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. 2017 Mar 8;37(8):1399–1405. doi: 10.1007/s10571-017-0470-8

Elevated Plasma Homocysteine Level Increased the Risk of Early Renal Impairment in Acute Ischemic Stroke Patients

Jingjuan Chen 1,#, Guode Li 1,#, Zuohang Xu 1,#, Chengguo Zhang 1,✉, Yukai Wang 1, Haiqun Xie 1, Yan Shao 1, Lingmei Peng 1, Jiancong Lu 1, Dahua Yuan 1
PMCID: PMC11482136  PMID: 28275883

Abstract

Renal insufficiency is associated with the prognosis of acute ischemic stroke (AIS) and homocysteine (Hcy) levels. This study investigated the association between plasma Hcy levels and renal insufficiency in patients with AIS. A total of 987 patients with AIS who had been treated at the First People’s Hospital of Foshan between 2011 and 2014 were retrospectively studied. Based on their cystatin C (Cys C) levels, the patients were divided into the normal renal function group (Cys C ≤ 1.25 mg/L) or the renal impairment group (Cys C > 1.25 mg/L). Multivariate regression analysis was applied to reveal the association between hyperhomocysteinemia (HHcy) and renal impairment. The renal impairment group showed more advanced age of onset, higher percentage of prior stroke and hypertension, higher baseline National Institute of Health Stroke Scale score, lower high-density lipoprotein cholesterol levels, and higher Hcy levels compared with the normal renal function group. A multivariate analysis revealed a relationship between early renal impairment and Hcy levels: an increase of Hcy by 1 μmol/L was associated with an increase of 12–18% of the risk of renal impairment among patients with AIS and HHcy. Patients with AIS and HHcy had a 2.42–3.51 fold increase of the risk of renal impairment compared with patients with normal Hcy level (P < 0.001). In conclusion, patients with stroke and HHcy could be more prone to renal impairment.

Keywords: Homocysteine, Cystatin C, Stroke, Glomerular filtration rate, Renal insufficiency

Introduction

Renal insufficiency is closely associated with a poor prognosis of acute ischemic stroke (AIS). In Europe, an observational study of 4780 patients with stroke treated with intravenous thrombolysis showed that renal insufficiency was independently associated with poor 3 month outcomes, mortality, and symptomatic intracranial hemorrhage (Gensicke et al. 2013). In addition, a decrease of the estimated glomerular filtration rate (eGFR) by 10 mL/min/1.73 m2 was equivalent to an increase of the National Institute of Health Stroke Scale (NIHSS) score by 1 point (Gensicke et al. 2013). In the China National Stroke Registry (CNSR) and its subgroup analyses (Luo et al. 2014), both low (<45 mL/min/1.73 m2) and high eGFRs (≥120 mL/min/1.73 m2) were independent predictors of all-cause mortality and other adverse outcomes in patients with type 2 diabetes mellitus after acute stroke. Factors responsible for renal insufficiency in patients with AIS include, among others, age, hypertension, smoking, dyslipidemia, and diabetes mellitus, but these risk factors do not fully explain the mortality rates of AIS (Power 2013; Saeed et al. 2009; Yahalom et al. 2009). Modifiable risk factors have to be identified to reduce the mortality rates.

Cysteine proteinase inhibitor C (Cys C) is a secreted protein whose blood levels are not influenced by age, gender, body surface area, muscle mass, diet, blood glucose, blood lipids, inflammation, and many drugs (Coll et al. 2000; Han et al. 2001). Plasma Cys C levels are relatively stable without significant circadian fluctuations (Coll et al. 2000; Han et al. 2001), which overcomes the disadvantages of serum creatinine levels and estimated glomerular filtration rate (eGFR) as they are easily affected by a number of confounding factors. These advantages make Cys C an ideal indicator of the glomerular filtration rate during early renal impairment (Helmersson-Karlqvist et al. 2014; Ingelfinger and Marsden 2013). Cys C is superior to the widely used serum creatinine and urinary proteins levels due to its highly specific and sensitive nature. In the present study, Cys C was used to categorize the patients based on their kidney function.

Hcy is an important intermediate product of methionine metabolism and has been identified as a marker of vascular injury (Homocysteine Studies 2002; Ji et al. 2015; Toole et al. 2004). Plasma Hcy levels are closely associated with the incidence of cerebrocardiovascular events. In particular, high plasma Hcy levels have been recognized as a crucial independent risk factor of stroke (Homocysteine Studies 2002; Ji et al. 2015; Toole et al. 2004). Hyperhomocysteinemia (HHcy) is widely recognized as a risk factor of AIS and is listed in the Chinese guidelines for the management of stroke. In general, the cut-off value for high Hcy is 10 µmol/L and any higher Hcy level is defined as HHcy (Sacco et al. 2006; Stanger et al. 2003). According to some studies, Hcy levels are a strong independent risk factor for AIS (Cui et al. 2008; Sacco et al. 2004).

Hcy has been associated with renal insufficiency in patients with chronic renal failure and diabetic nephropathy (Suliman et al. 2001; Wang et al. 2015), but the underlying mechanisms remain unclear. Only a few studies have focused on the relationship between Hcy and renal insufficiency in patients with AIS (Huo et al. 2015; Ji et al. 2015; Sacco et al. 2004). Because Hcy is a marker of vascular damage, we hypothesized that Hcy could represent the extent of renal damage in patients with AIS (Huo et al. 2015; Ji et al. 2015; Sacco et al. 2004). Therefore, this study investigated the association between plasma Hcy levels and renal insufficiency in patients with AIS.

Methods

Study Design

This was a retrospective case–control study. Study subjects were patients with AIS admitted to the neurology department of the First People’s Hospital of Foshan (a grade A tertiary hospital) from 2011 to 2014. The study was approved by the ethics committee of the First People’s Hospital of Foshan. Informed consent to participate was given by all subjects (or relatives if the patients were unable to communicate).

Patients

The inclusion criteria were (1) admitted at the neurology department during the first 7 days after onset; (2) signs and symptoms consistent with the China acute ischemic stroke treatment guidelines 2010 (CMA 2010); and 3) confirmed by clinical symptoms, head magnetic resonance imaging (MRI), and/or computed tomography (CT).

The exclusion criteria were (1) transient ischemic attack, hemorrhagic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage; (2) incomplete baseline data or lack of plasma Hcy and/or serum Cys C data during hospital stay; (3) cerebral infarction resulting from peripheral vascular disease, arteritis, malignant tumor, trauma, medication, hematologic disease, vascular malformation, or aneurysm; or (4) severe hepatic or renal diseases, thyroid diseases, renal tumors, or polycystic kidney disease.

From 1941 eligible patients, 954 were excluded based on the exclusion criteria. Finally, 987 patients were included in the analysis.

Grouping

The patients were grouped according to their Cys C levels at admission. The normal renal function group included patients with serum Cys C levels ≤1.25 mg/L and the renal impairment group included patients with serum Cys C levels >1.25 mg/L. The normal reference standard of the Cys C detection kit (immune-enhanced colloidal gold technique) is 0.63–1.25 mg/L.

Data Collection

Demographics, vascular risk factors (history of stroke, hypertension, dyslipidemia, diabetes mellitus, smoking, and alcohol drinking), stroke severity (NIHSS score), head CT/MRI and urinary ultrasound data, primary diagnosis, and secondary diagnosis were collected from the medical charts. According to the 2010 Chinese Guideline for the Management of Hypertension, hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, the use of any antihypertensive drugs, and/or a self-reported history of hypertension. Prior stroke was defined as history of cerebral infarction or hemorrhage. HHcy was defined as plasma Hcy levels >10μmol/L. H-type hypertension was defined as primary hypertension with HHcy (Xu 2008). Stroke severity was defined based on the NIHSS scores: 0–4, mild/minor stroke; 5–15, moderate stroke; 15–20, moderate-to-severe stroke; and 21–42, severe stroke.

Biochemistry

All blood samples were taken after a 12 h fast via venous puncture. Fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), fasting serum insulin, C-peptide, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and uric acid (UA) were determined using routine clinical methods. Patients with a history of diabetes mellitus underwent a 2 h postprandial glucose measurement after breakfast. Those without diabetes mellitus underwent a standard oral glucose tolerance test. Morning urine was used to measure the urinary albumin-to-creatinine ratio (UA/CR).

At our hospital, an Olympus AU5400 biochemistry analyzer (Olympus Corporation, Tokyo, Japan) was used during the study period: reagents for lipoprotein a (Lp[a]) were bought from Sekisui Chemical Co., Ltd (Osaka, Japan), while reagents for plasma apolipoprotein A1 (Apo-A1) and B (Apo-B) were from Beijing Leadman Biochemistry Co., Ltd (Beijing, China). All other biochemistry parameters were determined using biochemical liquid reagents provided by Siemens (Erlangen, Germany). High and low levels control serums were provided by the Guangdong Center for Clinical Laboratory. TG level was detected by an enzymatic method; HDL-C and LDL-C by direct blocking assay; Apo-A1 and Apo-B by immunoturbidimetry; TC by cholesterol enzymatic method; serum Cys C by immunochromatography; and Hcy by an enzymatic cycling assay.

Statistical Analysis

Continuous variables were expressed as mean ± standard deviation (SD) or median (inter-quartile range, [IQR]) and categorical variables as percentage. Univariate analyses of age, gender, history of stroke, hypertension, dyslipidemia, diabetes mellitus, renal calculus, urinary tract infection, Hcy, HbA1c, blood urea nitrogen (BUN), and serum creatinine (SCr) were performed. Multivariate analysis was used to reveal the relationships between early renal impairment and Hcy. All data were analyzed using the EmpowerStats software (X&Y Solutions, USA; www.empowerstats.com) with P < 0.05 being defined as a significant difference.

Results

Baseline Characteristics of the Patients

From the 1941 patients screened for inclusion, 954 were excluded and 987 were included for the subsequent analyses. Mean plasma Hcy levels were 13.9 ± 6.5 µmol/L. Among the 699 (78.5%) patients with HHcy, 498 (83.8%) were male. Among the 518 (58.1%) patients with H-type hypertension, 307 were classified in the renal insufficiency group; this group had more advanced age of onset and higher frequency of history of stroke, higher frequency of hypertension, higher baseline NIHSS score, lower HDL-C levels, and higher Hcy levels compared with the normal renal function group. There were no differences between the two groups for gender, cigarette smoking, alcohol drinking, diabetes, TG, TC, and LDL-C (see Table 1).

Table 1.

Baseline characteristics of patients

Variable names Total n = 987 Normal renal function n = 680 Renal insufficiency n = 307 P value
Age (mean ± SD, years) 66.06 ± 12.05 63.65 ± 11.80 71.39 ± 10.84 <0.001
Male, n (%) 653 (66.2%) 437 (64.3%) 216 (70.4%) 0.061
Prior stroke, n (%) 276 (28.0%) 184 (27.7%) 92 (30.1%) <0.001
History of cigarette smoking, n (%) 382 (38.7%) 262 (38.5%) 120 (39.4%) 0.37
Alcohol abuse, n (%) 198 (20.1%) 135 (19.9%) 63 (20.5%) 0.21
Hypertension, n (%) 697 (70.6%) 457 (67.2%) 240 (78.2%) <0.001
Hcy (μmol/L) 13.87 ± 6.50 12.41 ± 5.20 17.16 ± 7.83 <0.001
HHcy 699 (78.5%) 451 (73.1%) 248 (90.5%) <0.001
H-type hypertension 518 (58.1%) 322 (52.2%) 196 (71.5%) <0.001
Diabetes mellitus, n(%) 289 (29.3%) 199 (29.3%) 90 (29.3%) 0.987
Baseline NIHSS score, median (IQR) 6.9 (1–23) 6.3 (1–18) 8.3 (2–23) 0.041
HbA1C (%) 6.61 ± 1.76 6.67 ± 1.86 6.47 ± 1.50 0.102
TC (mmol/L) 4.84 ± 1.18 4.87 ± 1.15 4.76 ± 1.24 0.152
TG (mmol/L) 1.67 ± 1.11 1.66 ± 1.19 1.70 ± 0.93 0.534
Apo-A1 (g/L) 1.35 ± 0.27 1.38 ± 0.26 1.28 ± 0.27 <0.001
Apo-B (g/L) 1.03 ± 0.32 1.03 ± 0.31 1.02 ± 0.35 0.443
Apo-B/Apo-A1 0.79 ± 0.29 0.77 ± 0.25 0.83 ± 0.35 0.006
HDL-C (mmol/L) 1.11 ± 0.30 1.14 ± 0.30 1.04 ± 0.28 <0.001
LDL-C (mmol/L) 3.08 ± 1.00 3.10 ± 0.97 3.03 ± 1.07 0.336
Lp(a) (mg/L) 297.67 ± 316.49 289.10 ± 309.54 316.43 ± 330.93 0.213
A/G 1.37 ± 0.27 1.41 ± 0.27 1.27 ± 0.24 <0.001
BUN 5.50 ± 2.30 4.83 ± 1.16 6.97 ± 3.31 <0.001
SCr 95.21 ± 81.13 78.49 ± 17.76 132.25 ± 136.06 <0.001
Renal calculus 34 (3.4%) 19 (2.8%) 15 (4.9%) 0.095
Urinary tract infection 49 (5.0%) 21 (3.1%) 28 (9.1%) <0.001
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SD standard deviation, Hcy homocysteine, HHcy hyperhomocysteinemia, IQR inter-quartile range, HbA 1 C glycosylated hemoglobin, TC total cholesterol

TG triglyceride, Apo-A1 apolipoprotein A1, Apo-B apolipoprotein B

HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) = lipoprotein (a), A/G albumin-to-globulin ratio

BUN blood urea nitrogen, SCr serum creatinine

Univariate Analyses

Among all included patients with AIS, age, hypertension, plasma Hcy levels, and urinary tract infection were positively associated with early renal impairment (Table 2).

Table 2.

Univariate analysis of risk factors related to renal impairment

OR 95%CI P Value
Age 1.06 1.05–1.08 <0.001
Gender 0.76 0.57–1.0 0.061
Prior stroke 1.25 1.14–1.42 <0.001
Hypertension 1.76 1.29–2.42 <0.001
Diabetes mellitus 1.01 0.75–1.37 0.922
HbA1C 0.95 0.86–1.04 0.273
Plasma Hcy concentration 1.18 1.14–1.22 <0.001
Renal calculus 1.78 0.89–3.56 0.101
Urinary tract infection 3.70 2.03–6.74 <0.001
Severity of disease 1.90 1.2–3.1 0.007
HDL-C 0.31 0.19–0.52 <0.001
A/G 0.08 0.04–0.15 <0.001
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OR odds ratio, CI confidence interval, HbA 1 C glycosylated hemoglobin

HDL-C high-density lipoprotein cholesterol, A/G albumin-to-globulin ratio

Multivariate Regression Analysis

Gender, age, hypertension, diabetes, cigarette smoking, alcohol abuse, renal calculus, and urinary tract infection were included in three multivariate logistic regression models. The results showed that Hcy was independently associated with renal impairment, with a 1 µmol/L increase of Hcy corresponding to a 12 to 18% increased risk of renal impairment (model I: OR = 1.18, 95% CI 1.14–1.22, P < 0.0001; model II: OR = 1.15, 95% CI 1.11–1.19, P < 0.0001; model III: OR = 1.12, 95% CI 1.08–1.16, P < 0.0001). Patients with AIS and HHcy had a 2.42–3.51 fold higher risk of renal impairment (model I: OR = 3.51, 95% CI 2.26–5.46, P < 0.0001; model II: OR = 2.54, 95% CI 1.60–4.03, P = 0.0001; model III: OR = 2.42, 95% CI 1.47–4.00, P = 0.0005) compared with the normal renal function group (Table 3).

Table 3.

Multivariate regression models of plasma Hcy concentration and HHcy with renal impairment

Model Plasma Hcy concentration HHcy
OR 95% CI P value OR 95% CI P value
I 1.18 1.14–1.22 <0.0001 3.51 2.26–5.46 <0.0001
II 1.15 1.11–1.19 <0.0001 2.54 1.60–4.03 0.0001
III 1.12 1.08–1.16 <0.0001 2.42 1.47–4.00 0.0005
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Hcy homocysteine, HHcy hyperhomocysteinemia, OR odds ratio, CI confidence interval

Model I: no adjustment

Model II adjustment variables: gender, age, and hypertension

Model III adjustment variables: gender, age, hypertension, uric acid, diabetes, renal calculus, and urinary tract infection

Subgroup Analysis

The patients with stroke were divided into four groups: control (non-hypertensive and normal plasma Hcy levels), hypertensive (hypertensive with normal plasma Hcy levels), HHcy (normotensive with plasma Hcy concentration >10 µmol/L), and H-type hypertension (hypertensive with plasma Hcy concentration >10 µmol/L). Patients with stroke and H-type hypertension had a 4.33 fold (OR = 4.33, 95% CI 2.11–8.89, P < 0.001) and 2.1 fold higher risk of renal impairment compared with normotensive and hypertension patients with normal Hcy level (Table 4), respectively.

Table 4.

Subgroup correlation analysis of the control, hypertensive, HHcy, and H-type hypertension groups

Sample size (%) Renal impairment OR (95% CI) P value
Control 73 (8.2) 1.0
Hypertensive 119 (13.4) 1.19 (0.50–2.82) 0.701
HHcy 181 (20.3) 2.87 (1.33–6.18) 0.007
H-type Hypertension 518 (58.1) 4.33 (2.11–8.89) <0.001
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The control group contained non-hypertensive patients with normal plasma Hcy levels

The hypertensive group contained hypertensive patients with normal plasma Hcy levels

The HHcy group contained normotensive patients with plasma Hcy levels >10 µmol/L

The H-type hypertension group contained hypertensive patients with plasma Hcy levels >10 µmol/L

HHcy hyperhomocysteinemia, OR odds ratio, CI confidence interval

Discussion

The present study showed that renal impairment was associated with more advanced age of onset, higher frequency of prior stroke and hypertension, higher NIHSS score at admission, lower HDL-C levels, and higher Hcy levels compared with normal renal function. After adjustment for age, gender, hypertension, diabetes mellitus, smoking, alcohol drinking, renal calculus, and UTI, an increase of Hcy by 1 µmol/L corresponds to an increase of the risk of renal impairment by 12–18% among patients with AIS. Patients with AIS and HHcy had a 2.42–3.51 fold increase of the risk of renal impairment compared with patients with normal Hcy level. In addition, patients with AIS and H-type hypertension had a 4.33 fold increased risk of renal impairment.

Recently, the relationship between GFR and cerebrocardiovascular events has drawn wide attention among clinical researchers. Renal insufficiency is a proven risk factor of cerebrocardiovascular events and indicates poor prognosis in many patients (Liu et al. 2012). A study of patients with chronic kidney diseases showed that plasma Hcy levels were an independent factor for renal function (Leach et al. 2014), but it is worthy of investigating whether similar results can be obtained in a population of patients with stroke.

A study of the Chinese population showed that Hcy is a neglected but crucial risk factor for the high prevalence and continuous incidence of stroke (Li et al. 2003). Many epidemiological and genetic polymorphism studies identified China-specific factors such as genetic mutations (C677T polymorphism) and dietary habits with low folic acid intake, leading to HHcy and detrimental effects on the human body (Li et al. 2003). The 2010 Chinese Guideline for the Management of Hypertension has listed elevated plasma Hcy levels as a new key factor affecting cardiovascular prognosis among hypertensive patients. A survey of the hypertensive population across six cities in China showed that the prevalence of HHcy is around 75% (men, 91%; women, 60%) (Li et al. 2007). Results of our retrospective study in patients with AIS showed that HHcy affects about 78.5% of the total population, including 83.8% men and 67.7% women, indicating that HHcy is a serious challenge for patients with stroke. In case–control studies conducted in China, the risks of stroke, stroke recurrence, and all-cause mortality were significantly higher in patients with HHcy (≥16 μmol/L) (OR = 1.87, 95% CI 1.58–2.22 (Li et al. 2003); RR = 1.31, 95% CI 1.10–1.61 (Zhang et al. 2010); RR = 1.47, 95% CI 1.15–1.88 (Zhang et al. 2010).

The kidney is an important target organ of atherosclerotic damage. The present study indicated that there was a significantly positive association between plasma Hcy levels and GFR. Hcy was identified as a factor that affects the glomerular filtration rate and the effect was independent from hypertension, diabetes, renal calculus, and UTI. By studying the relationship between glomerular filtration and Hcy concentration in the AIS population, we infer that the elevation of Hcy concentration may increase renal workload through promoting the severity of renal atherosclerosis (Brattstrom and Wilcken 2000). Of note, we found that in the AIS population, an increased Hcy concentration by 1 μmol/L leads to a risk of renal impairment increased by 12–18% (depending upon models). We surmise that the elevation of Hcy can be taken as a potential risk factor for the progression of renal impairment in the AIS population. Similar results have been observed in acute coronary syndrome (Huo et al. 2015), in which Hcy elevation was closely associated with renal impairment, and in which the high plasma Hcy group had a higher incidence of renal failure compared with those with low plasma Hcy levels.

Hypertension is the primary risk factor of stroke. Previous studies showed that H-type hypertension is not simply the combination of hypertension and high Hcy levels but also that the risk of cerebrocardiovascular events doubles when hypertension coexists with HHcy (Huo et al. 2015). Thus, a subgroup analysis was performed based on the occurrence of hypertension. Graham et al. (Graham et al. 1997) showed that patients with H-type hypertension have a 25–30 fold increased risk of cerebrocardiovascular events compared with normal people. Some studies conducted in China and other countries have confirmed the significant synergetic effects of HHcy and hypertension on the vascular risk of atherosclerosis (Huo et al. 2015; Towfighi et al. 2010; Ueland and Refsum 1989). In the subgroup analysis, we also found a synergistic effect of HHcy and hypertension on GFR. Patients with H-type hypertension suffer from a 4.33 fold higher risk of renal impairment compared with those with hypertension and normal Hcy level. As Hcy levels rise in hypertensive patients, vascular impairment becomes more severe and renal complications are more easily present. This may be attributed to the cytotoxic effect of Hcy on the vascular endothelial cells (Kalra 2004; Sacco et al. 2004; Sarkar and Lambert 2001). Through oxidative stress, elevated Hcy causes endothelial cell dysfunction, inducing vascular smooth muscle cell proliferation, inducing collagen synthesis, damaging arterial elastic fibers, and accelerating atherosclerosis. Similar mechanisms affect the functions of renal endothelial cells and glomerular basement membrane cells, resulting in declined glomerular filtration function. Under the hypertensive state, glomerular capillary endothelial cells suffer from high shear stress that causes the impairment of glomerular epithelial cells. Consequently, the permeability of basement membrane increases and renal impairment worsens.

Limitations of the present study include the retrospective design, which cannot demonstrate a clear causality between HHcy and renal impairment. Secondly, follow-up data were unavailable. In our future longitudinal study, we will track the changes of renal function and outcomes of patients with stroke and HHcy.

In conclusion, patients with stroke become more prone to renal impairment as the HHcy levels increase, especially for those with H-type hypertension.

Acknowledgement

The present work was sponsored and funded by the Science and technology project of Guangdong Province, China (No.: 2010B080702029). We thank the chief physicians of the neurology department of the First People’s Hospital of Foshan, Dr. Chengguo Zhang and Dr. Yukai Wang, for their suggestions, assistance, and supervision in study design. We also thank the staff of the neurology and medical care departments for their help in data collection. Lastly, we thank the department of clinical laboratory for providing the laboratory instruments and experiment protocols and assisting in testing the blood samples.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Footnotes

Jingjuan Chen, Guode Li and Zuohang Xu contributed equally to this work.

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