Case 4 -

Superimposed Anti Glomerular Basement Membrane Antubody Disease Franco Ferrario San Gerardo Hospital and Milan Bicocca University Milan, Italy

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Clinical History CASE 1 A 35 years old Caucasian male with history of 10 years of insulin-dependent Diabetes Mellitus. He was admitted to our Nephrology Department for overt nephrotic syndrome (proteinuria 7,5 gr/24h - serum albumin 1,8 gr/dl),severe renal insufficiency (S.Creatinine 3,7 mg/dl)and severe anemia (Hb 6,9 gr/dl). He developed an oliguric rapid progression of renal insufficiency (S.Creatinine 10,1 mg/dl) necessitating haemodialysis. Serological tests for autoimmunity were negative (ANA,ENA,RF,anti ds.DNA,C3,C4,Immunoglobulin assay,Cryoglobulins and ANCA. Chest X-ray:Normal. Renal ultrasound examination:Normal Kidneys. Fundoscopic examination:proliferative Diabetic retinopathy. A renal biopsy was performed(see images). 15 days after renal biopsy the patient developed clinical syndrome characterized by shortness of Breath,fever,cough and episode of hemophthysis. CASE 2: A 69 years old Caucasian male with history of 4 years of insulin-dependent Diabetes Mellitus and Hipertension. He was admitted to our Nephrology Department for mild proteinuria(1,5 gr/24h)with normal renal function. All serological tests for autoimmunity were negative. Renal ultrasound examination:Normal Kidneys. Funduscopic examination:Diabetic retinopathy. A renal biopsy was performed(see images). Case 4 - Figure 1 The renal biopsy showed 20 glomeruli. All glomeruli were characterized by marked mesangial matrix expansion with nodular appearance. Moreover 90% of glomeruli showed circunferential cellular crescents. Case 4 - Figure 2 Other pictures showing the same lesions. Case 4 - Figure 3 Immunofluorescence showed strong linear deposits of IgG along glomerular basement membrane. Case 4 - Figure 4 The renal biopsy showed 15 glomeruli. All glomeruli where characterized by mild mesangial matrix expansion with segmental mesangial cells proliferation. No interstitial or vascular lesions were present. Case 4 - Figure 5 At higher magnification was possible to recognize the presence of mesangial deposits. Case 4 - Figure 6 Some Glomeruli showed a clear picture of necrotizing-extracapillary lesions. Case 4 - Figure 7 Immunofluorescence showed mesangial deposits of IgA and Fibrinogen in necrotic areas. Case 4 - Figure 8 By Electronmiscroscopy electron dense mesangial deposits were present. Introduction: A 35 years old Caucasian male with history of 10 years of insulino-dependent diabetes mellitus.He was admitted to our nephrology department for overt nephrotic syndrome(proteinuria 7,5 gr/24h),severe renal insufficiency (S creatinine 3,7 mg/dl) and severe anemia(Hb 6,9 gr/dl). He developed an oliguric rapide progression of renal insufficiency necessitating hemodialysis. Chest X-ray:normal. Renal ultrasound examination:normal Kidneys. Funduscopic examination:Proliferative diabetic retinopathy. Serological tests for autoimmunity were negative( ANA,ENA,RF,anti ds-DNA,C3,C4,Immunoglobulin essay,Cryoglobulin,ANCA) Differential Diagnoses: 1)Diabetic glomerulosclerosis with diffuse extracapillary proliferation. 2)Light chaine disease with diffuse extracapillari proliferation. 3)Renal vasculitis. 4)Antiglomerular basement membrane antibody disease superimposed to diabetic glomerulosclerosis. Final Diagnosis: The extremely rare presence of diffuse circumferential crescents in diabetic glomerulosclerosis and also in Light chaine disease(Kkappa or Lambda were negative at IF).Regarding Vasculitis the ANCA were negative and the morphological picture is usually:necrotizing-extracapillari nephritis) The strong positivity og IgG linear deposits coul suggest the presence of superimposed anti glomerular basement membrane antubody disease. In fact circulating anti-GBM antibodies were detected at hight titer and the patient developped after renal biopsy a clinical syndrome characterized by episode of hemophthisis. Final diagnosis: Anti-GBM antibody disease superimposed to diabetic glomerulosclerosis Case Discussion: The patient presented a long history of diabetes mellitus with sudden appearances of nephrotic syndrome(typical of diabetic glomerulosclerosis) but with contemporaneous presence of rapidli progressive renal failure necessitating hemodialysis(not very usual in diabetic neprhopathy.The picture at immunofluorescence could be of diabetic nephropathy(faint linear parietal deposition of IgG) but in this case the linear deposits were very strong(more similar to anti-GBM antibody disease-also massive crescents). The following serological tests and the clinical syndrome of hemophthisis confirmed this diagnostic hipotesis. Review of the Literature/Treatment Options (if applicable): Renal involvement in type 2 diabetes is a well-known clinical occurrence [1];however an heterogeneous pattern of renal lesions has been suggested in type 2 diabetes,the prevalence of which is difficult to assess from the literature.The discrepancy could be caused by various factors,such as the small number of cases investigated in single studies or geographic/ethnic factors.Also noteworthy could be different policies used by nephrological centers in performing renal biopsies,which could lead to discordant results,even in the same geographic areas. [2, 3, 4, 5] It has been suggested that in diabetes mellitus both the accumulation of GBM material in the mesangium and the decreased clearance of foreing materials or immunocomplex by mesangial cells might play a role in the developement of superimposed immune-mediate glomerulonephritis.In addition advanced glycosilation products(AGE),by modifying GBM components,may render some of them immunogenic,inducing the expression of non-tolerated antigens of the GBM itself. In recent Italian group of renal immunopathology study on 393 patients with type 2 diabetes and overt nephropathythe cases were divided in 4 classes [6]:Class 1:diabetic glomerulosclerosis(309);Class 2:chhronic vascular changes (91);Class 3a:glomerular diseases superimposed(106);Class 3b:unrelated to diabetic glomerulosclerosis.The most frequent glomerular diseases superimposed or unrelated are GNM and IgA nephropathy [6].Renal and patient survival were worst in patients with Class 3a(superimposed) [7] Conclusion(s): The pathologic evaluation in recent large multicentric series of type 2 diabetic patients with overt nephropathy definitly establishes thatrather frequently in such patients histologic patterns other than diabetic glomerulosclerosis can be found. Diabetic nephropathy predicts an ufavorable evolution,which is further worsened by the presence of a superimposed glomerular disease. Many data suggest a more extensiveuse of renal biopsy in diabetic patients not only for accurate diagnosis but also for prognostic and therapeutic purpuses. References: Olson JL:Diabetes mellitus.In Jennette SC et al:Heptinstall's Pathology of the Kidney.Philadelphia,PA,Lippincott-Raven,1998;1247-1286. Kleinknecht et al:Increased prevalence of non Diabetic renal Pathologyin type 2 diabetes mellitus.Nephrol Dial Transplant:1992;7:1258-1259. Richards NT et al:Increased prevalence of renal biopsy findings other than diabetic glomerulopathy in type 2 diabetes mellitus. Olsen S et al:How often is NIDDM complicated with non diabetic renal disease?An analysis of renal biopsies and literature.Diabetologia:1996;39:1638-1645. Curioni S et al:Anti-GBM nephritis complicating diabetic nephropathy.J Nephrol;2002:15;83-87. Mazzucco G et al:Different patterns of renal damage in type 2 diabetes mellitus:A multicentric study on 393 biopsies.Am J Kidney Dis:2002;39:713-720. Savoldi et al.Kidney and patient survival at 84 months in 580 type 2 diabetic nephropathies.ASN 2004-ABST.