Alfred J. Pennisi

Progression to end-stage renal disease in children with obstructive uropathy.

The course of 54 patients (35 boys and 19 girls) with end-stage renal disease resulting from obstructive uropathy was reviewed. The mean age at the initial sign of obstructive uropathy was 3.5 years. Twenty-two patients (41%) manifested evidence of obstructive uropathy during the first year of life. The mean age at the time of onset of ESRD (dialysis) was 12.2 years and was similar in boys and girls. The mean time interval between the first sign of obstructive uropathy and the initiation of dialysis was nine years. Fourteen patients operated upon at less than one year of age developed ESRD one to 20 years (mean ten years) following their initial surgery. Progression to ESRD occurred despite appropriate surgical management, including corrective as well as diversionary urologic procedures. However, because the patients were selectively referred for care of ESRD, no assessment of the incidence of ESRD caused by obstructive uropathy was possible. The data indicate that prolonged follow-up periods are necessary to assess the ultimate outcome of renal function in young patients with obstructive uropathy. Despite early intervention and intact renal function for many years during childhood, progression to ESRD may occur.

Focal glomerulosclerosis and renal transplantation

Eighteen patients with corticosteroid-resistant nephrotic syndrome developed end-stage renal disease and received one or more renal allografts. The lesion of focal segmental glomerulosclerosis and/or of focal glomerular obsolescence was demonstrable in the native kidneys of each patient. Following transplantation, nephrosis developed in three recipients. Two recipients developed nephrosis at two weeks and nine months posttransplant in association with rejection; the lesion of FGS was present in association with chronic rejection. Only one recipient developed recurrence of nephrosis and FGS unrelated to rejection. This was manifested by immediate onset of nephrosis in two successive allografts and histologic evidence of the lesion of FGS. The immediate recurrence in successive allografts suggests a circulating factor responsible for the renal lesion in this patient and indicates a separate etiology for a small number of patients with corticosteroid-resistant nephrosis and FGS.

SUCCESSFUL RENAL ALLOGRAFTS ACROSS A POSITIVE CROSS-MATCH FOR DONOR B-LYMPHOCYTE ALLOANTIGENS

Seven patients received a renal allograft with negative standard and T-lymphocyte microlymphocytotoxicity cross-matches, but a positive B-lymphocyte cross-match using donor lymphocytes. In spite of this presensitisation, none underwent hyperacute rejection and all are functioning from one and a half to six months after transplantation. This procedure may help in the detection of false-positive cross-matches and possibly in detection of enhancing antibodies against a specific donor.

Renal Transplantation in Children with Obstructive Uropathy

The outcome of renal transplantation was examined in 52 pediatric patients (mean age 13 years) whose primary renal disease was obstructive uropathy. The bladder was used at transplantation in 45 allograft recipients, 39 of whom had had a previous lower urinary tract operation or bladder defunctionalization. An ileal loop was used in 7 recipients. The 52 patients received 73 renal allografts from 58 cadaver and 15 live-related donors. Presently, 40 patients (77 per cent) have functioning allografts, 4 have returned to dialysis and 8 (15 per cent) have died. The results indicate that the outcome of renal transplantation in patients with obstructive uropathy is similar to that of other transplant recipients. Damaged and defunctionalized bladders may be used successfully in most cases. If necessary an ileal conduit is an effective alternative. Post-transplant urologic complications occur with increased frequency but with appropriate management allograft salvage and patient survival are excellent.

Minoxidil therapy in children with severe hypertension.

Six children, from 1.3 to 18 years of age, with severe hypertension associated with the hemolytic uremic syndrome, periarteritis, and renal transplant rejection received minoxidil, an antihypertensive agent, for three to 36 weeks. All had severe hypertension resistant to oral antihypertensive medications; five required frequent intravenous diazoxide therapy prior to minoxidil therapy. The mean pretreatment systolic and diastolic blood pressures were 176 and 117 mm Hg, respectively. Following treatment, the mean systolic and diastolic blood pressures were 133 and 82 mm Hg, respectively. Concomitant antihypertensive medications were decreased in all six patients once optimal blood pressure control was obtained. The initial dosage of minoxidil was 0.1 to 0.2 mg/kg/day; maximal dosage for blood pressure was 0.3 to 1.4 mg/kh/day. Major complications of therapy were fluid retention and hirsutism. Transient asymptomatic pericardial effusions occurred in two patients. Three patients on prolonged minoxidil therapy had persistent increases in right ventricular end diastolic diameters. Minoxidil is an effective oral antihypertensive agent for treatment of severe hypertension in pediatric patients. Avoidance of fluid retention is mandatory to prevent congestive heart failure.

Renal transplantation in children less than 5 years of age.

19 young children (less than 5 years old) have received 31 renal transplants from 4 live relatives and 27 cadaver donors. The 2-year allograft survival rate for the patients receiving their 1st allograft from the 4 live donors was 75 +/- 22% while for the patients receiving their 1st allograft from 15 cadaver donors was 26 +/- 11%. 10 children are currently surviving with functioning allographs (7 cadavers and 3 live relatives); 4 have died and 5 are undergoing dialysis after the loss of at least one allograft. Despite the poor allograft survival rate the fact that 7 children are surviving with cadaver allografts indicates that the lack of a living related donor should not prevent transplants in young children.

The adverse effect of anticonvulsant therapy on renal allograft survival. A preliminary report.

Administration of anticonvulsant medication to recipients of cadaver renal allografts appears to be associated with decreased allograft survival. The one-and two-year actuarial graft survival rates for 20 index grafts was significantly lower than for 92 control grafts. Since phenobarbital and diphenylhydantoin increase the metabolism of corticosteroids, it is proposed that renal allograft recipients receiving these anticonvulsants may have ineffective immunosuppression, leading to a higher incidence of graft failure.

Anti-B Lymphocytotoxins in Renal-Allograft Rejection

To determine the possible role of the B lymphocyte alloantigen system in renal-transplant rejection, we examined serum specimens from 81 allograft recipients for cytotoxic activity against a panel of normal B lymphocytes. Specimens from 22 of 25 recipients undergoing allograft rejection demonstrated strong B-lymphocyte cytotoxicity whereas only 13 of 56 recipients with normal allograft function showed similar B lymphocyte cytotoxocitiy (P less than 0.0001). In the serum samples of recipients with graft rejection who were followed sequentially, B-lymphocyte cytotoxicity preceded or was concurrent with the onset of functional impairment. The results show that anti-B-lymphocyte antibodies are associated with rejection, but it is quite possible that they are the products of rejection rather than the cause.

Cadaver renal transplantation in children with cystinosis.

Five children with end-stage renal disease resulting from cystinosis received seven cadaver renal allografts. Four recipients have functioning grafts eight to 55 months after receiving the transplant and one recipient lost two grafts at 17 and 26 months after the transplant. There was no florid recurrence of the Fanconi syndrome although proximal renal tubular dysfunction developed in two patients, in one in association with chronic rejection and in one without apparent etiology. Free cystine content of white blood cells, cultured skin fibroblasts and allograft tissue was significantly increased. Cystine crystals were observed in the mesangium of two grafts and in the interstitial tissue of all grafts; however, no cystine crystals were found in the tubules. The location of the cystine crystals, as well as the fact that the highest free level of cystine of allograft tissue was observed in the graft undergoing chronic rejection. led to the hypothesis that recipient cells infiltrating the graft were the source of cystine deposition. The data indicate that successful cadaveric transplantation does not correct the primary metabolic defect in cystinosis, thereby explaining the persistence of the extrarenal clinical manifestations, such as photophobia and hypothyroidism, after renal transplantation in cystinosis.

Long-term cadaver allograft survival in the recipient with a positive B lymphocyte crossmatch.

Over a 2 1/2-year period, prospective standard, T, and B lymphocyte crossmatches were performed in 45 cadaver renal transplants using the microlymphocytotoxicity technique. Twenty-three of the 45 recipients had a positive B lymphocyte crossmatch. Cumulative graft survival rates did not differ between recipients with a positive and negative B lymphocyte crossmatch. High levels of presensitization in routine lymphocytotoxic antibody screening or transplant number did not adversely affect graft survival in recipients with a positive B lymphocyte crossmatch. Five recipients had moderately positive standard crossmatches which were attributable to anti-B lymphocytotoxicity. Four of these five grafts are presently functioning with normal serum creatinine levels 9 to 14 months post-transplant. A positive B lymphocyte crossmatch is compatible with good long-term cadaveric renal allograft survival. In addition, a weakly positive standard crossmatch is not a contraindication to transplantation when the positive crossmatch is attributable to anti-B lymphocyte antibody.