Dietary Sugar and Artificial Sweetener Intake and Chronic Kidney Disease: A Review
2013; Elsevier BV; Volume: 20; Issue: 2 Linguagem: Inglês
10.1053/j.ackd.2012.12.005
ISSN1548-5609
AutoresVytas P. Karalius, David A. Shoham,
Tópico(s)Diet and metabolism studies
ResumoSugar consumption, especially in the form of fructose, has been hypothesized to cause kidney disease. This review provides an overview of the epidemiologic evidence that sugar consumption increases CKD risk. Research supports a causal role of sugar in several kidney disease risk factors, including increasing serum uric acid levels, diabetes, and obesity. Sugar may also harm the kidney via other mechanisms. There is no evidence that sucrose is any safer for the kidney than high fructose corn syrup (HFCS) because both are similar in composition. To date, 5 epidemiologic studies have directly evaluated the relationship between sugar consumption (in the form of sugar-sweetened beverages) and CKD. Although most studies suggest that the risk of CKD is elevated among consumers of sugar-sweetened beverages, only 2 studies report statistically significant associations. Three studies have also examined diet soda consumption, with two reporting positive and significant associations. Confounding by unmeasured lifestyle factors may play a role in the positive results whereas poor measurement of sugar and artificial sweetener intake could explain null results. Nevertheless, the hypothesis that sugar causes kidney disease remains plausible, and alternative research designs may be needed. Sugar consumption, especially in the form of fructose, has been hypothesized to cause kidney disease. This review provides an overview of the epidemiologic evidence that sugar consumption increases CKD risk. Research supports a causal role of sugar in several kidney disease risk factors, including increasing serum uric acid levels, diabetes, and obesity. Sugar may also harm the kidney via other mechanisms. There is no evidence that sucrose is any safer for the kidney than high fructose corn syrup (HFCS) because both are similar in composition. To date, 5 epidemiologic studies have directly evaluated the relationship between sugar consumption (in the form of sugar-sweetened beverages) and CKD. Although most studies suggest that the risk of CKD is elevated among consumers of sugar-sweetened beverages, only 2 studies report statistically significant associations. Three studies have also examined diet soda consumption, with two reporting positive and significant associations. Confounding by unmeasured lifestyle factors may play a role in the positive results whereas poor measurement of sugar and artificial sweetener intake could explain null results. Nevertheless, the hypothesis that sugar causes kidney disease remains plausible, and alternative research designs may be needed. Clinical Summary•Sugar consumption has been associated with the rising prevalence of CKD in the United States.•Several mechanisms may link sugar consumption—especially fructose—with CKD, including increased uric acid, diabetes, obesity, and hypertension.•To date, 5 studies have examined the relationship between sugar consumption (in the form of sugar-sweetened beverages) and CKD, with mixed methodologies and inconsistent findings.•Future research may need to use alternative data collection and modeling techniques. As of 2004, an estimated 13.1% of the adult United States population has CKD.1Coresh J. Selvin E. Stevens L.A. et al.Prevalence of chronic kidney disease in the United States.J Am Med Assoc. 2007; 298: 2038-2047Crossref PubMed Scopus (3868) Google Scholar The increased prevalence of CKD and ESRD is attributable to several factors, including rising diabetes2Muntner P. Coresh J. Powe N.R. Klag M.J. 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Second, excessive sugar intake may promote obesity if there is not a compensatory reduction in other macronutrients; fructose may especially promote central adiposity. In turn, obesity may directly or indirectly (via hypertension) promote kidney damage. Third, excessive sugar intake increases the risk of diabetes mellitus, an established risk factor for CKD. Finally, kidney damage may occur through other pathways that are independent of obesity, uric acid, and diabetes. One proposed mechanism by which dietary sugar is thought to play a role in kidney disease is through the relationship between fructose consumption and increased levels of uric acid in the body (hyperuricemia) and gout.15Rho Y.H. Zhu Y. Choi H.K. The epidemiology of uric acid and fructose.Semin Nephrol. 2011; 31: 410-419Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Uric acid, hyperuricemia, and gout are associated with all stages of CKD16Yamada T. Fukatsu M. Suzuki S. Wada T. Joh T. 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Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents.Circulation. 2007; 115: 2526-2532Crossref PubMed Scopus (387) Google Scholar whereas the other 2 focused on hyperuricemia32Choi H.K. Ford E.S. Li C. Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey.Arthritis Rheum. 2007; 57: 109-115Crossref PubMed Scopus (337) Google Scholar and gout32Choi H.K. Ford E.S. Li C. Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey.Arthritis Rheum. 2007; 57: 109-115Crossref PubMed Scopus (337) Google Scholar in adults. Substantial evidence supports the hypothesis that dietary sugar intake is related to obesity, particularly in the form of sugar-sweetened beverages.33Chaloupka F.J. Powell L.M. Chriqui J.F. Sugar-sweetened beverages and obesity prevention: policy recommendations.J Policy Anal Manage. 2011; 30: 662-664Crossref PubMed Scopus (10) Google Scholar, 34Hu F.B. Malik V.S. Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence.Physiol Behav. 2010; 100: 47-54Crossref PubMed Scopus (566) Google Scholar, 35Malik V.S. Popkin B.M. Bray G.A. Despres J.P. Hu F.B. Sugar-sweetened beverages, obesity, type 2 diabetes mellitus, and cardiovascular disease risk.Circulation. 2010; 121: 1356-1364Crossref PubMed Scopus (1125) Google Scholar In an intervention study of overweight subjects given supplements of sucrose or artificial sweeteners, those who consumed fairly large amounts of sucrose, mostly as beverages, had increased body weight, fat mass, and blood pressure; this pattern was not observed in a similar group who consumed artificial sweeteners.36Raben A. Vasilaras T.H. Moller A.C. Astrup A. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10 wk of supplementation in overweight subjects.Am J Clin Nutr. 2002; 76: 721-729PubMed Google Scholar Stanhope and colleagues allocated subjects to receive either glucose- or fructose-sweetened beverages for 10 weeks; they reported that both groups exhibited similar weight gain during the intervention, but that visceral adiposity was significantly increased only in the subjects consuming fructose-sweetened beverages.37Stanhope K.L. Schwarz J.M. Keim N.L. et al.Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Crossref PubMed Scopus (1256) Google Scholar Visceral adiposity appears to play a key role in the association between obesity and kidney disease.38Kramer H. Shoham D. McClure L.A. et al.Association of waist circumference and body mass index with all-cause mortality in CKD: the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study.Am J Kidney Dis. 2011; 58: 177-185Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Visceral adiposity, rather than BMI per se, appears to be the most significant predictor of the risk factors comprising metabolic syndrome,39Balkau B. Deanfield J.E. Despres J.P. et al.International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries.Circulation. 2007; 116: 1942-1951Crossref PubMed Scopus (555) Google Scholar and a growing body of literature shows that metabolic syndrome is a risk factor for CKD.40Thomas G. Sehgal A.R. Kashyap S.R. Srinivas T.R. Kirwan J.P. Navaneethan S.D. 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Flint A. et al.Increased postprandial glycaemia, insulinemia, and lipidemia after 10 weeks' sucrose-rich diet compared to an artificially sweetened diet: a randomised controlled trial.Food Nutr Res. 2011; 55: 721-729Crossref Scopus (67) Google Scholar Sugar consumption may also increase blood pressure. In a prospective analysis of 810 adults, a reduction in dietary sugar and sugar-sweetened beverages was significantly associated with reductions in blood pressure.45Chen L. Caballero B. 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Increased fructose associates with elevated blood pressure.J Am Soc Nephrol. 2010; 21: 1543-1549Crossref PubMed Scopus (145) Google Scholar Another National Health and Nutrition Examination Survey analysis of adolescents showed a positive and linear association between sugar-sweetened beverage consumption and blood pressure.47Nguyen S. Choi H.K. Lustig R.H. Hsu C.Y. Sugar-sweetened beverages, serum uric acid, and blood pressure in adolescents.J Pediatr. 2009; 154: 807-813Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar Paradoxically, artificial sweeteners have been linked with components of the metabolic syndrome. Nettleton and colleagues showed risk of type 2 diabetes is 167% higher in diet soda consumers versus nonconsumers.48Nettleton J.A. Lutsey P.L. Wang Y. Lima J.A. Michos E.D. Jacobs Jr., D.R. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).Diabetes Care. 2009; 32: 688-694Crossref PubMed Scopus (307) Google Scholar Duffey and colleagues similarly reported increased risk of metabolic syndrome components with increased diet soda consumption, although the associations were modified by overall dietary patterns.49Duffey K.J. Steffen L.M. Van Horn L. Jacobs Jr., D.R. Popkin B.M. Dietary patterns matter: diet beverages and cardiometabolic risks in the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) study.Am J Clin Nutr. 2012; 95: 909-915Crossref PubMed Scopus (110) Google Scholar It is possible that these associations with artificial sweeteners could arise from substitution behavior among those reducing prior sugary soft drink consumption. For example, participants followed over 20 years in the Coronary Artery Risk Development in Young Adults study reported a decline in prevalence of sugary soda consumption from 76.0 to 48.9%, although diet soda consumption was not reported. At the population level, work by Duffey and Popkin shows a 14% increase between 1965 and 2002 in the proportion of the U.S. population consuming diet beverages; however, the proportion consuming sugary sodas also grew 23% (to over 43%) in the same period.11Duffey K.J. Popkin B.M. Shifts in patterns and consumption of beverages between 1965 and 2002.Obesity (Silver Spring). 2007; 15: 2739-2747Crossref PubMed Scopus (215) Google Scholar In addition to dietary sugar being associated with CKD risk factors, data from animal studies do suggest that sugar consumption may independently affect kidney disease risk. One such study examining rats fed a specialized diet of fructose and dextrose for 6 weeks found that the high fructose, but not dextrose, accelerated CKD progression.50Gersch M.S. Mu W. Cirillo P. et al.Fructose, but not dextrose, accelerates the progression of chronic kidney disease.Am J Physiol Ren Physiol. 2007; 293: F1256-F1261Crossref PubMed Scopus (157) Google Scholar Glomerular sclerosis, tubular atrophy, tubular dilatation, and cellular infiltration were substantially higher in the kidneys from rats fed fructose versus rats fed dextrose. In a similar animal study, rats fed a high-fructose diet (60 vs 10%) developed kidney hypertrophy, glomerular hypertension, cortical vasoconstriction, and arteriolopathy of preglomerular vessels, suggesting that fructose-induced metabolic syndrome is associated with kidney disturbances.51Sanchez-Lozada L.G. Tapia E. Jimenez A. et al.Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats.Am J Physiol Ren Physiol. 2007; 292: F423-F429Crossref PubMed Scopus (258) Google Scholar Although animal studies directly show an association between sugar consumption and CKD, little research has been performed in humans. To date, at least 5 epidemiologic studies have focused specifically on sugar and kidney disease. All of these studies examined sugary soft drinks and not the full range of dietary sugar sources, which is extremely difficult to measure precisely. A significant proportion of added sugars in the United States comes in the form of sugar-sweetened beverages, which contribute nearly 10% of the total caloric intake.11Duffey K.J. Popkin B.M. Shifts in patterns and consumption of beverages between 1965 and 2002.Obesity (Silver Spring). 2007; 15: 2739-2747Crossref PubMed Scopus (215) Google Scholar We broke down the studies into cross-sectional and prospective cohort designs. One of the studies by Bomback and colleagues examined cross-sectional and prospective (incident) associations.52Bomback A.S. Derebail V.K. Shoham D.A. et al.Sugar-sweetened soda consumption, hyperuricemia, and kidney disease.Kidney Int. 2010; 77: 609-616Crossref PubMed Scopus (107) Google Scholar These studies are summarized in Table 1.Table 1Sugary Soft Drink Consumption and CKDStudyYearFirst AuthorStudy DesignTotal NumberExposure DefinitionOutcome or Case DefinitionAdjusted OR or Relative Risk (95% CI)Adjustment Factors1a2007SaldanaCase-control935≥2 regular colas/dDiagnosed kidney disease2.51 (1.44-4.38)BMI, income, proxy respondent, education, analgesic use, and diabetes.2a2008ShohamCross-sectional9358≥2 regular colas/dGender-specific UACR cutpoints1.40 (1.13-1.74)Consumption of ≥2 diet sodas per day, age, race-ethnicity, gender, and living below twice the poverty level.3a2010BombackCross-sectional15,642>1/dPrevalent CKD (eGFR < 60 mL/min)1.46 (0.96-2.22)Age, sex, total caloric intake, sodium intake, diabetes, hypertension, BMI, current tobacco and alcohol use, education, study site, and race.3b2010BombackProspective cohort15,642>1/dIncident CKD (eGFR < 60 mL/min)0.82 (0.59-1.16)Age, sex, caffeine intake, animal protein intake, hypertension, BMI, kidney function, current tobacco and alcohol use, study site, and race.42009BombackProspective cohort447≥7/wkClinically significant progression of CKD (by eGFR and albuminuria)1.51 (0.49-4.62)Baseline UACR, age, sex, race, education, field center, current smoking, BMI, hypertension, diabetes mellitus, dyslipidemia, phosphorous intake, protein intake, and total caloric intake.5a2011LinProspective cohort3318≥1 regular cola/deGFR decline ≥30%1.56 (0.84-2.91)Age, caloric intake, hypertension, BMI, diabetes, cigarette smoking, activity (METS/wk), and cardiovascular disease.Abbreviation: UACR, urine albumin-to-creatinine ratio. Open table in a new tab Abbreviation: UACR, urine albumin-to-creatinine ratio. The case-control and cross-sectional studies used various definitions of the exposure and the outcome. For example, the case-control study by Saldana and colleagues defined exposure as 2 or more regular colas per day and the outcome as diagnosed kidney disease.53Saldana T.M. Basso O. Darden R. Sandler D.P. Carbonated beverages and chronic kidney disease.Epidemiology. 2007; 18: 501-506Crossref PubMed Scopus (65) Google Scholar The study reports an odds ratio (OR) of 2.51 (95% confidence interval [CI] 1.44-4.38) for self-respondents (ie, individuals directly answered questions, rather than relying on a proxy such as a spouse). Shoham and colleagues used a similar exposure of 2 or more sugary drinks/sodas per day and an exposure of gender-specific urinary albuminuria-to-creatinine ratio cutpoints of more than 17 mg/g for males and more than 25 mg/g for females).54Shoham D.A. Durazo-Arvizu R. Kramer H. et al.Sugary soda consumption and albuminuria: results from the National Health and Nutrition Examination Survey, 1999-2004.PLoS One. 2008; 3: e3431Crossref PubMed Scopus (82) Google Scholar The study reported an OR of 1.40 (95% CI 1.13-1.74) after adjusting for consumption of 2 or more diet sodas per day, age, race-ethnicity, gender, and living below twice the poverty level; adjusting for serum uric acid levels did not appreciably alter the results. Bomback and colleagues defined exposure as consumption of more than 1 sugar-sweetened soda per day and the outcome as prevalent CKD (estimated glomerular filtration rate [eGFR] < 60 mL/minute/1.73 m2).52Bomback A.S. Derebail V.K. Shoham D.A. et al.Sugar-sweetened soda consumption, hyperuricemia, and kidney disease.Kidney Int. 2010; 77: 609-616Crossref PubMed Scopus (107) Google Scholar Bomback reported an OR of 1.46 (95% CI 0.96-2.22) after adjusting for age, sex, total caloric intake, sodium intake, diabetes, hypertension, BMI, current tobacco and alcohol use, education, and race. The prospective cohort studies that examined the association between sugar-sweetened beverages and kidney disease also differed by the exposure and outcome definitions. In 2010, Bomback and colleagues defined the exposure as consumption of more than 1 sugar-sweetened soda per day,52Bomback A.S. Derebail V.K. Shoham D.A. et al.Sugar-sweetened soda consumption, hyperuricemia, and kidney disease.Kidney Int. 2010; 77: 609-616Crossref PubMed Scopus (107) Google Scholar whereas in 2009 Bomback and colleagues defined exposure as consumption of 7 or more sugar-sweetened beverages per week.55Bomback A.S. Katz R. He K. Shoham D.A. Burke G.L. Klemmer P.J. Sugar-sweetened beverage consumption and the progression of chronic kidney disease in the Multi-Ethnic Study of Atherosclerosis (MESA).Am J Clin Nutr. 2009; 90: 1172-1178Crossref PubMed Scopus (24) Google Scholar Lin and Curhan used data from the Nurses' Health Study and defined exposure as consumption of 1 or more sugary sodas per day.56Lin J. Curhan G.C. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women.Clin J Am Soc Nephrol. 2010; 6: 160-166Crossref PubMed Scopus (57) Google Scholar The outcomes in this study were incident CKD defined as an eGFR less than 60 mL/minute/m2,52Bomback A.S. Derebail V.K. Shoham D.A. et al.Sugar-sweetened soda consumption, hyperuricemia, and kidney disease.Kidney Int. 2010; 77: 609-616Crossref PubMed Scopus (107) Google Scholar clinically significant progression of albuminuria or eGFR decline,55Bomback A.S. Katz R. He K. Shoham D.A. Burke G.L. Klemmer P.J. Sugar-sweetened beverage consumption and the progression of chronic kidney disease in the Multi-Ethnic Study of Atherosclerosis (MESA).Am J Clin Nutr. 2009; 90: 1172-1178Crossref PubMed Scopus (24) Google Scholar and an eGFR decline of 30% or more from baseline values.56Lin J. Curhan G.C. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women.Clin J Am Soc Nephrol. 2010; 6: 160-166Crossref PubMed Scopus (57) Google Scholar No prospective study reported a statistically significant and independent association between sugar-sweetened beverages and CKD after adjusting for potential mediators including hypertension, BMI, and diabetes. However, the studies by Bomback and colleagues and Lin and colleagues did suggest that sugar-sweetened beverage consumption elevates CKD risk. It should be noted that in the 2010 study by Bomback and colleagues, individuals with prevalent CKD at baseline were excluded and these individuals may have had the greatest lifetime exposures to sugar-sweetened beverages. Adjusting for mediating factors generally attenuates measures of association in an attempt to identify the independent effect of sugar-sweetened beverages on kidney disease risk. These prospective cohort studies that examined the association between sugar-sweetened beverages and kidney disease risk also examined the association between diet soft drink consumption and kidney disease, which are shown in Table 2. Saldana and colleagues’ case-control study found an OR of 4.21 (95% CI 1.21-14.61) for self-respondents only.53Saldana T.M. Basso O. Darden R. Sandler D.P. Carbonated beverages and chronic kidney disease.Epidemiology. 2007; 18: 501-506Crossref PubMed Scopus (65) Google Scholar Shoham reported an unadjusted OR for albuminuria for consumption of 2 or more diet sodas per day of 0.94 (95% CI 0.64-1.39) after adjusting for consumption of 2 or more sugary sodas per day, age, race-ethnicity, gender, and living below twice the poverty level.54Shoham D.A. Durazo-Arvizu R. Kramer H. et al.Sugary soda consumption and albuminuria: results from the National Health and Nutrition Examination Survey, 1999-2004.PLoS One. 2008; 3: e3431Crossref PubMed Scopus (82) Google Scholar Lin and Curhan reported an OR of 2.02 (95% CI 1.36-3.01) after adjusting for age, caloric intake, hypertension, BMI, diabetes, cigarette smoking, activity (METS/week), and cardiovascular disease.56Lin J. Curhan G.C. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women.Clin J Am Soc Nephrol. 2010; 6: 160-166Crossref PubMed Scopus (57) Google Scholar Overall, 2 of the diet beverage studies report an OR of greater than 1.0, whereas Shoham found null results. It is possible that case-control and cohort studies better capture long-term associations compared with a cross-sectional study design. On the other hand, confounding cannot be ruled out, especially the possibility that current diet soda consumption reflects a past history of sugary soda consumption, weight gain, and subsequent substitution of diet soda.Table 2Diet Soft Drink ConsumptionStudyYearFirst AuthorStudy DesignTotal NumberExposure DefinitionOutcome or Case DefinitionAdjusted OR or Relative Risk (95% CI)Adjustment Factors1b2007SaldanaCase-control935≥2 diet colas/dDiagnosed kidney disease4.21 (1.21-14.61)BMI, income, proxy respondent, education, analgesic use, and diabetes.2b2008ShohamCross-sectional9358≥2 diet/dGender-specific albuminuria cutpoints0.94 (0.64-1.39)Consumption of ≥2 sugary sodas per day, age, race-ethnicity, gender, and living below twice the poverty level.5b2011LinProspective cohort3318≥2 diet/deGFR decline ≥30%2.02 (1.36-3.01)Age, caloric intake, hypertension, BMI, diabetes, cigarette smoking, activity (METS/wk), and cardiovascular disease. Open table in a new tab One major limitation of all studies is the potential for confounding by lifestyle factors that is not captured through observational research. The potential misclassification of diet can lead to null findings.57Freedman L.S. Schatzkin A. Midthune D. Kipnis V. Dealing with dietary measurement error in nutritional cohort studies.J Natl Cancer Inst. 2011; 103: 1086-1092Crossref PubMed Scopus (314) Google Scholar On the other hand, positive findings may be due to confounders—factors that increase propensity to consume sugar-sweetened or diet beverages and increase the risk of kidney disease. Such confounders may include adiposity or other dietary factors such as sodium intake.58He F.J. Marrero N.M. MacGregor G.A. Salt intake is related to soft drink consumption in children and adolescents: a link to obesity?.Hypertension. 2008; 51: 629-634Crossref PubMed Scopus (253) Google Scholar The evidence that sugar and artificial sweeteners increase kidney disease risk is mixed. It is possible that studies that have found positive results have made their way into the literature whereas null findings have suffered from “publication bias.” As noted by Austin Bradford Hill many years ago, epidemiological evidence alone rarely establishes causal relationships; rather, evidence from many sources should be considered, including biologically plausible pathways and experimental evidence.59Hill A.B. The environment and disease: association or causation?.Proc R Soc Med. 1965; 58: 295-300PubMed Google Scholar The focus of this review has been on the observational epidemiologic evidence, but resolution of the debate may ultimately entail clinical trials that restrict sugar intake. One such pilot trial was conducted by Brymora and colleagues, demonstrating that among patients with CKD, fructose restriction reduced inflammatory markers and blood pressure.60Brymora A. Flisinski M. Johnson R.J. Goszka G. Stefanska A. Manitius J. Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease.Nephrol Dial Transplant. 2011; 27: 608-612Crossref PubMed Scopus (68) Google Scholar Given the current weight of the evidence, trials of sugar restriction for kidney disease per se are probably unwarranted. However, future clinical trials of sugar-restricted diets should at least include kidney disease as secondary outcomes. Because of likely confounding by lifestyle, well-designed randomized trials could give a clearer picture of the evidence for or against sugar's causal role in kidney disease risk.
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