Kidney Damage in Metabolic Syndrome: Nip It in the Bud

Obesity currently is a worldwide epidemic. It has become the sixth most important risk factor contributing to the overall burden of chronic disease worldwide,1 and foreshadowing events to come, obesity increasingly is observed in children.2 Obesity is closely associated with (although not identical to) metabolic syndrome, which is defined as a cluster of risk factors that increases cardiovascular risk and often is linked to obesity. This issue of the American Journal of Kidney Diseases contains a study by Alexander et al3 of the manifestations of kidney damage in patients with metabolic syndrome. To place this issue in context, it is useful to review the history of how metabolic syndrome was defined and how obesity was recognized as a kidney disease risk factor.

The clustering of risk factors with obesity was observed decades ago,4 but the concept that this cluster is related to insulin resistance (syndrome X) dates to the Banting lecture delivered to the American Diabetes Association by Gerald Reaven5 in 1988. Recently, there has been animated discussion about the very concept of metabolic syndrome, a model developed by the National Cholesterol Education Program Adult Treatment Panel.6, 7 It is of note that Dr Reaven, considered the father of syndrome X, wrote an article in 2005 titled “The Metabolic Syndrome: Requiescat in Pace [rest in peace],”8 in which he argued that the value of insulin resistance is that it provides the conceptual framework to understand pathophysiological characteristics, whereas in contrast, metabolic syndrome is a diagnostic category to identify individuals (defined by satisfying 3 of the 5 arbitrarily chosen criteria) to motivate these high-risk individuals to initiate lifestyle changes. This critique was extended further in joint statements by the American Diabetes Association and European Association for the Study of Diabetes,9 which correctly noted that: (1) there had been no clear basis for including or excluding specific cardiovascular risk factors to define metabolic syndrome, (2) the rationale to select risk-factor thresholds was not well defined, and (3) the cardiovascular risk associated with metabolic syndrome is no greater than the sum of its parts. Although these arguments undoubtedly are valid, the concept of metabolic syndrome remains popular. This popularity is justified, as argued by Grundy,10 because metabolic syndrome was designed as a counseling tool with the intention to promote public awareness; often the price one has to pay for improved awareness may be reliance on a less than optimal predictor of cardiovascular disease or diabetes and continued use of a suboptimal instrument for resolving scientific issues.

Recently, it has been recognized that obesity is not only a cardiovascular risk factor, but also a major risk factor for kidney failure.11, 12 A series of animal experiments in dogs given a high-fat diet provided valuable insights into some of the underlying pathogenic mechanisms of obesity-related kidney disease.13, 14 The dog model documents blood pressure increase as a result of increased renal tubular reabsorption of sodium and a shift of the pressure natriuresis relationship, as well as activation of pressure systems (mainly the sympathetic nervous system and renin-angiotensin system), hyperinsulinemia, and compression of the kidney as a result of visceral adiposity. The final common pathway involves preglomerular vasodilatation with resultant glomerular hypertrophy and hyperfiltration. This hyperfiltration ultimately results in glomerulosclerosis.15 Importantly, this sequence certainly is accentuated and aggravated by coexisting hypertension, which is common in patients with obesity.16

At first glance, it may appear paradoxical that hyperinsulinemia should be related to kidney damage in individuals with insulin resistance because these individuals fail to respond properly to insulin signaling. The explanation is that insulin resistance is demonstrable only in muscle, adipose tissue, liver, and so on, but is not demonstrable in the kidney17 or central nervous system.18 Furthermore, aldosterone has a key role. Plasma aldosterone levels increase in patients with metabolic syndrome and increased body weight.19 In an animal model of metabolic syndrome (SHR/N-cp [spontaneously hypertensive/National Institutes of Health-corpulent], a spontaneously hypertensive obese rat that serves as a model of type 2 diabetes), aldosterone was shown to have a role in the genesis of podocyte injury and proteinuria by increasing oxidative stress.20 A causal role of aldosterone is suggested by the efficacy of aldosterone receptor blockade in this model. It therefore is of interest that visceral adipocytes of obese animals and humans produce factors other than angiotensin II and adrenocorticotropic hormone (ACTH), presumably including polyunsaturated oxidized fatty acids21 that stimulate aldosterone production in the adrenal gland22 and sensitize the adrenal gland against angiotensin II.23

One of the common findings in patients with metabolic syndrome is microalbuminuria. There is ongoing discussion about whether microalbuminuria, including microalbuminuria in obesity and more specifically in visceral obesity,24, 25 reflects specific glomerular damage or is the marker of generalized endothelial cell malfunction. In view of the known podocyte/endothelial cell interaction, presumably both explanations are correct.

In metabolic syndrome, one tantalizing issue is the relationship of insulin resistance with hyperglycemia and renal manifestations. This issue can be placed into context by recalling case reports that described both diffuse26 and nodular27 diabetic “glomerulosclerosis” in individuals with impaired glucose tolerance, but without overt diabetes at the time of biopsy. Although it is difficult to absolutely exclude that kidney damage had occurred during earlier transient episodes of manifest diabetes type 2, these reports raise the possibility that, at least in a certain proportion of obese patients with metabolic syndrome, the onset of glomerular lesions and even “diabetic glomerulosclerosis” may occur at plasma glucose concentrations less than those in the current definition of type 2 diabetes.

Weisinger et al28 provided the first description of focal segmental glomerulosclerosis as a specific renal complication of morbid obesity. This observation has now been confirmed in many studies. The series documented by Kambham et al29 describes a progressive increase in the frequency of the diagnosis obesity-related focal segmental glomerulosclerosis noted in autopsy specimens during 1996 to 2000 compared with 1986 to 1990. It is difficult to directly prove causality, but indirect evidence has become available recently. For example, after weight loss induced by bariatric surgery, markers of kidney damage, including albuminuria and proteinuria, as well as kidney function, have improved in multiple case reports.30, 31 Impressively, this has even been documented in children.32 However, to date, histological evidence is lacking.

In a report by Chen et al,33 patients with obesity-related glomerulopathy had larger glomeruli, reduced numerical density of podocytes per glomerulus, a greater proportion of glomeruli with glomerulosclerosis and segmental sclerosis, and increased foot-process width compared with healthy controls. Notably, in an expansion of this study, more severe obesity was associated with increased foot-process width.34 Even in the absence of clinical manifestations, glomerular geometry is not normal in obese individuals. In moderately obese live kidney donors, Rea et al35 found that glomeruli in obese individuals were larger and had a greater glomerular planar surface area. More recently, glomerular pathological states were reported in morbidly obese patients with normal kidney function and normal fasting serum glucose levels less than 126 mg/dL undergoing bariatric surgery.36 These patients had glomerulomegaly, increased mesangial matrix, mesangial cell proliferation, and podocyte hypertrophy. Body mass index was a significant independent risk factor associated with glomerular lesions. Classic findings consistent with obesity-related focal segmental glomerulosclerosis were present in only a minority. Of note, the investigators emphasized the absence of interstitial and vascular lesions.

The present study by Alexander et al evaluates a series of patients undergoing unilateral nephrectomy for renal cell carcinoma; in the 12 individuals who fulfilled criteria defining metabolic syndrome, obesity was less pronounced than in the cited studies.34, 35, 36, 37 Notably, there is no indication that patients with metabolic syndrome had been more obese before nephrectomy or had lost weight because of cancer. An important strength of this study is that kidney samples of substantial size were available and evaluated in an unbiased and independent fashion by 2 renowned nephropathologists. Information about components of metabolic syndrome was available to the study investigators, and these investigators were able to match patients with metabolic syndrome to similar controls, consisting of patients without metabolic syndrome also undergoing nephrectomy for renal cell carcinoma. The study has obvious limitations: kidney function was defined by estimated glomerular filtration rate, which could be inaccurate in patients with cancer and those with estimated glomerular filtration rate greater than 60 mL/min/1.73 m2; information for baseline albuminuria was unavailable; and patients with metabolic syndrome had relatively high fasting glucose levels (136 ± 23 mg/dl), exceeding the definition of type 2 diabetes.

Findings in the present study differ remarkably from past reports. In the present study, glomerular volumes and cross-sectional surfaces did not differ between patients with and without metabolic syndrome. However, what is striking and very interesting is the high prevalence of tubular atrophy and interstitial fibrosis, as well as the presence of significant arterial sclerosis. In the absence of information about proteinuria and albuminuria, it is difficult to exclude proteinuria as a causal factor, although relatively prominent tubulointerstitial changes certainly point to additional pathogenic mechanisms beyond solely glomerular hypertension and hemodynamic abnormalities suggested by animal experiments.13 With respect to vascular changes, one may ask whether this reflects the high frequency of hypertension, illustrated by the high frequency of antihypertensive therapy in this population, or whether this is a specific result of metabolic syndrome. This question cannot be resolved definitely by the present study, which, like all good studies, raises more questions than it answers. Specifically, whether a potential underlying pathogenic mechanism (one of many) could involve increased plasma aldosterone levels19 with subsequent aldosterone-mediated target-organ damage, as seen in animal experiments,37 is unknown and is a task for future investigations.

Why is it important to know the earliest manifestations of kidney damage in patients with metabolic syndrome and the relationship of the clustering of cardiovascular risk factors on morphological characteristics of the kidney before clinically manifest abnormalities have supervened? By the time clinical signs pointing to kidney involvement are found, specifically proteinuria and reduced glomerular filtration rate, the horse has already left the barn (although there is some recent evidence of reversibility).30, 31, 32 It therefore is important to look at the very earliest changes, as done in the present study, to better understand the underlying pathophysiological state and devise targeted interventions. Although pathologists may disagree, morphological examination by necessity just scratches the surface of the problem and the real challenge remains to identify the underlying pathogenic mechanisms causing the kidney pathological states. Only then will we be able to nip obesity-related kidney disease in the bud.