Abstract
We herein report a rare case of acute bilateral renal and splenic infarctions occurring during chemotherapy for lung cancer. A 60-year-old man presented with acute and intensive upper abdominal and back pain during chemotherapy with cisplatin and etoposide for lung cancer. Contrast-enhanced computed tomography (CT) revealed bilateral renal and splenic infarctions. After the administration of unfractionated heparin his pain was relieved with a clearance of the infarctions in the CT findings and a recovery of renal dysfunction. Enhanced coagulation by lung cancer and arterial ischemia by chemotherapy may therefore contribute to the development of these infarctions.
Keywords: chemotherapy, lung cancer, renal and splenic infarction
Introduction
Renal infarction occurs due to embolic infarction in either the main or branched renal arteries. The main causes of such infarction are injury, aortic aneurysm, thrombosis with arrhythmias, systemic inflammatory disease, renal transplantation, and arterial angiography. The most frequent cause is embolic occlusion due to thrombus from atrial fibrillation. However, it is often difficult to diagnose because of its non-specific symptoms (1).
In malignant diseases, coagulation is enhanced and the incidence of thrombosis is known to increase. The thrombosis accompanied with malignant disease is known as Trousseau's syndrome (2). Lung cancer most often causes thrombosis among all malignant diseases, followed by pancreatic cancer and gastric cancer (3). However, renal thrombosis accompanied with malignant diseases is very rare. Such renal infarction often results in renal dysfunction, which thus makes it impossible to continue to administer platinum based combination chemotherapy. It is therefore important to make an early diagnosis and perform timely treatment for such renal infarction in malignant diseases. We herein report a case of acute bilateral renal and splenic infarctions occurring during chemotherapy for lung cancer, which improved with a recovery of renal dysfunction owing to an early diagnosis and the performance of timely treatment with heparin.
Case Report
A 60-year-old man came to our hospital because of hoarseness. He had a medical history of hypertension and had smoked one pack of cigarettes per day for 42 years. Chest X-ray revealed a 5 cm-sized tumor in left hilar with lympho-adenopathy. He was diagnosed to have small cell lung cancer (cT2bN3M1b: stage IV brain metastasis) and thus was admitted to undergo chemotherapy. Before starting the chemotherapy there was no perfusion defect in the bilateral kidney or spleen on contrast-enhanced computed tomography (CT). Cisplatin (80 mg/m2) was infused on the first day and etoposide (100 mg/m2) was infused on the second and third day. On the seventh day, he experienced abdominal pain, which resolved spontaneously. On the ninth day, he again suffered acute upper abdominal pain. The pain was intensive and accompanied with back pain. There was no rebound tenderness on the physical examination or any abnormal findings on abdominal X-rays. Urinalysis did not show hematuria. An electrocardiogram showed no signs of arrhythmia or myocardial infarction. Abdominal contrast-enhanced CT demonstrated perfusion defects in the bilateral kidneys and spleen (Fig. 1). Ultrasonic cardiography demonstrated neither intramural thrombus nor valvar heart disease. We diagnosed acute bilateral renal and splenic infarctions associated with lung cancer. No abnormal findings related to collagen diseases or congenital diseases were detected as shown in Table 1. Two days after starting the administration of unfractionated heparin and a calcium channel antagonist, the abdominal and back pain attenuated and then subsided with the clearance of perfusion defects in bilateral kidneys and spleen on abdominal CT (Fig. 1). The serum creatinine level was elevated to 2.97 mg/dL two days after the onset, while the D-dimer was elevated to 5.9 μg/mL and LDH to 3,138 IU/L. After administering anti-coagulant therapy these data all declined to the normal ranges on the 26th day (Fig. 2). A transient decrease in the platelet count by myelosuppression induced by chemotherapy was observed. The bimodal change pattern in D-dimer, which paralleled the changes in the platelet count, may be partially related to the myelosuppression induced by chemotherapy. From the 22nd day, whole brain radiation and next chemotherapy with etoposide (100 mg/m2) and carboplatin (AUC5) instead of cisplatin was restarted. Finally, he was discharged after three more serial cycles of this chemotherapy without any recurrence of renal infarction.
Figure 1.
A contrast-enhanced CT scan revealing perfusion defects (arrows) in the spleen (a), kidney (b, c) on the ninth day. The perfusion defects decreased significantly on the 29th day after treatment with unfractionated heparin (d-f).
Table 1.
Laboratory Findings at the Onset.
| Parameters | normal range | |
|---|---|---|
| WBC | 7,900 /μL | (3,900-9,800/μL) |
| Hb | 15.1 g/dL | (13.5-17.6g/dL) |
| Plt | 17.8×104/μL | (13.1-36.2×104/μL) |
| PT | 10.0 sec | (10.0-15.0sec) |
| APTT | 25.6 sec | (25.0-50.0sec) |
| Fibrinogen | 535 mg/dL | (200-400mg/dL) |
| D-Dimer | 2.7 μg/mL | (0.0-1.0μg/mL) |
| Antithombine III | 120 % | (80-120%) |
| Protein C activity | 110 % | (64-146%) |
| Protein S antigen (free) | 91 % | (60-150%) |
| Lupus anticoagulant | (-) | (-) |
| Anti-cardiolipin antibody | (-) | (-) |
| Glucose | 109 mg/dL | (60-100mg/dL) |
| ALT | 45 IU/L | (12-32IU/L) |
| AST | 40 IU/L | (5-36IU/L) |
| LDH | 437 IU/L | (116-230IU/L) |
| Mg | 1.7 mg/dL | (1.7-2.7mg/dL) |
| CRP | 3.8 mg/dL | (0.0-0.2mg/dL) |
| Urinary test | ||
| Protein | 30 mg/dL | (-) |
| Glucose | 100 mg/dL | (-) |
| Occult blood | (-) | (-) |
Figure 2.
Clinical course. CDDP: cisplatin, VP16: etoposide, CBDCA: carboplatin, WBRT: whole brain radiation therapy, LDH: lactate dehydrogenase, Plt: platelet counts, Cre: serum creatinine
Discussion
The main cause of renal infarction is thrombosis. Two major types of thrombosis related to renal infarction are known to exist. One is thromboemboli, which originates from a thrombus in the heart or aorta while another is in-situ thrombosis, which may cause the complete occlusion of the main renal artery or a segmental branch artery (4, 5). In the present case, in-situ thrombosis is thought to have mainly contributed to the onset of renal infarction because no thrombus in the heart or aorta was detected.
The development of thrombosis in this case was thought to be related to enhanced coagulation caused by cancer and arterial ischemia induced by chemotherapy. At first, we were concerned about the possibility of enhanced coagulation induced by cancer. Since Trousseau et al. have demonstrated that patients with malignant disease have potential risks for thrombosis. A case of excessive coagulation associated with cancer is known as Trousseau's syndrome (2, 6). There are multiple overlapping and interacting mechanisms of Trousseau's syndrome, such as mucin, tissue factor, cysteine proteinase and inflammatory cytokines that serve to activate endothelial and platelet adhesion molecules.
Secondly, arterial ischemia is known to be induced by chemotherapy, including cisplatin. Doll et al. reported that acute arterial ischemic events occurred most frequently after cisplatin based combination chemotherapy (7). Among such arterial ischemic events, myocardial infarction, stenosis in the cerebral artery and thrombus in the peripheral arteries has been reported (7, 8). The mechanisms of arterial ischemic events caused by cisplatin have been explained by drug-induced endothelial cell damage (9), arterial vasospasm due to hypomagnesemia (10) and enhanced alpha-adrenergic tone (11), perturbation of the clotting system (12), activation of platelets (13) or an abnormality of thromboxane-prostacyclin homeostasis (7). Dehydration due to nausea induced by chemotherapy may also possibly accelerate the arterial ischemia through an impaired blood flow as described in Virchow's triad (14).
In the present case, after the induction of chemotherapy renal infarction occurred with an acute onset because there was no embolus in CT scans before the start of chemotherapy. The acute onset was caused by the acute arterial ischemia induced by chemotherapy based on the enhanced coagulation caused by malignant disease.
Six previously reported cases of renal infarction with lung cancer were reviewed at Table 2 (15-20). Only two of these cases had undergone chemotherapy with CDDP. Renal infarction itself is a rare disease compared with cerebral and pulmonary infarction. There may be more such cases because this infarction is difficult to diagnose because of non-specific symptoms. The distribution, size and blood flow in renal artery may also be associated with the low incidence of this problem.
Table 2.
Renal Infarction in Lung Cancer Patients.
| Case | Age/sex | Histology | Previous treatment | Risk factors | Location or type of thrombi | Management | Reference |
|---|---|---|---|---|---|---|---|
| 1 | 54/Female | Adeno | None | Undescribed | Multiple brain infarction Renal infarction Nonbacterial thrombotic endocarditis | Undescribed | 15 |
| 2 | 70/Male | Large cell | Left lower Lobectomy | DM HT | Renal infarction | Observation | 16 |
| 3 | 50/Male | Adeno | None | APS | Brain infarction Pulmonary thromboembolism | Warfarin Ticlopidine | 17 |
| 4 | 46/Female | Non-small cell | Cisplatin GEM | Undescribed | Bilateral renal infarction | Aspirin ACEI | 18 |
| 5 | 67/Male | Squamous cell | CRT Pneumonectomy | HT Smoking | Bilateral renal infarction Splenic infarction Brain infarction | Embolectomy Dialysis | 19 |
| 6 | 52/Female | Adeno | Left upper lobectomy | None | Renal infarction | Dipyridamole | 20 |
| 7 | 60/Male | Small cell | Cisplatin VP16 | Smoking HT | Bilateral renal infarction Splenic infarction | Anticoagulation Ca antagonist | Present case |
In the present case, an early diagnosis and the administration of timely treatment for acute renal infarction made it possible to continue the administration of combination chemotherapy for lung cancer. The therapeutic management of renal infarction usually involves the administration of intravenous heparin followed by oral anticoagulants. When a thrombotic risk remains after the treatment, then the anticoagulant therapy should be continued. Despite the use of such treatments, nevertheless approximately 5% of such patients with renal infarction require hemodialysis due to severe renal dysfunction (5). In addition to this anticoagulant therapy, it is also important to administer magnesium to prevent the onset of vasospasm due to hypomagnesemia induced by cisplatin-based combination chemotherapy. Finally, it is very important to make an early diagnosis and provide timely treatment for renal infarction because renal dysfunction induced by the infarction often makes it impossible to continue administering chemotherapy for lung cancer.
In conclusion, a case of acute bilateral renal and splenic infarctions occurred during chemotherapy for lung cancer was herein reported. This case improved with a recovery of renal dysfunction owing to an early diagnosis and timely treatment with heparin.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors are indebted to J. Patrick Barron, Professor Emeritus of Tokyo Medical University, and Adjunct Professor, Seoul National University, Bundang Hospital, for his pro bono review of this manuscript. The authors would like to also thank all the anonymous reviewers for their great efforts in helping us to improve our paper.
References
- 1. Korzets Z, Plotkin E, Bernheim J, Zissin R. The clinical spectrum of acute renal infarction. Isr Med Assoc J 4: 781-784, 2002. [PubMed] [Google Scholar]
- 2. Trousseau A. Plegmasia alba dolens. Lectures on Clinical Medicine, Delivered at Hotel-Dieu, Paris 5: 281-332, 1865. [Google Scholar]
- 3. Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau's syndrome revisited. Blood 62: 14-31, 1983. [PubMed] [Google Scholar]
- 4. Paris B, Bobrie G, Rossignol P, Le Coz S, Chedid A, Plouin PF. Blood pressure and renal outcomes in patients with kidney infarction and hypertension. J Hypertens 24: 1649-1654, 2006. [DOI] [PubMed] [Google Scholar]
- 5. Bourgault M, Grimbert P, Verret C, et al. Acute renal infarction: a case series. Clin J Am Soc Nephrol 8: 392-398, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 110: 1723-1729, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Doll DC, Ringenberg QS, Yarbro JW. Vascular toxicity associated with antineoplastic agents. J Clin Oncol 4: 1405-1417, 1986. [DOI] [PubMed] [Google Scholar]
- 8. Mathews J, Goel R, Evans WK, Shamji F, Stewart DJ. Arterial occlusion in patients with peripheral vascular disease treated with platinum-based regimens for lung cancer. Cancer Chemother Pharmacol 40: 19-22, 1997. [DOI] [PubMed] [Google Scholar]
- 9. Licciardello JT, Moake JL, Rudy CK, Karp DD, Hong WK. Elevated plasma von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy. Oncology 42: 296-300, 1985. [DOI] [PubMed] [Google Scholar]
- 10. Vogelzang NJ, Torkelson JL, Kennedy BJ. Hypomagnesemia, renal dysfunction, and Raynaud's phenomenon in patients treated with cisplatin, vinblastine, and bleomycin. Cancer 56: 2765-2770, 1985. [DOI] [PubMed] [Google Scholar]
- 11. Rosenfeld CS, Broder LE. Cisplatin-induced autonomic neuropathy. Cancer Treat Rep 68: 659-660, 1984. [PubMed] [Google Scholar]
- 12. Walsh J, Wheeler HR, Geczy CL. Modulation of tissue factor on human monocytes by cisplatin and adriamycin. Br J Haematol 81: 480-488, 1992. [DOI] [PubMed] [Google Scholar]
- 13. Togna GI, Togna AR, Franconi M, Caprino L. Cisplatin triggers platelet activation. Thromb Res 99: 503-509, 2000. [DOI] [PubMed] [Google Scholar]
- 14. Bennett PC, Silverman SH, Gill PS, Lip GY. Peripheral arterial disease and Virchow's triad. Thromb Haemost 101: 1032-1040, 2009. [PubMed] [Google Scholar]
- 15. Fujishima S, Okada Y, Irie K, et al. Multiple brain infarction and hemorrhage by nonbacterial thrombotic endocarditis in occult lung cancer: a case report. Angiology 45: 161-166, 1994. [DOI] [PubMed] [Google Scholar]
- 16. Oura H, Hirose M, Aikawa H, Ishiki M. Abdominal organ infarction encountered immediately after surgery of primary lung cancer. Kyobu Geka 58: 137-142, 2005(in Japanese, Abstract in English). [PubMed] [Google Scholar]
- 17. Katsuoka H, Mimori Y, Kohriyama T, et al. An autopsy case of catastrophic antiphospholipid syndrome presenting with recurrent multiple cerebral infarction associated with lung cancer. No To Shinkei 52: 64-69, 2000(in Japanese, Abstract in English). [PubMed] [Google Scholar]
- 18. Cavdar C, Toprak O, Oztop I, Secil M, Cokmert S, Camsari T. Bilateral renal infarction in a patient with lung carcinoma treated with cisplatin and gemcitabine. Ren Fail 29: 923-925, 2007. [DOI] [PubMed] [Google Scholar]
- 19. Karzai W, Schmidt J, Jung A, Kroger R, Clausner G, Presselt N. Delayed emergence and acute renal failure after pneumonectomy: tumor emboli complicating postoperative course. J Cardiothorac Vasc Anesth 23: 219-222, 2009. [DOI] [PubMed] [Google Scholar]
- 20. Sawada T, Watanabe Y, Ohura H, Handa M. Abdominal organ infarction encountered after surgery for primary lung cancer. The Journal of the Japanese Association for Chest Surgery 23: 161-164, 2009. [Google Scholar]