Progression of valve heart disease in a cohort of patients undergoing renal replacement therapy

Abstract Introduction: Cardiovascular disease is an important cause of death among patients with chronic kidney disease (CKD). Valve calcification is a predictor of cardiovascular mortality and coronary artery disease. Objective: To assess heart valve disease frequency, associated factors, and progression in CKD patients. Methods: We conducted a retrospective study on 291 CKD patients at Hospital das Clínicas de Pernambuco. Inclusion criteria were age ≥ 18 with CKD and valve disease, while those on conservative management or with missing data were excluded. Clinical and laboratory variables were compared, and patients were categorized by dialysis duration (<5 years; 5–10 years; >10 years). Statistical tests, including chi-square, Fisher’s exact, ANOVA, and Kruskal-Wallis, were employed as needed. Simple and multivariate binary regression models were used to analyze valve disease associations with dialysis duration. Significance was defined as p < 0.05. Results: Mitral valve disease was present in 82.5% (240) of patients, followed by aortic valve disease (65.6%; 86). Over time, 106 (36.4%) patients developed valve disease. No significant association was found between aortic, pulmonary, mitral, or tricuspid valve disease and dialysis duration. Secondary hyperparathyroidism was the sole statistically significant factor for mitral valve disease in the regression model (OR 2.59 [95% CI: 1.09–6.18]; p = 0.031). Conclusion: CKD patients on renal replacement therapy exhibit a high frequency of valve disease, particularly mitral and aortic valve disease. However, no link was established between dialysis duration and valve disease occurrence or progression.


Data ColleCtion anD ProCeDures
All medical records were reviewed and the following data were collected: anthropometric data, clinical data, and supplementary exams.
Duration of dialysis therapy (DDT) was defined as the difference, in years, between the date of the first dialysis session and last dialysis session, visit, transplantation, or death.The patients were categorized into three groups and compared based on DDT (<5 years; 5-10 years; >10 years).
TTE was performed at the first visit and repeated during follow-up as deemed necessary by the attending physician.The severity and mode of valve dysfunction (i.e., calcification, stenosis, and/or regurgitation) were assessed according to the guidelines of the American Society of Echocardiography 16 .When present, valve dysfunction was described as mild, moderate, or severe.Progression of valve disease was defined as an increase of at least one degree between follow-up examinations.

statistiCal analysis
Data were analyzed descriptively using absolute frequencies and proportions.Pearson's chi-square test or Fisher's exact test was used to assess the association between categorical variables.The comparison of quantitative variables was performed using one-way ANOVA for variables with a normal distribution, or the Kruskal-Wallis test.Normality was assessed via the Shapiro-Wilk test.
The association between the occurrence of a given valve disease and DDT was confirmed using a binary logistic regression model, considering the presence of valve disease (individually) as a dependent variable and categorical DDT as an independent variable.In the case of a positive association, adjustments were made for baseline variables with statistically significant differences using a multivariate binary regression model.Odds ratios (OR) and 95% confidence intervals (95%CI) were presented as measures of association in the regression models.
Statistical analyses were performed on Statistical Package for the Social Sciences software version 20.0 (IBM, Armonk, NY, USA).The standard error used in every statistical test was 5%.

ethiCs
The study was evaluated and approved by the Institutional Research Ethics Committee, and given certificate 51098221.7.0000.8807.Data collection began only after approval was attained.Since this

IntRoductIon
Chronic kidney disease (CKD) is a global public health problem associated with significant morbidity, mortality, and costs to the healthcare system.The prevalence of CKD in developed countries varies between 10-15% 1,2 .In the last decade, a significant increase in the prevalence of the disease has been observed in Brazil.In 2019, 139,691 patients were on dialysis in Brazil 3 .
Cardiovascular disease (CVD) is the main cause of death among patients with CKD.Mitral and aortic valve calcification stand out, with the latter described as a strong predictor of cardiovascular mortality 1,4,5 .
Aortic valve disease is more prevalent and severe in individuals with CKD when compared to the general population 6 .Mitral calcification occurs in as many as 40% of patients with CKD and severe involvement has been linked with increased all-cause mortality 7 .
Dialysis patients appear to have a higher incidence and faster progression of valve disease, especially in the aortic valve, due to sustained inflammatory state, oxidative stress, and mineral and bone disorder [8][9][10][11] .However, three large studies -Framingham OS, MESA and CRIC -failed to establish a direct association between kidney dysfunction and aortic stenosis [11][12][13] .
The main treatment available for valve disease is valve replacement surgery.However, the procedure has its limitations: mechanical valves require lifelong anticoagulation therapy, while biological valves have a lifespan of 10-15 years 14 .
This study aimed to look into the progression of heart valve disease in patients with CKD.Secondary endpoints included frequency of occurrence of heart valve disease and other associated factors.

methods
This retrospective cohort study included patients with CKD followed up at the heart and kidney disease outpatient clinic of the Hospital das Clínicas of the Federal University of Pernambuco between March 2008 and October 2021.

stuDy PoPulation
The study included patients with ages ≥18 years with CKD, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) 15 initiative, diagnosed with valve disease based on transthoracic echocardiography (TTE).Patients with missing data on their medical records and individuals not undergoing renal replacement therapy (RRT) were excluded.
was a retrospective study, informed consent was not sought.

Results
A total of 568 medical records were first reviewed, of which 347 were deemed eligible for inclusion; however, another 56 were excluded after further review.The final population consisted of a total of 291 patients aged 53.5 years on average, with a predominance of females (51.5%).The baseline clinical characteristics of the study population are described in Table 1.
After adjustment for confounding variables, there was no association between occurrence of mitral or tricuspid valve disease and DDT.The presence of secondary hyperparathyroidism was the only explanatory variable that remained statistically significant in the regression model for mitral valve disease only (adjusted OR 2.59 [95% CI: 1.09-6.18];p = 0.031) (Table 3).Nevertheless, there were no differences in median serum PTH levels associated with presence of valve disease (Figure 1).

dIscussIon
Mitral and aortic valve disease are present in 30% and 15% of the patients with CKD, respectively.Other heart valves may be affected, although not as commonly [17][18][19] .In patients with CKD, the prevalence of mitral valve disease varies between 25% and 59% 18 .In our study, the frequency of valve disease was similar to that found in the literature, with mitral valve involvement being the most frequent.
Several factors may predispose patients with CKD to developing valve disease.Hypertension, diabetes, dyslipidemia and age have been related to valve calcification and atherosclerosis, suggesting that systemic atherosclerosis may play a role in the pathophysiology of calcification in individuals with CKD 20 .We analyzed the association between valve calcification in general or calcification in each specific heart valve and DDT, serum cholesterol levels, triglycerides levels, age, and presence of comorbid conditions, and found that only hyperparathyroidism was a predictor of mitral valve disease.
Several studies correlated valve calcification and progression of valve disease with phosphorus and calcium deposition 18,[21][22][23] .Current studies also suggest a role for inflammation and lipid deposition in calcification 21,23,24 .Although we observed a high frequency of calcium, phosphorus and lipid level disorders in our population, we found no association    between these variables and valve calcification.This is in agreement with the findings published by Ikee et al. 21and Cui et al. 22 , in which there was no association between mitral valve calcification and changes in bone mineral metabolism.
In our study, the presence of secondary hyperparathyroidism seemed to be a predictor of mitral valve disease.Nevertheless, serum PTH levels did not differ between patients with and without mitral valve disease, even when stratified by DDT.A possible explanation is the fact that more than half (50.7%) of the patients on dialysis for over 10 years had undergone parathyroidectomies to decrease serum PTH levels.
Hyperparathyroidism secondary to CKD has been previously described as an independent predictor of aortic valve stenosis 17 , while elevated PTH levels have been associated with severe aortic valve disease 25 .Presence of osteoblast-like cells, hydroxyapatite crystals, and overexpression of specific bone tissue proteins have been described in calcified valves 26 .These findings reinforce the relevance of the mechanism of calcification and cardiovascular degeneration, which are fundamentally related to the disruption of the calcium-phosphorus homeostasis, pathological bone remodeling, and reduction of calcification inhibitors 4 .
The pro-calcification and inflammatory state of CKD seems to accelerate the development of valve disease and the deterioration of biological tissue valves 19 .In our study, we found no association between valve disease progression and DDT.Two of the four patients given biological tissue valves developed calcification.In addition to serum PTH levels, the state of hyperparathyroidism depends on a combination of clinical factors, such as: changes in calcium-phosphorus metabolism, vitamin D activity, nutritional and inflammatory status.Secondary hyperparathyroidism in CKD may also occur due to rickets, malabsorption, and pseudohypoparathyroidism 27 .
Similarly, premature cardiovascular calcification syndrome in CKD depends on the state of secondary hyperparathyroidism, hyperphosphatemia, bone mineral disease, and uremia-related cardiovascular changes.RRT affects various cardiovascular risk factors differently, however it is speculative how these changes translate into different levels of valve calcification 28 .
This study has its limitations.It is a retrospective study carried out at a single center based on convenience sampling; data collection was affected negatively by the lack of standardization of medical records; echocardiograms were performed by different operators, which may have generated inconsistencies.
Despite these limitations, our study is valuable in that it looked into patients with CKD with pulmonary and tricuspid valve disease, subtypes studied less often in the literature.

conclusIon
We found a high frequency of valve disease in patients with CKD on RRT, involving particularly the mitral and aortic valves.No association was found between DDT, occurrence and/or progression of valve disease; only secondary hyperparathyroidism was associated with occurrence of mitral valve disease.

Figure 1 .
Figure 1.Comparison of serum PTH levels in relation to the presence of mitral valve disease and duration of dialysis therapy.PTH: Serum parathyroid hormone (pg/mL); p-value calculated by the Mann-Whitney test.

tAble 1
Baseline CliniCal CharaCteristiCs of the stuDy PoPulation stratifieD aCCorDing to Duration of Dialysis theraPy (DDT)valve replacement surgery, of which four were given biological tissue valves.After surgery, two (50%) of the patients given biological tissue valves developed calcification.More than half (53.6%; 156) of the patients developed hyperparathyroidism secondary to CKD, with parathyroidectomies performed in 11.3% of the cases.

tAble 3 simPle
Binary logistiC regression moDel aDjusteD for ConfounDing variaBles