An increase in serum uric acid (UA) occurs during the early and middle stages of chronic kidney disease (CKD) and aggravates the deterioration of kidney function. This study aims to explore the relation between UA and endothelial dysfunction in early CKD and its mechanisms in a murine model.
The experimental animals were randomly divided into three groups (n = 10): sham-operation group (control group), right nephrectomy only group (CKD group) and right nephrectomy with oxonic potassium group (CKD with hyperuricemia group). Furthermore, we analyzed the relation between UA and endothelial dysfunction indices in early CKD as well as its mechanisms.
Linear regression analysis showed that the level of serum UA had a significant positive correlation with serum endothelin-1 and the percentage of collagen I positive area, but a negative correlation with serum nitric oxide (NO) and NO/endothelin-1 ratio. In addition, the level of serum UA had significant positive correlations with serum malonaldehyde, serum C-reactive protein, serum oxidatively-modified low-density lipoprotein and serum low-density lipoprotein, but a negative correlation with serum superoxide dismutase.
Endothelial dysfunction in the CKD group was significant and had a positive correlation with the level of serum UA. Endothelial dysfunction in early CKD with hyperuricemia is perhaps related to oxidative stress, micro-inflammation and lipid oxidation.
Early chronic kidney disease; Endothelial dysfunction; Lipid oxidation; Micro-inflammation; Oxidative stress; Uric acid
Hyperuricemia is prevalent in chronic kidney disease (CKD); however data are limited on the relationship of uric acid levels with long term outcomes in this patient population.
Setting & Participants
The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N=840), conducted 1989–1993, to examine the effects of strict blood pressure control and dietary protein restriction on progression of stage 3–4 CKD. This analysis included 838 patients.
Outcomes & Measurements
The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular (CVD) mortality, and kidney failure.
Mean (SD) age was 52 (12) years, glomerular filtration rate was 33 (12) ml/min/1.73m2, and uric acid was 7.63 (1.66) mg/dl. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) from CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause (HR, 1.57 [95% CI, 1.07–2.32]) mortality, a trend towards CVD mortality (HR, 1.47 [95% CI, 0.90–2.39]) and no association with kidney failure (HR, 1.20 [95% CI, 0.95–1.51), compared to the lowest tertile. In continuous analyses, a 1-mg/dl higher uric acid was associated with 17% increased risk of all-cause (HR, 1.17 [95% CI, 1.05–1.30]), and 16% increased risk of CVD mortality (HR, 1.16 [95% CI, 1.01–1.33]), but was not associated with kidney failure (HR, 1.02 [95% CI, 0.97–1.07]).
Primary analyses were based on single measurement of uric acid. The results are primarily generalizable to relatively young white patients with predominantly non-diabetic CKD.
In stage 3–4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality but not kidney failure.
Background and Objectives
Cardiovascular disease is prevalent in chronic kidney disease (CKD). Uric acid is increased in subjects with CKD and has been linked with cardiovascular mortality in this population. However, no study has evaluated the relationship of uric acid with angiographically proven coronary artery disease (CAD) in this population. We therefore investigated the link between serum uric acid (SUA) levels and (i) extent of CAD assessed by the Gensini score and (ii) inflammatory parameters, including C-reactive protein (CRP) and pentraxin-3, in patients with mild-to-moderate CKD.
Material and Methods
In an unselected population of 130 patients with estimated glomerular filtration rate (eGFR) between 90 and 30 ml/min/1.73 m2, we measured SUA, serum pentraxin-3, CRP, urinary protein-to-creatinine ratio, lipid parameters and the severity of CAD as assessed by coronary angiography and quantified by the Gensini lesion severity score.
The mean serum values for SUA, pentraxin-3 and CRP in the entire study population were 5.5 ± 1.5 mg/dl, 6.4 ± 3.4 ng/ml and 3.5 ± 2.6 mg/dl, respectively. The Gensini scores significantly correlated in univariate analysis with gender (R = −0.379, p = 0.02), uric acid (R = 0.42, p = 0.001), pentraxin-3 (R = 0.54, p = 0.001), CRP (R = 0.29, p = 0.006) levels, eGFR (R = −0.33, p = 0.02), proteinuria (R = 0.21, p = 0.01), and presence of hypertension (R = 0.37, p = 0.001), but not with smoking status, diabetes mellitus, and lipid parameters. After adjustments for traditional cardiovascular risk factors, only uric acid (R = 0.21, p = 0.02) and pentraxin-3 (R = 0.28, p = 0.01) remained significant predictors of the Gensini score.
SUA and pentraxin-3 levels are independent determinants of severity of CAD in patients with mild-to-moderate CKD. We recommend a clinical trial to determine whether lowering uric acid could prevent progression of CAD in patients with CKD.
Chronic kidney disease; Coronary artery disease; Uric acid; Pentraxin-3
Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).
During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71–3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA1c, eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16–3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD.
In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.
Elevated serum uric acid has been associated with cognitive dysfunction and vascular cognitive impairment in the elderly. Serum uric acid is also commonly elevated in chronic kidney disease (CKD), but its relationship with cognitive function in these patients has not been addressed.
Subjects with CKD (defined as eGFR <60/ml/min/1.73 m2) were evaluated for cognitive dysfunction using the validated Standardized Mini-Mental State Examination (SMMSE). Individuals with dementia, depression or other psychiatric disorders were excluded, as were subjects on uric acid-lowering therapy or with serious illnesses such as severe anemia or active or ongoing cardiovascular or cerebrovascular disease.
247 subjects were enrolled. SMMSE scores showed stepwise deterioration with increasing quartile of serum uric acid (26.4; 26.1; 25.5; 25.3, score range 20–30, p = 0.019). Post-hoc analysis demonstrated that there was no linear trend and only groups 1 and 4 were different with respect to SMMSE scores (p = 0.025). Stepwise multivariate linear regression revealed that age, educational status, presence of cerebrovascular disease, and serum uric acid were independently related to SMMSE scores.
Serum uric acid levels are independently and inversely associated with mild cognitive dysfunction in subjects with CKD.
Cognitive function; Chronic kidney disease; Uric acid
High serum uric acid level (SUA) and chronic kidney disease (CKD) are risk factors for cardiovascular events (CVEs). However, their interactions as cardiovascular risk factors remain unknown. This subanalysis of the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study included 7629 patients, in whom the serum creatinine level was measured at least twice. The study examined the impact of hyperuricemia (SUA ⩾7 mg dl−1) on CVE according to the level of renal dysfunction and whether early changes in SUA predicted future glomerular filtration rates (GFRs). The mean follow-up period was 3.1 years. The patients were divided into three groups according to the baseline estimated GFR (eGFR): groups A, B and C with eGFR <45, 45–59 and ⩾60 ml min−1 per 1.73 m2, respectively. eGFR increased from 38.1 to 57.6, from 52.8 to 67.5 and from 74.7 to 80.7 ml min−1 per 1.73 m2 in groups A, B and C, respectively. In non-hyperuricemic patients, the CVE rate was 10.83, 4.98 and 4.21/1000 person-years in groups A, B and C, respectively, while in hyperuricemic patients, the corresponding values were 14.18, 17.02 and 5.93. Thus, hyperuricemia increased the risk of CVE only in group B (relative risk (RR) 3.43 (95% confidence interval (CI) 1.55 to 7.60); P<0.002). The final change in the eGFR was negatively correlated with the change in SUA from baseline to year 1 (P<0.001). CVEs were more frequent in those with a decrease in eGFR. Hyperuricemia may be a major determinant of increased cardiovascular risk in CKD stage 3A, and SUA may be involved in the progression of CKD. Changes in the GFR influence the rate of CVE.
cardiovascular disease; chronic kidney disease; glomerular filtration rate; uric acid
To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD).
Methods and results
Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m2). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12–1.85, P = 0.005) and 1.27 (1.02–1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70–1.31, P = 0.792) and 1.40 (1.08–1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74–1.33, P = 0.942) and 1.49 (1.19–1.86, P = 0.001), respectively (P for interaction, 0.033).
Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.
Heart failure; Hyperuricaemia; Chronic kidney disease; Outcomes
It is unknown what role uric acid may play in the increasing cardiovascular disease (CVD) among Alaska Eskimos. Uric acid is associated with both hypertension (HTN) and chronic kidney disease (CKD). We analyzed 1078 Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) participants. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine measures using the MDRD equation. CKD was defined by an eGFR of <60ml/min/1.73m2. We adjusted for age, sex, education, diabetes, hypertension (or eGFR), obesity, lipids, and smoking status; 7% (n=75) had prevalent CKD. eGFR decreased with increasing tertiles of serum uric acid. (p<0.001) Uric acid was independently associated with prevalent CKD (Adjusted Odds Ratio [OR] and 95% confidence interval [CI] of 2.04 (1.62–2.56), respectively). 21% (n=230) had prevalent HTN; Uric acid was independently associated with prevalent HTN (Adjusted OR 1.2, 95% CI 1.1–1.5). Uric acid is independently associated with prevalent CKD and HTN in this population.
Alaska Eskimos; chronic kidney disease; epidemiology; hypertension; uric acid
The short-term effects of multifactorial intervention for cardiovascular disease (CVD) prevention on renal function and serum uric acid (SUA) levels in patients with stage 3 chronic kidney disease (CKD) and multiple CVD risk factors are unclear. The aim of the study was to prospectively assess these effects.
Material and methods
This post hoc analysis of 5 "best practice" studies involved patients with multiple CVD risk factors. Estimated glomerular filtration rate (eGFR) was assessed using the Modification of Diet in Renal Disease (MDRD) formula. Among the 4,153 patients, 1,235 (29.7%) had stage 3 CKD (eGFR between 30 and 59 ml/min/1.73 m2). A baseline visit was followed by a concerted effort from previously trained physicians to improve adherence to lifestyle advice and optimize drug treatment, including a statin, for all vascular risk factors. After 6 months eGFR and SUA levels were re-evaluated.
The intervention improved compliance to lifestyle measures and increased the use of evidence-based medication, including a statin. There was also a 5.6% increase in eGFR (p < 0.001) in patients with stage 3 CKD and a 6.1% reduction in SUA levels (p < 0.001). Among patients with stage 3 CKD, 127 (10.3%) improved to stage 2 CKD and 9 (0.7%) advanced to stage 4 CKD by the end of the 6-month study period. There were no major side-effects.
Multitargeted intervention, including a statin, may improve renal function and reduce SUA levels within 6 months, thus offsetting 2 potential CVD risk factors in high-risk patients.
renal function; uric acid; dyslipidaemia; diabetes mellitus; hypertension; metabolic syndrome; multifactorial intervention; statin
Purpose of Review
To assess the current data suggesting that uric acid lowering therapy may be useful in the prevention or mitigation of chronic kidney disease (CKD).
Eleven observational studies assessing the potential role of serum uric acid in the prevalence and progression of CKD have been published in the last 2 years. Seven suggest an association, 4 do not. Recent experimental models and clinical trials have mechanistically linked serum uric acid and hypertension, an established risk factor for CKD.
Elevated serum uric acid is a marker for decreased renal function, may have a mechanistic role in the incidence and progression of renal functional decline and likely has a causal role in hypertension and vascular disease. Clinical trials are needed to determine if uric acid lowering therapy will be effective in preventing CKD.
Uric acid; CKD; Hypertension; diuretics; metabolic syndrome; cardiovascular disease
Background. Higher serum uric acid (SUA) levels have been shown to be associated with cardiovascular disease. SUA levels are also associated with hypertension, a strong risk factor for chronic kidney disease (CKD). However, it is unclear whether SUA is independently associated with CKD. We examined the hypothesis that higher SUA levels are positively associated with CKD.
Methods. We analysed data from the C8 Health Study, a population-based study of Appalachian adults aged ≥18 years and free of cardiovascular disease (n = 49,295, 53% women). SUA was examined as gender-specific quartiles. The outcome of interest was CKD (n = 2,980), defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 from serum creatinine.
Results. Overall, we observed a clear positive association between increasing quartiles of SUA and CKD, independent of confounders. Compared with the lowest quartile of SUA (referent), the multivariable odds ratios (95% confidence interval) for quartiles 2–4, respectively, of CKD were 1.53 (1.31, 1.78), 2.16 (1.86 2.50) and 4.67 (4.07, 5.36); P-trend < 0.0001. This observed positive association persisted in separate analysis among men (P-trend < 0.0001) and women (P-trend < 0.0001).
Conclusions. In conclusion, higher SUA levels are positively associated with CKD, suggesting that at least part of the reported association between SUA and cardiovascular disease may be mediated by CKD.
Appalachian; chronic kidney disease; creatinine serum; glomerular filtration rate; serum uric acid
Despite the advances in the management of patients with diabetes, diabetic nephropathy (DN) remains the most common cause of end stage renal disease (ESRD) in the US and worldwide. Inflammation and endothelial dysfunction appear to play a central role in the onset and the progression of DN. Recent evidence has emerged in the last decade to suggest uric acid is an inflammatory factor and may play a role in endothelial dysfunction. This has lead our group and others to explore the role of uric acid in the onset and progression of DN. In this review, we will highlight some of the animal and human studies that implicate uric acid in DN. Based on the evidence we review, we conclude the need for properly planned randomized controlled studies to lower uric acid levels and assess the impact of such therapy on diabetic kidney disease.
There have been many studies between serum uric acid (UA) and chronic kidney disease (CKD). However, as far as we know, little research has been done to examine the prospective association between serum UA and development of CKD in Korean men. This prospective cohort study was performed using 18,778 men who participated in a health checkup program both on January, 2005 and on December, 2009. CKD was defined as an estimated glomerular filtration rate < 60 mL/min per 1.73 m2. The odds ratio (OR) from binary logistic regressions for the development of CKD was determined with respect to the quintiles grouping based on serum UA. During 74,821.4 person-years of follow-up, 110 men were found to develop CKD. The OR for the development of CKD increased as the quintiles for baseline serum UA levels increased from the first to fifth quintiles (1.00 vs 1.22, 1.19, 2.59, and 3.03, respectively, p for linear trend < 0.001) after adjusting for covariates. The adjusted OR comparing those participants with hyperuricemia ( ≥ 7.0 mg/dL) to those with normouricemia ( < 7.0 mg/dL) was 1.96 (1.28-2.99). Elevated serum UA levels were independently associated with increased likelihood for the development of CKD in Korean men (IRB number: KBC10034).
Uric Acid; Kidney Failure, Chronic
The system of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play a key role in atherogenesis of chronic kidney disease (CKD) patients by its impact on matrix accumulation. Connections with inflammation, stress, or endothelial dysfunction are also probable. However, the data on correlations between these parameters in CKD patients are scarce in adults and absent in children. The aim of our study was to evaluate serum concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2, as well as their correlations with markers of stress response (Hsp90-α, anti-Hsp60), endothelial dysfunction (sE-selectin), and inflammation (high-sensitivity C-reactive protein) in CKD children treated conservatively. Thirty-seven patients were divided into two groups according to the CKD stage (gr.CKDI, 19 children with CKD stages 2–3; gr.CKDII, 18 subjects with CKD stages 4–5). Twenty-four age-matched healthy subjects served as controls. Serum concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, Hsp90-α, anti-Hsp60, and sE-selectin were assessed by ELISA. Median values of MMP-2, MMP-9, TIMP-1, and TIMP-2 were significantly higher in all CKD children vs. controls and were increased in patients with CKD stages 4–5 vs. CKD stages 2–3. Hsp90-α, anti-Hsp60, sE-selectin, and glomerular filtration rate predicted the values of MMPs and TIMPs. Chronic kidney disease in children is characterized by MMP/TIMP system dysfunction, aggravated by the progression of renal failure. Correlations between examined parameters, heat shock proteins, and markers of endothelial damage suggest the possibility of MMP/TIMP application as indicators of stress response and atherogenesis in children with CKD on conservative treatment.
Autoimmunity; Heat shock proteins; Inflammation; Lipids; Matrix destruction
Background. It is unclear whether the presence of kidney disease modifies the associations of uric acid with cardiovascular events and death.
Methods. In the limited access, public use Atherosclerosis Risk In Communities (ARIC) database, associations of serum uric acid levels with cardiovascular events and death were analysed using a parametric proportional hazards model and the modification of these associations by the presence of CKD was assessed using a likelihood ratio test.
Results. Of the 15 366 ARIC participants included in this analysis, 461 had CKD (eGFR <60 ml/min/1.73 m2). In both non-CKD and CKD sub-groups, participants with hyperuricaemia (≥ 7 mg/dl in men and ≥ 6 mg/dl in women) compared to those with normal serum uric acid levels had higher waist circumference and fasting serum insulin levels. In the entire cohort, in a multivariate parametric proportional hazards model, each mg/dl increase in serum uric acid was associated with an increased hazard of cardiovascular events (HR 1.09, 95% CI 1.05–1.12) and death. A multiplicative interaction term of serum uric acid and CKD when added to the above models was significant (P < 0.001). The likelihood ratio test of the models with and without the interaction term was also significant (P < 0.001). In the non-CKD population, a multivariate analysis after adjusting for comorbidities and metabolic syndrome showed a significant association between hyperuricaemia and mortality (HR 1.18, 95% CI 1.04–1.33) but not for cardiovascular events (HR 1.07, 95% CI 0.96–1.19). In the CKD population, the association was not significant for both mortality and cardiovascular events.
Conclusion. We conclude that hyperuricaemia is associated with insulin resistance and mortality in the non-CKD population. The presence of CKD attenuates the associations of uric acid with mortality. Interventional studies are warranted to establish the biological role of hyperuricaemia in mortality in non-CKD and CKD populations.
cardiovascular events; chronic kidney disease; insulin resistance; mortality; uric acid
Some experimental evidence suggests that uric acid impairs endothelial function. It is controversial if high uric acid levels and impaired endothelial function are related in healthy adults. In addition, the effect of uric acid on endothelial cells (ECs) of humans is unexplored.
Data of 107 healthy adult volunteers were analyzed. The association between serum uric acid and endothelial-dependant dilation (EDD) and endothelial-independent dilation (EID) was evaluated by linear regression models. We also examined the relations between uric acid and systemic and cellular markers of inflammation and oxidative stress in all or subsets of participants.
Uric acid levels and EDD were not related in unadjusted or adjusted models. There was a significant negative correlation between uric acid and EID in the pooled sample (r = −0.34, P = 0.005). This correlation remained significant after adjusting for demographics (P = 0.04) and was attenuated after adjusting for other cardiac risk factors (P = 0.12). Higher serum uric acid levels were found to correlate significantly with C-reactive protein (CRP) (r = 0.31, P = 0.002). Serum uric acid levels were not associated with brachial artery EC nuclear factor-κB (NF-κB) p65 or NADPH oxidase p47phox expression or with nitrotyrosine staining, but were inversely associated with EC manganese superoxide dismutase (MnSOD) expression (r = −0.5, P = 0.01, n = 25).
Elevated serum uric acid is not associated with endothelial dysfunction among healthy adults, but is inversely related to EID and EC MnSOD, and positively related to systemic inflammation. These findings may have implications for cardiovascular risk in healthy adults.
blood pressure; endothelium; hypertension; inflammation; uric acid
Hypertension is highly prevalent in patients with chronic kidney disease (CKD). As either the cause or the consequence of CKD, hypertension is an important independent factor determining the rate of loss of renal function. Hypertension is also a significant independent risk factor for cardiovascular events in patients with CKD, the leading cause of their morbidity and mortality.
Based on evidence from observational cohort studies and randomized clinical trials, the Canadian Hypertension Education Program (CHEP) recommends a target blood pressure (BP) of lower than 130/80 mmHg in hypertensive patients with nondiabetic CKD. The CHEP also endorses the use of renin-angiotensin system blockers for the BP-lowering regimen in nondiabetic patients with CKD and significant proteinuria. It is recognized that the majority of nondiabetic patients with CKD will require two or more BP-lowering drugs to attain target BP. Furthermore, extracellular fluid volume expansion is a major contributor to hypertension in patients with CKD, and diuretics should be part of the BP-lowering regimen in the majority of patients. Patients with CKD are recognized to be at high risk for cardiovascular events, and studies testing new emerging treatments of hypertension to reduce the burden of CKD on renal and cardiovascular outcomes are underway. In this regard, the CHEP will continue to review and update all its recommendations annually.
Blood pressure target; Chronic kidney disease; Hypertension; Proteinuria
Metabolic syndrome (MS) is common in patients with chronic kidney disease (CKD), but its contribution to arterial stiffness and endothelial dysfunction in CKD is not well defined. We hypothesized that risk factors for MS would independently predict arterial stiffness and endothelial dysfunction in CKD patients.
RESEARCH DESIGN AND METHODS
Risk factors for MS, carotid-femoral pulse wave velocity (CF-PWV) and flow-mediated dilation (FMD) as measures of arterial stiffness and endothelial dysfunction, respectively, were assessed in 113 minimally comorbid CKD patients and in 23 matched control subjects.
CF-PWV correlated with systolic blood pressure (SBP), waist circumference, and plasma glucose (r2 = 0.25, 0.09, and 0.09; P < 0.01 for all). FMD correlated with SBP (r2 = 0.09; P < 0.01) and waist circumference (r2 = 0.03; P < 0.05). CF-PWV increased progressively (r2 = 0.07; P < 0.01) with increasing number of risk factors for MS. In multiple linear regression, SBP and waist circumference were independent determinants of CF-PWV, whereas only SBP predicted FMD.
The number of MS risk factors is an important determinant of arterial stiffness in CKD patients irrespective of the degree of renal impairment. Although BP remains the major determinant of arterial stiffness and endothelial dysfunction, waist circumference independently predicts arterial stiffness. MS risk factors, particularly abdominal girth, are potential targets for future interventional studies in patients with CKD.
Arterial hypertension is very common in children with all stages of chronic kidney disease (CKD). While fluid overload and activation of the renin–angiotensin system have long been recognized as crucial pathophysiological pathways, sympathetic hyperactivation, endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension. Moreover, several drugs commonly administered in CKD, such as erythropoietin, glucocorticoids and cyclosporine A, independently raise blood pressure in a dose-dependent fashion. Because of the deleterious consequences of hypertension on the progression of renal disease and cardiovascular outcomes, an active screening approach should be adapted in patients with all stages of CKD. Before one starts antihypertensive treatment, non-pharmacological options should be explored. In hemodialysis patients a low salt diet, low dialysate sodium and stricter dialysis towards dry weight can often achieve adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are first-line therapy for patients with proteinuria, due to their additional anti-proteinuric properties. Diuretics are a useful alternative for non-proteinuric patients or as an add-on to renin–angiotensin system blockade. Multiple drug therapy is often needed to maintain blood pressure below the 90th percentile target, but adequate blood pressure control is essential for better renal and cardiovascular long-term outcomes.
Hypertension; Children; Chronic kidney disease; Pathophysiology; Antihypertension therapy; Life-style changes
We aimed to examine associations among serum 25-hydroxyvitamin D (25OHD) levels, 1,25-dihyroxyvitamin D (1,25OHD) levels, vitamin D receptor (VDR) polymorphisms, and renal function based on estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes.
In a cross-sectional study of 410 patients, chronic kidney disease (CKD) stage assessed by eGFR was compared with 25OHD, 1,25OHD, and VDR FokI (rs10735810) polymorphisms by an ordered logistic regression model adjusted for the following confounders: disease duration, calendar month, use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers or statins, and serum calcium, phosphate, and intact parathyroid hormone levels.
1,25OHD levels, rather than 25OHD levels, showed seasonal oscillations; peak levels were seen from May to October and the lowest levels were seen from December to February. These findings were evident in patients with CKD stage 3∼5 but not stage 1∼2. eGFR was in direct proportion to both 25OHD and 1,25OHD levels (P<0.0001), but it had stronger linearity with 1,25OHD (r = 0.73) than 25OHD (r = 0.22) levels. Using multivariate analysis, 1,25OHD levels (P<0.001), but not 25OHD levels, were negatively associated with CKD stage. Although FokI polymorphisms by themselves showed no significant associations with CKD stage, a significant interaction between 1,25OHD and FokITT was observed (P = 0.008). The positive association between 1,25OHD and eGFR was steeper in FokICT and CC polymorphisms (r = 0.74) than FokITT polymorphisms (r = 0.65).
These results suggest that higher 1,25OHD levels may be associated with better CKD stages in patients with type 2 diabetes and that this association was modified by FokI polymorphisms.
Obstructive sleep apnea (OSA) is an important clinical problem in the chronic kidney disease (CKD) population. OSA is associated with hypoxemia and sleep fragmentation, which activates the sympathetic nervous system, the renin-angiotensin-aldosterone system, alters cardiovascular hemodynamics, and results in free radical generation. In turn, a variety of deleterious processes such as endothelial dysfunction, inflammation, platelet aggregation, atherosclerosis, and fibrosis are triggered, predisposing individuals to adverse cardiovascular events and likely renal damage. Independent of obesity, OSA is associated with glomerular hyperfiltration and may be an independent predictor of proteinuria, a risk factor for CKD progression. OSA is also associated with hypertension, another important risk factor for CKD progression, particularly proteinuric CKD. OSA may mediate renal damage via several mechanisms, and there is a need to better elucidate the impact of OSA on incident renal disease and CKD progression.
Obstructive sleep apnea; Chronic kidney disease; Proteinuria; Hypertension
Prevention of chronic kidney disease (CKD) is a major public health issue. Although several studies have been performed on the association between alcohol consumption and CKD or renal function, it remains controversial. Numerous genetic polymorphisms have been reported to be associated with CKD and kidney function. Mitochondrial DNA cytosine/adenine (Mt5178 C/A) polymorphism is associated with longevity in Japanese. This polymorphism modifies the effects of alcohol consumption on blood pressure, risk of hypertension, serum triglyceride levels, risk of hyper-LDL cholesterolemia and serum uric acid levels. The objective of this study was to investigate whether Mt5178 C/A polymorphism modifies the effects of alcohol consumption on renal function in male Japanese health check-up examinees.
A total of 394 male subjects aged 29–76 years were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the combined effects of Mt5178 C/A polymorphism and habitual drinking on the risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2) was conducted.
For Mt5178A genotypic men, habitual drinking may increase eGFR (P for trend = 0.003) or reduce the risk of mildly decreased eGFR (P for trend = 0.003). Daily drinkers had a significantly higher eGFR than non-drinkers (P = 0.005). The crude odds ratio for decreased eGFR was significantly lower in daily drinkers than in non-drinkers (odds ratio = 0.092, 95% confidence interval: 0.012-0.727, P = 0.024). On the other hand, for Mt5178C genotypic men, habitual drinking does not appear to affect eGFR.
The present results suggest a joint effect of Mt5178 C/A polymorphism and alcohol consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects.
Alcohol; Chronic kidney disease; Estimated glomerular filtration rate; Mitochondrial DNA polymorphism
Objectives. The study was designed to evaluate associations between symmetric dimethylarginine (SDMA), inflammation, and superoxide anion (O2∙−) with endothelial function and to determine their potential for screening of endothelial dysfunction in patients with chronic kidney disease (CKD) and renal transplant (RT) recipients. Materials and Methods. We included 64 CKD and 52 RT patients. Patients were stratified according to brachial artery flow-mediated dilation (FMD). Results. Logistic regression analysis showed that high SDMA and high sensitive C-reactive protein (hs-CRP) were associated with impaired FMD in CKD and RT patients, after adjustment for glomerular filtration rate. The ability of inflammation, SDMA, and O2∙− to detect impaired FMD was investigated by receiving operative characteristic analysis. Hs-CRP (area under the curves (AUC) = 0.754, P < 0.001), IL-6 (AUC = 0.699, P = 0.002), and SDMA (AUC = 0.689, P = 0.007) had the highest ability to detect impaired FMD. SDMA in combination with inflammatory parameters and/or O2∙− had better screening performance than SDMA alone. Conclusions. Our results indicate a strong predictable association between hs-CRP, SDMA, and endothelial dysfunction in CKD patients and RT recipients. The individual marker that showed the strongest discriminative ability for endothelial dysfunction is hs-CRP, but its usefulness as a discriminatory marker for efficient diagnosis of endothelial dysfunction should be examined in prospective studies.
Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD).
We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification.
The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075).
Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.
Background. Chronic kidney disease (CKD) is a growing health problem worldwide that leads to end-stage kidney failure and cardiovascular complications. We aimed to determine the prevalence of CKD in Turkey, and to evaluate relationships between CKD and cardiovascular risk factors in a population-based survey.
Methods. Medical data were collected through home visits and interviews. Serum creatinine, blood glucose, total cholesterol, triglycerides, HDL, LDL and uric acid were determined from 12-h fasting blood samples, and spot urine tests were performed for subjects who gave consent to laboratory evaluation.
Results. A total of 10 872 participants were included in the study. The final analysis was performed on 10 748 subjects (mean age 40.5 ± 16.3 years; 55.7% women) and excluded 124 pregnant women. A low glomerular filtration rate (GFR) (< 60 mL/min/1.73 m2) was present in 5.2% of the subjects who were evaluated for GFR, while microalbuminuria and macroalbuminuria were observed in 10.2% and 2% of the subjects, respectively. The presence of CKD was assessed in subjects who gave consent for urinary albumin excretion measurement (n = 8765). The overall prevalence of CKD was 15.7%; it was higher in women than men (18.4% vs. 12.8%, P < 0.001) and increased with increasing age of the subjects. The prevalence of hypertension (32.7% in the general population), diabetes (12.7%), dyslipidaemia (76.3%), obesity (20.1%) and metabolic syndrome (31.3%) was significantly higher in subjects with CKD than subjects without CKD (P < 0.001 for all).
Conclusions. The prevalence of CKD in Turkey is 15.7%. Cardiovascular risk factors were significantly more prevalent in CKD patients.
chronic kidney disease; epidemiology and outcomes; risk factors