Fibroblast growth factor-23 is a strong predictor of insulin resistance among chronic kidney disease patients.

Insulin resistance (IR) is very common among chronic kidney disease (CKD) patients. Disturbance in mineral and bone metabolism (MBD) seems to play a role in the pathogenesis of insulin resistance. Fibroblast growth factor-23 (FGF23) is evolving as the most important link between MBD and many pathologic sequences of CKD. The aim was to evaluate IR in pre-dialysis CKD patients looking for a possible association to mineral metabolism among CKD patients. A total of 100 stage 3-5 CKD patients were selected beside 20 normal control subjects. Homeostatic model assessment of insulin resistance (HOMA-IR) was used to assess IR in selected cases. Both groups were compared for fasting blood glucose (FBG), fasting blood insulin (FBI), HOMA-IR, estimated glomerular filtration rate (eGFR), serum calcium (Ca), phosphorus (P), 25 hydroxy vitamin D (25 OH vit D), parathormone (PTH), and uric acid (UA). Correlation study between HOMA_IR and different studied parameters was performed. HOMA-IR is significantly higher in CKD (8.87 ± 3.48 vs. 3.97 ± 0.34 in CKD vs. control, respectively, p < .001). In addition CKD patients have significantly higher FGF23 (235 ± 22.96 vs. 139 ± 12.3 pg/mL, p < .001), PTH (76.9 ± 15.27 vs. 47.9 ± 2.52 pg/mL, p < .001), P (4.3 ± 0.67 vs. 3.6 ± 0.23 mg/dL, p < .001), and UA (5 ± 1.22 vs. 4.85 ± 0.48 mg/dL, p < .001) and significantly lower Ca (8.2 ± 0.3 vs. 8.9 ± 0.33 mg/dL, p < .001), and 25 (OH) vit D (17 ± 5.63 vs. 37 ± 3.43 ng/mL, p < .001). Stepwise linear regression analysis revealed that BMI, GFR, Ca, P, and FGF23 were the only significant predictors of HOMA IR. Increased IR in CKD is a consequence of the uremic status and is intimately associated with disturbed phosphate metabolism and FGF23. Further studies are needed to look for an underlying mechanism.

Vitamin D deficiency: an unrecognized cause of flank pain.

Loin pain is frequently not associated with any urinary abnormality. Musculoskeletal abnormalities are not uncommon as alternative cause of flank pain. Osteomalacia of the ribs was infrequently encountered as the cause of flank pain. Vitamin D deficiency has been reported as a common problem worldwide with special predilection to the Middle East area. In this study, we looked for vitamin D deficiency in patients with flank pain associated with tenderness over the tips of the lowermost ribs. Out of 783 patients presenting with unilateral or bilateral flank pain to a single center over a period of 3 years, 316 did not have a definite urologic cause (group B). One hundred and eighty-seven of these patients had distinct tenderness over the costal margin (group B1) that could not be explained by history and radiology. All patients of group B were tested for serum levels of 25(OH) vitamin D. Very low serum levels of 25(OH) vitamin D was detected in all cases of group B1 and in only in only 26.4% of the remaining cases of group B (group B2). Relief of flank pain was noticed within 2 months in 55.1% of vitamin D deficient cases. In patients presenting with flank pain, the existence of tenderness of the last ribs instead of the renal angle proper should alert to a possible cause in the rib cage. Estimation of serum vitamin D level should be performed in these cases.

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

The association between uric acid (UA) on one side and systemic hypertension (Htn), dyslipidemia, glucose intolerance, overweight, fatty liver, renal disease and cardiovascular disease (CVD) on the other side is well recognized. However, the causal relationship between UA and these different clinical problems is still debatable. The recent years have witnessed hundreds of experimental and clinical trials that favored the opinion that UA is a probable player in the pathogenesis of these disease entities. These studies disclosed the strong association between hyperuricemia and metabolic syndrome (MS), obesity, Htn, type 2 diabetes mellitus (DM), non-alcoholic fatty liver disease, hypertriglyceridemia, acute kidney injury, chronic kidney disease (CKD), coronary heart disease (CHD), heart failure and increased mortality among cardiac and CKD patients. The association between UA and nephrolithiasis or preeclampsia is a non-debatable association. Recent experimental trials have disclosed different changes in enzyme activities induced by UA. Nitric oxide (NO) synthase, adenosine monophosphate kinase (AMPK), adenosine monophosphate dehydrogenase (AMPD), and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase are affected by UA. These changes in enzymatic activities can lead to the observed biochemical and pathological changes associated with UA. The recent experimental, clinical, interventional, and epidemiologic trials favor the concept of a causative role of UA in the pathogenesis of MS, renal, and CVDs.

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

The recent discoveries in the fields of pathogenesis and management of diabetic nephropathy have revolutionized the knowledge about this disease. Little was added to the management of diabetic nephropathy after the introduction of renin angiotensin system blockers. The ineffective role of the renin- angiotensin system blockers in primary prevention of diabetic nephropathy in type 1 diabetes mellitus necessitated the search for other early therapeutic interventions that target alternative pathogenic mechanisms. Among the different classes of oral hypoglycemic agents, recent studies highlighted the distinguished mechanisms of sodium glucose transporter 2 blockers and dipeptidyl peptidase-4 inhibitors that settle their renoprotective actions beyond the hypoglycemic effects. The introduction of antioxidant and anti-inflammatory agents to this field had also added wealth of knowledge. However, many of these agents are still waiting well-designed clinical studies in order to prove their beneficial therapeutic role. The aim of this review of literature is to highlight the recent advances in understanding the pathogenesis, diagnosis, the established and the potential renoprotective therapeutic agents that would prevent the development or the progression of diabetic nephropathy.

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.

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.

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.