Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

Abstract

Introduction: Cobalamin C (cblC) deficiency is the most common inborn error of vitamin B₁₂ metabolism. Renal failure attributed to thrombotic microangiopathy (TMA) has occasionally been described in the late-onset presentation of cblC deficiency, but kidney lesions associated with cblC deficiency remain poorly defined. This study aims to describe the characteristics of kidney disease in cblC deficiency, and to provide a comparative histological analysis with cblC-independent renal TMA.

Methods: We performed a multicenter retrospective study including 7 patients with cblC deficiency and 16 matched controls with cblC-independent TMA. The patients included were aged 6 to 26 years at the time of the first manifestations. All patients presented with acute renal failure, proteinuria, and hemolysis; 5 patients required dialysis.

Results: The histological study revealed arteriolar and glomerular TMA in all patients. After comparison with the cblC-independent TMA control group, a vacuolated aspect of the glomerular basement membrane and the intensity of glomerular capillary wall IgM deposits were more present in cblC deficiency patients than in controls. Six patients were treated with hydroxycobalamin. All of them improved, with disappearance of hemolysis, and 3 of the 4 patients requiring renal replacement therapy were weaned off dialysis.

Conclusion: This study provides a precise description of kidney pathology in cblC deficiency. Due to major therapeutic implications, we suggest that patients with renal TMA be screened for cblC deficiency regardless of age, particularly when the kidney biopsy provides evidence of long-lasting TMA, including a vacuolated aspect of the glomerular basement membrane and glomerular capillary wall IgM deposition.

Keywords: cobalamin C deficiency; genetic kidney disease; renal pathology; thrombotic microangiopathy.

Figure 1

Intracellular cobalamin metabolism. AdoCbl, adenosylcobalamin; Cbl, cobalamin; MeCbl, methylcobalamin; MMACHC, methylmalonic aciduria cblC type with homocystinuria protein.

Figure 2

Glomerular and arteriolar lesions of thrombotic microangiopathy in patients with cobalamin C (cblC) deficiency. (a−f) Kidney biopsy. Light microscopy. (a) Arteriolar and glomerular thrombotic microangiopathy with thickening of capillary walls and arteriolar thrombus (patient 1; Masson trichrome staining; original magnification ×400). (b) Global thickening of glomerular capillary walls and endocapillary glomerular thrombi (patient 5; Masson trichrome staining; original magnification ×400). (c) Global thickening of glomerular capillary walls and duplication of the glomerular basement membrane (patient 5 [second biopsy]; Jones staining; original magnification ×400). (d) Massive juxtaglomerular arteriolar and glomerular thrombi (patient 6; Masson trichrome staining; original magnification ×400). (e) Glomerular ischemia and arteriolar fibrous plug (patient 2; Jones staining; original magnification ×400). (f) Glomerular thrombotic microangiopathy and arteriole occluded by fibrosis infiltered by foamy cells (patient 1; Masson trichrome staining; original magnification ×400).

Figure 3

Vacuolated aspect of the glomerular basement membrane (GBM) due to IgM deposits in patients with cobalamin C deficiency. (a) Light microscopy. Glomerular capillary wall thickening with vacuoles and spikes (patient 3; Jones staining; original magnification ×2000). (b) Immunofluorescence microscopy. Glomerular capillary wall granular IgM deposits (patient 1; immunofluorescence staining for IgM; original magnification ×400). (c,d) Electron microscopy. Patient 1. (c) Thickening of the glomerular capillary wall with intramembranous granular deposits and material leading to the vacuolated aspect of the GBM (original magnification ×16,000). (d) Intramembranous granular deposits and mesangial cell expansion in vacuolated GBM (original magnification ×50,000).