Approach to Hematuria, Proteinuria and Evaluation of Glomerulonephritis

An Evidence-Based Educational Resource for Residents and Renal Fellows

Part 1: Approach to Hematuria

Definition and Detection

Hematuria is defined as ≥3 RBCs per high-power field on microscopic examination of urinary sediment. A positive urine dipstick detects heme (hemoglobin/myoglobin), not necessarily intact RBCs - always confirm with microscopy.

If dipstick positive but no RBCs on microscopy: Consider hemoglobinuria or myoglobinuria. Centrifuge the sample - RBCs sediment; free hemoglobin and myoglobin remain in the supernatant.

Specimen Collection
  • First morning void, clean-catch midstream preferred (higher osmolality/lower pH preserve RBC morphology)
  • Examine within 1-2 hours of collection
  • Confirm on 2-3 separate urinalyses before pursuing workup
  • Exclude benign causes: UTI, menstruation, recent exercise, sexual activity, instrumentation
The Critical Branch Point: Glomerular vs. Non-Glomerular

This distinction drives the entire downstream evaluation.

Feature Glomerular Non-Glomerular
RBC morphology Dysmorphic (blebs, acanthocytes) Isomorphic (normal shape)
RBC casts Present (pathognomonic) Absent
Gross hematuria color Brown / tea / cola-colored Pink / red, may have clots
Proteinuria Often present Usually absent
Clots Absent May be present

Acanthocytes (ring-shaped RBCs with vesicle-shaped protrusions) are the most specific dysmorphic form. A threshold of 25% dysmorphic RBCs suggests glomerular origin. Specificity and PPV of dysmorphic RBCs and RBC casts for glomerular disease: 90-100%.

Glomerular Hematuria

Most common causes of isolated glomerular hematuria:

  • IgA nephropathy - most common immune-mediated GN worldwide; synpharyngitic gross hematuria
  • Thin basement membrane disease - familial; benign in most
  • Alport syndrome - X-linked most common; hearing loss, ocular abnormalities

→ Proceed to serologic workup and consider kidney biopsy

Non-Glomerular Hematuria

Primary concern: urinary tract malignancy

  • Risk factors: age 40, male, smoking, aromatic amine exposure, cyclophosphamide, pelvic XRT
  • Low/intermediate risk: Renal ultrasound acceptable
  • High risk: CT urography (sensitivity ~94%, specificity ~99%)
  • Cystoscopy: Recommended for patients ≥35 yr (AUA) with confirmed microhematuria

Anticoagulant/antiplatelet therapy does NOT explain hematuria - always evaluate.

Part 2: Approach to Proteinuria

Detection and Quantification

Normal urinary protein excretion: 150 mg/day total protein and 30 mg/day albumin. KDIGO 2024 recommends the urine albumin-to-creatinine ratio (UACR) on a spot sample as the preferred initial test (first morning void preferred).

KDIGO Category UACR (mg/g) UPCR (mg/g) Interpretation
A1 <30 <150 Normal to mildly increased
A2 30-300 150-500 Moderately increased
A3 >300 >500 Severely increased
Measurement Pearls
  • Dipstick: Detects albumin only (not light chains, tubular proteins); insensitive for UACR 30-300; false positives with concentrated/alkaline urine, gross hematuria
  • Spot UACR: Corrects for urinary concentration; correlates well with 24-hr collections
  • 24-hr urine: Reference standard for glomerular disease; averages circadian variation
  • Confirm abnormal results on ≥2 of 3 samples over 3-6 months
Classification by Mechanism
  • Glomerular: ↑ GFB permeability → predominantly albuminuria (GN, diabetic nephropathy, amyloidosis)
  • Tubular: Impaired proximal reabsorption of LMW proteins (β2-MG, RBP). Total protein ↑ but albumin relatively low (interstitial nephritis, Fanconi)
  • Overflow: Overproduction of LMW proteins (Bence Jones in myeloma, myoglobinuria). Dipstick may be negative
Transient vs. Persistent Proteinuria

Transient (Benign)

  • Functional: Fever, exercise, stress, CHF, sepsis, UTI - resolves with inciting factor
  • Orthostatic: Present only upright; diagnosed by negative first morning void + positive daytime sample. Most common cause of isolated proteinuria in adolescents. Benign prognosis.

Persistent

Present on ≥80% of random samples. Requires further evaluation - significant proportion have underlying renal pathology. Proceed to quantification, serologic workup, and consider biopsy.

Part 3: Nephrotic vs. Nephritic Syndrome

Feature Nephrotic Syndrome Nephritic Syndrome
Proteinuria ≥3.5 g/day (nephrotic-range) Sub-nephrotic (usually)
Hematuria Minimal / absent Prominent (dysmorphic RBCs, casts)
Edema Prominent (hypoalbuminemia-driven) Mild-moderate (fluid overload)
Serum albumin Low (<3.5 g/dL) Normal or mildly low
Complement Usually normal Often low (lupus, MPGN, post-infectious)
Common causes MCD, FSGS, membranous nephropathy, diabetic nephropathy, amyloidosis IgA nephropathy, lupus nephritis, ANCA vasculitis, anti-GBM disease, post-infectious GN

Key epidemiology: In the US, FSGS is the leading cause of primary nephrotic syndrome (especially in Black patients), followed by membranous nephropathy (most common in older white adults) and MCD. Diabetic nephropathy is the most common overall cause of nephrotic-range proteinuria.

Part 4: When to Biopsy

BIOPSY Indications for Kidney Biopsy
  • Nephrotic syndrome in adults (unless clearly diabetic with typical features)
  • Suspected GN with proteinuria ≥0.5 g/day
  • Unexplained persistent or increasing albuminuria
  • Cellular casts or dysmorphic RBCs with declining GFR
  • RPGN - urgent biopsy indicated
DEFER Biopsy May Be Deferred
  • Steroid-sensitive nephrotic syndrome in children
  • Post-streptococcal GN with classic presentation
  • Membranous nephropathy with positive anti-PLA2R in appropriate clinical context
  • Isolated hematuria without proteinuria, declining GFR, or hypertension (monitor serially)

Part 5: Serologic Workup - A Practical Framework

Complement as a Diagnostic Tool
Low C3 + Low C4
Classical pathway activation
  • Lupus nephritis
  • Cryoglobulinemia
Low C3, Normal C4
Alternative pathway activation
Normal C3 + C4
No complement consumption
  • IgA nephropathy
  • ANCA vasculitis
  • Anti-GBM disease
  • MCD / FSGS
  • Membranous nephropathy
Serologic Tests and Disease Associations
Serologic Test Disease Association
ANA + anti-dsDNALupus Nephritis
PR3-ANCA (c-ANCA)GPA (Wegener's)
MPO-ANCA (p-ANCA)MPA, EGPA
Anti-GBM AbGoodpasture Syndrome
Anti-PLA2R AbPrimary Membranous Nephropathy
ASO / anti-DNase BPost-Streptococcal GN
SPEP + Free Light ChainsAmyloidosis, MGRS, MIDD
HBV / HCV / HIVSecondary MN, MPGN, Cryoglobulinemia
Cryoglobulins + RFCryoglobulinemic Vasculitis
C3 Nephritic FactorC3 Glomerulopathy / DDD

Part 6: Comprehensive Glomerulopathy Reference Table