Faruk Turgut

Vascular calcification in chronic kidney disease.

VC (vascular calcification) is highly prevalent in patients with CKD (chronic kidney disease), but its mechanism is multifactorial and incompletely understood. In addition to increased traditional risk factors, CKD patients also have a number of non-traditional cardiovascular risk factors, which may play a prominent role in the pathogenesis of arterial calcification, such as duration of dialysis and disorders of mineral metabolism. The transformation of vascular smooth muscle cells into chondrocytes or osteoblast-like cells seems to be a key element in VC pathogenesis, in the context of passive calcium and phosphate deposition due to abnormal bone metabolism and impaired renal excretion. The process may be favoured by the low levels of circulating and locally produced VC inhibitors. VC determines increased arterial stiffness, left ventricular hypertrophy, a decrease in coronary artery perfusion, myocardial ischaemia and increased cardiovascular morbidity and mortality. Although current therapeutic strategies focus on the correction of phosphate, calcium, parathyroid hormone or vitamin D, a better understanding of the mechanisms of abnormal tissue calcification may lead to development of new therapeutic agents, which could reduce VC and improve cardiovascular outcome in CKD patients. The present review summarizes the following aspects: (i) the pathophysiological mechanism responsible for VC and its promoters and inhibitors, (ii) the methods for detection of VC in patients with CKD, including evaluation of arterial stiffness, and (iii) the management of VC in CKD patients.

Nigella sativa Oil for Prevention of Chronic Cyclosporine Nephrotoxicity: An Experimental Model

Nephrotoxicity is the main secondary effect of cyclosporine A (CsA) treatment. The antioxidant action of Nigella sativa oil (NSO) may explain the protective effect of these agents against various hepatotoxic and nephrotoxic models in vivo and in vitro. This study was designed to investigate the possible protective effects of NSO, in prevention of chronic CsA-induced nephrotoxicity in rats. Animals were randomly divided into four experimental groups: the control group received sunflower oil, the other groups were treated with CsA (25 mg/kg/day b.w. orally) or NSO (2 ml/kg orally) or CsA + NSO, respectively. Urine and serum creatinine levels, tissue superoxide dismutase, glutathione peroxidase and catalase enzyme activities, and nitric oxide and malondialdehyde levels were measured, and histological examination was performed. In our study, CsA caused a significant deterioration in the renal function, morphology and gave rise to severe oxidative stress in the kidney. NSO significantly improved the functional and histological parameters and attenuated the oxidative stress induced by CsA. In conclusion, our study demonstrated for the first time that NSO protects kidney tissue against oxygen free radicals, preventing renal dysfunction and morphological abnormalities associated with chronic CsA administration.

Magnesium in chronic kidney disease: challenges and opportunities.

Cardiovascular disease is the leading cause of mortality and morbidity in patients with chronic kidney disease, which is partly explained by the fact that 40–70% of patients receiving dialysis have significant coronary artery disease. Recent clinical studies have shown that lower serum magnesium (Mg) levels are associated with vascular calcification and cardiovascular mortality among patients with end-stage renal disease (ESRD). On the other hand, hypermagnesemia inhibits parathyroid hormone secretion, which is considered an important independent risk factor for vascular calcification, left ventricular hypertrophy and mortality in ESRD patients. Finally, increasing evidence points towards a link between Mg and cardiovascular disease, even in subjects without chronic kidney disease. The purpose of this review was to critically review the current literature examining the effects of plasma Mg levels on cardiovascular disease and parathyroid hormone homeostasis in ESRD, and renal transplant patients.

Serum Uric Acid Level and Endothelial Dysfunction in Patients with Nondiabetic Chronic Kidney Disease

Background: An elevated serum uric acid level is strongly associated with endothelial dysfunction and inflammation, both of which are common in chronic kidney disease (CKD). We hypothesized that endothelial dysfunction in subjects with CKD would correlate with uric acid levels. Materials and Methods: We evaluated the association between serum uric acid level and ultrasonographic flow-mediated dilatation (FMD) in 263 of 486 patients with recently diagnosed CKD (stage 3–5) (48% male, age 52 ± 12 years). To minimize confounding, 233 patients were excluded because they were diabetic, had established cardiovascular complications or were taking drugs (renin-angiotensin system blockers, statins) interfering with vascular function. Results: Serum uric acid level was significantly increased in all stages of CKD and strongly correlated with estimated glomerular filtration rate (eGFR-MDRD); FMD was inversely associated with serum uric acid (r = –0.49, p < 0.001). The association of serum uric acid with FMD remained after adjustment for age, gender, smoking, LDL cholesterol, eGFR, high-sensitivity C-reactive protein, systolic blood pressure, proteinuria, and homeostatic model assessment index (β = –0.27, p < 0.001). Conclusion: Increased serum uric acid is an independent predictor of endothelial dysfunction in subjects with CKD.

Causes and Mechanisms of Nondipping Hypertension

Growing evidence indicates that nondippers have worsened cardiovascular outcomes than dippers. Ambulatory blood pressure monitoring with a lack of nocturnal BP fall (nondipping) have also been shown to be more closely associated with target organ damage and worsened cardiovascular outcome than in patients with essential hypertension with dipping pattern. The underlying pathogenetic mechanisms potentially linking nondipping with cardiovascular disease are not fully understood. There are multiple possible underlying pathophysiologic mechanisms in the impaired BP decline during the night. Extrinsic and intrinsic factors including abnormal neurohormonal regulation, lack of physical activity, nutritional factors such as increased dietary sodium intake, and smoking of tobacco have been implicated for blunted circadian rhythm of BP. Certain diseases such as diabetes and chronic renal diseases also affect the circadian BP rhythm. Currently, the clinical importance of nondipping is known well; however, the relationship between certain disease states and nondipping has not been fully explained yet. This paper will attempt to address to clarify the underlying basis for nondipping and the specific associations with various disease states.

Regional citrate anticoagulation in critically ill patients with liver and kidney failure.

BACKGROUND Regional citrate anticoagulation (RCA) is being used increasingly in critically ill patients who require continuous renal replacement therapy (CRRT). RCA may be avoided in patients with liver disease because of perceived increased risk of metabolic complications. The study compares the circuit lifespan and metabolic complications using RCA for CRRT at varying levels of liver dysfunction. METHODS Data was collected retrospectively including the number of days on CRRT, number of circuit (re)initiations within that time and serum ionized and total calcium, bicarbonate, and sodium, repeatedly during treatment. Model for end-stage liver disease (MELD) scores were calculated and patients were divided into 4 groups according to MELD score quartiles. RESULTS A total of 697 patients were included in the present study. The median circuit survival time was not different between groups. The median minimum serum ionized calcium levels during treatment were significantly lower in groups 3 and 4 (p<0.001), but by the last day of treatment, mean serum ionized calcium levels were not different between groups. The median minimum bicarbonate levels were significantly lower in groups 3 and 4 compared with groups 1 and 2 (p<0.01), but this is not considered clinically significant. The median maximum and mean serum bicarbonate levels were not significant between groups. Total to ionized calcium ratio levels were similar in groups 1, 2 and 3, but significantly higher in group 4 compared with other groups. CONCLUSION RCA is a reasonably safe form of anticoagulation for maintaining efficiency and patency of the dialyzer in critically ill patients with liver dysfunction.

Relation between Serum Thyroid Hormone and ‘Nondipper’ Circadian Blood Pressure Variability

Currently, the pathogenesis of nondipper hypertension remains largely unclear in patients without any renal or endocrine pathology. It is well known that overt hypothyroidism is strongly associated with diastolic hypertension. However, no study has addressed the pathogenic role of TSH, free T3 (FT3), and free T4 (FT4) in nondipper hypertension. The aim of the present investigation is to evaluate if higher TSH, low FT3 and FT4 would be associated with a nondipper hypertension profile, in patients with normal renal function and without any overt thyroid hormone disorder. 131 subjects were screened and those who met the following inclusion criteria were enrolled: (1) glomerular filtration rate (GFR) >60 ml/min; (2) no history of thyroid disorders; (3) no history of thyroid hormone medication. All subjects underwent 24-hour ambulatory blood pressure monitoring on a usual working day. Of the total population, 59 patients (45%) were classified as dippers and 72 (55%) were classified as nondippers. The only significant differences between dipper and nondipper patients appear to be related to FT3 levels and GFR. Nondipper patients had lower FT3 levels (4.5 ± 0.6 vs. 4.0 ± 0.9 pmol/l, p = 0.02) and low GFR (80.5 ± 12.2 vs. 86.9 ± 16.9 ml/min, p = 0.03), compared to dipper patients. The final regression model included serum TSH, FT3 levels, and GFR; the only independent predictor of nondipper hypertension was FT3 (p = 0.04). In conclusion, even if the mechanisms of our findings remain incompletely understood, we demonstrate a graded independent relation between lower level of FT3 and the risk of nondipping. Further studies are warranted to confirm this relationship and to elucidate the pathogenetic mechanisms of this relationship.

Comparison of effects of darbepoetin alfa and epoetin alfa on serum endothelin level and blood pressure.

It is well known that epoetin alfa increases serum endothelin (ET)-1 and blood pressure. No data are available, however, on the effects of darbepoetin alfa on serum ET-1 and blood pressure. This study was conducted to compare the effects of darbepoetin alfa and epoetin alfa on serum ET-1 and blood pressure in patients on hemodialysis (HD). A total of 42 patients on HD were included in the study. Serum samples for measuring levels of ET-1 were taken 30 min after administration of epoetin alfa. After blood samples had been taken from all patients, epoetin alfa was changed to darbepoetin alfa. Three months after the start of darbepoetin alfa treatment, blood samples were taken to measure the same parameters. Mean arterial blood pressure was measured before recombinant human erythropoietin (EPO) administration and 30 min after EPO administration while patients were taking epoetin alfa or darbepoetin alfa. Injection of epoetin alfa or darbepoetin alfa significantly increased serum ET-1 levels compared with levels in those patients who were not on EPO therapy (P < .05). When the effects of epoetin alfa on serum ET-1 level were compared with those of darbepoetin alfa, the 2 types of EPO were found to increase serum ET-1 levels similarly (P > .05). Administration of epoetin alfa or darbepoetin alfa increased systolic and diastolic blood pressures significantly over values in the control group (P < .05). Serum systolic and diastolic blood pressures increased similarly after injection of epoetin alfa or darbepoetin alfa. Administration of darbepoetin alfa increased blood pressure in patients on HD in a way that was positively correlated with enhanced ET-1 release; a similar correlation was noted with epoetin alfa.

Oral β-Glucan Protects Kidney against Ischemia/Reperfusion Injury in Rats

Background: Ischemia-reperfusion (I/R) injury is one of the leading causes of acute renal failure. β-(1→3)-Glucans are glucose polymers with a variety of stimulatory effects on the immune system. We designed this study to determine the possible protective effect of the orally administered soluble β-glucan against I/R injury. Methods: 30 rats were randomly divided into 5 experimental groups (control, sham operated, β-glucan, I/R and I/R+β-glucan groups, n = 6 each). β-Glucan was administered orally to 6 rats of the β-glucan and I/R+β-glucan groups. The rats were subjected to bilateral renal ischemia followed by reperfusion in the I/R and I/R+β-glucan groups. All of the rats were then sacrificed and kidney function tests, serum and tissue oxidants and antioxidants were evaluated. Results: The serum urea and cystatin C levels were significantly higher in the I/R group compared to the I/R+β-glucan group (p < 0.01). The serum and tissue antioxidant markers (SOD, GSH-Px) were significantly lower in the I/R group than the I/R+β-glucan group (p < 0.01). The serum oxidant markers (NO and PC) were significantly higher in the I/R group than the I/R+β-glucan group (p < 0.01). Conclusion: Based on the present data, we conclude that increased antioxidants and decreased oxidants modulated by β-glucan attenuated the renal I/R injury.

Relation between Serum Calcium, Phosphate, Parathyroid Hormone and ‘Nondipper’ Circadian Blood Pressure Variability Profile in Patients with Normal Renal Function

Background and Aims: In patients with renal disease, an association between abnormal circadian blood pressure profile and abnormalities in bone and mineral metabolism, including vascular calcifications, is well known. However, such a link has not yet been reported in hypertensive patients with normal renal function. We aimed to evaluate if higher serum phosphate, calcium, parathyroid hormone (PTH) level and the calcium×phosphate (Ca×P) product would be associated with a nondipper hypertension, in patients with normal renal function and without any PTH disorder. Methods: 190 hypertensive subjects with the following inclusion criteria were enrolled: (1) normal phosphate and PTH levels; (2) glomerular filtration rate (GFR) >60 ml/min, and (3) no history of calcium, phosphate, vitamin D medication and hyperparathyroidism. Results: Of the total population, 76 patients (40%) were classified as dippers and 114 (60%) as nondippers. Nondipper patients had higher levels of phosphate (3.70 ± 0.61 vs. 3.35 ± 0.44 mg/dl, p = 0.001), Ca×P product (35.4 ± 6.5 vs. 31.5 ± 5.0, p = 0.001) and PTH (75.7 ± 28.8 vs. 46.6 ± 17.1 pg/ml, p = 0.000) compared to dipper patients. Independent predictors (multiple regression) for nondipper hypertension were PTH (β = 0.43, p = 0.001) and phosphate (β = 0.9, p = 0.03). Conclusion: We demonstrate a graded independent relation between higher levels of phosphate, PTH, Ca×P product and the risk of nondipping in hypertensive patients with an estimated GFR of >60 ml/min and normal mineral metabolism.