Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure.

We report a patient who presented with anophthalmia, panhypopituitarism, early onset of end stage renal failure, and craniofacial abnormalities. MRI at age 3 revealed that the pituitary was absent and renal biopsy demonstrated nephronophthisis as the cause of the renal failure. A similar syndrome has been associated with interstitial deletions of chromosome 14q22 and in one case hemizygosity for SIX6 was demonstrated. The patient reported here had a normal karyotype and Southern blot did not reveal loss of one copy of SIX6. We discuss other possible candidate genes that could be implicated in this syndrome.

Growth hormone and insulin-like growth factor in non-uremic acidosis and uremic acidosis.

Growth retardation is a cardinal feature of children with renal tubular acidosis. This is reversible by correcting the non-uremic acidosis with alkali therapy. Sodium bicarbonate solutions or citrate solutions have been used for this purpose. However, the odious taste of these medications almost invariably causes medical noncompliance. The persistent and often profound metabolic acidosis from medical noncompliance, precipitates hypercalciuria and hypocitraturia, and increases the risk of nephrocalcinosis. The mechanism of the growth retardation in renal tubular acidosis is thought to be related to a blunting of anterior pituitary growth hormone secretion. In experimental metabolic acidosis, the growth hormone secretory pulse areas are reduced. Just as importantly, hepatic growth hormone receptor expression and IGF-I mRNA were blunted in metabolic acidosis. In uremia, growth retardation is secondary to a host of factors including metabolic acidosis, renal osteodystrophy, and the side effects of treatment such as corticosteroids, which compound the growth retardation. Growth hormone secretion by individual pituitary cells was stimulated by corticosteroids but, paradoxically, the total number of somatotropes was suppressed. In uremia, the secretion of growth hormone was not different from controls at any level of growth-hormone-releasing hormone challenges. Hepatic IGF-I mRNA was markedly reduced in uremic rats. Growth hormone receptor expression was significantly reduced in uremic acidotic rats. The growth hormone and IGF-I expression on the growth plate of the long bone of uremic rats was reduced. IGF-I immunoreactivity was present in both the hypertrophic and proliferative zones. The lack of growth of the proliferative zones suggested growth hormone and IGF-I resistance in uremic chondrocytes.

Effects of uremia on growth in children.

Growth failure is a major complication of uremia in infancy and childhood. The influence of the primary renal disease leading to uremic growth retardation in children, the contributing factors leading to growth failure, such as metabolic acidosis, renal osteodystrophy, hyperparathyroidism, nutrition-endocrine and developmental disorders, are reviewed to update nephrologists on the complex issue of growth failure in children with uremia. The collaboration between endocrinologists and nephrologists in treating children with growth retardation is highlighted by a recently completed National Institutes of Health (NIH)-funded clinical trial on renal osteodystrophy plus the use of recombinant human growth hormone and insulin-like growth factor. Finally, this article concludes with a brief summary of an approach to reverse the effects of uremia on growth, including conservative nutritional management, treatment of anemia with erythropoietin, and selected aspects of growth and development after renal transplantation.

The kidney in acid-base balance.

The practitioner's approach to the pediatric patient with metabolic acidosis begins with calculation of the serum anion gap, which allows the clinician to place the patient in one of two categories of acid-base disturbance: a normal anion gap acidosis or high anion gap acidosis. Likewise, the patient with metabolic alkalosis can be categorized by urinary chloride concentration and the response to chloride replenishment as either chloride-responsive or chloride-resistant. The disease states associated with each category are reviewed in this article.

Insulin-like growth factor-I gene expression in the tibial epiphyseal growth plate of growth hormone-treated uremic rats.

To identify the molecular mechanisms involved in long bone growth of uremic animals, we evaluated the effects of recombinant human growth hormone (rhGH) supplementation on whole body growth, growth plate morphometrics, and insulin-like growth factor-I (IGF-I) gene expression in the tibial epiphyseal growth plates of uremic rats. Uremia was induced by a two-stage subtotal nephrectomy (Nx) of 30-day-old rats, followed by rhGH (N = 6) or saline (N = 6) treatment from day 56 to day 70 of age. Controls (N = 4) were sham decapsulated. Treatment with rhGH on Nx animals caused: (1) a significant increase in weight, (2) longitudinal growth similar to controls, and (3) increased total growth plate width predominantly due to an increase in hypertrophic zone width. rhGH increased IGF-I mRNA abundance in both zones, but the increase was greater in the proliferative zone. These changes were accompanied by concomitant alterations in IGF-I immunoreactivity. In uremic animals, therefore, rhGH treatment induces local IGF-I gene expression in the growth plate and increases the hypertrophic zone width but not the proliferative zone width. The latter suggests resistance to IGF-I action in that zone.

Nephrocalcinosis in a child with autosomal dominant polycystic kidney disease and a prolapsing ectopic ureterocele.

Although autosomal dominant polycystic kidney disease commonly presents in adults, it can occur in children. Usually, renal calcification in patients with autosomal dominant polycystic kidney disease is manifested as calculi or as hemorrhage into a renal cyst. An ectopic ureterocele is a well-known finding in patients with renal duplication. To our knowledge, this is the first case report of a child who had combined findings of autosomal dominant polycystic kidney disease, nephrocalcinosis, and an obstructing ectopic ureterocele.

Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase in rats with subtotal nephrectomy.

Chronic renal failure is associated with hyperlipidemia and atherosclerosis. The mechanism responsible for the observed increase of serum cholesterol in chronic renal disease is not certain. The objective of the present study was to characterize the effect of induced renal failure on 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and cholesterol 7 alpha-hydroxylase, the two rate determining enzymes of the cholesterol and bile acid biosynthetic pathways, respectively. Studies were carried out in rats with subtotal (75%) nephrectomy, which resulted in a marked elevation of blood urea nitrogen (371 +/- 44% of control, P < 0.001), and was accompanied by significant increases in the levels of serum cholesterol (133 +/- 7%, P < 0.005) and triglycerides (185 +/- 25, P < 0.01). In nephrectomized rats, an increase in the specific activity of HMG-CoA reductase (219 +/- 30% above control levels, P < 0.02) was observed. This increase occurred in the presence of elevated hepatic microsomal cholesterol concentrations (150 +/- 13% of controls, P < 0.01). Surprisingly, the increase in HMG-CoA reductase specific activity was not associated with parallel increases in HMG-CoA reductase steady-state mRNA levels and gene transcriptional activity. These uremic rats also exhibited a marked increase in the specific activity of cholesterol 7 alpha-hydroxylase (240 +/- 559% of controls, P < 0.05). There was no concomitant increase in cholesterol 7 alpha-hydroxylase steady-state mRNA levels or gene transcriptional activity. The factors responsible for the observed increases in HMG-CoA reductase and cholesterol 7 alpha-hydroxylase specific activity in renal failure remain to be determined.(ABSTRACT TRUNCATED AT 250 WORDS)

The peritoneal equilibration test in children.

Eight children, aged 15 months to 17 years 9 months, maintained by continuous ambulatory peritoneal dialysis (CAPD)/continuous cycling peritoneal dialysis and nine adults, aged 20-59 years, managed by CAPD were compared using a standardized peritoneal dialysis protocol, the peritoneal equilibration test (PET). The peritoneal glucose concentration tended to equilibrate with the serum glucose more rapidly in children, but the percentage of the glucose load absorbed was not different between the two age groups. There was an inverse trend between the percentage of glucose absorbed and age in children. Peritoneal creatinine clearance scaled to surface area in children was significantly less than that of the adults; however, the clearances became similar when adjusted for body weight. Peritoneal creatinine clearance scaled to surface area bore a positive and significant relationship to age which, when expressed per kilogram body weight, disappeared. Children had a significantly higher dialysate/plasma (D/P) creatinine ratio after the first 2 h of the PET, but this ratio approached unity by 4 h and was not different from adults. The fractional change in the creatinine D/P ratio during the PET was not different between the two age groups. Drain volume adjusted to surface area was significantly less in children than adults. This difference was reversed when drain volume was factored by weight. Similarly drain volume scaled to surface area demonstrated a significant and positive relationship to age, which disappeared when drain volume was expressed per kilogram body weight. Ultrafiltration, whether factored by weight or scaled to surface area, did not differ between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoid-induced changes in the quantity and secretory capacity of individual rat somatotropes.

Chronic glucocorticoid treatment is complicated by growth failure. The study presented here was designed to investigate the effect of cortisone on growth hormone (GH) secretion by individual pituitary cells in young male rats. Beginning at 37 days of age, animals were injected sc with cortisone acetate (CORT; 5.0 mg/rat per day) or the same volume of saline (SAL) for 8 days. At 45 days of age, the body weights of the CORT animals (134.5 +/- 5.5 g) were significantly less (P < 0.0005) than those of SAL controls (179.3 +/- 4.2 g). The secretory capacity of dispersed pituitary cells was assessed by the reverse hemolytic plaque assay. Cells were exposed to six concentrations of GH-releasing hormone (GHRH) ranging from 0.01 to 3.0 nM. CORT treatment significantly decreased the absolute number of somatotropes per pituitary gland (CORT, 1.23 +/- 0.03 x 10(6); SAL, 1.57 +/- 0.09 x 10(6); P = 0.025). Conversely, the mean plaque areas were significantly greater for CORT animals at all concentrations of GHRH tested, indicating that the amount of GH secreted by individual somatotropes was significantly increased by CORT. It was concluded that the paradoxical increase in the in vitro GHRH responsiveness, which is commonly observed after glucocorticoid treatment, was due to an increase in the capacity of fewer individual somatotropes to secrete GH.

The effect of growth hormone on the growth failure of chronic renal failure.

To investigate the effects of growth hormone (GH) on the reversal of growth failure in uremia, recombinant human GH (rhGH) was administered to rats with chronic renal failure (CRF). The dosage of rhGH was 3 IU/day (i.p.) for 13 days after the induction of CRF by 5/6 nephrectomy. Animals were classified into four groups: untreated nephrectomized rats (NX, n = 40), GH-treated nephrectomized rats (NX+GH, n = 18), sham-operated rats fed ad libitum (SHAMAL, n = 27), and sham-operated rats pair-fed with 10 NX rats (SHAMPF, n = 10). NX and NX+GH rats developed a similar and moderate degree of CRF, serum urea nitrogen being (mean +/- SEM) 49 +/- 3 and 54 +/- 4 mg/dl, respectively, compared with 16 +/- 4 and 19 +/- 0 mg/dl in SHAMAL and SHAMPF groups. Weight (56.0 +/- 3.3 g) and length (3.5 +/- 0.1 cm) gains of NX rats were lower than those of SHAMAL rats (94.2 +/- 4.0 g, P less than or equal to 0.0001 and 4.1 +/- 0.2 cm, P less than or equal to 0.01). Growth of the SHAMPF group and the matched NX rats was not significantly different. Weight (56.2 +/- 5.0 g) and length (3.4 +/- 0.2 cm) gains of NX+GH and NX rats were similar, the beneficial effect of GH therapy on growth being observed in only those animals with more severe degrees of uremia. This growth-promoting action resulted from greater food efficiency and not from stimulated food intake. The hypercholesterolemia seen in NX rats, 81 +/- 2 mg/dl versus 55 +/- 3 mg/dl in SHAMAL (P less than or equal to 0.0001), was not increased in the NX+GH group, 87 +/- 3 mg/dl. There was a positive and significant correlation between serum cholesterol and serum urea nitrogen values in NX and NX+GH animals. This study suggests that growth impairment of mild CRF is mainly due to malnutrition and is refractory to GH administration. GH therapy improves the growth rate of animals with advanced CRF without aggravating their lipid abnormalities.

Growth hormone secretory capacity of individual somatotropes in rats with chronic renal insufficiency.

Growth failure is a common consequence of chronic renal insufficiency (CRI) in children and may be due to a number of factors. With regard to growth hormone (GH), regulation is often abnormal in CRI patients. The present study investigated the effect of CRI on the GH secretory responsiveness to GH-releasing hormone in individual rat pituitary somatotropes. Male Sprague-Dawley rats underwent a 5/6 nephrectomy to produce CRI. Control rats (SHAM) received sham operations, which included kidney decapsulation but not removal. Two wk later, during a period of stable uremia, serum creatinine [CRI: 1.1 +/- 0.08 mg/dL (97 +/- 7 mumol/L); SHAM: 0.4 +/- 0.04 mg/dL (35 +/- 4 mumol/L)] and serum urea nitrogen [CRI: 60.7 +/- 8.3 mg/dL (21.7 +/- 3.0 mmol/L); SHAM: 15.8 +/- 1.2 mg/dL (5.6 +/- 0.4 mmol/L)] were significantly elevated in the CRI rats (p less than 0.0005). Weight gain (p less than 0.0005), length gain (p less than 0.0005), food intake (p less than 0.0005), and food efficiency (p less than 0.005) were all significantly lower in the CRI rats. The GH secretory capacity of individual somatotropes was determined using the reverse hemolytic plaque assay technique. Plaque areas were measured to assess relative amounts of GH secreted. The total number of pituitary cells per rat, the percentage of somatotropes, and the mean plaque areas were similar for the two groups. These findings compare favorably with our in vitro study of GH responsiveness in perifused rat pituitary cells under conditions of mild uremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone secretion from pituitary cells in chronic renal insufficiency.

To examine whether growth hormone (GH) secretion is adversely affected by chronic renal insufficiency (CRI), the GH secretory response of dispersed anterior pituitary cells perifused with GH-releasing hormone (GHRH) was investigated in 5/6 nephrectomized (CRI, N = 18) and sham-operated (N = 18) rats. Two weeks after nephrectomy, during a period of stable uremia, CRI rats had significantly higher serum concentrations (mean +/- SEM) of urea nitrogen and creatinine than sham rats, 16.8 +/- 1.4 mmol/liter (47 +/- 4 mg/dl) and 79.6 +/- 0.0 mumol/liter (0.9 +/- 0.0 mg/dl) versus 6.1 +/- 0.4 mmol/liter (17 +/- 1 mg/dl) and 35.4 +/- 0.0 mumol/liter (0.4 +/- 0.0 mg/dl), respectively (P less than 0.0001). Incremental gains in body weight and nose to tail-tip length of CRI rats over two weeks were also significantly depressed, 53.3 +/- 5.38 g (CRI) versus 87.0 +/- 3.78 g (sham; P less than 0.0001) and 3.2 +/- 0.2 cm (CRI) versus 3.6 +/- 0.1 cm (sham; P less than 0.05). The cumulative food intake as well as food efficiency (g food consumed/g weight gain) were also adversely influenced by the uremic state: food intake 304 +/- 1 g (CRI) versus 397 +/- 6 g (sham; P less than 0.0001) and food efficiency 0.173 +/- 0.013 g/g of weight gain (CRI) versus 0.219 +/- 0.008 g/g of weight gain (sham). No significant difference in GH secretory rate (ng/min/10(7) cells) was found between the uremic and sham animals under basal conditions, 65.2 +/- 2.1 (CRI) and 67.9 +/- 2.2 (sham) or in response to GH-releasing hormone, 282.8 +/- 42.4 (CRI) versus 306.2 +/- 42.6 (sham).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypercholesterolemia in rats with chronic renal insufficiency not aggravated by recombinant human growth hormone.

The lipid metabolic disorders in chronic renal insufficiency (CRI) are related to increased hepatic lipid synthesis, reduced triglyceride removal coupled with insulin insensitivity and impaired lipoprotein lipase activity. Growth hormone is lipolytic, and the effects of recombinant human growth hormone (rhGH) on the hypercholesterolemia of CRI are unsettled. To test this question, we gave rhGH for 14 days at a dosage of 3 units/day intraperitoneally to two-stage, 5/6 nephrectomized, male Sprague-Dawley rats (n = 18) compared to sex- and age-matched control (n = 27) and CRI (n = 40) rats. At the end of the study, CRI rats and those treated with rhGH had a similar degree of renal impairment, as assessed by serum concentrations (mean +/- SEM) of urea nitrogen (49 +/- 3 vs. 54 +/- 4 mg/dl), creatinine (0.9 +/- 0.0 vs. 1.0 +/- 0.1 mg/dl) and cumulative food intake (311 +/- 8 vs. 290 +/- 12 g). Serum urea nitrogen (16 +/- 4 mg/dl) and creatinine (0.4 +/- 0.1 mg/dl) concentrations as well as food intake (412 +/- 9 g) of control rats were significantly (p < 0.0001) different. Serum cholesterol concentration of CRI rats treated with rhGH (87 +/- 3 mg/dl) was not higher than those of CRI rats (81 +/- 2 mg/dl, p < 0.1338) but was significantly higher than in control rats (55 +/- 3 mg/dl, p < 0.0001). CRI rats treated with rhGH showed a similar serum albumin concentration and lower serum glucose than CRI rats (0.9 +/- 0.1 vs. 0.9 +/- 0.0 g/dl and 144 +/- 4 vs. 163 +/- 3 mg/dl, p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

X-linked hypophosphatemia. Genetic and clinical correlates.

X-linked hypophosphatemia is a hereditary form of rickets that results from an isolated renal tubular wasting of phosphate. The clinical features unique to this disorder, and the recent advances in our understanding of vitamin D metabolism and molecular genetics in X-linked hypophosphatemia are reviewed. Finally, a succinct critique of the controversial treatment modalities round up this review.

Cortisone effects on growth, food efficiency, and in vitro growth hormone release.

These studies were designed to investigate the cause of growth retardation during glucocorticoid treatment in rats. In young animals, body weights and amounts of food consumed were measured at two-day intervals, beginning at 29 days of age. Average food intake and food efficiency were calculated. Animals were treated with cortisone (CORT, 5 mg/rat/day, s.c.) or saline (SAL) for eight days between 37 and 44 days. Growth hormone (GH) release by dispersed pituitary cells in response to nine concentrations of GH-releasing hormone (GHRH) were tested by in vitro perifusion at 45 and 73 days. As previously shown, CORT caused a cessation of growth during the treatment period, and body weight failed to catch up. Food efficiency was decreased during CORT treatment. All parameters of in vitro GH release including basal GH secretory rate, overall GH response to GHRH, and the GHRH concentration-response curves were significantly increased by CORT in the 45-day-old animals. An age-related increase in GH release was also observed between the 45 and 73 day saline-treated animals. These results support the hypothesis that glucocorticoids inhibit growth by induction of changes in food metabolism and GH secretion. The effect on the pituitary gland itself paradoxically involves an increase in GH secretory capacity in response to GHRH.