Department of Nephrology, North Staffordshire Hospital, Stoke-on-Trent and School of Postgraduate Medicine, Keele University, UK
The problem
The rate at which small molecules cross the peritoneal membrane is now established as one of the more important characteristics of patients treated by peritoneal dialysis. A number of prospective studies have demonstrated that high solute transport is associated with less satisfactory clinical outcome, including increased technical failure and reduced patient survival [17]. This prediction of outcome is independent of other established factors, such as residual renal function, co-morbidity (including diabetic status), body size and plasma albumin. The mechanism of this influence is probably multifactorial, although it has been known for some time that high solute transport is a common causative factor in ultrafiltration failure. This is due to the rapid rate of glucose absorption resulting in the loss of osmotic gradient early in the dialysis cycle [8,9]. Furthermore, solute transport is the one characteristic of peritoneal membrane function that has been shown consistently to change with time on treatment [10,11]. It is at present the earliest functional correlate of the established problem of dialysis fluid bioincompatibility with cellular components of the peritoneal membrane. Extensive, predominantly in vitro studies have demonstrated the bio-incompatible effects of low pH, lactate, glucose and its advanced glycosylation end-products present in commercial dialysis fluid [12].
Twardowski, in his original description of the peritoneal equilibration test (PET) first drew attention to the large interpatient variability in solute transport characteristics [13]. Normally distributed, this parameter of membrane function can vary in excess of 100% in the dialysis population. Once residual renal function has gone it is second only to body size as a variable in dialysis prescription, and is a critical factor in fluid removal. The importance of peritoneal solute transport inevitably leads the clinician to ask a number of questions. What are the structural and functional components of the peritoneum that determine its solute transport characteristics? What are the differences between individual peritoneal membranes that account for the interpatient variability in solute transport? What are the anatomical and physiological changes that occur in the peritoneal membrane to account for the changes seen with time on treatment? Whilst the answers to these questions are not yet clear, this article will discuss them in the light of our current understanding of the peritoneal membrane.
Measuring solute transport
The introduction of the PET [13,14], and more recently the Standard Permeability Analysis (SPA) [15] and Peritoneal Dialysis Capacity (PDC) test [16], have provided the clinician with simple standardized methods to assess membrane function. Each provides a measurement of small solute transport, expressed as the mass transfer area coefficient (MTAC) in the SPA, and the area parameter in the PDC. Using the PET, solute transport is defined as the dialysate:plasma ratio of creatinine (D/Pcreat) at the end of a 4-h dwell, and this correlates closely with the MTAC for creatinine [17]. The relationship is not in fact linear, due mainly to the variable influence of achieved ultrafiltration across the range of solute transport [15]. High values for D/Pcreat are associated with lower net ultrafiltration volumes, causing a spuriously high dialysate creatinine concentration, thus low ratio. This effect is small, however, and can be ignored for the purposes of this discussion. What, then, are the factors determining the MTAC for a solute of the size and properties of creatinine?
Describing solute transport
A number of mathematical models, in particular the 3-pore model and the distributed model have been developed in an attempt to describe and understand the factors that determine the passage of solutes across the peritoneal membrane [1822]. Expression of these models usually takes the form of a number of complex equations, that are frequently indigestible for clinicians whose mathematics are only dimly recollected. In this qualitative discussion of what these models tell us, however, one relatively simple equation describing small solute transport (e.g. for creatinine) is essential [19,23]:
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Peritoneal surface area in contact with fluid
It is often said that the peritoneal surface area approximates to the body surface areabased on measurements made in a small numbers of cadavers [24]. If body surface area were that important, then a significant correlation with D/Pcreat would be anticipated. If present, then this relationship is weak, being essentially absent in large cross-sectional studies [25], although reported by Diaz-Alvarenga et al. [26]. In the Stoke PD Study, in which solute transport was measured prospectively in a large cohort every 6 months, significant correlations were seen at 6 months (r=0.19, P=0.037) and 12 months (r=0.22, P=0.029) [1,10]. The dominant factor in these correlations is the height of the patient, and it is of interest that no correlation was observed immediately after commencing treatment. We and others have observed a tendency for solute transport to increase during the first 6 months of treatment [10,11]. It is tempting to suggest that these early changes reflect an increase in the availability of the peritoneal membrane in contact with dialysate, allowing a relationship to become apparent. The lack of a correlation later in treatment might reflect the overriding influence of acquired changes in membrane function.
Further evidence that peritoneal membrane size is a significant factor in determining solute transport would be expected to come from the paediatric population. Initial studies using the PET suggested that if anything children have higher solute transport than adults [27], due to the influence of the instilled volume on the relationship between D/Pcreat and MTAC [28,29]. If MTAC is measured directly, however, these differences disappear and in absolute terms, MTAC is proportional to body size. Using the 3-pore model, total pore area is related to body surface area in a linear fashion [30], although if the MTAC is normalized to body surface area it is apparent that smaller children have a disproportionately high solute transport.
There is therefore clinical evidence to support a relationship between solute transport and BSA, but the question must remain as to why this is so weak. One explanation might be that the proportion of the peritoneal membrane in contact with dialysis fluid is highly variable between individuals. In fact, Henderson estimated from middle molecule clearances that only 70% of the anatomical peritoneum is in contact with dialysate [31], and recent studies using CT imaging would appear to suggest that this is closer to 30% [32]. Furthermore, animal studies have suggested that only a small fraction of the visceral peritoneum is in contact with dialysate, with the parietal peritoneum being the dominant surface available for solute transport [33]. The factors that might lead to interpatient variability in the proportion of peritoneal membrane in direct contact with dialysis fluid remain poorly understood.
Diffusive mass transport through the capillary wall
What are the factors that influence the mass transport of solutes through the capillary wall? Again, mathematical models tell us that several properties of the capillary circulation are important. They include the capillary perfusion rate, capillary surface area and the diffusive permeability of the capillary wall of the given solute. The relative importance of these three factors will vary according to the solute in question. For example, in the case of a small molecule to which cell membranes are highly permeable, such as carbon dioxide (CO2), blood flow through the capillaries becomes the rate-limiting factor [19]. For creatinine, the solute used by clinicians to define solute transport status in the PET/SPA, the 3-pore model tells us that capillary surface area is the dominant factor [20]. Creatinine passes through small pores, 46 nm, which make up >90% of the total pore area, and are thought to correspond to the gaps between the endothelial cells of the capillary circulation. A larger capillary surface area will therefore translate into a higher D/Pcreat, although because of the square root relationship indicated above, relatively large changes will be needed.
Could differences in capillary surface area account for the relatively large interpatient variability in solute transport? The fact that small-solute diffusion can be augmented by intraperitoneal nitroprusside would suggest that it can [34]. However, this interpatient variability is already present at the beginning of treatment, as we have already seen, and cannot be adequately accounted for by differences in patient size. One possible clue comes from the observation that diabetic patients, known to have abnormalities of their microcirculation, also tend to have higher peritoneal solute transport [3]. This, combined with the diabetiform changes to the microcirculation of the peritoneum with time on treatment [3537], in particular the increase in numbers of blood vessels, would seem to support this conclusion [38]. Care has to be taken, however, in assuming that differences in peritoneal anatomy accounting for interpatient variability at the beginning of treatment are necessarily the same as the changes in peritoneal anatomy occurring with time on treatment. More research, for example data from the Peritoneal Biopsy Registry [37], which has already begun to report, will help to answer these questions. It does, however, seem likely that capillary surface area is important.
Diffusive transport through the interstitium
The final component, the transport of small molecules through the interstitium, is perhaps the least well understood of the factors determining solute transport. Indeed, the idea that progressive thickening and scarring of the peritoneum with time on treatment might lead to increases in solute transport is somewhat counter-intuitive. The interstitium, however, is a complex structure, consisting of large molecules that entrap colloid-rich areas which form a barrier to water-soluble solutes [39]. Progressive scarring leads to loss of this organization, and combined with increased intraperitoneal pressure, overhydration is likely to occur. Paradoxically, the thickened but overhydrated space may allow creatinine to diffuse through more rapidly. Currently, experimental work to address this problem is confined to the animal, and it is not possible to say to what extent it influences solute transport in the human.
Conclusion
So how should the clinician view solute transport? Using the tool at his or her disposal, (PET, SPA or PDC), it is not possible to distinguish between the various factors that determine MTAC. However, parameters whose principal dimensions are related to area, namely actual membrane surface area in contact with dialysate and capillary/vascular surface area, are clearly dominantparticularly for a small molecule such as creatinine. The use of the term effective peritoneal surface area, is perhaps the most helpful in encapsulating a mental picture of what low-molecular-weight solute transport really is [40]. It avoids the use of the term permeability, which should be reserved to describe the leakiness of the membrane to larger molecules, a property that is related to both the effective surface area and the size of large pores through which these molecules pass. Interpatient variability can be seen either as differences in the effective area of membrane in contact with dialysate or differences in the density/recruitment of perfused capillaries, or both. The early changes with time on treatment are perhaps more likely to be related to the former, whereas long-term changes associated with peritoneal fibrosis are perhaps due to the latter in association with interstitial and vessel damage. The possibility that systemic inflammation, associated with cardiovascular co- morbidity and malnutrition, is associated with peritoneal microvascular changes, explaining the tendency for these patients to have higher solute transport is intriguing (S. A. Davies, unpublished data). The development of reliable markers of peritoneal function and fibrosis that are both simple to perform and non-invasive will aid the clinician in distinguishing these processes.
Acknowledgments
I am grateful to many colleagues, in particular Michael Flessner, Ray Krediet, Bengt Rippe, Nick Topley, and John Williams, for fruitful discussions of this complex issue.
Notes
Correspondence and offprint requests to: Dr S. J. Davies, Department of Nephrology, North Staffordshire Hospitals Trust, Princes Road, Hartshill, Stoke-on-Trent ST4 7LN, UK.
References