Igg4 Related Disease: Nephropathy And Bone Marrow Failure In A 2 Year-Old Child

Abstract Background and Aims IgG4 related disease (IgG4 RD) is a recently recognized systemic immune-mediated disorder. Pathophysiology of the disease is still unclear. It is characterized by fibro-inflammatory damage of the tissues, IgG-4 positive plasma-cells and often by elevated serum IgG4. This systemic disease can potentially affect every organ. Renal involvement can include tubulo-interstitial nephritis (TIN), membranous glomerulopathy (MGP) and retroperitoneal fibrosis. The epidemiology is still poorly described, but the disease seems more frequent in men over 50 years of age. Only few cases of IgG4 RD are reported in pediatric patients. Method We describe the first case of IgG4 related kidney disease (IgG4 RKD) in a child with concomitant bone marrow failure. Results M.C., a 2 year-old child, was diagnosed in 2017 with a trilinear bone marrow failure (HB 7.2 g/dL; PLT 6.000/mmc; PMC 923/mmc). Bone marrow biopsy showed poor and dyshomogeneous cellularity (20%) and lymphoplasmacytic infiltrate organized in two follicular structures. All investigations performed to rule out inherited bone marrow failure were negative (DEB test, telomere lenght measurement, c-Mpl mutation analysis, mithocondrial DNA analysis) IgG subclass analysis showed elevated serum levels of IgG4 subclass (353 mg/dL- normal level < 120 mg/dL). During the hospitalization, kidney failure with tubular acidosis was also found (creatinine 1.3 mg/dL, eGFR 28.5 mL/min/1.73 mq, bicarbonate 8.3 mEq/L). Urine analysis showed microematuria, proteinuria (1.07 g/L) and granular casts. Renal ultrasound did not demonstrate abnormal findings. A renal biopsy was performed and a kidney sample with up to 40 glomeruli was obtained. Light microscopy (H&E, JSM, PAS and Masson’s trichrome stains) showed tubule-interstitial inflammatory infiltrate (mainly composed of lymphoplasmacytic cells), irregular thickening of the glomerular basement membranes. IHC stains for C4D showed subepithelial deposits (++). IF was negative for IgA, IgM, C4 and C1q while showed subepithelial glomerular membrane IgG deposits (+++) with granular pattern and tubular wall deposits; glomerular deposits (+) and focal tubular deposits (+++) of C3. A diagnosis of MGP associated with TIN was made. IHC staining for IgG4 was also performed, which demonstrated plasmacells with overlapping positivity for IgG and IgG4. After the diagnosis of IgG4 RKD, an immune-suppressive therapy with steroids (1 mg/kg/die)– targeting both the haematological disorder and glomerulopathy - was started, without clinical response. Thereafter the patient underwent bone marrow transplant from HLA-identical family donor. Conclusion GMP indeed is a very uncommon disease in childhood. Moreover, the association of GMP with TIN is reported in few cases in the literature. Only in the last decade some case of TIN and GMP have been recognized as IgG4 RD and few cases have been reported in adults of IgG4 RKD with simultaneous TIN and GMP. To exclude primary GMP we will perform also the research of antiPLA2r1 antibodies in kidney biopsy. However, the specificity of antiPLA2r in children is lower than in adults and the association of primary GMP with IgG4 TIN is unlikely. IgG4 RD is an emerging systemic disease and it should be taken into account in differential diagnosis in systemic auto-immune diseases, also in the pediatric age. IgG4 RKD and bone marrow failure IgG4 RD are very rare in children but its real incidence among pediatric patients could be still underestimated.