What are the etiologies of nephrotic range proteinuria?

Etiologies of Nephrotic Range Proteinuria

Nephrotic range proteinuria is defined as urinary protein excretion ≥3.5 g/24 hours (or albumin-creatinine ratio ≥2.2 g/g for albumin), and can result from primary glomerular diseases, secondary systemic conditions, or less commonly from vascular and tubulointerstitial disorders. 1, 2, 3

Definition and Measurement

• Nephrotic range proteinuria is traditionally defined as total protein excretion >3.5 g/24 hours or protein-creatinine ratio >3.5 g/g 3, 4
• The equivalent threshold for albuminuria is 2.2 g/24 hours or albumin-creatinine ratio of 2.2 g/g 3
• KDIGO classifies this as severely increased albuminuria (A3) with urine albumin-creatinine ratio ≥300 mg/g (≥30 mg/mmol) 2
• The 3.5 g/24h threshold was selected arbitrarily and may not be reached in all cases despite severe glomerular permeability defects, particularly when concurrent liver disease reduces albumin synthesis 5

Primary Glomerular Causes

In Children

• Minimal change disease is the most common primary glomerular disease causing nephrotic range proteinuria in children, particularly those <12 years old 1, 2
• Focal segmental glomerulosclerosis (FSGS) is another important primary cause 2
• IgA nephropathy can present with nephrotic range proteinuria, though this is less common 1

In Adults

• Membranous nephropathy is a leading cause in adults and carries higher venous thromboembolism risk than other causes 1, 2
• Focal segmental glomerulosclerosis (FSGS) should be classified into primary, genetic, secondary, or undetermined cause categories to guide treatment 2
• Minimal change disease can occur in adults, particularly when associated with mesangial IgA deposits 1

Secondary Causes

Systemic Diseases

• Diabetic kidney disease is a major cause of nephrotic range proteinuria, with the traditional 3.5 g/24h threshold validated in this population 3, 6
• Systemic lupus erythematosus causing lupus nephritis, particularly class V (membranous) or mixed proliferative classes 1, 2
• Amyloidosis (both AL and AA types) can cause nephrotic range proteinuria even when concurrent liver involvement reduces albumin synthesis below typical thresholds 1, 5
• HIV-associated nephropathy (HIVAN) presents with variable proteinuria from minimal to nephrotic range, often with rapid progression to ESRD 1

Vascular Causes

• Renovascular disease with renal artery stenosis or thrombosis can cause nephrotic range proteinuria, characterized by marked elevation in filtration fraction (0.28 ± 0.04), high plasma renin activity, and asymmetric kidney sizes (mean difference 29 ± 10 mm) 7
• These patients typically have atherosclerotic vascular disease (93%), are smokers (85%), and have markedly elevated systolic blood pressure (203 ± 22 mm Hg) 7

Drug-Induced

• Nephrotoxic medications should be reviewed in all cases of nephrotic range proteinuria 2
• Indinavir can cause persistent sterile leukocyturia with reversible renal impairment in HIV-infected patients 1

Genetic Causes

• Congenital nephrotic syndrome due to mutations in NPHS1 (nephrin), NPHS2 (podocin), or other podocyte genes 1
• Genetic testing is indicated for patients with familial kidney disease, syndromic features, steroid-resistant FSGS, or history of prematurity 2

Secondary FSGS Etiologies

• Obesity-related (maladaptive) FSGS from hyperfiltration injury 2
• Reduced nephron mass from prematurity, reflux nephropathy, or prior kidney injury 2
• Viral infections including HIV, hepatitis B, and hepatitis C 1, 2

Atypical Presentations

Crescentic Glomerulonephritis

• Crescentic IgA nephropathy defined as >50% crescents with rapidly progressive renal deterioration requires treatment analogous to ANCA vasculitis with steroids and cyclophosphamide 1

Tubulointerstitial Disease

• When proteinuria is <2 g/24 hours, tubulointerstitial or vascular disorders are more likely than glomerular disease, though nephrotic range proteinuria generally indicates glomerular pathology 4

Clinical Pitfalls

• Do not assume glomerular disease exclusively: Renovascular disease can present with nephrotic range proteinuria and has distinct features including high filtration fraction, elevated renin-aldosterone, and asymmetric kidneys 7
• Consider liver disease: Concurrent hepatic dysfunction can result in nephrotic syndrome with proteinuria below 3.5 g/24h due to reduced albumin synthesis 5
• Evaluate for secondary causes systematically: Check for diabetes, lupus (ANA, anti-dsDNA, complement), infections (HIV, hepatitis B/C), medications, and malignancy before attributing to primary glomerular disease 1, 2
• Genetic testing timing: Obtain genetic testing early in steroid-resistant cases, those with family history, or syndromic features rather than waiting for treatment failure 2