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Journal of Atherosclerosis and Thrombosis logoLink to Journal of Atherosclerosis and Thrombosis
. 2017 Jun 1;24(6):630–642. doi: 10.5551/jat.37523

Hyperuricemia as a Predictive Marker for Progression of Nephrosclerosis: Clinical Assessment of Prognostic Factors in Biopsy-Proven Arterial/Arteriolar Nephrosclerosis

Kumiko Momoki 1, Hiroshi Kataoka 1,2,✉, Takahito Moriyama 1, Toshio Mochizuki 1,2, Kosaku Nitta 1
PMCID: PMC5453688  PMID: 27784849

Abstract

Aim: The influence of serum urate on kidney disease is attracting attention, but the effects of uric acid (UA) on nephrosclerosis have not been elucidated.

Methods: We reviewed data from 45 patients diagnosed with arterial/arteriolar nephrosclerosis. The renal outcomes of the arterial/arteriolar nephrosclerosis patients were assessed by performing logistic and Cox regression analyses. A Kaplan-Meier analysis was used to evaluate the impact of hyperuricemia (HU) on kidney survival. The renal outcomes of patients with and without HU were compared by using a propensity score-matched cohort.

Results: The logistic regression models showed no significant differences in renal outcomes, according to baseline parameters or follow-up parameters, except the serum UA value and body mass index (BMI). Baseline serum UA level had the highest odds ratio (OR) for estimated glomerular filtration rate (eGFR) decline (OR, 1.86; 95% confidence interval (CI), 1.12 to 3.45), among the parameters assessed. In the multivariate Cox regression analysis, HU (UA ≥ 8.0 mg/dL) (P = 0.01) and BMI (P = 0.03) were significantly associated with a ≥ 50% eGFR decline or ESRD. The Kaplan-Meier analysis in the propensity score-matched cohort indicated that the renal survival rate of the group of arterial/arteriolar nephrosclerosis patients with HU was significantly lower than that of the group without HU (log rank, P = 0.03).

Conclusion: The results of this study suggest that the baseline serum UA value can serve as a renal outcome predictor in arterial/arteriolar nephrosclerosis patients.

Keywords: Arterial/arteriolar sclerosis, Biopsy, Hyperuricemia, nephrosclerosis, Prognosis

Introduction

Chronic kidney disease (CKD) is affected by multiple risk factors for disease progression1, 2), and it is extremely important to identify these factors. Various clinical factors have been identified as independent predictors of CKD progression3, 4), including proteinuria5, 6), elevated serum creatinine level5), hypertension7), smoking8, 9), anemia4, 5), sex10), race4), genetic disorders11), diabetes12), metabolic syndrome13), overweight14, 15), and obesity15). The impact of serum uric acid (UA) on renal prognosis in CKD patients has attracted recent attention16).

Nephrosclerosis is a major cause of CKD and subsequent end-stage renal disease (ESRD)17–19). A previous study found that 32% of patients with biopsy-proven nephrosclerosis developed ESRD during a 13-year follow-up period17). However, not all of the risk factors for progression of nephrosclerosis to ESRD have been identified due to lack of biopsy evidence. Regardless of the underlying etiology of CKD, the clinical risk factors of CKD progression described above may have significant predictive power for the long-term outcome of nephrosclerosis. Nevertheless, it remains difficult to predict the renal outcome of individual nephrosclerosis patients. Clinically, understanding each renal prognostic factor of the different primary diseases associated with CKD is important to treat the individual patient meticulously. The aim of the present study was to identify clinical prognostic factors for kidney disease progression and to elucidate the predictive value of hyperuricemia (HU) in patients with biopsy-proven nephrosclerosis.

Materials and Methods

Patient Selection

We examined the cases of 90 patients diagnosed with nephrosclerosis by kidney biopsy at Tokyo Woman's Medical University Hospital between February 1995 and November 2011. All kidney tissue specimens were obtained by percutaneous needle biopsy. Nephrosclerosis was diagnosed on the basis of renal pathology showing sclerosis of renal arterioles and small arteries20). The inclusion criteria in the present study were: (1) duration of follow-up ≥ 1 year (which excluded 27 patients), (2) absence of any other renal disease, including malignant nephrosclerosis (which excluded 16 patients), and (3) estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 (which excluded 2 patients). The remaining 45 patients who met these criteria were ultimately enrolled in the present study (Fig. 1). eGFR for patients was calculated as previously described21).

Fig. 1.

Fig. 1.

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Flow chart of patient selection.

The 45 patients who did not meet the entry criteria were excluded from the 90 patients screened, and the other 45 patients were deemed eligible to enter this study.

The subjects' human rights and methods of protecting personal information were well considered. All the relevant and responsible staff adhered to the Helsinki Declaration (amended October 2013) and the Ethical Guidelines for Clinical Studies (revised July 31, 2008, referred to hereafter as the Clinical Studies Ethical Guidelines) in the execution of this study. This cohort study was approved by the Medical Ethics Committee of Tokyo Women's Medical University (#3667). Written informed consent for renal biopsy and use of clinical data at the time of the kidney biopsy, as well as subsequent histological data, was obtained from all patients.

Measurements of Covariates

The clinical parameters assessed at the time of the kidney biopsy (baseline) were as follows: age, gender, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), eGFR, serum creatinine, urea nitrogen, albumin, UA, total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglyceride (TG) levels, and proteinuria (g/day). We also investigated concomitant drug use and comorbidities at the time of the kidney biopsy22, 23). The concomitant drugs were antihypertensive drugs, diuretics, and drugs for the treatment of hyperuricemia, dyslipidemia, and diabetes mellitus. Comorbidities are defined in the next section.

The clinical parameters assessed at the time of the 6-month follow-up examinations were as follows: SBP, DBP, BMI, eGFR, eGFR slope per year, and serum creatinine, albumin, UA, TC, LDL-C, HDL-C, and TG levels.

Definition of Comorbidities

Hypertension: Being treated with an oral antihypertensive agent, SBP ≥ 140 mmHg, DBP ≥ 90 mmHg

Hyperuricemia (HU): Being treated with an oral antihyperuricemic agent, serum UA level ≥ 6.0 mg/dL, serum UA level ≥ 7.0 mg/dL, or serum UA level ≥ 8.0 mg/dL

Hypercholesterolemia: Being treated with an oral antidyslipidemic agent, serum TC level ≥ 220 mg/dL, or serum LDL level ≥ 140 mg/dL

Hypertriglyceridemia: Being treated with an oral antidyslipidemic agent or a serum TG level ≥ 150 mg/dL

Diabetes mellitus: Being treated with an antidiabetic agent or a history of diagnosis with diabetes mellitus

Outcome Evaluation (Endpoint)

The outcome variable of interest was kidney disease progression, defined as a ≥ 50% decline in eGFR from baseline (≥ 50% eGFR decline) or ESRD requiring dialysis.

Statistical Analysis

Continuous variables are reported as the mean ± SD, and categorical variables are reported as percentages, unless otherwise stated. We compared participant outcomes by performing an unpaired t-test, chi-square test, or Fisher's exact test. The patients whose renal outcome was a ≥ 50% eGFR decline or ESRD were assigned to the poor outcome group. The patients whose renal outcome was not a ≥ 50% eGFR decline or ESRD were assigned to the benign outcome group. Data are expressed as the mean ± standard deviation (SD). Logistic-regression models were prepared to estimate the risk of ≥ 50% eGFR decline or ESRD associated with baseline and follow-up parameters, including clinical and laboratory variables.

Our principal goal was to determine whether the baseline serum UA value is a prognostic indicator in nephrosclerosis patients. The optimal cut-off serum UA value for discriminating ≥ 50% eGFR decline or ESRD during follow-up examination was determined by performing receiver operating characteristic (ROC) analyses. Patients were divided into an HU group (i.e., a group of patients being treated with an oral antihyperuricemic agent or whose UA level was ≥ 8.0 mg/dL) and a non-HU group (i.e., a group of patients being not treated with an oral administration antihyperuricemic agent or whose UA value was < 8.0 mg/dL). We compared participant characteristics of the two groups using the unpaired t -test, chi-square test, or Fisher's exact test. Prognostic variables for renal outcome were assessed by the univariate and multivariate Cox proportional hazards method. We included covariates for age, sex, BMI, eGFR, urine protein, and comorbidities, including HU, at baseline in Cox proportional hazards models. Variables with P-values of less than 0.1 in the univariate model were included in the multivariate model. The renal outcome, which was a ≥ 50% eGFR decline or ESRD and interval estimates between the HU group and the non-HU group, was calculated by the Kaplan–Meier method and evaluated by the log-rank test.

To further assess whether the associations were consistent across clinically matched subgroups, we fit propensity score-matched models that included several potential modifying variables (age, sex, eGFR, SBP, and BMI) and performed subgroup analyses of the groups. The caliper-matching method was used with a maximum tolerance level of 0.2. The standardized differences were calculated to assess the appropriateness of matching. The 95% confidence intervals (CIs) were calculated. P values < 0.05 were considered statistically significant. All statistical analyses were performed by using the JMP Pro ver.12.1.0 software program (SAS Institute, Cary, NC, USA).

Results

Patients

The 45 subjects consisted of 29 males and 16 females, and their mean age at the time of the kidney biopsy was 49.4 ± 12.5 years (range 16–67 years). The mean SBP was 136.1 ± 17.3 mmHg, DBP 83.4 ± 14.6 mmHg, BMI 25.7 ± 4.3 kg/m2, proteinuria 0.8 ± 0.8 g/day, and eGFR 54.6 ± 21.0 mL/min/1.73 m2 (Supplemental Table 1). The concomitant drug data showed that 38 were being treated with an antihypertensive agent, 14 with an antihyperuricemic agent, 16 with an antidyslipidemic agent, 22 with an antiplatelet agent, 2 with an antidiabetic agent, and 3 with a diuretic. The comorbidity data showed that 41 patients had hypertension; 18 had severe HU (UA ≥ 8 mg/dL or treatment with an antihyperuricemic agent); 25 had hypercholesterolemia; 24 had hypertriglyceridemia; and 10 had diabetes mellitus. The overall follow-up period was 6.8 ± 4.5 years. The rate of progression as measured by eGFR slope was −2.6 ± 3.1 mL/min/1.73 m2/year, and 11 patients had reached the endpoint (≥ 50% eGFR decline or ESRD) during the follow-up period.

Supplemental Table 1. Baseline and follow-up patient characteristics according to renal outcome.

Variables Total
n = 45		 Poor outcome
n = 11		 Benign outcome
n = 34		 P-value
Clinical Findings
    Age (years) −49.4 ± 12.5 −53.8 ± 9.0 −48.0 ± 13.3 −0.2
    Gender (Male; %) −64.4 −63.6 −64.7 −0.9
    SBP (mmHg) −136.1 ± 17.3 −137.1 ± 15.4 −135.8 ± 18.0 −0.8
    DBP (mmHg) −83.4 ± 14.6 −80.5 ± 12.2 −84.3 ± 15.4 −0.5
    BMI (kg/m2) −25.7 ± 4.3 −28.8 ± 4.3 −24.7 ± 3.9     −0.005
Laboratory Findings
    Serum Albumin (g/dL) −4.1 ± 0.4 −4.1 ± 0.4 −4.1 ± 0.4 −0.9
    Blood Urea Nitrogen (mg/dL) −19.3 ± 6.9 −21.5 ± 7.8 −18.6 ± 6.6 −0.2
    Serum Creatinine (mg/dL) −1.20 ± 0.40 −1.23 ± 0.33 −1.19 ± 0.43 −0.8
    eGFR (mL/min/1.73 m2) −54.6 ± 21.0 −48.2 ± 15.0 −56.6 ± 22.4 −0.2
    Uric Acid (mg/dL) −6.8 ± 1.4 −7.7 ± 1.4 −6.5 ± 1.3   −0.02
    Total Cholesterol (mg/dL) −218.4 ± 42.4 −228.9 ± 50.9 −214.9 ± 39.5 −0.3
    LDL Cholesterol (mg/dL) −124.5 ± 31.2 −120.7 ± 29.6 −125.8 ± 32.0 −0.6
    HDL Cholesterol (mg/dL) −51.1 ± 18.9 −53.0 ± 27.7 −50.5 ± 15.5 −0.7
    Triglyceride (mg/dL) −199.0 ± 116.7 −249.7 ± 177.0 −182.6 ± 116.7 −0.1
    Proteinuria (g/day) −0.84 ± 0.80 −1.29 ± 0.97 −0.69 ± 0.70   −0.03
Concomitant drugs
    Antihypertensive agents (%) −84.4 −90.9 −82.4 −0.5
    Antihyperuricemic agents (%) −31.1 −36.4 −29.4 −0.7
    Antidyslipidemic agents (%) −35.6 −54.5 −29.4 −0.1
    Antiplatelet agents (%) −48.9 −72.7 −41.2 −0.1
    Antidiabetic agents (%) −4.4 −9.1 −2.9 −0.4
    Diuretics (%) −6.7 −9.1 −5.9 −0.7
Comorbidities
    Hypertension (%) −91.1 −90.9 −91.2 −1.0
    Hyperuricemia (UA ≧ 8 mg/dL) (%) −40.0 −63.6 −32.4 −0.1
    Hypercholesterolemia (%) 55.6 72.7 50.0   0.2
    Hypertriglyceridemia (%) 53.3 63.6 50.0   0.4
    Diabetes mellitus (%) 22.2 36.4 17.6   0.2
Clinical Findings (Follow-up Data)
    f/u SBP (mmHg) 127.3 ± 13.0 133.0 ± 9.5 125.5 ± 13.5 0.1
    f/u DBP (mmHg) 77.5 ± 8.3 80.4 ± 6.8 76.5 ± 8.6 0.2
    f/u BMI (kg/m2) 25.6 ± 3.9 27.6 ± 3.6 25.0 ± 3.8     0.048
Laboratory Findings (Follow-up Data)
    f/u Serum Albumin (g/dL) 4.2 ± 0.3 4.1 ± 0.3 4.2 ± 0.3 0.5
    f/u Uric Acid (mg/dL) 6.3 ± 1.0 6.7 ± 0.8 6.2 ± 1.0 0.2
    f/u Total Cholesterol (mg/dL) 198.6 ± 31.4 207.0 ± 28.8 195.6 ± 32.2 0.3
    f/u LDL Cholesterol (mg/dL) 108.9 ± 25.1 112.5 ± 20.2 108.0 ± 26.4 0.7
    f/u HDL Cholesterol (mg/dL) 59.2 ± 20.5 60.2 ± 21.2 58.9 ± 20.7 0.9
    f/u Triglyceride (mg/dL) 170.0 ± 68.2 197.6 ± 89.8 161.6 ± 59.4 0.1
    eGFR slope (mL/min/1.73 m2/year) −2.6 ± 3.1 −5.4 ± 2.6 −1.8 ± 2.8       0.0004
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Continuous values are expressed as means ± standard deviation. Count data are expressed as percentages. Abbreviation: n, number; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; eGFR, estimated glomerular filtration rate; HU (UA ≧ 8 mg/dL), Hyperuricemia (Uric Acid ≧ 8 mg/dL or with treatments); f/u, follow-up

Comparison of the Clinical and Pathological Findings between Groups According to Renal Outcome

The results of the comparison of clinical and laboratory findings at the time of the kidney biopsy in the two groups according to renal outcome are summarized in Supplemental Table 1. The following values were significantly higher in the poor outcome group than in the benign outcome group: BMI (28.8 ± 4.3 vs. 24.7 ± 3.9 kg/m2, P = 0.005), UA (7.7 ± 1.4 vs. 6.5 ± 1.3 mg/dL, P = 0.02), proteinuria (1.29 ± 0.97 vs. 0.69 ± 0.70 g/day, P = 0.03), f/u BMI (27.6 ± 3.6 vs. 25.0 ± 3.8 kg/m2, P < 0.05), and eGFR slope (−5.4 ± 2.6 vs. −1.8 ± 2.8 mL/min/1.73 m2/year, P = 0.0004). There were no significant differences between the groups in any of the other parameters.

Baseline Parameters and Serum Uric Acid Cut-Off Value as an Indicator of Kidney Disease Progression

We assessed the baseline and follow-up parameters of the nephrosclerosis patients. The logistic regression models showed no significant differences between the groups in any of the baseline parameters and follow-up parameters except BMI and serum UA level (Fig. 2). The baseline serum UA value yielded the highest odds for a ≥ 50% eGFR decline or ESRD (OR, 1.86; 95% CI, 1.12 to 3.45). Based on these results, we decided to use baseline parameters to predict kidney disease progression. We performed ROC analyses to identify the optimal UA cut-off value for discriminating a ≥ 50% eGFR decline or ESRD during the follow-up examination. The results of the ROC analyses showed that the optimal UA cut-off value was 8.0 mg/dL (AUC = 0.74, sensitivity = 54.6%, specificity = 85.3%, Fig. 3).

Fig. 2.

Fig. 2.

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Odds ratio for a decline in eGFR by ≥ 50% from baseline or end-stage renal disease during the follow-up examination period.

Fig. 3.

Fig. 3.

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Receiver operating characteristic analysis to identify the optimal serum uric acid cut-off value for predicting an eGFR decline by ≥ 50% from baseline or end-stage renal disease during the follow-up examination period.

Hyperuricemia as a Prognostic Indicator in Nephrosclerosis Patients

To determine whether severe HU (UA ≥ 8.0 mg/dL) at the time of the renal biopsy was an independent predictor of a decline in renal function, we performed univariate and multivariate regression analyses based on the Cox hazard model for associations between the clinical findings and a ≥ 50% eGFR decline or ESRD during the follow-up (Table 1). The results showed that HU [Hazard Ratio (HR) = 18.2, P = 0.01] and BMI (HR = 1.30, P = 0.03) were significantly associated with a ≥ 50% eGFR decline or ESRD.

Table 1. Univariate and multivariate analysis of risk factors associated with ≥ 50% eGFR decline or ESRD (Total cohort n = 45).

Variables Univariate analysis
 Multivariate analysis
Hazard Ratio
(95% CI)		 P-value Hazard Ratio
(95% CI)		 P-value
Age (1 year increase) 1.04 (0.99–1.11) 0.2 – –
Male (vs. female) 0.74 (0.21–2.93) 0.7 – –
BMI (1 kg/m2 increase) 1.22 (1.07–1.41) 0.003 1.30 (1.01–1.68) 0.03
eGFR (1 mL/min/1.73 m2 increase) 0.98 (0.95–1.02) 0.3 – –
U-Prot (1 g/day increase) 2.24 (1.19–4.10) 0.009 2.07 (0.85–5.75) 0.1
Hypertension (vs. no) 1.83 (0.32–35.5) 0.6 – –
Hypercholesterolemia (vs. no) 6.68 (1.59–45.8) 0.02 2.42 (0.52–18.9) 0.3
Hypertriglyceridemia (vs. no) 2.50 (0.68–11.8) 0.2 – –
Diabetes mellitus (vs. no) 1.04 (0.27–3.50) 1.0 – –
Hyperuricemia (UA ≧ 8 mg/dL) (vs. no) 5.81 (1.57–27.6) 0.01 18.2 (2.68–278.8) 0.01
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Abbreviation: CI = confidence interval; BMI, body mass index; eGFR, estimated glomerular filtration rate; U-Prot, urinary protein excretion; vs, versus

Comparison between the Clinical Findings in Groups According to Serum Uric Acid Levels in the Total Cohort

We compared the clinical characteristics of two groups according to the UA value at the time of the kidney biopsy (Table 2). The serum UA levels (7.8 ± 1.3 vs. 6.5 ± 1.1 mg/dL, P = < 0.0001), blood urea nitrogen levels (22.5 ± 7.4 vs. 17.2 ± 5.8 mg/dL, P = 0.01), and serum creatinine levels (1.35 ± 0.40 vs. 1.10 ± 0.37 mg/dL, P = 0.04) were significantly higher in the HU group than in the non-HU group, and eGFR (46.4 ± 17.9 vs. 60.0 ± 21.5 mL/min/1.73 m2, P = 0.03) was significantly lower in the HU group than in the non-HU group. The percentages of patients being treated with an antihyperuricemic agent (77.8% vs. 0.0%, P < 0.0001) and a diuretic (16.7% vs. 0.0%, P = 0.03) were significantly higher in the HU group than non-HU group.

Table 2. Patient characteristics divided by uric acid status at the kidney biopsy (Total cohort n = 45).

Variables Total cohort
Total
n = 45		 HU
(UA ≧ 8 mg/dL)
n = 18		 Non HU
(UA < 8 mg/dL)
n = 27		 P-value Standardized Differences
Clinical Findings
    Age (years) 49.4 ± 12.5 50.4 ± 13.2 48.8 ± 12.2 0.7 0.126
    Gender (Male; %) 64.4 61.1 66.7 0.7 0.117
    SBP (mmHg) 136.1 ± 17.3 133.8 ± 17.5 137.7 ± 17.2 0.5 0.225
    DBP (mmHg) 83.4 ± 14.6 80.5 ± 10.9 85.3 ± 16.6 0.4 0.342
    BMI (kg/m2) 25.7 ± 4.3 26.4 ± 4.0 25.3 ± 4.6 0.4 0.255
Laboratory Findings
    Serum Albumin (g/dL) 4.1 ± 0.4 4.1 ± 0.4 4.1 ± 0.4 1.0 0.000
    Blood Urea Nitrogen (mg/dL) 19.3 ± 6.9 22.5 ± 7.4 17.2 ± 5.8 0.01 0.797
    Serum Creatinine (mg/dL) 1.20 ± 0.40 1.35 ± 0.40 1.10 ± 0.37 0.04 0.649
    eGFR (mL/min/1.73 m2) 54.6 ± 21.0 46.4 ± 17.9 60.0 ± 21.5 0.03 0.687
    Uric Acid (mg/dL) 6.8 ± 1.4 7.8 ± 1.3 6.1 ± 1.1 < 0.0001 1.412
    Total Cholesterol (mg/dL) 218.4 ± 42.4 223.2 ± 36.1 215.1 ± 46.5 0.5 0.195
    LDL Cholesterol (mg/dL) 124.5 ± 31.2 126.7 ± 25.8 123.0 ± 34.7 0.2 0.121
    HDL Cholesterol (mg/dL) 51.1 ± 18.9 54.1 ± 24.6 49.1 ± 14.1 0.4 0.249
    Triglyceride (mg/dL) 199.0 ± 116.7 218.5 ± 94.1 186.0 ± 129.7 0.4 0.287
    Proteinuria (g/day) 0.84 ± 0.80 0.94 ± 0.69 0.77 ± 0.88 0.5 0.215
Concomitant drugs
    Antihypertensive agent (%) 84.4 94.4 77.8 0.1 0.494
    Antihyperuricemic agents (%) 31.1 77.8 0.0 < 0.0001 2.647
    Antidyslipidemic agents (%) 35.6 50.0 25.9 0.1 0.513
    Antiplatelet agent (%) 48.9 61.1 40.7 0.2 0.417
    Antidiabetic agents (%) 4.4 5.6 3.7 0.8 0.090
    Diuretics (%) 6.7 16.7 0.0 0.03 0.633
Comorbidities
    Hypertension (%) 91.1 94.4 88.9 0.5 0.200
    HU (UA ≧ 8 mg/dL) (%) 40.0 100.0 0.0 < 0.0001 –
    Hypercholesterolemia (%) 55.6 66.7 48.1 0.2 0.383
    Hypertriglyceridemia (%) 53.3 66.7 44.4 0.1 0.461
    Diabetes mellitus (%) 22.2 22.2 22.2 1.0 0.000
Clinical Findings (Follow-up Data)
    f/u SBP (mmHg) 127.3 ± 13.0 127.8 ± 10.9 126.9 ± 14.4 0.8 0.070
    f/u DBP (mmHg) 77.5 ± 8.3 77.7 ± 6.5 77.3 ± 9.4 0.9 0.049
    f/u BMI (kg/m2) 25.6 ± 3.9 25.9 ± 4.3 25.5 ± 3.6 0.4 0.101
Laborator Findings (Follow-up Data)
    f/u Serum Albumin (g/dL) 4.2 ± 0.3 4.2 ± 0.4 4.2 ± 0.3 0.8 0.000
    f/u Uric Acid (mg/dL) 6.3 ± 1.0 6.6 ± 1.1 6.2 ± 0.9 0.1 0.398
    f/u Total Cholesterol (mg/dL) 198.6 ± 31.4 205.0 ± 35.9 194.1 ± 27.8 0.3 0.339
    f/u LDL Cholesterol (mg/dL) 108.9 ± 25.1 111.0 ± 23.7 107.5 ± 26.5 0.7 0.139
    f/u HDL Cholesterol (mg/dL) 59.2 ± 20.5 59.8 ± 20.5 58.7 ± 21.1 0.9 0.053
    f/u Triglyceride (mg/dL) 170.0 ± 68.2 180.5 ± 72.2 162.4 ± 65.6 0.4 0.262
Clinical Findings
    Age (years) 49.9 ± 12.1 48.3 ± 13.3 51.5 ± 11.0 0.5 0.262
    Gender (Male; %) 66.7 66.7 66.7 1.0 0.000
    SBP (mmHg) 135.7 ± 18.4 135.2 ± 18.0 136.3 ± 19.5 0.9 0.059
    DBP (mmHg) 82.5 ± 14.9 81.1 ± 11.1 83.9 ± 18.3 0.6 0.185
    BMI (kg/m2) 26.4 ± 4.8 26.6 ± 4.3 26.2 ± 5.5 0.8 0.081
Laboratory Findings
    Serum Albumin (g/dL) 4.1 ± 0.4 4.1 ± 0.4 4.1 ± 0.4 0.8 0.000
    Blood Urea Nitrogen (mg/dL) 19.9 ± 7.0 21.1 ± 7.1 18.7 ± 6.9 0.3 0.343
    Serum Creatinine (mg/dL) 1.27 ± 0.38 1.27 ± 0.39 1.27 ± 0.38 1.0 0.000
    eGFR (mL/min/1.73 m2) 49.9 ± 18.1 50.0 ± 17.1 49.9 ± 19.7 1.0 0.005
    Uric Acid (mg/dL) 7.1 ± 1.3 7.8 ± 1.2 6.5 ± 1.1 0.004 1.129
    Total Cholesterol (mg/dL) 219.0 ± 42.3 222.7 ± 31.8 215.2 ± 51.6 0.6 0.175
    LDL Cholesterol (mg/dL) 123.7 ± 29.3 125.0 ± 25.9 122.3 ± 33.3 0.8 0.091
    HDL Cholesterol (mg/dL) 50.7 ± 20.0 56.0 ± 25.8 45.3 ± 10.1 0.1 0.546
    Triglyceride (mg/dL) 213.4 ± 129.9 216.3 ± 93.0 210.5 ± 162.1 0.9 0.044
    Proteinuria (g/day) 0.88 ± 0.86 0.88 ± 0.69 0.89 ± 1.02 1.0 0.011
Concomitant drugs
    Antihypertensive agent (%) 86.7 100.0 73.3 0.03 0.854
    Antihyperuricemic agents (%) 36.7 73.3 0.0 < 0.0001 2.343
    Antidyslipidemic agents (%) 36.7 46.7 26.7 0.3 0.424
    Antiplatelet agent (%) 46.7 53.3 40.0 0.5 0.269
    Antidiabetic agents (%) 6.7 6.7 6.7 1.0 0.000
    Diuretics (%) 3.3 6.7 0.0 0.3 0.379
Comorbidities
    Hypertension (%) 93.3 100.0 86.7 0.1 0.554
    HU (UA ≧ 8 mg/dL) (%) 50.0 100.0 0.0 < 0.0001 –
    Hypercholesterolemia (%) 53.3 66.7 40.0 0.1 0.555
    Hypertriglyceridemia (%) 58.6 73.3 42.9 0.1 0.648
    Diabetes mellitus (%) 26.7 20.0 33.3 0.4 0.304
Clinical Findings (Follow-up Data)
    f/u SBP (mmHg) 128.5 ± 13.3 127.1 ± 11.4 130.2 ± 15.5 0.6 0.228
    f/u DBP (mmHg) 78.1 ± 7.8 77.9 ± 6.6 78.3 ± 9.2 0.9 0.050
    f/u BMI (kg/m2) 26.0 ± 4.4 26.1 ± 4.7 26.0 ± 4.3 0.9 0.022
Laborator Findings (Follow-up Data)
    f/u Serum Albumin (g/dL) 4.3 ± 0.3 4.2 ± 0.4 4.3 ± 0.2 0.6 0.316
    f/u Uric Acid (mg/dL) 6.5 ± 0.8 6.7 ± 0.8 6.3 ± 0.8 0.1 0.500
    f/u Total Cholesterol (mg/dL) 197.1 ± 34.3 202.0 ± 36.6 191.3 ± 32.1 0.5 0.311
    f/u LDL Cholesterol (mg/dL) 108.2 ± 24.9 108.3 ± 22.2 108.2 ± 28.6 1.0 0.004
    f/u HDL Cholesterol (mg/dL) 58.2 ± 17.7 60.6 ± 21.7 55.3 ± 11.9 0.5 0.303
    f/u Triglyceride (mg/dL) 177.9 ± 73.8 177.5 ± 73.8 178.3 ± 76.8 1.0 0.011
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Continuous values are expressed as means ± standard deviation. Count data are expressed as percentages. Abbreviation: HU (UA ≧ 8 mg/dL), Hyperuricemia (Uric Acid ≧ 8 mg/dL or with treatments); Non HU (UA < 8 mg/dL), Non Hyperuricemia (Uric Acid < 8 mg/dL or without treatments); n, number; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; eGFR, estimated glomerular filtration rate; f/u, follow-up

We performed a Kaplan-Meier analysis to assess kidney survival with a ≥ 50% eGFR decline or ESRD as the end-point. According to the kidney survival curves, the kidney survival rate of the nephrosclerosis patients in the HU group was significantly lower than in the non-HU group (Fig. 4A). At the 10-year follow-up examination, at least a 50% decrease in eGFR value was observed in 80% of the HU group (log rank, P = 0.005).

Fig. 4A.

Fig. 4A.

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Kidney survival rate of the group with serum uric acid levels > 8 mg/dL and the group with serum uric acid levels < 8 mg/dL in the total cohort.

Comparison between the Clinical and Laboratory Findings in Groups According to Serum Uric Acid Levels in the Propensity Score-Matched Cohort

Since the serum UA levels may have been affected by age, sex, BMI, SBP, and kidney function, we created a propensity score-matched cohort of HU patients and non-HU patients. Comparisons between the clinical and laboratory findings at the time of kidney biopsy in the two groups are summarized in Table 2. There were no significant differences between the propensity score-matched groups in any of the parameters except the parameters associated with UA level and BMI value. The serum UA level in the HU group (7.8 ± 1.2 mg/dL) was significantly higher than in the non-HU group (6.5 ± 1.1 mg/dL, P = 0.004). The percentage of patients being treated with an antihyperuricemic agent (73.3% vs. 0.0%, P < 0.0001) was higher in the HU group than in the non-HU group. In this propensity score-matched cohort, we also performed univariate and multivariate regression analyses based on the Cox hazard model for associations between the clinical findings and a ≥ 50% eGFR decline or ESRD during the follow-up (Table 3). As is the case with the total cohort, HU (HR = 17.7, P = 0.02) was significantly associated with a ≥ 50% eGFR decline or ESRD.

Table 3. Univariate and multivariate analysis of risk factors associated with ≥ 50% eGFR decline or ESRD (Propensity score matched cohort n = 30).

Variables Univariate analysis
 Multivariate analysis
Hazard Ratio
(95% CI)		 P-value Hazard Ratio
(95% CI)		 P-value
Age (1 year increase) 1.03 (0.98–1.10) 0.2 – –
Male (vs. female) 0.60 (0.17–2.26) 0.4 – –
BMI (1 kg/m2 increase) 1.19 (1.04–1.36) 0.01 1.25 (0.96–1.62) 0.1
eGFR (1 mL/min/1.73 m2 increase) 0.99 (0.96–1.03) 0.7 – –
U-Prot (1 g/day increase) 1.91 (1.00–3.52) 0.04 2.20 (0.85–6.70) 0.1
Hypertension (vs. no) 1.53 (0.25–30.4) 0.7 – –
Hypercholesterolemia (vs. no) 6.49 (1.57–44.0) 0.02 3.08 (0.61–27.7) 0.2
Hypertriglyceridemia (vs. no) 3.39 (0.90–16.3) 0.09 0.22 (0.03–1.75) 0.1
Diabetes mellitus (vs. no) 1.05 (0.27–3.50) 0.9 – –
Hyperuricemia (UA ≧ 8 mg/dL) (vs. no) 4.14 (1.10–19.9) 0.04 17.7 (2.26–307.4) 0.02
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Abbreviation: CI = confidence interval; BMI, body mass index; eGFR, estimated glomerular filtration rate; U-Prot, urinary protein excretion; vs, versus

Lastly, we performed a Kaplan–Meier analysis to assess kidney survival with a ≥ 50% eGFR decline or ESRD as the end-point. According to the kidney survival curves, the kidney survival rate of the HU group of nephrosclerosis patients was significantly lower than in the non-HU group (Fig. 4B). At the 10-year follow-up examination, there was at least a 50% decrease in eGFR value or ESRD in 81.4% of the HU patients (log rank, P = 0.03).

Fig. 4B.

Fig. 4B.

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Kidney survival rate of the group with serum uric acid value > 8 mg/dL and the group with serum uric acid < 8 mg/dL in the propensity score-matched cohort.

Discussion

Several problems need to be solved in the research on nephrosclerosis. The first problem is that the diagnosis of nephrosclerosis is generally made on the basis of the characteristic clinical features, and confirmation by renal biopsy is rarely indicated. As a result, the pathophysiology of nephrosclerosis has not been fully elucidated.

The second problem is that there are several different opinions regarding the pathological diagnosis of nephrosclerosis20, 24–27). Because arterial and arteriolar sclerosis is generally accompanied by global glomerulosclerosis and interstitial fibrosis, glomerular and interstitial lesions tend to be included among the diagnostic criteria for nephrosclerosis, but their inclusion may cause confusion influenced by aging, primary glomerular disease, or primary interstitial disease. We chose simple diagnostic criteria for nephrosclerosis focusing on initiators of kidney injury. In the present study, nephrosclerosis was defined as the renal pathology associated with sclerosis of renal arterioles and small arteries from the pathophysiological point20).

The third problem, which is the main topic of this study, is that arterial/arteriolar nephrosclerosis can be influenced by various causes and multiple risk factors. Arterial/arteriolar nephrosclerosis is usually associated with hypertension20, 28). Hypertension is thought to be both a cause of arterial/arteriolar nephrosclerosis and a renal prognostic factor29). On the other hand, Hsu doubted the conventional theory that non-malignant hypertension is a common cause of CKD and ESRD, because there is little evidence30), and Tracy et al. reported finding that arterial/arteriolar nephrosclerosis precedes the development of hypertension31). Furthermore, renal vascular lesions are sometimes observed in the absence of hypertension in animal models32).

Based on the definition of nephrosclerosis as renal pathology associated with sclerosis of renal arterioles and small arteries20), we postulate that the etiology of arterial/arteriolar nephrosclerosis is multifactorial. In addition to hypertension33), other clinical factors, including aging26, 34), systemic atherosclerosis35), systemic vasculitis36, 37), obesity38), and diabetes mellitus39), may contribute to development of the pathological features of arterial/arteriolar nephrosclerosis. In the same manner, we also consider that arterial/arteriolar nephrosclerosis can have multiple renal risk factors. Since there is little evidence regarding prognostic risk factors of biopsy-proven nephrosclerosis, we attempted to identify clinical prognostic risk factors for biopsy-proven arterial/arteriolar nephrosclerosis, focusing especially on the UA level.

The results of our multivariate analysis of the Cox proportional hazards model showed that HU (P = 0.01) and BMI (P = 0.03) were significantly associated with a ≥ 50% eGFR decline or ESRD in the patients with biopsy-proven arterial/arteriolar nephrosclerosis (Table 1). Since the blood pressure of our cohort was relatively well controlled (mean SBP/DBP = 136/83 mmHg) with antihypertensive agents (84.4%), hypertension was not a significant prognostic risk factor. Rather, HU was proved to be the most significant prognostic risk factor of arterial/arteriolar nephrosclerosis in the blood pressure-controlled cohort. Furthermore, the Kaplan–Meier analysis showed that the kidney survival rate of the biopsy-proven arterial/ arteriolar nephrosclerosis patients with HU was significantly lower than that of arterial/arteriolar nephrosclerosis patients without HU in a propensity-matched cohort (Fig. 4B; P = 0.03).

HU has been found to be a risk factor for development of hypertension40–43), and the results of several epidemiologic studies have indicated the existence of an association between the development of CKD and HU44, 45). HU has been found to independently predict the progression of kidney disease in diabetic nephropathy46, 47), IgA nephropathy48–51), chronic allograft nephropathy52), and CKD45, 53, 54). However, although HU has been associated with the presence of kidney arteriolar sclerosis33, 50, 55, 56) in CKD patients, there is little evidence of an association between UA and disease progression of biopsy-proven nephrosclerosis. In animal models, HU has been found to induce systemic hypertension and afferent arteriolar sclerosis57, 58). Although the precise mechanism of the nephrotoxicity of HU has not been fully elucidated, recent data showed a direct harmful effect of UA on endothelial cells59) and smooth muscle cells60). In humans, it has been reported that serum uric acid level is independently associated with an elevated carotid intimamedia thickness61). Therefore, UA injures renal vessels, which are the major lesion of arterial/arteriolar nephrosclerosis.

Conclusion

In conclusion, the results obtained by using a propensity score-matched cohort in the present study showed that HU is a clinical predictive marker for progression of biopsy-proven arterial/arteriolar nephrosclerosis. Since treatment of hypertension has recently become widespread, treatment for HU will become more important in patients with arterial/arteriolar nephrosclerosis.

Competing Interests

The authors have declared that no competing interests exist.

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