|Year : 2021 | Volume
| Issue : 2 | Page : 481-487
|Prevalence and predicting factors of increased arterial stiffness in autosomal dominant polycystic kidney disease
Nada Sellami1, Rania Kheder-El Fekih2, Hela Jebali2, Ikram Mami2, Wided Smaoui2, Fethi Ben Hmida3, Mohamed Karim Zouaghi2, Lilia Ben Fatma2, Lamia Rais2
1 Department of Nephrology, Rabta Hospital; Faculty of Medicine of Tunis, University Tunis el Manar, Tunis, Tunisia
2 Department of Nephrology, Rabta Hospital, Tunis, Tunisia
3 Laboratory of Renal Pathology (LR00SP01), Charles Nicolle Hospital, Tunis, Tunisia
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|Date of Web Publication||11-Jan-2022|
| Abstract|| |
Carotid-femoral pulse wave velocity (cf-PWV) is the noninvasive gold standard technique for measuring aortic stiffness. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease in adults. It is associated with a high risk of cardiovascular complications. We aimed to assess the prevalence of increased arterial stiffness and its predicting factors in a population of ADPKD patients. Sixty-two patients with ADPKD underwent noninvasive measurement of cf-PWV using a COMPLIOR Analyse device. Recruitment period was 17 months and we used the cut-off of 10 m/s to define a high cf-PWV. Mean age was 51 ± 12.7 years. Gender ratio male/female was 0.63. Smoking, hypertension (HTN), and dyslipidemia were reported in 14%, 66%, and 27% of the cases, respectively. Mean glomerular filtration rate (GFR) was 47.7 ± 44 mL/min/1.73 m2. Among our patients, 39% had chronic kidney disease stages 1 or 2 and 45% stage 5 (40% stage 5D). Mean cf-PWV was 9 ± 2.4 m/s, and 31% of the patients had a high cf-PWV. In univariate analysis of all our patients, cf- PWV correlated with age (r = 0.565; P <10-3), GFR (r = -0.268;P = 0.035), C-reactive protein (r = 0.447; P = 0.007), peripheral systolic arterial pressure (r = 0.309; P = 0.015), and peripheral pulse pressure (r = 0.335; P = 0.008). Patients with high cf-PWV were on average nine years older than the others. Patients with HTN were 3.84 times more likely to have high cf-PWV (P = 0.046). cf-PWV did not seem to be lower with any antihypertensive treatment. A level of C-reactive protein higher than 10 mg/L was the only independent predicting factor of a high cf-PWV in multivariate analysis (P = 0.043). Our study confirmed the relationship between cf-PWV and age, renal failure, and HTN in patients with ADPKD. It also emphasized the close relationship between systemic inflammation and arterial stiffness in this nephropathy.
|How to cite this article:|
Sellami N, Fekih RK, Jebali H, Mami I, Smaoui W, Hmida FB, Zouaghi MK, Fatma LB, Rais L. Prevalence and predicting factors of increased arterial stiffness in autosomal dominant polycystic kidney disease. Saudi J Kidney Dis Transpl 2021;32:481-7
|How to cite this URL:|
Sellami N, Fekih RK, Jebali H, Mami I, Smaoui W, Hmida FB, Zouaghi MK, Fatma LB, Rais L. Prevalence and predicting factors of increased arterial stiffness in autosomal dominant polycystic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 28];32:481-7. Available from: https://www.sjkdt.org/text.asp?2021/32/2/481/335460
| Introduction|| |
Cardiovascular diseases are the leading cause of mortality in the world. Prevention is still the cheapest and most efficient way to control this public health problem. Indeed, identifying high-risk individuals allow initiating appropriate preventive measures. Speaking about cardiovascular risk stratification nowadays involves necessarily the evaluation of arterial stiffness. Carotid-femoral pulse wave velocity (cf-PWV) measurement is a simple and reproducible technique that is considered as the gold standard test to assess aortic stiffness in a non-invasive way.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary nephropathy in adults. Cardiovascular complications are the main cause of death in this population. Although several studies showed evidence of ciliopathy and endothelial dysfunction among polycystic patients, no consensus has been reached on the matter of a higher pulse wave velocity in this population. Kocyigit et al found a higher cf-PWV in normotensive ADPKD patients with preserved renal function compared to controls. In the study of Borresen, augmentation index but not PWV was significantly higher in young ADPKAD patients.
We aimed to state the prevalence of a high cf-PWV among this population and to identify its potential clinical or biological predicting factors.
| Material and Methods|| |
Patients were enrolled in the study between January 2016 and May 2017 in the nephrology, transplantation, and dialysis department. Recruited patients were hospitalized or followed either in our outpatient clinic or in our dialysis unit. ADPKD was confirmed by Pei’s unified criteria for ultrasonographic diagnosis if there were similar cases in the family, or by the presence of multiple renal cysts and increased kidney volume in the cases without family history. No genetic tests had been performed during this study. We included patients with all stages of chronic kidney disease (CKD). Hypertension (HTN) was defined as blood pressure (BP) ≥140/90 mm Hg or ongoing anti-hypertensive treatment. Obesity was defined as body mass index (BMI) ≥30 kg/m2 and overweight as BMI ≥25 kg/m2.
The following data had been collected: age, gender, cardiovascular history, ongoing treatment, active smoking, renal replacement therapy, and number of years since the beginning of dialysis. Systolic and diastolic BP, pulse rate, weight, and height were measured the same day as cf-PWV. OMRON M6 Confort automatic monitor was used for BP measurement after a 10 min supine rest.
Pulse wave velocity measurement
We used a validated COMPLIOR Analyse device to assess PWV between common carotid and common femoral arteries. We followed the recommendations of the European Society of Cardiology for measurement conditions. We used the cf-PWV value of 10 m/s as a cut-off in the prediction of cardiovascular events. We divided the studied population into two groups: patients with cf-PWV ≥10 m/s (high PWV) and patients with cf-PWV <10 m/s (normal PWV).
Venous blood samples were drawn after a 12 h fasting, with measurement for the following features: creatinine, urea, calcium, phosphorus, total cholesterol, triglycerides, uric acid, C-reactive protein (CRP), hemoglobin, and white blood cell count. Glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease formula. Anemia was defined as hemoglobin lower than 12 g/dL in women and 13 g/dL in men. High levels of uric acid were over 60 mg/L in women and 70 mg/L in men. Upper laboratory limit of CRP was 10 mg/L.
Only 45 patients had echocardiography during the study period. Left ventricular hypertrophy (LVH) and mitral valve abnormalities were detected, and left ventricular ejection fraction (LVEF) was measured.
| Statistical Analysis|| |
Statistical analysis was performed using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). We used Student’s t test to compare normally distributed continuous variables and Mann–Whitney test to compare not normally distributed variables. Qualitative variables were compared with the Chi-square test. We calculated Pearson correlation coefficients to examine the degree of association between variables. P <0.05 was considered significant. In the multivariate analysis, we excluded the role of age and estimated GFR (eGFR), considered as confounding factors.
| Results|| |
A total of 62 ADPKD patients (38 female and 24 male) were included in our study. Baseline epidemiological, clinical, and biological characteristics of our population are summarized in [Table 1]. cf-PWV was higher than the cut-off in 31% of the patients. Sixty-six percent of the patients had HTN with well-controlled BP, and the most used anti-hypertensive drugs were calcium channel blockers (CCB), renin angiotensin aldosterone system (RAAS) inhibitors, and beta blockers (BB) in, respectively, 32%, 30%, and 24% of the patients. cf-PWV distribution based on the CKD stage is summarized in [Table 2]. Correlation between cf-PWV and severity of CKD are summarized in [Table 3].
Mean age was significantly higher in patients with high cf-PWV (58.4 ± 12.3 years vs. 49 ± 12 years, P = 0.006). There was a positive linear correlation between cf-PWV and age (r = 0.565; P < 10-3). There were significant differences in systolic BP (140 ± 16.5 mm Hg vs. 131 ± 16 mm Hg, P = 0.033) and pulse pressure (55.5 ± 13 mm Hg vs. 48.5 ± 11.5 mm Hg, P = 0.037) between the two groups. In univariate analysis of all patients, cf-PWV correlated with both parameters [Figure 1].
|Figure 1: Correlation analysis between cfPWV, systolic blood pressure, and pulse pressure|
cfPWV: carotid-femoral pulse wave velocity
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Patients in stages 4 and 5 of CKD were 3.65 times more likely to have a high cf-PWV (P = 0.023). However, there was no difference in the prevalence of high cf-PWV between patients who received dialysis and the others.
eGFR was significantly lower in patients with high cf-PWV (28.6 ± 32.3 mL/min/1.73 m2 vs. 55.8 ± 45.6 mL/min/1.73 m2, P = 0.010). The univariate analysis showed a negative correlation between cf-PWV and eGFR (r = -0.268; P = 0.035). Hemoglobin levels were not different between the two groups, but patients with anemia seemed to present a greater risk for high cf-PWV (OR = 3.75; P 0.033). There was no association between levels of cholesterol, triglycerides, uric acid, calcium, and cf-PWV.
CRP correlated positively with cf-PWV and negatively with eGFR [Figure 2]. Prevalence of patients with a CRP level of more than 10 mg/L was higher in patients with an increased cf-PWV (OR = 7.93; P = 0.007). In the multivariate analysis, a CRP level of more than 10 mg/L was the only independent determinant of the acceleration of cf-PWV (β = 1.081; OR= 8.87; P =0.043).
|Figure 2: Correlation analysis between CRP, cfPWV, and eGFR.|
CRP: C-reactive protein, cfPWV: carotid-femoral pulse wave velocity, eGFR: estimated glomerular filtration rate.
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LVH prevalence was 31% in the general population and 40% in dialysis patients. Mean LVEF was 62% ± 10% (23%–73%). LVEF was less than 55% in seven patients, among whom four were in stage 5D. Mitral valve pathology was detected in nine patients (14%). We did not find any association between LVH and cf-PWV. There was a negative linear correlation between LVEF and cf-PWV (r= − 0.363; P = 0.020).
| Discussion|| |
With a prevalence of 1/400 to 1/1000, ADPKD is one of the most widely spread hereditary disease in the world. It is the first genetic hereditary cause of CKD in adults. Even though some authors had focused on arterial stiffness in ADPKD patients, the literature is not extensive.,,, To the best of our knowledge, our work is the first specific one in our country dealing with aortic stiffness in a group of patients with ADPKD. Literature on PWV in ADPKD shows some discrepancies, and this might be explained by the heterogeneity of the inclusion criteria and the limited number of patients involved. However, it appeared that arterial stiffness and endothelial dysfunction are early manifestations detected long before the onset of other complications such as HTN and renal failure.,
In 2001, Torres and all suggested the existence of an association between the mutations of PKD 1 and 2 genes and the cardiovascular complications in ADPKD. Polycystins 1 and 2 are key mechanosensor proteins expressed in the smooth muscle cells of the large and elastic arteries. The study showed that their expression is impaired in the aneurismal cerebral arteries of the patients. These results advocate for the presence of a structural damage of the arterial wall in ADPKD.
Different studies had established that age was a major independent factor of arterial stiffening in various populations.,,, This close association was confirmed in our work as we found that patients with high cf-PWV were in average 9.4 years older than patient with normal cf-PWV. Its role is enhanced by two major conditions in ADPKD: HTN and inflammation.
HTN is the main extrarenal manifestation of the disease, with a prevalence that varies from 52% to 86%.,, Polycystin mutation is the cornerstone of this complication. On the one hand, growing renal cysts cause renal ischemia and RAAS activation. On the other hand, altered expression of the polycystin in the cilium of the endothelial cells causes a lack in the perception of shear stress and in the liberation of nitrous monoxide (NO). Longitudinal data from the Framingham Heart study have shown a positive correlation between the initial level of aortic stiffness and the risk of incident HTN, suggesting that an initial abnormality in stiffness may antedate and contribute to the pathogenesis of HTN.
In a study comparing 50 patients with ADPKD to 50 healthy controls, Kocyigit et al found that ADPKD showed increased arterial stiffness despite a normal BP. Systemic inflammation was shown as an early and a chronic condition in ADPKD. They also reported higher CRP levels in non hypertensive patients with ADPKD (with an average eGFR of 83.9 mL/min/1.73 m2) versus healthy controls. In our study, we found a positive correlation between PWV and hypersensitive CRP (r = 0.617; P <0.001). The latter was an independent predictive factor of PWV (β = 0,317; P = 0.001). As CKD progresses, clearance of pro-inflammatory cytokines decreases. This inflammatory process worsens with the start of conventional dialysis because of bio-incompatibility with the membranes. Our work confirmed previous findings concerning the tight relationship between CRP and PWV as it appeared as an independent predictor factor of high cf-PWV in our patients.
Although we found that cf-PWV seemed to increase from stage 1 to stage 5 of CKD, the difference between the stages was not statistically significant (e.g. stage 1 versus stage 5: P = 0.079), and this is probably due to the small number of patients. Our findings still converge on many points with the study of Wang, especially concerning the linear negative relation between eGFR and PWV.
Numerous studies have addressed the best antihypertensive treatments in ADPKD. RAAS inhibitors stood out as the leading treatment of high BP in this population, given the hyperactivity of the RAAS during the disease. Their superiority to other antihypertensive treatments for reducing arterial stiffness is still to be proved in the general population. The meta-analysis of Shahin showed that there was no significant reduction of PWV under angiotensin converting enzyme inhibitors when compared to CCB, BB, and diuretics. Studies that examined the effect of antihypertensive drugs on PWV in ADPKD patients are rare. Nowak et al recently showed that 24 weeks of aldosterone antagonism (spironolactone) reduced systolic BP without changing cf-PWV in patients with early-stage ADPKD.
| Conclusion|| |
Major limitations of the present study are the cross-sectional design and the small size and heterogeneity of our sample. Our results are consistent with existing studies regarding the significant association between PWV and age, HTN, and kidney disease. Arterial stiffness in ADPKD seems to be detectable before the onset of HTN and might be an alternative way for early cardiovascular risk evaluation in this population. More clinical studies are needed to determine the best antihypertensive treatment in term of reducing PWV. NO system impairment, endothelial dysfunction, and chronic inflammation are “the hidden part of the iceberg” in ADPKD, and further investigations should lighten the impact of their control on reducing cardiovascular mortality.
Conflict of interest: None declared.
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Department of Nephrology, Rabta Hospital, Jabbary 1007 Tunis
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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