Progressive Renal Failure in a 24-Year-Old Man

A, B, and C are the best answers, as acute tubular necrosis (answer D) is unlikely to cause this level of chronic kidney disease (CKD), small atrophic kidneys, and advanced renal disease. We still need to consider other glomerular diseases in a young man, and the glomerular panel—including C3, C4, anti-nuclear antibodies, anti-neutrophil cytoplasmic autoantibodies, and anti-glomerular basement membrane—returned results within normal limits. With the family history and personal history of some ocular and hearing issues, hereditary nephritis (HN) should be considered. IgA nephropathy can also present in the setting of advanced renal disease (especially if it is crescenteric), but IgA nephropathy usually does not present with hearing and visual issues early in life. CKD can, in general, present with hearing loss.¹

Discussion. HN—otherwise known as Alport syndrome—is a rare genetic disorder collagen synthesis, affecting the basement membranes in several systems, including renal, auditory, and visual. Defects in synthesis of collagen-IV genes, particularly COL4A3, COL4A4, and COL4A5, account for the clinical findings seen in HN. HN is an X-linked, autosomal recessive or dominant disorder and carries significant risk for renal failure and end-stage renal disease (ESRD), sensorineural deafness, and eye abnormalities.²

When considering genetic testing, COL4A3–COL4A5, which affects the structure or function of a collagen-IV α-chain, can confirm a diagnosis of HN. When noted, other family members should be tested to determine their level of risk for HN. ESRD can be predicted with genetic testing as well, since hemizygous men with COL4A5 have a 90% risk of ESRD by age 40 years, while women with a heterozygous COL4A5 variant have up to a 30% likelihood of having ESRD by age 60 years.³ HN inheritance patterns include X-linked, autosomal recessive, and autosomal dominant means. About 80% of HN cases are X-linked type due to mutations in COL4A5 found on the X-chromosome.³ Autosomal recessive inheritance accounts for about 15% of individuals, related to mutations in both the alleles of either COL4A3 or COL4A4.⁴

Both ocular and vestibular abnormalities should be a clue to thinking about this disease, especially in younger patients, and diagnosis and intervention may help alleviate progression to CKD. Ocular issues such as lenticonus, corneal opacities, fleck retinopathies, and temporal retinal thinning have been described and can lead to cataracts.⁵ Early detection of these conditions should prompt physicians to think of HN as well. As far as auditory or sensorineural hearing loss, progressive bilateral high-frequency sensorineural hearing loss is commonly found in patients with HN. This is usually detected in school for children who later develop HN.⁶ 

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A tissue diagnosis for HN can come from renal or skin biopsies, but there are pros and cons to both. In a kidney biopsy specimen, finding a longitudinal splitting of the lamina densa of the GBM is diagnostic but may not be present in younger patients. Attenuation of the GBM is seen in young men with X-linked HN, women with X-linked HN, young men and women with autosomal recessive HN, and all patients with autosomal dominant HN.⁷ A skin biopsy can diagnose suspected X-linked HN. This looks for a monoclonal antibody against the α-5(IV) chain. If this is absent in a man, a diagnosis of X-linked HN can be made, and if it is normally expressed, then an alternate diagnosis may be present, including variants of HN. In these cases, a renal biopsy may be warranted.⁸ 

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