Abstracts
Introduction:
Endothelial dysfunction is important in the pathogenesis of cardiovascular disease (CVD) related to chronic kidney disease (CKD). Stromal cell-derived factor-1 (SDF-1) is a chemokine which mobilizes endothelial progenitor cells (EPC) and together with interleukin-8 (IL-8) may be used as markers of tissue injury and repair.
Objective:
This study investigated in vivo and in vitro the effect of uremic media on SDF-1 and IL-8 expression.
Methods:
Systemic inflammation was assessed by C-reactive protein (CRP) and interleukin-6 (IL-6). IL-8 and SDF-1 were measured as markers of endothelial dysfunction and tissue repair, respectively, by ELISA. In vitro studies were performed on human umbilical vein endothelial cells (HUVEC) exposed to healthy or uremic media.
Results:
The study included 26 hemodialysis (HD) patients (17 ± 3 months on dialysis, 52 ± 2 years, 38% men and 11% diabetic). Serum concentrations of CRP, IL-6, SDF-1 and IL-8 were 4.9 ± 4.8 mg/ml, 6.7 ± 8.1 pg/ml, 2625.9 ± 1288.6 pg/ml and 128.2 ± 206.2 pg/ml, respectively. There was a positive correlation between CRP and IL-6 (ρ = 0.57, p < 0.005) and between SDF-1 and IL-8 (ρ = 0.45, p < 0.05). In vitro results showed that after 6 hours treatment, SDF-1 expression by HUVEC treated with uremic media is lower compared to cells treated with healthy media (p < 0.05). After 12 hours of treatment there was an increase in IL-8 when HUVECs were exposed to uremic media (p < 0.005).
Conclusion:
We suggest that SDF-1 and IL-8 in HD patients can be used to measure the extent of damage and subsequent vascular activation in uremia.
chemokine CXCL12; chemokines; endothelium, vascular; interleukin-8; renal insufficiency, chronic; uremia
Introdução:
A disfunção endotelial é importante na patogênese da doença cardiovascular (DCV) relacionada à doença renal crônica (DRC). Stromal cell-derived factor-1 (SDF-1) é uma quimiocina que mobiliza células endoteliais progenitoras (EPC) e em conjunto com a interleucina-8 (IL-8) podem ser usadas como marcadores de reparo e lesão tecidual.
Objetivo:
Neste trabalho, foi investigado o efeito do meio urêmico na expressão de SDF-1 e IL-8 in vivo e in vitro.
Métodos:
A inflamação sistêmica foi avaliada por meio da proteína C-reativa (PCR) e interleucina-6 (IL-6). IL-8 e SDF-1 foram avaliados por ELISA como marcadores de disfunção endotelial e reparo tecidual, respectivamente. Os estudos in vitro foram realizados em células endoteliais umbilicais humanas (HUVEC) expostas ao meio urêmico ou saudável.
Resultados:
Foram incluídos nesse estudo 26 pacientes em hemodiálise (HD) (17 ± 3 meses em diálise, 52 ± 2 anos, 38% homens e 11% diabéticos). As concentrações séricas de PCR, IL-6, SDF-1 e IL-8 foram 4,9 ± 4,8 mg/ml, 6,7 ± 8,1 pg/ml, 2625,9 ± 1288,6 pg/ml e 128,2 ± 206,2 pg/ml, respectivamente. Houve correlação positiva entre PCR e IL-6 (ρ = 0,57; p < 0,005) e entre SDF-1 e IL-8 (ρ = 0,45; p < 0,05). Os resultados in vitro demonstraram que a expressão de SDF-1 pelas HUVEC após 6 horas de tratamento com meio urêmico é menor comparada ao tratamento com meio saudável (p < 0,05). Após 12 horas de tratamento, ocorreu aumento de IL-8 quando as HUVECs foram expostas ao meio urêmico (p < 0,005).
Conclusão:
Sugerimos que SDF-1 e IL-8 nos pacientes em HD podem ser usados para mensurar a extensão do dano e consequente ativação vascular na uremia.
endotélio vascular; insuficiência renal crônica; interleucina-8; quimiocina SDF-1; quimiocinas; toxicidade urêmica
Introduction
In advanced stages of chronic kidney disease (CKD), most patients are affected by
complications, most often correlated with cardiovascular disease (CVD) - including
vascular calcification and endothelial dysfunction.11. Drüeke TB, Massy ZA. Atherosclerosis in CKD: differences from the
general population. Nat Rev Nephrol 2010;6:723-35. DOI:
http://dx.doi.org/10.1038/nrneph.2010.143
http://dx.doi.org/10.1038/nrneph.2010.14...
,22. de Oliveira RB, Okazaki H, Stinghen AE, Drüeke TB, Massy ZA, Jorgetti
V. Vascular calcification in chronic kidney disease: a review. J Bras Nefrol
2013;35:147-61. DOI: http://dx.doi.org/10.5935/0101-2800.20130024
http://dx.doi.org/10.5935/0101-2800.2013...
It is believed that
the high concentration of circulating uremic toxins in this population may trigger
systemic and vascular inflammatory responses, thereby inducing endothelial
dysfunction,33. Stinghen AE, Pecoits-Filho R. Vascular damage in kidney disease:
beyond hypertension. Int J Hypertens 2011;2011:232683. PMID: 21876786 DOI:
http://dx.doi.org/10.4061/2011/232683
http://dx.doi.org/10.4061/2011/232683...
a factor that is knowingly
associated with CVD development and progression.
Studies led by our group showed that plasma markers of endothelial activation, such
as monocyte chemoattractant protein-1 (MCP-1) and vascular adhesion molecule-1
(VCAM-1) are increased and closely associated with other markers of systemic
inflammation in later CKD stages, such as CRP and IL-6. Furthermore, in
vitro studies have shown that endothelial cell exposure to uremic
environment increases MCP-1, interleukin-8 (IL-8) and VCAM-1 expression, suggesting a
relationship between vascular injury, systemic inflammation and uremic toxicity.44. Stinghen AE, Gonçalves SM, Martines EG, Nakao LS, Riella MC, Aita CA,
et al. Increased plasma and endothelial cell expression of chemokines and adhesion
molecules in chronic kidney disease. Nephron Clin Pract 2009;111:c117-26. PMID:
19147993 DOI: http://dx.doi.org/10.1159/000191205
http://dx.doi.org/10.1159/000191205...
Endothelial cells play an important role in regulating vascular tone, homeostasis,
blood pressure and vascular remodeling, and the endothelium's ability to synthesize
and release nitric oxide (NO) is an important regulator of these physiological
processes.55. Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol
Aspects Med 2005;26:33-65. DOI:
http://dx.doi.org/10.1016/j.mam.2004.09.003
http://dx.doi.org/10.1016/j.mam.2004.09....
Bone-marrow derived endothelial
progenitor cells (EPC) make up an endogenous endothelial repair system, protecting
the endothelium from developing atherosclerosis. Evidence suggests that upon uremia
there is a reduction in EPC availability and function, leading to a loss in repair
ability and endothelium regeneration, thus contributing to CVD development.66. Jie KE, Zaikova MA, Bergevoet MW, Westerweel PE, Rastmanesh M,
Blankestijn PJ, et al. Progenitor cells and vascular function are impaired in
patients with chronic kidney disease. Nephrol Dial Transplant 2010;25:1875-82. DOI:
http://dx.doi.org/10.1093/ndt/gfp749
http://dx.doi.org/10.1093/ndt/gfp749...
The stromal cell-derived factor-1 (SDF-1) is a pleiotropic action chemokine expressed
in various tissues such as the kidneys, bone marrow, liver, heart, thymus, spleen,
skeletal and smooth muscle cells, endothelial cells and macrophages.77. Braunersreuther V, Mach F, Steffens S. The specific role of
chemokines in atherosclerosis. Thromb Haemost 2007;97:714-21. PMID:
17479181
8. Ghadge SK, Mühlstedt S, Ozcelik C, Bader M. SDF-1 a as a therapeutic
stem cell homing factor in myocardial infarction. Pharmacol Ther 2011;129:97-108.
DOI: http://dx.doi.org/10.1016/j.pharmthera.2010.09.011
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-99. Karin N. The multiple faces of CXCL12 (SDF-1alpha) in the regulation
of immunity during health and disease. J Leukoc Biol 2010;88:463-73. Originally, the SDF-1 action was related to the stimulation of
T-lymphocytes, B-lymphocytes and monocytes.1010. Barbieri F, Bajetto A, Porcile C, Pattarozzi A, Schettini G, Florio
T. Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior
pituitary function. J Mol Endocrinol 2007;38:383-9. DOI:
http://dx.doi.org/10.1677/JME-06-0014
http://dx.doi.org/10.1677/JME-06-0014...
However, it has been discovered that this chemokine also plays a key role in the
pathophysiology of processes such as inflammation, angiogenesis, wound healing and
platelet aggregation.99. Karin N. The multiple faces of CXCL12 (SDF-1alpha) in the regulation
of immunity during health and disease. J Leukoc Biol 2010;88:463-73.,1111. Abi-Younes S, Sauty A, Mach F, Sukhova GK, Libby P, Luster AD. The
stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed
in atherosclerotic. Circ Res 2000;86:131-8. DOI:
http://dx.doi.org/10.1161/01.RES.86.2.131
http://dx.doi.org/10.1161/01.RES.86.2.13...
12. Bonavia R, Bajetto A, Barbero S, Pirani P, Florio T, Schettini G.
Chemokines and their receptors in the CNS: expression of CXCL12/SDF-1 and CXCR4 and
their role in astrocyte proliferation. Toxicol Lett 2003;139:181-9. PMID: 12628753
DOI: http://dx.doi.org/10.1016/S0378-4274(02)00432-0
http://dx.doi.org/10.1016/S0378-4274(02)...
-1313. Apostolakis S, Papadakis EG, Krambovitis E, Spandidos DA. Chemokines
in vascular pathology (review). Int J Mol Med 2006;17:691-701.
Studies have shown that chemokines, such as SDF-1 and IL-8 possibly facilitate the
migration of EPC to the injured endothelium. Indeed, SDF-1 has been described as an
inducer of neovascularization, and together with IL-8 it is responsible for the
recruitment of EPC to the ischemic tissue in CVD, such as acute myocardial
infarction.1414. Gössl M, Mödder UI, Gulati R, Rihal CS, Prasad A, Loeffler D, et al.
Coronary endothelial dysfunction in humans is associated with coronary retention of
osteogenic endothelial progenitor cells. Eur Heart J 2010;31:2909-14. DOI:
http://dx.doi.org/10.1093/eurheartj/ehq373
http://dx.doi.org/10.1093/eurheartj/ehq3...
,1515. Elmadbouh I, Haider HKh, Jiang S, Idris NM, Lu G, Ashraf M. Ex vivo
delivered stromal cell-derived factor-1alpha promotes stem cell homing and induces
angiomyogenesis in the infarcted myocardium. J Mol Cell Cardiol 2007;42:792-803.
PMID: 17350033 Recently, some studies have demonstrated that
SDF-1 plasma levels are raised in CKD, correlating with decreased levels of
EPCs.1616. Chen YT, Cheng BC, Ko SF, Chen CH, Tsai TH, Leu S, et al. Value and
level of circulating endothelial progenitor cells, angiogenesis factors and
mononuclear cell apoptosis in patients with chronic kidney disease. Clin Exp Nephrol
2013;17:83-91. DOI: http://dx.doi.org/10.1007/s10157-012-0664-9
http://dx.doi.org/10.1007/s10157-012-066...
These findings suggest a possible
beneficial role of SDF-1 in the repair of endothelial injury.
From this overview, we hypothetically suggest that in CKD there is constant endothelium exposure to uremic toxins, with consequent vascular damage, which causes the release of chemokines involved in tissue signaling and repair. Thus, the aim of this study was to investigate the effects of uremic serum on in vitro expression of SDF-1 and IL-8 and conduct a clinical study involving patients with stage 5 CKD on hemodialysis (HD).
Methods
Patient selection
The patients of the study were selected from a population sample which included 104 chronic renal patients on HD treatment from a single center of renal replacement therapy in the city of Curitiba - PR. After applying the inclusion and exclusion criteria listed below, we finally selected 26 patients to participate in the study. All patients were on a chronic HD program and performed three HD sessions per week (3.5 to 4 hours per session) using polysulphone dialysis membranes and dialysate with a final sodium bicarbonate concentration of 32 mEq/L and 3.5 mEq/L of calcium. We excluded patients in peritoneal dialysis; patients who underwent HD sessions through a central venous catheter as vascular access; patients with infectious disease or severe chronic inflammation or malignancies; active liver disease; autoimmune diseases; use of immunosuppressive or anti-inflammatory agents in the last 3 months prior to enrollment in the study, and those who had had cardiovascular events (i.e. myocardial infarction, unstable angina, stroke or myocardial revascularization) 3 months before the study began.
All patients signed an informed consent agreeing to participate in the study and the protocol was approved by the Ethics Committee in Human Research of the Federal University of Paraná (CEP/SD: 974.079.10.07 registration). For comparison purposes, we used serum samples from healthy volunteers (n = 10) as control.
Clinical data collection
During patient recruitment, we collected clinical and demographic data through interviews and physical examinations performed on the initial assessment day and analysis of the medical records. We used the following data: age, gender, race, comorbidities, CKD primary etiology, time in dialysis, percentage of patients on statins, aspirin and vitamin D.
Collection of laboratory data
Blood samples were collected immediately before the first HD session of the week, centrifuged and stored at -80 ºC. At baseline, we measured serum levels of total cholesterol, LDL and HDL cholesterol fractions; triglycerides; hemoglobin; albumin; calcium; phosphorus; parathyroid hormone (PTH), alkaline phosphatase and CRP in all patients.
In vivo experiments
Serum levels of systemic inflammation markers, SDF-1 and IL-8.
The C-reactive protein (CRP) test was performed by ultrasensitive automated immunoturbidimetry (ADVIA Chemistry System 1200, Siemens Healthcare, Deerfield, Illinois, USA), with a detection range between 0.5 to 15 mg/L. IL-6 concentration was measured by the Enzyme Linked Immunosorbent Assay (ELISA) sandwich (R & D Systems, Minneapolis, USA) with a detection range between 0.5 to 15 mg/L. SDF-1 concentration was measured using ELISA (R & D Systems, Minneapolis, USA) with a detection range of 1.0 pg/ml to 47 pg/ml. The absorbance values were detected in a microplate reader (Tecan, North Carolina, USA) at 570 nm. IL-8 concentrations were measured using the in-house ELISA method (R & D Systems antibody, Minneapolis, USA), with a detection range between 31.25 to 2000 pg/ml. The absorbance values were detected in a microplate reader (Tecan, North Caroline, USA) at 570 nm. The intra and inter assay variation coefficients for IL-8 were 8.0% and 7.7%, respectively.
In vitro experiments
Extraction and characterization of human umbilical vein endothelial cells (HUVEC)
The umbilical cords were collected immediately after birth and processed within
24 hours. The endothelial cells were extracted and cultured according to Jaffe
et al.1717. Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human
endothelial cells derived from umbilical veins. Identification by morphologic and
immunologic criteria. J Clin Invest 1973;52:2745-56. PMID: 4355998 DOI:
http://dx.doi.org/10.1172/JCI107470
http://dx.doi.org/10.1172/JCI107470...
adapted.44. Stinghen AE, Gonçalves SM, Martines EG, Nakao LS, Riella MC, Aita CA,
et al. Increased plasma and endothelial cell expression of chemokines and adhesion
molecules in chronic kidney disease. Nephron Clin Pract 2009;111:c117-26. PMID:
19147993 DOI: http://dx.doi.org/10.1159/000191205
http://dx.doi.org/10.1159/000191205...
Briefly, the umbilical cord
was cannulated, washed with saline phosphate buffer (PBS) (Sigma-Aldrich, USA)
and perfused with type II collagenase (Sigma-Aldrich, USA) at 0.3% in PBS for 7
minutes at 37 ºC. The suspension was centrifuged and resuspended; and the
pellet resuspended in medium 199 (Gibco, Grand Island, NY, USA) was
supplemented with 2 mM glutamine (Gibco, Grand Island, NY, USA), fetal bovine
serum (FBS) (Gibco, Grand Island, NY, USA) 10%, heparin 5,000 IU/ml
(Sigma-Aldrich, USA), 0.5 mg/ml hydrocortisone (Sigma-Aldrich, USA),
endothelial cell growth supplement at 15 g/ml (Sigma-Aldrich, USA);
β-endothelial human cell growth factor 25 µg/ml
(Sigma-Aldrich, USA); penicillin 10,000 IU/ml and streptomycin 50 µg/ml (Gibco,
Grand Island, NY, USA). The HUVEC were grown to subconfluence in culture flasks
of 25 cm2 pre-treated with 1% gelatin (Sigma-Aldrich, USA) and
incubated at 37 ºC in an atmosphere of 5% CO2. The cells were then
used for experiments between passages 3 and 4, when they were trypsinized with
0.25% trypsin-EDTA (Sigma-Aldrich, USA) and further cultured in 96-well plates
(10,000 cells/ml/well) pre-treated with 1% gelatin under the same conditions
described above. The endothelial cell origin was confirmed by morphology and by
immunocytochemistry with anti-CD31 monoclonal antibody (Dako Cytomation,
Glostrup, Denmark).
Endothelial cells cultured with human serum
To prepare the uremic and the healthy mediums, we used sera from patients/individuals as pool. For this purpose, equal volumes of serum from all patients in the study (i.e., n = 26) formed a single uremic pool, and equal volumes of serum from healthy individuals (i.e., n = 10) formed a single control pool.
The HUVEC were initially cultured in 96-well plates until they reached subconfluence when they were maintained for a period of 12h in a suppression medium (199 medium plus 3% FBS) without growth factors. Subsequently, they were incubated in healthy medium (199 + 10% of the healthy pool) and/or uremic medium (199 medium + 10% uremic pool). Five experiments were performed in duplicate. The supernatants were collected at times: 0, 6 and 12h of culture and then stored at -80 ºC until processing. For statistical analysis purposes we used the average of each duplicate.
Viability assay by the exclusion method with Trypan blue
The number of endothelial cells was determined by direct counting in a Neubauer
chamber by the exclusion method with Trypan blue (Sigma-Aldrich, USA). After
growing, the endothelial cells were treated with uremic and healthy media under
the same conditions described above, trypsinized and resuspended in 1 ml of
medium 199. Then, 10 µL of suspension were added to 10 µL of a 0.4% solution,
and then we counted them in a Neubauer chamber with the aid of a light
microscope (Nikon, Tokyo, Japan). The cells with dye uptake were deemed
non-viable, and the number of viable cells was calculated by subtracting the
number of non-viable cells from the total cell count.1818. Chitalia VC, Murikipudi S, Indolfi L, Rabadi L, Valdez R, Franses
JW, et al. Matrix-embedded endothelial cells are protected from the uremic milieu.
Nephrol Dial Transplant 2011;26:3858-65. DOI:
http://dx.doi.org/10.1093/ndt/gfr337
http://dx.doi.org/10.1093/ndt/gfr337...
Viability assay by the 3-[4,5-dimetiazol-2yl]-2,5-ifeniltetrazolium bromide (MTT)
In this assay, the HUVEC (104 cells/ml/well) were cultured in a
96-well culture plate and subjected to the same treatments as described above
with final treatment volume of 100 ml/well. The MTT (Sigma-Aldrich, USA) was
solubilized in PBS at a concentration of 5 mg/ml. Thereafter, the MTT solution
was diluted 1:10 with 199 MEM medium (final concentration of 0.5 mg/ml) and
added to the cells (100 ml/well). The plate was incubated for 4h at 37 ºC.
After this period, 100 µl of dimethyl sulfoxide (DMSO) (Sigma-Aldrich, USA)
were added to each well and the absorbance was measured at 570 nm.1919. Mosmann T. Rapid colorimetric assay for cellular growth and
survival: application to proliferation and cytotoxicity assays. J Immunol Methods
1983;65:55-63. PMID: 6606682 DOI:
http://dx.doi.org/10.1016/0022-1759(83)90303-4
http://dx.doi.org/10.1016/0022-1759(83)9...
SDF-1 and IL-8 concentrations in the cell supernatant
The supernatant samples were collected at times: 0, 6 and 12h of incubation and stored at -80 ºC until processing. The SDF-1 and IL-8 concentrations were measured by ELISA as described above.
Statistical analyzes
Statistical analyses were performed using the JMP statistical software for Windows version 7.0 (SAS Institute Inc., USA) and the SigmaStat version 3.5 software (Systat Software, Inc., Germany). Data was presented as mean ± mean standard error (MSE) or median (25th and 75th percentiles) as clinical and laboratory data for each parameter analyzed according to data symmetry or asymmetry. The results were analyzed by t test or one-way ANOVA for parametric data; and Mann-Whitney test for the nonparametric data. For multiple comparisons between the groups, we used the ANOVA on Rank's test followed by Dunnett's test. Correlation analyzes were performed using Spearman's test (ρ); and a p ≤ 0.05 was considered significant.
Results
The main clinical and laboratory characteristics of the 26 patients enrolled in the study are depicted on Tables 1 and 2, respectively.
The mean age was 52 ± 2 years, and 38% were male. Hypertensive nephrosclerosis was the main cause of CKD, and all patients in the sample were hypertensive. Only 11% of the patients had diabetes mellitus as an associated disease. The patients were treated with statins, aspirin and anti-hypertensive drugs in 30%, 43% and 100% of cases, respectively.
The median values found for total calcium, PTH, Kt/V, albumin and total cholesterol were within the reference range for patients on stage 5 CKD.
In vivo experiments
Markers of systemic inflammation and chemokines
The median serum concentrations of systemic inflammation markers, CRP and IL-6 were 4.9 ± 4.8 mg/ml and 6.7 ± 8.1 pg/ml, respectively. There was a positive correlation between CRP and IL-6 (ρ = 0.57, p < 0.005). SDF-1 and IL-8 concentrations were 2625.9 ± 1288.6 pg/ml and 128.2 ± 206.2 pg/ml, respectively. The correlation between the two chemokines is presented in Figure 1 (ρ = 0.455, p < 0.05). No significant differences were found between the median serum concentrations of SDF-1 and IL-8 considering the following variables: gender, ethnicity, primary renal disease and comorbidities. (data not shown). For the control group, SDF-1 and IL-8 serum concentrations were 1996.6 ± 259.7 pg/ml and 55.1 ± 33.9 pg/ml, respectively. There was no significant difference between serum levels of these two chemokines between the HD patients and the control group.
Correlation between IL-8 and SDF-1 serum concentrations in patients under hemodialysis treatment. IL-8: Interleukin 8; SDF-1: Stromal cell-derived factor-1.
In vitro experiments
Viability assay by the exclusion with Trypan blue method
The analysis of cell viability by the Trypan Blue exclusion method showed 95% viability for untreated HUVEC (control group, cells cultured with normal medium), 90% viability for HUVEC treated in healthy medium and 84% viability of cells treated with uremic medium. There was no significant difference between treatments when compared to the control group.
MTT viability assays
The MTT cell viability analysis showed no significant differences (t-test or one-way ANOVA) between normal culture medium, healthy medium or uremic medium applied to all treatments.
SDF-1 and IL-8 in vitro expression
Figure 2 depicts the effect of uremic environment in in vitro expression of SDF-1 (A) and IL-8 (B) (pg/ml) on the HUVEC. After 6 hours of treatment, there is a lower expression of SDF-1 when HUVEC are treated with a uremic medium (p < 0.05), when compared to treatment with a healthy medium (t-test or one way ANOVA). After 12 hours of treatment, there is a significant increase in IL-8 when HUVEC are treated with uremic medium compared to the treatment with healthy medium (p < 0.005).
A: In vitro SDF-1 (pg/ml) expression by HUVEC before and after (0 and 6h) treatment in uremic medium (HD). * p < 0.05 - Control 6h vs. HD 6h (test t); B: In vitro IL-8 (pg/ml) expression by HUVEC before and after (0 and 12h) treatment in uremic medium (HD). * p < 0.005 - Control 12h vs. HD 12h (test t).
Discussion
During the last decade, several studies have demonstrated the action of uremic toxins
as effector of endothelial dysfunction, contributing to CVD progression in patients
with CKD.2020. de la Sierra A, Larrousse M. Endothelial dysfunction is associated
with increased levels of biomarkers in essential hypertension. J Hum Hypertens
2010;24:373-9. DOI: http://dx.doi.org/10.1038/jhh.2009.91
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21. Burger D, Levin A. 'Shedding' light on mechanisms of
hyperphosphatemic vascular dysfunction. Kidney Int 2013;83:187-9. DOI:
http://dx.doi.org/10.1038/ki.2012.416
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link? Nephrol Dial Transplant 2001;16:1968-71. Patients with CKD have an imbalance in endothelium-dependent
vasodilation and increased circulating levels of endothelial dysfunction markers and
oxidative stress. They also have an abnormal balance between cell damage caused by
uremic toxicity and tissue repair (represented by decreased EPC migration), causing
severe endothelial injury.2323. Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P.
Vascular incompetence in dialysis patients-protein-bound uremic toxins and
endothelial dysfunction. Semin Dial 2011;24:327-37. DOI:
http://dx.doi.org/10.1111/j.1525-139X.2011.00925.x
http://dx.doi.org/10.1111/j.1525-139X.20...
The main findings
of this study show increased serum levels of IL-8 and SDF-1, markers of tissue injury
and repair, respectively, in HD patients. Conversely, it was also shown in
vitro that when endothelial cells are treated with uremic serum, they
have decreased expression of SDF-1, but increased IL-8, suggesting a possible link
between vascular activation and tissue repair in these patients.
The population included in this study comprised HD patients with chronic
glomerulopathy, nephrosclerosis and diabetic nephropathy as the leading causes of
CKD, and a high prevalence of CVD risk factors, such as hypertension. Regarding the
use of drugs, 45% were using vitamin D, 30% were on statins, 43% on aspirin and 100%
were under antihypertensive drugs. No significant differences were observed between
the study population and other previous studies conducted in HD patients,2424. de Moraes TP, Fortes PC, Ribeiro SC, Riella MC, Pecoits-Filho R.
Comparative analysis of lipid and glucose metabolism biomarkers in non-diabetic
hemodialysis and peritoneal dialysis patients. J Bras Nefrol 2011;33:173-9. DOI:
http://dx.doi.org/10.1590/S0101-28002011000200009
http://dx.doi.org/10.1590/S0101-28002011...
,2525. Bucharles S, Barberato SH, Stinghen AE, Gruber B, Piekala L,
Dambiski AC, et al. Impact of cholecalciferol treatment on biomarkers of inflammation
and myocardial structure in hemodialysis patients without hyperparathyroidism. J Ren
Nutr 2012;22:284-91. DOI:
http://dx.doi.org/10.1053/j.jrn.2011.07.001
http://dx.doi.org/10.1053/j.jrn.2011.07....
except for the low prevalence of diabetes mellitus and
dyslipidemia observed in our study. Serum markers of systemic inflammation, such as
CRP and IL-6 were increased, and were also similar to those found in other studies,
demonstrating that systemic inflammation is a common finding in HD patientS.2626. Rattanasompattikul M, Molnar MZ, Zaritsky JJ, Hatamizadeh P, Jing J,
Norris KC, et al. Association of malnutrition-inflammation complex and responsiveness
to erythropoiesis-stimulating agents in long-term hemodialysis patients. Nephrol Dial
Transplant 2013;28:1936-45. DOI:
http://dx.doi.org/10.1093/ndt/gfs368
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,2727. Stenvinkel P, Heimbürger O, Jogestrand T. Elevated interleukin-6
predicts progressive carotid artery atherosclerosis in dialysis patients: association
with Chlamydia pneumoniae seropositivity. Am J Kidney Dis 2002;39:274-82. DOI:
http://dx.doi.org/10.1053/ajkd.2002.30546
http://dx.doi.org/10.1053/ajkd.2002.3054...
Yet, SDF-1 and IL-8 concentrations were also in agreement with other
prior studies.44. Stinghen AE, Gonçalves SM, Martines EG, Nakao LS, Riella MC, Aita CA,
et al. Increased plasma and endothelial cell expression of chemokines and adhesion
molecules in chronic kidney disease. Nephron Clin Pract 2009;111:c117-26. PMID:
19147993 DOI: http://dx.doi.org/10.1159/000191205
http://dx.doi.org/10.1159/000191205...
,66. Jie KE, Zaikova MA, Bergevoet MW, Westerweel PE, Rastmanesh M,
Blankestijn PJ, et al. Progenitor cells and vascular function are impaired in
patients with chronic kidney disease. Nephrol Dial Transplant 2010;25:1875-82. DOI:
http://dx.doi.org/10.1093/ndt/gfp749
http://dx.doi.org/10.1093/ndt/gfp749...
,2828. Jie KE, Putten K, Bergevoet MW, Doevendans PA, Gaillard CA, Braam B,
et al. Short- and long-term effects of erythropoietin treatment on endothelial
progenitor cell levels in patients with cardiorenal syndrome. Heart 2011;97:60-5.
DOI: http://dx.doi.org/10.1136/hrt.2010.194654
http://dx.doi.org/10.1136/hrt.2010.19465...
,2929. Stenvinkel P, Lindholm B, Heimbürger M, Heimbürger O. Elevated serum
levels of soluble adhesion molecules predict death in pre-dialysis patients:
association with malnutrition, inflammation, and cardiovascular disease. Nephrol Dial
Transplant 2000;15:1624-30. DOI:
http://dx.doi.org/10.1093/ndt/15.10.1624
http://dx.doi.org/10.1093/ndt/15.10.1624...
The vascular endothelium has long been recognized as a complex endocrine organ, which
regulates several physiological functions such as vascular tone, migration and growth
of smooth muscle cells, vascular permeability to solutes and blood cells,
homeostasis, among other functions.3030. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP,
et al. Endothelial cells in physiology and in the pathophysiology of vascular
disorders. Blood 1998;91:3527-61.,3131. Malyszko J. Mechanism of endothelial dysfunction in chronic kidney
disease. Clin Chim Acta 2010;411:1412-20. PMID: 20598675 DOI:
http://dx.doi.org/10.1016/j.cca.2010.06.019
http://dx.doi.org/10.1016/j.cca.2010.06....
Endothelial
dysfunction can be broadly defined as a pro-inflammatory and pro-thrombotic
state3232. Moody WE, Edwards NC, Madhani M, Chue CD, Steeds RP, Ferro CJ, et
al. Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney
disease: cause or association? Atherosclerosis 2012;223:86-94. and it is a frequent finding in CKD
patients due to the constant exposure of the endothelium to uremic toxins, being
regarded as a forerunner in the pathogenesis of atherosclerosis and obstructive
arterial disease.3333. Shlipak MG, Massie BM. The clinical challenge of cardiorenal
syndrome. Circulation 2004;110:1514-7. PMID: 15381655 DOI:
http://dx.doi.org/10.1161/01.CIR.0000143547.55093.17
http://dx.doi.org/10.1161/01.CIR.0000143...
,3434. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular
diseases: the role of oxidant stress. Circ Res 2000;87:840-4. DOI:
http://dx.doi.org/10.1161/01.RES.87.10.840
http://dx.doi.org/10.1161/01.RES.87.10.8...
Thus, one can say that in these patients such
conditions are closely related, but above all, mutually affected by one another.3535. Ronco C, Chionh CY, Haapio M, Anavekar NS, House A, Bellomo R. The
cardiorenal syndrome. Blood Purif 2009;27:114-26. DOI:
http://dx.doi.org/10.1159/000167018
http://dx.doi.org/10.1159/000167018...
In fact, in response to cellular injury, we
have recently demonstrated in vivo and in vitro,
that the endothelium exposure to uremic plasma dependent on uremia levels and time,
increases the expression of MCP-1, soluble VCAM-1 (sVCAM-1) and IL-8, suggesting a
link between vascular activation and uremic toxicity.44. Stinghen AE, Gonçalves SM, Martines EG, Nakao LS, Riella MC, Aita CA,
et al. Increased plasma and endothelial cell expression of chemokines and adhesion
molecules in chronic kidney disease. Nephron Clin Pract 2009;111:c117-26. PMID:
19147993 DOI: http://dx.doi.org/10.1159/000191205
http://dx.doi.org/10.1159/000191205...
Also, some studies suggest that in CKD patients, there is an impaired
angiogenic response due to the decreased production of mesenchymal stem cells
mediated by SDF-1, vascular endothelial growth factor (VEGF) and VEGF receptor 1
(VEGFR1).3636. Noh H, Yu MR, Kim HJ, Jeon JS, Kwon SH, Jin SY, et al. Uremia
induces functional incompetence of bone marrow-derived stromal cells. Nephrol Dial
Transplant 2012;27:218-25. DOI: http://dx.doi.org/10.1093/ndt/gfr267
http://dx.doi.org/10.1093/ndt/gfr267...
SDF-1 is an important angiogenic factor released into the circulation in inflammatory
processes, and it is responsible for the mobilization of EPC from the bone marrow
into the circulation. The present study demonstrates that in HD patients, SDF-1 serum
concentrations are increased when compared to healthy controls, positively
correlating with IL-8. Such correlation occurs in parallel to the increase in CRP and
IL-6 - systemic inflammation markers. In agreement with our data, Jie et
al.,66. Jie KE, Zaikova MA, Bergevoet MW, Westerweel PE, Rastmanesh M,
Blankestijn PJ, et al. Progenitor cells and vascular function are impaired in
patients with chronic kidney disease. Nephrol Dial Transplant 2010;25:1875-82. DOI:
http://dx.doi.org/10.1093/ndt/gfp749
http://dx.doi.org/10.1093/ndt/gfp749...
- in studies involving
patients with different degrees of CKD - suggested that vascular regeneration is poor
even in the early stages of CKD, with increased levels of muscle progenitor cells
vis-à-vis a decline in kidney function; this occurs concomitantly with an increase in
SDF-1 plasma levels. Yet, studies show that after kidney transplantation, EPC levels
are restored in parallel to the decline in SDF-1 levels, clearly demonstrating the
role of uremia in cell injury and in regulating SDF-1 levels.3737. Herbrig K, Gebler K, Oelschlaegel U, Pistrosch F, Foerster S, Wagner
A, et al. Kidney transplantation substantially improves endothelial progenitor cell
dysfunction in patients with end-stage renal disease. Am J Transplant 2006;6:2922-8.
DOI: http://dx.doi.org/10.1111/j.1600-6143.2006.01555.x
http://dx.doi.org/10.1111/j.1600-6143.20...
In regards to vascular response activation of IL-8 production, our in
vitro data confirm the in vivo results and found that in
response to the uremic environment, endothelial cells increase the levels of this
chemokine, confirming uremia as the effector of cell injury. Conversely, in
vitro results demonstrate that SDF-1 expression is reduced in endothelial
cells upon exposure to uremic medium when compared to the cells exposed to the
healthy medium, suggesting that uremia acts somewhat inhibiting the expression of
this chemokine. In fact, Noh et al.3636. Noh H, Yu MR, Kim HJ, Jeon JS, Kwon SH, Jin SY, et al. Uremia
induces functional incompetence of bone marrow-derived stromal cells. Nephrol Dial
Transplant 2012;27:218-25. DOI: http://dx.doi.org/10.1093/ndt/gfr267
http://dx.doi.org/10.1093/ndt/gfr267...
reported the uremic interference on the transcription of the CXCL12
(SDF-1) gene, inhibiting the synthesis of messenger RNA (mRNA); thereby decreasing
the production of SDF-1. Also, Zaza et al.3838. Zaza G, Pontrelli P, Pertosa G, Granata S, Rossini M, Porreca S, et
al. Dialysis-related systemic microinflammation is associated with specific genomic
patterns. Nephrol Dial Transplant 2008;23:1673-81. DOI:
http://dx.doi.org/10.1093/ndt/gfm804
http://dx.doi.org/10.1093/ndt/gfm804...
observed in genomic studies of polymorphonuclear cells (PMN)
from patients on HD that the CXCL12 gene expression is reduced, which could result in
the accumulation of senescent PMN cells in the circulation.
Our in vitro results showed that after 6 hours of exposure to the
uremic medium, the endothelial cells present with decreased levels of SDF-1 when
compared to cells treated with the healthy medium. In part, this result can be
explained because SDF-1 is also produced by other cells such as bone marrow cells,
heart, liver, thymus, spleen, skeletal and smooth muscle cells, macrophages, kidneys
cells, and endothelial cells acting in a pleiotropic manner;77. Braunersreuther V, Mach F, Steffens S. The specific role of
chemokines in atherosclerosis. Thromb Haemost 2007;97:714-21. PMID:
17479181,88. Ghadge SK, Mühlstedt S, Ozcelik C, Bader M. SDF-1 a as a therapeutic
stem cell homing factor in myocardial infarction. Pharmacol Ther 2011;129:97-108.
DOI: http://dx.doi.org/10.1016/j.pharmthera.2010.09.011
http://dx.doi.org/10.1016/j.pharmthera.2...
,3939. Karin N. The multiple faces of CXCL12 (SDF-1alpha) in the regulation
of immunity during health and disease. J Leukoc Biol 2010;88:463-73. DOI:
http://dx.doi.org/10.1189/jlb.0909602
http://dx.doi.org/10.1189/jlb.0909602...
this multiple
production certainly reflects the serum levels of SDF-1 found in patients. Still,
some studies show that after acute myocardial infarction, much of the subsequent
angiogenic process is due to the joint action of SDF-1 and IL-8 in EPC recruitment to
the site of injury.1414. Gössl M, Mödder UI, Gulati R, Rihal CS, Prasad A, Loeffler D, et al.
Coronary endothelial dysfunction in humans is associated with coronary retention of
osteogenic endothelial progenitor cells. Eur Heart J 2010;31:2909-14. DOI:
http://dx.doi.org/10.1093/eurheartj/ehq373
http://dx.doi.org/10.1093/eurheartj/ehq3...
,1515. Elmadbouh I, Haider HKh, Jiang S, Idris NM, Lu G, Ashraf M. Ex vivo
delivered stromal cell-derived factor-1alpha promotes stem cell homing and induces
angiomyogenesis in the infarcted myocardium. J Mol Cell Cardiol 2007;42:792-803.
PMID: 17350033 These findings might explain the poor vascular
adaptation found in patients with CKD after ischemic events.4040. Becherucci F, Mazzinghi B, Ronconi E, Peired A, Lazzeri E, Sagrinati
C, et al. The role of endothelial progenitor cells in acute kidney injury. Blood
Purif 2009;27:261-70. DOI: http://dx.doi.org/10.1159/000202005
http://dx.doi.org/10.1159/000202005...
,4141. Yuen DA, Kuliszewski MA, Liao C, Rudenko D, Leong-Poi H, Chan CT.
Nocturnal hemodialysis is associated with restoration of early-outgrowth endothelial
progenitor-like cell function. Clin J Am Soc Nephrol 2011;6:1345-53. DOI:
http://dx.doi.org/10.2215/CJN.10911210
http://dx.doi.org/10.2215/CJN.10911210...
In conclusion, our in vivo results demonstrate that the action of uremia on HD patients may be associated with severe vascular damage, reflecting the increased circulating concentrations of IL-8 and SDF-1, suggesting a correlation between endothelial dysfunction and tissue repair. However, our study was limited to a small number of patients. We believe that studies with larger numbers of patients and additional in vitro tests are needed to evaluate possible causes for the in vitro reduction in SDF-1 levels.
-
National Council for Scientific and Technological Development (CNPq) and Araucária Foundation.
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29Stenvinkel P, Lindholm B, Heimbürger M, Heimbürger O. Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease. Nephrol Dial Transplant 2000;15:1624-30. DOI: http://dx.doi.org/10.1093/ndt/15.10.1624
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31Malyszko J. Mechanism of endothelial dysfunction in chronic kidney disease. Clin Chim Acta 2010;411:1412-20. PMID: 20598675 DOI: http://dx.doi.org/10.1016/j.cca.2010.06.019
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-
33Shlipak MG, Massie BM. The clinical challenge of cardiorenal syndrome. Circulation 2004;110:1514-7. PMID: 15381655 DOI: http://dx.doi.org/10.1161/01.CIR.0000143547.55093.17
» http://dx.doi.org/10.1161/01.CIR.0000143547.55093.17 -
34Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000;87:840-4. DOI: http://dx.doi.org/10.1161/01.RES.87.10.840
» http://dx.doi.org/10.1161/01.RES.87.10.840 -
35Ronco C, Chionh CY, Haapio M, Anavekar NS, House A, Bellomo R. The cardiorenal syndrome. Blood Purif 2009;27:114-26. DOI: http://dx.doi.org/10.1159/000167018
» http://dx.doi.org/10.1159/000167018 -
36Noh H, Yu MR, Kim HJ, Jeon JS, Kwon SH, Jin SY, et al. Uremia induces functional incompetence of bone marrow-derived stromal cells. Nephrol Dial Transplant 2012;27:218-25. DOI: http://dx.doi.org/10.1093/ndt/gfr267
» http://dx.doi.org/10.1093/ndt/gfr267 -
37Herbrig K, Gebler K, Oelschlaegel U, Pistrosch F, Foerster S, Wagner A, et al. Kidney transplantation substantially improves endothelial progenitor cell dysfunction in patients with end-stage renal disease. Am J Transplant 2006;6:2922-8. DOI: http://dx.doi.org/10.1111/j.1600-6143.2006.01555.x
» http://dx.doi.org/10.1111/j.1600-6143.2006.01555.x -
38Zaza G, Pontrelli P, Pertosa G, Granata S, Rossini M, Porreca S, et al. Dialysis-related systemic microinflammation is associated with specific genomic patterns. Nephrol Dial Transplant 2008;23:1673-81. DOI: http://dx.doi.org/10.1093/ndt/gfm804
» http://dx.doi.org/10.1093/ndt/gfm804 -
39Karin N. The multiple faces of CXCL12 (SDF-1alpha) in the regulation of immunity during health and disease. J Leukoc Biol 2010;88:463-73. DOI: http://dx.doi.org/10.1189/jlb.0909602
» http://dx.doi.org/10.1189/jlb.0909602 -
40Becherucci F, Mazzinghi B, Ronconi E, Peired A, Lazzeri E, Sagrinati C, et al. The role of endothelial progenitor cells in acute kidney injury. Blood Purif 2009;27:261-70. DOI: http://dx.doi.org/10.1159/000202005
» http://dx.doi.org/10.1159/000202005 -
41Yuen DA, Kuliszewski MA, Liao C, Rudenko D, Leong-Poi H, Chan CT. Nocturnal hemodialysis is associated with restoration of early-outgrowth endothelial progenitor-like cell function. Clin J Am Soc Nephrol 2011;6:1345-53. DOI: http://dx.doi.org/10.2215/CJN.10911210
» http://dx.doi.org/10.2215/CJN.10911210
Publication Dates
-
Publication in this collection
Apr-Jun 2014
History
-
Received
13 Mar 2013 -
Accepted
06 Feb 2014