Home About us Current issue Ahead of Print Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 897 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 

Table of Contents   
ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 4  |  Page : 701-709
Pentraxin-3 in hemodialysis patients: Relationship to comorbidities


1 Department of Clinical and Chemical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Click here for correspondence address and email

Date of Web Publication5-Jul-2016
 

   Abstract 

Hemodialysis (HD), despite being the most common treatment modality for endstage renal disease (ESRD), still carries a mortality rate higher than 20-50%/year resulting from various comorbidities. The aim of this study was to measure the plasma level of pentraxin-3 (PTX-3) in patients on maintenance HD and to assess its relationships to comorbidities such as malnutrition and associated comorbid diseases. This case-control study included 50 HD patients, 30 ESRD patients, and 30 healthy controls. HD patients were classified into different subgroups according to the Davies comorbidity index and malnutrition score. Plasma PTX-3 was analyzed by a sandwich ELISA technique. Plasma level of PTX-3 reached its highest levels in HD patients followed by ESRD patients as compared to healthy controls. Moreover, within the different subgroups, the highest levels and the highest odd ratio of PTX-3 were detected in the subgroups having the highest Davies comorbidity index or the highest malnutrition score as compared to the other subgroups. At a cutoff of 0.6 ng/mL, PTX-3 was able to discriminate HD patients with low Davies comorbidity index from those with both medium and high Davies comorbidity index with a diagnostic sensitivity of 92.5% and a diagnostic specificity of 70.0%. Meanwhile, the best cutoff of plasma PTX-3 for discriminating patients with mild malnutrition from severe and moderate malnutrition was 0.6 ng/mL with a diagnostic sensitivity of 90.9% and a diagnostic specificity of 41.2%. In conclusion, PTX-3 appears to be a clinically useful marker for the early identification of patients with renal failure on maintenance HD who are at substantially increased risk of morbidity. These patients may require care and aggressive follow-up in more specialized units and an early referral to a renal transplant center.

How to cite this article:
El Sebai AA, El Hadidi ES, Abdel Al H, El Sayed EY. Pentraxin-3 in hemodialysis patients: Relationship to comorbidities. Saudi J Kidney Dis Transpl 2016;27:701-9

How to cite this URL:
El Sebai AA, El Hadidi ES, Abdel Al H, El Sayed EY. Pentraxin-3 in hemodialysis patients: Relationship to comorbidities. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Oct 19];27:701-9. Available from: https://www.sjkdt.org/text.asp?2016/27/4/701/185226

   Introduction Top


It is generally admitted that alterations in the immune and host defense system occur in patients with end-stage renal disease (ESRD). Moreover, a chronic inflammatory condition associated with a state of malnutrition and cardiovascular complications is often prevalent in hemodialysis (HD) patients and could be responsible for more than 50% of the morbidity and mortality observed in these patients. [1],[2]

Pentraxin 3 (PTX-3) is a long PTX which is structurally related to, although distinct from, classic short PTXs, such as CRP and serum amyloid P. [3] PTX-3 is the first cloned long PTX as an interleukin-1b (IL-1b)-inducible gene in endothelial cells and a tumor necrosis factor (TNF-α)a stimulated gene (TSG14) in fibroblasts. PTX-3 expression occurs in a variety of cell types, including endothelial cells, mononuclear phagocytes, dendritic cells, smooth muscle cells, fibroblasts, adipocytes, and epithelial cells in response to inflammatory cytokines. [4],[5] A dramatic increase in the levels of PXT-3 has been reported in critically ill patients, with a gradient from systemic inflammatory response syndrome to septic shock, in addition to several other diseases such as acute coronary syndrome, acute respiratory distress syndrome, lung disease, and eclampsia. [5],[6]


   Aim of the study Top


The aim of this study was to measure the plasma level of PXT-3 in patients on maintenance HD and to assess its relationship to comorbidities such as malnutrition and associated comorbid diseases.


   Subjects and Methods Top


Subjects

This study was conducted at the Internal Medicine Department and the Renal Dialysis Unit of Ain Shams University Hospitals, Cairo, Egypt. All participants granted their consent to take part in this study.

Group I: Hemodialysis patients (n = 50)

This group included fifty adult patients with ESRD who were on maintenance HD for more than three months. They were 26 females and 24 males who were recruited from the Renal Dialysis Unit at Ain Shams University Hospitals.

Patients of this group were further categorized according to Davis comorbidity index into low, medium, and high comorbidity subgroups. [7]

Moreover, patients were classified according to the malnutrition score into three classes; mild malnutrition, moderate malnutrition, and severe malnutrition subgroups. [8]

Group II: End-stage renal disease patients (n = 30)

This group included thirty adult patients with ESRD defined by a glomerular filtration rate (GFR) <15 mL/min and who did not start any renal replacement therapy. They were 13 females and 17 males, who were recruited from the Internal Medicine Department at Ain Shams University Hospitals.

Group III: Healthy Controls (n = 30)

This group included thirty age-and sex-matched healthy subjects serving as a control group. They were 16 females and 14 males.

Exclusion criteria

Patients who received inadequate HD (defined as a urea reduction ratio [URR] <65%) or who were on maintenance HD for <3 months and patients with acute infections were excluded from the study. [9]

All participants in this study were subjected to full history taking and clinical examination with special emphasis on the nutritional state, diabetes mellitus, obstructive pulmonary disease, cardiovascular complications, collagen diseases, peripheral ischemia, malignancy, the assay of plasma PTX-3, and routine laboratory investigations (hemoglobin [Hb] concentration, erythrocyte sedimentation rate, high-sensitivity C-reactive protein, fasting blood sugar, 2 h postprandial blood sugar, liver profile, serum urea, and creatinine). In addition, Group I was subjected to the estimation of efficiency of HD by the calculation of URR, assessment of comorbidity score according to Davies comorbidity index, and calculation of malnutrition score. Finally, Group II was subjected to the measurement of the GFR by the calculation of the corrected creatinine clearance.

Sampling

Five milliliters of fasting morning venous blood (pre-dialysis in case of Group I) was withdrawn under complete aseptic conditions from each participant. Three milliliters of this was collected in a sterile dry vacutainer; serum was then separated by centrifugation and was used for the immediate assay of serum urea and creatinine. The remaining 2 mL was collected into an ethylenediamine tetraacetate tube for the immediate estimation of Hb concentration followed by sample centrifugation at 1000 ×g for 15 min within 30 min of collection. The separated plasma was stored at −70°C for subsequent assay of plasma PTX-3. For Group II patients, a 24-h urine sample was collected for the immediate measurement of GFR measured as corrected creatinine clearance; in addition, Group I patients were subjected to a post-dialysis venous blood sample collection for the assay of serum urea.


   Methods Top


Analytical methods

  1. Assay of serum urea and both serum and urinary creatinine was performed on Synchron CX-9 auto-analyzer (Beckman Instruments Inc., Scientific Instruments Division, Fullerton, CA92634-3100, USA).
  2. Hb concentration was done using Max M Coulter (Beckman Coulter, Inc., 22 RaioJuste-Olivier, 1260 Nyon, Switzerland).
  3. Plasma PTX-3 was carried out by a commercially available sandwich ELISA kit provided by Quantikine R&D International, Inc. (R&D International, Inc., 614 McKinly Place N.E., Minneapolis, MN55413, USA). The detection limit is 100 pg/mL and inter assay variability is 8-10%. In this technique, a streptavidin-coated plate is incubated with a biotinylated monoclonal antibody specific for PTX-3. Plate wells are washed, and pretreated standards and samples are added to the wells. Any PTX-3 present is bound by the immobilized biotinylated antibody. After washing away any unbound substance, an enzyme-linked conjugate specific for PTX-3 is added to the wells. Following a wash to remove any unbound conjugate, a substrate solution is added to the wells and color develops in proportion to the amount of PTX-3 bound. The color development is stopped and the intensity of the color is measured. A standard curve was constructed and from which concentration of PTX-3 (ng/mL) was deduced by interpolation. [10]


Methods of calculated parameters

  1. Calculation of URR was performed by the following equation: URR = [(pre-dialysis blood urea nitrogen "BUN" − post-dialysis BUN)/pre-dialysis BUN] %. [11]
  2. Calculation of corrected creatinine clearance was performed by the following equation: (urine creatinine × urine volume/serum creatinine) × (1.73/S.A × 1440). [12]
  3. Davies comorbidity index score: the score assigns 1 point for each of the following conditions; ischemic heart disease, left ventricular dysfunction, peripheral vascular disease, malignancy, diabetes, collagen vascular disease, and other significant pathologies (e.g., chronic obstructive pulmonary disease). The theoretical range is zero to seven. Accordingly, patients were categorized into patients with low Davies comorbidity index score (score 0), patients with medium Davies comorbidity index score (score from 1 to 3), and patients with high Davies comorbidity index score (score more than 3). [13]
  4. Malnutrition score was applied to assess the degree of malnutrition based on five parameters [body mass index, mid-upper arm circumference, hemoglobin level, clinical examination for signs of nutritional deficiencies, and gastrointestinal tract (GIT) manifestations]. Each parameter was given a score ranging from 3 to 6. The total score of malnutrition score ranged from a minimum of 15 to a maximum of 30, and accordingly patients were divided into patients with no malnutrition (score 15->21), patients with mild malnutrition (score 21- <24), patients with moderate malnutrition (score 24->27), and patients with severe malnutrition (score 27-30). [8]



   Statistical Analysis Top


Statistical analysis was carried out on a personal computer using Statistical Package for the Social Sciences (SPSS) version 8, (SPSS, Inc., Chicago, IL, USA). Nonparametric data were expressed as median and interquartile range. Comparative statistics was done by Kruskal-Wallis test, Wilcoxon's rank sum, and Chi-squared test. The odds ratio was calculated to study the relationship between two characteristics. Receiver operating characteristic curve (ROC) analysis was applied to assess the overall diagnostic performance of PTX-3 in the study. P >0.05 was considered nonsignificant, P <0.05 was considered significant, and P <0.01 was considered highly significant.


   Results Top


The results obtained in the present study are shown in [Table 1], [Table 2], [Table 3], [Table 4] and [Table 5] and [Figure 1], [Figure 2].
Figure 1: Receiver operating characteristic curve analysis showing the diagnostic performance of pentraxin-3 for discriminating patients with high and medium Davis comorbidity index from those with low Davis comorbidity index.

Click here to view
Figure 2: Receiver operating characteristic curve analysis showing the diagnostic performance of pentraxin-3 for discriminating patients with severe and moderate malnutrition score from those with mild malnutrition score.

Click here to view
Table 1: Descriptive and comparative statistics of the measured parameters between different studied groups.

Click here to view
Table 2: Descriptive and comparative statistics of pentraxin-3 levels among different hemodialysis patient subgroups according to Davis comorbidity index and malnutrition score.

Click here to view
Table 3: Between-groups comparison of pentraxin-3 levels in the different hemodialysis patient subgroups according to Davis comorbidity index and malnutrition score.

Click here to view
Table 4: Odds ratio of pentraxin-3 in different hemodialysis patient subgroups.

Click here to view
Table 5: Diagnostic performance of pentraxin-3 levels in different hemodialysis patient subgroups according to Davis comorbidity index and malnutrition score.

Click here to view


Descriptive and comparative statistics of the various measured parameters in the different studied groups is shown in [Table 1]. A significant difference was found between the three groups as compared to each other regarding serum urea, Hb, and plasma PTX-3 (P <0.001), while a nonsignificant difference was found between the three groups as regards age and sex (P >0.05). Meanwhile, a significant difference was found regarding serum creatinine in control group when compared to either HD or ESRD patient groups (P <0.001).

The descriptive and comparative statistics between the different HD patient subgroups regarding plasma PTX-3 is shown in [Table 2] and [Table 3]. When HD patients were classified according to the Davies comorbidity index, a highly significant difference was found between the three subgroups as regards plasma level of PTX-3 (P <0.001) being highest in patients with high comorbidity index and lowest in patients with low comorbidity index (median 36 ng/mL vs. 0.6 ng/mL). Classification of HD patients according to the malnutrition score revealed the presence of a highly significant difference in plasma PTX-3 only between patients with severe malnutrition as compared to either those with mild or moderate malnutrition (P <0.001), being highest in the former subgroup (median 41.5 ng/dL vs.0.95 and 1.2 ng/dL).

In the present study, the odds ratio for plasma PTX-3 was calculated to study the degree of its association with each of the Davis comorbidity index and malnutrition score [Table 4]. The analysis showed that plasma PTX-3 was significantly associated with high odds ratio for Davis comorbidity index (odds ratio 28; P <0.001) and malnutrition score (odds ratio 7; P <0.05).

The study of the diagnostic performance of plasma PTX-3 in the discrimination between different HD subgroups revealed that the best ROC cutoff of plasma PTX-3 in discriminating patients with high and medium Davis comorbidity index from those with low Davis comorbidity index was 0.6 ng/mL, with a diagnostic efficacy of 86.0%, sensitivity of 92.5%, specificity of 70%, positive predicative value (PPV) of 92.5%, negative predicative value (NPV) of 70.0%, and area under the curve (AUC) of 0.92 [Table 5] and [Figure 1]. Meanwhile, when patients were classified according to the malnutrition score, a cutoff of 0.6 ng/mL was found to discriminate patients with severe and moderate malnutrition from those with mild malnutrition with diagnostic efficacy of 74%, sensitivity of 90.9%, specificity of 41.2%, PPV of 75%, NPV of 70%, and AUC of 0.75 [Table 5] and [Figure 2].


   Discussion Top


In the present study, plasma PTX-3 demonstrated higher levels among ESRD group as compared to controls. This finding was supported by a study performed by Zhou et al, [2] showing the ability of PTX-3 to bind to the C1q component of the complement cascade and to participate in the clearance of apoptotic cells; hence suggesting an important role for PTX-3 in the regulation of inflammatory reactions and innate immunity. In addition, because PTX-3 is produced from vascular endothelial cells and macrophages, PTX-3 levels may directly reflect the inflammatory status.

The present study revealed the presence of higher plasma PTX-3 levels in HD patients than in those with ESRD. These findings were strengthened by Boehme et al, [14] Tong et al, [15] and Oldani et al, [5] who demonstrated the ability of HD procedure itself to exaggerate the already present pro-inflammatory state likely by the bio-incompatibility from HD membrane, exposure to exotoxins from dialysate water, and infected vascular access during the extracorporeal procedure. As a consequence, an increase in different pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IL-17 occurs with subsequent enhanced over-expression of PTX-3 in primary proximal tubular epithelial cells, primary mesangial cells, and renal fibroblasts, followed by its release into the systemic circulation in high concentrations. Being produced locally at the site of inflammation, the PTX-3 level is believed to be a true independent indicator of disease activity. [3],[16]

Aiming to evaluate the relationship between the plasma PTX-3 level and the comorbid diseases, HD patient group was divided according to Davies comorbidity index into three subgroups (low, medium, and high Davies comorbidity index). [7] Accordingly, the highest level of PTX-3 was detected in the high Davies comorbidity index followed by the medium Davies comorbidity index, then the low Davies comorbidity index. Similar data were reported by Davies et al [17] and Suliman et al, [6] who added that the association between PTX-3 and comorbidities is not surprising as the chronic inflammation may increase the pro-oxidant activity usually in generalized tissue damage, which could definitely trigger the occurrence of comorbid diseases such as ischemic heart disease, left ventricular dysfunction, peripheral vascular disease, malignancy, diabetes, systemic collagen disease, and other significant pathologies (e.g., chronic obstructive pulmonary disease and cirrhosis) in HD patients.

To evaluate the relationship between the level of plasma PTX-3 and the degree of severity of malnutrition in HD patients, the HD patients were divided according to malnutrition score into mild, moderate, and severe subgroups. [8] Accordingly, the plasma level of PTX-3 was significantly higher in severe malnutrition subgroup than in those with moderate or mild malnutrition. These findings were in accordance with that of Suliman et al [6] and Bonanni et al, [18] who mentioned that the occurrence of malnutrition in HD patients is not entirely accounted for inadequate nutrient intake, but increases progressively along with the loss of residual renal function. Moreover, the uremia-induced alterations in both protein metabolism (negative protein balance and negative energy balance) and gastrointestinal tract function (anorexia, hiccups, nausea, vomiting, uremic fetor associated with unpleasant taste, mucosal ulceration, peptic ulcer, diarrhea due to antibiotic treatment, and constipation) can exaggerate the malnutrition status, which, in turn, aggravates the inflammation leading to a decrease synthesis of negative acute-phase proteins (albumin, pre-albumin, transferrin, retinol binding protein, and insulin growth factor-1) by liver.

In the present study, the degree of association between PTX-3 level and each of Davies comorbidity index and malnutrition score showed that high plasma PTX-3 was significantly associated with high odds ratio for high Davies comorbidity index and severe malnutrition score (odds ratio 28 and 7, respectively).

In the present study, assessment of the diagnostic performance of plasma PTX-3 in discriminating between different HD subgroups was performed. The best plasma PTX-3 cutoff for discriminating patients with low Davies comorbidity index from those with both medium and high Davies comorbidity index was 0.6 ng/mL. This cutoff showed a diagnostic sensitivity of 92.5%, diagnostic specificity of 70.0%, negative predictive value of 70.0%, positive predictive value of 92.5%, the diagnostic efficacy of 86.0%, and an AUC of 0.92. Meanwhile, the best cutoff of plasma PTX-3 for discriminating patients with mild malnutrition from severe and moderate malnutrition was 0.6 ng/mL, with diagnostic sensitivity of 90.9%, diagnostic specificity of 41.2%, negative predictive value of 70.0%, positive predictive value of 75.0%, diagnostic efficacy of 74.0%, and an AUC of 0.75.


   Conclusion Top


PXT-3 appears to be a clinically useful marker for early identification of patients with renal failure on maintenance HD who are at substantially increased risk of morbidity. These patients may require care and aggressive follow-up in more specialized units and early referral to a renal transplant center.


   Limitation to the study Top


We did not measure PTX-3 after renal transplant; a randomized control study with measurement of PTX-3 after correction of nutritional status and post-renal transplant may be beneficial to prove the value of PTX-3.

Conflict of interest: None declared.

 
   References Top

1.
Kalantar-Zadeh K, Cano NJ, Budde K, et al. Diets and enteral supplements for improving outcomes in chronic kidney disease. Nat Rev Nephrol 2011;7:369-84.  Back to cited text no. 1
[PUBMED]    
2.
Zhou Y, Ni Z, Zhang J, et al. Plasma pentraxin 3 may be a better marker of peripheral artery disease in hemodialysis patients than Creactive protein. Vasc Med 2013;18:85-91.  Back to cited text no. 2
[PUBMED]    
3.
Lech M, Rommele C, Anders HJ. Pentraxins in nephrology: C-reactive protein, serum amyloid P and pentraxin-3. Nephrol Dial Transplant 2013;28:803-11.  Back to cited text no. 3
[PUBMED]    
4.
Inoue K, Kodama T, Daida H. Pentraxin 3: A novel biomarker for inflammatory cardiovascular disease. Int J Vasc Med Volume 2012, Article ID 657025, 6 pages.  Back to cited text no. 4
    
5.
Oldani S, Finazzi S, Bottazzi B, et al. Plasma pentraxin-3 as a marker of bio-incompatibility in hemodialysis patients. J Nephrol 2012;25:120-6.  Back to cited text no. 5
[PUBMED]    
6.
Suliman ME, Qureshi AR, Carrero JJ, et al. The long pentraxin PTX-3 in prevalent hemodialysis patients: Associations with comorbidities and mortality. QJM 2008;101:397-405.  Back to cited text no. 6
[PUBMED]    
7.
Fried L, Bernardini J, Piraino B. Comparison of the Charlson comorbidity Index and the Davies score as a predictor of outcomes in PD patients. Perit Dial Int 2003;23:568-73.  Back to cited text no. 7
[PUBMED]    
8.
Rodríguez-Carmona A, Pérez Fontán M, Cordido F, García Falcón T, García-Buela J. Hyperleptinemia is not correlated with markers of protein malnutrition in chronic renal failure. A cross-sectional study in pre-dialysis, peritoneal dialysis and hemodialysis patients. Nephron 2000;86:274-80.  Back to cited text no. 8
    
9.
Burrowes JD, Dalton S, Backstrand J, Levin NW. Patients receiving maintenance hemodialysis with low vs high levels of nutritional risk have decreased morbidity. J Am Diet Assoc 2005;105:563-72.  Back to cited text no. 9
[PUBMED]    
10.
Inoue K, Sugiyama A, Reid PC, et al. Establishment of a high sensitivity plasma assay for human pentraxin3 as a marker for unstable angina pectoris. Arterioscler Thromb Vasc Biol 2007;27:161-7.  Back to cited text no. 10
[PUBMED]    
11.
Jonathan H, Peale C, Gerald S. Hemodialysis. In: Brenner BM, Levine SA, eds. Brener & Rector's the kidney. 8th ed. Philadelphia, PA: Saunders; 2008. p. 1957-2006.  Back to cited text no. 11
    
12.
Levey AS, Greene T, Kusek JW, Beck GJ. Simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:828.  Back to cited text no. 12
    
13.
Davies SJ, Russell L, Bryan J, Phillips L, Russell GI. Comorbidity, urea kinetics, and appetite in continuous ambulatory peritoneal dialysis patients: Their interrelationship and prediction of survival. Am J Kidney Dis 1995;26:353-61.  Back to cited text no. 13
[PUBMED]    
14.
Boehme M, Kaehne F, Kuehne A, et al. Pentraxin 3 is elevated in haemodialysis patients and is associated with cardiovascular disease. Nephrol Dial Transplant 2007;22:2224-9.  Back to cited text no. 14
[PUBMED]    
15.
Tong M, Carrero JJ, Qureshi AR, et al. Plasma pentraxin 3 in patients with chronic kidney disease: Associations with renal function, protein-energy wasting, cardiovascular disease, and mortality. Clin J Am Soc Nephrol 2007;2:889-97.  Back to cited text no. 15
[PUBMED]    
16.
Speeckaert MM, Speeckaert R, Carrero JJ, Vanholder R, Delanghe JR. Biology of human pentraxin 3 (PTX3) in acute and chronic kidney disease. J Clin Immunol 2013;33:881-90.  Back to cited text no. 16
[PUBMED]    
17.
Davies SJ, Phillips L, Naish PF, Russell GI. Quantifying comorbidity in peritoneal dialysis patients and its relationship to other predictors of survival. Nephrol Dial Transplant 2002;17:1085-92.  Back to cited text no. 17
[PUBMED]    
18.
Bonanni A, Mannucci I, Verzola D, et al. Protein-energy wasting and mortality in chronic kidney disease. Int J Environ Res Public Health 2011;8:1631-54.  Back to cited text no. 18
    

Top
Correspondence Address:
Engy Yousry El Sayed
Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo
Egypt
Login to access the Email id


DOI: 10.4103/1319-2442.185226

PMID: 27424686

Rights and Permissions


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
   
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
   Introduction
   Aim of the study
   Subjects and Methods
   Methods
   Statistical Analysis
   Results
   Discussion
   Conclusion
    Limitation to th...
    References
    Article Figures
    Article Tables
 

 Article Access Statistics
    Viewed2215    
    Printed17    
    Emailed0    
    PDF Downloaded400    
    Comments [Add]    

Recommend this journal