Irene Restaino

Renal failure in the neonate associated with in utero exposure to non-steroidal anti-inflammatory agents

In utero exposure to non-steroidal anti-inflammatory agents (NSAIAs) can produce combinations of oligohydramnios, a bleeding diathesis, ileal perforation, premature closure of the ductus, and acute or chronic renal injury. NSAIAs induce renal dysgenesis in fetal monkeys and renal structural abnormalities in the developing human fetus. We report oligohydramnios and renal failure associated with in utero exposure to early, prolonged, high-dose indomethacin in four neonates, and to ibuprofen in one neonate. Four of the affected neonates were one of twins. In each set of twins, only one of the pair was affected. One set of twins was proven to be identical, whereas the other three sets seemed to be identical. It is possible that the histopathological findings of uncertain or incomplete tubular differentiation may be the result of a direct effect of NSAIAs on developing or “immature” tubules. Therefore, the advantages of NSAIAs as tocolytics need to be weighed against the complication of severe renal injury.

Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms tumor

The renal tubular Fanconi syndrome developed in five patients with Wilms tumor after treatment with ifosfamide, a derivative of cyclophosphamide. Glomerular filtration rates were severely decreased. Renal function was investigated because of the development of rickets. All patients had undergone reduction of renal mass by nephrectomy. None had preexisting renal tubular injury. The syndrome developed at cumulative doses of ifosfamide of 39 to 99 gm/m2. Low serum bicarbonate and phosphate concentrations with glucosuria, aminoaciduria, and hypochloremic metabolic acidosis were the manifestations of the Fanconi syndrome. Bicarbonate and phosphate replacement resulted in bone healing, but recovery of tubular and glomerular function did not occur. Monitoring of these laboratory values during ifosfamide therapy could allow earlier replacement therapy to prevent severe bone disease.

Nephrolithiasis, hypocitraturia, and a distal renal tubular acidification defect in type 1 glycogen storage disease

Renal stones containing calcium can occur in patients with type 1 glycogen storage disease. We studied 11 patients with glycogen storage disease. Five patients had renal calculi, nephrocalcinosis, or both, and five had hypercalciuria. Serum levels of calcium, phosphorus, parathyroid hormone, and urate were normal. Serum levels of 1,25-dihydroxyvitamin D were elevated in each patient. None of the patients had a metabolic acidosis, but all nine who were tested had evidence of impaired acid excretion. In response to an acid load, eight of the nine patients had subnormal titratable acid excretion, and nine had subnormal ammonia excretion; six of nine patients were unable to secrete hydrogen ions in response to bicarbonate administration. These data indicate that patients with type 1 glycogen storage disease have an incomplete form of distal renal tubular acidosis. This may be the cause of hypercalciuria and nephrocalcinosis in these patients.

Efficacy, Safety, and Pharmacokinetics of Candesartan Cilexetil in Hypertensive Children Aged 6 to 17 Years

This 4‐week randomized, double blind, placebo‐controlled study (N=240), 1‐year open label trial (N=233), and single‐dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy‐one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8–11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo‐corrected 4.9/3.0–7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6‐ to 12‐ and 12‐ to 17‐year‐olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well‐tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.

Mycophenolate mofetil, with cyclosporine and prednisone, reduces early rejection while allowing the use of less antilymphocytic agent induction and cyclosporine in renal recipients with delayed graft function.

Antilymphocytic agent induction (ALAI), with antithymocyte globulin or monoclonal antibody, is generally used in renal transplantation (TX) to spare renal allografts with poor initial function from the toxic effects of cyclosporine (CsA) and/or to augment immunosuppression (IS) in the patient at a high risk for early rejection. ALAI, unfortunately, increases the cost of TX and the risk to the patient, having been associated with many adverse side effects. An IS protocol, which results in a low incidence of early rejection while using less CsA and ALAI, is a worthwhile goal. 
We compare our experience with mycophenolate mofetil (MMF), CsA, and prednisone (MMFCP; n=62) to our azathioprine (AZA), CsA, and prednisone (AZACP; n=50) triple‐drug IS, with and without ALAI. The patient characteristics for age, race, first TX, cadaveric donor, pediatric recipient, and dialysis in the first post‐op week (DGF) were not different for the MMFCP versus AZACP groups. There were more females in the MMFCP group (51.6% versus 30.0%, p=0.022). 
We report that rejection‐free survival at 6 months (RF6) was better in the MMFCP versus AZACP group (83.9% versus 60.0%, p=0.005). Less ALAI and CsA were used in the MMFCP patients. At 1 year, actuarial graft survival was 91.9% in the MMFCP group and 81.9% in the AZACP group (p=0.116). Actuarial 1‐year patient survivals were not different in the two patient groups. In the sub‐population of patients with DGF, the RF6 in the MMFCP (n=13) group was 92.3% versus 57.1% in the AZACP (n=14) group (p=0.041). The reduction in early rejection episodes in the patients on MMFCP with DGF was accomplished while using half as much ALAI and lower CsA doses and levels. The African‐American recipient sub‐population on MMFCP also demonstrated an improvement in RF6 while using less ALAI and CsA (78.6% versus 48.0%, p=0.022). 
We conclude that the use of MMF‐based triple‐drug IS results in fewer rejection episodes while allowing for lower CsA levels and less ALAI, even in patients with delayed graft function.

Child abuse in an infant presenting as unexplained acute systemic hypertension

Abstract Hypertension in the infant is uncommon and is usually associated with renal vascular or parenchymal disease, coarctation or thrombosis of the aorta, or chronic lung disease. A 3-month-old infant who presented with unexplained acute systemic hypertension was subsequently discovered to have an undiagnosed femoral fracture secondary to child abuse. Undiagnosed fractures, which are often associated with child abuse, should be considered in the differential diagnosis of an infant presenting with unexplained systemic hypertension.