Inherited Hemolytic Uremic Syndrome in Adults Jeffrey S. Berns, MD, Bernard S. Kaplan, MB, BCh, Robert C. Mackow, MD, and Lawrence G. Hefter, MD • Familial hemolytic uremic syndrome (HUS) in children may be due to environmental factors or may be an inherited trait, usually with autosomal recessive inheritance. Familial HUS in adults is less well described, and can be associated with autosomal recessive or dominant inheritance. We report a family with autosomal dominant inheritance of HUS. The proband was an adult male. His adult sister developed HUS while taking oral contraceptives, and their mother developed HUS during the third trimester of pregnancy. The prognosis for these patients is poor. Pregnancy and oral contraceptive use may be risk factors for development of HUS in adult women with a family history of HUS or the related disorder thrombotic thrombocytopenic purpura (TTP). © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Hemolytic uremic syndrome; heredity; von Willebrand factor; oral contraceptive; pregnancy; thrombotic thrombocytopenic purpura.
H
EMOLYTIC uremic syndrome (HUS) and the related disorder thrombotic thrombocytopenic purpura (TTP) are characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Familial occurrences of HUS outside of endemic areas have primarily involved children with an autosomal recessive pattern of inheritance, 1 although adults may also be affected and autosomal dominant inheritance has been reported. 2 We report a family with autosomal dominant inheritance ofHUS. The proband was an adult male. His adult sister developed HUS while taking oral contraceptives, and their mother developed HUS during the third trimester of pregnancy. Based on our review of earlier reports of familial HUS in adults, we suggest that pregnancy and oral contraceptive use may be important risk factors for development of HUS in adult women with a family history of HUSorTTP. CASE REPORTS
Case J A previously healthy 26-year-old white man, living in Virginia, presented with several days of "flu-like" symptoms and shortness of breath. His blood pressure was 190/120 mm Hg. The physical examination was otherwise unremarkable. The blood urea nitrogen (BUN) was 14.0 mmol/L (40 mg/dL); serum creatinine 250 /Lmol/L (2.8 mg/dL); hematocrit 0.28; platelet count 58 X \09 /L; lactate dehydrogenase (LDH) 16.14 lUlL (970 U/L); and haptoglobin 0.02 gJL (2 mg/dL). Rare schistocytes and red blood cell (RBC) fragments were seen on the peripheral blood smear. Urinalysis showed 3+ protein, microscopic hematuria, and hyaline and granular casts. Coagulation studies, complement C3 and C4 levels, and an antinuclear antibody test were normal. Counter-immunoelectrophoresis of the patient's plasma demonstrated large von Willebrand factor multimers relative to control with von Willebrand factor-related antigen activity of 158%.
A diagnosis of HUS was made and, because of worsening azotemia, anemia, and thrombocytopenia, he was treated with plasma infusions, plasmapheresis, corticosteroids, and dipyridamole. There was no response to an extended course of therapy, and he required chronic hemodialysis. Findings from a percutaneous renal biopsy (Fig I) were consistent with the diagnosis of HUS, including an increase in mesangial matrix, foam cells, wrinkling of the glomerular basement membrane, and marked intimal swelling and fibrin thrombi of many small arteries, arterioles, and glomeruli. Electron microscopy showed splitting and reduplication of the glomerular basement membrane with subendothelial accumulation of loose, finely granular material, mesangial interposition, and endothelial cell swelling. No electron-dense deposits were seen. Focal glomerular immunofluorescent staining was noted (2+ to 3+) for C3, Clq, and fibrin.
Case 2 While vacationing in Spain 12 months earlier, the 21-yearold sister of patient I developed hypertension, edema, nausea and vomiting, hemolytic anemia, thrombocytopenia, and oliguric renal failure. She had been taking oral contraceptive pills (norethindrone 1 mg with mestranol 0.05 mg) for several years. The serum creatinine was 1,627 /Lmol/L (18.4 mg/dL); hematocrit 0.20; and platelet count 205 X \09 /L. There were numerous schistocytes on the peripheral blood smear. Urinalysis showed 4+ protein, many granular casts and 0 to 2 RBC per high-power field (HPF). A kidney biopsy showed collapse of glomerular capillaries with double contours, wrinkling, and thickening of the capillary basement membrane. Capillary microaneurysms with fibrin-like thrombi were seen. There was intimal proliferation and fibrin thrombi of small arterioles. Electron microscopy showed reduplication of the capillary basement membrane with mesangial interposition From the Division of Nephrology and Hypertension, The Graduate Hospital, Philadelphia, PA; the Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA; and the Fair/ax Hospital, Falls Church, VA. Address reprint requests to Jeffrey S. Berns, MD, Division ofNephrology and Hypertension, The Graduate Hospital, 19th and Lombard Streets, Philadelphia, PA 19146. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/1904-0004$3.00/0
American Journal of Kidney Diseases, Vol XIX, No 4 (April), 1992: pp 331-334
331
332
BERNS ET AL
Fig 1. Percutaneous renal biopsy specimen from case 1 (hematoxylin and eosin [H&E) demonstrates thickening of arteriolar wall with occlusion of lumen by fibrin-like material and glomerular consolidation. and subendothelial deposition of granular floccular material. No electron-dense deposits were seen. Immunofluorescence microscopy showed focal granular glomerular capillary deposition oflgA, IgM, C3, C4, and fibrinogen, focal segmental mesangial staining for IgA, IgM, and C3, and C3 staining of small arterioles. No specific treatment was given and the oral contraceptive was discontinued. She required hemodialysis for 6 months before recovering sufficient renal function to discontinue dialysis with a stable serum creatinine of 265 IlmoljL (3.0 mg/ dL), normal platelet count, and hematocrit of 0.30. She remains hypertensive. Two other adult female siblings have remained healthy. One had taken oral contraceptives and the other had a pregnancy terminated electively in the first trimester. This was unrelated to the family history of HUS.
Case 3 In 1966, the mother of patients I and 2, while living in Alabama, presented at age 29 years during the 36th week of pregnancy (carrying patient 2) with hemolytic anemia (hematocrit, 0.24), thrombocytopenia (platelet count, 81 X 109 / L), and oliguric renal failure with a serum creatinine of 1,150 IlmoljL (13 mg/dL). There had been no previous medical or obstetrical problems. Delivery was not complicated by abruptio placentae, hemorrhage, sepsis, hypotension, or eclampsia. Despite peritoneal dialysis, she died approximately 3 weeks postpartum. An open renal biopsy was interpreted at that time as "scleroderma kidney." Review of the specimen after resectioning of the original paraffin block showed intimal thickening and fibrinoid changes of interlobular arteries and small arterioles, and luminal hyaline thrombi in arterioles and glomeruli. These findings are consistent with a diagnosis of HUS (Fig 2). The maternal grandmother of the proband (patient I) died in 1944 at age 30 years with "Bright's disease."
group of siblings, onset of HUS occurred within a short period of time and was usually preceded by a typical prodrome of bloody diarrhea. The prognosis was relatively good with a mortality rate of less than 19% and there were no recurrences of HUS. These patients came from areas where HUS was endemic, and were thought to have developed HUS in response to environmental factors. In contrast, onset of HUS in the second group of siblings was separated by more than a year and the prodrome was usually atypical. The prognosis was poor (mortality rate of 68%) and some had recurrent episodes of HUS. Nearly all these children appeared to have inherited HUS by an autosomal recessive mode. It has subsequently become apparent that HUS and the related disorder TTP can also be inherited with an autosomal dominant pattern. 2 Inherited HUS in adults has not been as well described. We are aware of only 17 other families in which well-documented HUS developed in an adult and at least one other relative had HUS 3- 12 (and personal communication from International Registry for HUS) or TTPY·14 The mode of inheritance was autosomal recessive in eight families and autosomal dominant in nine kindreds. An autosomal dominant mode of inheritance of HUS in the family we report is also apparent. Since each episode occurred in widely separate locales over a span of more than two decades, it is unlikely that environmental factors alone played any significant role. Reports by Merrill et aIlS and Grottum et al 16 have not been included in this analysis because the exact nature of the disorders in these reports is unclear.
DISCUSSION
Kaplan et all suggested that there were two forms of HUS that occurred in families. In one
Fig 2. Renal biopsy specimen from case 3 (H&E) showing arteriole occluded by fibrin thrombus.
333
INHERITED HUS IN ADULTS
Including the patients we report here, 15 adults were from kindreds with a recessive mode of inheritance and 30 were from families with dominant inheritance. In some kindreds, children were also affected and other family members often were described as having had Bright's disease or other kidney disease not specifically identified. There were 25 women and 20 men. Only one of the patients (a male) had a typical prodrome of bloody diarrhea. Six of the 25 adult women (24%) were reported to be taking an oral contraceptive. However, this may be an underestimate, as many reports did not specifically mention oral contraceptive use. Eight women (32%), including two who were also receiving stilbestrol, developed HUS in association with pregnancy. Therefore, 56% of affected women in these families had pregnancy-related HUS or were taking oral contraceptives. There was an equal occurrence of pregnancy and contraceptive-related HUS in kindreds with recessive (5/9 women) and dominant (9/16 women) inheritance. Nearly all of the patients for whom information was provided developed end-stage renal failure or died, although a few patients survived with residual chronic renal insufficiency. Use of oral contraceptives has previously been suggested as a cause ofHUS in some women. 3 , 17 It is difficult to know what role to attribute to these agents, since HUS occurred in a male sibling in this family and in other reports, 4 and adult women in this and other kindreds lo did not develop HUS while taking oral contraceptives. However, since more than 30% of the women with HUS in these families reported use of an oral contraceptive or other estrogens (stilbestrol), a causal link between these agents and occurrence of familial HUS in adults remains a serious concern. However, it should be noted that this level of oral contraceptive use may simply reflect that of the age-matched general population. '8 Oral contraceptives may also playa role in the development of familial TTP. 19 Although postpartum renal failure is believed to be part of the HUS-TTP disease spectrum, onset of renal failure during the third trimester or the first few days postpartum has generally been regarded as a distinct entity.20 The development of renal failure, thrombocytopenia, and anemia with renal biopsy evidence of HUS during the third trimester of pregnancy in case 3, in light of
the subsequent family history, strongly suggests that pregnancy-related HUS is also part of this disease group. This concept is supported by other reports in women with HUS8 , 14 and TTP.z 1 A role for abnormalities of von Willebrand factor in the pathogenesis of nonfamilial HUS has been postulated. 22 •23 The elevated von Willebrand factor-related antigen activity and abnormally large von Willebrand factor multimers detected in case 1 suggest that disturbances of von Willebrand factor metabolism may also be involved in the pathogenesis of autosomal dominant hereditary HUS in adults. Finally, while it is obviously difficult to draw firm conclusions, the disparate outcomes of cases 1 and 2 deserve mention. Despite aggressive treatment with plasma infusion, plasmapheresis, and corticosteroids, our index patient (case 1) continues to require chronic hemodialysis and has chronic hemolytic anemia, while his untreated sister spontaneously recovered significant renal function. We therefore urge caution in the application of these unproven therapies to patients with familial forms of HUS. In conclusion, familial HUS in adults may be associated with either autosomal dominant or recessive patterns of inheritance, carries a very poor prognosis, and has not been shown to consistently respond to treatment with plasma infusion, plasmapheresis, anti platelet agents, heparin, or corticosteroids. An apparent association between the development of HUS and pregnancy or recent use of oral contraceptives suggests that factors other than simple mendelian inheritance may be operative in women. In view of our findings, women with a family history of HUS or TTP probably should avoid use of oral contraceptives, and perhaps should be cautioned regarding pregnancy as well. Identification of affected families is important for purposes of genetic counseling, as well as further understanding of the pathogenesis and prognosis of familial HUS. Studies of hormonal influences in inherited HUS-TIP may contribute to further clarification of the pathophysiology of these disorders. ACKNOWLEDGMENT The von Willebrand factor assay was performed by M. Helmsworth, Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA. The authors wish to express their appreciation to Dr Stephen Zemel, who provided us with information on case 2.
BERNS ET AL
334
REFERENCES I. Kaplan BS, Chesney RW, Drummond KN: Hemolytic
uremic syndrome in families. N Eng! J Med 292:1090-1093, 1975 2. Kaplan BS, Kaplan P: Hereditary hemolytic uremic syndrome, in Buyse ML (ed): Birth Defects Encyclopedia. New York, NY, Liss, 1990 3. Bergstein J, Michael A, Kjellstrand C, et al: Hemolyticuremic syndrome in adult sisters. Transplantation 17:487-490, 1974 4. Farr MJ, Roberts S, Morley AR, et al: The haemolytic uraemic syndrome-A family study. Q J Med 44:161-188, 1975 5. Karlsberg RP, Lacher JW, Bartecchi CE: Adult hemolytic-uremic syndrome. Arch Intern Med 137:1155-1157, 1977 6. Edelsten A, Tuck S: Familial hemolytic uremic syndrome. Arch Dis Child 53:255-256, 1978 7. Perret B, Gaze H, Zimmerman A, et al: Syndrome hemolytique uremique familial non endemique: Nephrectomie et transplantation. Helv Paediatr Acta 34:167-176,1979 8. Hogewind BL, de la Riviere GB, van Es LA, et al: Familial occurrence of the haemolytic uraemic syndrome. Acta Med Scand 207:73-77, 1980 9. Camba L, AI-Hilali MM, Shulji MMH, et al: Haemolytic-uraemic syndrome with renal failure: The effect of plasmapheresis. Haematologica 70:341-344, 1985 10. Pirson Y, Lefebvre C, Arnout C, et al: Hemolytic uremic syndrome in three adult siblings: A familial study and evolution. Clin Nephrol 28:250-255, 1987 11. Carreras L, Romero R, Requesens C, et al: Familial hypocomplementemic hemolytic uremic syndrome with HLA-A3,B7 haplotype. JAMA 245:602-604, 1981 12. Halgreen M, Andersen RH, Jorgensen JID: Familiaert haemolytisk uraemisk syndrom. Ugeskr Laeger 149:662-663, 1987 13. Hellman RM, Jackson DV, Buss DH: Thrombotic
thrombocytopenic purpura and hemolytic-uremic syndrome in HLA-identical siblings. Ann Intern Med 93:283-284, 1980 14. Kirchner KA, Smith RM, Gockerman JP, et al: Hereditary thrombotic thrombocytopenic purpura: Microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency occurring in consecutive generations. Nephron 30: 28-30, 1982 15. Merrill RH, Knupp CL, Jennette JC: Familial thrombotic microangiopathy. Q J Med 57:749-759, 1985 16. Grottum KA, Flatmark A, Myhre E, et al: Immunological hereditary nephropathy. Acta Med Scand 571:1-27, 1974 (suppl) 17. Brown CB, Robson JS, Thomson D, et al: Haemolytic uraemic syndrome in women taking oral contraceptives. Lancet 1:1479-1481, 1973 18. Russell-Briefel R, Ezzatti T, Perlman J: Prevalence and trends in oral contraceptive use in premenopausal females ages 12-54 years, United States, 1971-1980. Am J Public Health 75:1173-1176,1985 19. Paz RA, Elijovich F, BarcatJA, et al: Fatal simultaneous thrombocytopenic purpura in siblings. Br Med J 4:727-728, 1969 20. Hayslett JP: Postpartum renal failure. N Engl J Med 312:1556-1559, 1985 21. Fuchs WE, George IN, Dotin LN, Sears DA: Thrombotic thrombocytopenic purpura: Occurrence two years apart during late pregnancy in two sisters. JAMA 235:2126-2127, 1976 22. Helmsworth M, Ragin CS, Sherbotie J, et al: Abnormal factor VIII: von Willebrand (VIII:vWF) multimers in patients with hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) may predict thrombotic episodes. VIII Congress International Pediatric Association, Toronto, Canada, Aug 27, 1989 (abstr 10-006) 23. Rose PE, Enayat SM, Sunderland R, et al: Abnormalities offactor VIII related protein multimers in the haemolytic uraemic syndrome. Arch Dis Child 59: 1135-1140, 1984
H
EMOLYTIC uremic syndrome (HUS) and the related disorder thrombotic thrombocytopenic purpura (TTP) are characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Familial occurrences of HUS outside of endemic areas have primarily involved children with an autosomal recessive pattern of inheritance, 1 although adults may also be affected and autosomal dominant inheritance has been reported. 2 We report a family with autosomal dominant inheritance ofHUS. The proband was an adult male. His adult sister developed HUS while taking oral contraceptives, and their mother developed HUS during the third trimester of pregnancy. Based on our review of earlier reports of familial HUS in adults, we suggest that pregnancy and oral contraceptive use may be important risk factors for development of HUS in adult women with a family history of HUSorTTP. CASE REPORTS
Case J A previously healthy 26-year-old white man, living in Virginia, presented with several days of "flu-like" symptoms and shortness of breath. His blood pressure was 190/120 mm Hg. The physical examination was otherwise unremarkable. The blood urea nitrogen (BUN) was 14.0 mmol/L (40 mg/dL); serum creatinine 250 /Lmol/L (2.8 mg/dL); hematocrit 0.28; platelet count 58 X \09 /L; lactate dehydrogenase (LDH) 16.14 lUlL (970 U/L); and haptoglobin 0.02 gJL (2 mg/dL). Rare schistocytes and red blood cell (RBC) fragments were seen on the peripheral blood smear. Urinalysis showed 3+ protein, microscopic hematuria, and hyaline and granular casts. Coagulation studies, complement C3 and C4 levels, and an antinuclear antibody test were normal. Counter-immunoelectrophoresis of the patient's plasma demonstrated large von Willebrand factor multimers relative to control with von Willebrand factor-related antigen activity of 158%.
A diagnosis of HUS was made and, because of worsening azotemia, anemia, and thrombocytopenia, he was treated with plasma infusions, plasmapheresis, corticosteroids, and dipyridamole. There was no response to an extended course of therapy, and he required chronic hemodialysis. Findings from a percutaneous renal biopsy (Fig I) were consistent with the diagnosis of HUS, including an increase in mesangial matrix, foam cells, wrinkling of the glomerular basement membrane, and marked intimal swelling and fibrin thrombi of many small arteries, arterioles, and glomeruli. Electron microscopy showed splitting and reduplication of the glomerular basement membrane with subendothelial accumulation of loose, finely granular material, mesangial interposition, and endothelial cell swelling. No electron-dense deposits were seen. Focal glomerular immunofluorescent staining was noted (2+ to 3+) for C3, Clq, and fibrin.
Case 2 While vacationing in Spain 12 months earlier, the 21-yearold sister of patient I developed hypertension, edema, nausea and vomiting, hemolytic anemia, thrombocytopenia, and oliguric renal failure. She had been taking oral contraceptive pills (norethindrone 1 mg with mestranol 0.05 mg) for several years. The serum creatinine was 1,627 /Lmol/L (18.4 mg/dL); hematocrit 0.20; and platelet count 205 X \09 /L. There were numerous schistocytes on the peripheral blood smear. Urinalysis showed 4+ protein, many granular casts and 0 to 2 RBC per high-power field (HPF). A kidney biopsy showed collapse of glomerular capillaries with double contours, wrinkling, and thickening of the capillary basement membrane. Capillary microaneurysms with fibrin-like thrombi were seen. There was intimal proliferation and fibrin thrombi of small arterioles. Electron microscopy showed reduplication of the capillary basement membrane with mesangial interposition From the Division of Nephrology and Hypertension, The Graduate Hospital, Philadelphia, PA; the Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA; and the Fair/ax Hospital, Falls Church, VA. Address reprint requests to Jeffrey S. Berns, MD, Division ofNephrology and Hypertension, The Graduate Hospital, 19th and Lombard Streets, Philadelphia, PA 19146. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/1904-0004$3.00/0
American Journal of Kidney Diseases, Vol XIX, No 4 (April), 1992: pp 331-334
331
332
BERNS ET AL
Fig 1. Percutaneous renal biopsy specimen from case 1 (hematoxylin and eosin [H&E) demonstrates thickening of arteriolar wall with occlusion of lumen by fibrin-like material and glomerular consolidation. and subendothelial deposition of granular floccular material. No electron-dense deposits were seen. Immunofluorescence microscopy showed focal granular glomerular capillary deposition oflgA, IgM, C3, C4, and fibrinogen, focal segmental mesangial staining for IgA, IgM, and C3, and C3 staining of small arterioles. No specific treatment was given and the oral contraceptive was discontinued. She required hemodialysis for 6 months before recovering sufficient renal function to discontinue dialysis with a stable serum creatinine of 265 IlmoljL (3.0 mg/ dL), normal platelet count, and hematocrit of 0.30. She remains hypertensive. Two other adult female siblings have remained healthy. One had taken oral contraceptives and the other had a pregnancy terminated electively in the first trimester. This was unrelated to the family history of HUS.
Case 3 In 1966, the mother of patients I and 2, while living in Alabama, presented at age 29 years during the 36th week of pregnancy (carrying patient 2) with hemolytic anemia (hematocrit, 0.24), thrombocytopenia (platelet count, 81 X 109 / L), and oliguric renal failure with a serum creatinine of 1,150 IlmoljL (13 mg/dL). There had been no previous medical or obstetrical problems. Delivery was not complicated by abruptio placentae, hemorrhage, sepsis, hypotension, or eclampsia. Despite peritoneal dialysis, she died approximately 3 weeks postpartum. An open renal biopsy was interpreted at that time as "scleroderma kidney." Review of the specimen after resectioning of the original paraffin block showed intimal thickening and fibrinoid changes of interlobular arteries and small arterioles, and luminal hyaline thrombi in arterioles and glomeruli. These findings are consistent with a diagnosis of HUS (Fig 2). The maternal grandmother of the proband (patient I) died in 1944 at age 30 years with "Bright's disease."
group of siblings, onset of HUS occurred within a short period of time and was usually preceded by a typical prodrome of bloody diarrhea. The prognosis was relatively good with a mortality rate of less than 19% and there were no recurrences of HUS. These patients came from areas where HUS was endemic, and were thought to have developed HUS in response to environmental factors. In contrast, onset of HUS in the second group of siblings was separated by more than a year and the prodrome was usually atypical. The prognosis was poor (mortality rate of 68%) and some had recurrent episodes of HUS. Nearly all these children appeared to have inherited HUS by an autosomal recessive mode. It has subsequently become apparent that HUS and the related disorder TTP can also be inherited with an autosomal dominant pattern. 2 Inherited HUS in adults has not been as well described. We are aware of only 17 other families in which well-documented HUS developed in an adult and at least one other relative had HUS 3- 12 (and personal communication from International Registry for HUS) or TTPY·14 The mode of inheritance was autosomal recessive in eight families and autosomal dominant in nine kindreds. An autosomal dominant mode of inheritance of HUS in the family we report is also apparent. Since each episode occurred in widely separate locales over a span of more than two decades, it is unlikely that environmental factors alone played any significant role. Reports by Merrill et aIlS and Grottum et al 16 have not been included in this analysis because the exact nature of the disorders in these reports is unclear.
DISCUSSION
Kaplan et all suggested that there were two forms of HUS that occurred in families. In one
Fig 2. Renal biopsy specimen from case 3 (H&E) showing arteriole occluded by fibrin thrombus.
333
INHERITED HUS IN ADULTS
Including the patients we report here, 15 adults were from kindreds with a recessive mode of inheritance and 30 were from families with dominant inheritance. In some kindreds, children were also affected and other family members often were described as having had Bright's disease or other kidney disease not specifically identified. There were 25 women and 20 men. Only one of the patients (a male) had a typical prodrome of bloody diarrhea. Six of the 25 adult women (24%) were reported to be taking an oral contraceptive. However, this may be an underestimate, as many reports did not specifically mention oral contraceptive use. Eight women (32%), including two who were also receiving stilbestrol, developed HUS in association with pregnancy. Therefore, 56% of affected women in these families had pregnancy-related HUS or were taking oral contraceptives. There was an equal occurrence of pregnancy and contraceptive-related HUS in kindreds with recessive (5/9 women) and dominant (9/16 women) inheritance. Nearly all of the patients for whom information was provided developed end-stage renal failure or died, although a few patients survived with residual chronic renal insufficiency. Use of oral contraceptives has previously been suggested as a cause ofHUS in some women. 3 , 17 It is difficult to know what role to attribute to these agents, since HUS occurred in a male sibling in this family and in other reports, 4 and adult women in this and other kindreds lo did not develop HUS while taking oral contraceptives. However, since more than 30% of the women with HUS in these families reported use of an oral contraceptive or other estrogens (stilbestrol), a causal link between these agents and occurrence of familial HUS in adults remains a serious concern. However, it should be noted that this level of oral contraceptive use may simply reflect that of the age-matched general population. '8 Oral contraceptives may also playa role in the development of familial TTP. 19 Although postpartum renal failure is believed to be part of the HUS-TTP disease spectrum, onset of renal failure during the third trimester or the first few days postpartum has generally been regarded as a distinct entity.20 The development of renal failure, thrombocytopenia, and anemia with renal biopsy evidence of HUS during the third trimester of pregnancy in case 3, in light of
the subsequent family history, strongly suggests that pregnancy-related HUS is also part of this disease group. This concept is supported by other reports in women with HUS8 , 14 and TTP.z 1 A role for abnormalities of von Willebrand factor in the pathogenesis of nonfamilial HUS has been postulated. 22 •23 The elevated von Willebrand factor-related antigen activity and abnormally large von Willebrand factor multimers detected in case 1 suggest that disturbances of von Willebrand factor metabolism may also be involved in the pathogenesis of autosomal dominant hereditary HUS in adults. Finally, while it is obviously difficult to draw firm conclusions, the disparate outcomes of cases 1 and 2 deserve mention. Despite aggressive treatment with plasma infusion, plasmapheresis, and corticosteroids, our index patient (case 1) continues to require chronic hemodialysis and has chronic hemolytic anemia, while his untreated sister spontaneously recovered significant renal function. We therefore urge caution in the application of these unproven therapies to patients with familial forms of HUS. In conclusion, familial HUS in adults may be associated with either autosomal dominant or recessive patterns of inheritance, carries a very poor prognosis, and has not been shown to consistently respond to treatment with plasma infusion, plasmapheresis, anti platelet agents, heparin, or corticosteroids. An apparent association between the development of HUS and pregnancy or recent use of oral contraceptives suggests that factors other than simple mendelian inheritance may be operative in women. In view of our findings, women with a family history of HUS or TTP probably should avoid use of oral contraceptives, and perhaps should be cautioned regarding pregnancy as well. Identification of affected families is important for purposes of genetic counseling, as well as further understanding of the pathogenesis and prognosis of familial HUS. Studies of hormonal influences in inherited HUS-TIP may contribute to further clarification of the pathophysiology of these disorders. ACKNOWLEDGMENT The von Willebrand factor assay was performed by M. Helmsworth, Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA. The authors wish to express their appreciation to Dr Stephen Zemel, who provided us with information on case 2.
BERNS ET AL
334
REFERENCES I. Kaplan BS, Chesney RW, Drummond KN: Hemolytic
uremic syndrome in families. N Eng! J Med 292:1090-1093, 1975 2. Kaplan BS, Kaplan P: Hereditary hemolytic uremic syndrome, in Buyse ML (ed): Birth Defects Encyclopedia. New York, NY, Liss, 1990 3. Bergstein J, Michael A, Kjellstrand C, et al: Hemolyticuremic syndrome in adult sisters. Transplantation 17:487-490, 1974 4. Farr MJ, Roberts S, Morley AR, et al: The haemolytic uraemic syndrome-A family study. Q J Med 44:161-188, 1975 5. Karlsberg RP, Lacher JW, Bartecchi CE: Adult hemolytic-uremic syndrome. Arch Intern Med 137:1155-1157, 1977 6. Edelsten A, Tuck S: Familial hemolytic uremic syndrome. Arch Dis Child 53:255-256, 1978 7. Perret B, Gaze H, Zimmerman A, et al: Syndrome hemolytique uremique familial non endemique: Nephrectomie et transplantation. Helv Paediatr Acta 34:167-176,1979 8. Hogewind BL, de la Riviere GB, van Es LA, et al: Familial occurrence of the haemolytic uraemic syndrome. Acta Med Scand 207:73-77, 1980 9. Camba L, AI-Hilali MM, Shulji MMH, et al: Haemolytic-uraemic syndrome with renal failure: The effect of plasmapheresis. Haematologica 70:341-344, 1985 10. Pirson Y, Lefebvre C, Arnout C, et al: Hemolytic uremic syndrome in three adult siblings: A familial study and evolution. Clin Nephrol 28:250-255, 1987 11. Carreras L, Romero R, Requesens C, et al: Familial hypocomplementemic hemolytic uremic syndrome with HLA-A3,B7 haplotype. JAMA 245:602-604, 1981 12. Halgreen M, Andersen RH, Jorgensen JID: Familiaert haemolytisk uraemisk syndrom. Ugeskr Laeger 149:662-663, 1987 13. Hellman RM, Jackson DV, Buss DH: Thrombotic
thrombocytopenic purpura and hemolytic-uremic syndrome in HLA-identical siblings. Ann Intern Med 93:283-284, 1980 14. Kirchner KA, Smith RM, Gockerman JP, et al: Hereditary thrombotic thrombocytopenic purpura: Microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency occurring in consecutive generations. Nephron 30: 28-30, 1982 15. Merrill RH, Knupp CL, Jennette JC: Familial thrombotic microangiopathy. Q J Med 57:749-759, 1985 16. Grottum KA, Flatmark A, Myhre E, et al: Immunological hereditary nephropathy. Acta Med Scand 571:1-27, 1974 (suppl) 17. Brown CB, Robson JS, Thomson D, et al: Haemolytic uraemic syndrome in women taking oral contraceptives. Lancet 1:1479-1481, 1973 18. Russell-Briefel R, Ezzatti T, Perlman J: Prevalence and trends in oral contraceptive use in premenopausal females ages 12-54 years, United States, 1971-1980. Am J Public Health 75:1173-1176,1985 19. Paz RA, Elijovich F, BarcatJA, et al: Fatal simultaneous thrombocytopenic purpura in siblings. Br Med J 4:727-728, 1969 20. Hayslett JP: Postpartum renal failure. N Engl J Med 312:1556-1559, 1985 21. Fuchs WE, George IN, Dotin LN, Sears DA: Thrombotic thrombocytopenic purpura: Occurrence two years apart during late pregnancy in two sisters. JAMA 235:2126-2127, 1976 22. Helmsworth M, Ragin CS, Sherbotie J, et al: Abnormal factor VIII: von Willebrand (VIII:vWF) multimers in patients with hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) may predict thrombotic episodes. VIII Congress International Pediatric Association, Toronto, Canada, Aug 27, 1989 (abstr 10-006) 23. Rose PE, Enayat SM, Sunderland R, et al: Abnormalities offactor VIII related protein multimers in the haemolytic uraemic syndrome. Arch Dis Child 59: 1135-1140, 1984
![[Hemolytic-uremic syndrome in adults].](/assets/img/hold.png)
