Nephrology Board Review – Membranous Nephropathy Answers

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1.) How many histologic stages of Membranous Nephropathy are there?

A. 2

B. 3

C. 4

D. 5

Discussion: Four stages. Great LM and EM can be found here (AKJD Atlas).

  • Stage I: Subepithelial deposits with little change to GBM, but extensive foot process effacement
  • Stage II: Basement membrane “spikes” form between immune-complex
  • Stage III: “Spikes” extend and deposits become surrounded by new the basement membrane-like material
  • Stage IV: The basement membrane is overtly thickened (nice and membranous), and the deposits become more lucent with the spikes becoming less apparent. At this point you can have a double contour appearing membrane.

2.) The stages correlate with the clinical manifestations of MN.

A. True

B. False

Discussion: These changes can help identify duration of disease, but they don’t correlate with clinical manifestations or outcome.

3.) Which of the following are podocyte antigens?

A. suPAR

B. Neutral endopeptidase (NEP)

C. Paxillin

D. Phospholipase A1 Receptor (PLA2R)

Discussion: Both NEP (neutral endopeptidase) and PLA2R (phospholipase A1 Receptor) are podocyte antigens associated with iMN. PLA2R is highly specific for primary MN, and majority of patients with iMN have positive PLA2R antibodies. There is also clear association of anti-PLA2R with disease activity. NEP has been shown to be one of the causes of congenital MN. We see that mothers with a herditary absence of NEP become sensitized during pregnancy and then passively transfer anti-NEP to their infants, who are born with congenital MN.

4.) Which type of Ig is most commonly found in the granular subepithelial deposits pathognomonically seen in idiopathic MN?

A. IgA

B. IgG1

C. IgM

D. IgG3

E. IgG4

Discussion: IgG4 is the predominant Ig subclass found in primary MN, when you see positive staining for IgG1, IgG3, IgA and IgM (especially in the mesangium) think lupus as the etiology of the membranous nephropathy. Complement is activated in idiopathic MN and so it is normal to see positive C3 on biopsy as well.

5.) What treatment regimen would you recommend to a 34 year old male with idiopathic membranous proven by renal biopsy with 2 grams/day of proteinuria for the last 7 months with a serum creatinine of 1.1.

A. An alternating regimen of cyclophosphamide and glucocorticoids

B. An alternating regimen of chlorambucil and glucocorticoids

C. ACE-inhibitors and stains

D. A and C

E. B and C

Discussion: According to the landmark idiopathic membranous nephropathy (iMN) study by Cattran et al, patients with less than 4 grams over a six month period are considered low risk and have only a 5% risk of progression thus only conservative treatment is recommended. Conservative therapy for patients with idiopathic membranous nephropathy is similar to that of other nephrotic syndrome etiologies (blood pressure control which is arguably 125/75 for patients with at least a gram proteinuria/day, proteinuria reduction with ACE-i/ARB, statins, dietary sodium and protein restriction and volume management). Had this patient had 4-8g proteinuria/day with near normal renal function he would be considered medium risk and would have a 55% risk of developing chronic renal insufficiency. Patients in this category should be treated conservatively and monitored for 6 months. If there is no improvement then they should be started on what’s now known as the “Modified Pontichelli Protocol” of alternating Cyclophosphamide therapy given at a dose of 2.5 mg/kg per d in months 2, 4, and 6, and corticosteroid therapy initiated as methylprednisolone pulses of 1 g/d for 3 d at the beginning of months 1, 3, and 5 followed by oral prednisone 0.5 mg/kg on the remaining days of each of these months (answer choice A). This is called the modified Ponticelli protocol because the original study done by Pontichelli (“The Ponticelli Protocol”) was done using alternating chlorambucil and steroids (answer choice B). So there are low and medium risk category, so of course there must be a high risk category and that consist of patients with deteriorating renal function and/or persistent proteinuria >= 8g/day for 3-6 months. This group has a 66-88% probability of progression to CKD within 10 years and can be treated with the “modified ponticelli protocol” (but note that there has not been a randomized, controlled trial of cytotoxic plus corticosteroids in this high-risk patient group) or calcineurin inhibitors such as cyclosporine or tacrolimus. Again drug side effects and risk should be discussed with the patient at this point.

References:

  1. Beck Jr, L. H., Bonegio, R. G., Lambeau, G., Beck, D. M., Powell, D. W., Cummins, T. D., … & Salant, D. J. (2009). M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. New England Journal of Medicine, 361(1), 11-21.
  2. Nangaku, M., & Couser, W. G. (2005). Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clinical and experimental nephrology, 9(3), 183-191.
  3. Cattran, D. C., Pei, Y., Greenwood, C. M., Ponticelli, C., Passerini, P., & Honkanen, E. (1997). Validation of a predictive model of idiopathic membranous nephropathy: its clinical and research implications. Kidney international, 51(3), 901.
  4. Cattran, D. (2005). Management of membranous nephropathy: when and what for treatment. Journal of the American Society of Nephrology, 16(5), 1188-1194.
  5. Cattran, D. C., Greenwood, C., Ritchie, S., Bernstein, K., Churchill, D. N., Clark, W. F., … & Lavoie, S. (1995). A controlled trial of cyclosporine in patients with progressive membranous nephropathy. Kidney international,47(4), 1130-1135.
  6. Comprehensive Clinical Nephrology 3rd Edition. Jürgen Floege, Richard J. Johnson, John Feehally. Elsevier Health Sciences.


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