Experimental hemodialysis in diet-induced ketosis and the potential use of dialysis as an adjuvant cancer treatment.

Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate-lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague-Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI - 0.6 to 1.2). Plasma glucose levels were reduced by 36% (- 4.5 mmol/L), p < 0.05 (95% CI - 6.7 to - 2.5). Standard base excess was increased from - 3.5 mmol/L (IQR - 4 to - 2) to 0.5 mmol/L (IQR - 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal.

An experimental, simplified method for intradialytic cardiac output measurement.

Hypotension during hemodialysis (HD) is a frequent and troublesome treatment complication. A decrease in the cardiac output (CO) due to an imbalance in the rates of fluid ultrafiltration vs. tissue reabsorption is a major cause of such episodes; thus, routine repeated measurements of CO during HD sessions could be of use in preventing its occurrence. We tested an experimental method (EXP) for measuring CO during HD using hardware already supplied with current Gambro dialysis machines. In 12 HD patients, CO was measured twice during dialysis by injecting a small (2 mL) bolus of highly concentrated saline into the patient's bloodstream and measuring the subsequent increase in dialysate conductivity using the Diascan technology. CO was calculated with the Stewart-Hamilton method using the area under the conductivity curve, measured dialysate flow rate, and dialyzer clearance. Compared with ultrasound hemodilution measurements, the EXP showed no bias and limits of agreement of ±34.6%. The intradialytic trend correlated well between the two methods (r(2) = 0.63, concordance rate 100%). We propose that with further development and refining, reliable measurements of CO could be performed easily during routine HD treatment using this new methodology.

Dialysis as a Novel Adjuvant Treatment for Malignant Cancers.

Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels-thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.

Mathematical Representation of Standard Kt/V Including Ultrafiltration and Residual Renal Function.

A new formula for calculating standard Kt/V from clinical data has been derived mathematically. It is based on using the relation between eKt/V and the pre- and postdialysis concentrations in order to find the steady state concentrations. The resulting expression for standard Kt/V depends on the treatment schedule (number, length, and spacing of treatments), residual renal function, and eKt/V and relative ultrafiltration volume of each individual treatment. These results include the effects of ultrafiltration and residual renal function also in the case with unequal treatments that may be arbitrarily distributed over the week. The new formula is found to agree, within small fractions of a percentage, with standard Kt/V from simulations of 3 and 5 days per week schedules. Several approximations are also suggested and their accuracies analyzed. It is shown that the use of the midweek eKt/V and ultrafiltration for all treatments of the week is an acceptable approximation. In the presence of residual renal function, the timing of the treatments is an important factor, and particularly in this case, the new formula shows improved accuracy over previously published formulas.

Diffusive-convective mass transfer rates for solutes present on both sides of a dialyzer membrane.

The transport (J) of waste products across dialyzer membranes is known to be proportional to the blood inlet concentration (Cbi) according to J = KCbi, where K is the clearance. For solutes present on both sides of the membrane, like sodium chloride, it has been shown that under certain conditions the transport rate will depend linearly also upon the dialysis fluid inlet concentration Cdi according to J = KbCbi -KdCdi. Kb and Kd are generalized clearances, which depend upon flow rates and membrane permeability but are independent of the concentrations. We have extended the results of Ross et al. in three ways. First, they only considered ultrafiltration (UF) that is equally distributed along the dialyzer. This is an unrealistic assumption, especially in hemodiafiltration and hemofiltration treatments with large UF rates (Quf) leading to large pressure drops along the dialyzer. Our approach allows for an arbitrary UF distribution. Second, it was possible to incorporate the more realistic model of Villaroel et al. for the local combination of diffusion and convection. Finally, we allow an arbitrary distribution of blood among the different fibers. All of these results are valid in both cocurrent and countercurrent configurations. With a sieving coefficient of 1, a good approximation for small solutes, we were also able to show that Kd = Kb - Quf, irrespective of the UF distribution along the dialyzer. This is an important result that, for example, provides a theoretical foundation for allowing a nonzero Quf in conductivity based clearance measurements.

Theoretical basis for and improvement of Daugirdas' second generation formula for single-pool Kt/V.

PURPOSE: An empirically-derived equation to estimate hemodialysis treatment variable-volume single-pool Kt/V, where Kt/V = -In(R-GFAC × t) + (4-3.5 × R) × UFV/W, was published in 1993 (1) and quickly became a standard tool for the estimation of dialysis dose. We aim to find a theoretical basis for this equation. METHODS: A mathematical derivation is used to find the connection between Kt/V and modeled urea concentrations. RESULTS: There is a theoretical basis for the empirical structure of the estimating equation, but the estimation of the effect of ultrafiltration on Kt/V can be improved. Finally, we show that the accuracy of the formula may be suboptimal for some extreme dialysis schedules and propose a new equation that is more robust across atypical dialysis prescriptions. CONCLUSIONS: The currently used Kt/V estimating equation has a sound theoretical basis and an improved version is proposed that can maintain accuracy with a broader range of fluid removal.

Simplified Citrate Anticoagulation for CRRT Without Calcium Replacement.

Since 2012, citrate anticoagulation is the recommended anticoagulation strategy for continuous renal replacement therapy (CRRT). The main drawback using citrate as anticoagulant compared with heparin is the need for calcium replacement and the rigorous control of calcium levels. This study investigated the possibility to achieve anticoagulation while eliminating the need for calcium replacement. This was successfully achieved by including citrate and calcium in all CRRT solutions. Thereby the total calcium concentration was kept constant throughout the extracorporeal circuit, whereas the ionized calcium was kept at low levels enough to avoid clotting. Being a completely new concept, only five patients with acute renal failure were included in a short, prospective, intensely supervised nonrandomized pilot study. Systemic electrolyte levels and acid-base parameters were stable and remained within physiologic levels. Ionized calcium levels declined slightly initially but stabilized at 1.1 mmol/L. Plasma citrate concentrations stabilized at approximately 0.6 mmol/L. All postfilter ionized calcium levels were <0.5 mmol/L, that is, an anticoagulation effect was reached. All filter pressures were normal indicating no clotting problems, and no visible clotting was observed. No calcium replacement was needed. This pilot study suggests that it is possible to perform regional citrate anticoagulation without the need for separate calcium infusion during CRRT.

The measurement of hemodialysis access blood flow by a conductivity step method.

BACKGROUND AND OBJECTIVES: Measurement of blood flow rate (Qa) is used to monitor dialysis access, AV fistulas, and grafts. Indicator dilution measurements of the recirculation (R) induced by reversal of hemodialysis blood lines are commonly used. This plus the dialysis circuit flow (Qb) allows calculation of Qa. R also changes the conductivity, which can be measured by a conductivity cell in the spent dialysate. The change in conductivity caused by line reversal should vary with Qa. A methodology for Qa measurement utilizing this conductivity step is proposed. This study compares conductivity step methodology against the reference method of ultrasound dilution (Qa-Trans). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was an open diagnostic test study in a single academic hospital setting involving 15 hemodialysis-dependent patients. Each was studied over four hemodialysis treatments. During each treatment, two pairs of Qa measurements (conductivity step and Trans) were made. Pre- and postdialysis sodium levels were also measured. RESULTS: Average Qa-conductivity step was 1040 ml/min. Average Qa-Trans was 1030 ml/min. The difference was NS. The data pairs showed mean difference of 1.3 +/- 17% (SD). The SD indicates a relatively large variation between data pairs. There was significant linear correlation between the Qa-conductivity step and Qa-Trans results (r = 0.91, P < 0.001). Serum sodium rose slightly but significantly over dialysis (P < 0.001). CONCLUSIONS: Qa measurement by conductivity step may be an acceptable alternative to ultrasound dilution methodology. Care must be taken to prevent salt loading when the conductivity step is used.

Hemodialysis blood access flow rates can be estimated accurately from on-line dialysate urea measurements and the knowledge of effective dialyzer urea clearance.

Measurement of blood flow rate (Qa) is used to monitor arteriovenous fistulas and grafts that are used for hemodialysis blood access. Most Qa measurements use indicator dilution techniques to measure the recirculation that is induced by the reversal of hemodialysis blood lines. R plus the dialysis circuit flow (Qb) allows the calculation of Qa. The principle of needle reversal also can be used with a dialysate urea monitor (e.g., DQM 200 [Gambro]) without injection of diluent; the effect of the reversal on urea concentration is observed. Access blood water flow rate (Qaw) in relation to the effective clearance (K) is found from the urea concentrations in the dialysate with needles in the normal (Cn) and reverse (Cr) positions: K/Qaw = (Cn - Cr)/Cr. Qa is calculated by adjusting Qaw for hematocrit and protein. For testing of this theoretical relationship, 20 patients who were dialyzed on Integra (Hospal) and Centrysystem 3 (Cobe) machines that were fitted with DQM 200 were studied. During each treatment, lines were reversed and Qa was measured by ultrasound velocity dilution (Transonic HD01 monitor); at the same time, Cn and Cr were measured by DQM 200 and K was calculated. K1 was determined from a predialysis blood urea concentration (Cb), initial dialysate urea concentration (Cd), dialysate flow rate (Qd), and the relationship K x Cb = Qd x Cd (K1). K was determined separately from a conductivity step method using Diascan (Hospal) attached to Integra machines only (K2). With the use of K1, 127 comparisons were made; a correlation existed (r = 0.916), although Bland-Altman analysis showed that the dialysate urea method gave a mean value 5.3% +/- 15.3 (+/-SD) higher than that of Transonic (P < 0.001). With the use of K2, there also was a correlation of (r = 0.944; n = 63), and Bland-Altman testing showed an NS difference of +3.5% between the dialysate urea and Transonic methods. Qa can be estimated from on-line dialysate urea measurements that are taken before and after line reversal together with knowledge of K.