Search

Background: Insulin-like growth factor-1 (IGF-1) is an anabolic hormone that mediates most of the growth effects of growth hormone. This study tested the hypothesis that recombinant human IGF-1 (rhIGF-1) will induce an anabolic response in malnourished patients undergoing continuous ambulatory peritoneal dialysis (CAPD)., Methods: Six CAPD patients with protein-energy malnutrition underwent nitrogen balance studies in a clinical research center for 35 days each. Throughout the study, patients were maintained on their same CAPD regimen prior to hospitalization, and were fed a constant protein and energy intake that was similar to their diet prior to hospitalization. The first 15 hospital days were a baseline period; during the subsequent 20-day period, patients were given subcutaneous injections of rhIGF-1 (100 microg/kg/12 h), except for one patient who received 50 microg/kg/12 h for the first five days, followed by 100 microg/kg/12 h for the following 15 days., Results: During the treatment with rhIGF-1, serum IGF-1 increased by about 100% (P = 0.03), and nitrogen balance became strongly positive (+2.0 g/day, P = 0.015 vs. baseline). This anabolic effect was observed within hours after commencing the rhIGF-1 treatment and was largely caused by a 20% decrease in peritoneal dialysate effluent nitrogen. There was a proportionate reduction in urine nitrogen and serum urea nitrogen. This decrease in nitrogen output was sustained during the entire 20 day of treatment with rhIGF-1. Serum phosphorus decreased significantly during the first several days of rhIGF-1 treatment, whereas serum calcium increased significantly during the rhIGF-1 treatment. Serum potassium and albumin did not change during the rhIGF-1 injections. There was no change in body weight and body composition, as assessed by anthropometry during the baseline or treatment phases of the study. Some patients exhibited minor possible adverse events that included a reduction in blood pressure and transient tachycardia., Conclusion: Injections of rhIGF-1 induce a strong and sustained anabolic effect, as indicated by a positive nitrogen balance in CAPD patients with protein-energy malnutrition. rhIGF-1 administration may be an effective method for treating malnutrition in maintenance dialysis patients.

Background: Patients with acute renal failure (ARF) have high morbidity and mortality rates, particularly if they have serious comorbid conditions. Several studies indicate that in rats with ARF caused by ischemia or certain nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal function and suppresses protein catabolism., Methods: Our objective was to determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance the recovery of renal function and is safe in patients with ARF. The study was designed as a randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals. Seventy-two patients with ARF were randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of patients). At baseline, the mean (+/- SD) APACHE II scores in the rhIGF-I and placebo-treated groups were 24 +/- 5 and 25 +/- 8, respectively. In the rhIGF-I and placebo groups, the mean (median) urine volume and urinary iothalamate clearances (glomerular filtration rate) were 1116 +/- 1037 (887) and 1402 +/- 1183 (1430) ml/24 hr and 6.4 +/- 5.9 (4.3) and 8.7 +/- 7.2 (4.4) ml/min and did not differ between the two groups. Patients were injected subcutaneously every 12 hours with rhIGF-I, 100 microgram/kg desirable body weight, or placebo for up to 14 days. Injections were started within six days of the onset of ARF. The primary end-point was a change in glomerular filtration rate from baseline. Other end points included changes from baseline in urine volume, creatinine clearance and serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or ultrafiltration, and mortality rate., Results: During the treatment period, which averaged 10.7 +/- 4.1 and 10.6 +/- 4.5 days in the rhIGF-I and placebo groups, there were no differences in the changes from baseline values of the glomerular filtration rate, creatinine clearance, daily urine volume, or serum urea nitrogen, creatinine, albumin or transferrin. In patients who did not receive renal replacement therapy, there was also no significant difference in serum creatinine and urea between the two groups. Twenty patients in the rhIGF-I group and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve rhIGF-I-treated patients and 12 placebo-treated patients died during the 28 days after the onset of treatment., Conclusions: rhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity.

Rats and humans with chronic renal failure (CRF) are reported to have resistance to recombinant human insulin-like growth factor-1 (rhIGF-1). Because basal cytosolic calcium ([Ca2+]i), a second messenger, may be increased in CRF, this study was conducted to examine whether elevated basal [Ca2+]i may cause resistance to IGF-1. Cardiomyocytes from four groups of rats were studied: untreated CRF, CRF with parathyroidectomy (PTX), CRF with the calcium channel blocker felodipine (F), and sham operation of the kidney (SO). CRF was created by ligation of two-thirds of the left renal artery and contralateral nephrectomy. Rats from each group were pair-fed the same diet for 20 to 22 d. Basal [Ca2+]i in cardiomyocytes (nM) in the CRF rats (102.0 +/- 2.8; SEM), was significantly higher than in each of the CRF-PTX, CRF-F, and SO groups (65.2 +/- 1.9, 63.8 +/- 2.6, and 63.5 +/- 2.0, respectively; P < 0.01). rhIGF-1 increased cardiomyocyte [Ca2+]i in all four groups of rats. The rise in [Ca2+]i was significantly diminished in the CRF rats (P < 0.05) and did not differ among the CRF-PTX, CRF-F, and SO rats. Protein synthesis after incubation with 0, 50, 100, 200, or 400 ng/ml rhIGF-1 was lower in cardiomyocytes from CRF rats than in each of the other three groups (P < 0.05) and was significantly less in the CRF-F rats compared with SO animals. IGF-1 receptor mRNA and IGF-1 receptor number and affinity were not different among the four groups. These findings suggest that cardiomyocytes from CRF rats display elevated basal [Ca2+]i and attenuated rhIGF-1-induced increase in [Ca2+]i; basal protein synthesis is decreased, and IGF-1-stimulated protein synthesis is impaired; elevated basal [Ca2+]i seems to contribute to this diminished response to rhIGF-1.

Background: Recombinant human insulin-like growth factor-I (rhIGF-I) accelerates recovery from acute renal failure (ARF) in rats. IGF-I acts through the IGF-I receptor (IGF-IR) and its actions may be modified by IGF-I binding proteins (IGFBPs). It therefore would be of value to determine the effects of both ARF and rhIGF-I treatment on serum IGFBPs and mRNA for IGFBPs and IGF-IR., Methods: Rats with ARF and sham-operated control rats were randomized to receive rhIGF-I or vehicle injections thrice daily for 72 to 74 hours starting five hours after surgery. Serum IGFPBs 1 to 6 were measured serially, and mRNA for IGFBPs 1 to 6 and for IGF-IR were measured in several tissues obtained 72 to 74 hours after surgery., Results: At 72 to 74 hours, serum IGFBP-1 and IGFBP-2 levels were higher in rhIGF-I treated rats. Serum IGFBP-3 was affected by both ARF and rhIGF-I. IGFBP-4 rose transiently only in ARF groups. At 72 to 74 hours, mRNA for several IGFBPs was reduced in renal cortex of ARF rats. Low mRNA for IGFBP-4 and -6 was observed in renal medulla of the ARF rats, particularly in comparison to the sham-operated rats receiving vehicle. Renal medullary IGFBP-2 mRNA was decreased in ARF and sham rats given rhIGF-I as compared to sham animals given vehicle. Hepatic IGFBP-2 mRNA was higher in both rhIGF-I treated groups versus those given vehicle. Otherwise, there were no differences in IGFBP mRNAs among the four groups in lung, heart, and skeletal muscle. IGF-IR mRNA was decreased in renal cortex and medulla of both ARF groups and was not detected in liver in any group., Conclusions: Thus, ARF and rhIGF-I treatment each affected certain serum IGFBPs and jointly affected some IGFBPs. ARF suppressed gene transcription for renal cortical and medullary IGF-IR and some IGFBPs. rhIGF-I independently affected some renal cortical or medullary IGFBP mRNAs. rhIGF-I increased hepatic IGFBP-2 mRNA and serum IGFBP-2. These effects of ARF or rhIGF-I may influence rhIGF-I actions in rats with ischemic ARF.

The actions of insulin-like growth factor 1 (IGF-1) on protein turnover and of the IGF-1 receptor (IGF-1R) were examined in skeletal muscle of rats with chronic renal failure (CRF) and sham operated (SO), pair-fed controls. Acidemia was prevented in CRF rats with NaHCO3. Serum IGF-1 and skeletal muscle IGF-1 and IGF-1 mRNA were reduced in CRF rats. Dose-response studies revealed impaired stimulation of protein synthesis and suppressed inhibition of protein degradation by IGF-1 in epitrochlearis muscle of CRF rats. Neither IGF-1 analogues with low affinity to IGF binding proteins nor proteinase inhibitors obliterated the IGF-1 resistance. In CRF rats, skeletal muscle IGF-1R mRNA was increased; displacement ligand binding studies and affinity labeling of the IGF-1R alpha subunit indicated increased total skeletal muscle IGF-1R number with normal affinity. However, both autophosphorylation of the IGF-1R beta subunit (i.e., IGF-1R tyrosine kinase) and the IGF-1R tyrosine kinase activity towards exogenous insulin receptor substrate-1, a natural substrate for IGF-1R tyrosine kinase, were reduced in CRF fats. These data indicate that in skeletal muscle of CRF rats there is resistance to the IGF-1 effects on protein synthesis and degradation and decreased IGF-1 and IGF-1 mRNA levels; IGF-1R mRNA and number are increased; but activity of IGF-1R tyrosine kinase is impaired. This postreceptor defect may be a cause of the skeletal muscle resistance to IGF-1 in CRF.

The effects of insulin-like growth factor 1 (IGF-1) on renal handling of phosphorus, calcium, and sodium were evaluated in eight healthy men while they lived in a clinical research center for slightly more than 5 days. Subjects received a continuous intravenous infusion throughout the study of 0.45% saline and 2.5% d-glucose at 50 mL/hr (group 1, four subjects) or 150 mL/hr (group 2, four subjects). Recombinant human IGF-1 (rhIGF-1), 60 micrograms/kg body weight, was injected subcutaneously three times daily for 10 doses from day 2 until the beginning of day 5. After commencing the rhIGF-1 injections, there was a marked decrease in the fractional excretion of phosphorus in both groups that was sustained throughout the study. Urine phosphorus excretion also decreased significantly on days 2 to 5 in group 1 and on day 2 in group 2. In group 1, the fractional excretion of calcium decreased on day 2; urine calcium did not change. The fractional excretion of sodium decreased on days 2 and 4; urine sodium decreased significantly only on day 2. In group 2, the fractional and absolute urine excretion of calcium did not change. Fractional sodium excretion was not altered, and urine sodium increased only on day 5. The average serum phosphorus, calcium, and sodium did not change from baseline in groups 1 or 2. The pattern of the circadian rhythms for serum concentrations, urine excretion, and fractional excretion of phosphorus and calcium did not appear to be affected by the rhIGF-1 injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic renal failure is associated with abnormalities of skeletal muscle that include reduction in size, fibrosis, protein depletion, and functional disorders. These disorders may be caused by several factors, including protein-calorie malnutrition, acidemia, and superimposed illnesses. However, animal research suggests that these abnormalities may occur with chronic renal failure per se in the absence of the above complications. Insulin-like growth factor 1 (IGF-1) is an anabolic hormone that, in skeletal muscle, stimulates intracellular amino acid and glucose transport and protein synthesis, suppresses protein degradation, and causes hypertrophy. In chronic renal failure, there is evidence for inhibition of the actions of IGF-1. Studies in humans with chronic renal failure given a subcutaneous injection of recombinant human IGF-1 (rhIGF-1) indicate that the rhIGF-1 induced acute suppression of plasma amino acids, insulin, and C peptide is impaired. In skeletal muscle of rats with chronic renal failure, we observed reduced IGF-1 and IGF-1 mRNA levels, resistance to the rhIGF-1-induced suppression of protein degradation, and stimulation of protein synthesis, increased IGF-1 receptor mRNA and IGF-1 receptor number and impaired receptor tyrosine kinase activity. These findings suggest that in skeletal muscle in chronic renal failure there are several abnormalities in the physiology of IGF-1 and the sensitivity to IGF-1. It is possible that these alterations contribute to the disorders of skeletal muscle structure and function in chronic renal failure. Notwithstanding these abnormalities, repeated subcutaneous injections of rhIGF-1 in malnourished patients undergoing continuous ambulatory peritoneal dialysis led to strongly positive nitrogen balance that was sustained for the 20 days of study.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human insulin-like growth factor-1 (rhIGF-1) is currently used experimentally to treat patients with insulin-resistant diabetes mellitus, impaired growth, protein malnutrition, and osteoporosis. We report here the case of a marked transient alteration in consciousness in a healthy 22-year-old man who was given an IV infusion of a relatively low dose of rhIGF-1 for 1 hour. This individual developed the sudden onset of dizziness, nausea, coldness, air hunger, and pallor. He became unresponsive to simple questions and experienced diaphoresis, a feeling of warmth, and paresthesias. Although there was a mild fall in heart rate and blood pressure, these hemodynamic effects did not appear sufficient to cause the altered mentation. There were no changes in serum glucose, phosphorus, or potassium that could seem to account for these events. This individual recovered completely several minutes after stopping the rhIGF-1 infusion.

The acute metabolic effects of recombinant human insulin-like growth factor-1 (rhIGF-1) were studied after an overnight fast in six maintenance hemodialysis (MHD) patients, six chronic peritoneal dialysis (PD) patients and six normal subjects. Each subject received a subcutaneous injection of rhIGF-1, 50 or 100 micrograms/kg body wt, given in random order on two occasions separated by 7 to 21 days. After the rhIGF-1 injection, plasma insulin, C-peptide, cortisol, amino acids and glucose decreased. The magnitude of the decrease was greater with the larger rhIGF-1 dose. The fall in plasma insulin, C-peptide and many amino acid concentrations was less and the decrease in glucose was similar in the MHD and CAPD patients as compared to normals. With 50 micrograms rhIGF-1/kg, plasma insulin and C-peptide decreased more quickly and often to a greater magnitude in normal individuals. With 100 micrograms rhIGF-1/kg, the decrease in plasma insulin, C-peptide and amino acids in the MHD and CAPD patients was almost as frequent as in the normal subjects, but the magnitude of the fall was often significantly less. This impaired response occurred in both MHD and CAPD patients even though, with the 100 micrograms rhIGF-1/kg dose, their plasma IGF-1 was significantly higher than in normals during most of the first four hours after injection. These results provide the first in vivo evidence for resistance to the metabolic effects of rhIGF-1 in patients with advanced renal failure.

Six maintenance hemodialysis (MHD), six continuous ambulatory peritoneal dialysis (CAPD) and six normal adults underwent pharmacokinetic studies of insulin-like growth factor-1 (IGF-1). Each subject received two separate subcutaneous injections of recombinant human IGF-1 (rhIGF-1) (50 or 100 micrograms/kg) in random order separated by 7 to 21 days. Two different responses were observed. With the 50 micrograms/kg dose, serum IGF-1 levels and the pharmacokinetic parameters were not different between the three groups. With the 100 micrograms/kg dose, peak serum IGF-1 concentrations were significantly greater in the MHD and CAPD patients than in normals. However, by 12 to 14 hours after injection, serum IGF-1 was not different in the three groups. Although the Tmax, area under the curve and serum clearance of IGF-1 were similar in the three groups, the half-life and volume of distribution of rhIGF-1 was significantly decreased in both MHD and CAPD patients. These data indicate that IGF-1 pharmacokinetics are abnormal in maintenance dialysis patients.

This study evaluated whether recombinant human insulin-like growth factor-I (rhIGF-I) enhances recovery of renal function and reduces catabolism in rats with ischemic acute renal failure (ARF). ARF and sham rats received subcutaneous injections of either rhIGF-I or vehicle three times daily starting 5 h after surgery. Serum creatinine and urea, which initially rose similarly in the ARF+vehicle and ARF+rhIGF-I rats, increased more slowly after commencing the rhIGF-I injections. 72 h after surgery, the ARF+rhIGF-I rats, in comparison with ARF+vehicle animals, showed significantly greater renal plasma flow and filtration fraction, a fivefold higher glomerular filtration rate, greater renal cortical IGF-I levels, increased proliferating cell nuclear antigen expression in proximal tubule nuclei and enhanced DNA synthesis in the renal cortex, corticomedullary junction, glomeruli, and tubules as demonstrated by [3H]thymidine incorporation and in corticomedullary junction tubules as determined by autoradiography. Estimated total nitrogen output (ETNO) was greater in ARF+vehicle than in ARF+rhIGF-I or sham rats throughout the study. ETNO in ARF+rhIGF-I rats returned to sham values by the second day after surgery. 72 h after surgery, protein degradation was increased and protein synthesis reduced in the epitrochlearis muscle of ARF+vehicle as compared with ARF+rhIGF-I or sham+vehicle rats. Thus, treatment with rhIGF-I starting 5 h after inducing ischemic ARF in rats increases recovery of renal function, enhances formation of new renal tubular cells, lowers protein degradation, and increases protein synthesis in skeletal muscle and reduces net catabolism.

Acute and chronic studies in rats have shown that administration of human recombinant insulin-like growth factor I (rhIGF-I) lowers renal vascular resistance and increases RPF, GFR and proximal tubular phosphate absorption. In the present study we examined the effects of subcutaneous injections of rhIGF-I on glomerular and tubular function in eight normal men. Individuals were studied for 5.5 consecutive days in a clinical research center while they ate a constant diet. Four subjects were studied in a non-volume expanded state (Group 1) and four individuals were evaluated during a saline load. From the second to the fourth day, subjects received subcutaneous injections of rhIGF-I, 60 micrograms/kg, at 0800, 1400 and 2000 hours. After commencing the rhIGF-I injections, serum IGF-I levels rose quickly and remained at about three to four times that of baseline throughout the period of rhIGF-I injections. In both the normal and the saline loaded subjects, renal vascular resistance decreased and RPF and GFR (PAH and inulin clearances) rose quickly and were clearly altered within six hours after starting the rhIGF-I injections. RPF had increased by 32 +/- 3% and 33 +/- 2% (grand mean +/- SEM) in the normal and the saline loaded subjects, and GFR rose by 22 +/- 3% and 36 +/- 4% in the two groups. In both groups the absolute and the fractional excretion of phosphate decreased markedly during rhIGF-I treatment, but the absolute and fractional excretion of calcium did not change. The urinary fractional and absolute excretion of albumin and IgG also increased, although slightly, with rhIGF-I injections. There was no consistent effect of IGF-I on tubular sodium handling. These findings demonstrate that in normal men subcutaneous injections of rhIGF-I greatly increase RPF, GFR, and tubular phosphorus reabsorption and enhances microproteinuria.

This study examined whether maneuvers that chronically raise or lower serum insulin-like growth factor I (IGF-I), within physiological and pathophysiological ranges, will affect glomerular hemodynamics. Pair-fed Munich Wistar rats received, for 6 to 7 days, continuous s.c. infusions of human recombinant IGF-I (rhIGF-I; 125 micrograms/day), vehicle, or s.c. injection of a synthetic growth hormone-releasing hormone antagonist (GHRH-ANT) (N = 7 in each group). Infusion of rhIGF-I raised serum IGF-I to about 180% of control values, and GHRH-ANT injections lowered serum IGF-I to about 33% of control. The IGF-I infusion induced an increase in left kidney weight when expressed in absolute units but not when expressed as a percentage of body weight; there was also an increase in glomerular volume in the IGF-I treated rats. GFR, single nephron GFR, and single nephron plasma flow also rose with IGF-I infusion, and these changes were associated with decreased afferent and efferent arteriolar resistance and increased glomerular ultrafiltration coefficient. GHRH-ANT injection did not affect kidney weight or glomerular volume; however, GFR, single nephron GFR, and single nephron plasma flow were reduced in association with an increase in efferent arteriolar resistance. There also was a tendency, not significant, for the glomerular ultrafiltration coefficient to decrease. The findings that a low dose of rhIGF-I, which raised the serum IGF-I only modestly, increased glomerular ultrafiltration and that reducing serum IGF-I below control values decreased glomerular dynamics suggest that physiological or pathophysiological changes in IGF-I may affect and possible help to regulate glomerular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Since the development of recombinant DNA technology, there has been a rapid expansion of research concerning the use of recombinant DNA synthesized human growth hormone (rhGH) for the treatment of clinical disorders. rhGH has been used to treat patients with acute catabolic stress caused by surgery, trauma and sepsis, children with chronic renal insufficiency and impaired growth, patients undergoing maintenance hemodialysis who are malnourished, and individuals on weight reduction diets. These studies indicate that rhGH enhances protein balance in acutely stressed patients and in malnourished maintenance hemodialysis patients, promotes catch-up growth in children with chronic renal failure, and may reduce protein wasting and enhance lipolysis in obese individuals on weight reduction diets. Experimental studies suggest that in addition to enhancing anabolism, rhGH may increase both immune function and the rate of wound healing. Many, but not all, of the effects of rhGH are mediated through insulin-like growth factor I (IGF-I). For example, the hyperglycemic and lipolytic effects of rhGH do not seem to be caused by IGF-I. Animal or human studies suggest that with severe malnutrition or severe sepsis, rhGH treatment may neither increase serum IGF-I levels nor promote anabolism. These observations provide a rationale for administering IGF-I as an anabolic hormone for severely malnourished or septic patients with renal failure. Further studies will be necessary to examine both the short-term and long-term potential benefits and adverse effects of rhGH or rhIGF-I treatment in these conditions.

This study was undertaken to investigate the mechanisms by which an infusion of recombinant human insulin-like growth factor I (rhIGF-I) increases GFR and renal plasma flow (RPF) in rats. Glomerular micropuncture studies were carried out in 14 nonstarved Munich Wistar rats and in 12 rats deprived of food for 60-72 h. Animals were given an intravenous injection and infusion of either rhIGF-I or vehicle. In both nonstarved and starved animals, the IGF-I injection and infusion increased the serum IGF-I levels, left kidney GFR, single nephron glomerular filtration rate (SNGFR), single nephron blood flow rate (SNBF), and single nephron plasma flow rate (SNPF). The increase in SNPF and SNGFR was in part due to a fall in efferent arteriolar resistance (RE); there was a tendency, not significant, for afferent arteriolar resistance (RA) to fall in comparison to controls. The increase in SNGFR was partly caused by a rise in SNPF but was primarily due to an increase in glomerular ultrafiltration coefficient (LpA) to twice the control values. The increase in LpA resulted in an increase in SNGFR because the rats operated at ultrafiltration pressure disequilibrium. Control starved as compared with nonstarved rats had lower SNGFR, SNBF, and SNPF. This reduction was due to a tendency, not significant, for both RA and RE to be higher. Decreased SNGFR in food-deprived rats resulted from a reduced SNPF, a lower glomerular transcapillary hydrostatic pressure difference (delta P), and possibly a somewhat reduced LpA. These data indicate that IGF-I increases SNGFR, SNPF, and SNBF primarily by increasing LpA and also by decreasing RE without affecting delta P. Short-term starvation lowers SNGFR, SNPF, and SNBF primarily by decreasing delta P and possibly by lowering LpA and increasing RA and RE. IGF-I reverses some of the glomerular hemodynamic effects of short-term food deprivation.

An increase in plasma insulin-like growth factor I (IGF-I) levels by growth hormone injection or IGF-I infusion can raise renal plasma flow and glomerular filtration rate. However, it is not known whether a more physiological stimulus for IGF-I will also increase IGF-I in the kidney and whether the increase in renal or serum IGF-I is correlated with the increase in renal plasma flow and glomerular filtration rate. Male rats were pair fed either a high-protein (36% protein, N = 9) or a low-protein but isocaloric diet (9% protein, N = 9) for 10 to 14 days. Renal plasma flow and glomerular filtration rate were then estimated by clearance measurements, and IGF-I was measured in extracted serum, liver, renal cortical tissue, and glomeruli. Body weight gain and combined kidney weight were higher in high-protein rats as compared with low-protein animals (0.86 +/- 0.02 SEM versus 0.77 +/- 0.02 g/100 g body wt; P less than 0.05), but liver weights were not different. Serum, liver, and glomerular IGF-I levels were also higher in the high-protein rats as compared with the low-protein animals (serum, 1.12 +/- 0.03 versus 0.80 +/- 0.06 U/mL, P less than 0.05; liver, 183 +/- 17 versus 117 +/- 16 mU/g wet wt, P less than 0.05; glomeruli, 7.43 +/- 0.73 versus 4.81 +/- 0.59 mU/mg of protein, P less than 0.05). In contrast, the renal cortical IGF-I levels were not different in high-protein versus low-protein rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone increases renal plasma flow and glomerular filtration rate and reduces total renal vascular resistance. Evidence presented in this paper indicates that these effects of growth hormone are mediated by insulin-like growth factor I (IGF-I). Published literature indicates that growth hormone and IGF-I have a number of other physiological and morphological effects on the kidney. Further studies are indicated to evaluate under which conditions growth hormone and IGF-I are regulators of kidney function, and to identify the mechanisms of action. In addition, the role of both hormones, if any, in the development of progressive glomerular sclerosis and renal failure needs to be explored.

The mechanisms whereby growth hormone may increase renal plasma flow (RPF) and GFR are not known, but circumstantial evidence has implicated insulin-like growth factor I (IGF-I) as a mediator of this effect. This study examined whether an infusion of IGF-I will increase RPF and GFR, whether this effect occurs quickly, and if this effect is dependent on eicosanoids or peptide hormones known to affect renal function. Rats fasted for 3 d to reduce IGF-I and IGF-I plasma binding proteins were anesthetized; then the rats received an intravenous injection of 25 micrograms/kg IGF-I, and an infusion of 25 micrograms/kg IGF-I within 20 min. Controls received infusion of the vehicle. RPF (para-aminohippurate clearances), GFR (inulin clearances), renal vascular resistance (RVR), mean arterial blood pressure (MABP), plasma IGF-I, and glucose concentrations were measured repeatedly. At the end of the 20-min infusion, plasma IGF-I tended to be increased in the animals that received IGF-I (P = 0.069), but did not increase in the control rats. IGF-I induced a significant and sustained fall in RVR and rise in RPF and GFR without any change in MABP. A small, transient, but significant decrease in plasma glucose concentrations was observed during IGF-I but not during vehicle infusion. Indomethacin, but not somatostatin, blocked the renal response to IGF-I infusion. Thus, IGF-I infusion increases RPF and GFR and reduces RVR in fasted rats. This effect requires the presence of eicosanoids but does not seem to require other peptide hormones suppressed by somatostatin.

The temporal relationships between the changes in inulin and p-aminohippurate clearances and plasma growth hormone (GH) and insulin-like growth factor I (IGF I levels were examined in a man with hypothalamic GH deficiency before and during the first 6 days of treatment with daily GH injections. The patient ate a diet with a constant protein and salt content from 1 week before the study until it was completed. During the 4-hour period immediately after the first GH injection, plasma GH rose markedly, but plasma IGF I was not detectable, and effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) did not change from baseline. On the next day, before the second GH injection was given, plasma GH was only slightly elevated, plasma IGF I had increased, and ERPF and GFR had risen by +35.5 +/- 2.1% (SEM) and +22.7 +/- 2.8%, respectively. On the 4th and 7th days, immediately before the GH injections, there was no further rise in ERPF and GFR, both of which remained well above baseline values. At these times, plasma GH levels were at baseline, but plasma IGF I continued to rise progressively. These data are consistent with the thesis that the low ERPF and GFR in GH deficiency is due to the lack of synthesis of IGF I rather than the deficiency in GH per se. The data are also consistent with a stimulatory effect of IGF I on ERPF and GFR.