The Effect of Increased Frequency of Hemodialysis on Volume-Related Outcomes: A Secondary Analysis of the Frequent Hemodialysis Network Trials.

In previous reports of the Frequent Hemodialysis Network trials, frequent hemodialysis (HD) reduced extracellular fluid (ECF) and left ventricular mass (LVM), with more pronounced effects observed among patients with low urine volume (UVol). We analyzed the effect of frequent HD on interdialytic weight gain (IDWG) and a time-integrated estimate of ECF load (TIFL). We also explored whether volume and sodium loading contributed to the change in LVM over the study period. Treatment effects on volume parameters were analyzed for modification by UVol and the dialysate-to-serum sodium gradient. Predictors of change in LVM were determined using linear regression. Frequent HD reduced IDWG and TIFL in the Daily Trial. Among patients with UVol <100 ml/day, reduction in TIFL was associated with LVM reduction. This suggests that achievement of better volume control could attenuate changes in LVM associated with mortality and cardiovascular morbidity. TIFL may prove more useful than IDWG alone in guiding HD practice. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=441966.

Application of kinetic modeling to mineral metabolism management.

Patients with CKD face many consequences of renal failure, including disorders of bone and mineral metabolism. The current approach to management of these mineral metabolism issues lacks comprehensive quantitative assessment, so a kinetic modeling program has been designed to quantify intake and removal of phosphorus and calcium, as well as provide recommendations for treatment and prescriptions based on total mass balance and serum concentrations. This program is known as phosphorus kinetic modeling or PKM. The modeling program and associated graphical reports have been developed as a tool for clinicians in the management of mineral metabolism in CKD patients.

The KDIGO guideline for dialysate calcium will result in an increased incidence of calcium accumulation in hemodialysis patients.

The recently published KDIGO (Kidney Disease: Improvement of Global Outcomes) guideline (GL) for dialysate calcium suggests a narrow range of dialysate inlet calcium concentrations (C(di)Ca(++)) of 2.50-3.00 mEq/l. The work group's primary arguments supporting the GL were (1) there is a negligible flux of body Ca(++) during dialysis and (2) C(di)Ca(++) of 2.50 mEq/l will generally result in neutral Ca(++) mass balance (Ca(MB)). We believe we have shown that both of these arguments are incorrect. Kinetic modeling and analysis of dialyzer Ca(++) transport during dialysis (J(d)Ca(++)) demonstrates that more than 500 mg of Ca can be transferred during a single dialysis and that on average 76% of this Ca flux is from the miscible calcium pool rather than plasma pool. Kinetic modeling of intestinal calcium absorption (Ca(Abs)) shows a strong dependence of Ca(Abs) on the dose of vitamin D analogs and weaker dependence on the level of Ca intake (Ca(INT)). We used the Ca(Abs) model to calculate Ca(Abs) as a function of total Ca(INT) and prescribed doses of vitamin D analogs in 320 hemodialysis patients. We then calculated total dialyzer calcium removal (TJ(d)Ca(++)) and the C(di)Ca(++) that would be required to achieve TJ(d)Ca(++)=Ca(Abs), that is, Ca(MB)=0 over the whole dialysis cycle (that is, covering both the intra- and the inter-dialytic period). The results indicate that 70% of patients on Ca-based binders and 20-50% of patients on non-Ca-based binders would require C(di)Ca(++) <2.50 mEq/l to prevent long-term Ca accumulation.

Factors for increased morbidity and mortality in uremia: hyperphosphatemia.

Hyperphosphatemia is a metabolic abnormality present in the majority of patients treated by dialysis. Inorganic phosphorus (iP) can be categorized as a true uremic toxin given its known in vivo and in vitro effects and the ability to reduce these effects by normalizing iP levels. However, despite regular and adequate dialysis treatment, the goal of normalization of phosphorus levels rarely is achieved. This article briefly evaluates the significance of hyperphosphatemia in hemodialysis patients, current therapeutic approaches, and describes a new model for evaluating the dialysis prescription for iP balance.

Mechanisms determining the ratio of conductivity clearance to urea clearance.

BACKGROUND: Effective conductivity clearance (K(ecn)) has been reported to be a surrogate for effective urea clearance (K(eu)), where both are usually defined respectively as the dialyzer conductivity and urea clearances (K(cn), K(u)) corrected for access recirculation (R(ac)). However, many investigators have reported K(ecn)/K(eu) to be <1 and postulated anatomic distribution of Na in plasma water, cardiopulmonary recirculation (R(cp)), and high rates of urea clearance (K(u)) as causes. The aims of these studies were to devise analytic models of these mechanisms and to clinically evaluate the modeled relationships. METHODS: We modeled and measured: (1) Na osmotic distribution volume flow rate (Q(osmNa)) in dialyzer blood flow; (2) the separate and combined effects of R(ac) and R(cp) on K(u) and K(cn); and (3) a novel mechanism reducing the conductivity diffusion gradient during measurement of K(cn) by recirculation through the dialyzer (R(s)) of a change in systemic blood conductivity (Delta Cn(s)) induced by the abrupt changes in dialysate inlet Na (Delta C(diNa)) required for the measurement of K(cn). RESULTS: The ratio Q(osmNa)/Q(bi)= 1.00 +.03, N= 19 (Q(bi)= total blood water flow rate). Modeling showed that the effects of R(ac), R(cp), and R(s) on K(cn) can be quantified as K(ecn)= K(cn)(1 -Delta Cn(bi)/Delta Cn(di)), where Delta C(nbi) is any change in conductivity in the dialyzer blood inlet stream during a measurement, and the effect of a combination of these mechanisms is the product of the effects of individual mechanisms. A single-step dialysate profile (with R(ac)= 0) resulted in measured Delta C(biNa)/Delta C(diNa)= 2.5/15, K(ecn)/K(eu)= 0.83, N= 21 because of R(s) and R(cp), but with a two-step, high/low profile (P(h/L)) we found these respective values to be -0.6/20 and 0.97, N= 19. The ratio K(ecn)/K(eu3)= 1.06 +.02, M + SE, N= 35 (K(eu3)= Ku corrected to reflect both access and cardiopulmonary recirculation). The ratio K(ecn)/K(eu1) (K(eu1) is K(u) corrected to reflect access recirculation only) = 1.01 +.07, N= 297, with no bias on Bland Altman analysis. CONCLUSION: We conclude that (1) the osmotic Na distribution volume in blood is total blood water; (2) K(ecn) measured with a short, high/low, and asymmetric dialysate profile shows R(ac) effect but neither R(cp) nor R(s) effects on K(ecn) and K(ecn)/K(eu)= 1.0; (3) the K(ecn)/K(eu) ratio is strongly dependent on the type of dialysate profile used, which must be optimized to minimize net Na transfer to and from blood during measurement of conductivity clearance to avoid erroneous underestimation of K(ecn) and K(ecn)/K(eu) ratios <1.

Dialyzer performance in the HEMO Study: in vivo K0A and true blood flow determined from a model of cross-dialyzer urea extraction.

Inlet and outlet blood urea concentrations (Cin and Cout) can be used to directly measure dialyzer performance if simultaneous blood flow measurements (Qb) are available. Dialyzer clearance, for example, is the product of the urea extraction ratio [ER = (Cin - Cout)/Cin] and Qb. Urea concentrations are measured routinely in all hemodialysis clinics, but Qb is usually reported as the product of the pump rotational speed and pump segment stroke volume, which can be inaccurate at high flow rates. Dialyzer urea extraction is also a function of Qb, dialysate flow (Qd), and the membrane permeability-area coefficient (K0A) for urea. To determine true in vivo values for Qb and K0A in the absence of direct flow measurements, we developed a model based on an existing mathematical equation for hemodialyzer ER under conditions of countercurrent flow. Qb, K0A, and other variables were adjusted to fit the modeled ER to ER measured in 1,285 patients treated with Qb that ranged from 200 to 450 ml/min during the HEMO Study. Fitting was performed by least squares nonlinear regression using parametric and nonparametric methods for estimating true flow. As Qb rose above 250 ml/min, both methods for estimating actual Qb showed increasing deviations from the flow reported by the blood pump meter. Modeled values for K0A differed significantly among dialyzer models, ranging from 71% to 96% of the in vitro values. The previously described 14% increase in K0A, as Qd increased in vitro from 500 to 800 ml/min, was much less in vivo, averaging only 5.5 +/- 1.5% higher. Dialyzer reprocessing was associated with a 6.3 +/- 1.0% reduction in K0A and an approximate 2% fall in urea clearance per 10 reuses (p < 0.001). Multiple regression analysis showed a small but significant dialysis center effect on ER but no independent effects of other variables, including the ultrafiltration rate, diabetic status, race, ethnicity, sex, method of reuse, treatment time, access recirculation, and use of central venous accesses. The new algorithm allowed a more accurate determination of true Qb and in vivo K0A in the absence of direct flow measurements in a large population treated with a wide range of blood flow rates. Application of this technique for more than 1000 patients in the HEMO Study confirmed that in vitro measurements using simple crystalloid solutions cannot readily substitute for in vivo measurements of dialyzer function, and permitted a more accurate calculation of each patient's prescribed dialysis dose and urea volume.

Effective diffusion volume flow rates (Qe) for urea, creatinine, and inorganic phosphorous (Qeu, Qecr, QeiP) during hemodialysis.

In vivo solute clearances can be estimated from dialyzer blood (Qb) and dialysate (Qd) flow rates and a solute- and dialyzer-specific overall permeability membrane area product (KoA). However, these calculations require knowledge of the flow rate of the effective solute distribution volume in the flowing bloodstream (Qe) in order to calculate in vivo clearances and KoAs. We have determined Qe for urea, creatinine, and inorganic phosphorus from changes in concentrations across the blood compartment and mass balance between the blood and dialysate streams. We made four serial measurements over one dialysis in 23 patients and found that Qeu equals the total blood water flow rate, Qecr equals the plasma water flow rate plus 61% of red cell water flow rate, and QeiP is limited to the plasma water flow rate. Equations are derived to calculate Qe for each of these solutes from Qb and hematocrit and in vivo KoAs for each solute were calculated.

Daily dialysis: the long and the short of it.

There is considerable enthusiasm for daily hemodialysis despite the increased time commitment required of patients because of reported improvements in patient well-being, appetite and blood pressure control. To date, this therapy has been largely empirical and has been defined primarily by treatment time (t) and categorized as short daily hemodialysis (SDHD) with t about 2 h and long nocturnal hemodialysis (LNHD) with t 8-9 h. It is the authors' view that studies comparing clinical outcome with SDHD and LNHD to conventional hemodialysis (CHD) must have dialysis dosage well defined if they are to provide generalizable results. There is a broad range and overlap in the magnitude of solute removal in reported studies of SDHD, LNHD and CHD, which is illustrated here through kinetic consideration of four solutes: (1) urea; (2) inorganic phosphorus (iP); (3) beta(2)-microglobulin (beta(2)M) and (4) Na/water. The following observations can be made: (1) Patient subjective reports of increased appetite and protein intake may correlate poorly with kinetic calculation of protein catabolic rate. (2) A model of iP mass balance was developed and indicates that iP removal with CHD is inadequate; current SDHD is also inadequate to highly excessive depending on the dose of dialysis. (3) beta(2)M removal with SDHD is virtually the same as reported for LNHD, reflecting major differences in dialyzer membranes used. (4) The decrease in predialysis overhydration is a predictable function of the number of dialyses per week and may be one of the most important benefits of more frequent dialysis. (5) The standard K(t)/V (stdK(t)/V) provides a uniform method of dose calculation but the therapy prescription should also include consideration of the other solutes evaluated above.

A kinetic model of inorganic phosphorus mass balance in hemodialysis therapy.

BACKGROUND: There is growing evidence that inorganic phosphorus (iP) accumulation in tissues (dTiP/dt) is a risk factor for cardiac death in hemodialysis therapy (HD). The factors controlling iP mass balance in HD are dietary intake (GiP), removal by binders (JbiP) and removal by dialysis (JdiP). If iP accumulation is to be minimized, it will be necessary to regularly monitor and optimize GiP, JbiP and JdiP in individual patients. We have developed a kinetic model (iPKM) designed to monitor these three parameters of iP mass balance in individual patients and report here preliminary evaluation of the model in 23 HD patients. METHODS: GiP was calculated from PCR measured with urea kinetics; JdiP was calculated from the product of dialyzer plasma water clearance (K(pwiP)) and time average plasma iP concentration (TACiP) and treatment time (t); a new iP concentration parameter (nTAC(iP), the TACiP normalized to predialysis CoiP) was devised and shown to be a highly predictable function of the form nTAC(iP) = 1 - alpha(1 - exp[-betaK(pwiP). t/ViP]), where the coefficients alpha and beta are calculated for each patient from 2 measure values for nTAC(iP), K(pwiP).t/ViP early and late in dialysis; we measured 8-10 serial values for nTAC(iP), K(pwiP). t/ViP over a single dialysis in 23 patients; the expression derived for iP mass balance is DeltaTiP = 12(PCR) - [K(pwiP)(t) (N/7)][CoiP(1 - alpha(1 - exp[-beta(Kt/ViP)]))] - k(b).Nb. RESULTS: Calculated nTAC(iP) = 1.01(measured nTAC(iP)), r = 0.98, n = 213; calculated JdiP = 0.66(measured total dialysate iP) + 358, n = 23, r = 0.88, p < 0.001. Evaluation of 10 daily HD patients (DD) and 13 3 times weekly patients with the model predicted the number of binders required very well and showed that the much higher binder requirement observed in these DD patients was due to much higher NPCR (1.3 vs. 0.96). CONCLUSION: These results are very encouraging that it may be possible to monitor the individual effects of diet, dialysis and binders in HD and thus optimize these parameters of iP mass balance and reduce phosphate accumulation in tissues.

The kinetic spectrum of APD.

A generalized kinetic model to quantify the efficiency of cycler (CPD) and tidal peritoneal dialysis (TPD) is used to examine the relative efficiency of these techniques over a wide range of tidal volumes, drain profile characteristics, and hourly dialysate flow rates. In the patient with good catheter function, there is little difference in efficiency between CPD and TPD. In patients with long drain times or nonlinear drain profiles, greatly improved efficiency may theoretically be achieved with small tidal volume TPD. A generalized solution of the continuous flow PD (CFPD) kinetic model is used to demonstrate and contrast the kinetics of automated PD (APD) and CFPD.

Normalization of Dialysis Dose for Daily Dialysis.

The equilibrated Kt/V (eKtV) is widely used in hemodialysis (HD) as a measure of the intensity (magnitude) of an individual dialysis treatment. Adequate eKt/V for thrice-weekly hemodialysis (twHD) has been extensively studied, and a value in the range 1.0 - 1.1 per treatment (3.0 - 3.3 weekly) is generally considered to represent adequate therapy for this specific frequency of dialysis. However, for other schedules, summing eKt/V's and time-averaging the clearance is not appropriate. This was first demonstrated several years ago by the observation that a weekly eKt/V of 2.0 in continuous ambulatory peritoneal dialysis (CAPD) is therapeutically equal to a weekly eKt/V of 3.0 in twHD. That paradox has been resolved by the standard Kt/V (stdKt/V), which accounts for the first order nature of solute removal by dialysis, and which correctly predicts a normalized weekly stdKt/V of 2.0 for both CAPD and twHD. The equivalent renal clearance (EKR) has also been advanced as a method to normalize dose for varying treatment schedules. However, mathematical consideration shows that EKR is an exact time-averaged clearance. Analysis of data reported for daily dialysis by Piccoli et al. in the present issue of Hemodialysis International shows that the EKRc t/V calculated for daily dialysis is identical to the sum of eKt/V's for the individual dialyses. We therefore conclude that EKR is not a suitable parameter for normalizing the dialysis dose, because it fails to reflect the effect of dialysis frequency in HD therapy.

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.