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Oxidative stress and cardiovascular disease are risk factor of patients with chronic kidney disease (CKD) on maintenance hemodialysis. We used the fluorescence of low-density lipoprotein as an index of its proinflammatory potential to examine any role that high-density lipoprotein (HDL) might have in promoting this effect. The total body fat of the patients was measured by means of near-infrared interactance and their quality of life by means of SF36 questionnaires. In 189 randomly selected patients, followed for 30 months, HDL was found to be significantly anti-inflammatory but with a large standard deviation. Fully 17% of the patients had a decidedly proinflammatory index along with inferior SF36 scores. The patients were divided into 10% increments of total body fat percentages up to 40%. HDL was found to be progressively proinflammatory the higher the body fat content. Patients with a higher HDL proinflammatory index had a higher 30-month adjusted hazard ratio for death than those whose HDL were seen to be anti-inflammatory. Our findings suggest an important role of inflammatory HDL in patients with CKD leading to poor outcome.

Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

Individuals with chronic renal failure (CRF) have a high prevalence of protein-energy malnutrition. There are many causes for this condition, chief among which is probably reduced nutrient intake from anorexia. In nondialyzed patients with CRF, energy intake is often below the recommended amounts; in maintenance dialysis patients, both dietary protein and energy intake are often below their needs. Although a number of studies indicate that rats with CRF have increased protein catabolism in comparison to control animals, more recent evidence suggests that increased catabolism in CRF rats is largely if not entirely due to acidemia, particularly if these animals are compared to pair-fed control rats. Studies in humans with advanced CRF also indicate that acidemia can cause protein catabolism. Indeed, nitrogen balance studies and amino acid uptake and release and isotopic kinetic studies indicate that in nondialyzed individuals with CRF, who are not acidemic, both their ability to conserve body protein when they ingest low protein diets and their dietary protein requirements appear to be normal. For patients undergoing maintenance hemodialysis or chronic peritoneal dialysis, dietary protein requirements appear to be increased. The increased need for protein is due, in part, to the losses into dialysate of such biologically valuable nitrogenous compounds as amino acids, peptides, and proteins. However, the sum of the dietary protein needs for CRF patients (of about 0.60 g/kg/day) and the dialysis losses of amino acids, peptides and proteins do not equal the apparent dietary protein requirements for most maintenance dialysis patients. This discrepancy may be due to a chronic state of catabolism in the clinically stable maintenance dialysis patient that is not present in the clinically stable nondialyzed individual who has advanced CRF. Possible causes for such a low grade catabolic state include resistance to anabolic hormones (for example, insulin, IGF-1) and a chronic inflammatory state associated with increased levels of pro-inflammatory cytokines.

Background: The relationship between the protein-energy nutritional status and renal function was assessed in 1785 clinically stable patients with moderate to advanced chronic renal failure who were evaluated during the baseline phase of the Modification of Diet in Renal Disease Study. Their mean +/- SD glomerular filtration rate (GFR) was 39.8 +/- 21.1 mL/min/1.73 m2., Methods: The GFR was determined by 121I-iothalamate clearance and was correlated with dietary and nutritional parameters estimated from diet records, biochemistry measurements, and anthropometry., Results: The following parameters correlated directly with the GFR in both men and women: dietary protein intake estimated from the urea nitrogen appearance, dietary protein and energy intake estimated from dietary diaries, serum albumin, transferrin, percentage body fat, skinfold thickness, and urine creatinine excretion. Serum total cholesterol, actual and relative body weights, body mass index, and arm muscle area also correlated with the GFR in men. The relationships generally persisted after statistically controlling for reported efforts to restrict diets. Compared with patients with GFR > 37 mL/min/1.73 m2, the means of several nutritional parameters were significantly lower for GFR between 21 and 37 mL/min/1.73 m2, and lower still for GFRs under 21 mL/min/1.73 m2. In multivariable regression analyses, the association of GFR with several of the anthropometric and biochemical nutritional parameters was either attenuated or eliminated completely after controlling for protein and energy intakes, which were themselves strongly associated with many of the nutritional parameters. On the other hand, few patients showed evidence for actual protein-energy malnutrition., Conclusions: These cross-sectional findings suggest that in patients with chronic renal disease, dietary protein and energy intakes and serum and anthropometric measures of protein-energy nutritional status progressively decline as the GFR decreases. The reduced protein and energy intakes, as GFR falls, may contribute to the decline in many of the nutritional measures.

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: Protein-energy malnutrition is a strong predictor of mortality in maintenance hemodialysis (MHD) patients. This association has generally been described for serum chemistry measures of protein-energy malnutrition. We hypothesized that body weight-for-height relationships also predict survival in MHD patients., Methods: During the last three months of 1993, data were obtained on 12,965 men and women concerning clinical characteristics (height, postdialysis weight, age, gender, race, and presence or absence of diabetes mellitus) and laboratory measurements (predialysis serum albumin, creatinine and cholesterol, and the urea reduction ratio). Patient survival during the next 12 months was evaluated retrospectively., Results: In comparison to values for normal Americans determined from the National Health and Nutrition Evaluation Survey II data, weight-for-height relationships tended to be slightly lower than normal in African American men and women and Caucasian men undergoing MHD and were normal or slightly greater in the taller Caucasian women. In both men and women, the mortality rate decreased progressively as the patients' weight-for-height increased. MHD patients who weighed more than normal had the lowest mortality rates. After adjustment for clinical characteristics and laboratory measurements, the inverse relationship between mortality rates and weight-for-height percentiles was still highly significant for patients within the lower 50th percentile of body weight-for-height. Serum albumin correlated directly with weight-for-height in patients in the lower 50th percentile of weight-for-height. Serum creatinine and cholesterol correlated directly with weight-for-height in the entire population of men and women. In contrast, the urea reduction ratio was inversely correlated with weight-for-height., Conclusions: These data indicate that weight-for-height is a strong predictor of 12-month mortality in male and female MHD patients. Multivariate analyses indicate that body weight-for-height is an independent predictor of higher mortality in those patients who are in the lower 50th percentile for this measurement.

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.

There is a high prevalence of protein-energy malnutrition in both nondialyzed patients with advanced chronic renal failure and in those individuals with end-stage renal disease who are receiving maintenance hemodialysis or chronic peritoneal dialysis therapy. Approximately one-third of maintenance dialysis patients have mild to moderate protein-energy malnutrition, and about 6 to 8 percent of these individuals have severe malnutrition. These statistics are of major concern because markers of protein-energy malnutrition are strong predictors of morbidity and mortality. The causes of protein-energy malnutrition in patients with chronic renal failure include: (1) decreased energy or protein intake; (2) concurrent chronic illnesses, and superimposed acute illnesses and possibly increased inflammatory cytokines; (3) the catabolic stimulus of hemodialysis; (4) losses of nutrients into dialysate, particularly amino acids, peptides, protein (with peritoneal dialysis), glucose (when hemodialysis is performed with glucose-free dialysate) and water-soluble vitamins; and (5) diagnostic or therapeutic (e.g., prednisone therapy) procedures that reduce nutrient intake or engender net protein breakdown. Other theoretically possible causes for protein-energy malnutrition include (6) chronic blood loss; (7) endocrine disorders (especially resistance to insulin and insulin-like growth factor-I, hyperglucagonemia, hyperparathyroidism and deficiency of 1,25-dihydroxycholecalciferol); (8) products of metabolism that accumulate in renal failure and may induce wasting, such as organic and inorganic acids; (9) loss of the metabolic actions of the kidney; and (10) the accumulation of toxic compounds that are taken up from the environment (e.g., aluminum).

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.

Maintenance hemodialysis (MHD) patients are frequently malnourished, a condition associated with high morbidity and mortality. Amino acid (AA) losses in dialysate may enhance protein malnutrition in patients with low food intake. We studied the possibility of providing AA in dialysate during MHD to either prevent AA losses or as a nutritional supplement. Six clinically stable men were studied during three hemodialysis treatments. The first treatment was performed using the usual dialysate (0XAA). The two other treatments were performed using a dialysate containing an amount of AA equal to normal plasma AA concentrations (1XAA) or to three times the normal plasma AA concentrations (3XAA). During the OXAA treatment, the total AA losses were 10.0 +/- 0.9 (SEM) grams (g) and the total AA concentrations in plasma decreased by 49 +/- 4%. During the 1XAA treatment, the total AA balance was +0.8 +/- 1.8 g and there was no significant change in the postdialysis plasma total AA. With the 3XAA treatment, the patients gained 36.9 +/- 4.1 g of AA during the hemodialysis treatment and the plasma total AA levels increased by 45 +/- 9%. No side effects were observed. These findings indicate that it may be feasible to provide AA supplements to MHD patients by adding AA to hemodialysate.

The safety of dietary protein and phosphorous restriction was evaluated in the Modification of Diet in Renal Disease (MDRD) Study. In Study A, 585 patients with a glomerular filtration rate (GFR) of 25 to 55 ml/min/1.73 m2 were randomly assigned to a usual-protein diet (1.3 g/kg/day) or a low-protein diet (0.58 g/kg/day). In Study B, 255 patients with a GFR of 13 to 24 ml/min/1.73 m2 were randomly assigned to the low-protein diet or a very-low-protein diet (0.28 g/kg/day), supplemented with a ketoacid-amino acid mixture (0.28 g/kg/day). The low-protein and very-low-protein diets were also low in phosphorus. Mean duration of follow-up was 2.2 years in both studies. Protein and energy intakes were lower in the low-protein and very-low-protein diet groups than in the usual-protein group. Two patients in Study B reached a "stop point" for malnutrition. There was no difference between randomized groups in the rates of death, first hospitalizations, or other "stop points" in either study. Mean values for various indices of nutritional status remained within the normal range during follow-up in each diet group. However, there were small but significant changes from baseline in some nutritional indices, and differences between the randomized groups in some of these changes. In the low-protein and very-low-protein diet groups, serum albumin rose, while serum transferrin, body wt, percent body fat, arm muscle area and urine creatinine excretion declined. Combining patients in both diet groups in each study, a lower achieved protein intake (from food and supplement) was not correlated with a higher rate of death, hospitalization or stop points, or with a progressive decline in any of the indices of nutritional status after controlling for baseline nutritional status and follow-up energy intake. These analyses suggest that the low-protein and very-low-protein diets used in the MDRD Study are safe for periods of two to three years. Nonetheless, both protein and energy intake declined and there were small but significant declines in various indices of nutritional status. These declines are of concern because of the adverse effect of protein calorie malnutrition in patients with end-stage renal disease. Physicians who prescribe low-protein diets must carefully monitor patients' protein and energy intake and nutritional status.

This study was carried out to examine the mathematical relationships between the urea nitrogen appearance (UNA), total nitrogen appearance (TNA) and dietary nitrogen intake (DNI) in patients with chronic renal failure. Studies were conducted in 20 nondialyzed patients with advanced chronic renal failure (CRF) who were fed 27 constant protein diets for 24.8 +/- 9.5 days (SD) and eight patients undergoing continuous ambulatory peritoneal dialysis (CAPD), who ingested 13 constant protein diets for 20.3 +/- 4.9 days. All patients lived in a hospital research ward throughout the study and underwent full nitrogen balance measurements. Data were analyzed after patients attained equilibrium or near equilibrium with each dietary protein intake. In the CRF patients, using the mean values obtained during the equilibrium phase, there was a direct and precise correlation between the TNA and UNA, where TNA g/day = 1.19 UNA g/day + 1.27 g/day, r = 0.948. The correlation between DNI and UNA was also highly significant, but less precise, with somewhat greater 95% confidence intervals: DNI g/day = 1.20 UNA g/day + 1.74 g/day, r = 0.865. The relationship between DNI and TNA was not much more precise: DNI g/day = 0.97 TNA g/day + 0.65 g/day, r = 0.880. With the CAPD patients, the relationships were as follows: TNA g/day = 0.94 UNA g/day + 5.54 g/day, r = 0.956; DNI g/day = 0.97 UNA g/day + 6.80 g/day, r = 0.705; DNI g/day = 1.07 TNA g/day + 0.63 g/day, r = 0.760. For the CAPD patients, the lowest 95% confidence intervals were also found for the correlation between TNA and UNA. Thus, in both CRF and CAPD patients, the TNA is highly and precisely correlated with the UNA. The DNI is also significantly correlated with UNA and TNA, but the relationship is less precise. In both of these two groups of patients, the difference between the regression equations for TNA versus UNA and DNI versus UNA was, to a substantial degree, accounted for by the intercept.

There is a high prevalence of protein-energy malnutrition in patients with chronic renal failure who are undergoing maintenance dialysis therapy. The high prevalence of malnutrition is a potentially serious problem because indexes of protein-energy malnutrition are powerful predictors of mortality in maintenance dialysis patients. Although the data do not prove that improving nutritional intake will reduce mortality, nonrandomized studies suggest that provision of addition amino acids and energy to such patients is associated with reduced mortality. There are many causes for protein-energy malnutrition in maintenance dialysis patients. Among the three most important factors are the nutritional status of the patient before commencing dialysis therapy, inadequate protein and energy intakes after they become dialysis patients, and acute and chronic illnesses. Improving the nutrient intake of maintenance dialysis patients is a challenging task because most chronic renal failure patients with malnutrition are anorectic, and dietary counseling has had limited success at increasing their nutrient intake. Other methods for improving nutritional status in adults, infants, and children with chronic renal failure that have been tried with varying degrees of success include increasing the dose of dialysis and the use of food supplements and tube feeding. Less well-proven techniques for the treatment of protein-energy malnutrition include intradialytic parenteral nutrition. The use of appetite stimulants and such growth factors as rhGH and rhIGF-I are still in the experimental stage.

The African American Study of Kidney Disease and Hypertension (AASK) Pilot Study evaluated the feasibility of carrying out a randomized, multicenter, 7-year clinical trial to determine the effects of two goal levels of blood pressure control and three antihypertensive drug regimens on decline in glomerular filtration rate in African Americans with clinically diagnosed hypertensive nephrosclerosis. Participants were randomized to either a usual mean arterial blood pressure (MAP) goal group (102-107 mm Hg) or a low-MAP goal group (< or = 92 mm Hg) and to a drug regimen (initial therapy with either atenolol, amlodipine, or enalapril). Quality of life was assessed by the Medical Outcomes Short-Form 36 (MOS SF-36) at baseline and the last follow-up visit for 84 of the 94 participants of the AASK Pilot Study. Symptoms were assessed at baseline and throughout the course of therapy by participant self-report. Mean SF-36 scores increased significantly on physical functioning (9.2), role limitations (physical) (19.0), social functioning (9.0), and vitality dimensions (5.6) from baseline to the last follow-up visit in the usual MAP goal group. Scores for the eight health dimensions assessed by the MOS SF-36 did not change significantly during the same time period either in the low-MAP goal group or in any of the drug regimens. The mean score for general health perception was significantly lower at the last follow-up visit in the enalapril drug regimen (49.9) compared to drug regimens with atenolol (65.4) or amlodipine (63.9). Physical functioning, role limitations (emotional), social functioning, mental health, vitality, and general health perception scores were negatively correlated with self-reported symptoms during treatment. We conclude that selected dimensions of quality of life improved during the AASK Pilot Study only in participants randomized to the usual MAP goal group. Significant differences between MAP goal groups and drug regimens at the end of follow-up were observed for only a few health dimensions.

Nineteen malnourished chronic peritoneal dialysis patients who were ingesting a low protein intake underwent metabolic balance studies to test whether a dialysate that contained amino acids would improve their protein nutrition. Patients lived in the hospital for 35 days while they ate a constant diet and underwent their usual regimen of continuous ambulatory peritoneal dialysis (CAPD). The first 15 days served as a Baseline Phase. For the last 20 days, the usual dialysate was substituted with a dialysate of essentially the same composition except that it contained 1.1% essential and nonessential amino acids and no glucose. Patients received one or two dialysate exchanges with amino acids each day depending on the amount necessary to bring the individual's dietary protein plus dialysate amino acid intake to 1.1 to 1.3 g/kg body weight/day. During Baseline, patients were in neutral nitrogen balance; net protein anabolism was positive, as determined from 15N-glycine studies. After commencing intraperitoneal amino acid therapy, nitrogen balance became significantly positive, there was a significant increase in net protein anabolism, the fasting morning plasma amino acid pattern became more normal, and serum total protein and transferrin concentrations rose. Patients generally tolerated the treatment well, although some patients developed mild metabolic acidemia. These findings indicate that a dialysate containing amino acids may improve protein malnutrition in CAPD patients ingesting low protein intakes.

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.

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.

In preliminary studies, rats with chronic renal failure (CRF) demonstrated worsening renal function, as measured by urea clearance, when fed vitamin B-6-deficient diets. However, urea clearance is not a precise measure of glomerular filtration rate (GFR) and these studies did not indicate the mechanism for the reduced GFR. To measure renal function more precisely and to assess whether B-6 deficiency augments renal injury, we examined [14C]inulin clearance, urine oxalate excretion, and renal histopathology in rats with CRF pair fed to receive a pyridoxine-replete or -deficient diet for 3 or 6 wk. After 3 or 6 wk, pyridoxine-deficient rats had significantly lower [14C]inulin clearances and increased urine oxalate excretion. Histological evaluation indicated increased renal damage in kidneys from pyridoxine-deficient rats as compared with tissue from pyridoxine-replete rats. These findings suggest that in rats with CRF, vitamin B-6 deficiency reduces the GFR and increases renal scarring.

To evaluate the effects of long-term total parenteral nutrition (TPN) on eye function, 27 adults and 12 children in the UCLA Home TPN Clinic underwent ophthalmoscopic examination and visual-function testing. Direct inspection of the fundus showed a marked granularity of the retinal pigmented epithelium in some patients. About one-half of the children and one-third of the adults tested had at least one and usually two abnormalities in their electroretinogram. Determination of blood nutrients thought to affect vision revealed that zinc and vitamin E were within normal range. Vitamin A concentrations were above normal in 10 of 19 adults and selenium concentrations were below normal in 10 of 10 children and 17 of 21 adults tested. Linoleic and linolenic acid concentrations were low; plasma, platelet, and urine taurine concentrations were significantly lower than normal. Despite these diffuse nutrient abnormalities, only zinc and vitamin E concentrations correlated significantly with any index of visual function.

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.

Thirty-four adults undergoing long-term parenteral nutrition (TPN) were treated either with or without intravenous taurine for less than or equal to 24 mo. Statistical comparisons were carried out in eight patients randomly assigned to receive intravenous taurine, usually 10 mg.kg-1.d-1, and 10 patients not receiving taurine. Compared with normal adults, baseline plasma taurine and urine taurine-creatinine ratios were decreased in both groups and platelet taurine was reduced in the taurine-treated group. During taurine treatment the mean of the mean values for taurine became normal in plasma and platelets and remained normal in erythrocytes, granulocytes, and lymphocytes; urine taurine-creatinine ratios rose to approximately five times normal. During follow-up, patients not given taurine had plasma, erythrocyte, and granulocyte taurine and urine taurine-creatinine ratios below normal values and the concentrations of taurine-treated patients. Their platelet taurine was also subnormal. Thus, 10 mg taurine.kg-1.d-1 intravenously normalizes plasma and blood cell taurine concentrations in long-term TPN patients.

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)

People in developed nations such as the United States and Canada have an increased risk of colon cancer. Fecal mutagens have been detected in the feces of individuals at high risk for colon cancer. We describe a rapid, sensitive, reliable, reproducible high-pressure liquid chromatography (HPLC) method for detecting fecapentaenes, the most active and chief mutagen found in human stool. We found fecapentaene in all the stool samples of adults on typical high-fat, low-fiber Western diets. These fecapentaene concentrations remained largely constant when subjects consumed constant diets. Fecapentaene concentrations were reduced for total-parenteral-nutrition (TPN) patients with severe intestinal malabsorption. This finding with TPN patients may reflect changes in important variables of gut microflora in fecapentaene production. Studies with newborns and children showed that fecapentaenes appeared very early in life but are not present in stool at birth.

Although maintenance hemodialysis (MHD) patients are often wasted, little is known about their dietary energy needs. We studied four men and two women in a clinical research center while they received diets providing 45, 35 and 25 kcal/kg desirable body weight/day; diets were fed, in random order, for 21 to 23 days each. Protein intake, 1.13 +/- 0.02 (SEM) g protein/kg/day, was similar with all three diets. Body weight rose with 45 and 35 kcal/kg/day (P less than 0.05) and fell with 25 kcal/kg/day (P less than 0.05). Nitrogen balance, adjusted for estimated unmeasured losses, was neutral with 45 and 35 kcal/kg/day and negative with 25 kcal/kg/day. Balance was neutral or positive in 6 of 6, 4 of 6, and 0 of 6 patients fed 45, 35, 25 kcal/kg/day, respectively. Nitrogen balance, many plasma amino acids and changes in body weight, mid-arm circumference, mid-arm muscle area and body fat each correlated with energy intake. Resting energy expenditure was normal. The energy intake estimated from regression equations to maintain neutral nitrogen balance was 38.5 kcal/kg desirable weight/day; for body fat and weight, it was 32 kcal/kg/day. These data suggest that MHD patients have normal energy expenditure and approximately normal requirements for maintenance of protein balance, body weight and body fat. An average energy intake of about 38 kcal/kg desirable weight/day may be necessary to maintain nitrogen balance in these patients.

An oral protein load or infusion of amino acids induces a rise in renal hemodynamics in normal subjects, but the mechanisms mediating this phenomenon are unknown. We investigated whether glucagon may mediate the increase in RPF and GFR induced by an arginine infusion and whether prostaglandins are required for this effect. In four different studies, normal subjects underwent 13 inulin and PAH clearances of 30 minutes each. During the fourth and tenth clearance periods arginine HCl, 250 mg/kg, was infused over 30 minutes. At the beginning of the fifth clearance period several subjects ingested indomethacin, 150 mg, (N = 8) or ibuprofen, 800 mg (N = 6). Control subjects (N = 4) did not receive cyclooxygenase inhibitors. Six subjects underwent a similar protocol except that they were infused with glucagon, 6 ng/kg/min, instead of arginine, for 30 minutes during the fourth and tenth periods. They also ingested indomethacin, 150 mg, in the fifth period. In all four studies, a transient and significant rise in RPF and GRF and fall in RVR occurred during the first arginine or glucagon infusion. These changes in renal hemodynamics were blocked when the arginine or glucagon infusion was repeated after administration of indomethacin or ibuprofen. Urinary excretion of 6-keto-PGF1 alpha did not rise with either arginine infusion in the control subjects or in the individuals who received indomethacin. As predicted, urinary 6-keto-PGF1 alpha fell significantly after ingestion of indomethacin before the second infusion of arginine. Plasma norepinephrine and epinephrine concentrations were unaffected by the arginine infusions or by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic balance studies were conducted in five nondialyzed chronically uremic patients and four patients undergoing maintenance hemodialysis or peritoneal dialysis who had sustained an acute intercurrent illness. Nitrogen balance became negative in all patients. In eight patients who did not have marked fluid removal, serum total protein, albumin and transferrin fell significantly. Negative nitrogen balance was caused by three factors: 1) decreased nitrogen intake, which wasn't always readily apparent 2) increased urea nitrogen appearance, and 3) in peritoneal dialysis patients with peritonitis, protein losses into dialysate. In the chronically uremic patients, urea nitrogen appearance correlated closely with total nitrogen output and appears to be a good predictor of total nitrogen losses.

Until the last few years, maintenance peritoneal dialysis (PD) often was associated with progressive wasting due to frequent episodes of peritonitis, loss of considerable amounts of protein into the dialysate, and poor nutritional intake. Recently, available techniques have made PD a feasible alternative for the long-term care of the patient with end-stage renal failure. The incidence of peritonitis has been markedly reduced, and protein loss is only 4 to 20 gm. per dialysis treatment. Preliminary studies have shown no differences in the nutritional status of patients undergoing PD or hemodialysis, although both groups have evidenced malnutrition. In the patient undergoing PD, daily intakes of 1.2 to 1.5 gm. protein and 35 kcal per kilogram body weight are recommended. During times of stress, parenteral administration of nutrients may be necessary. Dietary supplements may often be required chronically. Careful studies are needed to difine the nutritional needs of the patient undergoing PD.

The many alterations in amino acid and protein metabolism in renal failure are often poorly defined, and the available data concerning them are usually descriptive. Nonetheless, certain factors play an important role in the altered amino acid and protein metabolism of uremia. These include malnutrition caused by poor nutrient intake, loss of nutrients during dialysis, and abnormal metabolism of nutrients. Other factors include uremic toxins, superimposed catabolic illnesses, endocrine disorders, and the reduced capacity of the failing kidney to synthesize or degrade certain hormones, amino acids, peptides, and small proteins. These aberrations have complex interrelationships which sometimes potentiate each other. It is possible that the administration of sufficient quantities of energy, vitamins, and minerals, as well as the dietary manipulation of protein, amino acid and ketoacid intake may improve the metabolism of amino acids and proteins. Vitamin B6 and zinc have special requirements that may affect protein or amino acid metabolism.

Since wasting and malnutrition are common problems in patients with renal failure, it is important to develop techniques for the longitudinal assessment of nutritional status. This paper reviews available methods for assessing the nutritional status; their possible limitations when applied to uremic patients are discussed. If carefully done, dietary intake can be estimated by recall interviews augmented with dietary diaries. Also, in a stable patient with chronic renal failure, the serum urea nitrogen (N)/creatinine ratio and the rate of urea N appearance reflect dietary protein intake. A comparison of N intake and urea N appearance will give an estimate of N balance. Anthropometric parameters such as the relationship between height and weight, thickness of subcutaneous skinfolds, and midarm muscle circumference are simple methods for evaluating body composition. Other methods for assessing body composition, such as densitometry and total body potassium, may not be readily applicable in patients with renal failure. More traditional biochemical estimates of nutritional status such as serum protein, albumin, transferrin, and selected serum complement determinations show that abnormalities are common among uremic patients. Certain anthropometric and biochemical measurements of nutritional status are abnormal in chronically uremic patients who appear to be particularly robust; thus, factors other than altered nutritional intake may lead to abnormal parameters in such patients. Serial monitoring of selected nutritional parameters in the same individual may improve the sensitivity of these measurements to detect changes. Standards for measuring nutritional status are needed for patients with renal failure so that realistic goals can be established optimal body nutriture.

Plasma tryptophan (Trp) levels and brain concentrations of Trp, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) were measured in chronically uremic rats fed either 11% or 18% casein diets for 8 to 12 weeks. Uremic rats had increased levels of plasma urea nitrogen and 5-HIAA when compared with sham-operated pair-fed controls. The level of plasma total Trp decreased in both uremic groups and the level of plasma free Trp increased only in those fed an 11% casein diet. Uremic rats fed 11% casein had a higher level of plasma free Trp than those fed 18% casein. The ratio of plasma total Trp to the sum of five amino acids competing for the blood-brain transport system was decreased in both uremic groups, and the ratio of plasma free Trp to the same amino acids was increased only in uremic rats fed 11% casein. The concentration of brain 5-HIAA increased in uremic rats fed 11% casein, and that of Trp and serotonin decreased in uremic rats fed 18% casein. These results indicate that uremic stress and changes in protein intake in chronic uremia alter plasma Trp levels and brain serotonin metabolism.

Chronic renal failure is associated with many abnormalities in plasma amino acids. Since patients with renal failure are frequently deficient in vitamin B-6, this study examined whether vitamin B-6 deficiency may be a cause of any of the abnormal plasma amino acid concentrations observed in chronic renal failure. Sham-operated and chronically azotemic rats were pair-fed diets deficient in or replete with vitamin B-6 for 21 d. By the end of 21 d, the EGOT index rose significantly in the B-6-deficient rats but not in the B-6-replete animals. There were several differences in plasma amino acid concentrations between azotemic and control rats. Azotemia and B-6 deficiency each lowered the plasma serine concentration and raised the glycine-to-serine ratio. Plasma glycine was affected by a two-way interaction between azotemia and vitamin B-6 deficiency whereby the highest values were found in the sham-operated vitamin B-6-deficient animals. Plasma alanine and asparagine were reduced by B-6 deficiency and unchanged by azotemia. These results suggest that vitamin B-6 deficiency may contribute to several of the abnormalities in the plasma aminograms observed in chronic renal failure.

This study evaluated the effects during hemodialysis of intravenous infusion of amino acids and glucose on plasma amino acid and glucose concentrations and amino acid losses. Eight men undergoing maintenance hemodialysis were each studied during two dialyses using glucose-free dialysate. During one hemodialysis, they were infused with 800 ml of normal saline. During the other hemodialysis, they were infused with an equal volume of water which contained 39.5 g of essential and non-essential free L-amino acids and 200 g of d-glucose. The solutions were infused throughout the dialysis procedure into the drip chamber of the venous outflow from the dialyzer. Subjects were fasted from the night before until the end of hemodialysis, and the order of administration of the two solutions was determined randomly. Plasma essential, non-essential, and total amino acids fell significantly during the infusion of normal saline and rose during the administration of amino acids and glucose. Dialysate total-free amino acid losses averaged 8.2 +/- 3.1 SD g during the infusion of normal saline and 12.6 +/- 3.6 g with the administration of amino acids and glucose. These findings indicate that the intravenous infusion of amino acids and glucose during hemodialysis prevents a fall in plasma amino acid and glucose concentrations and leads to only a slight increase in the losses of free amino acids into dialysate. Because most of the infused amino acids are retained, this technique may be used during hemodialysis to avoid a net outflow of amino acids, minimize disruption of amino acid and glucose pools, and provide a nutritional supplement.

Malnutrition is frequently present in patients with acute renal failure and may affect morbidity and mortality in this condition. When adequate nourishment cannot be given through the gastrointestinal tract, total parental nutrition with amino acids and hypertonic glucose may have beneficial results. Total parenteral nutrition has been reported to stabilize or reduce serum urea nitrogen, potassium and phosphorus levels, improve wound healing, enhance survival from acute renal failure, and possibly increase the rate of recovery of renal function. The optimal composition of the total parenteral nutrition infusate is unknown. Preliminary results of a double-blind study are reported in which one man received hypertonic glucose alone, two received glucose with essential amino acids (21 g/day), and three received glucose with essential (21 g/day) and nonessential (21 g/day) amino acids. All infusates were isocaloric. No differences were observed in serum urea nitrogen levels, serum urea nitrogen/creatinine ratios or urea appearance rates. Nitrogen balance was negative in all patients. The ratio of essential amino acids/nonessential amino acids were higher and the tyrosine/phenylalanine ratios were lower in plasma in the two patients receiving glucose with essential amino acids. No patient survived the hospitalization. In view of the markedly negative nitrogen balance frequently observed in these and earlier studies, the use of a different composition or quantity of amino acids, a higher energy intake, and anabolic hormones deserve further investigation.

Plasma taurine levels and urinary taurine excretion were measured in 12 strict vegetarian (vegan) males who had maintained a vegan diet for 53 +/- 26 mo (SD) and in 14 male nonvegetarian control subjects. Plasma taurine levels differed (45 +/- 7 vs 58 +/- 16 mumol/L, respectively). Urinary taurine excretion was lower (266 +/- 279 vs 903 +/- 580 mumol/d), urinary N pi-methylhistidine was barely detectable, and urinary N tau-methylhistidine was significantly reduced (296 +/- 87 vs 427 +/- 19 mumol/d) in the vegans. Analysis of 3-d dietary diaries kept by the vegans indicated marginal to adequate intake of protein, carbohydrate, vitamin B-6, methionine, and cystine; inadequate intake of zinc; and negligible intake of taurine. Prolonged absence of dietary taurine intake causes decreased plasma taurine and severely restricted urinary taurine output.

Nutritional status and lymphocyte transformation were examined in 30 clinically stable men who underwent maintenance hemodialysis for 1 to 141 months. The men displayed decreased relative body weight, triceps and subscapular skinfold thickness, midarm circumference, midarm muscle circumference, serum total protein, albumin, transferrin, IgG, IgA, IgM, and C3 concentrations. There were many abnormalities in the plasma amino acid pattern. Lymphocyte transformation stimulated by phytohemagglutin or pokeweed mitogen was reduced. Many nutritional parameters correlated with each other and with the rate of lymphocyte transformation. There was a tendency (p = 0.06) for higher mortality in the malnourished patients during a mean follow-up period of 43.3 months. These findings suggest that clinically stable men undergoing maintenance hemodialysis are typically malnourished. Poor nutritional status may be a cause of impaired lymphocyte function. Malnutrition or wasting may indicate that the patient is at risk for a higher mortality rate.

The losses of protein into dialysate have been considered a major limitation of maintenance peritoneal dialysis. We, therefore, undertook a comprehensive evaluation of protein losses in 30 patients undergoing maintenance intermittent peritoneal dialysis (IPD), 12 patients undergoing acute IPD, and 8 patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The weekly loss of protein based upon the usual treatments per week was relatively similar with the three modes of dialysis. Protein losses during repeated dialyses were similar for a given patient, but there was repeated dialyses were similar for a given patient, but there was marked interpatient variation. During maintenance IPD, protein loss was 12.9 +/- (SD) 4.4 g per 10 hours of dialysis; albumin loss was 8.5 g, and IgG loss was 1.3 g. Approximately 50% of the protein loss was from the ascitic fluid accumulated during the interdialytic interval, and concentrations of most proteins in the ascitic fluid correlated with their serum levels. Serum protein concentrations were in the low, normal range and did not change during dialysis. The development of peritonitis markedly increased protein losses. During acute IPD, 23.3 +/- 16.5 g of protein were lost per 36 hours of dialysis, lower losses than those previously reported. With CAPD, 8.8 +/- 1.7 g of protein were removed per 24 hours; also immunoglobulin losses correlated with their serum concentrations. The results of these studies suggest that, in the absence of peritonitis, dialysate protein losses do not appear to limit the usefulness of peritoneal dialysis.

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.

There is evidence that the kidney has a major role in the formation of the arginine used for extrahepatic protein synthesis. The effects of arginine-free diets were studied, therefore, in female Sprague-Dawley rats made uremic by partial left-renal artery ligation and contralateral nephrectomy. Uremic and sham-operated control rats were fed diets with amino acids proportioned as in casein or similar isonitrogenous diets in which the arginine was replaced by glutamic acid and alanine. Weight gain and the food efficiency ratio were determined, and 6 weeks after nephrectomy, a pulse dose of 14C-guanido arginine was administered. The rats were killed 2 hours later, and the radioactivity of proteins in various tissues was determined. Free arginine levels in tissues were also measured. Control rats fed diets devoid of arginine had reduced growth and a low food efficiency ratio. Free arginine levels in tissues and 14C-arginine incorporation into tissue protein in these rats were not different from controls receiving arginine except that 14C-incorporation into brain protein was decreased. Uremic rats fed an arginine-containing diet had a reduced growth rate as compared to control rats, and 14C-incorporation into brain protein was less. In uremic rats, when arginine was removed from the diet, there was no further effect on weight gain but the plasma arginine level was decreased and the incorporation of 14C-guanido arginine into protein of muscle and of kidney was reduced. Hence, the effects of an arginine-free diet appears to be different in chronically uremic as compared to control rats.

Taurine levels were measured in adult cats consuming casein-based diets supplemented with 0.2, 0.05, 0.02, 0.01 or 0% (wt/wt) taurine or with 0% taurine plus 5.0% L-cystine. Taurine concentrations in plasma, platelets, granulocytes and erythrocytes declined significantly with decreased dietary taurine. In the cats that did not receive the 5.0% cystine supplement, the relationship between dietary taurine intake and plasma and blood cell taurine level was nonlinear. The greatest increment in taurine concentrations occurred between the 0.02 and 0.05% taurine intakes. These findings suggest that the dietary taurine requirement for adult cats may be between 0.02 and 0.05%. Supplementation of the 0% taurine diet with 5.0% L-cystine raised taurine levels above those of the taurine-deficient diets in plasma and all blood cell types. The result of this study therefore suggest a close relationship between dietary taurine intake and blood cell taurine levels in cats. Five percent L-cystine stimulates taurine synthesis in these animals.

The rates of histidine degradation were investigated in six normal and three chronically uremic men who were not undergoing dialysis therapy. The nine men were studied in the postabsorptive state after they had ingested one or more of the following diets for the indicated periods of time: a 40 g protein diet providing about 1100 mg/day of histidine for 27 +/- 9 SD days (seven studies), an amino acid diet providing only 65 mg/day of histidine (histidine-deficient diet) for 33 +/- 3 days (eight studies), and an amino acid diet providing about 1125 mg/day of histidine (histidine-replete diet) for 32 +/- 7 days (six studies). Diets are listed in the order of administration; five men received all three diets. After fasting overnight, subjects received an intravenous injection of 25 microCi/70 kg body weight of L-[ring-2-14C]-histidine (eight men) or L-carboxyl-14C]-histidine (one man), and expiration of 14CO2 was measured continuously for 2 h. With both tracers, expiration of 14CO2 fell with ingestion of the histidine-deficient diet (p less than 0.005) and then increased with intake of the histidine-replete diet (p less than 0.05). Free histidine in plasma and muscle also decreased with the histidine-deficient diet and rose with the histidine-replete diet. If other tissue free histidine pools changed similarly and protein turnover was not very different with the three diets, then the 14CO2 expiration data and the estimated specific activity of 14C-histidine indicate that histidine degradation fell markedly with the histidine-deficient diet and then increased with the histidine-replete diet. In uremic patients as compared to normal subjects no differences in the magnitude of 14C-histidine degradation or in the pattern of 14CO2 expiration were observed.

Although nondialyzed, chronically uremic patients and patients undergoing maintenance hemodialysis often show evidence for wasting and calorie malnutrition and have low dietary energy intakes, their energy expenditure has never been systematically evaluated. It is possible that low energy intakes are an adaptive response to reduced energy needs; alternatively, energy expenditure could be normal or high and the low energy intakes would be inappropriate. Energy expenditure was therefore measured by indirect calorimetry in 12 normal individuals, 10 nondialyzed patients with chronic renal failure, and 16 patients undergoing maintenance hemodialysis. Energy expenditure was measured in the resting state, during quiet sitting, during controlled exercise on an exercise bicycle, and for four hours after ingestion of a test meal. Resting energy expenditure (kcal/min/1.73 m2) in the normal subjects, chronically uremic patients and hemodialysis patients was, respectively, 0.94 +/- 0.24 (SD), 0.91 +/- 0.20, and 0.97 +/- 0.10. There was also no difference among the three groups in energy expenditure during sitting, exercise, or the postprandial state. Within each group, energy expenditure during resting and sitting was directly correlated. During bicycling, energy expenditure was directly correlated with work performed, and the regression equation for this relationship was similar in each of the three groups. These findings suggest that for a given physical activity, energy expenditure in nondialyzed, chronically uremic patients and maintenance hemodialysis patients is not different from normal. The low energy intakes of many of these patients may be inadequate for their needs.

During continuous ambulatory peritoneal dialysis (CAPD), concentrations of serum urea nitrogen (SUN) have been reported that are lower than what would be predicted from estimated dietary protein intake and the calculated urea clearance by dialysis. Net urea generation (urea nitrogen appearance) and losses of various nitrogenous constituents were measured during 12 metabolic studies in patients undergoing CAPD. Patients ingested constant diets containing either 1.0 or 1.4 g or protein per kilogram of body wt per day; total daily urea "clearance" from peritoneal dialysis plus renal clearance averaged 10.8 +/- 0.3 liters/day. Urea nitrogen appearance was only 55 and 68% of total nitrogen output with the low and high protein diets, respectively, values that are substantially lower than those reported in normal subjects, patients with chronic renal failure, and those undergoing hemodialysis. The reduction fraction of nitrogen appearing as urea was largely accounted for by the loss of protein and free amino acids into the dialysate. These respective constituents accounted fro 11.5 and 4.4% of total nitrogen output. Urea nitrogen appearance correlated closely (r = 0.96) with total nitrogen output in the patients undergoing CAPD.