Nephrotic syndrome

Nephrotic syndrome is a collection of signs and symptoms indicating damage to the glomerular filtration barrier. It is characterized by massive proteinuria (> 3.5 g/24 hours), hypoalbuminemia, and edema. In adults, the most common causes of nephrotic syndrome include 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). Typical laboratory findings of nephrotic syndrome include hyperlipidemia and fatty casts on urinalysis. Treatment for FSGS, membranous nephropathy, and MCD usually includes immunosuppressive therapy. Nephrotic syndrome due to advanced renal disease is associated with a worse prognosis and is more difficult to treat.

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

• Nephrotic-range proteinuria: proteinuria > 3.5 g/24 hours ^[1]
• Nephrotic syndrome: nephrotic-range proteinuria PLUS hypoalbuminemia and edema ^[1]

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

• Primary (idiopathic) forms: The following types of nephrotic syndrome are commonly associated with other conditions. See the “Overview” section.
  • Minimal change disease
  • Focal segmental glomerulosclerosis
  • 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]

• Minimal change disease: 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 minimal change disease, which manifests with selective glomerular proteinuria) ^[7]
• If protein loss exceeds hepatic synthesis (usually with a loss of protein > 3.5 g/24 hours) → 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
  • Massive proteinuria > 3.5 g/24 hours
  • Edema
    • Typically starts with periorbital edema
    • Peripheral edema (pitting)
    • Pleural effusion
    • Pericardial effusion
    • Ascites
    • In severe cases, anasarca
  • Hypoalbuminemia
  • Hyperlipidemia
• Other clinical features
  • 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. Confirm nephrotic-range proteinuria.
2. Assess for potential concomitant and underlying conditions.
3. Assess for nephrotic syndrome complications.
4. Consider kidney biopsy to determine renal pathology.

Initial evaluation ^[12][22]

Confirmation of nephrotic-range proteinuria

• Qualitative assessment by urine dipstick (commonly used for screening)
  • Usually shows ≥ 3+ proteins
  • Hematuria may indicate concomitant glomerulonephritis.
• Quantitative assessment of urine protein excretion
  • 24-hour urine protein (test of choice): > 3.5 g/24 hours ^[23][24][25]
  • Spot urine protein/creatinine ratio: > 3.5 g/g ^[23][26]

Urine sediment microscopy ^[27]

• 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 (see “Diagnostics” in “Nephritic syndrome”).

Additional laboratory studies

• CBC: ↑ Hb/Hct may indicate hemoconcentration
• BMP: ↑ Cr and/or ↑ BUN may be seen; ↓ Na is commonly seen.
• Serum protein: ↓ total protein; , ↓ albumin (< 3 g/dL)
• Coagulation factors: ↓ ATIII, ↓ protein S, ↓ plasminogen ; ↑ fibrinogen, ↑ D-dimer ^[28][29]
• Lipid profile: Hyperlipidemia (↑ LDL, ↑ triglycerides) may be present.
• Vitamin D levels: ↓ 25-OH Vit-D
• Inflammatory markers: ↑ ESR, ↑ CRP may suggest underlying infection, inflammatory condition, or vasculitis.

Imaging

• Renal ultrasound: to assess kidney size and shape and rule out obstruction

Subsequent evaluation ^[12][22]

Additional testing to assess for potential concomitant conditions and underlying causes should be based on clinical suspicion. ^[30]

Renal biopsy ^[12][22]

• Indication: to confirm the diagnosis when the etiology of nephrotic syndrome is unclear and/or to guide management
  • Often required in adult patients to guide management.
  • Sometimes deferred when a likely cause of nephrotic symptoms is evident ^[31][32]
  • Consult nephrology to determine the necessity and timing of biopsy.
• Interpretation: See the “Pathology” section.

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).

• Minimal change disease
  • 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 minimal change disease)
  • 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

Management of symptoms and complications of nephrotic syndrome ^[1][12][22]

Edema ^[1][12][22]

• Dietary sodium restriction: < 3 g/day (usually 1.5–2 g/day) ^[1][12]
• Fluid restriction: < 1.5 liters/day ^[12][22]
• Diuretic therapy
  • Approach
    • Target weight loss: 0.5–2 kg per day (avoid over-aggressive diuresis) ^[12][22]
    • High diuretic doses often required because of diuretic resistance. ^[33]
    • Monitor serum electrolytes and renal function.
  • Options
    • First-line: oral loop diuretic (e.g., furosemide , bumetanide , torsemide ) ^[12][22]
    • Second-line:
      • Add oral thiazide or thiazide-like diuretic (e.g., metolazone )
      • AND/OR switch to IV loop diuretic (e.g., IV furosemide )
    • Consider adjunctive IV albumin 30–60 minutes prior to intravenous loop diuretic. ^[34]

Proteinuria ^[1][12][22]

Elimination or reduction of proteinuria; is a major treatment goal for nephrotic syndrome and can lead to increased serum albumin, decreased edema; , attenuation of the metabolic effects of heavy proteinuria (e.g., hyperlipidemia), reduction in risk of thromboembolism and infection, and slowing of the progression of chronic kidney disease.

• Antiproteinuric therapy
  • Indicated in most patients
  • RAAS inhibitor: ACEI (e.g., ramipril ) or ARB (e.g., losartan ) are commonly used. ; ^[1][22][35]
    • Effects
      • Reduces proteinuria
      • Treats hypertension
      • May slow progression of any underlying renal disease (e.g., diabetic nephropathy)
    • Avoid in patients with AKI, hyperkalemia, or abrupt onset of nephrotic syndrome.
    • Monitoring: blood pressure, serum potassium, and renal function
  • Other measures that may be beneficial in combination with an ACEI or ARB:
    • Low sodium diet (e.g., dietary sodium restriction to ∼ 1.2 g/day) ^[36]
    • Thiazide diuretic (e.g., hydrochlorothiazide ) ^[36]
    • Mineralocorticoid receptor antagonist (e.g., spironolactone ) ^[37]
• Dietary protein: avoid very high-protein diet but ensure adequate protein intake (0.8–1.0 g/kg daily). ^[38]

Dyslipidemia ^[1][22][39]

• Lipid-lowering therapy (e.g., atorvastatin )
• Indications similar to those in other patients with a high risk of cardiovascular disease (See “Treatment” in “Lipid disorders”)

Hypercoagulability ^[1][22][40]

All patients with nephrotic syndrome are at increased risk of thromboembolism, and this risk becomes progressively higher as serum albumin drops below 3.0 g/L.

• Prophylactic anticoagulation
  • The following parameters should be taken into account to decide whether prophylactic anticoagulation is indicated:
    • Serum albumin level: Prophylaxis is usually considered when serum albumin is < 2–2.5 g/dL.
    • Histological diagnosis: VTE risk is higher in primary membranous nephropathy
    • Coexistence of other risk factors for thromboembolism
      • Immobility due to edema, obesity, malignancy, intercurrent illness, or hospital admission ^[1]
      • Coexisting prothrombotic tendency or thrombophilic state ^[12][22][40]
      • Previous history of thromboembolic events ^[22]
      • Proteinuria > 10 g/day ^[40]
      • Body mass index > 35 kg/m^{2 [40]}
      • Recent abdominal or orthopedic surgery ^[40]
      • New York Heart Association class III to IV congestive heart failure ^[40]
    • Risk of bleeding: Avoid prophylactic anticoagulation in patients at high risk of bleeding (e.g., HAS-BLED score ≥ 3).
  • Options
    • Unfractionated heparin ^[1][40]
    • Low molecular weight heparin (e.g., enoxaparin ) ^[40]
    • Oral warfarin (target INR 2.0–3.0) ^[1][40]
    • Evidence for direct oral anticoagulants (DOACs) is lacking; consider only in patients who are unable to tolerate unfractionated heparin, low molecular weight heparin, or warfarin. ^[40]
  • Duration: until serum albumin is > 3.0 g/dL
• Therapeutic anticoagulation
  • Indications: arterial thrombosis, venous thrombosis, pulmonary embolism
  • Options
    • Low molecular weight heparin (e.g., enoxaparin ) ^[1][40]
    • Oral warfarin (target INR 2.0–3.0) ^[1]
    • DOACs may be carefully considered as alternative agents but evidence supporting their use is limited. ^[40]
    • See also “Treatment” in “Deep vein thrombosis” and “Pulmonary embolism” for more information.

Infectious risk ^[41]

• Screening: Consider screening for hepatitis B, HIV, latent TB, strongyloides, and/or syphilis based on geography, exposure history, and risk factors. ^[23]
• Preventive measures ^[1]
  • Pneumococcal vaccination
  • Annual vaccination for influenza
  • Consider monthly IV immunoglobulin in patients with repeated bacterial infections and serum IgG < 600 mg/dL. ^[1]
  • Consider pneumocystis pneumonia prophylaxis (e.g., trimethoprim-sulfamethoxazole ) in patients receiving high-dose steroids and/or other immunosuppressive therapy (see “PCP prophylaxis”).

Disease-specific measures ^[1][32]

• Primary forms of nephrotic glomerulopathies: often treated with immunosuppressive therapy
  • Immunosuppressive therapies may include:
    • Glucocorticoids (often used initially)
    • Additional immunosuppressants (e.g., cyclophosphamide, calcineurin inhibitors) in patients with steroid-resistant nephrotic syndrome or severe disease
  • Management in adults is usually guided by biopsy-based histological diagnosis.
  • Children are often treated initially with empiric corticosteroids for presumed MCD. ^[42]
• Secondary forms of nephrotic glomerulopathies: Treat the underlying cause.
• Expert consultation is advised.

Primary membranous nephropathy ^[1]

• Initial management: conservative therapy including an RAAS inhibitor (i.e., ACEI or ARB) ^[1]
• Consider immunosuppressive therapy for severe or refractory disease.
  • Prednisone AND cyclophosphamide ^[1]
  • Alternatives: cyclosporine, tacrolimus, OR rituximab

Primary (idiopathic) focal segmental glomerulosclerosis (FSGS) ^[1]

• Initial management: supportive therapy including an RAAS inhibitor (i.e., ACEI or ARB).
• Consider immunosuppressive therapy for all patients with nephrotic syndrome due to FSGS.
  • Prednisone ^[1]
  • Alternative: calcineurin inhibitor (cyclosporin OR tacrolimus)

Primary (idiopathic) minimal change disease (MCD) ^[1]

• Initial management: immunosuppressive therapy
  • Prednisone ^[1]
  • Alternative: cyclophosphamide OR calcineurin inhibitor

Diabetic nephropathy ^[43]

• Strict glycemic control
• RAAS inhibition (e.g., ACEI or ARB)
• Optimization of blood pressure control
• Close surveillance and timely referral to renal replacement therapy if ESRD is anticipated
• See “Diabetic nephropathy” for more information.

Amyloid nephropathy ^[44]

• Treatment of the underlying disease
  • AL amyloidosis: treatment of multiple myeloma or other plasma cell dyscrasia
  • AA amyloidosis: treatment of underlying inflammatory condition
• See “Amyloidosis” and “Multiple myeloma” for more information.

Lupus nephritis

• See “Treatment” in “Lupus nephritis.”

Thrombotic complications ^[45]

• Venous thromboembolism (e.g., deep vein thrombosis, pulmonary embolism)
• Arterial thromboembolism
• Renal vein thrombosis: thrombus formation in the renal veins or their branches ^[46]
  • Cause: hypercoagulable state (e.g., malignancies, antiphospholipid syndrome, nephrotic syndrome) ^[47]
  • 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 ^[45][48]

• 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 ^[49][50]

• 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 ^[51][52][53]
• Can cause hypocalcemia → ↑ serum parathyroid hormone (PTH) → bone disease (see “Secondary and tertiary hyperparathyroidism”) ^[54]

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 ^[55]

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 minimal change disease 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/day 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.