CASE REPORTS
Arterial Thrombosis in Nephrotic Syndrome Kantilal B. Parag, FCp, Sangeeta R. Somers, MBChB, Yackoob K. Seedat, MD, Sonia Byrne, AIMLS, Carlos M.A. Da Cruz, MBChB, and Gayle Kenoyer, MD • The nephrotic syndrome is characterized by profound changes in the turnover and concentration of most plasma proteins, including those involved in the coagulation pathways. Thromboembolic complications, especially venous, have been widely reported. Arterial thrombosis is a relatively rare complication and has been reported mainly in nephrotic children. In this report, an adult nephrotic patient who developed thromboses of his right middle cerebral and left femoral arteries is described. The patient died, and at postmortem no underlying arterial disease was found. Histology of the kidneys showed minimal change disease. © 1990 by the National Kidney Foundation, Inc. INDEX WORDS: Nephrotic syndrome; thromboembolic complications; arterial thrombosis.
T
HROMBOTIC complications in nephrotic syndrome l -3 have long been recognized as the sequelae of a hypercoagulable state ever since Addis in 19484 drew attention to the increased incidence of venous thromboses in this condition. Arterial thrombosis in nephrotic syndrome has been infrequently reported since the first reports by Fishberg 5 and has been observed mainly in nephrotic children. 6 -8 In this report from the renal unit at King Edward VIII Hospital, Durban, South Africa, an adult East Indian patient with nephrotic syndrome and arterial thromboses is described. The patient died and a post mortem histological examination was performed on the arteries and kidneys. CASE REPORT A 23-year-old East Indian operator in a tooling factory was admitted to a neurosurgical ward after sustaining an acute right middle cerebral artery occlusion. Following computed tomography (CT) scan confirmation of a cerebral infarct, the patient developed an occlusion of another artery, this time the left femoral, for which he was transferred to King Edward VIII Hospital for management. At embolectomy a bland thrombus was removed. The patient was transferred to a medical ward for investigation. It appeared that the patient was relatively well prior to the stroke and except for a heavy alcohol intake there were no significant findings in the past history. On examination there was a spastic left hemiplegia and the left femoral pulse was absent, although the limb was well perfused. There was marked swelling of the lower limbs, more so on the right. Pit-
From the Renal Unit and Departments of Medicine, Anatomical Pathology, Haernatology, and Surgery, Medical School, University of Natal. Natal. Republic of South Africa. Address reprint requests to Kantilal B. Parag. MD. Department of Medicine. University of Natal. PO Box 17039. Congella 4013. Natal. Republic of South Africa. © 1990 by the National Kidney Foundation. Inc. 0272-6386190/1502-0010$3.0010 176
ting edema extended up to the upper abdomen where there was marked tenderness and red induration, suggesting superficial cellulitis. Cardiac examination and electrocardiographic (ECG) results were normal and the blood pressure was 150/100 mm Hg. An urgent echocardiogram failed to show any mural thrombi or vegetations on the valves. Although an initial ward urine test was noted as normal, a subsequent result showed + + + + albumin and + + + + blood on dipstick. A full nephrological workup showed a 24-hour protein excretion of 10 g, serum albumin 7 gIL (0.7 g/dL), globulin 28 gIL (2.8 gl dL). Total cholesterol 16.1 mmollL (622 mg/dL), triglycerides 2.06 mmollL (180 mg/dL), urea 19.2 mmollL (115 mg/dL), creatinine 281 JLmollL (3.07 mg/dL), antinuclear antibodies, and lupus anticoagulant were negative and urine microscopy showed no casts. A comprehensive workup for a hypercoagulable state showed a markedly elevated fibrinogen assay of 1.44 gIL (1,440 mg/dL), factor VIII 337% (150 to 400 mg/dL), protein C 66% (range, 70% to 140%), antithrombin III (functional assay) 36% (range, 80% to 120%). hemoglobin 127 gIL (12.7 g/dL), platelets 585 x 109 /L. The patient was managed with intravenous furosemide, albumin, cephamandole, and heparin. He died 9 days after admission and at post mortem there was generalized edema, pleural effusions, ascites, and pulmonary edema. There were bland thrombi in the left femoral, right internal carotid, and middle cerebral arteries. No underlying arterial disease was found on either macroscopic or histological examination (Fig 1). The kidneys showed minimal change disease, with the only detectable findings being fusion of foot processes on electron microscopy.
DISCUSSION
The nephrotic syndrome is characterized by a profound change in the turnover and concentration of most plasma proteins. Abnormalities of coagulation factors are well known and thrombotic complications, especially of the venous type, have been widely reported. I -3 Nephrotic patients have been found to have elevated factors V, VII, VIII, IX, and fibrinogen, in addition to thrombocytosis with an increased tendency to hyperaggregation. Arterial thrombosis is much less common than ve-
American Journal of Kidney Diseases, Vol XV. No 2 (February). 1990: pp 176-177
177
ARTERIAL THROMBOSIS IN NEPHROTIC SYNDROME
thrombotic complications reported in the literature have been in patients with either membranous or mesangiocapillary glomerulonephritis. 11 ,12 Although the predominant histological type in the black patient with nephrotic syndrome is me sangiocapillary glomerulonephritis, thrombotic complications are rare and this may be related to the relatively normal levels of fibrinogen and antithrombin III in the mainly black patients that are treated in this hospital (unpublished data). The East Indian patient reported here had an extremely high fibrinogen level, which together with the low antithrombin III level, contributed to the hypercoagulable state. None of the predisposing factors reported in pediatric patients were present in this patient. At postmortem, the arterial tree was both macroscopically and histologically normal and it was assumed that the cause of the arterial thromboses was hypercoagulability due to the nephrotic state. ACKNOWLEDGMENT We wish to thank R. Billy for her secretarial assistance.
REFERENCES Fig 1. Section showing an organizing thrombus in the right internal carotid artery. The vessel wall shows no inflammatory changes.
nous thrombosis and has been reported mainly in children. 9 In a review of coagulation and thromboembolic complications in nephrotic syndrome by Cameron,3 thrombosis of mesenteric, axillary, femoral, ophthalmic, carotid, cerebral, renal, pulmonary, and coronary arteries have been reported. Femoral artery thromboses in children with nephrotic syndrome have been attributed mainly to femoral venipunctures. Other factors predisposing to thromboses in children are dehydration caused by over-zealous diuretic therapy7 and corticosteroid therapy. 10 The patient reported here is the first adult patient in the renal unit at King Edward VIII Hospital to have arterial thromboses as a complication of nephrotic syndrome. There have been two other episodes of venous thromboses in a 4-year period (1984 to 1987, during which time 578 renal biopsies were performed on patients with either nephritis or nephrotic syndrome. The majority of
I. Llach F: Hypercoagulability and thrombotic complications of nephrotic syndrome. Kidney Int 28:429-439, 1985 2. Vaziri ND: Nephrotic syndrome and coagulation and fibrinolytic abnormalities. Am J Nephrol 3:1-61, 1983 3. Cameron JS: Coagulation and thromboembolic complications in the nephrotic syndrome. Adv Nephrol13:75-114, 1984 4. Addis T: Glomerular Nephritis, Diagnosis and Treatment, vol 1. New York, NY, MacMillan, 1948, p 216 5. Fishberg AM: Hypertension and Nephritis (ed 5). Philadelphia, PA, Lea & Febiger, 1954, p 478 6. Goldbloom RM, Hillman DA, Santolli TV: Arterial thrombosis following femoral venipuncture in edematous nephrotic children. Pediatrics 40:450, 1967 7. Parrish RA, Scurry RB, Robertson AF III: Recurrent arterial thrombosis in nephrosis, Am J Dis Child 130:428, 1976 8. Cameron JS, Ogg CS, Ellis FG, et al: Femoral artery thrombosis in nephrotic syndrome. Arch Dis Child 46:216, 1971 9. Egli F, Eimiger P, Stalder G: Thromboembolism in nephrotic syndrome. Eur Soc Paediatr Nephrol Pediatr Res 8:903, 1974 (abstr 42) 10. Ozsoylu S, Strauss HS, Diamond LK: Effects of corticosteroids on coagulation of the blood. Nature 195:1214-1215, 1962 11. Llach F, Koffler A, Massry SG: Renal vein thrombosis and the nephrotic syndrome. Nephron 19:65-68, 1977 12. Llach F, Papper S, Masry SG: The clinical spectrum of renal vein thrombosis: Acute and chronic. Am J Med 69:819827, 1980
Arterial Thrombosis in Nephrotic Syndrome Kantilal B. Parag, FCp, Sangeeta R. Somers, MBChB, Yackoob K. Seedat, MD, Sonia Byrne, AIMLS, Carlos M.A. Da Cruz, MBChB, and Gayle Kenoyer, MD • The nephrotic syndrome is characterized by profound changes in the turnover and concentration of most plasma proteins, including those involved in the coagulation pathways. Thromboembolic complications, especially venous, have been widely reported. Arterial thrombosis is a relatively rare complication and has been reported mainly in nephrotic children. In this report, an adult nephrotic patient who developed thromboses of his right middle cerebral and left femoral arteries is described. The patient died, and at postmortem no underlying arterial disease was found. Histology of the kidneys showed minimal change disease. © 1990 by the National Kidney Foundation, Inc. INDEX WORDS: Nephrotic syndrome; thromboembolic complications; arterial thrombosis.
T
HROMBOTIC complications in nephrotic syndrome l -3 have long been recognized as the sequelae of a hypercoagulable state ever since Addis in 19484 drew attention to the increased incidence of venous thromboses in this condition. Arterial thrombosis in nephrotic syndrome has been infrequently reported since the first reports by Fishberg 5 and has been observed mainly in nephrotic children. 6 -8 In this report from the renal unit at King Edward VIII Hospital, Durban, South Africa, an adult East Indian patient with nephrotic syndrome and arterial thromboses is described. The patient died and a post mortem histological examination was performed on the arteries and kidneys. CASE REPORT A 23-year-old East Indian operator in a tooling factory was admitted to a neurosurgical ward after sustaining an acute right middle cerebral artery occlusion. Following computed tomography (CT) scan confirmation of a cerebral infarct, the patient developed an occlusion of another artery, this time the left femoral, for which he was transferred to King Edward VIII Hospital for management. At embolectomy a bland thrombus was removed. The patient was transferred to a medical ward for investigation. It appeared that the patient was relatively well prior to the stroke and except for a heavy alcohol intake there were no significant findings in the past history. On examination there was a spastic left hemiplegia and the left femoral pulse was absent, although the limb was well perfused. There was marked swelling of the lower limbs, more so on the right. Pit-
From the Renal Unit and Departments of Medicine, Anatomical Pathology, Haernatology, and Surgery, Medical School, University of Natal. Natal. Republic of South Africa. Address reprint requests to Kantilal B. Parag. MD. Department of Medicine. University of Natal. PO Box 17039. Congella 4013. Natal. Republic of South Africa. © 1990 by the National Kidney Foundation. Inc. 0272-6386190/1502-0010$3.0010 176
ting edema extended up to the upper abdomen where there was marked tenderness and red induration, suggesting superficial cellulitis. Cardiac examination and electrocardiographic (ECG) results were normal and the blood pressure was 150/100 mm Hg. An urgent echocardiogram failed to show any mural thrombi or vegetations on the valves. Although an initial ward urine test was noted as normal, a subsequent result showed + + + + albumin and + + + + blood on dipstick. A full nephrological workup showed a 24-hour protein excretion of 10 g, serum albumin 7 gIL (0.7 g/dL), globulin 28 gIL (2.8 gl dL). Total cholesterol 16.1 mmollL (622 mg/dL), triglycerides 2.06 mmollL (180 mg/dL), urea 19.2 mmollL (115 mg/dL), creatinine 281 JLmollL (3.07 mg/dL), antinuclear antibodies, and lupus anticoagulant were negative and urine microscopy showed no casts. A comprehensive workup for a hypercoagulable state showed a markedly elevated fibrinogen assay of 1.44 gIL (1,440 mg/dL), factor VIII 337% (150 to 400 mg/dL), protein C 66% (range, 70% to 140%), antithrombin III (functional assay) 36% (range, 80% to 120%). hemoglobin 127 gIL (12.7 g/dL), platelets 585 x 109 /L. The patient was managed with intravenous furosemide, albumin, cephamandole, and heparin. He died 9 days after admission and at post mortem there was generalized edema, pleural effusions, ascites, and pulmonary edema. There were bland thrombi in the left femoral, right internal carotid, and middle cerebral arteries. No underlying arterial disease was found on either macroscopic or histological examination (Fig 1). The kidneys showed minimal change disease, with the only detectable findings being fusion of foot processes on electron microscopy.
DISCUSSION
The nephrotic syndrome is characterized by a profound change in the turnover and concentration of most plasma proteins. Abnormalities of coagulation factors are well known and thrombotic complications, especially of the venous type, have been widely reported. I -3 Nephrotic patients have been found to have elevated factors V, VII, VIII, IX, and fibrinogen, in addition to thrombocytosis with an increased tendency to hyperaggregation. Arterial thrombosis is much less common than ve-
American Journal of Kidney Diseases, Vol XV. No 2 (February). 1990: pp 176-177
177
ARTERIAL THROMBOSIS IN NEPHROTIC SYNDROME
thrombotic complications reported in the literature have been in patients with either membranous or mesangiocapillary glomerulonephritis. 11 ,12 Although the predominant histological type in the black patient with nephrotic syndrome is me sangiocapillary glomerulonephritis, thrombotic complications are rare and this may be related to the relatively normal levels of fibrinogen and antithrombin III in the mainly black patients that are treated in this hospital (unpublished data). The East Indian patient reported here had an extremely high fibrinogen level, which together with the low antithrombin III level, contributed to the hypercoagulable state. None of the predisposing factors reported in pediatric patients were present in this patient. At postmortem, the arterial tree was both macroscopically and histologically normal and it was assumed that the cause of the arterial thromboses was hypercoagulability due to the nephrotic state. ACKNOWLEDGMENT We wish to thank R. Billy for her secretarial assistance.
REFERENCES Fig 1. Section showing an organizing thrombus in the right internal carotid artery. The vessel wall shows no inflammatory changes.
nous thrombosis and has been reported mainly in children. 9 In a review of coagulation and thromboembolic complications in nephrotic syndrome by Cameron,3 thrombosis of mesenteric, axillary, femoral, ophthalmic, carotid, cerebral, renal, pulmonary, and coronary arteries have been reported. Femoral artery thromboses in children with nephrotic syndrome have been attributed mainly to femoral venipunctures. Other factors predisposing to thromboses in children are dehydration caused by over-zealous diuretic therapy7 and corticosteroid therapy. 10 The patient reported here is the first adult patient in the renal unit at King Edward VIII Hospital to have arterial thromboses as a complication of nephrotic syndrome. There have been two other episodes of venous thromboses in a 4-year period (1984 to 1987, during which time 578 renal biopsies were performed on patients with either nephritis or nephrotic syndrome. The majority of
I. Llach F: Hypercoagulability and thrombotic complications of nephrotic syndrome. Kidney Int 28:429-439, 1985 2. Vaziri ND: Nephrotic syndrome and coagulation and fibrinolytic abnormalities. Am J Nephrol 3:1-61, 1983 3. Cameron JS: Coagulation and thromboembolic complications in the nephrotic syndrome. Adv Nephrol13:75-114, 1984 4. Addis T: Glomerular Nephritis, Diagnosis and Treatment, vol 1. New York, NY, MacMillan, 1948, p 216 5. Fishberg AM: Hypertension and Nephritis (ed 5). Philadelphia, PA, Lea & Febiger, 1954, p 478 6. Goldbloom RM, Hillman DA, Santolli TV: Arterial thrombosis following femoral venipuncture in edematous nephrotic children. Pediatrics 40:450, 1967 7. Parrish RA, Scurry RB, Robertson AF III: Recurrent arterial thrombosis in nephrosis, Am J Dis Child 130:428, 1976 8. Cameron JS, Ogg CS, Ellis FG, et al: Femoral artery thrombosis in nephrotic syndrome. Arch Dis Child 46:216, 1971 9. Egli F, Eimiger P, Stalder G: Thromboembolism in nephrotic syndrome. Eur Soc Paediatr Nephrol Pediatr Res 8:903, 1974 (abstr 42) 10. Ozsoylu S, Strauss HS, Diamond LK: Effects of corticosteroids on coagulation of the blood. Nature 195:1214-1215, 1962 11. Llach F, Koffler A, Massry SG: Renal vein thrombosis and the nephrotic syndrome. Nephron 19:65-68, 1977 12. Llach F, Papper S, Masry SG: The clinical spectrum of renal vein thrombosis: Acute and chronic. Am J Med 69:819827, 1980
