26 Adiposity and Kidney Disease

Adiposity and Kidney Disease

Srinivasan Beddhu

and Bonnie Ching-Ha Kwan

26

Abstract

The prevalence of chronic kidney disease is growing worldwide. Epidemiological data suggest there is a causal relationship with adiposity. There are also laboratory research and clinical studies showing that adiposity is involved in the development and the progression of kidney disease itself.

Mechanisms include adaptation to increased body mass, activation of sympathetic nervous and renin–angiotensin systems, effects of insulin resistance, lipid overload, and release of adipokines.

Kidney disease may also affect the association of adiposity with cardiovascular outcomes. In this chapter, the interactions of adiposity and kidney disease and their effects on clinical outcomes are examined.

Key Words: Adipose tissue; obesity; kidney disease; insulin resistance; cardiovascular outcomes.

1. INTRODUCTION

Chronic kidney disease (CKD) is increasingly common. From the Third National Health and Nutrition Examination Survey (NHANES III), it was found that the preva- lence of CKD in the US adult population was 11% (19.2 million), of which 7.6 mil- lion had stage 3 (glomerular filtration rate [GFR] 30 to 59 mL/min/1.73 m

) and 400,000 had stage 4 (GFR 15 to 29 mL/min/1.73 m

) (1). In 2002, the number of peo- ple with stage 5 CKD (GFR < 15 mL/min/1.73 m

) requiring dialysis in the United States was approx 310,000, representing an 86% increase over the past decade. This number is expected to rise exponentially, to affect more than 650,000 individuals by 2010 (2).

There is evidence that adiposity is involved in the development, and the progression, of kidney disease itself. Further, whereas adiposity is a well-known cardiovascular risk factor in the general population, epidemiological studies have raised uncertainties regarding the impact of adiposity on clinical outcomes in CKD and dialysis patients. In this chapter, we address these two issues: the effects of adiposity on kidney disease, and the effects of kidney disease on the associations of adiposity with cardiovascular risk fac- tors and cardiovascular disease.

From: Nutrition and Health: Adipose Tissue and Adipokines in Health and Disease Edited by: G. Fantuzzi and T. Mazzone © Humana Press Inc., Totowa, NJ

351

2. EFFECT OF ADIPOSE TISSUE ON PROGRESSION OF KIDNEY DISEASE

2.1. Epidemiological Data

There is evidence that in many populations, the rising trend of kidney disease in the population has also mirrored that of obesity (3–5). Obesity, which is mainly caused by an increase in adipose tissue, has a direct relationship to the development and progres- sion of diabetes mellitus, hypertension, and dyslipidemia. Diabetes and hypertension are well known to be the two most common causes of renal impairment. More than 40%

of the CKD and dialysis populations have diabetes as a cause of renal failure, whereas hypertension takes up around 28%. Analyses of the data from the Modification of Diet in Renal Disease (MDRD) (6) and Atherosclerosis Risk in Communities (ARIC) (7) studies showed that high triglyceride and low high-density lipoprotein (HDL) levels are related to the development of CKD.

Kidney damage is clinically manifest as loss of albumin in urine or decline in GFR.

Analysis of NHANES data further showed that abdominal obesity was associated with both a decrease in GFR and microalbuminuria (24-h urinary albumin excretion in the range of 150–300 mg/d) (5). This association was also seen with each of the other ele- ments of metabolic syndrome (i.e., insulin resistance, hypertension, hypertriglyceridemia, and low HDL level). Furthermore, there was a graded relationship between the number of components present and the corresponding prevalence of CKD and microalbuminuria.

Thus, the above data raise the question whether the association of adiposity with CKD is a mere reflection of associated diabetes, hypertension, and dyslipidemia or whether adiposity is an independent risk factor for kidney disease. In another analysis of the ARIC data, the odds ratio (OR) of developing CKD during a 9-yr follow-up period in participants with metabolic syndrome was 1.43, and remained 1.24 after adjusting for the subsequent development of diabetes and hypertension. Compared with participants with no traits of metabolic syndrome, those with one, two, three, four, or five traits of the metabolic syndrome had an OR of CKD of 1.13 (95% CI: 0.89–1.45), 1.53 (95% CI: 1.18–1.98), 1.75 (95% CI: 1.32–2.33), 1.84 (95% CI: 1.27–2.67), and 2.45 (95% CI: 1.32–4.54), respectively. Thus, metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults (8).

2.2. Renal Pathology in Adiposity

Histologically, renal biopsies of obese patients with renal failure have shown glomeru- lomegaly and focal segmental glomerulosclerosis (9,10). To date, it is not known whether obesity-related glomerulomegaly is a cause or just an associated feature of proteinuria. It is also not certain if glomerulomegaly is a precursor of obesity-related focal segmental glomerulosclerosis.

2.3. Mechanisms of Kidney Damage in Adiposity

There are several biological mechanisms through which adiposity could lead to kid-

ney damage (Table 1). Pathophysiology of increased microalbuminuria and proteinuria

may include glomerular hyperfiltration, increased renal venous pressure, glomerular

hypertrophy (due to mesangial cell hypertrophy and matrix production), and increased

synthesis of vasoactive and fibrogenic substances (including angiotensin II, insulin,

leptin, and transforming growth factor [TGF]-G1) (11). The following discussion elab- orates on these mechanisms.

2.3.1. A

I

B

M

Increased body mass leads to increased excretory load of nitrogen and metabolic waste. In the face of stable number of nephrons, this leads to increased workload with hyperperfusion and hyperfiltration of each single nephron. It has been shown that obesity- related glomerular hyperfiltration ameliorates after weight loss (12).

Second, obesity and increased body mass correlate positively with systemic hyper- tension. This causes increase in glomerular capillary pressure, proteinuria, endothelial dysfunction, vasculopathy, and fibrosis within the kidney, leading to nephronal damage.

2.3.2. A

E

A

O

-I

S

R

Obesity leads to activation of the sympathetic system, possibly caused, in part, by hyperleptinemia that stimulates the hypothalamic pro-opiomelanocortin pathway (13).

Angiotensin II, and hence the renin–angiotensin system, is upregulated. These cause vol- ume expansion and increased blood pressure. Further, excess visceral adipose tissue may lead to physical compression of the kidneys, medullary compression owing to accumu- lation of adipose tissue around the kidney, and increased extracellular matrix within the kidney (13,14), causing increasing intrarenal pressures and tubular reabsorption.

Because of increased tubular reabsorption of sodium, marked renal vasodilation and glomerular hyperfiltration set in to serve as compensatory mechanisms to maintain sodium balance (15). However, chronic renal vasodilation and increased systemic arte- rial pressure cause increased hydrostatic pressure and glomerular capillary wall stress.

Along with increased lipids and glucose intolerance, these may cause glomerular cell proliferation, matrix accumulation, and eventually glomerulosclerosis and loss of nephron function in obese subjects. This creates a slowly developing vicious cycle, with ever-increasing arterial pressure and urinary protein excretion leading to gradual but continual loss of nephron function.

2.3.3. D

I

E

H

/I

R

Adipose tissue is associated with insulin resistance. This causes systemic hyper- insulinemia, which contributes to renal vascular injury by stimulating smooth muscle cell Table 1

Mechanisms of Kidney Damage

Cardiovascular Hypertension

Renal Altered vascular structure and function

Enhanced renin–angiotensin–aldosterone system Enhanced sympathetic nervous system

Metabolic Hyperinsulinemia/insulin resistance Dyslipidemia

Hypercortisolemia

Inflammatory Hyperleptinemia

Hematological Hypercoagulability

Altered kallikrein–kinin system

proliferation (16). It also has both direct and indirect effects on the progression of glomerular damage. Direct effects include irreversible glycosylation of glomerular pro- teins—e.g., renal mesangial cells and stimulation of expression of inflammatory collagens (17). Hyperinsulinemia augments endothelial-dependent vasodilation (increased nitric oxide production via PI3-k/Akt pathway), thus contributing to preglomerular vasodilation and glomerular hypertension (15,18). Indirect effects include interaction with elevated intrarenal angiotensin II to augment angiotensin II-induced contraction of glomerular mesangial cells (19). In vitro studies have shown that hyperinsulinemia can induce glomerular hypertrophy both directly, or via insulin-like growth factor (IGF)-1 (20).

2.3.4. R

L

Overload of intracellular lipid leads to intracellular shunting of excess fatty acids toward synthesis of products that induce cell damage (21–23). This impairs function of the individual cells and causes apoptosis, leading to reduction of total cell mass.

Lipotoxicity is associated with progression of metabolic syndrome and can involve mul- tiple organs, including kidney, liver, skeletal, pancreas, and cardiac cells (21). Free fatty acids per se also increase oxidative stress (24). In the kidneys, dyslipidemia enhances the amount of lipoproteins being filtered in the Bowman’s capsule, damaging glomer- ular and tubular cells and enhancing endothelial dysfunction and atherosclerosis (25,26).

2.3.5. A

T

S

O

White adipose tissue can be considered as the largest secretory organ in the body. It releases a wide range of protein signals and factors, termed adipokines (27). A number of adipokines—including leptin, adiponectin, tumor necrosis factor (TNF)-F, inter- leukin (IL)-1 G, IL-6, monocyte chemoattractant protein-1, macrophage migration inhi- bitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor 1 and haptoglobin—are linked to inflammation and the inflammatory response. This leads to a low-grade inflammatory condition that is important in the causation and progression of hypertension and endothelial dysfunction.

Reduction of renal mass contributes to retention of proinflammatory adipokines, leading to adipokine imbalance (28), and augments the inflammatory state in end-stage renal disease (ESRD).

Leptin is a proinflammatory adipokine. Leptin is cleared by the kidney (29–31), and its concentration increases in renal impairment. In glomerular endothelial cells, leptin stimulates cellular proliferation, TGF-G1 synthesis, and type IV collagen production (32). In mesangial cells, leptin upregulates synthesis of TGF-G2 receptor (32) and type I collagen production (33,34). Physiologically, leptin activates sympathetic nervous activity (35), increases sodium reabsorption, and stimulates reactive oxygen species (36). All these contribute to extracellular matrix deposition and glomerulosclerosis, leading to hypertension, proteinuria (37), and progression of kidney disease. There is also evidence to suggest that leptin and TGF-G1 promote mesangial sclerosis by different mechanisms and act synergistically to potentiate mesangial matrix production.

Adiponectin, on the other hand, is anti-inflammatory. Plasma adiponectin level is neg-

atively associated with fat mass (38,39). It has been implicated in “absorbing” fat cells

from other organs and also reducing the degree of macrophage-to-foam cell transforma-

tion and TNF-F expression in macrophages and adipose tissue (40). This may lead to

reduced lipotoxicity and counteract inflammation. In addition, plasma adiponectin level has been found to be negatively associated with insulin sensitivity (39).

3. MANAGEMENT

There is substantial evidence that adipose tissue and obesity are related to the pro- gression of renal disease. If managed properly in the early stages, most of the physio- logical and structural changes may be reversible. On the other hand, prolonged increase in adipose tissue leads to a cycle of increased hypertension, renal damage, and further maladaptation mechanisms. Early interventions targeted toward hypertension, adipos- ity, and insulin resistance might minimize renal damage associated with obesity.

4. EFFECTS OF KIDNEY DISEASE ON ASSOCIATIONS OF ADIPOSITY WITH CARDIOVASCULAR RISK FACTORS AND CARDIOVASCULAR DISEASE

In contrast with the data for the general population, dialysis patients with higher body mass index have lower mortality compared with dialysis patients with normal BMI (41,42). Strikingly, these data have been consistent in several studies (43–45). Thus, it has been suggested that obesity is protective in dialysis patients (41). In other words, as the associations of body size with mortality appear to vary depending on the presence or absence of advanced kidney failure, it can be said that kidney disease is an effect modifier of this association.

However, there are three problems with the suggestion that adiposity is protective in dialysis patients. First, the real paradox of the “BMI paradox” in dialysis patients is the possible association of high BMI with inflammation, yet with decreased mortality.

Adipocytes are rich sources of proinflammatory cytokines such as IL-6 and TNF-F, which in turn stimulate the production of C-reactive protein (CRP) in the liver (46). It was shown in a cross-sectional study that abdominal adiposity is strongly associated with elevated CRP levels in dialysis patients (47). Further, the cross-sectional associa- tions of high BMI, abdominal adiposity, and other components of metabolic syndrome (48–50) with inflammation in stage III CKD have been demonstrated. Therefore, the current evidence suggests that in stages III and V of CKD, obesity is associated with inflammation as in the general population.

Second, high BMI might result from high muscle mass, fat mass, or both. It is pos- sible that high BMI owing to high muscle mass might be more protective than high BMI from high fat mass. In 70,028 patients initiated on hemodialysis in the United States from January 1996 to December 1998 with reported measured creatinine clearances at initiation of dialysis, BMI in conjunction with 24-h urinary creatinine excretion (an indicator of muscle mass) was used to estimate body composition, and the effects of estimated body composition on all-cause and cardiovascular mortality were examined (51). High body size was associated with better survival. However, compared with nor- mal BMI, normal or high-muscle patients, those with high BMI and low muscle mass had increased mortality, whereas those with high BMI and normal or high muscle mass had decreased mortality. These data suggest that high BMI is not uniformly associated with better survival, and body composition is important in high-BMI dialysis patients.

In another study of incident peritoneal dialysis patients, similar results were shown (52).

Third, previous studies have shown that in dialysis patients, adiposity and high BMI are associated with diabetes (53), inflammation (54), coronary calcification (55,56), and carotid atherosclerosis (57). These data raise the question that if adiposity is associated with diabetes, inflammation, coronary calcification, and atherosclerosis in dialysis patients, how is adiposity associated with better survival in dialysis patients?

We propose the following framework (Fig. 1) to integrate these seemingly contradict- ing data. In Fig. 1, dotted lines represent a negative effect, whereas the unbroken lines represent a positive effect.

When the association of high BMI with survival is examined in dialysis patients, there might actually be two issues that are examined—what is the effect of nutrition on survival, and what is the effect of adiposity on atherosclerotic events and cardiovascu- lar events? We hypothesize that the effects of nutrition on survival are much stronger than the effects of atherosclerotic events on survival in dialysis patients. Further, we also propose that the effects of nutrition on survival might differ based on body composition (muscle vs fat). Better nutrition, as evidenced by higher muscle mass, decreases the haz- ard of death from concomitant cardiovascular and noncardiovascular events, resulting in the lowest cardiovascular and noncardiovascular deaths. On the other hand, fat mass has dual effects: a negative effect on death as a result of nutrition, and a positive effect on death mediated through its association with inflammation and atherosclerosis. Thus, compared with undernutrition, adiposity decreases the hazard of death from concomi- tant disease processes but is associated with inflammation, oxidative stress, and athero- sclerotic events in dialysis patients as in the general population. In other words, adiposity confers a survival advantage over undernutrition but not compared with higher muscle mass in dialysis patients.

Further, as shown in Fig. 1, the above paradigm could also incorporate the current

theories on the association of inflammation with malnutrition, in particular, the

observed associations of inflammation with decreased muscle mass in dialysis patients

(58,59). In other words, the association of inflammation with loss of muscle mass does not contradict adipose tissue as a source of inflammation in CKD.

5. CONCLUSIONS

In summary, obesity is a risk factor for kidney damage, as evidenced by albuminuria and loss of GFR. The effects of kidney disease on the associations of adiposity with cardiovascular risk factors and cardiovascular disease remain controversial. It is possi- ble that in dialysis patients, despite the protective effect of adiposity with survival, it is still associated with insulin resistance, inflammation, and atherosclerosis. Further stud- ies will shed light on this complex area.

REFERENCES

1. Coresh J, Astor BC, Greene T, et al. Am J Kidney Dis 2003;41:1–12.

2. Hostetter TH, Lising M. J Am Soc Nephrol 2003;14:S114–S116.

3. Hoehner CM, Greenlund KJ, Rith-Najarian S, et al. J Am Soc Nephrol 2002;13:1626–1634.

4. Palaniappan L, Carnethon M, Fortmann SP. Am J Hypertens 2003;16:952–958.

5. Chen J, Muntner P, Hamm LL, et al. Ann Intern Med 2004;140:167–174.

6. Hunsicker LG, Adler S, Caggiula A, et al. Kidney Int 1997;51:1908–1919.

7. Muntner P, Coresh J, Smith JC, et al. Kidney Int 2000;58:293–301.

8. Kurella M, Lo JC, Chertow GM. J Am Soc Nephrol 2005;16:2134–2140.

9. Kasiske BL, Crosson JT. Arch Intern Med 1986;146:1105–1109.

10. Cohen AH. Am J Pathol 1975;81:117–130.

11. Adelman RD. Curr Opin Nephrol Hypertens 2002;11:331–335.

12. Chagnac A, Weinstein T, Herman M, et al. J Am Soc Nephrol 2003;14:1480–1486.

13. Hall JE, Jones DW, Kuo JJ, et al. Curr Hypertens Rep 2003;5:386–392.

14. Shimotomai T, Kakei M, Narita T, et al. Ren Fail 2005;27:323–328.

15. Hall JE, Henegar JR, Dwyer TM, et al. Adv Ren Replace Ther 2004;11:41–54.

16. Bruemmer D, Law RE. Am J Med 2003;115:87S–92S.

17. Abrass CK, Spicer D, Raugi GJ. Kidney Int 1994;46:613–620.

18. Sowers JR. Am J Physiol Heart Circ Physiol 2004;286:H1597–H1602.

19. Kreisberg JI. Proc Natl Acad Sci USA 1982;79:4190–4192.

20. Abrass CK, Raugi GJ, Gabourel LS, et al. Endocrinology 1988;123:2432–2439.

21. Unger RH, Orci L. Biochim Biophys Acta 2002;1585:202–212.

22. Unger RH. Trends Endocrinol Metab 2003;14:398–403.

23. Bagby SP. J Am Soc Nephrol 2004;15:2775–2791.

24. Unger RH. Endocrinology 2003;144:5159–5165.

25. Kamijo A, Kimura K, Sugaya T, et al. Kidney Int 2002;62:1628–1637.

26. Thomas ME, Schreiner GF. Am J Nephrol 1993;13:385–398.

27. Trayhurn P, Wood IS. Biochem Soc Trans 2005;33:1078–1081.

28. Axelsson J, Heimburger O, Lindholm B, et al. J Ren Nutr 2005;15:131–136.

29. Sharma K, Considine RV, Michael B, et al. Kidney Int 1997;51:1980–1985.

30. Cumin F, Baum HP, Levens N. Int J Obes Relat Metab Disord 1996;20:1120–1126.

31. Merabet E, Dagogo-Jack S, Coyne DW, et al. J Clin Endocrinol Metab 199782:847–850.

32. Wolf G, Hamann A, Han DC, et al. Kidney Int 1999;56:860–872.

33. Wolf G, Chen S, Han DC, et al. Am J Kidney Dis 2002;39:1–11.

34. Han DC, Isono M, Chen S, et al. Kidney Int 2001;59:1315–1323.

35. Haynes WG, Morgan DA, Walsh SA, et al. J Clin Invest 1997;100:270–278.

36. Bouloumie A, Marumo T, Lafontan M, et al. FASEB J 1999;13:1231–1238.

37. Ballermann BJ. Kidney Int 1999;56:1154–1155.

38. Vilarrasa N, Vendrell J, Maravall J, et al. Clin Endocrinol (Oxf) 2005;63:329–335.

39. Farvid MS, Ng TW, Chan DC, et al. Diabetes Obes Metab 2005;7:406–413.

40. Ouchi N, Kihara S, Funahashi T, et al. Curr Opin Lipidol 2003;14:561–566.

41. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, et al. Am J Clin Nutr 2005;81:543–554.

42. Kalantar-Zadeh K, Ikizler TA, Block G, et al. Am J Kidney Dis 2003;42:864–881.

43. Kopple JD, Zhu X, Lew NL, et al. Kidney Int 1999;56:1136–1148.

44. Leavey SF, McCullough K, Hecking E, et al.. Nephrol Dial Transplant 2001;16:2386–2394.

45. Leavey SF, Strawderman RL, Jones CA, et al. Am J Kidney Dis 1998;31:997–1006.

46. Bastard JP, Jardel C, Delattre J, et al. Circulation 1999;99:2221–2222.

47. Axelsson J, Qureshi AR, Heimburger O, et al. Am J Kidney Dis 2005;46:628–634.

48. Beddhu S, Kimmel PL, Ramkumar N, et al. Am J Kidney Dis 2005;46:577–586.

49. Menon V, Wang X, Greene T, et al. Am J Kidney Dis 2003;42:44–52.

50. Ramkumar N, Cheung AK, Pappas LM, et al. J Ren Nutr 2004;14:201–207.

51. Beddhu S, Pappas LM, Ramkumar N, et al. J Am Soc Nephrol 2003;14:2366–2372.

52. Ramkumar N, Beddhu S. Perit Dial Int, In press.

53. Beddhu S. Semin Dial 2004;17:229–232.

54. Stenvinkel P, Marchlewska A, Pecoits-Filho R. Kidney Int 2004;65:274–281.

55. Stompor T, Pasowicz M, Sullowicz W, et al. Am J Kidney Dis 2003;41:203–211.

56. Goodman WG, Goldin J, Kuizon BD, et al. N Engl J Med 2000;342:1478–1483.

57. Yamauchi T, Kuno T, Takada H, et al. Nephrol Dial Transplant 2003;18:1842–1847.

58. Kaizu Y, Ohkawa S, Odamaki M, et al. Am J Kidney Dis 2003;42:295–302.

59. Kaysen GA, Greene T, Daugirdas JT, et al. Am J Kidney Dis 2003;42:1200–1211.