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PubMed2006

mRNA expression of target genes in the urinary sediment as a noninvasive prognostic indicator of CKD.

BACKGROUND: Study of messenger RNA (mRNA) expression of target genes in urinary sediment was suggested as a noninvasive marker of renal damage in patients with chronic kidney diseases (CKDs). We studied the relationship between urinary mRNA expression of target genes and risk for renal function deterioration in patients with CKD. METHODS: We studied 131 patients with CKD with kidney biopsy. mRNA expression of 11 target genes in urinary sediment was measured by means of quantitative polymerase chain reaction. Patients then were followed up for 27.4 +/- 10.1 months. The primary end point is doubling of serum creatinine concentration or end-stage renal disease. RESULTS: Thirty-six patients (27.5%) reached the primary end point during follow-up. Univariate analysis showed that sex, age, proteinuria, estimated glomerular filtration rate, histological diagnosis, degree of tubulointerstitial scarring, percentage of glomerulosclerosis, and urinary mRNA expression of hepatocyte growth factor (HGF) were predictors of the primary end point. At 24 months, event-free survival rates were 90.9% and 64.3% for patients with low and high urinary HGF expression, respectively (log rank test, P = 0.002). After adjusting for other confounding factors by using a Cox proportional hazard model, urinary HGF expression remained an independent predictor of the primary end point, and a 1-fold increase in expression was associated with a 4.0% (95% confidence interval, 0.5 to 7.5; P = 0.024) increase in risk. CONCLUSION: In the target genes examined, urinary HGF expression is an independent prognostic indicator of CKD after adjusting for confounding clinical and histological factors. Measurement of urinary HGF mRNA expression may be a useful noninvasive tool for risk stratification of patients with CKD.

Biopsy↗
PubMed2006

A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD.

BACKGROUND: AST-120 (Kremezin; Kureha Chemical Industry Co Ltd, Tokyo, Japan) is an orally administered adsorbent showing adsorption ability superior to activated charcoal for certain organic compounds known to be precursors of substances that accumulate in patients with chronic kidney disease (CKD) and that are believed to accelerate the decline in kidney function. AST-120 is approved in Japan for prolonging time to hemodialysis therapy and improving uremic symptoms in patients with CKD. METHODS: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was designed to examine the nephroprotective effects of 3 doses of AST-120 versus placebo in adult patients with moderate to severe CKD and elevated serum indoxyl sulfate levels while following an adequate protein-intake diet. Eligible patients were randomly assigned to 1 of 3 doses of AST-120 (0.9, 2.1, or 3.0 g) or placebo 3 times daily for 12 weeks. RESULTS: AST-120 decreased serum indoxyl sulfate levels in a dose-dependent fashion. During the 12-week treatment period, AST-120 did not affect serum creatinine levels or 24-hour urine creatinine appearance. Significant improvements in malaise were observed in a dose-dependent fashion. All doses of AST-120 were well tolerated and did not adversely affect the general health status of patients. CONCLUSION: Results suggest that the dose of 3 g 3 times daily is an optimal dose for the US population, and it may be useful in the treatment of patients with CKD. Because AST-120 did not directly affect serum creatinine levels or 24-hour urine creatinine appearance, the composite end point of doubling of serum creatinine level, transplantation, and dialysis therapy would be appropriate for a confirmatory phase III therapeutic outcome study.

Adult↗
PubMed2006

Long-term treatment with EPO increases serum levels of high-density lipoprotein in patients with CKD.

BACKGROUND: Among lipid abnormalities observed in patients with chronic kidney disease (CKD) is a significant decrease in serum high-density lipoprotein cholesterol (HDL-C) levels. In a previously published randomized control trial, we showed that early erythropoietin (EPO) administration in a predialysis population slowed the progression of CKD. In the present nested substudy, we examine whether EPO has an influence on serum HDL-C levels in comparison to other lipid parameters in this population. METHODS: Eighty-eight patients with CKD stages 3 and 4 were enrolled in the study. Forty-five patients (group 1) were treated with EPO (50 U/kg/wk), targeting to increase hemoglobin levels to 13 g/dL or greater (>or=130 g/L). The other patients (group 2) remained without treatment until hemoglobin levels decreased to less than 9 g/dL (<90 g/L). The duration of the study was 12 months. RESULTS: At the end of the study, we observed a statistically significant decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides in both groups. However, serum HDL-C levels significantly increased in only group 1 (from 42.5 +/- 10.4 to 55.9 +/- 8.1 mg/dL [1.10 +/- 0.27 to 1.45 +/- 0.21 mmol/L]; P < 0.001), whereas they were unchanged in group 2. In addition, a significant decrease in atherogenic LDL-C/HDL-C ratio was observed in only group 1. Importantly, the increase in serum HDL-C levels correlated positively with the increase in hemoglobin values in EPO-treated patients. CONCLUSION: Our results show that EPO treatment of predialysis patients with CKD significantly increases serum HDL-C levels, which may represent an important antiatherogenic effect of this hormone.

Adult↗
PubMed2006

J-shaped mortality relationship for uric acid in CKD.

BACKGROUND: Hyperuricemia is a common feature in patients with chronic kidney disease (CKD). Hyperuricemia has been associated with increased cardiovascular mortality in the general population, but less is known about this association in patients with CKD. METHODS: To explore possible associations of serum uric acid with all-cause mortality and comorbidity in patients with CKD, we studied 294 incident patients with CKD stage 5 (185 men; age, 53 +/- 12 years) starting renal replacement therapy with a median glomerular filtration rate of 6.4 mL/min/1.73 m(2) (0.11 mL/s/1.73 m(2); range, 0.8 to 14.3 mL/min/1.73 m(2) [0.01 to 0.24 mL/s/1.73 m(2)]). Survival was determined from the day of examination and during a mean follow-up period of 27 months (range, 3 to 72 months); 94 patients died. Patients were divided into 3 groups based on serum uric acid levels (low quintile, 3 middle quintiles, and high quintile). RESULTS: In a nonadjusted analysis, patients in the high quintile, followed by patients in the low quintile, had greater all-cause mortality compared with patients in the 3 middle quintiles (log-rank test chi-square, 6.8; P = 0.03). After adjusting for age, sex, glomerular filtration rate, cholesterol level, phosphate level, C-reactive protein level, cardiovascular disease, diabetes mellitus, diuretics, and allopurinol treatment, the association showed a "J-shaped" association with hazard ratios of 1.96 (confidence interval, 1.10 to 3.48; P = 0.02) for the high quintile and 1.42 (confidence interval, 0.76 to 2.66; P = not significant) for the low quintile. Moreover, uric acid levels correlated positively with levels of triglycerides, phosphate, C-reactive protein, and intracellular adhesion molecule 1 and negatively with levels of calcium, high-density lipoprotein cholesterol, and apolipoprotein A. CONCLUSION: Serum uric acid levels showed a J-shaped association with all-cause mortality, with the lowest risk in the 3 middle quintiles. Moreover, uric acid level was associated with calcium/phosphate metabolism, dyslipidemia, and inflammation.

Adult↗
PubMed2006

Changes in fat mass correlate with changes in soluble sCD163, a marker of mature macrophages, in patients with CKD.

BACKGROUND: Recently, adipose tissue was shown to contain macrophages capable of contributing to systemic inflammation and cardiovascular disease (CVD). Here, we investigate this putative relationship in patients with chronic kidney disease (CKD) by using the novel macrophage marker soluble (s)CD163. METHODS: One hundred twenty patients with CKD stage 5 (mean glomerular filtration rate [GFR], 7 +/- 1 mL/min [0.12 +/- 0.02 mL/s; mean age, 53 +/- 1 years; 65% men), 38 patients with CKD stages 3 to 4 (mean GFR, 33 +/- 3 mL/min [0.55 +/- 0.05 mL/s]; mean age, 67 +/- 2 years; 68% men), and 28 healthy controls (mean GFR, 89 +/- 3 mL/min [1.48 +/- 0.05 mL/s]; mean age, 63 +/-2 years; 69% men) were characterized post hoc with a follow-up of up to 5 years (mean, 47 +/- 1 months). sCD163 levels, body composition (dual-energy x-ray absorptiometry), clinical parameters, and levels of circulating inflammatory markers (enzyme-linked immunosorbent assay) were assessed at baseline and, in a subset population, after 1 year of dialysis therapy (hemodialysis, n = 19; peritoneal dialysis, n = 30). RESULTS: sCD163 level increased in patients with both severe (median, 4.3 mg/L; range, 1.3 to 23.4 mg/L) and moderate (median, 3.6 mg/L; range, 1.6 to 9.8 mg/L) CKD compared with controls (median, 2.6 mg/L; range, 0.8 to 7.6 mg/L; P < 0.001). Furthermore, sCD163 levels correlated with both truncal (rho = 0.17; P < 0.05) and total (rho = 0.17; P < 0.05) fat mass, as well as with all measured markers of inflammation and endothelial adhesion molecules. After 1 year, patients who increased body fat mass (average, 11% +/- 5% versus -5% +/- 5%; P < 0.05) also showed a significant increase in sCD163 levels (median, 2.2 versus -0.97 mg/L; P < 0.01). Finally, patients with sCD163 levels greater than 4.0 mg/L had a statistically significantly worse outcome than patients with sCD163 levels less than this value, even after adjustment for age, sex, and diabetes mellitus (chi-square = 19.98; P < 0.001). However, this effect was lost after adjustment for either inflammation or CVD. CONCLUSION: We show that increasing fat mass is associated with increasing levels of sCD163, a circulating marker of macrophages also associated with inflammatory biomarkers. We thus hypothesize that adipose tissue macrophages may have a role in the proinflammatory state observed in patients with renal disease. Finally, we propose the term "uremic-metabolic syndrome" to describe this state of increased adipose tissue signaling in patients with uremia, a phenomenon that may share some characteristics with the metabolic syndrome of obesity.

Adipose Tissue↗
PubMed2005

Patterns of medication use in the RRI-CKD study: focus on medications with cardiovascular effects.

BACKGROUND: Patients with chronic kidney disease (CKD) stages 2-5 are known to suffer numerous complications and co-morbidities associated with kidney disease. The medication prescription patterns in this population are not well understood. We report on prescription data collected as part of a multicentre longitudinal study in patients with CKD, with a focus on medications with cardiovascular or cardioprotective effects. METHODS: Patients were recruited from four academic nephrology centres in the USA, with patient recruitment from June 2000 to March 2002. Medication data were captured at the time of first enrollment into the study. Individual medications were classified into medication groups, and those with predominant cardioprotective effects or for prevention of progression of kidney disease (e.g. medications for treatment of anaemia, lipid-lowering agents, antihypertensives, statins, etc.) were recorded for analysis. Descriptive statistics were used for medication prescription according to baseline demographics and co-morbidities. Predictors of epoetin and iron use were determined by logistic regression adjusting for age, race, sex, diabetes, glomerular filtration rate (GFR), haemoglobin and serum albumin. RESULTS: Medication data were available for 619 patients with stages 2-5 CKD. Patients were 60.6+/-16.0 years of age, and were prescribed 8+/-4 (range 1-28) medications. Overall, the proportion of patients prescribed different classes of medications included epoetin (20%), intravenous iron (13%), HMG-CoA reductase inhibitors (16%), angiotensin-converting enzyme (ACE) inhibitors (44%), angiotensin receptor blockers (13%), beta-blockers (46%), calcium channel blockers (52%) and aspirin (37%). There was a low use of epoetin (45%) and iron (20%) in patients with anaemia. Only 24% of patients with coronary artery disease were prescribed statins, and ACE inhibitors and angiotensin receptor blockers were used in only 58 and 23% of diabetic patients with proteinuria. Positive predictors of epoetin and iron therapy included white race and diabetes. Higher GFR and higher serum albumin were associated with lower odds of being prescribed epoetin. White race and diabetics were more likely to be prescribed iron. CONCLUSIONS: This study provides an overview of prescription practices in a cohort of CKD patients. Substantial underutilization of certain classes of cardioprotective medications is apparent, and systematic educational efforts in this direction may well prove worthwhile to impact outcomes.

Aged↗
PubMed2005

The validity of searching routinely collected general practice computer data to identify patients with chronic kidney disease (CKD): a manual review of 500 medical records.

BACKGROUND: We conducted a search of 12 practices' routinely collected computer data in three localities across the UK and found that 4.9% of the registered population had an estimated glomerular filtration rate (GFR) of <60 ml/min/1.73 m(2) (equivalent to stages 3-5 CKD). Only 3.6% of these were known to have renal disease. Although UK general practice is computerized, important clinical data might be recorded in letters or free-text computer entries and might therefore be invisible to the standard computer search tools. We therefore manually searched through all the records of patients with stages 3-5 CKD in one practice, to test the validity of the computer generated diagnosis and to see if other relevant information was missed by the computer search. METHODS: We identified 492 people with stages 3-5 CKD using computer searching and then manually searched their computer records and written notes for any missed data. The dataset included cardiovascular morbidities and risk factors including diabetes; drugs which may impair renal function; known renal disease; and terminal diagnoses and dementia. RESULTS: The manual searches only added four renal diagnoses to the 36 already identified. Although heart failure and stroke appear to be over-estimated by computer searches, other cardiovascular diagnoses were reliably recorded. Cardiovascular risk factors and drug recording is a strength of general practice computer data. It is complete and contemporary, though most patients had scope to have their cardiovascular risk reduced further. Eighty-four percent had a haemoglobin estimation, and a higher proportion with reduced renal function were anaemic (P<0.001). Testing for proteinuria was less well recorded; negative stick tests were not recorded. Clinical diagnoses of prostatism and bladder outflow problems made these data hard to interpret. CONCLUSIONS: Automated searching of general practice computer records could provide a reliable and valid way of identifying people with stages 3-5 CKD who could benefit from interventions readily available in primary care.

Adult↗
PubMed2005

Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD).

BACKGROUND: The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important. METHODS: In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls. RESULTS: There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04). CONCLUSION: These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

Animals↗
PubMed2005

A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD.

BACKGROUND: Although iron deficiency frequently complicates anemia in patients with nondialysis-dependent CKD (ND-CKD), the comparative treatment value of IV iron infusion and oral iron supplementation has not been established. METHODS: In a randomized, controlled multicenter trial, we compared the efficacy of iron sucrose, given as 1 g in divided IV doses over 14 days, with that of ferrous sulfate, given 325 mg orally thrice daily for 56 days in patients with ND-CKD stages 3 to 5, Hb < or =11 g/dL, TSAT < or =25%, and ferritin < or =300 ng/mL. Epoetin/darbepoetin therapy, if any, was not changed for eight weeks prior to or during the study. RESULTS: The proportion of patients achieving the primary outcome (Hb increase > or =1 g/dL) was greater in the IV iron treatment group than in the oral iron treatment group (44.3% vs. 28.0%, P= 0.0344), as was the mean increase in Hb by day 42 (0.7 vs. 0.4 g/dL, P= 0.0298). Compared to those in the IV iron group, patients in the oral iron treatment group showed a greater decline in GFR during the study (-4.40 vs. -1.45 mL/min/1.73m2, P= 0.0100). No serious adverse drug events (ADE) were seen in patients administered IV iron sucrose as 200 mg IV over two to five minutes, but drug-related hypotension, including one event considered serious, occurred in two females weighing less than 65 kg after 500 mg doses were given over four hours. CONCLUSION: IV iron administration using 1000 mg iron sucrose in divided doses is superior to oral iron therapy in the management of ND-CKD patients with anemia and low iron indices.

Administration, Oral↗
PubMed2005

Predictive cardiovascular risk factors in patients with chronic kidney disease (CKD).

BACKGROUND: Traditional cardiovascular risk factors and uremia-related specific factors have been identified in patients with CKD, explaining the highest risk for morbidity and mortality from cardiovascular disease. The aim of this study was to analyze the predictive power of several cardiovascular risk factors and markers in a population of stable patients with moderate CKD. METHODS: One hundred twenty-eight (78 M, 50 F) outpatients with estimated glomerular filtration rate (GFR) <60 mL/min were included in the study. Medical records about cardiovascular factors were recorded. Analytical parameters and cardiac markers were analyzed. The patients were prospectively followed, and the end points were fatal and nonfatal cardiovascular events. RESULTS: After a mean follow-up of 22.3 months, 27 patients had a cardiovascular event. The patients who suffered a cardiovascular event were older (P= 0.002), with more anemia (P= 0.014), higher pulse pressure (P= 0.011), and cTnT levels (P= 0.000). In addition, they had more prevalence of LVH (P= 0.001), diabetes (P= 0.013), previous coronary heart disease (P= 0.008), chronic heart failure (P= 0.000), vascular peripheral disease (P= 0.006), and had also a higher score of 10-year coronary heart disease predicted risk (P= 0.006). Age [hazard ratio (HR) 1.07, P= 0.02], previous coronary artery disease (HR 4.08, P= 0.0012), and cTnT levels (HR 1.64, P= 0.0000) independently predicted cardiovascular events on multivariate Cox analysis. CONCLUSION: In stable patients with CKD, age and previous coronary artery disease were the traditional cardiovascular risk factors more predictive for cardiovascular events. Cardiac troponin T is a powerful marker of cardiovascular events in CKD patients.

Aged↗
PubMed2026

Metabolomic Responses to Oral Glucose Tolerance Test and Hyperinsulinemic-euglycemic Clamp in CKD.

BACKGROUND: The oral glucose tolerance test (OGTT) captures integrated physiological responses involving intestinal glucose absorption, incretin signaling, and endogenous insulin secretion, whereas the hyperinsulinemic-euglycemic clamp (clamp) isolates insulin-mediated glucose uptake. Comparing plasma metabolomic responses to these two challenges may identify processes specific to intestinal nutrient delivery and how they vary in CKD. METHODS: Targeted plasma metabolomics was performed in 59 adults without diabetes (39 with CKD [eGFR <60 mL/min/1.73 m2] and 20 controls) from the Study of Glucose and Insulin in Renal Disease (SUGAR). Each participant underwent a 75-g OGTT and clamp approximately one week apart. Eighty-eight plasma metabolites were quantified at fasting and during each challenge. Metabolite levels were log-transformed and normalized using Systematic Error Removal Using Random Forest (SERRF). Metabolites were classified using adjusted regression slopes relating OGTT and clamp responses. RESULTS: The mean (SD) age and eGFR were 64 (13) years and 54 (26) mL/min/1.73 m2, respectively, and 41% were female. In the overall cohort, OGTT and clamp induced broad plasma metabolic changes, with 63 (72%) and 76 (86%) metabolites significantly altered from fasting, respectively. Seventy-three metabolites (83%) demonstrated a significant relationship between OGTT and clamp responses. Of these, 22 (25%) exhibited true concordance and 51 (58%) demonstrated similar directional changes but differed in magnitude. A total of 15 (17%) metabolites were discordant or non-corresponding, of which only three were discordant. The non-corresponding metabolites were enriched in amino acid metabolism. Eleven metabolites (13%) demonstrated differential responses between OGTT and clamp by CKD status, involving amino acid and glucose metabolism pathways. CONCLUSIONS: Metabolomic responses to OGTT and clamp were largely directionally concordant but differed in magnitude, with attenuation during OGTT. Discordant metabolites were rare, while non-corresponding metabolites were confined to amino acid pathways. CKD modified OGTT-clamp correspondence for metabolites involved in amino acid and glycolytic metabolism.

Journal Article↗
PubMed2002

Anemia in CKD: prevalence, diagnosis, and treatment. Case study of the anemic patient.

A point-in-time observational study was conducted in over 1,000 nephrology offices between November 1999 and December 2000 to determine the prevalence of anemia in patients with chronic kidney disease (CKD). Trends in hemoglobin (Hb) and serum creatinine (SCr) levels were assessed among 4,831 evaluable patients to determine the relationship between renal function and anemia. Results demonstrated that anemia is common in patients with CKD, with progressive increases in prevalence and severity as renal function deteriorates. Overall, 26.3% of these patients had Hb levels below 10 g/dL, 46.7% had Hb levels below 11 g/dL, and 63.9% had Hb levels below 12 g/dL. Despite the high percent of patients with anemia, only 31.3% were being treated for this condition. These data suggest that anemia is prevalent and undertreated in patients with CKD. Nephrology nurses can be influential in providing proactive management of anemia throughout the spectrum of CKD to improve anemia-related outcomes.

Aged↗
PubMed2005

4-Week repeated intravenous dose toxicity study of a new camptothecin anticancer agent CKD-602 in dogs.

CKD-602 is a new camptothecin derivative antitumor agent with a formula (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin) developed by Chong Kun Dang Pharmaceutical Company in Korea. In the present study, the subacute toxicity of CKD-602 was investigated after 4-week repeated intravenous administration of the test chemical in beagle dogs. The test chemical was administered intravenously at dose levels of 0, 0.001, 0.005, or 0.01 mg/kg/day for 4 weeks to male and female dogs (n = 3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. In the high dose group, an increase in the incidence of abnormal clinical signs and a decrease in food and water intake and body weight gain were observed in both sexes. Hematological investigations revealed decreased white blood cells (WBC) in both sexes and reduced red blood cells (RBC), hemoglobin and hematocrit in females. Histopathological examinations revealed an increase in the incidence of atrophy of the sternal and femoral marrow and spleen in both sexes and atrophy of the thymus and mesenteric lymph node in males. No treatment-related adverse effects were observed in both sexes of the low and middle dose groups. In conclusion, the 4-week repeated intravenous dose of CKD-602 to beagle dogs caused increases in the clinical signs and histopathological changes, and decreases in the body weight gain, food and water intake, RBC, hemoglobin, hematocrit and WBC at the dose level of 0.01 mg/kg/day. In the present experimental conditions, the target organs were determined to be bone marrow, blood cells, spleen, thymus, and mesenteric lymph node. The no-observed-adverse-effect levels (NOAEL) for males and females were considered to be 0.005 mg/kg/day, respectively.

Animals↗
PubMed2006

Management of vascular calcification in CKD patients.

Vascular calcification is common in patients with chronic kidney disease (CKD) and it may affect almost every artery. It is associated with a significant increase in morbidity and mortality. Therefore, the detection, prevention and treatment of vascular calcification in CKD patients are critical for the overall approach for the management of these patients. Hyperphosphatemia, especially when the blood levels of serum phosphorus are above 5.5 mg/dl, plays a major role in the development of vascular calcification. Hyperphosphatemia induces vascular calcification by both passive and active processes. By increasing calcium-phosphate product, hyperphosphatemia results in direct deposition of calcium salts in the arteries and in cardiac valves. The active process involves the uptake of phosphate by the smooth muscle cells of the arteries by a Na-P co-transporter. This increase in cell phosphate then induces phenotypic changes of these cells, rendering them into osteoblasts which in turn, begin laying calcium salts in the arterial walls. Therefore, it is critical that the blood levels of serum phosphorus be maintained below 5.5 mg/dl in CKD patients. Inflammation and the production of C-reactive protein (CRP) and interleukin 6 are also risk factors for vascular injury and vascular calcification. In a study of 254 dialysis patients with elevated blood levels of CRP (>1.0 mg/l) and 258 patients with CRP levels equal to or less than 1.0 mg/l, it was found that higher levels of CRP are significantly associated with the presence of both atheromatous and medial calcification of the aorta and hand arteries. Also, it was reported that a significant association between CRP levels and cardiac valves calcification in patients undergoing continuous ambulatory peritoneal dialysis. The reasons for the elevation in CRP in dialysis patients are not clear, but certainly, is more evident in those with obvious inflammatory processes. Therefore, any inflammation that is detected should be treated appropriately.

Calcinosis↗
PubMed2006

Evaluation of the toxic potentials of a new camptothecin anticancer agent CKD-602 on fertility and early embryonic development in rats.

This study examined the potential adverse effects of a new camptothecin anticancer agent, CKD-602, on the fertility and early embryonic development of Sprague-Dawley rats. Ninety-six rats of each gender were divided into four groups: three treatment groups and a control group. CKD-602 was administered intravenously to male rats at 0, 4.7, 14, and 42 microg/kg from 63 days prior to mating until the end of the mating period, and to female rats from 14 days before mating until day 6 of gestation. All the males were sacrificed after the end of the 14-day mating period, while all the females were subjected to a caesarean section on day 15 of gestation. In the high dose group, a high incidence of hair loss was observed in both genders. A decrease in the level of food consumption, followed by a decrease in body weight gain was also observed in both genders. At the scheduled necropsy, the gross postmortem examinations revealed an increase in the incidence of thymic atrophy, paleness of the thoracic and abdominal organs in both genders and an increase in the serum testosterone concentration. In addition, there was a decrease in the thymus weight of the males and an increase in the liver, spleen, kidneys, lung, and heart weights of the females. There was an increase in the number of fetal deaths and post-implantation losses as well as a decrease in the litter size found at the caesarean section of the dams. No treatment-related effect on the histopathological findings, sexual cycle, pre-coital time, mating index, fertility index, pregnancy index, and sperm parameters was observed. There were no adverse effects on the general findings and reproductive performance of the parent animals and early embryonic development in the low and medium dose groups. Overall, the no-observed-adverse-effect levels (NOAELs) of CKD-602 are believed to be 14 microg/kg for both general toxicity and early embryonic development, and more than 42 microg/kg for the reproductive performance of the parent animals.

Abnormalities, Drug-Induced↗
PubMed2003

Simple and sensitive determination of the new antitumor drug CKD-602 in human plasma by liquid chromatography.

A simple and sensitive high-performance liquid chromatographic with fluorescence detection method has been developed and validated for the determination of the new antitumor agent CKD-602 in human plasma. Plasma proteins were precipitated with methanol and the samples were acidified with 7% (v/v) perchloric acid. The supernatants were analyzed by HPLC using a Capcell Pak C(18) UG120 column and a mixture of methanol-0.1 M hexane-1-sulfonic acid in methanol-0.01 M TEMED in water at pH 6.0 (40:1:59, v/v) as the mobile phase. The lower limit of quantification was 0.2 ng/ml using 200 microliter plasma samples. Mean within-run precision and between-run precision at six tested concentrations (0.2-400 ng/ml) were </=10% and mean accuracy was </=15%. Stability studies showed that CKD-602 is stable in both plasma and methanol extracts for at least 3 months at -30 degrees C. The described method was used for the pharmacokinetic analysis of CKD-602 during clinical phase I studies, in patients with solid tumors.

Antineoplastic Agents↗
PubMed2005

Subcutaneous terbutaline use in CKD to reduce potassium concentrations.

BACKGROUND: Acute hyperkalemia is a frequent and potentially life-threatening medical problem in patients on maintenance hemodialysis therapy. beta-Adrenergic receptor (betaAR) stimulation causes potassium cellular influx and a decline in plasma potassium concentrations. Therefore, betaAR agonists are used in the treatment of patients with hyperkalemia. The goal of this study is to evaluate the utility of weight-based subcutaneous terbutaline dosing to reduce plasma potassium concentrations in a group of subjects with chronic kidney disease (CKD) requiring hemodialysis. METHODS: Fourteen subjects with CKD receiving long-term hemodialysis were administered terbutaline, 7 microg/kg, subcutaneously. Heart rate measurements and blood samples for potassium concentration determinations were made serially for 420 minutes. Effects of terbutaline on heart rate and potassium responses were determined in each subject. RESULTS: Terbutaline significantly reduced plasma potassium concentrations and significantly increased heart rates during the time course of the study (P < 0.001, repeated-measures analysis of variance). Mean reduction in peak potassium concentration (-1.31 +/- 0.5 [SD] mEq/L) and increase in peak heart rate (25.8 +/- 10.5 beats/min) were significantly different from baseline (P < 0.001, baseline versus peak for both responses). No subject reported significant adverse effects. CONCLUSION: Administration of subcutaneous terbutaline obviates the need for intravenous access and should be considered as an alternative to nebulized or inhaled beta-agonists to treat acute hyperkalemia in patients with CKD. As with the use of any beta-adrenergic agonist, close cardiovascular monitoring is necessary to avoid or minimize toxicity during therapy.

Adrenergic beta-Agonists↗
PubMed2005

Management of hypertension in patients with CKD: differences between primary and tertiary care settings.

BACKGROUND: Although most patients with moderate chronic kidney disease (CKD) are managed exclusively in primary care (PC), no data on blood pressure (BP) control in this setting are available. We compared hypertension management in patients with CKD followed up in PC and nephrology tertiary care (TC). METHODS: We studied hypertensive patients with estimated glomerular filtration rates (eGFRs) of 15 to 60 mL/min/1.73 m2 (0.25 to 1.00 mL/s) exclusively followed up for at least 1 year in PC (n = 259) or TC (n = 186). RESULTS: PC compared with TC patients were characterized by older age (73 +/- 10 versus 65 +/- 14 years; P < 0.0001), greater prevalences of previous cardiovascular events (59% versus 32%; P < 0.0001) and diabetes (36% versus 23%; P = 0.005), and slightly greater eGFRs (37 +/- 10 versus 34 +/- 11 mL/min/1.73 m2 ; P = 0.005). They showed higher BP levels (143 +/- 15/82 +/- 7 versus 136 +/- 18/78 +/- 11 mm Hg; P < 0.0001), with a lower prevalence of BP target (5.8% [95% confidence interval (CI), 2.9 to 8.6] versus 21.5% [95% CI, 15.6 to 27.4]; P < 0.0001). The risk for not achieving BP target in PC was 2.6 times greater, independently from age, sex, diabetes, and eGFR. Fewer antihypertensive drugs were prescribed in PC (1.9 +/- 1.1 versus 2.5 +/- 1.1; P < 0.0001). In both groups, inhibitors of the renin-angiotensin system were the most frequently prescribed drugs (>84%), followed by diuretics (50%). However, family physicians almost exclusively prescribed hydrochlorothiazide, whereas nephrologists preferentially prescribed furosemide, administered at a higher dose than in PC (47 +/- 41 versus 28 +/- 21 mg/d; P = 0.004). CONCLUSION: Control of CKD-related hypertension is significantly worse in PC despite a greater cardiovascular risk. Barriers to optimal BP control likely are represented by a low number of drugs and inadequate diuretic therapy.

Adult↗