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Department of Pharmacy Practice, Shree Devi College of Pharmacy, Mangalore, Karnataka, India
Thrombotic microangiopathy (TMA) is a rare but serious complication associated with gemcitabine therapy. A 57-year-old man who presented with fever, productive cough, and shortness of breath. Further evaluation with a PET-CT scan revealed a lesion in the left upper lobe of the lung along with multiple bilateral pulmonary nodules. A biopsy demonstrated fragments of skeletal muscle and non-small cell carcinoma, confirming the diagnosis of lung cancer. The patient was started on chemotherapy consisting of gemcitabine, carboplatin, and zoledronic acid. Following treatment, he developed pancytopenia. Laboratory investigations revealed normocytic normochromic anemia and thrombocytopenia. Ultrasonography of the abdomen showed bilateral grade II renal parenchymal changes. Due to worsening renal function, a renal biopsy was performed, which confirmed the presence of thrombotic microangiopathy. Based on the clinical findings and biopsy results, a diagnosis of gemcitabine-induced TMA was made. Gemcitabine was immediately discontinued, and the patient received supportive management, including antibiotics, corticosteroids, and blood transfusions. Despite these interventions, his renal function continued to deteriorate, ultimately progressing to dialysis-dependent kidney failure. Gemcitabine-induced TMA is an uncommon but potentially life-threatening adverse effect that can be challenging to diagnose because of its variable clinical presentation. Early recognition, prompt discontinuation of the offending agent, and timely renal biopsy can aid in diagnosis and management. Increased awareness among healthcare professionals is essential to improve patient outcomes and reduce the risk of irreversible renal damage.
Gemcitabine is a nucleoside analogue of cytarabine that was first approved by the United States Food and Drug Administration (FDA) in 1996. Owing to its favourable safety profile and relatively mild adverse effects, its use has expanded significantly over the years. Gemcitabine, either alone or in combination with other chemotherapeutic agents, is currently used as a first-line treatment in both adjuvant and palliative settings for several malignancies, including non-small cell lung cancer, pancreatic cancer, breast cancer, ovarian cancer, and urothelial carcinoma. In patients with advanced urothelial tumors, the combination of gemcitabine and cisplatin has demonstrated efficacy comparable to traditional regimens while producing fewer toxic effects, particularly in elderly patients. Consequently, it has become a preferred first-line treatment option in advanced disease. The most commonly reported adverse effects of gemcitabine are haematological, particularly thrombocytopenia and anaemia resulting from myelosuppression. Renal manifestations such as mild proteinuria, microscopic haematuria, and transient elevations in blood urea nitrogen (BUN) and serum creatinine levels may also occur but are usually of limited clinical significance. However, a rare yet potentially life-threatening complication associated with gemcitabine therapy is thrombotic microangiopathy (TMA), which can lead to severe renal impairment and irreversible kidney failure., The first case of gemcitabine-induced TMA was reported in 1994, and its estimated incidence ranges from 0.015% to 1.4%.[1,2] Previous studies have suggested that the risk of developing TMA may be increased when gemcitabine is administered in combination with other chemotherapeutic agents such as carboplatin, cisplatin, vinorelbine, tegafur, and docetaxel. Despite its rarity, gemcitabine-induced TMA carries a poor prognosis and often presents a diagnostic challenge because of its variable clinical manifestations. [3,4] Here, we report a case of gemcitabine-induced thrombotic microangiopathy in a patient with metastatic lung cancer, in whom a kidney biopsy was ultimately required to establish the diagnosis.
CASE REPORT
A 57-year-old male presented with a two-day history of fever, productive cough, and shortness of breath. On admission, the patient was conscious, alert, and oriented. He also reported a history of significant weight loss and persistent back pain over the preceding months. Further evaluation was performed to investigate the underlying cause of his symptoms. A positron emission tomography-computed tomography (PET-CT) scan revealed a lesion in the left upper lobe of the lung along with multiple bilateral pulmonary nodules, suggestive of metastatic disease. Histopathological examination demonstrated a 3.6 × 2.9 cm mass in the left upper lobe infiltrating the pleura and intercostal muscles. Biopsy specimens obtained from a lytic lesion involving the left 12th rib showed fragments of skeletal muscle infiltrated by malignant cells consistent with non-small cell lung carcinoma, favoring squamous cell carcinoma. A chest radiograph further supported the diagnosis. Baseline laboratory investigations revealed a haemoglobin level of 11.4 g/dL, platelet count of 97,000 cells/mm³, neutrophils of 69%, lymphocytes of 13%, monocytes of 16%, red blood cell count of 3.27 million cells/mm³, and serum creatinine of 0.9 mg/dL. Based on the clinical, radiological, and histopathological findings, the patient was diagnosed with metastatic non-small cell lung carcinoma (squamous cell carcinoma subtype).
Treatment Given
Prior to initiation of chemotherapy, the patient received the following premedications:
(Day 1- Gemcitabine, Day 8- Gemcitabine + carboplatin)
Patient received 4 cycles of chemotherapy
Day 8- Due because patient developed Pancytopenia.
As patient received chemotherapy, the chance of febrile neutropenia is high. Patient readmitted with complaints of breathing difficulty and weakness. Laboratory investigations showed few fragmented RBCs, RBC clumping and aggregates are seen in peripheral smear study. Histopathology report showed NORMOCYTIC NORMOCHROMIC ANEMIA, evidence of haemolysis and thrombocytopenia. Haemoglobin-6.8g/dl, Platelet- 22,000cells/cumm, RBC- 2.27cells/cumm, Creatinine- 2.0 mg/dl, LDH 809.8U/L, Alkaline phosphate- 260U/L, GGT- 157U/L. USG abdomen and pelvis showed bilateral renal grade II parenchymal changes. Patients’ creatinine level was persistently increasing and haemoglobin level was falling down.
Renal biopsy was carried out, patient diagnosed with CKD proving that patient developed TMA (thrombotic microangiopathy) due to injection Gemcitabine. Patient received one unit of PRBC and two units of PLATELET transfusion. Patient was advised for haemodialysis. Fluoroscopic guided right IJV permcath inserted. Haemodialysis done with free heparin. Patient treated with IV vancomycin, IV meropenem, Tab voriconazole, IV steroids’, bronchodilators, platelet and PRBC transfusion and CKD medicines. Patient had episodes of epistaxis, managed accordingly, patient clinically stable and discharged with home medications and advised for two days hemodialysis in a week.
DISCUSSION:
Thrombotic microangiopathy (TMA) is a spectrum of disorders that includes thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS). It is characterized by microvascular endothelial injury leading to microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, and varying degrees of organ dysfunction. Renal involvement is common and is characterized histologically by endothelial swelling, fibrin thrombi, platelet aggregation, arterial intimal fibrosis, and basement membrane proliferation. Several chemotherapeutic agents, including mitomycin, bleomycin, cisplatin, and 5-fluorouracil, have been implicated in the development of TMA, although the exact pathophysiological mechanism remains unclear. Since the introduction of gemcitabine into clinical practice, a limited number of cases of gemcitabine-induced TMA have been reported. The reported incidence ranges from 0.015% in clinical trials to 0.41% in single-center studies. [1,2] Although uncommon, this complication can result in significant morbidity and poor renal outcomes. Gemcitabine-induced TMA has been reported to occur at cumulative doses as low as 2,450 mg/m² and within three months of initiating therapy. However, the risk appears to increase substantially with cumulative doses approaching 20,000 mg/m² and after the administration of more than 18 treatment cycles. [8] While renal biopsy remains the gold standard for confirming the diagnosis, the presence of MAHA, thrombocytopenia, and acute kidney injury (AKI) is often sufficient to establish a clinical diagnosis. Early manifestations may include new-onset or worsening hypertension and proteinuria, which can precede overt clinical symptoms. Neurological and respiratory manifestations have also been described in association with gemcitabine-induced TMA. [9] The cornerstone of management is the immediate discontinuation of gemcitabine. Additional therapeutic approaches include plasmapheresis and corticosteroid therapy. In severe cases, renal replacement therapy may be required because of progressive AKI. More recently, rituximab has shown promising results in patients who fail to respond to conventional treatment with plasmapheresis and steroids. [9,10] Diagnosing chemotherapy-induced TMA can be particularly challenging in patients receiving palliative cancer treatment. Thrombocytopenia and anemia are frequently attributed to chemotherapy-induced myelosuppression, while AKI may result from drug-induced nephrotoxicity, tubular injury, or microangiopathy secondary to disseminated malignancy. Consequently, differentiating TMA from other causes of cytopenias and renal dysfunction is often difficult. Furthermore, the highly variable onset and clinical presentation of gemcitabine-induced TMA can delay diagnosis and treatment. In the present case, gemcitabine-induced TMA developed on a background of chronic disease but presented with acute clinical deterioration. The patient experienced dyspnea, productive cough, and progressive clinical decline approximately one month after initiation of gemcitabine therapy. Laboratory findings revealed pancytopenia with anemia and thrombocytopenia, while renal evaluation demonstrated worsening kidney function. A renal biopsy ultimately confirmed the diagnosis of TMA. Despite prompt discontinuation of gemcitabine and aggressive supportive management, including platelet transfusions, packed red blood cell transfusions, antibiotics, and corticosteroids, the patient's hematological parameters improved only gradually, and renal function deteriorated to the point of requiring long-term maintenance dialysis.
CONCLUSION
This case highlights a rare but serious complication of gemcitabine therapy in a patient with metastatic lung cancer. Gemcitabine-induced TMA should be considered in patients presenting with thrombocytopenia, anemia, hypertension, proteinuria, or unexplained acute kidney injury during treatment. Early recognition and prompt discontinuation of the offending agent are crucial to improving outcomes. Renal biopsy may be particularly valuable in diagnostically challenging cases. Clinicians should maintain a high index of suspicion and closely monitor renal function and hematological parameters in patients receiving gemcitabine, as delayed diagnosis can lead to irreversible kidney damage and dialysis dependence.
REFERENCES
Munishwara G.*, A Case of Gemcitabine-Induced Thrombotic Microangiopathy in a Patient with Metastatic Lung Carcinoma, Int. J. Med. Pharm. Sci., 2026, 2 (7), 82-86. https://doi.org/10.5281/zenodo.21108144
10.5281/zenodo.21108144