Renal Unit, University Hospital, Gent, Belgium
Keywords: neoangiogenesis; peritoneal membrane function; ultrafiltration failure
Introduction
Long-term preservation of peritoneal membrane function is a prerequisite for successful peritoneal dialysis (PD). The development of ultrafiltration failure (UFF) is the most important cause of technique failure next to recurrent peritonitis [1]. Its significance is likely to increase as the reduction in peritonitis rates makes PD a more viable option for a larger number of patients. The present overview briefly discusses the alterations in peritoneal membrane function that underlie loss of ultrafiltration capacity. In addition, the structural changes observed in the peritoneum of long-term PD patients will be addressed. Finally, an attempt will be made to provide a link between the functional and morphological alterations.
Functional alterations
Evaluation of peritoneal transport characteristics in patients with UFF reveals distinct mechanisms of impaired ultrafiltration capacity. The presence of low small solute transport rates is probably very rare and points to a major decrease in membrane surface area, usually due to adhesions or advanced stages of sclerosing peritonitis. Increased lymphatic reabsorption has been observed in some patients with UFF, based on the finding of a high macromolecular clearance from the peritoneal cavity [24]. In the majority of cases, however, impaired ultrafiltration can be ascribed to elevated small solute transport rates, as judged from a high D/P or MTAC creatinine [24]. This condition results in rapid absorption of glucose from the peritoneal cavity, leading to early dissipation of the osmotic gradient and thus reduced transcapillary ultrafiltration. Finally, impaired transcellular water flow may be causative of UFF. The three-pore model of peritoneal transport was expounded more than a decade ago, predicting the presence of transcellular water-only channels [5]. Subsequent discovery of aquaporins and demonstration of the presence of aquaporin-1 in endothelial cells of the peritoneal membrane provided a morphological substrate for this hypothesis [6]. As these water-only pores account for nearly half of the ultrafiltration during hypertonic dwells, it has been postulated that impaired transcellular water flow could contribute to UFF in some of the cases, adding a further layer to the complex pathophysiology of peritoneal membrane failure. The presence of reduced sodium sieving during a hypertonic dwell has been interpreted as evidence for impaired transcellular water transport in selected patients with UFF [34,7]. As this approach is subject to several pitfalls [89], definite proof that deficient aquaporin-mediated water flow may contribute to UFF is still lacking.
The natural history of peritoneal membrane transport over time on PD has been extensively explored. Some smaller studies have reported a stability of peritoneal membrane function, whereas others have found a significant increase in small solute transport rates accompanied by a reduction in ultrafiltration rate with treatment duration [10]. Several explanations for these apparent discrepancies can be forwarded. First, only a subgroup of patients may experience a rise in small solute transport and the effect on the average transport rates of the population may not be large enough to be discovered [11]. Second, high transporters with low ultrafiltration rates may drop out early, as they have a higher relative risk for death and technical failure, thereby introducing a systematic bias in favour of functional stability of the peritoneal membrane [12]. Finally, peritoneal transport rates obtained very early in the course of PD may overestimate actual peritoneal function due to transient increases in the effective vascular surface area [13].
Taken together, the extant evidence suggests that peritoneal ultrafiltration capacity decreases progressively with time on PD. In the majority of patients, loss of ultrafiltration capacity results from the presence of high solute transport rates with a rapid dissipation of the osmotic gradient. Increased lymphatic absorption and loss of functional transcellular water channels may be alternative causes of UFF, but as their assessment requires sophisticated testing, the true incidence of these conditions is at present undefined.
Structural alterations
How do these functional alterations of the peritoneal membrane reflect underlying structural changes? Mesothelial cells are most probably not an efficient barrier to solute transport [14]. The contribution of the interstitium to the barrier function of the peritoneal membrane is not very well known, but is considered not to be of critical importance [15]. The main resistance to solute and water transport lies within the vascular wall [89]. The transport of small solutes is not influenced by a size-selective restriction barrier but depends essentially on the available vascular surface area. The finding of a high small solute transport rate thus reflects an increased surface area. As it is unlikely that the size of the peritoneum changes, an elevated vascular surface area must be due to an increase in the number of capillaries that contribute to transport, either by recruitment of previously non-perfused capillaries or by formation of new capillaries. It can thus be derived that a stable increase of the transport rates of small solutes points to the presence of peritoneal neoangiogenesis. On the other hand, the transport of free water requires functional aquaporins in the vascular wall, as demonstrated by the reduction of transcellular water transport in aquaporin-1-deficient knockout mice [16] and after chemical inhibition of aquaporin-1 [6].
Although the presence of structural changes in the peritoneal microcirculation can be predicted from the alterations in transport characteristics, there is a dearth of direct morphological information on the peritoneal microvasculature. Thickening and reduplication of the basement membrane of stromal blood vessels has been reported [1719], as well as fibrosis and hyalinization of the media [2022]. Few studies evaluated the density of the peritoneal microvasculature. Extensive neovascularization, corresponding with treatment duration, was reported in biopsies of PD patients [2122]. In keeping with these findings, an upregulation of endothelial nitric oxide synthase, associated with an increased endothelial surface area, was found in the peritoneum of long-term PD patients [23]. In addition to these vascular changes, variable degrees of expansion of the interstitial matrix have been observed [19,21,24].
Functionstructure correlation
Little direct evidence is available to provide a link between the functional and structural alterations of the peritoneal membrane in long-term PD patients. As mentioned above, it can be inferred that rapid transport rates for small solutes reflect the presence of peritoneal neoangiogenesis. So far, no studies in humans have made correlations between small solute transport characteristics and peritoneal microvascular density. We have used experimental diabetes in the rat as a model for chronic exposure of the peritoneal microcirculation to high glucose concentrations in dialysate [25]. The peritoneal microcirculation in diabetic rats is characterized by extensive neoangiogenesis, associated functionally with increased transport of small solutes and enhanced permeability to macromolecules. The salient observation of this study was that both functional and structural alterations were prevented by treatment with neutralizing monoclonal antibodies to vascular endothelial growth factor (VEGF). The results thus implicate VEGF in the pathogenesis of these changes, but also provide evidence that peritoneal neoangiogenesis and high solute transport leading to UFF are directly linked.
Honda et al. [24] observed in peritoneal biopsy specimens of 14 PD patients, that the extent of interstitial fibrosis and of vascular sclerosis correlated inversely with ultrafiltration capacity. Whether a decrease in the hydraulic permeability of the interstitial tissue can be a cause of impaired ultrafiltration capacity is equivocal [9]. Other authors have reported that the degree of submesothelial fibrosis correlated nicely with vascular density [2122]. It is tempting to speculate that interstitial fibrosis and neoangiogenesis occur concomitantly as a consequence of the same pathophysiological process, but that impaired ultrafiltration results primarily from neoangiogenesis. Unfortunately, no morphometrical analysis of vascular density was performed by Honda et al. [24].
Whether changes in the function or structure of aquaporins are a cause of UFF is a contentious question in peritoneal pathophysiology. It has been suggested that glycation of aquaporins may interfere with their function and thus contribute to loss of ultrafiltration capacity [7], but direct evidence that this actually occurs is lacking.
Conclusion
Although reports on long-term peritoneal membrane function have been conflicting, the emerging picture is that ultrafiltration capacity decreases progressively with time on PD. Small solute transport rates increase in parallel, indicative of an enlargement of the effective peritoneal surface area. Few morphological studies have evaluated peritoneal vascular density, but a progressive rise with time on PD has been consistently found. Although a pathogenetic link between the loss of ultrafiltration capacity and peritoneal neoangiogenesis is a logical extrapolation from the available data, little direct clinical evidence supports this contention. Large prospective studies of peritoneal function and structure are warranted to firmly establish this link.
Notes
Correspondence and offprint requests to: An De Vriese, Renal Unit, University Hospital, OK12, De Pintelaan 185, B-9000 Gent, Belgium. Email: an.devriese{at}rug.ac.be
References