Urate-lowering drugs for chronic kidney disease with asymptomatic hyperuricemia and hypertension: a randomized trial.

INTRODUCTION: Xanthine oxidase (XO) inhibitors may slow down chronic kidney disease (CKD) progression. The comparative effectiveness of the different urate-lowering drugs is unknown. The aim of this study was to determine whether urate-lowering therapy with an XO inhibitor (febuxostat) and that with a uricosuric drug (benzbromarone) are comparable in slowing renal function decline in patients with CKD complicated with hypertension and hyperuricemia. METHODS: This study was an open-label randomized parallel-group clinical trial of 95 patients with stage G3 CKD in Japan. The patients had hypertension and hyperuricemia without a history of gout. They were randomized to receive febuxostat ( n  = 47; febuxostat group) or benzbromarone ( n  = 48; benzbromarone group) and titrated to reduce their serum urate level to <6.0 mg/dl. The primary end-point was change in estimated glomerular filtration rate (eGFR) from baseline to 52 weeks. The secondary end-points included changes in uric acid level, blood pressure, urinary albumin-to-creatinine ratio, and XO activity. RESULTS: Of the 95 patients, 88 (92.6%) completed the trial. There were no significant differences in change in eGFR (in ml/min/1.73 m 2 ) between the febuxostat [-0.23, 95% confidence interval (CI), -2.00 to 1.55] and benzbromarone (-2.18, 95% CI, -3.84 to -0.52) groups (difference, 1.95; 95% CI, -0.48 to 4.38; P  = 0.115) nor in the secondary end-points, except for XO activity. Febuxostat significantly reduced XO activity ( P  = 0.010). There were no significant differences in primary and secondary outcomes between the groups. A decrease in eGFR was significantly less in the febuxostat group than that of the benzbromarone group in the CKDG3a, but not in CKDG3b, in the subgroup analysis. There were no adverse effects specific to either drug. CONCLUSIONS: No significant differences were found in the effects of febuxostat and benzbromarone in renal function decline in stage G3 CKD complicated with hyperuricemia and hypertension.

Association of blood pressure and hyperuricemia with proteinuria and reduced renal function in the general population.

This study aimed to investigate the effect of hyperuricemia (HU) on the association of systolic blood pressure (SBP) with the prevalence of proteinuria and low estimated glomerular filtration rate (eGFR) in the general population. This cross-sectional study enrolled 24,728 Japanese individuals (11,137 men and 13,591 women) who underwent health checkups in 2010. The prevalence of proteinuria and low eGFR (< 60 mL/min/1.73 m2) among participants classified according to serum uric acid levels and SBP was compared. HU was defined as serum uric acid levels higher than the 75th percentile in male and female participants (> 7.2 and > 5.4 mg/dL, respectively). The odds ratio (OR) for proteinuria increased with elevated SBP. This trend was significantly evident in participants with HU. Moreover, there was an interactive effect of SBP and HU on the prevalence of proteinuria in the male (Pfor interaction = 0.04) and female (Pfor interaction = 0.04) participants. Next, we evaluated the OR for low eGFR (< 60 mL/min/1.73 m2) with and without proteinuria based on the presence of HU. The multivariate analysis revealed that the OR for low eGFR with proteinuria increased with elevated SBP, but that for low eGFR without proteinuria decreased. These trends of OR tended to be prevalent among those with HU. The association between SBP and the prevalence of proteinuria was more pronounced in participants with HU. However, the association between SBP and decreased renal function with and without proteinuria might be different regardless of HU.

Amplified Association Between Blood Pressure and Albuminuria in Overweight Patients With Biopsy-Proven Hypertensive Nephrosclerosis.

BACKGROUND: An overweight person is at high risk for hypertensive renal damage. The effect of weight on the association between systolic blood pressure (SBP) and albuminuria remains unknown in patients with histologically diagnosed hypertensive nephrosclerosis. METHODS: A total of 97 patients with biopsy-confirmed hypertensive nephrosclerosis were recruited from 13 centers throughout Japan. We examined the relationship between SBP and proteinuria among those who were overweight, which is defined as a body mass index ≥25 kg/m2, and those who were not. We examined the interaction of weight and SBP with albuminuria at baseline and with the changes in estimated glomerular filtration rate (eGFR) during the observational period. RESULTS: Our results included mean age (54 years old), blood pressure (138/80), eGFR (53 ml/min/1.73 m2), and urine albumin levels (0.2 g/day). SBP was significantly correlated with log-transformed urine albumin levels (r = 0.4, P = 0.01) in patients who were overweight (n = 38) compared with patients who were not overweight (n = 59). Multiple regression analysis revealed that the interaction between being overweight and SBP with respect to albuminuria was significantly correlated with the log-transformed urine albumin level (ß = 0.39, P = 0.047) and was independent of age, sex, and potential confounding factors. The interaction between weight and SBP ≥140 mm Hg was significantly associated with a greater decrease in eGFR in the following 3 years. CONCLUSIONS: Being overweight may enhance susceptibility to hypertensive glomerular damage and may eventually lead to renal progression in patients with hypertensive nephrosclerosis.

Hyponatremia and mortality among very elderly residents in a geriatric health service facility.

INTRODUCTION: Hyponatremia is common among elderly patients. This study aimed to examine the prognostic value of hyponatremia among elderly residents in a geriatric facility. METHODS: We retrospectively examined the association between serum sodium levels and mortality among 118 residents (82% female, mean age 85.5 years) in a single geriatric health service facility. We defined hyponatremia as Na < 135 mEq/L. On the basis of single measurements of serum sodium at periodic examinations, the patients were divided into hyponatremia and non-hyponatremia groups. Multivariable Cox proportional hazards models were used to evaluate the effect of hyponatremia on mortality from May 2005 to April 2007. RESULTS: Thirty-three patients (28%) had hyponatremia. Over a 1-year follow-up period, the cumulative survival rate was significantly lower in patients with hyponatremia than in those without hyponatremia. In a multivariate analysis, including traditional risk factors for death, hyponatremia was associated with an increased mortality risk (adjusted hazard ratio 2.73; 95% confidence interval 1.01-5.16; p = 0.047). CONCLUSIONS: Hyponatremia is common and is a predictor of mortality in the near future among very elderly residents of a geriatric facility.

Augmented Association Between Blood Pressure and Proteinuria in Hyperuricemic Patients With Nonnephrotic Chronic Kidney Disease.

BACKGROUND: Hyperuricemia (HU) may enhance susceptibility to hypertensive renal damage via disrupted autoregulation of glomerular hemodynamics. The effect of HU on the association between blood pressure (BP) and proteinuria remains unknown in patients with chronic kidney disease (CKD). METHODS: In total, 109 patients with nonnephrotic CKD (55 men and 54 females) who underwent renal biopsy were recruited. Arteriolar hyalinosis was semiquantitatively assessed via arteriole grading. Correlation between BP and urine protein (UP) level was examined based on the presence of HU, which was defined as the use of urate-lowering drugs or serum uric acid levels of ≥7 and ≥5 mg/dl in males and females, respectively, which were associated with increased risks of hyalinosis in our previous study. RESULTS: Median age, BP, estimated glomerular filtration rate, and UP level were 38 years, 124/74 mm Hg, 82 ml/min/1.73 m2, and 0.8 g/gCr, respectively. In patients with HU (n = 59), log-transformed systolic BP (SBP) was significantly correlated with log-transformed UP level (r = 0.49, P < 0.0001); this was not observed in patients without HU (n = 50). Multiple regression analysis (R2 = 0.21, P = 0.0001) revealed that the interaction between HU and log-transformed SBP with respect to proteinuria was significantly correlated with log-transformed UP level (ß = 7.0, P = 0.03), independent of age, sex, and potential confounding factors; however, this statistical significance was completely eliminated after adjustment for the arteriolar hyalinosis index. CONCLUSIONS: HU potentiates susceptibility to hypertensive glomerular damage via disrupted autoregulation in patients with nonnephrotic CKD.

Chronic kidney disease, inflammation, and cardiovascular disease risk in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA), a prototypic systemic autoimmune inflammatory condition, confers an increased risk of cardiovascular disease (CVD). Recently, chronic kidney disease (CKD) was suggested to increase the risk of CVD in RA patients, and inflammation was identified as a critical, nontraditional CKD-associated risk factor for CVD. This study aimed to examine the combined effects of CKD and CVD in RA patients. METHODS: In this retrospective evaluation of 428 RA patients, the outcome of interest was the incidence of CVD. CKD was defined as an estimated glomerular filtration rate of <60mL/min/1.73m2 and/or positive dipstick tests for proteinuria of ≥3 months duration. C-reactive protein (CRP) was used as an inflammation marker, and a high CRP level was defined as a mean CRP value of ≥0.57mg/dL during the first 6 months of follow-up. Patients were categorized as follows: non-CKD with low CRP, non-CKD with high CRP, CKD with low CRP, and CKD with high CRP. RESULTS: During a median follow-up of 89 months, 67 patients (16%) had CKD, and 38 (9%) developed CVD. Using patients with non-CKD and low CRP as a reference group, the adjusted hazard ratios (HR, 95% confidence interval) for CVD were 1.88 (0.25-9.44) for patients with CKD/low CRP and 9.71 (3.27-31.97) for those with CKD/high CRP. CONCLUSIONS: The coexistence of CKD and inflammation was associated with a higher risk of CVD than either condition alone in RA patients. Inflammation might increase the risk of CVD especially in patients with CKD.

Inflammation as a Risk of Developing Chronic Kidney Disease in Rheumatoid Arthritis.

OBJECTIVE: The relationship between chronic inflammation and the incidence of chronic kidney disease (CKD) remained not-clear in patients with rheumatoid arthritis (RA). This study aims to examine the relationship between persistently high C-reactive protein (CRP), a marker of inflammation, and the incidence of CKD in RA. METHODS: We retrospectively examined the relationship between the levels of CRP and incidence of CKD in 345 RA patients. The outcome of interest was incidence of CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and/or positive dipstick testing for proteinuria for ≥3 months. We defined high CRP, as >3.0 mg/L. On the basis of three measurements of CRP for 6-months period, patients were divided into three groups: group 1, including patients with no high CRP values; group 2, patients with transient high CRP values (once or twice) and group 3, patients with persistently high CRP values. RESULTS: During a median follow-up period of 89 months, 14% of all patients developed CKD. The cumulative incidence of CKD was 7% in group 1, 14% in group 2 and 22% in group 3 (P = 0.008, log-rank test). In a multivariate analysis, including classical risk factors for CKD, persistently high CRP was an independent predictor of the incidence of CKD (hazard ratio, 3.00; 95% confidence interval, 1.23-8.53; P = 0.01). CONCLUSIONS: Persistently high CRP was a significant risk factor for the incidence of CKD. Results suggest that persistent inflammation is a marker for the high risk of CKD in RA.

Interrelationship between brachial artery function and renal small artery sclerosis in chronic kidney disease.

Chronic kidney disease (CKD), characterized by senile inflammation, is a risk factor for cardiovascular disease. Conduit artery function and small artery structure relate to cardiovascular disease. We examined the correlations, determinants and interrelationships of arterial indices in association with CKD in a cross-sectional study of 139 patients (60% male; mean age 44 years) with CKD (stages 3-5, 39%) who underwent a renal biopsy. Conduit artery function and small artery sclerosis were assessed by brachial artery flow-mediated dilatation (FMD) and semiquantitative evaluation of small artery intimal thickening (SA-IT), respectively. The estimated glomerular filtration rate correlated with FMD (r=0.31, P=0.0002) and inversely correlated with SA-IT (r=-0.54, P<0.0001). Multiple regression analysis showed that FMD was inversely correlated with SA-IT and vice versa. In addition, high-sensitivity C-reactive protein (hs-CRP) was significantly correlated with SA-IT, but not FMD. Multiple logistic analysis revealed that higher hs-CRP concomitant with decreased FMD was further associated with the risk of severe SA-IT compared with their individual effects. These findings suggest that both conduit artery and small artery disease develop with mutual interaction in parallel with decreased kidney function. Coexistence of inflammation and conduit artery dysfunction may be closely related to renal small artery sclerosis in patients with CKD.

Hypertriglyceridemia accompanied by increased serum complement component 3 and proteinuria in non-nephrotic chronic kidney disease.

BACKGROUND: Hypertriglyceridemia (hTG) is a risk factor for progression of chronic kidney disease (CKD); however, it remains unknown whether the adipocytokine complement component 3 (C3) is involved in the association between hTG and CKD. METHODS: The study included 138 patients (54 % male) with non-nephrotic (serum albumin ≥3 g/dl) CKD who had undergone a renal biopsy and did not have hypocomplementemic disease. Renal arteriolopathy was assessed semi-quantitatively. We examined the cross-sectional associations between proteinuria and hTG with or without a higher serum C3 level (hC3), defined as equal or above the median value. RESULTS: The mean (SD) age of the patients was 42 (±17) years and urine protein was 1.2 (±1.2) g/gCr. Patients with hTG had a significantly higher urine protein than those without hTG. Subgroup analysis showed that the hTG+/hC3+ group had higher grade arteriolopathy and urine protein levels. Multiple logistic regression analysis adjusted for age, sex, and diabetes mellitus showed that hC3+ alone was associated significantly with higher levels of urine protein [odds ratio (OR), 2.98; 95 % confidence interval (CI) 1.19-7.46, p = 0.02]; however, hTG alone showed no such association. hTG+/hC3+ was a significant factor when hTG-/hC3- was used as the reference (adjusted OR 5.32; 95 % CI 1.40-20.17, p = 0.01), with this OR being decreased by adjustment for arteriolopathy. CONCLUSIONS: hTG accompanied by hC3 was associated with proteinuria in non-nephrotic CKD. Arteriolopathy may influence this association. A prospective study is needed to determine the predictive value of this association in CKD progression.

An association between uric acid levels and renal arteriolopathy in chronic kidney disease: a biopsy-based study.

Uric acid (UA) can induce renal arteriolopathy in animal models. Whether there is an association between UA and renal arteriolopathy in patients with chronic kidney disease (CKD) is unknown. Here, we examined the cross-sectional association of serum UA levels with renal arteriolar hyalinosis and wall thickening. Arteriolar parameters were assessed by semiquantitative grading (max: grade 3) of arterioles in 167 patients with CKD (mean age, 42.4 years; 86 men and 81 women) who underwent renal biopsy. The mean serum UA level was 6.4 mg dl(-1). We observed hyalinosis in 94 patients (56%) and wall thickening in 119 patients (71%). As the UA level tertile increased, the proportion of higher-grade (grade 2 and 3) hyalinosis and wall thickening increased (hyalinosis, P<0.0001 and wall thickening, P=0.0002, for trend). Multiple logistic analysis adjusted for age ≥40 years, sex, hypertension status, diabetes mellitus status and estimated glomerular filtration rate <60 ml min(-1) per 1.73 m(2) showed that hyperuricemia (UA ≥7 mg dl(-1)) was significantly associated with a higher risk of hyalinosis (adjusted odds ratio: 3.13; 95% confidence interval: 1.23-7.94; P=0.02) and higher-grade (equal to or higher than the mean value) wall thickening (adjusted odds ratio: 2.66; 95% confidence interval: 1.11-6.38; P=0.03). Hence, these results suggest that hyperuricemia may be related to renal arteriolar damage in patients with CKD.