Alport Syndrome

Generalized inherited disorder of basement membranes that involves type IV collagen, characterized by hematuria and progressive neurosensory deafness. Predominant in males. Ocular signs can be present. Renal failure occurs frequently.

Familial Hematuric Nephritis with Neurosensory Deafness.

First described in 1902 by L.B. Guthrie, the English Physician. It was not until 1927 that Arthur Cecil Alport, a South African physician, recognized the association of renal failure and progressive deafness.

Geographic variability. It is the most common form of hereditary glomerular disease and is estimated to account for approximately 2.5 to 3% of all cases of pediatric end-stage renal disease. Males are affected more often and more severely than females as the majority of cases are X-linked inherited, which usually affects females only mildly.

In 85% of patients, inheritance is X-linked caused by mutation on Xq22.3 affecting the gene encoding the α-5 chain of basement membrane collagen COL4A5 (see Pathophysiology). In the remaining 15%, inheritance is autosomal recessive (caused by mutation in either the COL4A3 or COL4A4 gene, which have been mapped to 2q36-q37 and 2q36-q37, respectively. Autosomal dominant inheritance has been described in isolated cases.

In the early stages of Alport syndrome, the glomeruli show segmental proliferation and/or sclerosis. An increase in mesangial matrix often is combined with a foamy appearance of glomerular and tubular epithelial cells secondary to intracellular depositions of fat and mucopolysaccharides. Progression of the disease results in extensive glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis. Electron microscopy allows detection of irregular thickening of the glomerular and tubular basement membrane. One of the main components of the basement membranes is type IV collagen, which consists of six subunits, a1 to a6. In Alport syndrome, depending on the mode of inheritance, subunit a3, a4, or a5 is altered, which all occur almost exclusively in basement membranes of the kidney, the cochlea, and the eye. This situation explains the unique distribution of the disease.

Based on the presence of three of the four major signs: familial history of microhematuria, typical lesions of the glomerular basement membrane, sensorineural deafness, and characteristic ocular abnormalities (anterior lenticonus, spherophakia, cataract, perimacular degeneration).

Generally, the disorder is more severe in males. Initially, patients most often present only with persistent hematuria (microhematuria with intermittent gross hematuria) starting in early childhood and a positive family history for hematuria. Other renal features include proteinuria, hypertension, and renal failure (occurs in >90% of male patients but only 3% of female patients after age 25 years). However, the typical histologic findings may not yet be present in young children. End-stage renal failure, sensorineural, high-frequency hearing loss (in >80% of males and >50% of females), and ophthalmic lesions appear later in life (usually between age 20 and 40 years). Other features may include hypoparathyroidism, thrombocytopenia, ichthyosis, and diffuse leiomyomatosis. This diffuse leiomyomatosis is typical in a subgroup of patients with the X-linked form of Alport syndrome, occurs in older children, and affects the tracheobronchial system and the esophagus. The condition in the former results in recurrent upper airway infections, cough, stridor, and even dyspnea, but in the latter may lead to dysphagia and vomiting. Bowel involvement with constipation has been reported. Genital leiomyomatosis (vulva and clitoris) in girls has been described. Fatal complications and extensive surgery (including esophagectomy) have been described in patients with diffuse leiomyomatosis.

Preoperative blood workup should include a complete blood count (renal anemia, thrombocytopenia) and serum concentrations of electrolytes, urea, creatinine, calcium, phosphate, and protein. Check the degree of proteinuria. Assess the severity of hearing loss. Severe thrombocythemia is a rare finding but should be treated preoperatively if severe and may be a contraindication to central neuraxial blockades. Assess the airway for signs of stridor, cough, and dyspnea and rule out tracheobronchial leiomyomatosis. Patients may have received treatment for asthma. If in doubt, obtain a radiograph or CT scan of the chest.

Depending on the extent of the procedure, invasive blood pressure monitoring may be required. If diffuse leiomyomatosis is present or suspected, a rapid sequence induction technique is recommended. If the airway is involved, spontaneous ventilation must be maintained, and continuous positive airway pressure may be beneficial. Hypoparathyroidism requires regular control of calcium and phosphate serum concentrations in the perioperative period.

Perioperative fluid management and drug doses should be adapted to renal function. Anesthetic drugs without renal metabolism are preferable. Aminosides should be used with care because of potential negative effects on renal function and hearing loss.

Fechtner Syndrome (Macrothrombocytopathy, Nephritis, Deafness, and Leukocyte Inclusion Syndrome; Alport Syndrome with Leukocyte Inclusions and Macrothrombocytopenia): Characterized by a combination of nephritis (with symptoms ranging from microhematuria to end-stage renal failure), high-frequency sensorineural deafness, congenital cataracts, macrothrombocytopenia, and inclusion bodies in neutrophils and eosinophils.

Epstein Syndrome: High-frequency sensorineural deafness and renal disease similar to that found in Alport syndrome. Macrothrombocytopenia results in prolonged bleeding time and impaired platelet aggregation in response to collagen.