|Year : 2020 | Volume
| Issue : 5 | Page : 927-936
|Prevalence, Location, and Determinants of Valvular Calcifications in Congolese Patients on Chronic Hemodialysis: A Multicenter Cross-Sectional Study
Yannick M Engole1, Yves N Lubenga2, Yannick M Nlandu1, Jean Robert R. Makulo1, Vieux M Mokoli1, Charles K Kahindo1, Marie France I. Mboliasa1, Evariste M Kadima1, Augustin L Longo1, Aliocha. Nkodila1, Justine B Bukabau1, François B Lepira1, Nazaire M Nseka1, Ernest K Sumaili1
1 Nephrology Unit, University Hospital of Kinshasa, Kinshasa, Democratic Republic of Congo
2 Cardiology Unit, University Hospital of Kinshasa, Kinshasa, Democratic Republic of Congo
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|Date of Web Publication||21-Nov-2020|
| Abstract|| |
Valvular calcifications (VCs) are one of the major cardiovascular complications in patients on chronic hemodialysis (HD) due to its prevalence and predictive morbidity and mortality. The current study assessed the prevalence, location, and risk factors of VC among chronic HD Congolese patients in Kinshasa. This observational study involved three HD centers in Kinshasa between March and August 2016. Consecutive consenting adults on maintenance HD for at least six months were recruited. VCs were defined as a luminous echo on one or more cusps of the aortic or mitral valve. Risk factors of VC were determined by multivariate analysis. Sixty patients (mean age: 52.5 ± 15.9 years) were enrolled. The mean serum calcium and phosphorus were7.9 ± 1.3 mg/dL and 5.7 ± 1.7 mg/dL, respectively. VCs were encountered in 38% of the whole group in aortic and mitral valvular location in 64% and 23%, respectively. Hypertension, age >60 years, tobacco use, and hyperphosphatemia were independently associated with VC. Despite a young age of patients, VCs were a common finding and associated with both traditional and chronic kidney disease-specific risk factors.
|How to cite this article:|
Engole YM, Lubenga YN, Nlandu YM, R. Makulo JR, Mokoli VM, Kahindo CK, I. Mboliasa MF, Kadima EM, Longo AL, Nkodila A, Bukabau JB, Lepira FB, Nseka NM, Sumaili EK. Prevalence, Location, and Determinants of Valvular Calcifications in Congolese Patients on Chronic Hemodialysis: A Multicenter Cross-Sectional Study. Saudi J Kidney Dis Transpl 2020;31:927-36
|How to cite this URL:|
Engole YM, Lubenga YN, Nlandu YM, R. Makulo JR, Mokoli VM, Kahindo CK, I. Mboliasa MF, Kadima EM, Longo AL, Nkodila A, Bukabau JB, Lepira FB, Nseka NM, Sumaili EK. Prevalence, Location, and Determinants of Valvular Calcifications in Congolese Patients on Chronic Hemodialysis: A Multicenter Cross-Sectional Study. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Dec 2];31:927-36. Available from: https://www.sjkdt.org/text.asp?2020/31/5/927/301199
| Introduction|| |
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in hemo-dialysis (HD). Mortality is 3 to 20 times higher than in the general population, due to many factors including the accelerated process of atherosclerosis, arteriosclerosis, arteriolosclerosis, and vascular calcifications in uremic patients. HD is associated with an increased risk of CVD manifested in its subclinical phase as heart valvular calcifications (VCs)., Indeed, it has been reported that heart VCs represent 38.4% of subclinical CVD in HD patients and are powerful predictors of CV morbidity and mortality., Pathogenetic pathways underlying VC in HD patients involve the interaction of both traditional (e.g., hypertension, diabetes, dyslipidemia, aging, and tobacco use) and uremia-specific risk factors (e.g., systemic inflammation, oxidative stress, protein-energy wasting, P-cresol, fetuin-A, osteopontin, osteoprotegerin, hyperphosphatemia, and high calcium × phosphorus product) resulting in vascular remodeling and accelerated atherosclerosis.,,,,, Vascular complications may have different locations and types and include intimal artery calcification or medial artery calcification, cardiac valve calcification, calciphylaxis, and tumor calcinosis. Therefore, early detection of VC and control of their underlying risk factors could help preventing or postponing the progression of accelerated atherosclerosis seen in HD patients. Echocardiography is a sensitive and specific method for the detection of VC.
In the Democratic Republic of the Congo, the prevalence of chronic kidney disease in adult people is estimated to be 12%, with 0.2% of patients having end-stage renal disease (ESRD) requiring renal replacement therapy. For 10 years, the activity of HD is growing in Kinshasa, the capital city, and associated with substantial mortality mainly of CV origin, with stroke and heart failure being the main underlying causes. This observation highlights the need for identifying HD at increased risk for CVD, and early detection of VC can serve this purpose. Therefore, the aim of the present study was to assess the prevalence and location of VC as well as associated risk factors among Congolese chronic HD patients.
| Methods|| |
We conducted a multicenter, descriptive, and analytical cross-sectional study including adult patients who are undergoing chronic HD three times a week for at least six months at the three HD centers (Kinshasa University Hospital, Ngaliema Medical Center, and Afia Medical Center) and performed Doppler transthoracic echocardiography between March and August 2016. For each patient, we analyzed demographic, clinical, biological data related to HD and echocardiography. Clinical data were retrieved from patients’ records and included age, sex, initial nephropathy, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). Data related to HD were vascular access, duration of HD (in months), interdialytic weight gain, and dialysis dose measured using Kt/V urea. Biological parameters were as follows: serum calcium, phosphorous, phosphorus-calcium product, urea, creatinine, uric acid, cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, hemoglobin, hematocrit, C-reactive protein (CRP), and 24-h proteinuria. For each of these parameters, the annual average value was calculated. HD was performed with acid concentrate (containing Na, K, Ca++, Mg++, glucose, etc.) and standard bicarbonate at least a week for 4 h. The dialysis dose was adequate for a weekly Kt/v urea value of ≥1.4. The dialysis schedule alternated conventional HD with hemodiafiltration using high-flux dialyzers. Doppler transthoracic echocardiography was performed 24h after the mid-week HD session using a VIVID 7 ultrasound system equipped with a 3.5 Hz transducer (General Electric, Boston, USA). All cardiac ultrasounds were performed by a unique cardiologist. This examination allowed to detect VC in cardiac valves, with continuous Doppler wave in large and minor axis parasternal incidence. The calcified heart valve was seen as a luminous echo of more than 1 mm on 1 or more cusps of the aortic or mitral valve. We defined some conditions as follows: diabetes which had been diagnosed during past patient visits or concomitant use of antidiabetic medications, hypertension (HTN), blood pressure ≥140/90 mm Hg in three successive samples in sitting position and after interval of 5 min between two consecutive measurements or current use of antihypertensive drugs, dyslipidemia with total cholesterol >200 mg/dL, LDL >110 mg/dL, HDL <40 mg/dL, and triglycerides >150 mg/dL.
The statistical analysis was carried out using IBM SSPS Statistics version 21.0 (IBM Corp., Armonk, NY, USA). Quantitative variables were expressed as mean ± standard deviation and qualitative variables as a percentage. Student's t-test and Chi-square were used to compare quantitative and qualitative variables, respectively. The determinants of VC in HD patients were identified using univariate and multivariate stepwise logistic regression analysis.
The study protocol was approved by the Clinical Research Ethics Committee of Kinshasa School of Public (number ESP/CE/ 013/2016).
| Results|| |
Sixty patients (males: 71.6%) participated in the study. Their mean age and duration of HD were 52.5 ± 15.9 years (range: 18–82 years) and 15.1 ± 3.7 months, respectively. The mean SBP, DBP, and PP were156.6 ± 15.7 mm Hg, 86.8 ± 14.5 mm Hg, and 69.7 ± 15.6 mm Hg, respectively [Table 1]. The main causes of ESRD were diabetic nephropathy (35%), nephro-angiosclerosis (30%), and chronic glomerulonephritis (25%). Biochemical values are shown in [Table 2]. The mean serum calcium, phosphate, and phosphorus–calcium product levels were7.9 ± 1.3 mg/dL, 5.7 ± 1.7 mg/dL, and 44.7 ± 14.1 mg2/dL2, respectively. Only 6% of patients were taking phosphorus chelators and 37% received Vitamin D+ calcium carbonate. Only one patient in this study was receiving an antivitamin K. The anti-hypertensive drugs used were the following: calcium channel blockers (69%), angiotensin-converting enzyme inhibitors (29%), diuretics (22%), β-blockers (17%), and angiotensin receptor antagonists (10%). The antidiabetic agents included insulin (10%) and oral anti-diabetic agents (4%). The mean serum albumin, CRP, and total cholesterol were 35.9 ± 5.4 g/L, 12.5 (8–19) mg/L, and 176.9 ± 34.4 mg/dL, respectively. There was no significant difference for echocardiographic parameters between men and women except E / A which was higher in males (1.01 ± 0.6) vs (1.6 ± 1.2), P = 0.026) [Table 3].
VCs were encountered in 23 patients (38%) encompassing aortic (64%) and mitral (23%) valvular location [Figure 1]. Compared to patients without VC [Table 4], those having VC had a significantly higher proportion of participants aged >60 years (70% vs. 22%, P <0.0001) and, on average, a significantly higher PP (77.4 ± 15.2 vs. 64.9 ± 13.9 mm Hg, P <0.002), phosphate (6.5 ± 1.8 vs. 5.2 ± 1.5 mg%, P <0.005), and phosphorus–calcium product (41.7 ± 14.7 vs. 49.6 ± 11.9 mg2/dL2, P <0.035) levels. In contrast, their DBP (80.5 ± 13.0 vs. 90.7 ± 14.1 mm Hg, P <0.007) was significantly lower.
|Table 4: General characteristics of the study population according to vascular calcifications status.|
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[Table 5] shows that HTN [adjusted odds ratio (OR): 4; 95% confidence interval (CI) (1.24–15.7)], age >60 years [adjusted OR: 4; 95% CI (1.67–30.10)], tobacco use [adjusted OR: 5, 95% CI (1.15–13.36)], and phosphatemia [aOR to 2; 95% CI (1.83-5.65)] were independently associated with VCs.
|Table 5: Uni- and multivariate factors associated with vascular calcifications using logistic regression analysis.|
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| Discussion|| |
The main findings of the present cross-sectional study are as follows: first, VC with mainly aortic and mitral location was a common finding in the present case series; second, traditional (mainly aging, tobacco use, and HTN) and uremia specific (phosphatemia) were both the main factors associated with VC. In the present study, VCs were seen in nearly four out of 10 HD patients. This frequency is within the range of VC prevalence reported in the literature. It is somewhat higher than that of 14%–92% reported by several previous studies (Kaze et al, Benamar et al, Sayarlioglu et al, Ezziani et al, Ellouali et al, Rosa-Diez et al, Mihailescue, Braun, and Renaud). This discrepancy can be justified by the low use of phosphorus chelators and the abusive use of Vitamin D + calcium carbonate without proper control of monitoring parameters. The dialysis itself may represent a certain risk with the occurrence of a metabolic alkalosis at each session of HD, which can promote the precipitation of calcium salts, decreasing the solubility of calcium in the extracellular space. The use of calcium carbonate as a phosphorus chelator, combined with three standard dialysis sessions, which are insufficient to completely eliminate dietary phosphorus intake, contributes to calcification. This value is, however, lower than 46% and 50% found by Selcoki et al in Turkey and Sanchez-Perales et al in Spain, respectively. In the present study, aortic and mitral valves were the most frequent location of VC, with aortic valve being mainly involved. Our finding agrees with previous reports by Cisse (aortic 10.5% vs. mitral 5.75%) and Rekik (aortic 52% vs. mitral 44.5%), who reported a higher frequency of aortic versus mitral VC., Indeed, aortic VC is the most common valvular abnormality in the general population as well as in patients on HD. Aortic valves are submitted to cyclic mechanical stress related to pressure gradients and turbulent blood flow resulting from the high acceleration rate and peak velocity when blood flows through the aortic valve. Over the lifespan, the repetitive mechanical stress causes fatigue and re-arrangement of bio-elastomers, leading to microfractures in the biomaterials ultimately resulting in fibrosis and calcification. Aortic stenosis was more common in calcified patients with a statistically significant difference, thus supporting Urena's et al study. However, it is in disagreement with previous reports by Hayrire (aortic 21.7% vs. mitral 23.3%) and Sanchez (aortic 7.8% vs. mitral 15.2%) of a lower frequency of aortic versus mitral VC., Similar frequency of aortic and mitral VC (aortic 41.2% and mitral 41.2%) was reported by Samia. The disparity between studies in VC frequency and location could be in part explained by the clinical profile of patients, their therapeutic background, the duration and type of HD as well as the definition used to define VC. VC is potentially dangerous because of association with valvular dysfunction, myocardial ischemia, conduction defects, infectious endocarditis, and heart failure. Calcification-related stiffness of vessels and valves reduce their compliance, contributing to left ventricular hypertrophy and increasing all-cause mortality.
In the present study, traditional (aging, tobacco use, and HTN) as well as uremic-specific (hyperphosphatemia) risk factors were both associated with VC. Indeed, aging process is a well-known vascular risk factor through associated-insulin resistance and subsequent clustering of multiple risk factors to vascular wall remodeling. HTN is an important risk factor for atherosclerosis, and its association with cardiac VC in HD patients has been already reported.,, Tobacco use may induce vascular remodeling and subsequent atherosclerosis through oxidative stress and subsequent inflammation, activation of sympathetic nervous system, and renin–angiotensin system. Frequent HTN in HD promotes phosphorus–calcium deposits in the tissues. The shear forces generated by arterial HTN are capable of inducing the synthesis of TGF-β1 by the vascular endothelium, which promotes the excessive elaboration of extracellular vascular matrix and the occurrence of calcifications. Diabetes mellitus, the main nephropathy in our study, is known as a risk factor for valvular calcifications. A recent study has shown that hyperglycemia reduces the binding of Vitamin D to its receptor, which could interfere with osteocalcin synthesis and thus increase the risk of soft-tissue calcification. As reported by Raggi et al, Qunibi et al, and Kahnooj et al,, our study found an association between a high phosphorus–calcium product and the occurrence of cardiac VC. In addition, hyperphosphatemia has been reported to be associated with the development of vascular calcifications and is a factor favoring cardiac fibrosis. Indeed, observational studies in HD patients found a statistically significant increase in the risk of cardiovascular and all-cause mortality with a phosphorus level >6.5 to 6.6 mg/dL.
| Limitations|| |
Our study has some limitations that must be acknowledged. First, the limitation of the study to only three centers of HD leads to a selection bias and does not allow the generalization of our findings to all hypertensive people. Second, the cross-sectional design of our study precludes the establishment of any causal relationship. Third, the small sample size does not give enough power to statistical tests to detect potential associations. Fourth, VCs were assessed using echocardiography, a tool less sensitive than electron beam computed tomography, and do not allow precise quantitation of calcium deposited on the cardiac valves. Fifth, VCs were assessed by only one investigator with subsequent risk of under or overestimation of measured values.
| Conclusion|| |
Despite a relatively young age of patients, the prevalence of VC in Congolese HD patients remains high due to the traditional risk factors and HD session. Those factors may be preventable by moderate changes in diet, lifestyle, and adequate HD.
Conflict of interest: None declared.
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Yannick M Engole
Nephrology Unit, University Hospital of Kinshasa, Kinshasa
Democratic Republic of Congo
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]