Kazufumi Nagahama

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 m2 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.

Hyperuricemia predicts future metabolic syndrome: a 4-year follow-up study of a large screened cohort in Okinawa, Japan

The aim of this study was to determine whether hyperuricemia could predict future metabolic syndrome (MetS) in a large screened cohort of Japanese male and female subjects. We evaluated 5936 subjects (3144 male subjects, 2792 female subjects; mean age 48.7 years) who underwent health checkup programs in 2006 and 2010, who were MetS free in 2006. At baseline, hyperuricemia was detected in 927 male subjects (29.5%) and 276 female subjects (9.9%). Subjects with baseline hyperuricemia had significantly higher MetS prevalence in 2010 than those without (male subjects: 34.8 vs. 20.6%, P<0.0001; female subjects: 15.6 vs. 4.8%, P<0.0001). Compared with subjects in the first quintile of uric acid levels at baseline, the age-adjusted odds ratios (ORs) for MetS cumulative incidence among subjects in the third, fourth and fifth quintiles were, 1.8 (95% confidence interval (CI): 1.4–2.4: P<0.0001), 2.1 (95% CI: 1.6–2.8: P<0.0001) and 3.2 (95% CI: 2.4–4.1: P<0.0001), respectively, for male subjects and 2.4 (95% CI: 1.3–4.7: P=0.0075), 3.0 (95% CI: 1.6–5.7: P=0.0010) and 4.8 (95% CI: 2.6–8.8: P<0.0001), respectively for female subjects. Multivariable logistic analysis revealed that hyperuricemia was significantly associated with MetS cumulative incidence in male subjects (OR 1.5: 95% CI: 1.3–1.8, P<0.0001) and female (OR 2.0, 95% CI: 1.3–3.0, P<0.0001). In conclusion, hyperuricemia is a significant and independent predictor of MetS in Japanese male and female subjects. For both genders, MetS risk increases with increased serum uric acid levels.

Associations between serum uric acid levels and the incidence of hypertension and metabolic syndrome: a 4-year follow-up study of a large screened cohort in Okinawa, Japan

The purpose of this study was to examine the associations between serum uric acid (SUA) levels and the incidences of hypertension and metabolic syndrome (MetS) in a large screened cohort of Japanese men and women. We evaluated 4812 subjects (males, 2528; females, 2284; mean age, 47.5 years) who underwent health checkups between 2006 and 2010 and were free of hypertension and MetS in 2006. After 4 years, 618 (13%), 764 (16%) and 158 (3%) subjects developed hypertension, MetS and hypertension with MetS, respectively. Increased SUA levels were significantly and positively associated with the incidences of hypertension, MetS and hypertension with MetS. Compared with the first quartile of SUA levels, the odds ratios (95% confidence intervals) for the third and fourth quartiles, respectively, were as follows: 1.5 (1.1–2.1; P=0.0128) and 1.8 (1.2–2.5; P=0.0022) for hypertension, 1.3 (0.9–1.9; P=0.1910) and 1.8 (1.2–2.7; P=0.0039) for MetS and 2.7 (1.1–6.6; P=0.0276) and 3.2 (1.3–8.0; P=0.0115) for hypertension with MetS. In conclusion, increased SUA levels were significantly and independently associated with the incidences of hypertension and MetS in subjects without hypertension or MetS at baseline. Increased SUA levels might also be correlated with the incidence of hypertension with MetS.

Effects of xanthine oxidase inhibitors on renal function and blood pressure in hypertensive patients with hyperuricemia

Hyperuricemia may promote the progression of hypertension and renal dysfunction. However, the effects of hyperuricemia treatment on blood pressure and renal function in adult hypertensive patients with hyperuricemia remain unclear. A total of 137 hypertensive patients with hyperuricemia (96 men and 41 women; mean age of 67 years) who recently started taking xanthine oxidase inhibitors (allopurinol or febuxostat) as outpatients were recruited. Serum uric acid level, estimated glomerular filtration rate (eGFR, ml min−1 per 1.73 m2) and blood pressure (mm Hg) were retrospectively compared immediately before and shortly after starting treatment with xanthine oxidase inhibitors. The mean blood pressure and the eGFR immediately before starting treatment were 128/71 mm Hg and 44.6 ml min−1 per 1.73 m2, respectively. Although the eGFR decreased from 46.6 to 44.6 ml min−1 per 1.73 m2 before starting treatment with xanthine oxidase inhibitors, it increased to 46.2 ml min−1 per 1.73 m2 (P=0.001, compared with immediately before treatment) without any significant changes in blood pressure after the administration of xanthine oxidase inhibitors. Multiple regression analysis revealed that the increase in eGFR after starting xanthine oxidase inhibitor treatment positively correlated with the changes in systolic blood pressure and negatively correlated with the changes in uric acid levels and the use of renin–angiotensin system inhibitors. These results suggest that xanthine oxidase inhibitors may delay the progression of renal dysfunction in adult hypertensive patients with hyperuricemia.

Proteinuria as a significant determinant of hypertension in a normotensive screened cohort in Okinawa, Japan.

To evaluate the influence of proteinuria on the development of hypertension in normotensive screened subjects. We studied 4,428 normotensive subjects without heart disease (2,888 men, 1,540 women, age 19–89 years) who were participants in a 1-day health evaluation in both 1997 and 2000. The 3-year frequency of developing hypertension was 6.0% in subjects without proteinuria, and 13.5% in subjects with proteinuria. The odds ratio for developing hypertension by age (year) increased approximately 1.6%. Obesity was associated with an approximately 40% increased risk of hypertension; proteinuria increased the risk of hypertension 2-fold. Proteinuria was a significant predictor of developing hypertension. Age, obesity, and initial blood pressure level also contributed to the development of hypertension. In conclusion, proteinuria is a powerful predictor of developing hypertension. Age and obesity are also associated with increased risk of hypertension. Lifestyle modification might thus be necessary, particularly in subjects with proteinuria.

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 (β = 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.