Nephrotic Syndrome

Essentials of Diagnosis

• Bland urine sediment (few if any cells or cellular casts)

• Nephrotic syndrome manifestations:

  • Heavy proteinuria (urine protein excretion > 3 g per 24 hours)

  • Hypoalbuminemia (albumin < 3 g/dL)

  • Peripheral edema

  • Hyperlipidemia

  • Oval fat bodies may be seen in the urine

General Considerations

• Causes

  • Diabetes mellitus (most common)

  • Minimal change disease

  • FSGS

  • Membranous nephropathy

  • Amyloidosis

• Any of these entities can present on the less severe end of the nephrotic spectrum with a bland urinalysis and proteinuria, or with the most severe presentation of the nephrotic syndrome

• Serum creatinine may be abnormal at the time of presentation, depending on the severity and acuity of the disease

Clinical Findings

• Patients with subnephrotic range proteinuria do not manifest symptoms of the kidney disease

• In those with the nephrotic syndrome, peripheral edema is present and is most likely due to sodium retention and hypoalbuminemia-induced low plasma oncotic pressure

• Edema

  • May develop solely in dependent regions, such as the lower extremities

  • May become generalized and include periorbital edema

• Dyspnea due to pulmonary edema, pleural effusions can occur

• Diaphragmatic compromise due to ascites can also occur

Laboratory Findings

• Urinalysis

  • Urinary dipstick is a good screening test for proteinuria; however, it detects only albumin

  • A spot urine protein to urine creatinine ratio ([Uprotein]/[Ucreatinine]) gives a reasonable approximation of grams of protein excreted per day (ratio < 0.2 is normal and corresponds to excretion of < 200 mg/24 hours); a 24-hour urine sample for protein excretion is rarely needed

  • Microscopically, the urinary sediment has relatively few cellular elements or casts

  • However, if marked hyperlipidemia is present, urinary oval fat bodies may be seen

    • Appear as "grape clusters" under light microscopy

    • Appear as "Maltese crosses" under polarized light

• Blood chemistries

  • Hypoalbuminemia (< 3 g/dL [30 g/L])

  • Hypoproteinemia (< 6 g/dL [60 g/L])

  • Hyperlipidemia

    • Occurs in over 50% of patients with early nephrotic syndrome

    • Becomes more frequent and worsens in degree as the severity of the nephrotic syndrome increases

  • Patients may become deficient in vitamin D, zinc, and copper from loss of binding proteins in the urine

  • Laboratory testing to determine the underlying cause may include

    • Complement levels

    • Serum and urine protein electrophoresis

    • Serum free light chains

    • Antinuclear antibodies

    • PLA₂R antibody titers

    • Serologic tests for viral hepatitides

Diagnostic Procedures

• Kidney biopsy

  • Often performed in adults with new-onset idiopathic nephrotic syndrome if a primary renal disease that may require immunosuppressive therapy is suspected

  • Chronically and significantly decreased GFR indicates irreversible kidney disease mitigating the usefulness of kidney biopsy

  • In the setting of long-standing diabetes mellitus type 1 or 2, proteinuric renal disease is rarely biopsied unless

    • Atypical features (such as significant glomerular hematuria or cellular casts) are also present

    • There is other reason to suspect an additional renal lesion

• Protein loss

  • In those with subnephrotic proteinuria or mild nephrotic syndrome, dietary protein restriction may be helpful in slowing progression of kidney disease

  • In those with proteinuria > 10 g/day, protein malnutrition may occur and daily protein intake should replace daily urinary protein losses

  • In both diabetic and nondiabetic patients, ACE inhibitors and ARBs

    • Lower urine protein excretion by reducing glomerular capillary pressure

    • Have antifibrotic effects

    • These agents can be used in patients with reduced GFR as long as significant hyperkalemia (potassium > 5.2–5.5 mEq/L or mmol/L) does not occur and serum creatinine rises < 30%

    • Patients should be monitored closely to avoid AKI and hyperkalemia

    • Combination therapy of an ARB and an ACE inhibitor increases risk for AKI and hyperkalemia and is not recommended

• Edema

  • Dietary salt restriction is essential for managing edema

  • Most patients also require diuretic therapy

  • Both thiazide and loop diuretics are highly protein bound; therefore, with hypoalbuminemia and decreased GFR, diuretic delivery to the kidney is reduced, and patients often require larger doses

  • A combination of loop and thiazide diuretics can potentiate the diuretic effect and may be needed for patients with refractory fluid retention

• Hyperlipidemia

  • Dietary modification and exercise should be advocated; however, effective lipid-lowering usually also requires pharmacologic treatment

  • There is significant risk of rhabdomyolysis in patients with CKD who take gemfibrozil in combination with statins

  • Combining fenofibrate or niacin with a statin may be safer

• Hypercoagulable state

  • Patients with serum albumin < 2 g/dL (20 g/L) can become hypercoagulable

  • Patients with nephrotic syndrome

    • Have urinary losses of antithrombin, protein C, and protein S and increased platelet activation

    • Are prone to renal vein thrombosis, pulmonary embolus, and other venous thromboemboli, particularly with membranous nephropathy

    • Anticoagulation therapy with warfarin is warranted for at least 3–6 months in patients with evidence of thrombosis in any location

  • Patients with renal vein thrombosis, pulmonary embolus, or recurrent thromboemboli require indefinite anticoagulation

When to Refer

• Any patient with the nephrotic syndrome should be referred immediately to a nephrologist for

  • Volume and blood pressure management

  • Assessment for kidney biopsy

  • Treatment of the underlying disease

• Proteinuria of more than 1 g/24 hours without the nephrotic syndrome also merits nephrology referral, though with less urgency

When to Admit

• Patients with edema refractory to outpatient therapy

• Patients with rapidly worsening kidney function that may require inpatient interventions