Pediatric Nephrology | 2021
A rare cause of subnephrotic proteinuria in an adolescent: Answers
Abstract
1. What are the main diagnostic considerations based on the kidney biopsy findings? The differential diagnosis includes C3 glomerulonephritis (GN), post-infectious GN, an atypical or secondary membranous nephropathy, and membranous-like glomerulopathy with masked immune deposits (MGMID). C3GN may be considered due to the presence of immune deposits which were C3 dominant and essentially C3-restricted. Although some C3GN may have predominantly subepithelial immune deposits [1], the only modest staining for C3, lack of proliferative features, and normal serum complement levels would be atypical for C3GN [2]. Similar to post-infectious GN, this case was C3 dominant and showed occasionally large “hump-like” subepithelial immune deposits. In contrast, however, there were no exudative features (glomerular neutrophilic influx) on light microscopy, nor clinical history of preceding infection or hypocomplementemia. An atypical or secondary membranous nephropathy is possible given the predominantly subepithelial pattern of immune complex deposition. The relationship to a systemic autoimmune phenomenon could be supported by the positive ANA and cutaneous rash. However, features of lupus nephritis—such as prominent IgG and C1q staining, extraglomerular immune deposits, endothelial tubuloreticular inclusions [3], or proliferative activity— were not present, and the subnephrotic presentation is uncommon for membranous nephropathy. Instead, this case has many of the characteristics of membranous-like glomerulopathy with masked IgG kappa deposits. 2. What test(s) were required to make the correct diagnosis? What is the correct diagnosis? Immunofluorescence performed on pronase-digested, paraffin-embedded tissue (IF-P) to “unmask” the immune deposits is the test required to diagnose MGMID, an unusual glomerulopathy. Direct immunofluorescence on frozen tissue (IF-F) is the preferred method for evaluating kidney disease, but IF-P is utilized as a salvage technique when frozen tissue is not available or lacks glomeruli [4]. Although less sensitive than IF-F in some diseases, IF-P is required to demonstrate immune complexes in other lesions, including in MGMID, membranoproliferative GN with masked monoclonal Ig deposits, and some cases of light chain proximal tubulopathy [4–6], the latter of which are generally adult diseases caused by monoclonal proteins. The mechanism by which immune deposits are “masked” in these cases is unknown; some suggest that antigenic epitopes may not be available for binding due to alterations in protein structure [5], or suggest disruption of immune complexes related to transport media [5, 7]. In this patient’s biopsy, IF-P showed granular capillary wall staining for IgG and kappa light chain (both 2+), without significant staining for lambda light chain, leading to a diagnosis of MGMID (Fig. 1).