H-type hypertension is a risk factor for chronic kidney disease: a case-control study

doi:10.21203/rs.3.rs-3992934/v1

Background: Previous studies have examined the relationship between hypertension or homocysteine and chronic kidney disease (CKD). However, the relationship between H-type hypertension and CKD remains uncertain. The aim of this study was to investigate the relationship between H-type hypertension and CKD and to provide a scientific basis for the prevention and treatment of CKD;

Methods: This case-control study included 514 study subjects, 257 in each of the case and control groups. The diagnostic criteria for CKD were structural or functional abnormalities of the kidneys for ≥ 3 months, which may or may not be accompanied by a decrease in eGRF, and which may be manifested by abnormalities of pathology or indicators of renal injury (including blood urine and composition or imaging tests). All patients were categorized into normal, Hcy (Hcy ≥10 μmol/L), hypertensive, and H-type hypertension groups according to their Hcy levels and whether they had hypertension.Univariate analysis and multivariate logistic regression models were used to assess the association between H-type hypertension and CKD, and subgroup analyses were performed for potential confounders;

Results: The differences between the CKD group and the control group in terms of age, education, exercise, BMI, TG, HDL, UA, Scr, BUN and hs-CRP were statistically significant (p < 0.05).Logistic regression modeling showed that after correcting for confounders, we found that the H-type hypertension group had the highest risk of CKD (OR=4.453; 95% CI: 2.075-9.560; P<0.001). There was no interaction of H-type hypertension with age, education level, physical activity, or TG on the development of CKD(P＞0.05);

Conclusions: The coexistence of Hcy and hypertension increases the risk of developing CKD, and H-type hypertension is a risk factor for CKD.

homocysteine

hypertension

H-type hypertension

chronic kidney disease

case-control study

Chronic kidney disease (CKD) is a chronic progressive disease characterized by structural dysfunction of the kidneys or a decrease in glomerular filtration rate (GFR) that is difficult to cure(1, 2).CKD is a global public health problem. The incidence of CKD is on the rise worldwide, with a global prevalence of 13.4%, and can cause 1.2 million deaths and 28 million years of life lost each year(3, 4).In China, the prevalence of CKD is 10.8%, and the number of people suffering from the disease is as high as 132 million, ranking first in the world(5).H-type hypertension is essential hypertension with elevated homocysteine (Hcy ≥ 10 umol/L)(6).There is a close causal relationship between hypertension and the occurrence and development of chronic kidney disease, and hypertension is one of the risk factors for chronic kidney disease(7, 8).Studies have shown that hypertension is closely related to the decline of renal function in patients with CKD(9).At the same time, hypertension is one of the most common serious complications of CKD, and the prevalence of hypertension increases as renal function declines(10).Therefore, the treatment of hypertension is very important for CKD patients. Since 70% of Hcy in the body is excreted through the kidneys, renal function is closely related to Hcy.Hcy has been found to be associated with progressive deterioration of renal function and cardiovascular complications in patients with CKD, and 80–90% of patients with end-stage renal disease have significantly higher concentrations of Hcy in their blood(11, 12).More than 70% of hypertensive patients in China have elevated plasma homocysteine levels(13).These findings suggest that H-type hypertension may imply double damage to the kidneys. In order to understand the relationship between H-type hypertension and CKD, this case-control study explored the relationship to provide a scientific basis for the prevention and treatment of CKD.

2.1 Study population

Using a case-control study, the study population was selected from 257 inpatients diagnosed with CKD in the Department of Nephrology of Hunan Provincial People's Hospital from December 2021 to December 2022 as a case group, and 257 patients not diagnosed with CKD from other departments as a control group. Inclusion criteria: (1) complete clinical information; (2) able to complete the entire survey independently; (3) voluntary participation in this survey and cooperation in completing the questionnaire and physical examination. Exclusion criteria: (1) female population during pregnancy or lactation; (2) patients with recent use of drugs that may affect blood pressure and Hcy levels; (3) patients with secondary hypertension caused by pheochromocytoma, sleep apnea syndrome, etc.; (4) patients with a clear history of renal disease, such as diabetic nephropathy, gouty nephropathy, lupus nephritis, etc.; and (5) patients with combined organ failure, hepatic cirrhosis at the stage of decompensated stage, and renal insufficiency. This study was reviewed and approved by the Medical Ethics Committee of Hunan Normal University (No. 034/2017), and all subjects signed an informed consent form before participating in this study.

2.2 Data collection

A self-administered questionnaire was used to conduct a "face-to-face" survey of all respondents. The survey included information on general demographic characteristics (age, sex, education, marital status), lifestyle habits (exercise, smoking, alcohol consumption), and past medical history (history of hypertension, history of taking antihypertensive drugs). Physical examination (including height, weight, heart rate and waist circumference). Laboratory tests include homocysteine (Hcy); total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), alanine aminotransferase (ALT), blood creatinine (CRE), and blood glucose. Low density lipoprotein cholesterol (LDL), alanine aminotransferase (ALT), creatinine (Scr), blood urea nitrogen (BUN), ultra-sensitive C-reactive protein (UCRP), and blood glucose (BG). ), hypersensitive C-reactive protein (hs-CRP).

Education level was categorized into four groups: elementary school and below, middle school, high school, and college and above. Marital status was categorized as single and married. Patients were judged to be exercising regularly based on the number of times they exercised in a week: 0 was no exercise, 1-3 was irregular exercise, and >3 was regular exercise. We defined current smoking as continuous or cumulative smoking of one or more cigarettes per day; current alcohol consumption was defined as at least 2 drinks per week.

2.3 Definition of H-type hypertension

Patients with essential hypertension whose plasma Hcy concentration exceeded 10 μmol/L were classified as H-type hypertension. All patients were categorized into a normal group, a simple hypertension group, a simple Hcy group (Hcy ≥10 μmol/L), and an H-hypertension group according to their Hcy levels and whether they had hypertension.

2.4 Definition of CKD

The diagnostic criteria for CKD were the presence of structural or functional abnormalities in the kidneys for ≥3 months, which may or may not be accompanied by a decrease in eGRF, and which may be manifested by abnormalities in pathology or markers of renal injury (including blood-urine and compositional or imaging tests).

2.5 Statistical methods

Data were statistically analyzed using SPSS 26.0, categorical variables were expressed as numbers and percentages (%), and the χ² test was used to compare differences between groups. Continuous variables are expressed as M (P₂₅ , P₇₅), and nonparametric comparisons of between-group differences were used. Multivariate logistic regression models were used to examine the association between H-type subgroups and CKD risk. We constructed 3 models: model 1 was unadjusted; in model 2, we adjusted for age, educational background, exercise, and BMI. model 3: TG, HDL, UA, Scr, BUN, and CRP were added to model 2. Subgroup analyses were performed and the interaction between H-type hypertension and related influencing factors on the development of CKD was further analyzed. Differences were statistically significant at P < 0.05.

3.1 Basic information

In this case-control study the control group of 257 cases had a median age of 63.00 years and an interquartile range of (47.00,68.00) years. The case group of 257 cases had a median age of 65.00 years and an interquartile range of (50.00,71.00) years. According to the presence or absence of CKD, Table 1 shows the baseline characteristics of the study population. It was found that the difference between the H-hypertension subgroups was statistically significant, and the prevalence of CKD was highest in the H-hypertension group (p < 0.05).Low education, insufficient physical activity, and obesity were risk factors for CKD compared to the control group. In addition, eGFR was significantly lower and TG, UA, Scr, BUN, and hs-CRP levels were significantly higher in CKD patients (P < 0.05).Table 1.

3.2 Correlation between H-type hypertension and CKD

Model 1 was built with the presence of H-type hypertension as the dependent variable (assignment: CKD = 1, control = 0) and H-type hypertension as the independent variable, and the results showed that the risk of CKD in the H-type hypertension group was significantly higher than that in both the Hcy and the hypertension groups (OR = 12.632,95% CI: 7.162-22.297; P < 0.001), and in a logistic regression model adjusting for some confounding factors ( educational background, exercise, BMI, TG, HDL, UA, Scr, BUN, hs-CRP) in a logistic regression model (Model 3), H-type hypertension could still increase the risk of CKD (OR = 4.453, 95% CI: 2.075-9.560; P < 0.001). Table 2.

3.3 Subgroup analysis

In order to more clearly define the relationship between H-type hypertension and the risk of developing CKD, further subgroup analyses of age, education level, exercise status and TG were performed, and the interactions between H-type hypertension and related influencing factors on the development of CKD were analyzed. The results showed that there was no interaction between H-type hypertension and age, education level, exercise status and TG on the development of CKD (P > 0.05). Figure 1.

This case-control study examined the relationship between H-type hypertension and CKD. Logistic regression revealed that the risk of CKD was associated with H-type hypertension, which was more closely associated with CKD. After adjusting for possible confounders, we obtained the same results. In all subgroups, the risk of CKD was higher in the H-type hypertension group than in the Hcy and hypertension groups.
CKD greatly reduces the quality of life of patients and imposes a heavy financial and psychological burden on patients and their families(14).There is a strong Association between CKD and hypertension and Hcy(15).The presence of decreased renal function in hypertensive patients may lead to incurable CKD(16).Hcy is a sulfur-containing amino acid, an intermediate product in the metabolism of methionine, one of the essential amino acids.And the kidney, as the main site of Hcy metabolism, plays an important role in the process of Hcy metabolism.Epidemiologic investigations have shown that increased levels of Hcy in the body play a key role in the development of CKD and are one of the major risk factors for the development of CKD(17).Some studies have found that Hcy can be used as an independent biomarker to predict the decline of renal function and the development of CKD(18).Liu et al.(19)who retrospectively analyzed 7240 hypertensive patients, found that patients with hyperhomocysteinemia had a higher rate of long-term decline in renal function compared to non-homocysteinemic patients(20).The results of the present study similarly found that Hcy levels were significantly higher in CKD patients than in non-CKD patients .The effect of Hcy on the prevalence of CKD and eGFR in Chinese patients with H-type hypertension was also found in a cross-sectional study of 12,873 Chinese adults with H-type hypertension between the ages of 27 and 75 years(21).Therefore, high attention should be paid to the development of H-type hypertension in the management of CKD.
Current experimental studies have found that Hcy can promote the development and progression of CKD by inducing oxidative stress, inflammatory response, hypomethylation and other pathways(22).Some studies have even found that renal vascular changes such as decreased vascular density, decreased blood flow and increased smooth muscle cell proliferation associated with Hcy are one of the causes of impaired renal function(19).Oxidative stress can also damage kidney cells affecting glomerular filtration rate and promoting the fibrotic process in the kidney(23).It is possible that the mechanism of CKD due to H-hypertension is because Hcy can affect glomerulosclerosis and interstitial fibrosis leading to progressive decline in CKD function(24).Meanwhile, the increase of Hcy can attenuate the vasodilatory effect of NO, induce oxidative stress(25),and stimulate the proliferation of vascular smooth muscle cells (26), which alters the elasticity of the vascular wall, increases vascular resistance, and ultimately leads to an increase in blood pressure(27).Both Hcy and hypertension can cause severe kidney damage(28).This suggests that both blood pressure changes and Hcy levels should be paid attention to in the early prevention of CKD, and that the dangers of H-type hypertension should be fully recognized in order to avoid more serious damage and poorer prognosis for CKD patients.
However, this study still has some limitations. Firstly, this study is a retrospective case-control study with weak causal argumentation to prove the causal relationship between H-type hypertension and CKD. This study also has some recall bias, which will have some influence on the results. Second, the subjects of this study were all from Hunan Provincial People's Hospital, and there was a certain selection bias; the results of this study can only represent the situation of patients in this hospital, and the conclusions obtained cannot be extrapolated to the whole population. Finally, this study did not adjust for other relevant confounding factors such as relevant disease history and diet that may have an impact on the results.

Our findings suggest that H-type hypertension is associated with chronic kidney disease.The risk of morbidity in the H-type hypertension group was higher than that in the Hcy and hypertension groups.Therefore, high attention should be paid to the development of H-type hypertension in the prevention and treatment of CKD.

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author Contributions

TL: research design, data analysis, and manuscript writing. LZ: data collection and research design. ZD: data collection and comments. TY: data collection and investigation. All authors contributed to the article and approved the submitted version. XH: funding acquisition, conceptualization, and writing—review and editing.

Ethics Approval and Consent to Participate

The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Hunan Normal University (No. 034/2017). The patients/participants provided their written informed consent to participate in this study.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Acknowledgment

We thank all those who participated in this study and Hunan Provincial People's Hospital for their support.

Funding

This study was funded by the National Natural Science Foundation of China (8177120863), Hunan Provincial Science and Technology Department (2020JJ4047), and Changsha Science and Technology Bureau (kq1801096). The funders had no role in the study design, data collection,and analysis, decision to publish, or preparation of the manuscript.

Consent for publication

Not applicable.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Table 1.Baseline characteristics of study participants according to CKD status
Characteristics	Total	Control group	CKDgroup	χ²/Z	P-value
Genders,n(%)				0.238	0.626
Female	367(71.40)	76(29.57)	71(27.63)
Male	147(28.60)	181(70.43)	186(72.37)
Education background,n(%)				14.730	0.002
Primary school and below	182(35.41)	86(33.46)	96(37.35)
Junior school	136(26.46)	55(21.40)	81(31.52)
Senior school	142(27.63)	79(30.74)	63(24.51)
College and above	54(10.51)	37(14.40)	17(6.61)
Marital status,n(%)				0.485	0.486
Single	90(17.51)	42(16.34)	48(18.68)
Married	424(82.49)	215(83.66)	209(81.32)
Exercise,n(%)				16.178	<0.001
No exercise	230(44.75)	105(40.86)	125(48.64)
Irregular exercise	159(30.93)	70(27.24)	89(34.63)
Regular exercise	125(24.32)	82(31.91)	43(16.73)
Smoking history,n(%)				0.036	0.850
Never smokes	166(32.30)	82(31.91)	84(32.68)
Current or former smokers	348(67.70)	175(68.09)	173(67.32)
Drinking history,n(%)				0.406	0.524
No	114(22.18)	60(23.35)	54(21.01)
Yes	400(77.82)	197(76.65)	203(78.99)
BMI,n(%)				8.171	0.043
<18.5 kg/m2	32(6.23)	17(6.61)	15(5.83)
18.5–23.9 kg/m2	277(53.89)	129(50.19)	148(57.59)
24.0-28.0kg/m2	167(32.49)	84(32.68)	83(32.30)
≥28.0 kg/m2	38(7.39)	27(10.50)	11(4.28)
H-type hypertension				94.22	<0.001
Normal group	129(25.10)	110(42.80)	19(7.39)
Hypertension group	119(23.15)	56(21.79)	63(24.51)
Hcy group	56(10.89)	25(9.27)	31(12.06)
H-type hypertension group	210(40.86)	66(25.68)	144(56.03)
age(year)	63.00(48.75,69.25)	63.00(47.00,68.00)	65.00(50.00,71.00)	-2.576	0.010
TG(mmol/L)	1.60(1.08,2.25)	1.50(0.99,2.06)	1.71(1.21,2.35)	-2.878	0.004
TC(mmol/L)	4.61(3.89,5.25)	4.61(3.94,5.32)	4.60(3.82,5.22)	-1.26	0.208
LDL(mmol/L)	2.63(2.08,3.23)	2.63(2.17,3.27)	2.63(1.98,3.18)	-1.093	0.274
HDL(mmol/L)	1.21(1.03,1.40)	1.27(1.08,1.44)	1.16(0.99,1.36)	-3.391	0.001
ALT(U/L)	18.00(13.00,26.13)	17.00(12.00,27.50)	19.00(13.68,25.99)	-1.708	0.088
UA(μmol/L)	314.00(261.00,390.00)	302.00(270.95,350.00)	358.00(154.00,431.45)	-2.375	0.018
Scr(μmol/L)	69.00(49.68,95.00)	64.50(54.00,78.00)	86.00(10.93,107.15)	-2.160	0.031
BUN(mmol/L)	5.89(4.46,8.46)	4.98(3.98,6.16)	8.03(5.46,29.57)	-11.355	<0.001
eGFR(mL/min)	61.90(33.10,91.28)	89.50(77.50,106.55)	33.80(2.54,50.80)	-18.886
hs-CRP(mg/L)	1.88(1.32,2.47)	1.63(1.09,2.15)	1.99(1.51,3.00)	-6.553	<0.001

Table 2.Association between H-type hypertension and CKD in different models
H-type hypertension	Model 1		Model 2		Model3
H-type hypertension	0R(95%CI)	P-value	0R(95%CI)	P-value	0R(95%CI)	P-value
Normal group	Reference		Reference		Reference
Hypertension group	6.513(3.555,11.934)	<0.001	7.858(4.179,14.777)	<0.001	3.217(1.418,7.299)	0.005
Hcy group	7.179(3.503,14.711)	<0.001	8.000(3.797,16.854)	<0.001	3.680(1.403,9.651)	0.008
H-type hypertension group	12.632(7.162,22.279)	<0.001	14.567(7.970,26.624)	<0.001	4.453(2.075,9.560)	<0.001
Model 1: we did not adjust any confounding factors.
Model 2: we adjusted age, education background,exercise,BMI
Model 3: we adjusted for model 2 plus TG,HDL,UA,Sc r,BUN,hs-CRP

No competing interests reported.

H-type hypertension is a risk factor for chronic kidney disease: a case-control study

Status:

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Abstract

Figures

1. Introduction

2. Materials and Methods

3. Results

4. Discussion

5. Conclusions

Declarations

References

Tables

Additional Declarations

Status:

Version 1