Nephrol Dial Transplant (2013) 28 (Suppl. 4): iv105–iv108 doi: 10.1093/ndt/gft391
Obesity and CKD progression: hard facts on fat CKD patients Francesca Mallamaci and Giovanni Tripepi
Calabria, Italy
Keywords: body mass index, chronic kidney disease, obesity
OBESITY METRICS AND CKD
Obesity is a worldwide epidemic and there is compelling evidence that excess fat is closely associated with chronic kidney disease (CKD) and end-stage kidney failure. In this review, we will describe some important mechanisms related with the pathogenesis and treatment of CKD in obesity by emphasizing the role of excess fat in renal haemodynamic and structural alterations.
In one of the largest surveys in a multiracial population, Hsu et al. [3] documented that body mass index (BMI) is strongly related to the risk of CKD. In this study, subjects with a BMI >40 kg/m2, i.e. the group with severe obesity, showed a risk for CKD seven times higher than that of the standard risk group with a normal BMI. Observational studies testing the association of BMI with the risk of progression of CKD provide useful information, but these studies should be considered with the proviso that the BMI is a less than ideal metric of obesity [4]. Although BMI is definitely the most used parameter to define obesity in the general population, and in various diseases, there is now strong evidence that waist circumference and waist-to-hip ratio (WHR) are better metrics of obesity, both at the community level [5], in pre-dialysis patients [6] and in dialysis patients [7]. Indeed, waist circumference is a much stronger predictor of adverse health outcomes than the BMI, including the risk of end-stage kidney disease (ESKD), both in individuals with CKD [8] and in dialysis patients [7]. Analyses based on the Atherosclerosis Risk in the Community study and the Cardiovascular Health Study have shown that metrics of central obesity are monotonically associated with the risk of CKD and death [8]. In the Framingham Heart Study, WHR, a measure of abdominal obesity, predicted the development of CKD better than the BMI and the relationship between abdominal obesity and risk of CKD was direct and independent from traditional Framingham risk factors, including diabetes and hypertension [9]. In the cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS), a population-based study which involved patients with stages 1–4 CKD, Kramer et al. [6] fully confirmed the relationship of both BMI and waist circumference with clinical outcomes in this population. The association between overweight or obesity and CKD has also been well documented in a clinical series of patients with IgA glomerulonephritis [10]. In these patients, overweight
INTRODUCTION Overweight and obesity have reached epidemic proportions worldwide. In the USA, more than one-third of US adults (35.7%) are obese (Centers for Disease Control and Prevention, http://www.cdc.gov/obesity/adult/index.html) and in European countries, the prevalence of obesity ranges from a minimum of 10% in Italy to a maximum of 26% in Ireland [1]. Obesity is associated with the development of multiple medical conditions and comorbid illnesses, including coronary artery disease, stroke, type II diabetes, chronic kidney disease (CKD) and premature death and reduced quality of life [2]. The observation that the incidence and prevalence rates of obesity in patients on chronic dialysis treatment in the USA are higher than in the contemporary general population [2] points to excess fat as a major driving force for the risk of progression to kidney failure. Even though there are epidemiological evidence that obesity is a strong risk factor for CKD, the mechanism(s) responsible for renal damage in obesity remain largely unknown. Furthermore, the link between obesity and CKD should be interpreted with caution due to the potential confounding effect of diabetes and hypertension. In this brief review, we will summarize some major issues related to the pathogenesis and treatment of CKD in obesity. © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
iv105
FULL REVIEW
A B S T R AC T
Downloaded from http://ndt.oxfordjournals.org/ at Temple University on September 1, 2014
Correspondence and offprint requests to: Francesca Mallamaci; E-mail: [email protected]
Nephrology, Dialysis and Transplantation Unit & CNR-IBIM, Reggio
(i.e. BMI >25 kg/m2) predicted a faster rate of progression to ESKD. Focal segmental glomerulosclerosis represents a common lesion in obese patients with CKD [11] and such a lesion is considered as a consequence of hyperfiltration, a common renal haemodynamic alteration in overweight and obese patients [11]. As we will discuss below, the relevance of hyperfiltration as a putative mechanism underlying obesityrelated CKD is highlighted by recent observations showing that the BMI appears to be a strong modifier of the nephrotective response to angiotensin converting enzyme (ACE) inhibition in proteinuric nephropathies [12].
Renal haemodynamic alterations triggered by excess adiposity appear well before individuals develop full-blown obesity (Figure 1). Indeed, there is an important decline in renal plasma flow with increasing body mass (see Figure 1) within a range of values excluding overt obesity (BMI > 30 kg/m2) [13]. This decline is not paralleled by simultaneous down-sloping of the GFR and, as a consequence, filtration fraction (the ratio of these two measurements) increases linearly (see Figure 1) with higher BMI values. In micro-haemodynamics terms, the only way to explain the maintenance of the GFR in the face of a declining effective renal plasma flow (ERPF) is arteriolar efferent vasoconstriction and/or afferent vasodilatation, in two haemodynamic parameters that increase glomerular pressure and trigger albuminuria. The glomerular hypertension/hyperfiltration hypothesis is supported by the results of interventional studies aimed at reducing arteriolar efferent vasoconstriction, i.e. ACE
A D I P O S E T I S S U E A N D I N F L A M M AT I O N
F I G U R E 1 : Association between BMI, renal plasma flow, glomerular filtration rate and filtration fraction in non-obese healthy subjects (redrawn from [13]). Continuous line: regression line. Dashed lines represent the 95% confidence intervals of the regression line.
The adipocyte is a modified macrophage and directly synthesizes pro-inflammatory cytokines such as IL-6 and TNF-α, i.e. two fundamental inflammatory cytokines which have been implicated in obesity-driven CKD [21]. Experimental studies, in Zucker rats, an animal model of obesity, show that glomerular hypertension triggered by angiotensin II and inflammation are inter-related phenomena [22]. Furthermore, it is well documented that in an animal model of obesity induced by high fat intake, macrophages accumulate in the kidney [23] and both mesangial matrix accumulation and macrophage infiltration in this model are almost abolished by the angiotensin II blockade. Adipocytes produce another protein, procalcitonin (PCT), a very powerful innate immunity marker commonly used for the diagnosis of bacterial sepsis. PCT is expressed in adipocytes and its circulating levels increase across waist circumference quartiles in CKD patients [24] a phenomenon implicating inflammation in obesity-related CKD. Thus, overweight and obesity may trigger and/or amplify renal disease and renal disease progression by several, partially overlapping mechanisms. However, evidence of the causative role of glomerular hypertension and inflammation in obesity associated CKD in humans still remain hypothetical. iv106
F. Mallamaci and G. Tripepi
Downloaded from http://ndt.oxfordjournals.org/ at Temple University on September 1, 2014
FULL REVIEW
G LO M E R U L A R H Y P E R F I LT R AT I O N / HYPERTENSION, ADIPOSITY AND ADIPOKINES
inhibitors. In the American African Study of Kidney disease (AASK) [14], ramipril was documented to cause efferent vasodilatation and reduce glomerular pressure. Moreover, in the AASK study, an initial fall of GFR was thereby followed by an attenuation in renal function loss in the follow-up. Glomerular hypertension and glomerular damage are in part controlled by anatomically remote cells like adipocytes. In fact, adipocytes produce a variety of factors that may affect renal micro-circulation such as Angiotensinogen, the precursor of angiotensin II, Leptin a cytokine which directly and indirectly triggers high sympathetic activity, i.e. a stimulus provoking efferent vasoconscriction. Furthermore, the adipose tissue is one of the sites where asymmetric dimethyl arginine (ADMA), the most important endogenous inhibitor of nitric oxide synthase, is produced. NO is a fundamental regulator of afferent vasoconstriction and therefore ADMA is a potentially relevant factor in glomerular hyperfiltration in CKD in the obese. Recent studies suggest a causal role of hyperaldosteronism in the pathway linking fat mass and increased levels of inflammatory biomarkers [15, 16]. In adipocytes, mineralocorticoid receptors promote inflammatory adipokine expression and may mediate a proadipogenic effect of aldosterone [17]. Experimental studies in obese diabetic mice document that mineralocorticoid receptor blockade reduces the expression of proinflammatory factors in adipose tissue and increases the expression of adiponectin, which is a potential protective mechanism [18]. In both normotensive and hypertensive patients, weight reduction decreases the plasma levels of aldosterone and improves insulin sensitivity [19, 20]. Taken together, these effects indicate that weight excess is associated with increased aldosterone production and that high circulating levels of aldosterone in turn may promote the metabolic syndrome [15].
patients. Although the limitations of a post hoc analysis require prudence in the conclusions, it makes sense to provisionally use these drugs as first-line agents in these patients.
C L I N I C A L T R I A L S A I M E D AT S T U DY I N G T H E RISK FOR CKD AND CKD PROGRESSION IN THE OBESE
cording to BMI categories. The reduction in urinary protein excretion (mean ± standard error) is calculated as follow-up—baseline values (redrawn from [12]).
Obesity and renal diseases are a major public health problem worldwide. Excess fat promotes renal dysfunction by several pathways and alterations in renal haemodynamics and inflammatory mechanisms largely overlap. Overweight and obese CKD patients are peculiarly sensitive to the nephroprotective effect of ACE inhibition by ramipril.
C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.
REFERENCES 1. Kosti RI, Panagiotakos DB. The epidemic of obesity in children and adolescents in the world. Cent Eur J Public Health 2006; 14: 151–159. 2. Kramer HJ, Saranathan A, Luke A et al. Increasing body mass index and obesity in the incident ESRD population. J Am Soc Nephrol 2006; 17: 1453–1459. 3. Hsu CY, McCulloch CE, Iribarren C et al. Body mass index and risk for end-stage renal disease. Ann Intern Med 2006; 144: 21–28. 4. Brown RN, Mohsen A, Green D et al. Body mass index has no effect on rate of progression of chronic kidney disease in non-diabetic subjects. Nephrol Dial Transplant 2012; 27: 2776–2780. 5. Yusuf S, Hawken S, Ounpuu S et al. INTERHEART Study Investigators. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case–control study. Lancet 2005; 366: 1640–1649. 6. Kramer H, Shoham D, McClure LA 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: 177–185. 7. Postorino M, Marino C, Tripepi G, Zoccali C; CREDIT (Calabria Registry of Dialysis and Transplantation) Working Group. Abdominal obesity and all-cause and cardiovascular mortality in endstage renal disease. J Am Coll Cardiol 2009; 53: 1265–1272. 8. Elsayed EF, Tighiouart H, Weiner DE et al. Waist-to-hip ratio and body mass index as risk factors for cardiovascular events in CKD. Am J Kidney Dis 2008; 52: 49–57. 9. Foster MC, Hwang S-J, Larson MG. Overweight, obesity, and the development of stage 3 CKD: the Framingham Heart Study. Am J Kidney Dis 2008; 52: 39–48. 10. Bonnet F, Deprele C, Sassolas A et al. Excessive body weight as a new independent risk factor for clinical and pathological progression in IgA nephritis. Am J Kidney Dis 2001; 37: 720–727. 11. Eknoyan G. Obesity and chronic kidney disease. Nefrologia 2011; 31: 397–403.
iv107 Obesity and CKD progression
FULL REVIEW
F I G U R E 2 : Anti-proteinuric effect of ramipril in CKD patients ac-
CONCLUSIONS
Downloaded from http://ndt.oxfordjournals.org/ at Temple University on September 1, 2014
In order to prove that obesity is directly implicated in CKD, randomized clinical trials on the impact of obesity on kidney disease progression are needed. Because obesity is an established strong risk factor for the cardiovascular system and other system trials where weight lowering intervention are omitted because it would be considered as unethical by most ethical committees and for this and other reasons, these are much unlikely to be performed. In order to gather circumstantial evidence on this issue, systematic meta-analyses and post hoc analysis of existing clinical trials are useful. In morbidly obese subjects in the general population, bariatric surgery is increasingly applied to reduce excessive body weight, but there is very limited information on the effect of bariatric surgery in CKD patients. The issue is of intuitive importance because a recent meta-analysis [25] reported an association between the severity of kidney disease and complications after bariatric surgery intervention, the risk of complications being three times higher in CKD stage 5 patients in comparison with the other groups with a better renal function. These data demonstrate higher risks of bariatric surgery among patients with advanced CKD, but whether the potential long-term health benefits of these outweigh the short-term risks in this population requires further studies. In small, short-duration studies in patients with CKD, non-surgical weight loss interventions reduce proteinuria and blood pressure (BP) [25]. In morbidly obese individuals with glomerular hyperfiltration, surgical interventions normalize GFR [26] and reduce BP and microalbuminuria [27]. Wider, long-term studies to analyse renal outcomes such as the risk of ESKD are needed. Apart from bariatric surgery and dietary intervention, a recent post hoc analysis in the Rein study has provided important new data supporting the role of glomerular hypertension in CKD progression. Indeed, in this study, the antiproteinuric effect of ramipril was maximal in obese patients, intermediate in overweight patients and minimal in patients with normal BMI (Figure 2). Thus, in this post hoc analysis, ACE inhibitors emerge as a particularly favourable class of drugs for nephroprotection in obese, proteinuric CKD
FULL REVIEW
20. Dall’Asta C, Vedani P, Manunta P et al. Effect of weight loss through laparoscopic gastric banding on blood pressure, plasma renin activity and aldosterone levels in morbid obesity. Nutr Metab Cardiovasc Dis 2009; 19: 110–114. 21. Spoto B, Zoccali C. Spleen IL-10, a key player in obesity-driven renal risk. Nephrol Dial Transplant 2013; 28: 1061–1064. 22. Xu ZG, Lanting L, Vaziri ND et al. Upregulation of angiotensin II type 1 receptor, inflammatory mediators, and enzymes of arachidonate metabolism in obese zucker rat kidney: reversal by angiotensin II type 1 receptor blockade. Circulation 2005; 19: 1962–1969. 23. Ma LJ, Corsa BA, Zhou J et al. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Am J Physiol Renal Physiol 2011; 300: F1203–F1213. 24. Mallamaci F et al. Innate immunity and CKD progression. In: 50th ERA-EDTA Congress, Istanbul, 17–21 May 2013 (Abstract). 25. Navaneethan SD, Yehnert H, Moustarah F et al. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009; 10: 1565–1574. 26. Navarro-Díaz M, Serra A, Romero R et al. Effect of drastic weight loss after bariatric surgery on renal parameters in extremely obese patients: long-term follow-up. J Am Soc Nephrol 2006; 17(12 Suppl 3): S213–S217. 27. Serpa Neto A, Bianco Rossi FM, Dal Moro Amarante R et al. Effect of weight loss after Roux-en-Y gastric bypass, on renal function and blood pressure in morbidly obese patients. J Nephrol 2009; 22: 637–646. Received for publication: 28.5.2013; Accepted in revised form: 6.8.2013
Nephrol Dial Transplant (2013) 28 (Suppl. 4): iv108–iv113 doi: 10.1093/ndt/gft258 Advance Access publication 17 July 2013
Obesity-related glomerulopathy and the nephron complement Nobuo Tsuboi, Yasunori Utsunomiya
Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
and Tatsuo Hosoya Correspondence and offprint requests to: Nobuo Tsuboi; E-mail: [email protected]
A B S T R AC T Obesity-related glomerulopathy (ORG) is a secondary form of glomerular disease that can occur in individuals with obesity. However, the absolute risk for an obese individual to develop © The Author 2013. Published by Oxford University Press on behalf of ERAEDTA. All rights reserved.
Keywords: glomerular density, glomerulomegaly, hyperfiltration, nephron number, obesity
progressive renal deterioration is low. Therefore, obesity alone appears to be insufficient to develop such severe renal injury, and there are likely other factors that contribute to the development of this entity. The glomerular hyperfiltration found in patients with ORG has been postulated to lead to structural
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12. Mallamaci F, Ruggenenti P, Perna A et al. REIN Study Group. ACE inhibition is renoprotective among obese patients with proteinuria. J Am Soc Nephrol 2011; 22: 1122–1128. 13. Bosma RJ, van der Heide JJ, Oosterop EJ et al. Body mass index is associated with altered renal hemodynamics in non-obese healthy subjects. Kidney Int 2004; 65: 259–265. 14. Douglas JG, Agodoa L. ACE Inhibition is effective and renoprotective in hypertensive nephrosclerosis: the African American Study of Kidney Disease and Hypertension (AASK) trial. Kidney Int Suppl 2003; 83: S74–S76. 15. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med 2009; 150: 776–783. 16. Ehrhart-Bornstein M, Arakelyan K, Krug AW et al. Fat cells may be the obesity-hypertension link: human adipogenic factors stimulate aldosterone secretion from adrenocortical cells. Endocr Res 2004; 30: 865–870. 17. Rondinone CM, Rodbard D, Baker ME. Aldosterone stimulated differentiation of mouse 3T3-L1 cells into adipocytes. Endocrinology 1993; 132: 2421–2426. 18. Guo C, Ricchiuti V, Lian BQ et al. Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines. Circulation 2008; 117: 2253–2261. 19. Tuck ML, Sowers J, Dornfeld L et al. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304: 930–933.
Obesity and CKD progression: hard facts on fat CKD patients Francesca Mallamaci and Giovanni Tripepi
Calabria, Italy
Keywords: body mass index, chronic kidney disease, obesity
OBESITY METRICS AND CKD
Obesity is a worldwide epidemic and there is compelling evidence that excess fat is closely associated with chronic kidney disease (CKD) and end-stage kidney failure. In this review, we will describe some important mechanisms related with the pathogenesis and treatment of CKD in obesity by emphasizing the role of excess fat in renal haemodynamic and structural alterations.
In one of the largest surveys in a multiracial population, Hsu et al. [3] documented that body mass index (BMI) is strongly related to the risk of CKD. In this study, subjects with a BMI >40 kg/m2, i.e. the group with severe obesity, showed a risk for CKD seven times higher than that of the standard risk group with a normal BMI. Observational studies testing the association of BMI with the risk of progression of CKD provide useful information, but these studies should be considered with the proviso that the BMI is a less than ideal metric of obesity [4]. Although BMI is definitely the most used parameter to define obesity in the general population, and in various diseases, there is now strong evidence that waist circumference and waist-to-hip ratio (WHR) are better metrics of obesity, both at the community level [5], in pre-dialysis patients [6] and in dialysis patients [7]. Indeed, waist circumference is a much stronger predictor of adverse health outcomes than the BMI, including the risk of end-stage kidney disease (ESKD), both in individuals with CKD [8] and in dialysis patients [7]. Analyses based on the Atherosclerosis Risk in the Community study and the Cardiovascular Health Study have shown that metrics of central obesity are monotonically associated with the risk of CKD and death [8]. In the Framingham Heart Study, WHR, a measure of abdominal obesity, predicted the development of CKD better than the BMI and the relationship between abdominal obesity and risk of CKD was direct and independent from traditional Framingham risk factors, including diabetes and hypertension [9]. In the cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS), a population-based study which involved patients with stages 1–4 CKD, Kramer et al. [6] fully confirmed the relationship of both BMI and waist circumference with clinical outcomes in this population. The association between overweight or obesity and CKD has also been well documented in a clinical series of patients with IgA glomerulonephritis [10]. In these patients, overweight
INTRODUCTION Overweight and obesity have reached epidemic proportions worldwide. In the USA, more than one-third of US adults (35.7%) are obese (Centers for Disease Control and Prevention, http://www.cdc.gov/obesity/adult/index.html) and in European countries, the prevalence of obesity ranges from a minimum of 10% in Italy to a maximum of 26% in Ireland [1]. Obesity is associated with the development of multiple medical conditions and comorbid illnesses, including coronary artery disease, stroke, type II diabetes, chronic kidney disease (CKD) and premature death and reduced quality of life [2]. The observation that the incidence and prevalence rates of obesity in patients on chronic dialysis treatment in the USA are higher than in the contemporary general population [2] points to excess fat as a major driving force for the risk of progression to kidney failure. Even though there are epidemiological evidence that obesity is a strong risk factor for CKD, the mechanism(s) responsible for renal damage in obesity remain largely unknown. Furthermore, the link between obesity and CKD should be interpreted with caution due to the potential confounding effect of diabetes and hypertension. In this brief review, we will summarize some major issues related to the pathogenesis and treatment of CKD in obesity. © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
iv105
FULL REVIEW
A B S T R AC T
Downloaded from http://ndt.oxfordjournals.org/ at Temple University on September 1, 2014
Correspondence and offprint requests to: Francesca Mallamaci; E-mail: [email protected]
Nephrology, Dialysis and Transplantation Unit & CNR-IBIM, Reggio
(i.e. BMI >25 kg/m2) predicted a faster rate of progression to ESKD. Focal segmental glomerulosclerosis represents a common lesion in obese patients with CKD [11] and such a lesion is considered as a consequence of hyperfiltration, a common renal haemodynamic alteration in overweight and obese patients [11]. As we will discuss below, the relevance of hyperfiltration as a putative mechanism underlying obesityrelated CKD is highlighted by recent observations showing that the BMI appears to be a strong modifier of the nephrotective response to angiotensin converting enzyme (ACE) inhibition in proteinuric nephropathies [12].
Renal haemodynamic alterations triggered by excess adiposity appear well before individuals develop full-blown obesity (Figure 1). Indeed, there is an important decline in renal plasma flow with increasing body mass (see Figure 1) within a range of values excluding overt obesity (BMI > 30 kg/m2) [13]. This decline is not paralleled by simultaneous down-sloping of the GFR and, as a consequence, filtration fraction (the ratio of these two measurements) increases linearly (see Figure 1) with higher BMI values. In micro-haemodynamics terms, the only way to explain the maintenance of the GFR in the face of a declining effective renal plasma flow (ERPF) is arteriolar efferent vasoconstriction and/or afferent vasodilatation, in two haemodynamic parameters that increase glomerular pressure and trigger albuminuria. The glomerular hypertension/hyperfiltration hypothesis is supported by the results of interventional studies aimed at reducing arteriolar efferent vasoconstriction, i.e. ACE
A D I P O S E T I S S U E A N D I N F L A M M AT I O N
F I G U R E 1 : Association between BMI, renal plasma flow, glomerular filtration rate and filtration fraction in non-obese healthy subjects (redrawn from [13]). Continuous line: regression line. Dashed lines represent the 95% confidence intervals of the regression line.
The adipocyte is a modified macrophage and directly synthesizes pro-inflammatory cytokines such as IL-6 and TNF-α, i.e. two fundamental inflammatory cytokines which have been implicated in obesity-driven CKD [21]. Experimental studies, in Zucker rats, an animal model of obesity, show that glomerular hypertension triggered by angiotensin II and inflammation are inter-related phenomena [22]. Furthermore, it is well documented that in an animal model of obesity induced by high fat intake, macrophages accumulate in the kidney [23] and both mesangial matrix accumulation and macrophage infiltration in this model are almost abolished by the angiotensin II blockade. Adipocytes produce another protein, procalcitonin (PCT), a very powerful innate immunity marker commonly used for the diagnosis of bacterial sepsis. PCT is expressed in adipocytes and its circulating levels increase across waist circumference quartiles in CKD patients [24] a phenomenon implicating inflammation in obesity-related CKD. Thus, overweight and obesity may trigger and/or amplify renal disease and renal disease progression by several, partially overlapping mechanisms. However, evidence of the causative role of glomerular hypertension and inflammation in obesity associated CKD in humans still remain hypothetical. iv106
F. Mallamaci and G. Tripepi
Downloaded from http://ndt.oxfordjournals.org/ at Temple University on September 1, 2014
FULL REVIEW
G LO M E R U L A R H Y P E R F I LT R AT I O N / HYPERTENSION, ADIPOSITY AND ADIPOKINES
inhibitors. In the American African Study of Kidney disease (AASK) [14], ramipril was documented to cause efferent vasodilatation and reduce glomerular pressure. Moreover, in the AASK study, an initial fall of GFR was thereby followed by an attenuation in renal function loss in the follow-up. Glomerular hypertension and glomerular damage are in part controlled by anatomically remote cells like adipocytes. In fact, adipocytes produce a variety of factors that may affect renal micro-circulation such as Angiotensinogen, the precursor of angiotensin II, Leptin a cytokine which directly and indirectly triggers high sympathetic activity, i.e. a stimulus provoking efferent vasoconscriction. Furthermore, the adipose tissue is one of the sites where asymmetric dimethyl arginine (ADMA), the most important endogenous inhibitor of nitric oxide synthase, is produced. NO is a fundamental regulator of afferent vasoconstriction and therefore ADMA is a potentially relevant factor in glomerular hyperfiltration in CKD in the obese. Recent studies suggest a causal role of hyperaldosteronism in the pathway linking fat mass and increased levels of inflammatory biomarkers [15, 16]. In adipocytes, mineralocorticoid receptors promote inflammatory adipokine expression and may mediate a proadipogenic effect of aldosterone [17]. Experimental studies in obese diabetic mice document that mineralocorticoid receptor blockade reduces the expression of proinflammatory factors in adipose tissue and increases the expression of adiponectin, which is a potential protective mechanism [18]. In both normotensive and hypertensive patients, weight reduction decreases the plasma levels of aldosterone and improves insulin sensitivity [19, 20]. Taken together, these effects indicate that weight excess is associated with increased aldosterone production and that high circulating levels of aldosterone in turn may promote the metabolic syndrome [15].
patients. Although the limitations of a post hoc analysis require prudence in the conclusions, it makes sense to provisionally use these drugs as first-line agents in these patients.
C L I N I C A L T R I A L S A I M E D AT S T U DY I N G T H E RISK FOR CKD AND CKD PROGRESSION IN THE OBESE
cording to BMI categories. The reduction in urinary protein excretion (mean ± standard error) is calculated as follow-up—baseline values (redrawn from [12]).
Obesity and renal diseases are a major public health problem worldwide. Excess fat promotes renal dysfunction by several pathways and alterations in renal haemodynamics and inflammatory mechanisms largely overlap. Overweight and obese CKD patients are peculiarly sensitive to the nephroprotective effect of ACE inhibition by ramipril.
C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.
REFERENCES 1. Kosti RI, Panagiotakos DB. The epidemic of obesity in children and adolescents in the world. Cent Eur J Public Health 2006; 14: 151–159. 2. Kramer HJ, Saranathan A, Luke A et al. Increasing body mass index and obesity in the incident ESRD population. J Am Soc Nephrol 2006; 17: 1453–1459. 3. Hsu CY, McCulloch CE, Iribarren C et al. Body mass index and risk for end-stage renal disease. Ann Intern Med 2006; 144: 21–28. 4. Brown RN, Mohsen A, Green D et al. Body mass index has no effect on rate of progression of chronic kidney disease in non-diabetic subjects. Nephrol Dial Transplant 2012; 27: 2776–2780. 5. Yusuf S, Hawken S, Ounpuu S et al. INTERHEART Study Investigators. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case–control study. Lancet 2005; 366: 1640–1649. 6. Kramer H, Shoham D, McClure LA 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: 177–185. 7. Postorino M, Marino C, Tripepi G, Zoccali C; CREDIT (Calabria Registry of Dialysis and Transplantation) Working Group. Abdominal obesity and all-cause and cardiovascular mortality in endstage renal disease. J Am Coll Cardiol 2009; 53: 1265–1272. 8. Elsayed EF, Tighiouart H, Weiner DE et al. Waist-to-hip ratio and body mass index as risk factors for cardiovascular events in CKD. Am J Kidney Dis 2008; 52: 49–57. 9. Foster MC, Hwang S-J, Larson MG. Overweight, obesity, and the development of stage 3 CKD: the Framingham Heart Study. Am J Kidney Dis 2008; 52: 39–48. 10. Bonnet F, Deprele C, Sassolas A et al. Excessive body weight as a new independent risk factor for clinical and pathological progression in IgA nephritis. Am J Kidney Dis 2001; 37: 720–727. 11. Eknoyan G. Obesity and chronic kidney disease. Nefrologia 2011; 31: 397–403.
iv107 Obesity and CKD progression
FULL REVIEW
F I G U R E 2 : Anti-proteinuric effect of ramipril in CKD patients ac-
CONCLUSIONS
Downloaded from http://ndt.oxfordjournals.org/ at Temple University on September 1, 2014
In order to prove that obesity is directly implicated in CKD, randomized clinical trials on the impact of obesity on kidney disease progression are needed. Because obesity is an established strong risk factor for the cardiovascular system and other system trials where weight lowering intervention are omitted because it would be considered as unethical by most ethical committees and for this and other reasons, these are much unlikely to be performed. In order to gather circumstantial evidence on this issue, systematic meta-analyses and post hoc analysis of existing clinical trials are useful. In morbidly obese subjects in the general population, bariatric surgery is increasingly applied to reduce excessive body weight, but there is very limited information on the effect of bariatric surgery in CKD patients. The issue is of intuitive importance because a recent meta-analysis [25] reported an association between the severity of kidney disease and complications after bariatric surgery intervention, the risk of complications being three times higher in CKD stage 5 patients in comparison with the other groups with a better renal function. These data demonstrate higher risks of bariatric surgery among patients with advanced CKD, but whether the potential long-term health benefits of these outweigh the short-term risks in this population requires further studies. In small, short-duration studies in patients with CKD, non-surgical weight loss interventions reduce proteinuria and blood pressure (BP) [25]. In morbidly obese individuals with glomerular hyperfiltration, surgical interventions normalize GFR [26] and reduce BP and microalbuminuria [27]. Wider, long-term studies to analyse renal outcomes such as the risk of ESKD are needed. Apart from bariatric surgery and dietary intervention, a recent post hoc analysis in the Rein study has provided important new data supporting the role of glomerular hypertension in CKD progression. Indeed, in this study, the antiproteinuric effect of ramipril was maximal in obese patients, intermediate in overweight patients and minimal in patients with normal BMI (Figure 2). Thus, in this post hoc analysis, ACE inhibitors emerge as a particularly favourable class of drugs for nephroprotection in obese, proteinuric CKD
FULL REVIEW
20. Dall’Asta C, Vedani P, Manunta P et al. Effect of weight loss through laparoscopic gastric banding on blood pressure, plasma renin activity and aldosterone levels in morbid obesity. Nutr Metab Cardiovasc Dis 2009; 19: 110–114. 21. Spoto B, Zoccali C. Spleen IL-10, a key player in obesity-driven renal risk. Nephrol Dial Transplant 2013; 28: 1061–1064. 22. Xu ZG, Lanting L, Vaziri ND et al. Upregulation of angiotensin II type 1 receptor, inflammatory mediators, and enzymes of arachidonate metabolism in obese zucker rat kidney: reversal by angiotensin II type 1 receptor blockade. Circulation 2005; 19: 1962–1969. 23. Ma LJ, Corsa BA, Zhou J et al. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Am J Physiol Renal Physiol 2011; 300: F1203–F1213. 24. Mallamaci F et al. Innate immunity and CKD progression. In: 50th ERA-EDTA Congress, Istanbul, 17–21 May 2013 (Abstract). 25. Navaneethan SD, Yehnert H, Moustarah F et al. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009; 10: 1565–1574. 26. Navarro-Díaz M, Serra A, Romero R et al. Effect of drastic weight loss after bariatric surgery on renal parameters in extremely obese patients: long-term follow-up. J Am Soc Nephrol 2006; 17(12 Suppl 3): S213–S217. 27. Serpa Neto A, Bianco Rossi FM, Dal Moro Amarante R et al. Effect of weight loss after Roux-en-Y gastric bypass, on renal function and blood pressure in morbidly obese patients. J Nephrol 2009; 22: 637–646. Received for publication: 28.5.2013; Accepted in revised form: 6.8.2013
Nephrol Dial Transplant (2013) 28 (Suppl. 4): iv108–iv113 doi: 10.1093/ndt/gft258 Advance Access publication 17 July 2013
Obesity-related glomerulopathy and the nephron complement Nobuo Tsuboi, Yasunori Utsunomiya
Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
and Tatsuo Hosoya Correspondence and offprint requests to: Nobuo Tsuboi; E-mail: [email protected]
A B S T R AC T Obesity-related glomerulopathy (ORG) is a secondary form of glomerular disease that can occur in individuals with obesity. However, the absolute risk for an obese individual to develop © The Author 2013. Published by Oxford University Press on behalf of ERAEDTA. All rights reserved.
Keywords: glomerular density, glomerulomegaly, hyperfiltration, nephron number, obesity
progressive renal deterioration is low. Therefore, obesity alone appears to be insufficient to develop such severe renal injury, and there are likely other factors that contribute to the development of this entity. The glomerular hyperfiltration found in patients with ORG has been postulated to lead to structural
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12. Mallamaci F, Ruggenenti P, Perna A et al. REIN Study Group. ACE inhibition is renoprotective among obese patients with proteinuria. J Am Soc Nephrol 2011; 22: 1122–1128. 13. Bosma RJ, van der Heide JJ, Oosterop EJ et al. Body mass index is associated with altered renal hemodynamics in non-obese healthy subjects. Kidney Int 2004; 65: 259–265. 14. Douglas JG, Agodoa L. ACE Inhibition is effective and renoprotective in hypertensive nephrosclerosis: the African American Study of Kidney Disease and Hypertension (AASK) trial. Kidney Int Suppl 2003; 83: S74–S76. 15. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med 2009; 150: 776–783. 16. Ehrhart-Bornstein M, Arakelyan K, Krug AW et al. Fat cells may be the obesity-hypertension link: human adipogenic factors stimulate aldosterone secretion from adrenocortical cells. Endocr Res 2004; 30: 865–870. 17. Rondinone CM, Rodbard D, Baker ME. Aldosterone stimulated differentiation of mouse 3T3-L1 cells into adipocytes. Endocrinology 1993; 132: 2421–2426. 18. Guo C, Ricchiuti V, Lian BQ et al. Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines. Circulation 2008; 117: 2253–2261. 19. Tuck ML, Sowers J, Dornfeld L et al. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304: 930–933.
