Abnormal Pediatric Glomerular Basement Membranes – Novel Genetic Associations
RAM Rawson, C Lassman, CC Nast. Cedars-Sinai Medical Center, Los Angeles, CA; UCLA Medical Center, Los Angeles, CA
Background: Abnormal glomerular capillary basement membranes (CBM) are a feature of known genetic renal diseases such as Alport, nail-patella, and Pierson syndromes. We identified unclassifiable CBM lesions in 5 pediatric patients and sought to determine the etiologies.
Design: Records were reviewed for clinical findings and family histories, and all biopsies were assessed in the standard fashion. 4 biopsies additionally were assessed for colα3 and α5(IV), laminin α2, α5 and β2, podocin, synaptopodin, α-actinin-4, nephrin and WT-1 by IF and by PTA stain for EM. One biopsy (P1) had additional staining only for colα3 and α5(IV). CBM thickness was evaluated by EM morphometric measurement of the thickest and thinnest part of all non-oblique CBM between cell plasma membranes in at least 2 glomeruli.
Results: Age, proteinuria at presentation and morphologic findings are in the table below. All patients had normal renal function; patient (P) 1 had transient hypocomplementemia and peri-orbital edema, all others had normal serologies and no signficiant physical findings. Ultrastructurally, P1 had foci of thin CBM and thick CBM due to irregular intramembranous lucencies and slight layering and was found to be nephrin deficient. P2 and P3 showed similar findings with areas of thick and thin CBM with uniform electron density; P3 had absent α actinin 4 and a family history of focal sclerosis. P4 and P5 were similar wtih markedly thick CBM having a "moth eaten” pattern, segmental areas of entrapped cytoplasm, and coarsely scalloped subepithelial contours but without identified protein abnormalities.
|Patient #||Age (yrs)||Proteinuria||Renal Family Hx||CBM Thickness in nm (Average)||Staining Results||Genetic Testing|
|1||2||Nephrotic||No||90-700 (280)||Colα3,α5(IV) normal||Absent nephrin|
|2||5||Pr/Cr 0.58||Yes||151-543 (305)||All normal||Not done|
|3||5||Pr/Cr 1.02||Yes||142-590 (323)||↓α actinin 4||Nephrin, WT-1, Lam-2 normal|
|4||8||Pr/Cr 0.94||Yes||266-2023 (886)||All normal||Not done|
|5||13||1.2 gms/24 hrs||Yes||516-2781 (1153)||All normal||Not done|