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Case Report: Cisplatin-lnduced Hemolytic Uremic Syndrome
Case Report: Cisplatin-Induced Hemolytic Uremic Syndrome TAWFIQ KHANSUR, MD,
ALAN KENNEDY, MD
ABSTRACT: Two patients developed noncardiogenic pulmonary edema (NCPE), following red blood cell transfusion in a setting of acute cisplatin nephropathy. One manifested the full picture of hemolytic uremic syndrome, the other had transient features following blood transfusion. We further reviewed the clinical records on blood transfusion for all patients with cisplatin nephropathy. A third case of (NCPE) was identified in a patient with acute renal dysfunction. However, none of the 16 patients with cisplatin-induced, mild stable chronic renal impairment had pulmonary dysfunction or other laboratory evidence for microangiopathy following transfusion. Hemolytic uremic syndrome may be a rare manifestation of cisplatin toxicity. Caution is indicated in transfusing patients with acute platinum nephropathy even in the absence of overt microangiopathy. The pathogenesis of this syndrome and the cause for NCPE is unclear. The literature is reviewed and discussed. KEY INDEXING TERMS: Cisplatin; microangiopathy; Hemolytic uremic syndrome. [Am J Med Sci 1991; 301(6):390-392.]
A
syndrome resembling hemolytic uremic syndrome (HUS) is known to result from the use of mitomycin C. l The occurrence is estimated to vary from 2 to 10% and is dose related. 2-4 This syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency. Systemic hypertension and NCPE have been described and are precipitated with blood transfusion. l •S•6 Neurologic abnormalities and fever are rare. Similar syndromes have been anecdotally reported with the use of other chemotherapeutic drugs, 7 particularly with the use of bleomycin and cisplatin combiDivision of Hematology/Oncology, Department of Veterans Affairs, Medical Center and University of Mississippi Medical Center, Jackson. Correspondence: Tawfiq Khansur, MD, Department of Veterans AffairsMed. Ctr. (151), 1500 E. Woodrow Wilson Drive, Jackson, MS 39216.
390
nations.S-l l Since bleomycin is common to these reported regimens, it has been suspected as the causative agent. 12 Thrombotic microangiopathy has also been reported with the use of Ara C, daunorubicin,13 and following the use of experimental drugs chlorozotocin,14 neocarzinostatin, l and methyl CCNU. lS We report two patients who developed NCPE following transfusion of red blood cells in a setting of acute cisplatin nephropathy. A review of transfusions in all patients with platinum nephropathy identified a third patient with NCPE. All patients had clinical features of HUS. Case Report Patient 1. A 60-year-old male Caucasian was diagnosed to have small cell lung cancer with metastasis to the thoracic spine. The patient refused chemotherapy and was followed for pain control. He presented six months later with headaches and generalized weakness. Neurologic evaluation was unremarkable. Staging work-up revealed a solitary left occipital cortex metastasis on computed tomography of the head and multiple thoracic and lumbar spine metastasis on bone scan. He had a white blood cell (WBe) count of 5,600, a platelet count of 288,000, and hematocrit of 44. His blood urea nitrogen (BUN) was 12 mg, creatinine 1.2 mg, bilirubin 1.1 mg, and lactate dehydrogenase (LDH) 180 i.u. The patient was started on irradiation to the head and a chemotherapy regimen consisting of cisplatin 100 mg per square meter and etoposide (VP -16) 120 mg per square meter for three days, repeated every three weeks. He was continued on outpatient radiation therapy. Three weeks following his first course of chemotherapy, the patient was re-admitted with backache, weakness of the legs, and episodic mental confusion. On admission, the patient was afebrile and the vital signs were within normal levels. Neurologic examination showed minimal left lower extremity weakness without sensory deficit. A computed tomography of the head showed the left occipital lesion unchanged. A magnetic resonance imaging of the spine showed no evidence of cord compression. He had a white blood cell count of 1,400, platelet count of 75,000, and a hematocrit of 40. Total bilirubin was 1.1 mg, BUN 22 mg, creatinine 1.6 mg, calcium 9.5 mg, inorganic phosphorus 3.4 mg, and magnesium 1.9 mg per 100 ml, all within normal limits. Sodium was 137 mEq and potassium 3.5 mEq. Urinalysis showed 1+ protein 3-5 RBC/high power field. Following admission he developed a mental obtundation and gross hematuria. A spinal tap showed normal cerebrospinal fluid (CSF). On the following day, his hematocrit dropped to 32 and the platelets to 52,000. His serum creatinine was 2.6 mg and BUN 31 mg on day 2 and 4.1 mg and 33 mg, respectively, on day 4. His sensorium fluctuated between lucidity and clouding. On the third day of admission, his hematocrit was 25 and numerous schistocytes were seen in the peripheral circulation. His indirect bilirubin was elevated to 3.8 mg, haptoglobin was at 10 and LDH was >350 i.u. He was cautiously transfused at this point, but following the administration of 200 ccs of blood he developed acute shortness of breath and his blood pressure June 1991 Volume 301 Number 6
Khansur and Kennedy
went up to 130/105. Chest radiograph showed bilateral diffuse alveolar infiltrate, and blood gases showed severe hypoxia. Central venous line pressures were within normal ranges. Coagulation profile was within normal limits and the Coombs test was negative. Blood transfused was re-evaluated for donor compatibility and found compatible. Although the possible reversible nature of the syndrome was explained to the patient and the family, they refused intubation and further aggressive management was abandoned at their request. The patient expired of respiratory failure. Patient 2. A 56-year-old male Caucasian was found to have a Stage III unresectable adenocarcinoma of the lung. His past history was significant for a Stage II malignant melanoma of the left forearm resected three years earlier for which he was being followed with no evidence of disease. Six thousand rads were administered to the chest lesion and he was followed in the clinic. Six months following radiation, he showed an increase in the size of the chest lesion. A staging work-up was negative for metastasis outside of the chest and he was placed on a chemotherapy regimen consisting of cisplatinum 100 mg per square meter and etoposide 120 mg per square meter, repeated every three weeks. Following the first cycle of chemotherapy, there was minimal tumor regression. He was admitted three days following his second cycle of chemotherapy complaining of headache, ataxia, fever, and mental confusion. No focal neurologic deficits were identified, though he had an unsteady gait. His complete blood count showed a white blood cell count of 7,200, hematocrit of 34, and a platelet count of 120,000. His serum creatinine was 3.8 mg, BUN 55 mg, sodium 140 mEq, potassium 2.6 mg, bilirubin 1.1 mg, calcium 9.9 mg, and magnesium 1.9 mg, all within normal limits. LDH was 262 i.u. A computed tomographic scan of the head and a spinal tap were obtained and both were unremarkable. His hematocrit continued to drop over the next two days. On the third day it was 23 and the platelet count was 100,000. Indirect bilirubin was 2.1 mg, LDH 350 i.u., and haptoglobin 35. Examination of the peripheral smear showed schistocytes. BUN was 73 mg and creatinine 4.2 mg. Coombs test was negative. He was transfused as he was complaining of dizziness. He developed severe shortness of breath following one unit of red blood cell. The chest x-ray showed bilateral alveolar infiltrate. Blood gases were P0 2 49, pCo2 61.5, and pH was 7.184. A Swan Ganz catheter was placed and pulmonary capillary wedge pressure estimated were within normal range. His blood pressure went up to 180/110. He was aggressively supported with positive airway pressure ventilation and placed on Prednisone 60 mg/d. His hematocrit and chest x-ray improved over three days, and his renal function gradually recovered. A review of the patients' records was made to identify the consequences of blood transfusion in patients with platinum induced nephropathy. Two patients with acute renal dysfunction and 16 patients with chronic stable nephropathy who had undergone red blood cell transfusion were identified. One patient with acute nephropathy had developed a mild respiratory distress with minimal alveolar infiltrate on chest radiograph following transfusion. This patient had received chemotherapy with cisplatin and 5-fluorouracil for a recurrent head and neck cancer. He had developed acute platinum nephropathy following his first round of cisplatin chemotherapy. The BUN was 64 mg and creatinine 4.2 mg. The platelet count was 46,000 and hematocrit 21 when he was transfused with 1 unit of red blood cells. This patient had minimal mental clouding, and acute hypertension developed following transfusion. Urinalysis showed microscopic hematuria and 1+ protein. The peripheral smear was not available for review. However, the LDH was elevated over 600 i.u. and the bilirubin was 2.5 mg. The Coombs was negative and the transfused blood had been analyzed and found compatible. Although his venous pressure was nQt estimated, there was no clinical evidence for fluid overload. The patient spontaneously recovered in 24 hours. Sixteen other patients with chronic stable renal dysfunctions had blood transfusions on 21 occasions with no untoward side effects.
Discussion
Microangiopathic syndrome, characterized by hemolytic anemia and thrombocytopenia, is seen in canTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
cer with certain hemangiomatous tumors. It is also seen in disseminated intravascular coagulation, with disseminated carcinoma, and as a complication of chemotherapy. The mitomycin C-induced hemolytic uremic syndrome was the prototype of chemotherapy-related syndrome first described in 1980.16 A registry established by the Georgetown University has since studied over 150 patients with this syndrome, and the clinical features have been well definedP Except for occasional anecdotal reports, the syndrome has not been well established with the use of other drugs. 7 A number of reports of bleomycin and platinum containing regimens causing a similar clinical syndrome have been made.8-11 Since bleomycin rather than cisplatin is common to these regimens, it has been thought to be the causative agent. 12 The clinical features of our patients fit the characteristics for chemotherapy-related hemolytic uremic syndrome. Cisplatin was the common drug in all three patients and was given with etoposide (VP-16) in two and 5-fluorouracil in one. Since these other drugs have not been reported to cause HUS syndrome, cisplatin probably was causative in our patients. This also may be true for previously reported patients who developed the syndrome while receiving bleomycin and platinum.8-11 Cisplatin has been described to cause seizures,IS,19 Coombs positive hemolytic anemia,20 and cortical blindness. IS The pathogenesis of these rare platinumrelated toxicities are not clear. As platinum crosses the blood brain barrier poorly, direct toxicity is unlikely. Acute and chronic renal toxicity is a well recognized side effect of platinum therapy. The latter is dose dependent and a dose limiting factor in the use of cisplatin. All three of our patients had acute renal toxicity with serum creatinine >3.5 mg. Two of our three patients had definite neurologic features - one had mental obtundation and the other had left lower extremity weakness. The third showed some mental clouding. Such neurologic features are seen in thrombotic thrombocytopenic purpura rather than in HUS, and the previously described cerebral syndrome of seizures and cortial blindness reported with this drug1S.19 may be secondary to microangiopathy. Thus, four of eight patients reported by Mead et al had renal dysfunction and two developed seizures six hours and two days following cisplatin administration. 19 In the report of Berman et aI, one patient had thrombocytopenia. IS NCPE and hypertension developed in all three of our patients. In fact, the pulmonary syndrome brought on following blood transfusions made the microangiopathy clinically obvious. Hematuria also occurred in all three, gross hematuria in two, and microscopic hematuria in one. Mild proteinuria was seen in all three patients. The syndrome developed following two cycles of chemotherapy in two and three weeks following the first cycle of chemotherapy in one patient. It does not appear to be significantly dose or time dependent. The syndrome was fulminant and fatal in one and reversed 391
Cisplatin-Induced Microangiopathy
spontaneously in another patient. In the third patient, aggressive respiratory support and high dose steroids were used. This patient completely reversed all manifestations. The pathogenesis of this syndrome remains unclear. There is good evidence for direct endothelial cell damage from mitomycin C.2l.22 However, mitomycin C and bleomycin containing regimens can cause renal vascular damage without evidence for microangiopathy.8,23.24 This suggests that other factors are involved in the pathogenesis of HUS. Circulating immune complexes have been found to be increased in patients with mitomycin C-induced syndrome. l These immune complexes have been further identified to cause platelet aggregation. l ,25 Direct or immune complex mediated endothelial damage could promote platelet aggregation via a number of possible mechanisms. These include: (1) decreased prostacyclin production; (2) altered abnormal von Willebrands factor multimer release; (3) decrease in plasminogen activator; or (4) alteration in protein C. Cisplatin administration has been shown to cause elevated von Willebrand factor levels.l l Such elevated levels have been believed to cause arterial occlusive syndrome associated with this drug. Microangiopathic syndrome may be similarly precipitated. References 1. Cantrell JE Jr, Phillips TM, Schein PS: Carcinoma-associated hemolytic-uremic syndrome: A complication of mitomycin C chemotherapy. J Clin Onco13:723-734, 1985. 2. Bruntsch V, Groos G, Tigges FJ, Gallmeier WM: Microangiopathic hemolytic anemia: A frequent complication of mitomycin therapy in cancer patients. Eur J Cancer Clin Onco120:905-909, 1984. 3. Valavaara R, Nordman E: Renal complications of mitomycin C therapy with special reference to total dose. Cancer 55:47-50, 1985. 4. Goldberg RM, Smith FP, Veno W, Ahlgren JD, Schein PS: 5fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Onco14:395-399, 1986. 5. Chang·Poon VY, Hwang WS, Wong A, Berry J, Klassen J, Poon MC: Pulmonary angiomatoid vascular changes in mitomycin C associated hemolytic-uremic syndrome. Arch Pathol Lab Med 109:877-878,1985. 6. Chow S, Roscoe J, Cattran, DC: Plasmapheresis and anti·platelet agents in the treatment of hemolytic uremic syndrome secondary to mitomycin. Am J Kidney Dis 7:407-412, 1986. 7. Jackson AM, Rose BD, Graff LG, Jacobs JB, Schwartz JH, Strauss GM, Yang JP, Rudnick MR, Elfenbein IB, Narins RG: Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 101:41-44, 1984.
392
8. Harrel RM, Sibley R, Vogelzang NJ: Renal vascular lesion after chemotherapy with vinblastine bleomycin cisplatin. Am J Med 73:429-433, 1982. 9. Boccia RV, Gelmann EP, Baker CC, Marti G, Longo DL: A hemolytic-uremic syndrome with the acquired immunodeficiency syndrome, letter. Ann Intern Med 101:716-717, 1984. 10. Desablens B, Fievet P, Pruna A, Claisse JF, Westeel PF, Tolani M, Fournier A: Hemolytic-uremic syndrome after cancer chemotherapy without mitomycin C, letter. Nephron 42:343-344, 1986. 11. Licciardello JT, Moake JL, Rudy CK, Karp DD, Hong WK: Elevated von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy. Oncology 42:296-300, 1985. 12. Murgo AJ: Thrombotic microangiopathy in cancer patients including those induced by chemotherapeutic agents. Sem Hematol 24:161-177,1987. 13. Byrnes JJ, Baquerizo H, Gonzalez M, Hensely GT: Thrombotic thrombocytopenic purpura subsequent to acute myelogenous leukemia chemotherapy. Am J Hematol 21:299-304, 1986. 14. Kressel BR, Ryan KP, Duong AJ, Berenberg J, Schein, PS: Microangiopathic hemolytic anemia thrombocytopenia, and renal failure in patients treated for adenocarcinoma. Cancer 48: 17381745, 198!. 15. Laffay DL, Tubbs RR, Valenzuela R, Hall PM, McCormack LJ: Chronic glomerular microangiopathy and metastatic carcinoma. Hum Pathol10:433-438, 1979. 16. Jones BG, Fielding JW, Newman CE, Howell A, Brookes VS: Intravascular haemolysis and renal impairment after blood transfusion in two patients on long-term 5-fluorouracil and mitomycin C. Lancet 14:1275-1277, 1980. 17. Rothschild N, Erickson B, Sisk R, Korec S, Lessene JB, Keller J, Arbus M, Chiazze L, Neefe JR, Wooley P: Cancer associated hemolytic uremic syndrome (C-HVS): A registry update and analysis of factors predicting for prolonged survival. Proceedings of the American Society of Clinical Oncology, Atlanta, Georgia, 1987, p 266. 18. Berman IJ, Mann MP: Seizures and transient cortical blindness associated with cis-platinum (II) diammine-dichloride (PDD) therapy in a thirty-year-old man. Cancer 45:764-766, 1980. 19. Mead GM, Arnold AM, Green JA, Macbeth FR, Williams CJ, Whitehouse JM: Epileptic seizures associated with cisplatin administration. Cancer Treat Rep 66:1719-1722, 1982. 20. Getaz EP, Beckley S, Fitzpatrick J, Dozier A: Cisplatin-induced hemolysis. N Engl J Med 302:334-335, 1980. 21. Cattell V: Mitomycin-induced hemolytic uremic kidney: An experimental model in rat. Am J Pathol121:88-95, 1985. 22. Duperray A, Tranqui L, Alix JL: The effect of mitomycin C on the biosynthesis of prostacyclin by primary culture of human umbilical cord vein endothelial cells. IX International Congress of Nephrology, Los Angeles, 1984, p. 448A. 23. Doll DC, Ringenberg QS, Yarbro JW: Vascular toxicity associated with antineoplastic agents. J Clin Oncol4:1405-1417, 1986. 24. Hanna WT, Krauss S, Regester RF, Murphy WM: Renal disease after mitomycin C therapy. Cancer 48:2583-2588, 1981. 25. Korec S, Schein PS, Smith FP, Neefe JR, Woodley PV, Goldberg RM, Phillips TM: Treatment of cancer-associated hemolytic uremic syndrome with staphylococcal protein A immunoperfusion. J Clin Oncol 4:210-215, 1986.
June 1991 Volume 301 Number 6
ALAN KENNEDY, MD
ABSTRACT: Two patients developed noncardiogenic pulmonary edema (NCPE), following red blood cell transfusion in a setting of acute cisplatin nephropathy. One manifested the full picture of hemolytic uremic syndrome, the other had transient features following blood transfusion. We further reviewed the clinical records on blood transfusion for all patients with cisplatin nephropathy. A third case of (NCPE) was identified in a patient with acute renal dysfunction. However, none of the 16 patients with cisplatin-induced, mild stable chronic renal impairment had pulmonary dysfunction or other laboratory evidence for microangiopathy following transfusion. Hemolytic uremic syndrome may be a rare manifestation of cisplatin toxicity. Caution is indicated in transfusing patients with acute platinum nephropathy even in the absence of overt microangiopathy. The pathogenesis of this syndrome and the cause for NCPE is unclear. The literature is reviewed and discussed. KEY INDEXING TERMS: Cisplatin; microangiopathy; Hemolytic uremic syndrome. [Am J Med Sci 1991; 301(6):390-392.]
A
syndrome resembling hemolytic uremic syndrome (HUS) is known to result from the use of mitomycin C. l The occurrence is estimated to vary from 2 to 10% and is dose related. 2-4 This syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency. Systemic hypertension and NCPE have been described and are precipitated with blood transfusion. l •S•6 Neurologic abnormalities and fever are rare. Similar syndromes have been anecdotally reported with the use of other chemotherapeutic drugs, 7 particularly with the use of bleomycin and cisplatin combiDivision of Hematology/Oncology, Department of Veterans Affairs, Medical Center and University of Mississippi Medical Center, Jackson. Correspondence: Tawfiq Khansur, MD, Department of Veterans AffairsMed. Ctr. (151), 1500 E. Woodrow Wilson Drive, Jackson, MS 39216.
390
nations.S-l l Since bleomycin is common to these reported regimens, it has been suspected as the causative agent. 12 Thrombotic microangiopathy has also been reported with the use of Ara C, daunorubicin,13 and following the use of experimental drugs chlorozotocin,14 neocarzinostatin, l and methyl CCNU. lS We report two patients who developed NCPE following transfusion of red blood cells in a setting of acute cisplatin nephropathy. A review of transfusions in all patients with platinum nephropathy identified a third patient with NCPE. All patients had clinical features of HUS. Case Report Patient 1. A 60-year-old male Caucasian was diagnosed to have small cell lung cancer with metastasis to the thoracic spine. The patient refused chemotherapy and was followed for pain control. He presented six months later with headaches and generalized weakness. Neurologic evaluation was unremarkable. Staging work-up revealed a solitary left occipital cortex metastasis on computed tomography of the head and multiple thoracic and lumbar spine metastasis on bone scan. He had a white blood cell (WBe) count of 5,600, a platelet count of 288,000, and hematocrit of 44. His blood urea nitrogen (BUN) was 12 mg, creatinine 1.2 mg, bilirubin 1.1 mg, and lactate dehydrogenase (LDH) 180 i.u. The patient was started on irradiation to the head and a chemotherapy regimen consisting of cisplatin 100 mg per square meter and etoposide (VP -16) 120 mg per square meter for three days, repeated every three weeks. He was continued on outpatient radiation therapy. Three weeks following his first course of chemotherapy, the patient was re-admitted with backache, weakness of the legs, and episodic mental confusion. On admission, the patient was afebrile and the vital signs were within normal levels. Neurologic examination showed minimal left lower extremity weakness without sensory deficit. A computed tomography of the head showed the left occipital lesion unchanged. A magnetic resonance imaging of the spine showed no evidence of cord compression. He had a white blood cell count of 1,400, platelet count of 75,000, and a hematocrit of 40. Total bilirubin was 1.1 mg, BUN 22 mg, creatinine 1.6 mg, calcium 9.5 mg, inorganic phosphorus 3.4 mg, and magnesium 1.9 mg per 100 ml, all within normal limits. Sodium was 137 mEq and potassium 3.5 mEq. Urinalysis showed 1+ protein 3-5 RBC/high power field. Following admission he developed a mental obtundation and gross hematuria. A spinal tap showed normal cerebrospinal fluid (CSF). On the following day, his hematocrit dropped to 32 and the platelets to 52,000. His serum creatinine was 2.6 mg and BUN 31 mg on day 2 and 4.1 mg and 33 mg, respectively, on day 4. His sensorium fluctuated between lucidity and clouding. On the third day of admission, his hematocrit was 25 and numerous schistocytes were seen in the peripheral circulation. His indirect bilirubin was elevated to 3.8 mg, haptoglobin was at 10 and LDH was >350 i.u. He was cautiously transfused at this point, but following the administration of 200 ccs of blood he developed acute shortness of breath and his blood pressure June 1991 Volume 301 Number 6
Khansur and Kennedy
went up to 130/105. Chest radiograph showed bilateral diffuse alveolar infiltrate, and blood gases showed severe hypoxia. Central venous line pressures were within normal ranges. Coagulation profile was within normal limits and the Coombs test was negative. Blood transfused was re-evaluated for donor compatibility and found compatible. Although the possible reversible nature of the syndrome was explained to the patient and the family, they refused intubation and further aggressive management was abandoned at their request. The patient expired of respiratory failure. Patient 2. A 56-year-old male Caucasian was found to have a Stage III unresectable adenocarcinoma of the lung. His past history was significant for a Stage II malignant melanoma of the left forearm resected three years earlier for which he was being followed with no evidence of disease. Six thousand rads were administered to the chest lesion and he was followed in the clinic. Six months following radiation, he showed an increase in the size of the chest lesion. A staging work-up was negative for metastasis outside of the chest and he was placed on a chemotherapy regimen consisting of cisplatinum 100 mg per square meter and etoposide 120 mg per square meter, repeated every three weeks. Following the first cycle of chemotherapy, there was minimal tumor regression. He was admitted three days following his second cycle of chemotherapy complaining of headache, ataxia, fever, and mental confusion. No focal neurologic deficits were identified, though he had an unsteady gait. His complete blood count showed a white blood cell count of 7,200, hematocrit of 34, and a platelet count of 120,000. His serum creatinine was 3.8 mg, BUN 55 mg, sodium 140 mEq, potassium 2.6 mg, bilirubin 1.1 mg, calcium 9.9 mg, and magnesium 1.9 mg, all within normal limits. LDH was 262 i.u. A computed tomographic scan of the head and a spinal tap were obtained and both were unremarkable. His hematocrit continued to drop over the next two days. On the third day it was 23 and the platelet count was 100,000. Indirect bilirubin was 2.1 mg, LDH 350 i.u., and haptoglobin 35. Examination of the peripheral smear showed schistocytes. BUN was 73 mg and creatinine 4.2 mg. Coombs test was negative. He was transfused as he was complaining of dizziness. He developed severe shortness of breath following one unit of red blood cell. The chest x-ray showed bilateral alveolar infiltrate. Blood gases were P0 2 49, pCo2 61.5, and pH was 7.184. A Swan Ganz catheter was placed and pulmonary capillary wedge pressure estimated were within normal range. His blood pressure went up to 180/110. He was aggressively supported with positive airway pressure ventilation and placed on Prednisone 60 mg/d. His hematocrit and chest x-ray improved over three days, and his renal function gradually recovered. A review of the patients' records was made to identify the consequences of blood transfusion in patients with platinum induced nephropathy. Two patients with acute renal dysfunction and 16 patients with chronic stable nephropathy who had undergone red blood cell transfusion were identified. One patient with acute nephropathy had developed a mild respiratory distress with minimal alveolar infiltrate on chest radiograph following transfusion. This patient had received chemotherapy with cisplatin and 5-fluorouracil for a recurrent head and neck cancer. He had developed acute platinum nephropathy following his first round of cisplatin chemotherapy. The BUN was 64 mg and creatinine 4.2 mg. The platelet count was 46,000 and hematocrit 21 when he was transfused with 1 unit of red blood cells. This patient had minimal mental clouding, and acute hypertension developed following transfusion. Urinalysis showed microscopic hematuria and 1+ protein. The peripheral smear was not available for review. However, the LDH was elevated over 600 i.u. and the bilirubin was 2.5 mg. The Coombs was negative and the transfused blood had been analyzed and found compatible. Although his venous pressure was nQt estimated, there was no clinical evidence for fluid overload. The patient spontaneously recovered in 24 hours. Sixteen other patients with chronic stable renal dysfunctions had blood transfusions on 21 occasions with no untoward side effects.
Discussion
Microangiopathic syndrome, characterized by hemolytic anemia and thrombocytopenia, is seen in canTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
cer with certain hemangiomatous tumors. It is also seen in disseminated intravascular coagulation, with disseminated carcinoma, and as a complication of chemotherapy. The mitomycin C-induced hemolytic uremic syndrome was the prototype of chemotherapy-related syndrome first described in 1980.16 A registry established by the Georgetown University has since studied over 150 patients with this syndrome, and the clinical features have been well definedP Except for occasional anecdotal reports, the syndrome has not been well established with the use of other drugs. 7 A number of reports of bleomycin and platinum containing regimens causing a similar clinical syndrome have been made.8-11 Since bleomycin rather than cisplatin is common to these regimens, it has been thought to be the causative agent. 12 The clinical features of our patients fit the characteristics for chemotherapy-related hemolytic uremic syndrome. Cisplatin was the common drug in all three patients and was given with etoposide (VP-16) in two and 5-fluorouracil in one. Since these other drugs have not been reported to cause HUS syndrome, cisplatin probably was causative in our patients. This also may be true for previously reported patients who developed the syndrome while receiving bleomycin and platinum.8-11 Cisplatin has been described to cause seizures,IS,19 Coombs positive hemolytic anemia,20 and cortical blindness. IS The pathogenesis of these rare platinumrelated toxicities are not clear. As platinum crosses the blood brain barrier poorly, direct toxicity is unlikely. Acute and chronic renal toxicity is a well recognized side effect of platinum therapy. The latter is dose dependent and a dose limiting factor in the use of cisplatin. All three of our patients had acute renal toxicity with serum creatinine >3.5 mg. Two of our three patients had definite neurologic features - one had mental obtundation and the other had left lower extremity weakness. The third showed some mental clouding. Such neurologic features are seen in thrombotic thrombocytopenic purpura rather than in HUS, and the previously described cerebral syndrome of seizures and cortial blindness reported with this drug1S.19 may be secondary to microangiopathy. Thus, four of eight patients reported by Mead et al had renal dysfunction and two developed seizures six hours and two days following cisplatin administration. 19 In the report of Berman et aI, one patient had thrombocytopenia. IS NCPE and hypertension developed in all three of our patients. In fact, the pulmonary syndrome brought on following blood transfusions made the microangiopathy clinically obvious. Hematuria also occurred in all three, gross hematuria in two, and microscopic hematuria in one. Mild proteinuria was seen in all three patients. The syndrome developed following two cycles of chemotherapy in two and three weeks following the first cycle of chemotherapy in one patient. It does not appear to be significantly dose or time dependent. The syndrome was fulminant and fatal in one and reversed 391
Cisplatin-Induced Microangiopathy
spontaneously in another patient. In the third patient, aggressive respiratory support and high dose steroids were used. This patient completely reversed all manifestations. The pathogenesis of this syndrome remains unclear. There is good evidence for direct endothelial cell damage from mitomycin C.2l.22 However, mitomycin C and bleomycin containing regimens can cause renal vascular damage without evidence for microangiopathy.8,23.24 This suggests that other factors are involved in the pathogenesis of HUS. Circulating immune complexes have been found to be increased in patients with mitomycin C-induced syndrome. l These immune complexes have been further identified to cause platelet aggregation. l ,25 Direct or immune complex mediated endothelial damage could promote platelet aggregation via a number of possible mechanisms. These include: (1) decreased prostacyclin production; (2) altered abnormal von Willebrands factor multimer release; (3) decrease in plasminogen activator; or (4) alteration in protein C. Cisplatin administration has been shown to cause elevated von Willebrand factor levels.l l Such elevated levels have been believed to cause arterial occlusive syndrome associated with this drug. Microangiopathic syndrome may be similarly precipitated. References 1. Cantrell JE Jr, Phillips TM, Schein PS: Carcinoma-associated hemolytic-uremic syndrome: A complication of mitomycin C chemotherapy. J Clin Onco13:723-734, 1985. 2. Bruntsch V, Groos G, Tigges FJ, Gallmeier WM: Microangiopathic hemolytic anemia: A frequent complication of mitomycin therapy in cancer patients. Eur J Cancer Clin Onco120:905-909, 1984. 3. Valavaara R, Nordman E: Renal complications of mitomycin C therapy with special reference to total dose. Cancer 55:47-50, 1985. 4. Goldberg RM, Smith FP, Veno W, Ahlgren JD, Schein PS: 5fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Onco14:395-399, 1986. 5. Chang·Poon VY, Hwang WS, Wong A, Berry J, Klassen J, Poon MC: Pulmonary angiomatoid vascular changes in mitomycin C associated hemolytic-uremic syndrome. Arch Pathol Lab Med 109:877-878,1985. 6. Chow S, Roscoe J, Cattran, DC: Plasmapheresis and anti·platelet agents in the treatment of hemolytic uremic syndrome secondary to mitomycin. Am J Kidney Dis 7:407-412, 1986. 7. Jackson AM, Rose BD, Graff LG, Jacobs JB, Schwartz JH, Strauss GM, Yang JP, Rudnick MR, Elfenbein IB, Narins RG: Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 101:41-44, 1984.
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8. Harrel RM, Sibley R, Vogelzang NJ: Renal vascular lesion after chemotherapy with vinblastine bleomycin cisplatin. Am J Med 73:429-433, 1982. 9. Boccia RV, Gelmann EP, Baker CC, Marti G, Longo DL: A hemolytic-uremic syndrome with the acquired immunodeficiency syndrome, letter. Ann Intern Med 101:716-717, 1984. 10. Desablens B, Fievet P, Pruna A, Claisse JF, Westeel PF, Tolani M, Fournier A: Hemolytic-uremic syndrome after cancer chemotherapy without mitomycin C, letter. Nephron 42:343-344, 1986. 11. Licciardello JT, Moake JL, Rudy CK, Karp DD, Hong WK: Elevated von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy. Oncology 42:296-300, 1985. 12. Murgo AJ: Thrombotic microangiopathy in cancer patients including those induced by chemotherapeutic agents. Sem Hematol 24:161-177,1987. 13. Byrnes JJ, Baquerizo H, Gonzalez M, Hensely GT: Thrombotic thrombocytopenic purpura subsequent to acute myelogenous leukemia chemotherapy. Am J Hematol 21:299-304, 1986. 14. Kressel BR, Ryan KP, Duong AJ, Berenberg J, Schein, PS: Microangiopathic hemolytic anemia thrombocytopenia, and renal failure in patients treated for adenocarcinoma. Cancer 48: 17381745, 198!. 15. Laffay DL, Tubbs RR, Valenzuela R, Hall PM, McCormack LJ: Chronic glomerular microangiopathy and metastatic carcinoma. Hum Pathol10:433-438, 1979. 16. Jones BG, Fielding JW, Newman CE, Howell A, Brookes VS: Intravascular haemolysis and renal impairment after blood transfusion in two patients on long-term 5-fluorouracil and mitomycin C. Lancet 14:1275-1277, 1980. 17. Rothschild N, Erickson B, Sisk R, Korec S, Lessene JB, Keller J, Arbus M, Chiazze L, Neefe JR, Wooley P: Cancer associated hemolytic uremic syndrome (C-HVS): A registry update and analysis of factors predicting for prolonged survival. Proceedings of the American Society of Clinical Oncology, Atlanta, Georgia, 1987, p 266. 18. Berman IJ, Mann MP: Seizures and transient cortical blindness associated with cis-platinum (II) diammine-dichloride (PDD) therapy in a thirty-year-old man. Cancer 45:764-766, 1980. 19. Mead GM, Arnold AM, Green JA, Macbeth FR, Williams CJ, Whitehouse JM: Epileptic seizures associated with cisplatin administration. Cancer Treat Rep 66:1719-1722, 1982. 20. Getaz EP, Beckley S, Fitzpatrick J, Dozier A: Cisplatin-induced hemolysis. N Engl J Med 302:334-335, 1980. 21. Cattell V: Mitomycin-induced hemolytic uremic kidney: An experimental model in rat. Am J Pathol121:88-95, 1985. 22. Duperray A, Tranqui L, Alix JL: The effect of mitomycin C on the biosynthesis of prostacyclin by primary culture of human umbilical cord vein endothelial cells. IX International Congress of Nephrology, Los Angeles, 1984, p. 448A. 23. Doll DC, Ringenberg QS, Yarbro JW: Vascular toxicity associated with antineoplastic agents. J Clin Oncol4:1405-1417, 1986. 24. Hanna WT, Krauss S, Regester RF, Murphy WM: Renal disease after mitomycin C therapy. Cancer 48:2583-2588, 1981. 25. Korec S, Schein PS, Smith FP, Neefe JR, Woodley PV, Goldberg RM, Phillips TM: Treatment of cancer-associated hemolytic uremic syndrome with staphylococcal protein A immunoperfusion. J Clin Oncol 4:210-215, 1986.
June 1991 Volume 301 Number 6