Alport syndrome: HLA association and kidney graft outcome

Abstract

Alport syndrome (AS) is a genetic disease of type IV collagen involving non-homogeneous patterns of inheritance characterized clinically by the presence of progressive haematuric nephritis leading to end-stage renal disease (ESRD), hearing loss and/or ophthalmologic abnormalities. The aim of this study was to investigate, in a cohort of AS patients who had undergone a kidney graft (KG) or who were still on a waiting list for a KG, (a) whether there is a correlation between AS and HLA antigen expression, and (b) long-term graft outcome in transplant patients. The AS cohort was represented by 34 ESRD patients, of whom 25 received a KG and the remaining nine were still on a waiting list. AS transplant patients represented 2.78% of 899 first KGs performed at our centre (Transplantation Department at S. Martino Hospital, Genoa) between 1983 and 2002. Grafts were procured from cadaveric donors in 18 cases and from living, related donors in seven cases. All AS transplant patients had a post-transplant follow-up period of at least 12 months. Results showed that: (i) the frequency of the HLA-DRB1*16 antigen was significantly increased in the whole AS cohort as compared to 128 healthy subjects (HS) (corrected P-value 0.0026; relative risk 7.20) as well as to 232 non-AS ESRD patients on a waiting list for KG (corrected P-values 0.0156; relative risk 4.67); (ii) 5- and 10-year graft survivals in the AS transplant patients were 80 and 73%, respectively, and did not differ from those of a control group represented by 25 non-AS KG recipients matched for sex, age, number of HLA mismatches and immunosuppressive treatment. Increased frequency of HLA-DRB1*16 in AS patients may reflect a linkage disequilibrium with genes coding for collagen synthesis.

Phacoemulsification and intraocular lens implantation in Alport syndrome with anterior lenticonus

“…The loss of these collagen molecules from the affected basement membranes results in an abnormal ultrastructural appearance. 2,13 The ocular and other clinical features of autosomal recessive Alport syndrome are identical to those seen in the X-linked disease, while retinopathy and cataracts are the only ocular abnormalities described in the rare autosomal dominant form. Hearing problems usually start in childhood in male patients and around 40 years of age in female patients.…”

“…9 The typical ocular associations are dot-and-fleck retinopathy, which occurs in about 85% of affected adult men; anterior lenticonus, which occurs in about 25%; and the rare posterior polymorphous corneal dystrophy. 1,2,5,6,9,10 The retinopathy and anterior lenticonus are not evident in childhood but become worse with time. 9 A retinal lesion is often present at the onset of renal failure, but signs of anterior lenticonus appear later.…”

“…2 These 6 chains are encoded by genes COL4A1 to COL4A6, respectively. 2 Genes COL4A1 and COL4A2 are located on chromosome 13, genes COL4A3 and COL4A4 are located on chromosome 2, and genes COL4A5 and COL4A6 are mapped to the long arm of chromosome X. 2,5 All mutations demonstrated to date in X-linked Alport syndrome have affected the COL4A5 gene, which encodes the alpha-5 chain of type IV collagen.…”

“…2 Genes COL4A1 and COL4A2 are located on chromosome 13, genes COL4A3 and COL4A4 are located on chromosome 2, and genes COL4A5 and COL4A6 are mapped to the long arm of chromosome X. 2,5 All mutations demonstrated to date in X-linked Alport syndrome have affected the COL4A5 gene, which encodes the alpha-5 chain of type IV collagen. 2 This protein is probably common to the basement membranes of the glomerulus, cochlea, retina, lens capsule, and cornea.…”

“…2,5 All mutations demonstrated to date in X-linked Alport syndrome have affected the COL4A5 gene, which encodes the alpha-5 chain of type IV collagen. 2 This protein is probably common to the basement membranes of the glomerulus, cochlea, retina, lens capsule, and cornea. However, the alpha-3 (IV), -4 (IV), and -5 (IV) collagen chains are usually absent from the affected basement membranes because the abnormal alpha-5 (IV) molecule interferes with the stability of all 3.…”