Response to ‘Water-only pores and peritoneal dialysis’

To the Editor: The excellent editorial by Michael Flessner implies that the idea of transcellular electrolyte-free water movement from peritoneal capillaries to peritoneal dialysis fluid during peritoneal dialysis, as a result of osmotic pressure-induced ultrafiltration, was not reported until the three-pore model of Rippe was published. Flessner states that, ‘Rippe was the first to realize the importance of the third pore or water-only channely .’ The three-pore model is a theoretical explanation for the characteristics of solute and water movements during peritoneal dialysis using hypertonic dialysis fluids and has been widely accepted. However, the first publication suggesting that a low electrolyte ultrafiltrate was generated during peritoneal dialysis was published by Nolph et al. This was a provocative suggestion at a time well before aquaporin channels were discovered. Karl D Nolph, the lead author of this 1969 work has indicated to me in a personal communication that one of the reviewers of this paper, when it was submitted to the Annals of Internal Medicine, critically argued that a biological membrane could not possibly sieve electrolytes during ultrafiltration and pointed to glomerular filtration as the prototype example; the reviewer recommended the paper be rejected. Nolph, in his rebuttal, replied to the reviewer that there was no other reasonable explanation for the data as reported. The paper was eventually published. In this paper, Nolph and his colleagues suggested the concept and term of ‘sodium sieving’ during peritoneal dialysis and presented a simple calculation for a ‘sieving coefficient’. Before this thought-provoking observation of ‘sodium sieving’ during hypertonic peritoneal dialysis exchanges, it was known and observed by others that serum sodium concentration tends to increase, and hypernetremia may develop, with successful hypertonic ultrafiltration. Until the 1969 study of Nolph et al., quantitative assessment of expected sodium removal per unit volume of ultrafiltrate and analysis of the variability of transperitoneal sodium transport in different patients during hypertonic exchanges had not been published. Three years later, Ahearn and Nolph in fact, suggested the possibility of transcellular water movement free of electrolytes and provided a figure showing a direct path through cells. ‘The net result would be the removal of extracellular water without sodium and associated anions via a transcellular water movement.’ The paper did not suggest a ‘channel’ through cells, but did suggest transcellular movement of electrolyte-free water. The concept of sodium sieving was quite stimulating because even though mesothelial and endothelial intercellular channels were known at that time, the paper was published well before aquaporin channels were discovered. An in vitro study in hollow fiber dialyzers by the Missouri group, examined the solute-sieving coefficients during UF with hydrostatic pressure, osmotic pressure with a nonpermeable solute (an anionic polymer with sodium as the counter ion ), and osmotic pressure with a permeable solute (glucose) and proposed that molecular interaction within the membrane (with glucose absorption countercurrent to the direction of ultrafiltration) impaired convective transport with ultrafiltration and could account for some solute sieving with osmotic pressure using a permeable osmotic agent. In a rat model of PD, Chen et al. from Missouri in 1991 calculated approximate sieving and reflection coefficients for various solutes present in plasma, sodium in particular. They also provided evidence that sodium sieving may be part of transcapillary hydrostatic ultrafiltration during peritoneal dialysis. At present, we know that this probably represents aquaporin water movement secondary to hydrostatic pressure. Ignoring to acknowledge such earlier landmark observations is a disservice to the contributions made by pioneers to the field of peritoneal physiology. If not corrected, I am afraid, this lapse will be perpetuated by future investigators.