Diabetic kidney disease needs to be mitigated

Developing new therapies is essential to reducing the impact of diabetes mellitus on people affected by the disease

Innovative therapies prevent DKD from progressing to its more advanced stages, reducing the disease’s morbidity and mortality

Diabetes mellitus (DM) is a chronic noncommunicable disease that affects 10% of the world’s population. It does not discriminate by age, sex, or race.

Didactically, DM is classified as type 1 (T1DM), which has an autoimmune component, or type 2 (T2DM), which is genetically inherited and is associated with well-known risk factors, such as age, obesity, and activity level.

Diabetic kidney disease (DKD) is one of the chronic complications of DM, forming part of a spectrum of the disease’s systemic impact together with vision and circulation problems, neuropathy, and cardio-cerebrovascular events.

It is the world’s leading reason for renal replacement therapy and is diagnosed in a lab by a reduction in the rate of glomerular filtration and the presence of albuminuria, both indicators of kidney problems.

Developing therapies that prevent DKD from progressing to its most advanced stages is of utmost importance to reducing the morbidity and mortality of the disease.

The most effective of the current treatment options include nonpharmacological measures, such as adopting a healthy lifestyle, and pharmacological measures that aim to manage blood glucose, albuminuria, blood pressure, and dyslipidemia (an imbalance in blood lipid levels).

As DKD progresses, several signaling pathways are dysregulated, such as those associated with inflammation, oxidative stress, cell death, autophagy, fibrosis, and senescence, which makes treating the disease one of the biggest challenges in clinical practice today.

The pillars of pharmacological therapy for DKD include its pathophysiological bases, aiming to control metabolic, hemodynamic, and inflammatory dysfunction.

The approach includes a combination of renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and mineralocorticoid receptor antagonists.

This pharmacological and nonpharmacological therapeutic arsenal can help to substantially limit the progression of DKD and reduces other complications, particularly cardio-cerebrovascular events.

Numerically, in DKD patients who use SRAA and iSGLT2 inhibitors, glomerular filtration rate decline is reduced from approximately 10 ml/min/1.73 m² to 2-3 ml/min/1.73 m². However, the decline still occurs faster than in the general population for people over 40 years of age (~0.7-0.9 ml/min/1.73 m²).

New treatment options

New therapies are thus needed to reduce the impact of DM on various organs and to improve the quality of life of patients affected by the disease.

For T1DM, studies into the differentiation of human embryonic and pancreatic cells have established a scientific basis for more recent research involving autologous fibroblasts, reprogrammed to differentiate into insulin producing cells, with promising early results.

The therapeutic potential of cells derived from bone marrow, including hematopoietic and mesenchymal cells, has been studied in relation to their rich secretome (the set of proteins and molecules secreted from the cell surface) and their impact on the modulation of pathways dysregulated by DM.

However, analyses of the safety and efficacy of cell therapy for T1DM, especially in the long term, are still in the early stages. Another approach involves using pancreatic islets from deceased donors to restore the pool of insulin-producing cells.

Several advances have been documented, such as adaption of the number of islets, their encapsulation to mitigate the effect of the immune system, the evaluation of different infusion sites, and more.

Despite being a safe and effective form of therapy, islet transplantation requires the use of immunosuppressive drugs that can alter the functioning of the islets, as well as causing other adverse advents, such as infection or changes in kidney function.

At the same time, T1DM treatment has been largely refined with the use of effective regimens of long-acting insulin combined with fast-acting or ultra-fast-acting insulins, carbohydrate counting, and the availability of insulin pumps.

Real-time glucose monitoring has improved the safety and effectiveness of glycemic control while allowing treatment to be tailored to the individual.

Other technological innovations include weekly insulin administration and automated insulin infusion systems, also known as “artificial pancreases,” which deliver the ideal dose of insulin needed to control glucose levels.

Among T2DM patients, the effect of insulin is initially resisted, so antidiabetics are administered orally or subcutaneously. The therapeutic regimen for these patients only begins to include insulin in more advanced stages of the disease.

When it comes to cell therapy for patients with DM2, especially involving mesenchymal stem cells, there are still major challenges to overcome.

These cells can be obtained from various sources, such as bone marrow, adipose tissue, and umbilical cords, among others. However, T2DM patients are generally older than patients with T1DM and usually have multiple comorbidities when DKD is diagnosed.

As a result, the biological properties of mesenchymal stem cells may be less effective, limiting their therapeutic potential in clinical practice. Chronic hyperglycemia also leads to genetic, structural, and functional alterations in the mesenchymal stem cell niche, further restricting its therapeutic potential.

However, mesenchymal stem cells are devoid of class II HLAs (human leukocyte antigens), allowing them to be “immune privileged,” meaning they are not rejected when obtained from another healthy individual. They also do not significantly differentiate into other cell types after infusion.

Cell banks

These characteristics allow for the prospect of mesenchymal stem cell banks, which could be used to treat various diseases “off-the-shelf.”

Initial studies of these cells in patients with DKD and T2DM demonstrated safety and efficacy in preserving renal function. However, several aspects have been debated in the literature, such as the ideal number of cells and infusions, the infusion interval, and the administration route.

Guidelines standardizing how the cells are used have enabled adequate comparison between studies and regulation of safety and efficacy analyses.

Thus, infection parameters and chromosomal stability are not only analyzed, they are also characterized through immunophenotyping, differentiation, and power.

A common point for the use of cell therapy in T1DM and T2DM patients is adequate blood glucose control during cell infusion, to ensure that they maintain effective functioning.

The potential of mesenchymal stem cells can also be increased by pre-infusion conditioning, including reduced oxygen conditions (hypoxia), medication, growth factor, and gene transfection.

Using the secretome of these cells (exosomes and microvesicles) has been explored in the context of DM and DKD.

Our research group at the Albert Einstein Teaching & Research Institute is investigating the therapeutic potential of mesenchymal stem cells and medications commonly used in patients with T2DM (empagliflozin and semaglutide) based on understanding the modulation of signaling pathways for inflammation, oxidative stress, cell death, and autophagy.

We used a model of T2DM and obesity in genetically modified rodents, which present similar structural and functional renal alterations to humans, making them the ideal model for evaluating the safety and efficacy of new therapies.

A greater biological understanding of the modulation of signaling pathways that are dysregulated in T2DM and obesity, with the use of multitarget therapy, will help advance human trials in preclinical research.

This research platform thus reinforces the importance of bench-to-bedside-to-bench studies to determine the best therapeutic approach for complex and multifaceted diseases such as DM and DKD.

Érika Bevilaqua Rangel is a physician with a master’s degree and doctorate in nephrology. She is a professor on the postgraduate program at the Albert Einstein Teaching & Research Institute, where she researches stem cells and heads the Einstein Intelligence Center (NIE), created to generate clear and reliable information about COVID-19 for health professionals and the public. She is also head of the Department of Renal Physiology and Pathophysiology at the Brazilian Society of Nephrology and is an assistant professor of nephrology at the School of Medicine of the Federal University of São Paulo (UNIFESP).

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