Usama A.A. Sharaf El Din

Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients

BACKGROUND Vascular calcification has detrimental consequences on chronic kidney disease (CKD) patients, yet its pathogenesis is not fully understood. Fibroblast growth factor-23 (FGF-23) is involved in the regulation of mineral metabolism which may in turn affect vascular calcification. Data on the relationship between FGF-23 and peripheral vascular calcification, using conventional radiographs, are conflicting, and less is known about its relation to aortic calcification. We conducted this study to investigate the relationship between FGF-23 and aortic calcification in a standard haemodialysis setting. METHODS The study included 65 haemodialysis patients (46 prevalent and 19 incident) on a three times 4-h dialysis schedule as well as 15 controls. Those with diabetes, oral anticoagulation or parathyroidectomy were excluded. Intact FGF-23, parathormone, lipids, calcium and phosphorus were measured. Aortic calcification index (ACI) was assessed by a non-contrast computerized tomography (CT) of the abdominal aorta. RESULTS FGF-23 levels were higher among haemodialysis patients (4681.3 +/- 3906.1 pg/mL) compared to controls (98.2 +/- 51.9 pg/mL), P = 0.005. ACI was higher in haemodialysis patients (14.1 +/- 12) than controls (3.2 +/- 3.6), P = 0.009. FGF-23 (P < 0.0001) and systolic blood pressure (BP) (P < 0.0001) were independently related to ACI in stepwise multiple regression analysis of pooled analysis of haemodialysis patients, R(2) = 0.476; in subgroup analysis, the independent factors relating to ACI among prevalent dialysis patients were systolic BP (P < 0.0001), FGF-23 (P = 0.002) and age (P = 0.012), R(2)=0.48; whereas in incident patients, only FGF-23 was associated with ACI (P = 0.007), R(2) = 0.37. CONCLUSIONS In haemodialysis patients, FGF-23 and ACI were significantly increased, and FGF-23 was independently associated with aortic calcification.

The Association between Fibroblast Growth Factor-23 and Vascular Calcification Is Mitigated by Inflammation Markers.

Background: Fibroblast growth factor-23 (FGF-23) has been linked to vascular calcification, ventricular hypertrophy and mortality in chronic kidney disease (CKD), although these links may not be direct and independent. Similar grave outcomes are associated with inflammation and oxidative stress in CKD. Recently, accumulating evidence has linked components of phosphate homeostasis to inflammation and oxidative stress. The interaction between the triad of inflammation, FGF-23 and cardiovascular outcomes is underinvestigated. Methods: We studied 65 patients with stage 5 CKD on hemodialysis. Serum levels of FGF-23, high-sensitivity C-reactive protein (hsCRP), endogenous soluble receptor of advanced glycation end products (esRAGE), advanced oxidation protein products (AOPP), parathormone, lipids, calcium and phosphorous were measured. The aortic calcification index (ACI) was determined using non-contrast CT scans of the abdominal aorta. Results: FGF-23 was elevated (mean: 4,681 pg/ml, SD: 3,906) and correlated with hsCRP, esRAGE, AOPP, dialysis vintage and phosphorus in univariate analysis. In multiple regression analysis, hsCRP, AOPP and phosphorus but not esRAGE were all significantly correlated to FGF-23 (R2 = 0.7, p < 0.001). In univariate analysis, ACI correlated with hsCRP, esRAGE, FGF-23, dialysis vintage, systolic blood pressure (BP) and serum cholesterol. In multiple regression analysis not including inflammation markers, ACI was associated with FGF-23. However, inclusion of inflammation markers in another multiple regression analyses showed that ACI correlated with hsCRP, BP, dialysis vintage and esRAGE but not with FGF-23 (R2 = 0.65, p < 0.001). Conclusion: FGF-23 is strongly correlated to various markers of inflammation and oxidative stress in hemodialysis patients. The association between FGF-23 and vascular calcification was mitigated when corrected for inflammation markers.

Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review

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Stop chronic kidney disease progression: Time is approaching

Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the anti-senescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression.

Diabetic nephropathy: Time to withhold development and progression - A review

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Comparing different calcification scores to detect outcomes in chronic kidney disease patients with vascular calcification

BACKGROUND There is no consensus on the most appropriate technique to diagnose vascular calcification in chronic kidney disease. This is primarily because of the absence of direct comparisons of predictive values of the various calcification scores, especially outside the coronary vascular beds, to detect clinical outcomes. METHODS We included 93 haemodialysis patients and performed 6 vascular calcification scores: two scores utilised simple X-rays of abdominal aorta and peripheral vessels. CT scans of the thoracic, upper abdominal and lower abdominal aorta were performed to calculate the aortic calcification index and CT of the pelvis for calcification of iliac vessels. Patients were followed for 63months (mean 46.8months) for first major cardiovascular events and mortality. RESULTS Nineteen cardiovascular events and 28 deaths occurred. Calcification was detected more sensitively in central and peripheral beds using CT scans compared to X-rays (p<0.001). CT scans detected calcification more frequently in distal than proximal vascular beds (p<0.001). Calcification of the pelvic vessels and lower abdominal aorta were most predictive of events including pre-existing cardiovascular disease O.R. 6.5 (95% C.I. 2-22; p=0.001) and O.R. 3 (95% C.I. 1.1-9; p=0.035); new major cardiovascular events H.R. 4.2 (95% C.I. 1.5-11; p=0.006) and H.R. 2 (95% C.I. 0.8-5.3; p=0.1) as well as mortality H.R. 2.8 (95% C.I. 1.3-6; p=0.01) and H.R. 2.2 (95% C.I. 1.04-5; p=0.04) respectively. CONCLUSIONS CT based techniques are more sensitive than plain X-rays at detecting peripheral and aortic vascular calcifications. Distal CT scans of the aorta and pelvic vessels have the highest predictive value for cardiovascular events and mortality.

FGF23 and inflammation

Systemic inflammation is a recognized feature in chronic kidney disease (CKD). The role of systemic inflammation in the pathogenesis of vascular calcification was recently settled. FGF23 was recently accused as a direct stimulus of systemic inflammation. This finding explains the strong association of FGF23 to vascular calcification and increased mortality among CKD.

Is Fibroblast growth factor 23 the leading cause of increased mortality among chronic kidney disease patients? A narrative review

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Vascular calcification: When should we interfere in chronic kidney disease patients and how?

Chronic kidney disease (CKD) patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifications affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho deficiency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, promotes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic inflammation and vascular calcification is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular calcification and the different medications and medical procedures that can help to prolong the survival of CKD patients.

Sevelamer hydrochloride and coronary artery calcification in chronic hemodialysis patients: a new mechanism of action

Background The non-calcium-based phosphate binder sevelamer hydrochloride was developed to provide chronic kidney disease patients with a polymer capable of managing hyperphosphatemia without an increase in the calcium load. These beneficial effects were postulated as the mechanism of decreased progression of vascular calcification observed with such compounds. Our objective was to investigate the effect of low-dose sevelamer hydrochloride against calcium carbonate as phosphate binders on the coronary artery calcification score (CCS) and the fibroblast growth factor 23 (FGF23) level in patients receiving regular hemodialysis for more than 1 year, in a trial to find out a novel mechanism for the decreased vascular calcification observed during sevelamer use. Patients and methods A total of 80 hemodialysis patients were allocated into two groups each of 40 patients. The first group received sevelamer hydrochloride 2400 mg/day (group 1), whereas the second continued on calcium carbonate 1500 mg/day (group 2). For each patient, coronary artery calcification was estimated twice, once before admission to the study and again at the end of the study period using noncontrast computed tomography. Serum calcium, phosphorus, intact parathyroid hormone (PTH), lipids, and FGF23 were also assessed in these two situations. Results Beside the significant decrease in serum calcium and phosphorus levels after the use of sevelamer for 6 months, there was a significant decrease in levels of FGF23 and the rate of CCS progress in group 1. Serum levels of total and low-density lipoprotein cholesterol decreased significantly in group 1. The serum PTH level did not show a significant change in either group. CCS showed a significant positive correlation with FGF23, but there was no significant correlation with serum calcium, serum phosphorus, or serum PTH in both groups. Conclusion Sevelamer hydrochloride suppressed the progression of coronary artery calcification, and decreased the FGF23 level significantly. The significant correlation between the serum FGF23 level and the CCS in the absence of any significant correlation between the latter on the one hand and the serum calcium, the serum phosphorus, or the serum PTH on the other might highlight a novel mechanism of action of sevelamer on the CCS.