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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.

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Nephrotic syndrome Last edited: Apr 08, 2025 Content policy Learned Summary 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 include ( ) and . In children, nephrotic syndrome is most commonly caused by ( ). Nephrotic syndrome can also be a manifestation of advanced renal disease in systemic conditions (e.g., diabetic nephropathy or ). Typical laboratory findings of nephrotic syndrome include hyperlipidemia and faKy casts on urinalysis. Treatment for , , and 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. COLLAPSE NOTES FEEDBACK Definitions Nephrotic-range proteinuria: proteinuria > 3.5 g/24 hours Nephrotic syndrome: nephrotic-range proteinuria PLUS hypoalbuminemia and edema COLLAPSE NOTES FEEDBACK QBANK SESSION causes of nephrotic syndrome focal segmental glomerulosclerosis FSGS membranous nephropathy minimal change disease MCD amyloid nephropathy FSGS membranous nephropathy MCD CoreIM podcast: 5 Pearls on Nephrotic Syndrome Nephritic and nephrotic syn- dromes [1] [1] OPTIONS High-yield Standard Clinician Key exam info on EN Urine protein quantification cutoffs for nephrotic-range proteinuria are somewhat arbitrarily defined (cutoffs used in the literature usually vary from 3.0–3.5 g/24 hoursor spot urine protein/creatinine ratio 3.0–3.5 g/g). Some patients with nephrotic syndrome may present with protein uriaslightly below traditional cutoff values.
Overview MAXIMIZE TABLE TABLE QUIZ Differential diagnoses of nephrotic syndrome Disease Epidemiology Associations Findings Treatment Minimal change disease ( ) Most common cause of nephrotic syndrome in children O@en idiopathic Secondary causes (rare) Immune stimulus (e.g., infection, immunization) Tumors (e.g., Hodgkin lymphoma) Certain drugs (e.g., NSAIDs) LM: no changes (possibly fat bodies in some proximal tubular cells) IM: negative EM: effacement of podocyte foot processes Selective glomerular proteinuria Responds well to prednisone Good prognosis Focal segmental glomerulosclerosis Most common cause of nephrotic syndrome in adults, especially in African American and Hispanic populations Can be idiopathic Heroin use HIV infection Sickle cell disease Massive obesity Interferon treatment Congenital malformations (e.g., Charcot-Marie-Tooth syndrome) NPHS1 and NHPS2 mutations LM: segmental sclerosis and hyalinosis IM Most commonly negative Possibly IgM, C1, and C3 deposits inside the sclerotic regions EM: effacement of podocyte foot processes (similar to ) Prednisone (o@en shows poor response) If necessary, PLUS other immunosuppressants (e.g., cyclosporine, tacrolimus) RAAS inhibitors Usually leads to ESRD if le@ untreated Membranous nephropathy Most common cause of nephrotic syndrome in adults of European, Middle Eastern, or North African descent Primary: Secondary: Infections (HBV, HCV, malaria, syphilis) Autoimmune diseases (e.g., SLE) Tumors (e.g., lung cancer, prostate cancer) Medications (e.g., NSAIDs, penicillamine, gold) LM Diffuse thickened glomerular capillary loops and basement membrane Granular subepithelial deposits of IgG and C3 (dense deposits) → spike and dome appearance RAAS inhibitors Prednisone (o@en shows poor response) PLUS other immunosuppressants (e.g., cyclophosphamide) in severe disease Usually leads to ESRD if le@ untreated Diabetic nephropathy Leading cause of ESRD in high- income countries Usually additional signs of other organ system complications (e.g., retinopathy, neuropathy) LM Thickening of the glomerular basement membrane (increased permeability) Eosinophilic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) EM Thickening of the glomerular basement membrane Mesangial matrix expansion Stringent glycemic control RAAS inhibitors [2][3][4][5][6] lipoid nephrosis [7] [8][9] minimal change disease anti-PLA2R antibodies [10] I 2 G End Stage Renal Disease 3 L
COLLAPSE NOTES FEEDBACK Segmental effacement of podocyte foot processes Amyloid nephropathy More commonly seen in elderly patients The kidney is the most commonly affected organ in systemic amyloidosis. Other organs might be involved simultaneously (e.g., the heart). Multiple myeloma(AL amyloidosis) Chronic inflammatory disease, e.g., tuberculosis, rheumatoid arthritis (AA amyloidosis) LM Mesangial proliferation Subendothelial and/or subepithelial immune complex deposition Thickening of the capillary walls (appear as wire loops) Congo red stain: amyloid deposition in the mesangium showing apple-green birefringence under polarized light Nodular glomerulosclerosis IM: positive for AA protein (AA amyloidosis), positive for kappa and lambda light chains (AL amyloidosis) EM: amyloid fibrils Melphalan, corticosteroids Treatment of underlying disease (e.g., bone marrow transplantation may be used for multiple myeloma) Membranoproliferative glomerulonephritis Usually manifests with nephritic sediment, which can indicate: Nephritic-nephrotic syndrome: if there is concomitant nephrotic-range proteinuria (> 3.5 g/24 hours) Pure nephritic syndrome: if there is no proteinuria or proteinuria is below nephrotic range (< 3.5 g/24 hours) See “Nephritic syndrome.” LM = light microscopy, IM = immunofluorescent microscopy, EM = electron microscopy [11] Minimal change disease Podocyte foot process- es fusion in minimal change disease Focal segmental glomerulosclerosis (FSGS) Focal segmental glomerulosclerosis Membranous nephropathy Membranous nephropathy Diabetic nephropathy Diabetic nephropathy Lupus nephritis Kidney involvement in amyloidosis (2 of 2) &
Etiology Nephrotic syndrome may be caused by primary glomerular disorders (80–90% of cases) and/or systemic diseases and toxic exposures (10–20% of cases). Primary (idiopathic) forms: The following types of nephrotic syndrome are commonly associated with other conditions. See the “Overview” section. Membranous nephropathy Membranoproliferative glomerulonephritis (can manifest as nephrotic or nephritic syndrome) Secondary forms Diabetic 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) COLLAPSE NOTES FEEDBACK Pathophysiology Damage of glomerular filtration barrier : cytokine-mediated damage of podocytes : sclerosis of glomeruli → damage and loss of podocytes : Anti-phospholipase A2 receptor antibodies ( ) bind to PLA2R (an autoantigen in glomerular podocytes) and thereby form immune complexes that activate the complement system, leading to podocyte injury. Membranoproliferative glomerulonephritis: See “Pathophysiology” in “Nephritic syndrome.” Diabetic glomerulonephropathy: See “Pathophysiology” in “Diabetic 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 Lupus nephritis: See “Pathophysiology” in “Lupus nephritis.” Sequelae of glomerular filter damage 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) [12] Minimal change disease Focal segmental glomerulosclerosis Amyloid nephropathy [13][14] Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy anti-PLA2R antibodies [15] Amyloid nephropathy [16] is classically not associated with immune complex deposition. FSGS [13][14] Although the pathophysiology of minimal change disease is not fully understood, it is most likely due to circulating cytokinesfollowing a T-cell response. S & S S S /
Podocyte damage and fusion → nonselective proteinuria (except in , which manifests with selective glomerular proteinuria) 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 ↓ Serum albumin → ↓ colloid osmotic pressure → edema (especially if albumin levels are < 2.5 g/dL) 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 ↑ Plasma levels of cholesterol, LDL, triglycerides, and lipoproteins (mainly LPA) to compensate for the loss of albumin → lipiduria (faPy casts) 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 COLLAPSE NOTES FEEDBACK Clinical features Classic manifestations Massive proteinuria > 3.5 g/24 hours Edema Typically starts with periorbital edema Peripheral edema (piPing) Pleural effusion Pericardial effusion Ascites In severe cases, anasarca Hypoalbuminemia Hyperlipidemia minimal change disease [7] [13][14] [17] [18][19] [20] [21] Cross section of renal corpuscle Renal glomeruli Because the damaged glomeruli continue to operate at the normal filtration rate, the renal function parameters remain largely unchanged while proteins are still released into the urine. Although the cause of lipiduriais not entirely understood, it is thought to involve increased permeability to lipoproteins. Unlike edema related to heart failure, the edema in hypoalbuminemia does not follow gravity. Instead, it appears throughout the entire body. The area around the eyes is usually the first clinically apparent localization of edema because connective tissue in this area is particularly loose, making edema very noticeable.
Nephrotic vs. nephritic syndrome Nephritic syndrome and nephrotic syndrome are both common clinical manifestations of glomerular diseases. Both syndromes are composed of characteristic clinical (e.g., edema, hypertension) and laboratory findings (e.g., glomerular hematuria, massive proteinuria), which result from damage to the glomeruli. Glomerular diseases are usually categorized by the syndrome they cause, which is either nephritic or nephrotic. [1][2] MAXIMIZE TABLE TABLE QUIZ Nephritic syndrome Nephrotic syndrome Presentation Proteinuria (< 3.5 g/day) (can be in nephrotic range in severe cases ) Hematuria with acanthocytes RBC casts in urine Mild to moderate edema Oliguria Azotemia Hypertension Sterile pyuria Rapidly progressive glomerulonephritis (RPGN) Heavy proteinuria (> 3.5 g/day) Hypoalbuminemia Generalized edema Hyperlipidemia and faIy casts in urine → frothy urine Hypertension ↑ Risk of thromboembolism: (via loss of antithrombin III) ↑ Risk of infection (via loss of IgG and tissue edema which compromises the local blood supply and immune response) Pathophysiology Inflammatory response within glomeruli → GBM disruption → loss of renally excreted RBCs (acanthocytes) and ↓ GFR → hematuria, oliguria, azotemia, and ↑ renin → edema and hypertension Damage to podocytes → structural damage of glomerular filtration barrier → massive renal loss of protein Causes Poststreptococcal glomerulonephritis IgA nephropathy (Berger disease) Granulomatosis with polyangiitis Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis Goodpasture disease (anti-GBM disease) Alport syndrome (hereditary nephritis) Thin basement membrane disease Lupus nephritis Due to primary or secondary podocyte damage Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Due to secondary podocyte damage Diabetic nephropathy Amyloid light-chain (AL) amyloidosis, light chain deposition disease Lupus nephritis All glomerular diseases can lead to acute and chronic kidney failure.
Other clinical features Hypercoagulable state with increased risk of thrombosis and embolic events (e.g., pulmonary embolism, ) 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.” COLLAPSE NOTES FEEDBACK Diagnosis Initial evaluation Confirmation of 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 Spot urine protein/creatinine ratio: > 3.5 g/g Urine sediment microscopy Nephrotic sediment Lipiduria, faJy 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 renal vein thrombosis [12][22] nephrotic-range proteinuria [23][24][25] [23][26] [27] Maltese cross sign Dipsticks have an increased sensitivity to albumin and the test may be falsely negativeif proteinuria is mainly due to excess immunoglobulins (e.g., Bence-Jones proteinsin multiple myeloma). False-positiveproteinuria may occur in the setting of concentrated urine (as indicated by high specific gravity). Test of choice for establishing a quantitative proteinuria baseline and monitoring treatment. 24-hour urine collection more accurately quantifies protein excretion than the spot urine protein/creatinine ratio, especially at very high levels of proteinuriaand when proteinuria is subnephrotic.
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 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 Additional testing to assess for potential concomitant conditions and underlying causes should be based on clinical suspicion. [28][29] [12][22] [30] MAXIMIZE TABLE TABLE QUIZ Work-up for concomitant conditions and underlying Suspected condition Recommended studies Diabetic nephropathy Serum glucose HbA1c Age-appropriate cancer screening Lupus nephritis ANA Anti-dsDNA C3, C4 Multiple myeloma and other plasma cell dyscrasias Serum protein electrophoresis and immune fixation Urine protein electrophoresis and immune fixation Chronic viral infection HIV Ab HBsAg HCV Ab Syphilis RPR FTA-ABS Cryoglobulinemia Cryoglobulins C3, C4 Congenital nephrotic syndromes Genetic testing causes of nephrotic syndrome Membranous nephropathy Anti-PLA R antibodies 2
Renal biopsy Indication: to confirm the diagnosis when the etiology of nephrotic syndrome is unclear and/or to guide management Interpretation: See the “Pathology” section. COLLAPSE NOTES FEEDBACK Pathology Classification of nephrotic syndrome is based on the pa@ern 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). EM: effacement of the foot processes of podocytes LM: no changes in glomeruli (possibly fat bodies in some proximal tubular cells) : damage to podocytes EM: effacement of the foot processes (similar to ) LM: segmental sclerosis and hyalinosis and loss of podocytes IM: rarely, focal deposits of IgM, C1, and C3 inside sclerotic lesion : 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) EM: amyloid fibrils LM Nodular glomerulosclerosis Apple-green birefringence (mesangial amyloid deposition) with Congo red stain under polarized light Serum protein elec- trophoresis in nephrotic syndrome [12][22] Minimal change disease Focal segmental glomerulosclerosis minimal change disease Membranous nephropathy Amyloid nephropathy
COLLAPSE NOTES FEEDBACK Treatment Management of symptoms and complications of nephrotic syndrome Edema Dietary sodium restriction: < 3 g/day (usually 1.5–2 g/day) Fluid restriction: < 1.5 liters/day Diuretic therapy Options First-line: oral loop diuretic (e.g., furosemide) 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 Proteinuria Elimination or reduction of proteinuria is a major treatment goal for nephrotic syndrome and can lead to increased serum albumin, decreased edema, aTenuation 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. Podocyte foot process- es fusion in minimal change disease Minimal change disease Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) Membranous nephropathy Diabetic nephropathy Diabetic nephropathy Lupus nephritis [1][12][22] [1][12][22] [1][12] [12][22] [12][22] [34] [1][12][22] [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. Other measures that may be beneficial in combination with an ACEI or ARB: Low sodium diet Thiazide diuretic (e.g., hydrochlorothiazide) Mineralocorticoid receptor antagonist (e.g., spironolactone) Dietary protein: avoid very high-protein diet but ensure adequate protein intake. Dyslipidemia 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 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 Options Unfractionated heparin Low molecular weight heparin (e.g., enoxaparin) Oral warfarin (target INR 2.0–3.0) 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. Infectious risk Preventive measures Pneumococcal vaccination Annual vaccination for influenza Disease-specific measures Primary forms of nephrotic glomerulopathies: oen treated with immunosuppressive therapy Immunosuppressive therapies may include: Glucocorticoids (oen 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 oen treated initially with empiric corticosteroids for presumed . Secondary forms of nephrotic glomerulopathies: Treat the underlying cause. [36] [36] [37] [38] [1][22][39] [1][22][40] [1][40] [40] [1][40] [40] [41] [1] [1][32] MCD [42]
Primary Initial management: conservative therapy including an RAAS inhibitor (i.e., ACEI or ARB) Consider immunosuppressive therapy for severe or refractory disease. Prednisone AND cyclophosphamide Alternatives: cyclosporine, tacrolimus, OR rituximab Primary (idiopathic) ( ) Initial management: supportive therapy including an RAAS inhibitor (i.e., ACEI or ARB). Consider immunosuppressive therapy for all patients with nephrotic syndrome due to . Prednisone Alternative: calcineurin inhibitor (cyclosporin OR tacrolimus) Primary (idiopathic) ( ) Initial management: immunosuppressive therapy Prednisone Alternative: cyclophosphamide OR calcineurin inhibitor Diabetic nephropathy 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. 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.” COLLAPSE NOTES FEEDBACK membranous nephropathy [1] [1] [1] focal segmental glomerulosclerosis FSGS [1] FSGS [1] minimal change disease MCD [1] [1] [43] Amyloid nephropathy [44]
Complications Thrombotic complications Venous thromboembolism (e.g., deep vein thrombosis, pulmonary embolism) Arterial thromboembolism Renal vein thrombosis: thrombus formation in the renal veins or their branches Cause: hypercoagulable state (e.g., malignancies, antiphospholipid syndrome, nephrotic syndrome) 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 Abnormal lipid metabolism in combination with a hypercoagulable state leads to an increased risk of atherosclerotic complications Manifestation: myocardial infarction, stroke Chronic kidney disease and in particular may progress to chronic kidney disease and ESRD. Increased risk of infection 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. [45] [46] [47] [45][48] FSGS membranous nephropathy [49][50]
Vitamin D deficiency Due to urinary loss of vitamin D binding protein (DBP) and bound 25-hydroxyvitamin D Can cause hypocalcemia → ↑ serum parathyroid hormone (PTH) → bone disease (see “Secondary and tertiary hyperparathyroidism”) 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 We list the most important complications. The selection is not exhaustive. COLLAPSE NOTES FEEDBACK Differential diagnoses See “Nephrotic vs. nephritic syndrome.” Lupus nephritis (e.g., diffuse proliferative glomerulonephritis) The differential diagnoses listed here are not exhaustive. COLLAPSE NOTES FEEDBACK Prognosis The prognosis for is usually excellent. With a wide variety of underlying diseases, the response to treatment can differ dramatically. Individuals with nephrotic syndrome oNen develop progressive renal failure despite treatment and go on to require dialysis. COLLAPSE NOTES FEEDBACK [51][52][53] [54] [55] minimal change disease
HINT USED A 6-year-old boy is brought to the physician because of increasing swelling around his eyes for the past 3 days. During this period, he has had frothy light yellow urine. He had a sore throat 12 days ago. He appears tired. His temperature is 37.0°C (98.6°F), pulse is 90/min, and blood pressure is 105/65 mm Hg. Examination shows periorbital edema and piMing edema of the lower extremities. Cardiopulmonary examination shows no abnormalities. Which of the following findings on urinalysis is most likely associated with this patient's condition? ADD NOTES MARK GET ANKI CARDS HINT USED in combination with frothy urine is suggestive of . The most common cause of in children is , which is most likely this child's diagnosis, especially considering his recent . GIVE FEEDBACK SHOW ALL EXPLANATIONS RESET QUESTION HIDE STATS KEY INFO ATTENDING TIP LABS Edema nephrotic syndrome nephrotic syndrome minimal change disease pharyngitis 4% A Epithelial casts 6% B WBC casts 7% C Waxy casts 12% D Hyaline casts 20% E RBC casts 3% G Muddy brown casts 50% FaDy casts are very common in the urinary sediment of patients with nephrotic syndrome. Massive proteinuria (> 3.5 g/24 h) results in low serum albumin, which reduces capillary oncotic pressure, thereby causing edema secondary to fluid leaking into tissue. Consequently, the liver increases all synthetic activity (involving albumin as well as other macromolecules, such as lipids) to compensate. Some of these excess lipids are reabsorbed by the proximal tubular epithelial cells. Once the cytoplasm becomes engorged, chunks of the cell can slough off into the tubular lumen, leading to the classic faMy casts on urinary sediment. Patients with nephrotic syndrome are at high risk of developing infections (due to urinary loss of IgG), hypocalcemia (due to vitamin D deficiency), and venous thrombus formation (due to urinary loss of antithrombin III and loss of fluid into the extravascular space). Nephrotic syndrome GIVE FEEDBACK F FaMy casts Maltese cross sign EXIT SESSION NEXT PREVIOUS T STUDENT Ctrl+K Ask a medical question frothy light yellow urine periorbital edema and pitting edema of the lower extremities
A 5-year-old boy is brought to the physician because of facial swelling that started 5 days ago. Two weeks ago, he had a sore throat that resolved spontaneously. His temperature is 37.0°C (98.6°F), pulse is 107/min, and blood pressure is 94/67 mm Hg. Examination shows piOing edema of the upper and lower extremities as well as periorbital edema. The abdomen is mildly distended. Laboratory studies show: A renal biopsy of this patient is most likely to show which of the following findings? ADD NOTES MARK GET ANKI CARDS HINT USED Large , , , and are indicative of . GIVE FEEDBACK Hemoglobin 13.1 g/dL Serum Albumin 2.1 g/dL Total cholesterol 290 mg/dL Triglycerides 210 mg/dL Urine Blood negative Glucose negative Protein 4+ Leukocyte esterase negative KEY INFO ATTENDING TIP LABS proteinuria hypoalbuminemia edema hyperlipidemia nephrotic syndrome 1% A SpliOing of the glomerular basement membrane on electron microscopy 2% B Mesangial proliferation on light microscopy 5% C Subepithelial dense deposits on electron microscopy 10% D Deposits of IgG and C3 at the glomerular basement membrane on immunofluoresence 1% E Linear deposition of anti-GBM antibodies on immunofluorescence 50% This patient most likely has minimal change disease (MCD), which manifests without visible changes on light microscopy. In this condition, circulating cytokines can cause effacement of podocytes, which is only visible on electron microscopy. MCD is the most common cause of nephrotic syndrome in children (especially < 10 years of age). It may be triggered by a recent infection (as seen in this case) or immunization. MCD responds very well to corticosteroids and has a good prognosis, which is why renal biopsy is usually not indicated for diagnosis. Nephrotic syndrome GIVE FEEDBACK F Normal light microscopy findings Minimal change disease EXIT SESSION PREVIOUS NEXT T STUDENT Ctrl+K Ask a medical question pitting edema Albugin 215/01 To tal cholesterol 290 ms/dl Protein At
SHOW ALL EXPLANATIONS RESET QUESTION HIDE STATS 7% G Granular subepithelial deposits of IgG, IgM, and C3 on immunofluorescence 1% H Apple-green birefringence with Congo red stain 23% I Effacement of foot processes of podocytes on light microscopy 0% J Segmental sclerosis on light microscopy Nephrotic syndrome GIVE FEEDBACK EXIT SESSION PREVIOUS NEXT
A 17-year-old boy is brought to the physician because of swelling of his face and legs for 5 days. He immigrated to the United States from Korea with his family 10 years ago. He has been healthy except for an episode of sore throat 2 weeks ago. His younger sister has type 1 diabetes mellitus. His temperature is 37.0°C (98.6°F), pulse is 90/min, and blood pressure is 145/87 mm Hg. Examination shows periorbital edema and 3+ piRing edema of the lower extremities. Laboratory studies show: Further evaluation is most likely to show which of the following additional findings? ADD NOTES MARK GET ANKI CARDS HINT USED This boy has features of , i.e., swelling of the face and extremities, , and heavy (4+ on ), and that is positive for . frequently occurs in association with , which is more common in some African and Asian countries (e.g., China and Korea). GIVE FEEDBACK Hemoglobin 13.9 g/dL Leukocyte count 8100/mm Serum Glucose 78 mg/dL Albumin 2.4 g/dL Hepatitis B surface antigen positive Hepatitis B surface antibody negative Complement C4 decreased Urine Blood negative Protein 4+ Glucose negative Protein/creatinine ratio 8.1 (N ≤ 0.2) 3 KEY INFO ATTENDING TIP LABS nephrotic syndrome hypoalbuminemia proteinuria urine dipstick serology hepatitis B Membranous nephropathy hepatitis B 2% B Eosinophilic nodules on renal biopsy 47% Subepithelial deposits of IgG and complement along the glomerular basement membrane (spike and dome appearance) are the classic finding in membranous nephropathy. The deposits can be seen on immunofluorescence microscopy and electron microscopy. In secondary membranous nephropathy, subendothelial deposits are also commonly seen. While membranous nephropathy is the most common cause of nephrotic syndrome in white adults, it is rare in the pediatric population. However, there are certain factors that increase the risk of membranous nephropathy in children and adolescents as well, such as early hepatitis B infection, transmiRed either vertically or horizontally. While membranoproliferative glomerulonephritis (MPGN) is also associated with hepatitis B, it is less common than membranous nephropathy and would show spliRing of basement membrane on renal biopsy. Nephrotic syndrome GIVE FEEDBACK A Subepithelial deposits on renal biopsy Membranous nephropathy EXIT SESSION PREVIOUS NEXT T STUDENT Ctrl+K Ask a medical question swelling of his face and legs Korea Albimin 2 . 48/dL Hepatitis B surface antigen + Ve Protein 44 Protein -
SHOW ALL EXPLANATIONS RESET QUESTION HIDE STATS 2% B Eosinophilic nodules on renal biopsy 17% C Antistreptolysin O titers in serum 4% D Antineutrophil cytoplasmic antibody level in serum 26% E Normal-appearing glomeruli on renal biopsy 5% F Increased IgA levels in serum EXIT SESSION PREVIOUS NEXT - -
HINT USED A 7-year-old boy is brought to the physician by his mother for evaluation of progressively worsening swelling around the eyes. He has no history of major medical illness. He had a sore throat and cough 2 weeks ago that resolved spontaneously. Physical examination shows moderate periorbital edema and 2+ piBing edema of the lower extremities bilaterally. A kidney biopsy specimen shows effacement of the podocytes on electron microscopy. Which of the following is most likely to be found on urinalysis? ADD NOTES MARK GET ANKI CARDS HINT USED This patient's finding of effacement of the indicates ( ), the most common cause of in children. A presentation of periorbital and a couple weeks a?er a potential viral infection (i.e., ) is consistent with this diagnosis. GIVE FEEDBACK SHOW ALL EXPLANATIONS RESET QUESTION HIDE STATS KEY INFO ATTENDING TIP LABS biopsy podocytes minimal change disease MCD nephrotic syndrome lower extremity edema sore throat 9% A Hyaline casts and immunoglobulins 12% B Red blood cell casts and acanthocytes 3% D White blood cell casts and eosinophils 4% E Granular casts and tubular epithelial cells 71% FaBy casts and albumin are the expected findings in MCD, in which structural damage to the podocytes and loss of the GBM negative charge results in a loss of protein (specifically, anionic albumin) into the urine. To compensate for the renal loss of albumin, the liver increases lipoprotein synthesis. Lipids are then seen in the urine as faBy casts because of the increased glomerular permeability. Nephrotic syndrome GIVE FEEDBACK C FaBy casts and albumin EXIT SESSION PREVIOUS NEXT T STUDENT Ctrl+K Ask a medical question swelling around the eyes. effacement of the podocytes on electron microscopy
An 8-year-old boy is brought to the office because of bilateral ankle swelling that occurred overnight. He has stopped wearing socks because they feel too tight. He has type 1 diabetes mellitus treated with insulin. He has received all scheduled immunizations. His temperature is 37.0°C (98.6°F), pulse is 90/min, respirations are 16/min, and blood pressure is 112/75 mm Hg. Cardiopulmonary and abdominal examinations show no abnormalities. There is moderate scrotal edema, and 2+ piQing edema of the lower extremities. Laboratory studies show: Treatment with prednisone is begun. Over the following weeks, there is a significant improvement in the patient's peripheral edema and urinalysis findings. Which of the following is the most likely diagnosis? ADD NOTES MARK GET ANKI CARDS HINT USED This patient's history of , , , and on indicates . In this patient, a would most likely show with a normal appearance on light microscopy and effacement of foot processes on . GIVE FEEDBACK Hemoglobin 13.5 g/dL Leukocyte count 5000/mm Platelet count 240,000/mm Serum Urea nitrogen 36 mg/dL Glucose 77 mg/dL Creatinine 0.8 mg/dL Albumin 2.6 mg/dL Urine Blood negative Glucose negative Protein 4+ RBC none WBC 0–1/hpf FaQy casts numerous 3 3 KEY INFO ATTENDING TIP LABS edema hypoalbuminemia proteinuria fa5y casts urinalysis nephrotic syndrome renal biopsy glomeruli podocyte electron microscopy 2% A Nodular glomerulosclerosis 2% B Membranoproliferative glomerulonephritis 1% C IgA nephropathy 2% E Focal segmental glomerulosclerosis 89% Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children. Immunosuppressive therapy is recommended for all patients with MCD; glucocorticoid therapy (e.g., with prednisone) is considered the first-line treatment, as most patients improve with this regimen alone. If complete remission does not occur, higher doses of steroid therapy or alternative immunosuppressive agents (e.g., cyclophosphamide, calcineurin inhibitors) may be needed. Edema should be controlled by sodium restriction and careful monitoring of fluid input and output. MCD has also been associated with hematologic malignancies (e.g., Hodgkin lymphoma). Nephrotic syndrome GIVE FEEDBACK D Minimal change disease EXIT SESSION PREVIOUS SEE ANALYSIS T STUDENT Ctrl+K Ask a medical question 8-year-old boy moderate scrotal edema bilateral ankle swelling 2+ piQing edema of the lower extremities Treatment with prednisone Albumin 2 , 6 mild Protein 4t fatty casts numerous
SHOW ALL EXPLANATIONS RESET QUESTION HIDE STATS 2% E Focal segmental glomerulosclerosis 5% F Membranous nephropathy EXIT SESSION PREVIOUS SEE ANALYSIS

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Nephrotic syndrome. - AMBOSS.pdf

  • 1.
    Nephrotic syndrome Lastedited: Apr 08, 2025 Content policy Learned Summary 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 include ( ) and . In children, nephrotic syndrome is most commonly caused by ( ). Nephrotic syndrome can also be a manifestation of advanced renal disease in systemic conditions (e.g., diabetic nephropathy or ). Typical laboratory findings of nephrotic syndrome include hyperlipidemia and faKy casts on urinalysis. Treatment for , , and 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. COLLAPSE NOTES FEEDBACK Definitions Nephrotic-range proteinuria: proteinuria > 3.5 g/24 hours Nephrotic syndrome: nephrotic-range proteinuria PLUS hypoalbuminemia and edema COLLAPSE NOTES FEEDBACK QBANK SESSION causes of nephrotic syndrome focal segmental glomerulosclerosis FSGS membranous nephropathy minimal change disease MCD amyloid nephropathy FSGS membranous nephropathy MCD CoreIM podcast: 5 Pearls on Nephrotic Syndrome Nephritic and nephrotic syn- dromes [1] [1] OPTIONS High-yield Standard Clinician Key exam info on EN Urine protein quantification cutoffs for nephrotic-range proteinuria are somewhat arbitrarily defined (cutoffs used in the literature usually vary from 3.0–3.5 g/24 hoursor spot urine protein/creatinine ratio 3.0–3.5 g/g). Some patients with nephrotic syndrome may present with protein uriaslightly below traditional cutoff values.
  • 2.
    Overview MAXIMIZE TABLE TABLEQUIZ Differential diagnoses of nephrotic syndrome Disease Epidemiology Associations Findings Treatment Minimal change disease ( ) Most common cause of nephrotic syndrome in children O@en idiopathic Secondary causes (rare) Immune stimulus (e.g., infection, immunization) Tumors (e.g., Hodgkin lymphoma) Certain drugs (e.g., NSAIDs) LM: no changes (possibly fat bodies in some proximal tubular cells) IM: negative EM: effacement of podocyte foot processes Selective glomerular proteinuria Responds well to prednisone Good prognosis Focal segmental glomerulosclerosis Most common cause of nephrotic syndrome in adults, especially in African American and Hispanic populations Can be idiopathic Heroin use HIV infection Sickle cell disease Massive obesity Interferon treatment Congenital malformations (e.g., Charcot-Marie-Tooth syndrome) NPHS1 and NHPS2 mutations LM: segmental sclerosis and hyalinosis IM Most commonly negative Possibly IgM, C1, and C3 deposits inside the sclerotic regions EM: effacement of podocyte foot processes (similar to ) Prednisone (o@en shows poor response) If necessary, PLUS other immunosuppressants (e.g., cyclosporine, tacrolimus) RAAS inhibitors Usually leads to ESRD if le@ untreated Membranous nephropathy Most common cause of nephrotic syndrome in adults of European, Middle Eastern, or North African descent Primary: Secondary: Infections (HBV, HCV, malaria, syphilis) Autoimmune diseases (e.g., SLE) Tumors (e.g., lung cancer, prostate cancer) Medications (e.g., NSAIDs, penicillamine, gold) LM Diffuse thickened glomerular capillary loops and basement membrane Granular subepithelial deposits of IgG and C3 (dense deposits) → spike and dome appearance RAAS inhibitors Prednisone (o@en shows poor response) PLUS other immunosuppressants (e.g., cyclophosphamide) in severe disease Usually leads to ESRD if le@ untreated Diabetic nephropathy Leading cause of ESRD in high- income countries Usually additional signs of other organ system complications (e.g., retinopathy, neuropathy) LM Thickening of the glomerular basement membrane (increased permeability) Eosinophilic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) EM Thickening of the glomerular basement membrane Mesangial matrix expansion Stringent glycemic control RAAS inhibitors [2][3][4][5][6] lipoid nephrosis [7] [8][9] minimal change disease anti-PLA2R antibodies [10] I 2 G End Stage Renal Disease 3 L
  • 3.
    COLLAPSE NOTES FEEDBACK Segmentaleffacement of podocyte foot processes Amyloid nephropathy More commonly seen in elderly patients The kidney is the most commonly affected organ in systemic amyloidosis. Other organs might be involved simultaneously (e.g., the heart). Multiple myeloma(AL amyloidosis) Chronic inflammatory disease, e.g., tuberculosis, rheumatoid arthritis (AA amyloidosis) LM Mesangial proliferation Subendothelial and/or subepithelial immune complex deposition Thickening of the capillary walls (appear as wire loops) Congo red stain: amyloid deposition in the mesangium showing apple-green birefringence under polarized light Nodular glomerulosclerosis IM: positive for AA protein (AA amyloidosis), positive for kappa and lambda light chains (AL amyloidosis) EM: amyloid fibrils Melphalan, corticosteroids Treatment of underlying disease (e.g., bone marrow transplantation may be used for multiple myeloma) Membranoproliferative glomerulonephritis Usually manifests with nephritic sediment, which can indicate: Nephritic-nephrotic syndrome: if there is concomitant nephrotic-range proteinuria (> 3.5 g/24 hours) Pure nephritic syndrome: if there is no proteinuria or proteinuria is below nephrotic range (< 3.5 g/24 hours) See “Nephritic syndrome.” LM = light microscopy, IM = immunofluorescent microscopy, EM = electron microscopy [11] Minimal change disease Podocyte foot process- es fusion in minimal change disease Focal segmental glomerulosclerosis (FSGS) Focal segmental glomerulosclerosis Membranous nephropathy Membranous nephropathy Diabetic nephropathy Diabetic nephropathy Lupus nephritis Kidney involvement in amyloidosis (2 of 2) &
  • 4.
    Etiology Nephrotic syndrome maybe caused by primary glomerular disorders (80–90% of cases) and/or systemic diseases and toxic exposures (10–20% of cases). Primary (idiopathic) forms: The following types of nephrotic syndrome are commonly associated with other conditions. See the “Overview” section. Membranous nephropathy Membranoproliferative glomerulonephritis (can manifest as nephrotic or nephritic syndrome) Secondary forms Diabetic 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) COLLAPSE NOTES FEEDBACK Pathophysiology Damage of glomerular filtration barrier : cytokine-mediated damage of podocytes : sclerosis of glomeruli → damage and loss of podocytes : Anti-phospholipase A2 receptor antibodies ( ) bind to PLA2R (an autoantigen in glomerular podocytes) and thereby form immune complexes that activate the complement system, leading to podocyte injury. Membranoproliferative glomerulonephritis: See “Pathophysiology” in “Nephritic syndrome.” Diabetic glomerulonephropathy: See “Pathophysiology” in “Diabetic 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 Lupus nephritis: See “Pathophysiology” in “Lupus nephritis.” Sequelae of glomerular filter damage 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) [12] Minimal change disease Focal segmental glomerulosclerosis Amyloid nephropathy [13][14] Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy anti-PLA2R antibodies [15] Amyloid nephropathy [16] is classically not associated with immune complex deposition. FSGS [13][14] Although the pathophysiology of minimal change disease is not fully understood, it is most likely due to circulating cytokinesfollowing a T-cell response. S & S S S /
  • 5.
    Podocyte damage andfusion → nonselective proteinuria (except in , which manifests with selective glomerular proteinuria) 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 ↓ Serum albumin → ↓ colloid osmotic pressure → edema (especially if albumin levels are < 2.5 g/dL) 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 ↑ Plasma levels of cholesterol, LDL, triglycerides, and lipoproteins (mainly LPA) to compensate for the loss of albumin → lipiduria (faPy casts) 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 COLLAPSE NOTES FEEDBACK Clinical features Classic manifestations Massive proteinuria > 3.5 g/24 hours Edema Typically starts with periorbital edema Peripheral edema (piPing) Pleural effusion Pericardial effusion Ascites In severe cases, anasarca Hypoalbuminemia Hyperlipidemia minimal change disease [7] [13][14] [17] [18][19] [20] [21] Cross section of renal corpuscle Renal glomeruli Because the damaged glomeruli continue to operate at the normal filtration rate, the renal function parameters remain largely unchanged while proteins are still released into the urine. Although the cause of lipiduriais not entirely understood, it is thought to involve increased permeability to lipoproteins. Unlike edema related to heart failure, the edema in hypoalbuminemia does not follow gravity. Instead, it appears throughout the entire body. The area around the eyes is usually the first clinically apparent localization of edema because connective tissue in this area is particularly loose, making edema very noticeable.
  • 6.
    Nephrotic vs. nephriticsyndrome Nephritic syndrome and nephrotic syndrome are both common clinical manifestations of glomerular diseases. Both syndromes are composed of characteristic clinical (e.g., edema, hypertension) and laboratory findings (e.g., glomerular hematuria, massive proteinuria), which result from damage to the glomeruli. Glomerular diseases are usually categorized by the syndrome they cause, which is either nephritic or nephrotic. [1][2] MAXIMIZE TABLE TABLE QUIZ Nephritic syndrome Nephrotic syndrome Presentation Proteinuria (< 3.5 g/day) (can be in nephrotic range in severe cases ) Hematuria with acanthocytes RBC casts in urine Mild to moderate edema Oliguria Azotemia Hypertension Sterile pyuria Rapidly progressive glomerulonephritis (RPGN) Heavy proteinuria (> 3.5 g/day) Hypoalbuminemia Generalized edema Hyperlipidemia and faIy casts in urine → frothy urine Hypertension ↑ Risk of thromboembolism: (via loss of antithrombin III) ↑ Risk of infection (via loss of IgG and tissue edema which compromises the local blood supply and immune response) Pathophysiology Inflammatory response within glomeruli → GBM disruption → loss of renally excreted RBCs (acanthocytes) and ↓ GFR → hematuria, oliguria, azotemia, and ↑ renin → edema and hypertension Damage to podocytes → structural damage of glomerular filtration barrier → massive renal loss of protein Causes Poststreptococcal glomerulonephritis IgA nephropathy (Berger disease) Granulomatosis with polyangiitis Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis Goodpasture disease (anti-GBM disease) Alport syndrome (hereditary nephritis) Thin basement membrane disease Lupus nephritis Due to primary or secondary podocyte damage Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Due to secondary podocyte damage Diabetic nephropathy Amyloid light-chain (AL) amyloidosis, light chain deposition disease Lupus nephritis All glomerular diseases can lead to acute and chronic kidney failure.
  • 7.
    Other clinical features Hypercoagulablestate with increased risk of thrombosis and embolic events (e.g., pulmonary embolism, ) 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.” COLLAPSE NOTES FEEDBACK Diagnosis Initial evaluation Confirmation of 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 Spot urine protein/creatinine ratio: > 3.5 g/g Urine sediment microscopy Nephrotic sediment Lipiduria, faJy 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 renal vein thrombosis [12][22] nephrotic-range proteinuria [23][24][25] [23][26] [27] Maltese cross sign Dipsticks have an increased sensitivity to albumin and the test may be falsely negativeif proteinuria is mainly due to excess immunoglobulins (e.g., Bence-Jones proteinsin multiple myeloma). False-positiveproteinuria may occur in the setting of concentrated urine (as indicated by high specific gravity). Test of choice for establishing a quantitative proteinuria baseline and monitoring treatment. 24-hour urine collection more accurately quantifies protein excretion than the spot urine protein/creatinine ratio, especially at very high levels of proteinuriaand when proteinuria is subnephrotic.
  • 8.
    BMP: ↑ Crand/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 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 Additional testing to assess for potential concomitant conditions and underlying causes should be based on clinical suspicion. [28][29] [12][22] [30] MAXIMIZE TABLE TABLE QUIZ Work-up for concomitant conditions and underlying Suspected condition Recommended studies Diabetic nephropathy Serum glucose HbA1c Age-appropriate cancer screening Lupus nephritis ANA Anti-dsDNA C3, C4 Multiple myeloma and other plasma cell dyscrasias Serum protein electrophoresis and immune fixation Urine protein electrophoresis and immune fixation Chronic viral infection HIV Ab HBsAg HCV Ab Syphilis RPR FTA-ABS Cryoglobulinemia Cryoglobulins C3, C4 Congenital nephrotic syndromes Genetic testing causes of nephrotic syndrome Membranous nephropathy Anti-PLA R antibodies 2
  • 9.
    Renal biopsy Indication: toconfirm the diagnosis when the etiology of nephrotic syndrome is unclear and/or to guide management Interpretation: See the “Pathology” section. COLLAPSE NOTES FEEDBACK Pathology Classification of nephrotic syndrome is based on the pa@ern 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). EM: effacement of the foot processes of podocytes LM: no changes in glomeruli (possibly fat bodies in some proximal tubular cells) : damage to podocytes EM: effacement of the foot processes (similar to ) LM: segmental sclerosis and hyalinosis and loss of podocytes IM: rarely, focal deposits of IgM, C1, and C3 inside sclerotic lesion : 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) EM: amyloid fibrils LM Nodular glomerulosclerosis Apple-green birefringence (mesangial amyloid deposition) with Congo red stain under polarized light Serum protein elec- trophoresis in nephrotic syndrome [12][22] Minimal change disease Focal segmental glomerulosclerosis minimal change disease Membranous nephropathy Amyloid nephropathy
  • 10.
    COLLAPSE NOTES FEEDBACK Treatment Managementof symptoms and complications of nephrotic syndrome Edema Dietary sodium restriction: < 3 g/day (usually 1.5–2 g/day) Fluid restriction: < 1.5 liters/day Diuretic therapy Options First-line: oral loop diuretic (e.g., furosemide) 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 Proteinuria Elimination or reduction of proteinuria is a major treatment goal for nephrotic syndrome and can lead to increased serum albumin, decreased edema, aTenuation 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. Podocyte foot process- es fusion in minimal change disease Minimal change disease Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) Membranous nephropathy Diabetic nephropathy Diabetic nephropathy Lupus nephritis [1][12][22] [1][12][22] [1][12] [12][22] [12][22] [34] [1][12][22] [1][22][35]
  • 11.
    Effects Reduces proteinuria Treats hypertension Mayslow progression of any underlying renal disease (e.g., diabetic nephropathy) Avoid in patients with AKI, hyperkalemia, or abrupt onset of nephrotic syndrome. Other measures that may be beneficial in combination with an ACEI or ARB: Low sodium diet Thiazide diuretic (e.g., hydrochlorothiazide) Mineralocorticoid receptor antagonist (e.g., spironolactone) Dietary protein: avoid very high-protein diet but ensure adequate protein intake. Dyslipidemia 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 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 Options Unfractionated heparin Low molecular weight heparin (e.g., enoxaparin) Oral warfarin (target INR 2.0–3.0) 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. Infectious risk Preventive measures Pneumococcal vaccination Annual vaccination for influenza Disease-specific measures Primary forms of nephrotic glomerulopathies: oen treated with immunosuppressive therapy Immunosuppressive therapies may include: Glucocorticoids (oen 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 oen treated initially with empiric corticosteroids for presumed . Secondary forms of nephrotic glomerulopathies: Treat the underlying cause. [36] [36] [37] [38] [1][22][39] [1][22][40] [1][40] [40] [1][40] [40] [41] [1] [1][32] MCD [42]
  • 12.
    Primary Initial management: conservativetherapy including an RAAS inhibitor (i.e., ACEI or ARB) Consider immunosuppressive therapy for severe or refractory disease. Prednisone AND cyclophosphamide Alternatives: cyclosporine, tacrolimus, OR rituximab Primary (idiopathic) ( ) Initial management: supportive therapy including an RAAS inhibitor (i.e., ACEI or ARB). Consider immunosuppressive therapy for all patients with nephrotic syndrome due to . Prednisone Alternative: calcineurin inhibitor (cyclosporin OR tacrolimus) Primary (idiopathic) ( ) Initial management: immunosuppressive therapy Prednisone Alternative: cyclophosphamide OR calcineurin inhibitor Diabetic nephropathy 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. 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.” COLLAPSE NOTES FEEDBACK membranous nephropathy [1] [1] [1] focal segmental glomerulosclerosis FSGS [1] FSGS [1] minimal change disease MCD [1] [1] [43] Amyloid nephropathy [44]
  • 13.
    Complications Thrombotic complications Venous thromboembolism(e.g., deep vein thrombosis, pulmonary embolism) Arterial thromboembolism Renal vein thrombosis: thrombus formation in the renal veins or their branches Cause: hypercoagulable state (e.g., malignancies, antiphospholipid syndrome, nephrotic syndrome) 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 Abnormal lipid metabolism in combination with a hypercoagulable state leads to an increased risk of atherosclerotic complications Manifestation: myocardial infarction, stroke Chronic kidney disease and in particular may progress to chronic kidney disease and ESRD. Increased risk of infection 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. [45] [46] [47] [45][48] FSGS membranous nephropathy [49][50]
  • 14.
    Vitamin D deficiency Dueto urinary loss of vitamin D binding protein (DBP) and bound 25-hydroxyvitamin D Can cause hypocalcemia → ↑ serum parathyroid hormone (PTH) → bone disease (see “Secondary and tertiary hyperparathyroidism”) 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 We list the most important complications. The selection is not exhaustive. COLLAPSE NOTES FEEDBACK Differential diagnoses See “Nephrotic vs. nephritic syndrome.” Lupus nephritis (e.g., diffuse proliferative glomerulonephritis) The differential diagnoses listed here are not exhaustive. COLLAPSE NOTES FEEDBACK Prognosis The prognosis for is usually excellent. With a wide variety of underlying diseases, the response to treatment can differ dramatically. Individuals with nephrotic syndrome oNen develop progressive renal failure despite treatment and go on to require dialysis. COLLAPSE NOTES FEEDBACK [51][52][53] [54] [55] minimal change disease
  • 15.
    HINT USED A 6-year-oldboy is brought to the physician because of increasing swelling around his eyes for the past 3 days. During this period, he has had frothy light yellow urine. He had a sore throat 12 days ago. He appears tired. His temperature is 37.0°C (98.6°F), pulse is 90/min, and blood pressure is 105/65 mm Hg. Examination shows periorbital edema and piMing edema of the lower extremities. Cardiopulmonary examination shows no abnormalities. Which of the following findings on urinalysis is most likely associated with this patient's condition? ADD NOTES MARK GET ANKI CARDS HINT USED in combination with frothy urine is suggestive of . The most common cause of in children is , which is most likely this child's diagnosis, especially considering his recent . GIVE FEEDBACK SHOW ALL EXPLANATIONS RESET QUESTION HIDE STATS KEY INFO ATTENDING TIP LABS Edema nephrotic syndrome nephrotic syndrome minimal change disease pharyngitis 4% A Epithelial casts 6% B WBC casts 7% C Waxy casts 12% D Hyaline casts 20% E RBC casts 3% G Muddy brown casts 50% FaDy casts are very common in the urinary sediment of patients with nephrotic syndrome. Massive proteinuria (> 3.5 g/24 h) results in low serum albumin, which reduces capillary oncotic pressure, thereby causing edema secondary to fluid leaking into tissue. Consequently, the liver increases all synthetic activity (involving albumin as well as other macromolecules, such as lipids) to compensate. Some of these excess lipids are reabsorbed by the proximal tubular epithelial cells. Once the cytoplasm becomes engorged, chunks of the cell can slough off into the tubular lumen, leading to the classic faMy casts on urinary sediment. Patients with nephrotic syndrome are at high risk of developing infections (due to urinary loss of IgG), hypocalcemia (due to vitamin D deficiency), and venous thrombus formation (due to urinary loss of antithrombin III and loss of fluid into the extravascular space). Nephrotic syndrome GIVE FEEDBACK F FaMy casts Maltese cross sign EXIT SESSION NEXT PREVIOUS T STUDENT Ctrl+K Ask a medical question frothy light yellow urine periorbital edema and pitting edema of the lower extremities
  • 16.
    A 5-year-old boyis brought to the physician because of facial swelling that started 5 days ago. Two weeks ago, he had a sore throat that resolved spontaneously. His temperature is 37.0°C (98.6°F), pulse is 107/min, and blood pressure is 94/67 mm Hg. Examination shows piOing edema of the upper and lower extremities as well as periorbital edema. The abdomen is mildly distended. Laboratory studies show: A renal biopsy of this patient is most likely to show which of the following findings? ADD NOTES MARK GET ANKI CARDS HINT USED Large , , , and are indicative of . GIVE FEEDBACK Hemoglobin 13.1 g/dL Serum Albumin 2.1 g/dL Total cholesterol 290 mg/dL Triglycerides 210 mg/dL Urine Blood negative Glucose negative Protein 4+ Leukocyte esterase negative KEY INFO ATTENDING TIP LABS proteinuria hypoalbuminemia edema hyperlipidemia nephrotic syndrome 1% A SpliOing of the glomerular basement membrane on electron microscopy 2% B Mesangial proliferation on light microscopy 5% C Subepithelial dense deposits on electron microscopy 10% D Deposits of IgG and C3 at the glomerular basement membrane on immunofluoresence 1% E Linear deposition of anti-GBM antibodies on immunofluorescence 50% This patient most likely has minimal change disease (MCD), which manifests without visible changes on light microscopy. In this condition, circulating cytokines can cause effacement of podocytes, which is only visible on electron microscopy. MCD is the most common cause of nephrotic syndrome in children (especially < 10 years of age). It may be triggered by a recent infection (as seen in this case) or immunization. MCD responds very well to corticosteroids and has a good prognosis, which is why renal biopsy is usually not indicated for diagnosis. Nephrotic syndrome GIVE FEEDBACK F Normal light microscopy findings Minimal change disease EXIT SESSION PREVIOUS NEXT T STUDENT Ctrl+K Ask a medical question pitting edema Albugin 215/01 To tal cholesterol 290 ms/dl Protein At
  • 17.
    SHOW ALL EXPLANATIONSRESET QUESTION HIDE STATS 7% G Granular subepithelial deposits of IgG, IgM, and C3 on immunofluorescence 1% H Apple-green birefringence with Congo red stain 23% I Effacement of foot processes of podocytes on light microscopy 0% J Segmental sclerosis on light microscopy Nephrotic syndrome GIVE FEEDBACK EXIT SESSION PREVIOUS NEXT
  • 18.
    A 17-year-old boyis brought to the physician because of swelling of his face and legs for 5 days. He immigrated to the United States from Korea with his family 10 years ago. He has been healthy except for an episode of sore throat 2 weeks ago. His younger sister has type 1 diabetes mellitus. His temperature is 37.0°C (98.6°F), pulse is 90/min, and blood pressure is 145/87 mm Hg. Examination shows periorbital edema and 3+ piRing edema of the lower extremities. Laboratory studies show: Further evaluation is most likely to show which of the following additional findings? ADD NOTES MARK GET ANKI CARDS HINT USED This boy has features of , i.e., swelling of the face and extremities, , and heavy (4+ on ), and that is positive for . frequently occurs in association with , which is more common in some African and Asian countries (e.g., China and Korea). GIVE FEEDBACK Hemoglobin 13.9 g/dL Leukocyte count 8100/mm Serum Glucose 78 mg/dL Albumin 2.4 g/dL Hepatitis B surface antigen positive Hepatitis B surface antibody negative Complement C4 decreased Urine Blood negative Protein 4+ Glucose negative Protein/creatinine ratio 8.1 (N ≤ 0.2) 3 KEY INFO ATTENDING TIP LABS nephrotic syndrome hypoalbuminemia proteinuria urine dipstick serology hepatitis B Membranous nephropathy hepatitis B 2% B Eosinophilic nodules on renal biopsy 47% Subepithelial deposits of IgG and complement along the glomerular basement membrane (spike and dome appearance) are the classic finding in membranous nephropathy. The deposits can be seen on immunofluorescence microscopy and electron microscopy. In secondary membranous nephropathy, subendothelial deposits are also commonly seen. While membranous nephropathy is the most common cause of nephrotic syndrome in white adults, it is rare in the pediatric population. However, there are certain factors that increase the risk of membranous nephropathy in children and adolescents as well, such as early hepatitis B infection, transmiRed either vertically or horizontally. While membranoproliferative glomerulonephritis (MPGN) is also associated with hepatitis B, it is less common than membranous nephropathy and would show spliRing of basement membrane on renal biopsy. Nephrotic syndrome GIVE FEEDBACK A Subepithelial deposits on renal biopsy Membranous nephropathy EXIT SESSION PREVIOUS NEXT T STUDENT Ctrl+K Ask a medical question swelling of his face and legs Korea Albimin 2 . 48/dL Hepatitis B surface antigen + Ve Protein 44 Protein -
  • 19.
    SHOW ALL EXPLANATIONSRESET QUESTION HIDE STATS 2% B Eosinophilic nodules on renal biopsy 17% C Antistreptolysin O titers in serum 4% D Antineutrophil cytoplasmic antibody level in serum 26% E Normal-appearing glomeruli on renal biopsy 5% F Increased IgA levels in serum EXIT SESSION PREVIOUS NEXT - -
  • 20.
    HINT USED A 7-year-oldboy is brought to the physician by his mother for evaluation of progressively worsening swelling around the eyes. He has no history of major medical illness. He had a sore throat and cough 2 weeks ago that resolved spontaneously. Physical examination shows moderate periorbital edema and 2+ piBing edema of the lower extremities bilaterally. A kidney biopsy specimen shows effacement of the podocytes on electron microscopy. Which of the following is most likely to be found on urinalysis? ADD NOTES MARK GET ANKI CARDS HINT USED This patient's finding of effacement of the indicates ( ), the most common cause of in children. A presentation of periorbital and a couple weeks a?er a potential viral infection (i.e., ) is consistent with this diagnosis. GIVE FEEDBACK SHOW ALL EXPLANATIONS RESET QUESTION HIDE STATS KEY INFO ATTENDING TIP LABS biopsy podocytes minimal change disease MCD nephrotic syndrome lower extremity edema sore throat 9% A Hyaline casts and immunoglobulins 12% B Red blood cell casts and acanthocytes 3% D White blood cell casts and eosinophils 4% E Granular casts and tubular epithelial cells 71% FaBy casts and albumin are the expected findings in MCD, in which structural damage to the podocytes and loss of the GBM negative charge results in a loss of protein (specifically, anionic albumin) into the urine. To compensate for the renal loss of albumin, the liver increases lipoprotein synthesis. Lipids are then seen in the urine as faBy casts because of the increased glomerular permeability. Nephrotic syndrome GIVE FEEDBACK C FaBy casts and albumin EXIT SESSION PREVIOUS NEXT T STUDENT Ctrl+K Ask a medical question swelling around the eyes. effacement of the podocytes on electron microscopy
  • 21.
    An 8-year-old boyis brought to the office because of bilateral ankle swelling that occurred overnight. He has stopped wearing socks because they feel too tight. He has type 1 diabetes mellitus treated with insulin. He has received all scheduled immunizations. His temperature is 37.0°C (98.6°F), pulse is 90/min, respirations are 16/min, and blood pressure is 112/75 mm Hg. Cardiopulmonary and abdominal examinations show no abnormalities. There is moderate scrotal edema, and 2+ piQing edema of the lower extremities. Laboratory studies show: Treatment with prednisone is begun. Over the following weeks, there is a significant improvement in the patient's peripheral edema and urinalysis findings. Which of the following is the most likely diagnosis? ADD NOTES MARK GET ANKI CARDS HINT USED This patient's history of , , , and on indicates . In this patient, a would most likely show with a normal appearance on light microscopy and effacement of foot processes on . GIVE FEEDBACK Hemoglobin 13.5 g/dL Leukocyte count 5000/mm Platelet count 240,000/mm Serum Urea nitrogen 36 mg/dL Glucose 77 mg/dL Creatinine 0.8 mg/dL Albumin 2.6 mg/dL Urine Blood negative Glucose negative Protein 4+ RBC none WBC 0–1/hpf FaQy casts numerous 3 3 KEY INFO ATTENDING TIP LABS edema hypoalbuminemia proteinuria fa5y casts urinalysis nephrotic syndrome renal biopsy glomeruli podocyte electron microscopy 2% A Nodular glomerulosclerosis 2% B Membranoproliferative glomerulonephritis 1% C IgA nephropathy 2% E Focal segmental glomerulosclerosis 89% Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children. Immunosuppressive therapy is recommended for all patients with MCD; glucocorticoid therapy (e.g., with prednisone) is considered the first-line treatment, as most patients improve with this regimen alone. If complete remission does not occur, higher doses of steroid therapy or alternative immunosuppressive agents (e.g., cyclophosphamide, calcineurin inhibitors) may be needed. Edema should be controlled by sodium restriction and careful monitoring of fluid input and output. MCD has also been associated with hematologic malignancies (e.g., Hodgkin lymphoma). Nephrotic syndrome GIVE FEEDBACK D Minimal change disease EXIT SESSION PREVIOUS SEE ANALYSIS T STUDENT Ctrl+K Ask a medical question 8-year-old boy moderate scrotal edema bilateral ankle swelling 2+ piQing edema of the lower extremities Treatment with prednisone Albumin 2 , 6 mild Protein 4t fatty casts numerous
  • 22.
    SHOW ALL EXPLANATIONSRESET QUESTION HIDE STATS 2% E Focal segmental glomerulosclerosis 5% F Membranous nephropathy EXIT SESSION PREVIOUS SEE ANALYSIS