Cardiovascular autonomic neuropathy in chronic kidney disease: A study of kidney biopsy cases

doi:10.21203/rs.3.rs-4844820/v1

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Cardiovascular autonomic neuropathy in chronic kidney disease: A study of kidney biopsy cases

https://doi.org/10.21203/rs.3.rs-4844820/v1

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Background

The interplay between cardiac and kidney functions is mediated by the autonomic nervous system. Cardiovascular autonomic neuropathy (CAN) is a well-documented dysfunction of this system, with heart rate variability (HRV) serving as the principal diagnostic tool. CAN is recognised as a prognostic marker for adverse kidney outcomes in diabetic kidney disease (DKD). However, the pathogenesis of CAN in patients with non-diabetic chronic kidney disease (CKD) remains underexplored. This study explored the clinicopathological correlates of CAN in individuals with non-diabetic CKD.

Methods

This cross-sectional analysis evaluated 162 non-diabetic patients with CKD who underwent kidney biopsy from 2020 to 2023. HRV was quantified using the coefficient of variation of the RR interval (CVRR). Clinicopathological characteristics were compared across tertile groups stratified according to CVRR values.

Results

The median patient age was 47.0 (34.0–57.0) years, and 50.9% were male. The median estimated glomerular filtration rate was 65.0 (42.0–85.0) mL/min/1.73 m², and the CVRR was 3.5 (2.4–4.7) %. Low CVRR group was frequently associated with kidney dysfunction, dyslipidemia, advanced interstitial fibrosis/tubular atrophy (IF/TA) and arteriosclerosis. Multivariable analysis revealed that IF/TA was associated with CVRR, independent of established risk factors for CAN (P = 0.045).

Conclusions

This investigation revealed that IF/TA was the renal histopathological feature most strongly correlated with CAN in patients with non-diabetic CKD

cardiorenal syndrome

chronic kidney disease

coefficient of variation of RR interval

heart rate variability

interstitial fibrosis/tubular atrophy

The functions of the cardiovascular and renal systems are very closely related. Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The combination of chronic heart failure and CKD, referred to as cardiorenal syndrome (CRS), is strongly associated with severe adverse clinical outcomes [1, 2]. CRS is a complex condition in which the dysfunction of one organ system promotes the deterioration of the other. Various pathological mechanisms of the aetiology of CRS have been proposed, including abnormalities in neurohormonal activation [3].

Cardiovascular autonomic neuropathy (CAN) is a common autonomic nervous system dysfunction in patients with diabetes [4, 5]. The impact of CAN on CRS has been frequently investigated in recent years [6–8], and CAN has been implicated as a risk factor for CVD development [9, 10]. Therefore, CAN is considered to be a major component of CRS pathogenesis. Rubinger et al. [11] reported that CAN improved after kidney transplantation in patients with end-stage kidney disease. A retrospective study by Muramatsu et al. [12] found that CAN increased the risk of a 40% decline in the estimated glomerular filtration rate (eGFR) from baseline in patients with diabetic kidney disease (DKD) and macroproteinuria. However, the pathological significance of CAN in CKD remains unclear. This is because autonomic neuropathy in CKD is currently only assessed in a limited number of patient subgroups.

Recent findings have suggested that nocturnal variations in circulatory patterns are linked to advanced glomerulosclerosis and tubulointerstitial injury. Kidney biopsy outcomes further implicate cardiovascular autonomic dysfunction in the progression of these histopathological changes [13, 14]. The current study aimed to evaluate the clinicopathological features associated with CAN in patients with non-diabetic CKD.

Participants

This retrospective, single-centre, cross-sectional study included patients who underwent percutaneous native kidney biopsies and measurement of the coefficient of variation of the RR interval (CVRR) at the Jikei University Hospital, Tokyo, Japan, from December 2020 to September 2023. The exclusion criteria were as follows: (i) diabetes mellitus (diabetes mellitus was defined using the National Glycohemoglobin Standardisation Program definition of HbA1c ≥ 6.5% or as patients receiving diabetic medications or insulin therapy at the time of kidney biopsy); (ii) nephrotic syndrome (defined as urinary protein excretion [UPE] ≥ 3.5 g/day with a serum albumin concentration ≤ 3.0 g/dL or serum total protein concentration ≤ 6.0 g/dL [15]); and (iii) uncalculated CVRR because of incident or history of cardiac disease and arrhythmia during measurement or patients who were taking medication affecting the heart rate, such as beta-blockers and diltiazem. Kidney biopsies and CVRR measurements were performed during the same hospitalisation period. The study protocol was approved by the ethics review board of the Jikei University School of Medicine (24–317 7083).

Definition

Heart rate variability (HRV) is a frequently used method for assessing the autonomic nervous system function [11, 16]. CVRR is a convenient, non-invasive HRV test that is widely used to assess cardiac autonomic function in patients with diabetes [4, 12].

CVRR measurements were performed according to previously published methods. Prior to ECG monitoring, the patients were maintained in a supine position for 15 min. The patient’s heart rate was sampled while taking deep breaths and recorded 100 times at a rate of 6 beats/min. All procedures were performed at room temperature. The CVRR was calculated using the following formula: CVRR = SD of R-R interval/mean of R-R interval × 100, where low CVRR indicates decreased heart rate variability and the presence of CAN pathology [4, 12, 17].

Measurements

Demographic data, including age, sex, body weight, blood pressure, medical history and hypertension frequency, were obtained from medical records at the time of diagnostic kidney biopsy. Laboratory measurements included albumin, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglyceride (TG), creatinine, eGFR and 24-hour UPE. The mean arterial pressure was defined as the diastolic blood pressure plus the pulse pressure divided by 3. Hypertension was defined as a systolic blood pressure > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg or the use of antihypertensive medications. Body mass index was defined as the body weight divided by the square of the height. eGFR was calculated using the following formula for Japanese subjects: eGFR (mL/min/1.73 m²) = 194 × Cr ^− 1.094 × age ^− 0.287 × (0.7399 for women) [18].

Histopathological analysis

All kidney tissue specimens were obtained via percutaneous needle biopsies. The tissues were embedded in paraffin, cut into 2- to 4-µm sections and stained with haematoxylin–eosin, periodic acid–Schiff, Masson’s trichrome and periodic acid–methenamine silver stain. Biopsies with fewer than five glomeruli were considered unsuitable for scoring and were excluded from the analysis.

Three candidate chronic kidney histopathological findings, including global glomerulosclerosis (GS), interstitial fibrosis/tubular atrophy (IF/TA), presence of arteriosclerosis and arteriolar hyalinosis, were evaluated. The severity of arteriosclerosis was evaluated based on the most severe lesions by comparing the thickness of the intima with that of the media in the same segment of the vessel and graded as 0 to 2 (Grade 0: absence of intimal thickening; Grade 1: intimal thickening < thickness of media; and Grade 2: intimal thickening ≥ media thickness). The arteriolar hyalinosis grade was evaluated based on the proportion of arteriolar arteries exhibiting hyalinosis as follows: Grade 0: absence of arteriolar hyalinosis; Grade 1: presence of hyalinosis but not the entire arteriolar circumference and Grade 2: hyalinisation of the entire arterial wall [19].

Statistical analyses

Continuous variables are presented as median and interquartile range or frequency (percentage). Differences in continuous and categorical variables were evaluated using the Mann–Whitney U and χ² tests, respectively. We used the Jonckheere–Terpstra test to identify trends in the baseline characteristics and morphological measurements according to the CVRR quartile.

We examined the risk factors for CVRR in a multiple regression analysis adjusted for known risk factors such as sex, age, eGFR, TG, proteinuria and smoking history [4, 16] as well as the tissue findings examined in this study. Statistical significance was defined according to a two-sided P < 0.05. All statistical analyses were performed using IBM SPSS Statistics for Windows version 29.0 (IBM Corp., Armonk, NY, USA)

Subject selection

A total of 235 patients with CKD aged ≥ 18 years underwent both CVRR measurement and kidney biopsy at our hospital between December 2020 and September 2023. Of these patients, 70 were excluded because of diabetes mellitus, nephrotic syndrome, arrhythmia and medication affecting the heart rate (e.g. beta-blockers and diltiazem) (Fig. 1).

Baseline characteristics of patients

The clinical and laboratory findings at the time of biopsy diagnosis are shown in Table 1. Overall, the median age was 47.0 (34.0–57.0) years, and 50.9% were male. The median eGFR was 65.5 (42.0–85.0) mL/min/1.73 m², the CVRR was 3.5 (2.4–4.7) %. Eighty-nine patients (54.3%) had hypertensive. Histopathological analysis revealed that the percentage of GS within one specimen was 12.9 (4.2–28.2) %, whereas that of IF/TA was 20.0 (10.0–30.0) %. In the low CVRR group (median CVRR, 2.0%), patients were older and also tended to have lower eGFR, lower HDL levels and higher TG levels (Table 1). Histologically, the low CVRR group had stronger atherosclerotic lesions and a more severe IF/TA (Table 2). Representative light microscopy findings for the low- and high-CVRR groups are shown in Fig. 2. Supplementary Table 1 shows the classification of diseases in this study, with IgA nephropathy (49.7%), nephrosclerosis (14.5%) and lupus nephritis (7.9%) accounting for the majority of the cases.

Table 1

Baseline characteristics at the time of kidney biopsy among all participants and according to the CVR-R tertile
	Overall N = 165	Low CVRR n = 55	Intermediate CVRR n = 55	High CVRR n = 55	P
Characteristics
Age (yr)	47.0 (34.0–57.0)	58.5 (50.0–70.0)	46.0 (38.0–53.0)	38.0 (29.0–47.0)	< 0.001
Male, n (%)	84 (50.9)	31 (56.4)	25 (45.5)	28 (50.9)	0.520
Current smoker, n (%)	57 (35.8)	25 (47.2)	17 (32.1)	15 (28.3)	0.101
Alcohol, n (%)	77 (49.4)	28 (52.8)	28 (52.8)	21 (42.0)	0.451
Statins, n (%)	34 (20.6)	12 (21.8)	13 (23.6)	9 (16.4)	0.618
Hypertension, n (%)	89 (54.3)	36 (65.5)	29 (52.7)	24 (44.4)	0.085
RAS blockades, n (%)	64 (38.8)	24 (43.6)	23 (41.8)	17 (30.9)	0.334
BMI (kg/m²)	22.0 (19.9–24.5)	21.9 (20.4–24.6)	22.6 (19.2–24.7)	21.5 (19.6–24.1)	0.447
MAP (mmHg)	88.7 (81.7–99.2)	91.0 (84.0-99.7)	89.7 (82.0-101.7)	85.7 (78.0-96.3)	0.055
Laboratory data
Cr (mg/dL)	0.9 (0.7–1.4)	1.2 (0.8–1.6)	0.8 (0.7–1.1)	0.8 (0.6–1.1)	0.001
eGFR (ml/min/1.73m²)	65.0 (42.0–85.0)	48.0 (28.0–71.0)	68.0 (45.0–88.0)	85.7 (78.0-96.3)	< 0.001
LDL-Cho (mg/dL)	118.0 (96.0-135.8)	117.0 (90.5-132.8)	117.5 (94.8-137.5)	120.0 (100.5-140.3)	0.280
HDL-Cho (mg/dL)	63.0 (51.0-78.5)	55.0 (48.0-72.5)	68.0 (56.8–81.0)	66.5 (51.8–81.3)	0.005
TG (mg/dL)	108.0 (74.3–152.0)	126.0 (84.5-189.5)	98.0 (66.8–155.0)	102.0 (73.0-131.5)	0.023
UPE (mg/day)	442.0 (210.8-855.8)	384.0 (180.0-1173.0)	543.0 (277.0-963.0)	337.5 (176.8–636.0)	0.483
Dietary protein intake (g/kg/day)	0.9 (0.7-1.0)	0.8 (0.7-1.0)	0.8 (0.8-1.0)	0.9 (0.8-1.0)	0.694
Dietary sodium intake (g/day)	4.7 (3.5–6.3)	4.6 (3.5–6.2)	4.6 (3.6–6.2)	4.8 (3.4–6.6)	0.567
CVR-R (%)	3.5 (2.4–4.7)	2.0 (1.8–2.4)	3.5 (3.1–3.9)	5.1 (4.7–6.1)	< 0.001
Note: Values are presented as median (interquartile range)
Cr in mg/dL to µmol/L, ×88.4.
Abbreviations: RAS blockades, renin-angiotensin system; CCB, calcium channel blocker; BMI, body mass index; MAP, mean arterial pressure; Alb, albumin; Cr, creatinine; eGFR, estimated glomerular filtration rate; LDL-Cho, Low-Density Lipoprotein cholesterol; HDL-Cho, High-Density Lipoprotein cholesterol; TG, triglyceride; UPE, urinary protein excretion; CVR-R, coefficient of the variation of the RR interval.
A total of 5 missing values.

Table 2

Pathological findings at the time of kidney biopsy among all participants and according to the CVR-R tertile
	Overall N = 165	Low CVRR n = 55	Intermediate CVRR n = 55	High CVRR n = 55	P
Pathological findings
Percent of global glomerulosclerosis (%)	12.9 (4.2–28.2)	16.7 (6.1–32.2)	10.5 (3.7–29.4)	12.1 (3.8–27.3)	0.215
Interstitial fibrosis/ tubular atrophy (%)	20.0 (10.0–30.0)	30.0 (18.8–50.0)	20.0 (10.0–30.0)	10.0 (10.0–20.0)	< 0.001
Arteriosclerosis					0.021
Grade 0, n (%)	61 (37.2)	14 (25.9)	17 (30.9)	30 (54.5)
Grade 1, n (%)	85 (51.8)	32 (59.3)	31 (56.4)	22 (40.0)
Grade 2, n (%)	18 (11.0)	8 (14.8)	7 (12.7)	3 (5.5)
Arteriolar hyalinosis					0.094
Grade 0, n (%)	108 (68.8)	29 (55.8)	37 (72.5)	42 (77.8)
Grade 1, n (%)	45 (28.7)	22 (42.3)	13 (25.5)	10 (28.7)
Grade 2, n (%)	4 (2.5)	1 (1.9)	1 (2.0)	2 (3.7)
Note: Values are presented as median (interquartile range)
CVR-R, coefficient of the variation of the RR interval.
A total of 8 missing values.

Table 3

The association of clinicopathological factors with CVRR in a multiple regression analysis
	Univariable		Multivariable
	95% CI	P value	95% CI	P value
Female	-0.145 ~ 0.149	0.975	-0.205 ~ 0.080	0.387
Age	-0.828 ~ -0.459	< 0.001	-0.893 ~ -0.415	< 0.001
Smoking	-0.314 ~ -0.002	0.048	-0.176 ~ 0.105	0.617
BMI	-0.451 ~ 0.431	0.964	-0.015 ~ 0.883	0.058
Hypertension	-0.326 ~ -0.035	0.015	-0.119 ~ 0.174	0.710
eGFR	0.191 ~ 0.466	< 0.001	-0.132 ~ 0.260	0.517
TG	-0.309 ~ -0.047	0.008	-0.296 ~-0.046	0.008
UPE	-0.072 ~ 0.067	0.942	-0.030 ~ 0.097	0.297
Arteriosclerosis Grade 2 (vs Grade0,1)	-0.458 ~ 0.010	0.060	-0.134 ~ 0.338	0.394
Arteriolar hyalinosis Grade 2 (vs Grade0,1)	-0.209 ~ 0.734	0.272	-0.077 ~ 0.717	0.113
Global glomerulosclerosis	-0.106 ~ 0.003	0.066	-0.006 ~ 0.124	0.074
Interstitial fibrosis/ tubular atrophy	-0.249 ~ -0.088	< 0.001	-0.213 ~-0.002	0.045
Abbreviations: CVR-R, coefficient of the variation of the RR interval.
BMI, body mass index; eGFR, estimated glomerular filtration rate; TG, triglyceride; UPE, urinary protein excretion.

Multivariable analyses of factors associated with the CVRR

Multivariable regression analyses were performed to identify the clinical and pathological factors associated with CVRR (Table 2). We performed multivariate regression analysis adjusted for known risk factors for CAN and found that IF/TA was positively associated with low CVRR (P = 0.045).

To the best of our knowledge, this study represents an inaugural exploration of the association between CAN, assessed using the coefficient of CVRR, and clinicopathological outcomes in non-diabetic patients with CKD. Multivariate analyses confirmed that the relationship between CAN and IF/TA persisted even after adjusting for established risk factors for CAN, including sex, age, hypertension, smoking habits, proteinuria, triglycerides and eGFR. These findings underscore the significant interconnection between CAN and tubulointerstitial damage in the renal pathology of non-diabetic patients with CKD. A reduction in the CVRR is indicative of parasympathetic autonomic dysfunction, which subsequently progresses to sympathetic dysfunction [20, 21]. Furthermore, a diminished CVRR may reflect sympathetic hyperactivity. Although the detailed pathophysiology linking CKD and sympathetic overactivity remains underexplored, numerous studies have documented elevated sympathetic nerve activity (SNA) in patients with CKD [22]. Notably, plasma norepinephrine levels, a critical neurotransmitter of the sympathetic nervous system, are significantly increased in patients with CKD having deteriorating kidney function [23]. Additionally, investigations into muscle SNA (MSNA) in patients with CKD revealed that resting MSNA is heightened in the early stages of CKD and escalates as the disease progresses [24]. Our findings also suggest a trend towards declining kidney function in patients with CAN, highlighting a potential intricate linkage between CAN and CKD progression. Crucially, the histopathological evaluations in this study revealed that IF/TA correlated with reduced CVRR, independent of kidney function. Previous investigations have linked IF/TA in patients with CKD to disturbances in the circadian rhythm. Haruhara et al. [14] identified an association between IF/TA and abnormalities in circadian blood pressure patterns. Oba et al. [13] observed that IF/TA correlates with non-dipping pulse rates. These findings suggest that sympathetic hyperactivity, which underlies circadian rhythm disturbances, is associated with IF/TA, potentially corroborating our observations regarding the relationship between IF/TA and CAN. We propose a deleterious cycle between CKD and CAN mediated by two primary mechanisms: The first involves hyperactivity of the renin–angiotensin system (RAS), where elevated urinary angiotensinogen levels are associated with the severity of IF/TA. Activation of RAS increases intraglomerular pressure, thereby exacerbating kidney injury and sympathetic overactivity [25]. The second mechanism involves the activation of the afferent sympathetic nerves. Animal and human studies have demonstrated that renal-derived neural signals amplify sympathetic outflow in CKD [26]. Kidney dysfunction results from IF/TA-induced stimulation of the afferent autonomic pathways. Experimental animal studies have shown that the activation of renal afferent nerves enhances the activity of efferent sympathetic nerves, which release norepinephrine. Furthermore, animal model research has revealed that norepinephrine contributes to IF/TA by promoting apoptosis and secretion of profibrotic factors, thereby facilitating the transformation of fibroblasts into myofibroblasts in tubular epithelial cells [27]. This study has several limitations. First, it was not possible to infer causality between CAN and IF/TA owing to its cross-sectional design. Second, the cohort comprised patients with CKD who underwent kidney biopsy, which might not be representative of the general CKD population, potentially introducing a selection bias. Third, the limited sample size precluded detailed disease-specific analyses based on kidney biopsy diagnoses. Lastly, while various diagnostic modalities for CAN exist, this study exclusively employed CVRR as a measure. Nevertheless, the simplicity and non-invasive nature of CVRR make it a valuable diagnostic tool for detecting CAN. Furthermore, the inclusion of patients who underwent kidney biopsies facilitated precise diagnoses and enabled comprehensive histopathological assessments. Although no pharmacological treatments for CAN have been proven effective, managing risk factors, such as obesity, hypertension, smoking and dyslipidemia, may help prevent its progression. Future research is essential to develop more effective therapeutic strategies for CAN.

This study demonstrated that IF/TA serves as a reliable histological indicator in non-diabetic CKD patients with CAN. However, additional longitudinal studies are required to clearly elucidate the relationship between CAN and CKD outcomes.

Ethics approval and consent to participate

The need for informed consent was waived by the Ethical Review Board of the Jikei University School of Medicine (approval number 24-317 7083).

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this article. Further inquiries can be directed to the corresponding authors

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable

Author Contributions

Conceptualisation, methodology, investigation, data curation and writing—original draft preparation: HK and GK; formal analysis: HK, TS and GK; resources: GK, KK, NT and TY; writing—review and editing: HK, GK, RO, TS, KH, KK, NT and TY; visualisation: HK; supervision: TY; project administration: GK. All authors contributed to the data interpretation and approved the final version of the manuscript.

Acknowledgements

The authors acknowledge the expert assistance of the staff at the Jikei University Hospital, Moeno Ishida. Portions of this study were presented at the International Society of Hypertension Meeting held in October 2022.

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Cardiovascular autonomic neuropathy in chronic kidney disease: A study of kidney biopsy cases

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Participants

Definition

Measurements

Histopathological analysis

Statistical analyses

Results

Subject selection

Baseline characteristics of patients

Multivariable analyses of factors associated with the CVRR

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1