Nephrotic Syndrome

Nephrotic syndrome is a clinical syndrome resulting from significantly increased glomerular permeability to protein. It is defined by heavy proteinuria (generally over 3 to 3.5 grams per 24 hours), hypoalbuminemia, edema, and, frequently, hyperlipidemia.

In children, minimal change disease accounts for the large majority of cases and typically responds well to corticosteroid therapy.

In adults, the underlying cause is more varied. It includes focal segmental glomerulosclerosis and membranous nephropathy. Membranous nephropathy may be primary, driven by autoantibodies against the PLA2R antigen, or secondary to an underlying cause such as malignancy, infection, or autoimmune disease.

Diabetic nephropathy is an increasingly common cause of nephrotic range proteinuria in adults, given the rising global prevalence of diabetes.

Periorbital and dependent edema is typically the presenting feature, often noticed first as facial puffiness on waking, and progressing to more generalized edema, ascites, and pleural effusion as the condition advances.

Frothy urine, reflecting the heavy proteinuria, is a symptom many patients notice themselves and volunteer if specifically asked. Fatigue and, in more advanced disease, breathlessness from fluid accumulation, may also be present.

Nephrotic syndrome carries several important, sometimes underappreciated, systemic consequences beyond the local effects of edema.

A hypercoagulable state arises from urinary loss of antithrombin and other regulatory proteins alongside a compensatory rise in hepatic procoagulant synthesis. It predisposes particularly to renal vein thrombosis and pulmonary embolism. Consider this risk in any nephrotic patient presenting with flank pain, hematuria, or respiratory symptoms.

Increased susceptibility to infection results from urinary loss of immunoglobulins, with particular vulnerability to encapsulated organisms. Spontaneous bacterial peritonitis is a recognized complication in nephrotic patients with ascites, analogous to the phenomenon seen in cirrhosis.

Hyperlipidemia results from increased hepatic lipoprotein synthesis, occurring as a compensatory response to the ongoing protein loss.

Urinalysis and quantification of proteinuria confirm the degree of proteinuria. Quantify by 24 hour urine collection or by a spot urine protein to creatinine ratio, a more practical and widely used alternative. Serum albumin is reduced, and a lipid profile typically shows significant hyperlipidemia.

Assess renal function (urea, creatinine, eGFR). Impairment at presentation carries prognostic significance and may point toward a specific underlying cause.

Renal biopsy is generally required in adults to establish the histological diagnosis, since this determines both prognosis and the most appropriate treatment.

In children, minimal change disease is presumed. A trial of steroids is often given first without biopsy, given how characteristically it responds.

Further investigation is directed toward identifying a secondary cause, particularly for membranous nephropathy:

PLA2R antibody testing supports a primary, autoimmune cause when positive. Other tests are age appropriate malignancy screening and hepatitis B and C serology.

Autoimmune screening including ANA and complement levels is used where a connective tissue disease such as systemic lupus erythematosus is suspected as an underlying driver.

The differential for the clinical syndrome of generalized edema also includes heart failure, cirrhosis, and protein losing enteropathy. The combination of heavy proteinuria and hypoalbuminemia on initial bloods and urinalysis typically distinguishes nephrotic syndrome from these fairly promptly.

General supportive measures apply regardless of the specific underlying cause. Salt restriction and diuretics, typically loop diuretics, are used to manage edema, titrated carefully since nephrotic patients can be intravascularly volume depleted despite visibly significant peripheral edema, given the low oncotic pressure driving fluid into the interstitial space.

ACE inhibitors or ARBs are used to reduce proteinuria and provide renal protection, a benefit that applies broadly across the different underlying causes of nephrotic syndrome, independent of blood pressure control alone.

Statin therapy addresses the associated hyperlipidemia. Prophylactic anticoagulation is considered in patients at particularly high thrombotic risk, guided by the degree of hypoalbuminemia and the specific underlying diagnosis, since the thrombotic risk varies somewhat by cause, being notably high in membranous nephropathy.

Specific treatment is directed by the underlying histological diagnosis once established by biopsy (or, in children, by the characteristic clinical response to steroids). Minimal change disease is treated with high dose oral corticosteroids, to which the large majority of children respond, with immunosuppressive agents such as calcineurin inhibitors or cyclophosphamide reserved for steroid resistant or frequently relapsing disease.

Focal segmental glomerulosclerosis is also treated with corticosteroids as first line therapy, though response rates are lower than in minimal change disease, with calcineurin inhibitors used for steroid resistant cases.

Membranous nephropathy management depends on the risk of progression, with observation and supportive care alone appropriate for lower risk disease, and immunosuppression, commonly rituximab or a calcineurin inhibitor based regimen, reserved for higher risk or progressive disease.

Diabetic nephropathy is managed with optimized glycemic control, blood pressure control with an ACE inhibitor or ARB as foundational therapy, and SGLT2 inhibitors, which have demonstrated significant renal protective benefit independent of glycemic effect.

Referral: nephrology for all adult onset nephrotic syndrome, given the need for renal biopsy and specific immunosuppressive management; pediatric nephrology for children with atypical features or steroid resistant disease.