In group 2 (CKD stages I and II ), there were mild to moderate increase of HGF levels with mean value of serum HGF was 713.3 ± 123.9 ng/L while there were more increase of the levels of serum HGF in group 3 ( CKD stages III and IV) with mean value was 1039 ± 165.8 ng/L (Table 3). These results were consistent with the study of Sugimura et al. (5) who revealed that non-dialysis patients with renal insufficiency had significantly higher serum HGF than normal subjects (p < 0.001), and the elevated serum HGF correlated with their serum creatinine levels. The increase of HGF levels on hemodialysis patients was more than the patients with chronic kidney stages (I, II, III and IV) (Table 3). These findings coincide with Libetta. et al. (6) who stated that hemodialysis causes a prompt and prolonged release of HGF into the circulation, raising HGF serum concentration up to 30 times.
We found in our study, as well, that there is a prompt increase of levels of serum HGF in group 4 (CKD stage V) with mean value of 1616.5 ± 324.5 ng/L (Table 3), (Fig 2). There was as well a high significant difference of group 4 from all others groups (Table 4). This is in agreement with Liu Y et al. (7) study findings. Different mechanisms might underlie the elevated HGF levels found in HD; Lohr J et al. (8) demonstrated that dialysis treatment induces release of interleukin-1 (IL-1) and tumor necrosis factor, which may act as HGF inducers (the so-called Injurins). The release in blood of cytokines results from the fact that extracorporeal circulation is associated with leukocyte activation. Activated peripheral blood leukocytes are a possible source of HGF. In addition, dialysis may cause the release of coagulation products that convert HGF into its active form. Thus, dialysis may induce the release of HGF either from activated peripheral blood leukocytes or from tissue cells stimulated by cytokines.
In addition, Alvarez et al. (9) confirmed that the release of HGF takes place even if dialysis is performed without heparin since it peaked early after the start of extracorporeal circulation in their study. This proves that it does not depend on heparin-induced shedding of receptor bound HGF from peripheral tissues.
Therefore, at least theoretically, increased HGF activity induced by dialysis may be pathophysiologically relevant in patients requiring renal replacement therapy. On the other hand, there was also significant increase of serum HGF levels with increasing age (Table 7). This is in agreement with Mizuno et al. (10), who stated the same finding. When considering that higher age is usually accompanied by higher prevalence of comorbidities including CVD and higher circulating concentrations of several inflammation markers (11), one may speculate that inflammation could be the common pathway linking HGF with higher age. This is supported by some studies showing that inflammatory cytokine stimulation induces up-regulation of HGF.
In our study, there was significant correlation between renal sonographic appearance and the levels of serum HGF with increasing the serum HGF level with increasing the degree of nephropathy (fibrosis). The mean level of HGF in normal kidneys ultrasonography was (1004) ng/L, in the grade I nephropathy was (1233) ng/L, in the grade II nephropathy was (1464) ng/L, in the grade III nephropathy (1739) ng/L and reaching to highest level in marked fibrosis when kidneys became shrunken up to (1800) ng/L (Table 6),(fig 3).
Sonographic determination of renal length and cortical echogenicity correlates with chronic, irreversible renal disease. For each histologic measure of disease (renal fibrosis), the correlation was substantially stronger with echogenicity than with renal length, combining kidney length and echogenicity provided much better discrimination of renal fibrosis as with increasing echogenicity of kidneys in ultrasonography, the degree of renal fibrosis increased (12).
In our study we found that the most common cause for CKD was diabetes (DM) and hypertension (26.2%) followed by hypertension alone (19%) then by DM alone (9.5%) and unknown causes represented (9.5%). This coincides with Redmon et al. (13) who mentioned that the most common recognized cause of CKD is diabetes mellitus. Others included idiopathic (i.e. unknown cause), hypertension, and glomerulonephritis, causing all together about 75% of all adult cases.
In our study we found that the most common associated disease was IHD in both patients with ESKD on regular hemodialysis and patients with CKD not on regular hemodialysis. This is in agreement with the well-known fact that evens a mildly reduced renal function results in a dramatically increased risk of premature CVD (14). That is of serious clinical importance since Cardiovascular disease (CVD) is the major cause of death in patients with ESRD. Additionally, impaired cardiac function can worsen renal function, a complex interaction known as the cardio-renal syndrome (15).
The current study revealed high significant difference among different groups as regarding serum albumin (P <0.001), mean value of serum albumin in group 1 (control group) was 4.8 ± 0.4 g/dl , mean value of serum albumin in group 2 (stages I and II) was 3.6 ± 0.8 g/dl, mean value of serum albumin in group 3 (stages III and IV) was 3.6 ± 0.5 g/dl, mean value of serum albumin in group 4 (stage V) was 3.5 ± 0.3 g/dl (Table 5).These results are going in harmony with the results obtained by Kikuchi et al.(16); They measured it in 1138 patients with CKD not on hemodialysis and found that these patients had a mild decrease of serum albumin with a mean value of 3.8 ± 0.6. Friedman and Fadem(17) measured it in ESKD patients on regular hemodialysis and found serum albumin level was significantly lower (3.3±0.6 g/dl; P<0.001). These low albumin values may be due to CKD associated abnormalities such as malnutrition, inflammation, infection, protein loss into urine and dialysate and over hydration (17). Its clinical significance comes from the association of hypoalbuminemia with protein-energy wasting (PEW) which is progressive loss of body protein mass and energy reserves linked to higher morbidity and mortality rates. This is among numerous complications of CKD, usually in advanced stages of CKD, possibly affecting 18%–75% of patients with ESRD.
Our study showed no statistically significant correlation among the 4 groups as regarding the liver enzymes AST and ALT (Table 5).This is in agreement with Trevizli et al. (18), who mentioned that inflammatory activity of the liver was significantly lower in HD patients with no difference of liver enzymes between HD patients and control group. Even in HD patients who are infected with HCV, serum aminotransferase levels were found usually normal or only slightly elevated (19)
Our study showed that there was no statistically significant correlation found among the 4 groups as regards gender. These results agree with Libetta et al. (20), who demonstrated that there was no statistically significant difference in serum HGF across gender.
Conclusion:
From the previously mentioned results we can conclude that there was an increase in the level of serum HGF levels in patients with chronic kidney disease with prompt increase in CKD stage V, especially ESKD on regular hemodialysis. Thus, serum HGF may be a good indicator for the degree of renal fibrosis in CKD patients.
Ethical Committee Approval: The local ethical committee of the Internal Medicine department, Theodor Bilharz research Institute, Cairo, Egypt, approved this work.
Human and Animal Rights: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent: “Informed consent was obtained from all individual participants included in the study”.
Conflict of interest: The authors have declared that no conflict of interest exists.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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