WASHINGTON – Caloric restriction, whether through diet, bariatric surgery, or new sodium-glucose cotransporter-2 inhibitor (SGLT2) medications, could help improve measures of kidney disease in obese patients, according to a Kidney Week 2019 presentation.

As people gain weight, their metabolic rate increases, said Holly J. Kramer, MD, MPH, a professor of public health sciences and medicine in the Division of Nephrology and Hypertension at Loyola University in Chicago, during a talk on the direct and indirect effects of adiposity on the kidney. The kidneys then have to do more, and meet the increased demands by increasing the glomerular diameter so it hypertrophies, yielding an increase in glomerular filtration rate and an increase in renal plasma flow.  

As of 2017, Kramer said, most states in this country had adolescent obesity rates approaching 15%. A 2006 study¹ of individuals ages 18 to 35 indicated that those with a body-mass index (BMI) of over 35 had a 500-600% higher risk of developing ESRD compared to those with a normal BMI.

“This is really important for the future of nephrology,” she said. “The thought is, if you have [obesity] at a young age, think of the time that you’re going to be exposed to that milieu of cytokines and hemodynamic alterations of obesity that can lead to loss of kidney function over time and ESRD.”

Metabolic health differs by obesity status, Kramer said, and where people deposit fat also matters and is determined by genetics. If fat is distributed in the abdominal area, a person is at higher risk of developing diabetes and hypertension than if it is deposited in the peripheral area. Feeding during childhood is an environmental factor that can influence the number of adipocytes, she noted. Children who are overweight or obese tend to have more adipocytes compared to those who are not obese. One study of fat cell turnover² indicated that in younger age, there is a dramatic increase in the number of adipocytes up until the teen years and it then stays stable.

“Once you become an adult, you’re not able to change the number of adipocytes you have and the ability to store fat is not altered,” Kramer said. “Even if you have bariatric surgery, it’s not going to decrease the number of adipocytes.”

One method to potentially turn things around is caloric restriction, according to studies in rats and in humans, Kramer said. Studies in rats have found the process ameliorates proteinuria and glomerular sclerosis and helps salvage podocytes, cells that wrap around capillaries of the glomerulus. The Look AHEAD study³ in people demonstrated that intervention with a low-calorie diet and exercise led to a 30-40% reduced risk of developing chronic kidney disease over a five-year period. Bariatric surgery also is “a great way to reduce calories” and improve kidney outcomes, she noted.

For those who are not candidates for bariatric surgery, SGLT2 inhibitors may provide an option to mimic caloric restriction or a fasting state, Kramer said. The medications inhibit glucose reabsorption in the proximal tubule and lower glucose levels without affecting insulin, she said.

“Normally, when you think of lowering glucose levels, we’re either decreasing insulin resistance so more glucose enters the cell, or we are giving more insulin or increasing insulin secretion,” she said. “This is one of the few drugs where we are able to lower glucose without affecting insulin.”

EMPA-KIDNEY is a clinical trial testing whether taking a single pill of empagliflozin every day prevents worsening of kidney disease or deaths from heart disease in people who have chronic kidney disease, she said.

Resources

1. Hsu CY, McCulloch CE, Iribarren C, et al. Body mass index and risk for end-stage renal disease. Ann Intern Med 2006 Jan 3; 14421-8.
2. Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans. Nature 2008; 453:783-7. doi: doi: 10.1038/nature06902 . Epub 2008 May 4.
3. Reboussin et al. Lancet Diabetes and Endocrinology pages 801-809, 2014.