Other hereditary kidney disorders

1. What is familial or inherited hematuria?

Familial (inherited) hematuria is defined as a group of genetic kidney disorders that are clinically characterized by the onset of persistent microscopic hematuria during childhood. The unifying feature of these conditions is an abnormality in the network of type IV collagen in the glomerular basement membrane (GBM). The major forms of familial hematuria are Alport syndrome and thin basement membrane nephropathy (TBMN).

2. How common is Alport syndrome?

Alport syndrome is a rare condition, occurring in 1 in 50,000 individuals.

3. What are the major clinical features in males with Alport syndrome?

Males with Alport syndrome have persistent microscopic hematuria beginning in infancy. Episodes of macroscopic hematuria may occur, but they become less frequent after adolescence. Proteinuria and progressive chronic kidney disease develop as early as the second decade of life but may not be present until well into adulthood. End-stage kidney disease (ESKD) develops in virtually all affected males, but the rate of progression of kidney disease is variable between families. Overall, about 50% of males reach ESKD by age 25, 90% by age 40, and 100% by 60 years.

4. What are the major clinical findings in females with Alport syndrome?

Females with Alport syndrome have a much milder course than do males, but should be characterized as “affected individuals” rather than “carriers” who have an “at risk” state. Microscopic hematuria is present in 95% of females, but significant proteinuria and progressive kidney dysfunction occur in 15% of females by the age of 60 years.

5. What other abnormalities may be associated with Alport syndrome?

High-frequency, sensorineural hearing loss typically begins in late childhood and ultimately develops in 70% of males with Alport syndrome by the age 40 years. Deafness ultimately develops in 80% of affected males. A minority of females with Alport syndrome develop hearing loss. About 40% of males with Alport syndrome exhibit characteristic ocular abnormalities. Twenty percent of patients have white or yellow perimacular flecks, which increase in number with age. Twenty percent of patients have anterior lenticonus, a protrusion of the central area of the lens into the anterior chamber, which can result in recurrent corneal erosion. Leiomyomatosis and platelet abnormalities are occasionally seen.

6. What are the characteristic kidney biopsy findings in Alport syndrome?

The pathognomonic kidney biopsy finding in Alport syndrome is diffuse thickening of the GBM with splitting of the lamina densa, giving a basket-weave appearance on electron microscopy. In young patients, both thickening and thinning of the GBM may be present, causing difficulty in distinguishing the early stages of Alport syndrome from TBMN. Light microscopy shows segmental or global glomerulosclerosis, interstitial fibrosis, and tubular atrophy.

7. How is Alport syndrome inherited?

The most common form of Alport syndrome is X-linked Alport syndrome (XLAS), which comprises 80% of cases. Autosomal-recessive Alport syndrome (ARAS) comprises 15% of cases, and autosomal-dominant Alport syndrome (ADAS) is rare, comprising only 5% of cases. Of children with XLAS, 10% to 15% have no family history of hematuria or kidney disease and are felt to represent de novo mutations.

8. What are the genetic abnormalities in Alport syndrome?

XLAS results from one of a variety of mutations in the gene for the alpha-5 chain of type IV collagen (COL4A5) on the X chromosome. The result is an alteration in the structure of the alpha-5 collagen chain, preventing normal incorporation of alpha-3 and alpha-4 collagen chains into basement membranes. ARAS results from homozygous or compound heterozygous mutations in both copies of either the COL4A3 or COL4A4 gene on chromosome 2. ADAS is caused by heterozygous mutations in either the COL4A3 or COL4A4 gene.

9. What treatment is available for Alport syndrome?

Currently, there is no definitive therapy for Alport syndrome. Treatment remains supportive in nature and should focus on the control of hypertension and the reduction of proteinuria to slow the progressive loss of kidney function over time. Angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers are useful agents and are recommended in patients with Alport syndrome with proteinuria greater than 200 mg/day, although there is some thought that the earlier initiation of ACEi before proteinuria develops may prove helpful. The metabolic consequences of chronic kidney disease should be carefully managed, and all affected family members should be identified by urine screening or genetic testing, if indicated.

10. Are there any special complications in patients with Alport syndrome following kidney transplantation?

Patients with XLAS who undergo transplant have survival rates similar to or better than those with other inherited kidney diseases. However, 3% to 5% of transplanted males with Alport syndrome develop post-transplant anti-GBM nephritis, leading to rapid decline in allograft function despite aggressive therapy. This condition results from an immunologic response by the recipient to the alpha-5 chain of type IV collagen, a previously unrecognized antigen in the transplant recipient. The subset of patients with Alport syndrome at highest risk for this complication includes males with significant deafness and the onset of ESKD before the age of 30 years.

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