CASE REPORT
TRANSPLANTATION
IN THE
HEMOLYTIC-UREMIC
SYNDROME
ANDREW
DrBARTOLOMEO,
M.D.
DONALD
L. PARKER,
M.D.
From Akron City Hospital, Akron, Ohio
ABSTRACT - A case history of ajfty-seven-year-old white woman with hemolytic-uremic syndro,me who was successfully transplanted with a cadaver homograft is reported. A review of the pertinent literature regarding the pathophysiology of the syndrome and the experience to date with transvlantation is vresented.
Gasser et al. in 1955l were the first to describe a syndrome characterized by severe hemolytic anemia, thrombocytopenia, and acute renal failure in infants and children. Since 1955 several hundred cases, mostly in children, have been published in the literature, and this syndrome has been labeled HUS (hemolytic-uremic syndrome). In this article we will describe the clinical course of a fifty-seven-year-old white woman with HUS, discuss the clinical features of the disease, and review the recent literature concerning the treatment of HUS in the adult patient. Case Report A fifty-seven-year-old white woman was transferred to our hospital from a small nearby community hospital. Two weeks prior to admission her family noticed the gradual onset of lethargy and pallor, in addition to bluish discoloration of her toes and pedal edema. There was no history of respiratory, gastrointestinal, or genitourinary symptoms of infection, preexistent renal disease or hypertension, or rectal bleeding, hematemesis, or jaundice. Physical examination revealed a well-developed, well-nourished, pale white female, lethargic, but appropriately responsive to verbal stimuli. Blood pressure monitoring showed systolic pressures of 200-160 mm. Hg and diastolic pressures of 100-110 mm. Hg. Bilateral basilar rales were present without friction rubs. Cardiac examination was not remarkable. Abdominal examination revealed decreased bowel
UROLOGY
/ JULY 1975
/ VOLUME
VI, NUMBER
1
sounds, no bruits, no organomegally, but a diffusely tender abdomen. Distal lower extremities were slightly edematous and cool to touch, with bluish discoloration of the toes of both feet. The fingers were also edematous, cool, and reddened. Petechiae were noticeable on both upper extremities. Pedal pulses were 1 plus, equal, and of normal contour. Initial laboratory values revealed: hemoglobin 5.9 Gm. per 100 ml., platelets 24,000 per cubic millimeter, sedimentation rate 54 mm. per hour, blood urea nitrogen 75 mg. and creatinine 9.8 mg. per 100 ml.; the peripheral smear showed evidence of microangiopathic-hemolytic anemia with many schistocytes and microspherocytes, nucleated red blood cells, and moderate anisopoikilocytosis; serum fibrin split products were positive at a 1:16 dilution; Coombs’ test, thrombin time, lupus erythematosus clot test, antinuclear factor, and rheumatoid factor were normal or negative; urinalysis revealed 1 plus protein, erythrocytes too numerous to count, and a few fine and coursely granular casts. Chest x-ray film was within normal limits. At this time, a diagnosis of hemolytic-uremic syndrome was considered, and the patient was placed on heparin therapy, antihypertensives, and hemodialysis. Urine output ranged from 20 cc. per twenty-four hours on admission to 600 cc. per twenty-four hours late in her hospital stay; but her renal function did not adequately recover during dialysis as exemplified by a creatinine of 6.2 mg. per 100 ml. after five weeks of treatment.
71
At four weeks, a needle biopsy of the patient’s kidney revealed fibrin deposits in the glomeruli; cystoscopy and retrograde pyelography revealed no structural changes in the urinary system. The patient was discharged after six weeks to be managed on hemodialysis twice a week, antihypertensives, and digitalis. She was maintained relatively well on a program of outpatient dialysis for two and one-half months. Approximately four months after her initial hospitalization, she was found to be compatible with a cadaver kidney and underwent renal transplantation. The operative procedure and postoperative course were unremarkable, and the patient was discharged from the hospital on azathioprine (Imuran) and prednisone. The patient is now thirty months post-transplantation, with good graft function and a creatinine clearance of 53 ml. per minute. Comment The exact incidence of HUS is unknown. Available data indicate that it is predominately a pediatric disease with 90 per cent of cases occurring in children under the age of four years. There also appears to be no sex preference in this syndrome. The cause of this disease is unknown, but a relationship to an infection of viral origin is suspected. This association is based on wellfounded clinical information. First, the majority of cases appear to be preceded by a typical virallike prodrome of gastroenteritis and/or upper respiratory tract infection. Second, the disease has been reported in epidemic outbreaks: the most striking encounter reported by Gianantonio et al2 who studied 58 infants and children with HUS in Argentina between 1960 and 1963. Third, various investigators 2-4 have isolated viral particles from these patients. Although the evidence is far from conclusive, it does suggest an infectious origin to HUS. Another etiologic point which can be made and which is the subject of active investigation is the clinical and pathologic similarity of HUS and two other clinical entities, namely, TTP (thrombotic thrombocytopenia purpura) and the generalized Schwartzman reaction. The significance of this is unclear, but perhaps HUS and TTP represent different degrees of the same Schwartzmanlike reaction in humans. The former, HUS, is limited primarily to the kidneys while TTP has a more generalized distribution involving multiple organ systems; but both are characterized pathologically by the rapid appearance of amorphous
72
eosinophilic thrombi in arterioles, capillaries, and venules of human organ systems.3*5 The clinical picture of HUS is complex and variable, but certain phenomena and findings appear to hallmark the disease. In most cases a prodrome occurs lasting two to three weeks prior to the onset of the acute disease. The acute episode is characterized by the sudden appearance of pallor, jaundice, weakness, purpura, and oliguria or anuria. The majority of patients also show neurologic disturbances, including convulsions and coma. Physical findings usually include mild jaundice, bleeding into the skin, occasionally gastrointestinal bleeding, and hypertension in approximately 50 per cent of patients. The laboratory findings include a microangiopathic-hemolytic anemia with low hemoglobin, low platelets, and reticulocytosis. The peripheral smear should show fragmentation of erythrocytes, microspherocytes, and nucleated red cells. Blood urea nitrogen and creatinine are elevated, and fibrin split products are usually present in the serum. The Coombs’ test is negative. Although HUS remains a predominantly pediatric disease, it has been described in the adult and adolescent population. In the literature we have found 26 cases which fit the criteria of HUS. Of these 26 cases, there are 11 survivors. Vitsky et al. ,5 Clarkson et al. ,6 Franklin et al. ,3 and Bolton, Cavallo, and Lewis’ have described gradual recovery of renal function in 6 patients by using both peritoneal and hemodialysis, and heparin therapy. Giromini and Laperrouza4 described the clinical recovery in a young woman with HUS after bilateral nephrectomy. Petersen and Olson* described successful treatment of HUS in a transplanted kidney with removal of the graft and later successful retransplantation. Eigler et aLg described survival of a fourteen-yearold with HUS after transplantation of a cadaver kidney. Bergstein et al. lo recently described 2 cases of adult sisters with HUS: one sister was unsuccessfully transplanted on two occasions and is now anephric and on dialysis, and in the other sister HUS developed in her solitary kidney after donating a kidney to her sister. We wish to add to this list our patient who has been successfully transplanted at age fifty-seven. There is a spectrum of possible outcomes when the results of therapy are evaluated in patients with HUS. The majority of adults and adolescents die in the early, acute stages of the disease from various sequelae of rapidly progressive renal failure, bleeding tendencies, and central nervous
UROLOGY
/ JULY 1975 / VOLUME
VI, NUMBER
1
system complications. Of those who survive the acute phase, three outcomes prevail. The first is that of gradual recovery of adequate renal function with progression to a normal or nearly normal state.3,5-7 The second course is that of attainment of adequate renal function, but continuance of varying degrees of hypertension. In this group most patients are manageable on antihypertensive medication5 but others may require bilateral nephrectomy for control of hypertension. The third group consists of those who do not reestablish adequate renal function and who require long-term dialysis to maintain life. This classification is probably an oversimplification as further experience with this disease in the adult may reveal other clinical courses. If the results of long-term follow-up of adults with HUS is similar to that of children, then chronic renal failure must be anticipated as the ultimate outcome in a significant number of patients. Gianantonio et uZ.~,” studied 76 pediatric patients following HUS, with clinical and laboratory evaluations: 44 per cent were considered to have recovered completely; 25 per cent were thought to be progressing adequately toward normalcy; 11 per cent had severe uremia, and in 20 per cent renal failure was gradually developing. It would appear that with earlier diagnosis and more aggressive management of the acute phase of HUS, more patients are going to survive with irreversible renal damage necessitating chronic dialysis. The alternative to long-term dialysis is renal transplantation. Although not all attempts have been successful, more recent reports have been encouraging. Duena et al., l2 Bergstein et al., lo and Clarkson et al. 6 reported unsuccessful efforts to transplant patients with HUS. Cerilli, Nelsen, and Dorfman, l3 however, reported 2 successful transplants in infants with HUS; and Eigler et aZ.,g and Petersen and Olsen8 have reported successful transplantation in young adults with HUS. In this article we have described an older adult who has been successfully rehabilitated with a functional homograft transplant. With more complete understanding of the etiologic and pathologic mechanisms involved in
UROLOGY /
JULY 1975 /
VOLUME VI, NUMBER 1
the hemolytic-uremic syndrome, and with earlier diagnosis and more successful therapy, the necessity for chronic dialysis and transplantation may be negated. At this time, however, our experience would lead us to recommend renal transplantation as a logical and beneficial method of rehabilitating those patients with end stage kidney disease due to HUS. Akron, Ohio 44309 (DR. DIBARTOLOMEO) References 1. GASSER, C., et al. : Hamolytisch-Uranische Syndrome: Bilaterale Nierenrindennekrosen bei Akuten Erworbenen Hamolytischen Anamien, Schweiz. Med. Wochenschr. 85: 905 (1955). C., et al. : The hemolytic-uremic syn2. GIANANTONIO, drome, J. Pediatr. 64: 478 (1964). The hemolytic-uremic syn3. FRANKLIN, W., et al.: drome, Arch. Pathol. 94: 230 (1972). 4. GIROMINI, M., and LAPERROUZA, C.: Prolonged survival after bilateral nephrectomy in an adult with haemolytic-uraemic syndrome, Lancet 2: 169 (1969). 5. VITSKY, B., YASUNOSUKE, S., STRAUSS, L., and CHURG, J. : The hemolytic-uremic syndrome: a study of renal pathologic alterations, Am. J. Pathol. 57: 627 (1969). 6. CLARKSON, A., LAWRENCE, J., MEADOWS, R., and SEYMOUR, A. : The haemolytic-uraemic syndrome in adults, Quart. J. Med. 39: 227 (1970). 7. BOLTON, W. K., CAVALLO, T., and LEWIS, E. J.: Renal cortical necrosis in a male adult: documented recovery, Arch. Intern. Med. 131: 265 (1973). 8. PETERSEN, V. P., and OLSEN, T. S.: Late renal transplant failure due to hemolytic-uremic syndrome, Acta Med. Stand. 189: 377 (1971). 9. EIGLER, J., et al. : Nierentransplantation bei Hamolytisch-Uramischem Syndrome, Klin. Wochenschr. 50: 648 (1972). 10. BERGSTEIN,J., et al. : Hemolytic-uremic syndrome in adult sisters, Transplantation 17: 487 (1974). 11. GIANANTONIO,C., VITACCO, M., MENDILAHARZU, F., and GALLO, G. : The hemolytic-uremic syndrome: renal status of 76 patients at long-term follow-up, J. Pediatr. 72: 757 (1968). 12. DUNEA, G., MUEHRCKE, R. C., NAKAMOTO,S., and SCHWARTZ, P. : Thrombotic thrombocytopenic purpura with acute anuric renal failure, Am. J. Med. 41: 1000(1966). 13. CERILLI, G., NELSEN, C., and DORFMAN,L.: Renal homotransplantation in infants and children with the hemolytic-uremic syndrome, Surgery 71: 66 (1972).
73
TRANSPLANTATION
IN THE
HEMOLYTIC-UREMIC
SYNDROME
ANDREW
DrBARTOLOMEO,
M.D.
DONALD
L. PARKER,
M.D.
From Akron City Hospital, Akron, Ohio
ABSTRACT - A case history of ajfty-seven-year-old white woman with hemolytic-uremic syndro,me who was successfully transplanted with a cadaver homograft is reported. A review of the pertinent literature regarding the pathophysiology of the syndrome and the experience to date with transvlantation is vresented.
Gasser et al. in 1955l were the first to describe a syndrome characterized by severe hemolytic anemia, thrombocytopenia, and acute renal failure in infants and children. Since 1955 several hundred cases, mostly in children, have been published in the literature, and this syndrome has been labeled HUS (hemolytic-uremic syndrome). In this article we will describe the clinical course of a fifty-seven-year-old white woman with HUS, discuss the clinical features of the disease, and review the recent literature concerning the treatment of HUS in the adult patient. Case Report A fifty-seven-year-old white woman was transferred to our hospital from a small nearby community hospital. Two weeks prior to admission her family noticed the gradual onset of lethargy and pallor, in addition to bluish discoloration of her toes and pedal edema. There was no history of respiratory, gastrointestinal, or genitourinary symptoms of infection, preexistent renal disease or hypertension, or rectal bleeding, hematemesis, or jaundice. Physical examination revealed a well-developed, well-nourished, pale white female, lethargic, but appropriately responsive to verbal stimuli. Blood pressure monitoring showed systolic pressures of 200-160 mm. Hg and diastolic pressures of 100-110 mm. Hg. Bilateral basilar rales were present without friction rubs. Cardiac examination was not remarkable. Abdominal examination revealed decreased bowel
UROLOGY
/ JULY 1975
/ VOLUME
VI, NUMBER
1
sounds, no bruits, no organomegally, but a diffusely tender abdomen. Distal lower extremities were slightly edematous and cool to touch, with bluish discoloration of the toes of both feet. The fingers were also edematous, cool, and reddened. Petechiae were noticeable on both upper extremities. Pedal pulses were 1 plus, equal, and of normal contour. Initial laboratory values revealed: hemoglobin 5.9 Gm. per 100 ml., platelets 24,000 per cubic millimeter, sedimentation rate 54 mm. per hour, blood urea nitrogen 75 mg. and creatinine 9.8 mg. per 100 ml.; the peripheral smear showed evidence of microangiopathic-hemolytic anemia with many schistocytes and microspherocytes, nucleated red blood cells, and moderate anisopoikilocytosis; serum fibrin split products were positive at a 1:16 dilution; Coombs’ test, thrombin time, lupus erythematosus clot test, antinuclear factor, and rheumatoid factor were normal or negative; urinalysis revealed 1 plus protein, erythrocytes too numerous to count, and a few fine and coursely granular casts. Chest x-ray film was within normal limits. At this time, a diagnosis of hemolytic-uremic syndrome was considered, and the patient was placed on heparin therapy, antihypertensives, and hemodialysis. Urine output ranged from 20 cc. per twenty-four hours on admission to 600 cc. per twenty-four hours late in her hospital stay; but her renal function did not adequately recover during dialysis as exemplified by a creatinine of 6.2 mg. per 100 ml. after five weeks of treatment.
71
At four weeks, a needle biopsy of the patient’s kidney revealed fibrin deposits in the glomeruli; cystoscopy and retrograde pyelography revealed no structural changes in the urinary system. The patient was discharged after six weeks to be managed on hemodialysis twice a week, antihypertensives, and digitalis. She was maintained relatively well on a program of outpatient dialysis for two and one-half months. Approximately four months after her initial hospitalization, she was found to be compatible with a cadaver kidney and underwent renal transplantation. The operative procedure and postoperative course were unremarkable, and the patient was discharged from the hospital on azathioprine (Imuran) and prednisone. The patient is now thirty months post-transplantation, with good graft function and a creatinine clearance of 53 ml. per minute. Comment The exact incidence of HUS is unknown. Available data indicate that it is predominately a pediatric disease with 90 per cent of cases occurring in children under the age of four years. There also appears to be no sex preference in this syndrome. The cause of this disease is unknown, but a relationship to an infection of viral origin is suspected. This association is based on wellfounded clinical information. First, the majority of cases appear to be preceded by a typical virallike prodrome of gastroenteritis and/or upper respiratory tract infection. Second, the disease has been reported in epidemic outbreaks: the most striking encounter reported by Gianantonio et al2 who studied 58 infants and children with HUS in Argentina between 1960 and 1963. Third, various investigators 2-4 have isolated viral particles from these patients. Although the evidence is far from conclusive, it does suggest an infectious origin to HUS. Another etiologic point which can be made and which is the subject of active investigation is the clinical and pathologic similarity of HUS and two other clinical entities, namely, TTP (thrombotic thrombocytopenia purpura) and the generalized Schwartzman reaction. The significance of this is unclear, but perhaps HUS and TTP represent different degrees of the same Schwartzmanlike reaction in humans. The former, HUS, is limited primarily to the kidneys while TTP has a more generalized distribution involving multiple organ systems; but both are characterized pathologically by the rapid appearance of amorphous
72
eosinophilic thrombi in arterioles, capillaries, and venules of human organ systems.3*5 The clinical picture of HUS is complex and variable, but certain phenomena and findings appear to hallmark the disease. In most cases a prodrome occurs lasting two to three weeks prior to the onset of the acute disease. The acute episode is characterized by the sudden appearance of pallor, jaundice, weakness, purpura, and oliguria or anuria. The majority of patients also show neurologic disturbances, including convulsions and coma. Physical findings usually include mild jaundice, bleeding into the skin, occasionally gastrointestinal bleeding, and hypertension in approximately 50 per cent of patients. The laboratory findings include a microangiopathic-hemolytic anemia with low hemoglobin, low platelets, and reticulocytosis. The peripheral smear should show fragmentation of erythrocytes, microspherocytes, and nucleated red cells. Blood urea nitrogen and creatinine are elevated, and fibrin split products are usually present in the serum. The Coombs’ test is negative. Although HUS remains a predominantly pediatric disease, it has been described in the adult and adolescent population. In the literature we have found 26 cases which fit the criteria of HUS. Of these 26 cases, there are 11 survivors. Vitsky et al. ,5 Clarkson et al. ,6 Franklin et al. ,3 and Bolton, Cavallo, and Lewis’ have described gradual recovery of renal function in 6 patients by using both peritoneal and hemodialysis, and heparin therapy. Giromini and Laperrouza4 described the clinical recovery in a young woman with HUS after bilateral nephrectomy. Petersen and Olson* described successful treatment of HUS in a transplanted kidney with removal of the graft and later successful retransplantation. Eigler et aLg described survival of a fourteen-yearold with HUS after transplantation of a cadaver kidney. Bergstein et al. lo recently described 2 cases of adult sisters with HUS: one sister was unsuccessfully transplanted on two occasions and is now anephric and on dialysis, and in the other sister HUS developed in her solitary kidney after donating a kidney to her sister. We wish to add to this list our patient who has been successfully transplanted at age fifty-seven. There is a spectrum of possible outcomes when the results of therapy are evaluated in patients with HUS. The majority of adults and adolescents die in the early, acute stages of the disease from various sequelae of rapidly progressive renal failure, bleeding tendencies, and central nervous
UROLOGY
/ JULY 1975 / VOLUME
VI, NUMBER
1
system complications. Of those who survive the acute phase, three outcomes prevail. The first is that of gradual recovery of adequate renal function with progression to a normal or nearly normal state.3,5-7 The second course is that of attainment of adequate renal function, but continuance of varying degrees of hypertension. In this group most patients are manageable on antihypertensive medication5 but others may require bilateral nephrectomy for control of hypertension. The third group consists of those who do not reestablish adequate renal function and who require long-term dialysis to maintain life. This classification is probably an oversimplification as further experience with this disease in the adult may reveal other clinical courses. If the results of long-term follow-up of adults with HUS is similar to that of children, then chronic renal failure must be anticipated as the ultimate outcome in a significant number of patients. Gianantonio et uZ.~,” studied 76 pediatric patients following HUS, with clinical and laboratory evaluations: 44 per cent were considered to have recovered completely; 25 per cent were thought to be progressing adequately toward normalcy; 11 per cent had severe uremia, and in 20 per cent renal failure was gradually developing. It would appear that with earlier diagnosis and more aggressive management of the acute phase of HUS, more patients are going to survive with irreversible renal damage necessitating chronic dialysis. The alternative to long-term dialysis is renal transplantation. Although not all attempts have been successful, more recent reports have been encouraging. Duena et al., l2 Bergstein et al., lo and Clarkson et al. 6 reported unsuccessful efforts to transplant patients with HUS. Cerilli, Nelsen, and Dorfman, l3 however, reported 2 successful transplants in infants with HUS; and Eigler et aZ.,g and Petersen and Olsen8 have reported successful transplantation in young adults with HUS. In this article we have described an older adult who has been successfully rehabilitated with a functional homograft transplant. With more complete understanding of the etiologic and pathologic mechanisms involved in
UROLOGY /
JULY 1975 /
VOLUME VI, NUMBER 1
the hemolytic-uremic syndrome, and with earlier diagnosis and more successful therapy, the necessity for chronic dialysis and transplantation may be negated. At this time, however, our experience would lead us to recommend renal transplantation as a logical and beneficial method of rehabilitating those patients with end stage kidney disease due to HUS. Akron, Ohio 44309 (DR. DIBARTOLOMEO) References 1. GASSER, C., et al. : Hamolytisch-Uranische Syndrome: Bilaterale Nierenrindennekrosen bei Akuten Erworbenen Hamolytischen Anamien, Schweiz. Med. Wochenschr. 85: 905 (1955). C., et al. : The hemolytic-uremic syn2. GIANANTONIO, drome, J. Pediatr. 64: 478 (1964). The hemolytic-uremic syn3. FRANKLIN, W., et al.: drome, Arch. Pathol. 94: 230 (1972). 4. GIROMINI, M., and LAPERROUZA, C.: Prolonged survival after bilateral nephrectomy in an adult with haemolytic-uraemic syndrome, Lancet 2: 169 (1969). 5. VITSKY, B., YASUNOSUKE, S., STRAUSS, L., and CHURG, J. : The hemolytic-uremic syndrome: a study of renal pathologic alterations, Am. J. Pathol. 57: 627 (1969). 6. CLARKSON, A., LAWRENCE, J., MEADOWS, R., and SEYMOUR, A. : The haemolytic-uraemic syndrome in adults, Quart. J. Med. 39: 227 (1970). 7. BOLTON, W. K., CAVALLO, T., and LEWIS, E. J.: Renal cortical necrosis in a male adult: documented recovery, Arch. Intern. Med. 131: 265 (1973). 8. PETERSEN, V. P., and OLSEN, T. S.: Late renal transplant failure due to hemolytic-uremic syndrome, Acta Med. Stand. 189: 377 (1971). 9. EIGLER, J., et al. : Nierentransplantation bei Hamolytisch-Uramischem Syndrome, Klin. Wochenschr. 50: 648 (1972). 10. BERGSTEIN,J., et al. : Hemolytic-uremic syndrome in adult sisters, Transplantation 17: 487 (1974). 11. GIANANTONIO,C., VITACCO, M., MENDILAHARZU, F., and GALLO, G. : The hemolytic-uremic syndrome: renal status of 76 patients at long-term follow-up, J. Pediatr. 72: 757 (1968). 12. DUNEA, G., MUEHRCKE, R. C., NAKAMOTO,S., and SCHWARTZ, P. : Thrombotic thrombocytopenic purpura with acute anuric renal failure, Am. J. Med. 41: 1000(1966). 13. CERILLI, G., NELSEN, C., and DORFMAN,L.: Renal homotransplantation in infants and children with the hemolytic-uremic syndrome, Surgery 71: 66 (1972).
73
