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Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn595
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Higher Daily Peritoneal Protein Clearance when Initiating Peritoneal Dialysis is Independently Associated with Peripheral Arterial Disease (PAD). A Possible New Marker of Systemic Endothelial Dysfunction?

Rafael Sánchez-Villanueva1, Auxiliadora Bajo1, Gloria del Peso1, M-Jose Fernandez-Reyes2, Elena González1, Sara Romero1, Patricia Estrada1 and Rafael Selgas1

1 Servicio de Nefrologia, Hospital Universitario La Paz, Madrid, Spain 2 Servicio de Nefrologia, Hospital General de Segovia, Segovia, Spain

Correspondence and offprint requests to: Rafael Sánchez-Villanueva, Servicio de Nefrologia, Hospital Universitario La Paz, P Castellana 261, 28046 Madrid, Spain. Tel: +34-91-207-1758; Fax: +34-91-358-5060; E-mail: rjsanchez.hulp{at}salud.madrid.org



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Patients starting peritoneal dialysis (PD) with active cardiovascular disease (CVD) show higher protein and albumin levels in peritoneal effluent. Peripheral arterial disease (PAD) is increasingly recognized as an entity particularly associated with higher mortality.

Methods. To explore whether higher daily peritoneal protein clearance (PrC) on starting PD is a cardiovascular risk marker, we have formulated the hypothesis that PAD, as an expression of the highest CVD grade, is specifically related to the amount of PrC.

Results. The average of 24-h effluent peritoneal protein losses (PPL) was 6.88 ± 3.31 g. The median of PrC was 94.43 ml/day and quartiles 1 and 4 were delimited by 56.25 and 114.18 ml/day, respectively. A significant positive correlation between PrC and peritoneal small solute transport was detected. Patients in the highest quintile of Cr-MTAC (>14.04 ml/min) demonstrated significantly greater PrC than the remainder. An inverse significant correlation with plasma albumin levels was also demonstrated (r = –0.52, P = 0.0001). Eighteen patients with PAD showed significantly higher PrC than patients with no PAD (130.62 ± 74.89 versus 88.77 ± 47.56 ml/day; P = 0.033). Other CVDs were not significantly associated with greater PrC. In the univariable logistic regression analysis, PAD was directly and significantly related to PrC, Charlson's index, gender, diabetes and age. Multivariable analysis confirmed that PAD was significantly related to PrC, independent of age (RR: 1.07, IC: 1.02–1.12, P = 0.006) and diabetes (RR: 11.29, IC: 2.9–42.60, P = 0.000).

Conclusion. Our study shows that daily peritoneal PrC on initiating PD is significantly and independently related to the presence of PAD. Peritoneal PrC appears to be a possible new marker of systemic endothelial dysfunction.

Keywords: daily peritoneal protein clearance; endothelial dysfunction; peripheral arterial disease



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Peritoneal dialysis (PD) patients may lose 2–4 g of amino acids and 5–15 g of proteins daily throughout the peritoneum. These losses increase considerably during peritonitis episodes [1–8]. Due to this situation, PD patients require additional protein intake (1.2 g/kg/day) to compensate for these losses, relative to the general population [9]. However, many PD patients show hypoalbuminaemia attributed also to other causes, such as inflammation and comorbidity [10–15]. Hypoalbuminaemia is an independent predictor of poor outcome in haemodialysis (HD) [16] and PD [17,18] patients, although this relationship is not present in non-kidney disease patients [19].

Another manifestation of capillary protein leak is microalbuminuria, which is recognized as an endothelial dysfunction marker [16]. The projection of systemic alteration in the glomerular endothelium allows the recognition of a general disorder affecting vessel walls. Albumin peritoneal losses in PD patients have been identified as something similar [20,21]. In fact, patients starting PD with active cardiovascular disease (CVD) show higher protein and albumin levels in peritoneal effluent [22]. This effect was independent of confounding factors such as former CVD or inflammatory status (serum reactive C protein) [20]. These same authors have confirmed that cardiovascular events are more frequent in patients with greater peritoneal albumin losses [20]. These findings suggest that peritoneal protein losses (PPL) could be an independent cardiovascular risk marker.

CVD is frequently present in chronic kidney disease (CKD) patients and is responsible for 50% of deaths [23]. Moreover, kidney disease per se is an independent cardiovascular risk factor [24]. In particular, peripheral arterial disease (PAD) is increasingly recognized as an entity associated with higher mortality [25–28], specifically among CKD patients [29].

Trying to confirm that higher daily peritoneal protein clearance (PrC) on starting PD is a cardiovascular risk marker, we have formulated the hypothesis that PAD, as an expression of the highest CVD grade, is specifically related to the intensity of PPL. Our secondary aim was to evaluate other factors potentially related to PrC and determine its influence on patient outcome.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
One hundred and thirty-three PD incident patients during the period 1980–2001 were included. These patients were selected from the group constituted for functional evaluation of peritoneum under baseline conditions. Their characteristics were previously published, and in all cases, prior evident normality (no major surgery or other cPD contraindications) of the abdominal cavity was required [30]. All patients were treated with continuous ambulatory peritoneal dialysis (CAPD) with conventional solutions. After 1995, some patients were transferred to automated PD and after 1998, some of them used icodextrin.

PPL in 24-h effluent and daily peritoneal PrC are routinely measured in every peritoneal kinetic study we perform. The collection of 24-h effluent is necessary to calculate the solute generation rate, which is required in the mathematical model.

Definitions

Coronary arterial disease: antecedents of angina, myocardial infarction, coronariography evidence, percutaneous coronary intervention or by-pass.
Congestive heart failure: NYHA criteria.
Peripheral arterial disease (PAD): patients referring intermittent claudication, or arterial by-pass, amputation, gangrene or acute arterial insufficiency, non-corrected thoracic or abdominal aorta aneurisms (larger than 5 cm).
Cerebral vascular disease: patients with antecedents of cerebrovascular accidents or transitory ischaemic attacks (with mild or no sequelae).

Clinical and laboratory data
Data at baseline were collected and used to define co-morbidity by the Charlson index modified by Beddhu [31]. Patient age was not included in the Charlson index, so that the influence of true co-morbidity and age on peritoneal function data and outcomes could be separately analysed.

All biochemical determinations were measured during the peritoneal kinetic study. Residual renal function (RRF) was estimated by the average of renal urea and creatinine clearances. Patients were considered anuric when RRF was <1 ml/min.

We performed the baseline peritoneal transport kinetic study 4–6 weeks after the initiation of PD. This study consisted of a 4-h dwell time exchange, taking six peritoneal effluent (at 0, 30, 60, 120, 180 and 240 min) and one blood sample to calculate the peritoneal mass transfer area coefficient (MTAC, ml/min) of urea and creatinine using a previously described mathematical model [32]. This coefficient represents the isolated diffusive capacity of the membrane under theoretically infinite dialysate flow [33]. High transport patients were considered as those in the fifth quintile of the creatinine-MTAC values distribution (Cr-MTAC > 14.04 ml/min). Patients fasted during each functional study, and they received no drugs except low doses of subcutaneous insulin, if necessary. All studies were performed without peritoneal inflammation (<100 white blood cells/µl with <50% neutrophil). Ultrafiltration rate (UF, ml) was estimated by the net negative difference between the weight of the bag before and after the test. This value represents convective transport capacity.

PPL were measured in 24-h peritoneal effluent by the sulphosalicilic method. In the understanding that peritoneal clearance (PrC) could represent the transport process throughout the peritoneal capillary system better than isolated protein losses and presuming that albumin represents more than 90% of the peritoneal protein determined [12,34,35], we selected PrC to present the overall analysis.

Daily peritoneal PrC was calculated by the following formula:

24-h dialysate protein/(serum albumin/0.4783) expres- sed in ml/day.

Statistical analysis
For statistical analysis, we used the SPSS-11 program. Values are expressed as percentages and mean (±SD). A value of P < 0.05 was considered statistically significant. Proportions were compared by the chi-square test and means by Student's t-test for non-paired data. The Pearson or Spearman tests were used for linear regression analysis. A univariable and multivariable analysis with forward logistic regression was performed to determine the relationships with the dependent variable, PAD. The survival analysis employed the Kapplan–Meier method and curves were compared by the log-rank method. To analyse the simultaneous effect of several variables on mortality, a Cox proportional hazards model was performed.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
The general characteristics of the studied population are described in Table 1. The causes of kidney disease were diabetes in 37 (27.8%), interstitial nephropathy in 24 (18%), glomerulonephritis in 18 (13.5%), nephrosclerosis or vascular in 19 (14.3%), polycystic kidney disease in 13 (9.8%), systemic disease in 12 (9%), unknown cause in 7 (5.3%), others in 2 (1.5%) and hereditary in 1 (0.8%).


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  		Table 1 General characteristics of the series

 
Data related to peritoneal transport are shown in Table 2. The average of 24-h effluent PPL was 6.88 ± 3.31 g (range: 0.98–20.95) and daily PrC 94.43 ± 53.69 (range: 14.20–289.54) ml/day. The medians of PPL and the PrC were 6.5 g/ 24 h and 78.70 ml/day, respectively. Quartiles 1 and 4 were delimited by 4.28–8.81 g/24 h and 56.25–114.18 ml/day, respectively.


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  		Table 2 Peritoneal transport kinetic studies

 
A mild but significant positive correlation between PrC (and PPL, data not shown) and peritoneal small solute transport (U-MTAC: r = 0.28, P = 0.001; Cr-MTAC: r = 0.34, P = 0.000) was detected. Patients in the highest quintile of Cr-MTAC (>14.04 ml/min) demonstrated significantly greater PrC than the remainder (120.74 ± 59.38 versus 88.04 ± 50.47 ml/day, P = 0.005). No correlation with UF capacity was found. An inverse significant correlation with plasma albumin levels was also demonstrated (r = –0.52, P = 0.0001).

Co-morbidity analysis
The Charlson index average value was 4.94 ± 2.21 (median: 5; range: 2–9). PrC was higher in 46 patients with Charlson's index over 5, and these differences were statistically significant (109.30 ± 58.26 versus 86.57 ± 49.68 ml/day; P = 0.020).

Patients with prior CVD demonstrated greater PrC than patients with no CVD (102.16 ± 58.52 versus 88.45 ± 49.20 ml/day), although these differences did not reach statistical significance (P = 0.145). However, 18 patients with PAD showed significantly higher PrC than patients with no PAD (130.62 ± 74.89 versus 88.77 ± 47.56 ml/day; P = 0.033). PAD patients were older (62.13 ± 11.52 versus 51.28 ± 14.94 years; P = 0.004) and presented a higher co-morbidity index (8.06 ± 1.92 versus 4.45 ± 4.82; P = 0.0001) than non-PAD patients. Other CVDs were not significantly associated with greater PrC. Patients with angina (104.81 ± 46.29 versus 93.40 ± 54.43 ml/day; P = 0.485), myocardial infarction (104.32 ± 40.52 versus 93.63 ± 54.67 ml/day; P = 0.547) and congestive heart failure (95.96 ± 65.12 versus 93.90 ± 49.53 ml/day; P = 0.867) did not reach significant differences. Hypertensive patients demonstrated similar PrC to non-hypertensive patients (94.39 ± 50.61 versus 94.68 ± 70.18 ml/day; P = 0.982).

In the univariable logistic regression analysis, PAD was directly and significantly related to PrC, Charlson's index, gender, diabetes and age (Table 3). There was no significant relationship with U-MTAC, Cr-MTAC (both expressed as continuous variable or in quintiles), RRF, plasma albumin or peritoneal UF capacity. Multivariable analysis confirmed that PAD was significantly related to PrC, independent of age (RR: 1.07, IC: 1.02–1.12, P = 0.006) and diabetes (RR: 11.29, IC: 2.9–42.60, P = 0.000). However, Charlson's index (RR: 1.19, IC: 0.99–1.42, P = 0.055), gender, Cr-MTAC, albumin, RRF, U-MTAC and UF did not enter into the prediction model.


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  		Table 3 Univariable logistic regression analysis for peripheral arterial disease

 
Mortality analysis
Forty-nine patients died during the follow-up, CVD being the most frequent cause (Table 1). A comparison of data from dead patients with those who remain alive is displayed in Table 4. It is noteworthy that patients who died were older, had a higher co-morbidity index and showed significant lower RRF and plasma albumin levels. There were no differences in outcome depending on peritoneal transport parameters or PrC. Figure 1 shows the survival curves constructed with values over/under the median and with that of the first and fourth PrC quartiles, demonstrating non-significant differences. When we analysed these values by decades, we found no differences relative to previous results (data not shown). Cox's analysis revealed that mortality was significantly associated with age (OR: 1.05, IC: 1.03–1.08) and Charlson's index (OR: 1.51, IC: 1.27–1.79), but not with PrC nor plasma albumin level.


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  		Table 4 Differences between dead patients and those who remain alive

 

Figure 1
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  		Fig. 1 Survival curves for different peritoneal protein clearance (PrC) values according to the median (A) and extreme quartiles (Q1–Q4) (B).

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Our study demonstrates a significant and independent relationship between the PPL on initiating PD and PAD. Taking for granted that peritoneal transported protein is the result of peritoneal endothelial capillary intrinsic permeability and that a dysfunctional endothelium is associated with greater protein permeability, an abnormal functional status of peritoneal endothelium can be proposed to explain this link. On the other hand, PPL do not seem to influence medium-term patients’ survival.

Capillary protein permeability as a marker of systemic endothelial dysfunction
Microalbuminuria has been recognized as a marker of systemic endothelial dysfunction [22,36]. The appearance of microalbuminuria is 6.5-fold in PAD when cognitive function, as representative of cerebrovascular status, is also impaired [37,38]. According to the representation by PPL of the systemic nature of endothelial dysfunction, they are the features exhibited in steroid-resistant nephrotic syndrome in children. The PPL in these patients are twice as great as in those without nephrotic syndrome, results consistent with the systemic effect of a ‘circulating factor’ in this condition [39].

CVD resulting from a dysfunctional endothelium
Among cardiovascular abnormalities, PAD is recognized as a severe condition. It has been independently associated with direct and indirect mortality in the general and uraemic populations [24,27,40–42]. It is notable that a relationship has been established between even borderline PAD and CVD risk, whereas this trend is not present for coronary artery disease and stroke [43]. Probably, PAD represents the most advanced cardiovascular abnormal status possible without detection.

Our study demonstrates that PrC and PPL on initiating PD are directly and independently related to PAD. These findings allow PrC to be considered as a true marker of systemic endothelial dysfunction also allocated in the peritoneal capillary endothelium. Greater peritoneal transported protein should be the result of peritoneal endothelial dysfunction, participating in this dysfunction with the remaining systemic endothelium.

Diabetes is associated with greater PAD independent of smoking, prevalent coronary heart disease, elevated fibrinogen and carotid wall thickness [44]. Our data from multivariable analysis corroborate that the relationship between PAD and PrC is independent of diabetes. This feature reinforces the close and particular relationship between PAD and PrC, and the role of PrC as a true independent PAD marker. Apart from this, diabetes per se does not seem to influence PPL in PD patients [45], as we have found.

The transport of big molecules throughout the peritoneal capillary endothelium is mostly conditioned by the vasodilation and intercellular fenestra status. We will speculate on two molecules, vascular endothelial growth factor (VEGF) and leptin, which have exhibited an influence on both mechanisms [46]. Both of them could have their origin in the adipose tissue of the peritoneum. An inflammatory status of adipose tissue causes high production of VEGF and leptin [47]. This inflammatory status can be caused by the high glucose concentration created by dialysate during PD. This situation should promote higher PPL. The isolated relationship between the highest small solute transporters (MTAC creatinine >14.04 ml/min) and PrC could be the result of a common mechanism, based on capillary vasodilatation and increase in fenestration (large pores of the peritoneal membrane). Lower levels of small solute transport (small pores) might be less sensitive to these vasodilation effects. The greater the molecular weight, the higher the capability to be influenced. On the other hand, these features suggest the relevance of higher PrC in peritoneal higher solute transport status, in determining the outcome of these patients.

PrC–PPL and subsequent mortality
Our study on mortality does not significantly demonstrate differences according to initial PrC. However, the survival curves defined by PrC values over and under the median (and also extreme quartiles, Figure 1) show a trend towards differentiating groups with a poorer survival for patients over the median, after 3 years on PD. The differences with the study by Szeto et al. who have shown that patients with higher peritoneal albumin losses starting PD have more frequent subsequent cardiovascular events [20,22] are probably due to intrinsic factors of each series.

The existence of an inverse correlation between PrC and plasma albumin levels (r = –0.52, P = 0.0001) indicates a partial repercussion of PrC on plasma proteins. This relationship is not more intense among higher transport patients. Plasma albumin levels have been proposed to be simply the consequence of greater peritoneal losses [12].

Limitations of our study
The lengthiness of our series could be a limitation for the survival analysis, and it is recommendable to confirm these features in larger series.

Other PAD risk factors (hyperuricaemia, CRP, hyperhomocysteinaemia) were unfortunately not included in our study [48], but these non-studied co-variables do not necessarily diminish the value of our main findings.

We have no differentiation data about the type of peritoneal effluent proteins determined in our population. It should be presumed that albumin represents >90% of the peritoneal protein determined [12,34,35].

In conclusion, our study shows that peritoneal PrC on initiating PD is significantly and independently related to the presence of PAD. This study in a short series of patients is hypothesis-generating and justifies further studies.



   Acknowledgments
 
This study was supported by grants FIS PI 050618 to M.A.B. and FIS PI 060098 to R.S.V. R.S.V. is the fellow of a grant provided by Baxter in the Extramural Grant Program 2007. This group is integrated in REDinREN (Red Renal de Investigación de la RETICS 06/0016, del Instituto de Salud Carlos III) and in Instituto Reina Sofía de Investigación Nefrológica (IRSIN).

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 23. 4.08
Accepted in revised form: 29. 9.08


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