Salama, Alan D. MBBS, PhD
Rates of obesity are on the rise in the United States, and we are fast catching up in Europe, with recent estimates in the United Kingdom of one in four adults and one in six children (age 2-15) being considered obese (body mass index [BMI] greater than 30 kg/m2).1 Projections suggest that by next year, one in three UK adults will be obese, a rate equal to those in the United States.
Alan D. Salama, MBBS...Image Tools
Obesity is associated with a number of chronic diseases, such as cardiovascular disease, diabetes, hypertension, and certain malignancies. Recent estimates suggest that obesity accounts for just under 7% of all deaths in the United Kingdom.
As a direct link between obesity and kidney disease is increasingly appreciated, obesity is becoming an issue with which all nephrologists have to familiarize themselves. Management of the condition will, in some cases, need to be spearheaded by nephrologists attempting to lessen the burden of chronic kidney disease (CKD) and slow rates of progression to end-stage kidney disease (ESKD).
While obesity can indirectly influence kidney disease by increasing rates of diabetes and hypertension—known risk factors for kidney disease—a more direct role has also been proposed, with obesity representing an independent risk factor for CKD.
In the Framingham Offspring Study, obesity was associated with a 23% increase in CKD rates.2 In another cohort study, a 3.1 odds ratio for developing end-stage kidney disease was found in long-term follow-up of patients with a body mass index greater than 30—a risk that was almost as great as that associated with moderate degrees of dipstick proteinuria.3
More recently, a specific form of obesity-associated glomerulopathy, glomerulomegaly with or without a form of focal and segmental glomerulosclerosis, has been proposed.4,5 It is caused by a number of obesity-related changes, including anatomical abormalities (increased kidney size, as well as mesangial and podocyte abnormalities), hemodynamic alterations (hyperfiltration, hypertension), and inflammatory changes (with alterations in adipokines).
This condition had increased tenfold from the late 1980s to late 1990s and is increasingly being recognized by pathologists, as histologic changes appear to precede the clinical onset of microalbuminuria.6
Role of Bariatric Surgery
Understanding the impact of obesity on the kidney has significant implications for patient management. Our current strategies for preventing CKD progression rely on treating blood pressure and minimizing proteinuria, most often through the use of renin-angiotensin pathway blockers.
However, data from small case series and case reports suggest that both nonsurgical and surgical treatment of obesity can significantly reduce proteinuria in patients with and without CKD,7 and renal impairment may stabilize or improve following significant weight reduction.
The reasons behind these improvements are multifactorial, and they include reduction in hyperfiltration, suppression of proinflammatory cytokines such as interleukin (IL)-6, and alterations in adipokines such as leptin and adiponectin, which can have direct effects on podocytes.
Since successful bariatric surgery can lead to reductions in hypertension, glycated hemoglobin, and glomerular hyperfiltration, surgical obesity treatment is most appealing for obese diabetic patients with renal impairment.
However, surgery can lead to complications—most significantly, the development of acute kidney injury, which was reported in 8.5% of patients in one case series and was more common in those taking concurrent angiotensin receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor than those who were not.8
Others have reported increased incidence of nephrolithiasis and rhabdomyolysis in patients undergoing bariatric surgery.7,9 Interestingly, obesity itself is associated with calcium oxalate and urate stones.
Effects of Fructose
Recent data suggests that a link connecting obesity, hyperuricemia, and renal impairment may be the increased ingestion of fructose, a monosaccharide found in sucrose and high-fructose corn syrup that is increasingly being used in various foods and beverages. Interesting epidemiologic data demonstrate that the increased production and use of high-fructose corn syrup in the United States parallels the rise in obesity.
Administration of fructose (in the same quantity as found in two cans of soft drink) leads to elevated blood pressure, while a more sustained intake can lead to hypertension and increased uric acid levels, which is inhibited by treatment with allopurinol.
Conversely, some studies suggest that administration of a low-fructose diet decreases blood pressure and, in some cases, uric acid levels in obese subjects.10 In addition, increased fructose intake can induce the metabolic syndrome in both humans and rodents, while high doses of fructose can augment proteinuria and accelerate renal dysfunction and glomerulosclerosis in an experimental model of CKD.10
Using a questionnaire-based approach to investigate the effects of drinking fructose-containing soft drinks on renal function, investigators found that drinking more than one can of soft drink per day was associated with an increased prevalence of hyperuricemia and impaired renal function, but these findings were not reproduced in a longitudinal study where subjects were followed for up to nine years.11
The debate about the relative importance of fructose intake in hypertension, hyperuricemia, and kidney disease therefore continues, and there are a number of ongoing trials examining the effect of uric acid levels on CKD, ESKD development, and cardiovascular morbidity.
What is required is a well-planned intervention study to clearly define what effect reducing fructose intake or uric acid levels has on CKD progression. Of course, if reducing either is found to alter the rate of CKD decline, then, like the recent addition of bicarbonate,12 we could have another potential intervention beyond renin-angiotensin system blockade to provide to our CKD patient cohorts.
Furthermore, the prospective investigation of bariatric surgery on renal endpoints is an area of active research, with 17 open studies recorded on ClinicalTrials.gov. These studies are examining the impact of bariatric surgery on direct renal endpoints (CKD progression) or indirect parameters (insulin resistance, diabetes).
There is no doubt that obesity and obesity-related glomerulopathy will influence most nephrologists' practice in the future, and we need to know how to manage these problems optimally so that we can best serve our patients.
While at this time bariatric surgery is mostly reserved for morbidly obese subjects, more intensive weight-loss strategies, including surgery, may be needed for our renal patients with less-severe forms of obesity.
Ideally, prevention of the rising obesity epidemic would be the best and most direct option to deal with not only kidney-related morbidity but cardiovascular and diabetic complications. This is now becoming a global issue that has to be tackled at governmental and societal levels, but, until that goal is achieved, nephrologists should familiarize themselves with how best to recognize and manage obesity-related kidney disease.
Fox CS, Larson MG, Leip EP, Culleton B, Wilson PW, Levy D. Predictors of new-onset kidney disease in a community-based population. JAMA
Hsu CY, Iribarren C, McCulloch CE, Darbinian J, Go AS. Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med
Kambham N, Markowitz GS, Valeri AM, Lin J, D'Agati VD. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int
Ritz E, Koleganova N, Piecha G. Is there an obesity-metabolic syndrome-related glomerulopathy? Curr Opin Nephrol Hypertens
Goumenos DS, Kawar B, El Nahas M, et al. Early histological changes in the kidney of people with morbid obesity. Nephrol Dial Transplantation 2009;24:3732–3738.
Currie A, Chetwood A, Ahmed AR. Bariatric surgery and renal function. Obes Surg
Thakar CV, Kharat V, Blanck S, Leonard AC. Acute kidney injury after gastric bypass surgery. Clin J Am Soc Nephrol 2007;2:426–430.
de Freitas Carvalho DA, Valezi AC, de Brito EM, de Souza JC, Masson AC, Matsuo T. Rhabdomyolysis after bariatric surgery. Obes Surg
Johnson RJ, Sanchez-Lozada LG, Nakagawa T. The effect of fructose on renal biology and disease. J Am Soc Nephrol
Bomback AS, Derebail VK, Shoham DA, et al. Sugar-sweetened soda consumption, hyperuricemia, and kidney disease. Kidney Int
de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol
© 2011 Lippincott Williams & Wilkins, Inc.