Gemcitabine-sirolimus synergy associated thrombotic microangiopathy in a renal transplant recipient with mesenteric leiomyosarcoma: A case report

Abstract

BACKGROUND

Mesenteric leiomyosarcoma, a rare tumor originating from the smooth muscle of the mesentery, that may require treatment with gemcitabine based chemotherapy in advanced stages. Gemcitabine usage has been associated with the development of thrombotic microangiopathy, a risk which can be increased by concurrent use of sirolimus.

CASE SUMMARY

We present the case of a young Caucasian woman with a renal transplant who developed an aggressive leiomyosarcoma. While on gemcitabine, she was noted to have acute kidney injury. Biopsy of the renal allograft revealed histological findings consistent with thrombotic microangiopathy. Sirolimus was replaced with tacrolimus, and gemcitabine was discontinued. Despite treatment with eculizumab, the allograft function continued to decline, leading to graft failure, and the patient had to be started on renal replacement therapy.

CONCLUSION

This case highlights the possible synergy of gemcitabine and sirolimus in the pathogenesis of de novo thrombotic microangiopathy.

Key Words: Mesenteric leiomyosarcoma; Gemcitabine; Sirolimus; Thrombotic microangiopathy; Renal transplantation; Case report

Core Tip: Thrombotic microangiopathy represents a rare yet serious complication in renal transplant patients, potentially causing rapid loss of allograft function. Various medications, including gemcitabine and sirolimus, have been implicated in its pathogenesis. Even with discontinuation of causative agents and anticomplement therapy, allograft function may progressively worsen.

INTRODUCTION

Immunosuppression is the cornerstone of modern renal transplantation, contributing significantly to the prevention of acute and chronic allograft rejection[1]. While immunosuppression is effective, it can be associated with an increase in risk of malignancies besides other side effects. Patients on immunosuppressive therapy can have up to a three time increase in incidence of malignancies compared to the general population, with prolonged immunosuppressive therapy being a key contributing factor[2]. Moreover, these patients are also more susceptible to rare malignancies including mesenteric leiomyosarcoma[3].

Mesenteric leiomyosarcoma is a rare malignant tumor, with an estimated incidence of 1:350000[4]. It typically arises from smooth muscle cells within the mesentery, most frequently involving the small intestine[5]. The treatment of leiomyosarcoma depends on the extent of the tumor and may require surgical resection, neoadjuvant therapy, or palliative care. Common neoadjuvant regimens include doxorubicin-based therapies or a combination of gemcitabine and docetaxel, which is selected based on individual patient and tumor characteristics[4,6].

Gemcitabine based regimens are the first-line therapy options for advanced leiomyosarcoma, demonstrating both good tolerability and high activity against the tumor[6,7]. While gemcitabine generally has a favorable safety profile with predictable adverse effects, it is associated with thrombotic microangiopathy (TMA), a rare but serious complication that has an incidence of 0.015% to 1.4%[8]. In renal transplant recipients who subsequently develop malignancy, the risk of TMA may be increased by the concurrent use of immunosuppressive agents, such as calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors[9]. The occurrence of TMA in this patient group is of particular clinical significance, given its association with allograft loss in one-third of the cases[10].

The case presented highlights the occurrence of TMA in a post-renal transplant patient undergoing treatment for a rare malignancy, likely due to the possible combined effects of antineoplastic and immunosuppressive agents.

CASE PRESENTATION

Chief complaints

A 25-year-old Caucasian female, 5 years post renal transplant and undergoing treatment for mesenteric leiomyosarcoma, presented to the transplant clinic for routine follow-up where she was found to have an elevation in serum creatinine.

History of present illness

The patient underwent a deceased donor kidney transplant 5 years ago and had been receiving treatment for mesenteric leiomyosarcoma for the past 16 months. Her maintenance immunosuppressive regimen included sirolimus (1.5 mg, once daily; goal: 4-6 ng/mL) and mycophenolate mofetil (250 mg, twice daily). Her baseline systolic blood pressure was 110-120 mmHg, and her baseline serum creatinine was 1-1.25 mg/dL. Her home anti-hypertensive regimen consisted of carvedilol (6.25 mg, twice daily). She presented to the transplant clinic for a scheduled follow-up visit, and the laboratory evaluation revealed a rise in serum creatinine to 1.69 mg/dL from her baseline of approximately 1.0 mg/dL. She had recently completed seven cycles of gemcitabine for mesenteric leiomyosarcoma (with a cumulative exposure of 11700 mg/m²).

History of past illness

Her diagnosis of mesenteric leiomyosarcoma was made in January 2024 after she presented with left lower quadrant abdominal pain rated 5/10. The pain was non radiating and not related to food intake. She did not report any fever or diarrhea. The pain was worse during bowel movements. The left lower quadrant was tender to palpation. A contrast-enhanced computed tomography (CT) scan of the abdomen and pelvis demonstrated a solid progressively enhancing mass in the left hemi-abdomen, concerning a mesenchymal tumor (Figure 1). A biopsy confirmed the diagnosis of high grade leiomyosarcoma (T4N0M0, G3, stage IIIB). The tumor was surgically resected; tacrolimus was switched to sirolimus 1.5 mg once daily with a goal serum level of 4-6 ng/mL and mycophenolate mofetil was discontinued. Adjuvant chemotherapy of doxorubicin (60 mg/m²) and dacarbazine (750 mg/m²) was initiated. After four cycles over 12 weeks, the treatment regimen was switched to gemcitabine (900 mg/m²) and docetaxel (75 mg/m²). This switch was made due to an interval CT chest, abdomen, and pelvis showing development of an irregular 1.6 cm spiculated pulmonary nodule in the right lower lobe of lung concerning pulmonary metastasis. After six cycles of gemcitabine and docetaxel, the patient was switched to gemcitabine single agent therapy due to side effects related to docetaxel, which included alternating constipation and diarrhea, intermittent chills and fevers.

Figure 1 Contrast enhanced computed tomography of the abdomen demonstrating a 5.7 cm × 7.3 cm × 6.7 cm solid, progressively enhancing mass in the left hemi-abdomen, suspicious for a mesenchymal tumor.

Personal and family history

There was no relevant personal or family history contributing to the presenting illness.

Physical examination

At the time of admission for worsening renal function, her vital signs were: Heart rate 93 bpm, blood pressure 152/105 mmHg, respiratory rate 18/minute, oxygen saturation 100% on room air, and temperature 98.6 °F.

Laboratory examinations

Based on elevated blood pressure and serum creatinine (1.69 mg/dL from a baseline of approximately 1 mg/dL), she was admitted for further workup of acute kidney injury. Hemoglobin was 8.2 g/dL and platelet count was normal at 240 × 10⁹/L. Urine studies demonstrated significant proteinuria with a urine protein-to-creatinine ratio of 1263 mg/g. Prior to presentation, serum sirolimus levels had ranged from 3.6 ng/mL to 7.0 ng/mL; the level at admission was 3.6 ng/mL. Human leucocyte antigen donor-specific antibodies were negative for both class I and II. Renal ultrasound showed a right lower quadrant transplanted kidney with no sonographic evidence of hydronephrosis, nephrolithiasis, or transplant renal artery stenosis. Further evaluation revealed elevated serum lactate dehydrogenase (LDH) of 578 U/L and undetectable haptoglobin level, consistent with ongoing hemolysis. Peripheral blood smear showed schistocytes. The direct Coombs test was negative. Complement levels were within normal limits, with a C3 of 105 mg/dL (normal: 80-160 mg/dL), C4 of 27 mg/dL (normal: 19-52 mg/dL), and total complement activity (CH50) of 58 U/mL (normal: 30-75 U/mL). Genetic testing for complement mutations was not performed due to low suspicion for atypical hemolytic uremic syndrome.

Given these findings, a renal allograft biopsy was performed. Histopathology of the allograft revealed arteriolar thrombotic lesions with fibrin deposition and red blood cell fragments (Figure 2A). Glomeruli demonstrated mesangiolysis, endothelial swelling with a bloodless appearance, and capillary wall remodeling with double contours (Figure 2B-D). Moderate tubular atrophy and interstitial fibrosis involved 25%-30% of the cortex. Immunohistochemical stains for SV40 (BK virus) and cytomegalovirus were negative. There was no glomerulitis, or peritubular capillaritis. C4d and immunofluorescence studies were negative for immune complex deposition.

Figure 2 Immunohistochemical stains. A: Arteriole with intraluminal fibrin thrombus (arrowhead); B: Silver-stained glomerulus with mesangiolysis (arrowhead); C: Mesangiolysis, endothelial cell swelling, and capillary wall remodeling with formation of double contours (arrowhead); D: Capillary wall remodeling with double contours (arrowhead).

Imaging examinations

No evidence of hydronephrosis, nephrolithiasis, or transplant renal artery stenosis was noted on renal ultrasound at the time of presentation.

FINAL DIAGNOSIS

A diagnosis of chronic active drug-induced TMA was established based on the clinical course and histopathologic findings.

TREATMENT

In response to the biopsy-confirmed TMA, gemcitabine was discontinued. Sirolimus was also discontinued and replaced with tacrolimus, titrated to maintain a target serum level of 3-5 ng/L. Belatacept was considered as an alternative immunosuppressive strategy but was not initiated due to limited inpatient availability. The patient’s serum creatinine doubled from baseline to 2.93 mg/dL, and there was worsening proteinuria, with a urine protein-to-creatinine ratio of 3655 mg/g. Given the worsening of allograft function, eculizumab therapy was initiated during the index hospitalization. She received an induction dose of eculizumab at 900 mg. For meningococcal infection prophylaxis, she was started on oral penicillin V 500 mg twice daily and received the meningococcal vaccines (Menveo for immunization against meningococcus serogroups A, C, W, Y and Bexero for immunity against meningococcus serogroup B).

OUTCOME AND FOLLOW-UP

Despite anti-complement therapy, the renal function of the patient continued to deteriorate. The course was further complicated by readmission for an episode of gram-negative rod bacterial meningitis, necessitating discontinuation of eculizumab (after two doses). Unfortunately, serum creatinine continued to rise, and renal replacement therapy was started. Tyrosine kinase inhibitor pazopanib (600 mg, oral daily) was initiated on an outpatient basis for the continued treatment of leiomyosarcoma. The timeline of clinical events leading to this outcome is shown in Figure 3, and the trend of serum creatinine during the clinical course is shown in Figure 4.

Figure 3 Chronological sequence of major clinical events in relation to thrombotic microangiopathy presentation. TMA: Thrombotic microangiopathy.

Figure 4 Increasing trend in serum creatinine from the time of presentation. The green arrow indicates initiation of eculizumab and subsequent dosing, and the orange arrow shows the occurrence of bacterial meningitis.

DISCUSSION

The incidence of de-novo TMA among renal allograft recipients is reported to be 1.5%[9]. In the post-transplantation period the precipitating factors include the use of calcineurin inhibitors, mTOR inhibitors, antibody-mediated rejection, ischemia reperfusion injury and viral infections[9]. However, TMA may also result from causes common to the general population which include complement regulatory gene mutations, autoimmune conditions, and exposure to drugs such as quinine and gemcitabine[11,12]. Given the patient’s exposure history, sirolimus and gemcitabine stand out as possible causative agents in our clinical case.

Sirolimus, an mTOR inhibitor, has been approved by the United States Food and Drug Administration for immunosuppressive use since 1999[13]. Most reported cases of TMA involve the combined use of calcineurin inhibitors with sirolimus; however, cases related to sirolimus monotherapy have also been documented[9,10,14-16]. The proposed mechanism likely involves endothelial injury, driven by both its thrombogenic potential and suppression of vascular endothelial growth factor expression in the kidneys[17]. When used in combination with calcineurin inhibitors, the risk of TMA may be increased by the additional endothelial toxicity of these agents.

Like sirolimus, gemcitabine (a nucleoside analogue) has also been associated with TMA; particularly in oncologic settings where it is administered as a chemotherapeutic agent. TMA has been most frequently observed in patients receiving gemcitabine for pancreatic, pulmonary, and breast cancers[8]. Although the exact pathogenesis is not fully understood, it may result from gemcitabine-induced endothelial glycocalyx injury through reduction of terminal sialic acids from suppressed ST6Gal1 expression and increased inflammatory cytokines production[18]. In this case, gemcitabine-induced endothelial injury, compounded by the synergistic effects of sirolimus, may have contributed to the development of TMA. The timing of drug exposure further supports a possible contributory role of both agents in the development of TMA in this case.

TMA typically occurs within 3 months to 6 months following transplantation; however, cases have been reported ranging from immediately after reperfusion to several months post-transplant[9,19]. Ozaki et al[19] reported a case of TMA developing two years after transplantation. The occurrence of TMA with gemcitabine has been reported to occur within 5-8 months[20]. The clinical presentation of TMA depends on the extent of disease, whether it is limited to the renal allograft or has systemic involvement[9,21]. Systemic TMA is usually associated with more severe clinical manifestations, frequently involving neurologic, gastrointestinal, and cardiovascular complications[21]. In our case, TMA presented 4.5 years after transplantation and 9 months after initiation of gemcitabine therapy for leiomyosarcoma. The clinical course was severe and consistent with systemic TMA.

The laboratory workup of suspected TMA generally begins with hematologic workup, which demonstrates anemia and a decreasing hematocrit trend. Schistocytes are usually seen on the peripheral blood smear, consistent with microangiopathic hemolytic anemia[9]. Elevated LDH levels and low haptoglobin further support the presence of intravascular hemolysis. Renal involvement is reflected by rising serum creatinine, the presence of proteinuria and new onset or worsening hypertension[22]. Additionally, sirolimus levels in our case were in therapeutic range; however, TMA can still develop even when they are within this range.

Kidney biopsy is the gold standard for diagnosing TMA[9]. Histological findings in acute cases include fibrin thrombi in arterioles and small arteries, congested glomerular capillaries, and endothelial swelling. In chronic cases, changes include vascular remodeling, the presence of sclerosis, and double contouring of basement membrane[22]. Electron microscopy and immunofluorescence further support the diagnosis. In our case, the histological findings were consistent with mixed acute-chronic TMA.

The management of TMA depends on identifying and addressing the underlying trigger. In cases of drug-induced TMA, the first step involves discontinuing the offending agent. If necessary, it should be replaced with an alternative immunosuppressive agent. In case of sirolimus-associated TMA reported by Barone et al[14], withdrawal of sirolimus followed by initiation of daclizumab and later cyclosporine resulted in resolution of TMA. Similarly, Crew et al[16] reported that in one case of sirolimus-associated de novo TMA, withdrawal of sirolimus and initiation of tacrolimus led to graft recovery, while in the other, sirolimus dose reduction with plasma exchange, intravenous immunoglobulin, vincristine, azathioprine, and prednisone failed to prevent progression to end-stage renal disease. We also switched from sirolimus to tacrolimus; however, the renal function continued to decline.

Similarly, management of gemcitabine-induced TMA typically starts with discontinuation of the offending agent, a strategy that is also employed in sirolimus-associated TMA. In cases where drug discontinuation alone is insufficient, eculizumab (a C5 complement inhibitor) is used. Martin et al[23] reported a patient with pancreatic adenocarcinoma who developed TMA on gemcitabine; the drug was discontinued, eculizumab was initiated, and the patient was subsequently transitioned to 5-fluorouracil. In another approach reported by Efe et al[24], a renal transplant recipient with cholangiocarcinoma was restarted on gemcitabine following the initiation of eculizumab. While gemcitabine was tolerated, the malignancy continued to progress, and the patient died two months after transitioning to palliative care. In our case, in coordination with the oncology team a decision was made to withhold gemcitabine hoping for improvement in allograft function.

The use of eculizumab has been shown to be beneficial in a study conducted in France, as well as in multiple reported cases of gemcitabine -induced TMA. In a multicenter study by Grall et al[25], conducted across five centers between 2011 and 2016, over 80% of patients who received eculizumab had hematological remission[23,25,26]. The intervention group showed better renal outcomes compared to the control group. Similar positive responses have been reported in individual case studies[23,26]. However, in our case, the allograft function of the patient did not improve despite the use of eculizumab.

The prognosis of TMA is influenced by several factors, with the site of involvement playing a major role. Outcomes tend to be more favorable when TMA is limited to the renal allograft. In a study by Schwimmer et al[27], 54% of patients with systemic TMA required dialysis, whereas none of the patients with renal-limited TMA needed dialysis. Further, graft loss occurred in 39% of the systemic TMA group but was absent in the renal-limited group. Maisons et al[28] reported that renal-limited TMA was associated with lower rates of cardiovascular events, dialysis, and mortality compared to TMA with hematologic involvement. These findings are consistent with the poor prognosis observed in our case of systemic TMA.

CONCLUSION

De novo thrombotic microangiopathy is a major complication in the post transplantation period that can significantly impact both graft function and patient outcomes. In renal allograft recipients with post-transplant malignancies, the risk of thrombotic microangiopathy may be increased by concurrent use of mTOR inhibitors, calcineurin inhibitors and chemotherapeutic agents such as gemcitabine. Our case is unique as it highlights the potential synergism between gemcitabine and sirolimus contributing to TMA in this rare post-transplant malignancy. Clinicians should remain vigilant for drug-related thrombotic microangiopathy which may be complicated by loss of allograft function and return to dialysis.