**1. Introduction**

112 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Sarkar A, Mitra S, Mehta S, Raices R, & Wewers MD. (2009). Monocyte derived microvesicles deliver a cell death message via encapsulated caspase-1. *PLoS One* 4: e7140. Schindler R, Beck W, Deppisch R, Aussieker M, Wilde A, Goehl H, & Frei U. (2004). Short

Siekevitz P. (1972) Biological membranes: the dynamics of their organization. *Annu Rev* 

Singh AK, Coyne DW, Shapiro W, Rizkala AR. (2007). Predictors of the response to

Stenvinkel P, Heinburger O, Paultre F, Diczfalusy U, Wang T, Berglund L, & Jogestrand T..

Stenvinkel P. (2001). Malnutrition and chronic inflammation as risk factors for cardiovascular disease in chronic renal failure. *Blood Purif.* 19:143–151. Tetta C, Haeffner-Cavaillon N, Navino C, David S, Franceschi C, Mariano F, & Camussi G

\* Tetta C, David S, Marcelli D, Cogliati P, Formica M, Inguaggiato P, & Panichi V. (2006). Clinical effects of online dialysate and infusion fluids. *Hemodial Int* 10: S60–S66 Tetta C, Roy T, Gatti E, & Cerutti S. (2011). The rise of hemodialysis machines: new

Tielemans C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem JL. (1990).

US Renal Data System. Excerpts from the USRDS 1997 annual data report. (1997) *Am J* 

Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, Sawyer DB,

Wratten ML, Tetta C, Ursini F, & Sevanian A. (2000). Oxidant stress in hemodialysis: prevention and treatment strategies. Kidney Int. Suppl. 2000, 76: S126-32. Wright S, Steinwandel U, & Ferrari P. (2010) Citrate anticoagulation during long-term haemodialysis. Nephrology (Carlton). Nov 3. [Epub ahead of print] Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, & Farber DB. (2009). Transfer of microRNAs by embryonic stem cell microvesicles. *PLoS One* 4: e4722 Ziouzenkova O, Asatryan L, Akmal M, Tetta C, Wratten ML, Loseto-Wich G, Jürgens G,

infarction: The Framingham Heart Study. *Circulation* 107:1486–1491. Vaslaki L, Karatzon A, Voros P, Maior L, Pethoe F, Ladanyi E, Weber C, Mitteregger R, &

atherogenesis caused by hemodialysis. *J Biol Chem.* 274(27):18916-24. Zwaal RF, Comfurius P, & Bevers EM, Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. *Biochim Biophys Act* 1636: 119-128.

hemodiafiltration. *Nephrol Dial Transplant*. 15, Suppl 1: 74–78.

bacterial DNA fragments: Detection in dialysate and induction of cytokines. *J Am* 

treatment in anemic haemodialysis patients with high serum ferritin and low

(1999). Strong associations between malnutrition, inflammation and atherosclerosis

(1996). The role of platelet-activating actor in the biocompatibility of hemodialysis

technologies in minimizing cardiovascular complications. Expert Rev. Cardiovasc.

Anaphylactoid reactions during hemodialysis on AN69 membranes in patients

Wilson PW, D'Agostino RB: Framingham Heart Study (2003). Inflammatory markers and risk of heart failure in erderly subjects without prior myocardial

Falkengagen D. (2000). Can sterile and pyrogen-free on-line substitution fluid be rotuineley delivered? A multicentre study on the microbiological safety of on-line

Heinecke J, & Sevanian A. (1999). Oxidative cross-linking of ApoB100 and hemoglobin results in low density lipoprotein modification in blood. Relevance to

Ross R. (1999) Atherosclerosis: An inflammatory disease. *N Engl J Med.* 340:115–126.

*Soc Nephrol.* 15:3207–3214.

transferring saturation. *Kidney Int* 71: 1163-1171.

in chronic renal failure. *Kidney Int* 55: 1899-1911,

receiving ACE inhibitors. *Kidney Int.* 38(5):982-4.

membranes. *Adv Exp Med Biol.* 416:243-8.

*Physiol* 34: 117-140.

Ther. 9(2), 155–164.

*Kidney Dis.* 30:S1–S195.

The incidence of kidney disease is rapidly increasing worldwide, fueled by the increasing incidences of diabetes and obesity (Centers for Disease Control and Prevention, 2010), and thus, more patients with hypertension and diabetes develop end-stage renal disease (ESRD). Maintenance hemodialysis has become an established protocol for treating ESRD patients. This process is facilitated by two physical phenomena that facilitate mass transfer in purifying blood during maintenance hemodialysis. Diffusion caused by a concentration gradient between blood and dialysate contributes to the removal of uremic solutes, particularly small-size molecules. The removal of excess body water and mid-size molecules depends primarily on convective mass transfer, which results from hydraulic and osmotic pressure gradients (Daugirdas & Van Stone, 2000).

Remarkable improvements have been made in the technologies used for renal supportive dialysis treatment in ESRD patients. Polymeric membranes better prevent the transfer of pyrogenic substances into the blood stream and membrane biocompatibilities are much improved (Weber et al., 2004). The sharp molecular cut-offs of these membranes also prevent further loss of albumin during high-dose convective treatment (Ahrenholz et al., 2004). Narrow pore size distributions and improved hydraulic properties in the membrane field are matched by the evolution of various modalities for renal supportive treatment. Furthermore, better outcomes achieved by convective treatment have encouraged the use of synthetic membranes with high water permeability and sieving characteristics in clinical setups (Woods & Nandakumar, 2000), to the extent that hemodiafiltration (HDF) and volume-controlled highflux hemodialysis (HD) are now regarded as preferred forms of convective therapy, because the retention of middle to large-sized molecules by chronic renal failure patients is closely related to renal-failure associated mortality (Leypoldt et al., 1999).

Volume-controlled high-flux HD adequately clears mid-size solutes without sterile fluid infusion. Forward filtration exceeding desired volume removal is compensated for by backfiltration (Ofsthun & Leypoldt, 1995), and thus, this modality can provide a simpler form of dialysis treatment than other treatment methods. The convective dose delivered during high-flux HD has been shown to reduce mortality in patients at risk, as defined by a serum albumin level of <4 g/dl (Locatelli et al., 2009). However, overall patient survival remains comparable to that of low-flux HD (Eknoyan et al., 2002), which presumably is caused by the limited amount of internal filtration involved due to limitations imposed by fluid dynamics and the geometric nature of the hemodialyzer.

Pulse Push/Pull Hemodialysis: Convective Renal Replacement Therapy 115

Fig. 1. Blood and Dialysate Pressure Gradient along Dialyzer Length. The sum of hydraulic and osmotic pressures is termed TMP, as TMP = ∆Pb- ∆Pd-∆π. Here, ΔPb represents the average value of arterial and venous blood pressure, ΔPd for average hydraulic dialysate

> 4 *<sup>L</sup> P Q <sup>d</sup>*

Where, ΔP is the pressure drop, µ is the fluid viscosity, L and d are the length and diameter of the flow path, and Q the flow rates. Thus, blood and dialysate pressures drop along the dialyzers. However, because blood and dialysate flow in opposite directions, these pressure drops occur with opposing gradients, and in some region, hydraulic blood and dialysate pressures overlap (Fig. 1). In a normal countercurrent dialysis setup, the sum of hydraulic and osmotic pressures, termed transmembrane pressure (TMP), is positive in the proximal region of a hollow fiber dialyzer, and plasma moves to the dialysate compartment across the membranes (forward filtration). However, fluid movement occurs in the opposite direction in the distal region, because hydraulic blood pressures are below the sum of dialysate compartment pressure and osmotic pressure, and thus, backward filtration occurs and

Even though forward and backward filtration rates are highly dependent on membrane permeabilities and the degree of membrane fouling, they remain directly proportional to the positive and negative TMPs, respectively. As shown in Fig. 1, resulting TMP gradients can be readily increased by increasing blood and/or dialysate pressure drops (Fiore & Ronco, 2004, 2007). For blood, the pressure drop is proportional to blood viscosity and tube length in accord with Poiseuille's equation (Eq. 1), which shows that tube length increases pressure

(1)

pressures, and Δπ is oncotic pressures.

compensates for fluid loss in the proximal region.

**2.1.1 Factors influencing internal HDF** 

Therefore, HDF is considered the gold standard for high-dose convective therapy, and has even been reported to reduce mortality risk as compared with high-flux HD (Canaud et al., 2006). HDF, which describes an intermittent renal supportive therapy of combined simultaneous diffusive and convective solute transport, is characterized by a large filtration volume that far exceeds the desired volume removal, and hence, external substitution is essential. In early HDF trials, a large number of sterile bags were used to supply substitution fluid, which was costly and complicated (Ledebo, 2007). However, technical advances made in the production of pyrogen-free ultrapure water allow sterile dialysate to be readily produced, which enables on-line based HDF to be used on a clinical basis. Several types of on-line HDF are clinically available that differ in terms of the ways in which external replacement fluid is administered, such as, by pre- or postdilution. Due to their unique benefits, mixed forms of pre- and post-infusion have also been devised, such as, mixed-dilution or mid-dilution HDF (Krieter & Canaud, 2008, Pedrini & De Cristofaro, 2003). However, the inevitable complexities associated with HDF machines and patient monitoring, and the requirement for the exogenous infusion of replacement fluid is still problematic. Therefore, various modifications of HDF strategies have been proposed to integrate HDF and HD modes, that is, to increase convective dose without the requirement for external infusion. These modifications can be classified into three developmental categories; (1) to increase the internal filtration rate by increasing pressure gradients along the hemodialyzer, (2) to use independent domains for forward filtration and backfiltration, or ultrafiltration and diffusion, and (3) to alternate forward and backward filtration procedures.

In this chapter, the trials on HDF strategies undertaken without exogenous substitution infusion will be discussed in terms of their technical aspects, *in vivo* and *in vitro* efficacies and applicabilities for clinical use. This is followed by an in-depth review on pulse push/pull hemodialysis (PPPHD), a recently introduced pulsatile technique that provides infusion-free HDF.
