This article on Diabetic Kidney Disease published on HealthViews India is co-authored by Hrushikesh Kulkarni, Anil Bhanudas Gaikwad – Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Vidya Vihar, Pilani, Rajasthan 333031, India.
Abstract: Diabetes is a growing epidemic affecting the global population due to a sedentary and inactive lifestyle. An alarming fact is that India is now considered the diabetes capital of the world, necessitating quick action. Amongst other microvascular complications of diabetes, diabetic kidney disease (DKD) is becoming more common worldwide. Standard treatments include blood sugar level and pressure control via different therapies; however, they don’t address the entire complex pathophysiology of DKD. Newer medications, including SGLT2 inhibitors, RAAS modulators, and GLP-1 receptor agonists, not only counter the detrimental effects of diabetes but also protect our kidneys in a multidimensional approach. Clinicians say, nonetheless, that the one-treatment strategy against DKD is insufficient; combining many therapies may produce a better effect. The article also discusses Klotho, a renoprotective protein whose levels drop in DKD patients, and how improving drug delivery techniques to administer Klotho is receiving more attention in studies. Precision medicine strategies that mix traditional medicines with creative biological treatments like Klotho supplementation hold the future of DKD therapy, maybe changing DKD from a progressive disease to one where kidney damage might be avoided or even reversed.
Keywords: Diabetes, Diabetic kidney disease, Combination therapy, Klotho, Health
Introduction: Diabetic kidney disease (DKD)
Imagine, for a routine medical checkup, you have gone to a medical facility to monitor your blood sugar levels, only to find an alarming alert of declining kidney functional parameters. Despite being diligent and adhering to all the recommended guidelines put forth by your doctor, following the controlled diet, and exercising every day, you discover that your kidneys are at an increased risk of deterioration. You might wonder, “But I’m already taking my diabetes medication. Isn’t that enough?” Unfortunately, for many people with diabetes, it often isn’t.
Diabetic kidney disease (DKD) is a grave problem globally and requires utmost attention. The number of patients with DKD is steadily increasing, and various standard drug therapies are utilized to address this issue. For decades, the standard approach to treating DKD has been controlling blood sugar and blood pressure, mainly using RAAS inhibitors (ACE inhibitors and ARBs) 1. On the other hand, the good news is that fewer people with diabetes are developing chronic kidney disease (CKD) thanks to better diabetes care. Research shows that 34.4% of people in India have DKD. Additionally, a multi-centre study found that 62.3% of people with diabetes have diabetic CKD 2.
“Numerous patients are shocked to learn that their kidneys are damaged in spite of good control over their hyperglycemia,” says Dr Maya Patel, a senior nephrologist. “It’s important to understand that diabetes damages kidneys through multiple pathways, which is why we now focus on combination approaches rather than single medications.”
When it comes to therapy, patients with diabetes are told to follow multiple instructions like a strict diet, drinking a lot of fluids, exercising, and administering a plethora of drugs.
Hyperglycemia, or increased blood glucose level, is just the beginning – it clears the path for more macro- and micro-vascular complications. Different pathomechanisms like inflammation, oxidative stress, apoptosis, and fibrosis add fuel to the flames 3. Here’s where the combination approach comes into the picture. In this article, we’ll explore how combination therapy, including emerging Klotho treatment, is changing the way we approach DKD management—giving hope to millions at risk of kidney disease.
A Chain of Chaos – Diabetes and Kidney Diseases
Measuring blood sugar makes DKD detection seem simple; however, it’s a quiet, slow process that usually escapes patient attention. But the question arises, how does diabetes impact the kidneys in actuality? To understand this, scientists have explored numerous pathways involving a linkage between high blood sugar, inflammation and kidney function.
The kidneys are responsible for the filtration and the elimination of metabolic wastes, excess fluids from the blood, etc. Simultaneously, they also retain essential nutrients, including glucose, from excreted urine. However, in people with diabetes, persistently high blood sugar levels cause structural and functional damage to these nephrons, leading to gradual kidney deterioration 4. Because too much glucose in the blood causes the kidneys to work harder, glomerular hyperfiltration, a condition in which the glomeruli become hyperactive, increases urine output and eventually destroys these filtering structures 5. In the long term, elevated blood glucose levels lead to oxidative stress and inflammation, which increase renal fibrosis, or kidney scarring. This results in a steady decline in kidney function over time 6.
“I had diabetes for the past fifteen years, and I thought that I’m managing it well,” shares a 55-year-old government employee. “I never realized that my kidneys were slowly being damaged, until my doctor, during a routine check-up, found protein as well as glucose in my urine,” he adds.
Currently, in clinical setups, doctors have prescribed blood sugar control and blood pressure management to slow DKD progression. Regardless of these efforts, countless patients still are diagnosed with kidney disorders 7. The reason? Because DKD is not just about hyperglycemia – it also involves a complex interplay of different mechanisms such as inflammation, oxidative stress, fibrosis, and declining levels of protective molecules like α-Klotho, and there is currently not a single therapy available to counter this. Therefore, nowadays, a combination approach has proven to be more reliable.
Let us imagine our kidneys as a “fortress” with constant attacks in the form of oxidative stress (reactive oxygen species, ROS), hyperglycemia, hypertension, and fibrosis, among others, that are slowly damaging the fortress. Traditional treatments like blood sugar and blood pressure control are like reinforcing the front gates, but the walls are still vulnerable. Here’s where the combinatorial approach comes into the picture 8. For example, along with blood pressure and sugar control, SGLT2 Inhibitors (e.g., Empagliflozin, Dapagliflozin) and GLP-1 Receptor Agonists (e.g., Semaglutide, Liraglutide), aid in combating DKD by reducing the stress on the kidneys. Similarly, combining the Renin-angiotensin-aldosterone system (RAAS) inhibitors (ACE Inhibitors & ARBs) (e.g., Lisinopril, Losartan) helps in strengthening the structural weakening of blood vessels in the kidneys 9.
“The combination of an SGLT2 inhibitor with standard therapy reduced kidney disease progression by nearly 40% in our patients,” notes Dr. Kiran Shah, senior endocrinologist at City Hospital. “But even with these advances, we’re still looking for ways to actually restore kidney function, not just slow its decline.”
In addition to all this, one must also remember that combination treatments can have side effects. SGLT2 inhibitors might lead to diabetic ketoacidosis and genital infections in rare cases 10. When starting GLP-1 receptor agonists, many people experience nausea. RAAS inhibitors can cause a dry cough and higher potassium levels in some individuals 11.
Apart from combining drugs, scientists are today focussing on developing newer methodologies to increase the concentration of nephroprotective proteins inside the body. One such protein is the anti-ageing, transmembrane protein, known as Klotho. Klotho is a unique protein that is present in your body in two primary forms: one that is circulating in your bloodstream and the other that is affixed to cell surfaces. Different forms known as α-Klotho, β-Klotho, and γ-Klotho are released when certain enzymes (ADAM 10 and 17) cleave the connected form 12. Each kind has distinct functions and is present in various organs. Klotho was initially identified by scientists as a protein that aids in anti-ageing. According to more recent studies, one type (α-Klotho) may be particularly helpful in the diagnosis and treatment of renal disorders 13. In DKD, Klotho levels decline significantly, leading to worsening inflammation, fibrosis, and oxidative stress 14.
Klotho has many important functions in your body:
- Helps regulate vitamin D
- Maintains proper phosphate levels
- Supports mineral balance
- Reduces inflammation
- Protects against oxidative damage
- Prevents cell death
- Slows ageing processes.
These properties make Klotho an important target for treating DKD 13. With the addition of emerging therapies like Klotho supplementation, we may be moving toward a more effective strategy for preventing kidney failure in diabetes, as proved by Gaikwad, A. B., et al 15. Therefore, combining Klotho with current therapies can be an effective approach to treating DKD patients in the clinical setup (Figure 1).
Practical Advice for Patients
If you have diabetes, here are steps you can take now to protect your kidneys while research advances:
- Get regular kidney function tests: Ask your doctor for urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) tests at least once a year.
- Discuss newer medications: If you have diabetes and signs of kidney disease, ask your healthcare provider if SGLT2 inhibitors or GLP-1 receptor agonists might be appropriate for you.
- Maintain tight control of both blood sugar and blood pressure.
- Reduce sodium intake to help control blood pressure and reduce kidney strain.
- Stay informed about clinical trials: If you have advancing kidney disease, ask about participating in clinical trials testing new therapies, including Klotho-based treatments 16.
Also Read: What Is Chronic Kidney Disease? Causes, Symptoms & Treatment
Conclusion and Future Perspectives
The way we treat DKD is evolving, with doctors increasingly focused on medicines that work together to target numerous issues at once. Current drugs such as SGLT2 inhibitors, GLP-1 receptor agonists, and RAAS inhibitors assist slow down kidney damage, but they don’t treat all the underlying problems causing the condition. Adding the protein Klotho as a therapy is one interesting new idea.
People with DKD have lower amounts of this protective protein. Klotho regulates kidney metabolism, scarring, oxidative stress (cell damage), and inflammation. Adding Klotho to the body might do more than simply halt kidney deterioration; it might really assist restore kidney function by enhancing the natural defences of the kidney cells. Used in conjunction with current drugs, Klotho might be a booster that lowers cell damage even more, enhances the body’s insulin response, and stops kidney scarring. Before Klotho becomes a regular therapy, researchers need to tackle several difficulties. It breaks down swiftly in the body. It’s tough to distribute to the kidneys. More large-scale human investigations are needed.
The future of treating DKD will likely incorporate individualised therapy and regenerative techniques that address multiple facets of the illness at once. By combining current meds with novel therapies like Klotho, physicians aim to not just halt kidney disease but perhaps reverse it. As research progresses, these combination therapies might become the new norm, giving improved results for those with diabetic kidney disease.
Figure 1: Combination approach for DKD
Acknowledgements
A.B.G sincerely acknowledges the Anusandhan National Research Foundation (ANRF) – Core Research Grant (CRG), Department of Science and Technology, Government of India [CRG/2023/000338] for their financial support.
This article on Diabetic Kidney Disease published on HealthViews India is co-authored by Hrushikesh Kulkarni, Anil Bhanudas Gaikwad – Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Vidya Vihar, Pilani, Rajasthan 333031, India. Phone: +91 1596 255814, Fax: +91 1596 244183, Email ID: [email protected]
References
1. Correa-Rotter R, Maple-Brown LJ, Sahay R, et al. New and emerging therapies for diabetic kidney disease. Nature Reviews Nephrology. 2024;20(3):156-160.
2. Verma M, Das M, Sharma P, et al. Epidemiology of overweight and obesity in Indian adults – A secondary data analysis of the National Family Health Surveys. Diabetes Metab Syndr. 2021;15(4):102166.
3. Tuttle KR, Agarwal R, Alpers CE, et al. Molecular mechanisms and therapeutic targets for diabetic kidney disease. Kidney international. 2022;102(2):248-260.
4. Młynarska E, Buławska D, Czarnik W, et al. Novel insights into diabetic kidney disease. International journal of molecular sciences. 2024;25(18):10222.
5. Efiong EE, Bazireh H, Fuchs M, et al. Crosstalk of Hyperglycaemia and Cellular Mechanisms in the Pathogenesis of Diabetic Kidney Disease. International Journal of Molecular Sciences. 2024;25(20):10882.
6. Bell DS, Jerkins T. The potential for improved outcomes in the prevention and therapy of diabetic kidney disease through ‘stacking’of drugs from different classes. Diabetes, Obesity and Metabolism. 2024;26(6):2046-2053.
7. Zhang R, Wang Q, Li Y, et al. A new perspective on proteinuria and drug therapy for diabetic kidney disease. Frontiers in Pharmacology. 2024;15:1349022.
8. Neuen BL, Yeung EK, Rangaswami J, et al. Combination therapy as a new standard of care in diabetic and non-diabetic chronic kidney disease. Nephrology Dialysis Transplantation. 2025;40(Supplement_1):i59-i69.
9. van Raalte DH, Bjornstad P, Cherney DZ, et al. Combination therapy for kidney disease in people with diabetes mellitus. Nature Reviews Nephrology. 2024;20(7):433-446.
10. Gajewska A, Wasiak J, Sapeda N, et al. SGLT2 inhibitors in kidney diseases—a narrative review. International Journal of Molecular Sciences. 2024;25(9):4959.
11. Zhao M, Cao Y, Ma L. New insights in the treatment of DKD: recent advances and future prospects. BMC nephrology. 2025;26:72.
12. Kale A, Sankrityayan H, Anders H-J, et al. Klotho in kidney diseases: a crosstalk between the renin–angiotensin system and endoplasmic reticulum stress. Nephrology Dialysis Transplantation. 2023;38(4):819-825.
13. Hajare AD, Dagar N, Gaikwad AB. Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases. Molecular Biomedicine. 2025;6(1):19.
14. Ruiz-Andres O, Sanchez-Niño MD, Moreno JA, et al. Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms. American Journal of Physiology-Renal Physiology. 2016;311(6):F1329-F1340.
15. Gaikwad AB, Hajare AD, Kulkarni H, et al. Combination of α-Klotho and telmisartan attenuates diabetic kidney disease via mitigating EMT, inflammation and apoptosis. Biochemical and Biophysical Research Communications. 2025;760:151711.
16. Pesce F, Vadalà M, Almeida E, et al. International Nephrology Masterclass in Chronic Kidney Disease: Rationale, Summary, and Future Perspectives. Life. 2024;14(12):1668.
