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Nephrol Dial Transplant (2000) 15: Editorial Comments
Nephrol Dial Transplant (2000) 15: 1120–1123
Peritoneal solute transport—we know it is important, but what is it?
Simon J. Davies
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
[1–7]. 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 bioincompatible 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
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.
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/P ) at the end of a 4-h dwell, and this
creat
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/P
creat
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 [18–22]. 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]:
A
B
peritoneal surface
D/P 3MTAC =
creat
creat
in contact with fluid
SA
×
BA
B
diffusive mass transport
diffusive transport
×
through capillary wall
through interstitium
© 2000 European Renal Association–European Dialysis and Transplant Association
Nephrol Dial Transplant (2000) 15: Editorial Comments
It can be seen from this that three major factors
influence the MTAC (see also Figure 1). It is also
evident that the dominant factor is the peritoneal surface
area in contact with the fluid—a direct linear relationship, whereas the other factors have a square root
relationship. In other words larger changes or differences
have to occur in diffusion through the capillary wall or
the interstitium to have an equivalent impact on MTAC.
What are the physiological and clinical correlates with
these main factors?
Peritoneal surface area in contact with fluid
It is often said that the peritoneal surface area approximates to the body surface area—based on measurements
made in a small numbers of cadavers [24]. If body
surface area were that important, then a significant
correlation with D/P
would be anticipated. If precreat
sent, 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
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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/P
and MTAC [28,29]. If
creat
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.
Fig. 1. An idealized diagram showing the principal factors influencing the rate of solute transport (for creatinine) across the peritoneal
membrane. The route for creatinine molecules is indicated by the bold, broken arrow. Solute transport is proportional to the surface area
of peritoneum in contact with dialysate, the density of small, intercellular pores, and the diffusive transport through the interstitium
(see equation in text).
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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 (CO ), blood flow through the capillaries becomes
2
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, 4–6 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/P ,
creat
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 [35–37], 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
Nephrol Dial Transplant (2000) 15: Editorial Comments
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 dominant—particularly 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-molecularweight 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 longterm 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 comorbidity 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
Nephrol Dial Transplant (2000) 15: Editorial Comments
fibrosis that are both simple to perform and noninvasive will aid the clinician in distinguishing these
processes.
Acknowledgements. 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.
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