**7. Peritoneal ultrafiltration**

#### **7.1 Peritoneal membrane**

The peritoneum is the most extensive serous membrane in the body, with a total surface of about 1.8 m<sup>2</sup> . Human skin has a similar overall surface area. It helps to protect and separate the internal structures of the abdomen and pelvis.

The functions of the peritoneum:


Peritonitis is inflammation of the peritoneum. Inflammation most often occurs as a result of a fungal or bacterial infection. Microorganisms can enter the abdomen due to an abdominal injury, some other condition such as perforation of a gastric ulcer, or during therapeutic procedures such as dialysis, esophagogastroduodenoscopy, gastrostomy. Inflammation of the peritoneum is a severe condition that requires urgent treatment. There are several types of peritonitis: acute and chronic by course, serous, fibrous, purulent, hemorrhagic by sort, diffuse, and circumscribed by localization. It can be divided into primary, secondary, and tertiary.

#### *7.1.1 Structure of the peritoneal membrane*

It consists of two layers: the parietal peritoneum (the outermost parietal layer), which surrounds the abdomen and pelvis, and the visceral peritoneum (inner visceral layer), which wraps around the abdominal organs. A potential space between the two layers contains small amounts of serous fluid (water, electrolytes, and immune cells). This fluid is a form of protection and acts as a lubricant between the layers. The parietal peritoneum covers the abdominal and pelvic walls and the diaphragm. The visceral peritoneum covers the intraperitoneal organs and forms various folds throughout the abdominal cavity. The greater omentum is a large fold of the visceral peritoneum and extends from the stomach downwards. Another fold of visceral peritoneum is the lesser omentum, which extends from the lesser curvature of the stomach to the liver. In addition to pain, the parietal peritoneum is sensitive to temperature, pressure, and laceration. The pain from the visceral peritoneum is poorly localized. It is only susceptible to extension and chemical irritation.

The visceral and parietal peritoneum has a similar histological structure: mesothelium, basal lamina, and submesothelial stroma. While mesothelium and basal lamina appear similarly throughout the abdomen, the submesothelial stroma may vary in thickness. Mesothelial cells are of mesodermal origin and, under specific conditions, can become even more similar to mesenchyme [61]. The mesothelial cells were considered inactive and contributed only to lubrication. It is known today that they play a crucial role in peritoneal homeostasis and produce a whole range of enzymes, cytokines, growth factors, and proteoglycans. They also provide the first line of defense against microorganisms and harmful chemical substances, which is why it is essential that the mesothelium can regenerate quickly and smoothly after injury.

At the basal surface, mesothelial cells are supported by the basal lamina. It consists of a layer of extracellular matrix less than 100 nm thick, composed of type IV collagen and laminin.

Connective tissue or stroma supports the mesothelial cells and the basal lamina. This supportive layer comprises collagen, mainly type I fibers, proteoglycans, fibronectin, (myo)fibroblasts, adipocytes, and blood and lymphatic vessels [62].

#### *Advanced Treatment of Refractory Congestive Heart Failure by Peritoneal Ultrafiltration… DOI: http://dx.doi.org/10.5772/intechopen.114022*

According to its structure, the peritoneum is a semipermeable membrane. Through its intercellular junctions and stomata, passive transport of liquids and dissolved substances takes place, as well as active transport through the formation of pinocytic vesicles. The transport of dissolved substances and small molecules through the peritoneum occurs quickly because the stroma, basal lamina, and mesothelium do not create resistance [63]. Transportation of large molecules is possible due to the network of collagen, fibronectin, elastin, and transcellular carriers in mesothelial cells [64]. The capacity of the peritoneum to transport fluids enables peritoneal UF/dialysis. Due to dialysate in the peritoneal cavity, UF and diffusion of water, salt, and uremic toxins through the membrane occur. Chronic exposure of the peritoneum to the dialysate evokes functional and morphological adaptions of the peritoneum. Chronic inflammation, progressive fibrosis, and angiogenesis thickening of the submesothelial stroma eventually lead to its loss of UF and blood purification capacity [65].

#### *7.1.2 Aquaporins*

The capillary endothelium, the interstitial space of the peritoneum, and the mesothelium represent a barrier to the exchange of soluble substances and water in the capillaries of the peritoneal cavity [66]. It should be emphasized that with this transport through the "pore" of the capillary walls, solutes larger than glucose are excessively lost, and the interstitium also modifies the transport of solutes *via* the barrier mentioned above [67]. The fluid exchange across the peritoneal membrane during PD is best explained with a "three-pore" model. The spaces between individual endothelial cells (inter endothelial clefts) represent the primary route for small-solute and fluid exchange. The radius of these clefts ("small pores") is cca. 40–50 Å. The small pores markedly impede the transit of albumin (36 Å) and ultimately prevent the passage of larger molecules, such as α2-macroglobulin and immunoglobulins. The transendothelial pathways of the "large pores" (radius approx. 250 Å) are responsible for the penetration of large proteins into the interstitium and the peritoneal cavity [68]. Osmotic water transport occurs through ultra-small, water-only pores (radius approx. 2.5 Å), to which the capillary wall is highly susceptible.

Aquaporins (AQPs) are a family of integral plasma membrane proteins. Their discovery gave us insight into the molecular mechanisms for water transport through biological membranes. AQPs are usually specific for water permeability and exclude the passage of other solutes. All AQPs are impermeable to charged solutes, and water molecules traverse the AQP channel in a single file. It was assumed that water leaked through biological membranes, but the rapid movement of water across some cells remained unexplained. Although it had been predicted that water pores must exist in very leaky cells, it was not until 1992 that Peter Agre at Johns Hopkins University identified a specific transmembrane water pore later called aquaporin-1 (AQP1). AQP1 comprises a single peptide chain consisting of approximately 270 amino acids. It is distributed in the endothelium of capillaries, venules, and small veins of the peritoneum and is functionally identical to ultra-small pores [69].

An experimental mouse model showed that AQP1 is the most represented member of the AQP family in the peritoneum and is the only one found in the capillary endothelium. It was also experimentally shown that deletion of AQP1 does not affect the expression of other AQPs and the diameter or density of peritoneum capillaries. These data prove that AQP1 is important in peritoneal transport mechanisms [70].

Under non-PD conditions, approximately 60% of the net capillary UF occurs through small and 40% through large pores. Only 1–2% of total peritoneal transport occurs through ultra-small, water-only pores.

Under PD conditions, fluid removal is mainly reinforced by an osmotic agent in the peritoneal cavity. The osmosis mechanism is markedly affected by the type of osmotic agent used. For example, glycerol (radius approx. 3 Å) is a small osmotic agent with a weak effect on small pores and primarily on ultra-small, water-only pores. Unlike glycerol, glucose (radius approx. 3.7 Å) performs its ultrafiltration effect equally through ultra-small and small pores. Polyglucose (radius approx. 15–20 Å), a high-molecular-weight osmotic agent, ultrafilters liquid mainly through small pores. Polyglucose (radius approx. 15–20 Å), a high-molecular-weight osmotic agent, ultrafilters liquid mainly through small pores [71]. It is believed that AQP1 mediates 40–50% of osmotic-induced UF. A drop in dialysate sodium concentration is expected after 60 to 90 minutes of the dwell, as free water is transported through these pores, and this phenomenon is known as sodium sieving.

The relationship between AQPs, UF capacity, and sodium filtration is still debated in PD. On the other hand, understanding the molecular structure and role of ultrasmall pores is vital for clinical practice regarding patient volume optimization.

#### *7.1.3 Physiologic considerations*

The final net UF in the peritoneal technique results from multiple transport mechanisms within the tissue surrounding the peritoneal cavity. Free water is transported through ultra-small pores, and an adequate volume of dialysate forces water and dissolved matter into the surrounding tissue. To achieve adequate UF from the capillaries of the peritoneum, it is necessary to maintain a high osmotic pressure in the peritoneal cavity. The osmotic pressure in the interstitium is lower than that in the peritoneal cavity. It is equal to the osmotic pressure in the plasma already in the first millimeter of tissue next to the peritoneum. Pure ultrafiltrate without dissolved substances results from the difference in osmotic pressure in the blood capillary and is produced by AQP1. If intraperitoneal pressure is too high, insufficient UF occurs. The most common reason for this is peritoneum inflammation when, due to capillary hyperpermeability, the osmotic agent quickly dissipates. Fibrosis of the peritoneum is the second possible reason because there is a reduced osmotic pressure near the blood supply, and there is no force to transport the fluid through the scar to the cavity. To solve problems in net UF, the key is to lower the volume and, secondary, the intraperitoneal pressure. Preventive measures are necessary to reduce chronic inflammation and peritonitis and preserve the peritoneal membrane and its transport characteristics.

The osmosis process is vital for transperitoneal water transport. Water moves from a low to high solute concentration area across a semipermeable membrane across all three pores. The effective surface area of the peritoneal membrane, the hydraulic conductance of the peritoneal membrane, the concentration and type of the osmotic agent used, and the influence of hydrostatic and oncotic pressure gradients across the peritoneal capillary are the factors that are responsible for the transcapillary water movement.

In the initial phase, the intraperitoneal volume is dominated by transcapillary UF. It is influenced by the crystalloid osmotic gradient created by glucose. On the other hand, it also governs relatively constant hydrostatic and oncotic pressure gradients (so-called "Starling forces") [72]. Intraperitoneal volume increases as the

#### *Advanced Treatment of Refractory Congestive Heart Failure by Peritoneal Ultrafiltration… DOI: http://dx.doi.org/10.5772/intechopen.114022*

transcapillary UF rate exceeds lymphatic and tissue absorption [73]. The transcapillary UF rate decreases because of the steep decline in glucose concentration. A positive net UF occurs due to fluid transport imbalance because transcapillary UF exceeds lymphatic absorption. A state of balance in fluid transport that does not increase intraperitoneal volume is reached when the transcapillary UF rate drops to a value equal to the lymph flow rate. At that point, the intraperitoneal volume peak is reached. The negative net UF due to fluid absorption results from a difference between the decreasing transcapillary UF rate and the constant lymphatic tissue absorption, representing a new state of fluid transport imbalance.

A linear and stable decline is the second and last phase of intraperitoneal volume change. The peritoneal cavity's drainage time is responsible for the net clinical effect of peritoneal fluid movement. The drained volume may approach or even be less than the instilled volume if drainage is delayed until the end of the final phase.

Using glucose as an osmotic agent leads to the deterioration of the peritoneal membrane. Its well-known harmful effects on the peritoneum may lead to failure of the PD treatment in the mid-to-long term. With this in mind, an extensive effort has been made to find more biocompatible dialysis solutions, including icodextrin.

#### *7.1.4 Advantages and safety considerations related to icodextrin solution*

The icodextrin was launched in the mid-1990s, and its use has increased over time as more than 30,000 patients globally were receiving icodextrin treatment [74].

Different glucose concentrations in the PD solution are primarily used to meet the different UF needs. However, glucose has short-lived effects as an osmotic agent and degrades quickly in the peritoneum. Longer dwells of glucose solutions can often result in net fluid reabsorption from the dialysate into the patient rather than the expected outcome. Furthermore, glucose degradation products are formed, which harm the peritoneum, resulting in its damage in terms of fibrosis. These changes result in the peritoneum's functional inefficiency and the treatment method's viability [75]. Finally, these solutions lead to metabolic disorders such as hyperinsulinemia, hyperlipidemia., and hyperglycemia. Using icodextrin provides improved UF for long dwells compared to glucose solutions. It is also more efficient in volume status control. Further, Goossen et al.'s systematic review and meta-analysis demonstrated decreased mortality with icodextrin use [76]. Additional benefits from icodextrin are glucosesparing properties, lipid status improvements, and echocardiographic parameters with reduced left ventricular mass.

The UF properties of icodextrin depend on the dwell time, whereby the maximum effect of icodextrin concerning glucose is achieved at a prolonged dwell time of 10–14 hours. Sometimes, full results are achieved as early as 10 hours of dwell, with minimal UF effect after that time. Compared to conventional glucose-based dialysates, icodextrin may offer improved peritoneal membrane biocompatibility by reducing glucose exposure, iso-osmolarity, and lesser carbonyl stress [77, 78]. Furthermore, the study of Posthum et al. showed that the concentrations of various peritoneal membrane markers (interleukin-8, CA125, amino-terminal propeptide of type III procollagen, and carboxyterminal propeptide of type III) did not differ between patients treated with glucose and icodextrin over 2 years [79]. Other clinical studies have confirmed that icodextrin is a safe and well-tolerated osmotic alternative solution to glucose [80]. The most significant side effect reported from using icodextrin is a skin hypersensitivity reaction [81]. Most likely, the hypersensitivity reaction is mediated by the immune complex. The peritonitis rate does not differ

between patients treated with icodextrin and those treated with glucose solutions only, which has been confirmed in several randomized, controlled studies [82]. Longterm intraperitoneal use of icodextrin can permanently increase the plasma's maltose, maltotriose, and other oligosaccharides. This is significant because elevated maltose levels can interfere with specific glucose and amylase tests [83]. Therefore, one should be careful when interpreting the results of such tests when using icodextrin.

The most common antibiotics used to treat peritonitis (vancomycin, cephalosporins, and gentamicin) are compatible and stable with icodextrin [84]. Finally, the use of icodextrin has been associated with falls in serum sodium concentration and slight increases in serum osmolality, which are usually not clinically significant.

#### **7.2 Rationale for peritoneal ultrafiltration in congestive heart failure**

PUF is a treatment modality aimed at patients with diuretic-resistant CHF to control fluid retention adequately. While extracorporeal UF is more commonly used to treat acute decompensated HF, PUF has been proposed for long-term treatment of RCHF, especially in elderly patients, as a soothing therapeutic modality or as a bridge to definitive surgery or HTx. The potential benefits of this treatment modality include a quality-of-life improvement since it is a home-based therapy, better control of congestion and no need for central venous access (no problems associated with anticoagulation), and a reduction in hospitalization rates [85].

However, still unanswered questions show a need for future studies, starting with the patient inclusion criteria. According to Bertoli et al., an ideal candidate for PUF would be a patient with both CHF and CKD, on optimal medical therapy and at least three hospitalizations in the previous year. Secondly, it is still being determined if PUF would be suitable for patients with all HF types since, in most studies, patients had left ventricular systolic dysfunction [86].

#### **7.3 Peritoneal ultrafiltration prescription in congestive heart failure**

The global prevalence of HF is increasing due to aging populations, insufficiently controlled cardiovascular risk factors, and prolonged survival. Significant progress has been made in treating HF in recent decades due to new disease-modifying drugs and increasingly sophisticated devices [87]. However, the effectiveness of treatment is limited in some patients, and palliative care is the only option to improve the quality of life. Although progress has been made in the treatment of heart failure with improved survival, RCHF remains a growing health problem, already a significant cause of hospitalization, with associated costs [88]. CRS is dominated by a comprehensive pathophysiology in HF, regardless of EF. It is associated with poorer outcomes, more than 40% of all-cause mortality, and is a significant driver of repeat hospitalizations. Renal venous congestion and arterial insufficiency lead to "excretory renal failure" due to critical changes in intraglomerular filtration pressure. This results in inadequate volume control that causes recurrent cardiac decompensation [89]. Extracorporeal HD or UF is an alternative for treating congestion in case of diuretic resistance. HD is conventionally reserved for patients with concomitant ESRD, and UF is more commonly used in patients without ESRD [90]. There are conflicting results from clinical studies comparing UF with pharmacological therapy. In the UNLOAD study, patients treated with UF had better control of volume status and a lower frequency of hospitalization for HF than those treated with diuretics. However, in the CARESS-HF study, there was no difference in weight loss between

*Advanced Treatment of Refractory Congestive Heart Failure by Peritoneal Ultrafiltration… DOI: http://dx.doi.org/10.5772/intechopen.114022*

patients treated with UF and those treated with higher doses of diuretics [3, 91]. More elevated serum creatinine values were observed in the group of patients treated with UF, which the authors assumed was due to a transient decrease in intravascular volume during this procedure.

More recently, there has been increased interest in UF via the peritoneal membrane with the updated terminology of PUF, reflecting the goal of fluid extraction across the peritoneal membrane [92]. PUF in RCHF reduces the incidence of decompensation episodes, which is particularly significant as each episode incrementally adds to mortality. Compared to extracorporeal therapies, this method offers potential advantages such as better preservation of residual renal function, tighter control of sodium balance, less neurohumoral activation, and the possibility of daily treatment in the home environment [93].

On the other hand, PUF offers excellent flexibility in a prescription best suited for a given patient. Success has been reported using a single-night time exchange with icodextrin. It is recommended to start the therapy with a smaller volume of the single-night icodextrin exchange and gradually increase it to the maximum tolerable level, which gives us an appropriate UF rate. The icodextrin exchange can be done twice daily in cases of greater hypervolemia. Such a prescription should be used for up to 2 weeks and then turn into one single-day exchange. An incremental therapeutic approach of the single-night exchange can be continued after achieving volume optimization of the patient, including regular outpatient monitoring. This implies pausing the therapy one or more days a week, according to the instructions of the supervising medical staff.

### **8. Conclusions**

The presence of CKD is a poor prognostic factor in patients with CHF, and a number of these patients develop resistance to conventional medical therapy, primarily diuretics. PUF is a viable modality for both the short- and long-term managements of patients with RCHF. The role of PUF in short-term control is limited to situations where extracorporeal UF is not possible or available. However, for the long-term management of patients with RCHF, PUF should be the therapy of choice for ambulatory UF. It can be used as a bridge therapy for definitive interventions or palliative treatment for these patients. Using an intraperitoneal solution such as icodextrin promotes a slow and efficient PUF that better preserves residual renal function, is less invasive and is better tolerated by cardiac patients, improving clinical symptoms and quality of life.

Patients with CHF are usually fragile, with multiple comorbidities. The proper anesthesia technique and surgical approach for PD catheter placement in CHF patients must be based on the patient's characteristics (including comorbidities and previous operations), available equipment, and surgeon's experience. An open approach using a TAP block for PD catheter placement in patients with CHF is strongly recommended.

However, there is a need for controlled trials to define subgroups of patients with RCHF who are most likely to benefit from this treatment method. Nonrandomized but more extensive observational studies should also be performed to provide more information and establish the best protocol for managing RCHF in patients without ESRD. Cost-benefit analyses and reimbursement policies should be implemented. All this may lead to a more widespread use of PUF with icodextrin in this group of patients.
