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• W2002821665 abstract "Related Article, p. 303 Related Article, p. 303 The obesity epidemic is a recent phenomenon and remains the biggest threat for reversing positive trends in health indicators observed over the past century. The current spate of kidney disease in the United States may be attributed in large part to the obesity epidemic combined with the aging of the population.1Ejerblad E. Fored C.M. Lindblad P. Fryzek J. McLaughlin J.K. Nyren O. Obesity and risk for chronic renal failure.J Am Soc Nephrol. 2006; 17: 1695-1702Crossref PubMed Scopus (482) Google Scholar, 2Hsu C.Y. McCulloch C.E. Iribarren C. Darbinian J. Go A.S. Body mass index and risk for end-stage renal disease.Ann Intern Med. 2006; 144: 21-28Crossref PubMed Scopus (1051) Google Scholar Obesity is now recognized as an important risk factor for the development of kidney failure treated by dialysis and transplant (end-stage renal disease).2Hsu C.Y. McCulloch C.E. Iribarren C. Darbinian J. Go A.S. Body mass index and risk for end-stage renal disease.Ann Intern Med. 2006; 144: 21-28Crossref PubMed Scopus (1051) Google Scholar However, neither the underlying pathogenic mechanisms nor the relationship of obesity to earlier stages of chronic kidney disease (CKD) is understood. In this issue of the American Journal of Kidney Diseases, Wuerzner et al3Wuerzner G. Pruijm M. Maillard M. et al.Marked association between obesity and glomerular hyperfiltration: a cross-sectional study in an African population.Am J Kidney Dis. 2010; 56: 303-312Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar examined the association between obesity and glomerular hyperfiltration, a potential antecedent of CKD. Their findings highlight several issues with regard to the hypothesis of kidney symmorphosis, which is defined as the quantitative matching of structural components to functional demands.4Weibel E.R. Symmorphosis: On Form and Function in Shaping Life (The John M. Prather Lectures). Harvard University Press, Cambridge MA2000Google Scholar, 5Singer M.A. Of mice and men and elephants: metabolic rate sets glomerular filtration rate.Am J Kidney Dis. 2001; 37: 164-178Abstract Full Text PDF PubMed Scopus (130) Google Scholar To address symmorphosis in kidney function, glomerular filtration rate (GFR) is traditionally indexed to body surface area (BSA), thereby providing comparable estimates across a range of body size. However, as the obesity epidemic widens and skews the distribution of body size in the population, indexing measured and estimated GFR for body size in both clinical and research settings deserves increased attention and discussion. In this editorial, we review the study by Wuerzner et al3Wuerzner G. Pruijm M. Maillard M. et al.Marked association between obesity and glomerular hyperfiltration: a cross-sectional study in an African population.Am J Kidney Dis. 2010; 56: 303-312Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar and address the clinical and research implications of 3 issues: (1) the origin of BSA correction for GFR and appropriate uses and misuses, (2) the paucity of data on measured GFR in representative populations, and (3) the implications of hyperfiltration as a risk factor for CKD. Wuerzner et al examined 301 nondiabetic adults of African ancestry from 66 families living in Seychelles, an island nation off the eastern coast of Africa.3Wuerzner G. Pruijm M. Maillard M. et al.Marked association between obesity and glomerular hyperfiltration: a cross-sectional study in an African population.Am J Kidney Dis. 2010; 56: 303-312Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The prevalence of glomerular hyperfiltration, defined as an inulin clearance rate >140 mL/min, was 3-fold higher (27.1% vs 7.2%) among obese participants (body mass index [BMI] ≥30 kg/m2) compared to lean participants (BMI <25 kg/m2). Higher BMI was also associated with higher effective renal plasma flow estimated by para-aminohippuric acid clearance. In contrast, after adjustment for BSA, no significant differences in GFR, effective renal plasma flow, or filtration fraction (GFR/ effective renal plasma flow) were noted across BMI groups. Other than a lower effective renal plasma flow across all BMI groups, the findings are consistent with other previous studies.6Chagnac A. Weinstein T. Korzets A. Ramadan E. Hirsch J. Gafter U. Glomerular hemodynamics in severe obesity.Am J Physiol Renal Physiol. 2000; 278: F817-F822PubMed Google Scholar, 7Schmieder R.E. Veelken R. Schobel H. Dominiak P. Mann J.F. Luft F.C. Glomerular hyperfiltration during sympathetic nervous system activation in early essential hypertension.J Am Soc Nephrol. 1997; 8: 893-900PubMed Google Scholar The authors suggest that indexing of GFR to BSA may not be appropriate in obese individuals since it obscures hyperfiltration, and suggest indexing by BMI instead. The Du Bois and Du Bois formula for estimation of BSA was proposed in 1916,8Du Bois D. Du Bois E. A formula to estimate the approximate surface area if height and weight be known.Arch Intern Med. 1916; 17: 863-871Crossref Scopus (4133) Google Scholar and the BSA adjustment for kidney function was first introduced in 1928 to reduce sample population variability in measured urea clearances.9McIntosh J.F. Moller E. Van Slyke D.D. Studies of Urea Excretion III: the influence of body size on urea output.J Clin Invest. 1928; 6: 467-483Crossref PubMed Google Scholar The rationale for the surface area adjustment is based on observations in mammals that physiologic parameters including GFR and effective renal plasma flow are proportional to kidney size, and kidney size is typically proportional to body size. Furthermore, the proportionality of kidney function to body size “makes sense” since the main function of the kidneys is to regulate the volume and composition of body fluid by excretion of waste products from metabolic processes, and both body fluid volume and quantity of metabolic waste vary in proportion to body size. Across mammalian species, the wide differences in GFR and effective renal plasma flow are a function of increasing glomerular number and tuft volume with increasing size of the species.10Holt J.P. Rhode E.A. Similarity of renal glomerular hemodynamics in mammals.Am Heart J. 1976; 92: 465-472Abstract Full Text PDF PubMed Scopus (26) Google Scholar Based on a mammal's weight, GFR, effective renal plasma flow, glomerular tuft volume, and glomerular number can all be predicted according to a power law equation (y = aX)b, where X is weight in kilograms.11Edwards N.A. Scaling of renal functions in mammals.Comp Biochem Physiol A Comp Physiol. 1975; 52: 63-66Crossref PubMed Scopus (67) Google Scholar In 1974, Edwards expanded upon the allometric scaling work completed by Adolph in 194912Adolph E.F. Quantitative relations in the physiological constitutions of mammals.Science. 1949; 109: 579-585Crossref PubMed Scopus (372) Google Scholar by pooling data from para-aminohippuric acid and inulin clearance studies among 26 mammalian species, excluding Homo sapiens. This led to the development of a power law equation for GFR (y = 5.36 × weight [kg]0.72) and effective renal plasma flow (y = 21.79 × weight [kg]0.77).11Edwards N.A. Scaling of renal functions in mammals.Comp Biochem Physiol A Comp Physiol. 1975; 52: 63-66Crossref PubMed Scopus (67) Google Scholar Based on this equation, Table 1 shows predicted GFR and effective renal plasma flow to meet the metabolic demands for a man with an ideal weight, an overweight man, or an obese man, assuming constant height. These data suggest less effect of weight on GFR adjusted for BSA than on GFR unadjusted for BSA.Table 1Predicted Glomerular Filtration Rate and Effective Renal Plasma Flow by Weight Based on Power Law EquationsIdeal Weight BMI 18.5 kg/m2Overweight BMI 25 kg/m2Obese BMI 30 kg/m2Weight (kg)58.679.295.1BSA1.521.731.87Resting metabolic rate (calories/d)1506.11712.01870.7GFR mL/min100.5124.8142.4GFR mL/min/1.73m2 BSA114.1124.8131.9ERPF500.7631.4726.9ERPF/1.73 m2 BSA569.9631.4673.1Filtration fraction0.200.200.20Note: Power law equations calculated for a 40-year old man with a height of 178 cm (5 feet 10 inches). Resting metabolic rate32Mifflin M.D. St Jeor S.T. Hill L.A. Scott B.J. Daugherty S.A. Koh Y.O. A new predictive equation for resting energy expenditure in healthy individuals.Am J Clin Nutr. 1990; 51: 241-247Crossref PubMed Scopus (1651) Google Scholar: 9.99 × weight (kg) + 6.25 × height (cm) – 4.92 × age (y) + 5. GFR and ERPF calculated using power law equations: GFR = 5.36 × weight (kg)0.72; ERPF = 21.79 × weight (kg).0.77 Filtration fraction = GFR/ERPF; body surface area = 0.007184 × weight (kg)0.425 × height (cm)0.7.Abbreviations: BMI, body mass index; BSA, body surface area; ERPF, effective renal plasma flow; GFR, glomerular filtration rate. Open table in a new tab Note: Power law equations calculated for a 40-year old man with a height of 178 cm (5 feet 10 inches). Resting metabolic rate32Mifflin M.D. St Jeor S.T. Hill L.A. Scott B.J. Daugherty S.A. Koh Y.O. A new predictive equation for resting energy expenditure in healthy individuals.Am J Clin Nutr. 1990; 51: 241-247Crossref PubMed Scopus (1651) Google Scholar: 9.99 × weight (kg) + 6.25 × height (cm) – 4.92 × age (y) + 5. GFR and ERPF calculated using power law equations: GFR = 5.36 × weight (kg)0.72; ERPF = 21.79 × weight (kg).0.77 Filtration fraction = GFR/ERPF; body surface area = 0.007184 × weight (kg)0.425 × height (cm)0.7. Abbreviations: BMI, body mass index; BSA, body surface area; ERPF, effective renal plasma flow; GFR, glomerular filtration rate. Current recommendations of the National Kidney Disease Education Program are as follows13National Kidney Disease Education Programhttp://www.nkdep.nih.gov/Date: 2010Google Scholar: (1) for comparison of individuals to normative values and thresholds for definition of CKD, measured and estimated GFR should be adjusted for BSA, and (2) for individual drug dosing, recommendations should be based on unadjusted GFR to anticipate drug excretion in the individual. Since estimated GFR is reported by most clinical laboratories when serum creatinine is measured, clinicians and pharmacists can use the following formula to convert BSA-adjusted estimated GFR to unadjusted estimated GFR: estimated GFR (mL/min) = estimated GFR (mL/min/1.73 m2) × BSA/1.73 m2. There are challenges to the application of the BSA adjustment in obesity.14Delanaye P. Radermecker R.P. Rorive M. Depas G. Krzesinski J.M. Indexing glomerular filtration rate for body surface area in obese patients is misleading: concept and example.Nephrol Dial Transplant. 2005; 20: 2024-2028Crossref PubMed Scopus (168) Google Scholar, 15Turner S.T. Reilly S.L. Fallacy of indexing renal and systemic hemodynamic measurements for body surface area.Am J Physiol. 1995; 268: R978-R988PubMed Google Scholar First, the Du Bois and Du Bois formula may not be accurate for assessment of BSA in the severely obese. Second, the number of nephrons in humans is set at birth and does not change with weight gain. Thus, the increase in GFR to meet metabolic needs in obesity must occur by increasing single-nephron GFR, which may be pathogenic rather than physiologic as assumed by the concept of kidney symmorphosis. Third, the use of the surface area correction in clinical medicine has not been rigorously evaluated in adults. Studies in children show that the mean value for BSA-adjusted GFR level in children over the age of 2 years is similar to that of young adults.16Rubin M. Bruck E. Rapoport M. Maturation and growth of renal function: dosing renally cleared drugs.J Clin Invest. 1949; 28: 1144-1162Crossref Google Scholar However, comprehensive data are not available in adults, and it has been suggested that large population studies are needed to determine normal values of GFR for age, sex, and body size in adults.14Delanaye P. Radermecker R.P. Rorive M. Depas G. Krzesinski J.M. Indexing glomerular filtration rate for body surface area in obese patients is misleading: concept and example.Nephrol Dial Transplant. 2005; 20: 2024-2028Crossref PubMed Scopus (168) Google Scholar, 15Turner S.T. Reilly S.L. Fallacy of indexing renal and systemic hemodynamic measurements for body surface area.Am J Physiol. 1995; 268: R978-R988PubMed Google Scholar, 17Albrecht G.H. Gelvin B.R. Hartman S.E. Ratios as a size adjustment in morphometrics.Am J Phys Anthropol. 1993; 91: 441-468Crossref PubMed Scopus (164) Google Scholar, 18Tanner J.M. Fallacy of per-weight and pre-surface area standards, and their relation to spurious correlation.J Appl Physiol. 1949; 2: 1-15PubMed Google Scholar If it is correct that GFR rises in proportion to BSA, then the association between unadjusted GFR and BSA should totally disappear when GFR is indexed for BSA. Normal values for GFR in adults are based largely on studies of inulin clearance carried out primarily in young white men and women in the mid-20th century.19Wesson L.G. Physiology of the Human Kidney. Grune & Stratton, Inc, New York, NY1969Google Scholar Generally accepted mean values in young whites are approximately 130 mL/min/1.73 m2; values are approximately 8% higher in men than women, and approximately 10 mL/min/1.73 m2 lower per decade after age 40 years. While there are no studies of measured GFR in large representative samples of populations of other racial and ethnic groups, there are several lines of thought that suggest the possibility for differences in normal GFR among racial and ethnic groups. First, some small studies in other racial and ethnic groups report lower values for measured GFR.20Ma Y.C. Zuo L. Chen L. et al.Distribution of measured GFR in apparently healthy Chinese adults.Am J Kidney Dis. 2010; 56: 420-421Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 21Barai S. Gambhir S. Prasad N. et al.Levels of GFR and protein-induced hyperfiltration in kidney donors: a single-center experience in India.Am J Kidney Dis. 2008; 51: 407-414Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 22Eastwood J.B. Kerry S.M. Plange-Rule J. et al.Assessment of GFR by four methods in adults in Ashanti, Ghana: the need for an eGFR equation for lean African populations.Nephrol Dial Transplant. 2010; 25: 2178-2187Crossref PubMed Scopus (109) Google Scholar However, these studies are limited by differences in GFR measurement methods and by incomplete ascertainment of diet (since normal GFR is affected by habitual protein intake and acute protein loads).23King A.J. Levey A.S. Dietary protein and renal function.J Am Soc Nephrol. 1993; 3: 1723-1737PubMed Google Scholar Second, there is some question about variation of glomerular number by race; it has been hypothesized that racial and ethnic minorities have lower numbers.24Brenner B.M. Hostetter T.H. Olson J.L. Rennke H.G. Venkatachalam M.A. The role of glomerular hyperfiltration in the initiation and progression of diabetic nephropathy.Acta Endocrinol Suppl (Copenh). 1981; 242: 7-10PubMed Google Scholar Third, there are marked differences in metabolic rate among racial and ethnic groups,25Gallagher D. Albu J. He Q. et al.Small organs with a high metabolic rate explain lower resting energy expenditure in African American than in white adults.Am J Clin Nutr. 2006; 83: 1062-1067PubMed Scopus (98) Google Scholar with potential for consequent difference in GFR if the physiologic basis for symmorphosis in kidney function is to match production and excretion of metabolic wastes (Table 1). Fourth, there are marked racial and ethnic disparities in the incidence of treated kidney failure in the United States.26US Renal Data System.USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2008Google Scholar Large studies of measured GFR in representative populations including multiple racial and ethnic groups are necessary to remedy this gap in knowledge. Until this information is available, it will be difficult to interpret studies of the relationship of GFR and obesity across racial and ethnic groups. Glomerular hyperfiltration in humans has been hypothesized to reflect increased glomerular capillary pressure, which is a primary mediator of glomerular capillary damage in rat models of subtotal nephrectomy.27Hostetter T.H. Olson J.L. Rennke H.G. Venkatachalam M.A. Brenner B.M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation.Am J Physiol. 1981; 241: F85-F93PubMed Google Scholar, 28Hostetter T.H. Rennke H.G. Brenner B.M. Compensatory renal hemodynamic injury: a final common pathway of residual nephron destruction.Am J Kidney Dis. 1982; 1: 310-314PubMed Scopus (81) Google Scholar Since glomerular capillary pressure cannot be directly measured in humans, measured GFR or filtration fraction are used as surrogate markers of glomerular capillary pressure.5Singer M.A. Of mice and men and elephants: metabolic rate sets glomerular filtration rate.Am J Kidney Dis. 2001; 37: 164-178Abstract Full Text PDF PubMed Scopus (130) Google Scholar However, hyperfiltration itself may not necessarily represent increased glomerular capillary pressure because substantial increases in GFR can be achieved by increasing glomerular capillary surface area and by altering afferent and efferent arteriole resistance, thereby increasing single-nephron plasma flow with only minor changes in glomerular capillary pressure.29Griffin K.A. Kramer H. Bidani A.K. Adverse renal consequences of obesity.Am J Physiol Renal Physiol. 2008; 294: F685-F696Crossref PubMed Scopus (192) Google Scholar In addition, although body size is strongly and positively correlated with glomerular diameter, body size does not correlate with percent sclerosed glomeruli.30Kasiske B.L. Napier J. Glomerular sclerosis in patients with massive obesity.Am J Nephrol. 1985; 5: 45-50Crossref PubMed Scopus (93) Google Scholar Possibly, the consequences of weight gain may be more detrimental in individuals with low nephron number29Griffin K.A. Kramer H. Bidani A.K. Adverse renal consequences of obesity.Am J Physiol Renal Physiol. 2008; 294: F685-F696Crossref PubMed Scopus (192) Google Scholar or certain genetic variants such as those associated with the MYH9 gene.31Kopp J.B. Smith M.W. Nelson G.W. et al.MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.Nat Genet. 2008; 40: 1175-1184Crossref PubMed Scopus (593) Google Scholar Future studies should examine the interaction between genetic variants, nephron number, and obesity on risk of developing CKD and kidney failure. In conclusion, we do not fully understand the mechanisms by which obesity may affect kidney function and cause kidney disease. Larger body size in both humans and animals is associated with higher measured GFR and effective renal plasma flow not indexed for BSA, but the clinical implications have not been fully elucidated. Future studies are needed to examine normative values of measured GFR and other physiologic parameters across a wide range of racial and ethnic groups, age, and body size. The independent role of glomerular hyperfiltration and increased filtration fraction and their interaction with nephron number and genetic variants on the development and progression of CKD need to be explored. Such studies could help to elucidate the mechanisms by which weight gain influences risk of kidney disease and help identify individuals at highest risk for prevention and intervention efforts. Financial Disclosure: The authors declare that they have no relevant financial interests. Marked Association Between Obesity and Glomerular Hyperfiltration: A Cross-sectional Study in an African PopulationAmerican Journal of Kidney DiseasesVol. 56Issue 2PreviewObesity and African American ethnicity are established independent risk factors for the development of chronic kidney disease. No data exist about the association between obesity and renal hemodynamics in the African region. Full-Text PDF The Importance of Considering Metabolism When Indexing the GFRAmerican Journal of Kidney DiseasesVol. 56Issue 6PreviewI would like to expand upon Levey and Kramer's1 thoughtful discussion about the appropriateness of indexing glomerular filtration rate (GFR) by body surface area (BSA) to standardize measurements by different body sizes. The BSA adjustment is premised upon proportional relationships between renal physiologic parameters, such as GFR, kidney size, and body size, relationships that can be summarized in an allometric power law equation that takes into account body weight.2 The presumed relevance of body weight is its linkage to metabolic load; that is, a large body is expected to generate more waste than a smaller one, with the kidney modifying its excretory and other capabilities accordingly to meet the body's demands. Full-Text PDF" @default.
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• W2002821665 title "Obesity, Glomerular Hyperfiltration, and the Surface Area Correction" @default.
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