**2.1 Principles: diffusion, ultrafiltration, and convection**

Despite major improvements in technologies from the first experimental hemodialysis (HD) in 1924 to the first continuous arteriovenous hemofiltration (CAVH) circuit in 1977, general principles guiding the removal of water and solutes for almost any type of extracorporeal renal replacement therapies initiated in the ICU remain the same: diffusion, convection, ultrafiltration and sometimes adsorption (see **Figure 1**) [4]. These three major concepts will be integrated according to the renal replacement therapy (RRT) modality chosen. The notable exception is peritoneal dialysis (PD), which, nowadays, is rarely initiated in acute setting such as AKI in ICU adult populations. However, PD for AKI is often used in children and has been shown useful in resource-limited settings (e.g., no reliable access to electricity or CRRT devices) as well as in extraordinary circumstances when usual CRRT capacities have been overflowed (e.g., recent COVID19 pandemic). Nevertheless, in most centers, PD as a modality of RRT is restricted to ESRD patients requiring maintenance dialysis and is rarely an option in ICUs. For these reasons, only blood-based extracorporeal renal replacement therapies will be reviewed in this Chapter.

**Figure 1.** *Principles guiding blood-based extracorporeal RRT.*

**Diffusion**, as used in HD, is the movement of solutes across a semipermeable membrane. The direction and intensity of that movement are driven by the concentration gradient (from higher to lower). Circulating blood and the dialysate in opposite direction on each side of the semipermeable membrane (countercurrent flow) maximizes concentration gradient and potentiates solute clearance. Another key aspect driving diffusion-based clearance is the size of the solute, where smaller solutes (<100 Daltons) cross the membrane faster than larger molecules. Other important properties are protein binding, distribution volume, and electrical charge [5].

**Ultrafiltration** (UF) is the movement of fluid across a semipermeable membrane using pressure differential (from higher to lower pressure) to generate the ultrafiltrate. In RRT, net UF represents the total amount of fluid removed to obtain the net fluid balance, which can be prescribed per hour (e.g., 50 mL/h) during CRRT or per session (e.g., 2 liters) during intermittent HD.

**Convection**, as used in hemofiltration, is the clearance of dissolved solutes along plasma crossing the semipermeable membrane (ultrafiltrate) (a mechanism sometimes called "solvent drag"). When used alone, convection requires to generate a large amount of ultrafiltrate (containing dissolved toxins/solutes) to achieve adequate clearance. Hence, a substantial amount of sterile solution needs to be reinjected to the patient to compensate for the volume removed by convection to maintain volume and solutes homeostasis. Convection can remove larger, middle-sized molecules at which diffusion is inefficient [5, 6].

**Adsorption** is the adherence of a molecule to the surface of a polymer, or a charged membrane exposed to the blood. As opposed to convection, where middle and small molecules completely cross the membrane and are therefore removed by the effluent fluid, the polymer/membrane will be progressively saturated by those molecules, leading to a progressive reduced adsorptive capacity for longer treatments. There is an increasing interest in the potential of adsorption to reduce the inflammatory response by adsorbing cytokines, endotoxins, or exotoxins mostly in septic shock. Mixed results on the true added benefit of this technology have been reported and dialyzer/cartridge generating adsorption is not widely used in the current practice [7].

## **2.2 Modalities characteristics: IHD, PIRRT/SLED, and CRRT**

All extra-corporeal RRT technologies used in ICUs can be separated into three modalities: intermittent hemodialysis (IHD), prolonged intermittent RRT (PIRRT) (also called sustained low-efficiency dialysis [SLED]), and continuous RRT (CRRT). Their ability in fluid and solute removal is all based on one or on the combination of the basic principles described above (See **Figure 2**).

In HD (A) and CVVHD (B), blood and dialysate circulate on each side of the semipermeable membrane. Diffusion is the driving force that contributes to solute clearance. For all RRT devices, pressure differential between the two compartments, using dedicated pumps to generate transmembrane pressure (TMP), controls convection flow and ultrafiltration rate. The removed liquid containing waste is usually called effluent for all modalities.

In CVVH (C), convection is the main mechanism used to provide solute clearance. The generation of ultrafiltrate is continuously compensated by the reinjection of replacement fluid. That replacement can be injected before the filter, after the filter, or a combination of both (called pre- vs. post-filter reinjection ratio). Adding prefilter replacement fluid dilutes blood and its components, notably its hematocrit reducing the overall thrombogenicity. Hence, increasing pre-filter/post-filter ratio reduces the risk of circuit clotting. On the opposite, a proportional increase in hematocrit at the end of the filter will occur when increasing the convection volume in a 100% post-filter CVVH configuration.

CVVHDf (D) results from the combination of (B) and (C) where both convection and diffusion achieve solute clearance. The replacement fluid may be mixed pre- and post-filter as well in addition to using a countercurrent dialysate flow. However, diluting blood pre-filter also decreases the concentration gradient, which is a major driving force in diffusion. The prescription should be adapted according.

### **Figure 2.**

*Schematic representation of IHD and CRRT circuits' configuration. (A) HD: A dedicated intermittent HD device generates large volumes of physiological dialysate using sterile water and chemical concentrates. Up to 800 mL/min of new dialysate can be constantly generated for most HD devices. The composition/prescription of this dialysate can be individualized according to the patient's need. (B)(C)(D) a dedicated CRRT machine uses commercially available bags of physiological solution, using low effluent flow (20–35 mL/kg/h).*

Net fluid balance (net UF) can be obtained in all modalities: in IHD and CVVHD, by generating a TMP, which leads to ultrafiltrate. In CVVH and CVVHDF, the volume of reinjection needs to be slightly lower than the ultrafiltrate generates, which leads to a negative fluid balance.

It should be noted that some centers can generate high volumes of convection when using intermittent RRT. This modality is named hemodiafiltration (HDF), requires an adapted dialysis machine, and is increasingly used in Europe and Asia for ESRD patients. However, its implementation in ICU settings remains limited, partly due to the need to maintain a water treatment system adapted to HDF [8]. As a result, when reporting intermittent RRT in the ICU, we generally consider only IHD.

From a clinical standpoint, each modality is associated with typical blood flow rates (Qb) and dialysate flow rates (Qd) which translates into conventional treatment durations and frequencies (see **Table 1**).

PIRRT represents the application of intermittent hemodialysis technology (machine, filter, dialysate) with a modification of the typical IHD prescription. The objective is to provide a better hemodynamic tolerability than IHD. Hence, in centers offering this modality, PIRRT is generally used in place of CRRT such as in patients with hemodynamic instability, especially if a substantial negative fluid balance (net UF rate) is desired. PIRRT is typically delivered 8 hours with slower blood and dialysate flows than IHD. However, this modality is not optimal for acute RRT indication such as severe hyperkalemia or intoxication with dialyzable substances (e.g., salicylates, methanol, and ethylene glycol) because of its lower flow rates. In some centers, a dedicated HD nursing staff is required to deliver a PIRRT treatment.


*IHD: intermittent hemodialysis, HDf: intermittent hemodiafiltration; SLED: sustained low-efficiency dialysis, SLEDf; sustained low-efficiency hemodiafiltration.*

### **Table 1.**

*Typical prescribing patterns of RRT modalities.*

CRRT is characterized by small flow rates, notably reinjection, dialysis, and UF rates. It allows reducing the hemodynamic effects of fluid and solute changes. However, this continuous modality requires a permanent connection to the CRRT machine, supervision and is at high risk of clotting if no anticoagulation is prescribed. In most centers, an adequately trained ICU nurse can manage a CRRT treatment.
