Is obesity a major cause of chronic kidney disease?

Is Obesity a Major Cause of Chronic Kidney Disease? John E. Hall, Jeffrey R. Henegar, Terry M. Dwyer, Jiankang Liu, Alexandre A. da Silva, Jay J. Kuo, and Lakshmi Tallam Excess weight gain is a major risk factor for essential hypertension and for end-stage renal disease (ESRD). Obesity raises blood pressure by increasing renal tubular sodium reabsorption, impairing pressure natriuresis, and causing volume expansion because of activation of the sympathetic nervous system and renin-angiotensin system and by physical compression of the kidneys, especially when visceral obesity is present. Obesity also causes renal vasodilation and glomerular hyperfiltration that initially serve as compensatory mechanisms to maintain sodium balance in the face of increased tubular reabsorption. In the long-term, however, these changes, along with the increased systemic arterial pressure, create a hemodynamic burden on the kidneys that causes glomerular injury. With prolonged obesity, there is increasing urinary protein excretion and gradual loss of nephron function that worsens with time and exacerbates hypertension. With the worsening of metabolic disturbances and the development of type II diabetes in some obese patients, kidney disease progresses much more rapidly. Weight reduction is an essential first step in the management of obesity, hypertension, and kidney disease. Special considerations for the obese patient, in addition to adequately controlling the blood pressure, include correction of the metabolic abnormalities and protection of the kidneys from further injury. © 2004 by the National Kidney Foundation, Inc. Index Words: End-stage renal disease; type II diabetes; hypertension; sympathetic nervous system; renin-angiotensin system; glomerular filtration rate; lipids; insulin resistance; inflammation.

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t is difficult to escape warnings of the obesity “epidemic” in newspapers, magazines, television programs, and alerts from various medical and public service organizations. These warnings do not appear to be just more media hype if one considers the dramatic increase in the prevalence of obesity in most industrialized countries during the past 2 to 3 decades. According to National Health and Nutrition Examination Survey, over 64% of the adult population in the United States is overweight with a body mass index (BMI) greater than 25.1 Almost one third of the population is obese with a BMI greater than 30.1 Similar trends have been reported in most industrialized countries, and there appears to be no abatement of this worldwide “epidemic.” In children and adolescents, the prevalence of obesity is rising even more rapidly, suggesting that obesity-associated medical problems are likely to worsen in the future unless these trends can be attenuated or reversed.2,3 Overweight and physical inactivity are estimated to cause more than 300,000 premature deaths each year in the United States, especially from cardiovascular disease, the number one killer of adults.4 Obesity initiates a

complex cascade of disorders including insulin resistance, glucose intolerance, dyslipidemia, atherosclerosis, and hypertension that all increase the risk of cardiovascular disease. This cluster of disorders is often referred to as the “metabolic syndrome,” “syndrome X,” or “insulin-resistance syndrome,” although excess weight gain is the primary cause in most patients. In the past, although kidney disease has not been recognized as a major component of the metabolic syndrome, there is little doubt that excess weight gain is a major cause of hypertension and type II diabetes, which together account for approximately 70% of end-stage renal disease (ESRD). Accumulating evidence also suggests that even in non-diabetic obese From the Department of Physiology and Biophysics and Center of Excellence in Cardiovascular-Renal Research, The University of Mississippi Medical Center, Jackson, MS. Supported by a grant from the National Heart, Lung and Blood Institute (P01 HL 51971). Address correspondence to John E. Hall, PhD, University of Mississippi Medical Center, Department of Physiology and Biophysics, 2500 North State Street, Jackson, MS 39216-4505. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 1073-4449/04/1101-0006$30.00/0 doi:10.1053/j.arrt.2003.10.007

Advances in Renal Replacement Therapy, Vol 11, No 1 (January), 2004: pp 41-54

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patients, there is some degree of renal dysfunction that can lead to more serious injury to the kidneys as metabolic and hemodynamic disturbances worsen with prolonged obesity.5,6 In this brief review, we discuss the mechanisms that link obesity to hypertension and kidney disease.

Obesity as a Common Cause of Essential Hypertension Considerable evidence suggests that excess weight gain is the most common cause of human essential hypertension. Epidemiological studies have clearly shown a close association between obesity and hypertension, and excess adiposity is one of the best known predictors for subsequent development of hypertension.6-10 This association has been observed in diverse populations throughout the world and in ethnic groups of similar origin living in different locations.7-10 Moreover, the association between body mass and arterial pressure is found not only for obese hypertensive subjects but also for normotensive subjects with normal body weight.9 In general, there appears to be a continuous relationship between BMI and arterial pressure.9 The full impact of obesity on hypertension has been difficult to estimate from cross-sectional population studies because its effects on blood pressure are likely to worsen as obesity is sustained for many years and as target organ injury develops. Nonlinear, synergistic relationships may also exist among the multiple effects of obesity (eg, hyperlipidemia, glucose intolerance, and hypertension) in increasing the risk for cardiovascular and kidney disease. Unfortunately, these complex, timedependent effects of obesity are difficult to assess in population studies. Nevertheless, risk estimates from the Framingham Heart Study suggest that about 78% of hypertension in men and 65% in women can be directly attributed to excess body weight.8 Further support for a close relationship between obesity and elevated blood pressure is the finding that most hypertensive subjects are overweight.11 Clinical studies have also shown the therapeutic value of weight loss in reducing blood pressure in normotensive as well as hypertensive obese subjects.12,13,14 Although some

Figure 1. Effect of weight gain to shift the frequency distribution of blood pressure to higher levels. Not all obese subjects have blood pressures in the hypertensive range (⬎140/90 mm Hg), but excess weight gain raises blood pressure above the baseline level for an individual.

overweight or obese persons do not have blood pressures greater than 140/90 and are therefore not considered to be “hypertensive,” weight loss usually lowers their blood pressure. This suggests that in “normotensive” obese persons blood pressure is higher than it would be at a lower body weight. Excess weight gain appears to increase the probability of being hypertensive by shifting the frequency distribution of blood pressure toward higher levels (Fig 1). Whether reduction in blood pressure with pharmacological therapy in normotensive obese persons provides protection against future development of cardiovascular and kidney disease, however, remains to be tested. Studies in experimental animals also emphasize the importance of excessive weight gain in raising blood pressure and provide insights into the mechanisms of obesity-induced hypertension and kidney disease. Weight gain induced by feeding a high fat diet for several weeks causes a reproducible rise in blood pressure in rats, rabbits, and dogs. Moreover, the cardiovascular, kidney, endocrine, and metabolic changes observed in animal models of diet-induced obesity mimic very closely those found in obese humans5,6 (Table 1).

Kidney Dysfunction as a Cause of Obesity Hypertension Abnormal kidney function appears to be an important cause as well as a consequence of

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Table 1. Hemodynamic, Neurohumoral, and Renal Changes in Experimental Obesity Caused by a HighFat Diet and in Human Obesity

Model Obese Rabbits (high fat diet) Obese Dogs (high fat diet) Obese Humans

Arterial Heart Cardiac Pressure Rate Output

Renal Sympathetic Activity

Plasma Renin Na⫹ Renal Tubular Activity Balance Reabsorption GFR*

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

Abbreviation: GFR, glomerular filtration rate. *The GFR changes refer to the early phases of obesity before major loss of nephron function has occurred.

obesity hypertension. A central feature of obesity hypertension is increased renal sodium reabsorption and extracellular fluid volume expansion that initiate a rise in blood pressure.5,6 Increased sodium reabsorption impairs renal-pressure natriuresis and necessitates increased blood pressure to maintain a balance between the intake and urinary output of sodium in obese subjects.5 Some evidence suggests that increased sodium reabsorption occurs at a site beyond the proximal tubule, possibly in the loop of Henle.6,11 However, there have been few studies that have examined directly the impact of excessive weight gain on sodium reabsorption in different renal tubular segments. Increased renal tubular sodium reabsorption is accompanied by a compensatory rise in glomerular filtration rate (GFR) that helps to maintain sodium balance in obese subjects. Although the precise mechanisms responsible for the rise in GFR in obesity are not fully understood, some evidence suggests that this may be mediated primarily by a macula densa feedback mechanism that is activated by increased renal sodium reabsorption before the macula densa.15 This could explain why obesity is associated with renal vasodilation, glomerular hyperfiltration, and stimulation of renin release despite sodium retention and extracellular fluid volume expansion.5,6,16 Although the initial rise in GFR acts as a compensatory mechanism to maintain sodium balance, with prolonged obesity the renal vasodilation and glomerular hyperfiltration, coupled with the increases in arterial pressure and metabolic abnormalities, may cause renal injury and a decline in GFR. This

gradual decrease in GFR toward normal, and eventually to levels below normal, causes further impairment of pressure natriuresis and more severe hypertension, as discussed later. Three mechanisms appear to be especially important in stimulating sodium reabsorption and altering pressure natriuresis in obesity (Fig 2): (1) increased sympathetic nervous system (SNS) activity; (2) activation of the reninangiotensin system (RAS); and (3) physical compression of the kidneys, especially when there is significant visceral obesity. With chronic obesity, additional mechanisms related to vascular and renal injury may become important in exacerbating the hypertensive effects of these mechanisms.

Figure 2. Summary of mechanisms by which obesity causes hypertension and injury to the kidneys by activating the sympathetic nervous system, the renin-angiotensin system, by physical compression of the kidneys, and by metabolic abnormalities.

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Role of the Sympathetic Nervous System in Increasing Renal Sodium Reabsorption in Obesity Several lines of evidence suggest that activation of the SNS contributes to obesity hypertension.17 SNS activity, especially in the kidneys, is increased in obese subjects18,19 and pharmacologic blockade of adrenergic activity lowers blood pressure to a greater extent in obese compared to lean subjects.20 Moreover, denervation of the kidneys markedly attenuates sodium retention and hypertension associated with a high-fat diet in experimental animals.21 These observations suggest that obesity-induced sympathetic activation raises blood pressure primarily through the renal nerves rather than by other effects such as vasoconstriction in nonrenal tissues. The SNS response to excess weight gain may be modulated by multiple factors including race, gender, and body fat distribution.22,23 In black men, SNS activity is higher, and hypertension is more prevalent than in white men despite comparable levels of obesity.22 In young, overweight black women, increased SNS activity is closely associated with increasing levels of adiposity.22 Differences in fat mass distribution may also be important in determining sympathetic activity. For reasons that are still unclear, abdominal obesity appears to elicit greater sympathetic activation than lower body obesity.24 Unfortunately, SNS activity during normal daily activity has not been assessed, and most studies have measured SNS activity in skeletal muscle, rather than in the kidneys, the primary pathway by which sympathetic activation causes chronic hypertension. Also, a comprehensive analysis of the multiple factors that influence the relationships among obesity, SNS activity, and hypertension in diverse populations has not been conducted.

II), and altered baroreflex sensitivity.17 Increased levels of leptin appear to be one of the most promising of these mechanisms for chronic SNS activation in obesity.17,25 Plasma leptin rises in proportion to the degree of adiposity, and leptin from the plasma crosses the blood-brain barrier to act on various regions in the hypothalamus, especially the arcuate nucleus.26 Leptin regulates energy balance not only by reducing appetite but also by increasing energy expenditure through SNS stimulation.26 Acute increases in plasma leptin concentrations increase renal SNS activity,27 and chronic leptin infusions raise arterial pressure.28 The hypertensive effects of leptin are enhanced when nitric oxide synthesis is inhibited,29 as often occurs in obese subjects with endothelial dysfunction. Adrenergic activation mediates the chronic hypertensive effects of leptin because they are completely abolished by ␣- and ␤-adrenergic blockade.30 Evidence that leptin may contribute to obesity hypertension in rodents comes from the observation that leptin-deficient, obese mice and obese rats with leptin receptor mutations have little or no increase in blood pressure compared with their lean controls.17,31 Similar observations have been reported in obese children with homozygous missense mutations of the leptin gene.32 In these children, morbid obesity and severe metabolic disturbances, including insulin resistance and hyperinsulinemia, occur at a very early age, but there is no indication of sympathetic activation or hypertension.32 In fact, children with missense mutations of the leptin gene have impaired sympathetic activity, postural hypotension, and attenuated renin responses to upright posture.32 Thus, observations in mice and in humans suggest that hyperleptinemia might be an important factor in linking obesity with SNS activation and hypertension.

Possible Role of Leptin in ObesityInduced SNS Activation

Possible Role of Hypothalamic Melanocortins in Obesity-Induced SNS Activation

Although the mechanisms that activate the SNS in obesity are still unclear, several candidates have been suggested including hyperinsulinemia, hyperleptinemia, increased levels of long-chain fatty acids, angiotensin II (ANG

Emerging evidence suggests that leptin’s stimulatory effect on SNS activity may be mediated, in part, by interactions with the pro-opiomelanocortin pathway. For example, the acute effects of leptin to increase renal SNS

Obesity and Chronic Kidney Disease

activity were completely abolished by antagonism of the melanocortin 3/4 receptor (MC3/4-R).33 Moreover, chronic blockade of the MC3/4-R causes rapid weight gain with little or no increase in arterial pressure in rats.34 Because excess weight gain usually raises blood pressure, these findings are consistent with the possibility that MC3/4-R activation is important in linking obesity with hyperleptinemia, increased SNS activity, and hypertension. Humans with missense mutations of the MC4-R have early onset, morbid obesity, but there have been no reports, to our knowledge, on blood pressure and SNS activity in these patients. Further studies in humans are therefore are needed to determine the role of hypothalamic pro-opiomelanocortin pathway in obesity hypertension.

Role of the Renin-Angiotensin System in Increasing Renal Sodium Reabsorption in Obesity Obesity in experimental animals and in humans is associated with modest increases in plasma renin activity, angiotensinogen, angiotensin converting enzyme (ACE) activity, and plasma aldosterone concentration despite marked sodium retention and extracellular fluid volume expansion.11,35 Although renin released from the kidneys undoubtedly causes increased ANG II formation in obesity, adipose tissue has also been suggested to contribute to activation of the RAS.35 The functional importance of the adipose RAS in mediating obesity hypertension, however, is still unclear. Studies in humans and experimental animals suggest an important role for ANG II in stimulating renal sodium reabsorption and in mediating obesity hypertension. For example, blockade of the RAS attenuates sodium retention and increased arterial pressure in obese dogs fed a high fat diet.36 In obese Zucker rats, there appears to be increased sensitivity to the blood pressure effects of ANG II because RAS blockade lowers blood pressure to a greater extent than in lean rats despite comparable, or perhaps even lower, plasma renin activity.37 In the only clinical trial published on the efficacy of RAS blockade in obese humans, ACE inhibition was shown to be effective in

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lowering blood pressure, although especially in young and white subjects.38 However, there have been no large trials that have tested the effectiveness of ANG II receptor antagonists or ACE inhibitors compared with other antihypertensive drugs in obese compared with lean hypertensive subjects. Retrospective analysis of the Antihypertensive Lipid Lowering Heart Attack Trial data should provide some useful information because there were many overweight and obese subjects in this trial and an ACE inhibitor was compared with other types of antihypertensive therapy.39 There are several theoretical reasons why ACE inhibitors and ANG II receptor antagonists should be beneficial as antihypertensive agents for obese patients. Not only are they effective in lowering blood pressure, but they also have beneficial metabolic effects, improving insulin sensitivity and causing no adverse effects on lipid profiles.40 ACE inhibitors and ANG II receptor blockers have also been shown to be more effective than other antihypertensive drugs in slowing the progression of renal injury in obese patients with type II diabetes.40,41 Because these agents attenuate glomerular hyperfiltration and microalbuminuria, conditions known to be associated with obesity, they may also be useful in preventing injury to the kidneys in obese subjects before diabetes develops. However, clinical studies are needed to test this possibility.

Visceral Obesity Causes Compression of the Kidneys Excess accumulation of adipose tissue in the viscera initiates multiple changes that cause compression of the kidneys and increased intrarenal pressures. For example, excess retroperitoneal adipose tissue encapsulates the kidneys and penetrates the renal hilum into the renal medullary sinuses, causing compression of the renal medulla and increased interstitial fluid hydrostatic pressures.6,36 Large amounts of visceral adipose tissue may also raise intra-abdominal pressure causing further renal compression. Studies in humans have found that intra-abdominal pressure rises in proportion to sagittal abdominal diameter, reaching levels as high as 35 to 50 mm Hg in some subjects.42

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Figure 3. Percentage of patients without renal insufficiency in patients who were lean (BMI ⬍ 25, solid line) or obese (BMI ⬎ 30, dashed line) at the time of unilateral nephrectomy. (Data from Praga et al.44).

Physical compression of the kidneys may be an important cause of increased extracellular matrix formation in the renal medulla of obese subjects.5,6,11 Because the kidney is surrounded by a tight capsule, with a low compliance, accumulation of renal medullary extracellular matrix could further exacerbate intrarenal compression and raise interstitial fluid hydrostatic pressures. The increased intrarenal pressures, in turn, compress the loops of Henle and vasa recta, thereby slowing flow in the renal tubules and vasa recta, and increasing tubular sodium reabsorption.6,36 These changes could explain, in part, why visceral obesity is more closely associated with hypertension than lower body or subcutaneous obesity.43

the prevalence of ESRD in the past 2 decades has been paralleled by increasing obesity and diabetes.11 In fact, most of the increasing prevalence of ESRD has been attributed to increasing type II diabetes. In addition to causing renal injury through diabetes and hypertension, obesity also exacerbates the effects of other primary renal insults, such as unilateral nephrectomy.44 In patients with a BMI greater than 30 who had undergone unilateral nephrectomy an average of 13.6 ⫾ 8.6 years before, 92% developed proteinuria or renal insufficiency, whereas only 12% of patients with BMI less than 30 developed these disorders44 (Fig 3). In patients with immunoglobulin A (IgA) nephropathy, those who had a BMI greater than 25 at the time of renal biopsy had more severe renal lesions and increased proteinuria, as well as a much faster decline of renal function and progression to chronic renal failure when compared to patients with a BMI less than 2544 (Fig 4). Being overweight was also shown to be an independent risk factor for the development of hypertension in patients with IgA nephropathy.45 Moreover, moderate weight loss in overweight patients with chronic nondiabetic proteinuric nephropathies induced a marked reduction in protein-

Is Obesity a Major Cause of Glomerular Injury and Nephron Loss? As discussed earlier, obesity is not widely recognized as a major cause of kidney disease. However, the importance of obesity as perhaps the single most important risk factor for kidney disease becomes evident, if we consider the fact that the two most important causes of ESRD are diabetes and hypertension, both of which are closely associated with excess weight gain. Moreover, the rapid rise in

Figure 4. Percentage of lean (BMI ⬍ 25, solid line) compared with overweight (BMI ⬎ 25, dashed line) patients who did not develop chronic kidney failure for up to 20 years after the diagnosis of IgA nephropathy. (Data from Bonnet et al.45)

Obesity and Chronic Kidney Disease

uria, whereas in overweight subjects who did not lose weight, renal function worsened with time.46 These observations suggest that obesity may have additive or synergistic effects to worsen renal function in patients with preexisting glomerulopathies and that weight loss may lessen the impact of renal injury from other causes.

Early Functional and Structural Changes in Kidneys of Obese Subjects There have been only a few studies of kidney structure and function soon after the onset of obesity, before the development of diabetes or marked kidney dysfunction. Early functional changes in the kidneys of obese animals and humans include renal vasodilation, increased blood flow, glomerular hyperfiltration, and increased tubular sodium reabsorption.16 The parallel increases in GFR and renal plasma flow suggest dilation of preglomerular vessels and increased glomerular hydrostatic pressure in obesity.16,47 This preglomerular vasodilation would permit increased transmission of elevated systemic arterial pressure to the glomeruli, thereby further increasing glomerular hydrostatic pressure and wall stress. Although the mechanisms responsible for renal vasodilation in obesity have not been fully elucidated, a macula densa feedback mechanism may play a role. As discussed earlier, obesity is associated with increased sodium reabsorption at a segment before the macula densa, possibly the loop of Henle.15 Increased sodium reabsorption in the loop of Henle would initially reduce macula densa sodium chloride delivery, thereby initiating a macula densa feedback that would cause vasodilation of afferent arterioles and increased renin secretion despite sodium retention and volume expansion. With a compensatory vasodilation of preglomerular blood vessels and a rise in GFR, sodium balance would eventually be restored but at the expense of increased glomerular wall stress. Not all investigators have reported increased renal blood flow and glomerular hyperfiltration in obese subjects. This may be due to the fact that increases in total GFR are time dependent, with an early increase and later on, as injury to the kidneys and nephron

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loss occur, a gradual decrease toward normal or below normal. In addition, GFR or renal plasma flow are sometimes expressed in terms of body surface area or body weight. However, this type of normalization tends to underestimate nephron hyperfiltration in obese subjects. Although kidney size may increase with the development of obesity, the number of nephrons does not increase so that each surviving nephron is exposed to increased rates of glomerular filtration. With declining kidney mass, the burden of glomerular hyperfiltration becomes even greater for surviving nephrons. Obesity is also associated with increased albumin excretion that rises progressively with increasing severity of obesity.48,49 With morbid obesity, proteinuria can become severe enough to produce nephrotic syndrome in a small percentage of patients.49 At least part of the increased protein excretion has a hemodynamic basis because reductions of blood pressure and GFR attenuate the proteinuria.50,51 Studies in experimental animals suggest that obesity-induced glomerular injury may develop rather rapidly. In dogs fed a high-fat diet, substantial histologic, biochemical, and kidney functional changes were noted after only 7 to 9 weeks.52 These changes included expansion of Bowman’s capsule, glomerular cell proliferation, thickening of the glomerular and tubular basement membranes, increased glomerular mesangial matrix, and increased glomerular transforming growth factor ␤1 expression. Significant histological changes in the renal medulla, including expansion of extracellular matrix and increased levels of glycosaminoglycans, such as hyaluronan, have also been found in the kidneys of obese dogs and rabbits fed a high fat diet for only 5 to 12 weeks.6,11,53 The evolution of changes in kidney structure and function after excessive weight gain in humans has not, to our knowledge, been reported. However, obesity-induced pathologic changes in the kidneys have been observed even in children. Adelman et al54 found in 7 black adolescents with severe obesity remarkable renal pathology, including proteinuria and focal segmental glomerulosclerosis, glomerular hypertrophy, and in-

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creased mesangial matrix. One of these patients had dramatic improvement of kidney function and reduced proteinuria with weight reduction, whereas one 15-year-old obese patient developed ESRD.54 Based on these observations, the authors recommended that obese children be monitored for proteinuria and evidence of kidney disease. Unfortunately, there are no large-scale studies in children examining the impact of obesity on kidney disease and the development of hypertension, diabetes, and other metabolic abnormalities that accompany long-standing obesity. Glomerulosclerosis is the most common lesion found in obese patients with proteinuria.55 Kambham et al,55, in a review of 6,818 native renal biopsies received from 1986 to 2000, found a progressive increase in the incidence of obesity-related glomerulopathy, defined morphologically as FSGS and glomerulomegaly. During the 15-year period of study, there was a 10-fold increase in the incidence of obesity-related glomerulopathy. Another finding in some obese patients was the presence of focal “diabetoid” changes characterized by mesangial sclerosis and thickening of glomerular basement membranes and tubular basement membranes, similar to our observations in obese dogs.52 Glomerular foot process effacement was also observed in approximately 40% of renal biopsies in obese patients with glomerulopathy.55

Can Caloric Restriction and Weight Loss Prevent Kidney Disease? There is compelling evidence in experimental animals that food restriction protects against the development of chronic kidney disease. Zucker fatty rats, for example, usually die of ESRD, but restriction of their food intake by only 7% to 18% between 4 and 40 weeks of age markedly reduced renal injury, increased their life span, and reduced deaths attributable to ESRD from 91% to 64% in obese male rats and from 93% to 51% in obese female rats56 (Fig 5). Similar beneficial effects of food restriction in preventing kidney disease and prolonging life have been observed in other strains of rats.57 Not surprisingly, caloric restriction early in the life of obese rats provides the greatest renal protection.58

Figure 5. Effect of food restriction on the cumulative death rate attributed to end stage kidney disease in female lean and obes Zucker rats. Another group of obese Zucker rats was pair fed the same amount as ingested by the lean rats. (Data from Stern et al.56)

Although there have been no long-term studies of food restriction or weight loss on progression of kidney disease in humans, there is little doubt that weight loss reduces hypertension and prevents or reverses the development of type 2 diabetes, the 2 main risk factors for development of ESRD. In nondiabetic obese subjects functional renal abnormalities, including glomerular hyperfiltration and albuminuria, improve substantially after weight loss.51,59 Moderate weight loss also has beneficial effects on the kidneys in overweight patients with chronic nondiabetic proteinuric nephropathies.46 This improvement is likely because of a combination of reduced arterial pressure and attenuated vasodilation of preglomerular vessels, changes that reduce glomerular hydrostatic pressure and wall stress. The benefits of weight loss to the kidneys appear to occur regardless of whether they are induced by diet and exercise or by surgical methods (eg, gastroplasty), although there have been no large studies directly comparing the effectiveness of different methods of weight loss on progression on kidney dysfunction. Also, most studies have lasted only a few weeks or months and the long-term consequences of weight loss in protecting against kidney disease have not been rigorously tested in humans. Studies lasting for at least a

Obesity and Chronic Kidney Disease

year, however, have shown remarkable reductions in proteinuria (⬎80%) with a weight loss of about 12%.51 Unfortunately, weight loss is usually transient in most obese patients except for those who undergo surgical procedures such as gastric bypass.

Possible Mechanisms of ObesityInduced Glomerular Injury and Nephron Loss Role of Hemodynamics: Systemic Arterial and Glomerular Hypertension Increased arterial pressure and renal hemodynamic changes play a major role in mediating obesity-induced injury to the kidneys. Systemic arterial hypertension causes approximately 27% of all ESRD, and obesity accounts for a large fraction of the risk for human essential hypertension. Clinical studies have also shown the importance of controlling arterial pressure in preventing the development and progression of kidney disease. In fact, adequate control of blood pressure may be as effective or even more effective than adequate control of plasma glucose in obese type 2 diabetic patients in preventing development of serious kidney disease.60 The effect of arterial hypertension on renal hemodynamics is amplified by preglomerular renal vasodilation in obese subjects, resulting in greater transmission of the elevated arterial pressure to the glomerular capillaries, as discussed earlier. Therefore, compared with other forms of hypertension that are associated with increased preglomerular vascular resistance and normal GFR, obesity-induced hypertension would be expected to cause greater increases in glomerular capillary wall stress, increased extracellular matrix formation, and more fibrosis. Glomerular hyperfiltration is also likely to be a major factor in causing microalbuminuria, which, in turn, may promote glomerular inflammatory responses. Prevention and treatment of obesity-induced injury to the kidneys should be aimed at normalizing glomerular hydrostatic pressure, as well as systemic arterial pressure. Antihypertensive drugs that dilate the efferent arterioles, such as ACE inhibitors and

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ANG II receptor antagonists, are therefore the most effective antihypertensive agents known in preventing the progression of injury to the kidneys of obese type 2 diabetic patients. Unfortunately, there are no studies, to our knowledge, that have compared the effectiveness of ACE inhibitors or ANG II receptor antagonists with other antihypertensive drugs in preventing injury to the kidneys of nondiabetic, obese patients.

Role of the RAS: Does ANG II Cause Renal Disease Independent of Its Hemodynamic Effects? There is little doubt that blockade of the RAS, with ACE inhibitors or ANG II receptor antagonists, can slow the progression of kidney disease in obese subjects with type 2 diabetes. In nondiabetic obese patients, blockade of the RAS markedly reduces glomerular hyperfiltration and proteinuria, effects that should be beneficial in slowing the onset of injury to the kidneys.50 What has been less clear is whether the deleterious renal effects of excessive activation of the RAS are because mainly of direct tissue-specific actions of ANG II or to the multiple hemodynamic effects of ANG II. Physiological studies do not support the concept that moderate increases in ANG II, in the absence of increased arterial pressure, promote injury to the kidneys. For example, activation of the RAS by sodium depletion does not cause renal injury. Also, there does not appear to be any evidence of glomerular injury in the clipped kidney of the 2-kidney, 1-clip model of Goldblatt hypertension that is chronically exposed to very high levels of ANG II but protected from increased arterial pressure by the clip on the renal artery.61 In contrast, the unclipped kidney that is exposed to high blood pressure and moderate increases in ANG II has severe injury.61 Despite these observations, ANG II is widely believed to contribute to target organ damage by directly promoting tissue fibrosis. This belief is based largely on in vitro studies showing that ANG II can directly cause vascular hypertrophy and increase collagen formation in various tissues, including mesangial cells, and on reports that RAS blockade may reduce injury to the kidneys and proteinuria

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through mechanisms that are independent of reductions in blood pressure.62 Most in vitro studies, however, are limited because of the high concentrations of ANG II (often 10⫺6 moles/L or higher) needed to produce tissue fibrosis. Many of the in vivo studies are complicated by the fact that blood pressure has usually been measured intermittently with indirect methods. Studies in which blood pressure was measured directly by radiotelemetry, 24 h/d, suggest that reductions in blood pressure may be primarily responsible for the protection of the kidneys associated with RAS blockade.63 Clinical trials in both diabetic and nondiabetic nephropathy have shown some benefit of RAS blockade, compared with other antihypertensive therapies, in slowing progression of kidney disease. However, most of these studies have not assessed blood pressure throughout the day to determine accurately the hemodynamic load on the kidneys. Results from 2 major clinical trials, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan and Irbesartan Diabetic Nephropathy, show the limitations of the usual approach in assessing the role of hemodynamics in renal disease.64,65 Patients with diabetic nephropathy who were treated with angiotensin receptor antagonists had a decline in GFR of approximately 5 mL/min per year, whereas diabetic patients treated with other antihypertensive drugs had a decline in GFR of approximately 6 mL/min per year. Because the usual rate of decline in GFR in patients with diabetic nephropathy and untreated hypertension is about 12 mL/min per year, all antihypertensive therapies that effectively lowered blood pressure appear to protect the kidneys.66 The further GFR protection of 1 mL/min per year observed with ANG II receptor blockade, compared with other therapies, was modest and might be explained by the slightly greater reductions in blood pressure observed in this group.66 Therefore, results from clinical trials and from animal studies in which very accurate measurements of arterial pressure have been made, 24 h/d, suggest that reductions in systemic arterial pressure and glomerular hydrostatic pressure may explain most, if not all, of the beneficial renal effects of RAS blockade. In obesity, the

hemodynamic actions of ANG II may play a significant role in mediating injury to the kidneys. Do Hyperinsulinemia and Insulin Resistance Contribute to Kidney Disease? Excess weight gain, especially when associated with visceral obesity, leads to glucose intolerance, insulin resistance, and a compensatory hyperinsulinemia.67 Not all tissues share in this insulin resistance, however, and increased insulin concentrations have been suggested to mediate obesity-induced hypertension by stimulating sympathetic activity, by directly increasing renal sodium reabsorption, and by causing vascular smooth muscle hypertrophy.67 To the extent that hyperinsulinemia and insulin resistance contribute to increased blood pressure and vascular smooth muscle injury, they could also contribute to obesity-induced injury to the kidneys. Evidence supporting this concept comes from the finding that insulin resistance and hyperinsulinemia are correlated with blood pressure in obese subjects and from acute studies indicating that insulin infusion causes modest sympathetic activation and sodium retention.67 The correlation between insulin and blood pressure, however, is not surprising in view of the fact that obesity causes insulin resistance as well as hypertension. However, most of the available evidence suggests that chronic hyperinsulinemia does not mediate obesity hypertension.17,36,68 In humans and dogs, neither acute nor chronic hyperinsulinemia impairs renal-pressure natriuresis or increases arterial pressure. In fact, insulin infusions at rates that raise plasma concentrations to about the same levels found in obesity cause peripheral vasodilation and decreased arterial pressure. Hyperinsulinemia per se also does not appear to cause atherosclerosis or hypertension in humans. For example, in patients with insulinoma who have very high levels of insulin there is no indication of hypertension or atherosclerosis.69 Likewise, there is no evidence that insulin therapy in obese, diabetic patients exacerbates hypertension, atherosclerosis, or kidney disease. Another hypothesis suggests that impaired vasodilator actions of insulin, because of the

Obesity and Chronic Kidney Disease

development of insulin resistance, may contribute to obesity hypertension. However, we found that chronic hyperinsulinemia did not increase arterial pressure even in obese dogs that were resistant to the metabolic and vasodilator actions of insulin. This observation suggests that impaired vasodilator effects of insulin associated with obesity and insulin resistance do not cause chronic hypertension. The weak association between insulin and blood pressure in obese subjects that has been observed in several different ethnic groups, including American Indians, blacks, Hispanics, and whites, appears to be explained largely by increased adiposity.70 Although hyperinsulinemia may not be a key factor in linking obesity with hypertension, the metabolic consequences of insulin resistance likely contribute to renal disease. Insulin resistance is the first step in the eventual development of type 2 diabetes that certainly plays a major role in causing kidney disease in some obese subjects. However, more subtle abnormalities of glucose and lipid metabolism associated with insulin resistance may contribute to injury to the kidneys. Thus, the adverse effects of insulin resistance on hypertension and kidney disease may be mediated primarily through metabolic consequences rather than the effects of hyperinsulinemia per se. Obesity-Induced “Lipotoxicity” The term “lipotoxicity” was coined to describe the array of disorders caused by excessive non–␤-oxidative metabolism of fatty acids in non-adipose tissues, including skeletal muscle, pancreatic islets, and myocardium.71 Fatty acid delivery to nonadipose tissues is normally coupled with the need for metabolic fuel. During chronic overnutrition, fatty acid delivery to the tissues exceeds usage, causing a compensatory increase in fatty acid oxidation that helps to prevent accumulation of unoxidized lipids.71 However, with increased non–␤-oxidative fatty acid metabolism, several substances that can injure cells may be released, including the products of lipid peroxidation as well as triglycerides, which may cause programmed cell death and fibrosis in nonadipocytes.71 For example, liver fibrosis is a common finding in obese patients with ex-

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cessive fatty triglyceride deposition, and abnormal fibrosis also occurs in the hearts and pancreatic islets of obese rats.71 There is considerable evidence suggesting that leptin may be important in compensatory ␤-oxidation of excess fatty acids in nonadipose tissue. For example, in rodents with loss of function mutations of genes encoding leptin or its receptor, there is a loss of leptinmediated protection against deposition of lipids in nonadipose tissue.71 Although there is little doubt that increased accumulation of lipids has deleterious effects on various tissues such as the heart, liver, and pancreatic ␤ cells, the role of renal lipotoxicity is unclear. Studies in experimental animals and in humans indicate that obesity is associated with marked accumulation of fatty tissue, especially in the renal sinuses.11,72 Lipid peroxidation stress biomarkers are markedly elevated in glomeruli and renal microvessels in type 2 diabetes and lipid-lowering agents (eg, 3-Hydroxy-3 methyl-glutaryl-CoA [HMG CoA] reductase inhibitors [statins]) reduce proteinuria and the rate of progression of kidney disease in patients with hypercholesterolemia and proteinuria.73 Administration of peroxisome proliferator activated receptor ␥ (PPAR-␥) agonists, which reduce lipogenesis in nonadipose tissue while increasing lipid deposition in adipocytes, also attenuates heart disease in diabetic or prediabetic Zucker fatty rats.71 Whether these drugs are effective in reducing renal lipotoxicity, however, remains to be determined. Potential Role of Inflammatory Cytokines Released From Adipocytes Obesity has been suggested to initiate lowgrade inflammation as a result of increased formation of inflammatory cytokines such as tumor necrosis factor ␣, interleukin-6, and Creactive protein, sometimes referred to as “adipokines” because they are produced by adipocytes.74 There is general consensus that renal glomerular and interstitial fibrosis and irreversible accumulation of extracellular matrix in the kidneys are associated with inflammation. Whether renal inflammation and fibrosis are mediated by adipokines or by other

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factors (eg, hemodynamic events) in obese subjects is still unclear. Studies examining the time course of renal interstitial fibrosis in Zucker obese rats suggest that it develops in 2 phases. The first phase begins as early as 3 months of age in the obese rat and occurs in the absence of any lymphocyte or macrophage infiltration.75 However, after 6 months interstitial fibrosis worsens with concomitant macrophage infiltration.75 These observations suggest that inflammation cannot explain the initial onset of renal interstitial fibrosis that occurs in obese Zucker rats but may aggravate renal fibrosis once it begins. Treatment with ligands that activate the peroxisome proliferator activated receptor ␥ has been found to reduce plasma levels of various adipokines and to improve endothelial function as well as glucose regulation.74 Whether these agents have beneficial longterm effects on the kidney, however, has not been established. It is also not known whether long-term treatment with aspirin or other nonsteroidal anti-inflammatory drugs reduces the level of inflammatory cytokines and kidney disease in obese patients. Therefore, further studies are needed to assess the contribution of adipokines in initiating and exacerbating kidney disease associated with obesity. Role of Oxidative Stress Increased levels of superoxide radicals have been shown to be involved in raising blood pressure in animal models of hypertension, possibly through decreasing the availability of endogenous nitric oxide and impairment of endothelium-dependent vascular relaxation.76 Obesity in humans and experimental animals increases various markers of oxidative stress.77,78 In obese rats fed a high-fat diet, renal lipid peroxides as well as urinary isoprostanes were significantly increased.77 The mechanisms that link excess weight gain with oxidative stress are likely to be multifactorial, including inflammation and oxidation of excess lipids. However, there have been no studies, to our knowledge, that have clearly shown an important role for oxidative stress in linking obesity with chronic renal disease.

Conclusions Obesity has reached “epidemic” proportions throughout the industrialized world and is now the leading cause of hypertension and kidney disease. Obesity hypertension appears to be closely linked to abnormal kidney function caused by activation of the RAS and SNS and physical compression of the kidneys when visceral obesity is present. Obesity is also a major risk factor for chronic kidney disease via hypertension and type 2 diabetes. However, emerging evidence indicates that obesity also causes injury to the kidneys through a cascade of hemodynamic and metabolic mechanisms. There are currently few guidelines for the treatment of obesity hypertension and kidney disease and a paucity of data comparing the efficacy of different therapies in obese patients. Special considerations for obese hypertensive patients, in addition to reducing weight and controlling systemic arterial pressure, are correcting metabolic abnormalities (eg, hyperlipidemia and glucose intolerance) and protecting the kidneys from injury by preventing glomerular hyperfiltration. Perhaps more important, we need new strategies for the treatment and prevention of obesity per se, rather than focusing only on cardiovascular and kidney disease associated with obesity.

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