Assessing transport across the peritoneal membrane: Precision medicine in dialysis

Peritoneal dialysis (PD) is the leading form of home-based dialysis therapy for patients with kidney failure. The efficiency of PD depends on its ability to remove excess of water and small uremic solutes from the organism, through fundamental mechanisms of osmosis and diffusive and convective transport across the peritoneal membrane. According to Fick’s laws of diffusion, the transport of small solutes across the peritoneal membrane (named the peritoneal solute transport rate, PSTR) is primarily determined by the effective peritoneal surface area (i.e. the number of perfused peritoneal capillaries in contact with the dialysate), the intrinsic permeability of the membrane, its thickness and the concentration gradient between blood and dialysate. The PSTR can readily be measured by the peritoneal equilibration test (PET), formalized by Twardowski, Nolph and colleagues in 1987. Patients starting PD present a large variability in PSTR, conditioning the maintenance of the osmotic gradient, and thus the rate of ultrafiltration (UF) across the membrane. Higher PSTR has been associated with a greater risk of technique failure and with an excessive risk of death among patients on PD. It can be mitigated by PD prescription, that is, shortening dialysate dwell time or using alternate osmotic agents. A proper assessment of membrane transport properties at baseline and during exposure to PD is thus of major importance for individualized prescription and for precision dialysis. The peritoneal membrane consists of three major components layered between the plasma and the dialysate: the capillary endothelium, the interstitial tissue and the mesothelium. The capillary endothelium represents the rate-limiting barrier for water and solute transport during PD, restricting the solute exchange to less than 0.1% of its total surface area. In the capillary endothelium, the major route for small solute and fluid exchange corresponds to the small pores, located to interendothelial clefts. The functional radius (approximately 40–50 Å) of these small pores restricts the leak of albumin and other large molecules, such as immunoglobulins, across the endothelium. A small number of large pores (radius approximately 250 Å), which account for only 0.01% of the total pore population, allows the permeation of large proteins into the peritoneal cavity, driven by hydrostatic pressure. A third population of ultrasmall pores (radius approximately 2.5 Å), corresponding to the water channel aquaporin-1 (AQP1), is present in the endothelium, facilitating water transport driven by an osmotic gradient generated by crystalloid agents (typically, glucose). The AQP1-mediated water flow explains the rapid dilution of the dialysate sodium concentration during the first part of the dwell (denoted ‘sodium sieving’), best observed when using hypertonic (3.86%) glucose dialysate. To date, AQP1 is the only molecular counterpart to peritoneal transport identified in the peritoneal membrane. Modelling and experimental studies indicated that the AQP1 water channels mediate up to half of the UF when using hypertonic glucose dialysate and that their integrity is reflected by the sodium sieving. Further studies confirmed that the type of osmotic agent influences the kinetics of water transport. Very small osmotic agents (e.g. glycerol) will exert a low osmotic effect on the small pores, and thereby act primarily on water-only pores. Glucose, the typical crystalloid agent, will drive water flows equally partitioned between ultrasmall and small pores. High molecular weight polymeric glucose molecules, such as icodextrin, will drive water mainly via colloid osmosis across the small pores. Despite the importance of assessing peritoneal membrane transport for individual dialysis prescription, more