Net Renal Uptake Research Articles

Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia.

Asymmetrical dimethylarginine (ADMA) is capable of inhibiting nitric oxide synthase enzymes, whereas symmetrical dimethylarginine (SDMA) competes with arginine transport. The potential role of inflammation in the metabolism of ADMA has been elucidated in an in vitro model using tumour necrosis factor-alpha, resulting in a decreased activity of the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH). The kidney probably plays a crucial role in the metabolism of ADMA by both urinary excretion and degradation by DDAH. We aimed to further elucidate the role of the kidney in a rat model under basal conditions and during endotoxaemia. Twenty-five male Wistar rats weighing 275-300 g were used for this study. The combination of arteriovenous concentration differences and kidney blood flow allowed calculation of net organ fluxes. Blood flow was measured using radiolabelled microspheres according to the reference sample method. Concentrations of ADMA, SDMA and arginine were measured by high-performance liquid chromatography. The kidney showed net uptake of both ADMA and SDMA and fractional extraction rates were 35% and 31%, respectively. Endotoxaemia resulted in a lower systemic ADMA concentration (P = 0.01), which was not explained by an increased net renal uptake. Systemic SDMA concentrations increased during endotoxaemia (P = 0.007), which was accompanied by increased creatinine concentrations. The rat kidney plays a crucial role in the regulation of concentrations of dimethylarginines, as both ADMA and SDMA were eliminated from the systemic circulation in substantial amounts. Furthermore, evidence for the role of endotoxaemia in the metabolism of dimethylarginines was obtained as plasma levels of ADMA were significantly lower in endotoxaemic rats.

Renal substrate exchange and gluconeogenesis in normal postabsorptive humans.

Release of glucose by the kidney in postabsorptive normal humans is generally regarded as being wholly due to gluconeogenesis. Although lactate is the most important systemic gluconeogenic precursor and there is appreciable net renal lactate uptake, renal lactate gluconeogenesis has not yet been investigated. The present studies were therefore undertaken to quantitate the contribution of lactate to renal gluconeogenesis and the role of the kidney in lactate metabolism. We determined systemic and renal lactate conversion to glucose as well as renal lactate net balance, fractional extraction, uptake, and release in 24 postabsorptive humans by use of a combination of isotopic and renal balance techniques. For comparative purposes, accumulated similar data for glutamine, alanine, and glycerol are also reported. Systemic lactate gluconeogenesis (1.97 +/- 0.12 micromol x kg(-1) x min(-1)) was about threefold greater than that from glycerol, glutamine, and alanine. The sum of gluconeogenesis from these precursors, uncorrected for tricarboxylic acid (TCA) cycle carbon exchange, explained 34% of systemic glucose release. Renal lactate uptake (3.33 +/- 0.28 micromol x kg(-1) x min(-1)) accounted for nearly 30% of its systemic turnover. Renal gluconeogenesis from lactate (0.78 +/- 0.10 micromol x kg(-1) x min(-1)) was 3.5, 2.5, and 9.6-fold greater than that from glycerol, glutamine, and alanine. The sum of renal gluconeogenesis from these precursors equaled approximately 40% of the sum of their systemic gluconeogenesis. When the isotopically determined rates of systemic and renal gluconeogenesis were corrected for TCA cycle carbon exchange, gluconeogenesis from these precursors accounted for 43% of systemic glucose release and 89% of renal glucose release. We conclude that 1) in postabsorptive normal humans, lactate is the dominant precursor for both renal and systemic gluconeogenesis; 2) the kidney is an important organ for lactate disposal; 3) under these conditions, renal glucose release is predominantly, if not exclusively, due to gluconeogenesis; and 4) liver and kidney are similarly important for systemic gluconeogenesis.

Renal amino acid metabolism during endotoxemia in the rat.

The kidney has an important function in the exchange of nitrogenous metabolites. Glutamine is the most important substrate for renal ammoniagenesis and thus plays a crucial role in acid-base homeostasis. Furthermore, the kidney is the main endogenous source for de novo arginine production from citrulline, which in turn is derived from intestinal glutamine metabolism. Sepsis is a condition in which glutamine availability is reduced, whereas the need for arginine biosynthesis may be increased. Limited bioavailability of glutamine may affect arginine synthesis, which may have consequences for nitric oxide (NO) synthesis. Therefore, we studied renal glutamine and arginine metabolism in a rat model of endotoxemia and related this to NO metabolism. Rats were subject to double hit endotoxemia, and control rats received 0.9% NaCl. Renal blood flow was measured using para-aminohippuric acid. Concentrations of plasma amino acids and nitrate were measured in the aorta and renal vein to calculate net renal uptake or release of amino acids and address NO production. The arterial concentrations of glutamine and ammonia were not changed in endotoxemic rats. Although renal glutamine uptake was reduced, total renal ammonia production was not changed during endotoxemia. The arterial concentration of citrulline and renal citrulline uptake was not altered in endotoxin-treated rats, but renal arginine production was increased. However, no effect was observed on nitric oxide production. Although the kidney has very important functions in the excretion of waste products and in interorgan metabolism, this study suggests that the kidney has a limited role in glutamine, arginine, and NO metabolism during late endotoxemia in rats.

Regulation of splanchnic and renal substrate supply by insulin in humans

To determine the effects of peripheral insulin infusion on total, hepatic, and renal glucose production and on the percent contribution to glucose production of gluconeogenesis versus glycogenolysis, 10 healthy subjects had arterialized hand and hepatic vein catheterization after an overnight fast and the results were compared with data from 12 age- and weight-matched subjects with renal vein catheterization during a 180-minute infusion of either insulin (0.25 mU/kg x min) with dextrose, or saline. Endogenous, hepatic, and renal glucose production was measured with [6,6(-2)H2]glucose, regional lactate, alanine, and glycerol balance by arteriovenous difference; hepatic blood flow by indocyanine green clearance; and renal blood flow by p-aminohippurate clearance, before and every 30 minutes during each infusion period. Insulin increased from about 42 to 98 pmol/L and blood glucose remained constant in all studies (3.8 +/- 0.2 v4.4 +/- 0.1 micromol/ml, hepatic vrenal vein). In response to insulin infusion, endogenous, hepatic, and renal glucose production decreased immediately (30 minutes) and reached a lower plateau value (10.8 +/- 0.8 v6.4 +/- 0.7, 10.4 +/- 1.1 v7.8 +/- 1.0, and 2.8 +/- 0.6 v 1.5 +/- 0.6 micromol/kg x min, respectively) between 120 and 180 minutes (all P < .05). Net renal uptake of lactate (2.4 +/- 0.4 v0.9 +/- 0.6) decreased earlier (30 minutes) and returned to baseline between 120 and 180 minutes (2.4 +/- 0.5 micromol/kg x min), whereas net splanchnic uptake of lactate (5.7 +/- 0.7 v 0.7 +/- 0.6) and alanine (1.8 +/- 0.1 v 1.0 +/- 0.5 micromol/kg x min) decreased later (120 to 180 minutes). Net renal (0.3 +/- 0.1 v 0.1 +/- 0.1) and splanchnic (0.7 +/- 0.3 v 0.4 +/- 0.2 micromol/kg x min) glycerol uptake decreased 90 to 180 minutes after insulin and increased (P < .05) with saline infusion (0.4 +/- 0.1 v0.6 +/- 0.3 and 1.0 +/- 0.5 v1.8 +/- 0.4 micromol/kg x min, respectively). These data indicate that the rapid suppression of endogenous glucose production by insulin reflects primarily a decrease in hepatic glucose release, most likely due to inhibition of net glycogenolysis, combined with suppression of renal gluconeogenesis. Inhibition of hepatic gluconeogenesis presumably occurs later during hyperinsulinemia. We conclude that peripheral insulin, in addition to its inhibition of glycogen degradation, regulates endogenous glucose production, in part, by modifying the splanchnic and renal substrate supply.

Renal arginine metabolism in fasted rats with subacute short bowel syndrome

1. Arginine can be produced in the kidney from citrulline. An important source of circulating citrulline is the intestinal breakdown of glutamine. Consequently, partial enterectomy leads to decreased plasma citrulline levels. The aim of the present study was to investigate the effect of diminished arterial citrulline levels on renal arginine production and total-body free arginine pools.2. Renal amino acid metabolism was studied 24 h after 75% small bowel resection in rats fasted overnight (16 h) (n=12; total fast 40 h). Sham-operated (n=9) and non-operated 16-h and 40-h fasted controls were studied in parallel (n=8/n=7). During anaesthesia, L-(2, 3-3H)-arginine and para-aminohippuric acid were infused until steady state. Subsequently, arterial and renal venous blood samples were taken. Concentrations of para-aminohippurate and amino acids and specific activity of arginine and citrulline were measured to calculate renal plasma flow, net renal uptake or release, and unidirectional influx or efflux of arginine and citrulline, as well as whole-body arginine turnover.3. Arterial citrulline was decreased in enterectomized rats compared with sham-operated rats (23+/-3 versus 44+/-6 microM). Net renal citrulline uptake and arginine release were almost stoichiometric (-36+/-7 and 38+/-6 nmol.min-1. 100 g-1 body weight respectively in sham-operated rats) and were both diminished by 50% in enterectomized versus sham-operated rats. In all groups, net renal arginine production accounted for less than 10% of whole-body rate of arginine appearance (488 nmol.min-1.100 g-1 body weight in the sham group). Despite decreased net renal citrulline consumption and renal arginine production in enterectomized rats, whole-body rate of arginine appearance and arterial arginine did not change significantly.4. In conclusion, net renal arginine production is reduced 24 h after 75% enterectomy in fasted rats. However, this does not have important effects on whole-body arginine production.

Renal arginine metabolism in fasted rats with subacute short bowel syndrome

1.Arginine can be produced in the kidney from citrulline. An important source of circulating citrulline is the intestinal breakdown of glutamine. Consequently, partial enterectomy leads to decreased plasma citrulline levels. The aim of the present study was to investigate the effect of diminished arterial citrulline levels on renal arginine production and total-body free arginine pools. 2.Renal amino acid metabolism was studied 24 ;h after 75% small bowel resection in rats fasted overnight (16 ;h) (n = 12; total fast 40 ;h). Sham-operated (n = 9) and non-operated 16-h and 40-h fasted controls were studied in parallel (n = 8/n = 7). During anaesthesia, l-(2,3-3H)-arginine and para-aminohippuric acid were infused until steady state. Subsequently, arterial and renal venous blood samples were taken. Concentrations of para-aminohippurate and amino acids and specific activity of arginine and citrulline were measured to calculate renal plasma flow, net renal uptake or release, and unidirectional influx or efflux of arginine and citrulline, as well as whole-body arginine turnover. 3.Arterial citrulline was decreased in enterectomized rats compared with sham-operated rats (23±3 versus 44±6 ;μM). Net renal citrulline uptake and arginine release were almost stoichiometric (-36±7 and 38±6 ;nmol·min-1·100 ;g-1 body weight respectively in sham-operated rats) and were both diminished by 50% in enterectomized versus sham-operated rats. In all groups, net renal arginine production accounted for less than 10% of whole-body rate of arginine appearance (488 ;nmol·min-1·100 ;g-1 body weight in the sham group). Despite decreased net renal citrulline consumption and renal arginine production in enterectomized rats, whole-body rate of arginine appearance and arterial arginine did not change significantly. 4.In conclusion, net renal arginine production is reduced 24 ;h after 75% enterectomy in fasted rats. However, this does not have important effects on whole-body arginine production.

No net renal extraction of homocysteine in fasting humans

The pathophysiological mechanism of hyperhomocysteinemia in chronic renal failure in humans is unknown. The loss of a putative renal homocysteine extraction in chronic renal failure has been hypothesized as significant homocysteine uptake has been demonstrated in the normal rat kidney. We studied homocysteine extraction in the normal human kidney. We measured plasma total (free and protein-bound) and free homocysteine (tHcy and fHcy, respectively) in arterial and renal venous blood sampled from the aorta and right-side renal vein during cardiac catheterization in 20 fasting patients with normal renal function. Renal homocysteine extraction was calculated as the arteriovenous difference divided by the arterial levels times 100%. No significant renal extraction was demonstrated either for tHcy: 0.9% (SD 5.8; 95% CI -1.8 to +3.6) or for fHcy: -0.2% (11.0; -5.4 to +4.9). We conclude that no significant net renal uptake of homocysteine occurs in fasting humans with normal renal function. The loss of such uptake, therefore, cannot cause hyperhomocysteinemia in patients with renal failure.

The Ob protein (leptin) and the kidney

Mutation of the Ob gene, which encodes for leptin, or mutation of the leptin receptor leads to obesity in mice. Humans, for the most part, have a positive correlation of leptin with body fat mass suggesting possible defects in leptin effector mechanisms that may contribute to obesity. As patients on hemodialysis have difficulty with appetite, we investigated whether leptin is cleared by the kidney and is elevated in hemodialysis patients. In patients with intact renal function there was a net renal uptake of 12% of circulating leptin, whereas in patients with renal insufficiency there was no renal uptake of leptin. In a separate cohort of 36 patients with end-stage renal disease (ESRD), peripheral leptin levels factored for body mass index was increased by fourfold as compared to a group of healthy controls (N = 338). The leptin receptor exists in a long and short form, with the long form primarily expressed in the hypothalamus but also in the lungs and kidneys of the mouse. Further studies are necessary to clarify the role of leptin in regulating appetite in patients with ESRD and the role of leptin in directly affecting kidney function via its receptors.

Plasma leptin is partly cleared by the kidney and is elevated in hemodialysis patients

Leptin, the gene product of the ob gene, is important in the control of appetite in rodents and may have an important role in humans. The clearance of leptin from the circulation is unknown. As the leptin receptor is present in the kidney, we evaluated the role of the kidney in removing circulating leptin in humans. We measured leptin in aortic and renal vein plasma in 8 patients with intact renal function and 6 patients with impaired renal function who were undergoing elective cardiac catheterization. Renal blood flow was measured in all patients to calculate net mass balance across the kidney. In patients with intact renal function there is net renal uptake of 12% of circulating leptin, whereas in patients with renal insufficiency there is no renal uptake of leptin. In a separate cohort of 36 patients with end-stage renal failure on hemodialysis, peripheral leptin levels factored for body mass index was increased by > fourfold as compared to a group of healthy controls (N = 338). In addition, plasma leptin is not cleared by hemodialysis with a modified cellulose membrane. Additional studies are required to evaluate the role of leptin in mediating the anorexia of uremia.

Net uptake of plasma homocysteine by the rat kidney in vivo

Hyperhomocysteinemia is a common finding in dialysis-dependent end-stage renal disease (ESRD) patients, but its etiology and refractoriness to standard homocysteine-lowering B-vitamin therapy are poorly understood. In the absence of actual in vivo data, it has been hypothesized that loss of normal renal parenchymal uptake and metabolism of homocysteine is an important determinant of hyperhomocysteinemia in ESRD, given that urinary homocysteine excretion by healthy kidneys is trivial. We assessed net renal uptake and metabolism of homocysteine using an established rat model for measuring arteriovenous amino acid differences across the rat kidney, along with simultaneous determination of renal plasma flow, urine flow, and urinary homocysteine concentration. Substantial homocysteine uptake and metabolism by normal rat kidneys was demonstrated, and we also confirmed that urinary homocysteine excretion is minimal. These data suggest that loss of the sizable homocysteine metabolizing capacity of the intact kidneys may be an important determinant of the refractory, potentially atherothrombotic hyperhomocysteinemia frequently observed in ESRD.

Renal oxygen consumption, thermogenesis, and amino acid utilization during i.v. infusion of amino acids in man

The renal contribution to the amino acid-induced whole body thermogenesis was examined. Using indirect calorimetry and catheter techniques, pulmonary and renal oxygen uptake and blood flow, blood temperatures, and net renal exchange of amino acids, glucose and lactate were measured in eight healthy men before and during 3 h of intravenous infusion of 720 kJ of an amino acid solution. During the infusion, the pulmonary oxygen uptake increased from 252 +/- 12 to 310 +/- 8 ml/min, cardiac output increased from 5.9 +/- 0.3 to 6.8 +/- 0.3 l/min, and the arterial blood temperature increased from 36.34 +/- 0.04 to 36.68 +/- 0.07 degrees C. Renal oxygen consumption, heat production, blood flow, and net glucose exchange remained unchanged during the infusion. The net renal uptake of amino acid energy from the blood rose from 2 +/- 2 to 11 +/- 4 W. The total renal energy expenditure was 9-10 W throughout the study period. It is concluded that intravenous amino acid infusion greatly augments the uptake and utilization of amino acids in the kidneys but does not stimulate the renal oxygen consumption, heat production, blood flow, or glucose release.

Metabolic adaptation of the kidney to hyperammonemia during chronic liver insufficiency in the rat

The aim of this study was to evaluate the role of renal ammonia and glutamine metabolism in the metabolic adaptation to chronic liver insufficiency-induced hyperammonemia in the rat. To this purpose, urinary excretion, renal net exchange and tissue concentrations of ammonia and amino acids were measured in anesthetized, normal control rats that did not undergo surgery, in control rats that underwent sham surgery, in rats that underwent portacaval shunting and in rats that underwent both portacaval shunting and bile duct ligation. Rats that underwent sham surgery and portacaval shunting were pair-fed with rats that underwent portacaval shunting and biliary obstruction, to correct for anorexia in that group, and all rats that were operated on were studied 7 and 14 days after surgery. Arterial ammonia and glutamine levels were elevated in groups that underwent portacaval shunting and portacaval shunting plus biliary obstruction at all time points. At days 7 and 14, total renal ammonia production decreased in rats that underwent portacaval shunting and in rats that underwent portacaval shunting plus biliary obstruction, associated with a 50% decrease in net renal glutamine uptake and strongly diminished net ammonia release into the renal vein, which was most prominent in the group that underwent portacaval shunting plus biliary obstruction. Urinary ammonia excretion was similar in rats that underwent portacaval shunting and in those that underwent sham surgery but was increased more than 200% at days 7 and 14 in rats that underwent portacaval shunting plus biliary obstruction. In this group, in contrast to portacaval-shunted rats, the kidney appeared to be an organ of net ammonia disposal from the body. In separate experiments in unanesthetized, unrestrained rats, similar changes in urinary ammonia excretion were observed without changes in arterial pH, excluding an effect of anesthesia or pH on the obtained results. These results indicate that the kidney plays an important role in the metabolic adaptation to hyperammonemia during chronic liver insufficiency in the rat.

Renal synthesis of arginine in chronic renal failure: In vivo and in vitro studies in rats with 5/6 nephrectomy

Synthesis of arginine (Arg) from citrulline (Cit) by the kidney is a major source of Arg for the body. The high level of plasma Cit in chronic renal failure is often thought to result from the impairment of the renal conversion of Cit to Arg. To verify this assumption, we performed two studies in Sprague-Dawley rats with 5/6 nephrectomy (CRF rats) and in sham-operated rats (CONT rats). In study I synthesis of Arg by isolated proximal convoluted tubules (PCT; the nephron segment exhibiting the highest Arg synthesis) was measured in vitro with two concentrations of Cit (200 or 50 microM) corresponding to those observed in plasma of rats with or without renal failure. In study II the net renal uptake of Cit and release of Arg were determined in vivo by measuring PAH clearance and arterial and renal venous Arg, and Cit concentrations in anesthetized rats. The in vitro results showed that Arg synthesis increased only in proportion to the hypertrophy of remnant PCT (+50%), and was highly and similarly dependent on Cit concentration in PCT of remnant and normal kidneys (Arg production with 200 microM Cit was 3 times higher than with 50 microM Cit for both CONT and CRF). The in vivo results showed that renal Cit uptake and Arg release were not altered in CRF: -286 +/- 28 versus -326 +/- 16 nmol Cit.min-1 (NS), and + 390 +/- 47 versus + 399 +/- 22 nmol Arg.min-1 (NS) in CONT and CRF rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of Progressive Tumor Growth on Glutamine Metabolism in Skeletal Muscle and Kidney

The effects of progressive malignant growth on glutamine metabolism in skeletal muscle and in kidney were investigated. Fast-growing tumors consume considerable quantities of glutamine and lead to a decrease in circulating glutamine concentrations. Experiments were performed at various stages of tumor growth in rats implanted subcutaneously with the non-metastasizing methylcholanthrene-induced (MCA) fibrosarcoma and in pair-fed non tumor-bearing controls. Tumor growth stimulated a twofold increase in hindquarter (muscle) glutamine release, which was not due to an increase in blood flow, but rather to a doubling in the fractional release rate. Consequently, a progressive decrease in skeletal muscle glutamine concentrations was observed over time. Simultaneously, the activity of glutamine synthetase (GS), the principal enzyme of de novo glutamine biosynthesis, increased more than twofold. This increase in muscle GS activity was accompanied by an increase in GS mRNA but the augmentation in GS expression apparently could not match the increased rate of efflux since muscle depletion developed. In rats with large tumors and severe glutamine depletion, GS activity was not elevated. Glutamine feeding increased muscle glutamine concentrations and glutamine synthetase specific activity. Although tumor growth led to the development of mild systemic acidemia, the classic renal adaptations normally observed, i.e., elevated glutaminase activity and accelerated renal glutamine utilization, were not present in acidotic tumor-bearing rats. Instead, renal GS activity was increased in tumor-bearing animals and ammoniagenesis was enhanced, in spite of a reduction in net renal glutamine uptake. These data suggest that marked alterations in muscle and renal glutamine handling occur in the host with cancer; the enhanced muscle glutamine release in conjunction with no increase in renal consumption is consistent with increased glutamine uptake in other organs, most likely the tumor itself and the liver.

Transport and utilization of alpha-ketoglutarate by the rat kidney in vivo.

In order to establish the characteristics of net renal transport and utilization of alpha-ketoglutarate (alpha-KG) in the rat, we have precisely quantified the renal blood flow, the urinary flow and the rates of alpha-KG delivery, filtration, reabsorption or secretion, excretion, uptake or production by an in vivo rat kidney preparation. In normal rats, alpha-KG uptake was higher than alpha-KG reabsorption at both endogenous and elevated plasma alpha-KG concentrations; thus, a net peritubular transport, which was the main supplier of alpha-KG to the renal cells, took place. Saturation of reabsorption and peritubular transport of alpha-KG occurred at blood alpha-KG concentrations about 30 and 150 times above normal, respectively. Acute metabolic acidosis was found to have no effect on renal handling of alpha-KG. At endogenous plasma alpha-KG concentrations, alkalosis converted net renal uptake into net renal production of alpha-KG resulting in addition of alpha-KG by the renal cells both to blood and to the luminal fluid. Elevation of blood alpha-KG concentration restored the renal uptake of alpha-KG. This uptake, which was entirely accounted for by the peritubular transport of alpha-KG, reached a maximum which was lower than that observed in normal and acidotic rats.

Net release or uptake of histidine and carnosine in kidney of dogs.

Previous studies are equivocal as to whether the dog kidney produces histidine. Because one possible source of renal histidine is carnosine (beta-alanyl-L-histidine), we investigated net renal production (release) or utilization (uptake) (Qmet) of histidine and carnosine in 19 female dogs after they were fed histidine-free (9 dogs) or histidine-containing diets (10 dogs). Diets were fed in short-(2-11 days) or long-term (52-57 days) studies. Dogs were infused with half-normal saline for 120 min followed by an infusion of half-normal saline containing carnosine, 50 mumol/min. Renal Qmet histidine, calculated from either plasma or whole blood values, was positive during infusion of half-normal saline. During carnosine infusion, Qmet histidine increased markedly, and there was net renal uptake of carnosine. The Qmet histidine and carnosine were not different in the dogs fed histidine-free vs. histidine-containing diets. Thus there is net renal release of histidine in female dogs that increases when carnosine is administered. Qmet histidine or carnosine do not change adaptively when dogs are fed histidine-free diets.

Role of the kidney in the metabolism of fructose in 60-hour fasted humans.

Arterial (A) and renal venous (RV) concentrations and net splanchnic exchange of glucose, fructose, lactate, pyruvate, glycerol, and alanine were studied in the basal state and during a 135-min intravenous infusion of fructose at 2 mmol/min in healthy subjects after a 60-h fast. After 45 min of the fructose infusion, somatostatin (9 microgram/min) was infused for 60 min to induce hypoglucagonemia. Fructose infusion resulted in a net uptake of this hexose by the kidney as well as the splanchnic bed. Estimated renal uptake of fructose could account for the disposal of 20% of the administered fructose load while splanchnic uptake accounted for 38%. The fructose infusion resulted in a rise in blood glucose of 0.9 mmol/L, a 35% increase in net glucose output from the splanchnic bed, and a consistent net output of glucose from the kidney (A-RV = -0.17 +/- 0.05 mmol/L as compared with 0 +/- 0.03 in the basal state, P less than 0.02). Net glucose release from the kidney could account for 55% of the net renal uptake of fructose. The fructose infusion also resulted in a marked change in renal lactate balance from a net uptake in the basal state (A - RV = 0.05 +/- 0.01 mmol/L) to a net output during fructose administration (A - RV = -0.10 +/- 0.04). Administration of somatostatin resulted in a fall in arterial glucagon levels and a 35% decrease in splanchnic glucose output but failed to alter the arterial-renal venous difference for glucose observed during the fructose infusion. We conclude that in 60-h fasted man: (a) intravenous infusion of fructose results in a net uptake of this hexose by the kidney as well as the liver, (b) this uptake is accompanied by stimulation of renal as well as hepatic glucose production and renal production of lactate, and (c) hypoglucagonemia inhibits splanchnic but not renal glucose output during fructose infusion. These data indicate that the kidney is an important site of fructose disposal and that glucose and lactate are end products of renal fructose metabolism.

Calculation of net renal uptake curves without use of a blood pool agent.

The usual method of generating net Hippuran renal uptake curves involves the administration of a blood pool agent. Two techniques are presented which permit the determination of net renal uptake curves from data intrinsic to the Hippuran study. This reduced the complexity of the procedure, as well as reducing its cost and decreasing the radiation exposure. The new procedures were tested in 9 patients and showed excellent correlation with the blood pool agent technique.

Renal substrate exchange in human diabetes mellitus.

Renal substrate exchange was examined in five male patients with insulin-dependent diabetes mellitus of several years' duration. Insulin was withheld for twenty-four hours prior to the study. A renal vein was catheterized from the femoral vein, and PHA-clearance was employed for the determination of effective renal blood flow. None of the patients was in ketoacidosis, but all were moderately hyperglycemic in the fasting states (16.8 +/- 1.5 mmol/L.) (225-384 mg./100 ml.). Nevertheless, no net release of glucose from the kidney was detectable. Instead, there was a significant net renal uptake of glucose (320 +/- 80 mumol/min.). In addition, there was a significant net uptake of glycerol and a net release of pyruvate. Renal amino acid exchange was similar to that reported for healthy subjects: glutamine, glycine, proline, and citrulline were taken up and serine, alanine, cystine, tyrosine, and threonine were released by the kidney. It is concluded that (a) in nonketoacidotic diabetics there is no net production of glucose by the kidney; (b) renal amino acid exchange in diabetics is similar to that of healthy individuals; and (c) the kidney is not an important gluconeogenic organ in human diabetes.

Amino acid metabolism during prolonged starvation.

Plasma concentration, splanchnic and renal exchange, and urinary excretion of 20 amino acids were studied in obese subjects during prolonged (5-6 wk) starvation. Splanchnic amino acid uptake was also investigated in postabsorptive and briefly (36-48 hr) fasted subjects.A transient increase in plasma valine, leucine, isoleucine, methionine, and alpha-aminobutyrate was noted during the 1st wk of starvation. A delayed, progressive increase in glycine, threonine, and serine occurred after the 1st 5 days. 13 of the amino acids ultimately decreased in starvation, but the magnitude of this diminution was greatest for alanine which decreased most rapidly during the 1st week of fasting. In all subjects alanine was extracted by the splanchnic circulation to a greater extent than all other amino acids combined. Brief fasting resulted in an increased arterio-hepatic venous difference for alanine due to increased fractional extraction. After 5-6 wk of starvation, a marked falloff in splanchnic alanine uptake was attributable to the decreased arterial concentration. Prolonged fasting resulted in increased glycine utilization by the kidney and in net renal uptake of alanine. It is concluded that the marked decrease in plasma alanine is due to augmented and preferential splanchnic utilization of this amino acid in early starvation resulting in substrate depletion. Maintenance of the hypoalaninemia ultimately serves to diminish splanchnic uptake of this key glycogenic amino acid and is thus an important component of the regulatory mechanism whereby hepatic gluconeogenesis is diminished and protein catabolism is minimized in prolonged fasting. The altered renal extraction of glycine and alanine is not due to increased urinary excretion but may be secondary to the increased rate of renal gluconeogenesis observed in prolonged starvation.