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“Aetiology of secondary MN

“Aetiology of secondary MN

“Aetiology of secondary MN

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[1] Systemic lupus erythematosus: almost 10-20 % of ptns with lupus nephritis have MN, called class V lupus nephritis. Some ptns with membranous lupus present only with renal disease with no Sms or serologic evidence of lupus, despite they may arise several mo after appearance with NS. Lupus should be expected in any 👉 young woman with idiopathic MN. Moreover, there’re some histologic criteria on IF (IgG2, IgG3, IgA, IgM, & C1q stain) & EM (subendothelial + subepithelial deposits + tubuloreticular structures in glomerular endothelial cells) denoting underlying lupus. PLA2R AB are 👉 typically negative in class V lupus nephritis. However, ptns with PLA2R-related primary MN may also have +ve ANA if they also have non-renal SLE. Additional features, e.g., +ve PLA2R, lack of C1q st., predominant IgG4, absolute subepithelial dense deposits, & absent tubular BM staining will help DD primary MN from class V lupus nephritis.  

[2] Drugs: Exposure to medications treating rheumatoid arthritis has been involved in developing MN, including NSAIDs, penicillamine, parenteral gold salts, alemtuzumab, mercurial salt, elemental mercury & possibly anti-TNF agents (etanercept, infliximab).  3 criteria in favor of accusing NSAID👉:

1)    No other evident cause for MN

2)    Resolution of proteinuria after NSAID cessation

3)    Lack of recurrent proteinuria at follow-up.

Many of the ptns who developed MN had been ttt with diclofenac, but probably any NSAID can be involved, including COX 2 inhibitors. Incidence of MN may reach 7 % in penicillamine & 1-3 % in parenteral gold (risk of oral gold is lower). Tiopronin is like penicillamine, used for cystine stones (incidence is rare). High-dose captopril, with free thiol group, has also been implicated. Lupus-associated HLA alleles DRB1*0301 (DR3) & DQA1*0501 > susceptible to develop MN, as well as drug-induced lupus, after gold salts. These alleles have also been identified as risk alleles for primary MN in Caucasians.  

Proteinuria may develop within 1st 6-12 mo of therapy but can occur as late as 3-4 y. Drug withdrawal > resolution of proteinuria, but with penicillamine & gold,  proteinuria may persistently rise for 1st 1-12 mo (2 mo) after holding therapy. Mean time to resolution of proteinuria is 9-12 months. Gold & NSAIDs can also lead to minimal change disease, whilst penicillamine can > immune complex crescentic GN. Anti-TNF > new onset lupus nephritis & pauci-immune necrotizing & crescentic GN.

[3] Infections

  • Hepatitis B virus: MN of HBV primarily seen in children in endemic zones, many cases are asymptomatic without active hepatitis. Liver transaminases usually normal or only slightly raised, & serology is +ve for HBs Ag, anti-core AB, & e Ag. It seems that the e Ag & anti-e AB are mainly deposited in the glomeruli.
  • HBV + lupus > only form of MN that may be associated with hypocomplementemia. Spontaneous resolution of proteinuria is commonly seen in children but NOT in adults, who may exhibit progressive illness.
  • Hepatitis C virus: MN is uncommonly observed with chronic HCV hepatitis.  
  • Syphilis: either congenital or secondary have been correlated with MN. Treponema Ags have been recognized in glomeruli by IF, results from glomerular deposits with anti-Treponema pallidum AB. Moreover, ttt of syphilis can resolve the glomerular lesions.  
  • Scabies (See picture).

[3] Malignancy:  about👉 5-20 % of adult MN ptns, especially > 65 ys, have been reported to show underlying malignancies, mostly solid tumours (e.g., carcinoma prostate, lung, breast, bladder, or GIT), less commonly hematologic malignancy, e.g., CLL. Risk of malignancy with MN may be from 2-12 times higher than general population. The postulated mechanism: deposited tumour Ags upon glomeruli > AB deposition & complement activation, > epithelial & GBM injury, & proteinuria. On contrary for these reports, other cases may show coincident disease, rather than direct relation, as:

  • Theory with tumours is common in males > 50 ys, same cohort tends to have MN.
  • Remission of NS with removal of tumour does not mean a therapeutic effect, as a high rate of spontaneous remission can be seen MN.

[4] IgG4-related disease.

[5] Membranous-like nephropathy with masked IgG-kappa.

[6] MN with light chain-restricted deposits: 

[7] Hematopoietic cell Tx & graft-vs-host disease: NS observed in recipients of allogeneic stem cell or less commonly observed, bone marrow Tx, usually transient.    

[8] Others: include hepatosplenic schistosomiasis, quartan malaria, sarcoidosis, Sjögren's syndrome, & formaldehyde intoxication.  

 

Primary vs secondary MN: Several histological criteria by IM & EM have been recognised that may help DD between primary & secondary types of MN:

1)    Tubuloreticular structures in the glomerular endothelial cells (caused by interferon a) is robust indicator for lupus MN seen prior to the typical systemic & serologic criteria of SLE. 

2)    Primary MN: electron-dense deposits on EM are typically subepithelial & intramem-branous. Mesangial deposits are not common. Secondary MN are often mesangial and/or subendothelial deposits, suggesting circulating immune cx.

3)    Tubular BM staining for IgG on IM is rare in primary MN but is common in secondary MN e.g., SLE. Some ptns develop anti-tubular BM AB with tubulointerstitial nephritis.

4)    The subepithelial immune deposits in primary MN predominantly stain +ve for IgG & C3 by IF. Presence of IgA, M, & C1q (= "full house" pattern) suggest > secondary aetiology e.g., class V lupus nephritis. 

5)    IgG deposits in primary MN are mainly IgG4, other isotypes hv bn observed in some causes of secondary MN, e.g., lupus-associated MN, IgG1 & 3 may predominate; by contrast, predominant IgG1&2 has been observed in putative malignancy-with MN.

6)    Ag phospholipase A2 receptor (PLA2R) or thrombospondin type-1