Younger Chronic Kidney Disease Patients Research Articles

Classical and myocardial deformation echocardiographic indices in chronic kidney disease patients; effects of aging and comparison to healthy controls

Abstract Funding Acknowledgements Type of funding sources: None. Background Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease compared to the general population. Classic echocardiographic indices of left ventricular (LV) function may not be sensitive enough in detecting early myocardial deterioration in CKD patients while LV speckle tracking (2DSTE) analysis has shown promising results. Dipyridamole stress echocardiography (DIPSE), mostly used to measure coronary flow reserve (CFR), assesses coronary macrovascular and/or microvascular dysfunction in a non-invasive way. Purpose To investigate differences in classic, 2DSTE-related indices, CFR and other DIPSE-induced changes in various echocardiographic parameters between 1) healthy controls and age-matched (younger) CKD patients, 2) younger versus older CKD patients with similar clinical characteristics. Methods We prospectively evaluated 30 healthy controls and 60 consecutive CKD patients 40-75 years old who were followed-up at the CKD outpatient clinic of a University Hospital in Western Greece. A standard echocardiographic analysis including 2DSTE analysis was performed in all subjects before and after dipyridamole infusion. CFR in left anterior descending artery was also assessed. Results The median age of the CKD patients was 63 years and most of them were males (70%). Younger patients with CKD (i.e. <60 years old) had higher E/e" ratio (7.80 ± 2.71 vs 6.06 ± 1.37, p = 0.019), LVMI (114.7 ± 41.1 vs 89.6 ± 21.2, p = 0.017) and relative wall thickness (0.47 ± 0.08 vs 0.40 ± 0.06, p = 0.031) and lower E" (10.6 ± 2.6 vs 2.3 ± 2.9 cm/s, p = 0.045) compared to age and gender-matched healthy controls. Older CKD patients had lower E/A (0.80 ± 0.19 vs 1.03 ± 0.33, p = 0.007) and E" (8.5 ± 1.8 vs 10.6 ± 2.6 cm/s, p = 0.003) compared to younger CKD patients. CFR was higher in healthy controls compared to both younger (3.93 ± 1.25 versus 3.1 ± 0.75, p = 0.009) and older CKD patients (3.93 ± 1.25 versus 2.89 ± 0.88, p < 0.001); no significant difference in CFR was observed between younger and older CKD patients. Dipyridamole-induced changes in other studied echocardiographic indices did not differ significantly among groups. Conclusions In the current study, impaired coronary microcirculation, LV diastolic function and increased LV mass with concentric remodeling were shown to be the principal findings early in the process of CKD. These results may have pathophysiological implications for cardiorenal syndrome type 4 and targeted cardiac assessment in CKD patients. Future studies are needed to assess whether any therapeutic efforts aiming to delay or reverse these changes may have an impact on the cardiovascular prognosis in CKD patients.

The burden of subclinical cardiovascular disease in children and young adults with chronic kidney disease and on dialysis.

BackgroundCardiovascular disease (CVD) is a common cause of morbidity and mortality even in young people with chronic kidney disease (CKD). We examined structural and functional CV changes in patients ˂30 years of age with CKD Stages 4 and 5 and on dialysis.MethodsA total of 79 children and 21 young adults underwent cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima-media thickness (cIMT), carotid–femoral pulse wave velocity (cfPWV) and echocardiography. Differences in structural (CAC, cIMT z-score, left ventricular mass index) and functional (carotid distensibility z-score and cfPWV z-score) measures were examined between CKD Stages 4 and 5 and dialysis patients.ResultsOverall, the cIMT z-score was elevated [median 2.17 (interquartile range 1.14–2.86)] and 10 (10%) had CAC. A total of 16/23 (69.5%) patients with CKD Stages 4 and 5 and 68/77 (88.3%) on dialysis had at least one structural or functional CV abnormality. There was no difference in the prevalence of structural abnormalities in CKD or dialysis cohorts, but functional abnormalities were more prevalent in patients on dialysis (P < 0.05). The presence of more than one structural abnormality was associated with a 4.5-fold increased odds of more than one functional abnormality (95% confidence interval 1.3–16.6; P < 0.05). Patients with structural and functional abnormalities [cIMT z-score >2 standard deviation (SD) or distensibility <−2 SD) had less carotid dilatation (lumen:wall cross-sectional area ratio) compared with those with normal cIMT and distensibility.ConclusionsThere is a high burden of subclinical CVD in young CKD patients, with a greater prevalence of functional abnormalities in dialysis compared with CKD patients. Longitudinal studies are required to test these hypothesis-generating data and define the trajectory of CV changes in CKD.

Effect of age and isolated systolic or diastolic hypertension on target organ damage in non-dialysis patients with chronic kidney disease.

The aim of this study was to investigate associations between age-dependent variations in isolated systolic/diastolic hypertension (ISH/IDH) with target organ damage in chronic kidney disease (CKD). A cross-sectional study was conducted among 2,459 CKD patients with ambulatory blood pressure monitoring. Blood pressure was categorized into four groups: normotension, ISH, IDH, and systolic-diastolic hypertension. The outcome measurements were left ventricular mass index (LVMI), estimated glomerular filtration rate(eGFR), and urinary albumin creatinine ratio (ACR). Older patients (≥60-years-old) had a higher prevalence of ISH and a lower prevalence of IDH than younger patients (<60-years-old). In multivariate analysis, compared with the normotension group, younger patients with ISH were associated with higher LVMI (+14.4 g/m2), lower eGFR (−0.2 log units), and higher ACR (+0.5 log units); but younger patients with IDH were only associated with lower eGFR (−0.2 log units) and higher ACR (+0.4 log units). Among older patients, ISH was correlated with higher LVMI (+8.8 g/m2), lower eGFR (−0.2 log units), and higher ACR (+1.0 log units), whereas IDH was not associated with these renal/cardiovascular parameters. In conclusion, ISH was associated with a relatively high risk of target organ damage irrespective of age, whereas IDH was only correlated with renal injury in younger CKD patients.

Relation of Maximum Lifetime Body Mass Index with Age at Hemodialysis Initiation and Vascular Complications in Japan

Objective: The aim of this study was to investigate the association of the maximum lifetime body mass index (max BMI) with hemodialysis initiation and comorbidities in Japanese hemodialysis patients. Methods: In a retrospective cross-sectional study on 724 hemodialysis patients, max BMI, age at hemodialysis initiation, and comorbidities including sleep apnea syndrome, cerebro-cardiovascular diseases, and proliferative diabetic retinopathy (PDR) were analyzed. Early hemodialysis initiation was defined as age <50 years. Result: Diabetes patients showed a higher max BMI and prevalence of atherosclerotic diseases than nondiabetes patients, despite almost the same age at hemodialysis initiation. Patients with early hemodialysis initiation showed higher male ratio, prevalence of PDR, and max BMI than those with later initiation, despite almost equal prevalence of diabetes. Receiver-operating characteristic curve analysis determined a max BMI of 28.4 kg/m² as a reliable cutoff value for predicting early hemodialysis initiation, and this parameter was identified as an independent predictor of early hemodialysis initiation using bivariate logistic regression analysis. Vitrectomy for PDR also tended to contribute independently to early hemodialysis initiation. Conclusion: A high max BMI contributed to early hemodialysis initiation independent of diabetes. Furthermore, PDR was associated with a high max BMI and early hemodialysis initiation. These results suggest that weight reduction in young chronic kidney disease patients with obesity may prevent hemodialysis and blindness.

The Association between Nitric Oxide Pathway, Blood Pressure Abnormalities, and Cardiovascular Risk Profile in Pediatric Chronic Kidney Disease.

Cardiovascular disease (CVD) is common in chronic kidney disease (CKD), while major CV events are rare in young CKD patients. In addition to nitric oxide (NO)-related biomarkers, several surrogate markers have been assessed to stratify CV risk in youth with CKD, including 24-h ambulatory blood pressure monitoring (ABPM), carotid artery intima-media thickness (cIMT), pulse wave velocity (PWV), ABPM-derived arterial stiffness index (AASI), flow-mediated dilatation (FMD), and left ventricular mass index (LVMI). The aim of this study was to identify subclinical CVD through the analysis of indices of CV risk in children and adolescents with CKD. Between 2016 and 2018, the prospective observational study enrolled 125 patients aged 3 to 18 years with G1–G4 CKD stages. Close to two-thirds of young patients with CKD exhibited blood pressure (BP) abnormalities on ABPM. CKD children with abnormal office BP showed lower plasma arginine levels and arginine-to-asymmetric dimethylarginine (ADMA) ratio, but higher ratios of ADMA-to-symmetric dimethylarginine (SDMA) and citrulline-to-arginine. High PWV and AASI, indices of arterial stiffness, both strongly correlated with high BP load. Additionally, LV mass and LVMI exhibited strong correlations with high BP load. Using an adjusted regression model, we observed the citrulline-to-arginine ratio was associated with 24-h systolic and diastolic BP, systolic blood pressure (SBP) load, and diastolic blood pressure (DBP) load. Early assessments of NO-related parameters, BP load abnormalities, arterial stiffness indices, and LV mass will aid in early preventative care toward decreasing CV risk later in life for children and adolescents with CKD.

Abstract MP12: Cardiovascular Health Promoting Behaviors in Older Patients With Chronic Kidney Disease

Background: The chronic kidney disease (CKD) epidemic continues to grow, and cardiovascular disease (CVD) is the leading cause of death. To modify CVD risk, CKD patients are asked to engage in health promoting behaviors. However, older patients with CKD likely face challenges to engage in healthy behaviors due to social and health factors. This study examined the relationship of social and health factors to health promoting behaviors among younger and older CKD patients and the association of these behaviors with CVD events, death, and CKD progression. Methods: Data from the Chronic Renal Insufficiency Cohort (CRIC) Study were analyzed using latent class analysis (LCA) to identify health promoting behavior clusters, stratified by &lt;65 and ≥65 years of age. LCA was based on: BMI of &gt;20 and ≤25kg/m 2 vs. other, healthy diet vs. not, physical activity ≥150min/week vs. not, blood pressure ≤140/90mmHg vs. greater, never/past smoker vs. current, and &lt;7.0% hemoglobin A1c vs. greater. Social factors (self-efficacy, social support, education, income, insurance) and health factors (depressive symptoms, cognition, co-morbidities) were measured by validated surveys and self-report. Logistic regression assessed the association of social and health factors to the behavior clusters. Cox proportional hazards models estimated risk of clusters to CVD events (myocardial infarction/revascularization, peripheral arterial disease, or stroke), CKD progression (incident end-stage renal disease or 50% decline in eGFR), and death from any cause. Results: All social and health factors significantly differed between age groups. Three clusters with varying levels of engagement in health promoting behaviors were identified separately among &lt;65 and ≥65 years of age. Among &lt;65 years, the cluster with the highest level of engagement in healthy behaviors was associated with more self-efficacy and lower depressive symptoms. In this age group, in multivariable adjusted models, the clusters with less healthy behavior engagement had a statistically significant increased risk of CVD events (32-81%), death (29-78%), and CKD progression (32-38%). Among ≥65 years, the cluster with the highest level of engagement in healthy behaviors was associated with higher self-efficacy, social support, cognition, and less depressive symptoms. In this age group, in multivariable adjusted models, the clusters with less healthy behaviors had a statistically significant 49% increased risk of death. Conclusion: This study demonstrated three clusters of health promoting behaviors that distinguish risk for CVD and other outcomes among older and younger CKD patients. These clusters could identify high-risk groups and be targeted for aggressive management. Clusters with less health promoting behaviors were associated with self-efficacy and depressive symptoms, which could serve as potential targets for intervention.

Chronic kidney disease stage affects small, dense low-density lipoprotein but not glycated low-density lipoprotein in younger chronic kidney disease patients: a cross-sectional study.

ABSTRACTBackgroundSmall, dense low-density lipoprotein (sd-LDL) and glycated LDL (g-LDL) have been associated with cardiovascular disease (CVD) in chronic kidney disease (CKD) in patients >60 years of age. Since young adult and paediatric patients have shorter exposure to Framingham-type risk factors, our study aims to determine whether younger CKD patients exhibit the same sd-LDL and g-LDL pattern.MethodsAfter ethics board approval, this cross-sectional study was conducted at two universities with 44 patients (mean ± standard deviation age 12.6 ± 4.9, range 2–24 years) with CKD stage of 1–5. Laboratory parameters studied were Cystatin C (CysC), CysC estimated glomerular filtration rate (eGFR) (calculated from the Filler formula), sd-LDL, g-LDL and albumin. Lipid samples were measured for sd-LDL and g-LDL using ELISA. Non-linear correlation analysis was performed to determine the relationship between g-LDL, sd-LDL and eGFR. Clinical Trials Registration is at clinicaltrials.gov, NCT02126293, https://clinicaltrials.gov/ct2/show/NCT02126293.ResultsTriglycerides, but not total cholesterol and calculated LDL, were associated with CKD stages (ANOVA P = 0.0091). As in adults, sd-LDL was significantly associated with CKD stages (ANOVA P = 0.0133), CysC eGFR (r = −0.6495, P < 0.00001), and body mass index (r = −0.3895, P = 0.0189), but not with age. By contrast, there was no significant correlation between g-LDL and CKD stages or CysC eGFR (P = 0.9678).ConclusionsOur study demonstrates that only triglycerides and sd-LDL were associated with CKD stages in this young cohort without confounding Framingham-type CVD risk factors. While larger studies are needed, this study suggests that lowering sd-LDL levels may be a potential target to ameliorate the long-term CVD risks in paediatric CKD patients.

Haematuria increases progression of advanced proteinuric kidney disease.

BackgroundHaematuria has been traditionally considered as a benign hallmark of some glomerular diseases; however new studies show that haematuria may decrease renal function.ObjectiveTo determine the influence of haematuria on the rate of chronic kidney disease (CKD) progression in 71 proteinuric patients with advanced CKD (baseline eGFR <30 mL/min) during 12 months of follow-up.ResultsThe mean rate of decline in eGFR was higher in patients with both haematuria and proteinuria (haemoproteinuria, HP, n=31) than in patients with proteinuria alone (P patients, n=40) (-3.8±8.9 vs 0.9±9.5 mL/min/1.73m2/year, p<0.05, respectively). The deleterious effect of haematuria on rate of decline in eGFR was observed in patients <65 years (-6.8±9.9 (HP) vs. 0.1±11.7 (P) mL/min/1.73m2/year, p<0.05), but not in patients >65 years (-1.2±6.8 (HP) vs. 1.5±7.7 (P) mL/min/1.73m2/year). Furthermore, the harmful effect of haematuria on eGFR slope was found patients with proteinuria >0.5 g/24 h (-5.8±6.4 (HP) vs. -1.37± 7.9 (P) mL/min/1.73m2/year, p<0.05), whereas no significant differences were found in patients with proteinuria < 0.5 g/24 h (-0.62±7.4 (HP) vs. 3.4±11.1 (P) mL/min/1.73m2/year). Multivariate analysis reported that presence of haematuria was significantly and independently associated with eGFR deterioration after adjusting for traditional risk factors, including age, serum phosphate, mean proteinuria and mean serum PTH (β=-4.316, p=0.025).ConclusionsThe presence of haematuria is closely associated with a faster decrease in renal function in advanced proteinuric CKD patients, especially in younger CKD patients with high proteinuria levels; therefore this high risk subgroup of patients would benefit of intensive medical surveillance and treatment.

Capillary rarefaction: an early marker of microvascular disease in young hemodialysis patients.

BackgroundPediatric patients with chronic kidney disease (CKD) are at increased risk of early cardiovascular disease and premature death. Abnormalities in microvascular structure and function may presage end-organ damage including vascular calcification and myocardial ischemia associated with disordered mineral metabolism. Early detection of microvascular rarefaction (reduced density of capillaries) may identify at-risk patients and prompt timely therapeutic interventions. Our objective was to study capillary rarefaction in pediatric hemodialysis (HD) patients and to determine possible associations with mineral metabolism and cardiac risk biomarkers.MethodsCapillary density (CD) was measured by nailfold capillaroscopy in 19 pediatric HD patients and 20 healthy controls. Demographic and biochemical markers were collected at entry and 6-month follow-up.ResultsCD was significantly decreased in HD patients compared with controls with a deficit of 24 and 31% at baseline and subsequent follow-up. Maximal CD correlated significantly with intact parathyroid hormone (iPTH) (r = −0.45; P = 0.005), serum calcium (r = −0.38; P = 0.02) and 25(OH) vitamin D levels (r = +0.36; P = 0.03) in HD patients. Capillary functional measures were similar to controls. By multivariate analysis, the primary negative determinants of CD were African American race and hyperparathyroidism; whereas, glomerular disease had a positive influence on capillary rarefaction (R2 = 64.2% variance; P = 0.001).ConclusionPediatric HD patients demonstrate a ‘structural deficit’ in CD but show preserved ‘functional integrity’. Capillary rarefaction, an early risk factor of incipient vascular calcification, was strongly associated with biomarkers of altered mineral metabolism. Further studies are warranted to determine the impact of optimizing blood pressure and metabolic control on changes in capillary rarefaction in young CKD patients.

Fibroblast growth factor-23 and calcium phosphate product in young chronic kidney disease patients: a cross-sectional study

BackgroundFibroblast growth factor-23 (FGF-23), a novel marker of bone disease in chronic kidney disease (CKD) has been shown to correlate with vascular calcifications. We aimed to describe the effect of the calcium phosphate product (Ca*P) on FGF-23 concentrations in children and young adults without confounding cardiovascular disease.MethodsPediatric and young adult patients with CKD stages I-V were recruited in this cross sectional study to measure FGF-23, cystatin C, vitamin D-metabolites and other serum markers of bone metabolism. FGF-23 levels were determined with an enzyme-linked immunosorbent assay. The association between FGF-23 and (Ca*P) was assessed using non-parametric methods. Patients were divided into two age groups, less than 13 years of age and greater than 13 years of age.ResultsThis cross-sectional study measured serum FGF-23, in 81 patients (42 females, 51.9%) at London Health Sciences Centre, aged 2 to 25 years, with various stages of CKD (Cystatin C estimated glomerular filtration rate, eGFR=10.7-213.0 ml/min). For the whole entire group of patients, FGF-23 levels were found to correlate significantly with age (Spearman r= 0.26, p=0.0198), Cystatin C eGFR (Spearman r=−0.40 p=0.0002), CKD stage (Spearman r=0.457, p<0.0001), PTH (Spearman r=0.330, p=0.0039), ionized calcium (Spearman r=−0.330, p=0.0049), CysC (Spearman r= 0.404, p=0.0002) and 1,25-dihydroxyvitamin D (Spearman r=−0.345, p=0.0034) concentrations. No significant correlation was found between FGF-23 levels and calcium phosphate product (Spearman r= 0.164, p=0.142). Upon classification of patients into two age groups, less than 13 years of age and more than 13 years of age, correlational results differed significantly. FGF-23 correlated with CysC eGFR( Spearman r= −0.633, p<0.0001), CKD stage (Spearman r=0.731, p<0.0001), phosphate (Spearman r= 0.557, p<0.0001), calcium phosphate product (Spearman r=0.534, p<0.0001), 125(OH)2 Vit D (Spearman r=−0.631, p<0.0001), PTH (Spearman r= 0.475, p=0.0017) and ionized calcium (Spearman r= −0.503, p=0.0015) only in the older group. The relationship between FGF-23 and Ca*P for the older group could be expressed by the exponential model FGF-23= 38.15 e0.4625Ca*P.ConclusionAbnormal values of FGF-23 in adolescents and young adults with CKD correlate with Ca* P in the absence of vascular calcifications, and may serve as a biomarker for the risk of cardiovascular calcifications.

Red blood cell transfusion use in patients with chronic kidney disease

There is limited data available on the use of red blood cell (RBC) transfusions in younger chronic kidney disease patients not on dialysis (CKD-ND), for whom the consequences of developing antibodies to foreign antigens (allosensitization) may be particularly relevant. We used the Ingenix medical claims database, comprising data on ∼40 million commercially insured US individuals, to identify annual (2002-08) cohorts of patients 18-64 years of age with newly diagnosed CKD. We followed each cohort for 1 year to estimate RBC transfusion rates and used Cox proportional hazards regression to identify patient characteristics associated with time to first transfusion. We identified 120 790 newly diagnosed CKD patients for the years 2002-08; 54% were 50-64 years of age. Overall, the transfusion rate was 2.64/100 person-years (PYs) (95% CI: 2.52-2.77). Rates were higher among those with diagnosed anemia [9.80/100 PYs (95% CI: 9.31-10.3)] and among those who progressed to end-stage renal disease (ESRD) [28.0/100 PYs (95% CI: 23.7-33.0)]. For those progressing to ESRD, transfusion rates more than doubled between 2002 and 2008. Of the factors evaluated, transfusion history and the presence of heart failure and diabetes were most strongly associated with a receipt of a transfusion. RBC transfusions are relatively common and on the rise among younger CKD-ND patients who are anemic and progress to ESRD. Efforts to decrease the use of transfusions may be important for potential transplant candidates who progress to ESRD.

Heart ventricular activation in VAT difference maps from children with chronic kidney disease

Children with chronic kidney disease (CKD) are affected by cardiovascular complications, including disturbances in the intraventricular conduction system. Body surface potential mapping (BSPM) is a non-invasive method of assessing the cardioelectrical field. Our aim was to investigate conduction disturbances in young CKD patients using ventricular activation time (VAT) maps. Our study comprised 22 CKD children (mean age: 13.1 ± 2.5 years) treated conservatively and 29 control patients. For each child 12-lead electrocardiogram (ECG) readings were taken, and blood pressure and serum concentrations of iPTH, Pi, t-Ca, creatinine, Fe+3, ferritin, and Hb, as well as eGFR were measured. All children underwent registration in the 87-lead BSPM system, and group-mean VAT maps and a difference map, which presents statistically significant differences between the groups, were created. The VAT map distribution in CKD patients revealed abnormalities specific to left anterior fascicle block. The difference map displays the areas of intergroup VAT changes, which are of discriminative value in detecting intraventricular conduction disturbances. Intraventricular conduction impairments in the left bundle branch may occur in children with CKD. BSPM enables conduction disturbances in CKD children to be detected earlier than using 12-lead ECG. The difference map derived from the group-mean isochrone maps precisely localizes the sites of disturbed conduction in the heart intraventricular conduction system.

Interrelationship between aortic stiffness and proteinuria in chronic kidney disease

Aortic stiffness and proteinuria are cardiovascular risk factors that are generally associated with each other. We analysed whether this is true for patients with chronic kidney disease (CKD). We hypothesized that in CKD patients of young age and predominant sole renal disease, aortic stiffness has no predictive value for proteinuria. In a cross-sectional setting, 144 patients with severe-to-mild CKD (estimated glomerular filtration rate (eGFR) 0 to <90 ml min(-1) 1.73 m(-2)) were analysed for stiffness, as measured using carotid-femoral pulse wave velocity (C-F PWV), and proteinuria, as determined using protein-creatinine ratio from morning spot urine. In stepwise linear regression analysis, C-F PWV predicted protein-creatinine ratio and vice versa. Younger patients (<50 years) with proteinuria had predominant glomerulonephritis. These were characterized by lower C-F PWV despite similar renal function when compared with younger patients without glomerulonephritis. We conclude that in CKD patients a general relationship exists between aortic stiffness and proteinuria. It is noted that this relation is lost in young CKD patients with predominant sole renal disease. In this study, C-F PWV is not predictive for proteinuria as renal disease is the leading cause of proteinuria.

The correlation between dental calculus and disturbed mineral metabolism in paediatric patients with chronic kidney disease

Vascular calcifications have been documented in children with end-stage renal disease. However, only a few reports have described abundant dental calculus formation in children suffering from chronic kidney disease (CKD). Moreover, dental calculus scores (DCS) and their correlation with renal disease severity have not been studied. DCS in 74 young CKD patients were evaluated: 25 pre-dialytic (PrD), 18 on dialysis (D) and 31 with transplants (T) compared to 32 healthy participants (C). Saliva and serum analysis included creatinine (Cr), urea (U), calcium (Ca), phosphorous (P), magnesium (Mg) as well as intraoral pH levels. All patient groups presented high DCS. DCS and pH levels were higher in the D group with a positive correlation between pH and lower incisor DCS (r = 0.56, P = 0.017). The highest salivary Ca was found in the PrD group. Salivary P in the PrD group was found to be higher than in the T and C groups. The lowest salivary Mg was found in the D group while the highest salivary Ca x P product was found in the PrD group. In all patient groups, salivary U was higher than in the C group with a 2.5-fold increase in the D group. Salivary Cr resembled the U salivary concentrations. Alterations in salivary Ca, P, Mg, U, Cr and intraoral pH levels were observed in the patient groups. DCS correlated with renal disease severity and therefore may be a reflection of other tissue calcification pathologies found in these patients.