Perit Dial Int
27(Supplement_2):
228-232
2007
© 2007 International Society for Peritoneal Dialysis
Part 6: Cardiovascular Complications in PD |
THE "HEART" OF PERITONEAL DIALYSIS
Angela Yee-Moon Wang, Recipient of the John Maher Award
University Department of Medicine, Queen Mary Hospital, University of
Hong Kong, Hong Kong SAR, PR China
Correspondence to: A.Y.M. Wang, University Department of Medicine, Queen Mary
Hospital, University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong SAR, PR
China.
aymwang{at}hku.hk
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ABSTRACT
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Cardiovascular disease accounts for more than half of all deaths in
end-stage renal disease patients receiving chronic peritoneal dialysis (PD)
treatment. The recent demonstration of the important association between
residual renal clearance (but not PD clearance) and overall and cardiovascular
survival in chronic PD patients has led us to further explore the mechanisms
that can potentially explain the close link between residual renal function
and cardiovascular disease in this population. This John Maher Award Lecture
provides a review of my own work and that of other groups that provides
support for the importance of residual renal function not only in providing
small-solute clearance but also in maintaining the cardiovascular health,
nutrition status, and wellbeing of PD patients. Data are provided to
demonstrate why preservation of residual renal function may be the key to
improving survival and cardiovascular outcomes in PD patients.
KEY WORDS: Residual renal function; cardiovascular disease; nutrition; inflammation; calcification.
Cardiovascular disease is the leading cause of morbidity and mortality in
end-stage renal disease (ESRD) patients on maintenance dialysis. In a previous
study by my group (1), cardiac
and cerebrovascular causes accounted for 65% of the mortality in ESRD patients
receiving long-term peritoneal dialysis (PD). Notably, residual glomerular
filtration rate (GFR) was a highly important predictor of mortality and
cardiovascular death. Every increase of 1 mL/min/1.73 m2 in
residual GFR conferred a nearly 50% reduction in all-cause mortality and
cardiovascular death (1). Those
results are in keeping with earlier cohort studies that showed the importance
of residual renal function (RRF) in predicting the survival of PD patients
(2,3).
Conversely, PD clearance is almost insignificant in multivariate Cox
regression models for all-cause mortality and cardiovascular death
(1). That finding provided
important evidence that the contributions of RRF and of PD clearance to the
overall survival of PD patients are not equivalent. Indeed, a further
re-analysis of data from the CANUSA study clearly showed that predictive power
for mortality is attributable to RRF and not to PD dose
(4).
Those results should not lead to the assumption that the dose of PD is
unimportant; however, it does suggest a more important contribution of RRF
than of PD clearance to the overall survival of PD patients. The present
article provides evidence to support the importance of preserving RRF in PD
patients and suggests potential mechanisms that explain the associations
between RRF and overall and cardiovascular survival in PD patients
(Figure 1).
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Figure 1 — Mechanisms of associations between loss of residual renal function
and mortality in peritoneal dialysis patients.
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RESIDUAL RENAL FUNCTION AND LEFT VENTRICULAR HYPERTROPHY
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Left ventricular hypertrophy (LVH) is well recognized as an important
predictor of mortality and cardiovascular death in PD patients, as confirmed
in a previous survey, which showed that more than 90% of prevalent PD patients
have LVH (1). Moreover, LVH was
observed to have an important inverse relationship with RRF, in that anuric PD
patients suffered the most severe degree of LVH, and no relationship was found
between PD clearance and degree of LVH
(5).
Several mechanisms may potentially explain the association between RRF and
LVH, one of which is the role of RRF in maintaining fluid balance. The link
between RRF and volume control is evidenced by the extracellular volume
expansion found in PD patients with a lesser degree of RRF
(6). Extracellular volume
overload is increasingly recognized as a frequent complication in chronic PD
patients that has important prognostic implications
(7). Indeed, one study observed
worse LVH and dilatation and worse systolic and diastolic function among PD
patients who had a previous history of volume overload
(8). Anuric PD patients have
been noted to have worse blood pressure than patients with RRF, and that
situation may again be partly attributable to poor volume control
(9,10).
In the re-analysis of the CANUSA study data, every 250 mL of urine output
was associated with a 36% reduction in overall mortality. In addition, the
presence of urine output displaced renal small-solute clearance from the
multivariate Cox regression model
(4), providing indirect
evidence that any degree of sodium and water removal by the diseased kidneys
continues to have a major influence on the survival of PD patients.
Alternatively, the link between RRF loss and worsening of LVH may be partly
explained by greater anemia with loss of erythropoietin production, greater
hypoalbuminemia, and higher arterial pulse pressure
(5,10),
all of which are known risk factors for LVH in PD patients. The findings that
RRF (but not PD small-solute clearance) was significantly associated with LVH
independent of hypertension, anemia, and hypoalbuminemia
(5) suggest that some
non-dialyzable uremic toxins may play a role in mediating LVH in PD
patients.
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RESIDUAL RENAL FUNCTION AND INFLAMMATION
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Inflammation plays a pivotal role in the initiation and progression of
atherosclerosis, and inflammation is considered a major nontraditional risk
factor for accelerated atherosclerosis in dialysis patients
(11,12).
A previous study by my group showed that more than one third of prevalent
Chinese PD patients had evidence of inflammation as denoted by a
high-sensitivity C-reactive protein (CRP) serum level 5 mg/L or higher. In
addition, CRP is an important predictor of mortality and cardiovascular death
in PD patients (13).
The degree of inflammation is not only closely linked with atherosclerotic
vascular disease, it is also associated with RRF, in that anuric PD patients
show the greatest inflammatory response as measured either by CRP
(13) or by soluble vascular
cell adhesion molecule 1 (14).
The exact mechanism underlying this latter association remains unclear. Loss
of RRF (or uremia per se) has been suggested to possibly enhance an
inflammatory response by increasing oxidative stress—a response that may
lead to monocyte activation and cytokine production
(15). The involvement of the
kidneys in cytokine handling, as evidenced by impaired cytokine clearance in
nephrectomized rats (16), has
also been suggested as another possible mechanism that can explain the link
between loss of RRF and inflammation.
On the other hand, inflammation has been closely linked with arterial
stiffening, LVH and dilatation, and systolic dysfunction in PD patients
(1). Importantly, loss of RRF,
inflammation, and LVH are not only closely interrelated, they also combine
adversely to increase the mortality and cardiovascular death risk in chronic
PD patients (1). Similarly,
circulating soluble vascular cell adhesion molecule 1 is also associated with
RRF and LVH in PD patients.
In addition, the association between loss of RRF and increased mortality
and cardiovascular event risk is partly mediated via the close associations of
RRF with inflammation and endothelial activation
(14). In PD patients, the
combination of inflammation and endothelial activation confers a higher risk
of mortality and of cardiovascular event occurrence than either factor does
alone (14).
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RESIDUAL RENAL FUNCTION, PHOSPHORUS CONTROL, AND VALVULAR CALCIFICATION
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Cardiovascular calcification is increasingly recognized as a frequent and
important complication in patients on dialysis. It is largely attributed to
deranged mineral metabolism with resulting abnormal calcium–phosphorus
control. A previous survey showed that, in at least 40% of chronic PD
patients, serum phosphorus was elevated above 1.78 mmol/L
(17), the target currently
recommended by the Kidney Disease Outcomes Quality Initiative. More
importantly, that study observed a strong inverse relationship between
residual GFR and phosphorus control even when the average residual GFR of the
PD patients fell below 2 mL/min/1.73 m2
(17). Among patients with
well-preserved RRF, residual GFR was second to dietary protein intake as the
most important determinant of phosphorus control. However, because PD
clearance becomes the only means of phosphorus removal in anuric patients, and
because such removal may be inadequate, the result is a greater prevalence of
valvular calcification observed in the anuric PD population (unpublished
data).
Another survey reported that at least one third of prevalent PD patients
had heart valve calcification
(18). Apart from the important
association with CaxP product, heart valve calcification was
demonstrated to be closely linked to inflammation and malnutrition in PD
patients. Even among patients without an excessive CaxP product, the
presence of inflammation and malnutrition was associated with an increased
risk of valvular calcification
(18), providing further
evidence to support the involvement of inflammation in valvular calcification.
Indeed, evidence is accumulating that, rather than being passive, degenerative
processes, vascular and valvular calcification are dynamic and active
cell-mediated processes that involve a switch in the phenotype of vascular
smooth muscle cells to osteoblast-like cells.
A recent study showed that serum fetuin-A, a circulating calcification
inhibitory protein and a negative acute-phase reactant, is inversely
associated with valvular calcification independent of CRP and a high
CaxP product. Furthermore, serum fetuin-A is predictive of mortality and
cardiovascular death in PD patients. However, no association was observed
between RRF and serum fetuin-A
(19), suggesting that
increased valvular calcification in anuric PD patients is unlikely to be
mediated by depletion of circulating fetuin-A.
Valvular calcification was recently identified as an important predictor of
mortality and cardiovascular death in PD patients
(20). Notably, PD patients
exhibiting both valvular calcification and atherosclerotic vascular disease
(as compared with patients having either or neither of these complications)
had the highest mortality and cardiovascular death. Furthermore, for patients
with either valvular calcification or atherosclerotic vascular disease,
overall survival and cardiovascular event-free survival were comparable
(20). Those results, together
with recent findings of an association between heart valve calcification and
carotid atherosclerosis (21),
provide important evidence that valvular calcification represents a marker of
atherosclerosis as well as a reflection of poor calcium and phosphorus control
in PD patients.
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RESIDUAL RENAL FUNCTION AND NUTRITION
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Residual renal function makes an important contribution to the overall
nutrition status of PD patients—whether assessed using serum albumin,
subjective global assessment, or handgrip strength
(22–24).
A previous study showed that handgrip strength, a reliable marker of lean body
mass, was strongly predictive of survival and cardiovascular outcome in PD
patients, independent of inflammation and RRF
(24).
Using a locally validated food frequency questionnaire, an important
association was demonstrated between total weekly urea clearance and dietary
protein and energy intake in PD patients
(23). Intake of
micronutrients, including vitamin A and most water-soluble vitamins
(B1, B2, B6, B12, folic acid,
niacin, and C), plus minerals including calcium, phosphorus, iron, and zinc,
was also associated with total weekly urea clearance
(25). More importantly, the
associations of total weekly urea clearance with dietary macronutrient and
micronutrient intake were largely attributable to RRF and not to PD urea
clearance
(23,25).
Peritoneal urea clearance, when considered as a separate factor, showed no
relationship with any of the nutritional indices, including subjective global
assessment, handgrip strength, or dietary macronutrient or micronutrient
intake
(23–25).
That finding provides important evidence that the contributions of RRF and PD
clearance to the overall nutrition status of PD patients are indeed not
equivalent and not simply additive. Whether this indicates a differential
capacity of PD and RRF to remove middle-molecule uremic toxins remains to be
determined.
Loss of RRF may also contribute to malnutrition in PD patients through its
close relationship with increased resting energy expenditure
(26). Resting energy
expenditure accounts for 60%–80% of total energy expenditure. A
sustained increase may lead to an energy imbalance and malnutrition if not
compensated for by an increase in energy intake. Previous work by my group
showed that resting energy expenditure not only increases in patients with
malnutrition–inflammation–atherosclerosis syndrome, but more
importantly, shows a strong inverse relationship with RRF in PD patients. No
association was observed between resting energy expenditure and PD clearance.
In addition, resting hypermetabolism mediated increased mortality and
cardiovascular death in PD patients partly through its close association with
RRF (26).
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CONCLUSIONS
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Previous work has clearly demonstrated that residual renal clearance and PD
clearance cannot be assumed to be equivalent in PD patients. Apart from
providing small-solute clearance, RRF continues to serve important metabolic
and hemodynamic functions and plays a crucial role in maintaining
cardiovascular health, nutrition status, and wellbeing
(10,27).
It also contributes significantly to the overall survival of PD patients.
These data suggest that the important goal of preserving RRF should continue
even after ESRD patients are started on long-term PD. More effective
therapeutic strategies are needed to preserve RRF in PD patients.
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ACKNOWLEDGMENTS
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The work described here is supported by funds from the Hong Kong Health
Service Research Grant Number 6901023, Hong Kong Society of Nephrology
Research Grants and the Baxter Extramural Grant Program, of which Angela
Yee-Moon Wang is the principal investigator.
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RESIDUAL RENAL FUNCTION AND...
