Solomon C. Huang, MD Nephrology Fellow

Department of Nephrology OVMC

Patient is a 58 yo HM with DM, HTN, and dyslipidemia, who was referred to renal clinic for evaluation of proteinuria.

Patient was in his usual state of health until July 2012 when he started developing lower extremity edema, visited OV ED, was referred to diabetic clinic and started on Benazepril 40mg and lasix 40mg daily. Patient had lost follow up until July 2013 when he visit ED again for worsening edema and dyspnea on exertion. He was referred to renal clinic and was initially seen on 08/22/2013, and lasix was increase to 40mg BID. Labs and work ups were sent, and patient was scheduled to return in 2 month.

Patient returned to renal clinic on 10/31/13. He complained of worsening lower extremity edema, dyspnea on exertion, and orthopnea without PND. He denied of dysuria, sensation of incomplete voiding, or NSAID use.

He could ambulate for >5 blocks or 2 flights of stairs in 2012, and now can only walk 1/2 block before stopping.

DM – previously on metformin 500mg BID until 03/2013 in which it was only controlled with diet

HTN

Dyslipidemia

NKDA No surgeries

Meds:

Lipitor 80mg Benazepril 40mg Lasix 80mg BID ASA 81mg Multivitamin

VS: 36.3, 95, 18, 155/84

GENERAL: Not in acute distress

HEENT: PERRLA, EOMI

LUNGS: Mild bibasalar crackles

CVS: RRR, S1,S2, no m/r/g

ABDOMEN: soft, nt/nd, not appreciable shifting dullness, BS+

EXT: 3+ pitting edema up to mid thigh bilaterally

MENTAL: AAO x 4 •

Na 137

K 4.3

CL 107

CO2 28

BUN 16

Cr. 0.97

Albumin 2.4

Na 139

K 4.1

CL 113

CO2 25

BUN 38

Cr. 0.99

Albumin 1.3

WBC 7.9 H&H: 12.9/36.3 Plt: 182

UA:

6.5/1.015/600/trace/wbc 1/RBC 13

Microalb/crea: 2727

WBC 7.5 H&H: 12.5/36.6 Plt: 195

UA: 6.5/1.017/600/100/wbc 4,

RBC 9

UPC 6.883

Hgba1c 5.2 6.0

Hep Panel: neg HIV: neg RPR: neg C3 normal C4 normal CH 50 normal ANA: neg ANCA: neg SPEP/UPEP: neg for monoclonal Serum and urine IF: neg

•

09/06/13:

Right 12.8, left 11.8, small pockets of ascites noted, no hydronephrosis, isoechoic, bilateral renal veins pattern, and no evidence of RAS.

Height 171cm, 86.2kg

Retinal scan was negative for diabetic retinopathy

2D echo showed 60 – 65% EF with grade I impaired LV relaxation

Given the degree of proteinuria and normal retinal scan

Patient was scheduled for renal biopsy on 10/30/13

Light Microscopy: 4 glomeruli with thicken capillary walls and subepithelial

and intramembraneous fuchsinophilic deposits.

2 glomeruli are globally sclerotic

No mesangial hypercellularity, segments of sclerosis, or crescents

Mild tubular atrophy with interstitial fibrosis

Immunofluorescence: 5 glomeruli, 1 globally sclerotic

Remaining glomeruli have capillary wall staining IgG (4+), C3 (2-3+), fibrin (1+), kappa (2-3+), lambda (2+)

Electron Microscopy: Capillary walls are considerably thicken Mesangial regions are neither expanded nor hypercellular, no

global sclerosis, segmental sclerosis or crescents Three glomeruli reveal large subepithelial and

intramembranous electron dense deposits, evidence of lateral spikes of basement membrane material from subepitheal deposits

Podocyte foot processes are extensively effaced No electron dense deposits in mesangial regions, nor are there

tubulo-reticular structures or increase in mesangial matrix material

•

1. Membranous Glomerulonephritis

2. Arteriolar Nephrosclerosis

Primary (idiopathic) – approx. 75% May represent Ab against a potocyte antigen such as

PLA2R

Secondary SLE (class V), Sarcoidosis (uncommon)

penicillamine, gold salts, anti-TNF therapy, NSAID

Hep B, hep C (rare), Malnignancy (solid tumor)

Hematopoeitic cell transplant/GVHD

Post renal transplantation

Primary: Electron dense deposit are exclusively subepithelial and

intramembranous Predominantly IgG4 (isotype-specific stain not routinely done)

Secondary: Presence of Tubuloreticular structure (tubular structures in ER

of endothelial cells) – lupus nephritis Mesangial or subendothelial deposits – suggest circulating

immune complexes Tubular BM staining IgG - SLE IgG1 and IgG3, IgA, IgM, C1q may predominate LN IgG1 and IgG2 reported in Malignancy-associated MN

Pathophysiology: Th2 humoral immune response IgG and complement

formation& deposits in outer glomerular capillary wall.

Endogenous vs. exogenous antigens Ab binds exogenous Ag localizes to subepitheal surface due

to their cationic charge and small size

Ab-Ag complex trapped in capillary wall, traverse GBM, then deposits to subepithelium

Endogenous Ag in subepitheal structures (podocyte membrane protein) -->immune complex formation

Heymann Nephritis models: Megalin – (gp330) 516-kd glycoprotein – endocytic receptor

on podocyte processes

Immunize rats with antigens

Subepithelial immune deposits activating complement, C5b - C9 (MAC) insertion into podocyte plasma membrane podocyte damage

proteinuria from loss of pododyte slit diaphram integrity

GBM expansion by overproduction of Type IV collegen and laminin by injured podocytes

M-type phospholipase A2 receptor PLA2R – 185kD glycoprotein Serum reactive/autoantibody formations in 26/37

Idiopathic MN patients ( 70%) – IgG4 But absence in secondary MN due to lupus or hep B or

other causes of proteinuria --- NEJM 2009

In patients with remission, there was decline or disappearance of anti-PLA2R antibodies before the proteinuria fully resolved.

Disease activity: “Anti-PLA2R Ab correlate with clinical status in

idiopathic MN” -- CJASN 2011

77.8% (14 pts) had Abs reactive, total of 18 patients

Ab levels correlate strongly with both clinical status and proteinuria (r = 0.73, P <0.01)

Spontaneous Remission “Anti-PLA2R ab titer and subclass in idiopathic

MN” -- JASN 2012

117 caucasian pts, 72% and 74% antibody positive with IIF or ELISA

Ab titer significantly correlates with baseline proteinuria (P = 0.02)

Less frequent spontaneous remission (38% vs. 4% with high titer) (P < 0.05)

Response to Immunosuppressive Therapy 25/35 patients (71%) was PLA2R-ab positive

Observed Ab titer decline or disappear after Rituximab (17 pts, 68%), with observed partial or complete remission

• -- JASN 2011

Predicts Long term outcome: Retrospective PLA2R- Ab titers

90 months follow up

Higher PLA2R – Ab titers are linked to active disease and higher risk of declining renal function during follow up.

• -- Kidney Int. 2013

Neural endopeptidase: Maternal anti – NEP Ab to fetus/neonate leading to MN which resolves

months after birth

Intracellular Antigens

PLA2R, Alpha enolase, aldose reductase, superoxide dismutase 2

Cationic bovine serum albumin Absorbed from the underdeveloped pediatric GI tracts, serve as a

planted antigen within the glomerular capillary wall

Others from secondary MN DS-DNA, thyroglobulin, hep B antigen, treponemal antigen, CEA and

PSA in malignancy – pathogenesis unproven

Low Risk (mild): Normal serum Cr. and stable over 6 months with

proteinuria < 4gm/day = less than 5% chance of progression

Medium Risk (moderate):

Normal or near normal Cr. with persistent proteinuria 4 – 8gm/day over 6 months despite conservative treatment

High Risk (Severe):

Deteriorating renal function and/or persistent proteinuria >8gm/day for < 3 – 6 months of observation

Indication for treatment (with immunosuppre): KDIGO – GN -2012:

Nephrotic range proteinuria + one of the following: Persistent proteinuria > 4g despite conservative measure for 6

months

Presence of severe, disabling, or life threatening symptoms from nephrotic syndrome

Cr. Risen by 30% or more within 6-12 months from time of diagnosis, but eGFR remain > 25 – 30mL/min

Consider not to treat: Cr. Persistently > 3.5mg/dL or

eGFR < 30ml/min, or

Kidney sizes less than 8cm in length from ultrasound, or

Potentially life-threatening infections

Always ACE/ARB !!! May significantly reduce rate of disease progression,

acting at least in part by lowering intraglomerular pressure

Spanish group (GLOSEN)

Anticoagulation: Treat after venous thromboembolic event

Prophylasix: Lacking prospective, randomized control study to

compare risk of undiagnosed venous thrombosis with risk of long term anticoagulation.

Complete remission = less than 0.3g/day

Partial remission = less than 3.5g/day and a 50% reduction from peak proteinuria.

Importance of attaining complete remission: A cohort of 348 patients with iMN from toronto

5 year follow up renal function in patients who had not received Ims vs. who had received Ims

In a subset of high risk patients, those who had received Ims had an independent risk-reduction in terms of progression to renal failure

• --- Kidney International 2004

Corticosteroid alone

Cytotoxic + Corticosteroid

Calcineurin Inhibitors

MMF, Rituximab, Eculizumab, Synthetic ACTH

Published in NEJM 04/12/1984 Randomized controlled trial

67 pts with proteinuria >3.5gm/day Methylprednisolone 1gm x 3 days, then 0.4mg/kg/day x 27 days

then stop (cycle A) Start chlorambucil 0.2mg/kg/day x 1 month (cycle B) Cycle A alternate with cycle B for 6 months

Treated:

12/32 in CR No change in Cr.

Control:

2/32 in CR Progressive decrease in Cr.

Treatment group: Survival without ESRD: 92%

Probability of PR or CR: 88%

Control group: Survival without ESRD: 60%

Probability of PR or CR: 47%

Steeper slope of the mean reciprocal of plasma Cr.

Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 1995; 48:1600.

Hogan SL, Muller KE, Jennette JC, Falk RJ. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis 1995; 25:862.

Schieppati A, Mosconi L, Perna A, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med 1993; 329:85.

Troyanov S, Wall CA, Miller JA, et al. Idiopathic membranous nephropathy: definition and relevance of a partial remission. Kidney Int 2004; 66:1199.

Glassock RJ. Idiopathic membranous nephropathy: getting better by itself. J Am Soc N

Ponticelli C, Zucchelli P, Passerini P, Cesana B. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian Idiopathic Membranous Nephropathy Treatment Study Group. N Engl J Med 1992; 327:599. ephrol 2010; 21:551.

KDIGO. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl 2012; 2:209.

Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 1998; 9:444.

Branten AJ, Vervoort G, Wetzels JF. Serum creatinine is a poor marker of GFR in nephrotic syndrome. Nephrol Dial Transplant 2005; 20:707.

Cattran DC, Greenwood C, Ritchie S, et al. A controlled trial of cyclosporine in patients with progressive membranous nephropathy. Canadian Glomerulonephritis Study Group. Kidney Int 1995; 47:1130.

Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol 2012; 23:1416.