Total Body Urea Research Articles

Comparison of hemodialysis urea clearance using spent dialysate and Kt/Vurea equations.

Dialysis adequacy is traditionally calculated from pre- and post-hemodialysis session serum urea concentrations and expressed as the urea reduction ratio, or Kt/Vurea. However, with increasing hemodiafiltration usage, we wished to determine whether there were any differences between standard Kt/Vurea equations and directly measured spent dialysate urea clearance. Urea clearance was measured from collected effluent dialysate and compared with various other methods of Kt/Vurea calculation, including change in total body urea from measuring pre- and post-total body water with bioimpedance and the Watson equation, by standard Kt/V equations, and online clearance measurements using effective ionic dialysance (OLC). We compared urea clearance in 41 patients, 56.1% male, mean age 69.3 ± 12.6 years with 87.8% treated by hemodiafiltration. Reduction in total body urea was greater when estimating changes in total body urea, compared to measured dialysate losses of 58.4% (48.5-67.6) vs 71.6% (62.1-78), p < 0.01. Sessional urea clearance (Kt/Vurea) was greater using the online Solute-Solver program compared to OLC, median 1.45(1.13-1.75) vs 1.2 (0.93-1.4), and 2nd generation Kt/V equations1.3 (1.02-1.66), p < 0.01, but not different from estimated total body urea clearance 1.36 (1.15-1.73) and dialysate clearance 1.36 (1.07-1.76). The mean bias compared to the Solute-Solver program was greatest with OLC (-0.25), compared to second-generation equations (-0.02), estimated total body clearance (-0.02) and measured dialysate clearance (-0.01). This study demonstrated that the result from equations estimating urea clearance indirectly from pre- and postblood samples from hemo- and hemodiafiltration treatments was highly correlated with direct measurements of dialysate urea clearance.

Comparison of Total Body Urea Production Potential with Total Body Carbamoyl Phosphate Synthetase (CPS-1) Activity in Newborn Piglets Infused with Alanine at 50% of Resting Energy Expenditure for 36 Hours

The calculated rate of urea production [U(p); mmol urea/(h. kg(0. 75))], based on urinary urea-N (UUN) excretion and changes in total body urea-N, was compared with the calculated total body V(max) of carbamoyl phosphate synthetase (CPS-1) of 24 neonatal piglets from four treatments as follows: 6 h baseline control (n = 8), 18 h of alanine intravenously (IV) at 50% of resting energy expenditure (REE; n = 4), 36 h of alanine IV at 50% of REE (n = 6), or 36 h of glucose IV at 50% of REE (n = 6). The following significant increases from baseline were seen in piglets infused with alanine for 36 h: 1) UUN excretion [10.6 +/- 5.9 mg N/(h. kg(0.75)) to 53.2 +/- 11.1]; 2) BUN concentrations (9.1 +/- 3.0 mmol urea N/L to 51.2 +/- 7.0); 3) calculated urea production [0.34 +/- 0.21 mmol urea/(h. kg(0.75)) to 2.39 +/- 0.53]; and 4) CPS-1 V(max) [2.0 +/- 0.81 mmol citrulline/(h. kg (0.75)) to 4.4 +/- 1.5], (P < 0.05). With the exception of CPS-1 activity, significant decreases from baseline were seen in these values in piglets infused with glucose for 36 h (P < 0.05). Comparison of calculated urea production with calculated total body CPS-1 V(max) at baseline, 18 or 36 h after the start of infusion of alanine or glucose revealed a positive relationship (slope = 0.263; P < 0.002). At all enzyme activities, infusion of alanine resulted in a significant increase in the rate of urea production compared with controls (P < 0.001). Total body CPS-1 activity varied from 1.8 to 5.8 times that of urea production, suggesting that CPS-1 did not limit urea production.

In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle

Urea cycle disorders are a group of inborn errors of hepatic metabolism that result in often life-threatening hyperammonemia and hyperglutaminemia. Clinical and laboratory diagnosis of partial deficiencies during asymptomatic periods is difficult, and correlation of phenotypic severity with either genotype and/or in vitro enzyme activity is often imprecise. We hypothesized that stable isotopically determined in vivo rates of total body urea synthesis and urea cycle-specific nitrogen flux would correlate with both phenotypic severity and carrier status in patients with a variety of different enzymatic deficiencies of the urea cycle. We studied control subjects, patients, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet. On a separate occasion the subjects either received a higher protein intake or were treated with an alternative route medication sodium phenylacetate/benzoate (Ucephan), or oral arginine supplementation. Total urea synthesis from all nitrogen sources was determined from [(18)O]urea labeling, and the utilization of peripheral nitrogen was estimated from the relative isotopic enrichments of [(15)N]urea and [(15)N]glutamine during i.v. co-infusions of [5-(amide)(15)N]glutamine and [(18)O]urea. The ratio of the isotopic enrichments of (15)N-urea/(15)N-glutamine distinguished normal control subjects (ratio = 0.42 +/- 0.06) from urea cycle patients with late (0.17 +/- 0.03) and neonatal (0.003 +/- 0.007) presentations irrespective of enzymatic deficiency. This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of argininosuccinate synthetase deficiency (0. 22 +/- 0.03), argininosuccinate lyase deficiency (0.35 +/- 0.11), and partial ornithine transcarbamylase deficiency (0.26 +/- 0.06) from normal controls. Administration of Ucephan lowered, and arginine increased, urea synthesis to the degree predicted from their respective rates of metabolism. The (15)N-urea/(15)N-glutamine ratio is a sensitive index of in vivo urea cycle activity and correlates with clinical severity. Urea synthesis is altered by alternative route medications and arginine supplementation to the degree that is to be expected from theory. This stable isotope protocol provides a sensitive tool for evaluating the efficacy of therapeutic modalities and acts as an aid to the diagnosis and management of urea cycle patients.

Evaluation and management of urea cycle disorders using stable isotope infusions

Diagnosing partial urea cycle deficiencies based on clinical and laboratory data is difficult and there is often poor correlation between genotype, in vitro enzyme activity, and phenorypic expression. We have used stable isotope infusions to measure total body glutamine and urea flux for the evaluation of patients with urea cycle disorders. We have previously determined the rate of total body urea production by measuring blood 13C-urea isotopic enrichment during an infusion with the stable isotope 13C-urea, and the proportional contribution of peripheral nitrogen to urea synthesis by measuring the incorporation of 15N from 15N glutamine into 15N urea. The ratio of the isotopic enrichments of 15N urea/15N-glutamine (15N-U/G) allowed us to distinguish carriers for omithine transcarbamylase deficiency (OTCD) both from their affected offspring and from normal control subjects (Lee et. al., submitted). Collectively these data suggest that the flux from 15N glutamine to 15N urea is a sensitive measure of urea cycle activity and is capable of differentiating female carriers for OTCD from normal controls.We have now applied this method to the 1) diagnosis of asymptomatic at risk partial OTCD females, 2) titration of dietary protein tolerance for managing a severe OTCD male patient, and 3) comparison of differences in the bioavailability of enteral vs. systemic sources of nitrogen for total body urea production. By determining the 15N-U/G ratio in 5 at-risk females in two OTCD sibships in whjch mutations were not found in the index case, we were able to measure normal and abnormal urea production and determine carrier status. In the second case, we determined total body glutamine flux at 1.2 gm/kg/day and at 0.8 gm/kg/day protein intake in a 7 month null activity OTCD male to titrate protein tolerance and guide dietary therapy. In the third case, we tested the hypothesis that intestinally generated ammonia and alanine are more effective immediate precursors for urea synthesis than peripherally generated glutamine and as a consequence individuals who have a compromised urea cycle activity would metabolize excessive dietary protein more effectively than peripherally generated protein. By comparing the transfer of 15N from oral and intravenous 15NH4Cl to urea, we found that individuals who have partial urea cycle activity metabolize excessive dietary protein more efficiently, underlying the observation thai these patients are particularly susceptible to stress and fasting. In conclusion this approach may also lead to improvements in the nutritional management of patients with urea cycle defects and those who are severely catabolic during critical illness.

Tracer methods underestimate short-term variations in urea production in humans.

Urea production rate (Ra) is commonly measured using a primed continuous tracer urea infusion, but the accuracy of this method has not been clearly established in humans. We used intravenous infusions of unlabeled urea to assess the accuracy of this technique in normal, postabsorptive men under the following four different conditions: 1) tracer [13C]urea was infused under basal conditions for 12 h (control); 2) tracer [13C]urea was infused for 12 h, and unlabeled urea was infused from hours 4 to 12 at a rate twofold greater than the endogenous Ra ("step" infusion); 3) tracer [13C]urea was infused for 12 h, and unlabeled urea was infused from hours 4 to 8 ("pulse" infusion); and 4) tracer [13C]urea was infused for 9 h, and unlabeled alanine was infused at a rate of 120 mg.kg-1.h-1 (1.35 mmol.kg-1.h-1) from hours 4 to 9. Urea Ra was calculated using the isotopic steady-state equation (tracer infusion rate/tracer-to-tracee ratio), Steele's non-steady-state equation, and urinary urea excretion corrected for changes in total body urea. For each subject, endogenous urea Ra was measured at hour 4 of the basal condition, and the sum of this rate plus exogenous urea input was considered as "true urea input". Under control conditions, urea Ra at hour 4 was similar to that measured at hour 12. After 8-h step and 4-h pulse unlabeled urea infusions, Steele's non-steady-state equation underestimated true urea input by 22% (step) and 33% (pulse), whereas the nonisotopic method underestimated true urea input by 28% (step) and 10% (pulse). Similar conclusions were derived from the alanine infusion. These results indicate that, although Steele's non-steady-state equation and the nontracer method more accurately predict total urea Ra than the steady-state equation, they nevertheless seriously underestimate total urea Ra for as long as 8 h after a change in true urea Ra.

Protein and energy intake, nitrogen balance and nitrogen losses in patients treated with continuous ambulatory peritoneal dialysis

The aim of this investigation was to analyze factors which influence the dietary protein intake (DPI), the energy intake and the utilization of ingested protein, and to determine the relationship between various types of nitrogen losses in stable continuous ambulatory peritoneal dialysis (CAPD) patients. We performed 23 nitrogen balance (NB) studies of 6 to 11 days duration in 12 CAPD patients. One study was performed in all patients 3.4 +/- 1.2 months after starting CAPD (early studies). The study was then repeated in nine patients after 12.1 +/- 2.6 months, and two of these patients were studied again after 16 and 24 months, respectively (late studies). Before each NB study, the dietary intakes prior to the study were assessed in diaries and interviews. During a few days preceding the NB periods and during the NB periods each patient received an individualized diet composed so as to resemble the patients' spontaneously chosen diet regarding DPI and dietary energy intake (DEI). Total nitrogen, protein, urea and creatinine were analyzed in the dialysate and urine collected daily. Total nitrogen was also analyzed in the feces, collected over the whole NB period. Total nitrogen appearance (TNA), non-protein nitrogen appearance (NPNA) and urea nitrogen appearance (UNA) were calculated by correcting total nitrogen output, non-protein nitrogen output, that is, TNA minus the total protein losses (PL) and urea nitrogen output for changes in total body urea nitrogen. Glucose was determined in the collected dialysate and the daily glucose absorption was calculated. DPI varied between 0.62 and 2.09 g/kg/day, DEI between 21 and 42 kcal/kg/day and the peritoneal energy (glucose) intake (PEI) between 4 and 13 kcal/kg/day. DPI (but not DEI) correlated with Kt/V(urea) and Kt/VCr and with total and renal clearances for urea and creatinine. NB (not corrected for "unmeasured" nitrogen losses) was positive in most studies, and it correlated with DPI and the total energy intake (TEI) in the early studies, but only with TEI in the late studies. DPI correlated with TNA, NPNA, UNA, non-protein-non-urea nitrogen loss and fecal nitrogen loss. UNA was highly correlated with TNA and NPNA (r = 0.95). We used data from 33 NB studies in CAPD patients (our present data combined with data from the literature) to calculate regression equations describing the relationship between TNA and NPNA, respectively, and UNA.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of lactulose on urea metabolism and nitrogen excretion in cirrhotic patients

The mechanism of action of lactulose is not known, although in vitro evidence suggests that lactulose may increase ammonia utilization and decrease ammonia production by gut flora. If these changes occur in patients, they should be reflected in altered urea metabolism and nitrogen excretion. In seven studies conducted in 6 cirrhotic patients, the effects of lactulose on the kinetics of urea metabolism and nitrogen excretion were determined. Lactulose caused a fall in urea production (−24%, P < 0.005) that was reflected in a decrease in both urea degradation and urinary urea excretion. Likewise, lactulose caused a decrease in the total body urea pool. The fall in urinary urea was accompanied by a large (two- to threefold) increase in stool nitrogen that was of a similar magnitude of the fall in urinary urea. Although urea degradation fell after lactulose, the intestinal (extrarenal) clearance of urea did not, indicating that the fall in urea degradation was due to the observed fall in the urea pool. The results indicate that: (a) Lactulose decreases urea production by increasing the fecal output of nitrogen, a finding compatible with altered ammonia metabolism by gut flora, (b) Lactulose decreases urea degradation, although this effect is primarily the result of a fall in the urea pool and connot be attributed to an inhibition of urea of breakdown in the gut lumen.

Parenteral nutrition with essential amino acids in pretransplantation anephrics.

The effect of intravenous hyperalimentation with essential amino acids and hypertonic dextrose on nitrogen metabolism, total body urea and creatinine was studied in 16 patients with end-stage renal disease prior to and after bilateral nephrectomy, splenectomy and appendectomy. Parenteral essential amino acids and hypertonic dextrose are effective in lowering blood urea nitrogen in anephric patients who are incapable of improving renal function. The inclusion of essential amino acids in hypertonic dextrose increases nutritional value far beyond that which can be attributed to the caloric concentration of the amino acids themselves.

Urea excretion in the hibernating Columbian ground squirrel (Spermophilus columbianus).

Hibernation was induced in Columbian ground squirrels by placing them in refrigerated cages equipped with urine-collection pans. On arousal, urine and blood were collected from each animal, which was then allowed to reenter hibernation. After several days the animal was sacrificed and bladder urine and another blood sample were taken. In addition, four active non-hibernating ground squirrels were placed in a cage at room temperature with neither food or water. Urine was collected at 9 and 26 hours and blood was collected at 0 and 26 hours. Although only seven of ten hibernating squirrels had a higher blood-urea level when sacrificed than during the previous arousal, the other three had very high levels in the arousal period and probably further excreted urea before entering hibernation. When total body urea was calculated on a body weight basis, all except one animal showed a greater level of urea during hibernation than in the previous arousal. During their period of dehydration, the non-hibernating summer squirrels showed a marked decrease in blood urea. The osmotic concentration of the urine from these squirrels was due less to urea than that excreted during arousal by hibernating squirrels. Thus, it appears that urea accumulates in the blood during hibernation and is excreted in the urine during arousal.