Time-averaged Concentration Of Urea Research Articles

Fibroblast growth factor 23 (FGF23) level is associated with ultrafiltration rate in patients on hemodialysis

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. High circulating FGF23 levels are associated with increased mortality in patients with chronic kidney disease and those on dialysis. Current data also suggest higher circulating levels of FGF23 are associated with cardiovascular mortality, vascular calcification, and left ventricular hypertrophy; however, evidence on the role of FGF23 in patients on dialysis is incomplete, and some of the data, especially those on cardiovascular disease (CVD), are controversial. This study aimed to evaluate factors associated with FGF23 in hemodialysis patients with or without CVD. Randomly selected 76 patients on maintenance hemodialysis at a single hemodialysis center were enrolled. After the exclusion of eight patients with extremely outlying FGF23 levels, 68 patients, including 48 males and 46 patients with a CVD history, were included in the study. The mean age was 64.4 ± 12.1 years, and the mean dialysis duration was 12.7 ± 7.1 years. Dialysis duration, time-averaged concentration of urea (TAC-urea), ultrafiltration rate (UFR), blood pressure during hemodialysis session, laboratory data, and echocardiographic parameters including interventricular septum thickness (IVST), left ventricular mass indices (LVMI), and ejection fraction were included in univariate and multivariate analyses. The median lgFGF23 levels in the overall cohort and in those with and without CVD were 2.14 (interquartile range, IQR − 0.43 to − 4.23), 2.01 (− 0.52 to 4.12), and 2.59 (0.07 to 4.32), respectively, and there was no difference between the patients with and without CVD (p = 0.14). The univariate analysis revealed that FGF23 was significantly associated with age (r = − 0.12, p < 0.01), duration of hemodialysis (r = − 0.11, p < 0.01), TAC-urea (r = 0.29, p = 0.01), UFR (r = 0.26, p = 0.04), alkaline phosphatase (ALP; r = − 0.27, p = 0.03), corrected serum calcium (cCa; r = 0.32, p < 0.01), serum phosphate (iP, r = 0.57, p < 0.01), intact parathyroid hormone (iPTH; r = 0.38, p < 0.01), IVST (r = 0.30, p = 0.01), and LVMI (r = 0.26, p = 0.04). In multivariate regression analysis, FGF23 was significantly associated with cCa (F = 25.6, p < 0.01), iP (F = 22.5, p < 0.01), iPTH (F = 19.2, p < 0.01), ALP (F = 5.34, p = 0.03), and UFR (F = 3.94, p = 0.05). In addition, the univariate analysis after the categorization of patients according to CVD indicated that FGF23 was significantly associated with cCa (r = 0.34, p = 0.02), iP (r = 0.41, p < 0.01), iPTH (r = 0.39, p = 0.01), and TAC-urea (r = 0.45, p < 0.01) in patients with CVD, whereas only IVST (r = 0.53, p = 0.04) was associated with FGF23 in those without CVD. FGF23 levels in hemodialysis patients were extremely high and associated not only with mineral bone disease-related factors but also with UFR. Additionally, dialysis efficacy might be associated with lower FGF23 levels in patients with CVD.

Association of dialysis adequacy with nutritional and inflammatory status in patients with chronic kidney failure.

The number of patients with dialysis-dependent renal failure has increased in the past years worldwide. Several parameters have been introduced for the quantitative assessment of dialysis adequacy. The National Cooperative Dialysis Study results indicated that Kt/V and time-averaged concentration of urea (TAC) are predictors of mortality in patients who receive maintenance hemodialysis (HD). Also, the protein catabolic ratio (PCR), which is an indicator of nutritional status, can predict patients' mortality. Our aim was to assess the impact of parameters that show dialysis adequacy on indices of nutrition or inflammation. A total of 46 patients were included in the study; eight patients were excluded during the course of the study and 38 patients were enrolled in the final analysis. All patients were receiving HD for at least for three months. HD was administered three times per week and the study lasted for two months. Kt/V, TAC and PCR were assessed at the beginning of the study based on patients' urea and blood urea nitrogen in the first week of our study; these calculations were repeated at the end of the first and second months using the mean of the mentioned values in the month. Both adequacy indices significantly and positively correlated with changes in PCR (P <0.001). However, no significant correlation was detectable between Kt/V and TAC with either body mass index and albumin or C-reactive protein. Based on the Kt/V values, patients with adequate dialysis had slower decrease in the PCR (P <0.001). Our results indicate that adequacy of dialysis is correlated with patients' nutritional status. No correlation was observed between dialysis adequacy and inflammatory status.

Home hemodialysis: Present state of the evidence

disappointing results suggested that the high mortality associated with hemodialysis could not be impacted upon with relatively small increases in solute clearance. It also further questioned the rationale of focusing on Kt/V as a measure of dialysis adequacy. The mortality rate for hemodialysis patients in the U.S. is high at approximately 24.4 deaths/100 patient-years.4 The high mortality rate has persisted despite progressive increases in Kt/V over the past two decades, from 1.11 in 1991 to 1.52 in 2002.5 In addition, despite this increase in Kt/V, the complications of hypertension,6 malnutrition,7 congestive heart failure,8 and bone and mineral disorders9 have remained unacceptably high. These outcome data clearly indicate that dialysis adequacy cannot be simply measured in terms of Kt/V. Given these persistently poor outcomes

Dialysis session length (“t”) as a determinant of the adequacy of dialysis

Several studies have shown an association between the hemodialysis session length (the t of Kt or Kt/V) and favorable outcomes for patients on maintenance hemodialysis. In a single randomized controlled trial that systematically varied hemodialysis session length, shorter session length was associated with an increased risk for morbidity and mortality, independent of the time-averaged concentration of urea. Observational studies of dialysis session length have yielded conflicting results, although virtually all studies have confounded hemodialysis session length with hemodialysis efficiency or dose. Limited observational data from nocturnal hemodialysis programs more strongly suggest an independent beneficial effect of longer session length. In aggregate, data on the effects of hemodialysis session length are inconclusive. Future studies should evaluate hemodialysis session length independent of efficiency, and should consider the evaluation of dose by using other clearance parameters and the adequacy of ultrafiltration in addition to solute kinetics.

Simple and accurate quantification of dialysis in acute renal failure patients during either urea non-steady state or treatment with irregular or continuous schedules.

The quantification of dialysis in critically ill acute renal failure (ARF) patients requires a unifying expression that can establish kinetic equivalence amongst patients treated with irregular or frequent intermittent haemodialysis (IHD) schedules or with differing renal replacement therapies. EKRjc is a generalized form of the equivalent urea renal clearance (EKRc), and represents the equivalent continuous urea clearance that will result in the given time-averaged concentration of urea, for the given amount of urea removal. The suitability of EKRjc for the measurement of dialysis dose in this setting is examined. 420 weeks of renal replacement therapy (IHD and continuous renal replacement therapy) were simulated in 15 virtual 'patients' using a variable volume double pool urea kinetic model. Additional data from eight ARF patients were used to exemplify calculations. 1260 EKRjc values were calculated using both formal urea kinetic modelling, as well as a simplified method that requires input of changes in patient fluid state and blood urea nitrogen concentrations over a period of observation, in addition to an initial estimate of patient post-dialysis urea distribution volume (V(T)). EKRjc is shown to provide a unifying expression of dialysis dose irrespective of IHD schedule or renal replacement therapy. EKRjc is shown to be independent from the assumption of the urea steady state, and intrinsically normalized to patient urea distribution volume to allow dose comparisons between patients of different size. Residual renal urea clearance is easily incorporated where present. EKRjc is easily calculated using the simplified method without the need for iterative urea kinetic modelling. The accuracy of this simplified method is maintained when the initial estimation of V(T) is both 25% greater or smaller than the true value. Calculation of EKRjc is exemplified using the clinical data. EKRjc is the most suitable urea kinetic expression for the quantification of dialysis in critically ill ARF patients.

Carbamylated Hemoglobin as a Therapeutic Marker in Hemodialysis

Carbamylation requires isocyanic acid derived from urea. Carbamylation of hemoglobin (Hb) produces carbamylated Hb (carbHb), which could serve as a marker of posttranslational protein modification possibly associated with such uremic complications as atherosclerosis. Since relative carbHb levels are determined by mean urea concentration and duration of exposure, they could be used to assess the adequacy of a patient’s hemodialysis (HD) regimen. We therefore determined the relationship between carbHb and urea kinetics in patients with chronic renal failure (CRF) undergoing maintenance HD. In pre-HD determinations as well as in nondialyzed subjects including healthy subjects and CRF patients without dialysis, carbHb correlated well with blood urea nitrogen (BUN) concentrations, especially with BUN averaged for the preceding 1–3 months. In HD patients, carbHb correlated significantly with urea kinetics (time-averaged concentration of urea, or TAC_urea, K_t/V and urea reduction rate). The estimated mean urea concentration in HD patients calculated from the relationship between carbHb and averaged BUN over 3 months in the nondialyzed groups was lower than TAC_urea, suggesting that TAC_urea may be an overestimate. Pre-HD BUN is not a good nutritional index since detrimental decreases in urea elimination from the body can elevate pre-HD BUN independently of nutrition. We therefore devised a new nutritional index, BUN/carbHb, which correlated significantly with serum albumin as well as the normalized protein catabolic rate. These results demonstrate that carbHb accurately reflects uremic control and the BUN/carbHb ratio could serve as an index of nutritional state in HD patients.

Modeling the Dose of Home Dialysis.

The growing interest in daily dialysis and combined continuous and intermittent dialysis treatments has created the need for a dialysis dosing model that is valid over a wide range of dosing frequency and intensity. Three models have been described for this purpose and are reviewed here. They have in common the concept of a continuous clearance value which is equivalent to the summed intermittent dialysis prescribed. The continuous clearance models all define a point on the saw-toothed blood urea nitrogen (BUN) concentration profile and calculate the continuous clearance required to achieve this at the same urea generation rate. The points modeled are the peak predialysis concentration (pkKt/V), the average Co (standard Kt/V, stdKt/V), and time-averaged urea concentration (TAC), which is termed equivalent renal clearance (EKRt/V). At the present time the only data for evaluation of clinical relevance of the three models is continuous ambulatory peritoneal dialysis (CAPD) outcome. The stdKt/V predicts that optimal CAPD outcome requires weekly stdKt/V 2.0, while the pkKt/V and EKRt/V models predict optimal doses of 1.8 and 3.0. These results suggest that the stdKt/V is the most realistic model, but data over much higher levels of therapy are not yet available to judge generalizability. The stdKt/V model was used to assess dose in two hemodialysis studies with 5 to 6 dialyses per week and showed that in one study the stdKt/V was only 2.0, while in the second study it was 5.6. These results show that dose can vary widely with a similar number of dialyses per week and point to the need for a generalized dosing model to guide and compare studies of daily home dialysis.

Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure

The aim of this study was to describe a relationship between intensive care unit (ICU) patient acuity, delivered dialysis dosing, and patient mortality from newly acquired acute renal failure (ARF) requiring dialytic support. A prospectively collected ICU ARF registry formed the basis for data comparison. All data was verified. Eight hundred forty-four ICU patients were identified who met biochemical or clinical criteria of ARF and required first-time dialytic support. An acute dialysis scoring system was established using 23 independent variables identified with univariant analysis, and reduced to eight variables with multiple regression analysis in 512 patients. These eight variables were assigned a weighted score derived from their odds ratio, and the scoring system was than validated prospectively to either registry data not involved in the generation of the system (n = 148), or double-blinded score assignment at time of first dialysis (n = 130). Several established scoring systems were also appliedto the database for external comparison. Dialysis dosing was analyzed using either direct dialysate quantification or blood side urea kinetics once appropriate formulae were identified from paired blood/dialysate results. Using our database and four published ARF acuity/predictive models (Lohr, Cioffi, Bullock, Acute Physiology and Chronic Health Evaluation [APACHEii]), outcome predictions were grossly inaccurate. Application of the Cleveland Clinic Foundation (CCF) ARF acuity score showed highly predictable outcomes when compared using the Lemeshow, Hosmer goodness-of-fit statistics, and highly reproducible results in both the prospective database and double-blinded prospective clinical trials. When comparing dialytic support techniques received (intermittent dialysis v continuous therapies), the CCF scoring system remained highly predictive of mortality. When one compares dose of delivered dialysis to patients with ARF in the ICU setting, there seems to be no effect on outcome at the two ends of the scoring system. Those with very low (<4) and very high (>15) CCF scores had survivals of 78% and 0%, respectively, regardless of the dose of dialysis. Patients with intermediate scores seemed to be the most effected by dialysis dose delivery, with higher delivery (>58% urea reduction ratio for intermittent hemodialysis; <45 mg/dL time-averaged concentration of urea (TAC UREA) for continuous renal replacement therapy [CRRT]) associated with a significant reduction in mortality when compared with the same CCF scoring quartile with low-dialysis dose delivery. While underlying patient comorbidity has a significant effect on survival in ARF, the dose of delivered dialysis also seems to play a major role in patients with moderated levels of severity. Methods that allow a higher delivered dialysis dose to this group of patients will be rewarded with improved patient outcome.

Carbamylated hemoglobin: A potential marker for the adequacy of hemodialysis therapy in end-stage renal failure

Urea can dissociate in vivo to form isocyanic acid which can react with hemoglobin to form carbamylated hemoglobin. Previous work has shown that formation of carbamylated hemoglobin depends upon both the severity and the duration of renal failure. To determine whether carbamylated hemoglobin can be used as an assessment of the adequacy of hemodialysis treatment, we prospectively studied 55 stable patients who regularly attended our hospital dialysis program. Carbamylated hemoglobin was greater in those patients with a Kt/V of < or = 1.1 compared to those with a Kt/V of > 1.1 (120 +/- 8 micrograms VH/gHb versus 99 +/- 7, P < 0.01), and there was a negative correlation with Kt/V (r = -0.37, P = 0.007). There were positive correlations between carbamylated hemoglobin and the time-averaged urea concentration (r = 0.4, P = 0.004), and a negative correlation with the urea reduction ratio (r = -0.37, P = 0.01). Carbamylated hemoglobin may therefore be a useful marker of the degree of uremia, just as glycosylated hemoglobin is used in the assessment of patients with diabetes mellitus.

Citrate compared to low molecular weight heparin anticoagulation in chronic hemodialysis patients

Citrate and nadroparin calcium, a low molecular weight heparin (LMWH), were compared in a randomized cross-over trial in 21 chronic hemodialysis patients regarding anticoagulation, calcium and magnesium kinetics, biocompatibility, dialysis efficiency, and aluminum contamination. Citrate was infused into the arterial line at a minimum rate of 0.68 mmol/min, combined with a calcium and magnesium-free dialysate and intravenous supplementation of calcium and magnesium at rates of 0.22 and 0.10 mmol/min, respectively. Seven patients with a dialysis session of six hours, received 2/3 of the nadroparin dose predialysis, and 1/3 after 2.5 hours (divided dose (DD) group). A single predialysis bolus injection of nadroparin was administered to eight patients not on coumarins [single dose (SD) group] and to six patients on coumarins [single dose + coumarins (SD + C) group], all with a dialysis session of four hours. Nineteen patients received a nadroparin dose of 200 ICU/kg. Two patients with a single dose, one of them on coumarins, received a dose of 150 ICU/kg because of a hematocrit < 0.30. With citrate systemic whole blood activated clotting time (ACT) remained unchanged, indicating efficient regional anticoagulation. After two hours of dialysis with nadroparin, systemic ACT increments, that is, the increase compared to predialysis, of the DD, SD, and SD + C groups were 8.8 +/- 1.5, 18.7 +/- 4.7, and 33.3 +/- 6.1 seconds, respectively (mean +/- SEM). Postdialysis ACT increments in these groups were 1.5 +/- 3.4, 17.7 +/- 6.8, and 30.3 +/- 8.0 seconds. Two hour increments of systemic activated partial thromboplastin time (APTT) of the DD, SD, and SD + C groups during nadroparin were 5.0 +/- 1.2, 15.1 +/- 2.7, and 32.2 +/- 5.5 seconds, respectively, and the corresponding postdialysis APTT increments were 2.9 +/- 1.4, 7.8 +/- 2.4, and 15.8 +/- 2.6 seconds. Two-hour anti-Xa increments of the DD, SD, and SD + C groups amounted to 0.34 +/- 0.07, 0.67 +/- 0.07, and 0.80 +/- 0.08 IU/ml. The respective postdialysis anti-Xa increments were 0.21 +/- 0.06, 0.58 +/- 0.06, and 0.71 +/- 0.08 IU/ml (All ACT, APTT and anti-Xa increments were significant; P < 0.05), except for the ACT increments and the postdialysis APTT increment of the DD group). These increments, together with unchanged prothrombin fragments 1 and 2 (PTF1 + 2), indicate systemic anticoagulation with nadroparin. The increments of serum calcium and magnesium during citrate were comparable to the increments observed with a dialysate containing 1.5 mmol/liter calcium and 0.75 mmol/liter magnesium used in combination with nadroparin. Ionized calcium increments during citrate were significant after the end of dialysis, while the dialysate containing 1.5 mmol/liter calcium induced significant increments during and postdialysis. No differences were observed between citrate and nadroparin regarding biocompatibility), (expressed as dialysis-induced leukopenia and thrombocytopenia), and dialysis efficiency [measured as dialyzer urea and creatinine clearance, normalized weekly whole body urea clearance (Kt/Vurea) and time averaged urea concentration (TACurea)]. The citrate solution, if sterilized in glass bottles, contained 2 to 3 micrograms aluminum per mmol citrate, the nadroparin solution 0.009 microgram per 1,000 ICU. Aluminum contamination of the citrate solution was prevented by sterilizing the solution in polypropylene bottles. In conclusion, citrate anticoagulation is regional and is indicated for hemodialysis patients with an active or recently active bleeding focus. However, the citrate solution should be sterilized in polypropylene containers to prevent aluminum contamination. LMWHs induce systemic anticoagulation during hemodialysis, and this effect is enhanced by concomitant coumarin use and mitigated by a divided LMWH dose regimen. For hemodialysis patients not at risk of bleeding, LMWHs provide a simple anticoagulation regimen.

A simple nomogram for adequate haemodialysis

The publishers wouldl like to apologise for an error that occured in the printing of the abstract by Dr van der Meulen et al. We republish below the abstract along with the correct accompanying figure. HD is adequate when 3 sessions per week result in a time-averaged concentration of urea (TACu) of ± 19 mmol/1. Determinants of TACu are dialyser clearance (K), dialysis time (t), volume of distribution (V), and daily protein intake (DPI). Assuming single-pool kinetics, sufficient DPI, and no residual diuresis; the relations between PREu and POSTu are: Kt/V = ln[(Postu/PreuUF/W] and DPI= [157*(Preu-Postu)]sol;(T3sol;l) + 0.176, where UF is ultrafiltrate, W postdialysis weight, and T3/1 the longest interval. From these equations a nomogram for DPI (curves) and domain of adequate HD (shaded area) can be made. Combining row Postu/Preywith WL i.e. UF as %W gives Kt/V.

Carbamylated haemoglobin--a retrospective index of time-averaged urea concentration.

Carbamylated haemoglobin--a retrospective index of time-averaged urea concentration.

The Peak Concentration Hypothesis: A Urea Kinetic Approach to Comparing the Adequacy of Continuous Ambulatory Peritoneal Dialysis (CAPD) and Hemodialysis

The KT/V urea index (K, clearance; T, treatment time; V, volume of urea distribution) has become an established index of hemodialysis (HD) adequacy, values of KT/V less than 0.8 being associated with overt uremic toxicity. For the typical continuous ambulatory peritoneal dialysis (CAPD) regimen of 4 X 2 L exchanges/day, the equivalent KT/V approximately 0.6. Paradoxically, overt uremic toxicity is not commonly observed in CAPD patients with this typical therapy prescription. Application of the urea kinetic model demonstrates that HD and CAPD have the same time-averaged urea concentration at the same KT/V. However, as HD is an intermittent therapy, the urea concentration in HD exceeds the time-averaged concentration for about half the hours in the week. If uremic toxicity is related to the peak rather than the time-averaged urea concentration, a higher KT/V would be required in HD to achieve a peak concentration at or below the steady-state CAPD concentration. This peak concentration hypothesis predicts, based on the results of the National Cooperative Dialysis Study, that underdialysis with CAPD would occur at KT/V less than 0.4 for a protein intake of 1.1 gm/kg/day.