Susan B. Conley

Complications of cyclosporine-prednisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years.

The therapeutic efficacy of cyclosporine (CsA) as an immunosuppressive agent was complemented by a modest, long-term incidence of toxic complications in 402 renal allograft recipients engrafted one to five years prior to analysis. The overall patient and graft survivals at one year were 97% and 84% (actual), and at five years 92% and 67% (actuarial). The immunosuppressive therapeutic index was excellent: only 12% of allografts were lost from rejection, with 5% of patients succumbing to infection. While infections were common, tending to emanate in the urinary tract or to be viral in etiology, they were generally mild and readily controlled. Only four patients displayed malignancies; none succumbed to this cause. The most common toxic complication was hypertrichosis, which was accentuated in pediatric patients. While tremors occurred in 20% of patients, primarily during the first three months, other neuroectodermal complications of parethesias, depression, somnolence, and seizures were rare. Hepatotoxicity, which was noted in 50% of patients, particularly recipients of cadaveric grafts, generally was first seen as a transaminase elevation, at least partially reversible by dose-reduction and abating by the third year. Associated disturbances of cholelithiasis and pancreatitis were occasionally observed. Nephrotoxicity was the only persistent, long-term complication. Hypertension occurred in 72% of patients during the first month, 36% in the second year, and about 15% thereafter. Hyperuricemia, which occurred in about 30% of recipients during the first two years, was occasionally associated with symptomatic gout. The mean serum creatinine level remained elevated throughout the follow-up period at 1.8—1.9 mg/dl, suggesting persistent, but nonprogressive, drug-induced renal injury. The present analysis documents the relative safety of CsA for long-term therapy, and highlights the need for new approaches to ameliorate drug-induced nephrotoxicity.

Nephropathic cystinosis with central nervous system involvement

Nephropathic cystinosis is associated with end-stage renal failure, retinal damage, and hypothyroidism. Patients may now survive past the first decade of life with the use of dialysis and renal transplantation. Examination of a 24-year-old woman with this disorder revealed ovarian failure, mildly abnormal results on a glucose tolerance test, intermittent confusion, short-term memory loss, and cerebral atrophy on computerized axial tomography. Autopsy examination at age 25 years revealed cystine storage in multiple tissues including the atrophic ovaries, pancreatic islet cells, the aorta, and the brain. Dysfunction of multiple organ systems may develop in patients with cystinosis who survive into adulthood. This emphasizes the need for a systemic therapy for cystinosis.

Use of cyclosporine in pediatric renal transplant recipients

Cyclosporine and prednisone were used in combination to produce immunosuppression in 18 pediatric recipients of renal allografts. Ten children received cadaveric kidneys and eight received kidneys from living related donors. With a mean follow-up of 16.5 months (range 7 to 33 months), the patient survival rate is 100% (18 of 18) and the graft survival rate is 83% (15 of 18). Two grafts were lost for nonimmunologic reasons. Currently the group mean (±SE) serum creatinine concentration is 1.22±0.11 mg/dl and creatinine clearance is 69.3±4.79 ml/min/1.73m 2 . Cyclosporine nephrotoxicity has not caused irreversible allograft injury nor led to graft loss in this population. The incidence of treated rejection episodes has been 39% (seven of 18). Only 39% (seven of 18) of children have required hospital readmissions since the initial transplant discharge. There have been no opportunistic infections. In the 15 children with functioning grafts, some linear growth has occurred in 10 of 11 prepubertal and two of four postpubertal patients. Cyclosporine and prednisone have constituted a safe, efficacious immunosuppressive regimen for pediatric renal allograft recipients. Longer follow-up will be necessary to confirm whether these advantages persist beyond 2 years.

Fungal peritonitis in children treated with peritoneal dialysis and gastrostomy feeding

Feeding gastrostomies were placed in three children treated with chronic peritoneal dialysis at our center because of persistent, severe malnutrition and inadequate growth. Two had frequent fungal infections of the gastrostomy site and all three developedCandida peritonitis which occurred at 1 month, 2 months and 2 years after insertion of gastrostomy. Complications included multiple intra-abdominal adhesions, abscess formation and loss of peritoneal function necessitating transfer to hemodialysis. The presence of a gastrostomy may predispose to the development of fungal peritonitis with its high morbidity and should be avoided in children on chronic peritoneal dialysis.

Intermittent Clean Catheterization: An Alternative to diversion in Continent Transplant Recipients with Lower Urinary Tract Dysfunction

A total of 3 renal transplant recipients who were candidates for urinary diversion underwent successful transplantation using a planned program of intermittent clean catheterization. The urinary tract dysfunction was caused by a lower motor neuron neurogenic bladder, prune belly syndrome and myelodysplasia. The patients remain dry between catheterizations and maintain serum creatinine levels of 1.1, 0.8 and 0.5 mg. per cent, respectively, with a followup of 6 to 25 months. There has been only 1 urinary tract infection during 42 patient-months at risk while on self-catheterization. Pre-transplant urologic evaluation and patient education are mandatory. The ideal candidate for intermittent clean catheterization is a patient with a low pressure bladder that fails to empty and who is continent between catheterizations. Intermittent clean catheterization is a safe and effective alternative to diversion in continent transplant recipients with lower urinary tract dysfunction.

Parent-to-child transplantation with cyclosporine immunosuppression

The use of cyclosporine, a fungal endecapeptide immunosuppressive agent, has greatly improved the outcome of haploidentical transplantation in adults, but less impressively improved the result of parent to child transplantation. The incidence of allograft loss and treated rejection episodes was much greater in pediatric than in adult recipients, and the evidences of nephrotoxicity lessened. Although resistance of the childs immune system to the effects of the drug cannot be excluded, it appears more likely that this relates to the rapid clearance of the agent in the pediatric age group (39.6 mL/min/kg) versus in adults (12.3 mL/min/kg), thereby reducing the area under the serum concentration curve from 765±593 to 386±277 ng/mL/hr per mg/kg (mean±SD). This effect caused trough serum levels measured by radioimmunoassay to be below the putative threshold. These findings demonstrate the need for higher cyclosporine doses and frequency in pediatric compared with adult patients.

Combined hypothyroidism and hypoparathyroidism in an infant after maternal 131I administration

tire pathway components. In the absence of specific antibody to activate the classical pathway, this impairment of the alternative pathway may well prejudice the newborn infants early response to infection. Previous reports of low serum IgG concentrations were not substantiated. Comparison O f the total protein and serum albumin concentrations demonstrates the ability of SGA newborn infant to maintain normal values despite the inability of the maternoplacental supply line to transfer sufficient substrate to permit optimal fetal growth. In this respect the SGA neonate resembles the marasmic child, whose serum protein and complement values are well preserved in comparison with those in kwashiorkor? .... With the exception of lower C3 levels, we have not demonstrated any significant impairments in the complement system and immunoglobulin concentrations of term SGA infants relative to AGA controls. If there are more infections among these infants, these aspects of humoral immunity do not appear to be implicated to a major degree.

Unilateral hydrothorax in small children on chronic continuous peritoneal dialysis

Three small children whose weights were under 15kg and who were on continuous ambulatory peritoneal dialysis or continuous cycling peritoneal dialysis developed massive unilateral hydrothorax. The occurrence of hydrothorax was late, 3–22 months after the initiation of dialysis. Two of the three fluid collections were leftsided. Each episode was preceded by retention of dialysate. After drainage of the hydrothorax a modified peritoneal dialysis regimen was successful in sustaining patients for a few weeks until further therapy for end-stage renal disease could be pursued.

Hypertension in a Child With Type IA Glycogen Storage Disease

Hypertension and proteinuria were observed in a 2-year-old child with type IA (von Gierkes) glycogen storage disease (GSD). She had evidence of hyperfiltration and had elevated selective renal vein renins. On renal biopsy, increased mesangial cell matrix and cellularity were observed with focal thickening and irregularity of the basement membrane. This case may be representative of the early renal findings in type IA GSD.

Parent-to-Child Transplantation With Cyclosporine Immunosuppression

The use of cyclosporine, a fungal endecapeptide immunosuppressive agent, has greatly improved the outcome of haploidentical transplantation in adults, but less impressively improved the result of parent to child transplantation. The incidence of allograft loss and treated rejection episodes was much greater in pediatric than in adult recipients, and the evidences of nephrotoxicity lessened. Although resistance of the childs immune system to the effects of the drug cannot be excluded, it appears more likely that this relates to the rapid clearance of the agent in the pediatric age group (39.6 mL/min/kg) versus in adults (12.3 mL/min/kg), thereby reducing the area under the serum concentration curve from 765 +/- 593 to 386 +/- 277 ng/mL/hr per mg/kg (mean +/- SD). This effect caused trough serum levels measured by radioimmunoassay to be below the putative threshold. These findings demonstrate the need for higher cyclosporine doses and frequency in pediatric compared with adult patients.