Is Valvular Calcification a Part of the Missing Link between Residual Kidney Function and Cardiac Hypertrophy in Peritoneal Dialysis Patients?

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1 Is Valvular Calcification a Part of the Missing Link between Residual Kidney Function and Cardiac Hypertrophy in Peritoneal Dialysis Patients? Angela Yee-Moon Wang,* Christopher Wai-Kei Lam, Mei Wang,* Iris Hiu-Shuen Chan, Siu-Fai Lui,* and John E. Sanderson* Departments of *Medicine and Therapeutics and Chemical Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong; and Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology Foundation, Taipa, Macau Background and objectives: Residual renal function (RRF) predicts survival and shows an important inverse relation with cardiac hypertrophy in peritoneal dialysis (PD) patients. We hypothesized that valvular calcification and the calcification milieu may be part of the process linking loss of RRF and cardiac hypertrophy. Design, setting, participants, & measurements: A cross-sectional study was conducted by performing two-dimensional echocardiography on 230 PD patients to assess valvular calcification and left ventricular (LV) mass and collecting 24-h urine for estimation of RRF. Results: Patients having valvular calcification had lower RRF than those without. Patients with no RRF showed higher calcium-phosphorus product (Ca P) and C-reactive protein (CRP). Using multiple logistic regression analysis, every 1-ml/min per 1.73 m 2 increase in residual GFR was associated with a 28% reduction in the risk for valvular calcification. The association was lost after additional adjustment for Ca P and CRP. Using multiple linear regression analysis, loss of RRF showed significant association with increased LV mass index, but this association was lost after additional adjustment for CRP, Ca P, and valvular calcification. Patients with all three calcification risk factors, namely inflammation, high Ca P, and no RRF, showed the highest prevalence of valvular calcification and had the most severe cardiac hypertrophy. Conclusions: The association among loss of RRF, valvular calcification, and cardiac hypertrophy was closely linked to increased inflammation and high Ca P in PD patients. These data suggest that valvular calcification and the calcification milieu are part of the processes linking loss of RRF and worsening cardiac hypertrophy in PD. Clin J Am Soc Nephrol 4: , doi: /CJN Left ventricular hypertrophy (LVH) is one of the major cardiovascular complications in patients with ESRD and an important determinant of survival (1). Many factors are responsible for the development of LVH in patients with ESRD, including advanced age, hypertension, poor extracellular volume control, anemia, and hypoalbuminemia (2,3). A previous study showed that LVH was inversely related to residual renal function (RRF) in long-term peritoneal dialysis (PD) patients (4). Although the exact mechanisms for this association require further elucidation, our study suggested that worsening anemia, uremia, hypoalbuminemia, and increasing arterial pulse pressure Received May 10, Accepted July 29, Published online ahead of print. Publication date available at A.Y.-M.W. s and M.W. s current affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. J.E.S. s current affiliation is Department of Cardiovascular Medicine, University of Birmingham, Edgbaston, Birmingham, United Kingdom. Correspondence: Dr. Angela Yee-Moon Wang, University Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pok Fu Lam Road, Hong Kong. Phone: ; Fax: ; aymwang@hku.hk with decline in RRF all may contribute to the link between RRF and cardiac hypertrophy in PD patients (4). Conversely, patients with ESRD are at a heightened risk for developing vascular and valvular calcification. As shown previously, cardiac valvular calcification is strongly associated with inflammation (5) and predicts mortality in PD patients (6); however, the relationship between RRF and valvular calcification, if any, in PD patients has so far not been reported. C-reactive protein (CRP) is an important predictor of mortality and cardiovascular disease in patients with ESRD (7,8) and is linked to LVH in PD patients (9). An elevated CRP was observed with decline in RRF in both predialysis (10) and PD patients (11) and was partly explained by reduced renal clearance of CRP and inflammatory cytokines (12) as well as increased inflammatory response secondary to uremia. In this study, we aimed first to test the hypothesis that loss of RRF is associated with valvular calcification. Second, we evaluated whether valvular calcification may represent part of the process that links loss of RRF and LVH that is, whether the calcification risk profile may increase in association with loss of RRF and may additively contribute to LVH in long-term PD patients. Copyright 2009 by the American Society of Nephrology ISSN: /

2 1630 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: , 2009 Materials and Methods The study protocol was approved by the Human Research Ethics Committee of the Chinese University of Hong Kong. Informed consent was obtained from all study participants. Study Patients Patients were considered eligible for study inclusion when they had been on continuous PD treatment for 3 mo. Exclusion criteria were underlying malignancy, chronic liver disease, systemic lupus erythematosus, chronic rheumatic heart disease or congenital heart disease, or incomplete data. On the basis of the inclusion and exclusion criteria, 230 long-term PD patients were recruited at the dialysis unit of the Prince of Wales Hospital in Hong Kong, and they represented 86% of the total PD population (n 270) at the unit. All patients are of Chinese origin and were undergoing dialysis using conventional lactate-buffered glucose-based PD solutions. Echocardiography Two-dimensional echocardiography was performed (Vivid 5; GE- VingMed Sound AB, Horten, Norway) using a 3.3-mHz multiphase array probe on all patients lying in the left decubitus position. Twodimensional assessment of the aortic valve and mitral valve together with continuous-wave Doppler ultrasound was performed on the basis of the parasternal long-axis, parasternal short-axis, and apical views. Echocardiography was performed according to the recommendations of the American Society of Echocardiography (13), and images were analyzed by a single experienced cardiologist who was blinded to all of the clinical details. Left ventricular mass (LVM) was indexed by body height 2.7 because the indexing of LVH by height 2.7 is volume independent. LVH was defined as LVM index (LVMI) 47 g/m 2.7 in women and 50 g/m 2.7 in men (14). The ejection fraction was obtained using a modified biplane Simpson s method from apical two- and four-chamber views. Mitral inflow velocities and diastolic filling were assessed by Doppler echocardiography as described previously (15). Valvular calcification was defined as bright echoes of 1 mmonone or more cusps of the aortic valve or mitral valve or mitral annulus. Sensitivity and specificity for echocardiographic detection of calcium in the mitral valve or mitral annulus and aortic valve were reported to be 76 and 89 to 94%, respectively (16). The intraobserver agreement for the echocardiographic detection of valvular calcification was 90% ( 0.76) in our study. Aortic and mitral stenosis was defined according to that previously described by Otto et al. (17). Clinical and Demographic Data Collection Patients age, gender, dialysis duration, underlying cause of ESRD, smoking habit, presence of diabetes, and symptomatic coronary artery disease were recorded at study entry. Symptomatic coronary artery disease was defined as the presence of history of angina or previous myocardial infarction with or without coronary artery bypass surgery or stenting. Systolic and diastolic BP measured every follow-up at 6- to 8-wk intervals were averaged for the 12 mo preceding echocardiography. Arterial pulse pressure was calculated as the difference between systolic and diastolic BP. Use of erythropoietin, antihypertensive medication, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, calcium-based phosphorus binder, and vitamin D therapy were recorded at the time of echocardiography. Biochemical Assays At the time of echocardiography, fasting venous blood was collected for measurement of high-sensitivity C-reactive protein (hs-crp), serum albumin, calcium, phosphorus, parathyroid hormone (PTH), and fasting lipid profile (total cholesterol and triglyceride). Serum albumin, calcium, and phosphorus concentrations were measured using dyebinding methods on the Dimension AR automatic analyzer (DuPont Co., Wilmington, DE). Intact PTH (ipth) was determined by chemiluminescence immunoassay on the Immulite analyzer (Diagnostic Products Corp., Los Angeles, CA). Total cholesterol and triglycerides were measured enzymatically, and hs-crp was measured using the Tinaquant CRP (Latex) ultrasensitive assay (Hitachi 911 analyzer; Roche Diagnostics GmbH, Mannheim, Germany). The coefficient of variation of the hs-crp assay was 4.7 and 1.6% at concentrations of 4.3 and 2.0 mg/l, respectively. Measurement of RRF and Dialysis Adequacy Twenty-four-hour urine and dialysis fluid were collected at the time of baseline blood collection for measurement of residual GFR, dialysis, and total weekly urea and creatinine clearance. Residual GFR was measured as the average of 24-h urine urea and creatinine clearance (18). Total weekly urea clearance and creatinine clearance were measured using standard methods (19). Statistical Analysis Continuous data were expressed as mean SD or median (interquartile range) where appropriate and categorical data as percentages. Comparisons between groups were performed by the unpaired t test, Mann-Whitney test, or 2 test where appropriate. We performed univariate and multiple logistic regression analysis to evaluate the association, if any, between RRF and valvular calcification (with valvular calcification being the dependent variable). Log-hs-CRP and calciumphosphorus product (Ca P), which have been previously shown to be significantly associated with valvular calcification, were added to the stepwise multiple logistic regression model, including RRF (basic model), to determine how their entry may influence the possible association between RRF and valvular calcification. In addition, we performed univariate and multiple linear regression analysis for LVMI. We included log-hs-crp, Ca P, and valvular calcification in the stepwise multiple linear regression model for LVMI (basic model) to determine how entry of these three variables may influence the association between RRF and LVMI. In view that a significant proportion of patients had no RRF and the distribution of hs-crp was markedly skewed, RRF was recoded as a dichotomous variable (with patients who had no RRF recoded as 0 and those with RRF recoded as 1), and hs-crp was log-transformed using base 10 before performing the regression analysis. Statistical analyses were performed using SPSS 14.0 (SPSS, Inc., Chicago, IL). Results The characteristics of the study patients are shown in Table 1. The underlying cause of ESRD was chronic glomerulonephritis in 75 (32.6%), diabetic nephropathy in 54 (23.5%), hypertensive nephrosclerosis in 31 (13.5%), obstructive uropathy in 13 (5.7%), polycystic kidney disease in 12 (5.2%), tubulointerstitial disease in six (2.6%), and not identified in 39 (17.0%) patients. Among the 230 patients, 30 had aortic valve calcification and 38 had mitral valve calcification. Eleven had calcification of both the aortic and mitral valves. Only one patient with valvular calcification had moderately severe aortic stenosis with a jet velocity of 3.7 m/s. None had severe aortic or mitral stenosis. The PD regimen was 4.5 L/d in four (1.7%), 5 L/d in one (0.4%), 6 L/d in 167 (72.6%), 8 L/d in 55 (22.2%), and 10 L/d in seven (3%) patients.

3 Clin J Am Soc Nephrol 4: , 2009 Valve Calcification in Dialysis 1631 Table 1. Characteristics of study subjects Characteristic Value Age (yr; mean SD) Gender (M/F) 117/113 Dialysis (mo; mean SD) Positive smoking history (%) 37 Diabetes (%) 30 Symptomatic coronary artery disease (%) 19 SBP (mmhg; mean SD) DBP (mmhg; mean SD) Arterial pulse pressure (mmhg; mean SD) Hemoglobin (g/dl; mean SD) Serum albumin (g/l; mean SD) Ca P (mmol 2 /L 2 ; mean SD) ipth (pmol/l; mean SD) hs-crp (mg/l; median IQR ) 2.60 (0.91 to 8.04) Total cholesterol (mmol/l; mean SD) Triglyceride (mmol/l; mean SD) With residual renal function (%) 54 Residual GFR (ml/min per 1.73 m 2 ; median IQR ) 0.63 (0.00 to 1.94) Total weekly Kt/V (mean SD) Total weekly CCr (L/wk per 1.73 m 2 ; mean SD) Medication use erythropoietin (%) 39.1 no. of antihypertensive drugs (mean SD) ACEI or ARB (%) 24.8 vitamin D analogs (%) 37.4 calcium-based binder (%) 86.5 total daily dosage of elemental calcium (g/d; mean SD) aluminum-based binder (%) 19.7 ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCr, creatinine clearance; DBP, diastolic BP; IQR, interquartile range; SBP, systolic BP. Compared with patients with RRF, those with no RRF had higher Ca P ( versus mmol 2 /L 2 ; P 0.005), higher hs-crp (median 3.91 mg/l [interquartile range 1.05 to 11.81] versus 1.66 [0.82 to 5.12]; P 0.009), greater prevalence of valvular calcification (32.1 versus 18.5%; P 0.018), but lower hemoglobin ( versus g/dl; P 0.001) and lower serum albumin ( versus g/dl; P 0.034). A total of 218 (94.8%) patients displayed LVH on echocardiography. Detailed echocardiographic measurements of study patients are shown in Table 2. None of the 12 patients with normal LVMI had valvular calcification. Patients with mitral valvular calcification had greater LVMI ( and g/m 2.7 ; P 0.001) than those without. There was no significant difference in LVMI for patients with and without aortic valvular calcification ( and ; P 0.19). Controlling for age, male gender, positive smoking history, diabetes, arterial pulse pressure, and ipth, every 1-ml/min per 1.7 3m 2 increase in residual GFR was significantly associated with a 28% reduced risk for valvular calcification (Table 3, basic model); however, the association between residual GFR and valvular calcification became insignificant when additional adjustment was made for Ca P and log 10 hs-crp (Table 3, final model). On univariate analysis, RRF, log 10 hs-crp, Ca P, and valvular calcification each were significantly associated with LVMI (Table 4). Use of vitamin D analogs showed no significant association with LVMI (P 0.8). Controlling for age, male gender, diabetes, coronary artery disease, duration of dialysis, hemoglobin, arterial pulse pressure, high peritoneal transport, daily ultrafiltration volume, and ipth, RRF showed significant and independent association with LVMI (Table 4, basic model); however, the association between RRF and LVMI was marginally lost (P 0.071) when additional adjustment was made for log 10 hs-crp, Ca P, and valvular calcification (Table 4, final model). Patients with all three calcification risk factors, namely inflammation (as denoted by hs-crp 5 mg/l), higher Ca P (as denoted by Ca P 4.5 mmol 2 /L 2 ), and no RRF, showed the highest prevalence of valvular calcification (Figure 1A) and had the most severe LVH (Figure 1B). Considering valvular calcification as one of the factors associated with LVH, there was a graded increase in LVMI across

4 1632 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: , 2009 Table 2. Echocardiographic measurements Parameter All Patients (n 230) With Valvular Calcification (n 57) No Valvular Calcification (n 173) P LVMI (g/m 2.7 ; mean SD) IVSd (cm; mean SD) IVSs (cm; mean SD) LVPWd (cm; mean SD) LVPWs (cm; mean SD) LADs (cm; mean SD) LVVd index (ml/m 2 ; mean SD) Ejection fraction (%; mean SD) Fractional shortening (%; mean SD) E, s (mean SD) A, s (mean SD) E/A ratio (mean SD) Diastolic function pattern (% of patients) normal abnormal relaxation pattern restrictive filling pattern pseudonormal pattern Percentages may not add up to 100 because of rounding of decimal places. IVSd, interventricular septal thickness at enddiastole; IVSs, interventricular septal thickness at end-systole; LVPWd, left ventricular posterior wall thickness at end-diastole; LVPWs, left ventricular posterior wall thickness at end-systole; LADs, left atrial diameter at end-systole; LVVd, left ventricular volume at end-diastole indexed by body surface area; E, early diastolic transmitral flow velocity; A, late diastolic transmitral flow velocity; E/A, ratio of early to late transmitral flow velocity. Table 3. Univariate and multiple logistic regression analysis for valvular calcification Parameter Univariate Analysis Multiple Logistic Regression Analysis Basic Model Final Model OR (95% CI) P OR (95% CI) P OR (95% CI) P Age (yr) 1.05 (1.02 to 1.08) (1.01 to 1.08) (1.01 to 1.09) Male gender 0.91 (0.50 to 1.66) (0.17 to 1.03) (0.14 to 0.93) Positive smoking history 2.32 (1.26 to 4.27) (1.38 to 8.03) (1.74 to 11.84) Diabetes 2.62 (1.40 to 4.89) (1.14 to 4.59) (1.52 to 6.95) Pulse pressure (mmhg) 1.03 (1.01 to 1.06) (0.98 to 1.04) (0.98 to 1.04) 0.56 ipth (pmol/l) 1.01 (1.00 to 1.01) (1.00 to 1.01) (0.99 to 1.01) 0.68 Residual GFR (ml/min per 0.74 (0.58 to 0.94) (0.55 to 0.96) (0.61 to 1.06) m 2 ) Ca P (mmol 2 /L 2 ) 1.41 (1.09 to 1.82) (1.25 to 2.39) Log 10 hs-crp (mg/l) 2.16 (1.32 to 3.54) (0.97 to 3.12) CI, confidence interval; OR, odds ratio. patients with increasing number of risk factors (P 0.001), and patients who had valvular calcification as well as all three calcification risk factors, namely inflammation, high Ca P, and no RRF, showed the greatest LVMI (Figure 2). Discussion In this study of PD patients, we showed for the first time that loss of RRF was associated with an increased risk for valvular calcification, but this association was lost when controlling also for Ca P and inflammation. In addition, patients who lost RRF showed more inflammation and worse calcium and phosphorus control. Putting together these data suggests that the link between loss of RRF and valvular calcification was closely related to high Ca P and inflammation in PD patients. Our previous study showed a significant contribution of RRF to the overall phosphorus control in PD patients and that PD alone is unlikely to achieve adequate phosphorus control in patients with anuria (20). Of note, patients who had all three calcifica-

5 Clin J Am Soc Nephrol 4: , 2009 Valve Calcification in Dialysis 1633 Table 4. Univariate and multiple linear regression analysis for LVMI Univariate Analysis Multivariate Analysis Basic Model Multivariate Analysis Final Model Parameter Estimated Mean (95% CI) P Estimated Mean (95% CI) P Estimated Mean (95% CI) P Age (yr) 0.57 (0.13 to 1.02) ( 0.26 to 0.63) ( 0.45 to 0.46) 0.98 Male gender 3.23 ( to 7.19) ( 7.49 to 12.26) ( 7.25 to 11.73) 0.64 Diabetes 7.78 ( 3.60 to 19.16) ( to 11.02) ( to 10.22) 0.91 Coronary artery disease (9.52 to 35.38) (5.53 to 29.58) (2.61 to 25.94) Duration of dialysis (mo) 0.28 (0.11 to 0.45) ( 0.10 to 0.28) ( 0.12 to 0.24) 0.52 Pulse pressure (mmhg) 0.89 (0.53 to 1.25) (0.11 to 0.85) (0.03 to 0.75) ipth (pmol/l) 0.16 (0.05 to 0.27) (0.02 to 0.22) ( 0.04 to 0.16) 0.24 Hemoglobin (g/dl) 7.54 ( to 4.61) ( 8.58 to 2.72) ( 7.75 to 2.08) Total ultrafiltration volume (L/d) 5.33 ( to 0.05) ( 5.62 to 4.51) ( 7.40 to 2.41) 0.32 High peritoneal transport ( 0.03 to 28.60) ( 5.58 to 20.81) (0.26 to 26.10) Presence of RRF ( to 12.94) ( to 4.12) ( to 0.86) Log 10 hs-crp (mg/l) (10.83 to 26.96) (1.43 to 17.67) Ca P (mmol 2 /L 2 ) 8.58 (4.25 to 12.92) (2.04 to 9.35) Valvular calcification (13.76 to 36.99) (3.78 to 25.44) CI, confidence interval. tion risk factors, namely loss of RRF, inflammation, and high Ca P, showed the greatest prevalence of valvular calcification. Our cross-sectional data also provided some suggestion that valvular calcification and the calcification milieu (inflammation and high Ca P) may represent part of the process linking loss of RRF and LVH in PD patients and warrant further longitudinal evaluation. In contrast to the study by Ventura et al. (21) showing that increased transaortic flow velocities or pressure gradients promote LVH in hemodialysis patients with aortic valvular calcification and stenosis, our data suggest that the relationship between valvular calcification and LVH in PD patients is unlikely to be explained by valvular stenosis, because only one patient with valvular calcification had moderately severe aortic stenosis and none had mitral stenosis. As shown in our study, lower RRF, more inflammation as denoted by higher hs-crp, and higher Ca P all were associated with valvular calcification and were each associated with greater LVMI. Of novelty, the association between RRF and LVH was lost when additional adjustment was made for valvular calcification, hs-crp, and Ca P. This suggests that apart from conventional risk factors for LVH, inflammation, high Ca P, and valvular calcification, which showed important inverse relations with loss of RRF, all were interrelated factors associated with LVH in PD patients. Indeed, patients who had valvular calcification in addition to all three calcification risk factors were noted to have the most severe LVH. Our current findings extend further the previous observation of an important association between loss of RRF and LVH in PD patients (4) and provide supporting evidence that valvular calcification together with the calcification milieu, namely inflammation and high Ca P, may be part of the missing link between loss of RRF and worsening LVH in PD patients and will require further longitudinal confirmation. It is worth mentioning that the association between PTH and LVMI was lost after including CRP, Ca P, and valvular calcification in the multiple regression model. The loss of statistical significance can be secondary to closed relationships between Ca P, valvular calcification, and PTH. Indeed, poor calcium-phosphorus control results not only in vascular calcification but also in calcifications of other soft tissues, such as heart valves and the myocardium. Autopsy study demonstrated myocardial calcification with myocardial fiber degeneration and dense interstitial fibrosis in patients who had uremia and were undergoing dialysis (22,23). More pronounced intermyocardiocytic fibrosis was observed in patients with uremia compared with patients with hypertension or type 2 diabetes (24). The myocardial calcium content was strongly and positively correlated with Ca P (25). No correlation was observed between myocardial calcium content and PTH concentration (25), indicating that poor calcium-phosphorus control may have more important contribution than PTH hyperactivity to myocardial calcification in patients with uremia. In an experimental uremic model, a high-phosphorus diet and hyperphosphatemia also aggravated cardiac fibrosis and arterial wall thickening (26). Taking our current findings that a higher Ca P and valvular calcification were associated with

6 1634 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: , 2009 Figure 1. (A and B) Prevalence of valvular calcification (A) and severity of cardiac hypertrophy (B) as denoted by LVMI (mean SEM) in relation to the presence of none, any, one, two, and all three calcification risk factors, namely inflammation (as denoted by hs-crp 5 mg/l), increased Ca P (as denoted by a Ca P 4.5 mmol 2 /L 2 ), and no RRF. Figure 2. Severity of cardiac hypertrophy as denoted by LVMI (mean SEM) in relation to the presence of none, any, one, two, three, and all four risk factors, namely presence of inflammation (as denoted by hs-crp 5 mg/l), increased Ca P (as denoted byaca P 4.5 mmol 2 /L 2 ), no RRF, and valvular calcification. more LVH, we speculate that the more severe cardiac hypertrophy among patients with valvular calcification may partly reflect more severe myocardial calcification and fibrosis and warrants further investigation. The other factor that explained greater LVH and dilation and more diastolic dysfunction among PD patients with valvular calcification than those without may relate to increased arterial stiffening. The presence and extent of vascular calcification is widely known to predict increased stiffness of large capacity, elastic-type arteries in patients with ESRD (27). The abnormal pressure pattern increases LV afterload, leading to LVH and altered coronary perfusion in hemodialysis patients (28). A

7 Clin J Am Soc Nephrol 4: , 2009 Valve Calcification in Dialysis 1635 study of hemodialysis patients reported greater LVH and more diastolic dysfunction among those with vascular calcification (29). Given the positive correlations between valvular and vascular calcification in patients with ESRD (30), we speculate that the association between valvular calcification and LVH in our PD patients may also be partly explained by arterial stiffening and will need further investigation. There is increasing evidence that calcification in patients with uremia involves not only calcium-phosphorus deposition but also an active inflammatory and cellular-mediated process (31). A previous study reported an important link between inflammation and valvular calcification (5). In this study, hs-crp was associated with LVMI in the fully adjusted model that included not only conventional risk factors but also terms for RRF, Ca P, and valvular calcification, further confirming the important link between inflammation and cardiac hypertrophy (9). As shown by our data, the association between hs-crp and LVH may be partly linked to its close associations with loss of RRF (9) and valvular calcification (5) in PD patients. It may also possibly be partly attributed to long-term volume overload, which is a frequent complication in PD patients and is associated with immune activation (32) and LVH (3). The independent association between high peritoneal transport and LVMI in the multiple regression analysis suggests that reduced fluid removal secondary to high peritoneal transport may indeed be one of the factors accelerating cardiac hypertrophy in these patients. Icodextrin, which has been shown to improve volume control (33), may have a beneficial role for cardiovascular protection in PD patients. We speculated the possible link between loss of RRF, increased Ca P, inflammation, valvular calcification, and LVH in long-term PD patients in Figure 3. Our cohort of continuous ambulatory PD patients showed an extremely high prevalence of LVH. This is somewhat higher compared with a prevalence of approximately 75% reported in the white population (1); however, the study (1) combined both hemodialysis and PD patients, and echocardiographic data were obtained shortly after initiation of dialysis in contrast to Figure 3. Potential link among loss of RRF, increased Ca P, inflammation, valvular calcification, and LVH in long-term PD patients are depicted in bold type with bold arrow mo on PD in our patients. A previous study from the same group (34) showed that 65% of hemodialysis and 90% of PD patients had LVH. This was comparable to the prevalence in our cohort, suggesting indeed more severe LVH among PD patients. It is also worth noting that a very strong inverse association was observed between hemoglobin and LVMI in this cohort of PD patients. Our study has several limitations that need considering. First, echocardiography instead of electron-beam computed tomography was used to detect valvular calcification and does not allow quantification of calcium in the heart valves and other vasculature. Second, our study was of cross-sectional design; therefore, we were unable to infer any cause-and-effect relationship. Nevertheless, given our current findings, further longitudinal study will be needed to elucidate possible mechanistic links between loss of RRF, inflammation, increased Ca P, valvular calcification, and LVH in PD patients. Conclusions Our data suggest that the associations between loss of RRF and valvular calcification and LVH in PD patients are closely related to increased Ca P and inflammation. These data suggest that valvular calcification and the calcification milieu may be part of the process linking loss of RRF and cardiac hypertrophy in long-term PD patients and warrant further longitudinal investigation. Acknowledgments This study was supported by the Hong Kong Health Service Research Grant (Grant Number ) of which A.Y.-M.W. is the principal investigator. Disclosures None. References 1. Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, Murray DC, Barre PE: Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 47: , Harnett JD, Kent GM, Barre PE, Taylor R, Parfrey PS: Risk factors for the development of left ventricular hypertrophy in a prospectively followed cohort of dialysis patients. 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