Growth In Uremia Research Articles

Growth Plate Disturbances in Renal Failure

The development of diminished linear growth and bone deformities in pediatric patients with chronic renal insufficiency sugests disturbances in the growth plate (GP) cartilage at the end of long bones. In rodent models of renal failure, the width of the GP has been reported to be increased, decreased, or unchanged compared to rats with intact renal function. Because of the potential role of the various subtypes of renal osteodystrophy on the GP abnormalities in renal failure, we created a model of severe secondary hyperparathyroidism through dietary phosphororous supplementation and we found a similar markedly disorganized GP and diminished expression of the PTH/PTHrP receptor in the GP chondrocytes. In contrast, adynamic renal osteodystrophy induced by dietary calcium supplementation resulted significantly wider GP, particularly of the hypertrophic zone, associated with disturbances in osteoclastic/chondroclastic activity and matrix degradation. These results suggests that renal osteodystrophy may contribute to poor growth in renal failure and the mechanisms differ among the subtypes of renal bone disease. Additionally, disturbances in the growth hormone-insulin-like growth factor (GH-IGF) axis may play a role in impaired linear growth in uremia. At the level of the growth plate, decreased expressions of the IGF-I and GH receptor expression was seen only with combined treatment with GH and IGF-I. Further studies may provide novel insights into the regulation of endochondral bone growth in renal failure, thereby resulting in more effective strategies to prevent and treat growth failure in these patients.

Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia

Exogenous growth hormone (GH) stimulates the endogenous production of IGF-I and improves growth in uremia. We investigated whether exogenous IGF-I is also able to improve uremic growth failure in rats and whether the growth promoting effects of GH and IGF-I are additive. In female 150 g uremic (subtotal nephrectomy, NX) Sprague-Dawley rats, both rhGH in doses from 2 X 1.25 to 2 X 10 IU/kg bid s.c. and rhIGF-I in doses from 2 X 0.5 to 2 X 4.0 mg/kg bid s.c. caused a dose-dependent increase in weight gain and length gain. However, endogenous production of GH was suppressed by both agents. Peptide hormone treatment did not affect cumulative food intake, but significantly increased food efficiency ratio (weight gain/food intake). Concomitant s.c. treatment with maximally effective doses of rhGH (12 X 5 IU/kg bid) and of rhIGF-I (2 X 2 mg/kg bid) resulted in additive growth promoting effects in NX and pair-fed control (CO) animals during the observation period of 12 days. Cumulative length gain was 3.2 +/- 0.5 cm in solvent-treated NX-animals, 4.1 +/- 0.5 cm with rhGH (+ 28% above solvent), 4.2 +/- 0.6 cm with rhIGF-I (+ 31%) and 4.9 +/- 0.5 cm with both peptides (+ 53%). The food efficiency ratio was 0.16 +/- 0.05 in solvent NX, 0.33 +/- 0.04 with rhGH (+ 106% above solvent), 0.23 +/- 0.02 with rhIGF-I (+ 44%), and 0.38 +/- 0.02 with both peptides (+ 138%). Histomorphometric analysis and measurements of length gain by fluorescence microscopy in the upper tibial metaphysis confirmed the growth promoting effects of both peptide hormones. The serum concentrations of IGF binding protein (BP)-4 (Western ligand blotting analysis) and of IGFBP-2 (immunoblot) were increased in uremic animals whereas IGFBP-3 was unchanged. Treatment with IGF-I and/or rhGH increased serum concentration of IGF-I but did not change the IGFBP pattern. rhIGF-I lowered blood glucose levels within one to two hours after injection. The effect was most pronounced during the first treatment day and declined thereafter. Concomitant treatment with rhGH attenuated the glucose lowering effect of rhIGF-I (glucose serum concentration at day one: 120 +/- 11 mg% in solvent NX, 50 +/- 21 mg% with rhIGF-I, 80 +/- 24 mg% with both peptides). It is concluded that: (i) IGF-I is able to stimulate growth in NX animals but suppresses endogenous GH production in the long run; (ii) the concomitant treatment with IGF-I and GH has additive effects on growth; and (iii) concomitant treatment with rhGH prevents hypoglycemia that is noted with rhIGF-I alone.

Carbohydrate metabolism in uremia.

Abnormalities of insulin and glucose metabolism, namely glucose intolerance, inhibition of insulin secretion and insulin resistance, are present in children with chronic renal failure. Insulin resistance is universal among children with end-stage renal disease and may be caused by uremic toxins accumulated because of reduced renal function. The normal response of the beta cell is to enhance insulin secretion to overcome the insulin resistance. In patients with secondary hyperparathyroidism, this increase in insulin secretion is inhibited, resulting in glucose intolerance. Presence of glucose intolerance may be responsive for the growth retardation in uremic children. Improvements in glucose tolerance correlate with improvements in linear growth in uremic children. Further research should be directed towards investigation of the mechanisms by which abnormal energy utilization may affect growth in uremia and development of indices of glucose metabolism as predictors of growth in uremia.

Disturbed growth in uremia: are hormonal factors responsible?

Disturbed growth in uremia: are hormonal factors responsible?

Somatomedin inhibitor in uremia.

In uremia, poor growth occurs despite normal to increased levels of insulin and GH. Since serum somatomedin levels measured by RIA and radioreceptor assay are normal in patients with renal failure, while serum somatomedin activity measured by bioassay is low but increased by dialysis, we asked if somatomedin activity could be decreased due to the presence of a low mol wt inhibitor(s). Serum was obtained from eight normal adults and eight uremic patients before hemodialysis treatment and was fractionated by gel filtration. Somatomedins and high mol wt inhibitors were separated on Sephadex G-50, pH 2.4, and high and low mol wt inhibitors were separated on Sephadex G-25, pH 7. Somatomedins were measured by stimulation of SO4 uptake by hypophysectomized rat costal cartilage in vitro, and inhibitor levels were determined by the blunting of stimulation produced by somatomedins in normal serum. Total biologically active somatomedin levels were comparable in uremic and normal sera. High mol wt somatomedin inhibitors (as found in malnutrition and diabetes) also were detected at similar levels in uremic and normal sera. In contrast, serum from uremic patients had increased levels of a low mol wt somatomedin inhibitor(s) [151 +/- 23% (mean +/- SEM) of serum stimulation inhibited vs. 47 +/- 9%; P less than 0.001]. Peak inhibitory activity was found at approximately 940 mol wt (range, 800-1100); an inhibitor of similar size was found in normal urine. Uremic serum fractions blunted cartilage sulfate uptake that was stimulated by whole serum, somatomedins (dissociated from serum carrier proteins), and insulin and lowered uridine and thymidine uptake that was stimulated by whole serum (all P less than 0.005). Lineweaver-Burk analysis indicated that somatomedin-inhibitor interactions on cartilage were noncompetitive, consistent with observations that direct exposure of cartilage to inhibitor decreased SO4 uptake to 30 +/- 3% below buffer levels (P less than 0.001). Despite these marked effects on cartilage, no alterations in basal or insulin-stimulated glucose oxidation occurred after addition of inhibitory serum fractions to adipose tissue incubations. Exposure of the inhibitor to proteolytic enzymes led to a significant decrease in inhibitory activity, indicating that the inhibitor may be a peptide. These studies suggest that decreased circulating somatomedin activity and impaired growth in uremia may reflect the accumulation of a circulating peptide inhibitor that would normally be cleared by the kidneys. Measurements of this factor may provide an index of growth potential in uremic children and help guide therapy of renal failure in both children and adults.

Effect of vitamin D3 and 1.25 (OH)2 D3 on growth in experimental uremia(EU)

Growth retardation is a major unsolved problem in children with chronic renal failure. A stimulatory effect of D, on growth rate in EU has been demonstrated (Mehls et al. Am.J.Clin.Nutr.,1978),but clinical results are conflicting. Chesney et al.(New Eng.J.Med.,1978)reported increased growth velocity in uremic children treated by 1.25 (OH)2D3 who had failed to respond to high dosage D3.The present study was designed to compare the efficacy of D3 and 1.25(OH)2D3 (application i.p.;3-point dose response curve) on growth in rats with EU. Methods: 90g Sprague-Dawley rats with stable uremia(2-stage subtotal nephrectomy) of 2 weeks' duration(CCR 18% of normal). All animals fed ad lib. Five groups: I: NX solvent; II and III: NX+D3 (0.5 and 1.0 μg/70g/day); IV and V: NX+1,25 (OH)2 D3 ( 0.625 and 1.25 ng/70g/day). Results: Serum Ca increased (p<0.01) to the same extend in NX+D3 and NX+1.25(OH)2D3. Compared to NX solvent animals (5.9 ±0.2cm/14 days;21±5g/14 days,n=14), the growth rate was significantly better in NX+D3 (6.4±0.3cm/14 days;31±6g/14 days;n=12) and in NX+1.25(OH)2D3 (6.6±0.3cm/14 days; 32±6 g/14 days;n=12). The difference between NX+D3 and NX+1.25(OH)2D3 was not significant. Conclusion: The present study can not confirm that 1.25 (OH)2D3 has a more beneficial effect on growth in uremia than D3.

SKELETAL GROWTH IN UREMIA

Skeletal growth (linear apposition rate in diaphyses, longitudinal growth/day and accumulated growth rate in metaphyses) were measured in uremic rats by tetracycline labelling. Cellular proliferation rates were evaluated autoradiographically by 3H-thymidine. The effect of hyperparathyroidism was determined by parathyroidectomy. Growth plates and metaphyseal spongiosa were studied by scanning electron microscopy. Whereas skeletal growth was significantly reduced in uremic rats (Co 16.5-3.1 /u, U 13.1 ± 1.4/u) the proliferation rate of cartilage cells was clearly elevated (3H-index Co 8, 1%, U 13.3). After parathyroidectomy the proliferation rate was markedly reduced in uremic animals (4.2%). Experimental acidosis (NH4C) and urea administration (without renal insufficiency) had no influence on apposition rates. In order to prevent impairment of longitudinal growth in uremia the effects of a long term treatment with vitamin D3, D-metabolites and D-analogs were studied in this experimental model.