H. Jorge Baluarte

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.

Urolithiasis in Childhood

Urolithiasis occurs less frequently in children than it does in adults living in contemporary industrialized nations. However, renal calculi continue to be identified with greater frequency in certain children: those who live in some areas of North America (e.g., the Southeastern United States), in those with relatively common metabolic disorders such as idiopathic hypercalciuria or with congenital urinary tract malformations, and in patients who have remained immobilized for long periods. Evaluation of children with suspected urolithiasis should include a careful history and physical examination to identify associated symptoms and signs and factors known to predispose to calculus formation, appropriate radiographic and blood studies, and timed urine collections. Appropriate management varies with etiology but should include maintaining adequate fluid intake, and long-term monitoring of the activity of the stone disease.

Analysis of hypertension in children post renal transplantation —a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

Hypertension is common in children after renal transplantation and is associated with multiple factors. Data regarding the prevalence of post-transplant hypertension and the relationship between immunosuppressive drugs and the presistence of hypertension in a large population of North American children have not been available. This study was designed by the North American Pediatric Renal Transplant Cooperative Study to evaluate in a large diverse multicenter population of children the prevalence of hypertension post transplantation, the type of antihypertensive medication used to treat this hypertension and to determinc the relationship between the blood pressure control and the immunosuppressive therapy. Analysis of 277 patients showed the following: (1) 70% of recipients required antihypertensive medications 1 month post transplant compared with 48% pre transplant; the incidence decreased to 59% at 24 months; (2) the majority of children received multiple drug therpay to control blood pressure; (3) hypertension can be controlled effectively despite inherent etiological factors, such as allograft source, prior hypertension and immunosuppressive therapy.

Outcomes in pediatric solid‐organ transplantation

LaRosa C, Jorge Baluarte H, Meyers KEC. Outcomes in pediatric solid‐organ transplantation. 
Pediatr Transplantation 2011: 15:128–141.

Neurologic development of children with severe chronic renal failure from infancy

A literature review was conducted to summarize current understanding of the effects of severe chronic renal failure (CRF), when present from infancy, on neurologic development. Data were obtained from the results of 95 examinations performed in 85 patients, most of whom had been studied after 12 months of age, or following initiation of maintenance dialysis or successful transplantation. CRF was diagnosed at birth or during the neonatal period in 71.7% of these patients; serum creatinine concentrations or calculated clearances were ≥2.0 mg/dl (177 μmol/l) or <15 ml/min per 1.73 m2, respectively, in 75.8%. Head circumferences were >2 standard deviations below the mean for age in 33 of 51 (64.7%) patients. Developmental delay was identified in 63.2% of all cases, and in 29 of 48 (60.4%), 16 of 19 (84.2%), and 4 of 13 (30.7%) patients studied while receiving conservative management or maintenance dialysis, or following successful transplantation, respectively. Moderate to severe delays were commoner for gross motor and language development. No significant relationships could be identified between age or severity of CRF at diagnosis and either the prevalence or severity of developmental delay. Other factors that may have contributed to observed developmental delays are also discussed, including aluminum loading, hyperparathyroidism, undernutrition, and psychosocial problems. New data are presented and discussed, and recommendations for future studies provided.

Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: Superiority of response to corticosteroid therapy over histopathologic patterns

To determine the utility of steroid response in classifying childhood nephrotic syndrome, we reviewed 119 biopsies in 92 children aged 1 to 16 years who had been followed for a mean of 7.2 years. Steroid responses were classified as steroid resistant, steroid dependent, and frequent relapser as defined by the International Study of Kidney Disease in Children. Biopsy specimens were classified as showing focal glomerulosclerosis (FSGS) in 39 children, as showing lipoid nephrosis in 28, and as questionable in another 25 with either focal global sclerosis, IgM nephropathy, or mesangial prominence and tubular changes. A strong agreement (p less than 0.01) was found between children whose FSGS was steroid resistant and children whose lipoid nephrosis resulted in frequent relapses. The length of the remission after therapy with chlorambucil or cyclophosphamide was determined in 84 children. A significantly shorter length of remission after cytotoxic drug therapy (p less than 0.05) was identified for patients with FSGS versus those with lipoid nephrosis; this difference became more significant for steroid-resistant patients in comparison with those who were steroid dependent or were frequent relapsers (p less than 0.005). Among all steroid-resistant patients, those with FSGS had shorter remissions than patients with other histologic changes (p less than 0.001). The data suggest that patterns of response to corticosteroid therapy correlate with the histologic abnormality. Thus steroid-sensitive patients need not undergo renal biopsy before receiving cytotoxic drugs. Steroid-resistant patients would benefit from a biopsy, because the findings tend to predict the outcome.

Linear growth and anthropometric and nutritional measurements in children with mild to moderate renal insufficiency: A report of the growth failure in children with renal diseases study

During the control period of the Growth Failure in Children With Renal Diseases Study, investigators at 23 centers were able to observe and characterize growth and to make anthropometric and nutritional measurements in 82 children with mild to moderate renal insufficiency. As a multicenter, controlled clinical trial designed to study the relative efficacy of 1,25-dihydroxyvitamin D3 and dihydrotachysterol in the treatment of renal osteodystrophy, no prior vitamin D exposure and a creatinine clearance of 25 to 75 ml/min/1.73 m2 were criteria for entrance into the clinical trial. Ages ranged from 18 months to 11 years (mean 5.6 +/- 3.1 years), and distribution by age category was as follows: 38%, 1 to 3 years; 28%, 4 to 6 years; and 34%, 7 to 10 years. There was a 3:1 male/female ratio; 72% of the patients had congenital disease by the International Classification of Diseases (ninth revision). Mean creatinine clearance was 49.5 +/- 20 ml/min/1.73 m2. The C-terminal parathyroid hormone values (1121 +/- 1562 pg/ml) were well above 2 SD of the mean of a normal growing population of similar age. Parathyroid hormone values correlated with degree of renal insufficiency (r = -0.57) and with height by bone age but not with chronologic height or growth velocity. The bone age/height age ratio, a predictor of growth potential in normal children, was low for the entire series of patients (0.88 +/- 0.35) but failed to correlate with growth velocity and was negatively correlated with rising parathyroid hormone levels. Average values for height, weight, triceps skin fold, mid-arm muscle circumference, and body mass index were within 2 SD of the mean of the normal population, although measurements for the 1- to 3-year age group were significantly less than those of the older patients. Total energy intake averaged less than 86% of the recommended dietary allowances; total protein intake was more than 161% of the allowance. Nitrogen balance in 23 patients was positive and correlated most significantly with increasing energy intake (r = 0.6). Growth velocity, calculated from the interval gain during the month control period, averaged +0.3 SD, with the highest growth velocity z scores recorded for those with acquired disease. A growth velocity index, expressed as the slope of the regression between change in height SD and growth velocity z score, was used to describe the growth accomplished in the control period by age category.(ABSTRACT TRUNCATED AT 400 WORDS)

Solid-Organ Transplantation in Childhood: Transitioning to Adult Health Care

Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for ones own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.

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.

Urinary Tract Infections in Children with Posterior Urethral Valves After Kidney Transplantation

The records of 14 boys with posterior urethral valves who had renal failure and subsequently underwent renal transplantation were reviewed to determine the postoperative incidence of urinary tract infection relative to that of 29 male transplant children without valves, who served as controls. There were no significant differences between the posterior urethral valve patients and controls with regard to age, donor source, immunosuppression, followup after transplantation or mean calculated creatinine clearance. Vesicoureteral reflux was found in 1 child with posterior urethral valves and 3 of the children in the control group (p not significant). A total of 15 urinary tract infections occurred in 5 children (36%) with posterior urethral valves, for a rate of 1 per 30 patient-months of followup, and 6 urinary tract infections occurred in 2 controls (7%), for a rate of 1 per 216 patient-months of followup (p < 0.05). However, only 1 of 26 controls (4%) without vesicoureteral reflux had urinary tract infection, for a rate 1 per 1,144 patient-months (p < 0.01). Conversely, the rate of urinary tract infections in controls with vesicoureteral reflux was similar to that of children with posterior urethral valves. Of the 5 children with posterior urethral valves 4 had the initial urinary tract infection within 2 months of transplantation and 10 of 15 episodes occurred within the first 4 months. Antimicrobial prophylaxis did not appear to decrease the rate of infection in children with posterior urethral valves. A history of posterior urethral valves increases the frequency of urinary tract infection after renal transplantation but the usefulness of antimicrobial prophylaxis and the relationship to long-term graft function remain to be determined. Urinary tract infection rarely develops in other transplanted boys without vesicoureteral reflux.