Nephrotic syndrome

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Nephrotic Syndrome

Definition

Nephrotic syndrome is defined as proteinuria >3.5 g/24 hours in adults, with serum albumin <3.5 g/dL, accompanied by hyperlipidemia and clinically apparent edema. A spot urine protein:creatinine ratio correlates with the 24-hour collection and can substitute for it in practice.

The unifying pathological mechanism is impairment of glomerular charge and size selectivity - normally maintained by the glomerular basement membrane (GBM), endothelial cells, and podocytes - resulting in massive protein loss into the urine.

National Kidneys Foundation Primer on Kidney Diseases, 8e, p. 189

Etiology and Classification

Fig. 16.1 - Most common etiologies of nephrotic syndrome (NKF Primer on Kidney Diseases, 8e)

Primary (Glomerular) Causes

Disease	Epidemiology	Key Features
Minimal Change Disease (MCD)	~15% of adult NS; 70-90% of pediatric NS	Normal light microscopy; diffuse foot process effacement on EM
Focal Segmental Glomerulosclerosis (FSGS)	~25% of adult NS; most common in African descent	Focal/segmental scarring; podocyte injury
Membranous Nephropathy (MN)	Most common cause of adult NS in whites; 4th-5th decade; M:F = 2:1	Subepithelial immune deposits; anti-PLA2R antibodies in ~70% primary MN

Secondary Causes

Metabolic: Diabetic kidney disease (most common secondary cause globally), amyloidosis
Autoimmune: Lupus nephritis (SLE), Henoch-Schonlein purpura
Infections: Hepatitis B/C (associated with MN), HIV (collapsing FSGS), parvovirus B19
Drugs: NSAIDs, heroin, pamidronate, interferon, gold salts
Malignancy: Solid tumors (associated with MN), Hodgkin lymphoma (associated with MCD)
Genetic: Mutations in podocyte genes - NPHS1 (nephrin), NPHS2 (podocin), ACTN4, APOL1

NKF Primer, pp. 189-192; Tietz Textbook of Laboratory Medicine, 7th Ed.

Pathophysiology

The glomerular filtration barrier has three components: the fenestrated endothelium, the GBM, and podocyte foot processes connected by slit diaphragms. In nephrotic syndrome, damage primarily targets the podocytes, leading to:

Loss of charge selectivity - the GBM normally carries a net negative charge repelling albumin (also negatively charged). This is disrupted in NS.
Foot process effacement - the hallmark on electron microscopy across all causes of primary NS.
Massive proteinuria leading to all downstream consequences.

Edema mechanisms - two models:

Underfill: Protein loss → hypoalbuminemia → reduced plasma oncotic pressure → fluid shifts to interstitium → low effective circulating volume → RAAS activation → sodium retention. Seen classically in MCD.
Overfill: Primary renal sodium and water retention (independent of oncotic pressure) with expanded plasma volume and suppressed RAAS. Seen in most other causes.

Brenner and Rector's The Kidney, 2-Vol Set, p. 2277

Clinical Features

Symptoms: Peripheral edema (often anasarca), foamy urine, fatigue, dyspnea

Signs: Hypertension, generalized dependent pitting edema, ascites, pleural effusions. Less common: Muehrcke's lines (white transverse bands on nails due to hypoalbuminemia), eruptive xanthomata, xanthelasma.

Laboratory:

Proteinuria >3.5 g/24 hr (or spot protein:creatinine ratio >3.5)
Serum albumin <2.5-3.5 g/dL
Hyperlipidemia (total cholesterol usually >180 mg/dL; elevated LDL, triglycerides)
Lipiduria (oval fat bodies, "Maltese cross" under polarized light)
Bland urinary sediment (minimal hematuria, unlike nephritic syndrome)

Frameworks for Internal Medicine; Tietz Laboratory Medicine, 7th Ed.

Complications

1. Hypercoagulability (10-40% develop thromboembolic events)

Mechanisms of hypercoagulability in nephrotic syndrome (Brenner & Rector's The Kidney)

Urinary loss of anticoagulant proteins: antithrombin III, protein C, protein S, plasminogen
Increased hepatic synthesis of procoagulant proteins: fibrinogen, factors V and VIII
Platelet hyperaggregability from hypercholesterolemia
Hemoconcentration from intravascular volume depletion
Steroid therapy and circulating immune complexes compound the risk

Renal vein thrombosis is the most classic complication, especially with severe proteinuria (>10 g/24 hr) and severe hypoalbuminemia (<2 g/dL). Risk is highest in membranous nephropathy and amyloidosis. DVT and pulmonary embolism also occur.

2. Infection

Loss of IgG (small molecule), reduced complement activity, and diminished T-cell function → susceptibility to encapsulated organisms (Streptococcus pneumoniae), cellulitis, and spontaneous bacterial peritonitis.

3. Acute Kidney Injury

Low effective circulating volume
Acute tubular necrosis (especially MCD in patients >50 years)
NSAIDs causing acute interstitial nephritis in MCD
Renal vein thrombosis
Crescentic GN superimposed on existing disease

4. Nutritional/Metabolic Deficiencies from protein loss

Protein Lost	Consequence
Transferrin	Iron deficiency anemia
Vitamin D-binding protein	Vitamin D deficiency, hypocalcemia
IgG, complement	Immunodeficiency
Thyroxine-binding globulin	Low total T4 (free T4 normal)
Albumin-bound drugs	Altered drug pharmacokinetics

Diagnosis

Approach in adults: Kidney biopsy is almost always indicated in adults, as the underlying cause determines management. Exceptions: known diabetic nephropathy with classic clinical picture, or typical MCD presentation (bland sediment, rapid response to steroids in a young patient).

Evaluation:

24-hour urine protein OR spot urine protein:creatinine ratio
Serum albumin, lipid panel, renal function (BUN, creatinine, eGFR)
Urinalysis with microscopy
Serology: ANA, anti-dsDNA (SLE), ANCA, complement C3/C4, anti-PLA2R (membranous nephropathy), hepatitis B/C serology, HIV, serum/urine protein electrophoresis
Kidney biopsy with light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM)

Specific Diseases

Minimal Change Disease (MCD)

LM: Normal
IF: Negative
EM: Diffuse foot process effacement (>90%)
Treatment: Corticosteroids (high response rate in children; variable in adults). Anti-CD20 agents (rituximab) show promise in steroid-resistant or frequently relapsing disease.
In children: Often treated empirically without biopsy.

FSGS

LM: Focal (some glomeruli) and segmental (part of glomerulus) sclerosis
EM: Foot process effacement - >80% effacement favors primary FSGS; <80% favors secondary
Primary FSGS: Corticosteroids, calcineurin inhibitors (tacrolimus/cyclosporine), mycophenolate mofetil. High risk of recurrence post-transplant.
Secondary FSGS: Treat underlying cause; antiproteinuric therapy; avoid immunosuppression.
Collapsing FSGS: Strongly associated with HIV and COVID-19; aggressive course.
APOL1 risk alleles: Associated with high-risk FSGS in African ancestry patients.

Membranous Nephropathy (MN)

LM: Thickened GBM with "spike and dome" pattern on silver stain
IF: Granular IgG and C3 along GBM
EM: Subepithelial electron-dense deposits
Natural history: "Rule of thirds" - 1/3 spontaneous complete remission, 1/3 partial remission, 1/3 progress to ESKD
Markers: Anti-PLA2R antibody (~70% primary MN) - useful for diagnosis and monitoring
Treatment: Reserved for persistent NS or declining GFR. Options include calcineurin inhibitors, cyclophosphamide + corticosteroids (Ponticelli regimen), rituximab (increasingly preferred).

Management

Non-Specific (All Causes)

Strategy	Details
Diet	Low-salt diet; protein restriction 0.8-1 g/kg/day
RAAS blockade	ACE inhibitor or ARB - reduces proteinuria, edema, dyslipidemia, and progression
Diuretics	Loop diuretics for edema. Note: hypoalbuminemia reduces furosemide protein binding, enlarging its volume of distribution and requiring higher doses
Statins	For hyperlipidemia-associated cardiovascular risk
Anticoagulation	For those at high thromboembolic risk (especially MN with albumin <2.5 g/dL)
Vaccinations	Pneumococcal and other vaccines due to infection risk

Diuretic Resistance

A more logical approach is to reduce proteinuria first (with ACE inhibitor/ARB), then add loop diuretics. Volume-expanded (overfill) vs. volume-contracted (underfill) states should be distinguished, as diuretics alone are safe for overfill but can worsen underfill edema.

Brenner and Rector's The Kidney, p. 2277; NKF Primer, p. 190

Nephrotic vs. Nephritic - Quick Comparison

Feature	Nephrotic	Nephritic
Proteinuria	>3.5 g/day	Sub-nephrotic (<3.5 g/day)
Hematuria	Minimal/absent	Prominent (RBC casts)
Edema	Marked (oncotic)	Mild-moderate (volume)
BP	Variable	Hypertension
Mechanism	Permeability defect (podocytes)	Inflammatory (GN)
GFR	Usually preserved initially	Often reduced

Recent Evidence (2024-2026)

A 2025 Cochrane systematic review examined interventions for idiopathic steroid-resistant nephrotic syndrome in children (PMID: 40337980), reflecting ongoing challenges in this population.
A 2026 meta-analysis examined rituximab-induced hypogammaglobulinemia in childhood NS (PMID: 41843217) - a clinically important adverse effect to monitor when using anti-CD20 therapy.
A 2024 systematic review documented NS associated with solid malignancies (PMID: 38965515), reinforcing the need to screen adult-onset NS for occult malignancy, especially in MN.

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