Sheena SurindranGrand Rounds 10/26/2010

Immune mediated disease characterized by accumulation of sub epithelial deposits leading to complement activation and podocyte injury

Organ specific autoimmune disease First described by David Jones in 1957.Name is derived from thickened basement

membrane evident in light microscopy at later stages.

Studies on Heymann rats confirmed the autoimmune nature of the disease but the ag in rats- Megalin is absent in humans.

Significant spontaneous complete remission– 5-30% and 20-40% partial remission at 5yrs.

946 pts in Japan with IMN 96% had renal survival at 5yr (cr <3)

Prospective study of 100 patients who were not treated showed 65 % complete or partial remission at the end of 5 yrs Schieppati, A, Mosconi, L, Perna, A, et al, N Engl J Med 1993; 329:85.

M2 Phospholipase A2 receptor (PLA2 R) has been recognized as the target antigen in Idiopathic membranous nephropathy (IMN)

NEJM Jul 2009- Beck at el

Methods:- Used kidney tissue and serum samples from patient s with primary and secondary membranous and other glomerular disease and normal controls.

Performed western blotting on extracts of normal glomeruli with serum from 37 patients with IMN.

A 185-KD protein band was detected in 26 samples (70%) of IMN.

Antibodies against PLA2 R identified a glomerular protein band of the same size as that recognized in the serum of pts with IMN

Distribution of PLA2 R in normal glomeruli suggests that it is located on podocytes as are megalin in rat models of MN

Presence of these abs in primary membranous and not in other proteinuric diseases suggest these are the cause rather than a consequence of podocyte injury

Abs are predominantly IgG4 which is same as the immune deposits seen in IMN

Thickened glomerular membrane showing spikes

Subepithelial depositsGranular Ig staining usually IgG and C3 along

capillary walls on immunofluoresence

Poor prognosis Factors influencing PPV for disease progression

Male

Age >50yrs

Nephrotic range protein

Elevated creatinine

Persistant proteinuria over 6mths

Creat clearance at presentation <60ml

Slope of decline of renal fn and proteinuria

Low risk- proteinuria <4gm and normal renal fn- <8% progression at 5yrs

Moderate risk- 4-8gm protein for 6mths and normal/near normal renal fn- 50% prog at 5yr

High risk-> 8gm protein for 3mths or abnormal renal fn- 75 % progression at 5 yrs

GLOSEN trial- multicenter cohort of 328 patient who where initially treated conservatively- 32% attained remission.

In the sub grp that had remission one of the significant important independent predictors was use of ACE / ARB

J Am Soc Nephrol. 2010 Apr;21(4):697-704

Compared steroids with both chlorambucil and cytoxan

95 patients- 45 in cytoxan and 50 in chlorambucil arm

Pontecelli et al, JASN- 1997

Multicenter RTC – Monotherapy with Tacrolimus could induce remission in 80% of patients compared to control group 24% but most in the treatment group had partial remission

50% of patient in the treatment arm had relapse on stopping Tacrolimus

Kidney International (2007) 71, 924–930.

Pilot study using Rituxan in 15 patient s with IMN who where refractory to ACE inhibition- received it 2 doses 1gm each 2 weeks apart and then at 6mths- out of this 2 achieved complete and 6 partial remission.

Kidney Int- 2008 -FC Fervenza and et al

Study population- 20 patients with idiopathic Membranous nephropathy who had

- Creatinine clearance >30ml- Proteinuria > 5gm/day inspite of

treatment with max dose ACEI/ARB &statin

- Biopsy proven IMN

Fervenza et al CJASN Aug,2010

Conservative treatment for 4mthsUsed 4 weekly doses of 325mg/m2 Rituxan

and re-dosed at 6mths Methylprednisone 100mg given before 1st

dose Target for CD19 count depletion to <5 cells

/microl

No difference in the response rate at 12mths with RTX 1gm every 2 weeks versus RTX 375mg weekly for 4 doses

More profound B cell suppression with higher doses

22% complete response, 67% partial response and 2 had limited response.