Vascular calcification is associated with significant cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Factors unique to patients with CKD, such as ...hyperphosphatemia, predispose these patients to early and progressive vascular calcification. Hyperphosphatemia appears to be involved in a number of mechanisms that trigger and advance the progression of vascular calcification, including (1) transition of vascular smooth muscle cells (VSMCs) from a contractile to an osteochondrogenic phenotype and mineralization of VSMC matrix through sodium-dependent phosphate cotransporters, (2) induction of VSMC apoptosis, (3) inhibition of monocyte/macrophage differentiation into osteoclast-like cells, (4) elevation of fibroblast growth factor 23 levels, and (5) decreases in klotho expression. Whether vascular calcification can be prevented or reversed with strategies aimed at maintaining phosphate homeostasis presently is unknown. This review discusses these mechanisms in depth, exploring the interplay among vascular calcification promoters, inhibitors, and substrate that affect phosphorus handling leading to vascular calcification in individuals with CKD.
Uric Acid as a Target of Therapy in CKD Jalal, Diana I., MD; Chonchol, Michel, MD; Chen, Wei, MD, PhD ...
American journal of kidney diseases,
01/2013, Letnik:
61, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The prevalence of chronic kidney disease (CKD) has increased and will continue to increase in the United States and worldwide. This is alarming considering that CKD is an irreversible condition and ...patients who progress to chronic kidney failure have reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have shown several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this article, we offer a critical review of the experimental evidence linking hyperuricemia to CKD, highlight gaps in our knowledge on the topic as it stands today, and review the observational and interventional studies that have examined the potential nephroprotective effect of decreasing uric acid levels in patients with CKD. Although uric acid also may be linked to cardiovascular disease and mortality in patients with CKD, this review focuses only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression.
Background Chronic kidney disease is common and is associated with cardiovascular disease, cerebrovascular disease, and cognitive function, although the nature of this relationship remains uncertain. ...Study Design Cross-sectional cohort using baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT). Setting & Participants Participants in SPRINT, a randomized clinical trial of blood pressure targets in older community-dwelling adults with cardiovascular disease, chronic kidney disease, or high cardiovascular disease risk and without diabetes or known stroke, who underwent detailed neurocognitive testing in the cognition substudy, SPRINT−Memory and Cognition in Decreased Hypertension (SPRINT-MIND). Predictors Urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Outcomes Cognitive function, a priori defined as 5 cognitive domains based on 11 cognitive tests using z scores, and abnormal white matter volume quantified by brain magnetic resonance imaging. Results Of 9,361 SPRINT participants, 2,800 participated in SPRINT-MIND and 2,707 had complete data; 637 had brain imaging. Mean age was 68 years, 37% were women, 30% were black, and 20% had known cardiovascular disease. Mean eGFR was 70.8 ± 20.9 mL/min/1.73 m2 and median urine ACR was 9.7 (IQR, 5.7-22.5) mg/g. In adjusted analyses, higher ACR was associated with worse global cognitive function, executive function, memory, and attention, such that each doubling of urine ACR had the same association with cognitive performance as being 7, 10, 6, and 14 months older, respectively. Lower eGFR was independently associated with worse global cognitive function and memory. In adjusted models, higher ACR, but not eGFR, was associated with larger abnormal white matter volume. Limitations Cross-sectional only, no patients with diabetes were included. Conclusions In older adults, higher urine ACR and lower eGFR have independent associations with global cognitive performance with different affected domains. Albuminuria concurrently identifies a higher burden of abnormal brain white matter disease, suggesting that vascular disease may mediate these relationships.
Background Pregnancy in kidney disease is considered high risk, but the degree of this risk is unclear. We tested the hypothesis that kidney disease in pregnancy is associated with adverse maternal ...and fetal outcomes. Study Design Retrospective study comparing pregnant women with and without kidney disease. Setting & Participants Using data from an integrated health care delivery system from 2000 through 2013, a total of 778 women met the criteria for kidney disease. Using a pool of 74,105 women without kidney disease, we selected 778 women to use for matches for the women with kidney disease. These women were matched 1:1 by age, race, and history of diabetes, chronic hypertension, liver disease, and connective tissue disease. Predictor Kidney disease was defined using the NKF-KDOQI definition for chronic kidney disease or International Classification of Diseases, Ninth Revision codes prior to pregnancy or serum creatinine level > 1.2 mg/dL and/or proteinuria in the first trimester. Outcomes & Measurements Maternal outcomes included preterm delivery, delivery by cesarean section, preeclampsia/eclampsia, length of stay at hospital (>3 days), and maternal death. Fetal outcomes included low birth weight (weight < 2,500 g), small for gestational age, number of admissions to neonatal intensive care unit, and infant death. Results Compared with women without kidney disease, those with kidney disease had 52% increased odds of preterm delivery (OR, 1.52; 95% CI, 1.16-1.99) and 33% increased odds of delivery by cesarean section (OR, 1.33; 95% CI, 1.06-1.66). Infants born to women with kidney disease had 71% increased odds of admission to the neonatal intensive care unit or infant death compared with infants born to women without kidney disease (OR, 1.71; 95% CI, 1.17-2.51). Kidney disease also was associated with 2-fold increased odds of low birth weight (OR, 2.38; 95% CI, 1.64-3.44). Kidney disease was not associated with increased risk of maternal death. Limitations Data for level of kidney function and cause of death not available. Conclusions Kidney disease in pregnancy is associated independently with adverse maternal and fetal outcomes when other comorbid conditions are controlled by matching.
Background There is a gap of knowledge in the long-term outcomes of patients who have complete recovery of kidney function after an episode of acute kidney injury (AKI). We sought to determine ...whether complete recovery of kidney function after an episode of AKI is associated with the development of incident stage 3 chronic kidney disease (CKD) and mortality in patients with normal baseline kidney function. Design Retrospective cohort study. Setting & Participants 3,809 patients from an integrated health care delivery system who had a hospitalization between January 1, 1999, and December 31, 2009, with follow-up through March 31, 2010. Predictor AKI defined by International Classification of Diseases, Ninth Revision ( ICD-9 ) codes and using the AKI Network (AKIN) definition, with complete recovery defined as a decrease in serum creatinine level to less than 1.10 times the baseline value. Outcomes and Measurements Incident stage 3 CKD persistent for 3 months and all-cause mortality. Results After a median follow-up of 2.5 years, incident stage 3 CKD occurred in 15% and 3% of those with and without AKI, respectively, with an unadjusted HR of 5.93 (95% CI, 4.49-7.84) and HR of 3.82 (95% CI, 2.81-5.19) in propensity score–stratified analyses. Deaths occurred in 35% and 24% of those with and without AKI, respectively, with an unadjusted HR of 1.46 (95% CI, 1.27-1.68). In propensity score–stratified analyses, HR decreased to 1.08 (95% CI, 0.93-1.27). Limitations Measurements of albuminuria were not available. Conclusions Complete recovery of kidney function after an episode of AKI in patients with normal baseline kidney function is associated with increased risk of the development of incident stage 3 CKD, but not all-cause mortality.
CKD and Nonalcoholic Fatty Liver Disease Targher, Giovanni, MD; Chonchol, Michel B., MD; Byrne, Christopher D., MB BCh
American journal of kidney diseases,
10/2014, Letnik:
64, Številka:
4
Journal Article
Recenzirano
The possible link between nonalcoholic fatty liver disease and chronic kidney disease (CKD) recently has attracted considerable scientific interest. Accumulating clinical evidence indicates that the ...presence and severity of nonalcoholic fatty liver disease is associated significantly with CKD (defined as decreased estimated glomerular filtration rate and/or proteinuria) and that nonalcoholic fatty liver disease predicts the development and progression of CKD, independently of traditional cardiorenal risk factors. Experimental evidence also suggests that nonalcoholic fatty liver disease itself may exacerbate systemic and hepatic insulin resistance, cause atherogenic dyslipidemia, and release a variety of proinflammatory, procoagulant, pro-oxidant, and profibrogenic mediators that play important roles in the development and progression of CKD. However, despite the growing evidence linking nonalcoholic fatty liver disease with CKD, it has not been definitively established whether a causal association exists. The clinical implication for these findings is that patients with nonalcoholic fatty liver disease may benefit from more intensive surveillance or early treatment interventions to decrease the risk of CKD. In this review, we discuss the evidence linking nonalcoholic fatty liver disease with CKD and the putative mechanisms by which nonalcoholic fatty liver disease contributes to kidney damage. We also briefly discuss current treatment options for this increasingly prevalent disease that is likely to have an important future impact on the global burden of disease.
Background Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies ...evaluating this relationship in humans are lacking. Study Design Prospective longitudinal cohort study. Setting & Participants 953 participants enrolled in the Cardiovascular Health Study. Predictor Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples. Outcomes Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision ( ICD-9 ) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion. Results Median uromodulin level was 25.9 (IQR, 17.3-38.9) μg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93 μg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio IRR, 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26 μg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58). Limitations Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations. Conclusions High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.
Background Uric acid levels are increased in patients with kidney dysfunction. We tested the hypothesis that uric acid may be associated with kidney disease progression. Study Design Cohort study. ...Setting & Participants 5,808 participants of the Cardiovascular Health Study. Predictor Uric acid levels. Outcomes & Measurements Kidney disease progression was defined as a decrease in estimated glomerular filtration rate (GFR) of 3 mL/min/1.73 m2 per year or greater (≥0.05 mL/s) and as incident chronic kidney disease (CKD). Measures of kidney function were estimated GFR using the Modification of Diet in Renal Disease Study equation. Results Higher quintiles of uric acid levels were associated with greater prevalences of estimated GFR less than 60 mL/min/1.73 m2 (<1.00 mL/s) of 7%, 14%, 12%, 25%, and 42% for quintiles 1 (≤4.41 mg/dL ≤262 μmol/L), 2 (4.41 to 5.20 mg/dL 262 to 309 μmol/L), 3 (5.21 to 5.90 mg/dL 310 to 351 μmol/L), 4 (5.91 to 6.90 mg/dL 352 to 410 μmol/L), and 5 (>6.90 mg/dL >410 μmol/L), respectively. In comparison, there was only a modest, but significant, association between quintiles of uric acid levels and progression of kidney function decrease, with adjusted odds ratios of 1.0, 0.88 (95% confidence interval CI, 0.64 to 1.21), 1.23 (95% CI, 0.87 to 1.75), 1.47 (95% CI, 1.04 to 2.07), and 1.49 (95% CI, 1.00 to 2.22) for quintiles 1 through 5, respectively. No significant association was found between uric acid level and incident CKD (adjusted odds ratio, 1.00; 95% CI, 0.89 to 1.14). Limitations Measurements of albuminuria were not available. Conclusions Uric acid levels are associated strongly with prevalent CKD. In comparison, greater uric acid levels had a significant, but much weaker, association with progression of kidney disease.
Background Menopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates ...urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown. Study Design & Setting Cross-sectional study of ambulatory individuals with prevalent cardiovascular disease. Predictors Sex and, in women, use or nonuse of estrogen. Outcomes Serum phosphorus, tubular maximum reabsorption of phosphorus indexed to glomerular filtration rate (TMP/GFR), and plasma FGF-23 concentrations. Results For 987 participants, mean age was 67 ± 11 years, 182 (18%) were women, and 46 (25%) were using estrogen. Mean estimated GFR was 71 ± 23 (SD) mL/min/1.73 m2 . Compared with women who were not using estrogen, both women on estrogen therapy and men had significantly lower serum phosphorus concentrations, lower TMP/GFR values (indicating higher urine phosphorus excretion), and lower FGF-23 concentrations with adjustment for age, demographics, and kidney function ( P < 0.001 for each). Mean FGF-23 levels were 68.7 (95% CI, 59.7-79.0) relative units (RU)/mL in non–estrogen-using women, 43.8 (95% CI, 41.2-46.5) RU/mL in men, and 45.1 (95% CI, 35.2-57.4) RU/mL in women using estrogen in adjusted analysis ( P < 0.001). Limitations Most participants were men. Estrogen therapy was not randomly assigned. Conclusions Older women who are not using estrogen have higher FGF-23 levels than either men or women using estrogen. In the context of prior literature, these data suggest that postmenopausal phosphorus retention may stimulate higher FGF-23 concentrations after menopause.
Objectives This study sought to determine the efficacy of dietary sodium restriction (DSR) for improving vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic ...blood pressure (SBP) (130–159 mm Hg) and the associated physiological mechanisms. Background Vascular endothelial dysfunction develops with advancing age and elevated SBP, contributing to increased cardiovascular risk. DSR lowers BP, but its effect on vascular endothelial function and mechanisms involved are unknown. Methods Seventeen subjects (11 men and 6 women; mean age, 62 ± 7 years) completed a, randomized crossover study of 4 weeks of both low (DSR) and normal sodium intake. Vascular endothelial function (endothelium-dependent dilation; EDD), nitric oxide (NO)/tetrahydrobiopterin (BH4 ) bioavailability, and oxidative stress-associated mechanisms were assessed following each condition. Results Urinary sodium excretion was reduced by ∼50% (to 70 ± 30 mmol/day), and conduit (brachial artery flow-mediated dilation FMDBA ) and resistance (forearm blood flow responses to acetylcholine FBFACh ) artery EDD were 68% and 42% (peak FBFACh ) higher following DSR (p < 0.005). Low sodium markedly enhanced NO-mediated EDD (greater ΔFBFACh with endothelial NO synthase inhibition) without changing endothelial NO synthase expression/activation (Ser 1177 phosphorylation), restored BH4 bioactivity (less ΔFMDBA with acute BH4 ), abolished tonic superoxide suppression of EDD (less ΔFMDBA and ΔFBFACh with ascorbic acid infusion), and increased circulating superoxide dismutase activity (all p < 0.05). These effects were independent of ΔSBP. Other subject characteristics/dietary factors and endothelium-independent dilation were unchanged. Conclusions DSR largely reversed both macro- and microvascular endothelial dysfunction by enhancing NO and BH4 bioavailability and reducing oxidative stress. Our findings support the emerging concept that DSR induces “vascular protection” beyond that attributable to its BP-lowering effects.
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