| Japanese Journal of Clinical Oncology | Pages |
Introduction
Case Report
Discussion
References
Mitomycin-C Induced Hemolytic Uremic Syndrome: a Case Report and Literature Review
INTRODUCTION
The thrombotic microangiopathic disorder hemolytic uremic syndrome (HUS) was first described by Moschcowitz in 1924, and later expanded by Gasser in 1955 (1). The clinical and pathophysiological relationships of this disease are still unknown in spite of many hypotheses and theories. Ischemia and infarction of the kidneys have been postulated as the most likely etiology of HUS.
Hemolytic uremic syndrome has been classified into diarrhea-related and non-diarrhea related types in some reports (1). About 90% of diarrhea-related HUS occurs in early childhood and presents with bloody diarrhea. The etiology of non-diarrhea-related hemolytic uremic syndrome can be collagen vascular disease, carcinoma-associated, due to chemotherapeutic agents or idiopathic (1,2).
Chemotherapeutic agents reportedly associated with this syndrome include bleomycin, cyclosporin, cisplatin, fluorouracil and fludarabine, but the most commonly reported agent is still mitomycin-C (MMC), the incidence quoted being around 2-10% (2). Most reported cases of MMC-induced HUS die of renal failure rather than the primary malignant disease (3). The renal toxicity seems to be associated with glomerular tuft involvement (4), and is very much dose-related, being <2% at doses <50 mg/m2 (5,6); see also Table 1. Above 70 mg/m2, there is a 28% or higher risk of renal dysfunction. The onset of MMC-induced hemolytic uremic syndrome is commonly 4-8 weeks after completion of therapy, but may occur immediately after therapy or up to nine months later.
MMC-induced HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and renal thrombotic microangiopathy; other accompanying abnormalities include rash, fever, central neurologic dysfunction, interstitial pneumonitis, hematuria and proteinuria. Systemic hypertension and non-cardiogenic pulmonary edema commonly occur during the clinical course of the syndrome (7).
The understanding of possible pathogenic mechanisms of the syndrome has been greatly expanded during recent years. There is evidence that MMC can directly damage vascular endothelial cells of the kidneys (8,9). A decrease in prostacyclin synthesis can promote platelet aggregation and results in microthrombi formation in the kidneys according to some reports. The von Willebrand factor has been reported as playing a role in the development of thrombotic microangiopathy (10,11). However, the roles of Shiga toxin, interleukin (IL-1) and tumour necrosis factor are still elusive in the development of localized renal damage by thrombotic microangiopathy (12,13).
Table 1
| Cumulative dose (mg/m2) |
Underlying diseases |
No. of patients |
Survival | References |
| 40 | Gastric cancer | 1 | >26 months | Present report |
| 40 | Cholangiocarcinoma | 1 | 10 days | Verwey (26) |
| 40-80 | Gastric, breast, colon cancer, cancer of unknown primary site | 12 | 1-10 months | Cantrell (15) |
| 47-68 | Gastrointestinal cancer | 5 | 11-36 months | Valvavaara (5) |
| 48 | Breast cancer | 1 | >20 months | Guribotto (19) |
| 58.8-74.8 | Gastric cancer | 3 | 9-34 days | Julivet (23) |
| 70.7 | Cancer of unknown primary site |
3 | Kambhu (27) | |
| 80 | Rectal cancer | 1 | 8 months | Hanna (3) |
| 105 | Breast cancer | 1 | 2 months | Liu (4) |
The laboratory findings are remarkable for a moderately severe anemia, and the peripheral smear is characterized by erythrocyte fragmentation with many schistocytes. The platelet count is almost always below 100 000 cells/µl. Histological section of the kidneys has revealed microthrombi occluding the glomerular capillaries and afferent arterioles, marked glomerular sclerosis, hypocellularity and necrosis with sclerotic vascular channels and interstitial fibrosis (14).
Treatment of nephrotoxicity and microangiopathic hemolytic anemia secondary to MMC has been largely ineffective. Many methods have been attempted in the treatment of HUS, including steroids, heparin, antiplatelet agents, prostacyclin, immunosuppressive agents, plasma infusion and exchange and, recently, staphylococcus protein A dialysis (15-17). Steroids, heparin and platelet inhibitors have all been tried in small numbers of patients without success (18). Plasmapheresis has had mixed success. It normalizes the hematologic abnormalities (platelet and hemoglobin) but renal insufficiency is rarely reversed by this procedure (19,20) although there are case reports of recovery from HUS post plasmapheresis (8). Continuous immunoperfusion with fresh frozen plasma also seems to be effective in other reports, but is time consuming and exposes the patient to an enormous amount of foreign protein. There are controversies surrounding the effect of prostacyclin infusion and immunosuppressive agents. The outlook for HUS patients has improved since the efficacy of protein A immunoadsorption was reported (21,22).
CASE REPORT
A 42-year-old female patient was endoscopically diagnosed as having poorly differentiated gastric adenocarcinoma in July 1994. She underwent radical subtotal gastrectomy with Billroth II gastrojejunostomy and lymph node dissection. Her staging was established as stage III, T3N0M0. After operation, adjuvant chemotherapy was recommended because of the high tumour grading; starting in August 1994 she received mitomycin-C 10 mg/m2 once every four weeks to a cumulative dose of 40 mg/m2 over four courses. Minimal nausea was the only side effect. The last dose of chemotherapy was given in November 1994. In early January 1995, the patient complained of anorexia, weight gain and generalized weakness. Physical examination revealed a very pale patient, with generalized anasarca. Her blood pressure was 180/100 mmHg, pulse rate 72/min and bilateral basal rales were noted on auscultation. The complete blood count revealed a hemoglobin of 5.7 g/dl, WBC 4550 cells/µl and a platelet count of 96 000 cells/µl. BUN and creatinine were 35 mg/dl and 2.4mg/dl respectively. Peripheral blood smears demonstrated microangiopathic hemolytic anemia; there was a predominance of spherocytes and fragmented cells were prominent. Serum haptoglobin was <38 mg/dl. Her DIC (disseminated intravascular coagulation) profile (including prothrombin time, partial thromboplastin time, D-dimer, protamine sulphate test and fibrinogen) was within normal limits. Lactate dehydrogenase was 258 IU.
Mitomycin-C associated hemolytic uremic syndrome was considered a possibility. The patient was initially reluctant to undergo plasmapheresis, and she was given daily transfusions of frozen plasma and hydrocortisone 400 mg daily in divided doses, but only a minimal increment in hemoglobin and platelet count was seen, lasting a very short time. Eventually, plasmapheresis was performed twice, one week apart. After plasmapheresis, blood pressure rose to 180/90 mmHg and persisted for up to six hours, and it was not reversed by sedation. Severe thrombocytopenia also developed after pheresis: hemoglobin of 11.7 g/dl (post transfusion), white cell count of 6100 cells/µl and platelet count of 44 000 cells/µl. Platelet antibody was checked and found to be negative and serum creatinine dropped from 3 mg/dl to 1.8 mg/dl.
In early February, the patient fell because she felt dizzy (BP = 180/100 mmHg); she sustained a scalp laceration with massive bleeding, and there was associated grand mal seizure twice. There was no prior history of hypertension or seizures. Imaging studies of the brain were negative and her platelet count was around 40 000 cells/µl. After suturing and blood component transfusion, a third course of plasmapheresis was performed five days later. Sustained high blood pressure persisted in spite of a normal serum renin level; atenolol, captopril, adalat, lasix and doxaben were inadequate in controlling her blood pressure. By this point her hemoglobin was stable around 7 g/dl, WBC was 4100cells/µl, platelet count 87 000 cells/µl, BUN:Cr was 32 mg/dl:2 mg/dl and repeated blood smears showed absence of red cell fragmentation. Unfortunately, progressive renal impairment and hyperkalemia were noted two weeks later. BUN:Cr was 47 mg/dl:2.8mg/dl, potassium 5.6 mmol/l and LDH was 300 IU. Serum immune complex (C1q) was 31 µg Eq/ml (normal <20 µg Eq/ml), and staphylococcus column A (Prosorba column) dialysis was arranged. It was performed weekly for three consecutive weeks in April. Shortness of breath developed after each dialysis. The symptoms improved after diuretic administration, blood pressure and potassium levels slowly returned to normal and serum creatinine was maintained around 2.6 mg/dl. The hemoglobin was around 9 mg/dl and there was no thrombocytopenia. Bone marrow biopsy revealed a hypocellular marrow. Erythropoietin was prescribed. The HUS remains in remission; hemoglobin was 11 mg/dl and BUN:Cr was 30-40mg/dl:1.8-3mg/dl. Creatinine clearance was checked before discharge after stabilization of HUS, and also 6 months and 12 months later, when it was 12-15 ml/min and 24hr potassium excretion was <5 mEq/24hours. In July 1996, she relapsed and presented with peritoneal carcinomatosis, ascites (containing tumour cells), and partial intestinal obstruction, and has been initiated on high dose weekly fluorouracil and leucovorin with good objective response.
DISCUSSION
Our patient presented with the clinical features of HUS after only 40 mg/m2 of MMC. The onset of this syndrome was three months after the last dose of MMC. However, the LDH level was within normal limits during the entire clinical course, in spite of original laboratory evidence of intravascular hemolysis; C1q was slightly elevated. Plasmapheresis interrupted the process of renal damage for a short time, at the expense of moderate platelet count reduction after each pheresis. Whether thrombocytopenia was attributed to technical problems or through immunological involvement is still unknown.
Jones et al. (6) described a rapid deterioration after transfusion with packed erythrocytes but Ritva (5) countered that blood transfusion did not seem to precipitate clinical deterioration. Our patient received blood transfusion with packed red blood cells to ameliorate the severe anemia, but the disease activity did not increase. Bone marrow biopsy was done on account of pancytopenia and revealed hypocellularity. Erythropoietin was instituted for her anemia. Hyperkalemia resulted from inadequate clearing of potassium by the kidneys (an average of 5 mEq/24hours); with a creatinine clearance rate of 12-15 ml/min, sodium polystyrene sulphonate had to be prescribed.
Fluctuation in blood pressure was observed in our patient during the clinical course of MMC-induced hemolytic uremic syndrome. The pathogenesis of the hypertension is still unknown. Verwey (8) reported an inappropriately high renin level in his patient and suggested that an angiotensin-converting enzyme inhibitor would have a better effect in controlling the hypertension, but our patient had a low plasma renin activity; in addition to the renin effect, sodium retention might be another factor resulting in hypertension after steroid prescription as part of her initial ineffective treatment. In our patient, calcium channel blockers, beta blockers, angiotensin-converting enzyme (ACE) inhibitors and diuretics were used, but the antihypertensive effect was disappointing until the alpha blocker was added, and then the blood pressure became stable.
In fact, ACE inhibitors were contraindicated in our patient because they seemed to compromise the patient's renal function, which recovered somewhat after discontinuation of the drug. The drug might have decreased prostaglandin production and caused a decrease in renal perfusion in the absence of prostaglandin- mediated vasodilatation. However, it may protect against further renal damage according to some reports. The adjustment of antihypertensive agents will be a challenge in the future.
Our patient developed respiratory distress after platelet and fresh frozen plasma transfusion; the chest film showed an alveolar pattern and pulmonary edema was considered. After intravenous diuretic use and fluid restriction, there was an improvement in hypoxemia. Non-cardiogenic pulmonary edema occurs commonly in chemotherapy-related HUS, particularly after transfusion of even small volumes of blood (2). The change in permeability of the pulmonary capillaries due to immune complex is a possible mechanism of non-cardiogenic pulmonary edema (23).
Because of deterioration of the HUS, pheresis with staphylococcus column A was instituted. After staphyloccoccal protein A (SPA) (Prosorba) dialysis, the disease activity finally abated, the patient having undergone prior ineffective therapy with steroids, daily plasma transfusion, and plasmapheresis. Earlier institution of SPA dialysis might have been able to keep the renal damage to a minimum. SPA is a cell wall component of pathogenic staphyloccocci. It binds to the Fc portion of the IgG molecule nonspecifically (24). SPA immunoadsorption is thought to be the most effective therapy for HUS, especially in patients with tumour in remission (25).
In conclusion, we report a gastric cancer patient with MMC- induced HUS at a cumulative dose of 40 mg/m2. She manifested symptoms of fluid retention in the form of anasarca and non- cardiogenic pulmonary edema, hypertension, microangiopathic hemolytic anemia and renal impairment with resulting hyperkalemia. Her labile hypertension was correlated with the HUS disease activity, but use of an ACE inhibitor seemed to compromise her renal function. Grade 4 thrombocytopenia complicated every plasmapheresis; non-cardiogenic pulmonary edema developed after every staphylococcus column A dialysis, but the dialysis was effective in controlling the HUS in this patient. Our patient required sodium polystyrene sulphonate to maintain her potassium homeostasis and had to receive 2000 units of erythropoietin/month to maintain her hemoglobin level. Our patient also showed prolonged survival after development of the syndrome.
References
Abbreviations: HUS, hemolytic uremic syndrome; MMC, mitomycin-C; IL-1, interleukin-1; C1q, Serum immune complex; ACE, angiotensin- converting enzyme; SPA, staphylococcal protein A; DIC, disseminated intravascular coagulation.
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Copyright© Japanese Journal of Clinical Oncology, 1997.
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