Alan B. Gruskin

Carbonic Anhydrase II Deficiency in 12 Families with the Autosomal Recessive Syndrome of Osteopetrosis with Renal Tubular Acidosis and Cerebral Calcification

Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. In 1983, we reported a deficiency of carbonic anhydrase II, one of the isozymes of carbonic anhydrase, in three sisters with this disorder. We now describe our study of 18 similarly affected patients with this syndrome in 11 unrelated families of different geographic and ethnic origins. Virtual absence of the carbonic anhydrase II peak on high-performance liquid chromatography, of the esterase and carbon dioxide hydratase activities of carbonic anhydrase II, and of immunoprecipitable isozyme II was demonstrated on extracts of erythrocyte hemolysates from all patients studied. Reduced levels of isozyme II were found in obligate heterozygotes. These observations demonstrate the generality of the findings that we reported earlier in one family and provide further evidence that a deficiency of carbonic anhydrase II is the enzymatic basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. We also summarize the clinical findings in these families, propose mechanisms by which a deficiency of carbonic anhydrase II could produce this metabolic disorder of bone, kidney, and brain, and discuss the clinical evidence for genetic heterogeneity in patients from different kindreds with this inborn error of metabolism.

The 1989 report of the North American Pediatric Renal Transplant Cooperative Study - This report is prepared under the auspices of the scientific advisory committee 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.

Laboratory evaluation of renal function.

The clinical utility and interpretation of laboratory tests available to the pediatrician in the evaluation of renal function are discussed, as well as some aspects of growth and development which differentiate the evaluation of renal diseases in children from their evaluation in adults.

Early diagnosis of juvenile renal osteodystrophy

Renal osteodystrophy has assumed growing importance as a major and frequently disabling complication of chronic renal failure in children since the advent of successful hemodialysis and renal transplantation programs. The frequency and severity of renal osteodystrophy appears greatest in younger children with congenital diseases of the kidney and urinary tract, who experience long intervals of chronic renal failure prior to reaching end-stage. Twenty-nine children with varying degrees of chronic renal failure were studied to learn: (1) how early renal osteodystrophy can be diagnosed; and (2) how the various clinical, biochemical, and hormonal abnormalities correlate with abnormal bone histomorphometry as determined from percutaneous transilial bone biopsies. Results showed: (1) marked-to-moderate reductions in GFR (mean = 35 ml/minute/1.73 m2; range 11 to 65 ml/minute/1.73 m2); (2) elevations of serum PTH concentrations in all patients with a GFR < 45 ml/minute/1.73 m2; (3) abnormal bone histomorphometry in all patients with elevated PTH concentrations; (4) early renal osteodystrophy (elevated PTH concentrations and abnormal bone histomorphometry but normal serum chemistry values and radiographs) in one quarter of the patients; (5) poor correlations of serum chemistry values and radiographs with bone histomorphometry; and (6) a wide range of histologic abnormalities including predominant osteomalacia (n = 7), predominant hyperparathyroidism (n = 6), or a mixed picture (n = 11).

Chlorambucil dosage in frequently relapsingnephrotic syndrome: A controlled clinical trial

A controlled clinical trial was performed using two dosage regimens of chlorambucil to treat children with frequently relapsing nephrotic syndrome. All children concurrently received prednisone (60 mg/m2 on alternate days). Ten children (Group I) were given chlorambucil as a stable dose (0.2 mg/kg/day) for 56 to 60 days, and 11 children (Group II) received increasing doses (0.2 to 0.63 mg/kg/day) for 42 to 77 days. Two children in each group subsequently relapsed. Follow-up averaged 28.6 and 27.2 months in Groups I and II, respectively. Three children in Group II developed infectious complications. The data indicate that a stable dosage regimen for chlorambucil is as effective as an increasing dose regimen in achieving long-term remission of frequently relapsing nephrotic syndrome.

Uric acid in childhood essential hypertension.

Serum uric acid concentrations and the fractional excretion of uric acid were determined in 31 children from 3 1/2 to 18 years of age with essential hypertension. While on an unrestricted sodium intake, elevated serum values of uric acid were found in 13 of 31 (42%) of the children. After ingesting a low-sodium diet (200 mg/day) for three days, mean serum uric acid values increased by 0.7 mg/dl (P less than 0.001). There was a significant inverse correlation between the serum uric acid concentrations and fractional excretion of uric acid during the normal and low-sodium diet. This study indicates that the major factor leading to hyperuricemia in our hypertensive patients was a decrease in urate clearance. Insofar as hyperuricemia may represent a cardiovascular risk factor, this abnormality already exists in a significant fraction of hypertensive children and adolescents.

Serum sodium abnormalities in children.

Even though multiple mechanisms operate to maintain the serum sodium concentration within a narrow range, serum sodium concentration is frequently abnormal in hospitalized children. This article defines terms clinically useful in categorizing such disorders and provides an overview of the physiology of sodium and water homeostasis. The recognition and treatment of disorders associated with an abnormal serum sodium are then considered.

Hypochloremic alkalosis in infants associated with soy protein formula.

Thirteen infants, 2 to 10 months of age, developed hypochloremic alkalosis (serum chloride 59 to 92 mEq/l) while taking Neo-Mull-Soy (Syntex), a soy-based formula low in chloride (measured to be 0 to 2 mEq/l) but with considerable potassium citrate. Range of symptoms included lethargy, anorexia, mild spitting up, diarrhea, hematuria, and growth failure. Urine chloride excretion was less than 3 mEq/l. Plasma renin activity or aldosterone, measured in six infants, was elevated. All responded promptly to supplemental salt. One infant receiving Neo-Mull-Soy redeveloped alkalosis when supplemental salt was discontinued. Two of nine apparently normal infants receiving Neo-Mull-Soy also had hypochloremia (85, 86 mEq/l). Three of four receiving Prosobee (Mead Johnson; Cl content 7 mEq/l) had urine chloride concentration less than 20 mEq/l. The chloride content of some infant formulas is insufficient to offset salt losses following mild stress.

Serum concentrations of parathyroid hormone in infants, children, and adolescents†

Serum concentrations of immunoreactive parathyroid hormone (iPTH) were measured by double-antibody radioimmunoassay employing guinea pig antiserum to bovine PTH which cross-reacted with human PTH in the serum of normal subjects and of patients with primary and secondary hyperparathyroidism. Data are expressed in terms of a purified bovine PTH standard. iPTH was detectable in 39% of cord sera and in the sera of 80% of randomly selected children and adults. The serum iPTH concentration was significantly higher in pregnant women at term (155±74 [SD] pg/ml, bovine PTH equivalents) than in normal adult males and nonpregnant females (93±32 pg/ml). In 76 children (0.1–18.0 yr) the mean serum iPTH concentration was 125±70 pg/ml. iPTH concentrations were increased in children with chronic renal insufficiency (N=14), vitamin D-resistant rickets (N=1), vitamin D-deficiency rickets (N=1), pseudohypoparathyroidism (N=1), and in five children receiving anticonvulsant medications because of seizure disorders. In a child with hyperparathyroidism secondary to chronic renal disease administration of aluminum hydroxide was followed by decline in serum concentrations of iPTH and phosphorus and increase in serum calcium levels. Serum iPTH concentrations fell abruptly following successful renal homotransplantation in this patient. The radioimmunoassay for PTH provides an important tool for the study of parathyroid gland function in normal infants and children and in patients with disorders of mineral metabolism and renal function. Determination of iPTH concentrations is useful in following the course of such disease processes and in evaluating the efficacy of therapy.

Single-dose treatment of uncomplicated urinary tract infections in children

Thirty-six girls, aged two to 17 years, with culture-proven, acute, uncomplicated lower urinary tract infections and without signs or symptoms of upper urinary tract infection, were randomized to receive either single-dose amoxicillin or conventional therapy for ten days. Twenty-six patients completed the study, ten in the single-dose group and 16 in the conventional therapy group. The patients treated with single-dose therapy had cure rates (70% vs 75%), relapse rates (30% vs 25%), and reinfection rates (0% vs 12%) comparable to those of conventionally treated patients. A significant difference in the induction of resistant organisms was seen between treatment groups (P less than .05). All single-dose relapses were due to failure to clear a sensitive organism from the urinary tract. All relapses on conventional therapy resulted from an initially sensitive organism becoming resistant to amoxicillin during treatment. Single-dose antibiotic therapy of uncomplicated urinary tract infections in children is effective in patients with culture-proven infections selected by clinical criteria, and appears to be safe when combined with conscientious long-term follow up and radiographic evaluation. Single-dose therapy offers the advantage of selecting significantly fewer resistant organisms from the gut flora than do conventional antibiotic regimens.