Magdalena Madero

Uric Acid and Long-term Outcomes in CKD

BACKGROUND Hyperuricemia is prevalent in patients with chronic kidney disease (CKD); however, data are limited about the relationship of uric acid levels with long-term outcomes in this patient population. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N = 840) conducted from 1989 to 1993 to examine the effects of strict blood pressure control and dietary protein restriction on progression of stages 3 to 4 CKD. This analysis included 838 patients. PREDICTOR Uric acid level. OUTCOMES & MEASUREMENTS The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular disease (CVD) mortality, and kidney failure. RESULTS Mean age was 52 +/- 12 (SD) years, glomerular filtration rate was 33 +/- 12 mL/min/1.73 m(2), and uric acid level was 7.63 +/- 1.66 mg/dL. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) died of CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause mortality (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.07 to 2.32), a trend toward CVD mortality (HR, 1.47; 95% CI, 0.90 to 2.39), and no association with kidney failure (HR, 1.20; 95% CI, 0.95 to 1.51) compared with the lowest tertile. In continuous analyses, a 1-mg/dL greater uric acid level was associated with 17% increased risk of all-cause mortality (HR, 1.17; 95% CI, 1.05 to 1.30) and 16% increased risk of CVD mortality (HR, 1.16; 95% CI, 1.01 to 1.33), but was not associated with kidney failure (HR, 1.02; 95% CI, 0.97 to 1.07). LIMITATIONS Primary analyses were based on a single measurement of uric acid. Results are generalizable primarily to relatively young white patients with predominantly nondiabetic CKD. CONCLUSIONS In patients with stages 3 to 4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality, but not kidney failure.

Adiponectin and Mortality in Patients with Chronic Kidney Disease

Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney disease. The Modification of Diet in Renal Disease study was a randomized, controlled trial that was conducted between 1989 and 1993. Adiponectin was measured in frozen samples that were obtained at baseline (N = 820). Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with all-cause and cardiovascular mortality. Mean +/- SD age was 52 +/- 12 yr, and mean +/- SD glomerular filtration rate (GFR) rate was 33 +/- 12 ml/min per 1.73 m2. Eighty-five percent of participants were white, and 60% were male. Mean +/- SD adiponectin was 12.8 +/- 8.0 mug/ml. Triglycerides, insulin resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In multivariable adjusted Cox models, a 1-mug/ml increase in adiponectin was associated with a 3% (hazard ratio 1.03; 95% confidence interval 1.01 to 1.05; P = 0.02) increased risk for all-cause and 6% (hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; P < 0.001) increased risk for cardiovascular mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

Serum cystatin C as a marker of glomerular filtration rate

Purpose of reviewGlomerular filtration rate is widely accepted as the best overall measure of kidney function. Currently available methods to estimate glomerular filtration rate have strengths and limitations. Cystatin C is a novel endogenous filtration marker being considered as a potential replacement for serum creatinine. This review summarizes the currently available glomerular filtration rate estimating equations based on cystatin C and the literature comparing cystatin C and creatinine as filtration markers. Recent findingsIn most cystatin C estimating equations, inclusion of age and sex did not substantially improve their performance. Equations yield different glomerular filtration rate estimates for the same level of cystatin C. Variation among equations may be due to differences among the assays or populations in the individual studies. Studies comparing cystatin C with creatinine or creatinine-based estimating equations show heterogeneous results, with some showing improved performance and others showing equivalent performance even in similar populations. These heterogeneous results may be due to inappropriate comparisons between equations developed in one population with those developed in another, or to the differences between assays or population characteristics. SummaryCystatin C shows promise as an alternative to serum creatinine but several important questions remain before it can be recommended for use in clinical practice.

Cognitive function in chronic kidney disease.

Chronic kidney disease (CKD) is a growing public health problem. The incidence of kidney failure is rising in all age groups but particularly in older adults. Individuals in all stages of CKD are at higher risk for development of cognitive impairment and this may be a major determinant in their quality of life. Furthermore, cognitive impairment is associated with an increased risk of death in dialysis patients. Cerebrovascular disease is a strong risk factor for development of cognitive impairment and vascular disease is a more likely cause of cognitive impairment than Alzheimer’s disease in patients with CKD. Both traditional and nontraditional vascular risk factors are more common in CKD and dialysis patients may also be at risk for cognitive impairment via nonvascular risk factors and the hemodialysis procedure itself. Unfortunately, because risk factors for cognitive impairment in CKD have not been thoroughly ascertained, evaluation of potential treatments has been limited. Given the high prevalence of cognitive impairment in all stages of CKD, additional studies are needed to evaluate potential risk factors and treatments in this vulnerable population.

Review: Cognitive Function in Chronic Kidney Disease

Chronic kidney disease (CKD) is a growing public health problem. The incidence of kidney failure is rising in all age groups but particularly in older adults. Individuals in all stages of CKD are at higher risk for development of cognitive impairment and this may be a major determinant in their quality of life. Furthermore, cognitive impairment is associated with an increased risk of death in dialysis patients. Cerebrovascular disease is a strong risk factor for development of cognitive impairment and vascular disease is a more likely cause of cognitive impairment than Alzheimer’s disease in patients with CKD. Both traditional and nontraditional vascular risk factors are more common in CKD and dialysis patients may also be at risk for cognitive impairment via nonvascular risk factors and the hemodialysis procedure itself. Unfortunately, because risk factors for cognitive impairment in CKD have not been thoroughly ascertained, evaluation of potential treatments has been limited. Given the high prevalence of cognitive impairment in all stages of CKD, additional studies are needed to evaluate potential risk factors and treatments in this vulnerable population.

The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: a randomized controlled trial

One of the proposed causes of obesity and metabolic syndrome is the excessive intake of products containing added sugars, in particular, fructose. Although the ability of excessive intake of fructose to induce metabolic syndrome is mounting, to date, no study has addressed whether a diet specifically lowering fructose but not total carbohydrates can reduce features of metabolic syndrome. A total of 131 patients were randomized to compare the short-term effects of 2 energy-restricted diets-a low-fructose diet vs a moderate natural fructose diet-on weight loss and metabolic syndrome parameters. Patients were randomized to receive 1500, 1800, or 2000 cal diets according to sex, age, and height. Because natural fructose might be differently absorbed compared with fructose from added sugars, we randomized obese subjects to either a low-fructose diet (<20 g/d) or a moderate-fructose diet with natural fruit supplements (50-70 g/d) and compared the effects of both diets on the primary outcome of weight loss in a 6-week follow-up period. Blood pressure, lipid profile, serum glucose, insulin resistance, uric acid, soluble intercellular adhesion molecule-1, and quality of life scores were included as secondary outcomes. One hundred two (78%) of the 131 participants were women, mean age was 38.8 ± 8.8 years, and the mean body mass index was 32.4 ± 4.5 kg/m(2). Each intervention diet was associated with significant weight loss compared with baseline. Weight loss was higher in the moderate natural fructose group (4.19 ± 0.30 kg) than the low-fructose group (2.83 ± 0.29 kg) (P = .0016). Compared with baseline, each intervention diet was associated with significant improvement in secondary outcomes. Reduction of energy and added fructose intake may represent an important therapeutic target to reduce the frequency of obesity and diabetes. For weight loss achievement, an energy-restricted moderate natural fructose diet was superior to a low-fructose diet.

Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake

Fructose induces metabolic syndrome in rats; but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake. Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid, and markers of inflammation were assessed. Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with up-regulation of fructose-dependent transporter Glut5 and fructokinase. Fatty liver and low-grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro. Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver, and type 2 diabetes mellitus in male breeder rats; and the effects are independent of excess energy intake.

Biomarkers of renal function, which and when?

PURPOSE OF THE REVIEW Acute kidney injury (AKI) and chronic kidney disease (CKD) are conditions that substantially increase morbidity and mortality. Although novel biomarkers are being used in practice, the diagnosis of AKI and CKD is still made with surrogate markers of GFR, such as serum creatinine (SCr), urine output and creatinine based estimating equations. SCr is limited as a marker of kidney dysfunction in both settings and may be inaccurate in several situations, such as in patients with low muscle mass or with fluid overload. New biomarkers have the potential to identify earlier patients with AKI and CKD and in the future potentially intervene to modify outcomes. RECENT FINDINGS In particular KIM-1 and NGAL are considered excellent biomarkers in urine and plasma for the early prediction of AKI; however cycle arrest biomarkers have emerged as novel markers for risk stratification of AKI. Urine TIMP-2 and IGFBP7 performed better than any other biomarkers reported to date for predicting the development of moderate or severe AKI. Biomarker combinations are required to increase diagnostic accuracy in an acute setting. NGAL, cystatin C, and FGF-23 are promising and accurate biomarkers for CKD detection. Equations combining cystatin C and SCr perform better than the equations using either cystatin C or SCr alone, especially in situations where CKD needs to be confirmed. Combining creatinine, cystatin C and urine albumin to creatinine ratio improves risk stratification for kidney disease progression and mortality. SUMMARY Recent advances in molecular biology have resulted in promising biomarkers for AKI and CKD diagnoses; however more research is necessary to implement them successfully into clinical practice in order to facilitate early diagnosis, guide interventions and monitor disease progression. The following review describes the most important biomarkers studied in kidney disease and will discuss the use and the value of these biomarkers in different clinical settings.

Association of pulse pressure, arterial elasticity, and endothelial function with kidney function decline among adults with estimated GFR >60 mL/min/1.73 m(2): the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND The association of subclinical vascular disease and early declines in kidney function has not been well studied. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS Multi-Ethnic Study of Atherosclerosis (MESA) participants with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) with follow-up of 5 years. PREDICTORS Pulse pressure, small (SAE) and large arterial elasticity (LAE), and flow-mediated dilation. OUTCOMES Kidney function decline. MEASUREMENTS SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was assessed by eGFR based on serum creatinine (eGFR(SCr)) and cystatin C (eGFR(SCysC)). RESULTS For 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared with persons with pulse pressure of 40-50 mm Hg, eGFR(SCysC) declines were 0.29 (P = 0.006), 0.56 (P < 0.001), and 0.91 (P < 0.001) mL/min/1.73 m(2)/y faster in persons with pulse pressure of 50-60, 60-70, and >70 mm Hg, respectively. Compared with the highest quartile of SAE (most elastic), eGFR(SCysC) declines were 0.26 (P = 0.009), 0.35 (P = 0.001), and 0.70 (P < 0.001) mL/min/1.73 m(2)/y faster for the second, third, and fourth quartiles, respectively. For LAE, compared with the highest quartile, eGFR(SCysC) declines were 0.28 (P = 0.004), 0.58 (P < 0.001), and 0.83 (P < 0.001) mL/min/1.73 m(2)/y faster for each decreasing quartile of LAE. Findings were similar for eGFR(SCr). In contrast, for 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not associated significantly with kidney function decline. For every 1-standard deviation greater flow-mediated dilation, eGFR(SCysC) and eGFR(SCr) changed by 0.05 (P = 0.3) and 0.06 mL/min/1.73 m(2)/y (P = 0.04), respectively. LIMITATIONS We had no direct measure of GFR, in common with nearly all large population-based studies. CONCLUSIONS Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were associated linearly and independently with faster kidney function decline in persons with eGFR ≥60 mL/min/1.73 m(2). Future studies should investigate whether treatments to decrease the stiffness of large and small arteries may slow the rate of kidney function loss.

Dietary Fructose and Hypertension

The association between fructose and increased blood pressure is still incompletely defined, because experimental studies have produced dissimilar conclusions. Amplified vasopressor responses to minimal stimuli and differing responses to fructose in peripheral versus central sites may explain the controversy. Fructose induces systemic hypertension through several mechanisms mainly associated with deleterious effects on target organs (kidney, endothelium, heart) exerted by the byproducts of its metabolism, such as uric acid. The kidney is particularly sensitive to the effects of fructose because high loads of this sugar reach renal tissue. In addition, fructose increases reabsorption of salt and water in the small intestine and kidney; thus the combination of salt and fructose has a synergistic effect in the development of hypertension. Clinical and epidemiologic studies have also linked fructose consumption with hypertension. Further studies are warranted in order to understand the role of fructose in the development of hypertension.