Renal Manifestations of Common Variable Immunodeficiency

Abstract

Background: Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiency syndromes, affecting one in 25,000-50,000 people. Renal insufficiency occurs in approximately 2% of patients with CVID. To date, there are no case series of renal biopsies from patients with CVID, making it difficult to determine whether individual cases of renal disease in CVID represent sporadic events or are related to the underlying pathophysiology. We performed a retrospective analysis of renal biopsy specimens in our database from patients with a clinical history of CVID (n=22 patients, 27 biopsies).

Methods: Light, immunofluorescence, and electron microscopy were reviewed. IgG subclasses, PLA2R immunohistochemistry, and THSD7A, EXT1, and NELL1 immunofluorescence were performed on all membranous glomerulopathy cases. CD3, CD4, CD8, and CD20 immunohistochemistry was performed on cases of tubulointerstitial nephritis.

Results: AKI and proteinuria were the leading indications for renal biopsy in patients with CVID. Immune-complex glomerulopathy was present in 12 of 22 (54.5%) cases, including nine cases with membranous glomerulopathy, one case with a C3 glomerulopathy, and one case with membranoproliferative GN with IgG3κ deposits. All membranous glomerulopathy cases were PLA2R, THSD7A, EXT1, and NELL1 negative. The second most common renal biopsy diagnosis was chronic tubulointerstitial nephritis, affecting 33% of patients. All tubulointerstitial nephritis cases showed tubulitis and a lymphocytic infiltrate with >90% CD3⁺ T cells. Other renal biopsy diagnoses within our cohort included acute tubular injury (n=1), amyloid light-chain amyloidosis (n=1), diabetic glomerulosclerosis (n=1), thin basement membranes (n=1), pauci-immune GN (n=1), and arterionephrosclerosis (n=1).

Conclusions: Membranous glomerulopathy and tubulointerstitial nephritis were the predominant pathologic findings in patients with CVID. Membranous glomerulopathy cases in patients with CVID were IgG1 subclass dominant and showed mesangial immune deposits. Four of the membranous glomerulopathy cases had associated proliferation, with mesangial and/or endocapillary hypercellularity, with or without crescent formation. CVID should be considered as a potential cause when membranous glomerulopathy or chronic tubulointerstitial nephritis is seen in a young patient with a history of recurrent infections.

Keywords: Glomerular and Tubulointerstitial Diseases; Glomerular disease; Immunodeficiency; Membranous nephropathy; Renal biopsy; Tubulointerstitial nephritis.

Graphical abstract

Figure 1.

MG in patients with CVID is IgG1 subclass restricted. A PAS stain showing a glomerulus with mild mesangial expansion and prominent capillary loops (A). A JMS stain showing thickened glomerular capillary loops with formation of holes (B). IgG subclasses showing IgG1 granular capillary loop deposits (C), which were negative for IgG2 (D), IgG3 (E), and IgG4 (F) immune deposits. CVID, common variable immunodeficiency; JMS, Jones methenamine silver; MG, membranous glomerulopathy; PAS, periodic acid–Schiff.

Figure 2.

Proliferative changes are identified within glomeruli in patients with CVID with MG. (A) PAS stain showing a membranoproliferative pattern of glomerular injury, magnification ×400. (B) PAS stain showing mesangial and endocapillary hypercellularity, magnification ×400. (C) Cellular crescent formation on JMS stain, magnification ×400. (D) Focus of fibrinoid necrosis in a glomerulus with endocapillary hypercellularity, hematoxylin and eosin stain, magnification ×400; arrow indicates area of fibrinoid necrosis. (E) Segmental sclerosis, PAS stain, magnification ×400; arrow indicates region of segmental sclerosis. (F) Subepithelial and mesangial electron-dense deposits seen by electron microscopy.

Figure 3.

Some cases of tubulointerstitial nephritis in CVID are CD8⁺ T cell–predominant. A haematoxylin and eosin (H&E) stained section shows replacement of renal parenchyma with a diffuse lymphocytic infiltrate (A). Scattered CD68⁺ histiocytes are seen within the infiltrate (B). Immunohistochemistry shows that the infiltrate is comprised of predominantly CD3⁺ T cells (C), with rare CD20⁺ B cells (D). The infiltrate shows few CD4⁺ T cells (E) and is CD8⁺ T cell dominant (F), with a reduced CD4/CD8 ratio.