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Part 3: Clinical Experiences |
Unidad de Investigación Médica en Enfermedades Renales, UMAE Hospital de Especialidades, CMNO, IMSS, Guadalajara, Mexico
Correspondence to: A.M. Cueto-Manzano, Unidad de Investigación Médica en Enfermedades Renales, Hospital de Especialidades, CMNO, IMSS, Belisario Domínguez No. 1000, Col. Independencia, Guadalajara, Mexico. a_cueto_manzano{at}hotmail.com
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ABSTRACT |
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 TOP ABSTRACT FACTORS ASSOCIATED WITH...CONSEQUENCES OF RAPID PERITONEAL...REASONS FOR HIGHER MORTALITY...STRATEGIES FOR TREATING PATIENTS...SUMMARYREFERENCES |
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This review focuses on the physiologic and clinical consequences of
rapid solute transport in the peritoneum. The concept, the current
understanding of related factors, and the possible causes implicated in rapid
solute transport are discussed first. Then, the consequences, with particular
emphasis on mortality, are highlighted. Finally, based on recent advances and
clinical studies, some strategies for the treatment of fast peritoneal
transport are reviewed.
KEY WORDS: Rapid solute transport; peritoneal physiology; high peritoneal transport.
The worldwide utilization of peritoneal dialysis (PD) as a renal replacement therapy is about 10%–15%; however, in countries such as Mexico or Hong Kong, the PD modality is used in about 80% of patients with end-stage renal disease. In contrast to the declining use of PD in the United States, Canada, and Europe, PD is still growing at a rate of 10% annually in Mexico (1).
In the clinical context, patients on PD are easily seen to display a great variability in small-solute transport rate (STR) and ultrafiltration (UF) capacity. Thanks to Twardowski et al. (2), these variables can be evaluated in a standardized way by means of the simple but invaluable peritoneal equilibration test (PET). The PET is a rudimentary description of membrane function and UF, but because of its simplicity, it has been extensively used worldwide.
"High" or "fast" peritoneal transport characterizes a special group of patients who differ significantly from the others. The term "high" is more appropriately used to describe the four-group classification of peritoneal transport in which the mean ± standard deviation (and extreme values) of a given population are taken in account (2). The term "fast" transport is probably more appropriate to describe the velocity with which small-solute equilibration between dialysate and plasma (D/P ratio, as a dimensional variable) is achieved (3). But whichever term is used, the increased diffusive peritoneal transport rate for small solutes (creatinine, urea, sodium) in high or fast transporters results in a higher D/P ratio than in "low" or "slow" transporters. On the other hand, because of rapid glucose absorption and loss of osmotic gradient, patients with fast transport show a lower net UF. Thus, in spite of an increased transport rate for small solutes, a lesser removal of fluid may result in a total solute removal after 4–6 hours (as with urea, for example) that is significantly lower in fast transporters than in patients of other transport types.
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FACTORS ASSOCIATED WITH VARIABILITY OF PERITONEAL SOLUTE TRANSPORT |
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TOPABSTRACTFACTORS ASSOCIATED WITH...CONSEQUENCES OF RAPID PERITONEAL...REASONS FOR HIGHER MORTALITY...STRATEGIES FOR TREATING PATIENTS...SUMMARYREFERENCES |
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Rapid solute transport and low UF can be found at the initiation of PD and after patients have spent 4–5 years on PD therapy (6). In inherent fast transport (present from the beginning of dialysis or shortly after), genetics, inflammation, comorbid conditions, and a large peritoneal or vascular surface (or both) are commonly implicated (7,8). When fast transport is acquired (developed after the patient has spent some time on dialysis), the change has been related to the bioincompatible composition of dialysate (glucose degradation products, glucose concentration, acid pH, lactate) and to peritonitis (6,8,9).
The lack of sufficient adequately designed studies correlating histopathologic to functional characteristics in PD makes any comprehensive analysis in particular cases of fast peritoneal transporters difficult. Not all patients develop significant alterations in PD, but on the other hand, several abnormalities probably associated with rapid STR are present in uremic subjects before the start of PD. Structural changes include loss of mesothelial cells, increase in the thickness of the submesothelial compact zone, and a plethora of changes in the structure and number of blood vessels, which range from classical small-vessel atherosclerosis to venular changes, and replication of capillary basement membrane (10). Although uremia per se (and associated conditions such as diabetes) may be associated with these changes even before dialysis, it seems clear that a great proportion of patients develop increasingly significant alterations in a time-dependent manner after continuous exposure to conventional dialysis solutions (10). In addition, an increased peritoneal STR associated with an increased surface area of peritoneal microvessels has been reported, especially in patients on long-term PD treatment (11). Recently, epithelial-to-mesenchymal transition of mesothelial cells—an important pathophysiologic mechanism of peritoneal damage (12)—has been suggested to be a frequent morphology change in the peritoneal membrane during the first 2 years of PD, and high solute transport status has been suggested to possibly be associated with this transition, but not with an increased number of peritoneal vessels (13).
Certain genetic characteristics may also predispose patients to develop changes or alterations in peritoneal transport once they initiate PD. Axelsson et al. (14) recently summarized current studies looking at the presence of polymorphisms probably related to peritoneal transport, including those in genes for plasminogen activator inhibitor type 1, endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), and interleukin 6 (IL-6). This issue is not completely elucidated, but it is probable that certain polymorphisms of the latter three genes may influence the presence of fast peritoneal transport at the start of PD or some time afterwards.
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CONSEQUENCES OF RAPID PERITONEAL TRANSPORT OF SOLUTES |
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TOPABSTRACTFACTORS ASSOCIATED WITH...CONSEQUENCES OF RAPID PERITONEAL...REASONS FOR HIGHER MORTALITY...STRATEGIES FOR TREATING PATIENTS...SUMMARYREFERENCES |
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REASONS FOR HIGHER MORTALITY IN PATIENTS WITH RAPID STR |
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TOPABSTRACTFACTORS ASSOCIATED WITH...CONSEQUENCES OF RAPID PERITONEAL...REASONS FOR HIGHER MORTALITY...STRATEGIES FOR TREATING PATIENTS...SUMMARYREFERENCES |
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A search for pathophysiologic causes has led to a hypothesis [Figure 1(A)] that fast transporters experience increased mortality because their membrane characteristics induce cardiovascular, metabolic, and nutrition alterations, which subsequently lead to death.
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A rapid solute transport rate has also been positively correlated with serum concentrations of total cholesterol, low-density and very-low-density lipoprotein cholesterol, triglycerides, and apolipoprotein(b), and negatively correlated with high-density lipoprotein cholesterol (19). All these lipid alterations have been extensively documented as risk factors for cardiovascular disease and death.
Similarly, patients with fast peritoneal transport have been repeatedly shown to have lower levels of serum albumin, which may in turn be a result (at least in part) of higher protein loss through the dialysate (20). Serum albumin inversely correlates with low-density lipoprotein cholesterol and apolipoprotein(a) (21) and possesses vasculoprotective antioxidant effects (22); thus, increased protein loss into dialysate may contribute to hypoalbuminemia, lipid abnormalities, edema, and loss of antioxidant capacity. Malnutrition and hypoalbuminemia are strong predictors of mortality in dialysis (23); but although hypoalbuminemia can be a marker of malnutrition, low serum albumin in dialysis reflects several conditions besides malnutrition (24). Whether protein loss in dialysate causes a more pronounced malnutrition in high peritoneal transporters remains controversial. In cross-sectional studies, our group (25) observed no association between rapid peritoneal transport and malnutrition (evaluated using a composite index of nutrition); however, others have reported a direct association between these variables (26). Prospective studies on this subject are still awaited.
A second hypothesis [Figure 1(B)] suggests that a rapid peritoneal transport rate may be a consequence of a systemic vascular disorder such as that observed in diabetes mellitus, hypertension, atherosclerosis, smoking, or sepsis. Endothelial vascular disorder is also closely related to the malnutrition, inflammation, and atherosclerosis (MIA) syndrome, which may also explain the increased mortality observed in patients with high transport.
Atherosclerosis is now generally recognized as an inflammatory disease (27). In addition, the cytokines released during chronic inflammation and malignancy act on the central nervous system to alter the release and function of key neurotransmitters, thereby altering appetite and metabolic rate alike. The common pathway for all the metabolic derangements is related to an excess of protein degradation relative to protein synthesis (28). Particularly in the case of dialysis patients, Stenvinkel et al. (29) proposed the existence of the MIA syndrome. In continuous ambulatory PD (CAPD), some incident patients with malnutrition (as compared with well-nourished patients) seemed to show higher serum levels of C-reactive protein (CRP), IL-6, vascular cell adhesion molecule, and hyaluronan, and a higher prevalence of cardiovascular disease. Additionally, fast peritoneal transport was observed more frequently in patients with MIA syndrome (30). Patients with faster peritoneal transport rates have also been observed to show higher serum and dialysate levels of IL-6, CRP, and VEGF than do patients with slower transport (31,32), although these findings have not been replicated by others (33). Moreover, some studies have shown that older age, higher inflammation, higher peritoneal transport, and lower residual renal function are the most significant predictors for mortality in PD patients (34).
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STRATEGIES FOR TREATING PATIENTS WITH RAPID PERITONEAL SOLUTE TRANSPORT |
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TOPABSTRACTFACTORS ASSOCIATED WITH...CONSEQUENCES OF RAPID PERITONEAL...REASONS FOR HIGHER MORTALITY...STRATEGIES FOR TREATING PATIENTS...SUMMARYREFERENCES |
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The use of nocturnal intermittent PD (NIPD) varies from the use of
continuous cycling PD (CCPD) because, between the intermittent cycler
treatments, the peritoneal cavity is left empty ("dry day"). In a
small crossover clinical trial involving patients with high and high-average
transport (37), our group
observed that a change from CAPD to NIPD was accompanied by a significant
reduction in serum CRP, a trend toward lower tumor necrosis factor 
and
IL-6, and significantly better UF (associated with a decrease in weight, blood
pressure, and dialysate glucose content). However, these beneficial effects
were reversed after the patients were switched to CCPD from NIPD. Contrary to
the hypothesis that a reduction in contact time between dialysate and the
peritoneal membrane could reduce the stimulus for local production of
inflammatory mediators, dialysate concentrations of cytokines did not decrease
with NIPD. An alternative explanation for the decrease in systemic
inflammation may be the better volume control achieved with NIPD. The
beneficial effect of NIPD in reducing systemic inflammation in high and
high-average transporters could be regarded as temporary (residual renal
function allows patients to remain on such therapy for a time); however, that
time period could be extremely important. Thus, NIPD may be justified in high
transporters to achieve better clinical outcomes, volume control, and lower
systemic inflammation.
Although APD improves the notoriously poor UF in fast transporters, the APD technique still uses a day dwell that may be substantially longer than the overnight dwell in CAPD, resulting in even more fluid reabsorption. Icodextrin, a high molecular weight glucose polymer, offers the concomitant advantages of reduced glucose absorption and increased UF as compared with conventional hypertonic glucose-containing solutions. Interestingly, high transport status seems to predict a higher UF response to icodextrin (38). In randomized controlled trials, icodextrin used by high transporters for the long dwell resulted in significant improvement in UF and reduction of extracellular fluid volume and of left ventricular mass (39–41); nonetheless, some care has to be taken with the use of icodextrin to avoid a too-rapid volume depletion that might jeopardize residual renal function (42) and to avoid potentially fatal hypoglycemia, because maltose interferes with measurement methods (monitor and test strips) that are nonspecific for glucose (43). In settings in which icodextrin is not broadly available, strategies such as using 1 or 2 diurnal manual exchanges may be used to improve UF.
Currently, prevention of long-term peritoneal membrane damage (increase in solute transport and reduction in osmotic conductance) is the best option. The hope is that use of less-hypertonic glucose dialysate and newer biocompatible solutions will prevent the occurrence of such damage, although no long-term data are available at present.
Several drugs have been used to improve UF, although none specifically address the case of high transporters. Hyaluronan (44), verapamil (45), angiotensin converting-enzyme inhibitors and angiotensin II receptor blockers (46) have been proved to be successful in increasing UF in PD.
Finally, some issues of fast peritoneal transport deserve further investigation, including its associations with growth and body mass gain (47) and bone turnover (48) in children, and its relationship with acid–base status (49).
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SUMMARY |
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TOPABSTRACTFACTORS ASSOCIATED WITH...CONSEQUENCES OF RAPID PERITONEAL...REASONS FOR HIGHER MORTALITY...STRATEGIES FOR TREATING PATIENTS...SUMMARYREFERENCES |
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TOPABSTRACTFACTORS ASSOCIATED WITH...CONSEQUENCES OF RAPID PERITONEAL...REASONS FOR HIGHER MORTALITY...STRATEGIES FOR TREATING PATIENTS...SUMMARYREFERENCES |
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This article has been cited by other articles:
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  A. Davenport and M. K. Willicombe Hydration Status Does Not Influence Peritoneal Equilibration Test Ultrafiltration Volumes Clin. J. Am. Soc. Nephrol., July 1, 2009; 4(7): 1207 - 1212. [Abstract] [Full Text] [PDF]
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