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Abstract
Chronic kidney disease (CKD) has a prevalence of approximately 13% and is most frequently caused by diabetes and hypertension. In population studies, CKD etiology is often uncertain. Some experimental and observational human studies have suggested that high-protein intake may increase CKD progression and even cause CKD in healthy people. The protein source may be important. Daily red meat consumption over years may increase CKD risk, whereas white meat and dairy proteins appear to have no such effect, and fruit and vegetable proteins may be renal protective. Few randomized trials exist with an observation time greater than 6 months, and most of these were conducted in patients with preexisting diseases that dispose to CKD. Results conflict and do not allow any conclusion about kidney-damaging effects of long-term, high-protein intake. Until additional data become available, present knowledge seems to substantiate a concern. Screening for CKD should be considered before and during long-term, high-protein intake.
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Affiliation(s)
- Anne-Lise Kamper
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark;
| | - Svend Strandgaard
- Department of Nephrology, Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark;
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Devassy JG, Wojcik JL, Ibrahim NHM, Zahradka P, Taylor CG, Aukema HM. Mixed compared with single-source proteins in high-protein diets affect kidney structure and function differentially in obese fa/fa Zucker rats. Appl Physiol Nutr Metab 2017; 42:135-141. [PMID: 28079397 DOI: 10.1139/apnm-2016-0301] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2023]
Abstract
Questions remain regarding the potential negative effects of dietary high protein (HP) on kidney health, particularly in the context of obesity in which the risk for renal disease is already increased. To examine whether some of the variability in HP effects on kidney health may be due to source of protein, obese fa/fa Zucker rats were given HP (35% of energy from protein) diets containing either casein, soy protein, or a mixed source of animal and plant proteins for 12 weeks. Control lean and obese rats were given diets containing casein at normal protein (15% of energy from protein) levels. Body weight and blood pressure were measured, and markers of renal structural changes, damage, and function were assessed. Obesity alone resulted in mild renal changes, as evidenced by higher kidney weights, proteinuria, and glomerular volumes. In obese rats, increasing the protein level using the single, but not mixed, protein sources resulted in higher renal fibrosis compared with the lean rats. The mixed-protein HP group also had lower levels of serum monocyte chemoattractant protein-1, even though this diet further increased kidney and glomerular size. Soy and mixed-protein HP diets also resulted in a small number of damaged glomeruli, while soy compared with mixed-protein HP diet delayed the increase in blood pressure over time. Since obesity itself confers added risk of renal disease, an HP diet from mixed-protein sources that enables weight loss but has fewer risks to renal health may be advantageous.
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Affiliation(s)
- Jessay G Devassy
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- b Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, MB R2H 2A6, Canada
| | - Jennifer L Wojcik
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- b Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, MB R2H 2A6, Canada
| | - Naser H M Ibrahim
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- b Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, MB R2H 2A6, Canada
| | - Peter Zahradka
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- b Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, MB R2H 2A6, Canada
- c Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Carla G Taylor
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- b Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, MB R2H 2A6, Canada
- c Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- d Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Harold M Aukema
- a Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- c Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- d Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
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McGraw NJ, Krul ES, Grunz-Borgmann E, Parrish AR. Soy-based renoprotection. World J Nephrol 2016; 5:233-257. [PMID: 27152261 PMCID: PMC4848148 DOI: 10.5527/wjn.v5.i3.233] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 01/16/2016] [Accepted: 03/14/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is a significant public health problem as risk factors such as advanced age, obesity, hypertension and diabetes rise in the global population. Currently there are no effective pharmacologic treatments for this disease. The role of diet is important for slowing the progression of CKD and managing symptoms in later stages of renal insufficiency. While low protein diets are generally recommended, maintaining adequate levels of intake is critical for health. There is an increasing appreciation that the source of protein may also be important. Soybean protein has been the most extensively studied plant-based protein in subjects with kidney disease and has demonstrated renal protective properties in a number of clinical studies. Soy protein consumption has been shown to slow the decline in estimated glomerular filtration rate and significantly improve proteinuria in diabetic and non-diabetic patients with nephropathy. Soy’s beneficial effects on renal function may also result from its impact on certain physiological risk factors for CKD such as dyslipidemia, hypertension and hyperglycemia. Soy intake is also associated with improvements in antioxidant status and systemic inflammation in early and late stage CKD patients. Studies conducted in animal models have helped to identify the underlying molecular mechanisms that may play a role in the positive effects of soy protein on renal parameters in polycystic kidney disease, metabolically-induced kidney dysfunction and age-associated progressive nephropathy. Despite the established relationship between soy and renoprotection, further studies are needed for a clear understanding of the role of the cellular and molecular target(s) of soy protein in maintaining renal function.
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Marckmann P, Osther P, Pedersen AN, Jespersen B. High-protein diets and renal health. J Ren Nutr 2014; 25:1-5. [PMID: 25091135 DOI: 10.1053/j.jrn.2014.06.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 05/21/2014] [Accepted: 06/06/2014] [Indexed: 12/16/2022] Open
Abstract
High-protein diets (i.e., protein content of more than 25% of energy or more than 2 g/kg body weight per day) based on meat and dairy products are repeatedly promoted for weight reduction and better health, but the evidence supporting these notions is quite dubious. As described in the present review, there is a reason to be concerned about adverse effects of such diets, including glomerular hyperfiltration, hypertensive effects of a concomitant increase in dietary sodium, and an increased risk of nephrolithiasis. These diet-induced physiological consequences might lead to an increase in the prevalence of chronic kidney disease in the general population without preexisting kidney disease. Accordingly, we find medical reasons to refrain from promoting high-protein diets, in particular those based on meat and dairy products, until clear-cut evidence for the safety and for the superiority of such diets on human health has been provided.
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Affiliation(s)
- Peter Marckmann
- Section of Nephrology, Department of Internal Medicine, Roskilde Hospital, Roskilde, Denmark.
| | - Palle Osther
- Department of Urology, Fredericia Hospital - a part of Hospital Littlebelt, University of Southern Denmark, Fredericia, Denmark
| | - Agnes N Pedersen
- Department of Nutrition, DTU Food, National Food Institute, Technical University of Denmark, Soeborg, Denmark
| | - Bente Jespersen
- Department of Nephrology, Aarhus University Hospital, Aarhus, Denmark
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Tsukamoto Y, Jha V, Becker G, Chen HC, Perkovic V, Prodjosudjadi W, Tungsanga K, Wang H, Morad Z. A challenge to chronic kidney disease in Asia: The report of the second Asian Forum of Chronic Kidney Disease Initiative. Nephrology (Carlton) 2010; 15:248-52. [PMID: 20470287 DOI: 10.1111/j.1440-1797.2009.01269.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND The Asian Forum of Chronic Kidney Disease Initiative started in 2007 in Hamamatsu, Japan when delegates from 16 countries joined together to facilitate collaboration in studying chronic kidney disease (CKD) in the Asia-Pacific region. Based on the outcome of the first meeting, the second meeting was organized as a consensus conference to frame the most relevant issues, and develop research recommendations and action plan. PROCEEDINGS The meeting was held on 4 May 2008 as a pre-conference meeting to the 11th Asian Pacific Congress of Nephrology in Kuala Lumpur. This meeting consisted of three sessions: Session I was dedicated to the estimation of glomerular filtration rate and the standardization of serum creatinine measurements. Session II discussed specific considerations in the aetiology of and risk factors for end-stage renal disease in Asia. We concluded that there were regional specific problems that might lead to a very high prevalence of end-stage renal disease. Session III discussed the issue of facilitation of coordination and integration of the CKD initiative between developed and developing countries in the Asia-Pacific region. CONCLUSION The following action plans were formulated: (i) validating the existing global estimated glomerular filtration rate equation or creating a new one using serum creatinine standardized by a central laboratory; (ii) establishing a pan-Asian CKD registry to facilitate risk analysis of CKD and its comorbidities; (iii) adapting existing clinical practice guidelines for CKD detection and management to address specific problems in this region; and (iv) working closely with other international professional organizations to promote manpower development and education in different aspects of CKD in developing countries.
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Affiliation(s)
- Yusuke Tsukamoto
- Department of Nephrology, Shuwa General Hospital, Saitama, Japan.
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Higashiyama A, Watanabe M, Kokubo Y, Ono Y, Okayama A, Okamura T. Relationships between protein intake and renal function in a Japanese general population: NIPPON DATA90. J Epidemiol 2010; 20 Suppl 3:S537-43. [PMID: 20351475 PMCID: PMC3920380 DOI: 10.2188/jea.je20090222] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2009] [Accepted: 02/15/2010] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND It has been considered that reducing protein intake is one of important measures to delay the progression of chronic kidney disease (CKD). However, the relationship between protein intake and renal function is still uncertain, especially in relatively healthy general population. METHODS 7404 individuals (3099 men and 4305 women) who participated in both National Survey on Circulatory Disorders and National Nutrition Survey in 1990 and were free from past history of renal diseases were included in the present study. We estimated sex-specific age- and multivariate-adjusted glomerular filtration rate (GFR) and odds ratios for the presence of CKD according to the quartiles of protein (total, animal, vegetable) intake per body weight (kg). RESULTS There were significant differences in each protein intake among the age groups in both men and women. Both participants with and without CKD took more protein intake than that of each recommended level. There were positive relationships between GFR and the quartiles of each protein intake in both sexes. The odds ratios for the presence of CKD were significantly decreased in the higher quartile of protein intake in women. CONCLUSIONS The higher protein intake was associated with higher GFR in both sexes and low prevalence of CKD in women. However, further studies are needed to conclude the relationships between protein intake and renal function.
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Affiliation(s)
- Aya Higashiyama
- Lifestyle-Related Disease Prevention Center, Shiga University of Medical Science, Otsu, Japan.
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Iseki K, Iseki C, Ikemiya Y, Kinjo K, Takishita S. Risk of developing low glomerular filtration rate or elevated serum creatinine in a screened cohort in Okinawa, Japan. Hypertens Res 2007; 30:167-74. [PMID: 17460387 DOI: 10.1291/hypres.30.167] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
There are no known predictors of renal dysfunction, particularly for a community-based screening. We evaluated the changes in serum creatinine (SCr) and glomerular filtration rate (GFR) among screenees who participated in the screening program of the Okinawa General Health Maintenance Association both in 1983 and 1993. A total of 4,662 screenees at least 30 years of age at the 1983 screening were analyzed to examine whether they developed high SCr (>or=1.4 mg/dl for men, >or=1.2 mg/dl for women) or low GFR (<60 ml/min/1.73 m2). Overall, mean GFR (mean+/-SD) decreased slightly from 72.7+/-11.7 ml/min/1.73 m2 to 70.8+/-15.0 ml/min/1.73 m2. In 1983, the prevalences of high SCr and low GFR were 3.6% and 13.2%, respectively, and in 1993, they were 8.1% and 24.2%, respectively. Among the variables studied, dipstick proteinuria was the strongest predictor: the adjusted odds ratio (95% CI) was 1.282 (1.076-1.527, p<0.01) for high SCr and 1.215 (1.116-1.322, p<0.01) for low GFR. Dipstick proteinuria was best for detecting subjects who might develop low GFR in a screening setting. In subjects without proteinuria, systolic blood pressure was a significant predictor for low GFR (the adjusted odds ratio [95% CI] was 1.015 [1.009-1.020, p<0.01]) and for high SCr (the adjusted odds ratio [95% CI] was 1.028 [1.016-1.040, p<0.01]). In conclusion, the present study suggests that a dipstick urine test for proteinuria and both systolic and diastolic blood pressure are useful to identify those who are at risk of developing high SCr and low GFR and consequently end-stage renal disease.
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Affiliation(s)
- Kunitoshi Iseki
- Dialysis Unit and Third Department of Internal Medicine, University Hospital of the Ryukyus, Japan.
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Imai E, Horio M, Iseki K, Yamagata K, Watanabe T, Hara S, Ura N, Kiyohara Y, Hirakata H, Moriyama T, Ando Y, Nitta K, Inaguma D, Narita I, Iso H, Wakai K, Yasuda Y, Tsukamoto Y, Ito S, Makino H, Hishida A, Matsuo S. Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient. Clin Exp Nephrol 2007; 11:156-163. [PMID: 17593516 DOI: 10.1007/s10157-007-0463-x] [Citation(s) in RCA: 210] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2006] [Accepted: 01/30/2007] [Indexed: 10/25/2022]
Abstract
BACKGROUND The number of patients with end-stage renal disease (ESRD) in Japan has continuously increased in the past three decades. In 2005, 36,063 patients whose average age was 66 years entered a new dialysis program. This large number of ESRD patients could be just the tip of the iceberg of an increasing number of patients with chronic kidney disease (CKD). However, to date, a nationwide epidemiological study has not been conducted yet to survey the CKD population. METHODS Data for 527,594 (male, 211,034; female, 316,560) participants were obtained from the general adult population aged over 20 years who received annual health check programs in 2000-2004, from seven different prefectures in Japan: Hokkaido, Fukushima, Ibaraki, Tokyo, Osaka, Fukuoka, and Okinawa prefectures. The glomerular filtration rate (GFR) for each participant was estimated from the serum creatinine values, using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation modified by the Japanese coefficient. RESULTS The prevalences of CKD stage 3 in the study population, stratified by age groups of 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80-89 years, were 1.4%, 3.6%, 10.8%, 15.9%, 31.8%, 44.0%, and 59.1%, respectively, predicting 19.1 million patients with stage 3 CKD in the Japanese general adult population of 103.2 million in 2004. CKD stage 4 + 5 was predicted in 200,000 patients in the Japanese general adult population. Comorbidity of hypertension, diabetes, and proteinuria increased as the estimated GFR (eGFR) decreased. The prevalence of concurrent CKD was significantly higher in hypertensive and diabetic populations than in the study population overall when CKD was defined as being present with an eGFR of less than 40 ml/min per 1.73 m(2) instead of less than 60 ml/min per 1.73 m(2). CONCLUSIONS About 20% of the Japanese adult population (i.e., approximately 19 million people) are predicted to have stage 3 to 5 CKD, as defined by a GFR of less than 60 ml/min per 1.73 m(2).
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Affiliation(s)
- Enyu Imai
- Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
| | - Masaru Horio
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kunitoshi Iseki
- Dialysis Unit, University Hospital of The Ryukyus, Okinawa, Japan
| | - Kunihiro Yamagata
- Department of Nephrology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
| | - Tsuyoshi Watanabe
- Third Department of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Shigeko Hara
- Health Medical Center, Toranomon Hospital, Tokyo, Japan
| | - Nobuyuki Ura
- Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Yutaka Kiyohara
- Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideki Hirakata
- Nephrology and Dialysis Center, Fukuoka Red Cross Hospital, Fukuoka, Japan
| | | | - Yasuhiro Ando
- Department of Nephrology, Jichi Medical School, Tochigi, Japan
| | - Kosaku Nitta
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Ichiei Narita
- Division of Nephrology and Rheumatology, Niigata University, Niigata, Japan
| | - Hiroyasu Iso
- Department of Public Health, Osaka University Graduate School of Medicine, Osaka, Japan
| | | | - Yoshinari Yasuda
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Sadayoshi Ito
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Hirofumi Makino
- Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Akira Hishida
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Seiichi Matsuo
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Iseki K, Kohagura K, Sakima A, Iseki C, Kinjo K, Ikemiya Y, Takishita S. Changes in the Demographics and Prevalence of Chronic Kidney Disease in Okinawa, Japan (1993 to 2003). Hypertens Res 2007; 30:55-62. [PMID: 17460372 DOI: 10.1291/hypres.30.55] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
To compare the risk factor demographics and the prevalence of chronic kidney disease (CKD), we analyzed two databases from the 1993 (N=143,948) and 2003 (N=154,019) mass screenings in Okinawa, Japan (Okinawa General Health Maintenance Association registry). We estimated the glomerular filtration rate (GFR) using serum creatinine (SCr) levels. SCr was measured by the modified Jaffe method in 1993 and by enzyme assay in 2003; the relation between the two methods was: SCr (Jaffe) = 0.194 + 1.079 x SCr (enzyme). CKD prevalence was compared using the estimated GFR calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. SCr was measured in 66.2% (1993) and 69.8% (2003) of the total screenees. Proteinuria was present in 3.4% (1993) and 4.3% (2003) of the total screened population, respectively. The prevalence of CKD (GFR<60 ml/min/1.73 m(2)) was similar between the two databases, being 15.7% in 1993 and 15.1% in 2003. However, the demographics of the CKD risk factors changed during the study period. The mean level of systolic blood pressure decreased, whereas the prevalence of obesity and the mean levels of serum cholesterol and fasting plasma glucose increased. In 2003, the estimated prevalence of metabolic syndrome in the general population of Japan calculated using the modified National Cholesterol Education Program (NCEP) criteria was 19.1%. The prevalence of CKD was significantly associated with that of metabolic syndrome: the age- and sex-adjusted odds ratio was 1.332 (95% confidence interval [CI], 1.277-1.389; p<0.0001). In conclusion, the demographics of the participants of the general screenings in Okinawa, Japan differed between the 1993 and 2003 screenings, but the prevalence of CKD seemed to be similar, or at least did not increase substantially, between the two databases.
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Affiliation(s)
- Kunitoshi Iseki
- Dialysis Unit, University Hospital of the Ryukyus, Okinawa, Japan.
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Tanaka H, Shiohira Y, Uezu Y, Higa A, Iseki K. Metabolic syndrome and chronic kidney disease in Okinawa, Japan. Kidney Int 2006; 69:369-74. [PMID: 16408128 DOI: 10.1038/sj.ki.5000050] [Citation(s) in RCA: 155] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We assessed the prevalence of chronic kidney disease (CKD) in a hospital-based screening program in Okinawa, Japan. The significance of metabolic syndrome as a determinant of CKD was examined using multivariate logistic regression analysis. A total of 6980 participants, aged 30-79 years, participated in a screening program in Tomishiro Chuo Hospital. Metabolic syndrome was defined according to the criteria of the Adult Treatment Panel III (ATP III). Data were also analyzed according to the modified criteria of the National Cholesterol Education Program (NCEP) that defines abdominal obesity as a waist circumference of > oe =85 cm in men and > or =90 cm in women. CKD was defined as dipstick proteinuria (> or =1+) or a reduced glomerular filtration rate (GFR). GFR was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) formula. The prevalence of metabolic syndrome and CKD was 12.8 and 13.7%, respectively. Metabolic syndrome was a significant determinant of CKD (adjusted odds ratio (OR) 1.537 and 95% confidence interval (CI) 1.277-1.850, P<0.0001). The adjusted OR (95% CI) was 1.770 (1.215-2.579, P=0.0029) for those with four metabolic syndrome risk factors compared to those with no metabolic syndrome risk factors. Metabolic syndrome was a significant determinant for younger participants (<60 years; OR 1.686, 95% CI 1.348-2.107, P<0.0001), but not for older participants (> or =60 years; OR 1.254, 95% CI 0.906-1.735, NS). The relationship between the number of metabolic syndrome risk factors and the prevalence of CKD was linear using the modified criteria. The results suggest that metabolic syndrome is a significant determinant of CKD in men under 60 years of age, in Okinawa, Japan.
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Affiliation(s)
- H Tanaka
- Tomishiro Chuo Hospital and Dialysis Unit, University Hospital of The Ryukyus, Okinawa, Japan
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