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Idiopathic Membranous Nephropathy Paul M. Johnson UNC Internal Medicine AM Report August 4, 2009

Overview Epidemiology Pathophysiology Clinical Presentation Diagnosis/Work Up Prognosis Treatment Our patient…6 months later Oval fat body under polarized light showing maltese cross.

Epidemiology 13.4 cases per million in adults onset most commonly 4th to 5th decade (idiopathic) 75% idiopathic FSGS has overtaken MN as most common cause of nephrotic syndrome in adults 2:1 males : females

Secondary Membranous Nephropathy Ponticelli C. Membranous nephropathy J Nephrol 2007;20:268-287.

Pathophysiology circulating IgG antibodies directed against endogenous antigens on or near podocyte foot processes form immune complexes C5b-9 (MAC) causes cell signaling -> silt diaphragm protein disruption redistribution of actin GBM expansion by injured podocytes antigens?: dsDNA, thyroglobulin, hepatitis B surface antigen, treponemal antigen, and not yet discovered….

Pathophysiology Glassock RJ. N Engl J Med 2009;361:81-83.

Membranous Nephropathy Normal Glomerulus thin GBM (equivalent to tubular basement membrane) mesangium limited to stalk of capillary tuft (double arrows) Membranous Nephropathy thick GBM (in relation to tubular basement membrane) mesangial expansion (asterisks) images from www.uptodate.com

Immunofluorescence Silver Stain diffuse granular IgG deposits along GBM Silver Stain spike pattern in GBM highlights deposits between new GBM images from www.uptodate.com

Normal EM Membranous EM thin, homogenous GBM epithelial cell with foot processes fenestrated endothelial cell (arrow) Membranous EM thick GMB, with deposits (D) effacement of foot processes

Clinical Presentation 80% present with nephrotic syndrome hypoalbuninemia and hyperlipidemia most often present sublinical to more than 20 g/day of proteinuria 70% have normal BP and normal GFR

Diagnosis/Work Up U/A, microscopy, UP/C Rule Out Secondary Causes > 3.5 g/day oval fat bodies, lipid droplets, fatty casts Rule Out Secondary Causes ANA/Complement SPEP/UPEP Hepatitis Serologies, RPR, HIV cyroglobulins

Diagnosis/Work Up Kidney biopsy is needed for diagnosis, and should be done in all patients with unexplained nephrotic syndrome Lipids 5-20% over 65 have malignancy age appropriate screening

Prognosis “rule of thirds” complete: 5-30% at 5 y partial: (<2 g) 25-40% at 5 y ESRD: 14% at 5 y, 35% 10 y, 41 % 15 y Toronto Glomerulonephritis Registry Schieppati, A, et al, N Engl J Med 1993; 329:85. Figure www.uptodate.com

Prognosis Good Prognosis Poor Prognosis female young age normal creatinine <4 g proteinuria /day for 6 mos no tubulointerstitial disease Poor Prognosis > 8 g proteinuria/day for 6 months Creatinine levels in patient with complete remission of idiopathic membranous nephropathy Ponticelli C. J Nephrol 2007;20:268-287.

Treatment: Low Risk ACE I or ARB: act, at least in part, to lower intraglomerular pressure Goal BP <130/80 may require diuretics Lipid-lowering: statins most often needed low salt diet anticoagulation: controversial highest risk: >12 g/day, albumin <2

Treatment: Moderate and High Risk Moderate: 4-8 g/day x 6 months (45% will have spontaneous remission) if no better in 6 mos: immunosuppression High: > 8 g/day x 6 months or worsening renal function (75% progress to ESRD) cyclophosphamide OR cyclosporine/tacrolimus PLUS glucocorticoids trial of rituximab Transplant: if ESRD – 10-30% recurrence

Our Patient….. UP/C is 5.12 (almost 50% reduction) Creatinine stable CH 238, HLD 95, LDL 125 Taking enalapril 10, lipitor 40 Continues to ride long distances on bike

Key Points Membranous nephropathy only about ¼ of all causes of nephrotic syndrome 75% idiopathic, but must rule out secondary causes Rule of Thirds Treat symptoms of low risk patients Immunosuppression in high risk patieints

References www.uptodate.com Schieppati, A, Mosconi, L, Perna, A, et al, N Engl J Med 1993; 329:85. Ponticelli C. Membranous nephropathy J Nephrol 2007;20:268-287. Wasserstein AG. Membranous glomerulonephritis J Am Soc Nephrol 1997;8:664-674. Glassock RJ. Human idiopathic membranous nephropathy--a mystery solved? N Engl J Med 2009;361:81-83.