Causes of Nephrotic Syndrome: Understanding the Underlying Diseases and Their Impact

Nephrotic syndrome is a kidney disorder characterized by significant protein loss in the urine, low levels of protein in the blood, and often accompanied by swelling, high cholesterol, and other systemic symptoms. To be clinically diagnosed, patients typically exhibit more than 3.5 grams of protein in a 24-hour urine collection and serum albumin levels below 30 g/L. While the symptoms are well-defined, the underlying causes vary widely and can stem from both primary kidney conditions and secondary systemic diseases.

Primary Kidney Diseases Leading to Nephrotic Syndrome

Primary causes originate within the kidneys themselves, where damage occurs directly to the glomeruli—the tiny filtering units responsible for removing waste while retaining essential proteins. These conditions are not linked to other systemic illnesses but rather result from intrinsic kidney pathology.

Minimal Change Disease

This is the most common cause of nephrotic syndrome in children, though it also affects adults. Microscopically, the kidney tissue appears nearly normal, hence the name "minimal change." Despite this, patients experience massive proteinuria due to dysfunction in the podocytes—specialized cells that help prevent protein leakage. The condition often responds well to corticosteroid therapy, especially in younger patients.

Membranous Nephropathy

More prevalent among middle-aged and older adults, membranous nephropathy involves thickening of the glomerular basement membrane. It's one of the leading causes of adult-onset nephrotic syndrome. Autoimmune mechanisms play a key role, with antibodies targeting antigens like PLA2R commonly found in these patients. A portion of cases may resolve spontaneously, while others progress to chronic kidney disease if left untreated.

Focal Segmental Glomerulosclerosis (FSGS)

FSGS refers to scarring in specific segments of certain glomeruli. It can arise from genetic factors, viral infections (such as HIV), obesity, or prolonged adaptive responses in remaining kidney tissue after injury. Proteinuria tends to be severe, and progression to kidney failure is more likely compared to other forms. Treatment includes immunosuppressants, ACE inhibitors, or ARBs to reduce protein loss.

Membranoproliferative Glomerulonephritis (MPGN)

Also known as mesangiocapillary glomerulonephritis, MPGN features both structural thickening and increased cellularity in the glomeruli. It's frequently associated with abnormal immune complex deposition or complement system dysregulation. Early signs include hypocomplementemia—particularly low C3 levels—and anemia. This form often has a poorer prognosis and may require targeted therapies based on the underlying immune mechanism.

Secondary Causes: Systemic Conditions Triggering Nephrotic Syndrome

In many cases, nephrotic syndrome develops as a complication of broader medical disorders. Identifying and managing the root disease is crucial for effective treatment and long-term kidney protection.

Diabetic Nephropathy

One of the most common secondary causes worldwide, diabetic nephropathy results from prolonged high blood sugar damaging the delicate filtration system of the kidneys. Initially presenting with microalbuminuria, it progresses to overt proteinuria and eventually full-blown nephrotic syndrome in advanced stages. Tight glycemic control, blood pressure management, and medications like SGLT2 inhibitors or GLP-1 receptor agonists are vital in slowing progression.

Lupus Nephritis

Systemic lupus erythematosus (SLE) can severely affect the kidneys, particularly in Class V lupus nephritis, which predominantly presents with nephrotic-range proteinuria. Immune complexes deposit in the glomeruli, triggering inflammation and scarring. Patients may also experience hematuria, hypertension, and impaired kidney function. Treatment usually involves corticosteroids and immunosuppressive agents such as mycophenolate mofetil or cyclophosphamide.

Henoch-Schönlein Purpura (HSP) Nephritis

Commonly seen in children following an upper respiratory infection, HSP is a vasculitic condition that can involve the kidneys. When renal involvement occurs, it may mimic nephrotic syndrome with heavy protein loss and edema. Most cases are mild and self-limiting, but a subset progresses to chronic kidney disease, requiring close monitoring and sometimes immunomodulatory therapy.

Beyond these, other less frequent contributors include amyloidosis, multiple myeloma, hepatitis B or C infection, and certain drug toxicities. Early diagnosis through biopsy, serologic testing, and imaging helps tailor treatment strategies effectively. Managing nephrotic syndrome requires a comprehensive approach—addressing both symptom relief and the root cause—to preserve kidney function and improve patient outcomes.