By skyforbes 
Diabetic nephropathy is a serious kidney disease caused by long-term diabetes. Persistently high blood sugar and high blood pressure damage the tiny blood vessels in the kidneys. This leads to protein loss in urine (albuminuria), reduced kidney function (eGFR), and, in severe cases, kidney failure. It is one of the most common causes of chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Early diagnosis and treatment can slow its progression and protect kidney function.
How Does Diabetic Nephropathy Develop?
Diabetic nephropathy worsens over time, usually in stages. The main causes are high blood sugar, increased pressure in kidney filters, inflammation, and scarring. These changes weaken kidney function and, if untreated, lead to kidney failure.
1. Early Stage: Overworked Kidneys (Glomerular Hyperfiltration)
In the early years of diabetes, the kidneys work harder than normal to filter extra glucose from the blood. This overactivity, called glomerular hyperfiltration, increases blood flow and pressure inside the kidney’s filtering units (glomeruli). While this may seem helpful at first, it stresses and weakens the tiny blood vessels over time.
At this stage, kidney function still appears normal in tests, and there are no symptoms. However, the constant strain on the kidneys sets the stage for long-term damage, especially if blood sugar and blood pressure remain uncontrolled.
2. Silent Damage: Inflammation and Early Protein Loss
As diabetes continues, high blood sugar damages the lining of blood vessels, making them stiff and inflamed. This process, called endothelial dysfunction, raises blood pressure inside the kidneys and reduces their ability to filter blood properly.
At the same time, excess sugar triggers the formation of harmful molecules called advanced glycation end-products (AGEs), which increase inflammation and oxidative stress. The kidneys respond by releasing inflammatory chemicals that attract immune cells, worsening the damage.
At this stage, tiny amounts of albumin start leaking into the urine (microalbuminuria), an early sign of kidney disease. However, kidney function still seems stable (as measured by eGFR), and symptoms are usually absent.
3. Worsening Damage: Protein Loss and Scarring
As kidney injury continues, the filtering barrier weakens, allowing larger proteins like albumin to leak into the urine at higher levels (proteinuria). This signals that the disease is advancing.
At the same time, the kidneys start developing scar tissue (fibrosis). Inflammation triggers excess collagen production, making kidney tissue thicker and stiffer. Over time, this hardens the glomeruli, reducing their ability to filter waste properly. Waste products like urea and creatinine begin to build up in the blood.
At this stage, patients may start noticing swelling in the legs (edema), high blood pressure, and foamy urine due to protein loss. Blood tests show a declining estimated glomerular filtration rate (eGFR), meaning kidney function is getting worse.
4. Advanced Kidney Disease: Waste and Fluid Build-Up
As kidney function declines, the body struggles to remove excess fluid and waste. Sodium and water build up, leading to worsening high blood pressure and swelling. The kidneys also lose their ability to balance acids and minerals, causing metabolic acidosis, a condition where excess acid builds up in the blood.
Potassium levels may rise dangerously (hyperkalemia), increasing the risk of irregular heartbeats and cardiac arrest. Other problems, such as anemia and bone disease, occur because the kidneys no longer make enough erythropoietin (a hormone that helps produce red blood cells) or process vitamin D properly.
At this stage, eGFR falls below 30 mL/min/1.73m², meaning kidney disease is advanced (CKD stage 4-5). Symptoms become more severe, including fatigue, nausea, and trouble breathing.
5. End-Stage Kidney Disease (ESKD): Kidney Function Below 15%
In the final stage, the kidneys can no longer filter blood properly. Toxins build up in the body (uremia), causing confusion, nausea, loss of appetite, and extreme fatigue. Fluid retention worsens, leading to severe swelling and shortness of breath. Blood pressure becomes harder to control.
At this stage, patients need dialysis or a kidney transplant to survive. Dialysis removes waste and excess fluid from the blood but does not restore kidney function. A kidney transplant is a more permanent solution but requires a donor.
Key Medications for Diabetic Nephropathy
1. ACE Inhibitors and ARBs
ACE inhibitors (lisinopril, enalapril) and ARBs (losartan, valsartan) are first-line treatments for diabetic nephropathy. They lower blood pressure, reduce protein loss in urine, and relieve pressure on the kidneys by relaxing blood vessels and reducing strain on the glomeruli. These medications help slow kidney function decline and are used even in patients with normal blood pressure if proteinuria is present.
Both classes work by blocking the renin-angiotensin-aldosterone system (RAAS), a hormone system that regulates blood pressure and fluid balance. By inhibiting or blocking angiotensin II, a hormone that narrows blood vessels and raises blood pressure, ACE inhibitors and ARBs help the blood vessels relax. This reduces glomerular hypertension, a key driver of kidney damage in diabetes.
2. SGLT2 Inhibitors
SGLT2 inhibitors, such as empagliflozin and dapagliflozin, lower blood sugar by increasing glucose excretion in urine. More importantly, they reduce high pressure in the kidney’s filters, which helps protect kidney function. They lower albuminuria, slow kidney disease progression, and reduce inflammation.
Beyond kidney protection, these medications lower blood pressure, reduce fluid overload, and decrease the risk of heart failure. Their heart and kidney benefits make them an essential part of treatment, even in people without severe hyperglycemia.
3. GLP-1 Receptor Agonists
GLP-1 receptor agonists, such as semaglutide and liraglutide, lower blood sugar, reduce inflammation, and promote weight loss—all of which help slow kidney disease. Since insulin resistance is a major cause of diabetic kidney disease, weight loss helps reduce stress on the kidneys.
Early studies show that tirzepatide, a dual GLP-1 and GIP receptor agonist, may offer even greater benefits. It provides tighter blood sugar control and leads to greater weight loss than other GLP-1 receptor agonists. This may further reduce insulin resistance and kidney strain, though more research is needed.
4. Finerenone
Finerenone (branded as Kerendia) is a non-steroidal mineralocorticoid receptor antagonist that helps reduce inflammation and scarring in the kidneys. Unlike ACE inhibitors and ARBs, which mainly lower blood pressure, finerenone targets fibrosis and sodium retention, slowing kidney disease progression.
Studies show that finerenone reduces albuminuria and protects kidney function, especially in patients who still have proteinuria despite being on ACE inhibitors or ARBs. It also lowers cardiovascular risk, making it a valuable option for high-risk patients. Since it does not lower blood pressure much, it is useful for people needing extra kidney protection without major blood pressure changes.
5. Spironolactone
Spironolactone is a steroidal mineralocorticoid receptor antagonist that helps reduce protein loss and protect kidney function in patients with diabetic nephropathy. Like finerenone, it blocks aldosterone, a hormone that promotes inflammation, fibrosis, and sodium retention in the kidneys.
Although effective at lowering albuminuria, spironolactone carries a higher risk of hyperkalemia (high potassium levels) compared to finerenone. This makes it less ideal for patients with advanced kidney disease or those at high risk for potassium buildup. However, in selected patients with diabetic kidney disease and resistant hypertension, spironolactone can provide additional kidney and cardiovascular protection when used carefully.
The Takeaway
Diabetic nephropathy is a serious but preventable complication of diabetes. Early treatment with ACE inhibitors, ARBs, SGLT2 inhibitors, and GLP-1 receptor agonists can slow its progression. Lifestyle changes, including blood pressure control, glucose management, and a kidney-friendly diet, also help protect kidney health.
Regular monitoring of eGFR and urine albumin levels allows for early detection and better treatment adjustments. By taking a proactive approach, people with diabetes can significantly reduce their risk of kidney failure and improve their long-term health.
About Dr. Gerti Tashko, MD
Dr. Gerti Tashko, MD, is a board-certified endocrinologist based in Montgomery County, Maryland. He is uniquely certified in endocrinology, lipidology, hypertension, and obesity medicine. His practice offers comprehensive, root-cause-focused metabolic and endocrine care, available both virtually and in person. He uses advanced diagnostics, personalized nutrition, and preventive medicine to optimize long-term health outcomes.
