Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome

Abstract

IntroductionAlport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children.MethodsTo determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood).ResultsAll patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse.DiscussionThus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome

“…Previously, it was reported that male patients with XLAS with positive staining for a5(IV) in kidney tissue tended to show milder clinical phenotypes and carried nontruncating mutations (mostly missense mutations). 7,16 In our cohort, three of seven patients carrying nontruncating transcriptional variants were a5(IV) positive. In contrast, no patients carrying nontruncating transcriptional variants were a5(IV) positive (Supplemental Table 4).…”

An overview of the multi-pronged approach in the diagnosis of Alport syndrome for 22 children in Northeast China

“…For P19, in addition to the manifestation of nephrotic range proteinuria, the patient also had hearing loss when he was diagnosed. Similarly, Samar et al [ 23 ] stated that negative staining of α5 chain was correlated with the worse prognosis and more severe ultrastructural alterations in AS men. Additionally, eight patients had intact staining of α 5 chain.…”

A review of multi-dimensional diagnosis of Alport syndrome in 22 children in Northeast China

“…For P19, besides presenting proteinuria of nephrotic range, he had hearing loss when he was diagnosed. Similarly, Samar et al [16] stated that negative staining for α5 chain correlates with worse prognosis and more severe ultrastructural alterations in males with Alport Syndrome. There were still 8 patients who had intact staining for α 5 chain.…”