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Uric Acid Level as a Predictor of Long-Term Mortality in Advanced Age Population
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Uric acid level as a predictor of long-term mortality in advanced age population Marwan Abu Sneineh MD , Yuval Schwartz MD , Gideon Nesher MD , Yossi Freier Dror MA , Gabriel S. Breuer MD PII: DOI: Reference:
S0002-9629(19)30377-5 https://doi.org/10.1016/j.amjms.2019.10.017 AMJMS 946
To appear in:
The American Journal of the Medical Sciences
Received date: Accepted date:
9 July 2019 31 October 2019
Please cite this article as: Marwan Abu Sneineh MD , Yuval Schwartz MD , Gideon Nesher MD , Yossi Freier Dror MA , Gabriel S. Breuer MD , Uric acid level as a predictor of long-term mortality in advanced age population, The American Journal of the Medical Sciences (2019), doi: https://doi.org/10.1016/j.amjms.2019.10.017
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation.
Uric acid level as a predictor of long-term mortality in advanced age population Marwan Abu Sneineh, MD1, Yuval Schwartz, MD1, Gideon Nesher, MD1,2,4, Yossi Freier Dror, MA3 and Gabriel S. Breuer, MD1,2,4 1. Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem, Israel 2. Hebrew University School of Medicine, Jerusalem, Israel 3. Mashav Applied Research, Jerusalem, Israel 4. Rheumatology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
Correspondence: Dr Gabriel S Breuer, Head, Rheumatology Unit, Shaare Zedek Medical Center P O Box 3235 Jerusalem 9103102 Israel. Phone 972-2-6555687 Fax 972-2-6666049 [email protected]
Authors’ Email: MAS:[email protected], YS: [email protected], GN: [email protected], YFD: [email protected], GSB: [email protected]
No conflict of interest relevant to this work. No funding resources apply to this work.
Key Words: Uric Acid, Hyperuricemia, Mortality, Prediction, Long Term
1
1
Abstract: Background: Hyperuricemia is associated with the development, progression and outcome of several diseases. The purpose of this study is to evaluate the serum uric acid (UA) levels as predictor of long-term mortality in older population (age 60 years and above). Methods: Patients older than 60 years who were hospitalized in the departments of geriatrics and internal medicine in Shaare Zedek Medical Center in Jerusalem during a period of 4 months (March-June 2014) were included in this observational study. Association between hyperuricemia and long-term mortality were analyzed using multiple logistic regression, KaplanMeier and Cox proportional hazards regressions analysis. Results: A total of 624 patients were included in our study with mean age of 77.2 ± 14.6 years. Overall, 381 patients died during the follow up period (61.1%). Mortality rate in the hyperuricemic group (> 7 mg/dl) was higher (69.1%) than in the normo-uricemic group 58.4%. (P = .004). The median survival for hyperuricemic patients was significantly shorter compared to normo-uricemic patients (606 and 1018 days, respectively, P < .0001). High levels of UA were significantly associated with higher long-term mortality in patients with cardiovascular disease at their admission (P < .000). Conclusions: Elevated levels of UA in older patients in acute settings is a predictor of long-term mortality.
2
2
Introduction Uric acid (UA) is the end product of the metabolism of purine compounds in humans and some primate species. UA is produced in the liver from degradation of dietary and endogenously synthesized purine compounds. Urate production involves the breakdown of the purine mononucleotides, guanylic acid, inosinic acid, and adenylic acid, ultimately into the purine bases, guanine and hypoxanthine. These latter two compounds are then metabolized to xanthine, which is irreversibly oxidized by xanthine oxidase to produce UA. Hyperuricemia is known to be associated with development of gout and nephrolithiasis. Reports in recent years described associations between hyperuricemia and both renal diseases, cardiovascular diseases (CVD), and the metabolic syndrome.1-10 Hyperuricemia on admission to cardiac care unit (CCU) was reported to be associated with short-term mortality in myocardial infarction patients.6 High levels of serum UA were associated with long-term major adverse cardiovascular events including CVD death, myocardial infarction and stroke.11 Two recent studies evaluated the prognostic impact of UA on patients with heart failure, elevated UA levels at discharge were associated with a long-term worse outcome, the increased risk associated with serum UA was additive to clinical, biochemical and therapeutic predictors of adverse outcome.12,13 Some studies even showed that elevated serum UA is a marker of CVD risk in healthy populations.4 Hyperuricemia was also associated with accelerated kidney failure and allcause mortality in patients with chronic kidney disease (CKD).8,9,10 These and other studies support the assumption that UA in itself conveys an increased mortality risk and should be addressed in a much broader context. We have already reported that hyperuricemia was a predictor of short-term, in-hospital mortality in a cohort of 829 elderly patients admitted to internal medicine and geriatric departments at the Shaare Zedek Medical Center in Jerusalem, [7]. In this continuation study we determined the long-term survival in patients from this cohort, following their 2014 admission.
3
3
Methods Waiver of informed consent was approved by the Medical Center Helsinki Committee (Number 0092-18 SZMC).
Patients older than 60 years who were hospitalized in the departments of geriatrics and internal medicine in Shaare Zedek Medical Center in Jerusalem during a period of 4 months (March-June 2014) were included in this observational study. This reflects the consecutive nature of the study on the given population in the departments. This age group represents the patients in those departments due to the structure of the Department of Medicine. Data on clinical parameters and UA levels were collected during the first 48 hours of their hospitalization. The short-term mortality of this cohort was previously reported,7 and we have now collected mortality data on this cohort 3.5 years later. Mortality data were collected from databases of the Ministry of Internal Affairs, and the major medical centers in Jerusalem. Patients were excluded if mortality data were missing (unknown date of mortality or unknown status). The following data were collected on admission (March-June 2014): sex, age, admission diagnosis, blood pressure, comorbidities, and laboratory results including UA serum levels within 48 hours from admission. The UA level upon admission was compared to the mortality data using accepted statistical methods.
All measurements of biochemical markers were performed in the Medical Center’s laboratory by Architect-c16000 (Abbott). The reference values of UA are 2.6 – 6mg/dl for women and 3.5 – 7.2mg/dl for men. In our study hyperuricemia was defined as UA level >7mg/dl in accordance with the highest normal level in Harrisson's Principals of Medicine 19Ed p. 2764. The biochemical values represent the first blood test upon admission. Most patients were in an acute state of their condition and not in a steady state.
4
4
Statistical method Means and standard deviations were calculated for all continuous variables. Differences between the groups were evaluated using t-test. For all nominal variables, absolute frequencies were calculated, and differences between groups were assessed using Chi-sqaure test. The effect of admission UA serum levels and all relevant confounding parameters on all-cause mortality were assessed using regression analysis. All statistical analyses were conducted using SPSS statistical software (version 20).
5
5
Results A total of 624 patients were included in our study (Figure 1), 318 (51%) were females. The mean age was 77.2 ± 14.6 years, mean level of creatinine levels was 1.4 ± 1.4 mg/dl (normal level - 0.52-1.04 mg/dl), the mean UA level was 6.0 ± 2.4 mg/dl (normal level 3.5-7.0 mg/dl ). Overall, 381 patients died during the follow up period (61.1%). Mortality rate in the hyperuricemic group (> 7 mg/dl) was higher than in the normo-uricemic group (69.1% vs. 58.4%, respectively; P = .004). Kaplan-Meier survival curve shows significantly higher mortality in patients with UA greater than 7 mg/dl. (Figure 2). The median survival for hyperuricemic patients was significantly shorter compared to normo-uricemic patients (606 days vs. 1018 days, respectively; P < .0001). High levels of UA were significantly associated with higher long-term mortality in patients with cardiovascular disease at their admission (P < .0001) (Table1). Following Cox regression analysis, the only significant predictor of overall mortality, after adjusting for age, was UA serum level (odds ratio 1.394, CI 1.126-1.725; P = .002).
6
6
Discussion
Hyperuricemia can be due to many factors, including genetics, insulin resistance, iron overload, hypertension, hypothyroidism, chronic kidney disease, obesity, diet, use of diuretics and consumption of excess alcoholic beverages. There are three functional types of hyperuricemia: Decreased excretion of uric acid, increased production of uric acid, and mixed type. High levels of purine in the diet and increased purine metabolism can cause increased production. Decreased excretion can be due to kidney disease, certain drugs, and competition for excretion between uric acid and other molecules. Mixed causes include high levels of alcohol and/or fructose in the diet, and starvation.
This observational study shows that hyperuricemia in older adults at the time of admission to acute-care non-surgical setting was associated with increased long-term mortality during a period of 3.5 years. This adds to the previously reported association with short-term inhospital mortality.7 The main limitation of this study is the lack of patients' data after their hospital discharge, including UA levels, added medications, and development of new comorbidities. Also, causes of mortality were not available to us.
Our results are consistent with results of other studies where UA level was an independent risk factor for mortality in elderly patients.14-16 In a prospective study with 5 years follow up, Heras et al14 showed an association between high levels of UA and mortality in 80 clinically stable elderly patients, mortality rate reached 80% in patients with UA > 7.5 mg/dl in comparison to patients with UA <7.5mg/dl. In another community-based study, 15083 participants were randomly recruited from Geriatric and Nephrology consultation services. Their median age was 83 years, 3,980 deaths occurred during the median follow up period of 22.7 years. A strong relationship was observed between elevated UA and all-cause mortality and hyperuricemia was associated with 39% greater in-study mortality.15 UA was an independent predictor of mortality in another study.16 This prospective cohort of 650 consecutive patients admitted to a department of internal medicine during a period of 3 months showed a significant
7
7
association between serum UA and in-hospital mortality. Serum UA was significantly higher in patients who died (7.7 ± 4.9 mg/dl) compared to 6.0 ± 2.5mg/dl in patients who were alive at the time of discharge. An earlier report of the current cohort showed an association between increasing UA levels and short-term in-hospital mortality: 21% mortality of patients with UA 7.5 – 9.4 mg/dl at the time of admission, and 35% mortality when UA levels were > 9.5 mg/dl [7]. Further studies are needed to address possible effects of treatment of hyperuricemia on survival. A double-blind, long term study comparing prognosis of patients with hyperuricemia with and without UA lowering treatment would be the optimal method to answer the question of treating asymptomatic hyperuricemic patients.
8
8
Author Contributions
MAS: Data Collection, manuscript writing YS Data collection GN: Research design, manuscript writing YFD: Statistical analysis GSB: Research design, manuscript writing
9
9
References:
1. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey. JAMA 2000:10;283(18):2404-10. 2. Niskanen LK, Laaksonen DE, Nyyssönen K, et al. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004:26;164(14):1546-51. 3. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003: 22;107(15):1991-7. 4. Kivity S, Kopel E, Maor E, et al. Association of serum uric acid and cardiovascular disease in healthy adults. Am J Cardiol. 2013:111(8):1146-51 5. Johnson RJ, Segal MS, Srinivas T, et al. Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link? J Am Soc Nephrol. 2005:16(7):1909-19. 6. Mora-Ramírez M, Estevez-Garcia IO, Irigoyen-Camacho ME, et al. Hyperuricemia on admission predicts short-term mortality due to myocardial Infarction in a population with high prevalence of cardiovascular risk factors, Rev Invest Clin. 2017:69(5):247253. 7. Breuer GS, Schwartz Y, Freier-Dror Y, et al. Uric acid level as predictor of mortality in the acute care setting of advanced age population. Eur J Intern Med. 2017:44:74-76. 8. Chonchol M, Shlipak MG, Katz R, et al. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis. 2007:50(2):239-47. 9. Weiner DE, Tighiouart H, Elsayed EF, et al. Uric acid and incident kidney disease in the community. J Am Soc Nephrol. 2008:19(6):1204-11. 10. Obermayr RP, Temml C, Gutjahr G, et al. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol. 2008; 19(12):2407-13.
10
11
11. Tscharre M, Herman R, Rohla M, et al. Uric acid is associated with long-term adverse cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Atherosclerosis 2018;270:173–9. 12. Mantovania A, Targhera G, Temporelli PL, et al. On behalf of the GISSI-HF Investigators. Prognostic impact of elevated serum uric acid levels on long-term outcomes in patients with chronic heart failure: a post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. Metabolism 2018; 83:205–15. 13. Coiro S, Carluccio E, Biagioli P, et al. Elevated serum uric acid concentration at discharge confers additive prognostic value in elderly patients with acute heart failure. Nutr Metab Cardiovasc Dis 2018; 28:361–8. 14. Heras M, Fernández-Reyes MJ, Sánchez R, et al. Serum uric acid as a marker of allcause mortality in an elderly patient cohort, Nefrologia. 2012:32(1):67-72. 15. Juraschek SP, Tunstall-Pedoe H, Woodward M. Serum uric acid and the risk of mortality during 23 years follow-up in the Scottish Heart Health Extended Cohort Study,. Atherosclerosis. 2014;233:623-9. 16. Wasserman A, Shnell M, Boursi B, et al. Prognostic significance of serum uric acid in patients admitted to the department of medicine. Am J Med Sci. 2010:339:15-21.
11
11
Figure Legend
Figure 1. Study flow diagram outlining the study. * Twenty-nine patients included in the 1st cohort that were excluded due to lack of information were included in the current study after missing data was obtained.
12
12
Figure 2: Kaplan-Meier mortality curve during the follow-up period.
13
13
Table 1. Distribution of patients according to uric acid (UA) levels.a Uric Acid levels
UA ≤ 7 mg/dl (n=441)
UA > 7 mg/dl (n =183)
n (%)
n (%)
Age, years
76.3 (15.3)
79.5 (12.3)
.012
Sex, female
230 (52.1)
89 (48.6)
.476
1.2 (1.3)
1.7 (1.3)
<.001
253 (57.3)
128 (69.9)
.004
1018
606
<.001
209 (47.4)
63 (34.4)
.004
Cardiovascular
43 (9.8)
42 (23.0)
<.000
Renal
29 (6.6)
24 (13.1)
.012
Stroke
28 (6.3)
2 (1.1)
.003
Gastrointestinal
35 (7.9)
12 (6.6)
.669
Pulmonary
25 (5.7)
12 (6.6)
.809
Malignancy
13 (2.9)
4 (2.2)
.789
Hematology
3 (0.7)
7 (3.8)
.009
Creatinine, mg/dl Deaths
P-Value
Survival time, days Median Infectious
a
Data are presented as mean and standard deviation unless otherwise noted.
14
14
Table 2. Data comparison according to follow up outcome Long-term mortality
Yes (n=381)
No (n =243)
P-Value
M (SD)
M (SD)
Age, years
80.6 (12.0)
72.1 (16.6)
<.001
Sex female, n (%)
185 (48.5)
134 (55.1)
.128
Uric acid, mg/dl
6.2 (2.6)
5.5 (2.1)
<.001
Creatinine, mg/dl
1.4 (1.3)
1.2 (1.4)
.070
15
15
Uric acid level as a predictor of long-term mortality in advanced age population Marwan Abu Sneineh MD , Yuval Schwartz MD , Gideon Nesher MD , Yossi Freier Dror MA , Gabriel S. Breuer MD PII: DOI: Reference:
S0002-9629(19)30377-5 https://doi.org/10.1016/j.amjms.2019.10.017 AMJMS 946
To appear in:
The American Journal of the Medical Sciences
Received date: Accepted date:
9 July 2019 31 October 2019
Please cite this article as: Marwan Abu Sneineh MD , Yuval Schwartz MD , Gideon Nesher MD , Yossi Freier Dror MA , Gabriel S. Breuer MD , Uric acid level as a predictor of long-term mortality in advanced age population, The American Journal of the Medical Sciences (2019), doi: https://doi.org/10.1016/j.amjms.2019.10.017
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation.
Uric acid level as a predictor of long-term mortality in advanced age population Marwan Abu Sneineh, MD1, Yuval Schwartz, MD1, Gideon Nesher, MD1,2,4, Yossi Freier Dror, MA3 and Gabriel S. Breuer, MD1,2,4 1. Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem, Israel 2. Hebrew University School of Medicine, Jerusalem, Israel 3. Mashav Applied Research, Jerusalem, Israel 4. Rheumatology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
Correspondence: Dr Gabriel S Breuer, Head, Rheumatology Unit, Shaare Zedek Medical Center P O Box 3235 Jerusalem 9103102 Israel. Phone 972-2-6555687 Fax 972-2-6666049 [email protected]
Authors’ Email: MAS:[email protected], YS: [email protected], GN: [email protected], YFD: [email protected], GSB: [email protected]
No conflict of interest relevant to this work. No funding resources apply to this work.
Key Words: Uric Acid, Hyperuricemia, Mortality, Prediction, Long Term
1
1
Abstract: Background: Hyperuricemia is associated with the development, progression and outcome of several diseases. The purpose of this study is to evaluate the serum uric acid (UA) levels as predictor of long-term mortality in older population (age 60 years and above). Methods: Patients older than 60 years who were hospitalized in the departments of geriatrics and internal medicine in Shaare Zedek Medical Center in Jerusalem during a period of 4 months (March-June 2014) were included in this observational study. Association between hyperuricemia and long-term mortality were analyzed using multiple logistic regression, KaplanMeier and Cox proportional hazards regressions analysis. Results: A total of 624 patients were included in our study with mean age of 77.2 ± 14.6 years. Overall, 381 patients died during the follow up period (61.1%). Mortality rate in the hyperuricemic group (> 7 mg/dl) was higher (69.1%) than in the normo-uricemic group 58.4%. (P = .004). The median survival for hyperuricemic patients was significantly shorter compared to normo-uricemic patients (606 and 1018 days, respectively, P < .0001). High levels of UA were significantly associated with higher long-term mortality in patients with cardiovascular disease at their admission (P < .000). Conclusions: Elevated levels of UA in older patients in acute settings is a predictor of long-term mortality.
2
2
Introduction Uric acid (UA) is the end product of the metabolism of purine compounds in humans and some primate species. UA is produced in the liver from degradation of dietary and endogenously synthesized purine compounds. Urate production involves the breakdown of the purine mononucleotides, guanylic acid, inosinic acid, and adenylic acid, ultimately into the purine bases, guanine and hypoxanthine. These latter two compounds are then metabolized to xanthine, which is irreversibly oxidized by xanthine oxidase to produce UA. Hyperuricemia is known to be associated with development of gout and nephrolithiasis. Reports in recent years described associations between hyperuricemia and both renal diseases, cardiovascular diseases (CVD), and the metabolic syndrome.1-10 Hyperuricemia on admission to cardiac care unit (CCU) was reported to be associated with short-term mortality in myocardial infarction patients.6 High levels of serum UA were associated with long-term major adverse cardiovascular events including CVD death, myocardial infarction and stroke.11 Two recent studies evaluated the prognostic impact of UA on patients with heart failure, elevated UA levels at discharge were associated with a long-term worse outcome, the increased risk associated with serum UA was additive to clinical, biochemical and therapeutic predictors of adverse outcome.12,13 Some studies even showed that elevated serum UA is a marker of CVD risk in healthy populations.4 Hyperuricemia was also associated with accelerated kidney failure and allcause mortality in patients with chronic kidney disease (CKD).8,9,10 These and other studies support the assumption that UA in itself conveys an increased mortality risk and should be addressed in a much broader context. We have already reported that hyperuricemia was a predictor of short-term, in-hospital mortality in a cohort of 829 elderly patients admitted to internal medicine and geriatric departments at the Shaare Zedek Medical Center in Jerusalem, [7]. In this continuation study we determined the long-term survival in patients from this cohort, following their 2014 admission.
3
3
Methods Waiver of informed consent was approved by the Medical Center Helsinki Committee (Number 0092-18 SZMC).
Patients older than 60 years who were hospitalized in the departments of geriatrics and internal medicine in Shaare Zedek Medical Center in Jerusalem during a period of 4 months (March-June 2014) were included in this observational study. This reflects the consecutive nature of the study on the given population in the departments. This age group represents the patients in those departments due to the structure of the Department of Medicine. Data on clinical parameters and UA levels were collected during the first 48 hours of their hospitalization. The short-term mortality of this cohort was previously reported,7 and we have now collected mortality data on this cohort 3.5 years later. Mortality data were collected from databases of the Ministry of Internal Affairs, and the major medical centers in Jerusalem. Patients were excluded if mortality data were missing (unknown date of mortality or unknown status). The following data were collected on admission (March-June 2014): sex, age, admission diagnosis, blood pressure, comorbidities, and laboratory results including UA serum levels within 48 hours from admission. The UA level upon admission was compared to the mortality data using accepted statistical methods.
All measurements of biochemical markers were performed in the Medical Center’s laboratory by Architect-c16000 (Abbott). The reference values of UA are 2.6 – 6mg/dl for women and 3.5 – 7.2mg/dl for men. In our study hyperuricemia was defined as UA level >7mg/dl in accordance with the highest normal level in Harrisson's Principals of Medicine 19Ed p. 2764. The biochemical values represent the first blood test upon admission. Most patients were in an acute state of their condition and not in a steady state.
4
4
Statistical method Means and standard deviations were calculated for all continuous variables. Differences between the groups were evaluated using t-test. For all nominal variables, absolute frequencies were calculated, and differences between groups were assessed using Chi-sqaure test. The effect of admission UA serum levels and all relevant confounding parameters on all-cause mortality were assessed using regression analysis. All statistical analyses were conducted using SPSS statistical software (version 20).
5
5
Results A total of 624 patients were included in our study (Figure 1), 318 (51%) were females. The mean age was 77.2 ± 14.6 years, mean level of creatinine levels was 1.4 ± 1.4 mg/dl (normal level - 0.52-1.04 mg/dl), the mean UA level was 6.0 ± 2.4 mg/dl (normal level 3.5-7.0 mg/dl ). Overall, 381 patients died during the follow up period (61.1%). Mortality rate in the hyperuricemic group (> 7 mg/dl) was higher than in the normo-uricemic group (69.1% vs. 58.4%, respectively; P = .004). Kaplan-Meier survival curve shows significantly higher mortality in patients with UA greater than 7 mg/dl. (Figure 2). The median survival for hyperuricemic patients was significantly shorter compared to normo-uricemic patients (606 days vs. 1018 days, respectively; P < .0001). High levels of UA were significantly associated with higher long-term mortality in patients with cardiovascular disease at their admission (P < .0001) (Table1). Following Cox regression analysis, the only significant predictor of overall mortality, after adjusting for age, was UA serum level (odds ratio 1.394, CI 1.126-1.725; P = .002).
6
6
Discussion
Hyperuricemia can be due to many factors, including genetics, insulin resistance, iron overload, hypertension, hypothyroidism, chronic kidney disease, obesity, diet, use of diuretics and consumption of excess alcoholic beverages. There are three functional types of hyperuricemia: Decreased excretion of uric acid, increased production of uric acid, and mixed type. High levels of purine in the diet and increased purine metabolism can cause increased production. Decreased excretion can be due to kidney disease, certain drugs, and competition for excretion between uric acid and other molecules. Mixed causes include high levels of alcohol and/or fructose in the diet, and starvation.
This observational study shows that hyperuricemia in older adults at the time of admission to acute-care non-surgical setting was associated with increased long-term mortality during a period of 3.5 years. This adds to the previously reported association with short-term inhospital mortality.7 The main limitation of this study is the lack of patients' data after their hospital discharge, including UA levels, added medications, and development of new comorbidities. Also, causes of mortality were not available to us.
Our results are consistent with results of other studies where UA level was an independent risk factor for mortality in elderly patients.14-16 In a prospective study with 5 years follow up, Heras et al14 showed an association between high levels of UA and mortality in 80 clinically stable elderly patients, mortality rate reached 80% in patients with UA > 7.5 mg/dl in comparison to patients with UA <7.5mg/dl. In another community-based study, 15083 participants were randomly recruited from Geriatric and Nephrology consultation services. Their median age was 83 years, 3,980 deaths occurred during the median follow up period of 22.7 years. A strong relationship was observed between elevated UA and all-cause mortality and hyperuricemia was associated with 39% greater in-study mortality.15 UA was an independent predictor of mortality in another study.16 This prospective cohort of 650 consecutive patients admitted to a department of internal medicine during a period of 3 months showed a significant
7
7
association between serum UA and in-hospital mortality. Serum UA was significantly higher in patients who died (7.7 ± 4.9 mg/dl) compared to 6.0 ± 2.5mg/dl in patients who were alive at the time of discharge. An earlier report of the current cohort showed an association between increasing UA levels and short-term in-hospital mortality: 21% mortality of patients with UA 7.5 – 9.4 mg/dl at the time of admission, and 35% mortality when UA levels were > 9.5 mg/dl [7]. Further studies are needed to address possible effects of treatment of hyperuricemia on survival. A double-blind, long term study comparing prognosis of patients with hyperuricemia with and without UA lowering treatment would be the optimal method to answer the question of treating asymptomatic hyperuricemic patients.
8
8
Author Contributions
MAS: Data Collection, manuscript writing YS Data collection GN: Research design, manuscript writing YFD: Statistical analysis GSB: Research design, manuscript writing
9
9
References:
1. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey. JAMA 2000:10;283(18):2404-10. 2. Niskanen LK, Laaksonen DE, Nyyssönen K, et al. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004:26;164(14):1546-51. 3. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003: 22;107(15):1991-7. 4. Kivity S, Kopel E, Maor E, et al. Association of serum uric acid and cardiovascular disease in healthy adults. Am J Cardiol. 2013:111(8):1146-51 5. Johnson RJ, Segal MS, Srinivas T, et al. Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link? J Am Soc Nephrol. 2005:16(7):1909-19. 6. Mora-Ramírez M, Estevez-Garcia IO, Irigoyen-Camacho ME, et al. Hyperuricemia on admission predicts short-term mortality due to myocardial Infarction in a population with high prevalence of cardiovascular risk factors, Rev Invest Clin. 2017:69(5):247253. 7. Breuer GS, Schwartz Y, Freier-Dror Y, et al. Uric acid level as predictor of mortality in the acute care setting of advanced age population. Eur J Intern Med. 2017:44:74-76. 8. Chonchol M, Shlipak MG, Katz R, et al. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis. 2007:50(2):239-47. 9. Weiner DE, Tighiouart H, Elsayed EF, et al. Uric acid and incident kidney disease in the community. J Am Soc Nephrol. 2008:19(6):1204-11. 10. Obermayr RP, Temml C, Gutjahr G, et al. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol. 2008; 19(12):2407-13.
10
11
11. Tscharre M, Herman R, Rohla M, et al. Uric acid is associated with long-term adverse cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Atherosclerosis 2018;270:173–9. 12. Mantovania A, Targhera G, Temporelli PL, et al. On behalf of the GISSI-HF Investigators. Prognostic impact of elevated serum uric acid levels on long-term outcomes in patients with chronic heart failure: a post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. Metabolism 2018; 83:205–15. 13. Coiro S, Carluccio E, Biagioli P, et al. Elevated serum uric acid concentration at discharge confers additive prognostic value in elderly patients with acute heart failure. Nutr Metab Cardiovasc Dis 2018; 28:361–8. 14. Heras M, Fernández-Reyes MJ, Sánchez R, et al. Serum uric acid as a marker of allcause mortality in an elderly patient cohort, Nefrologia. 2012:32(1):67-72. 15. Juraschek SP, Tunstall-Pedoe H, Woodward M. Serum uric acid and the risk of mortality during 23 years follow-up in the Scottish Heart Health Extended Cohort Study,. Atherosclerosis. 2014;233:623-9. 16. Wasserman A, Shnell M, Boursi B, et al. Prognostic significance of serum uric acid in patients admitted to the department of medicine. Am J Med Sci. 2010:339:15-21.
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Figure Legend
Figure 1. Study flow diagram outlining the study. * Twenty-nine patients included in the 1st cohort that were excluded due to lack of information were included in the current study after missing data was obtained.
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Figure 2: Kaplan-Meier mortality curve during the follow-up period.
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Table 1. Distribution of patients according to uric acid (UA) levels.a Uric Acid levels
UA ≤ 7 mg/dl (n=441)
UA > 7 mg/dl (n =183)
n (%)
n (%)
Age, years
76.3 (15.3)
79.5 (12.3)
.012
Sex, female
230 (52.1)
89 (48.6)
.476
1.2 (1.3)
1.7 (1.3)
<.001
253 (57.3)
128 (69.9)
.004
1018
606
<.001
209 (47.4)
63 (34.4)
.004
Cardiovascular
43 (9.8)
42 (23.0)
<.000
Renal
29 (6.6)
24 (13.1)
.012
Stroke
28 (6.3)
2 (1.1)
.003
Gastrointestinal
35 (7.9)
12 (6.6)
.669
Pulmonary
25 (5.7)
12 (6.6)
.809
Malignancy
13 (2.9)
4 (2.2)
.789
Hematology
3 (0.7)
7 (3.8)
.009
Creatinine, mg/dl Deaths
P-Value
Survival time, days Median Infectious
a
Data are presented as mean and standard deviation unless otherwise noted.
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Table 2. Data comparison according to follow up outcome Long-term mortality
Yes (n=381)
No (n =243)
P-Value
M (SD)
M (SD)
Age, years
80.6 (12.0)
72.1 (16.6)
<.001
Sex female, n (%)
185 (48.5)
134 (55.1)
.128
Uric acid, mg/dl
6.2 (2.6)
5.5 (2.1)
<.001
Creatinine, mg/dl
1.4 (1.3)
1.2 (1.4)
.070
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