The pharmacokinetics of enalapril in children and infants with hypertension.

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First-dose and steady-state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first-dose and steady-state AUCs, the accumulation of enalaprilat in children ranged from 1.13- to 1.45-fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half-life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

Systemic lupus erythematosus and thrombotic thrombocytopenic purpura: a case and review.

Thrombotic thrombocytopenic purpura (TTP) is rare in children with systemic lupus erythematosus (SLE). We report a 15-year-old female who simultaneously presented with TTP and SLE. Kidney biopsy showed membranous nephropathy. Her condition improved with plasmapheresis, intravenous cyclophosphamide, and prednisone pulse therapy. We also reviewed the literature for this association in pediatric patients comparing presenting sequence and renal pathology with cases documented in the adult literature.

The pharmacokinetics of irbesartan in hypertensive children and adolescents.

An open-label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1-12 years) and adolescents (13-16 years) with hypertension. Patients received single once-daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (+/- nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high-performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day 1, and up to 48 hours after the final dose. The plasma concentration-time profiles were similar between the 6- to 12-year and the 13- to 16-year age groups and to that previously determined from a study of adult subjects receiving approximately 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and may be a treatment option for pediatric hypertensive patients.

Urea resolves gross hematuria in a 15 year old with hemoglobin C trait.

Hematuria is a rare complication seen in patients with hemoglobin C trait. We report a 15-year-old African-American female with hemoglobin C trait, who presented with persistent hematuria. None of the urological, serological or histological workups revealed any other pathology. Hematuria failed to respond to all conventional modalities used in the treatment of the same condition seen in sickling hemoglobinopathies. This case is the first known case of persistent hematuria in a pediatric patient with hemoglobin C trait, which resolved with intravenous urea administration.

Fatal cytomegalovirus disease in a high-risk renal transplant recipient.

The incidence of CMV infection in pediatric renal transplant recipients has increased as immunosuppression levels deepen following the use of newer immunosuppressive agents. It has been thought that 3-5 months of anti-CMV prophylaxis offers sufficient protection for these patients. We present a case of late-onset fatal CMV disease in a pediatric renal transplant recipient who received prolonged anti-CMV prophylaxis while on "quadruple" immunosuppression with daclizumab, mycophenolate, tacrolimus, and prednisone. Our case has prompted us to reassess CMV surveillance, prophylaxis, and immunosuppression levels in our pediatric renal transplant patients.

Nicardipine is a safe and effective agent in pediatric hypertensive emergencies.

Nicardipine is the first dihydropyridine calcium channel blocker capable of intravenous administration. Seven pediatric patients with hypertensive emergencies attributable to various pathological processes were treated with intravenous nicardipine, starting at 1 microg/kg/min. Nicardipine appeared to be safe and effective in controlling hypertension in these patients. Two patients who received nicardipine through peripheral lines developed superficial thrombophlebitis. None of the five patients receiving nicardipine through a central line experienced phlebitis, and no other adverse effects were noted.

The role of fludrocortisone in a child with cerebral salt wasting.

Cerebral salt wasting (CSW) is a syndrome of hyponatremia due to excessive natriuresis described in patients with central nervous system insult. We present a 29-month-old black male with tuberculous meningitis who developed CSW with depressed mineralocorticoid activity. The patient required hypertonic saline and ionotropic support. Mineralocorticoid supplementation effectively treated CSW.

125Iodine-iothalamate clearance in children. A simple method to measure glomerular filtration.

Glomerular filtration rate (GFR) is the most widely used test to evaluate renal function. Several clearance markers have been used to measure GFR in adults. In children, however, a simple and reliable method to measure GFR is not available. Renal 125iodine (I)-iothalamate clearance, after a single subcutaneous injection, is a simple and accurate test to measure GFR in adults. The validity of unlabelled iothalamate, as a marker for measurement of GFR in children, was reported recently. Unfortunately, the unlabelled iothalamate assay is arduous. We report our experience with a single subcutaneous injection of 125I-iothalamate to measure GFR in normal children and those with renal disease. A weight-adjusted dosing regimen was adopted. This regimen resulted in sufficient above-background radioactivity in both blood and urine for reproducible measurement of GFR. Intra-test variability for GFR was not affected by the degree of renal insufficiency. The test was well tolerated with only 2 patients developing mild headache during the procedure. Our study showed that renal clearance of 125I-iothalamate is reproducible, simple, and practical in healthy children and those with mild and advanced renal disease.

Renal replacement therapies for critically ill pediatric patients.

It could be a great challenge for a nephrologist to prescribe a renal replacement therapy for a critically ill, hemodynamically unstable pediatric patient. Intermittent hemodialysis and peritoneal dialysis frequently fall short of being an optimal renal replacement therapy for such a patient. Continuous hemofiltration is offering new alternatives that can deliver sufficient clearance to meet the needs of a critically ill child. High fluid intake required for total parenteral nutrition and medications can easily be fulfilled by these modalities without compromising the cardivascular system. Of these techniques, continuous veno-venous hemofiltration is superior to continuous arterio-venous hemofiltration because it delivers a consistent ultrafiltration rate dependent on pump-driven blood flow and does not require the insertion of a large-bore catheter into an artery. Thus, various modalities of hemofiltration can offer an alternative to the critically ill child with acute renal failure.

Reversible idiopathic acute renal failure in children with primary nephrotic syndrome.

We describe the clinical features of four pediatric patients (20 months to 10 years of age) in whom reversible idiopathic acute renal failure (RIARF) developed during the course of primary nephrotic syndrome (PNS). All patients had severe PNS and were in relapse at the onset of RIARF. This complication of PNS was preceded by primary peritonitis in three of four patients. Renal biopsy done in the early phases of RIARF showed tubular epithelial changes similar to those observed in acute tubular ischemia. All patients required dialysis. Recovery of renal function followed fluid removal in three of four patients. The RIARF lasted from 12 days to 1 year and was followed by complete recovery of renal function in all patients. We conclude that (1) RIARF is a potential complication in children with severe PNS, (2) RIARF is associated with primary ischemic renal tubular injury, and (3) recognition of the reversibility of this complication of PNS could alter long-term plans for management of renal failure in these patients.

Noncardiogenic pulmonary edema in childhood.

Pulmonary edema is caused by transudation of fluid from pulmonary capillaries into the alveolar spaces and the bronchiolus. It is most frequently secondary to either increased pulmonary capillary hydrostatic pressure (cardiogenic pulmonary edema) or increased pulmonary capillary permeability (noncardiogenic pulmonary edema). Numerous systemic and pulmonary insults are capable of damaging the capillary endothelium and/or alveolar epithelium, resulting in noncardiogenic pulmonary edema. Although clinically similar, the presence of noncardiogenic pulmonary edema requires a different therapeutic approach from that of cardiogenic pulmonary edema.

Hyperphosphatemia in tumor lysis syndrome: the role of hemodialysis and continuous veno-venous hemofiltration.

We report a 4-year-old boy who developed tumor lysis syndrome complicated by severe hyperphosphatemia and acute renal failure, following chemotherapy for T-cell acute lymphoblastic leukemia. Despite successful treatment of hyperphosphatemia with hemodialysis, there was an immediate rebound in the high serum phosphorus level. The patient underwent a second treatment with hemodialysis which was then followed by continuous veno-venous hemofiltration (CVVH). CVVH maintained his serum phosphorus at a stable level until his renal function improved. CVVH can be used in conjunction with hemodialysis to successfully treat the hyperphosphatemia associated with tumor lysis syndrome.

Intracellular distribution of cystine in cystine-loaded proximal tubules.

Cellular cystine loading with cystine dimethyl ester has been shown to inhibit transport in proximal convoluted tubules perfused in vitro and decrease the rate of oxygen consumption in suspensions of proximal tubules. The present study was designed to examine the intracellular distribution of cystine in this model of the Fanconi syndrome of cystinosis and to determine whether cystine or its degradation product, cysteine, is the cytotoxic agent in cystine-loaded rabbit proximal tubules. Tubules were incubated with 2 mmol/L cystine dimethyl ester for 10 min at 37 degrees C and subjected to cellular fractionation. The intralysosomal cystine content (272 +/- 125 nmol/mg protein) was significantly higher than that measured in the nucleus (8.7 +/- 2.0 nmol/mg protein) and cytosol (9.8 +/- 4.0 nmol/mg protein (p < 0.05). Electron micrographs of tubules loaded with cystine depicted large swollen lysosomes. To determine whether cystine or its breakdown product, cysteine, was the cytotoxic agent in tubules incubated with cystine dimethyl ester, the intracellular cystine and cysteine contents were measured and found to be 86.5 +/- 14.8 and 5.7 +/- 1.7 nmol/mg protein, respectively. These tubules had a 50% decrease in the rate of O2 consumption. To examine whether the increased level of intracellular cysteine played a role in this decrease in O2 consumption, we loaded tubules with 2 mmol/L cysteine methyl ester for 10 min. Despite an intracellular cysteine concentration of 59.6 +/- 5.8 nmol/mg protein, cysteine-loaded tubules had a rate of O2 consumption equal to that measured in control tubules. Thus, intracellular cystine loading significantly increases intralysosomal cystine content.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular cystine loading causes proximal tubule respiratory dysfunction: effect of glycine.

The present study examined proximal tubular respiration in control proximal tubules and proximal tubules loaded with cystine using 2 mmol/L cystine dimethyl ester. Basal oxygen consumption was significantly less in cystine-loaded tubules (20.6 +/- 0.5 versus 12.1 +/- 0.6 nmol O2.min-1.mg protein-1, p < 0.001). In the presence of 10(-4) mol/L ouabain, an inhibitor of the NaK ATPase, oxygen consumption was 10.2 +/- 0.7 nmol O2.min-1.mg protein-1 in control tubules and 11.4 +/- 1.0 nmol O2.min-1.mg protein-1 in cystine-loaded tubules. Thus, proximal tubular intracellular cystine loading specifically inhibits oxygen metabolism directed toward transport. Compared with control proximal tubules, cystine-loaded proximal tubules also had a lower rate of O2 consumption when the cells were permeabilized to sodium with nystatin and when mitochondrial respiration was uncoupled. Glycine, an amino acid that is cytoprotective to hypoxic proximal tubule injury, ameliorated the respiratory dysfunction observed in cystine-loaded tubules.

Systemic lupus erythematosus in a child receiving long-term interferon therapy.

Systemic lupus erythematosus (SLE) developed in a 10 1/2-year-old white boy with juvenile laryngeal papillomatosis who had been treated with interferon alfa-n1 for 7 years. His age, gender, and fast recovery after discontinuation of interferon therapy and institution of appropriate treatment for SLE are compatible with a diagnosis of drug-induced SLE. Autoimmune disorders may occur as a complication of interferon therapy.

Idiopathic Fanconi syndrome in a family. Part I. Clinical aspects.

Fanconi syndrome is a rare cause of rickets in children. Only six families with Fanconi syndrome following an autosomal dominant pattern of inheritance have been reported. In this report, the results of clinical studies performed in three generations of a family of 39 members with autosomal dominant Fanconi syndrome are presented. Twenty-one members of this family provided blood and urine for biochemical evaluation. Many family members have one or more tubular reabsorptive abnormalities; however, the complete Fanconi syndrome was not present in most members. Three children with the complete syndrome all occur in the last generation. When the characteristic features of this family were compared with those of previously reported families with autosomal dominant Fanconi syndrome, several differences became apparent. Two serious manifestations, diabetes mellitus and renal failure, which occur in previous reports did not occur in this family. This report provides information on apparently the largest number of affected individuals in a single family with Fanconi syndrome. In addition, variable expressivity of tubular reabsorptive defects in a family with Fanconi syndrome has never been reported.