Persistent or recurrent microscopic or gross hematuria, especially when a relative also has it, when proteinuria or CKD are also present, or when extrarenal features (sensorineural hearing loss, ocular findings) cluster with the urinary phenotype.
Two splits do most of the work. Glomerular versus urologic: dysmorphic red cells, red cell casts, and any proteinuria point glomerular; isolated hematuria with normal sediment can be urologic (stones, anatomy, malignancy). Familial versus sporadic: a first-degree relative with hematuria or unexplained CKD reframes everything.
Alport syndrome (type IV collagen)
- Alport syndrome: most commonly X-linked COL4A5; autosomal recessive COL4A3 or COL4A4; autosomal dominant rare. Hematuria from early childhood plus sensorineural hearing loss plus ocular changes (anterior lenticonus, dot-and-fleck retinopathy) plus progressive CKD. The defining family-history pattern is CKD in male maternal relatives (X-linked).
Thin basement membrane nephropathy
- Heterozygous COL4A3 or COL4A4. Persistent isolated microscopic hematuria, historically called "benign familial hematuria." Most cases are non-progressive, but a meaningful minority of carriers develop proteinuria and CKD over decades; the "benign" framing is being revised. Family history of hematuria without CKD is the classic story.
IgA nephropathy
- The most common glomerulonephritis worldwide. Not classically a single-gene disease but has familial clustering and is in the differential for hematuria plus mesangial proliferation on biopsy.
Storage and metabolic disease
- Fabry disease: X-linked GLA. Proteinuria and hematuria are typical, accompanied by acroparesthesias, angiokeratomas, hypohidrosis, corneal verticillata, cardiomyopathy. Enzyme replacement (or chaperone) therapy is available and modifies progression.
Complement-driven glomerulopathy
- C3 glomerulopathy (C3 glomerulonephritis, dense deposit disease) from complement regulation defects (CFH, CFI, C3, CFHR5). Hematuria, proteinuria, low C3.
Macrothrombocytopenia plus nephritis
- MYH9-related disorders (Epstein, Fechtner, Sebastian, May-Hegglin). Large platelets on smear, sensorineural hearing loss, cataracts (variable), progressive nephropathy.
Branchio-oto-renal spectrum
- EYA1, SIX1, SIX5. Renal anomalies (hypoplasia, agenesis, cysts) plus preauricular pits plus branchial cleft fistulae plus mixed hearing loss.
- Hematuria plus sensorineural hearing loss plus a male maternal relative with CKD is Alport until proven otherwise.
- Persistent isolated microhematuria in a family with hematuria but no CKD points to thin basement membrane nephropathy; still follow it.
- Acroparesthesias plus angiokeratomas plus proteinuria in a young man means a Fabry test today.
- Macrothrombocytopenia on a routine CBC plus proteinuria reframes the renal workup toward MYH9.
- Urinalysis with microscopy (dysmorphic cells, red cell casts), spot protein-to-creatinine, 24-hour urine if needed.
- Audiometry for any familial hematuria.
- Ophthalmologic exam for lenticonus, dot-and-fleck retinopathy, corneal verticillata.
- Renal ultrasound for structural disease.
- Targeted genetics: Alport gene panel (COL4A3/4/5) for hematuria-plus-CKD or hematuria-plus-hearing-loss; GLA enzyme assay in males and sequencing in females suspected of Fabry; renal panel for ambiguous familial cases.
- Renal biopsy when proteinuria progresses, when CKD develops, or to confirm Alport (basement membrane thinning, splitting, lamellation on electron microscopy).
- Hematuria plus SNHL plus a maternal-uncle dialysis story equals Alport.
- A "benign familial hematuria" patient still needs annual urine protein and blood pressure; some progress.
- Don't miss Fabry in a young man with proteinuria and acroparesthesias; it has disease-modifying therapy.
- Macrothrombocytopenia plus renal disease rewrites the whole differential toward MYH9.