Introduction
A strong relationship between CKD and cardiovascular disease (CVD) has been reported (1 2 3 4 1 stroke , a cerebrovascular disease (5 6
Cerebral microbleeds (MBs), focal deposits of hemosiderin in the brain, are induced by previous leakage of bleeding from small vessels. The findings suggest that the blood vessels are prone to bleed in an advanced stage of microangiopathy. Indeed, a high prevalence of MBs has been reported in patients with stroke or CVD (7
Previously, we showed that decreased renal function was a significant factor for MBs in predialysis CKD, independent of the presence of hypertension (8 et al. (9
Materials and Methods
Study Population and Protocol
This was a prospective cohort study. All patients in this study were screened from patients with CKD admitted to Osaka City University Hospital or Ohno Memorial Hospital for education, evaluation of complications, and/or treatment for CKD, including elective dialysis initiation, from January of 2008 to January of 2011. CKD was diagnosed by the criteria proposed by the Japanese Society of Nephrology (10 11
This study protocol was developed in accordance with the Declaration of Helsinki and approved by the ethics review committee of Osaka City University Hospital (no. 1415); informed consent was obtained from all patients before their participation in this study. This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry as accepted by the International Committee of Medical Journal Editors (UMIN identification no. 000009783).
In total, 438 consecutive patients with predialysis CKD were assessed for eligibility. Patients with rapidly progressive GN, polycystic kidney disease, postrenal failure, and malignancy were excluded from this investigation, and 34 patients were excluded because of a past history of stroke (n =9), ischemic heart disease (n =4), malignancy (n =2), or polycystic kidney disease (n =7); 12 declined to participate because of claustrophobia. In total, 404 patients enrolled in this study (Figure 1 ). These patients were prospectively followed until May of 2012 at intervals of 1–6 months after baseline studies.
Figure 1.: Patient flow diagram. Composite outcome is stroke , cardiovascular event (ischemic heart disease or peripheral arterial disease ), doubling of serum creatinine, and development of ESRD. Cardiovascular disease (CVD) outcome is stroke , ischemic heart disease, and peripheral arterial disease . Kidney outcome is doubling of serum creatinine and development of ESRD.
The primary outcome was the composite of CVD outcomes and renal outcomes. The CVD outcomes included cardiovascular death, the new onset of myocardial infarction, coronary revascularization, stroke , and amputation/revascularization because of peripheral arterial event or death. Renal outcomes included doubling of the serum creatinine level and development of ESRD requiring dialysis or transplantation.
We reviewed the medical records for potential events. The cardiovascular events were on the basis of the diagnosis by the attending physicians who did not know the baseline magnetic resonance imaging (MRI) findings. Initiation of dialysis/renal transplantation and decline of eGFR were on the basis of the records of such events and laboratory tests. We did not perform central adjudication of the outcomes for this observational cohort study.
Measurements and Definitions
CKD was defined as the presence of kidney damage as reported by the KDIGO. The baseline characteristics, including a self-administered questionnaire covering medical history and medication completed by the patients, were evaluated when MRI was performed. BP was measured with the patients resting in a supine position for at least 10 minutes on the day of MRI using a standard mercury sphygmomanometer and cuffs appropriate to their arm circumference. In this study, hypertension was defined by (1 ) administration of antihypertensive agents or a history of hypertension, (2 ) systolic BP ≥140 mmHg, or (3 ) diastolic BP ≥90 mmHg. Diabetes mellitus was defined by (1 ) administration of insulin or oral antidiabetic agents or (2 ) prior diagnosis according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the American Diabetes Association (12
The eGFR was calculated using the following formula: eGFR (milliliters per minute per 1.73 m2 ) =194× (serum creatinine)−1.084 × (age)−0.287 . The value was multiplied by 0.739 for women. This formula represents the eGFR for Japanese people reported by the Japanese Society of Nephrology (11 13 2 (stage G1), 60–89 ml/min per 1.73 m2 (stage G2), 30–59 ml/min per 1.73 m2 (stage G3), 15–29 ml/min per 1.73 m2 (stage G4), and <15 ml/min per 1.73 m2 (stage G5).
All participating patients underwent a brain MRI that used a superconducting magnet at a field strength of 1.5 T on proton density, T1–weighted fluid-attenuated inversion recovery images, and two–dimensional T2*–weighted MRI in axial planes with 5-mm-thick slices and an interslice gap of 1.5 mm without intravenous administration of paramagnetic substances. MBs (Figure 2 ) were defined as focal areas of signal loss on T2*-weighted images without a history of stroke or transient ischemic attack. The MRI images were assessed independently by two trained physicians who were not aware of the clinical information. In cases of discordance, although rare, the two raters discussed until they reached consensus.
Figure 2.: Cerebral microbleeds (MBs) examined by T2*–weighted magnetic resonance imaging . T2*–weighted magnetic resonance imaging clearly shows the presence of MBs (allows). MBs, focal deposits of hemosiderin in the brain, are induced by previous leakage of bleeding from small vessels. A, anterior; L, left; P, posterior; R, right.
Statistical Analyses
We did not perform power analyses for the sample size determination by the given event rates in those with and without MBs, the prevalence of MBs, and other factors. Instead, we estimated the needed events for multivariate Cox analysis. We set the events per variable equal to 10. We planned to include approximately 10 variables in the model. Therefore, we needed ≥100 patients experiencing the composite outcomes. We performed this analysis when the number of such patients reached 124.
All data are expressed as means±SD. Differences between groups were examined by the unpaired t test. Categorical variables were compared using the chi-squared test. Log rank analysis was performed to determine whether MBs were associated with a higher end point rate.
Cox regression analysis was performed with the presence of MBs as the key exposure variable and renal, cardiovascular, and composite outcomes as the outcome variables using several models. Renal and CVD outcomes share some risk factors, such as age, sex, diabetes, and hypertension. Dyslipidemia is a risk factor of CVD, whereas it is not an established risk factor of kidney outcomes. Inflammation/protein-energy wasting, renal anemia, and CKD-mineral bone disease (CKD-MBD) are factors affecting CVD and mortality, whereas the contributions of these CKD–related risk factors to kidney outcomes are largely unknown. Therefore, we first used an unadjusted model (model 1), and then, we intended to adjusted the models by the shared risk factors (model 2: the main model adjusted for age, sex, diabetes, and systolic BP) and the CKD-related factors in addition to the shared risk factors (model 3: model 2, eGFR, and urinary protein; model 4: model 2, body mass index, serum albumin, and C-reactive protein; model 5: model 2 and hemoglobin; model 6: model 2, serum calcium, phosphate, and intact parathyroid hormone [PTH]; and model 7: model 2, HDL cholesterol, non-HDL cholesterol, and smoking).
All tests were two tailed, and a probability value of <0.05 was considered significant. These analyses were performed using JMP9 (SAS Institute Inc., Cary, NC).
Results
Baseline Characteristics
Of the 404 patients with CKD, 83 (20.5%) were found to have MBs. The clinical diagnoses of their underlying renal diseases were GN (n =137), diabetic nephropathy (n =121), nephrosclerosis (n =48), and others (n =98). The baseline eGFR ranged between 3.3 and 126.6 ml/min per 1.73 m2 . In Table 1 , the baseline clinical characteristics according to the absence (without MBs) or presence of MBs (with MBs) are shown. The patients with MBs were significantly older, had higher systolic and diastolic BPs, and had higher pulse pressure than patients without MBs. The higher levels of BUN and serum creatinine and lower eGFR in patients with MBs suggest more decreased renal function than in those without MBs. Furthermore, hemoglobin levels were significantly lower and serum phosphate and intact PTH levels were significantly higher in patients with MBs. Also, the prevalence of MBs was significantly higher in patients with a history of hypertension and those on anticoagulants or antiplatelet agents than in those without a history of hypertension and those not on those agents. There were no significant differences in the other clinical parameters, including the presence of diabetes, the presence of dyslipidemia, and smoking behavior, between those with and without MBs.
Table 1. -
Baseline characteristics of patients with and without
microbleeds
Characteristics
Total, n =404
Without MBs, n =321
With MBs, n =83
P Value
Age, yr
60.2±16.4
57.9±17.1
69.3±8.7
<0.001
Sex, men
241 (59.7%)
180 (56.1%)
61 (73.5%)
0.22
BMI, kg/m2
23.2±4.3
23.3±4.5
23.2±3.4
0.95
Systolic BP, mmHg
130.4±22.2
125±18
152±21
<0.001
Diastolic BP, mmHg
70.2±10.8
69±11
75±10
<0.001
Pulse pressure, mmHg
60.2±18.6
56±15
78±20
<0.001
Serum creatinine, mg/dl
2.66±2.48
2.30±2.28
4.05±2.74
<0.001
BUN, mg/dl
34.7±25.7
30.4±21.7
51.4±32.6
<0.001
eGFR, ml/min per 1.73 m2
38.6±31.0
43.1±31.9
21.1±18.6
<0.001
Proteinuria, g/Cre
2.86±3.42
2.78±3.44
3.12±3.30
0.44
Total protein, g/dl
6.2±1.0
6.2±1.0
6.2±0.9
0.87
Albumin, g/dl
3.3±0.7
3.3±0.7
3.3±0.6
0.62
Total cholesterol, mg/dl
211.2±78.9
214.9±81.4
196.9±66.9
0.06
Triglyceride, mg/dl
155.5±84.7
159.2±85.6
141.4±80.0
0.09
HDL cholesterol, mg/dl
50.1±16.9
50.6±17.0
48.2±16.7
0.25
Non-HDL cholesterol, mg/dl
161.1±73.8
164.3±76.6
148.7±60.9
0.09
CRP, mg/dl
0.09 (0.03–0.28)
0.08 (0.03–0.25)
0.12 (0.06–0.46)
0.67
Hemoglobin, g/dl
11.8±2.5
12.0±2.5
10.9±2.1
<0.001
Calcium, mg/dl
9.47±0.63
9.50±0.63
9.35±0.62
0.05
Phosphate, mg/dl
4.17±1.10
4.02±0.92
4.72±1.50
<0.001
iPTH, pg/ml
133.3±193.2
111.3±137.0
200.5±298.8
<0.001
Smoking behavior
142 (35.1%)
108 (33.6%)
34 (41.0%)
0.25
Presence of diabetes
166 (41.1%)
127 (39.6%)
39 (47.0%)
0.26
Presence of dyslipidemia
149 (36.9%)
114 (35.5%)
35 (42.2%)
0.31
Presence of hypertension
247 (61.1%)
174 (43.1%)
73 (88.0%)
<0.001
Anticoagulation and/or antiplatelet therapy
107 (26.5%)
77 (19.1%)
30 (36.1%)
0.04
MB, silent cerebral microbleed; BMI, body mass index; Cre, creatinine; CRP, C-reactive protein; iPTH, intact parathyroid hormone.
Follow-Up and End Points
The median follow-up duration was 2.3 years (25th to 75th percentiles, 1.6–3.4 years). Table 2 shows the outcomes by the presence of MBs in this study. Fifteen patients showed doubling of serum creatinine before being initiated on RRT, and 98 patients developed ESRD. The primary composite outcome was significantly more frequent in patients with MBs than in those without MBs. Patients with MBs had a significantly higher frequency of events of doubling of serum creatinine and ESRD than those without MBs. Cardiovascular events occurred in 44 patients (48 cases: 15 cases were ischemic heart disease, 11 cases underwent amputation [two cases were both ischemic heart disease and amputation], four cases were brain hemorrhage, and 18 cases were brain infarction). Deaths from cardiovascular causes were not different, but rates of ischemic heart disease and amputation or intervention because of arteriosclerosis obliterans were significantly higher in patients with MBs than in those without MBs. In addition, the frequency of stroke events was significantly higher in patients with MBs than in those without MBs.
Table 2. -
Outcomes by presence of
microbleeds
Variable
Overall, n =404
With MBs, n =83
Without MBs, n =321
P Value
a
Composite outcome
124 (30.7%)
56 (67.5%)
68 (21.1%)
<0.001
Kidney outcome
Doubling of S-Cre and/or ESRD
113 (28.0%)
51 (61.4%)
62 (19.3%)
<0.001
CVD outcome
(1 ) Death of CVD
12 (3.0%)
4 (4.8%)
8 (2.5%)
0.28
(2 ) Ischemic heart disease and/or PAD
22 (5.4%)
11 (13.3%)
11 (3.4%)
<0.001
(3 ) Stroke
22 (5.4%)
13 (15.7%)
9 (2.8%)
<0.001
1 + 2 + 3
40 (9.9%)
22 (26.5%)
18 (5.6%)
<0.001
Lost to follow-up
b
12 (3.0%)
2 (2.4%)
10 (3.1%)
0.28
The CVD outcomes included cardiovascular death, new onset of myocardial infarction, coronary revascularization, stroke , and amputation/revascularization because of PAD. Stroke event is brain infarction or brain hemorrhage. MB, microbleed; S-Cre, serum creatinine; CVD, cerebrovascular and cardiovascular disease ; PAD, peripheral arterial disease .
a Log rank tests were used to explore the difference in time to each outcome.
b Lost patients due to moving or changing hospital.
Kaplan–Meier analyses on the basis of the presence of MBs for cardiovascular, kidney, and composite outcomes are shown in Figure 3 . The group with MBs had a significantly higher frequency of each outcome than the group without MBs.
Figure 3.: Kaplan–Meier analyses of cumulative rates for each outcome. MB, microbleed.
Predictors of Vascular Morbidity (Kidney and Cardiovascular Outcomes; Model 1)
Table 3 shows the results of univariate Cox proportional hazard analyses of the composite outcome. Among many factors that could predict composite outcome, the presence of MBs showed a very high hazard ratio of 4.62 (95% confidence interval, 3.22 to 6.62).
Table 3. -
Univariate regression analyses of composite outcome
Variable
Unit Change
Univariate
Hazard Ratio
95% CI
P Value
MBs
4.62
3.22 to 6.62
<0.001
Age
1 yr
1.03
1.02 to 1.05
<0.001
Sex
0.86
0.59 to 1.23
0.42
BMI
1 kg/m2
0.98
0.94 to 1.02
0.34
Systolic BP
10 mmHg
1.31
1.23 to 1.40
<0.001
Diastolic BP
10 mmHg
1.17
1.00 to 1.36
0.05
Pulse Pressure
10 mmHg
1.41
1.30 to 1.52
<0.001
eGFR
1 ml/min per 1.73 m2
0.91
0.89 to 0.92
<0.001
Proteinuria
1 g/Cre
1.10
1.06 to 1.14
<0.001
Albumin
1 g/dl
0.71
0.57 to 0.90
0.004
Total cholesterol
1 mg/dl
0.99
0.99 to 1.00
<0.001
Triglyceride
1 mg/dl
1.00
0.99 to 1.00
0.001
HDL cholesterol
1 mg/dl
0.98
0.97 to 1.00
<0.01
Non-HDL cholesterol
1 mg/dl
0.80
0.70 to 0.90
<0.001
Hematocrit
1%
0.90
0.89 to 0.92
<0.001
Hemoglobin
1 g/dl
0.66
0.60 to 0.72
<0.001
Blood glucose
1 mg/dl
1.00
1.00 to 1.01
0.08
HbA1c
1%
1.04
0.91 to 1.17
0.57
Glycoalbumin
1%
1.05
1.01 to 1.08
0.01
C-reactive protein
1 mg/dl
1.15
1.06 to 1.22
0.003
Calcium
1 mg/dl
0.39
0.32 to 0.49
<0.001
Phosphate
1 mg/dl
2.00
1.75 to 2.27
<0.001
Intact PTH
1 pg/ml
1.00
1.00 to 1.00
<0.001
Smoking behavior
1.14
0.79 to 1.65
0.45
Presence of diabetes
1.77
1.24 to 2.54
0.002
Presence of hypertension
3.31
2.14 to 5.33
<0.001
Anticoagulation and/or antiplatelet therapy
1.99
1.38 to 2.85
<0.001
95% CI, 95% confidence interval; MB, silent cerebral microbleed; BMI, body mass index; Cre, creatinine; HbA1c, hemoglobin A1c; PTH, parathyroid hormone.
Multivariate Regression Analyses for Composite Outcome, Kidney Outcome, and CVD Outcome by Presence of MBs
Table 4 shows the results of multivariate Cox proportional hazard analyses for composite, kidney, and CVD outcomes by the presence of MBs. Model 1 is the unadjusted model. Model 2 is adjusted by shared CVD risk factors. Model 3 is adjusted by kidney cause factors in addition to model 2 factors. Model 4 is adjusted by inflammation/protein–energy wasting factors in addition to model 2 factors. Model 5 is adjusted by anemia in addition to model 2 factors. Model 6 is adjusted by CKD-MBD in addition to model 2 factors. Model 7 is adjusted by dyslipidemia factors in addition to model 2 factors. For each outcome except that of model 6, the presence of MBs showed significant differences.
Table 4. -
Multivariate regression analyses
Model
Adjustment
HR
95% CI
P Value
Composite outcome
1
Unadjusted
4.62
3.22 to 6.62
<0.001
2
Age, sex, DM, and systolic BP
2.58
1.68 to 3.96
<0.001
3
Model 2, eGFR, and UP
2.61
1.69 to 4.04
<0.001
4
Model 2, BMI, Alb, and CRP
3.18
2.04 to 4.97
<0.001
5
Model 2 and Hb
2.58
1.70 to 3.92
<0.001
6
Model 2, Ca, P, and iPTH
1.67
0.99 to 2.80
0.06
7
Model 2, HDL cholesterol, non-HDL cholesterol, and smoking
2.51
1.64 to 3.87
<0.001
Kidney outcome
1
Unadjusted
4.25
2.91 to 6.17
<0.001
2
Age, sex, DM, and systolic BP
2.41
1.55 to 3.77
<0.001
3
Model 2, eGFR, and UP
2.51
1.58 to 4.00
<0.001
4
Model 2, BMI, Alb, and CRP
3.08
1.93 to 4.92
<0.001
5
Model 2 and Hb
2.51
1.62 to 3.89
<0.001
6
Model 2, Ca, P, and iPTH
1.52
0.88 to 2.61
0.13
7
Model 2, HDL cholesterol, non-HDL cholesterol, and smoking
2.36
1.50 to 3.69
<0.001
CVD outcome
1
Unadjusted
5.34
2.87 to 10.09
<0.001
2
Age, sex, DM, and systolic BP
3.46
1.62 to 7.43
0.001
3
Model 2, eGFR, and UP
3.37
1.57 to 7.30
0.002
4
Model 2, BMI, Alb, and CRP
4.41
2.01 to 9.79
<0.001
5
Model 2 and Hb
3.54
1.66 to 7.58
0.001
6
Model 2, Ca, P, and iPTH
1.96
0.74 to 5.25
0.18
7
Model 2, HDL cholesterol, non-HDL cholesterol, and smoking
3.33
1.53 to 7.25
0.003
HR, hazard ratio; 95% CI, 95% confidence interval; DM, diabetes mellitus; UP, proteinuria; BMI, body mass index; Alb, albumin; CRP, C-reactive protein; Hb, hemoglobin; Ca, calcium; P, phosphate; iPTH, intact parathyroid hormone; CVD, cardiovascular disease .
Stratified Analyses
Figure 4 shows the association between MBs and the composite outcome stratified by age, sex, diabetes mellitus, systolic BP, proteinuria, and eGFR at baseline using the model adjusted for the four variables as shown in model 2 in Table 2 . The higher risk in patients with MBs was almost consistently found, regardless of these factors.
Figure 4.: Forest plots of the composite outcome. Association between baseline cerebral microbleeds (MBs) and composite outcome during follow-up stratified by age, sex, systolic BP, diabetes mellitus, proteinuria, or eGFR. The graphs indicate hazard ratios (95% confidence intervals) adjusted for age, sex, systolic BP, and diabetes mellitus.
Discussion
In this study, the presence of MBs was clearly shown to predict composite outcome, including future cardiovascular events and reduction of renal function, in patients with predialysis CKD.
T2*-weighted MRI for patients with nondialysis CKD showed that 83 patients (20.5%) had MBs. The prevalence of MBs in healthy populations without cerebrovascular disease was reported to be around 3.1%–8.5%; however, the prevalence of MBs was nearly 10-fold greater in cohorts with spontaneous intracerebral hemorrhage compared with in healthy elderly patients (14 15 16 8
The presence of MBs has been reported to be a risk for CVDs (8 17 18 19 8
Indeed, the prevalence of hypertension was significantly higher in patients with MBs than in those without MBs. On pathologic examination, MBs represent minor blood leakage from perforating branches of cerebral arteries (19–21 8 22
What is the pathophysiologic mechanism for the observed association of cerebral MBs with both CVD and kidney outcomes? There are small and short vessels called strain vessels (22 22 22 23 24 25
Patients with CKD who had MBs had poorer kidney outcomes, including doubling of creatinine level and ESRD, than those without MBs in this study in each CKD stage. Previously, there was no cohort report of MBs that mentioned renal outcomes of patients with predialysis CKD. There were two studies that showed that the presence of silent cerebral infarction was a prognostic factor for reduction of renal function in patients with CKD (26 27 19–21
The presence of MBs was not a predictor for composite and kidney outcomes and CVD events on multivariate regression analysis in model 6 in this study. This model was adjusted with calcium, phosphorus, and intact PTH, factors related to CKD-MBD, in addition to model 2 factors (age, sex, diabetes mellitus, and systolic BP). The phosphorus-to-fibroblast growth factor 23 ratio was reported to be an independent risk factor for CVD (28 29 30–33
This study has several limitations. First, the sample size was relatively small as was the number of CVD events. In this study, there were 22 strokes, 22 cardiovascular events, and 40 CVD events. The small number of CVD events did not permit correction for all potential predictors. The cause of this may be the short observation period. However, there were enough events of kidney function loss during this observation period. Second, there was the possibility of unmeasured or residual confounding. Third, this study was an observational study. These results were not discussed as cause and effect associations.
In conclusion, this is the first report that clearly shows that the presence of MBs is a strong predictor for composite outcome, which included poor kidney outcome and CVD events, in patients with predialysis CKD. This study shows the high prevalence of MBs in patients with predialysis CKD and suggests the brain-kidney association.
Disclosures
None.
Acknowledgments
We thank Dr. Kaeko Kitamura and Dr. Tetsuo Nakayama for their careful readings of brain magnetic resonance imaging .
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