thrombotic microangiopathy ( tma ) encompasses a spectrum of diseases characterized by microangiopathic hemolytic anemia , thrombocytopenia and acute renal failure .
various treatment options have been tried for this condition , with varying degrees of treatment response . here
, we describe a case of gemcitabine - induced tma with atypical presentation treated with rituximab .
a 74-year - old caucasian female was referred to our nephrology clinic for an evaluation of worsening renal function . her past medical history was significant for multiple sclerosis , gastroesophageal reflux disease and ovarian cancer .
following surgery , she had been treated with platinum - based chemotherapy with cisplatin , which was completed in 2012 . in 2013
, she had a relapse of the disease ( clinically as well as an elevation in tumor marker ca-125 ) , for which platinum - based chemotherapy was repeated using carboplatin and doxorubicin .
she was resistant to this treatment following which gemcitabine monotherapy was initiated in 2013 . after the fifth cycle of gemcitabine therapy ( cumulative dose of 9,460 mg ) , her creatinine level started increasing ( to 7.3 mg / dl from a baseline of 1.1 mg / dl ) .
she denied any history of smoking , drug abuse or alcohol use . on physical examination , her vital signs were stable , with a temperature of 98 f , a blood pressure of 162/100 mm hg , a pulse rate of 78 beats / min and a respiratory rate of 18 breaths / min .
her urine dipstick revealed 4 + proteinuria , and her urine protein - to - creatinine ratio was 2.4 g / g creatinine .
renal ultrasound was unremarkable . in view of the drop in hemoglobin level , elevated lactate dehydrogenase ( ldh ) ,
schistocytes in the peripheral smear , new - onset hypertension and acute kidney injury , the possibility of tma was considered .
a complement study showed a c3 level of 113 mg / dl ( range 82185 ) and a c4 level of 19 mg / dl ( range 1553 ) .
antinuclear antibodies , anti - dsdna , hepatitis panel , hiv , anti - scl-70 , antineutrophil cytoplasmic antibody and anticardiolipin ab were negative .
a renal biopsy was performed , which showed glomeruli with mesangial lysis and endothelial cell swelling .
electron microscopy showed capillary loops with swollen endothelium , occlusion of the lumen with cells , cell debris and electron - dense material ( possibly fibrin ) .
there was focal duplication of the basement membrane and diffuse effacement of epithelial cell foot cytoplasm ( fig . 1 , 2 ) .
since gemcitabine has been considered as a cause of tma and there were no other etiologies for tma in this patient , the final diagnosis was tma secondary to gemcitabine .
treatment with plasma exchange was started , but the creatinine level remained unchanged even after 5 daily sessions .
the creatinine level at 2 months after treatment with rituximab was 2 mg / dl .
there was no change in ldh ( in fact , ldh increased over time likely due to the cancer )
. a repeat peripheral smear after 1.5 months of treatment with rituximab did not demonstrate schistocytes .
the patient did not receive any further doses of gemcitabine . since the ovarian cancer continued to progress relentlessly , the patient decided to go on hospice care .
gemcitabine is a pyrimidine antimetabolite that was introduced in 1987 for the treatment of solid tumors .
the standard treatment of tma varies from simple drug discontinuation and supportive care to the use of plasmapheresis , steroids or hemodialysis . despite the use of aggressive treatment
the pathogenesis of tma is believed to be endothelial damage , which leads to platelet aggregation , fibrin formation and thrombus deposition .
the role of immune complexes has been described in the pathogenesis of tma : formed as a result of the underlying disease process , they trigger aggregation and deposition of platelets around areas of toxin - related endothelial damage in the kidney microvasculature .
these cytokines might inhibit vascular endothelial cell growth factor ( vegf ) in glomerular endothelial cells .
other postulated mechanisms include generation of the adamts13 inhibitor and abnormal immune response to the von willebrand factor - cleaving protease [ 9 , 10 ] . in our case , the absence of immunofluorescence in renal biopsy makes an immune complex theory less likely .
similarly , normal adamts13 and antibody to adamts13 do not support the involvement of adamts13 .
hence , direct endothelial damage from the drug leading to platelet aggregation , fibrin formation and thrombus formation is the most likely possibility .
there are multiple reports of drug - induced tma ( especially mitomycin c ) and the role of direct endothelial injury described in the literature .
some of the histopatholgical findings seen in our case might support this view . in an animal study on rats treated with mitomycin ,
subsequently , at 1 week of exposure to mitomycin , many glomerular capillary lumens were reduced or obliterated by platelets , mononuclear cells and swollen endothelium .
in addition , at 1 month , there was extensive obliteration of foot process of the visceral epithelium , mesangial interposition in the basement membrane ( splitting of the basement membrane ) and mononuclear inflammation of the interstitium . in our case
, there were similar histopathological findings ( electron microscopy ) , which might favor the role of direct endothelial injury with gemcitabine .
this might also prove the role of progressive damage to glomeruli following the initial insult with gemcitabine .
the onset of clinically evident disease is often delayed , frequently occurring months after chemotherapy has been discontinued .
the initial insult might have happened way earlier , and changes in biochemical parameters might have occurred once the injury is well established .
the cumulative effect of glomerular endothelial damage might also play a role in the development of clinically evident tma .
our case is unique due to absence of marked hemolysis and thrombocytopenia , as previous cases presented with all the classical features including thrombocytopenia and hemolysis . in this case , although hemolysis was evidenced by the presence of schistocytes and a mild elevation in ldh , other features like a dramatic drop in hemoglobin level , a low haptoglobin level and elevated unconjugated hyperbilirubinemia were absent .
moreover , thrombocytopenia was also absent . in this context , it is notable that drug - induced tma may occur in the absence of other systemic features including microangiopathic hemolytic anemia or thrombocytopenia .
hence , in the absence of clinical suspicion , these cases might be missed , resulting in inadvertent outcomes .
affected patients typically present with slowly progressive renal failure , new or exacerbated hypertension and relatively bland urine sediment .
rituximab is a monoclonal antibody that selectively targets cd20-positive b cells and has been used in the treatment of tma resulting from gemcitabine . in our case ,
the exact mechanism by which rituximab improves tma is not fully elucidated and there are different theories about how the use of rituximab may result in the improvement in tma .
rituximab might act as an immune modulator in controlling the disease , especially in scenarios where immune complexes or antibodies to adamts13 might be playing a role in the pathogenesis .
there might be a mechanism similar to that seen in patients treated with rituximab for rheumatoid arthritis .
the depletion of b cells may reduce the production of b - cell - dependent cytokines that drive endothelial dysfunction [ 13 , 14 , 15 ] . in our case
, this might be the most likely mechanism for improvement in renal function with rituximab treatment although the contribution of plasma exchange in the form of a late response could not be completely ruled out .
the standard definition for refractory disease in disorders like thrombotic thrombocytopenic purpura ( non - response to 7 daily plasma exchange treatments ) may not be applicable to all tmas ( moreover , our patient had only received 5 days of plasma exchange therapy ) .
although a randomized , controlled trial of rituximab in gci - tma may be difficult due to the rarity of this complication , more case reports like ours with a salutary effect may underscore the possibility of using rituximab as a first - line or alternative treatment strategy for patients with tma secondary to gemcitabine .
these are patients who already have a poor prognosis , and the development of renal failure may further increase the risk of mortality .
hence , it is essential to early identify renal toxicity and initiate appropriate intervention , including the discontinuation of gemcitabine therapy , thereby improving survival even if only for a few weeks or months .
 gemcitabine is a potent and widely used anticancer drug . 
 we report a case of gemcitabine - induced thrombotic microangiopathy ( gci - tma ) , a known but not widely recognized complication of gemcitabine use , and our experience of treating gci - tma with rituximab . 
 a 74-year - old woman was referred to our clinic for an evaluation of worsening renal function . 
 she has recently been treated for ovarian cancer ( diagnosed in 2011 ) with surgery ( tumor debulking and bilateral salpingo - oophorectomy ) along with cisplatin chemotherapy in 2012 , followed by carboplatin / doxorubicin in 2013 and recent therapy for resistant disease with gemcitabine . 
 laboratory tests showed anemia , normal platelets and elevated lactate dehydrogenase . 
 a peripheral smear revealed numerous schistocytes , and a kidney biopsy showed acute as well as chronic tma . 
 the patient continued on gemcitabine therapy , and treatment with plasma exchange was started . 
 since there was no response to treatment even after 5 sessions of plasma exchange , one dose of rituximab was given , which was associated with a drop in the creatinine level to 2 mg / dl . 
 the pathogenesis of renal injury could be the effect of direct injury to the endothelium mediated by cytokines . 
 usual treatment includes withdrawing the drug and initiation of treatment with plasmapheresis with or without steroids . in cases resistant to plasmapheresis , treatment with rituximab 
 can be tried . 
 the mechanism of action of rituximab might be due to the reduced production of b - cell - dependent cytokines that drive endothelial dysfunction by depleting b cells . 
 patients receiving gemcitabine chemotherapy should be monitored for the development of tma , and early treatment with plasma exchange along with rituximab might benefit these patients who already have a bad prognosis . 
Introduction
Case Report
Discussion
Conclusion
Disclosure Statement