•Introduction of Y set in PD
•PD dose
•Unplanned and urgent start PD
The Peritoneal Membrane/Cavity as a Therapeutic Tool
Rene Dutrochet was the first to describe the process of osmosis in the 18th century. This was later followed by Thomas Graham’s (19th century) description of the difference between “crystalloids” and “colloids” in his “Bakerian lecture on osmotic forces” [1, 2]. In the late 19th century, Clark, Orlo and Wegner demonstrated that the instillation of hypertonic solution (salt, concentrated sugars, glycerol) in the peritoneal cavity increases the peritoneal cavity volume in animal experiments [3]. The evidence for “bi-directional permeability” (blood to peritoneal cavity and vice-versa) of the peritoneal membrane was provided later by Babb et al. [4]. Based on the transport behavior of solutes like methylene blue, Putnam’s description of the peritoneum as a membrane with “punched out holes” that allowed larger molecules (now interpreted as middle molecules) to pass through, later helped in the understanding of the mechanism of large solute removal by PD [3]. Advances in cell biology and advent of electron microscopy subsequently led to the emergence of the 3-pore theory; including the recognition of the role of aquaporins [5]. Interestingly, the prediction that the water transport across the peritoneal membrane occurred via transcellular pathways had already been made earlier [6].
PD Solutions
It was recognized early on that to remove uremic solutes effectively, a hypertonic solution will need to be instilled in the peritoneal cavity. The early PD solutions led to adverse events like post instillation pain (due to lack of acetate/lactate resulting in low Ph), hyperchloremic metabolic acidosis, volume overload, and hypertension [7], were mainly related to higher concentration of sodium in these solutions (Na and Cl concentration of 136 mEq/L). Subsequent formulations of PDS were appropriately modified in an effort to make them more physiological as well as to promote sodium removal by diffusion (sodium 130–135 mEq/L, chloride 99–100 mEq/L). Heusser [3] recognized that dextrose could be utilized as an osmotic agent to achieve ultrafiltration in the PDS. Although many other agents (e.g., glycerol, amino acids etc.) have since been tried, dextrose continues to be the preferred osmotic agent in the PDS. However, prolonged exposure to dextrose is associated with several unwanted effects that include hyperglycemia and new onset diabetes mellitus, weight gain, and dyslipidemia [8]. Also, prolonged exposure to dextrose can adversely affect the peritoneal membrane causing mesothelial toxicity, neo-angiogenesis, and formation of advanced glycosylation end products leading to loss of ultrafiltration and other adverse sequalae [9].
Table 1. Advantages of biocompatible solutions
PDS contain lactate as the buffer. The use of lactate (pH 5.5) buffered PDS has been implicated with in-flow pain. The stimulation of the polyol pathway by lactate may enhance glucose-related mesothelial cell toxicity [9]. PDS are heat-sterilized prior to use. Heat sterilization results in the production of glucose degradation products that are cytotoxic to the peritoneal membrane. The need for more biocompatible PDS (with lower proinflammatory profile and lower propensity to cause changes in peritoneal structure, function, and defense mechanisms) thus became increasingly apparent.
Since their introduction, biocompatible PDS have been widely used in Europe but they have not been available in the US with the exception of Icodextrin (7.5%), which was introduced in the 1990s. The 1.1% amino acid solution, lactate and lactate/bicarbonate buffered solution are some of the other biocompatible PDS [9] (Table 1).
Longer PD vintage predisposes to structural and functional changes of the peritoneal membrane resulting in ultrafiltration failure and reduced solute clearance, ultimately resulting in technique failure. The recognition of transforming growth factor β1 as a target molecule to reduce peritoneal fibrosis has led to the use of agents like aminoguanidine, pyridoxamine, pentoxyphilline, diltiazem, and dipyridamole. In this context, the reported utility of renin-angiotensin aldosterone blockers in the prevention of peritoneal fibrosis is noteworthy [9, 10].
PD Technique Evolution
Georg Ganter was the first to study the effects of instilling hypertonic saline in 2 cases with renal failure [1]. Heusser and Wegner attempted peritoneal lavage with 2 catheters (inflow and outflow) for mercury poisoning but despite biochemical improvement, the patients ultimately died [1]. World War II brought with it a tsunami of crush injuries associated acute renal failure with very high mortality rate. In 1946, encouraged by their adaptation of the Wegner continuous flow technique and painstaking attention to sterility, Frank, Seligman and Fine from Boston reported renal recovery and eventual survival of an anuric acute renal failure patient after 4 days of peritoneal lavage. Approximately, 150 cases of acute renal failure were subsequently treated in such manner, although mortality remained very high [3].
Early investigators used 2 catheters in PD: one as an inflow catheter between the diaphragm and liver, and the other for outflow, in the lower peritoneal cavity. The peritoneal lavage was thus continuous in nature. This technique was associated with several complications including leakage of PD solution and infections resulting in high mortality. As a result, this practice was quickly abandoned and the technique using a single catheter for both inflow and outflow (hence the term intermittent) was adopted. It should be noted that the current terminology differentiates continuous and intermittent PD based on the presence or absence of PD solution within the peritoneal cavity for a continuous or intermittent period. For example, intermittent PD has “dry periods during a 24-h time frame during which there is no solution in contact with the peritoneal membrane.
Peritoneal access remained a major challenge in the early days of PD. Different materials and prototypes were tried including Foley catheters, mushroom tip catheters, whistle tip catheters, polyethylene tubes, simple soft rubber tubes with or without side holes, stainless steel sump drains (similar to the metal-perforated suction tubes, used in operating theatres) and even glass drains [11, 12]. Leakage and intraluminal or extraluminal obstruction limited their use, and since the catheter needed to be changed repeatedly over few days, infection risk remained high. It was not until 1950s and 1960s, when investigators like Maxwell, Doolan, Weston and Roberts [3] modified the catheter and improved insertion techniques that the benefit to