27 year old man presents with hypertension and leg swelling

CLINICAL HISTORY

A 27 year old man presents to the emergency room with a 1 week history of lower extremity edema and fatigue.  He has not seen a physician in over 10 years.  He is originally from Costa Rica and recalls that while living there 15 years ago he was told of a possible problem with his kidneys, but he did not follow-up and cannot recall what the concerns were based on. At presentation his blood pressure was 180/120 and he had 1+ lower extremity edema. Laboratory work-up shows serum creatinine of 9.77 mg/dL, hematocrit of 29% and albumin of 2.5 mg/dL.  Urinalysis reveals 3+ protein, moderate blood and 5-10 RBC/hpf. Spot urine protein:creatinine ratio is approximately 3. Serologic evaluation was negative or normal for ANA, anti-DNA, HepB surface antigen, HepC ab, HIV, ANCA, anti-GBM, C3 and C4. Ultrasound is notable for echogenic kidneys measuring 9.5 and 10 cm. A renal biopsy was performed.

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FINAL DIAGNOSIS

Hereditary nephritis with advanced cortical scarring (near end stage kidney)

DISCUSSION

Hereditary nephritis (HN) is an inherited disorder of type IV collagen, an important component of the glomerular basement membrane. HN was first described by Alport in 1927 as a progressive familial nephropathy commonly associated with hearing loss and primarily affecting males. HN and Alport syndrome are often used interchangeably in the literature though some believe the term Alport syndrome should be reserved for males with nephropathy along with extrarenal manifestations such as hearing loss.

The earliest clinical manifestation of HN is persistent microscopic hematuria.  As the disease progresses, proteinuria develops and renal insufficiency follows.  Typically, males with X-linked disease progress to ESRD by age 30. Hearing loss is a common extrarenal manifestation, involving up to 80% of males with HN and ocular abnormalities are seen in approximately 25% of males. Female carriers of the X-linked form of HN may also develop renal disease, though it is typically less severe.

The pathologic findings by light microscopy in patients with HN are non-specific and highly dependent on the stage at which the patient is biopsied.  In childhood when hematuria is the only symptom glomeruli are typically normal appearing and there is no significant scarring.  Once proteinuria develops, the finding of interstitial foam cells is common (though any disease with unremitting proteinuria may show interstitial foam cells). With disease progression, glomeruli develop segmental and global sclerosis. Standard immunofluorescence stains are negative but specialized staining for specific alpha chains of collagen IV are now available and can sometimes provide valuable information.  Electron microscopy is typically what establishes the diagnosis of HN and classically shows splitting and lamellation of the glomerular basement membranes resulting in segmental thickening and thinning.  Early in HN, GBM thinning may be the only ultrastructural manifestation, making it difficult to differentiate HN from thin basement membrane nephropathy early in the disease process.  Genetic testing as a diagnostic tool is not yet commercially viable for screening purposes due to the large size of the collagen IV genes and the heterogeneity of mutations seen.

Significant advances in understanding of the structure of type IV collagen have clarified the genetic basis of HN. The type IV collagen gene family is composed of 6 alpha chains and within the glomerular basement membrane, the alpha 3, 4 and 5 subunits combine to form a triple helix which is integral to the GBM.  A mutation in any one of these subunits disrupts formation of a normal triple helix.  Importantly, the alpha 5 chain is encoded on the X-chromosome and is the most commonly mutated chain, accounting for the X-linked inheritance seen in 80% of HN cases. The alpha 3 and 4 chains are encoded on autosomes and mutations in these chains typically show an autosomal recessive inheritance, but occasional autosomal dominant forms of disease associated with the alpha 3 and 4 chains have been described.  The severity of disease typically depends on the severity of the mutation – with large deletions and frameshift mutations causing more severe disease than smaller missense or splice site mutations. Females who are “carriers” of alpha 5 chain mutations may develop significant renal disease, depending on the pattern of X-inactivation and the severity of the mutation that they carry.  There is increasing recognition that the phenotype of thin basement membrane nephropathy is often caused by carrying one copy of a mutation in the autosomally inherited alpha 3 or 4 chains.

REFERENCES

Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport’s syndrome, Goodpasture’s syndrome and type IV collagen. N Engl J Med 348: 2543-56, 2003.
Kashtan CE. Familial hematurias: what we know and what we don’t. Pediatr Nephrol 20:1027-1035, 2005.

CORRESPONDANCE
Leal C. Herlitz M.D. Assistant Professor of Pathology
Columbia University Medical Center, Departement of Pathology, Division of Renal Pathology