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Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: a systematic review.

BACKGROUND: Vascular calcification (VC) is a recognized process involved in senescence and atherosclerosis. Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are conditions associated with metabolic disorders related to soft tissue calcification. METHODS: We performed a systematic review of the literature confined to patients with CKD or ESRD with clinical observations of VC. Case reports of calciphylaxis were excluded. We identified 30 studies over 20 years: 11 prospective cohort, 7 cross-sectional, 11 case-control, and 1 retrospective cohort; n = 2918 subjects, mean age 51 years, 59% men and 41% women. Imaging methods used included: x-ray 43%, computed tomography 30%, ultrasound 17%, and other methods 10%. RESULTS: The most consistent determinants of VC were older age and dialysis vintage. Eight analyses determined a relationship between VC and measures of calcium-phosphate balance while 20 analyses specifically did not find such a relationship. Three studies suggested the degree of calcium loading, treatment with phosphate binders, or treatment with vitamin D analogues were related to VC. When taken into consideration, the lipid profile (primarily low high-density lipoprotein cholesterol, elevated triglycerides, elevated low-density lipoprotein, and elevated total cholesterol) were predictive factors in four analyses. CONCLUSIONS: VC is a common observation in CKD and ESRD and is mainly related to age, length of time on dialysis therapy, and possibly dyslipidemia. The calcium-phosphorus balance and its related treatments are likely not related to this unique form of vascular calcification. Further research into the determinants and potential treatments for vascular calcification is warranted.

Age Factors↗

Hyperhomocysteinemia in relation to plasma free amino acids, biomarkers of inflammation and mortality in patients with chronic kidney disease starting dialysis therapy.

BACKGROUND: Plasma levels of total homocysteine (tHcy) and free amino acids (AAs) are influenced by nutritional status in patients with chronic kidney disease (CKD), whereas the role of chronic inflammation is not clear. METHODS: In a cross-sectional analysis, fasting levels of plasma tHcy, total cysteine (tCys), AA, serum albumin (Alb), and several inflammation markers, including C-reactive protein (CRP), were analyzed in a cohort of 250 patients with CKD starting renal replacement therapy. Patients were followed up during a 4-year period to assess overall mortality in relation to basal tHcy level. RESULTS: Ninety-three patients (37%) with signs of inflammation (CRP > or = 1 mg/dL) had significantly lower levels of tHcy, tCys, and serum Alb than 157 noninflamed patients. tHcy and tCys levels correlated positively with serum Alb levels and negatively with CRP levels (rho = -0.24; P < 0.0001; rho = -0.15; P < 0.05, respectively) and other inflammation markers. tHcy and tCys correlated significantly with levels of several AAs. The presence of both inflammation and malnutrition was associated with lower tHcy levels than when malnutrition was present without inflammation. Multivariate analysis showed that serum Alb, CRP, plasma folate, and vitamin B12 levels were independently associated with tHcy levels after adjustment for other variables. tHcy, but not tCys, level was significantly greater in survivors than nonsurvivors, and Kaplan-Meier analysis showed that greater tHcy level was associated with better survival. CONCLUSION: Plasma tHcy and tCys levels are interrelated to plasma AA levels and were lower in patients with inflammation. Thus, inflammation may contribute to the reverse association between tHcy level and mortality in patients with CKD starting renal replacement therapy.

Amino Acids↗

Association of obesity with inflammation in chronic kidney disease: a cross-sectional study.

OBJECTIVE: As adipose tissue releases inflammatory cytokines, obesity is associated with elevated C-reactive protein (CRP) levels in the general population. We examined the cross-sectional association of body mass index (BMI) with CRP in patients with chronic kidney disease (CKD). DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Ninety-four CKD patients with varying levels of renal function seen at the University of Utah outpatient renal clinic were studied. METHODS: Data on demographics (age, gender, race), comorbidity (diabetes mellitus, hypertension, myocardial infarction/angina, cerebrovascular disease, peripheral vascular disease, and smoking) and anthropometry (height and weight) were obtained by patient interview and chart reviews. High-sensitivity CRP was measured by the N-latex assay on a BN II nephelometer. MAIN OUTCOME MEASURE: Risk factors of high CRP. RESULTS: In a multivariable logistic regression model, when compared with patients with a BMI < 25, the odds of CRP > 3.0 mg/L were 2.5-fold (95% CI, 1.02 to 5.99) higher in patients with BMI > or = 30. In a stepwise multiple linear regression model, BMI (regression coefficient [beta] = 0.06; 95% CI, 0.03 to 0.1; P < .01), serum creatinine (beta = 0.16; 95% CI, 0.04 to 0.3; P = .01) and age (beta = 0.01; 95% CI, -0.001 to 0.03; P = .05) were significantly associated with log transformed CRP. CONCLUSION: These data suggest that as in the general population, in CKD patients, obesity, a traditional risk factor for atherosclerosis, is associated with inflammation, a novel risk factor for atherosclerosis.

Adult↗

Angiotensin II regulation of TGF-beta in murine mesangial cells involves both PI3 kinase and MAP kinase.

INTRODUCTION: Chronic activation of the angiotensin II (AngII) type 1 receptor (AT-1) is a central event in the development of chronic kidney disease (CKD), in part through enhanced expression of TGF-beta, and AT-1 receptor blockade inhibits the progression to CKD in a variety of disease states. The AT-1 receptor is a heptahelical Gaq/11-coupled receptor that initiates phospholipase C activity and release of intracellular calcium; recent data suggest that the AT-1 receptor can also activate the epidermal growth factor receptor (EGFR), although the roles of specific EGF-mediated signaling cascades in AT-1 effects on mesangial cell biology are uncertain. We hypothesized that 2 EGFR-activated pathways, PI3 kinase and MAP kinase, are stimulated by the AT-1 receptor and, in part, regulate the effects of AngII on TGF-beta1 levels in mesangial cells. METHODS: We examined the effects of AT-1 receptor activation on EGFR, PI3 kinase, and MAP kinase activation in murine mesangial cells. Upon achieving 60-80% confluence, the medium was changed to low-serum for 48 hr and cells were exposed to either the AT-1 receptor blocker, losartan, the EGFR blocker, AG1478, or control medium, and then stimulated with AngII. Similar experiments were performed using LY294002 and U0126, specific inhibitors of PI3 kinase and MEK, respectively. Total cellular protein lysates and RNA were isolated. Activation of the receptors and pathways was evaluated by immunoblotting and levels of TGF-beta mRNA were measured using real-time quantitative RT-PCR. RESULTS: AngII induced autophosphorylation of EGFR (pY1068) and activated Akt and ERK, downstream targets of PI3 kinase and MAP kinase, respectively. AngII-mediated EGFR autophosphorylation was inhibited by losartan and AG1478. AG1478 also inhibited both basal and AngII-mediated activation of Akt and ERK. Finally, AngII-mediated increase in TGF-beta mRNA was inhibited by losartan, AG1478, LY249002, and U0126. CONCLUSIONS: Stimulation of the AT-1 receptor in murine mesangial cells results in activation of the EGF receptor with subsequent signaling through PI3 kinase and MAP kinase, thereby regulating TGF-beta mRNA levels. These data suggest that AT-1 receptor signaling pathways through EGFR may serve as a therapeutic target to inhibit the development of CKD.

Angiotensin II↗

The hypothalamic-pituitary axis in men and women with chronic kidney disease.

Although the precise abnormalities that lead to failure of the hypothalamic-pituitary-gonadal axis in men and women with chronic kidney disease (CKD) and end-stage renal disease (ESRD) remains undefined, evidence exists for defects in both the hypothalamus and the pituitary. The lack of appropriate cyclic release of gonadotropin-releasing hormone (GnRH) by the hypothalamus leads to loss of normal pulsatile luteinizing hormone (LH) release by the pituitary, which results in impaired ovulation in women and reduced testosterone and sperm production in men. The cause of impaired cyclic release of GnRH is unclear, but hyperprolactinemia, elevated endorphins, and high levels of GnRH and LH caused by reduced clearance may contribute. Perturbations of the hypothalamic-pituitary-gonadaotropin axis in CKD lead to high rates of infertility, dysfunctional uterine bleeding, and impaired puberty in children. Only through additional study of the complex effects of CKD on the hypothalamic-pituitary-gonadal axis will the precise abnormalities in hormonal control of reproduction be explained.

Chronic Disease↗

Pharmacokinetics of estrogen and progesterone in chronic kidney disease.

Estradiol, estrone, and estrone sulfate are the primary circulating estrogens in women; the relative amounts depend on the menopausal status of the women. Administration of oral estradiol or conjugated equine estrogens (CEE) results in a high ratio of estrone to estradiol, whereas use of nonoral routes (dermal, vaginal, or parenteral) results in approximately equal plasma concentrations of estradiol and estrone. Although estradiol and estrone are predominately eliminated by metabolism, and little is excreted unchanged in the urine, evidence indicates that chronic kidney disease (CKD) alters the pharmacokinetics of estradiol. Free and total estradiol plasma concentrations are higher in women with end-stage renal disease (ESRD) after an oral estradiol dose, but no change occurs in estrone concentrations. Neither estradiol nor estrone is removed in the dialysate. These studies suggest that women with CKD should receive a least a 50% reduction in oral estradiol doses. No information is available on the pharmacokinetics of any of the progestins in CKD. In the future, knowledge of the concentration effect relationship for the treatment of symptoms of menopause, as well as prevention of osteoporosis, will benefit all postmenopausal women who choose to use hormone replacement therapy.

Chronic Disease↗

[Physical working capacity and muscle strength in chronic renal failure are improved by exercise].

Patients with chronic kidney disease (CKD) show a decline in maximal exercise capacity and muscle strength as renal function decreases. Renal anaemia, skeletal muscle dysfunction, tiredness and increasing inactivity are the major causes of this deterioration. Exercise training improves maximal exercise capacity, muscle strength and endurance in young, middle-aged and elderly patients at all stages of CKD. Preferably exercise training should be started during the predialysis stage, however, it is equally effective in dialysis patients and after renal transplantation. It has a positive effect on muscle catabolism and counteracts weight loss and malnutrition. Moreover, exercise training has positive effects on functional capacity and health related quality of life. Exercise training should be prescribed by a neph-rologist and administered by a trained nephrological physiotherapist. Exercise training is an integral part of care of the CKD patient. It not only reduces suffering but also costs, resulting in major potential benefits for the patient, the health care system and society.

Exercise↗

Calcium antagonists: a more expansive role in treating persons with reduced kidney function?

Most recent studies have supported inhibition of the renin-angiotensin-aldosterone system (RAAS) with diuretic as initial hypertensive therapy in patients with chronic kidney disease (CKD). The recommended role of calcium channel blockers (CCB) in CKD patients had diminished due to class-specific differences in antiproteinuric effects and lesser efficacy in reducing composite renal clinical outcomes when compared to RAAS inhibition. However, the demonstrated safety and efficacy of CCB in combination with RAAS inhibition, and the recognized need for effective antihypertensive agents to achieve the low target blood pressures, has prompted a more expanded use of calcium channel blockers in this difficult to treat CKD population.

Black or African American↗

Herbal treatment for renal diseases.

Renal fibrosis is a common consequence of chronic kidney diseases (CKD). Standard therapy to prevent progression of CKD in western medicine includes dietary protein restriction, blood pressure control, angiotensin-converting enzyme inhibition and angiotensin receptor blockade. However, little is known about the renoprotective effects of Chinese herbal medicine. Cumulative evidence suggests that some Chinese herbal medicines, including Astragalus and a mixture of Astragalus plus Angelica, Ligusticum, Triptolide and Rhubarb, have a beneficial role in slowing the progression of CKD. This effect is multi-functional and multi-targeted, and is often associated with a reduction in proteinuria and the amelioration of dyslipidaemia, but not with changes in systemic blood pressure. These mechanisms include anti-inflammation and inhibition of TGF-b overproduction. On the other hand, some Chinese herbal medicines may be hazardous to patients with renal diseases. In this review, we discuss recent advances in the research of some Chinese herbs for pharmacological intervention of progressive renal diseases and kidney-related injuries.

Animals↗

Chronic kidney disease in the elderly; a silent epidemic.

Chronic kidney disease has been shown to be associated with significant increases in mortality and morbidity even in early stages. Despite this it is rarely diagnosed, actively investigated or managed in the elderly. We set out to establish the prevalence of CKD and identify causative factors in a consecutive series of referrals to a geriatric medical clinic. We calculated glomerular filtration rates (GFR) for 101 patients attending a geriatric medical clinic using the Cockroft and Gault formula, and collected data on medications and relevant past medical history. Mild CKD (GFR <60ml/min) was present in 80% of the group. Only 10% of these patients had serum creatinine >130(mmol/L. hypertension was present in 50% and only 9% were diabetic. Almost one third were on inappropriate drugs or dosages; most commonly non-steroidal anti-inflammatory drugs (99%). Chronic kidney disease is extremely common in older people attending a geriatric medical clinic and carries significant risks. CKD will not be detected by serum creatinine alone in 90% of cases. Routine calculation of GFR should be used to provide a more accurate measure of renal impairment and allow earlier intervention, risk factor reduction and improve prescribing practices.

Aged↗

Systemic hypertension and nondiabetic chronic kidney disease: the best evidence-based therapeutic approach today.

Despite the high prevalence and significant morbidity and mortality associated with high chronic kidney disease (CKD) in patients with hypertension, it remains vastly under-diagnosed and under-treated. Consequently, many patients develop kidney failure requiring dialysis or kidney transplant. Moreover, patients with CKD represent the group at highest risk from cardiovascular complications, even greater than patients with diabetes mellitus. Therefore, management of hypertension in such patients needs to be more aggressive compared to those with normal kidney function. This review provides guidelines for treatment of hypertension in patients with non-diabetic CKD based on updated evidence from clinical trials data. Following these recommendations is likely to minimize the risk of development of kidney failure and cardiovascular disease.

Albuminuria↗

The benefits of IV iron therapy in treating anemia in patients with renal disease and comorbid cardiovascular disease.

It is important for nephrology nurses to understand the relationship that exists between renal disease, cardiac disease, and anemia. Even mild cases of chronic kidney disease (CKD) have been associated with an increase in adverse cardiovascular outcomes. And anemia, which can result from both CKD and congestive heart failure, has been shown to exacerbate the adverse consequences of these conditions. An early, aggressive correction of anemia in patients with CKD can be implemented to break this cycle and stop disease progression. Studies have shown that anemia correction improves both cardiac and renal function and can result in increased hemoglobin levels, decreased number of hospital days, and improved quality of life. An effective strategy for managing anemia in patients with renal disease and comorbid cardiovascular disease includes the administration of both recombinant human erythropoietin and intravenous iron. In addition, the nephrology nurse plays an integral role in managing anemia and improving outcomes in these patients. Therefore, the nephrology nurse should have an increased awareness of the link between anemia and renal/cardiac disease as well as available treatment options.

Anemia↗

Nutritional therapy in chronic kidney disease.

In patients with chronic kidney disease (CKD), specialized nutritional therapy may help reduce the risk of electrolyte imbalances, vitamin deficiencies, and protein energy malnutrition. Protein-restricted diets may slow the progression of renal disease and decrease the risk of morbidity and mortality in patients with CKD. In this review, we discuss some of the major nutritional concerns in individuals with CKD and offer practical recommendations for dietary therapy.

Adolescent↗

Antibody-mediated pure red-cell aplasia (PRCA): the Spanish experience.

BACKGROUND: The incidence of antibody (Ab)-mediated pure red-cell aplasia (PRCA) in patients with chronic kidney disease (CKD) has increased between 1998 and 2002. After initially responding to treatment with recombinant human erythropoietic agents for CKD-associated anemia, patients became treatment-refractory and severely anemic. Although most PRCA cases have occurred in Europe, the varying epidemiologies among individual countries have not been well characterized. METHODS: We investigated Ab-mediated PRCA in 12 Spanish patients treated with epoetin alfa alone or prior to treatment with epoetin beta (n=1) or darbepoetin alfa (n=1). Serum Abs against epoetin alfa were detected by radioimmunoprecipitation (RIP) assay or bioassay. Following diagnosis of PRCA, erythropoietic treatment was stopped and patients received immunosuppressive therapy alone (n=11) or in combination with renal transplant (n=1). RESULTS: Treatments were administered for 16 months (average) before diagnosis of PRCA in bone marrow aspirates (n=8) or biopsies (n=4). At diagnosis, patients had an average of 0.68% blood reticulocytes and blood hemoglobin (Hb) level of 7.13 g/dL. Eight patients had anti-epoetin Abs detected by RIP, and 5 had neutralizing Abs measured in the bioassay. As of December 2003, 4 patients had died, 3 had no recovery, and 5 had recovered from anemia (blood Hb level, 9.9 g/dL). All 5 recovering patients received corticosteroid therapy alone, and 1 received a renal transplant as well as corticosteroids. CONCLUSIONS: Sudden onset of treatment-refractory anemia in CKD patients suggests a course of treatment cessation followed by diagnostic procedures for Ab-mediated PRCA, and immunosuppressive therapy. This study may serve as a model for a centralized global PRCA registry.

Antibodies↗

Aortic pulse wave velocity and arterial wave reflections predict the extent and severity of coronary artery disease in chronic kidney disease patients.

BACKGROUND: Increased aortic stiffness markers - aortic pulse wave velocity (PWV) and augmentation index (AIx) - are powerful predictors of survival in ESRD patients - well-recognized for the high prevalence of coronary artery disease (CAD) and unusually high PWV and AIx. Recently, decreased aortic compliance has been shown to be predictive of primary coronary events in hypertensive patients with normal renal function. We aimed to explore relationships between arterial stiffness and CAD in cohorts of patients with chronic kidney disease (CKD). METHODS AND RESULTS: 46 patients with chronic kidney disease (33 males, aged 55.7+/- 13.2 years, 20 on dialysis, 18 post renal transplantation, and 8 with glomerular filtration rate (GFR) between 10 and 25 ml/min) underwent coronary angiography for the assessment of CAD. PWV and aortic AIx were determined from pulse waveform analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCortm device. The atherosclerosis burden score was calculated by adding the percentage luminal reduction of the most severe lesion in each artery. Patients with normal angiograms had significantly less arterial stiffness (as reflected by both a lower PWV=8.42+/-1.53 m/s and a lower AIx=17.9+/-5.55 %) compared with the 35 subjects with evidence of obstructive coronary disease at angiography (PWV=9.21+/-1.15 m/s and AIx=23.4+/-5.4 %, P<0.05 for both). Moreover, as more coronary vessels were affected, PWV and AIx increased proportionally. Based on receiver operating characteristics (ROC) curve analysis mean PWV levels showed an optimal cut-off point at 8.35 m/s (sensitivity=0.77; specificity=0.60), while mean AIx levels showed an optimal cut-off point at 17% (sensitivity=0.87; specificity=0.70). There was a statistically significant linear relationship between the atherosclerosis burden and both measures of arterial stiffness: PWV (r=0.31, p=0.007) and AIx (r=0.46, p=0.003). Independent predictors for the arterial stiffness parameters in this CKD population (multiple stepwise regression analysis) were age (r=0.69 for PWV and r=0.62 for AIx), and mean arterial pressure (MAP) (for AIx, p<0.0001). CONCLUSION: This study provides the first direct evidence in a cross-sectional investigation that PWV and AIx are related to the extent of coronary obstruction in CKD patients.

Adult↗

[Effects of intermittent treatment with sevelamer hydrochloride on parathyroid hyperplasia and vascular calcification in rats with chronic kidney disease].

Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic kidney disease (CKD). Rats were fed a diet containing adenine for 4 weeks to establish CKD. Animals were then offered a diet containing sevelamer hydrochloride (sevelamer) or a normal diet for alternating 2 week periods over 8 weeks. Adenine-treated rats showed marked elevations of serum phosphorus, PTH and FGF23 levels associated with parathyroid hyperplasia and aortic calcification. Serum phosphorus, PTH and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, intermittent treatment with sevelamer successfully inhibited parathyroid hyperplasia and aortic calcification. In conclusion, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CKD. Setting up a period of reduced serum phosphorus levels, even if it is intermittent, is worthwhile for the inhibition of the development of parathyroid hyperplasia and aortic calcification.

Adenine↗

Assessment of hypertension control in chronic kidney disease patients by ambulatory blood pressure monitoring.

BACKGROUND: Inadequate control of blood pressure (BP) increases cardiovascular mortality and morbidity in chronic kidney disease (CKD) and renal transplant patients. 24 hour ambulatory BP was recorded to evaluate the adequacy of BP control in these patients. METHODS: 60 CKD patients (25 conservative therapy, 16 maintenance hemodialysis, 19 renal transplant patients) were studied prospectively. After achieving clinic BP control, 24 hour ambulatory BP was recorded at 1 and 6 months. The patients were followed up for one year. RESULTS: Mean daytime and nighttime systolic blood pressure (SBP) both at 1 month and at 6 month was higher in non-survivors than in survivors. The survivors had better control of their daytime (p=0.018) as well as nighttime SBP levels (p=0.018) at 6 months compared to those at 1 month. Survivors achieved nocturnal dipping of SBP at 1 and 6 months (p=0.047, p=0.025, respectively). Non-survivors failed to achieve lower daytime (p=0.375) or nighttime SBP (p=0.254) at 6 months as compared to SBP at 1 month in spite of optimizing antihypertensive therapy. Daytime (p=0.022) and nighttime (p=0.029) diastolic BP (DBP) in the non-survivors was higher than in survivors. Nocturnal dip in DBP was not seen in either survivors at 1 (p=0.177) and 6 months (p=0.434) or non-survivors at 1 (p=0.408) and at 6 months (p=0.081). Renal transplant patients did not exhibit nocturnal dipping of BP. CONCLUSION: We conclude that, unlike survivors, there was worsening of 24 hour BP control in non-survivors. ABPM has a role in better management of total BP burden in CKD patients.

Adult↗

[Elevated plasma homocysteine and glutathione level in patients with renal failure].

The levels of homocysteine (Hcy) and glutatione (Glt) were determined in plasma of 219 patients with different stages of chronic kidney disease (CKD) (94 patients received chronic bicarbonate hemodialysis and 125 patients were at predialysis stage). The elevated Hcy level was detected in an early stage of CKD and reached maximal values and spreading in the hemodialysis patients. The levels of total and reduced Hcy (tHcy and rHcy, respectively) were also higher in CKD patients: the proportion of rHcy in total pool of plasma Hcy was significally higher than in healthy subjects. In the group of non-dialysed patients the reverse dependance between glomerular filtration rate (GFR) value and Hcy plasma concentration was found. We did not find any correlation between Glt and GFR in predialysis patients, but there was direct dependance between Glt and tHcy plasma levels in this group. Glt plasma levels in dialysis patients were reliably lower than in predialysis ones. There was a lack of some correlation between Glt and tHcy in the haemodialysis group.

Chromatography, High Pressure Liquid↗