Common Causes of Secondary Nephrotic Syndrome

Secondary nephrotic syndrome arises not as a primary kidney disorder but as a consequence of underlying systemic conditions or external factors. Unlike primary forms that originate directly in the kidneys, secondary cases are triggered by diseases or exposures that indirectly damage renal function. Identifying these root causes is crucial for effective treatment and long-term management.

Major Underlying Conditions Leading to Secondary Nephrotic Syndrome

Several systemic diseases are strongly associated with the development of secondary nephrotic syndrome. Among the most prevalent are diabetes mellitus, hepatitis B virus infection, lupus nephritis, and Henoch-Schönlein purpura (also known as IgA vasculitis). These conditions initiate immune-mediated or metabolic injury to the glomeruli—the filtering units of the kidneys—leading to excessive protein leakage into the urine.

Diabetic Nephropathy: The Most Common Cause

Diabetic nephropathy stands out as the leading cause of secondary nephrotic syndrome worldwide, particularly in patients with long-standing type 1 or type 2 diabetes. The progression of kidney damage in diabetes typically follows a well-defined five-stage pattern:

Stage I – Hyperfiltration Phase: During this early stage, the kidneys exhibit increased filtration rates due to diabetic metabolic changes. Although kidney function appears heightened, there is no detectable protein in the urine, making it asymptomatic and often undiagnosed.
Stage II – Silent Microalbuminuria Phase: Structural changes begin to develop in the glomerular basement membrane. Protein leakage is minimal and only evident after physical exertion. Routine urinalysis during rest may still appear normal.
Stage III – Early Diabetic Kidney Disease (Microalbuminuria): This stage marks the onset of persistent microalbuminuria, with urinary protein excretion ranging between 30 and 300 mg per 24 hours. It represents a critical window for intervention to slow disease progression.
Stage IV – Overt Proteinuria (Clinical Nephropathy): Protein loss exceeds 300 mg/24h and continues to rise over time. Many patients at this stage meet the diagnostic criteria for nephrotic syndrome, characterized by heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia.
Stage V – End-Stage Renal Disease (ESRD): Kidney function deteriorates significantly, often requiring dialysis or transplantation.

Infections and Immune-Mediated Kidney Damage

Viral infections such as hepatitis B can lead to immune complex deposition in the glomeruli, triggering inflammation and proteinuria. Similarly, systemic autoimmune disorders like systemic lupus erythematosus (SLE) frequently result in lupus nephritis, where autoantibodies attack kidney tissues. Another notable cause is Henoch-Schönlein purpura, an IgA-dominant vasculitis that affects small blood vessels, including those in the kidneys, especially in children and young adults.

Environmental and Pharmacological Triggers

Exposure to certain environmental toxins and medications has also been linked to secondary nephrotic syndrome. Heavy metals such as mercury, lead, and cadmium can induce direct nephrotoxicity, disrupting glomerular integrity. Additionally, some widely used medications—particularly newer targeted cancer therapies—have emerged as potential culprits. Drugs like tyrosine kinase inhibitors and immune checkpoint inhibitors, while effective in treating malignancies, have been reported to cause minimal change disease or membranous nephropathy in susceptible individuals.

Given the growing use of these advanced oncology treatments, healthcare providers must remain vigilant for signs of kidney injury, including unexplained proteinuria or sudden-onset edema. Early detection and timely adjustment of therapy can prevent irreversible kidney damage.

Conclusion and Clinical Implications

Recognizing the diverse etiologies behind secondary nephrotic syndrome is essential for accurate diagnosis and tailored treatment. Clinicians should consider patient history, comorbidities, medication use, and exposure risks when evaluating proteinuric kidney disease. With proper management of the underlying condition, many patients can achieve remission or stabilization of their renal function, improving overall prognosis.