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Venous thromboembolism in end-stage renal disease
Venous Thromboembolism in End-Stage Renal Disease Liam F. Casserly, MD, Suman M. Reddy, MD, and Laura M. Dember, MD ● Venous thromboembolic disease is considered an uncommon event in the end-stage renal disease (ESRD) population. We report five cases of venous thromboembolism (VTE) occurring in dialysis patients within a 1-year period at a single center. Analysis of these cases and review of the literature suggest that risk factors for VTE in the ESRD population are similar to those of the general population. Chronically ill, debilitated patients appear to be those most likely to develop VTE. © 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Thromboembolic disease; pulmonary embolism (PE); deep venous thrombosis (DVT); end-stage renal disease (ESRD).
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EEP VENOUS thrombosis (DVT) and pulmonary embolism (PE) are considered uncommon events in chronic dialysis patients. They have been described as “vanishingly rare” and “exceedingly uncommon” in this population.1,2 This impression, which has evolved from accumulated clinical experience and retrospective autopsy series, may result in missed diagnosis and delayed treatment of venous thromboembolism (VTE) when such an event occurs in a patient with end-stage renal disease (ESRD). Risk factors for PE and DVT in the general population have been well described.3 A variety of conditions, including obesity, congestive heart failure, malignancy, postoperative state, and immobility, as well multiple inherited disorders of hemostasis, have been strongly associated with thromboembolism. With the exception of inherited disorders of coagulation, most of these predisposing factors are common in the ESRD population. In addition, vascular access poses additional risks for VTE that are unique to the dialysis population. We report two cases of pulmonary embolus and three cases of DVT in patients with ESRD that occurred within a 12month period among a population of 200 ESRD patient-years at our institution. Each patient had a risk factor that has been associated with thromboembolism in the non-ESRD population, and none of the events was related to hemodialysis vascular access. CASE REPORTS
Case 1 A 51-year-old black woman with ESRD secondary to hypertension presented with retrosternal chest pain and dyspnea at rest. The pain was relieved with supplemental oxygen and sublingual nitroglycerin. Past medical history was notable for multiple episodes of chest pain. Cardiac catheterization performed 2 years earlier showed normal
coronary arteries. A prior echocardiogram showed normal ventricular and valvular function. She was maintained on chronic ambulatory peritoneal dialysis. Her mother had died of PE. Physical examination showed blood pressure of 135/75 mm Hg; pulse, 74 beats/min; respiratory rate, 16 breaths/ min; and oxygen saturation, 98% on 3 L of supplemental oxygen. Cardiac and pulmonary examinations were normal, and the patient appeared comfortable. There was no peripheral edema or discrepancy in lower-extremity diameter. Electrocardiogram (ECG) showed sinus rhythm without acute changes, and a chest radiograph was normal. Serial ECGs and cardiac enzyme levels were not suggestive of myocardial infarction. Oxygen saturation decreased to 90% with ambulation, and an arterial blood gas on room air showed PO2 of 76 mm Hg, with an alveolar-arterial difference of 25 mm Hg. A ventilation-perfusion scan showed a large segmental mismatched defect in the right lower lobe that was interpreted as high probability for PE. Protein C and S activity, antithrombin III level, and anticardiolipin antibody levels were within normal limits. Factor V Leiden mutation was not present. The patient has had no further thromboembolic events on chronic warfarin therapy.
Case 2 A 55-year-old black woman with ESRD secondary to diabetes mellitus was admitted after an episode of hypotension during hemodialysis. She reported several days of nausea, vomiting, diarrhea, intermittent abdominal pain, and lightheadedness. Past medical history was significant for hypertension and peripheral vascular disease. She had undergone amputation of the 4th and 5th left toes 2 years before admission and skin grafting on the left heel 1 month before
From the Renal Unit, Evans Memorial Department of Medicine, Boston University School of Medicine, Boston, MA. Received September 17, 1999; accepted in revised form March 10, 2000. Address reprint requests to Laura M. Dember, MD, Renal Unit, Evans Memorial Department of Medicine, Boston University School of Medicine, 88 East Newton St, Boston, MA 02118. E-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3602-0013$3.00/0 doi:10.1053/ajkd.2000.8983
American Journal of Kidney Diseases, Vol 36, No 2 (August), 2000: pp 405-411
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admission. She was residing in a nursing home, where she received physical therapy. Blood pressure was 80/40 mm Hg; pulse, 106 beats/min; and temperature, 98.4°F. She was obese and unable to ambulate without assistance. Respiratory and cardiovascular examinations were unremarkable. Rectal examination showed a large amount of stool that was positive for occult blood. The left foot did not show evidence of infection. There was no peripheral edema. ECG showed left ventricular hypertrophy, the chest radiograph was clear, and computed tomography (CT) of the abdomen showed a 16- ⫻ 16-cm rectal impaction. The patient was treated with manual disimpaction and intravenous fluids. Despite broad-spectrum antibiotics, she had persistent low-grade fevers and leukocytosis. Colonoscopy performed for rectal bleeding showed three large rectal ulcers. Transesophageal echocardiography, magnetic resonance imaging of the left foot, and repeated abdominal CT did not show the source of fever. Multiple red blood cell transfusions were required for rectal bleeding. Hemodialysis was performed through an upper-extremity arteriovenous graft without anticoagulation. Venous compression boots were prescribed; however, compliance by the patient was intermittent. The patient received physical therapy throughout her hospitalization. Twenty-seven days after admission, she had a cardiac arrest while ambulating to the bathroom. Resuscitative efforts were unsuccessful. Postmortem examination showed a large recent embolus of the left main pulmonary artery. The only other significant findings were esophageal and rectal ulcers.
Case 3 A 60-year-old white man with a history of coronary artery disease and renal calculi presented with fatigue, myalgia, and subjective fever and chills for 2 months. On presentation, creatinine level was 3.3 mg/dL, and urinary sediment showed muddy brown casts. Serum creatinine level increased rapidly over the subsequent few days. Renal biopsy findings were consistent with polyarteritis nodosa. The patient was treated with oral cyclophosphamide and prednisone, and hemodialyis was initiated through a subclavian vein catheter. The hospital course was complicated by seizures believed to be caused by central nervous system vasculitis, bleeding from an intrarenal aneurysm, and subsequent infection of the renal hematoma. Eight weeks after beginning dialysis, asymmetric enlargement of his right lower extremity was noted, and the patient became increasingly dyspneic and hypoxic. A duplex ultrasound showed continuous thrombus from the right common femoral vein to the proximal tibial vein. Because the patient was believed to be a poor candidate for anticoagulation, an inferior vena caval filter was placed. Ventilation-perfusion scanning was interpreted as intermediate probability for PE. Bronchoscopy performed because of persistent pulmonary infiltrates showed Pneumocystis carinii. Despite treatment with trimethoprim-sulfamethoxazole, the patient developed adult respiratory distress syndrome and died after a spontaneous pneumothorax 15 weeks after admission. Postmortem examination showed evidence of bilateral bronchopneumonia and bullous emphysema without PE.
CASSERLY, REDDY, AND DEMBER
Case 4 A 63-year-old black woman undergoing chronic hemodialysis for renal failure caused by autosomal dominant polycystic kidney disease presented with 1 day of fever and hypotension. Six months before admission, she underwent cadaveric renal transplantation but remained dialysis dependent because of primary graft nonfunction. The patient sustained a right hip fracture 6 weeks before admission. She underwent open reduction and internal fixation and was discharged on low-molecular-weight heparin therapy. The patient was admitted to the intensive care unit and administered vasopressors, antibiotics, and stress-dose glucocorticoids. Venous compression boots were applied beginning the day of admission. Physical examination showed asymmetric swelling of the left lower extremity. Duplex ultrasound showed thrombi in the left greater saphenous, superficial femoral, and popliteal veins. Ventilation-perfusion scan was interpreted as intermediate probability for PE. Spiral CT confirmed an occlusion of a subsegmental branch of the right pulmonary artery. The patient was treated with heparin and became hemodynamically stable. Osteomyelitis of the right hip was identified, and debridement was performed. Because of a significant risk for falls, chronic anticoagulation was not instituted. An inferior vena caval filter was placed, and the patient was discharged to a rehabilitation facility.
Case 5 A 76-year-old black woman with a history of diabetes mellitus, hypertension, and ESRD was admitted with a thrombosed arteriovenous fistula. Dialysis was provided through an internal jugular catheter. The patient underwent surgical thrombectomy, revision of the fistula, and removal of the jugular catheter under general anesthesia. Her postoperative course was complicated by lower gastrointestinal bleeding requiring 6 U of packed red blood cells. The patient underwent hemodialysis during this period without heparin. A right femoral catheter was placed for the administration of blood transfusions and medications. Colonoscopy showed multiple diverticulae in the descending and sigmoid colon, and esophagogastroduodenoscopy showed nonspecific gastritis. CT of the abdomen without intravenous contrast showed ascites and shrunken kidneys. Two days after colonoscopy, the patient developed a fever. Blood cultures grew Enterococcus and Clostridium spp. Intravenous antibiotics were administered, but the patient’s condition rapidly deteriorated. She became hemodynamically unstable and required urgent intubation. On hospital day 19, left lower-extremity swelling was noted, and a Duplex ultrasound showed DVT of the left common femoral vein. Neither subcutaneous heparin nor venous compression boots had been used during the hospitalization. Because of her deteriorating condition, the patient’s family decided to withdraw life support, and the patient died after extubation on hospital day 24. Postmortem examination showed disseminated uterine papillary serous carcinoma.
DISCUSSION
The retrospective autopsy studies listed in Table 1 provide information about the epidemio-
VENOUS THROMBOEMBOLISM IN ESRD Table 1.
Reference
Rotter et al,4 1973 Mossey et al,6 1982 Guntupalli et al,7 1990 Wiesholzer et al,8 1999
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Autopsy Series of VTE in Patients With ESRD ESRD Non-ESRD Mean Age of No. of NonESRD Patients With Patients With Patients With ESRD Patients With Significant Significant ESRD (y) Patients DVT (%) PE* (%) PE (%)
Deaths Autopsied (%)
No. of Patients With ESRD
1949-NA
NA
326
NA
17,901†
2‡
0.6
8.2
1969-1981
NA
95
59§
2,160
NA
0㛳
10
1970-1987
NA
80
NA
NA
NA
4
NA
1987-1996
100¶
185
69
8,051
NA
6.5
16
Years Data Collected
Abbreviation: NA, not available. *Significant is defined as PE that were macroscopic (Mossey et al6) or considered fatal or contributory to death (Rotter et al,4 Guntupalli et al,7 and Wiezholzer et al8). †Number obtained from Roettger and Jorns.5 ‡Eleven percent in nondialyzed patients with chronic renal failure and 25% in all adult autopsies. §Calculated using the midpoint of each age group provided in Table 2 of the article. 㛳Microscopic emboli present in 9.5%. ¶One hundred percent of hospitalized patients with ESRD and 93% of hospitalized patients without ESRD.
logical characteristics of PE in the ESRD population. In contrast to an 8.2% prevalence of PE in all adult autopsies, Rotter and Roettger4 found PE in 2 of 326 autopsies (0.6%) performed on hemodialysis patients. An analysis of 2,255 autopsies by Mossey et al6 showed microscopic or macroscopic PE in 32%. Nine of the 95 patients (9%) in this series with chronic renal failure had a microscopic PE, and none had a macroscopic PE. Guntupalli et al7 identified three cases of PE in a review of 80 autopsies performed in patients with ESRD between 1970 and 1987. One patient had a prior history of PE, and another patient had metastatic prostate cancer. The series by Wiesholzer et al8 is the first study suggesting that preterminal thromboembolism is a relatively common event in the ESRD population. These investigators reviewed autopsies performed at a single center over a 10-year period, during which 100% of 185 chronic hemodialysis patients and 93% of 8,660 nondialysis patients had postmortem examination. The prevalence of PE was 12.5% and 22% in the dialysis and nondialysis patients, respectively. Among the hemodialysis patients with PE, the embolism was believed to have caused or contributed to death in 52%, suggesting that 6.5% of hospital deaths in the patients with ESRD were attributable to thromboembolism. When one considers that a total of 360 patients underwent chronic
hemodialysis during the study period, these findings suggest that at least 3% of all hemodialysis patients in this cohort developed life-threatening PE. The greater prevalence of PE in this study compared with previous autopsy series may be because of the older age of the autopsied patients, greater degree of comorbid illnesses, or changes in dialysis practices occurring in the mid-1980s. Although the prevalence was not reported, ESRD was listed as an associated diagnosis among patients who died of an unsuspected PE in an analysis of autopsy reports from one of the centers participating in the Prospective Investigation of Pulmonary Embolism Diagnosis study.9 In addition, Dalen and Alpert10 included a case of PE in a patient with ESRD in a series of angiographically proven cases of PE. The conclusions that can be drawn from autopsy series are limited for several reasons. First, the prevalence of VTE may be underestimated because typically a small proportion of patients undergo postmortem examination. Greater than 75% of hospitals in the United States surveyed in 1994 had autopsy rates less than 13.5%.11 Second, postmortem diagnosis often provides little information about the clinical significance of thromboembolic events. Finally, because of the retrospective nature of these studies, risk factors for the events are difficult to ascertain.
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CASSERLY, REDDY, AND DEMBER Table 2.
Reference
Guntupalli et al,7 1990 Guntupalli et al,7 1990 Guntupalli et al,7 1990 Guntupalli et al,7 1990 Wagner et al,20 1996 Maruyama et al,21 1994
Published Cases of Non–Vascular Access–Associated VTE in Patients With ESRD
Sex
Age (y)
Dialysis Duration/ Modality
Comorbid Illnesses
M
64
10 y/HD
M
61
PD
Chest pain, hypotension, RV failure Peritonitis
NA
NA
NA
DM, HTN, COPD, A Fib COPD, CABG ⫻2 Prostate CA
NA
Immobility, postoperative state Metastatic prostate CA
NA
NA
NA
Venous stasis
NA
Previous PE
M
60
8 mo/HD
57
13 y/HD
DVT (developed as outpatient) DVT (developed as outpatient)
Small-cell lung CA
M
Systemic sclerosis Chronic GN
Acute Medical Condition
VTE Risk Factors
Sedentary lifestyle
Acquired protein C deficiency
Abbreviations: A Fib, atrial fibrillation; HD, hemodialysis; CA, cancer; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; GN, glomerulonephritis; NA, not available; HTN, hypertension; PD, peritoneal dialysis; PE, pulmonary embolus; RV, right ventricular.
Most individual case reports of VTE in patients with ESRD have described emboli arising from thrombosed or infected hemodialysis vascular accesses.12-16 Ifudu et al1 reported three cases of lower extremity DVT within 3 months after femoral vein catheterization. Smits et al17 and Swan et al18 found PE by ventilation-perfusion scanning after thrombolysis of forearm arteriovenous grafts in 35% and 59% of patients, respectively. In both studies, the vast majority of patients had no clinical manifestations of PE, although two procedure-related deaths from PE were reported in the study by Swan et al.18 Beathard19 found no clinical evidence of PE in a series of 568 vascular access thrombolysis procedures. Table 3.
Clinical Features of Five Patients With VTE
Dialysis Modality
Serum Albumin (g/dL)
Hct (%)
5
PD
3.7
30
2
F
1
HD
2.4
29*
27
60
M
0.2
HD
2.0
30*
60
4
63
F
6.5
HD
2.4
31
1
5
76
F
0.8
HD
1.9
39*
19
Case No.
Age (y)
Sex
1
51
F
2
55
3
Dialysis Duration (y)
Table 2 lists previous case reports of VTE unrelated to vascular access occurring in patients with ESRD. At least three of these events occurred in the outpatient setting. Risk factors for VTE in these patients included sedentary lifestyle, postoperative state, malignancy, and acquired protein C deficiency. The clinical features of the five patients comprising our series of VTE in ESRD are listed in Table 3. Although a hypercoagulable condition was not identified in case 1, given the family history, it is likely that the patient had an inherited thrombophilia. The other patients in our series were chronically ill, debilitated, and immobile, as were the two patients with VTE reported by Guntupalli et al.7 One patient (case 5) also
Hospital Day Thrombosis Identified
Abbreviations: PD, peritoneal dialysis; HD, hemodialysis; Hct, hematocrit. *Administered multiple red blood cell transfusions during hospitalization before thrombosis.
Risk Factor for Thrombosis
Probable inherited thrombophilia Obesity, general debilitation Prolonged hospitalization, general debilitation Hip surgery, general debilitation Malignancy, general debilitation
VENOUS THROMBOEMBOLISM IN ESRD
had a malignancy, a known risk factor for VTE in the non-ESRD population. None of the patients had previous femoral vein catheterization. Of note, routine prophylaxis with venous compression boots was ineffective in two of the patients who developed VTE while hospitalized. The development of thrombosis requires an imbalance between procoagulant and anticoagulant forces. It has been suggested that the platelet dysfunction associated with renal failure reduces the frequency of thrombotic events in these patients.6 However, several of the metabolic abnormalities associated with uremia may increase procoagulant activity. The following discussion reviews possible prothrombotic factors present in patients with renal failure. However, it should be noted that a role in ESRD-associated VTE has not been established for any of these factors. Elevated serum homocysteine levels are present in most dialysis patients and have been associated with cardiovascular disease in the ESRD population22 and with venous thrombotic disease in the general population.23,24 Levels of procoagulant factors, such as thrombin-antithrombin III complex, D-dimer, fibrinogen, fibrinopeptide A, and von Willebrand factor, are elevated in ESRD.25,26 The observation of Sagripanti et al25 that thrombin-antithrombin III complex, Ddimer, and tumor necrosis factor levels are elevated in patients undergoing dialysis compared with nondialyzed uremic patients implicates the dialysis procedure as a contributor to procoagulant activity in the patient with ESRD. Acquired protein C deficiency has been reported in several series of long-term dialysis patients.27,28 This deficiency has also been found in patients with calciphylaxis,29 and one report linked functional protein C deficiency with the development of DVT in a dialysis patient.21 Consistent with the theory that anemia diminishes platelet–endothelial cell interactions30 is the reported association between recombinant erythropoietin use and arteriovenous graft thrombosis.31,32 Such a relationship has not been reported with non–access-related VTE. In their autopsy series, Wiesholzer et al8 found that the prevalence of PE remained constant in the years before and after the introduction of recombinant erythropoietin, leading them to conclude that
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erythropoietin therapy had no influence on the occurrence of thromboembolic disease. However, it is possible that an effect of erythropoietin use on VTE was not evident in their study because hematocrit goals were lower during the early years of erythropoietin use than they are currently. Hypoalbuminemia is one of the strongest predictors of adverse outcomes in the ESRD population33,34 and was the strongest predictor of graft thrombosis in the Canadian Hemodialysis Morbidity Study.35 An association between malnutrition, hypoalbuminemia, and whole-blood hyperviscosity has been reported in epidemiological studies, and hyperviscosity has in turn been linked with a variety of cardiovascular diseases.36,37 Reduced levels of heparin cofactor II and antithrombin III have been reported in malnourished elderly patients without ESRD.38 Although it is notable that four of the five patients with VTE reported in the present series had marked hypoalbuminemia at the time of thrombosis or thromboembolism, a role for hypoalbuminemia or malnutrition in the pathogenesis of VTE has not been shown. During the past 10 years, the number of patients with ESRD in the United States has increased from 150,000 to 335,000, and the average age has increased from 58 to 62 years.39 As a result of the older age and the willingness of nephrologists to initiate chronic renal replacement therapy in patients with poor functional status, comorbidities of the ESRD population have increased dramatically. These demographic changes, as well as changes in dialysis practices, such as more aggressive correction of anemia and improved dialysis clearances, may be resulting in an increase in the incidence of VTE in this population. Our series of five dialysis patients presenting with VTE within a 12-month period serves to emphasize the need to reconsider the perception that this clinical entity is rare. An examination of current DVT prophylaxis practices among nephrologists may be warranted. REFERENCES 1. Ifudu O, Delaney VB, Barth RH, Friedman EA: Deep vein thrombosis in end-stage renal disease. ASAIO J 40:103105, 1994
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2. Holley JL: Acute complications during hemodialysis, in Rose BR (ed): Up to Date. Wellesley, MA, Up to Date Inc, 1999 3. Hyers TM: Venous thromboembolism. Am J Respir Crit Care Med 159:1-14, 1999 4. Rotter W, Roettger P: Comparative pathologic-anatomic study of cases of global renal insufficiency with and without preceding hemodialysis. Clin Nephrol 1:257-265, 1973 5. Roettger P, Jorns U: Statistiche Untersuchungen zur Lungenembolie-Haufigkeit im Sektionsgut. Zenbl allg Path path Anat 114:106, 1971 (abstr) 6. Mossey RT, Kasabian AA, Wilkes BM, Mailloux LU, Susin M, Bluestone PA: Pulmonary embolism. Low incidence in chronic renal failure. Arch Intern Med 142:16461648, 1982 7. Guntupalli K, Soffer O, Baciewicz P: Pulmonary embolism in end-stage renal disease. Intensive Care Med 16:405407, 1990 8. Wiesholzer M, Kitzwogerer M, Ferdinand H, Barbieri G, Hauser A-C, Pribasnig A, Bankl H, Balcke P: Prevalence of preterminal pulmonary thromboembolism among patients on maintenance hemodialysis treatment before and after introduction of recombinant erythropoietin. Am J Kidney Dis 33:702-708, 1999 9. Stein PD, Henry JW: Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 108:978-981, 1995 10. Dalen JE, Alpert JS: Natural history of pulmonary embolism. Prog Cardiovasc Dis 17:259-270, 1975 11. Hanzlik R, Baker P: Case of the month: Institutional autopsy rates. Arch Intern Med 158:1171-1172, 1998 12. Francioli P, Masur H: Complications of Staphylococcus aureus bacteremia. Occurrence in patients undergoing long-term hemodialysis. Arch Intern Med 142:1655-1658, 1982 13. Goodwin NJ, Castronuovo JJ, Friedman EA: Recurrent septic pulmonary embolization complicating maintenance hemodialysis. Ann Intern Med 71:29-38, 1969 14. Kjellstrand CM, Marion GE, Maurer SM, Casali R, Buselmeier TJ: Complications of percutaneous femoral catherization for hemodialysis. Clin Nephrol 4:37-40, 1975 15. Nsouli KA, Lazarus JM, Schoenbaum SC, Gottlieb MN, Lowrie EG, Shocair M: Bacteremic infection in hemodialysis. Arch Intern Med 139:1255-1258, 1979 16. Schmidt P, Zargornick J, Kopsa H, Kotzaurek R: Septicaemia and pulmonary embolism complicating maintenance hemodialysis. Lancet 1:1129, 1972 (letter) 17. Smits HFM, Van Rijk PP, Van Isselt JW, Mali WPTM, Koomans HA, Blankestijn PJ: Pulmonary embolism after thrombolysis of hemodialysis grafts. J Am Soc Nephrol 8:1458-1461, 1997 18. Swan TL, Smyth SH, Berman SS, Pond GD: Pulmonary embolism following hemodialysis access thrombolysis/thrombectomy. J Vasc Intervent Radiol 6:683-686, 1995 19. Beathard GA: Thrombolysis versus surgery for the treatment of thrombosed dialysis access grafts. J Am Soc Nephrol 6:1619-1624, 1995 20. Wagner R, Mattes J, Traindl O: Deep venous throm-
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bosis in hemodialysis patients—A pointer to the presence of malignancy. Nephrol Dial Transplant 11:879-880, 1996 21. Maruyama H, Geyjo F, Hanano M, Arakawa M: Acquired type 2 protein C deficiency in a long-term hemodialysis patient. Nephron 66:348-350, 1994 22. Bostom AG, Lathrop L: Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int 52:1020, 1997 23. Den Heijer M, Blom HJ, Gerritis WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ: Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis? Lancet 345:882-885, 1995 24. Den Heijer M, Koster T, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR: Hyperhomocysteinemia as a risk factor for deep-vein thombosis. N Engl J Med 334:759-762, 1996 25. Sagripanti A, Cupisti A, Baicchi U, Ferdeghini M, Morelli E, Barsotti G: Plasma parameters of the prothrombotic state in chronic uremia. Nephron 63:273-278, 1993 26. Irish A: Cardiovascular disease, fibrinogen and the acute phase response: Associations with lipids and blood pressure in patients with chronic renal disease. Atherosclerosis 137:133-139, 1998 27. Camici M, Evangelisti L, Balestri P, Cioni L, Rindi P, Sagripanti A, Meriggioli M, Giordani R: Coagulation activation in extracorporeal hemodialysis. Int J Artif Organs 20:163165, 1997 28. Alwakeel J, Gader AM, Hurieb S, al-Momen AK, Mitwalli A, Abu Aisha H: Coagulation inhibitors and fibrinolytic parameters in patients on peritoneal dialysis and hemodialysis. Int J Urol Nephrol 28:255-261, 1996 29. Mehta RL, Scott G, Sloand JA, Francis CW: Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med 88:252-257, 1990 30. Eberst ME, Berkowitz LR: Hemostasis in renal disease: Pathophysiology and management. Am J Med 96:168179, 1994 31. Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, Evans RW, Friedman EA, Graber SE, Haley R, Korbet S, Krantz SB, Lundin AP, Nissenson AR, Ogden DA, Paganini EP, Rader B, Rutsky EA, Stivelman J, Stone WJ, Teschan P, Van Stone JC, Van Wyck DB, Zuckerman K, Adamson JW: Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase 3 multicenter clinical trial. Ann Intern Med 111:992-1000, 1989 32. Churchill DN, Muirhead N, Goldstein M, Posen G, Fay W, Beecroft ML, Gorman J, Taylor DW: Probability of thrombosis of vascular access among hemodialysis patients treated with recombinant human erythropoietin. J Am Soc Nephrol 4:1809-1813, 1994 33. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE: Hypoalbuminemia, cardiac morbidity and mortality in end-stage renal disease. J Am Soc Nephrol 7:728-736, 1996 34. Bergstrom J, Lindholm B: Malnutrition, cardiac disease and mortality: An integrated point of view. Am J Kidney Dis 32:834-841, 1998
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35. Churchill DN, Taylor W, Cook RJ, La Plante P, Barre P, Cartier P, Fay WP, Goldstein MB, Jindal K, Mandin H, McKenzie JK, Muirhead N, Parfrey PS, Posen GA, Slaughter D, Ulan RA, Werb R: Canadian hemodialysis morbidity study. Am J Kidney Dis 19:214-234, 1992 36. Lowe GDO, Drummond MM, Lorimer AR, Hutton I, Forbes CD, Prentice CRM, Barbenel JC: Relation between extent of coronary artery disease and blood viscosity. Br Med J 280:673-674, 1980
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37. Junker R, Henrich J, Schulte H, Schonfeld R, Kohler E, Assmann G: Relationship between plasma viscosity and the severity of coronary heart disease. Arterioscler Thromb Vasc Biol 18:870-875, 1998 38. Kario K, Matsuo T, Kobayashi H: Heparin cofactor 2 deficiency in the elderly: Comparison with antithrombin 3. Thromb Res 66:489-498, 1992 39. US Renal Data System: Incidence and prevalence of ESRD. Am J Kidney Dis 32:S38-S49, 1998 (suppl 1)
D
EEP VENOUS thrombosis (DVT) and pulmonary embolism (PE) are considered uncommon events in chronic dialysis patients. They have been described as “vanishingly rare” and “exceedingly uncommon” in this population.1,2 This impression, which has evolved from accumulated clinical experience and retrospective autopsy series, may result in missed diagnosis and delayed treatment of venous thromboembolism (VTE) when such an event occurs in a patient with end-stage renal disease (ESRD). Risk factors for PE and DVT in the general population have been well described.3 A variety of conditions, including obesity, congestive heart failure, malignancy, postoperative state, and immobility, as well multiple inherited disorders of hemostasis, have been strongly associated with thromboembolism. With the exception of inherited disorders of coagulation, most of these predisposing factors are common in the ESRD population. In addition, vascular access poses additional risks for VTE that are unique to the dialysis population. We report two cases of pulmonary embolus and three cases of DVT in patients with ESRD that occurred within a 12month period among a population of 200 ESRD patient-years at our institution. Each patient had a risk factor that has been associated with thromboembolism in the non-ESRD population, and none of the events was related to hemodialysis vascular access. CASE REPORTS
Case 1 A 51-year-old black woman with ESRD secondary to hypertension presented with retrosternal chest pain and dyspnea at rest. The pain was relieved with supplemental oxygen and sublingual nitroglycerin. Past medical history was notable for multiple episodes of chest pain. Cardiac catheterization performed 2 years earlier showed normal
coronary arteries. A prior echocardiogram showed normal ventricular and valvular function. She was maintained on chronic ambulatory peritoneal dialysis. Her mother had died of PE. Physical examination showed blood pressure of 135/75 mm Hg; pulse, 74 beats/min; respiratory rate, 16 breaths/ min; and oxygen saturation, 98% on 3 L of supplemental oxygen. Cardiac and pulmonary examinations were normal, and the patient appeared comfortable. There was no peripheral edema or discrepancy in lower-extremity diameter. Electrocardiogram (ECG) showed sinus rhythm without acute changes, and a chest radiograph was normal. Serial ECGs and cardiac enzyme levels were not suggestive of myocardial infarction. Oxygen saturation decreased to 90% with ambulation, and an arterial blood gas on room air showed PO2 of 76 mm Hg, with an alveolar-arterial difference of 25 mm Hg. A ventilation-perfusion scan showed a large segmental mismatched defect in the right lower lobe that was interpreted as high probability for PE. Protein C and S activity, antithrombin III level, and anticardiolipin antibody levels were within normal limits. Factor V Leiden mutation was not present. The patient has had no further thromboembolic events on chronic warfarin therapy.
Case 2 A 55-year-old black woman with ESRD secondary to diabetes mellitus was admitted after an episode of hypotension during hemodialysis. She reported several days of nausea, vomiting, diarrhea, intermittent abdominal pain, and lightheadedness. Past medical history was significant for hypertension and peripheral vascular disease. She had undergone amputation of the 4th and 5th left toes 2 years before admission and skin grafting on the left heel 1 month before
From the Renal Unit, Evans Memorial Department of Medicine, Boston University School of Medicine, Boston, MA. Received September 17, 1999; accepted in revised form March 10, 2000. Address reprint requests to Laura M. Dember, MD, Renal Unit, Evans Memorial Department of Medicine, Boston University School of Medicine, 88 East Newton St, Boston, MA 02118. E-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3602-0013$3.00/0 doi:10.1053/ajkd.2000.8983
American Journal of Kidney Diseases, Vol 36, No 2 (August), 2000: pp 405-411
405
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admission. She was residing in a nursing home, where she received physical therapy. Blood pressure was 80/40 mm Hg; pulse, 106 beats/min; and temperature, 98.4°F. She was obese and unable to ambulate without assistance. Respiratory and cardiovascular examinations were unremarkable. Rectal examination showed a large amount of stool that was positive for occult blood. The left foot did not show evidence of infection. There was no peripheral edema. ECG showed left ventricular hypertrophy, the chest radiograph was clear, and computed tomography (CT) of the abdomen showed a 16- ⫻ 16-cm rectal impaction. The patient was treated with manual disimpaction and intravenous fluids. Despite broad-spectrum antibiotics, she had persistent low-grade fevers and leukocytosis. Colonoscopy performed for rectal bleeding showed three large rectal ulcers. Transesophageal echocardiography, magnetic resonance imaging of the left foot, and repeated abdominal CT did not show the source of fever. Multiple red blood cell transfusions were required for rectal bleeding. Hemodialysis was performed through an upper-extremity arteriovenous graft without anticoagulation. Venous compression boots were prescribed; however, compliance by the patient was intermittent. The patient received physical therapy throughout her hospitalization. Twenty-seven days after admission, she had a cardiac arrest while ambulating to the bathroom. Resuscitative efforts were unsuccessful. Postmortem examination showed a large recent embolus of the left main pulmonary artery. The only other significant findings were esophageal and rectal ulcers.
Case 3 A 60-year-old white man with a history of coronary artery disease and renal calculi presented with fatigue, myalgia, and subjective fever and chills for 2 months. On presentation, creatinine level was 3.3 mg/dL, and urinary sediment showed muddy brown casts. Serum creatinine level increased rapidly over the subsequent few days. Renal biopsy findings were consistent with polyarteritis nodosa. The patient was treated with oral cyclophosphamide and prednisone, and hemodialyis was initiated through a subclavian vein catheter. The hospital course was complicated by seizures believed to be caused by central nervous system vasculitis, bleeding from an intrarenal aneurysm, and subsequent infection of the renal hematoma. Eight weeks after beginning dialysis, asymmetric enlargement of his right lower extremity was noted, and the patient became increasingly dyspneic and hypoxic. A duplex ultrasound showed continuous thrombus from the right common femoral vein to the proximal tibial vein. Because the patient was believed to be a poor candidate for anticoagulation, an inferior vena caval filter was placed. Ventilation-perfusion scanning was interpreted as intermediate probability for PE. Bronchoscopy performed because of persistent pulmonary infiltrates showed Pneumocystis carinii. Despite treatment with trimethoprim-sulfamethoxazole, the patient developed adult respiratory distress syndrome and died after a spontaneous pneumothorax 15 weeks after admission. Postmortem examination showed evidence of bilateral bronchopneumonia and bullous emphysema without PE.
CASSERLY, REDDY, AND DEMBER
Case 4 A 63-year-old black woman undergoing chronic hemodialysis for renal failure caused by autosomal dominant polycystic kidney disease presented with 1 day of fever and hypotension. Six months before admission, she underwent cadaveric renal transplantation but remained dialysis dependent because of primary graft nonfunction. The patient sustained a right hip fracture 6 weeks before admission. She underwent open reduction and internal fixation and was discharged on low-molecular-weight heparin therapy. The patient was admitted to the intensive care unit and administered vasopressors, antibiotics, and stress-dose glucocorticoids. Venous compression boots were applied beginning the day of admission. Physical examination showed asymmetric swelling of the left lower extremity. Duplex ultrasound showed thrombi in the left greater saphenous, superficial femoral, and popliteal veins. Ventilation-perfusion scan was interpreted as intermediate probability for PE. Spiral CT confirmed an occlusion of a subsegmental branch of the right pulmonary artery. The patient was treated with heparin and became hemodynamically stable. Osteomyelitis of the right hip was identified, and debridement was performed. Because of a significant risk for falls, chronic anticoagulation was not instituted. An inferior vena caval filter was placed, and the patient was discharged to a rehabilitation facility.
Case 5 A 76-year-old black woman with a history of diabetes mellitus, hypertension, and ESRD was admitted with a thrombosed arteriovenous fistula. Dialysis was provided through an internal jugular catheter. The patient underwent surgical thrombectomy, revision of the fistula, and removal of the jugular catheter under general anesthesia. Her postoperative course was complicated by lower gastrointestinal bleeding requiring 6 U of packed red blood cells. The patient underwent hemodialysis during this period without heparin. A right femoral catheter was placed for the administration of blood transfusions and medications. Colonoscopy showed multiple diverticulae in the descending and sigmoid colon, and esophagogastroduodenoscopy showed nonspecific gastritis. CT of the abdomen without intravenous contrast showed ascites and shrunken kidneys. Two days after colonoscopy, the patient developed a fever. Blood cultures grew Enterococcus and Clostridium spp. Intravenous antibiotics were administered, but the patient’s condition rapidly deteriorated. She became hemodynamically unstable and required urgent intubation. On hospital day 19, left lower-extremity swelling was noted, and a Duplex ultrasound showed DVT of the left common femoral vein. Neither subcutaneous heparin nor venous compression boots had been used during the hospitalization. Because of her deteriorating condition, the patient’s family decided to withdraw life support, and the patient died after extubation on hospital day 24. Postmortem examination showed disseminated uterine papillary serous carcinoma.
DISCUSSION
The retrospective autopsy studies listed in Table 1 provide information about the epidemio-
VENOUS THROMBOEMBOLISM IN ESRD Table 1.
Reference
Rotter et al,4 1973 Mossey et al,6 1982 Guntupalli et al,7 1990 Wiesholzer et al,8 1999
407
Autopsy Series of VTE in Patients With ESRD ESRD Non-ESRD Mean Age of No. of NonESRD Patients With Patients With Patients With ESRD Patients With Significant Significant ESRD (y) Patients DVT (%) PE* (%) PE (%)
Deaths Autopsied (%)
No. of Patients With ESRD
1949-NA
NA
326
NA
17,901†
2‡
0.6
8.2
1969-1981
NA
95
59§
2,160
NA
0㛳
10
1970-1987
NA
80
NA
NA
NA
4
NA
1987-1996
100¶
185
69
8,051
NA
6.5
16
Years Data Collected
Abbreviation: NA, not available. *Significant is defined as PE that were macroscopic (Mossey et al6) or considered fatal or contributory to death (Rotter et al,4 Guntupalli et al,7 and Wiezholzer et al8). †Number obtained from Roettger and Jorns.5 ‡Eleven percent in nondialyzed patients with chronic renal failure and 25% in all adult autopsies. §Calculated using the midpoint of each age group provided in Table 2 of the article. 㛳Microscopic emboli present in 9.5%. ¶One hundred percent of hospitalized patients with ESRD and 93% of hospitalized patients without ESRD.
logical characteristics of PE in the ESRD population. In contrast to an 8.2% prevalence of PE in all adult autopsies, Rotter and Roettger4 found PE in 2 of 326 autopsies (0.6%) performed on hemodialysis patients. An analysis of 2,255 autopsies by Mossey et al6 showed microscopic or macroscopic PE in 32%. Nine of the 95 patients (9%) in this series with chronic renal failure had a microscopic PE, and none had a macroscopic PE. Guntupalli et al7 identified three cases of PE in a review of 80 autopsies performed in patients with ESRD between 1970 and 1987. One patient had a prior history of PE, and another patient had metastatic prostate cancer. The series by Wiesholzer et al8 is the first study suggesting that preterminal thromboembolism is a relatively common event in the ESRD population. These investigators reviewed autopsies performed at a single center over a 10-year period, during which 100% of 185 chronic hemodialysis patients and 93% of 8,660 nondialysis patients had postmortem examination. The prevalence of PE was 12.5% and 22% in the dialysis and nondialysis patients, respectively. Among the hemodialysis patients with PE, the embolism was believed to have caused or contributed to death in 52%, suggesting that 6.5% of hospital deaths in the patients with ESRD were attributable to thromboembolism. When one considers that a total of 360 patients underwent chronic
hemodialysis during the study period, these findings suggest that at least 3% of all hemodialysis patients in this cohort developed life-threatening PE. The greater prevalence of PE in this study compared with previous autopsy series may be because of the older age of the autopsied patients, greater degree of comorbid illnesses, or changes in dialysis practices occurring in the mid-1980s. Although the prevalence was not reported, ESRD was listed as an associated diagnosis among patients who died of an unsuspected PE in an analysis of autopsy reports from one of the centers participating in the Prospective Investigation of Pulmonary Embolism Diagnosis study.9 In addition, Dalen and Alpert10 included a case of PE in a patient with ESRD in a series of angiographically proven cases of PE. The conclusions that can be drawn from autopsy series are limited for several reasons. First, the prevalence of VTE may be underestimated because typically a small proportion of patients undergo postmortem examination. Greater than 75% of hospitals in the United States surveyed in 1994 had autopsy rates less than 13.5%.11 Second, postmortem diagnosis often provides little information about the clinical significance of thromboembolic events. Finally, because of the retrospective nature of these studies, risk factors for the events are difficult to ascertain.
408
CASSERLY, REDDY, AND DEMBER Table 2.
Reference
Guntupalli et al,7 1990 Guntupalli et al,7 1990 Guntupalli et al,7 1990 Guntupalli et al,7 1990 Wagner et al,20 1996 Maruyama et al,21 1994
Published Cases of Non–Vascular Access–Associated VTE in Patients With ESRD
Sex
Age (y)
Dialysis Duration/ Modality
Comorbid Illnesses
M
64
10 y/HD
M
61
PD
Chest pain, hypotension, RV failure Peritonitis
NA
NA
NA
DM, HTN, COPD, A Fib COPD, CABG ⫻2 Prostate CA
NA
Immobility, postoperative state Metastatic prostate CA
NA
NA
NA
Venous stasis
NA
Previous PE
M
60
8 mo/HD
57
13 y/HD
DVT (developed as outpatient) DVT (developed as outpatient)
Small-cell lung CA
M
Systemic sclerosis Chronic GN
Acute Medical Condition
VTE Risk Factors
Sedentary lifestyle
Acquired protein C deficiency
Abbreviations: A Fib, atrial fibrillation; HD, hemodialysis; CA, cancer; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; GN, glomerulonephritis; NA, not available; HTN, hypertension; PD, peritoneal dialysis; PE, pulmonary embolus; RV, right ventricular.
Most individual case reports of VTE in patients with ESRD have described emboli arising from thrombosed or infected hemodialysis vascular accesses.12-16 Ifudu et al1 reported three cases of lower extremity DVT within 3 months after femoral vein catheterization. Smits et al17 and Swan et al18 found PE by ventilation-perfusion scanning after thrombolysis of forearm arteriovenous grafts in 35% and 59% of patients, respectively. In both studies, the vast majority of patients had no clinical manifestations of PE, although two procedure-related deaths from PE were reported in the study by Swan et al.18 Beathard19 found no clinical evidence of PE in a series of 568 vascular access thrombolysis procedures. Table 3.
Clinical Features of Five Patients With VTE
Dialysis Modality
Serum Albumin (g/dL)
Hct (%)
5
PD
3.7
30
2
F
1
HD
2.4
29*
27
60
M
0.2
HD
2.0
30*
60
4
63
F
6.5
HD
2.4
31
1
5
76
F
0.8
HD
1.9
39*
19
Case No.
Age (y)
Sex
1
51
F
2
55
3
Dialysis Duration (y)
Table 2 lists previous case reports of VTE unrelated to vascular access occurring in patients with ESRD. At least three of these events occurred in the outpatient setting. Risk factors for VTE in these patients included sedentary lifestyle, postoperative state, malignancy, and acquired protein C deficiency. The clinical features of the five patients comprising our series of VTE in ESRD are listed in Table 3. Although a hypercoagulable condition was not identified in case 1, given the family history, it is likely that the patient had an inherited thrombophilia. The other patients in our series were chronically ill, debilitated, and immobile, as were the two patients with VTE reported by Guntupalli et al.7 One patient (case 5) also
Hospital Day Thrombosis Identified
Abbreviations: PD, peritoneal dialysis; HD, hemodialysis; Hct, hematocrit. *Administered multiple red blood cell transfusions during hospitalization before thrombosis.
Risk Factor for Thrombosis
Probable inherited thrombophilia Obesity, general debilitation Prolonged hospitalization, general debilitation Hip surgery, general debilitation Malignancy, general debilitation
VENOUS THROMBOEMBOLISM IN ESRD
had a malignancy, a known risk factor for VTE in the non-ESRD population. None of the patients had previous femoral vein catheterization. Of note, routine prophylaxis with venous compression boots was ineffective in two of the patients who developed VTE while hospitalized. The development of thrombosis requires an imbalance between procoagulant and anticoagulant forces. It has been suggested that the platelet dysfunction associated with renal failure reduces the frequency of thrombotic events in these patients.6 However, several of the metabolic abnormalities associated with uremia may increase procoagulant activity. The following discussion reviews possible prothrombotic factors present in patients with renal failure. However, it should be noted that a role in ESRD-associated VTE has not been established for any of these factors. Elevated serum homocysteine levels are present in most dialysis patients and have been associated with cardiovascular disease in the ESRD population22 and with venous thrombotic disease in the general population.23,24 Levels of procoagulant factors, such as thrombin-antithrombin III complex, D-dimer, fibrinogen, fibrinopeptide A, and von Willebrand factor, are elevated in ESRD.25,26 The observation of Sagripanti et al25 that thrombin-antithrombin III complex, Ddimer, and tumor necrosis factor levels are elevated in patients undergoing dialysis compared with nondialyzed uremic patients implicates the dialysis procedure as a contributor to procoagulant activity in the patient with ESRD. Acquired protein C deficiency has been reported in several series of long-term dialysis patients.27,28 This deficiency has also been found in patients with calciphylaxis,29 and one report linked functional protein C deficiency with the development of DVT in a dialysis patient.21 Consistent with the theory that anemia diminishes platelet–endothelial cell interactions30 is the reported association between recombinant erythropoietin use and arteriovenous graft thrombosis.31,32 Such a relationship has not been reported with non–access-related VTE. In their autopsy series, Wiesholzer et al8 found that the prevalence of PE remained constant in the years before and after the introduction of recombinant erythropoietin, leading them to conclude that
409
erythropoietin therapy had no influence on the occurrence of thromboembolic disease. However, it is possible that an effect of erythropoietin use on VTE was not evident in their study because hematocrit goals were lower during the early years of erythropoietin use than they are currently. Hypoalbuminemia is one of the strongest predictors of adverse outcomes in the ESRD population33,34 and was the strongest predictor of graft thrombosis in the Canadian Hemodialysis Morbidity Study.35 An association between malnutrition, hypoalbuminemia, and whole-blood hyperviscosity has been reported in epidemiological studies, and hyperviscosity has in turn been linked with a variety of cardiovascular diseases.36,37 Reduced levels of heparin cofactor II and antithrombin III have been reported in malnourished elderly patients without ESRD.38 Although it is notable that four of the five patients with VTE reported in the present series had marked hypoalbuminemia at the time of thrombosis or thromboembolism, a role for hypoalbuminemia or malnutrition in the pathogenesis of VTE has not been shown. During the past 10 years, the number of patients with ESRD in the United States has increased from 150,000 to 335,000, and the average age has increased from 58 to 62 years.39 As a result of the older age and the willingness of nephrologists to initiate chronic renal replacement therapy in patients with poor functional status, comorbidities of the ESRD population have increased dramatically. These demographic changes, as well as changes in dialysis practices, such as more aggressive correction of anemia and improved dialysis clearances, may be resulting in an increase in the incidence of VTE in this population. Our series of five dialysis patients presenting with VTE within a 12-month period serves to emphasize the need to reconsider the perception that this clinical entity is rare. An examination of current DVT prophylaxis practices among nephrologists may be warranted. REFERENCES 1. Ifudu O, Delaney VB, Barth RH, Friedman EA: Deep vein thrombosis in end-stage renal disease. ASAIO J 40:103105, 1994
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2. Holley JL: Acute complications during hemodialysis, in Rose BR (ed): Up to Date. Wellesley, MA, Up to Date Inc, 1999 3. Hyers TM: Venous thromboembolism. Am J Respir Crit Care Med 159:1-14, 1999 4. Rotter W, Roettger P: Comparative pathologic-anatomic study of cases of global renal insufficiency with and without preceding hemodialysis. Clin Nephrol 1:257-265, 1973 5. Roettger P, Jorns U: Statistiche Untersuchungen zur Lungenembolie-Haufigkeit im Sektionsgut. Zenbl allg Path path Anat 114:106, 1971 (abstr) 6. Mossey RT, Kasabian AA, Wilkes BM, Mailloux LU, Susin M, Bluestone PA: Pulmonary embolism. Low incidence in chronic renal failure. Arch Intern Med 142:16461648, 1982 7. Guntupalli K, Soffer O, Baciewicz P: Pulmonary embolism in end-stage renal disease. Intensive Care Med 16:405407, 1990 8. Wiesholzer M, Kitzwogerer M, Ferdinand H, Barbieri G, Hauser A-C, Pribasnig A, Bankl H, Balcke P: Prevalence of preterminal pulmonary thromboembolism among patients on maintenance hemodialysis treatment before and after introduction of recombinant erythropoietin. Am J Kidney Dis 33:702-708, 1999 9. Stein PD, Henry JW: Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 108:978-981, 1995 10. Dalen JE, Alpert JS: Natural history of pulmonary embolism. Prog Cardiovasc Dis 17:259-270, 1975 11. Hanzlik R, Baker P: Case of the month: Institutional autopsy rates. Arch Intern Med 158:1171-1172, 1998 12. Francioli P, Masur H: Complications of Staphylococcus aureus bacteremia. Occurrence in patients undergoing long-term hemodialysis. Arch Intern Med 142:1655-1658, 1982 13. Goodwin NJ, Castronuovo JJ, Friedman EA: Recurrent septic pulmonary embolization complicating maintenance hemodialysis. Ann Intern Med 71:29-38, 1969 14. Kjellstrand CM, Marion GE, Maurer SM, Casali R, Buselmeier TJ: Complications of percutaneous femoral catherization for hemodialysis. Clin Nephrol 4:37-40, 1975 15. Nsouli KA, Lazarus JM, Schoenbaum SC, Gottlieb MN, Lowrie EG, Shocair M: Bacteremic infection in hemodialysis. Arch Intern Med 139:1255-1258, 1979 16. Schmidt P, Zargornick J, Kopsa H, Kotzaurek R: Septicaemia and pulmonary embolism complicating maintenance hemodialysis. Lancet 1:1129, 1972 (letter) 17. Smits HFM, Van Rijk PP, Van Isselt JW, Mali WPTM, Koomans HA, Blankestijn PJ: Pulmonary embolism after thrombolysis of hemodialysis grafts. J Am Soc Nephrol 8:1458-1461, 1997 18. Swan TL, Smyth SH, Berman SS, Pond GD: Pulmonary embolism following hemodialysis access thrombolysis/thrombectomy. J Vasc Intervent Radiol 6:683-686, 1995 19. Beathard GA: Thrombolysis versus surgery for the treatment of thrombosed dialysis access grafts. J Am Soc Nephrol 6:1619-1624, 1995 20. Wagner R, Mattes J, Traindl O: Deep venous throm-
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bosis in hemodialysis patients—A pointer to the presence of malignancy. Nephrol Dial Transplant 11:879-880, 1996 21. Maruyama H, Geyjo F, Hanano M, Arakawa M: Acquired type 2 protein C deficiency in a long-term hemodialysis patient. Nephron 66:348-350, 1994 22. Bostom AG, Lathrop L: Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int 52:1020, 1997 23. Den Heijer M, Blom HJ, Gerritis WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ: Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis? Lancet 345:882-885, 1995 24. Den Heijer M, Koster T, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR: Hyperhomocysteinemia as a risk factor for deep-vein thombosis. N Engl J Med 334:759-762, 1996 25. Sagripanti A, Cupisti A, Baicchi U, Ferdeghini M, Morelli E, Barsotti G: Plasma parameters of the prothrombotic state in chronic uremia. Nephron 63:273-278, 1993 26. Irish A: Cardiovascular disease, fibrinogen and the acute phase response: Associations with lipids and blood pressure in patients with chronic renal disease. Atherosclerosis 137:133-139, 1998 27. Camici M, Evangelisti L, Balestri P, Cioni L, Rindi P, Sagripanti A, Meriggioli M, Giordani R: Coagulation activation in extracorporeal hemodialysis. Int J Artif Organs 20:163165, 1997 28. Alwakeel J, Gader AM, Hurieb S, al-Momen AK, Mitwalli A, Abu Aisha H: Coagulation inhibitors and fibrinolytic parameters in patients on peritoneal dialysis and hemodialysis. Int J Urol Nephrol 28:255-261, 1996 29. Mehta RL, Scott G, Sloand JA, Francis CW: Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med 88:252-257, 1990 30. Eberst ME, Berkowitz LR: Hemostasis in renal disease: Pathophysiology and management. Am J Med 96:168179, 1994 31. Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, Evans RW, Friedman EA, Graber SE, Haley R, Korbet S, Krantz SB, Lundin AP, Nissenson AR, Ogden DA, Paganini EP, Rader B, Rutsky EA, Stivelman J, Stone WJ, Teschan P, Van Stone JC, Van Wyck DB, Zuckerman K, Adamson JW: Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase 3 multicenter clinical trial. Ann Intern Med 111:992-1000, 1989 32. Churchill DN, Muirhead N, Goldstein M, Posen G, Fay W, Beecroft ML, Gorman J, Taylor DW: Probability of thrombosis of vascular access among hemodialysis patients treated with recombinant human erythropoietin. J Am Soc Nephrol 4:1809-1813, 1994 33. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE: Hypoalbuminemia, cardiac morbidity and mortality in end-stage renal disease. J Am Soc Nephrol 7:728-736, 1996 34. Bergstrom J, Lindholm B: Malnutrition, cardiac disease and mortality: An integrated point of view. Am J Kidney Dis 32:834-841, 1998
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35. Churchill DN, Taylor W, Cook RJ, La Plante P, Barre P, Cartier P, Fay WP, Goldstein MB, Jindal K, Mandin H, McKenzie JK, Muirhead N, Parfrey PS, Posen GA, Slaughter D, Ulan RA, Werb R: Canadian hemodialysis morbidity study. Am J Kidney Dis 19:214-234, 1992 36. Lowe GDO, Drummond MM, Lorimer AR, Hutton I, Forbes CD, Prentice CRM, Barbenel JC: Relation between extent of coronary artery disease and blood viscosity. Br Med J 280:673-674, 1980
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