Dichloroacetate therapy attenuates the blood lactate response to submaximal exercise in patients with defects in mitochondrial energy metabolism.

We determined acute and chronic effects of dichloroacetate (DCA) on maximal (MAX) and submaximal (SUB) exercise responses in patients with abnormal mitochondrial energetics. Subjects (n = 9) completed a MAX treadmill bout 1 h after ingesting 25 mg/kg DCA or placebo (PL). A 15-min SUB bout was completed the next day while receiving the same treatment. After a 1-d washout, MAX and SUB were repeated while receiving the alternate treatment (acute). Gas exchange and heart rate were measured throughout all tests. Blood lactate (Bla) was measured 0, 3, and 10 min after MAX, and 5, 10, and 15 min during SUB. MAX and SUB were repeated after 3 months of daily DCA or PL. After a 2-wk washout, a final MAX and SUB were completed after 3 months of alternate treatment (chronic). Average Bla during SUB was lower (P < 0.05) during both acute (1.99 +/- 1.10 vs. 2.49 +/- 1.52 mmol/liter) and chronic (1.71 +/- 1.37 vs. 2.39 +/- 1.32 mmol/liter) DCA vs. PL despite similar exercise intensities between conditions ( approximately 75 and 70% maximal exercise capacity during acute and chronic treatment). Thus, although DCA does not alter MAX responses, acute and chronic DCA attenuate the Bla response to moderate exercise in patients with abnormal mitochondrial energetics.

The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis.

In 27 of 28 children with congenital lactic acidosis, cerebrospinal fluid lactate was higher than venous blood lactate. The mean +/- SEM difference between these variables was 2.4 +/- 0.3 mmol/L (P =.0001). Girls or patients with pyruvate dehydrogenase deficiency had higher cerebrospinal fluid lactate concentrations than boys or patients with respiratory chain defects or mitochondrial DNA mutations.

Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess.

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 enzyme activity (11 beta HSD2). The 11 beta HSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME. All of the patients had characteristic signs of a severe 11 beta HSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of end-organ damage after 2-13 yr of treatment in six patients demonstrated significant improvement in all patients. The urinary metabolites of cortisol demonstrated an abnormal ratio with predominance of cortisol metabolites, i.e. tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone was 6.7-33, whereas the normal ratio is 1.0. Infusion of [11-3H]cortisol resulted in little release of tritiated water, indicating the failure of the conversion of cortisol to cortisone. Thirteen mutations in the HSD11B2 gene have been previously published, and we report three new genetic mutations in two patients, one of whom was previously unreported. All of the patients had homozygous defects except one, who was a compound heterozygote. Our first case had one of the most severe mutations, resulting in the truncation of the enzyme 11 beta HSD2, and died at the age of 16 yr while receiving treatment. Three patients with identical homozygous mutations from different families had varying degrees of severity of clinical and biochemical features. Due to the small number of patients with identical mutations, it is difficult to correlate genotype with phenotype. In some cases, early and vigilant treatment of AME patients may prevent or improve the morbidity and mortality of end-organ damage such as renal or cardiovascular damage and retinopathy. The outcome of treatment in more patients may establish the efficacy of treatment.

A new point mutation in a hypoxanthine phosphoribosyltransferase-deficient patient.

A 12-year-old boy was referred because of abdominal pain, gross hematuria, and passage of stones. Further evaluation showed growth delay, low average range of intellectual functioning, and a speech articulation disorder. No signs of self-mutilation or self-injurious behavior were present. He had hyperuricemia, hyperuricosuria, uric acid crystalluria, uric acid calculi, macrocytosis, megaloblastic bone marrow changes, and mild anemia. Hypoxanthine phosphoribosyltransferase (HPRT) enzyme activity was reduced to approximately 26% of normal. Polymerase chain reaction-single strand conformational polymorphism analysis of the HPRT gene in DNA isolated from the patient's blood lymphocytes revealed a single nucleotide substitution at codon 200 in exon 8. The base change was a guanine to cytosine transversion, resulting in the conservative amino acid substitution of threonine in place of arginine. To our knowledge, this mutation has not previously been reported.

Renal brush border sodium-sulfate cotransport in guinea pig: effect of age and diet.

Renal adaptation to changes in inorganic sulfate intake and age was studied by comparing sulfate uptake by proximal tubule brush border membrane vesicles (BBMV) from guinea pigs of different ages on relatively high- or low-sulfate diets. Adult (> 60 days) or young guinea pigs (< 25 days) were fed either a control diet (0.28% sulfur content), a sulfur-free diet, or a high-sulfate diet. After 5 days on the diet, BBMV were obtained and kinetic analysis of 35sulfate uptake was determined. In adult guinea pigs, the low-sulfate diet produced a significant increase in apparent maximal velocity (Vmax). In young guinea pigs, a lower sulfate intake did not appreciably increase Vmax, but a high-sulfate intake produced a reduction in Vmax. The affinity for sulfate (Km) was not changed in either age group. The dietary sulfate intake did not alter sodium gradient dependent-D-glucose or 32phosphate Vmax. In conclusion, our data indicate that renal inorganic sulfate BBMV uptake is regulated and responds to conditions of increased need (i.e., during the growth phase in young animals and during periods of decreased sulfate availability in adult animals) by increasing BBMV Vmax.

Tetany in a child with AIDS receiving intravenous tobramycin.

Aminoglycosides have been reported to cause tetany by inducing renal wasting of magnesium and secondary hypocalcemia. A 9-year-old girl with AIDS was brought to the emergency department because of tetany. She had just finished a 3-week course of intravenous tobramycin for bronchiectasis and had an elevated serum tobramycin trough level 1 week before the onset of tetany. Hypomagnesemia, hypokalemia, and hypocalcemia had developed. The urine revealed inappropriately high levels of magnesium and potassium despite critically low serum levels, with an appropriately low urine calcium level. This pattern is suggestive of renal toxicity due to tobramycin. Over the next several months, she continued to require supplemental calcium, magnesium, potassium, and phosphorus. She also had nephrotic range proteinuria. Aminoglycoside renal mineral wasting has not previously been described in a child.

Kidney function in long-term pediatric survivors of acute lymphoblastic leukemia following allogeneic bone marrow transplantation.

Renal dysfunction may occur in survivors of bone marrow transplantation (BMT). The renal function of children who have survived 5 to 10 years after BMT has not been reported. Bone marrow transplantation was performed in 55 children with acute lymphoblastic leukemia less than 18 years of age at the University of Florida between September 1983 and October 1992. All received a uniform conditioning regimen of high-dose cystosine arabinoside and fractionated total body irradiation. Twenty-three are currently surviving. The survival average period following transplantation is 79 +/- 6.6 (SD) months. The longest survival is 129 months after BMT. We retrospectively examined data evaluating kidney function prior to transplantation, within 150 days after transplantation, and at each child's most recent clinic visit (1.7 to 10 years after transplantation). We were able to collect follow-up data regarding renal function for 17 survivors. Two children (11%) have renal dysfunction in the form of hypertension, glucosuria, and hematuria. One of them had acute renal insufficiency during the first 100 days following BMT. An unexpected finding was the presence of hyperfiltration in 10 patients. In conclusion, in this homogeneous group of children, allogenic BMT did not lead to significant long-term renal dysfunction.

Several homozygous mutations in the gene for 11 beta-hydroxysteroid dehydrogenase type 2 in patients with apparent mineralocorticoid excess.

Four deleterious mutations are described in the gene for HSD11B2, which encodes the type 2 isoenzyme of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD2). In seven families with one or more members affected by apparent mineralocorticoid excess, this disorder is shown to be the result of a deficiency in 11 beta HSD2. Surprisingly, the patients are all homozygous for their mutation. This results from consanguinity in two families and possibly from endogamy or a founder effect in four of the other five families. The absence of compound heterozygotes remains to be investigated.

Hyponatremia in pediatric patients with HIV-1 infection.

Hyponatremia has been recognized as a complication in adults with acquired immunodeficiency syndrome (AIDS). We did a retrospective study evaluating the medical records of 86 children (age 4 months to 21 years) with human immunodeficiency virus (HIV-1) infection to determine the frequency and clinical associations of hyponatremia. Twenty-two children (26%) developed hyponatremia (serum sodium < 135 mEq/L; range 104 to 134 mEq/L; mean 130 mEq/L). Fourteen were male; 18 of the 22 patients were black and 4 were white. At the time of hyponatremia, the children frequently had comorbid associations, including 8 (35%) with AIDS encephalopathy; 3 (14%) with cardiomyopathy; 3 (14%) using diuretics; 1 (5%) using pentamidine; 3 (14%) with bacterial pneumonia; 2 (9%) requiring gastric lavage feedings; 2 (9%) with tuberculosis meningitis; 2 (9%) with gastroenteritis; 1 (5%) with infection caused by Mycobacterium avium-intracellulare; 1 (5%) each with brain tumor and tumor metastasis to brain. The cause of hyponatremia was attributed to syndrome of inappropriate antidiuretic hormone in 8 children; poor sodium intake and/or excessive diarrheal losses in 5; and the use of diuretics in 3 patients. Mild hyponatremia with no identifiable cause was found in 5 patients.

Clinical versus laboratory tumor lysis syndrome in children with acute leukemia.

Renal and metabolic complications of tumor lysis syndrome (TLS) were recognized frequently in the 1960s and 1970s. Strategies were designed to prevent TLS. We conducted a retrospective chart review study to identify the current TLS risk in children with acute leukemia. Children were considered to have "laboratory tumor lysis syndrome" (LTLS) if two of the following metabolic changes occurred within 4 days of the start of chemotherapy: a 25% increase in serum phosphate, potassium, uric acid, or blood urea nitrogen levels, or a 25% decline in serum calcium concentration. Clinical TLS (CTLS) was defined as LTLS plus a serum potassium level higher than 6.0 mmol/L or acute renal failure. Twenty-one of 30 children developed LTLS; one developed CTLS. Absolute blast count, pretreatment white blood cell count, pretreatment lactic dehydrogenase, and sex or tumor DNA index did not correlate with the development of LTLS. LTLS is still frequent in children undergoing chemotherapy for acute leukemia; CTLS, however, is much less common.

Peritoneal membrane failure in children on peritoneal dialysis.

Peritoneal dialysis (PD) success depends on adequate renal function replacement. Reports in adult dialysis populations indicate the risk of ultrafiltration failure (UF) increases with the time on dialysis. Type 1 UF is the most common. For children, dialysis modalities are temporizing measures until renal transplantation, considered optimal therapy for end-stage renal disease in children, can be performed. Children are frequently on dialysis for less than 2 years prior to transplantation. Thus if type 1 UF frequency increases with time on dialysis, it would be expected to occur less frequently in children, because they often are on dialysis for shorter periods. A retrospective chart review was performed to determine the cause of ultrafiltration failure in children; 172 children, mean age 8.0 +/- 5.5 (SD) years received a mean of 15 +/- 11.9 (SD) months of chronic PD; 39 patients received only continuous ambulatory peritoneal dialysis, 18 received only continuous cycling peritoneal dialysis, 22 received only tidal PD, and 94 received more than one type of PD. Ten patients (5.8%) developed type 2 UF failure as sequellae of atypical peritonitis, Candida albicans (6 patients), Mycobacterium foruitum (2), Achromatium spp. (1), and Pseudomonas aeruginosa (1). There was no significant difference in time on dialysis for children who developed membrane failure. No patients with type 1 or type 3 UF could be identified. It appears that the causes of peritoneal membrane failure in children are different from those in adults.

Increased antibody responsiveness to blood transfusions in pediatric patients.

Heightened immune responsiveness has been proposed as one of the reasons underlying suboptimal renal transplant results in very young children or African American recipients. Because multiple factors influence graft outcome, it has been difficult to provide experimental evidence to confirm or refute this suggestion. In the present study we measured IgG antibodies with confirmed HLA specificity produced in response to blood transfusions. The patients evaluated were renal transplant candidates who had not had previous pregnancies or transplants. The overall incidence of HLA sensitization was 12%. Age was the most influential factor in sensitization: patients < 20 years old were 4-5 times as likely to produce anti-HLA antibodies than patients > 20 (P = 0.0018). Female patients were also high responders. However, this was explained by the higher proportion of children among nulliparous female patients rather than by differences in gender. In contrast, the antibody response of black and white recipients was similar. The antibody levels in most patients were low and decreased significantly with time. We conclude that the immunoregulatory influences in patients < 20 years old favor the production of anti-HLA antibodies in response to blood transfusions, a fact that may explain some clinical observations in pediatric transplant recipients.

Oral rehydration therapy. North Florida physicians' attitudes.

This study assessed primary care physicians' familiarity and attitudes toward oral rehydration therapy in the management of mild, moderate or severe diarrheal dehydration in children. An anonymous questionnaire was distributed to a cross-sectional representation of pediatricians, family practitioners and pediatric residents in North Central Florida. All were familiar with this type of therapy. Fewer were familiar with the Florida Oral Rehydration Therapy Program. Pediatricians reported significantly higher self-assessment scores than family practitioners or residents, and more of them were familiar with the American Academy of Pediatrics' recommendations for treatment of dehydration. Pediatric residents used intravenous therapy more frequently than pediatricians or family practitioners. The major obstacles to oral rehydration therapy use were identified as parental acceptance, compliance, and lack of a specific treatment area. The findings of this study suggest that pediatricians are more confident in their assessment, management and use of this type of therapy in children. Efforts to increase its use should focus on educational programs for physicians and parents. Dissemination of information to parents and pediatric providers may promote early treatment which should prevent more severe degrees of dehydration, decrease hospitalization and possibly prevent unnecessary deaths.

Renal artery stenosis associated with melorheostosis.

Melorheostosis is a benign, rare, congenital disorder of hyperostosis of one or more bones. In this report, we describe a 5-year-old girl with melorheostosis of the left iliac wing, femur, and tibia who developed severe hypertension secondary to left renal artery stenosis. Numerous soft tissue and vascular anomalies have been reported in patients with melorheostosis. To our knowledge this is the first case where renal artery stenosis has been associated with melorheostosis. Several hypotheses for bone and vascular involvement in melorheostosis are reviewed.

The ABC's of evaluating children with hematuria.

Hematuria is a common problem in children. Microscopic hematuria is more frequent than gross hematuria. Hematuria is often the initial finding in patients with urinary tract disease, and it is important to differentiate treatable renal involvement from untreatable, or benign, hematuria. The ABC's of hematuria in children were developed to teach the evaluation of children with hematuria to medical students and house staff. The ABC mnemonic helps physicians remember the differential diagnosis: Anatomy, Boulders, Cancer, Drug-related, Exercise, Foreign body, Glomerulonephritis, Hematology and Infection. A clinical algorithm is provided to guide the evaluation of children with hematuria.

Developmental differences in renal sulfate reabsorption: transport kinetics in brush border membrane vesicles.

Renal tubular reabsorption of inorganic sulfate is greater in younger than older guinea pigs. To determine the mechanism of this difference, we studied the transport of inorganic sulfate in renal brush border membrane vesicles (BBMV) obtained from young (< 25 days) and adult guinea pigs (> 60 days). BBMV were obtained by mechanical and osmotic disruption of dissected renal cortices followed by magnesium precipitation and differential centrifugation. After the membranes were incubated for 10 s in solutions containing inorganic sulfate at several concentrations (0.1-10 mM) and trace amounts of 35sulfate, intravesicular uptake was measured. Based on 35sulfur uptake, reabsorption transport kinetics (Vmax and Km) were estimated. BBMV obtained from young guinea pigs demonstrated higher sodium-sulfate cotransport, Vmax (51.79 +/- 4.34 pmol/mg protein per s) than those obtained from adult animals (Vmax = 34.28 +/- 9.17 pmol/mg per s), P < 0.05. Vmax values are represented as means plus or minus standard deviation. No differences in Km were observed. Our results indicate that age-related differences in renal inorganic sulfate reabsorption are due to a higher Vmax for sodium-sulfate cotransport in the younger animals, suggesting a higher density of sodium-sulfate cotransporters or an increased cotransport turnover rate in this age group.

Oral hydration therapy for children in Florida.

Eighty-six children in Florida died of complications associated with diarrhea between 1985 and 1990, deaths which constituted an important preventable fraction of infant mortality. The state will support health professionals in reducing the number of hospitalizations and deaths due to diarrheal complications, Governor Lawton Chiles announced in September 1991, and the Florida Department of Health and Rehabilitative Services is being awarded a $100,000 grant from the Centers for Disease Control for a three-year study on the effectiveness and utilization of oral rehydration therapy. During the last 20 years, a worldwide experience has developed indicating that sodium-glucose cotransport is preserved in both secretory diarrhea (cholera) and diarrhea produced by loss of surface area. This experience indicates that almost no one would die (adult or infant) if oral rehydration solutions and someone with knowledge in their use were readily available. This presentation has three objectives: (1) increase physicians' awareness regarding the state's oral rehydration therapy project; (2) provide a ready practical guide for those using oral rehydration therapy; and (3) promote use of the therapy as treatment for infantile dehydration rather than the more expensive intravenous 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.