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End-organ resistance to growth hormone and IGF-I in epiphyseal chondrocytes of rats with chronic renal failure. We tested the hypothesis that there is direct end-organ resistance to growth hormone (GH) and IGF-I in chronic renal failure (CRF) independent of circulating inhibitors. Male Sprague-Dawley rats underwent 5/6 nephrectomy and were pair-fed with weight matched (100 g) sham operated controls for two weeks. Rats with CRF had significantly higher serum creatinine and blood urea nitrogen (P < 0.01 in both cases) and gained significantly less weight and length (P < 0.01 in both cases) compared with controls. Epiphyseal chondrocytes were grown in 10% fetal calf serum (FCS). Both CRF cells and control cells maintained chondrogenic phenotypes, and showed immunohistochemical staining with antibodies to collagen II and proteoglycan (aggrecan). Distribution of the cell subpopulations according to cell size (by flow cytometry) and alkaline phosphatase activity of CRF and control chondrocyte cultures were not different. Growth responses of CRF chondrocytes were reduced (P < 0.01) compared with control chondrocytes when grown in 10% FCS and 10% normal rat serum. Under serum free conditions, growth responses of CRF chondrocytes were reduced to GH and IGF-I at concentrations of 10, 30 and 100 ng/ml, and to insulin at 100, 300 and 1,000 ng/ml compared with controls cells (P < 0.01). To show that this resistance is specific for the GH/IGF system, growth responses to fibroblast growth factor and transforming growth factor β1 were studied and showed no difference between CRF and control cells. Thus, the present study provides direct evidence of specific end-organ resistance to GH, IGF-I in CRF chondrocytes in the absence of circulating factors.

Insulin sensitivity was studied before and after 3 mo of continuous cycling peritoneal dialysis (CCPD) in seven uremic patients, before and after 3 mo of hemodialysis (HD) in another seven uremic patients, and in seven healthy controls. There were no significant differences in the height, weight, anthropometric measures, or intakes of protein and total calories between the CCPD and the HD groups before and after the 3 mo of dialysis therapy. There were no differences in other biochemical parameters between patients on CCPD and patients on HD either at the initiation of dialysis or at the end of 3 mo of dialysis therapy. Residual renal function was not different between the two groups. Mean Kt/Vurea in the CCPD group was 2.10/wk and that for the HD group was 1.20/session. The CCPD group and the HD group both had higher fasting glucose concentrations (p < 0.02), but normal fasting serum immunoreactive insulin concentrations compared with controls. The hyperinsulinemic euglycemic clamp technique was used to measure insulin sensitivity. Before dialysis, insulin sensitivity was low in both patient groups (CCPD 128 +/- 11 mg/m2/min; HD 130 +/- 11) compared with controls (320 +/- 26) (p < 0.01 in both cases) but not different between the patient groups. After 3 mo of dialysis therapy, insulin sensitivity increased by 80 +/- 7% in the CCPD group and by 38 +/- 4% in the HD group (p < 0.01 compared with predialysis values in both groups). Insulin sensitivity in both groups after 3 mo of dialysis was still lower than in the control group (p < 0.01 in both cases). However, both the percentage increase as well as the final insulin sensitivity were significantly higher in the CCPD group (230 +/- 19 mg/m2/min) than the HD groups (179 +/- 16) (p < 0.01 in both cases).

To determine whether anemia is important in the pathogenesis of metabolic abnormalities in insulin, amino acid, and lipid metabolism in uremia.Twelve adolescents (15 +/- 1 years of age) undergoing long-term dialysis were studied before and after correction of their anemia by human recombinant erythropoietin at a mean interval of 6 months. Six patients received hemodialysis, and six received continuous-cycling peritoneal dialysis. Insulin sensitivity was measured by the euglycemic clamp technique and insulin secretion by the hyperglycemic clamp technique in these patients.Hematocrit increased from 0.219 +/- 0.006 to 0.344 +/- 0.007 (p0.01). Ferritin concentration did not change significantly (11,252 +/- 356 mg/dl to 785 +/- 226 mg/dl). Serum iron concentration decreased from 134 +/- 13 mg/dl to 83 +/- 11 mg/dl, and percentage saturation decreased from 56 +/- 4 to 41 +/- 5 (p0.05 in both cases). There were no significant changes in weight, height, blood pressure, caloric intake, triceps skinfold thickness, or arm muscular area. There were also no significant changes in serum calcium, phosphate, bicarbonate, albumin, creatinine, or blood urea nitrogen concentration. Insulin sensitivity increased by 33% (p0.01), but insulin secretion did not change significantly. Insulin sensitivity during the euglycemic clamp studies in patients before erythropoietin therapy was lower (145 +/- 10 mg/m2 per minute; p0.01) than published normal values (201 +/- 12 mg/m2 per minute) and was normal after erythropoietin therapy (193 +/- 11 mg/m2 per minute). Insulin secretion was low in patients before erythropoietin therapy (44 +/- 8 microU/ml) compared with published normal values (68 +/- 6 microU/ml) and did not change after erythropoietin therapy (46 +/- 4 microU/ml). Plasma concentrations of branched-chain amino acids and lipids in the patients were compared with values from eight healthy adolescents. Plasma concentrations of valine, leucine, and isoleucine were low before treatment and were normal after 6 months of erythropoietin therapy. Plasma concentrations of triglycerides, total cholesterol, and low-density lipoprotein cholesterol were all high before treatment and were normal after treatment of anemia.Treatment of anemia by erythropoietin reversed insulin resistance as well as amino acid and lipid abnormalities in adolescents undergoing dialysis.

We studied glucose metabolism using the hyperglycemic technique in a cross-section of 23 children (15 pubertal, 8 prepubertal) with stable chronic renal failure as a possible cause of their poor growth. Linear growth was expressed as growth velocity standard deviation score (GVSDS). GVSDS correlated with glucose disposal rate but not with insulin sensitivity index in the pubertal (r = 0.87, P0.001) and prepubertal (r = 0.86, P0.02) children with chronic renal failure. Thirteen children were followed longitudinally during medical suppression of hyperparathyroidism with dietary phosphate restriction and high-dose phosphate binders. Following significant suppression of serum parathyroid hormone (PTH) levels back to the normal range (932 +/- 240 ng/l to 199 +/- 50 ng/l), GVSDS, glucose disposal rate and insulin secretion all increased significantly (p0.01), with no change in insulin sensitivity index and renal function. The changes in GVSDS correlated with the changes in glucose disposal rate (r = 0.86, P0.02) and with the changes in insulin secretion (r = 0.80, P0.01). However, the changes in GVSDS did not correlate with the changes in PTH. The hypothesis that insulin may be more important than PTH in the pathogenesis of growth failure in chronic renal disease deserves further investigation.

This report describes the serum osteocalcin values in children with mild to moderate, but relatively stable, renal dysfunction followed in the Growth Failure in Children With Renal Diseases Study. This report is derived from data obtained during the control period (6 months) before the initiation of vitamin D therapy. Up to three measurements per patient were obtained. Serum osteocalcin concentration was compared with creatinine clearance (glomerular filtration rate) calculated by the Schwartz formula; with serum concentrations of alkaline phosphatase, parathyroid hormone, and bicarbonate; and with the percentages of the recommended dietary allowances of calories and protein ingested. By standard correlation techniques, there appeared to be an inverse correlation between calculated creatinine clearance and serum osteocalcin concentration, and a direct correlation between serum osteocalcin and parathyroid hormone values. However, when we employed a statistical technique that takes into account repeated measures in the same patient, no correlation was found between calculated glomerular filtration rate and serum osteocalcin concentration, and no direct correlation was found between serum osteocalcin and parathyroid hormone values. The lack of a correlation between calculated glomerular filtration rate and serum osteocalcin values may be due to large fluctuations in the serum osteocalcin concentration, even though renal function is relatively stable.

The first reports of renal osteodystrophy came from Europe in the late 19th century. A case report by Davies Colley in 1883 probably represented the first ever description of renal rickets. Although these reports were mostly descriptive with little or no discussion of the pathophysiological relationship, some of the recommendations for treatment were amazingly insightful and would still be valid by today’s standards. The significance of dietary protein/phosphate restriction with vitamin D supplementation was already emphasized in these early days. Studies into the pathophysiology of renal rickets started in the early 20th century. A summary of the literature in the understanding of renal rickets is provided up to the 1940s.

The pathogenesis of growth failure in uremia is not clear. Male Sprague Dawley rats (100 g) underwent 5/6 nephrectomy. Uremic (U) rats gained less weight and length (p < 0.01) compared with sham-operated pair-fed control(C) rats over a 2 week period. Tibial epiphyseal chondrocytes were grown in 10% fetal calf serum (FCS) and then studied for 72 hr in serum free media(SFM) with various growth factors. In 10% FCS, U cells grew less well (p < 0.01) than C cells. Growth responses of U cells were reduced (p < 0.001) to insulin-like growth factor(IGF)-I at concentrations of 10, 30 and 100 ng/ml in SFM compared with C cells. However, growth of U cells was normal in response to fibroblast growth factor and transforming growth factor beta-1. Growth responses of U cells were reduced (p < 0.001) to des-IGF-I and long R3, IGF-I analogues with reduced affinity for IGF binding proteins (IGFBP). Western ligand blot of conditioned media from U cells showed decreased IGFBPs. Affinity cross-linking studies showed that IGF-I binding to the IGF-I receptor was normal in U cells. Also, IGF type I receptor mRNA (RNase protection assay) and protein (immunoblot) was normal in U cells. Tyrosine phosphorylation of insulin receptor substrate 1 was reduced in U cells. Thus growth failure in uremia is associated with specific end-organ IGF-I resistance of epiphyseal chondrocytes. This resistance is not due to increased local IGFBPs, nor to abnormal expression or binding affinity of the IGF type I receptor; but rather to abnormal signal transduction of the activated IGF type I receptor.

Glucose and insulin metabolism was studied in 16 adolescents with uremia on hemodialysis. Glucose tolerance was measured by i.v. glucose tolerance tests (IVGTT). Insulin sensitivity was measured by the euglycemic clamp technique. Insulin secretion during constant hyperglycemia was measured by the hyperglycemic clamp technique. Controls consisted of eight healthy young adults. These patients could be further subdivided into two groups with respect to their growth velocity SD score (GVSDS). Group one consisted of eight patients with GVSDS more than —2. This group had normal l,25(OH)2D3 and demonstrated insulin resistance, hyperinsulinemia, and normal glucose tolerance when compared with adult controls. Group two consisted of eight patients with GVSDS less than —2. This latter group had low l,25(OH)2D3, insulin resistance, but normoinsulinemia and glucose intolerance compared with adult controls. Published data in the literature showed that normal pubertal adolescents demonstrated insulin resistance and hyperinsulinemia compared with normal adults. Compared with normal values of insulin sensitivity in adolescents, both groups of patients on hemodialysis were still insulin resistant. The insulin secretion values in group one was similar to reported values for normal adolescents, whereas the values in group two were lower. GVSDS correlated significantly only with insulin secretion and not with glucose tolerance, insulin sensitivity, l,25(OH)2D3, or PTH. Normal adolescents demonstrate an increase in insulin secretion as they go into puberty. It seems that the puberty growth spurt in adolescents both with normal health and renal failure may require increased insulin secretion as one of its hormonal requirements.