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IdiopathicIdiopathicMembranous Membranous NephropathyNephropathy

Paul M. JohnsonPaul M. JohnsonUNC Internal MedicineUNC Internal Medicine

AM ReportAM ReportAugust 4, 2009August 4, 2009

OverviewOverview

► EpidemiologyEpidemiology► PathophysiologyPathophysiology► Clinical PresentationClinical Presentation► Diagnosis/Work UpDiagnosis/Work Up► PrognosisPrognosis► TreatmentTreatment► Our patient…6 months laterOur patient…6 months later

Oval fat body under polarized light showing maltese cross.

EpidemiologyEpidemiology

►13.4 cases per million in adults13.4 cases per million in adults►onset most commonly 4onset most commonly 4thth to 5 to 5thth decade decade

(idiopathic)(idiopathic)►75% idiopathic75% idiopathic►FSGS has overtaken MN as most FSGS has overtaken MN as most

common cause of nephrotic syndrome common cause of nephrotic syndrome in adultsin adults

►2:1 males : females2:1 males : females

Secondary Membranous Secondary Membranous NephropathyNephropathy

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

PathophysiologyPathophysiology

► circulating IgG antibodies directed against circulating IgG antibodies directed against endogenous antigens on or near podocyte endogenous antigens on or near podocyte foot processes form immune complexesfoot processes form immune complexes

► C5b-9 (MAC) causes cell signaling -> C5b-9 (MAC) causes cell signaling -> silt diaphragm protein disruptionsilt diaphragm protein disruption redistribution of actin redistribution of actin GBM expansion by injured podocytesGBM expansion by injured podocytes

► antigens?: dsDNA, thyroglobulin, hepatitis B antigens?: dsDNA, thyroglobulin, hepatitis B surface antigen, treponemal antigen, and surface antigen, treponemal antigen, and not yet discovered….not yet discovered….

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

PathophysiologyPathophysiology

► Membranous Membranous NephropathyNephropathy thick GBM (in relation thick GBM (in relation

to tubular basement to tubular basement membrane)membrane)

mesangial expansion mesangial expansion (asterisks)(asterisks)

► Normal GlomerulusNormal Glomerulus thin GBM (equivalent thin GBM (equivalent

to tubular basement to tubular basement membrane)membrane)

mesangium limited mesangium limited to stalk of capillary to stalk of capillary tuft (double arrows)tuft (double arrows)

images from www.uptodate.com

► ImmunofluorescencImmunofluorescencee diffuse granular IgG diffuse granular IgG

deposits along GBMdeposits along GBM► Silver StainSilver Stain

spike pattern in GBM spike pattern in GBM highlights deposits highlights deposits between new GBMbetween new GBM

images from www.uptodate.com

► Membranous EMMembranous EM thick GMB, with thick GMB, with

deposits (D)deposits (D) effacement of foot effacement of foot

processesprocesses

► Normal EMNormal EM thin, homogenous thin, homogenous

GBMGBM epithelial cell with epithelial cell with

foot processesfoot processes fenestrated fenestrated

endothelial cell endothelial cell (arrow)(arrow)

Clinical PresentationClinical Presentation

►80% present with nephrotic syndrome80% present with nephrotic syndrome►hypoalbuninemia and hyperlipidemia hypoalbuninemia and hyperlipidemia

most often presentmost often present►sublinical to more than 20 g/day of sublinical to more than 20 g/day of

proteinuriaproteinuria►70% have normal BP and normal GFR70% have normal BP and normal GFR

Diagnosis/Work UpDiagnosis/Work Up

►U/A, microscopy, UP/C U/A, microscopy, UP/C > 3.5 g/day > 3.5 g/day oval fat bodies, lipid droplets, fatty castsoval fat bodies, lipid droplets, fatty casts

►Rule Out Secondary CausesRule Out Secondary Causes ANA/ComplementANA/Complement SPEP/UPEPSPEP/UPEP Hepatitis Serologies, RPR, HIVHepatitis Serologies, RPR, HIV

►cyroglobulinscyroglobulins

Diagnosis/Work UpDiagnosis/Work Up

►Kidney biopsy is needed for diagnosis, Kidney biopsy is needed for diagnosis, and should be done in all patients with and should be done in all patients with unexplained nephrotic syndromeunexplained nephrotic syndrome

►LipidsLipids►5-20% over 65 have malignancy5-20% over 65 have malignancy

age appropriate screeningage appropriate screening

PrognosisPrognosis

► ““rule of thirds”rule of thirds”► complete: 5-30% at 5 complete: 5-30% at 5

yy► partial: (<2 g) 25-partial: (<2 g) 25-

40% at 5 y40% at 5 y► ESRD: 14% at 5 y, ESRD: 14% at 5 y,

35% 10 y, 41 % 15 y35% 10 y, 41 % 15 y► Toronto Toronto

Glomerulonephritis Glomerulonephritis RegistryRegistry

Schieppati, A, et al, N Engl J Med 1993; 329:85. Figure www.uptodate.com

PrognosisPrognosis► Good PrognosisGood Prognosis

femalefemale young ageyoung age normal creatininenormal creatinine <4 g proteinuria /day <4 g proteinuria /day

for 6 mosfor 6 mos no tubulointerstitial no tubulointerstitial

diseasedisease► Poor PrognosisPoor Prognosis

> 8 g proteinuria/day > 8 g proteinuria/day for 6 monthsfor 6 months

Creatinine levels in patient with complete remission of idiopathic membranous nephropathy

Ponticelli C. J Nephrol 2007;20:268-287.

Treatment: Low RiskTreatment: Low Risk

►ACE I or ARB: act, at least in part, to ACE I or ARB: act, at least in part, to lower intraglomerular pressurelower intraglomerular pressure

►Goal BP <130/80Goal BP <130/80 may require diureticsmay require diuretics

►Lipid-lowering: statins most often neededLipid-lowering: statins most often needed► low salt dietlow salt diet►anticoagulation: controversialanticoagulation: controversial

highest risk: >12 g/day, albumin <2highest risk: >12 g/day, albumin <2

Treatment: Moderate and High Treatment: Moderate and High RiskRisk

► Moderate: 4-8 g/day x 6 monthsModerate: 4-8 g/day x 6 months (45% will have spontaneous remission)(45% will have spontaneous remission) if no better in 6 mos: immunosuppressionif no better in 6 mos: immunosuppression

► High: > 8 g/day x 6 months or worsening High: > 8 g/day x 6 months or worsening renal functionrenal function (75% progress to ESRD)(75% progress to ESRD) cyclophosphamide OR cyclosporine/tacrolimus cyclophosphamide OR cyclosporine/tacrolimus

PLUS glucocorticoidsPLUS glucocorticoids trial of rituximabtrial of rituximab

► Transplant: if ESRD – 10-30% recurrenceTransplant: if ESRD – 10-30% recurrence

Our Patient…..Our Patient…..

► UP/C is 5.12 (almost UP/C is 5.12 (almost 50% reduction)50% reduction)

► Creatinine stableCreatinine stable► CH 238, HLD 95, LDL CH 238, HLD 95, LDL

125125► Taking enalapril 10, Taking enalapril 10,

lipitor 40lipitor 40► Continues to ride Continues to ride

long distances on long distances on bikebike

Key PointsKey Points

►Membranous nephropathy only about Membranous nephropathy only about ¼ of all causes of nephrotic syndrome¼ of all causes of nephrotic syndrome

►75% idiopathic, but must rule out 75% idiopathic, but must rule out secondary causessecondary causes

►Rule of ThirdsRule of Thirds►Treat symptoms of low risk patientsTreat symptoms of low risk patients► Immunosuppression in high risk Immunosuppression in high risk

patieintspatieints

ReferencesReferences

► 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 Glassock RJ. Human idiopathic membranous nephropathy--a mystery solved? nephropathy--a mystery solved? N Engl J Med N Engl J Med 2009;361:81-83. 2009;361:81-83.