurred, and (c) if the diagnosis correlated with outcome. We found that (1) chronic rejection is uncommon in the first 6 months posttransplant; it was documented in only 27 (2.4%) of 1117 renal allografts and was preceded by acute rejection in all but 3 recipients (for these 3, the first biopsy specimen showed both acute and chronic rejection). (2) Chronic vascular rejection was seen in 1 recipient as early as 1 month posttransplant; the incidence increased over time and was associated with an actual graft survival rate of only 35%. (3) The most frequent cause of arterial intimal fibrosis in the first 6 months posttransplant was arteriosclerotic nephrosclerosis (ASNS) of donor origin. Long-term graft function for recipients with ASNS was 67%. (4) Early-onset ischemia or thrombosis was seen in 14 recipients and predicted poor outcome: only 35.7% of these recipients had long-term graft function. (5) Cyclosporine (CsA) toxicity was implicated in only 3 recipients, who had mild diffuse interstitial fibrosis in association with elevated CsA levels. Other variables (including systemic hypertension, urinary tract infection, obstructive uropathy, neurogenic bladder, cobalt therapy, and recurrent disease) were not significantly associated with chronic renal lesions in the first 6 months posttransplant. A significant number of biopsies were originally interpreted as showing chronic rejection, but the diagnosis was changed upon reevaluation in conjunction with clinical data. We conclude that many factors coexist to produce chronic lesions in biopsies during the first 6 months posttransplant, so clinical correlation is needed before establishing a diagnosis of chronic rejection.

Use of ganciclovir for cytomegalovirus infection.

Ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl) guanine, DHPG) is an acyclovir analog with excellent antiviral activity against human cytomegalovirus (CMV). Clinically, CMV infection occurs in from 60 to 90% of all renal transplant recipients and it is responsible for significant patient morbidity and graft loss. The likelihood of infection is closely related to the CMV status of both donor and recipient, with the greatest risk arising in the combination of a seronegative patient receiving a seropositive organ. Intracellularly, DHPG is converted to DHPG-triphosphate, which competitively inhibits DNA polymerase. This conversion is accelerated up to 10-fold in virally infected cells, providing some selectivity of action. Uncontrolled studies demonstrated DHPG efficacy in CMV disease, but experience in children remains limited. Although bone marrow suppression is a major immediate toxicity, long-term concerns about carcinogenesis and infertility mandate careful patient selection. Recently at the University of Minnesota, 93 solid organ recipients (45 renal transplants) including some children have been treated for tissue-invasive CMV with DHPG. All had a characteristic clinical picture and either a positive CMV culture or a biopsy with CMV inclusions. The patients received i.v. DHPG (10 mg/kg/day) with appropriate adjustments for renal function. In renal allograft recipients, 89% recovered within 30 days, although 21% had to be retreated with DHPG. Although no patient died, allograft survival was significantly reduced (P = 0.02). An additional subgroup of patients (N = 18) who had both biopsy-proven rejection and invasive CMV disease were simultaneously treated for both processes. All of these patients recovered from their CMV infection, but two grafts were lost to rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Overview of pediatric renal transplantation.

Over 35 years, renal transplantation in infants and children has evolved dramatically. Once a desperate effort, transplantation is now the therapy of choice for virtually all children with end-stage renal disease (ESRD). The number of children less than 10 years old living with ESRD has more than doubled in the last 7 yr, but during that same interval the children with functioning transplants has quadrupled. Since 1963, 386 children and 21 infants have received 495 renal transplants at the University of Minnesota. When examined, several variables strongly influence the outcomes. Primary renal transplants, grafts from living-related donors, and transplants performed since 1979 have all been associated with markedly improved outcomes. But age of the recipient has no impact on either patient or graft survival. Beneficially, transplanted infants experience significantly accelerated head growth, returning them to the normal range. Their development test scores also significantly improve, again bringing them into the normal range. Finally, statural growth regularly improves following successful transplantation. These results support a strategy of early, aggressive support; prompt renal transplantation; and the use of dialysis primarily as a critical "bridge" to elective transplant surgery.

Successful renal transplantation accelerates development in young uremic children.

To examine the impact of renal transplantation on subsequent development of children with chronic renal failure, 37 children undergoing primary renal transplantation at or before 30 months of age whose allograft functioned for at least 1 year were prospectively studied. Psychometric tests were performed an average of 4 months before transplantation; reevaluation was done an average of 14 months after surgery. Comparison of individual pretransplantation and posttransplantation mental development scores in 33 patients, assessed by either Bayley Mental Development Index or Stanford-Binet Intelligence Quotient, revealed an average increase of 12.6 (P less than .001). After transplantation, there was a significant improvement in mental performance in 12 of 18 patients (P less than .02) from the range of mild delay (Mental Development Index or Stanford-Binet IQ score = 50 to 69) to the range of normal mental development (greater than or equal to 70). The Bayley Psychomotor Development Index scores were frequently lower than Mental Development Index scores and also increased an average of 14.4 (P less than .01) after transplantation in all 12 patients with paired data. Significant individual improvement in occipital-frontal circumference standard deviation score (P less than .001) was noted in 24 children after transplantation. It is concluded that successful renal transplantation in young children with chronic renal failure is often associated with significant improvements in cognitive and psychomotor function, as well as improved cephalic growth.

The 1989 report of the North American Pediatric Renal Transplant Cooperative Study.

This report of the North American Pediatric Transplant Cooperative Study summarizes data contributed by 57 participating centers on 754 children with 761 transplants from 1 January 1989 to 16 February 1989. Data collection was initiated in October 1987 and follow-up of all patients is ongoing. Transplant frequency increased with age; 24% of the patients were less than 5 years, with 7% being under 2 years. Common frequent diagnoses were: aplastic/dysplastic kidneys (18%), obstructive uropathy (16%), and focal segmental glomerulosclerosis (12%). Preemptive transplant, i.e., transplantation without prior maintenance dialysis, was performed in 21% of the patients. Dialytic modalities pretransplant were peritoneal dialysis in 42% and hemodialysis in 25%. Bilateral nephrectomy was reported in 29%. Live-donor sources accounted for 42% of the transplants. Among cadaveric donors, 41% of the donors were under 11 years old. During the first post-transplant month, maintenance therapy was used similarly for live-donor and cadaver source transplants, with prednisone, cyclosporine, and azathioprine used in 93%, 83%, and 81%, respectively. Triple therapy with prednisone, cyclosporine, and azathioprine was used in 78%, 75%, and 75% of functioning cadaver source transplants at 6 months, 12 months, and 18 months as opposed to 60%, 63%, and 54% for live-donor procedures, with single-drug therapy being uncommon. Rehospitalization during months 1-5 occurred in 62% of the patients, with treatment of rejection and infection being the main causes. Additionally, 9% were hospitalized for hypertension. During months 6-12 and 12-17, 30% and 28% of the patients with functioning grafts were rehospitalized. Times to first rejection differed significantly for cadaver and live-donor transplants. The median time to the first rejection was 36 days for cadaver transplants and 156 days for live-donor transplants. Overall, 57% of treated rejections were completely reversible although the complete reversal rate decreased to 37% for four or more rejections. One hundred and fifty-two graft failures had occurred at the time of writing, with a 1-year graft survival estimate of 0.88 for live-donor and 0.71 for cadaver source transplants. In addition to donor source, recipient age is a significant prognostic factor for graft survival. Among cadaver donors, decreasing donor age is associated with a decreasing probability of graft survival. Thirty-five deaths have occurred; 16 attributed to infection and 19 to other causes. The current 1-year survival estimate is 0.94. There have been 9 malignancies.

Renal transplantation in infants.

The timing of renal transplantation in infants is controversial. Between 1965 and 1989, 79 transplants in 75 infants less than 2 years old were performed: 23 who were 12 months or younger, 52 who were older than 12 months; 63 donors were living related, 1 was living unrelated, and 15 were cadaver donors; 75 were primary transplants and 4 were retransplants. Infants were considered for transplantation when they were on, or about to begin, dialysis. All had intra-abdominal transplants with arterial anastomosis to the distal aorta. Sixty-four per cent are alive with functioning grafts. The most frequent etiologies of renal failure were hypoplasia (32%) and obstructive uropathy (20%); oxalosis was the etiology in 11%. Since 1983 patient survival has been 95% and 91% at 1 and 5 years; graft survival has been 86% and 73% at 1 and 5 years. For cyclosporine immunosuppressed patients, patient survival is 100% at 1 and 5 years; graft survival is 96% and 82% at 1 and 5 years. There was no difference in outcome between infants who were 12 months or younger versus those who were aged 12 to 24 months; similarly there was no difference between infants and older children. Sixteen (21%) patients died: 5 after operation from coagulopathy (1) and infection (4); and 11 late from postsplenectomy sepsis (4), recurrent oxalosis (3), infection (2), and other causes (2). Routine splenectomy is no longer done. There has not been a death from infection in patients transplanted since 1983. Rejection was the most common cause of graft loss (in 15 patients); other causes included death (with function) (7), recurrent oxalosis (3), and technical complications (3). Overall 52% of patients have not had a rejection episode; mean creatinine level in patients with functioning grafts is 0.8 +/- 0.2 mg/dL. Common postoperative problems include fever, atelectasis, and ileus. At the time of their transplants, the infants were small for age; but with a successful transplant, their growth, head circumference, and development have improved. Transplantation in infants requires an intensive multidisciplinary approach but yields excellent short- and long-term survival rates that are no different from those seen in older children or adults. Living donors should be used whenever possible. Patients with a successful transplantation experience improved growth and development, with excellent rehabilitation.

Results of pediatric kidney transplantation at the University of Minnesota.

In all, 473 renal transplants were performed at the University of Minnesota in 386 children 1-17 years old between August 14, 1963 and December 31, 1988. Standard immunosuppressive protocols, pretransplant blood transfusions, and discontinuation of routine splenectomy have led to improving graft and patient survival rates. Children receiving living-related donor kidneys had better graft and patient survival rates, compared to cadaver kidneys. Graft and patient survival rates were better in children who received primary grafts, compared to retransplants. Children who received DST plus conventional immunosuppression had poorer graft survival, compared to quadruple immunosuppression during the same era. Recently, 1-year graft survival rates with quadruple immunosuppression are equal for children receiving primary, living-related donor or cadaver kidneys. Graft and patient survival rates in children 1-4 years old are identical to those in children 5-17 years old. Age no longer appears to be a risk factor for children undergoing kidney transplantation. Good patient and graft survival rates can be achieved at centers specializing in kidney transplantation for small children. Currently, transplantation is the treatment of choice for all children who are candidates for renal replacement therapy.

The outcome of 304 primary renal transplants in children (1968-1985).

Of 304 children who received primary renal transplants at the University of Minnesota between January 1, 1968, and December 31, 1985, 48 (16%) were under the age of 24 months, 60 (20%) were 2-5 years old, and 196 (64%) were 6-17 years old at transplantation. Currently, 254 (84%) are alive at 2 months to 18 years following their first transplants, 77% with functioning grafts (188 first, 45 retransplants) and 7% on dialysis. Overall, patient and graft survival were not significantly different from the primary graft outcome of nondiabetic adults. The actuarial primary graft function rates at 1, 5, and 10 years were 100, 100, and 90% in 16 HLA-identical sibling kidneys; 84, 64, and 52% in 210 mismatched related kidneys; and 72, 54, and 47% in 78 cadaver kidneys (p less than 0.002). The 1-year patient survival and primary graft function rates in 44 mismatched related recipients under the age of 24 months were 92 and 88%. The use of deliberate, pretransplant random blood transfusion since 1979 has been associated with a decreased rejection rate. Primary graft function of mismatched related kidneys in children receiving standard immunosuppression has significantly improved from 78% at 1 year in the pretransfusion era to 91% (p less than 0.01) in the transfusion era. The overall primary cadaver graft function rate, however, did not improve in the transfusion era. Whether cyclosporine use will improve the cadaver renal allograft function in very young recipients remains to be established. However, with the use of related donors, even very young children can be transplanted safely and with excellent results.

Renal failure as a complication of acute antihypertensive therapy.

Adult patients with long-standing hypertension have been reported to experience an impairment in renal function when treatment with potent vasodilating agents is initiated. To document that this sequence may occur in children as well, we report the case of a 4-year-old boy with renal disease in whom reduction of blood pressure to normal levels was accompanied on three occasions by oliguric renal failure. During each episode, the correlation between reduction in blood pressure and increase in serum creatinine level was significant (P less than .05); furthermore, the slope of the relationship was similar with each episode. This phenomenon suggests an impairment of renal autoregulation in this patient. Maintenance of normal blood pressure for several months was accompanied by a gradual return of renal function to pretreatment levels. This case suggests that particular attention should be paid to renal function during the initiation of antihypertensive therapy, particularly in patients with renal vascular damage. Present evidence does not appear to warrant modification of the current therapeutic philosophy of aggressive management in patients with severe hypertension.

The association of familial liver disease, subepidermal immunoproteins, and membranoproliferative glomerulonephritis.

Herein we report a new familial form of hepatic disease. Each of the four patients had splenomegaly, hypersplenism, a small liver, biochemical evidence of hepatic excretory dysfunction and hepatocellular damage, kidneys without demonstrable cysts, and normal blood pressue. An evaluation of serum immunoproteins, autoantibodies, histocompatibility antigens, and mixed lymphocyte reactivity further defined the immunologic features of this syndrome. Extrahepatic manifestations included a papulosquamous dermatitis with deposition of immunoglobulins and complement in both normal and abnormal skin, a membranoproliferative glomerulonephritis with subendothelial deposits, arthritis, and pericardial, pleural, and synovial effusions.