Association of Circulating Osteoprotegerin Level with Blood Pressure Variability in Patients with Chronic Kidney Disease

Circulating osteoprotegerin (OPG) is a biomarker for cardiovascular complications that are closely related to chronic kidney disease (CKD). To investigate the association between circulating OPG level with long-term visit-to-visit blood pressure variability (BPV) in patients with pre-dialysis CKD, a total of 1855 subjects with CKD from stage 1 to pre-dialysis stage 5 from a prospective cohort were analyzed. Long-term visit-to-visit BPV was determined by average real variability (ARV), standard deviation (SD), and coefficient of variation (CoV) of systolic and diastolic blood pressure (SBP and DBP). ARV of SBP (Adjusted β coefficient 0.143, 95% confidence interval 0.021 to 0.264) was significantly associated with serum OPG level. Although SD and CoV of SBP were not significantly associated with serum OPG level in multivariate linear regression analyses, restricted cubic spline visualized the linear correlation of serum OPG level with all of ARV, SD, and CoV. The association between serum OPG level and DBP variability was not significant. Subgroup analyses revealed that the association of serum OPG with BPV is more prominent in the subjects with Charlson comorbidity index ≤3 and in the subjects without history of diabetes mellitus. In conclusion, circulating OPG level is potentially associated with long-term visit-to-visit BPV in patients with pre-dialysis CKD.ope

Relationship between Cardiac Geometry and Serum Hepcidin in Chronic Kidney Disease: Analysis from the KNOW-CKD Study

Background: Few studies have examined the relationship between cardiac function and geometry and serum hepcidin levels in patients with chronic kidney disease (CKD). We aimed to identify the relationship between cardiac function and geometry and serum hepcidin levels. Methods: We reviewed data of 1,897 patients in a large-scale multicenter prospective Korean study. Logistic regression analysis was used to identify the relationship between cardiac function and geometry and serum hepcidin levels. Results: The mean relative wall thickness (RWT) and left ventricular mass index (LVMI) were 0.38 and 42.0 g/m(2.7), respectively. The mean ejection fraction (EF) and early diastolic mitral inflow to annulus velocity ratio (E/e') were 64.1% and 9.9, respectively. Although EF and E/e' were not associated with high serum hepcidin, RWT and LVMI were significantly associated with high serum hepcidin levels in univariate logistic regression analysis. In multivariate logistic regression analysis after adjusting for variables related to anemia, bone mineral metabolism, comorbidities, and inflammation, however, only each 0.1-unit increase in RWT was associated with increased odds of high serum hepcidin (odds ratio, 1.989; 95% confidence interval, 1.358-2.916; P < 0.001). In the subgroup analysis, the independent relationship between RWT and high serum hepcidin level was valid only in women and patients with low transferrin saturation (TSAT). Conclusion: Although the relationship was not cause-and-effect, increased RWT was independently associated with high serum hepcidin, particularly in women and patients with low TSAT. The relationship between cardiac geometry and serum hepcidin in CKD patients needs to be confirmed in future studies.ope

Gentamicin induced apoptosis of renal tubular epithelial (LLC-PK1) cells

Nephrotoxicity is a major limiting factor in the use of aminoglycoside antibiotics, the mechanisms for which are still speculative. To clarify the mechanisms of renal tubular cell death induced by aminoglycosides, we examined the renal proximal tubule-like cell line, LLC-PK1, after inducing apoptosis through a chronic treatment with gentamicin (GM). Changes in the expression of the Fas were also investigated. On flow cytometric analysis, 5.7 +/- 3.3% of the control cells appeared in a region of decreased forward light scatter and increased side light scatter, where both indices represent the characteristics of apoptotic cell death. Compared to the control, treatment with 10 mM of GM for 15 days significantly increased the proportion of cells in the apoptotic region to 23.9 +/- 8.5%. This finding was supported by electrophoretic analysis of the DNA extracted from the GM-treated cells, where a series of bands corresponding to integer multiples of 180 to 200 base pairs was visualized. However, the 15-day GM treatment did not cause a significant elevation in the expression of the 45 kD Fas protein, the cell surface molecule that stimulates apoptosis, by Western blot analysis. In conclusion, long-term exposure to GM induces apoptosis of the renal tubular epithelial cells, and this process may contribute to some of the aminoglycoside nephrotoxicities. Further studies are needed on the mechanism(s) of apoptosis induced by GM.ope

Proper Use of Diuretics

Diuretics are among the most commonly used drugs. They primarily block active reabsorption of sodium at different sites in the nephron, thereby increasing urinary losses of NaCl and H2O. This ability to induce a negative fluid balance has made these drugs particularly useful in the treatment of a variety of conditions, edematous: congestive heart failure, nephrotic syndrome, liver cirrhosis, chronic renal failure, idiopathic edema, and nonedematous states: hypertension, hypercalcemia, nephrolithiasis, and syndrome of inappropriate antidiuretic hormone secretion. The diuretics are generally divided into three major classes, which are distinguished by the sites at which they impair the sodium reabsorption: loop diuretics at the thick ascending limb of the loop of Henle, thiazide-type diuretics at the distal tubule, and potassium-sparing diuretics at the cortical collecting tubule. The loop diuretics that are generally the most potent are furosemide, torasemide, and ethacrynic acid. The thiazide-type diuretics include chlorothiazide and metolazone. Spironolactone and amiloride are potassium-sparing diuretics. Diuretics should be started at an effective single dose and given intermittently with a subsequent increase in dose or frequency of administration. As a general rule, the rate of diuresis in an edematous patient should not exceed 1 to 2kg weight loss per day. In renal failure patients, loop diuretics at a higher than normal dose are required to get the desired diuretic effect because the diuretic excretion is often limited, in part due to the retention of organic anions. The patients with liver cirrhosis are responsive to spironolactone. After the administration of diuretics, even if a net diuresis is induced, the response is short-lived as a new steady state is rapidly established because the diuretic-induced sodium losses are counterbalanced by neuro-humorally mediated increases in tubular reabsorption at nondiuretic sensitive sites. This process is called compensatory antidiuresis or diuretic tolerance. Therefore sodium restriction is important when a patient is taking loop diuretics, and the concurrent use of a thiazide diuretic can inhibit downstream NaCl reabsorption, resulting in an exaggeration of diuresis. The most common side-effects are those encountered in virtually all the effective drugs: hypovolemia, hypokalemia and potassium depletion, hyperuricemia, and metabolic alkalosis. Other side-effects include hyperglycemia, hyperlipidemia, hyperuricemia, ototoxicity and sexual dysfunction. In addition, diuretics have the potential to increase the toxicity of several other agents. Nonsteroidal antiinflammatory drugs may antagonize the natriuretic effects of diuretics. The combination of potassium-sparing diuretics and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers may result in severe hyperkalemia.ope

The Causes of Early Death in End - stage Renal Disease Patients

Background : Despite improvements in dialysis care, the mortality of patients with end-stage renal disease(ESRD) remains high. Patients who die within the first 90 days after beginning dialysis are not included in mortality rates and may be absent from incidence count. Therefore, the identification of modifiable characteristics associated with the risk of death during the first 90 days of treatment could lead to improved survival during this interval. Methods : We performed a retrospective analysis in 986 patients(at least 1 year survival from initiating dialysis were 920 patients, and 66 patients died within 90 days after dialysis) who were initiated renal replacement therapy first at Yonsei Medical Center from Jan 1994 to Jun 1999. Results : The 1 year mortality rate of total patients was 10.4%, and early death rate was 6.9%. The mean survival duration was 28.9±23.0 days. Characteristics independently associated with increased risk of early death included older age, inflammation, nutritional impairment, more comorbid condition and previous history of cardiovascular disease at starting dialysis. But Diabetes was not increased early death rate. By multivariate logistic regression analysis, old age, combined comorbid conditions, especially malignancy and congestive heart failure, low serum album and elevated C-reactive protein level were the independent risk factors affecting early death. Other variables such as sex, dyslipidemia, hypertension and diabetes mellitus were not significant risk factors. The leading cause of death in early death group was infection rather than cardiovascular accidents. Conclusion : Proper treatment of infection and improved nutritional status by adequate predialytic managements may contribute to their prolonged survival on dialysis patients.ope

Serum uric acid is associated with coronary artery calcification in early chronic kidney disease: a cross-sectional study

Background: Although uric acid (UA) is regarded as a risk factor for cardiovascular disease, whether UA is an independent risk factor contributing to coronary artery calcification in chronic kidney disease (CKD) is not well known. We evaluated whether UA level is associated with coronary artery calcium (CAC) score in a predialysis CKD cohort. Methods: A total of 1,350 subjects who underwent coronary computed tomography as part of the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease were analysed. We conducted a logistic regression analysis to evaluate the association between UA and the presence of CAC. Results: CAC was detected in 705 (52.2 %) patients, and the level of UA was significantly higher in CAC > 0 patients. UA showed a positive relationship with CAC > 0 in age- and sex-adjusted logistic regression analysis (Odds ratio (OR) 1.11, 95 % confidence interval (CI) 1.04-1.19, P = 0.003). However, UA showed no association with CAC > 0 in multivariate analysis. Further analysis showed that UA showed a positive association with CAC > 0 only in estimated glomerual filtration rate (eGFR) > 60 ml/min/1.73 m2 (OR 1.23, 95 % CI 1.02-1.49, P = 0.036) but not in eGFR 30-59 ml/min/1.73 m2 (OR 0.92, 95 % CI 0.78-1.08, P = 0.309) or < 30 ml/min/1.73 m2 (OR 0.92, 95 % CI 0.79-1.08, P = 0.426). Conclusions: UA level was significantly associated with CAC in early CKD, but not in advanced CKD.ope

Association between serum osteoprotegerin level and renal prognosis in nondialysis patients with chronic kidney disease in the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease (the KNOW-CKD Study)

Background: Osteoprotegerin is an important regulator of bone metabolism and vascular calcification. The association between serum osteoprotegerin level and chronic kidney disease (CKD) progression has not been elucidated. We investigated the prognostic value of serum osteoprotegerin levels in nondialysis CKD patients. Methods: We analyzed 2,082 patients enrolled in the Korean Cohort Study for Outcomes in Patients with CKD between 2011 and 2016. Patients were divided into quartiles by their serum osteoprotegerin levels. The primary outcome was the occurrence of ≥1 of the following: dialysis initiation, kidney transplantation, a two-fold increase in serum creatinine level from baseline, or a 50% decrease in the estimated glomerular filtration rate (eGFR). Cox proportional hazard regression models were used to investigate the prognostic value of the serum osteoprotegerin level to CKD progression. Results: The median follow-up period was 48.9 months, and 641 patients (30.8%) experienced the primary outcome. The hazard ratio of serum osteoprotegerin for renal progression in the full extended Cox proportional hazard model was 1.064 (95% confidence interval, 1.041-1.088). Subgroup analyses by age, presence of diabetes, and eGFR showed significant results consistent with the overall analysis results. Conclusion: Serum osteoprotegerin level is independently associated with renal prognosis and could have prognostic importance in CKD progression.ope

Association of Body Weight Variability with Adverse Cardiovascular Outcomes in Patients with Pre-Dialysis Chronic Kidney Disease

To investigate the association of body weight variability (BWV) with adverse cardiovascular (CV) outcomes in patient with pre-dialysis chronic kidney disease (CKD), a total of 1867 participants with pre-dialysis CKD from Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) were analyzed. BWV was defined as the average absolute difference between successive values. The primary outcome was a composite of non-fatal CV events and all-cause mortality. Secondary outcomes were fatal and non-fatal CV events and all-cause mortality. High BWV was associated with increased risk of the composite outcome (adjusted hazard ratio (HR) 1.745, 95% confidence interval (CI) 1.065 to 2.847) as well as fatal and non-fatal CV events (adjusted HR 1.845, 95% CI 1.136 to 2.996) and all-cause mortality (adjusted HR 1.861, 95% CI 1.101 to 3.145). High BWV was associated with increased risk of fatal and non-fatal CV events, even in subjects without significant body weight gain or loss during follow-up periods (adjusted HR 2.755, 95% CI 1.114 to 6.813). In conclusion, high BWV is associated with adverse CV outcomes in patients with pre-dialysis CKD.ope

A Prospective Study of the Effect of Calcitriol Treatment according to Administration Route in CAPD Patients

To determine the optimal administration route of calcitriol in CAPD patients with secondary hyperparathyroidism, we conducted a prospective study on 33 patients who performed CAPD for more than 6 months an d whose intact parathyroid hormone(iPTH) level was higher than 250pg/mL. The patients were randomized into 3 groups:IP(n=11); 1.0μg of calcitriol once daily via intraperitoneal route by overnight retention with dialysate, SC(n=11); 1.0μg of calcitriol three times a week via subcutaneous route, and PO (n=11); 1.0μg of calcitriol three times a week by ingestion. 11 out of 33 patients(6 in IP, 4 in SC, and 1 in PO) dropped out during the 6-months study period, and 5 among the 6 patients in IP were due to recurrent peritonitis. Biochemical data including calcium, phosphorus, iPTH, alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin and 1,25(OH)2D3 were measured regularly, and the data of 22 patients who had completed the 6-months study were analyzed. There was a statistically significant decrease in iPTH level(pg/mL) in the three groups after 6-months calcitriol therapy(IP; 812.0±276.7 vs. 354.7±129.4, PO; 571.8±330.7 vs. 159.6±192.3, SC; 786.1±535.0 vs. 551.8±729.9, respectively, P<0.05), but there were no differences in the percentage of decrease in iPTH from baseline values among the three groups. Alkaline phosphatase, bone- specific alkaline phosphatase and osteocalcin also decreased significantly in all three groups(IP; 50.1±14.6, 33.5±11.6, 52.3±10.9% of baseline value; SC; 80.9±14.8, 67.4±20.80, 54.4±11.1% of baseline value; PO; 48.8±24.4, 36.6±23.5, 54.2±11.6% of baseline value, respectively, P<0.05), but they were not different with each other. Among 22 patients who completed the 6-months study, hypercalcemia(Ca≥10.5 mg/dL) occurred in 7 patients(31.8%). IP(2/5, 40%) and SC groups(5/7, 71.4%) had significantly higher incidence of hypercalcemia than PO group(0/10, 0%) (P<0.05). IP group(2/5, 40%) also experienced significantly higher incidence of hyperphosphatemia than SC(1/7, 14.3%) and PO groups(1/10, 10%). Peritonitis occurred significantly more in IP than in SC and PO groups(P<0.05). In conclusion, calcitriol treatment resulted in a significant decrement in iPTH levels in CAPD patients and no significant differences were noted in the iPTH-suppressive effect of calcitriol according to the administration route. Because of higher incidence of peritonitis and hypercalcemia in IP and SQ groups, oral ingestion may be the most optimal route for calcitriol treatment in CAPD patients with secondary hyperparathyroidism.ope

The Study on the Mechanism of Cyclosporine A Induced Apoptosis in Renal Tubular Epithelial Cells

A major limiting factor in the use of cyclosporine A (CsA) is nephrotoxicity, but the mechanisms of nephrotoxicity are not fully understood. In order to elucidate the pathogenesis of CsA tubulotoxicity, we examined mechanisms (DNA synthesis, necrosis and apoptosis) of cellular injury induced by CsA in cultured LLC-PK1 renal tubular cell line. The possible role of Fas antigen in the mediation of CsA-induced cell death and the hypothesis that CsA-mediated injury activates the glucose transporter GLUT1, a stress response gene in renal tubular cells were also investigated. CsA treatment for 24 hours in LLC-PK1 cells showed significantly decreased 3H-thymidine uptake in a dose dependent manner (0.1 μg/ml to 1 mg/ml), indicating that DNA damage is a sensitive indicator of CsA induced nephrotoxicity. A dose of 10 μg/ml CsA caused a significant increase in LDH release (M S.D., 11.0 3.0% vs 27.0 9.8, p＜0.05). On flow cytometric analysis, 9.9 4.2% of control cells appeared in a region of decreased forward light scatter and increased side scatter, respectively. Both indices representing characteristics of apoptotic cell death. Compared to control, treatment with 10 ng/ml of CsA for 24 hours significantly increased the proportion of cells in apoptotic region to 38.9 13.5%. This finding was supported by electrophoretic analysis of the DNA extracted from CsA-treated cells, where a series of bands corresponding to integer multiples of 180 to 200 base pairs was visualized. CsA (0.1 μg/ml) treatment for 24 hours was seen to cause a significant elevation in the expression of the 45 kD Fas protein by Western blot analysis. In addition, the exposure to CsA was also associated with an increase of GLUT1 protein levels up to 2.2 fold (mean) on Western blot analysis. In conclusion, CsA is directly toxic to tubular cells with inhibiting DNA synthesis and inducing cell death in the form of necrosis or apoptosis. Fas antigen-ligand system and glucose transporter GLUT1 may play roles in mediating CsA induced tubular cytotoxicity.ope