Dialysis apparatus which ultra-filters blood and a related method

Abstract

This invention relates to a dialysis apparatus which ultra-filters blood and to a related method of ultra-filtering blood ex-vivo. More preferably the invention relates to haemodiafiltration using protein-losing membranes and a secondary ultrafiltration and partial re-infusion of haemodiafiltrate for increasing extraction of middle molecules and protein bound uraemic toxins and reducing albumin loss.

Claims

1. A hemodialysis apparatus for ultrafiltering blood from a patient, the hemodialysis apparatus comprising: a first dialyzer circuit which includes a first hemodialyzer including a blood compartment and a dialysate compartment separated by a first hemodialyzer membrane which filters blood in that is forced into the blood compartment thereof by at least a first pump, the dialysate compartment being fed with dialysate pumped thereinto by at least a second pump through a first side of a first balance chamber and outputting hemodiafiltrate into a blood compartment of a second hemodialyzer, an output of the blood compartment of the first hemodialyzer being combined with an output of the blood compartment of the second hemodialyzer to generate blood out; a second dialyzer circuit which facilitates dissociation of plasma protein bound uremic toxins, the second dialyzer circuit including the second hemodialyzer with a second hemodialyzer membrane which separates the uremic toxins from the plasma protein by ultrafiltration to output a residue of the hemodiafiltrate containing concentrated plasma protein from the blood compartment of the second hemodialyzer for recirculation to the blood out to the patient, at least a third pump being connected between an output from the first hemodialyzer and an input to the blood compartment of the second hemodialyzer, and a dialysate compartment output comprising a filtrate of the hemodiafiltrate from the second hemodialyzer being pumped through a second side of the first balance chamber; and a second balance chamber connected to the second hemodialyzer, the first hemodialyzer membrane is more porous than the second hemodialyzer membrane.

2. The hemodialysis apparatus according to claim 1, wherein: an additional pump is connected to an output of the second hemodialyzer and is operative to control a volume flow rate of net fluid removal from an extracorporeal blood circuit.

3. The hemodialysis apparatus according to claim 1, wherein: the second hemodialyzer ultra filters at least 90% of a volume of filtered hemodiafiltrate passing therethrough.

4. The hemodialysis apparatus according to claim 1, wherein: the at least the third pump is operative to vary a volume flow rate of the hemodiafiltrate that is passed to the second hemodialyzer.

5. The hemodialysis apparatus according to claim 1, wherein; at least a fourth pump operative to vary a proportion of hemodiafiltrate that is infused to the patient via a venous (return) side of an extracorporeal blood circuit.

6. The hemodialysis apparatus according to claim 1, wherein: a pressure source ensures that hydraulic pressure in a section of a fluid pathway between the at least the third pump and at least a fourth pump operated within operational limits required for accurate volumetric performance of the at least the third pump and the at least the fourth pump.

7. The hemodialysis apparatus according to claim 6, wherein: the pressure source is a pump.

8. The hemodialysis apparatus according to claim 1, wherein: the at least the second pump and an additional pump operate to ensure a volume flow rate of hemodiafiltration replacement fluid enters the first dialyzer circuit for infusion into a venous side of an extracorporeal blood circuit.

9. The hemodialysis apparatus according to claim 8, wherein: the first balance chamber is connected to the at least the second pump and to at least a fifth pump, whereby the first balance chamber ensures correct volume flow rates for the hemodiafiltrate to be infused into the patient in event of a failure of any of the at least the first pump, the at least the second pump, the at least the third pump, and at least a fourth pump.

10. The hemodialysis apparatus according to claim 1, wherein: the second balance chamber is connected to the first balance chamber and to the at least third pump; and the second balance chamber is operative to ensure that a volume flow rate of the hemodiafiltrate is at least equal to a volume flow rate of incoming fresh dialysate.

11. The hemodialysis apparatus according to claim 1, wherein: at least a fourth pump is operative, in dependence upon operator specified criteria, to vary an ultrafiltration volume flow rate in the first hemodialyzer.

12. The hemodialysis apparatus according to claim 1, further comprising: a first sensor configured to transmit a signal indicative of hydraulic pressure in the first dialyzer circuit and the second dialyzer circuit; a second sensor configured to transmit a signal indicative of a pumping pressure; a third sensor configured to transmit a signal indicative of a pumping speed; a fourth sensor configured to transmit a signal indicative of a saline concentration; a fifth sensor configured to transmit a signal indicative of an electrical conductance of a solute in the hemodiafiltrate; and a sixth sensor configured to transmit a signal indicative of a concentration of a solute in the hemodiafiltrate.

13. The hemodialysis apparatus according to claim 12, further comprises: a control means to vary a volume of the ultrafiltered hemodiafiltrate passing from the second hemodialyzer and to vary a proportion of the protein concentrated hemodiafiltrate for infusion into a venous side of an extracorporeal blood circuit.

14. The hemodialysis apparatus according to claim 12, further comprising: a memory configured to record the patient's details, patient related data, a dialysis start time, a dialysis end time, and operational data relating to pumping data.

15. The hemodialysis apparatus according to claim 14, further comprising: a memory configured to record data from the first sensor through the sixth sensor.

16. The hemodialysis apparatus according to claim 1, further comprises: a means to vary a volume flow rate of the hemodiafiltrate to a venous side of an extracorporeal blood circuit.

17. The hemodialysis apparatus according to claim 1, further comprises: a sensor configured to sense a state of a membrane performance with treatment time, and a processor configured to determine a risk of membrane rupture and to trigger an alarm.

18. The hemodialysis apparatus according to claim 1, further comprises: a sensor arranged to sense back filtration from the second hemodialyzer and to trigger an alarm.

19. The hemodialysis apparatus according to claim 1, further comprising: a processor operative to initiate pulses of raised pressure in the dialysate compartment of the first hemodialyzer and/or the second hemodialyzer.

20. The hemodialysis apparatus according to claim 1, wherein: the first hemodialyzer membrane is housed within a removable cartridge.

21. The hemodialysis apparatus according to claim 1, further comprising: a monitor configured to monitor a preset patient criterion and to trigger an alarm when the preset patient criterion is not satisfied.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 (PRIOR ART) shows graphs of sieving coefficients against molecular weight of different molecules;

(2) FIG. 2 is a graph of probability density against membrane pore size and the differential of normalized total membrane ultrafiltration rate against membrane pore size;

(3) FIG. 3 is a graph of sieving coefficient against molecular size;

(4) FIG. 4 is a functional block diagram of one embodiment of a dialysis apparatus which ultra-filters blood and to a related method of ultra-filtering blood ex-vivo; and

(5) FIG. 5 is functional block diagram of a second embodiment of a dialysis apparatus which ultra-filters blood and to a related method of ultra-filtering blood ex-vivo.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

(6) Referring to FIGS. 4 and 5, which each show alternative embodiments of the dialysis apparatus, comprises two dialyzer circuits, the first departs from prior art HDF only in that the first hemodialyzer may consist of an MCO, HCO or other protein-losing membrane.

(7) In the second dialyzer circuit the effluent hemodiafiltrate from the first hemodialyzer/dialysis circuit passes through the blood compartment of a second MCO or HCO hemodialyzer. Ultrafiltration of between 90% and 97% of the volume of hemodiafiltrate passing through the hemodialyzer leaves 3% to 10% of protein concentrated hemodiafiltrate for reinfusion into the venous/return side of the extracorporeal blood circuit.

(8) The proportion of the volume of hemodiafiltrate ultrafiltered in the second hemodialyzer (1f) and therefore the proportion infused into the venous side of the extracorporeal blood circuit (f) is a modifiable parameter. The mechanism by which this parameter is set differs between the two preferred embodiments of the dialysate/hemodiafiltrate fluid pathway shown in FIGS. 4 and 5 whose control algorithms are as follows:

(9) FIG. 4, First Embodiment Pathway (1) 1. Operator set blood pump (P.sub.1) volume flow rate 2. Operator set first hemodialyzer ultrafiltration rate (x) according to blood flow within safety constraints programmed into the processor 3. Operator set dialysate inflow pump (P.sub.2) volume flow rate (d) 4. Processor set first hemodialyzer HDF pump (P.sub.3)=(d+x) 5. Operator set f (0.05 in the example shown in FIG. 4) 6. Processor set second hemodialyzer outflow pump (P.sub.4)=0.05 (d+x) 7. Operator set patient net ultrafiltration pump (P.sub.6) volume flow rate (y) 8. Processor set HDF replacement fluid pump (P.sub.7)=xy0.05 (d+x) 9. Allow pressure sensor driven processor adjustments to P4, within a certain tolerance, so that flow in the system remains continuous

(10) FIG. 5, Second Embodiment Pathway (2) 1. Operator set blood pump (P.sub.1) volume flow rate 2. Operator set first hemodialyzer ultrafiltration rate (x) according to blood flow within safety constraints programmed into the processor 3. Operator set dialysate inflow pump (P.sub.2) volume flow rate (d) 4. Processor set first hemodialyzer dialysate/ultrafiltration pumps (P.sub.3/P.sub.4) to d and x respectively 5. Operator set patient net ultrafiltration pump (P.sub.6) volume flow rate (y)

(11) In the First Embodiment f is preset by the machine operator (0.05 in the example shown in FIG. 4). In the second pathway f is not preset but follows automatically from the operator of the dialysis apparatus choice of x, y and d.

(12) Both embodiments incorporate at least two balance chambers. These (or an equivalent technical device) are essential for ensuring correct volume flow rates for the dialysate/hemodiafiltrate and to guarantee patient safety in the event of major loss of calibration of any of the pumps. A balance chamber effectively comprises a volume separated into two portions by a membrane. It is appreciated that two pairs of balance chambers operate in tandem.

(13) Theoretical Explanation

(14) Despite the technical differences between these two Embodiments the same mathematical model can be applied to the analysis of solute extraction. A unidimensional model of the HDF process in the first hemodialyzer and the subsequent ultrafiltration of the hemodiafiltrate in the second hemodialyzer is presented in the following paragraphs.

(15) The membrane transfer of solutes, such as albumin, with very low mass transfer coefficients, even across the more permeable types of membrane, may be analyzed as being solely due to convection. If: .sub.x=the volume flow per unit time of the remaining hemodiafiltrate (water volume flow rate for dilute solutions) at a point (x) located along the blood compartment of the second hemodialyzer m.sub.x=the mass of solute passing x per unit time then m.sub.x/v.sub.x=C.sub.x=the solute concentration at x

(16) For present purposes, an expression linking solute extraction to the cumulative level of ultrafiltration, without reference tox, will suffice. The expression can be derived by analyzing the solute mass flow rate at positions along the blood compartment of the secondary hemodialysis in terms of m.sub., where represents the remaining hemodiafiltrate volume flow rate. As .fwdarw.0 ( being positive in the direction opposite to the flow of hemodiafiltrate) m.sub..fwdarw.m.sub.S(m.sub./)v
C.sub.=C.sub.C.sub.=m.sub./[(S1)/]C.sub.[(S1)/]
where S=the convection coefficient of the solute and:
.sub.C.sub..sup.C.sup.iC.sub./C.sub.=(S1).sub..sup..sup.i/
where .sub.i is the initial volume flow rate of the hemodiafiltrate in the second hemodialyzer
ln C.sub..sub.iln C.sub.=(S1)(ln v.sub.iln v)
ln C.sub.ln C.sub..sub.i=(S1)(ln vln v.sub.i)
C.sub./C.sub..sub.i=(/.sub.i).sup.S-1

(17) Letting

(18) $f=\frac{v}{v_i}$
where is the proportion of hemodiafiltrate returned to the patient.

(19) $\frac{C_v}{C_{v_i}}=f^{S-1}\mathrm{Extraction}\left(E\right)=1-f\left(\frac{C_v}{C_{v_i}}\right)=1-f^S$

(20) As an example, if 50 L of plasma with an albumin concentration of 40 g/l passes through the first hemodialyzer with an albumin extraction of 0.01, 20 g of albumin will pass into the hemodiafiltration. If this hemodiafiltrate is then passed through a second hemodialyzer in which S for albumin=0.02 and f=0.05, albumin extraction is 0.058 and only 1.16 g of the original 20 g of albumin in the hemodiafiltrate is ultimately lost.

(21) Analysis of ultrafiltration of hemodiafiltration with regard to the extraction of smaller, more diffusible, LMWP for whom S is less than unity requires a model that takes account of both convection and diffusion.

(22) The ultrafiltration process in the second hemodialyzer may be configured such that the flow of ultrafiltrate runs in a concurrent or countercurrent direction with respect to the flow of the hemodiafiltrate. In either case, given dynamic equilibrium, the sum of the solute fluxes entering and leaving any small segment of the blood compartment between two points (x and x+x) along the active portion of the second hemodialyzer must equal zero, where x.sub.0 is the beginning of the active portion and x is positive in the direction of flow of the hemodiafiltrate. Q.sub.x, the hemodiafiltrate volume flow rate, will change with x because of ultrafiltration, as will C.sub.x the concentration of the solute. Qe.sub.x and Ce.sub.x correspond to the volume flow rate and solute concentration respectively in the ultrafiltrate compartment of the second hemodialyzer.

(23) The solute mass conservation equation within the blood compartment of the second hemodialyzer at dynamic equilibrium accords with the equation previously derived for prior art HDF: Letting q.sub.UF(x)=the ultrafiltration volume flow rate per unit length of hemodialyzer at x K=the mass transfer (diffusion) coefficient per unit length of hemodialyzer at x Asx.fwdarw.0:

(24) $\begin{array}{cc}{Q}_x{C}_x-\left(Q_x-q_{\mathrm{UF}\left(x\right)}x\right)C_{x+x}-q_{\mathrm{UF}\left(x\right)}S\left(\frac{C_x{e}^{\frac{q_{\mathrm{UF}\left(x\right)S}}{K}}-{\mathrm{Ce}}_x}{e^{\frac{q_{\mathrm{UF}\left(x\right)}S}{K}}-1}\right)x0Q_x{C}_x\left(Q_x-q_{\mathrm{UF}\left(x\right)}x\right)\left(C_x+C_x\right)+q_{\mathrm{UF}\left(x\right)}S\left(\frac{C_x{e}^{\frac{q_{\mathrm{UF}\left(x\right)S}}{K}}-{\mathrm{Ce}}_x}{e^{\frac{q_{\mathrm{UF}\left(x\right)}S}{K}}-1}\right)x{C}_x\frac{q_{\mathrm{UF}\left(x\right)}x}{Q_x-q_{\mathrm{UF}\left(x\right)}x}\left[C_x-S\left(\frac{C_x{e}^{\frac{q_{\mathrm{UF}\left(x\right)S}}{K}}-{\mathrm{Ce}}_x}{e^{\frac{q_{\mathrm{UF}\left(x\right)}S}{K}}-1}\right)\right].& 1\end{array}$

(25) C.sub.x can therefore be derived by numerical integration starting with C.sub.x.sub.0 as long as Q.sub.x, q.sub.UF(x) and Ce.sub.x can be defined. When the value of S is less than unity, using C.sub.x to calculate C.sub.x between x and x+x tends to underestimate solute extraction. The degree of error is reduced by splitting the active portion of the hemodialyzer into a large number of segments (two hundred in the case of the analysis underlying the results presented in Table 1).

(26) In the case of concurrent flow, Ce.sub.x can be derived from the boundary conditions:

(27) $Q_x+{\mathrm{Qe}}_x=Q_{x_o}{Q}_x{C}_x+{\mathrm{Qe}}_x{\mathrm{Ce}}_x=Q_{x_o}{C}_{x_o}$
so that:

(28) ${\mathrm{Ce}}_x=\frac{Q_{x_o}{C}_{x_o}-Q_x{C}_x}{Q_{x_o}-Q_x}$

(29) Q.sub.x and q.sub.UF(x) are related by the fact that

(30) $q_{\mathrm{UF}\left(x\right)}=-\frac{{\mathrm{dQ}}_x}{\mathrm{dx}}.$
The overall ultrafiltration rate is set by the product of (1f) and the volume flow rate of the hemodiafiltrate. The distribution of ultrafiltration along the length of the second hemodialyzer is set by the ratio between two hydraulic coefficients, one governing the volume flow rate of the hemodiafiltrate, the other the ultrafiltration rate across the membrane.

(31) As the hemodiafiltrate passes through the blood compartment of the second hemodialyzer its protein solute content becomes progressively more concentrated. It is assumed ere that this increase in protein concentration has a negligible effect on viscosity and that:

(32) $\begin{array}{cc}{Q}_x=-k\frac{{\mathrm{dP}}_x}{\mathrm{dx}}.& 2\end{array}$
where P.sub.x=the hydraulic pressure within the blood compartment. (At x.sub.0 a typical albumin concentration within hemodiafiltrate would be of the order of one hundredth of that in the plasma, rising to a little less than a fifth at the end of the active second hemodialyzer if f=0.05.)

(33) The loss of hemodiafiltrate from the blood compartment of the second hemodialyzer due to ultrafiltration is given by:

(34) $\begin{array}{cc}\frac{{\mathrm{dQ}}_x}{\mathrm{dx}}=-h\left(P_x-P_e\right).& 3\end{array}$
where h is the hydraulic conductivity per unit length of hemodialyzer, whose actual numerical value, as with that of k, can come from experimental observation. It is assumed that the ultrafiltrate compartment of the second hemodialyzer provides a considerably lower resistance pathway for longitudinal fluid flow than the fibre lumina and therefore that the negative hydraulic pressure (P.sub.e) required for ultrafiltration remains relatively constant throughout that compartment.

(35) (In support of this assumption, the technical datasheet accompanying the Baxter Corporation Theranova MCO hemodialyzer indicates a pressure drop in the blood compartment with bovine blood and Q.sub.b=300 ml/min of 130 mmHg. The pressure drop in the dialysate compartment with Q.sub.D=500 ml/min is quoted as 30 mmHg.)

(36) From equation 3:

(37) $\frac{d^2{Q}_x}{{\mathrm{dx}}^2}=-h\frac{{\mathrm{dP}}_x}{\mathrm{dx}}$

(38) Combining with equation 2:

(39) 0$\frac{d^2{Q}_x}{{\mathrm{dx}}^2}=\frac{h}{k}{Q}_x$

(40) This has a general solution:

(41) $Q_x={\mathrm{Ae}}^{-{\left(\frac{h}{k}\right)}^{\frac{1}{2}}x}+{\mathrm{Be}}^{{\left(\frac{h}{k}\right)}^{\frac{1}{2}}x}$ A and B can be determined from the following boundary conditions: Q.sub.x=Q.sub.x.sub.0 when x=x.sub.0 Q.sub.x.sub.L=fQ.sub.x.sub.0 when x=L, where L=the length of the active portion of the hemodialyzer
A+B=Q.sub.X.sub.0
therefore:

(42) $A=Q_{x_o}\left[\frac{e^{{\left(\frac{h}{k}\right)}^{\frac{1}{2}}L}-f}{e^{{\left(\frac{h}{k}\right)}^{\frac{1}{2}}L}-e^{-{\left(\frac{h}{k}\right)}^{\frac{1}{2}}L}}\right]\mathrm{and}B=Q_{x_o}\left[\frac{f-e^{-{\left(\frac{h}{k}\right)}^{\frac{1}{2}}L}}{e^{{\left(\frac{h}{k}\right)}^{\frac{1}{2}}L}-e^{-{\left(\frac{h}{k}\right)}^{\frac{1}{2}}L}}\right]$

(43) Numerical integration of equation 1 provides the value for C.sub.x.sub.L and the extraction of solute from hemodiafiltrate=

(44) $E=1-f\frac{C_{x_L}}{C_{x_o}}$

(45) For countercurrent flow the boundary conditions for mass conservation within the hemodialyzer are:

(46) $C_x{Q}_x-C_{x_L}{Q}_{x_L}={\mathrm{Ce}}_x{\mathrm{Qe}}_x{\mathrm{Ce}}_{x_o}{\mathrm{Qe}}_{x_o}+C_{x_L}{Q}_{x_L}=C_{x_o}{Q}_{x_o}{C}_{x_o}{Q}_{x_o}-C_x{Q}_x={\mathrm{Ce}}_{x_o}{\mathrm{Qe}}_{x_o}-{\mathrm{Ce}}_x{\mathrm{Qe}}_x$

(47) Combining the first and second of these boundary conditions and then subtracting the third gives:

(48) ${\mathrm{Ce}}_x=\frac{C_x{Q}_x-C_{x_L}{Q}_{x_L}}{Q_x-Q_{x_L}}$

(49) This can be used to provide values of Ce.sub.x for numerical integration given a certain value for C.sub.x.sub.L. An iterative process is therefore required which, in achieving internal consistency as to C.sub.x.sub.L, establishes its correct value. For larger LMWP, whose extraction is the main focus of the dialysis apparatus and for whom convection is a more important mechanism, calculations show that whether the hemodiafiltrate and ultrafiltrate are directed to run in concurrent or countercurrent directions makes very little difference to the extraction values produced by the model.

(50) Predictions of In Vivo Solute Extraction

(51) To illustrate the impact of this technique on solute extraction using MCO and/or HCO hemodialyzers, values of K.sub.oA and S, taken to be representative of four molecular size classes, were tested using the mathematical model. The four classes of molecule were: small solutes (for example phosphate), smaller LMWP (e.g. B2 microglobulin), larger LMWP (e.g. interleukin 6) and large plasma proteins (e.g. albumin). The values of K.sub.oA and S assigned to the various hemodialyzer/solute molecular class combinations were estimated using the product information sheets and promotional literature pertaining to the Nippro Elisio High Flux hemodialyzer, the Theranova MCO hemodialyzer (Baxter Healthcare Corporation) and the SepteX HCO hemodialyzer (Gambro-Baxter, Hechingen, Germany) and the results of an earlier study.

(52) For this illustration the direction of flow of the hemodiafiltrate in the second hemodialyzer is taken to be concurrent with that of the ultrafiltrate. For all four classes of molecule, it has been assumed that the effective distribution volume, at least for the duration of a single transit of the hemodialyzer, is the plasma water.

(53) Example volume flow rate parameters chosen for the illustration were a plasma water volume flow rate (Q.sub.b.sub.e) of 200 ml/min, dialysate volume flow rates (d) of 600 ml/minor 1200 ml/min and a primary hemodialyzer hemofiltration rate (x) of 70 or 80 ml/min. The internal filtration rates (IFR) of the three types of hemodialyzer were set at different levels to reflect their differing hydraulic conductivities. The patient net ultrafiltration rate was set to either zero or 10 ml/min as shown.

(54) Three different combinations of these volume flow rate parameters were studied using the model. The results shown in Table 1 were calculated on the assumption that Pathway 1 was operative whereas in Tables 2 and 3 Pathway 2 was operative.

(55) In the absence of actual experimental data, as a guide to the relationship between Q.sub.x and distance (x) along the second hemodialyzer, estimates of the two hydraulic coefficients k and h (see above) were derived as follows:

(56) Assuming a distance-averaged volume flow rate of circa 300 cm.sup.3/min in the blood compartment and an overall pressure gradient of 100 mmHg along a hemodialyzer of 20 cm active length, equation 2 was used to provide an estimate of k=60 cm.sup.4/mmHgmin.

(57) Assuming an average ultrafiltration rate of 30 cm.sup.3/min per cm of active hemodialyzer with a uniform negative dialysate compartment pressure of 300 mmHg and an average positive pressure within the fibre lumina of +50 mmHg, equation 3 was used to provide an estimate of h=(30/350) cm.sup.2/mmHg min.

(58) TABLE-US-00001 TABLE 1 (Pathway 1) A comparison of the extraction of solutes of differing molecular weight by HDF using High Flux (HF), Medium Cut Off (MCO) and High Cut Off (HCO) haemodialyzers (first three columns) and (last three columns) the dialysis apparatus utilises Dialysate Pathway 1 (primary and secondary haemodialyzers as shown, 95% ultrafiltration of haemodiafiltrate, reinfusion of the residual 5%). Q.sub.b.sub.e = 200 ml/min d = 600 ml/min HCO primary x = 70 ml/min Single HF Single MCO Single HCO with MCO f = 0.05 IFR = 20 ml/min IFR = 30 ml/min IFR = 40 ml/min Dual MCO Dual HCO secondary (net UF = 0) K.sub.oA S E.sub.1 K.sub.oA S E.sub.1 K.sub.oA S E.sub.1 E.sub.2 E.sub.1 .Math. E.sub.2 E.sub.2 E.sub.1 .Math. E.sub.2 E.sub.2 E.sub.1 .Math. E.sub.2 Small molecule 500 1 0.953 700 1 0.986 1000 1 0.998 0.95 0.937 0.95 0.948 0.95 0.948 (e.g. PO.sub.4) (98% of (99% of (99% of single HF) single HF) single HF) Smaller LMWP 40 0.6 0.351 80 1 0.559 160 1 0.745 0.95 0.531 0.95 0.708 0.95 0.708 (e.g. 2M) (151% of (202% of (202% of single HF) single HF) single HF) Larger LMWP 2 0.2 0.089 6 0.6 0.256 18 0.7 0.342 0.833 0.213 0.876 0.300 0.833 0.285 (e.g. IL6) (239% of (337% of (320% of single HF) single HF) single HF) Large plasma 0 0.002 0.00092 0.2 0.02 0.0102 0.6 0.053 0.0304 0.057 0.00058 0.145 0.0044 0.057 0.00173 proteins e.g. (63% of (478% of (188% of albumin single HF) single HF) single HF) Expected albumin 1.77 grams 19.6 grams 58.4 grams 1.11 grams 8.45 grams 3.32 grams loss per session assuming 48 litres of plasma processed and average [albumin] 40 g/l E.sub.1 = solute extraction by the primary haemodialyzer, E.sub.2 = solute extraction by ultrafiltration of the haemodiafiltrate in the secondary haemodialyzer, E.sub.1 .Math. E.sub.2 = overall solute extraction. K.sub.oA = mass transfer area coefficient (ml/min), S = convection coefficient, Q.sub.b.sub.e = plasma volume flow rate, d = volume flow rate of fresh dialysate, x = primary haemodialyzer haemofiltration rate, IFR = internal filtration rate.

(59) TABLE-US-00002 TABLE 2 (Pathway 2) A comparison of the extraction of solutes of differing molecular weight by HDF using high flux (HF), medium cut off (MCO) and high cut off (HCO) haemodialyzers (first three columns) and (last three columns) the dialysis apparatus n incorporating Dialysate Pathway2 (primary and secondary haemodialyzers as shown, 89.7% ultrafiltration of haemodiafiltrate, reinfusion of the residual 10.3%). Q.sub.b.sub.e = 200 ml/min d = 600 ml/min x = 80 ml/min Single HF Single MCO Single HCO HCO primary with f = 0.103 IFR = 20 ml/min IFR = 30 ml/min IFR = 40 ml/min Dual MCO Dual HCO MCO secondary net UF = 10 ml/min K.sub.oA S E.sub.1 K.sub.oA S E.sub.1 K.sub.oA S E.sub.1 E.sub.2 E.sub.1 .Math. E.sub.2 E.sub.2 E.sub.1 .Math. E.sub.2 E.sub.2 E.sub.1 .Math. E.sub.2 Small molecule 500 1 0.960 700 1 0.989 1000 1 0.999 0.90 0.890 0.90 0.899 0.90 0.899 (e.g. PO.sub.4) (93% of (94% of (94% of single HF) single HF) single HF) Smaller LMWP 40 0.6 0.379 80 1 0.590 160 1 0.769 0.90 0.531 0.90 0.692 0.90 0.692 (e.g. 2M) (140% of (183% of (183% of single HF) single HF) single HF) Larger LMWP 2 0.2 0.104 6 0.6 0.287 18 0.7 0.374 0.743 0.213 0.796 0.298 0.743 0.278 (e.g. IL6) (205% of (287% of (267% of single HF) single HF) single HF) Large plasma 0 0.002 0.0011 0.2 0.02 0.0117 0.6 0.053 0.0342 0.044 0.0005 0.113 0.0039 0.044 0.0015 proteins e.g. (45% of (355% of (136% of albumin single HF) single HF) single HF) Expected albumin 2.11 grams 22.4 grams 65.7 grams 0.96 grams 7.49 grams 2.88 grams loss per session assuming 48 litres of plasma processed and average [albumin] 40 g/l E.sub.1 = solute extraction by the primary haemodialyzer, E.sub.2 = solute extraction by ultrafiltration of the haemodiafiltrate in the secondary haemodialyzer, E.sub.1 .Math. E.sub.2 = overall solute extraction. K.sub.oA = mass transfer area coefficient (ml/min), S = convection coefficient, Q.sub.b.sub.e = plasma volume flow rate, d = volume flow rate of fresh dialysate, x = primary haemodialyzer haemofiltration rate, IFR = internal filtration rate.

(60) TABLE-US-00003 TABLE 3 (Pathway 2) A comparison of the extraction of solutes of differing molecular weight by HDF using High Flux (HF), Medium Cut Off (MCO) and High Cut Off (HCO) haemodialyzers (first three columns) and (last three columns) the dialysis apparatus incorporates Dialysate Pathway 2 (primary and secondary haemodialyzers as shown, 94.5% ultrafiltration of haemodiafiltrate, reinfusion of the residual 5.5%). Q.sub.b.sub.e = 200 ml/min d = 1200 ml/min HCO primary x = 80 ml/min Single HF Single MCO Single HCO with MCO f = 0.055 IFR = 20 ml/min IFR = 30 ml/min IFR = 40 ml/min Dual MCO Dual HCO secondary net UF = 10 ml/min K.sub.oA S E.sub.1 K.sub.oA S E.sub.1 K.sub.oA S E.sub.1 E.sub.2 E.sub.1 .Math. E.sub.2 E.sub.2 E.sub.1 .Math. E.sub.2 E.sub.2 E.sub.1 .Math. E.sub.2 Small molecule 500 1 0.969 700 1 0.993 1000 1 0.999 0.945 0.938 0.945 0.944 0.945 0.944 (e.g. PO.sub.4) (97% of (97% of (97% of single HF) single HF) single HF) Smaller LMWP 40 0.6 0.377 80 1 0.594 160 1 0.777 0.945 0.561 0.945 0.734 0.945 0.734 (e.g. 2M) (149% of (195% of (195% of single HF) single HF) single HF) Larger LMWP 2 0.2 0.101 6 0.6 0.284 18 0.7 0.371 0.823 0.234 0.868 0.322 0.823 0.305 (e.g. IL6) (232% of (319% of (302% of single HF) single HF) single HF) Large plasma 0 0.002 0.00106 0.2 0.02 0.0114 0.6 0.053 0.033 0.056 0.00064 0.141 0.0047 0.056 0.00185 proteins e.g. (60% of (443% of (175% of albumin single HF) single HF) single HF) Expected albumin 2.04 grams 21.9 grams 63.4 grams 1.23 grams 9.02 grams 3.55 grams loss per session assuming 48 litres of plasma processed and average [albumin] 40 g/l E.sub.1 = solute extraction by the primary haemodialyzer, E.sub.2 = solute extraction by ultrafiltration of the haemodiafiltrate in the secondary haemodialyzer, E.sub.1 .Math. E.sub.2 = overall solute extraction. K.sub.oA = mass transfer area coefficient (ml/min), S = convection coefficient, Q.sub.b.sub.e = plasma volume flow rate, d = volume flow rate of fresh dialysate, x = primary haemodialyzer haemofiltration rate, IFA = internal filtration rate.

(61) These results show that it is possible to increase the extraction of smaller and larger LMWP to varying degrees (with increases of between 51% and 237% in the examples given in Tables 1, 2 and 3) using the dialysis apparatus and to achieve those increases without excessive loss of albumin. The Second Embodiment (Pathway 2) requires twice the volume flow rate of fresh dialysate to achieve similar levels of LMWP as the First Embodiment (Pathway 1) making the latter the likely preferred option from an economic and sustainability perspective.

(62) Although the normal physiological rate of renal albumin loss is only 600 mg per day, daily turnover of albumin is approximately 10 grams. On this basis a thrice weekly albumin loss from therapy of 8.45 grams using two HCO hemodialyzers. The dialysis apparatus might be considered reasonable, however the option that appears to provide the best compromise between higher LMWP extraction and minimal albumin loss involves the use of an HCO membrane as the primary hemodialyzer and an MCO membrane as the secondary hemodialyzer. Under these circumstances, assuming 95% ultrafiltration of hemodiafiltrate with Pathway 1, a minor reduction (1-2%) in the extraction from plasma water of small solutes compared to prior art treatment may be anticipated, however the impact of this reduction on aggregate small solute removal over the entire course of a dialysis treatment session will be marginal, inter compartmental solute kinetics being a far more important limiting factor.

(63) The invention may also be deployed to remove protein bound uremic toxins (PBUT), such as indoxyl sulphate (IS) and p-cresylsulphate (pCS) which are small solutes actively secreted from the peritubular capillary blood of healthy kidneys into the lumen of the proximal tubule. Albumin is the predominant binding protein for these toxins leaving a free fraction of circa 0.1 for IS and 0.07 for pCS. Albumin binding significantly reduces the efficiency of IS and pCS extraction by prior art high flux membrane hemodialysis with or without high volume ultrafiltration. The predominant mechanism(s) by which albumin binding reduces PBUT extraction is uncertain but the conclusion of the analysis presented below is that the effect on volume of distribution (VD) is unlikely to be the sole cause of the modest post treatment reductions in PBUT concentration (20% to 30%) that are observed.

(64) If it is assumed that during hemodialysis treatment PBUT are effectively restricted to the plasma compartment and that the kinetics of their dissociation from albumin and the kinetics of their mass transfer, including those between the blood and dialysate compartments of the hemodialyzer, are not rate limiting then their reduction ratio following a session of hemodialysis treatment can be estimated as follows:

(65) Assuming a total blood volume of 5 L and a haematocrit of 30% the total plasma volume will be 3.5 L. If the free fraction of the PBUT for example CS is taken to be 0.07 its V.sub.D will be approximately:

(66) $3.5\left(1+\frac{93}{7}\right)=50L$

(67) If the blood volume flow rate to the hemodialyzer were 300 ml/min i.e. 210 ml/min in terms of plasma flow, the dialysate flow rate were 600 ml/min and PBUT mass transfer kinetics were non rate limiting, the extraction of PBUT by the hemodialyzer would be:

(68) $\frac{600}{600+200\left(1+\frac{93}{7}\right)}=0.167$

(69) The above calculation also depends upon the assumption that serum albumin, as part of the V.sub.D of the PBUT, constitutes a non-saturable compartment, at least over the range of PBUT concentrations found in practice. In the absence of any definitive data with respect to albumin PBUT binding capacity, and binding affinities, it is acknowledged that this assumption can only be seen as a first approximation. Assuming single compartment kinetics the equation governing the extraction of PBUT from plasma is therefore:

(70) $\frac{d\left[\mathrm{PBUT}\right]}{\mathrm{dt}}=\frac{-0.167201\left(1+\frac{93}{7}\right)}{50,000}\left[\mathrm{PBUT}\right]=-0.01\left[\mathrm{PBUT}\right]$

(71) If a dialysis session were of 240 minutes duration it follows that:

(72) $\frac{\left[\mathrm{PBUT}\right]}{{\left[\mathrm{PBUT}\right]}_0}=0.09$

(73) That is a 91% reduction ratio (RR).

(74) As this level of reduction ratio is not observed in practice using prior art hemodialysis and HDF techniques the assumptions that the effective V.sub.D of PBUT is restricted to the plasma compartment and/or that the kinetics of PBUT albumin dissociation and their mass transfer kinetics, including that across the hemodialyzer, are not limiting factors, must come into question. Approximately 40% of total extracellular albumin is found in the plasma compartment with the remaining 60% in the interstitial fluid. If this extra V.sub.D is included in the reduction ratio calculation (with an additional 10 L to allow for the expansion of the interstitial fluid compartment in dialysis patients) this would make a total V.sub.D of 135 L.

(75) Even with this adjustment the predicted single compartment kinetics reduction ratio becomes 59%, still well in excess of what is seen using prior art hemodialysis related techniques. One published mathematical model of PBUT kinetics during hemodialysis includes the intracellular water as part of the V.sub.D for PBUT. This would add approximately another 30 L to the V.sub.D but the V.sub.D so created is very unlikely to function as a uniform compartment. It is also somewhat counterintuitive to assume that a potentially toxic metabolite such as PCS, secreted by the liver and, in renal health, destined for secretion in the proximal tubule, would also be taken up by other cells in the body thereby reducing the efficiency of its elimination.

(76) Published rate constants for the dissociation of PBUT are not readily available however the binding interaction appears to be relatively weak, reliant upon van der Waals forces, which suggests that the dissociation rate constants are likely to be quite high. The focus is therefore on the kinetics of PBUT diffusive mass transfer including that from the blood to the dialysate compartments of the hemodialyzer. Their albumin binding suggests that the diffusive transfer of PBUT may also be impaired by interactions with other large proteins.

(77) For example, if the first hemodialyzer has an albumin sieving coefficient of 0.1 and the haemofiltration rate were 70 ml/min with a plasma flow rate of 210 ml/min then, considering only PBUT dissociation from albumin in the hemodiafiltrate and ignoring diffusive flux of unbound PBUT across the hemodialyzer membrane, PBUT clearance into the primary hemodiafiltrate would be:

(78) 0$70+\left(700.1\frac{0.93}{0.07}\right)=163\mathrm{ml}/\min$

(79) The volume into which these PBUT are then distributed is expanded by a dialysate flow of 600 ml/min and therefore, assuming non saturable PBUT albumin binding, the proportion found free in the hemodiafiltrate will be:

(80) $\frac{670}{670+93}=0.88$

(81) If 95% of the volume of hemodiafiltrate is removed by the secondary ultrafiltration process and all of the albumin is returned, the proportion of unbound PBUT in hemodiafiltrate extracted by the secondary ultrafiltration process is:

(82) $0.880.95=0.836$
the resulting clearance of PBUT is:

(83) $0.836163\mathrm{ml}/\min =136\mathrm{ml}/\min$
as a proportion of total V.sub.D (including interstitial albumin) the removal rate is:

(84) $\frac{136}{135,000}=1{10}^{-3}\mathrm{per}\mathrm{minute}$

(85) Over the 240 minutes of a treatment session the resulting contribution to the PBUT reduction ratio would be approximately 21%, exclusive of any components due to diffusive flux and/or albumin losses across the second hemodialyzer.

(86) Similar calculations based on the flow parameters shown in Tables 2 and 3, indicate that increasing the flow of fresh dialysate (d) from 600 to 1200 ml/min only increases the reduction in post sessional PBUT concentration from 23% to 25% (again ignoring diffusive flux and losses associated with albumin).

(87) Greater increases in post sessional PBUT concentration reduction can be achieved by employing first hemodialyzers with higher albumin sieving coefficients. Based on the volume flow rate parameters shown in Table 1 but using a first hemodialyzer with an albumin sieving coefficient of unity the expected reduction would be 51% increasing to 65% if the dialysate volume flow rate is increased to 1200 ml/min. The use of very porous membranes in the first hemodialyzer will tend to increase albumin losses. However, if the potential for increasing PBUT extraction is seen as the major therapeutic advantage of the invention then the use of less porous membranes, for example standard high flux hemodialyzers, as the second hemodialysis in combination with a highly porous first hemodialyzer would allow high levels of PBUT extraction to be achieved whilst keeping albumin losses to a minimum albeit sacrificing the increase in LMWP extraction that could otherwise be achieved

(88) The invention has been described by way of examples only and it will be appreciated that variation may be made to the aforementioned embodiments, without departing from the scope of protection, as defined by the claims.