Growth hormone treatment for patients with renal failure.
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Blood Urea Nitrogen↗
Biomedical subjects
R Hirschberg
Publications and source records attributed to R Hirschberg.
Multicenter trial of L-carnitine in maintenance hemodialysis patients. I. Carnitine concentrations and lipid effects.
Previous studies have reported conflicting results of carnitine supplementation on plasma lipids in patients with chronic renal failure. We therefore performed a four center, double-blind placebo controlled trial to evaluate the effects of post-hemodialysis intravenous injection of L-carnitine in ESRD patients on maintenance hemodialysis. Thirty-eight patients received up to six months of L-carnitine infusions (20 mg/kg) post-dialysis and 44 patients received placebo infusions. In both groups of patients, baseline pre-dialysis plasma and red blood cell total carnitine levels were normal, but pre-dialysis plasma-free carnitine concentrations and free/total ratios were subnormal, and plasma acyl levels were elevated. Post-dialysis plasma free and total carnitine concentrations were also subnormal. Plasma and red blood cell total carnitine levels rose eightfold in carnitine recipients, but were unchanged from baseline in those receiving placebo. There were no significant changes observed in plasma triglycerides, HDL-cholesterol or other lipoprotein parameters in either the carnitine or placebo treated groups. We conclude that carnitine metabolism is altered in uremia. Furthermore, in a randomly-selected hemodialysis population, L-carnitine injection at the dose of 20 mg/kg results in significant increases in blood (and perhaps tissue) carnitine levels, but this is not associated with any major effects on lipid profiles.
Carnitine↗
Multicenter trial of L-carnitine in maintenance hemodialysis patients. II. Clinical and biochemical effects.
Since carnitine deficiency has been reported in some patients undergoing maintenance hemodialysis, we studied the effects of intravenous infusion of L-carnitine or placebo at the end of each dialysis treatment. The trial, which lasted seven months (one month baseline, 6 months treatment) was multicenter, double blind, placebo controlled, and randomized. Eighty-two long-term hemodialysis patients, who were given either carnitine (N = 38) or placebo (N = 44), completed this study. In each group, clinical and biochemical parameters during treatment were compared with baseline values. Intra-dialytic hypotension and muscle cramps were reduced only in the carnitine treated group, while improvement in post-dialysis asthenia was noticed in both carnitine and placebo groups. Maximal oxygen consumption, measured during a progressive work exercise test, improved significantly in the carnitine group (111 +/- 50 ml/min. P less than 0.03) and was unchanged in the placebo group. L-carnitine treatment was associated with a significant drop in pre-dialysis concentrations of serum urea nitrogen, creatinine and phosphorus (means +/- SEM, 101 +/- 4.5 to 84 +/- 3.9, 16.7 +/- 0.67 to 14.7 +/- 0.64, and 6.4 +/- 0.3 to 5.5 +/- 0.4 mg/dl, respectively, P less than 0.004). No significant changes in any of these variables were noticed in the placebo group. Mid-arm circumference and triceps skinfold thickness were measured in 11 carnitine and 13 placebo treated patients. Calculated mid-arm muscle area increased in the carnitine patients (41.37 +/- 2.68 to 45.6 +/- 2.82 cm2, P = 0.05) and remained unchanged in the placebo patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Carnitine↗
Physiological effects of growth hormone and insulin-like growth factor I on the kidney.
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.
Gonadotropins↗
The delayed effect of growth hormone on renal function in humans.
Growth hormone is reported to increase renal plasma flow (RPF) and glomerular filtration rate (GFR) in some but not all studies. The discrepant results could be due to a delay in the effects of growth hormone on renal function. We therefore examined whether a growth hormone injection does increase RPF and GFR, whether this increase is delayed, and whether elevation in RPF and GFR is associated with increased plasma levels of insulin-like growth factor I (IGF-I). Seven normal adults received a single intramuscular injection of growth hormone, 0.15 mg/kg, and serial PAH and inulin clearances were then monitored for three consecutive days. Plasma growth hormone levels peaked an average of 2.25 hours after injection, at 128 +/- 12 SEM ng/ml, and then began to decrease; on the second day values were only slightly elevated and on the third day they were not different from baseline. Plasma IGF-I, analyzed by direct radioimmunoassay, did not change on the first day during 5.5 hours of measurements after injection. By the second day, plasma IGF-I was elevated to over twice baseline levels (P less than 0.05) and remained elevated on the third day (P less than 0.05). RPF and GFR did not change from baseline (546 +/- 19 and 100 +/- 3 ml/min/1.73 m2, respectively) during the 5.5 hours after injection on the first day.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Changes in gene expression during nitrogen starvation in Anabaena variabilis ATCC 29413.
When the filamentous, nitrogen-fixing cyanobacterium Anabaena variabilis ATCC 29413 was subjected to nitrogen starvation under aerobic conditions, a complex series of events was initiated which resulted in heterocyst formation and derepression of the ability to fix dinitrogen. Using DNA-RNA hybridization techniques, we monitored the expression of several genes during nitrogen starvation and correlated changes in the mRNA levels with changes in enzyme activity, protein levels, and morphology. Nitrogenase mRNA was first observed after about 8.5 h of nitrogen starvation, as was nitrogenase activity. Late proheterocysts were present at that time. The level of nitrogenase mRNA increased for 5 to 6 h and then leveled off. Phycocyanin and allophycocyanin mRNA levels decreased rapidly within 1 h of nitrogen starvation; the levels increased later, as nitrogen starvation was alleviated, first by protein breakdown and then by nitrogen fixation. The average half-life of A. variabilis mRNA was determined by pulse-labeling techniques to be 16 to 18 min. Hybridization analysis showed that cpc and apc mRNAs also had half-lives of 16 to 18 min; the half-lives were not significantly different under nitrogen starvation conditions. Our results support the idea that the changes induced by nitrogen starvation are primarily the result of transcriptional regulation.
Aerobiosis↗
Cyclosporine augments renal mitochondrial function in vivo and reduces renal blood flow.
The in vivo action of cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS (30 mg.kg-1.day-1) given orally to rats for 30 days caused an augmentation of renal mitochondrial oxidative phosphorylation. The ADP-stimulated respiratory rate was increased by 37.0% with glutamate plus malate as respiratory substrates (P less than 0.025) but not with succinate-supported respiration, indicating enhancement of mitochondrial complex I activity. This reaction may be a response to the 32.5% reduction of renal blood (P less than 0.005) in the CS-treated group, possibly serving to maximize ATP synthesis during ischemia. Ligation-induced decreases in renal blood flow also resulted in enhancement of mitochondrial complex I activity.
Animals↗
Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats.
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.
Animals↗
Effects of growth hormone and IGF-I on renal function.
There have now been many studies on the effects of growth hormone (GH) on renal function. Chronically elevated GH levels, such as occur in acromegaly, are associated with an increase in renal plasma flow (RPF), glomerular filtration rate (GFR) and kidney size. When GH falls in these individuals (such as, after hypophysectomy in acromegalic patients), RPF, GFR and renal size decrease. A rapid increase in plasma GH in normal or growth hormone deficient adults, such as occurs after GH injection, causes an increase in RPF and GFR. However, these effects on renal function are delayed, occurring between 5.5 and 23 hours after the GH injection and in association with an elevation in the plasma concentrations of insulin-like growth factor I (IGF-I). These observations suggest that IGF-I may mediate the GH stimulated increase in RPF and GFR. We evaluated this question in rats starved for three days. A 20 minute infusion of IGF-I causes an increase in RPF and GFR in these animals. This effect could be blocked by indomethacin but not by somatostatin. These findings suggest that: 1) GH injection does increase RPF and GFR; 2) this effect on GH, which is delayed for several hours seems to be mediated by IGF-I; and 3) a 20-minute IGF-I infusion itself increases RPF and GFR in starved rats. The effect of IGF-I on renal function seems to require the presence of eicosanoids. Further studies will be necessary to examine whether IGF-I is a physiological regulator of renal function.
Adult↗
Regulation of nitrogenase gene expression in anaerobic cultures of Anabaena variabilis.
Derepression of nitrogenase gene expression was studied at the mRNA and enzyme activity levels in anaerobic cultures of Anabaena variabilis 29413. Cells, previously grown with ammonium chloride, were incubated in the absence of fixed nitrogen compounds under an Ar atmosphere with dichlorophenyldimethyl-urea present to inhibit oxygen evolution. The appearance of nitrogenase mRNA (measured by dot blot hybridization analysis) and nitrogenase activity (measured as acetylene-reducing activity) was followed, and the cells were also observed by phase-contrast microscopy. Nitrogenase mRNA could be detected after 1.5 to 2.0 h of nitrogen starvation; enzyme activity appeared about 1 h later. Although enzyme activity increased for many hours, mRNA levels reached a steady state rapidly. Neither heterocysts nor proheterocysts formed under these conditions; however, the cells were observed to shrink and become chlorotic. When anaerobic, derepressed cultures were exposed to oxygen, nitrogenase mRNA levels decreased very rapidly.
Anaerobiosis↗
Effect of nitrogenous compounds on nitrogenase gene expression in anaerobic cultures of Anabaena variabilis.
The effects of several organic and inorganic nitrogen compounds on nitrogenase mRNA and enzyme activity levels were examined in anaerobic cultures of Anabaena variabilis 29413. Even low concentrations of exogenous ammonia (20 microM) prevented nitrogenase gene expression. Nitrate, in contrast, had little effect, even at very high concentrations. Neither compound had a significant direct effect on existing enzyme activity. The amino acids glutamine and glutamate did not repress nif gene expression. Methionine sulfoximine, but not 7-azatryptophan, was shown to eliminate the repressive effect of ammonia, and this action occurred at the mRNA level. Low concentrations of carbamyl phosphate caused a rapid decrease in nitrogenase mRNA levels. These results are consistent with the ideas that nif gene regulation in Anabaena spp. occurs primarily at the mRNA level and that ammonia, and possibly also glutamine and glutamate, is not the immediate effector of regulation.
Ammonia↗
Structure and regulation of genes encoding phycocyanin and allophycocyanin from Anabaena variabilis ATCC 29413.
Gene clones encoding phycocyanin and allophycocyanin were isolated from an Anabaena variabilis ATCC 29413-Charon 30 library by using the phycocyanin (cpc) genes of Agmenellum quadruplicatum and the allophycocyanin (apc) genes of Cyanophora paradoxa as heterologous probes. The A. variabilis cpcA and cpcB genes occur together in the genome, as do the apcA and apcB genes; the two sets of genes are not closely linked, however. The cpc and apc genes appear to be present in only one copy per genome. DNA-RNA hybridization analysis showed that expression of the cpc and apc genes is greatly decreased during nitrogen starvation; within 1 h no cpc or apc mRNA could be detected. The source of nitrogen for growth did not influence expression of the genes; vegetative cells from nitrogen-fixing and ammonia-grown cultures had approximately the same levels of cpc and apc mRNAs. Heterocysts had less than 5% as much cpc mRNA as vegetative cells from nitrogen-fixing cultures. Northern hybridization (RNA blot) analysis showed that the cpc genes are transcribed to give an abundant 1.4-kilobase (kb) RNA as well as two less prominent 3.8- and 2.6-kb species. The apc genes gave rise to two transcripts, a 1.4-kb predominant RNA and a minor 1.75-kb form.
Cyanobacteria↗
Captopril augments the renal response to an amino acid infusion in diabetic adults.
This study examined whether patients with insulin-dependent diabetes mellitus and normal renal function have an altered response to an amino acid infusion when they are pretreated with a converting-enzyme inhibitor. Three groups of adults received amino acid infusions for 20 min on two occasions separated by a 240-min interval. Groups 1 (6 normals) and 2 (6 diabetics) ingested captopril (12.5 mg) 120 min before starting the second infusion. Group 3 (4 diabetics) did not receive captopril. Diabetics had normal base-line renal plasma flow, as indicated by para-aminohippuric acid clearance (CPAH), and glomerular filtration rate (GFR). In group 1, the maximum increase in CPAH was significant and similar with both infusions, 23 +/- 5 vs. 15 +/- 3% (SE); maximal changes in GFR were also significant and similar, 20 +/- 5 vs. 20 +/- 6%. In Group 2, the maximal increase in CPAH and GFR with the first infusion was 28 +/- 7 and 23 +/- 6%, respectively. After captopril, the increases in CPAH and GFR were significantly greater than with the first infusion (64 +/- 8%, P less than 0.002, and 67 +/- 9%, P less than 0.002, respectively). In Group 3 diabetics, there was no difference in either CPAH or GFR with the first vs. the second infusion. Thus captopril enhances the renal hemodynamic response to an amino acid load in diabetic patients but not in normal adults.
Adult↗
Effects of keto acid supplements on renal function and histology in azotemic rats fed high-protein diets.
The mechanism by which keto-acid-supplemented diets may retard the progression of renal failure is not known. We examined whether the protective effect of keto acids may be independent of a low nitrogen intake. Azotemic subtotally nephrectomized Sprague-Dawley rats were pair-fed a 30% casein diet supplemented with a 10% keto acid mixture (n = 10) or 10% cornstarch (n = 10) for 18 weeks. No differences were observed between the two groups of rats with regard to survival, weight gain, plasma urea, blood pressure, albuminuria, or, at the termination of the study, PAH and inulin clearances. Creatinine clearances, measured weekly during the study, were transiently higher in the keto acid group. There was no difference in the incidence or severity of segmental glomerulosclerosis or tubular atrophy in the two groups. These results indicate that the keto acid mixture used did not exert a protective effect against glomerular sclerosis and progressive albuminuria in azotemic rats fed high-protein diets.
Albuminuria↗
Glomerular filtration rate in response to an acute protein load.
The effect of a protein load on the glomerular filtration rate (measured as creatinine clearance) was studied in normal subjects, healthy vegetarians, patients with advanced liver disease, patients with moderate renal failure and in normal volunteers being pretreated with aspirin or sulindac. Only patients with liver disease were not capable of increasing their glomerular filtration rate after the protein challenge, a finding which suggests that the liver might be of importance for the adequate renal reserve. It is of note that neither the application of nonsteroidal anti-inflammatory drugs nor the existence of a moderate renal failure modify the response to a protein load.
Anti-Inflammatory Agents, Non-Steroidal↗
Long-term application of 1,25-dihydroxyvitamin D3. Effect on its serum level in dialysis patients and on the calcium content of various organs in experimental uremia.
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Animals↗
Effects of captopril on renal function in patients with cirrhosis and ascites.
Blockade of angiotensin-converting enzyme has been variously reported to increase or to decrease sodium excretion in patients with cirrhosis and ascites. We administered captopril (50-150 mg) to 11 patients with cirrhosis and ascites to determine the effects on blood pressure, renal blood flow and sodium excretion. Plasma renin activity increased and mean blood pressure fell (by 14 mm Hg). Para-aminohippurate clearances increased from 321 +/- 53 to 559 +/- 83 ml/min (P less than 0.005), but inulin clearances were minimally altered (73 +/- 8 to 76 +/- 7 ml/min), suggesting preferential dilation of glomerular efferent arterioles. Despite unchanged glomerular delivery of sodium, urinary sodium excretion fell in all subjects (from 2.70 +/- 1.00 to 0.48 +/- 0.21 mEq/h), urinary volume was reduced (377 +/- 55 to 182 +/- 42 ml/h, P less than 0.005), and the natriuretic effect of furosemide was blunted. The antinatriuretic effect of captopril may be mediated by reduced angiotensin II-mediated sodium excretion, by decreased prostaglandin production, and/or by indirect effects of reduced blood pressure. Captopril impairs rather than promotes sodium excretion.
Adult↗
Role of growth hormone in the amino acid-induced acute rise in renal function in man.
To examine whether plasma growth hormone is necessary for the amino acid-induced rise in effective renal plasma flow (ERPF, PAH clearance) and GFR (inulin clearance), arginine HCl, 500 mg/kg, was infused for 30 minutes into eight normal and six growth hormone-deficient individuals. During infusion, ERPF increased in the normal and growth hormone-deficient subjects by 28.9 +/- 11.4 SD-% (P less than 0.01) and 46.5 +/- 14.4% (P less than 0.001). GFR rose by 23.7 +/- 5.9% (P less than 0.05) and 42.7 +/- 29.1% (P less than 0.001) in the two groups. Plasma growth hormone rose only in the normal subjects, while glucagon increased in both groups. Infusion of arginine HCl, 200 mg/kg, into normals increased ERPF and GFR without increasing plasma osmolality. Lower arginine doses essentially did not affect ERPF, GFR, growth hormone, or glucagon. Infusion of D-glucose into normals raised plasma osmolality as high as with arginine HCl, 500 mg/kg, but increased ERPF only slightly and not GFR; D-glucose infusion caused a delayed rise in growth hormone that was unassociated with an increase in ERPF or GFR. An infusion of ammonium chloride with sodium chloride, which provided an amount of chloride similar to the 500 mg/kg arginine HCl dose, did not change ERPF and GFR; this suggests that the chloride load did not cause the altered renal hemodynamics stimulated by arginine HCl. These findings indicate that neither normal plasma growth hormone levels nor a rise in growth hormone mediates the arginine-induced acute increase in ERPF or GFR. This effect is also not due to the osmolar load but could be caused by the rise in plasma glucagon.
Adult↗