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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest/financial disclosure
  8. References

Objective

Persistent elevation of urinary albumin excretion (UAE), even within normal range, is an independent predictor for cardiovascular disease. Accumulating research suggests that low levels of vitamin D and high levels of parathyroid hormone (PTH) also increase cardiovascular disease risk. This study is intended to investigate the relationship between PTH, vitamin D levels and UAE.

Methods

We examined 2897 adults aged 50 and above, participating in the second year of the fifth Korea National Health and Nutrition Examination Survey (KNHANES V-2). Anthropometric and laboratory measurements were performed. Elevated UAE was defined as spot urinary albumin creatinine ratio equal or above 10.

Results

The proportion of elevated UAE (21·8%, 23·2%, 23·2%, 31·8%; P for trend = 0·002) rose with increasing quartiles of PTH. The odds ratio for elevated UAE in the highest quartile of PTH was 72% higher than the lowest quartile group. There was no relationship between vitamin D and elevated UAE.

Conclusions

Elevated PTH levels are associated with elevated UAE in Korean adults aged 50 and above. Additional studies are needed to clarify this relationship.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest/financial disclosure
  8. References

Persistent elevation of urinary albumin excretion (UAE) is an independent predictor for cardiovascular disease (CVD) in many prospective studies.[1-3]

Elevation of UAE (albuminuria) is traditionally defined as levels of urinary albumin creatinine ratio (UACR) above 30 mg/g.[4] Recent meta-analysis studies showed that higher levels of albumin excretion within normal range (high normal albuminuria, UACR 10–30 mg/g), under the definition for albuminuria, are associated with increased cardiovascular mortality additive to conventional risk factors.[5, 6]

In subjects without kidney disease, elevation of UAE is recognized as a signal of systemic endothelial dysfunction in kidney.[7] However, the causes of UAE elevation or pathophysiology by which elevated UAE increases cardiovascular risk are unknown.

Vitamin D and parathyroid hormone (PTH) are both responsible for maintaining extracellular calcium homoeostasis, and for that purpose, both vitamin D and PTH operate within a well-controlled feedback system.[8] For example, in a circumstance of low-serum calcium level, PTH release is triggered and PTH increases calcium reabsorption at skeletal sites at the expense of an increased risk of fracture. PTH also increases active vitamin D level by 1-alpha hydroxylase, and in turn, active vitamin D increases intestinal absorption of calcium. However, in addition to these traditional roles, many prospective studies showed that low levels of vitamin D increase CVD risk independent of other established risk factors. Although the evidence was far less than for vitamin D, a community-based prospective study demonstrated that elevated PTH level predicted cardiovascular mortality.[9]

Low levels of vitamin D and high levels of PTH may be related to the elevation of UAE and the pathophysiology that elevated UAE increases CVD risk. Chronic vitamin D deficiency and secondary hyperparathyroidism are associated with increased insulin resistance,[10, 11] activation of renin–angiotensin–aldosterone (RAA) system[12, 13] and endothelial dysfunction.[14, 15] Also, both decreased vitamin D level and increased PTH level are associated with hypertension,[16-18] obesity[19, 20] and metabolic syndrome,[21, 22] all of which are risk factors for elevated UAE.

With vitamin D, cross-sectional studies showed that decreased vitamin D levels result in higher relative risk of UAE level above UACR 30 mg/g.[23] However, to the best of our knowledge, there is no study that investigated the relationship between PTH level and UAE. Therefore, we examined the relationship between PTH, vitamin D and UAE in persons older than 50. Also, we checked the association between these two hormones to high normal albuminuria within normal range of UAE (UACR 10–30 mg/g), which has been noticed as a novel risk factor for CVD risk.[10, 11]

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest/financial disclosure
  8. References

Study participants and data collection

This study is based on data from 2011, the second year of the fifth Korea National Health and Nutrition Examination Survey (KNHANES V-2). KNHANES V collected nationally representative statistics of health status, health-related behaviour and actual conditions of diet and nutritional status of Korean people by the Division of Chronic Disease Surveillance under the Korea Centers for Disease Control and Prevention (KCDC), from 2010 to 2012. A stratified, multistage probability sampling was used for the selection of household units, and 3840 households were extracted and surveyed. KNHANES consisted of a health interview survey, a nutrition survey and a health examination survey. Data on demographic characteristics, diet and health-related variables were collected through personal interview and self-administered questionnaire. Physical examination, blood sampling and urine sampling were carried out at a mobile examination centre.

A total of 8518 persons participated in KNHANES V-2, including 3444 persons aged 50 and above. Among them, 2953 persons (85·7%) underwent measurement of serum 25(OH) vitamin D, intact parathyroid hormone, urine albumin and urine creatinine. Fifty-six individuals with missing covariates were excluded. Therefore, in total, 2897 subjects were enrolled in our analyses.

All subjects in the study participated voluntarily under informed consent. The study protocol was approved by the Institutional Review Board of the KCDC.

Anthropometric measurements

Weight and height were measured wearing light clothing but no shoes. Body mass index (BMI) was calculated by following formula: weight divided by the square of height (kg/m2). Waist circumference was measured at the narrowest point between the lowest rib margin and the iliac crest. Systolic blood pressure and diastolic blood pressure were measured three times with an appropriately sized cuff after at least 5 min rest by well-trained technicians. The average values of the second and third measurement were used for the analysis.

Biochemical measurements

Blood samples were collected from the antecubital vein of each participant after overnight fasting. Blood samples were properly processed, kept under refrigeration at 2–8 °C and transported to the Central Testing Institute in Seoul, Korea. Blood samples were analysed within 24 h of transportation.

Analyses of fasting glucose, total cholesterol and triglyceride were performed by Hitachi Automatic Analyzer 7600 (Hitachi, Tokyo, Japan) and by enzymatic methods using commercially available kits (Daiichi, Tokyo, Japan). Serum and urine creatinine was measured with the same equipment by kinetic colorimetric method.

Serum 25(OH) vitamin D was measured using 125I RIA kit (Diasorin, Stillwater, MN, USA) with gamma-counter (1470 WIZARD; PerkinElmer, Turku, Finland) by radioimmunoassay method. Intact PTH was measured using N-tact PTH assay with LIAISON (Diasorin) by chemiluminescence immunoassay method. Urine albumin was measured by turbidimetric assay method using Hitachi 7600 (Hitachi).

The definition of categorical variables

BMI was classified as normal (<23 kg/m2), overweight (23–25 kg/m2) and obese (≥25 kg/m2). Waist circumference was defined as normal or abdominal obesity, classified as waist above 90 cm for men or 85 cm for women.[24]

Diabetes status was divided as diabetes, prediabetes and normal. Diabetes was defined as any use of diabetes medication (insulin or oral hypoglycaemic agents) or fasting glucose ≥126 mg/dl. Prediabetes was classified as fasting glucose ≥100 mg/dl in the absence of diabetes. Hypertension status was classified as hypertension, prehypertension and normal. Hypertension was defined as any use of antihypertensive medication or systolic pressure ≥140 mmHg or diastolic pressure ≥90 mmHg. Prehypertension was classified as systolic pressure ≥120 mmHg or diastolic pressure ≥80 mmHg in the absence of hypertension. Lipid status is classified as high, borderline and normal. High lipid status was defined as any use of medication for dyslipidaemia or serum total cholesterol ≥240 mg/dl. Borderline lipid status was defined as serum total cholesterol ≥200 mg/dl in the absence of high lipid status.

Smoking status was divided into three categories: current smoker, former smoker and never smoker based on self-reported questionnaire. Current smoker was defined as those who have smoked more than five packs of cigarettes during their lifetimes and were smoking currently. Former smoker was defined as those who smoked more than five packs of cigarettes during their lifetimes but not smoking currently. Alcohol drink status was classified as regular drinking or none. Regular drinking was defined as drinking alcohol more than two to four times per month. Physical activity was categorized into four groups: no exercise, mild exercise, moderate exercise and vigorous exercise. Mild exercise was defined as ≥10 min of walking more than 5 days per week. Moderate exercise was defined as ≥10 min of moderate physical activity in which the subject was tired compared with an ordinary level or breathing slightly hard more than 5 days per week. Vigorous exercise was defined as ≥10 min of vigorous physical activity in which the subject was exhausted compared with an ordinary level or breathing hard more than 3 days per week.

Estimated glomerular filtration rate (eGFR) was calculated from age, sex, race/ethnicity and serum creatinine concentration using the Modification of Diet in Renal Disease (MDRD) equation.[25] eGFR was arbitrarily divided into quartiles.

Level of albuminuria was calculated using the urine albumin creatinine ratio (UACR), and UACR was expressed in units of milligrams per gram. According to UACR, urine albumin excretion (UAE) was categorized into optimum (<10 mg/g), high normal albuminuria (10–30 mg/g), high albuminuria (30–300 mg/g) and very high albuminuria (≥300 mg/g). Elevated UAE, the primary study outcomes, was defined as UAE equal or above high normal albuminuria (≥10 mg/g) based on the recent studies.[5]

Statistical analysis

Analyses were conducted using sas (version 9.2; SAS Institute, Cary, NC, USA) and weighted to the Korean population to provide nationally representative estimates.

Participants' characteristics were presented by UAE status using chi-square or independent t-test according to variable's characteristics. We examined the relations of vitamin D and PTH levels with UACR using multiple linear regression adjusted for covariates (sex, age, BMI, waist circumference, diabetes, hypertension, lipid, smoking, alcohol, physical activity status, eGFR, PTH for vitamin D and vitamin D for PTH). PTH and UACR were log-transformed before analysis, because they were right skewed. In multiple linear regression model, eGFR was entered as a continuous variable.

The association of vitamin D and PTH with elevated UAE (present or not) was examined using logistic regression models. To estimate odds of elevated UAE according to decrease in vitamin D or increase in PTH, PTH and vitamin D level were arbitrarily divided into quartiles. Independent variables for logistic regression analysis were quartile of vitamin D and PTH and potential confounders (sex, age, BMI, waist circumference, diabetes, hypertension, lipid, smoking, alcohol and physical activity status). Separate model (model 2) additionally included a potential mediator (eGFR, quartiles), because of well-known association between PTH and eGFR. Participants in the lowest quartile of PTH and in the highest quartile of vitamin D served as the referent groups.

To show combined associations of vitamin D and PTH with elevated UAE, another logistic regression analysis was performed (model 3). Combined association was assessed by entering both variables into the regression model at the same time. In sequence, we repeated the analysis using high normal albuminuria as a dependent variable, excluding those with high albuminuria and very high albuminuria (model 4). We also repeated the same analyses among subjects with normal kidney function whose PTH level could be increased secondarily due to vitamin D insufficiency or deficiency (participants with eGFR ≥60 ml/min and vitamin D <30 ng/ml).

Tests for a linear trend were conducted by entering the categorical vitamin D and PTH into the regression models as an ordinal term. All tests of hypotheses were based upon a type I error rate of 0·05 using two-sided tests.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest/financial disclosure
  8. References

Proportions of persons with vitamin D <10 and 30 ng/ml (suggested definition of vitamin D deficiency and insufficiency[26]) were 4·37% and 95·27%, respectively, in Korean adults above 50 years of age. Percentages of subjects with PTH level <10 and 60 pg/ml (normal range of PTH: 10–60 pg/ml) were 0·04% and 55·44%, and proportions of persons with UAE: optimum, high normal albuminuria, high albuminuria and very high albuminuria were 74·78%, 13·89%, 9·50% and 1·84%, respectively.

In Table 1, variables related to elevated UAE were age (< 0·001), waist circumference (< 0·001), diabetes (P < 0·001), hypertension (P < 0·001) and PTH quartiles (P = 0·001), whereas sex (P = 0·949), BMI (P = 0·429), lipid status (P = 0·470), eGFR (P = 0·246), smoking (P = 0·174), physical activity (P = 0·117), alcohol use (P = 0·852) and vitamin D (P = 0·899) did not show significant associations.

Table 1. Characteristics of study participants by elevated UAE
VariablesOptimal UAE (UACR <10 mg/g)Elevated UAE (UACR ≥10 mg/g)P valuea
  1. UAE, urinary albumin excretion; UACR, urinary albumin creatinine ratio; eGFR, estimated glomerular filtration rate.

  2. Data are presented as weighted percentage (S.E.).

  3. a

    P values were obtained by chi-square or independent t-test.

Unweighted, n2169728 
Sex
Male46·9 (1·1)47·1 (2·4)0·949
Female53·1 (1·1)52·9 (2·4)
Age (year)
50–5952·8 (1·4)37·3 (2·4)<0·001
60–6927·6 (1·1)31·2 (2·0)
70–7916·7 (0·9)24·3 (1·8)
Above 803·0 (0·4)7·3 (1·0)
BMI (kg/m2)
Normal37·6 (1·5)35·5 (2·2)0·429
Overweight28·3 (1·1)26·9 (2·1)
Obesity34·1 (1·4)37·6 (2·2)
Waist circumference (cm)
Normal67·5 (1·5)59·0 (2·2)<0·001
Abdominal obesity32·5 (1·5)41·0 (2·2)
Diabetes status
Normal66·1 (1·3)48·7 (2·1)<0·001
Prediabetes27·0 (1·2)29·7 (2·0)
Diabetes6·9 (0·7)21·6 (1·9)
Hypertension status
Normal44·1 (1·4)26·4 (2·1)<0·001
Prehypertension40·7 (1·3)43·3 (1·2)
Hypertension15·3 (1·0)19·1 (1·1)
Lipid status
Normal56·7 (1·4)58·2 (2·3)0·470
Borderline32·9 (1·3)30·3 (2·2)
High10·3 (0·9)11·6 (1·5)
Quartiles of eGFR (ml/min)
1st (≥95·8)27·2 (1·5)24·6 (1·9)0·246
2nd (85·7–95·8)25·5 (1·3)24·4 (2·0)
3rd (76·3–85·7)25·8 (1·3)25·2 (2·0)
4th (<76·3)21·5 (1·2)25·8 (2·0)
Smoking status
None55·3 (1·2)53·2 (2·4)0·174
Former25·5 (1·2)23·6 (2·1)
Current19·0 (1·1)23·2 (1·9)
Alcohol status
None59·3 (1·2)59·8 (2·3)0·852
Regular drinking40·7 (1·2)40·2 (2·3)
Exercise status
None47·7 (1·4)53·1 (2·6)0·117
Mild31·8 (1·3)31·1 (2·2)
Moderate7·5 (0·7)5·6 (1·0)
Vigorous13·0 (1·1)10·2 (1·4)
Vitamin D (ng/ml)18·8 (0·3)18·9 (0·4)0·899
PTH (pg/ml)64·8 (0·7)71·5 (1·5)<0·001

When UACR was examined as a continuous outcome variable, PTH level was positively associated with UACR (in fully adjusted model: beta coefficient = 0·336, P = 0·003; data not shown). However, vitamin D level did not show a significant association with UACR (in fully adjusted model: beta coefficient = 0·001, P = 0·852; data not shown).

A stepwise increase in proportion of elevated UAE (21·8%, 23·2%, 23·2%, 31·8%; P for trend = 0·002) was observed with increasing quartiles of PTH (Fig. 1). In logistic regression analysis, after adjusting for potential confounders (sex, age, BMI, waist circumference, diabetes, hypertension, lipid, smoking, alcohol, physical activity status), a similar stepwise increase in odds ratio was observed with increasing PTH quartiles (Table 2, model 1, P for trend = 0·001). This association remained significant even after further adjustment was made for eGFR and vitamin D (Table 2, model 2, P for trend = 0·001; model 3, P for trend = 0·001). Subjects in the highest quartile of PTH levels had an increased likelihood of elevated UAE compared to those with lowest PTH levels in adjusted model (Table 2, model 3, odds ratio (OR) 1·72, 95% confidence interval (CI) 1·26–2·33, P for trend = 0·001). In contrast, there were no significant relationships between vitamin D and elevated UAE in any models (Table 3).

Table 2. Adjusted odds ratios of elevated UAE by quartiles of PTH
 Quartiles of PTH (pg/ml)P for trenda
1st (<50·2)2nd (50·2–62·1)3rd (62·1–77·9)4th (≥77·9)
  1. UAE, urinary albumin excretion; eGFR, estimated glomerular filtration rate; UACR, urinary albumin creatinine ratio.

  2. Data are presented as odds ratio (95% confidence intervals).

  3. Model 1 was adjusted for age, sex, body mass index, waist circumference, diabetes, hypertension, lipid, smoking, alcohol and exercise status.

  4. Model 2 was adjusted for all variables in model 1 plus eGFR (quartiles).

  5. Model 3 was adjusted for all variables in model 2 plus vitamin D levels.

  6. Model 4 analysis excluded participants with UACR ≥30 mg/g.

  7. a

    P values were obtained by multiple logistic regression analyses.

Model 11·00 (reference)1·07 (0·77–1·49)1·11 (0·82–1·48)1·67 (1·24–2·30)0·001
Model 21·00 (reference)1·07 (0·77–1·48)1·10 (0·82–1·48)1·69 (1·25–2·30)0·001
Model 31·00 (reference)1·06 (0·76–1·48)1·11 (0·83–1·48)1·72 (1·26–2·33)0·001
Model 41·00 (reference)1·28 (0·82–2·00)1·47 (0·95–2·28)1·94 (1·31–2·87)0·001
Table 3. Adjusted odds ratios of elevated UAE by quartiles of vitamin D levels
 Quartiles of vitamin D (ng/ml)P for trenda
1st (<14·1)2nd (14·1–18·1)3rd (18·1–22·7)4th (≥22·7)
  1. UAE, urinary albumin excretion; eGFR, estimated glomerular filtration rate; UACR, urinary albumin creatinine ratio.

  2. Data are presented as odds ratio (95% confidence intervals).

  3. Model 1 was adjusted for age, sex, body mass index, waist circumference, diabetes, hypertension, lipid, smoking, alcohol and exercise status.

  4. Model 2 was adjusted for all variables in model 1 plus eGFR (quartiles).

  5. Model 3 was adjusted for all variables in model 2 plus PTH levels.

  6. Model 4 analysis excluded participants with UACR ≥30 mg/g.

  7. a

    P values were obtained by multiple logistic regression analyses.

Model 10·88 (0·63–1·23)1·08 (0·80–1·46)0·88 (0·62–1·26)1·00 (reference)0·700
Model 20·88 (0·62–1·26)1·08 (0·80–1·46)0·88 (0·62–1·26)1·00 (reference)0·695
Model 30·99 (0·70–1·39)1·19 (0·88–1·61)0·94 (0·66–1·34)1·00 (reference)0·708
Model 41·08 (0·72–1·63)1·33 (0·90–1·95)1·10 (0·74–1·64)1·00 (reference)0·485
image

Figure 1. Weighted proportion for elevated UAE by quartile of PTH level.

Download figure to PowerPoint

The association of PTH level with high normal albuminuria, assessed by excluding participants with high and very high albuminuria from analysis, showed the same pattern (Table 2, model 4, P for trend = 0·001). In participants with normal kidney function but vitamin D insufficiency or deficiency (90·23% of the participants), there was also a significant relationship between PTH and elevated UAE after adjusting for all potential confounders (model 3: P for trend = 0·002, model 4: P for trend = 0·002; data not shown).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest/financial disclosure
  8. References

The present study is the first report that shows high PTH levels are associated with an increased prevalence of elevated UAE in general population aged 50 and above. This association persisted after adjusting for confounders such as age, sex, obesity, abdominal obesity, diabetes, hypertension, dyslipidaemia, smoking, alcohol, physical activity and kidney function. Moreover, a similar trend between PTH levels and UAE was observed within normal range of albuminuria (UACR <30 mg/g). These findings suggest that increased PTH level may be a predictor for UAE elevation.

Our findings could not be interpreted as mild elevation of PTH level is a risk factor for deterioration in renal function. Although kidney failure is one of the long-term complications of primary hyperparathyroidism (PHPT), the evidence is inadequate that mild PHPT is associated with the development of renal insufficiency. In recent epidemiologic study, however, it was observed that patients with mild PHPT had high risk of renal failure.[27] During the period of medical observation (median follow-up of 2·9 year) for mild asymptomatic PHPT cohort, the relative risk of developing renal failure was 19·30 compared with the healthy controls. The result of this study could reflect our findings that high PTH levels are associated with UAE elevation.

Because of the limitations of observational studies, we could not know the underlying mechanisms that explain the associations between PTH level and UAE. However, there is some research that points at an association between those. Above all, evidence has accumulated that aldosterone, a major hormone of the RAA system, is related to PTH. Several animal and human studies showed that PTH stimulated aldosterone secretion from adrenal glands directly or indirectly and aldosterone levels were decreased after surgical parathyroidectomy for primary hyperparathyroidism.[13, 28, 29] Aldosterone had no effect on intraglomerular haemodynamics, but could cause inflammation and fibrosis within kidney.[30] Aldosterone may be related to general vascular function, and many studies showed that increased levels of aldosterone are associated with endothelial dysfunction.[31, 32] Although long-term effects on renal outcomes were largely unknown, many experimental studies showed that mineralocorticoid receptor antagonist such as spironolactone and eplerenone reduced albuminuria regardless of diabetes.[33] Therefore, increased secretion of aldosterone due to elevated PTH may modulate the development of albuminuria.

In addition, the link between elevated PTH and elevated UAE may be explained by hypertension[18, 34] and metabolic syndrome,[22] established risk factors for albuminuria and possibly related to PTH.

In the present study, there were no significant relationships between vitamin D levels and UAE. The results were inconsistent with previous studies that showed a significant relationship between vitamin D concentrations and elevated UAE (UACR ≥30 mg/g).[23] De Boer et al.[23] analysed the data from the US Third National Health and Nutritional Examination Survey and showed that the group with the lowest quartile of vitamin D (3·5–17·6 ng/ml) had a higher risk of microalbuminuria (relative risk 1·28, 95% confidence intervals 1·03–1·59) than the group in the highest quartile (32·0–97·6 ng/ml). In Korea, the prevalence of vitamin D deficiency has been reported to be very high,[35] and in this study, most participants (95·3% of total participants) were categorized into vitamin D insufficiency or deficiency. Therefore, a skewed distribution of vitamin D levels and lack of adequate number of sufficient level of vitamin D may affect the results. Moreover, the relationship between vitamin D and albuminuria might be mediated by PTH level. Namely, secondarily elevated PTH level due to decreased vitamin D might be a cause of development of albuminuria.

As expected, in the present study, there was a significant but weak negative correlation between vitamin D level and PTH (Pearson correlation, r = −0·19, < 0·001). This reflects the fact that PTH secretion is stimulated by decreased vitamin D level. Although we could not confirm the correlation between vitamin D and UAE, we verified the relationship of PTH and UAE in participants with normal kidney function and vitamin D insufficiency or deficiency.

This study has several limitations. Subjects were limited to adults aged 50 and above, and therefore, the result of the study could not be applicable to younger adults. With vitamin D levels, most subjects in this study were in a state of vitamin D deficiency or insufficiency, and the narrow range of vitamin D concentrations might affect the result. We did not evaluate the time of measurement of vitamin D levels and use of vitamin D supplements. However, because all participants in KNHANES were randomly selected through all seasons and effect of use of vitamin supplements may be reflected by serum vitamin D levels, these factors are not likely to confound the association we found. With UAE, we did not evaluate information about antihypertensive medication such as angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, although such medications are not known to affect serum vitamin D or PTH levels. The use of a single, untimed urine sample might affect the accuracy of UACR although this method has been recommended[4]. The cross-sectional nature of this study does not allow the inference of casualty or temporal relationship between high PTH level and elevated UAE, and there may be unknown confounders between those two factors.

In conclusion, we found that elevated PTH levels are associated with elevated UAE in Korean adults aged 50 and above after adjusting other confounders. Our study calls for additional studies to confirm the relationship of PTH with elevated UAE, extending to whole age group and various populations. Prospective studies are also needed to evaluate the aetiologic roles of vitamin D and PTH in the development of albuminuria.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest/financial disclosure
  8. References
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