help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Malyszko, J.
Right arrow Articles by Mysliwiec, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Malyszko, J.
Right arrow Articles by Mysliwiec, M.
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4620-4627
Copyright © 2004 by The Endocrine Society

Adiponectin Is Related to CD146, a Novel Marker of Endothelial Cell Activation/Injury in Chronic Renal Failure and Peritoneally Dialyzed Patients

Jolanta Malyszko, Jacek S. Malyszko, Szymon Brzosko, Slawomir Wolczynski and Michal Mysliwiec

Department of Nephrology and Transplantology, Department of Endocrinological Gynecology, Medical University, 15-540 Bialystok, Zurawia 14, Poland

Address all correspondence and requests for reprints to: Jolanta Malyszko, Department of Nephrology and Transplantology, Medical University, 15-540 Bialystok, Zurawia 14, Poland. E-mail: jolmal{at}poczta.onet.pl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Adiponectin has antiatherogenic properties and attenuates endothelial inflammatory responses. CD146 is a novel cell adhesion molecule localized at the endothelial junction. In renal failure, endothelial dysfunction and atherosclerosis are almost universal. We studied possible correlations between adiponectin, CD146, and other markers of endothelial cell injury in patients with chronic renal failure (CRF) on conservative treatment and patients with and without diabetic nephropathy maintained on chronic ambulatory peritoneal dialysis (CAPD).

We assessed adiponectin, tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1), thrombin-activatable fibrinolysis inhibitor, and endothelial function/injury markers: von Willebrand factor, thrombomodulin, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule, and CD146.

Adiponectin was elevated in patients with CRF and on CAPD. It correlated significantly, with PAI-1, thrombin-activatable fibrinolysis inhibitor, intercellular adhesion molecule, VCAM, and CD146 in nondiabetics on CAPD. In diabetics, CAPD adiponectin correlated positively with C146 and VCAM and negatively with PAI and TFPI. In multivariate regression analysis, only CD146 remained a positive predictor of adiponectin in all CAPD patients. In CRF, adiponectin correlated with CD146. In healthy volunteers, adiponectin correlated with TFPI and CD146.

Elevated adiponectin related to CD146 may be the expression of a counterregulatory response aimed at mitigating the consequences in endothelial damage and increased cardiovascular risk in renal failure.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ADIPOSE TISSUE IS now known to express and secrete a variety of hormones and cytokines, including leptin, TNF{alpha}, plasminogen activator inhibitor (PAI) type 1, and tissue factor, which may contribute to the development of cardiovascular disease (CVD) (1, 2, 3, 4). They are collectively known as adipocytokines. Adiponectin is the most abundant adipose tissue protein in human plasma (5). This cytokine is a collagen-like protein that belongs to the soluble defense collagen superfamily and has a structural homology with collagen VIII and X and complement factor C1q (6, 7). A physiological role for adiponectin has not been fully established. However, experimental data suggest that adiponectin may have antiatherogenic and antiinflammatory properties (8, 9). Indeed, adiponectin accumulates in injured vessel walls and dose-dependently inhibits TNF{alpha}-induced cell adhesion in human aortic endothelial cells, which is an early step of atherosclerosis (8, 9, 10, 11). Adiponectin is thought to inhibit the endothelial expression of adhesion molecules vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and E-selectin, which is triggered by inflammatory cytokines such as TNF{alpha} (9, 11). Low plasma adiponectin levels have been reported in coronary artery disease, as well as in association with some risk factors of CVDs such as male sex, obesity, and type 2 diabetes mellitus (8, 12, 13, 14, 15).

CD146 is a novel cell adhesion molecule localized at the endothelial junction (16). It is constitutively expressed in all human endothelium irrespective of anatomical site or vessel calibers (17). Moreover, an increase of CD146 expression is detectable on human umbilical vein endothelial cells treated with inflammatory cytokines (17), suggesting that endothelial activation modulates its expression. Recently, Bardin et al. (18) reported an increased plasma CD146 levels in chronic renal failure (CRF), probably due to endothelial junctional alteration.

In renal failure, endothelial dysfunction and atherosclerosis are almost universal, as well as cardiovascular complications. Lindner et al. (19) first drew attention to the excessive incidence of atherosclerotic cardiovascular mortality in hemodialyzed uremic patients. The importance of cardiovascular deaths in chronic ambulatory peritoneal dialysis (CAPD) was further emphasized by Bloembergen et al. (20) and Wang et al. (21). In CAPD patients, atherosclerosis may be particularly promoted by such factors as hyperglycemia, hyperinsulinemia, obesity, and hypoalbuminemia (22). Endothelial dysfunction may be also responsible for accelerated atherosclerosis in patients with CRF. Ours (23) and other previous studies (24) indicated that CAPD patients presented a hypercoagulable state. According to Zoccali et al. (12), elevated adiponectin in hemodialyzed patients and nephrotic syndrome (13), two entities prone to cardiovascular events, may act as a protective factor against atherosclerosis in these patients. In hypertensive patients, adiponectin was found to be higher than in normotensive patients (25). Due to the fact that endothelial cell damage or injury is invariably associated with such clinical conditions as thrombosis, hypertension, renal failure, and atherosclerosis, and adiponectin is considered as a novel modulator for endothelial adhesion molecules, the aim of the study was to assess adiponectin in correlation with markers of endothelial cell injury in patients with CRF on conservative treatment or maintained on CAPD.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Open-label, unblinded evaluation of the pathological differences between four groups of subjects was used: CRF patients, diabetic and nondiabetic CAPD patients, and healthy volunteers. The study was performed on 39 nondiabetic patients with CRF on conservative treatment (age range, 24–69 yr; 22 females, 17 males) admitted to the hospital to undergo kidney biopsy, 43 nondiabetic patients maintained on CAPD (age range, 23–70 yr; 24 females, 19 males), and 19 diabetic CAPD patients (age range, 48–77 yr; 6 females, 13 males) who met the following criteria: a stable clinical state, no thrombosis or inflammation (C-reactive protein within normal range), without uncontrolled hypertension, no oral contraception in women of child-bearing age, stable, and no more than twice the normal alanine aminotransferase and asparaginine aminotransferase activities (upper range 45 U/liter). None of the patients investigated had received blood transfusions for at least 1.5 months, and no drugs known to affect hemostasis were administered for at least 2 wk prior to the study. All the CRF subjects were biopsied, and histopathological diagnosis was established as follows: IgA nephropathy in 14 cases, membrano-proliferative glomerulonephritis in eight cases, membranous nephropathy in six cases, focal segmental glomerulosclerosis in four cases, and submicroscopic glomerulonephritis in one case. Biopsy was not diagnostic in six cases. During the study, none of the patients received prednisone, anticoagulants, or cytotoxic drugs. In nondiabetic CAPD patients, renal failure was due to glomerulonephritis (n = 28; biopsy-proven glomerulonephritis, n = 21), chronic interstitial nephritis (n = 10), polycystic kidney disease (n = 4), and unknown cause (n = 1). CAPD patients with diabetic nephropathy (n = 19) due to type 2 diabetes mellitus were also included in the study (glycosylated hemoglobin, 8.5± 1.2%). All the diabetic CAPD patients were treated with sc insulin. All the patients were informed about the aim of the study and gave their consent. The study was approved by the local ethics committee (Medical University, Bialystok, Poland).

Blood was drawn in the morning between 0800 and 0900 h to avoid circadian variations (26) and anticoagulated with 3.8% sodium citrate (volume corrected for hematocrit). The dialyzed patients were on CAPD for 1–5 yr (mean time on CAPD for nondiabetic patients was 24 months vs. 18 months for diabetic CAPD patients, P > 0.05). All the CAPD patients were performing four 2-l exchanges a day. According to the peritoneal equilibration test, none of the patients had highly permeable peritoneal membrane. They were using the Baxter Twin Bag system or the Fresenius Stay Safe system. Dwell times were generally 4–6 h during the day and 8 h overnight. The glucose concentration ranged from 1.36–3.86%. None of the patients was administered with icodextrin. The osmotic pressure of CAPD fluid was adjusted in accordance with the extent of ultrafiltration in each patient. Dialysis adequacy was assessed by measuring urea kinetic modeling (mean urea kinetic modeling, 2.38 ± 0.44). The control group consisted of 33 healthy volunteers (age range, 26–62 yr; 19 females, 14 males) recruited mainly from the medical staff and their families. Venous blood samples were collected into 3.8% sodium citrate in 9:1 volume ratio. The blood was centrifuged at 2500 x g for 15 min at room temperature to yield platelet-poor plasma. Samples were aliquoted and stored at –40 C before assay.

All the tests performed can be categorizing as follows: for assessment of coagulation, tissue factor pathway inhibitor (TFPI) (also considered as a marker of endothelial dysfunction); for assessment of fibrinolysis, PAI-1 and thrombin-activatable fibrinolysis inhibitor (TAFI); and for assessment of endothelial function/injury, von Willebrand factor (vWF), thrombomodulin, VCAM, ICAM, and CD146.

Plasma adiponectin was assayed using a commercially available RIA (Human Adiponectin RIA kit; Linco Research, St. Charles, MO).

Markers of endothelial cell injury (vWF and thrombomodulin) and adhesion molecules (ICAM and VCAM) were studied by ELISA using commercially available kits from American Diagnostica (Greenwich, CT) and R&D Systems (Quantikine, Abingdon, UK), respectively. CD146 was assayed by ELISA using kits from Biocytex (Marseille, France; CyQuant ELISA). PAI was assayed using commercially available kits from Bioopol (Umea, Sweden). TFPI was studied using kits from American Diagnostica. TAFI concentration was assayed using kits from Affinity Biologicals (Hamilton, Ontario, Canada). Hemoglobin, erythrocyte count, platelet count, fibrinogen, total protein, cholesterol, triglycerides, and albumin concentration were measured by standard laboratory methods.

Data given were analyzed using Statistica 5.1 computer software. Normality of variable distribution was tested using the Shapiro-Wilk W test. If possible, data were logarithmically transformed to achieve normal distribution (thrombomodulin, age). Data were reported as means ± SD. ANOVA (with post hoc Tukey test for unequal groups) or Kruskall-Wallis ANOVA (the difference between the mean of two variables was calculated by Mann-Whitney U test) were used to compare differences between groups with P < 0.05 considered statistically significant, when appropriate. Linear regression analysis employed Pearson or Spearman coefficients as appropriate. Multiple regression analysis was used to determine independent factors affecting dependent variables. Factors showing linear correlation with adiponectin were included in multiple regression analysis.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Basal clinical characteristics of the studied groups are presented in Table 1Go. Healthy volunteers and both groups of patients with CRF (on dialyses and on conservative treatment) did not differ significantly regarding age and body mass index. In diabetic CAPD patients, platelet count was significantly higher when compared with nondiabetic CAPD patients, CRF patients, and healthy volunteers. Fibrinogen was significantly elevated in the three groups of patients with renal failure relative to the healthy volunteers. Fibrinogen was significantly higher in diabetic and nondiabetic CAPD patients relative to CRF. Triglycerides and cholesterol were elevated in diabetic and nondiabetic CAPD patients when compared with the control group and CRF patients, whereas total protein and albumin were significantly lower in nondiabetic and diabetic CAPD subjects when compared with CRF and the control group.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Biochemical characteristics of patients with CRF, peritoneally dialyzed subjects with diabetic nephropathy (CAPD + DM) and without diabetic nephropathy (CAPD), and the control group

 
Markers of endothelial cell injury, thrombomodulin, vWF, ICAM, VCAM, and CD146, were significantly elevated in nondiabetic and diabetic CAPD patients and CRF patients when compared with healthy volunteers with the highest values observed in CAPD patients. Concentrations of TFPI were significantly higher in patients with renal failure when compared with the healthy volunteers. Concentrations of TAFI were higher in diabetic and nondiabetic CAPD patients than in CRF patients. TAFI concentration in healthy volunteers was significantly lower when compared with three groups of patients with renal failure. Adiponectin in CAPD patients was significantly higher when compared with patients with CRF on conservative treatment. Adiponectin in diabetic CAPD patients tended to be lower than in nondiabetic CAPD subjects; however, the difference did not reach statistical significance (P = 0.09). In diabetic CAPD patients, levels of TAFI, ICAM, and CD146 were significantly higher when compared with nondiabetic CAPD patients.

Patients with CRF on the conservative treatment had no preexisting CVD (ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease). Seventeen CAPD patients (both diabetic and nondiabetic) with CVD (ischemic heart disease, n = 14; and myocardial infarction, n = 3) were older than 45 patients on CAPD without CVD (56.07 ± 10.67 vs. 47.59 ± 12.82 yr, P < 0.001), had lower serum high-density lipoprotein (39.33 ± 4.30 vs. 52.67 ± 9.61 mg/dl, P < 0.01), higher plasma PAI levels (15.05 ± 4.25 vs. 11.68 ± 2.59 ng/ml, P < 0.01), and lower serum adiponectin (28.91 ± 9.31 vs. 46.27 ± 13.79 µg/ml, P < 0.001). The rest of the studied parameters did not differ significantly between these two groups. Adiponectin did not depend upon histopathological diagnosis in CRF patients or underlying disease in CAPD patients (glomerulonephritis vs. chronic interstitial nephritis), except diabetes in these subjects.

Adiponectin correlated significantly with CD146 (r = 0.46; P < 0.01; Fig. 1Go), ICAM (r = 0.40; P < 0.05; Fig. 2Go), VCAM (r = 0.29; P < 0.05; Fig. 3Go), PAI concentration (r = –0.50; P < 0.05), and TAFI concentration (r = –0.41; P < 0.0.05) in nondiabetic CAPD patients. In CAPD patients with diabetic nephropathy, adiponectin was related negatively to PAI concentration (r = –0.65; P < 0.05), TFPI concentration (r = –0.56; P < 0.05) and positively to VCAM (r = 0.53; P < 0.05) and CD146 (r = 0.55; P < 0.05; Fig. 4Go). In addition, CD146 correlated with vWF (r = 0.51; P < 0.05) in diabetic CAPD patients. In patients with CRF on conservative treatment, adiponectin correlated with CD146 (r = 0.32; P < 0.05; Fig. 5Go), whereas in healthy volunteers, adiponectin correlated with CD146 (r = 0.44; P < 0.05; Fig. 6Go) and TFPI concentration (r = –0.51; P < 0.05).



View larger version (23K):
[in this window]
[in a new window]
  		FIG. 1. Correlation, in univariate analysis, between plasma adiponectin and plasma CD146 in nondiabetic patients maintained on CAPD.

 


View larger version (23K):
[in this window]
[in a new window]
  		FIG. 2. Correlation between plasma adiponectin and plasma ICAM in nondiabetic patients maintained on CAPD (linear regression analysis, r = 0.40, P < 0.05).

 


View larger version (20K):
[in this window]
[in a new window]
  		FIG. 3. Correlation between plasma adiponectin and plasma VCAM in nondiabetic patients maintained on CAPD (linear regression analysis, r = 0.29, P < 0.05).

 


View larger version (23K):
[in this window]
[in a new window]
  		FIG. 4. Correlation between plasma adiponectin and plasma CD146 in diabetic patients maintained on CAPD (linear regression analysis, r = 0.55, P < 0.05).

 


View larger version (21K):
[in this window]
[in a new window]
  		FIG. 5. Correlation between plasma adiponectin and plasma CD146 in patients with CRF on conservative treatment (linear regression analysis, r = 0.32, P < 0.05).

 


View larger version (19K):
[in this window]
[in a new window]
  		FIG. 6. Correlation between plasma adiponectin and plasma CD146 in healthy volunteers (linear regression analysis, r = 0.40, P < 0.05).

 
Multiple regression analysis in CAPD patients without diabetic nephropathy showed that adiponectin was independently related only to CD146 (ß-value, 0.44; P < 0.01). The equation explained 52% of the variation of adiponectin in this group. ß-values were as follows: for PAI-1, –0.41, P = 0.05; for TAFI, –0.25, P = 0.2; for ICAM, –0.2, P = 0.92; and for VCAM, 0.19, P = 0.35. Multiple adjusted r2 for variables in the equation was 0.52 (F = 6.2179; P < 0.00479; SE of estimate = 0.38627).

In multiple regression analysis (all CAPD patients with and without diabetic nephropathy), adiponectin was also independently related only to CD146 (ß-value, 0.41; P = 0.001). The equation explained 33% of the variation of adiponectin in this group. ß-values were as follows: for PAI, –0.34, P = 0.05; for VCAM, 0.18, P = 0.16; and for TFPI, 0.21, P = 0.09. Multiple adjusted r2 for variables in the equation was 0.29 (F = 8.0069; P < 0.00020; SE of estimate =0.38242).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We have reported for the first time that adiponectin is related to CD146, a novel endothelial cell injury marker, in patients with renal failure maintained on conservative treatment or peritoneal dialyses and healthy volunteers. Moreover, plasma CD146 is a positive predictor of adiponectin in CAPD patients (nondiabetic and diabetic). We have also shown correlations between adiponectin and other markers of endothelial cell injury as well as with PAI in CAPD patients.

Adipose tissue secretes various bioactive substances, including leptin, TNF{alpha}, adiponectin, and PAI-1 (an important source), and may thus contribute to the CVD. PAI is closely involved in the development of atherosclerosis. In CAPD patients, prone to atherosclerosis and cardiovascular complications, adiponectin was inversely related to PAI in both diabetic and nondiabetic peritoneally dialyzed subjects. In the recent study, Maruyoshi et al. (27) reported a similar correlation in patients with stable angina. Moreover, in multiple regression analysis, PAI, in addition to sex and angina pectoris, was an independent determinant of hyperadiponectinemia. In our study, PAI was higher and adiponectin was lower in CAPD patients with CVD than in patients without CVD. However, in patients with CVD, correlation between adiponectin and PAI did not reach statistical significance (r = –0.51, P = 0.084). Correlation between PAI-1 and adiponectin in CAPD patients (both diabetic and nondiabetic) may support the hypothesis that adiponectin acts as a protective factor for the cardiovascular system. Adiponectin binds to the major collagen components of the vascular intima and accumulates in the vascular wall when the endothelium is damaged (11). Adiponectin suppresses the attachment of monocytes to endothelial cells (8), the fundamental step of experimental vascular damage as well as an early event in the atherosclerotic process. Adhesion molecules, i.e. E-selectin, ICAM-1, and VCAM-1, have been detected in human atherosclerotic lesions (28). In our recent study (29), we reported CRF patients (n = 23), particularly maintained on CAPD (n = 24), exhibited an evidence of endothelial cell injury. In this study, we further evaluated correlation between adiponectin and markers of endothelial damage in larger population and found that adiponectin was related to CD146 and adhesion molecules in CAPD patients. In patients without renal failure, hypoadiponectinemia is closely related to endothelial dysfunction (30, 31). In hypertensive patients (essential hypertension), adiponectin was positively related to endothelium-dependent vasodilation (31) or to peak forearm blood flow and total reactive hyperemic flow in men (30). Moreover, in the recent study, Tan et al. (32) showed an association between low adiponectin and impaired endothelium-dependent vasodilation. This association was independent of diabetes mellitus (type 2). In contrast, endothelium-independent vasodilation was related to adiponectin in healthy volunteers but was not significantly associated with adiponectin in impaired fasting glucose, glucose intolerance, or type 2 diabetes mellitus (33). It has been suggested that adiponectin appeared to be significantly related to vascular dysfunction in apparently healthy humans (33). On the other hand, in these studies, no correlations between adiponectin and renal function as well as adiponectin and other markers of endothelial cell injury were evaluated. In nephrotic syndrome, adiponectin was inversely related to glomerular filtration rate (13), whereas in our study on patients with renal failure without nephrotic syndrome, adiponectin was not related to GRF or proteinuria In the study of Stenvinkel et al. (34), no significant correlations among adiponectin, age, and renal function (assessed as glomerular filtration rate) were observed in hemodialyzed patients. Insulin-dependent diabetes mellitus patients (n = 17) have significantly higher adiponectin than nondiabetic patients (n = 71) and noninsulin-dependent diabetes mellitus (n = 19) patients. Adiponectin between nondiabetic patients and noninsulin-dependent diabetes mellitus subjects did not differ significantly, as we observed in our study. In the study of Zoccali et al. (12), only hemodialyzed diabetic women had lower adiponectin than nondiabetic women. In contrast to the former study (12), no difference in adiponectin was noted comparing 70 hemodialyzed patients without a history of CVD and 37 patients with a history of CVD (34). Our CAPD patients with a history of CVD had significantly lower adiponectin than patients without a history of CVD. As stated by Stenvinkel et al. (34), the classification in CVD in their study was made only on the basis of clinically manifest events; therefore, the true prevalence of atherosclerotic vascular disease might have been underestimated (35). CAPD patients are particularly prone to atherosclerosis due to additional glucose load into the peritoneum, hyperinsulinemia, and hypoalbuminemia (22). Our findings of significantly lower adiponectin in CAPD patients with a history of CVD when compared with those without history of CVD corroborate with the report of Zoccali et al. (12) and others (36, 37).

The reason(s) why patients with CRF or maintained on dialyses have elevated adiponectin levels are not evident. The role of the kidney in the metabolism of adiponectin has been barely investigated. Chudek et al. (38) revealed that successful kidney transplantation is accompanied by a significant reduction of adiponectin concentration. Their findings suggest that kidneys play a role in adiponectin degradation and/or elimination. Koshimura et al. (39) found that patients with advanced diabetic nephropathy (mean serum creatinine 2.00 mg/dl) had elevated adiponectin despite increased urinary adiponectin excretion relative to diabetic patients with normo- and microalbuminuria and normal renal function. They suggested that adiponectin synthesis in adipose tissue and its secretion into the blood might be enhanced to mitigate microvascular damage. Adiponectin receptors are expressed in human vascular cells, indicating a direct effect of adiponectin on endothelium (40). However, in hemodialyzed patients, Zoccali et al. (12) suggested that biologic phenomenon underlying the cardioprotective role of adiponectin had to be down-regulated, probably at the receptor level, thus resetting at a higher plasma concentration the association between adiponectin and cardiovascular complications.

CD146, a member of the immunoglobulin superfamily, was characterized as a novel cell adhesion molecule involved in the control of the cell-cell cohesion (16). It is constitutively and highly expressed by the endothelium, located at the endothelial junction but outside the adherens (16). For the first time, Bardin et al. (18) found that in CRF, CD146 levels were significantly higher when compared with healthy volunteers and suggested that CD146 was a novel endothelial marker. They also found an increased expression of CD146 on kidney biopsies from five patients with renal failure. However, they did not study correlations between CD146 and other markers of endothelial cell injury. We observed that CD146 were significantly higher in CRF, particularly in CAPD patients. Moreover, CD146 was significantly elevated in diabetic CAPD patients relative to nondiabetic CAPD patients. In our study, we found statistically significant correlations between CD146 and adiponectin in CRF, CAPD, and in the healthy volunteers. In hemodialyzed patients, Zoccali et al. (12) described a slight inverse correlation between adiponectin and vWF in women (r = –0.19, P = 0.04) but not in men (r = –0.17, P = 0.098). In diabetic CAPD patients, CD146 correlated positively with vWF. It may support the hypothesis that CD146 could serve as a novel marker of endothelial cell injury.

Bardin et al. (18) suggested that elevation of CD146 in patients with CRF could be due to an increased release or to a reduced elimination. However, they did not study CD146 correlation with renal function. Mean serum creatinine in our study was very similar to that in the study of Bardin et al. (18). In our study, CD146 was not related to renal function in healthy volunteers or patients with CRF on conservative treatment or on CAPD. On the other hand, CD146 molecules are also found in activated T cells (41). In CRF, a decreased T cell number, reduced T cell life span and increased susceptibility to early activated T cell apoptosis are observed (42). Because CRF and renal replacement therapy are associated with T lymphopenia and progressive immunodeficiency (43), we could speculate that conditions affecting junctional functions may modify CD146 levels. In CRF and dialysis therapy, uremic toxins may alter the regulation of vessel permeability. Thus, elevated CD146 may reflect altered endothelial permeability. Moreover, increased urinary CD146 excretion was observed in CRF (18). On the basis of our findings and the study of Bardin et al. (18), we may suggest that elevated CD146 in CRF and dialysis patients is due to enhanced release of this molecule from its junctional localization.

In conclusion, we have reported for the first time a significant correlation between adiponectin and CD146, a novel marker of endothelial dysfunction, in patients with renal failure on conservative treatment and peritoneal dialyses. Adiponectin may take part in an equilibrium between the release of adhesion molecules and other substances from endothelium in patients with renal failure. Elevated adiponectin may be the expression of a counterregulatory response aimed at mitigating the endothelial damage and cardiovascular risk in renal failure.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Hemostasis in patients with CRF, peritoneally dialyzed subjects with diabetic nephropathy (CAPD + DM) and without diabetic nephropathy (CAPD), and the control group

 

   Footnotes
 
S.B. receives a scholarship from the Foundation for Polish Science.

Abbreviations: CAPD, Chronic ambulatory peritoneal dialysis; CRF, chronic renal failure; CVD, cardiovascular disease; ICAM, intercellular adhesion molecule; PAI, plasminogen activator inhibitor; TAFI, thrombin-activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; VCAM, vascular cell adhesion molecule; vWF, von Willebrand factor.

Received February 27, 2004.

Accepted June 1, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Zhang Y, Proenca R, Maffei M, Barone M, Friedman JM 1994 Positional cloning of the mouse obese and its human homologue. Nature 372:425–432[CrossRef][Medline]
  2. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabonowitz D, Lallone RL, Burley SK, Friedman JM 1995 Weight-reducing effects of the plasma proteins encoded by the obese genes. Science 269:543–546[Abstract/Free Full Text]
  3. Hotamisligil GS 1999 The role of TNF{alpha} and TNF receptors in obesity and insulin resistance. J Intern Med 245:621–625[CrossRef][Medline]
  4. Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y 1996 Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 2:800–803[CrossRef][Medline]
  5. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K 1996 cDNA cloning and expression of a novel adipose specific collagen-like factor, apMI (adipose most abundant gene transcript 1). Biochem Biophys Res Commun 221:286–289[CrossRef][Medline]
  6. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749[Abstract/Free Full Text]
  7. Hu E, Liang P, Spiegelman BM 1996 AdipoQ is a novel adipocyte-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703[Abstract/Free Full Text]
  8. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y 1999 Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100:2473–2476[Abstract/Free Full Text]
  9. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y 2000 Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-{kappa}B signaling through a c-AMP-dependent pathway. Circulation 102:1296–1301[Abstract/Free Full Text]
  10. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y 2000 Adiponectin, a new member of the family of soluble defence collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96:1723–1732[Abstract/Free Full Text]
  11. Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T, Yamashita S, Miyagawa J, Funahashi T, Matsuzawa Y 2000 An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 32:47–50[Medline]
  12. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M, Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y 2002 Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 13:134–141[Abstract/Free Full Text]
  13. Zoccali C, Mallamaci F, Panuccio V, Tripepi G, Cutrupi S, Parlongo S, Catalano F, Malatino Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y 2003 Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors. Kidney Int 63(Suppl 84):S98–S102
  14. Arita Y, Kihara S, Okamoto Y, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipocyte-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83[CrossRef][Medline]
  15. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599[Abstract/Free Full Text]
  16. Bardin N, Anfosso F, Masse JM, Cramer E, Sabatier F, Le Bivic A, Sampol J, Dignat-George F 2001 Identification of CD146 as a component of the endothelial junction in the control of cell-cell cohesion. 98:3677–3684
  17. Bardin N, George F, Mutin M, Brisson C, Horschowski N, Frances V, Lesaule G, Sampol J 1996 S-Endo 1, a pan-endothelial monoclonal antibody recognizing a novel human endothelial antigen. Tissue Antigens 548:531–539
  18. Bardin N, Moal V, Anfosso F, Daniel L, Brunet P, Sampol J, Dignat George F 2003 Soluble CD146, a novel endothelial marker, is increased in physiopathological settings linked to endothelial junctional alteration. Thromb Haemost 90:915–920[Medline]
  19. Lindner A, Charra B, Sherrad DJ, Scribner BH 1974 Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290:697–701
  20. Bloembergen WE, Prot FK, Mauger EA, Wolfe RA 1995 A comparison of cause of death between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol 6:184–191[Abstract]
  21. Wang AYM, Wang M, Woo J, Lam CWK, Li PKT, Lui SF, Sanderson JE 2003 Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: a prospective study. J Am Soc Nephrol 14:159–168[Abstract/Free Full Text]
  22. Kawaguchi Y, Kubo H, Yamamoto H, Nakayama K, Shigematsu T, Sakai O 1996 Is atherosclerosis accelerated by CAPD? Perit Dial Int 16(Suppl 1):S23–S30
  23. Malyszko J, Malyszko JS, Mysliwiec M 2001 Comparison of hemostatic disturbances between patients on CAPD and HD. Perit Dial Int 21:158–165[Abstract/Free Full Text]
  24. Kobayashi M, Yorioka N, Yamakido M 1997 Hypercoagulability and secondary hyperfibrinolysis may be related to abnormal lipid metabolism in patients treated with continuous ambulatory peritoneal dialysis. Nephron 76:56–61[Medline]
  25. Mallamaci F, Zoccali C, Cuzzola F, Tripepi G, Cutrupi S, Parlongo S, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y 2002 Adiponectin in essential hypertension. J Nephrol 15:507–511[Medline]
  26. Malyszko J, Urano T, Knofler R, Taminato A, Yoshimi T, Takada Y, Takada A 1994 Daily variations of platelet aggregation in relation to blood and plasma serotonin in diabetes. Thromb Res 75:569–576[CrossRef][Medline]
  27. Maruyoshi H, Kojima S, Funahashi T, Miyamoto S, Hokamaki J, Soejima H, Sakamoto T, Kawano H, Yoshimura M, Kitagawa A, Matsuzawa Y, Ogawa H 2004 Adiponectin is inversely related to plasminogen activator inhibitor 1 in patients with stable exertional angina. Thromb Haemost 91:1026–1030[Medline]
  28. Davies MJ, Gordon JL, Gearing AJ, Pigott R, Woolf N, Katz D, Kyriakopoulos A 1993 The expression of the adhesion molecules ICAm-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 171:223–229[CrossRef][Medline]
  29. Malyszko J, Malyszko JS, Mysliwiec M 2004 Endothelial cell injury markers in chronic renal failure on conservative treatment and continuous ambulatory peritoneal dialysis (CAPD). Kidney Blood Press Res 27:71–77[CrossRef][Medline]
  30. Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N, Tagawa T, Ueda S, Shimomura I, Funahashi T, Matsuzawa Y 2003 Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 88:3236–3240[Abstract/Free Full Text]
  31. Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H, Kumada M, Ohashi K, Okamoto Y, Nishizawa K, Kishida K, Maeda K, Nagasawa A, Kobayashi H, Hiraoka H, Komai N, Kaibe M, Rakugi H, Ogihara T, Matsuzawa Y 2003 Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42:231–234[Abstract/Free Full Text]
  32. Tan KC, Xu A, Chow WS, Lam MC, Ai VH, Tam SC, Lam KS 2004 Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. J Clin Endocrinol Metab 89:765–769[Abstract/Free Full Text]
  33. Fernandez-Real JM, Castro A, Vazquez G, Casamitjana R, Lopez-Bermejo A, Penarroja G, Ricart W 2004 Adiponectin is associated with vascular function independent of insulin sensitivity. Diabetes Care 27:739–745[Abstract/Free Full Text]
  34. Stenvinkel P, Marchlewska A, Pecoits-Filho R, Heimburger O, Zhang Z, Hoff C, Holmes C, Axelsson J, Arvidsson S, Schalling M, Barany P, Lindholm B, Nordfors L 2004 Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin. Kidney Int 65:274–281[CrossRef][Medline]
  35. Stenvinkel P, Pecoits-Filho R, Lindholm B 2003 Coronary artery disease in end-stage renal disease: no longer a simple plumbing problem. J Am Soc Nephrol 14:1927–1939[Free Full Text]
  36. Dzielinska Z, Januszewicz A, Wiecek A, Demkow M, Makowiecka-Ciesla M, Prejbisz A, Kadziela J, Mielniczuk R, Florczak E, Janas J, Januszewicz M, Ruzyllo W 2003 Decreased plasma concentration of a novel anti-inflammatory protein-adiponectin in hypertensive men with coronary artery disease. Thromb Res 110:365–369[CrossRef][Medline]
  37. Kojima S, Funahashi T, Sakamoto T, Miyamoto S, Soejima H, Hokamaki J, Kajiwara I, SugiyamaS, Yoshimura M, Fujimoto K, Miyao Y, Suefuji H, Kaiatagawa A, Ouchi N, Kihara S, Matsuzawa Y, Ogawa H 2003 The variation of plasma concentration of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction. Heart 89:667–668[Free Full Text]
  38. Chudek J, Adamczak M, Karkoszka H, Budzinski G, Ignacy W, Funahashi T, Matsuzawa Y, Cierpka L, Kokot F, Wiecek A 2003 Plasma adiponectin concentration before and after successful kidney transplantation. Transplant Proc 35:2186–2189[CrossRef][Medline]
  39. Koshimura J, Fujita H, Narita T, Shimotomai T, Hosoba M, Yoshioka N, Kakei M, Fujishima H, Ito S 2004 Urinary adiponectin excretion is increased in patients with overt diabetic nephropathy. Biochem Biophys Res Commun 316:165–169[CrossRef][Medline]
  40. Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, Manabe I, Utsunomiya K, Nagai R 2004 Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun 314:415–419[CrossRef][Medline]
  41. Pickl WF, Majdic O, Fischer GF, Petzelbauer P, Fae I, Waclavicek M, Stockl J, Scheinecker C, Vidicki T, Aschauer H, Johnson JP, Knapp W 1997 MUC18/ MCAM (CD146), an activation antigen of human T lymphocytes. J Immunol 158:2107–2115[Abstract]
  42. Meier P, Dayer E, Blanc E, Wauters JP 2002 Early T cell activation correlates with expression of apoptosis markers in patients end-stage renal failure. J Am Soc Nephrol 13:204–212[Abstract/Free Full Text]
  43. Moser B, Roth G, Brunner M, Lilaj T, Deicher R, Wolner E, Kovar J, Boltz-Nitulescu G, Vychytil A, Ankersmit HJ 2003 Aberrant T cell activation and heightened apoptotic turnover in end-stage renal failure patients: a comparative evaluation between non-dialysis, haemodialysis, and peritoneal dialysis. Biochem Biophys Res Commun 308:581–585[CrossRef][Medline]



This article has been cited by other articles:


Home page
 CLIN APPL THROMB HEMOSTHome page
J. Malyszko, J.S. Malyszko, P. Kozminski, K. Pawlak, and M. Mysliwiec
Adipokines, Linking Adipocytes and Vascular Function in Hemodialyzed Patients, May Also Be Possibly Related to CD146, a Novel Adhesion Molecule
Clinical and Applied Thrombosis/Hemostasis, July 1, 2008; 14(3): 338 - 345.
[Abstract] [PDF]

Home page
 Nephrol Dial TransplantHome page
M. I. Yilmaz, M. Saglam, J. J. Carrero, A. R. Qureshi, K. Caglar, T. Eyileten, A. Sonmez, E. Cakir, M. Yenicesu, B. Lindholm, et al.
Serum visfatin concentration and endothelial dysfunction in chronic kidney disease
Nephrol. Dial. Transplant., March 1, 2008; 23(3): 959 - 965.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Pilz, H. Mangge, B. Wellnitz, U. Seelhorst, B. R. Winkelmann, B. Tiran, B. O. Boehm, and W. Marz
Adiponectin and Mortality in Patients Undergoing Coronary Angiography
J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4277 - 4286.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
M. Nishimura, T. Hashimoto, H. Kobayashi, S. Yamazaki, K. Okino, H. Fujita, N. Inoue, H. Takahashi, and T. Ono
Association of the circulating adiponectin concentration with coronary in-stent restenosis in haemodialysis patients
Nephrol. Dial. Transplant., June 1, 2006; 21(6): 1640 - 1647.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. G. Schalkwijk, N. Chaturvedi, M. T. Schram, J. H. Fuller, C. D. A. Stehouwer, and the EURODIAB Prospective Complications Study Group
Adiponectin Is Inversely Associated with Renal Function in Type 1 Diabetic Patients
J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 129 - 135.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Malyszko, J.
Right arrow Articles by Mysliwiec, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Malyszko, J.
Right arrow Articles by Mysliwiec, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals