The coverage of obesity in the keynote address during Kidney Week last November and its focus as a keynote topic during World Kidney Day this year demonstrates an understanding among nephrologists of the importance of treatment for obesity as a preventative measure or treatment for renal disease.

The relationship between extreme obesity and kidney diseases, such as glomerulopathies, nephrolithiasis, and poor graft survival, has been known for years.1,2 The obesity-kidney disease connection has been confirmed in a number of studies, including a study of 320,252 participants enrolled in the Kaiser Permanente health system between 1964 and 1985 showing a 600% increase in end-stage renal disease in subjects with a body mass index exceeding 40 kg/m2.3

The increased prevalence of chronic kidney disease has paralleled the rise in obesity,3 which is a known risk factor for cardiovascular disease, diabetes, hypertension, hyperuricemia, and metabolic syndrome, all of which are independent risk factors for CKD.4,5

Overweight and obesity are one of the greatest global health challenges; obesity currently affects 46% of the world’s population.6 Obesity occurs in two-thirds of persons with hypertension and 90% of those with diabetes.7 Hypertension and diabetes alone account for more than 70% of CKD cases. (This does not include the numbers with metabolic syndrome and other obesity-related conditions who have neither diabetes nor hypertension.) 8 In other words, the most common underlying cause of renal disease, including CKD, nephrolithiasis, gout, and renal cell carcinoma, is potentially preventable.9,10,11,12,13

The direct risks of obesity and kidney disease

Until recently, the role of obesity in kidney disease has been assumed to be merely an indirect association of obesity as a risk factor for hypertension and diabetes, the most commonly recognized causes of renal disease.14 The failure to recognize obesity as a disease state (AMA resolution H-440-842 adopted in 2013)15 rather than a lifestyle choice associated with adverse health outcomes has obscured the understanding that obesity is not merely a risk factor, but rather a common pathway to diabetes and hypertension, and that obesity may also lead directly to kidney disease.

Adding to the confusion regarding the role of obesity in renal disease is the so-called “obesity paradox,” describing the finding that some patients with obesity and higher BMIs have a lower risk of developing ESRD, have improved survival rates with kidney disease, and better survival on dialysis.16,17

BMIs remains the “gold standard” for the diagnosis of overweight and obesity and is the justification for medical and surgical interventions (including kidney transplantation).18 BMI, however, does not differentiate between lean and fat mass, nor the anatomical distribution of fat in visceral and ectopic depots.7,19 The direct correlation between obesity and kidney disease as well as cardiovascular disease is manifest when substituting waist circumference, waist-to-hip ratio, or visceral fat mass for BMI.3,7,19,20 Understanding the role of visceral adipose tissue as a highly bioactive endocrine organ responsible for insulin resistance and pro-inflammatory cytokine (adipokine) production is critical to our understanding of obesity as the underlying mediator of obesity-related disease.21 Moreover, modification of diet in renal disease (MDRD) e-GFR calculations based on serum creatinine may underestimate the presence and prevalence of renal disease in patients with obesity. Creatinine levels correlate with muscle mass, which is often reduced in patients with obesity. The use of direct or Cystatin-C GFR calculations may be a better option for persons with obesity, since they are not influenced by muscle mass.3,7

New tools

The Obesity Algorithm (Obesity Medicine Association; www.obesityalgorithm.org), is a clinical tool developed by obesity medicine specialists for the evaluation, diagnosis, and treatment of obesity. The tool provides a better understanding of obesity and its role in kidney disease by dividing obesity into “sick fat” disease (adiposopathy) and fat mass disease.22 Sick fat is a consequence of the metabolic derangements mediated by impaired adipocytes that lead to insulin resistance and inflammation; fat mass disease represents the deleterious effects of excess fat storage and fat mass on bodily activities and function. The kidney disease-obesity paradox, as well as other paradoxical relationships between obesity and health (cardiovascular outcomes, normal weight and metabolically unhealthy, obesity and metabolically healthy, etc.), is better explained when obesity is understood as a disease of fat function and fat mass rather than BMI.22

The Obesity Algorithm defines obesity as a “chronic, relapsing, multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.”22 Visceral adipose tissue produces a number of pro-inflammatory cytokines that lead to insulin resistance, oxidative stress, inflammation, hyperinsulinemia, and impaired glucose metabolism.7 The metabolic syndrome (MetS)—defined by central adiposity, elevation of blood pressure, dysglycemia and dyslipidemia—could be considered the hallmark of sick fat disease. The odds ratio for kidney disease is 1.89 when even one criterion of MetS is present, jumping to 5.85 when of all five components of MetS are clustered in an individual. Thus, each component of MetS is an independent risk for kidney disease, including renal cell carcinoma.23,24,25

Fat mass disease is the second subcategory of obesity described in the Obesity Algorithm. Fat mass refers to conditions directly or indirectly caused by biomechanical and structural changes due to the presence of excess fat and fat mass. There is often an overlap between the sick fat and fat mass effects of obesity, since fat accumulation often triggers an adiposopathic metabolic response and vice versa. “Metabolically healthy” patients with obesity and incident renal disease tend to have a higher CRP, indicating that inflammation remains a factor in the obesity-kidney disease link.26 In experimental animals, structural changes in the kidney may be seen within a few weeks of rapid weight gain.

In patients with obesity, the larger fat mass increases metabolic needs, thereby resulting in increased renal plasma flow, hyperfiltration, and increased glomerular capillary pressure progressing to proteinuria and GFR reduction.3,23 Among patients with extreme obesity with no overt kidney disease who underwent renal biopsy prior to bariatric surgery, pathological changes consistent of early kidney disease were present.27,28,29 Ectopic perinephric fat independent of visceral adiposity or BMI increases the risk of hypertension and CKD, suggesting the role of fat mass disease via compression and structural distortion.

BMI and transplantation

An overlooked consequence of fat mass is the BMI limitation for renal transplantation in ESRD. A BMI greater than 35 kg/m2 is associated with worse post-transplantation outcomes. Delayed graft function and graft failure are associated with increased BMI. Current data do not identify BMI limits for kidney transplantation. Survival and quality of life needs to be compared against the risks of transplantation in patients with more severe obesity.30,31,32

Bariatric surgery has been shown to improve CKD in many patients and should be considered for patients who fail to respond to non-surgical interventions, patients with more severe obesity, and patients with diabetes. Each incremental stage of renal disease increases the post-operative complication rates 1.3 times; in absolute terms, the complication rate is low.17 Bariatric surgery may be a way to reduce a patient’s weight enough that it reduces transplantation risks.31

The BMI-centric approach to obesity diagnosis and treatment ignores normal-weight individuals with adiposopathic disease and often postpones early interventions that could prevent the progression to established obesity-related disease. The Obesity Algorithm presents a scenario of early versus late intervention: initiating therapy with lifestyle modalities prior to established obesity, versus waiting until obesity is well established and requires specific treatment for conditions such as hypertension, diabetes, obstructive sleep apnea, and others. If weight gain is combined with muscle loss and MetS parameters, there is a lost opportunity for potentially life-saving intervention.

Non-surgical lifestyle intervention for prevention and early-stage CKD are well supported in literature, but there is little data regarding the benefits or risks of this intervention in later-stage CKD, dialysis, and post-transplantation. Optimal nutritional recommendations for obesity prevention and treatment at various stages of kidney disease, including post-transplantation, are not established.

Summary

The current obesity epidemic is largely the result of an obesogenic environment with no shortage of unhealthy foods combined with very little reason or opportunity to exert physical energy. Eating is the response to various ever-present stimuli, which is driven by genetics, addiction, insulin resistance, or lack of sleep; even weight loss itself can increase physiological hunger.

Currently more than a billion people worldwide are affected by obesity;4 within the next decade, the prevalence of obesity is expected to grow by 40%.33 Though the prevention and treatment of obesity is complex and poorly understood by much of the medical community, evidence shows that lifestyle intervention can effectively reduce the disease in persons with obesity and prevent progression of the disease in individuals at risk. Growing evidence indicates a connection between obesity and renal disease; both diseases share many of the same risk factors, including hypertension and diabetes.

References

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