Brazilian researchers investigate the link between diabetic kidney disease and cardiovascular problems

A group at the University of São Paulo has shown how metabolic alterations lead to a buildup of cholesterol in the cells of diabetic patients.

By Luciana Constantino  |  Agência FAPESP – Researchers at the University of São Paulo (USP) in Brazil have investigated how certain metabolic alterations in patients with diabetic kidney disease can favor an accumulation of cholesterol in the arteries and increase the risk of cardiovascular disorders.

The study was supported by FAPESP and is reported in an article published in the Journal of Diabetes and Its Complications.

The study involved 49 patients who had had type 2 diabetes for at least ten years and had kidney disease in different stages but had similar blood sugar levels. It showed that albumin, a protein produced by the liver, is more susceptible in these patients to carbamoylation, a spontaneous reaction that modifies albumin so as to impair the removal of cholesterol.

In people with diabetic kidney disease, albumin undergoes more intense carbamoylation, and as a result of this alteration, it impairs cholesterol removal from cells by high-density lipoprotein [HDL], often called “good cholesterol”. HDL performs the function of carrying excess cholesterol from blood vessels back to the liver by reverse transport. When this is inhibited, cholesterol accumulates in macrophages and favors atherosclerosis. 

World Kidney Day, observed every year on the second Thursday in March, is a joint initiative of the International Society of Nephrology (ISN) and the International Federation of Kidney Foundations (IFKF) to raise awareness of the importance of the kidneys to overall health and the impact of kidney disease on the world’s population and health services. About 850 million people are estimated to suffer from kidney disease with different causes – 10 million in Brazil, according to the Health Ministry. Kidney disease affects 20%-40% of diabetes patients.

According to Márcia Silva Queiroz, last author of the article, the literature shows that people with diabetes and chronic kidney disease risk hypertension and high cholesterol, and are more likely to die from cardiovascular problems, but the mechanisms underlying the connection and the build-up of fat in the arteries are poorly understood.

“It’s a jigsaw puzzle. Our study slotted in one more piece relating to the physiopathogenic mechanism, and contributes to a better understanding of the reasons for which these patients have more cardiovascular events,” said Queiroz, who at the time of the study was a professor at the University of São Paulo’s Medical School (FM-USP) and is now at UNINOVE (Universidade Nove de Julho).

The organism of a person with kidney disease retains urea and other toxic substances that the kidneys should expel in urine. Too much urea in the body modifies several proteins via carbamoylation, a problem intensified by severe kidney disease. Too much blood sugar in a diabetic modifies proteins via glycation, a similar process in which sugars bind to proteins and prevent them from functioning as they should. Glycation is responsible for many complications of diabetes.

Both carbamoylation and glycation can lead to a buildup of low-density lipoprotein (LDL, or “bad cholesterol”), while inhibiting the action of HDL and hence potentially contributing to cardiovascular problems. Atherosclerosis (hardening of the arteries due to a buildup of cholesterol and other substances) is one of the main causes of heart attack and stroke, which typically occurs when a blood clot forms on an atherosclerotic plaque in a blood vessel in the brain and blocks blood flow to that part of the brain.

Diabetics often suffer from cardiovascular disease because their organism does not produce enough insulin or cannot use it properly to control the level of blood sugar. Some 13 million people have diabetes in Brazil, or about 7% of the population, according to the Brazilian Diabetes Society.

Methodology

The 49 participants in the study, selected at Hospital das Clínicas (HC), the hospital complex run by FM-USP, gave samples of their blood after fasting for 12 hours, and these were analyzed for measurement of fructosamine, glycemia, triglycerides, total cholesterol, HDL cholesterol, creatinine and urea.

The subjects were divided into five groups according to glomerular filtration rate, the standard metric used to assess kidney function: more than 60 milliliters per minute (mL/min); 60-45 mL/min, 45-30 mL/min, 30-15 mL/min, and less than 15 mL/min, the latter being considered a sign of kidney failure. The normal range for healthy young adults is 90-100 mL/min.

“One of the reasons for this division was to find out whether having diabetes and an altered glomerular filtration rate worsened glycation or carbamoylation, and to assess the impact on reverse transport of cholesterol,” Queiroz explained.

The study, which resulted from the PhD research of endocrinologist Aécio Lopes de Araújo Lira, also used a control group comprising eight age- and gender-matched subjects without either diabetes or chronic kidney disease.

The researchers concluded that carbamoylation was greater in albumin isolated from subjects with low glomerular filtration rates, and that carbamoylated albumin impaired cholesterol removal by HDL from macrophages.

According to Marisa Passarelli, joint leader of the study alongside Queiroz, further research is under way to analyze the effects of glycation and altered glycemic control on cardiovascular complications of diabetes and diabetic kidney disease.

“Our results pointed to impairment of cellular cholesterol removal by HDL due to albumin glycation and carbamoylation,” Passarelli told Agência FAPESP. “Modified albumin causes cellular stress, preventing cholesterol removal by HDL and its transport to the liver, from where it should be eliminated from the body in bile and feces. This problem doesn’t show up in routine laboratory tests but heightens the risk of atherosclerosis.”

Passarelli is a professor at UNINOVE and co-lead of HC-FM-USP’s Lipid Laboratory. She is participating in a study of the mechanisms involved in glycemic control and chronic complications of diabetes as part of a Thematic Project funded by FAPESP.

The article “Serum albumin modified by carbamoylation impairs macrophage cholesterol efflux in diabetic kidney disease” by Aécio Lopes de Araújo Lira, Monique de Fátima Mello Santana, Raphael de Souza Pinto, Carlos André Minanni, Rodrigo Tallada Iborra, Adriana Machado Saldiba de Lima, Maria Lúcia Correa-Giannella, Marisa Passarelli and Márcia Silva Queiroz is at: www.sciencedirect.com/science/article/abs/pii/S1056872721001665?via%3Dihub.