Nephrotic syndrome

Nephrotic syndrome is characterized by massive proteinuria (e.g., > 3.5 g/24 h), hypoalbuminemia, and edema and indicates damage to the glomerular filtration barrier. In adults, the most common types of nephrotic syndrome are focal segmental glomerulosclerosis (FSGS) and membranous nephropathy. In children, nephrotic syndrome is most commonly caused by minimal change disease (MCD). Nephrotic syndrome can also be a manifestation of advanced renal disease in systemic conditions (e.g., diabetic nephropathy or amyloid nephropathy). Additional laboratory findings of nephrotic syndrome include hyperlipidemia and fatty casts on urinalysis. Management is based on the underlying cause. General management of symptoms and complications of nephrotic syndrome includes treatment for edema (e.g., sodium restriction, diuretics), proteinuria (e.g., RAS inhibitors), and hypercoagulability (e.g., thromboprophylaxis), and management of increased infectious risk (e.g., immunizations). Nephrotic syndrome due to advanced renal disease is associated with a worse prognosis and is more difficult to treat than nephrotic syndrome due to other causes.

See “Core IM podcast 5 pearls on nephrotic syndrome” for their complete show notes on this topic.

• Nephrotic syndrome: nephrotic-range proteinuria PLUS hypoalbuminemia, edema, and/or severe hyperlipidemia [1]
• Nephrotic-range proteinuria: either of the following [1]
  • Proteinuria on 24-hour urine collection > 3.5 g/24 h
  • Spot urine protein-creatinine ratio ≥ 3000 mg/g

Nephrotic syndrome may be caused by primary glomerular disorders (80–90% of affected individuals) and/or systemic diseases and toxic exposures (10–20% of affected individuals). [12]

• Primary (idiopathic) forms: The following types of nephrotic syndrome are commonly associated with other conditions. See the “Overview” section.
  • MCD
  • Focal segmental glomerulosclerosis [1]
    • Genetic
    • Viral infections (e.g., HIV)
    • Specific drugs (e.g., anthracyclines, lithium)
    • Glomerular hyperfiltration (e.g., in obesity)
  • Membranous nephropathy
  • Membranoproliferative glomerulonephritis (can manifest as nephrotic or nephritic syndrome)
• Secondary forms
  • Diabetic nephropathy
  • Amyloid nephropathy: can be associated with multiple myeloma (AL amyloidosis) or ; chronic inflammatory disease such as rheumatoid arthritis (AA amyloidosis)
  • Lupus nephritis (can manifest as nephrotic or nephritic syndrome)

Damage of glomerular filtration barrier [13][14]

• MCD: cytokine-mediated damage of podocytes
• Focal segmental glomerulosclerosis: sclerosis of glomeruli → damage and loss of podocytes
• Membranous nephropathy: Anti-phospholipase A2 receptor antibodies (anti-PLA2R antibodies) bind to PLA2R (an autoantigen in glomerular podocytes) and thereby form immune complexes that activate the complement system, leading to podocyte injury. [15]
• Membranoproliferative glomerulonephritis: See “Pathophysiology” in “Nephritic syndrome.”
• Diabetic glomerulonephropathy: See “Pathophysiology” in “Diabetic nephropathy.”
• Amyloid nephropathy
  • Deposition of amyloid (e.g., AL amyloidosis, AA amyloidosis) in various organs (the kidney is the most commonly involved organ)
  • Amyloid deposition in glomeruli → mesangial expansion → nodular sclerosis [16]
• Lupus nephritis: See “Pathophysiology” in “Lupus nephritis.”

FSGS is classically not associated with immune complex deposition.

Sequelae of glomerular filter damage [13][14]

• Structural damage of glomerular filtration barrier → massive renal loss of protein (hyperproteinuria) → reactively increased hepatic protein synthesis
  • Loss of negative charge of glomerular basement membrane → loss of selectivity of barrier (especially for negatively charged albumin)
  • Podocyte damage and fusion → nonselective proteinuria (except in MCD, which manifests with selective glomerular proteinuria) [7]
• If protein loss exceeds hepatic synthesis (usually with a loss of protein > 3.5 g/24 h) → hypoproteinemia/hypoalbuminemia, initially with both normal GFR and creatinine ; [13][14]
  • ↓ Serum albumin; → ↓ colloid osmotic pressure → edema (especially if albumin levels are < 2.5 g/dL) [17]
  • Loss of antithrombin III, protein C, and protein S, increased synthesis of fibrinogen, and loss of fluid into the extravascular space → hypercoagulability
  • Loss of transport proteins
    • Loss of thyroglobulin transport protein → thyroxin deficiency
    • Vitamin D binding protein → vitamin D deficiency
  • Loss of plasma proteins → ↓ plasma protein binding → increase in free plasma drug concentration, but drug toxicity is usually not increased [18][19][20]
• ↑ Plasma levels of cholesterol, LDL, triglycerides, and lipoproteins (mainly LPA) to compensate for the loss of albumin → lipiduria (fatty casts) [21]
• Loss of immunoglobulins → increased risk of infection, especially Streptococcus pneumoniae infection (pulmonary edema also increases the risk for S. pneumoniae infection)
• Sodium retention → possible hypertension

• Classic manifestations [12]
  • Edema
    • Typically starts with periorbital edema
    • Peripheral edema (pitting)
    • Pleural effusion, pulmonary edema
    • Pericardial effusion
    • Ascites
    • In severe cases, anasarca
  • Weight gain
  • Fatigue
• Other clinical features [12]
  • Hypercoagulable state with increased risk of thrombosis and embolic events (e.g., pulmonary embolism, renal vein thrombosis)
  • Increased susceptibility to infection
  • Hypertension in some cases
  • Possibly frothy urine
  • Symptoms of hypocalcemia (e.g., tetany, paresthesia, muscle spasms)
  • Symptoms of the underlying disease (e.g., malar rash in lupus nephritis)
• See also “Nephrotic vs. nephritic syndrome.”

Approach [1][12]

• Confirm nephrotic-range proteinuria.
• Obtain serum albumin levels and a lipid panel.
• Refer to nephrology for specialist evaluation.
• Advanced studies typically include renal biopsy and laboratory studies for associated conditions in nephrotic syndrome.
• For additional workup of clinical features of nephrotic syndrome, see “Diagnosis” in “Peripheral edema.”

Initial evaluation

Identification of nephrotic syndrome [1][12]

Nephrotic syndrome is typically defined by the presence of nephrotic-range proteinuria and hypoalbuminemia. Mild to severe dyslipidemia and peripheral edema may be present. [1]

• Confirmation of nephrotic-range proteinuria [1]
  • 24-hour urine collection (most accurate if adequate collection)
    • Protein ≥ 3.5 g/24 h
    • Urine protein/creatinine ratio (UPCR) on a sample from a 24-hour urine collection: ≥ 3000 mg/g
  • Alternative: spot UPCR (ideally early morning) ≥ 3000 mg/g
• Confirmation of additional features of nephrotic syndrome [1]
  • Serum albumin: typically < 3 g/dL, ; with ↓ total protein
  • Lipid profile: variable findings; no specific cutoff (e.g., hyperlipidemia, ↑ LDL, ↑ triglycerides, ↑ cholesterol).
  • Edema: often present

Additional studies [1][12]

• BMP
  • ↑ Cr (with ↓ GFR) and/or ↑ BUN may occur.
  • ↓ Na is common.
• CBC: ↑ Hb/Hct may indicate hemoconcentration.
• Inflammatory markers: ↑ ESR, ↑ CRP may suggest underlying infection, inflammatory condition, or vasculitis.
• Liver chemistries: elevated in, e.g., viral hepatitis
• Additional markers of CKD: (e.g., low vitamin D levels)
• Urine dipstick: used for screening, but false positives and false negatives occur.
  • Usually shows ≥ 3 proteins
  • Hematuria may indicate concomitant glomerulonephritis.
• Urinalysis with microscopy: all patients with an abnormal urine dipstick or suspicion for glomerular disease
  • Nephrotic sediment
    • Lipiduria, fatty casts with Maltese cross appearance under polarized light
    • Renal tubular epithelial cell casts
  • Hematuria with acanthocytes and/or RBC casts may indicate concomitant glomerulonephritis (i.e., nephritic sediment).
• Renal ultrasound (e.g., if ↓ GFR)

Advanced studies [1][12]

• Renal biopsy
  • Typically mandatory in adult patients with nephrotic syndrome to determine etiology and guide management
  • Exceptions: Anti-PLA₂R antibody detected (see “Minimal change disease”), or contraindication to biopsy present
  • Interpretation: See “Pathology.”
• Further laboratory studies
  • Identify underlying causes (e.g., infections, autoimmune conditions)
  • See table “Laboratory studies for associated conditions in nephrotic syndrome.” [22]
• Cancer screening: age-appropriate studies (e.g., in membranous nephropathy)

Classification of nephrotic syndrome is based on the pattern of injury as seen on light microscopy (LM) of a renal biopsy specimen. For a complete assessment, all biopsy specimens should be analyzed using LM, immunofluorescence microscopy (IM), and electron microscopy (EM).

• MCD
  • EM: effacement of the foot processes of podocytes
  • LM: no changes in glomeruli (possibly fat bodies in some proximal tubular cells)
• Focal segmental glomerulosclerosis: damage to podocytes
  • EM: effacement of the foot processes (similar to MCD)
  • LM: segmental sclerosis and hyalinosis and loss of podocytes
  • IM: rarely, focal deposits of IgM, C1, and C3 inside sclerotic lesion
• Membranous nephropathy: deposition of antibodies between podocytes and the basal membrane
  • EM: subepithelial dense deposits (IgG and C3); with a spike and dome appearance
  • LM: diffuse thickening of glomerular capillary loops and basal membrane
  • IM: granular subepithelial deposits of immune complexes and complement
• Diabetic glomerulonephropathy: light microscopy shows mesangial matrix expansion, thickening of glomerular membrane, and/or nodular eosinophilic glomerulosclerosis (Kimmelstiel-Wilson lesions)
• Lupus nephritis: light microscopy shows mesangial proliferation, subendothelial and/or subepithelial immune complex deposition; , and thickening of the capillary walls (appear as wire loops)
• Amyloid nephropathy
  • EM: amyloid fibrils
  • LM
    • Nodular glomerulosclerosis
    • Apple-green birefringence (mesangial amyloid deposition) with Congo red stain under polarized light

General principles

Early specialist consultation (e.g., nephrology, hematology, rheumatology) is advised.

• Monitor weight (e.g., daily in inpatients), blood pressure, serum electrolytes, and renal function.
• Provide symptom control and supportive care.
• Manage and prevent infectious and thrombotic complications.
• Provide management for AKI or management for CKD.
• Additional management depends on the underlying cause: See “Disease-specific management.”

Symptom management and supportive care [1]

• Lifestyle modifications: See “ASCVD prevention.”
• Dietary restrictions
  • Sodium restriction: < 2 g/day
  • Moderate protein restriction: Avoid protein malnutrition. [23]
• Diuretic therapy: to reduce edema
  • Loop diuretic (e.g., oral furosemide , bumetanide ) [1][12]
  • Titrate dose to clinical response. [1]
  • Aim for weight loss of 1–2 kg per day. [12]
• RAAS inhibitor: to manage proteinuria and/or hypertension
  • Options
    • ACEI (e.g., ramipril )
    • OR angiotension receptor blocker (e.g., losartan )
  • Effects
    • Reduces proteinuria
    • Treats hypertension
    • May slow progression of any underlying renal disease (e.g., diabetic nephropathy)
  • Avoid in AKI, hyperkalemia, or abrupt onset of nephrotic syndrome.
• Lipid-lowering agent: to manage persistent hyperlipidemia; See “Treatment of hyperlipidemia” for indications and dosages.

Elimination or reduction of proteinuria can increase serum albumin, decrease edema, improve hyperlipidemia, reduce thromboembolic and infectious risks, and slow progression of CKD.

Prevention and management of complications [1]

• Infections
  • Primary prevention
    • Pneumococcal vaccination
    • Annual influenza vaccination
    • Herpes zoster vaccination
    • Consider pneumocystis pneumonia prophylaxis (e.g., trimethoprim-sulfamethoxazole) in patients receiving high-dose glucocorticoids and/or other immunosuppressive therapy.
  • Screen for and treat latent infections (e.g., syphilis, HIV, TB, strongyloides, HBV, HCV) before initiating immunosuppressive therapy.
  • Acute bacterial infection: low threshold for blood cultures and IV antibiotics
• Prevention of thrombosis (e.g., DVT, VTE at unusual sites, arterial thrombosis)
  • Prophylactic anticoagulation is typically indicated for patients with low serum albumin (e.g., < 2.5 g/dL) and any of the following: [1]
    • Proteinuria > 10 g/24 h
    • BMI > 35 kg/m²
    • Membranous nephropathy
    • Congestive heart failure with NYHA class III-IV
    • Recent orthopedic or abdominal surgery
    • Prolonged immobilization
  • Options: oral or parenteral anticoagulation (e.g., warfarin, low-dose low molecular weight heparin)
  • See also “Risk factors for VTE.”
• Management of thrombosis: therapeutic anticoagulation (see “Treatment” in “Deep vein thrombosis” and “Pulmonary embolism”)

There is insufficient evidence to support the use of DOACs in nephrotic syndrome; warfarin or low molecular weight heparin is preferred. [24]

All patients with nephrotic syndrome are at increased risk of thromboembolism, and this risk increases as serum albumin drops < 3 g/dL. [1]

Glomerular disease secondary to systemic conditions is discussed separately (e.g, management of lupus nephritis and diabetic nephropathy).

General principles [12]

• Children: often includes empiric glucocorticoids for presumed MCD [25]
• Adults: usually guided by biopsy-based histological diagnosis
  • Immunosuppression: used for many glomerular pathologies, in combination with treatment of any identified underlying cause
    • Glucocorticoids: often used initially
    • Additional immunosuppressants (e.g., cyclophosphamide, calcineurin inhibitors) in patients with glucocorticoid-resistant nephrotic syndrome or severe disease

Membranous nephropathy [1]

• Kidney biopsy may not be needed if anti-PLA₂R antibody is detected.
• Evaluate for associated conditions, e.g.:
  • Chest x-ray for sarcoidosis
  • Age-appropriate cancer screening [1]
• Initial management: conservative therapy including an RAAS inhibitor (i.e., ACEI or ARB) [1]
• Secondary membranous nephropathy: Treat the underlying cause.
• Consider immunosuppressants for severe or refractory disease.
  • Prednisone AND cyclophosphamide
  • Alternatives: cyclosporine OR tacrolimus OR rituximab
• Consider prophylactic anticoagulation based on assessment of thrombotic risk.

Patients with membranous nephropathy have the highest risk of thrombotic events of patients with nephrotic syndrome. [1]

Focal segmental glomerulosclerosis (FSGS) [1]

• Initial management: supportive therapy, including an RAAS inhibitor (e.g., ACEI or ARB)
• Secondary FSGS: Treat the underlying cause. [1]
• Primary FSGS with nephrotic syndrome: immunosuppressants
  • Prednisone [26]
  • Alternative: calcineurin inhibitor (cyclosporin OR tacrolimus)

FSGS may manifest with proteinuria but without nephrotic syndrome.

Minimal change disease (MCD)

• Immunosuppressants: recommended for all patients
  • Prednisone (16-week trial in adult patients) [26]
  • Alternative: cyclophosphamide OR calcineurin inhibitor
• Consider supportive treatment (e.g., RAAS inhibitors) for adult patients.

In children, MCD is the most common cause of nephrotic syndrome.

Membranoproliferative glomerulonephritis (MPGN)

• Treat the underlying cause.
• See "Overview of membranoproliferative glomerulonephritis" in "Glomerular diseases" for additional details of management.

Thrombotic complications [27]

• Venous thromboembolism (e.g., deep vein thrombosis, pulmonary embolism)
• Arterial thromboembolism
• Renal vein thrombosis: thrombus formation in the renal veins or their branches [28]
  • Cause: hypercoagulable state (e.g., malignancies, antiphospholipid syndrome, nephrotic syndrome) [29]
  • Manifestations
    • Flank pain
    • Hematuria
    • ↑ LDH
    • Anuria/renal failure in bilateral thrombosis
    • Scrotal edema
  • Diagnostics
    • CT angiography or MR venography (preferred modality in patients with renal injury or failure)
    • Doppler ultrasonography if no other diagnostic modality is available
  • Treatment
    • Anticoagulation
    • Thrombolysis or thrombectomy in selected patients
  • Complications: rupture of renal capsule, pulmonary embolism, kidney injury

Atherosclerotic complications [27][30]

• Abnormal lipid metabolism in combination with a hypercoagulable state leads to an increased risk of atherosclerotic complications
• Manifestation: myocardial infarction, stroke

Chronic kidney disease

• FSGS and membranous nephropathy in particular may progress to chronic kidney disease and ESRD.

Increased risk of infection [31][32]

• Most likely resulting from hypogammaglobulinemia caused by urinary protein loss
• E.g., respiratory tract infections, peritonitis, urinary tract infections, sepsis
• Especially with encapsulated bacteria (e.g., Streptococcus pneumoniae)

Protein malnutrition

• Loss in lean body mass due to proteinuria may be masked by weight gain caused by concurrent edema.

Vitamin D deficiency

• Due to urinary loss of vitamin D binding protein (DBP) and bound 25-hydroxyvitamin D [33][34][35]
• Can cause hypocalcemia → ↑ serum parathyroid hormone (PTH) → bone disease (see “Secondary and tertiary hyperparathyroidism”) [36]

Anemia

• Due to urinary loss or impaired synthesis of transferrin (causing hypochromic microcytic anemia), transcobalamin (causing megaloblastic anemia), copper (causing sideroblastic anemia), erythropoietin, and iron [37]

We list the most important complications. The selection is not exhaustive.

• See “Nephrotic vs. nephritic syndrome.”
• Lupus nephritis (e.g., diffuse proliferative glomerulonephritis)

The differential diagnoses listed here are not exhaustive.

• The prognosis for MCD is usually excellent.
• With a wide variety of underlying diseases, the response to treatment can differ dramatically. Individuals with nephrotic syndrome often develop progressive renal failure despite treatment and go on to require dialysis.

Amboss has partnered with the popular Core IM podcast to bring you digestible internal medicine content on complex medical topics. In this section, you’ll find their 5 clinical pearls on the diagnosis and management of nephrotic syndrome. Check out their website for the full show notes and listen to our coproduced episode on your favorite podcast platform.

• Pearl 1: Don’t be fooled by the UA!
  • Review of urine dipstick vs. UA
    • Urine dipstick: done at the bedside; not looked at under microscope but provides a rough estimation of protein, blood, pH, specific gravity, leukocyte esterase/nitrites, ketones, glucose, bilirubin
    • UA: done in lab; microscopic examination of WBCs, RBCs, casts, crystals
  • Don’t brush off + 1 protein or a few RBCs.
  • Don’t ignore the specific gravity.
  • Follow-up with a UPCR.
• Pearl 2: key information to obtain from a patient with new nephrotic syndrome
  • Defining nephrotic syndrome
    • Nephrotic-range proteinuria: ≥ 3.5 g/24 h proteinuria
    • Nephrotic syndrome: nephrotic-range proteinuria with low albumin and edema/anasarca and/or hyperlipidemia, thromboses
  • Framework: Different subtypes are defined by the extent and pattern of injury to the podocyte.
    • Minimal change disease (MCD): so “minimal” that podocyte effacement can only be seen on electron microscopy
    • Focal segmental glomerulosclerosis (FSGS): focal and segmental scarring; can be considered a more severe form of MCD
    • Membranous nephropathy: circulating antibody or other unidentified toxin causes epithelial and surrounding podocyte damage
    • Other: amyloidosis, preeclampsia, diabetes
  • Summary: Ask about chronic illnesses, cancer screening, viral infections and STIs, drugs, and family history.
• Pearl 3: what a generalist needs to know about a kidney biopsy
  • Who should we biopsy?
    • Most patients with nephrotic syndrome and no clear cause
    • Diabetes that appears atypical
  • MCD refractory to treatment (could represent missed FSGS)
  • Are kidney biopsies safe?
    • Kidney biopsies are relatively safe, with bleeding observed in < 1% of biopsies.
    • Biopsies may be made safer by controlling blood pressure, holding anticoagulants, holding pressure, and prebiopsy dialysis to lower uremic platelet dysfunction.
• Pearl 4: practical management of the edematous state
  • Use higher doses of diuretics.
  • Hearing loss appears to be rare and is reversible.
  • Albumin does not routinely need to be given with diuretics; there are some short-term effects that do not affect long-term outcomes.
  • Recommend a food diary to help with food restriction.
• Pearl 5: anticoagulation in nephrotic syndrome
  • Membranous nephropathy is associated with the highest risk of thrombosis.
  • Risk is inversely related to the level of albumin.
  • Prophylaxis or treatment generally includes warfarin or LMWH.