Thursday, May 20, 2010

Drug-induced autoimmune disease of the kidney

Drug-induced autoimmune diseases of the kidney include SLE-like disease and drug-induced vasculitis (DIV). As many as 10% of all diagnosed Lupus cases in the US may be drug-induced Lupus (DIL).

These syndromes typically develop after drug treatment for a prolonged period of time (at least 6 months and up to decades). Symptoms often include rash, fever, arthralgias, myalgias, serositis, vasculitis / glomerulonephritis and pulmonary hemorrhage. The diseases often resolve upon cessation of the drug.

Many drugs were implicated in triggering autoimmunogenicity including:
  • Hydralazine
  • Isoniazid
  • Procainamide
  • Methimazole
  • Prophylthiouracil
  • Etanercept
  • Carbamazepine
  • Phenytoin
  • Methyldopa
  • Minocycline
  • Sulfasalazine
  • Penicillamine
The incidence of DIL with long-term Hydralazine therapy has been reported to be as high as 5% and in some studies even higher.

1. DIL is of later onset than SLE, affects males and females equally and presents in general with less severe symptoms. Anti nuclear antibodies (ANA) are often directed against Histones and rarely against dsDNA. Some proposed drug-induced pathomechanisms are hypomethylation leading to T cell activation, change of nucleosomes by epitope liberation, macrophage inhibition causing decreased uptake of apoptotic cells and last but not least genetic predisposition. Case reports suggest that family members of affected patients are at higher risk for developing a drug-induced auto-immune response.

2. Drug-induced vasculitis (DIV) typically involves antibody formation against more than one cytoplasmic neutrophil antigen leading typically to a perinuclear staining pattern (p-ANCA). Cytoplasmic antigens identified include MPO (Myeloperoxidase), HLE (Human Leucocyte Elastase), Azurocidin, Cathepsin G and Lactoferrin.

Differences between DIV vs. idiopathic disease include significantly higher titers of anti-MPO and multi-specific ANCA (more than one target Antigen in addition to MPO). One proposed pathomechanism is that certain drugs transform into highly cytotoxic metabolites in presence of neutrophils triggering autoimmunogenicity and thereby ANCA formation.

These tables summarize the difference between drug-induced vs. idiopathic disease:

Drug-induced lupus vs. SLE

  • Anti-histone Ab: common vs. rare
  • Anti-dsDNA Ab: rare vs. common
  • ANCA: common (multiple Antigens) vs. rare
  • Anti-phospholipid Ab: common vs. common
  • Immune complexes: can be seen vs. common

Drug-induced vasculitis vs. Idiopathic vasculitis

  • Anti-histone Ab: can be seen vs. absent
  • Anti-dsDNA Ab: absent vs. absent
  • ANCA: common (multiple Ag) vs. common (single Ag)
  • Anti-phospholipid Ab: common vs. rare
  • Immune complexes: rare vs. absent


Matt Sparks said...

Hakan, what about cocaine induced vasculitis. I saw an interesting patient a few years ago with this.

Kenar D Jhaveri( kidney 007) said...

Besides an anti histone induced lupus in hydralazine, there is a histone negative( but DsDNA and ANCA positive) nephritis seen with hydralazine as well. We have had two cases so far of that. Actually, just stopping the drug might not be enough, treating with immunosuppresion might be needed!
Singulair is another drug associated with cases of anti GBM disease.

Hakan Toka said...

Hi Matt and Kenar, I haven't seen or heard about a case related to cocaine but pretty much any drug can trigger autoimmunogenicity. I know of ACEi (Lisinopril) triggering disease. I agree that just stopping the drug is often not enough except in mild cases of drug-induced Lupus. I had a case with hydralazine-induced vasculitis, we treated her based on kidney biopsy with steroids and cytoxan.
Thanks for great comments!

Matt Sparks said...

Hakan, I guess the cocaine syndromes are actually termed pseudovasculitis.
Interesting is that the patient did not have any pathologic vasculitis by biopsy, but did require dialysis mainly from hypertensive kidney diesase.

here is a good review

Hakan Toka said...

Thanks for the review Matt. I thought in terms of cocaine and kidney injury always ischemia and MHA often occuring tissue specific without systemic evidence. However apparently cocaine can cause all sorts of different renal injuries, even antiglomerular basement membrane antibody-mediated glomerulonephritis and acute interstitial nephritis have been reported in cocaine users. I will add pseudovasculitis to my differential! That's a cool diagnosis ;-) Thank you.