B-type natriuretic peptide and interdialytic fluid retention are independent and incremental predictors of mortality in hemodialysis patients.

AIM: Management of fluid homeostasis remains a major challenge in hemodialysis patients. We aimed to establish whether the cardiac strain marker B-type natriuretic peptide (BNP) could help to identify hypervolemic patients at increased risk of death. METHODS: BNP levels were determined before dialysis in the entire HD population at our institution (n = 57). IDWG and BNP were stratified above or below 1.5 kg or the median value, respectively. All patients were prospectively followed for 35 months. The influence of IDWG and BNP on mortality was assessed with a Cox proportional hazards model, adjusted for each other, as well as for demographics, comorbidities, cardiac function, residual diuresis, dialysis duration and efficiency and complications of renal failure. RESULTS: Median BNP was 303 (135 - 692) and 21 (36%) patients displayed an average IDWG below 1.5 kg. During follow up a total of 25 (44%) patients died, 5 (26%) in the low IDWG group and 20 (53%) in the high IDWG group (adjusted hazard ratio (adjusted HR) 5.31 95% CI (1.47 - 19.1), p = 0.011). In the low BNP group 7 (25%) patients died and in the high BNP Group 18 (62%) patients died (adjusted HR 3.53 95 CI (1.37 - 9.09), p = 0.009). When both factors were considered simultaneously, patients with low BNP and low IDWG had an 11 times lower risk of death compared to patients with high BNP and high IDWG (HR. 0.08 95% CI (0.01 - 0.6129, p = 0.015). CONCLUSIONS: BNP and IDWG are independent and incremental predictors of mortality in HD patients. These findings suggest that BNP guided fluid management could improve survival in these patients.

[Liver cirrhosis in diabetes mellitus; a complication not always recognized]. / Levercirrose bij diabetes mellitus, een niet altijd onderkende complicatie.

Non-alcoholic fatty liver disease is common among diabetic patients and carries the risk of non-alcoholic steatohepatitis (NASH) and progressive fibrosis and cirrhosis. This is illustrated by three patients with diabetes mellitus, two women aged 76 and 59, and a man aged 58. The first patient was referred to our clinic with ascites that appeared to be due to a previously unrecognized NASH associated with diabetes and which resulted in liver cirrhosis. She was treated with diuretics and subsequently remained stable. The male patient, suffering from overweight, had silently developed liver cirrhosis prompting referral to a transplantation centre. For this procedure he was put on a weight reduction programme. The third patient also had diabetes-associated liver cirrhosis, but was referred for transplantation when liver failure became inevitable. Because of the increasing prevalence of overweight and diabetes, there will be an increase in the number of patients with diabetes associated NASH and liver failure requiring transplantation.

Anthropometry-based equations overestimate the urea distribution volume in hemodialysis patients.

BACKGROUND: Protein intake in hemodialysis patients can be estimated indirectly from the protein equivalent of total nitrogen appearance (PNA) during the interdialytic period. A reliable estimate of the patient's urea distribution volume (UDV) is required to assess protein intake from PNA values. UDV values are derived frequently from simple anthropometric equations. METHODS: UDV values based on anthropometric methods were compared with UDV values determined by direct dialysate quantitation (DDQ) in 54 stable chronic hemodialysis patients. The anthropometric methods included the following: the Watson equations (WAT), a fixed proportion of postdialysis body weight, 58% for males and 55% for females (% body wt), and skinfold thickness measurements (SFT). Postdialysis blood samples were drawn at 15-minutes postdialysis. RESULTS: UDV(WAT) and UDV(SFT) overestimated UDV(DDQ) by about 8 L [limits of agreement (LOA): 2.6 to 14.2 L] in males and about 6 L (LOA: -0.8 to 12.4 L) in females. The overestimation by UDV(%BW) was even larger: 10.5 L (LOA: 2.0 to 19.0 L) in males and 11.1 L (LOA: 2.1 to 20.1 L) in females. The difference between UDV(%BW) and UDV(DDQ) correlated with the percentage of body fat (r = 0.57) and body mass index (r = 0.48). In a subgroup of seven patients, UDV was also determined by dilution (DIL) of the stable isotope [(13)C]urea. UDV(WAT) and UDV(%BW) overestimated UDV(DIL) significantly. In contrast, UDV(DDQ) was significantly smaller than UDV(DIL), even after correction for incomplete postdialysis equilibration. PNA values calculated using the various UDV estimates were compared with dietary protein intake (DPI) assessed from food records. PNA(DDQ) (61 +/- 10 g/day) did not differ significantly from DPI (63 +/- 13 g/day), but the agreement in individual patients varied considerably (LOA, -24 to 20 g/day). Anthropometric-based PNA values overestimated DPI by 8 to 16 g/day. CONCLUSIONS: Anthropometry-based equations overestimate UDV values in hemodialysis patients, leading to an overestimation of PNA values. Although PNA measurements by DDQ appear to be more reliable for assessing protein intake, PNA(DDQ) values should be interpreted with caution in individual hemodialysis patients.

Relating protein intake to nutritional status in haemodialysis patients: how to normalize the protein equivalent of total nitrogen appearance (PNA)?

BACKGROUND: The protein equivalent of total nitrogen appearance (PNA) is assumed to be a reliable estimate of dietary protein intake in haemodialysis patients. Protein requirements are related to body size. In order to standardize PNA to individual differences in body size, PNA is normalized to various terms related to the patient's body weight. It is not clear which is the most appropriate method to normalize PNA. METHODS: We calculated five commonly used variants of normalized PNA and related them to indices of nutritional status in 57 stable chronic haemodialysis patients, 57 +/- 15 (mean +/- SD) years of age. PNA, determined by direct dialysate quantification, was normalized to actual post-dialysis dry body weight (DBW), normal body weight (DBWnormal), lean body mass (LBM), normal lean body mass (LBMnormal), and 'normalized' body weight (N). Nutritional status was assessed using an index of nutrition composed of anthropometry derived parameters and plasma albumin concentration. RESULTS: PNA(DBW) (0.85 +/- 0.14 g/kg/d) tended to be higher than PNA(DBWnormal) (0.81 +/- 0.14 g/kg/d). PNA(LBM) (1.17 +/- 0.19 g/kg/d) did not differ from PNA(LBMnormal) (1.19 +/- 0.21 g/kg/d). PNA(N) (1.06 +/- 0.14 g/kg/d) was significantly higher than PNA(DBW) and PNA(DBWnormal), but lower than PNA(LBM) and PNA(LBMnormal). Actual PNA (61 +/- 13 g/d) correlated significantly with DBW (r=0.52) and LBM (r=0.63) indicating that large patients eat more protein. Interestingly, actual PNA correlated with plasma albumin (r=0.33) and with the overall index of nutrition (r=0.27) as well. PNA(DBW) correlated negatively with relative DBW (r=-0.32), expressed as a percentage of normal values, indicating that PNA(DBW) is relatively high in underweight patients. In contrast, PNA(DBWnormal) correlated positively with all nutritional parameters as well as with the overall index of nutrition (r=0.33). PNAN and PNA(LBM) did not correlate with the nutritional status, but PNA(LBMnormal) correlated positively with relative DBW (r=0.50) and with overall nutritional status (r=0.34). PNA(DBWnormal) and PNA(LBMnormal) in well-nourished patients showed overlap with the values in patients with evident malnutrition, despite the positive correlation of the normalized PNA values with nutritional status. CONCLUSIONS: Normalizing PNA by DBWnormal and LBMnormal appeared to be the most appropriate method to standardize protein intake in haemodialysis patients. Since actual PNA is the purest estimate of protein intake that correlated with nutritional status, we recommend to evaluate actual PNA as well in studies that relate protein intake to patient outcome.

Assessing dialysis adequacy and dietary intake in the individual hemodialysis patient.

BACKGROUND: Urea kinetic modeling (UKM) and food records are widely used to assess the dialysis adequacy. Clinicians use these methods in individual patients to decide whether the dialysis prescription should be adjusted. We determined the variation in UKM parameters and dietary intake within individual patients in order to determine the required number of UKM measurements, and the number of food recording days to assess dialysis adequacy and dietary intake reliably. METHODS: Session-to-session variation in urea reduction ratio (URR), Kt/V, urea distribution volume (UDVDDQ), and protein catabolic rate (PCR) was determined during three mid-week dialysis sessions in 50 stable hemodialysis patients on three-times per week hemodialysis with a Kt/V of 0.98 +/- 0.13 (mean +/- SD). The dialysis prescription was kept constant. The day-to-day variation in dietary protein intake (DPI) and dietary energy intake (DEI) was determined from seven-day food records. The 90th percentile value of the coefficient of variation (CV) was used to determine the number of measurements. RESULTS: The variation in URR [CV, 2.4% (0.3 to 9.5) median (range)] and in Kt/V [CV, 4.0% (0.6 to 11.6)] was small in the majority of the patients. The variation in UDVDDQ [CV, 4.9% (0.3 to 25.7)] and PCR [CV, 9.3% (0.8 to 28.5)] was considerably larger. The variation in DPI [CV, 17.3% (8.4 to 64.0)] was larger than that in DEI [CV, 12.9% (5.0 to 33.0)]. To assess the URR within +/- 10% of its true value, the average of two measurements was required. Reliable assessment of Kt/V required three measurements. URR and Kt/V could be assessed reliably from a single measurement in 86 and 66% of the patients, but we were not able to distinguish these patients beforehand. Reliable estimation of UDVDDQ required six measurements. The required number of measurements for PCR, DPI, and DEI was determined using a precision of +/- 20%. To assess PCR reliably, three measurements were needed. Estimation of DPI and DEI required seven and five food recording days, respectively. CONCLUSIONS: The session-to-session variation in URR and Kt/V is small in stable hemodialysis patients. Nevertheless, the averaged value of two to three measurements is required to assess the dose of dialysis reliably. Assessment of dietary intake requires at least three PCR measurements or food records for at least one week. Basing clinical decisions on a single dialysis adequacy assessment is an unjustified practice that should be abandoned.

Determination of urea kinetics by isotope dilution with [13C]urea and gas chromatography-isotope ratio mass spectrometry (GC-IRMS) analysis.

1. Stable urea isotopes can be used to study urea kinetics in humans. The use of stable urea isotopes for studying urea kinetic parameters in humans on a large scale is hampered by the high costs of the labelled material. We devised a urea dilution for measurement of the distribution volume, production rate and clearance of urea in healthy subjects and renal failure patients using the inexpensive single labelled [13C]urea isotope with subsequent analysis by headspace chromatography-isotope ratio MS (GC-IRMS) of the [13C]urea enrichment. 2. The method involves measurement of the molar percentage excess of [13C]urea in plasma samples taken over a 4 h period after an intravenous bolus injection of [13C]urea. During the sample processing procedure, the plasma samples together with calibration samples containing a known molar percentage excess of [13C]urea are acidified with phosphoric acid to remove endogenous CO2, and are subsequently incubated with urease to convert the urea present in the plasma samples into CO2. The 13C enrichment of the generated CO2 is analysed by means of GC-IRMS. This method allows measurement of the molar percentage excess of [13C]urea to an accuracy of 0.02%. 3. Reproducibility studies showed that the sample processing procedure [within-run coefficient of variation (CV) < 2.8% and between-run CV < 8.8%] and the GC-IRMS analysis (within-day CV < 1.3% and between-day CV < 1.3%) could be repeated with good reproducibility. 4. In clinical urea kinetic studies in a healthy subject and in a renal failure patient without residual renal function, reproducible values of the distribution volume, production rate and clearance of urea were determined using minimal amounts of [13C]urea (25-50 mg). 5. Because only low [13C]urea enrichments are needed in this urea dilution method using GC-IRMS analysis, the costs of urea kinetic studies are reduced considerably, especially in patients with renal failure.

The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl.

The pharmacodynamics and pharmacokinetics of a new non-depolarizing neuromuscular blocking agent, Org 9426, were investigated. Ten patients undergoing elective head and neck surgery and anaesthetized with nitrous oxide, halothane and fentanyl, received a bolus dose of Org 9426 (1 mg.kg-1, 3 x ED90). The isometric contractions of the adductor pollicis muscle following ulnar nerve stimulation (0.1 Hz and intermittent TOF) were measured. Blood and urine were sampled over 8 and 24 hr, respectively. Concentrations of Org 9426 and its possible metabolites in plasma and urine were determined using HPLC. Pharmacokinetic variables were calculated by iterative linear least square regression analysis. Intubation conditions were excellent one minute after administration at a neuromuscular block of 88 (13)% (Mean (CV]. Onset time until maximum block, duration until 25% recovery of twitch height, and recovery from 25 until 75% of twitch height were 1.7 (32), 53 (19) and 20 (37) min, respectively. The TOF reached a ratio of 0.7 after 87 (19) min. Half lives were 1.8 (33), 19 (34), 131 (62) min, respectively, in a three exponential decay; distribution volume at steady-state and plasma clearance were 0.264 (56) L.kg-1 and 4.0 (21) ml.kg-1.min-1, respectively. Plasma concentration at 25% recovery of the twitch height was 1.0 mg.L-1. Within 24 h, 33 (37)% of Org 9426 was excreted unchanged in the urine. Metabolites were absent both in plasma and urine. We conclude that the difference in potency between Org 9426 and vecuronium is similar to the difference between their effective concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.