Red-cell transport defect in patients with cystic fibrosis and in their parents.

The ouabain-sensitive and the ethacrynic acid-sensitive sodium efflux from erythrocytes of patients with cystic fibrosis are both decreased. Furthermore, the ouabain-sensitive adenosine triphosphatase activity is diminished in the red blood cell ghosts of these patients. Perhaps of greater significance is the fact that ethacrynic acid-sensitive sodium efflux is clearly diminished in the erythrocytes of the asymptomatic parents of these sick children. This defect in sodium transport may be valuable for detecting the heterozygous carrier state.

Inherited WT1 mutation in Denys-Drash syndrome.

Patients with the Denys-Drash syndrome (Wilms' tumor, genital anomalies, and nephropathy) have been demonstrated to carry de novo constitutional mutations in WT1, the Wilms' tumor gene at chromosome 11p13. We report three new cases, two carrying a previously described WT1 exon 9 mutation and one with a novel WT1 exon 8 mutation. However, unlike patients in previous reports, one of our three patients inherited the affected allele from his phenotypically unaffected father. This observation indicates that the WT1 exon 9 mutation affecting 394Arg demonstrated in over one-half of the patients with the Denys-Drash syndrome may exhibit incomplete penetrance. Consequently, familial studies in patients affected by this syndrome are recommended.

Effect of puberty on markers of glomerular hypertrophy and hypertension in IDDM.

Epidemiological data implicate puberty as a factor in the initiation of diabetic nephropathy. However, the mechanism remains unclear. We hypothesized that puberty would result in an increase in glomerular hypertrophy and hypertension; these two early concomitant events are seen as pivotal to the pathophysiology of diabetic nephropathy. We studied the effect of pubertal duration on three surrogate markers of glomerular hypertrophy/hypertension: kidney volume (KV), microalbuminuria (MA), and Na-Li countertransport (CT). We recruited 177 subjects (87 female and 90 male; aged 6.2-22.1 years) with IDDM of 5 to 10 years' duration (6.8 +/- 1.6 years) into three groups with different pubertal duration: prepubertal since IDDM diagnosis; prepubertal at diagnosis, now pubertal; or early puberty at diagnosis, now postpubertal. KV was measured by ultrasound and corrected for body surface area; MA was defined as urinary albumin excretion of 15-200 micrograms/min in two of three 24-h samples, and Na-Li CT was measured in erythrocytes. As pubertal duration increased, there was a disproportionate increase in mean KV (prepubertal, 247 +/- 6 [SE] ml/1.73 m2; pubertal, 282 +/- 7/1.73 m2; postpubertal, 295 +/- 7/1.73 m2, P = 0.001), prevalence of nephromegaly (KV > 300 ml/1.73 m2) (14, 31, and 45%, respectively, P = 0.001), and prevalence of MA (0, 9.7, and 20.5%, respectively, P = 0.003). Subjects with KV > 300 ml/1.73 m2 were eight times more likely to have MA than those with KV < 300 (odds ratio 8.1, 95% confidence interval 2.4-27.4, P = 0.0001). There was no effect of pubertal duration on Na-Li CT. Multiple regression with KV as the dependent variable found an association with pubertal duration, MA, Na-Li CT, and current HbA1c (P < 0.0001). Our findings indicate that pubertal duration is an important determinant of both KV and MA and suggest that nephromegaly precedes microalbuminuria. We postulate that these effects are attributable to the influence of the pubertal milieu on glomerular hypertrophy/hypertension.

Ambulatory blood pressure monitoring and left ventricular mass and function after successful surgical repair of coarctation of the aorta.

Late cardiovascular morbidity and mortality remain significant despite apparently successful surgical repair of aortic coarctation. Alterations in cardiac function have been reported in normotensive patients who have had successful repair, the reasons for which remain unclear. This study addresses the relation between ambulatory blood pressure measurements and alterations in left ventricular performance in 20 patients with normotension at rest after successful repair of aortic coarctation. Exercise testing, ambulatory blood pressure monitoring and two-dimensional echocardiographic studies in 13 boys and 7 girls (mean age 14.2 +/- 2.31 and 14.7 +/- 3 years, respectively) who had no evidence of recoarctation were compared with the findings in 20 matched control subjects. No difference was found in systolic blood pressure at rest or peak exercise between patients and control subjects. Male patients developed a significant arm/leg gradient at peak exercise. Systolic ambulatory blood pressure was higher throughout the day in the male group. In the female group, systolic blood pressure was higher only during sleep. No difference was found in diastolic blood pressure or heart rate. The transverse aortic arch was smaller and the left ventricular mass greater in all patients. The relation of wall stress to rate-corrected velocity of shortening was 2 SD above normal in 8 of the 20 patients, suggesting that some have enhanced contractility. The E/A ratio on the atrial echocardiogram was significantly reduced in the patient group. Successfully treated patients who are normotensive at rest after operation are still at risk for developing end organ damage, which is probably explained by incipient mild hypertension documented by ambulatory blood pressure monitoring.

Sodium-lithium transport in adolescents with IDDM. Relationship to incipient nephropathy and glycemic control.

OBJECTIVE: The aims of this study were to examine genetic and environmental influences in the development of early diabetic nephropathy and to assess the value of measuring membrane sodium transport as a marker for early nephropathy. RESEARCH DESIGN AND METHODS: We measured erythrocyte sodium-lithium (Na-Li) countertransport, blood pressure (BP), HbA1c, and microalbuminuria (MA) in 84 adolescents with insulin-dependent diabetes mellitus (IDDM), 29 of whom had MA. Twenty-nine non-MA patients were selected and matched for age, sex, and IDDM duration with the 29 diabetic subjects with MA. The 84 diabetic adolescents were also compared with 85 nondiabetic siblings. RESULTS: The erythrocyte Na-Li countertransport was significantly greater in the IDDM group than in the sibling group (mean +/- SD, 0.41 +/- 0.14 vs. 0.30 +/- 0.11 mmol Li.liters of erythrocytes-1.h-1, respectively, P < 0.0001), but a significant correlation was noted between the results in IDDM subjects and their siblings (r = 0.42, P < 0.0008). Na-Li countertransport was not different in the diabetic subjects with or without MA (0.43 +/- 0.13 vs. 0.37 +/- 0.13 mmol Li.liters of erythrocytes-1.h-1, respectively). There was a significant correlation in the IDDM group between recent diabetic control (HbA1c) and Na-Li countertransport (r = 0.37, P < 0.003). Diastolic BP was significantly higher in the IDDM group with MA than in those without MA (60 +/- 6 vs. 55 +/- 6 mmHg, respectively, P < 0.03). CONCLUSIONS: These results suggest that erythrocyte Na-Li countertransport is influenced by the diabetic milieu. However, there was also evidence in our subjects of a genetic contribution to Na-Li countertransport as seen by the correlation between levels in the IDDM subjects and their siblings. Using Na-Li countertransport, we were not able to segregate those IDDM adolescents with and without early nephropathy.

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.

Effectiveness and nutritional consequences of amino acid-based vs glucose-based dialysis solutions in infants and children receiving CAPD.

Excessive glucose absorption and dialysate amino acid and protein losses contribute to malnutrition in children on glucose-based continuous ambulatory peritoneal dialysis (CAPD). We used 2.5 and 4.25% glucose and 1.1 and 2.0% amino acid dialysates to assess short-term effectiveness and nutritional consequences of amino acid-based dialysis solutions. Plasma and effluent urea and creatinine concentrations were similar with amino acid and glucose dialysis although 16% less fluid was removed with amino acid dialysates. Absorption of 77.3 +/- 5.3% of dialysate amino acids exceeded losses of amino acids and protein in glucose effluent. With amino acid dialysates, fasting plasma glucose concentrations were maintained while plasma amino acid levels rose, peaked at 1 h, and, excepting methionine, isoleucine, and phenylalanine with the 2.0% solution, returned to initial levels after 5 h. Compared with glucose, amino acid dialysates provide reduced but satisfactory fluid and waste removal, maintain normoglycemia, and more than compensate for effluent losses of amino acids and protein.

Membranoproliferative glomerulonephritis in childhood cirrhosis associated with alpha1-antitrypsin deficiency.

Three alpha1-antitrypsin (alpha1AT) deficient, protease inhibitor type ZZ children who died from cirrhosis and its complications had membranoproliferative glomerulonephritis at postmortem examination. During life, all three had clinical and laboratory evidence of renal disease which became apparent when hepatic decompensation developed. Immunofluorescence studies and electron microscopy performed in one patient revealed subendothelial deposits of alpha1AT, complement, and immune globulins along the glomerular basement membrane. The pathogenesis of these renal lesions is speculative. Glomerular lesions were not observed in kidney sections of 16 children who died from cirrhosis but who were not alpha1AT-deficient. The present study suggests that renal involvement may be yet another manifestation of disease associated with alpha1AT deficiency.

Naproxen-associated renal failure in a child with arthritis and inflammatory bowel disease.

Renal failure occurred in a 14-year-old girl with peripheral arthritis associated with inflammatory bowel disease while she was being treated with naproxen. She had previously received aspirin and tolmetin sodium and had no complications. A renal biopsy showed a severe tubulointerstitial nephritis. Although her renal function improved somewhat with corticosteroid treatment, it worsened when the steroids were discontinued. This case emphasizes that renal failure can develop insidiously in children on nonsteroidal anti-inflammatory drug therapy and that such children must be monitored closely for signs of nephrotoxicity.

Role of the renin-angiotensin-aldosterone system in hypertensive children with coarctation of the aorta.

To investigate the role of the renin-angiotensin-aldosterone system as a cause of hypertension, 20 hypertensive patients with coarctation of the aorta were studied during normal and low sodium intake and after diuresis with flurosemide. Eight patients with essential hypertension and 13 control subjects were similarly studied. Plasma renin activity values in patients with coarctation were similar to those in patients with essential hypertension and in control patients during normal and low sodium diets. However, after the administration of furosemide, plasma renin activity values were significantly higher in the patients with coarctation than in the other two groups (P less than 0.005 and less than 0.01, respectively). The values for urinary aldosterone, plasma volume and extracell fluid volume (bromide space) were increased in patients with coarctation during both normal and low sodium intake. These renin and aldosterone responses and body fluid spaces in patients with coarctation suggest that their hypertension resembles a one-kidney Goldblatt model. The data help to better define the role of the renin-angiotensin-aldosterone system in the hypertension of coarctation and thus may help guide the clinician in therapeutic interventions.

Penoscrotal transposition: a case report and review.

We report on a boy born with complete penoscrotal transposition, normal scrotum, twisted penile shaft with hypoplastic penile urethra, meatal stenosis, normal bladder, and bilateral cystic dysplastic kidneys. The patient died of renal failure at 2.5 months. This is the 13th reported case of complete penoscrotal transposition with normal scrotum. The possible pathogenesis is discussed and the literature is reviewed.

Autosomal recessive inheritance of vasopressin-resistant diabetes insipidus.

We report on 2 intellectually normal sisters with vasopressin-resistant (nephrogenic) diabetes insipidus (NDI). The sex of the patients, the history of parental consanguinity, and the fact that both parents formed normally concentrated urine suggested that the NDI in the 2 sisters was the result of inheritance of an autosomal recessive mutation affecting renal tubular water reabsorption. The results of DNA analysis of the DXS52 locus with the use of St14 as probe, shown by Knoers et al. [1988] to be tightly linked to the NDI locus on the X-chromosome, showed that each girl inherited different Xq28 regions of the maternal X chromosomes, ruling out a diagnosis of classical X-linked NDI.

Brachydactyly-short stature-hypertension (Bilginturan) syndrome: report on two families.

We report on two families with autosomal dominant brachydactyly of hands and feet and hypertension. All affected members of the first family had proportionate short stature. However, the propositus and the affected relatives in the second family were only short compared to unaffected relatives. The hypertension was medically responsive in all cases. The propositus in the second family had poor compliance and a striking generalized vasculopathy. All patients were of normal intelligence and had a normal facial appearance. The brachydactyly-short stature-hypertension syndrome was first reported by Bilginturan et al. [1973] in a Turkish family and the families reported by us are Caucasian and Hispanic. The gene causing this condition in the original Turkish family was recently mapped to 12p. Our report expands our existing knowledge and the ethnic diversity of this syndrome.

Nosocomial transmission of tuberculosis (TB) associated with care of an infant with peritoneal TB.

Nosocomial transmission of tuberculosis (TB) after exposure to infected peritoneal fluid has not been described. We report the exposure of 111 healthcare workers to infected dialysate from an infant with TB peritonitis. Two (5%) of 39 primary-care nurses, but no doctors or environmental service workers, had apparent tuberculin skin test conversions, raising the concern that patients with peritoneal TB may be a source for nosocomial transmission of TB.

Ultrasound biomicroscopy of the eye in cystinosis.

OBJECTIVE: To describe the ocular ultrasound biomicroscopy (UBM) findings in patients with cystinosis. METHODS: Six patients with infantile nephropathic cystinosis, aged 16 to 25 years, and 6 controls (matched for age and spherical refractive error) were examined clinically and with UBM. Scleral reflectivity, corneal and iris thickness, central anterior chamber depth, angle width, trabecular meshwork to ciliary process distance, and ciliary sulcus width were measured. RESULTS: No patient had glaucoma or posterior synechiae, but all had crystals in the trabecular meshwork apparent with gonioscopy. Using UBM, the cornea and iris appeared similar in both groups, but the scleral reflectivity was increased in patients (P =.003). The angle was narrower in patients (mean +/- SD, 20 degrees +/- 7 degrees ) than controls (31 degrees +/- 5 degrees, P<. 001). The anterior chamber was shallower in patients (2556 +/- 197 microm) than controls (2968 +/- 284 microm, P<.001). The ciliary sulcus was closed or narrow in all patients (83 +/- 112 microm) compared with controls (339 +/- 135 microm, P<.001), with a reduction in the trabecular meshwork to ciliary process distance. CONCLUSIONS: This report of ocular UBM findings in cystinosis demonstrated narrowing of the angle and a ciliary body configuration similar to that reported for plateau iris syndrome. Gonioscopy demonstrated crystals in the trabecular meshwork. These findings may explain the predisposition of these patients to glaucoma.

Cadaveric renal transplants in children under 6 years of age.

Thirty-nine cadaveric renal allografts were performed in 28 children under 6 years of age. Common primary renal diseases were glomerulonephritis, dysplasia/hypoplasia, and reflux/obstructive nephropathy. After a mean follow-up of 40 months of patients with surviving grafts, 19 patients had functioning grafts, 3 had returned to dialysis, and 6 had died. These children required an extraordinary amount of care postoperatively because of anorexia, diarrhea, and ileus. Their psychomotor and physical development was retarded prior to transplant; this reversed dramatically after transplant, but catch-up growth occurred in only 4 patients. Many patients were noticeably more active and distractible for 1 to 2 years post-transplant. Major causes of graft failure were primary nonfunction of 5 donor kidneys (4 from donors under 1 year old) and renal vessel thrombosis in 5 recipients (3 with native kidneys in place who received kidneys from donors over 10 years old). Other causes were recurrence of hemolytic uremic syndrome and Wilms tumor, rejection, and sepsis. Kidneys from donors under 1 year old proved unsatisfactory, and large donor kidneys in small children tended to thrombose, especially when native kidneys with high urine output were left in situ.

Comparisons between oral and intraperitoneal 1,25-dihydroxyvitamin D3 therapy in children treated with peritoneal dialysis.

Recent studies in adults have suggested that parenteral 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may have advantages over oral therapy in the management of renal osteodystrophy. The purpose of this study was to determine whether there were clear differences between oral and IP 1,25(OH)2D3 treatments in children who did not pose a treatment problem. Seven children (5 males, 2 females, aged 1.8 to 16 years, median 4.8 years) undergoing peritoneal dialysis were initially treated with oral 1,25(OH)2D3 for a one month equilibration period They were randomly assigned to 3 months of either oral or intraperitoneal (IP) therapy with 1,25(OH)2D3 followed by 3-months-treatment using the alternative route. No significant differences in serum creatinine, phosphate, or parathyroid hormone concentrations were found between the different routes of administration in the patients. No significant differences in height standard deviation scores or renal osteodystrophy scores were found over the six-month study. Paired oral and IP pharmacokinetic studies were performed on these 7 patients and 2 other children who had been treated for at least 2 months using either oral or IP 1,25(OH)2D3. Serum was taken prior to one of the usual 1,25(OH)2D3 doses and 0.5, 1.5, 3, 6, and 24 h afterward. The highest measured concentrations of 1,25(OH)2D3 were found at 1.5 h for both oral and IP treatments (mean Cmax [SD]: oral 116 [23] pmol/l, IP 121 [24] pmol/l, p > 0.05). The AUC's for oral and IP therapy were similar (1701 [276] and 1645 [301] pmol/h/l, respectively). In the paired pharmacokinetic studies no significant differences were found between oral and IP treatments for the serum half life (27.4 [11.6] h and 19.2 [8.1] h, respectively) and total body clearance (15.3 [2.1] h and 18.4 [3.3] h, respectively) of 1,25(OH)2D3. In children who respond appropriately to oral 1,25(OH)2D3 there is no biological advantage to the use of IP 1,25(OH)2D3.

Allograft renal-artery stenosis: increased peripheral plasma renin activity as an early indicator of uncontrollable hypertension.

We measured indices of the renin-aldosterone system and body-fluid spaces in 11 adolescents who had received a renal transplant after removal of their own diseased kidneys. None had hypervolemia but 6 had hypertension. Renal angiography revealed greater than 50% luminal occlusion by allograft renal-artery stenosis (RAS) in only the 3 patients who had severe hypertension refractory to conventional medical therapy. Excessive peripheral plasma renin activity (PRA) distinguished these patients from those who had less severe stenosis or normal angiogram, and diuretic stimulation heightened the PRA differences. We conclude that significant allograft RAS does not necessarily act like a typical single-kidney Goldblatt model until after volume depletion. Our findings indicate that peripheral PRA values can be used to assess the degree of graft ischemia clinically. This permits early identification of patients who have severe RAS that probably will be difficult to control medically, and, therefore, should be followed closely with a view of reconstructive vascular surgery before further deterioration of renal function.

Wilms' tumor and glomerular disease. Occurrence with features of membranoproliferative glomerulonephritis and secondary focal, segmental glomerulosclerosis.

A case of bilateral Wilms' tumor occurred in which a renal biopsy performed for proteinuria showed features of membranoproliferative glomerulonephritis (MPGN) type 1 and focal segmental glomerulosclerosis (FSGS). A review of the literature for similar cases revealed 24 patients with Wilms' tumor associated with glomerular disease; MPGN was present in one of these cases and FSGS in six. In our patient, circulating immune complexes were detected in the serum and likely played a role in the pathogenesis of the MPGN; the FSGS may have resulted from hyperperfusion of the remaining glomeruli in a kidney that was largely replaced by Wilms' tumor.

The use of alternative peritoneal dialysis solutions in pediatric patients.

Changes in the formulation of peritoneal dialysis solutions will continue. For the present, dextrose dialysis will remain the osmotic solute of choice. How amino acids and glucose polymers as solute replacements for glucose fit into the dialysis prescription remains to be seen. The lower concentration of calcium and magnesium appears to be gaining acceptance in many centers. It is feasible that in the next few years the challenge of adding bicarbonate to the peritoneal dialysis solution will be circumvented, because there appears to be a real clinical need for such an improvement. Pediatric modifications will be necessary, appreciating that such changes will have an economic penalty, and thus must have proven value.