Thrombotic microangiopathy (TMA) can
come in many forms- HUS and TTP might being the two most extreme versions.
Gemcitabine induced TMA is a drug induced TMA that can result from dose
dependent use of the agent or an immune mediated phenomenon.
In immune-mediated TMA,
the drug induces formation of antibodies that react with multiple cells,
including platelets, neutrophils, and endothelial cells, but strong binding
only occurs in the presence of the drug (or drug metabolite). Therefore, these
antibodies are described as drug-dependent antibodies. Toxicity-mediated
(ie, non-antibody-mediated) TMA may develop by multiple mechanisms. Many cases
are dose related, occurring only after large cumulative exposure over a period
of time or exposure to large single doses of a drug. Gemcitabine induced TMA is
thought to be due to both the above mechanisms.
Recent review found
that of 78 substances to have previously been reported to cause thrombotic
microangiopathy (TMA), 22 had definite evidence supporting causal association.
However, 9 (clopidogrel, cyclosporine, estrogen/progesterone, gemcitabine,
interferon, mitomycin, quinine, tacrolimus, and ticlopidine) accounted for 76%
of reports.
Initial management involves
immediate discontinuation of suspected drug, or reduction of dose when
discontinuation is not a medical option.
What about pheresis or anti
complement therapy specifically for Gemcitabine induced TMA?
A twitter pole I did showed these
results
Drug induced TMA? Example gemcitabine induced. Would you use Pheresis and or complement inhibitors after holding culprit agent ? #onconephrology— Kenar Jhaveri (@kdjhaveri) January 27, 2018
Here is the summary from the Pheresis society guidelines https://www.ncbi.nlm.nih.gov/pubmed?term=27322218
In all cases of Gemcitabine induced
TMA, ADAMTS13 levels were typically normal. In literature review, among 26
patients not treated with pheresis, 56% recovered from TMA, whereas 30% of 18
patients who received TPE. So based on that data, doubt pheresis will help TMA
associated with gemcitabine.
There have been reports
of patients with toxicity-mediated DITMA attributed to gemcitabine, case
reports have described patients with acute kidney injury attributed to
gemcitabine who improved after treatment with anti-complement therapy. However,
these case reports do not provide confidence that anti-complement therapy is
appropriate. Often the patients have received multiple chemotherapeutic agents,
and the selection of gemcitabine as the possible cause-effect cannot be
confirmed.
Often a kidney biopsy
to document TMA has not been done. Although these preliminary observations do
not provide confidence that anticomplement therapy is appropriate, some experts
do feel it might be reasonable to consider the use of eculizumab in
persistent drug toxicity-mediated TMA that does not improve with supportive
care and withdrawal of the offending agent and especially if there is risk for progressive
CKD.
So in summary
1. Most important- stop the offending agent
2. Data on use of pheresis- poor and in some instances might be not recommended
3. Data on use of complement inhibitor- poor and unclear at this point- probably would avoid but there might be mixed opinion on this matter in the literature.
So in summary
1. Most important- stop the offending agent
2. Data on use of pheresis- poor and in some instances might be not recommended
3. Data on use of complement inhibitor- poor and unclear at this point- probably would avoid but there might be mixed opinion on this matter in the literature.
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