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Clinical spectrum of postpartum renal failure
Clinical Spectrum of Postpartum Renal Failure
FREDRIC 0. FINKELSTEIN, M.D.’ MICHAEL KASHGARIAN, JOHN P. HAYSLETT,
M.D.+
M.D.r
New Haven, Connecticut
Four patients in whom renal functional abnormalities developed in the postpartum period are discussed. Two patients had a fulminant, fatal course, typical of most of the previously reported cases of postpartum renal failure. The other two patients, however, had only mild, transient renal abnormalities. Pathologically, all four pattents showed changes suggestive of fibrin deposition in the renal vasculature. It is suggested that postpartum renal failure includes a spectrum of disease from fulminant renal failure with extensive fibrin deposition to minor renal dysfunction with minimal fibrin deposition. The syndrome of renal failure occurring at the time of delivery or during the postpartum period has been characterized by a sudden and unexplained rapid decline in renal function in association with an apparent uncomplicated pregnancy, signs of a microangiopathic hemolytic anemia and deposition of fibrin in glomerular capillaries [l-12]. In each of the 26 reported cases [l-12] irreversible renal failure occurred, so that this complication is considered to have a universally grave prognosis. In this report four patients with postpartum renal failure with typical hematologic and renal pathologic changes are described. Two women had severe uremia; the other two had a milder clinical course with complete restoration of renal function. It seems likely, therefore, that whatever mechanism is responsible, the spectrum of severity in this syndrome correlates with the initial renal injury.
Case 1. A 21 year old white woman (L.B., YNHH No. 67-51-82), gravida 1,
From the Departments of Medicine, Pediatrics and Pathology, Yale University School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Dr. Fredric 0. Finkelstein. Department of Internal Medicine, Yale School of Medicine, 333 Cedar Street, New Haven. Connecticut. Manuscript accepted December 2!7, 1973. * Recipient of Metabolism Training Grant TR-60, Veterans Administration Hospital, West Haven, Connecticut. 7 Recipient of Research Career Development Award HE 13 683, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland. z Established Investigator, American Heart Association.
para 1, was transferred to the Yale-New Haven Hospital (YNHH) for evaluation of acute renal failure, 12 days postpartum. Her pregnancy was uncomplicated until the 7th month when hypertension (90 to 100 mm Hg, diastolic), mild dependent edema and 2-t proteinuria occurred. Treatment with bendroflumethiazide was initiated. One month later she was admitted to her local hospital because of headaches, nausea and vomiting. Hypertension (190/l 10 mm Hg) and peripheral edema were found. Laboratory studies showed an elevated blood urea nitrogen level of 23 mg/lOO ml and 4-k proteinuria. After reducing her blood pressure with reserpine, apresoline and magnesium sulfate, a cesarean section was performed on the 2nd hospital day and a healthy 1,824 g infant was delivered. Spinal anesthesia was used for delivery, and no evidence of hypotension was recorded. During the subsequent 11 days her course was complicated by severe renal failure and anemia. The blood urea nitrogen level rose from 19 to 104 mg/lOO ml, urine volume fell from 2.000 to less than 200 ml/ day and the hemoglobin level declined from 14 to 7 g/100 ml despite the administration of 3 units of blood and no evidence of blood loss. On admission to the YNHH the blood pressure was 140/8O mm Hg, the fundi were normal, and there was moderate peripheral edema. Pertinent
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laboratory studies included a hematocrit value of 22 per cent with numerous fragmented red blood cells on blood film, a reticulocyte count of 18 per cent, platelet count of 90,000/mm3, 3-l- proteinuria and cellular casts in the urine sediment. The blood urea nitrogen was 108 mg/iOO ml, serum creatinine was 10 mg/iOO ml, and the lupus erythematosus preparation, antinuclear test and Coombs’ test were negative. Additional studies revealed a normal fibrinogen level, prothrombin time and partial thromboplastin time. Throughout the hospital course the patient was oliguric and had moderate hypertension (90 to 100 mm Hg, diastolic). Anemia persisted with hematocrit values of approximately 25 per cent and many fragmented red blood cells on blood film. Despite peritoneal dialysis and removal of necrotic placental tissue, she died on the 19th hospital day. The most prominent pathologic findings at autopsy were in the heart and kidney. The heart was enlarged with hypertrophy of the left ventricle and dilatation of all chambers. Foci of myocardial necrosis were seen microscopically. The kidneys were enlarged and pale with small petechial hemorrhages on the surface. The glomeruli contained organizing thrombi with some mesangial and endothelial hyperplasia. Some arterioles showed evidence of fibrinoid necrosis of the arteriolar wall, and the intrarenal artery showed varying degrees of intimal edema and hyperplasia. In some vessels subendothelial fibrin deposition, demonstrated by Putt’s modification of Lendrum’s fibrin stain [ 131, was prominent.
Case 2. A 21 year old white woman (A.P., YNHH No. 6705-85), gravida 1, para 1, was admitted to YNHH 3 months postpartum for evaluation of oliguria and renal failure. Her
antepartum course was not complicated by any signs of preeclampsia; her renal function remained normal; and a normal, full-term infant was delivered. She remained asymptomatic until the 3rd month postpartum, when she noticed weakness, anorexia and a decrease in her urine output. She was admitted to YNHH where physical examination showed a blood pressure of 160190 mm Hg, normal fundi and 1-t peripheral edema. Urine output was 200 cc/day. Laboratory data included a hematocrit of 23 per cent with fragmented red blood cells on peripheral blood smear, platelet count of 72,000/mm3, urinalysis with 3-fprotein and several red and white blood cells/hpf in the urinary sediment, serum creatinine of 18 mg/lOO ml and a negative lupus erythematosus preparation, antinuclear factor and Coombs’ test. Clotting studies showed a normal fibrinogen, prothrombin time and partial thromoplastin time. Weekly peritoneal dialyses were performed for the remainder of her hospital stay. Mild hypertension developed, but diastolic blood pressures were kept about 100 mm Hg with Aldomet@ therapy. The patient had several grand mal seizures which were controlled with diphenylhydantoin therapy. She died 2 months after admission. The immediate cause of death was unknown. Autopsy examination revealed vascular changes in the kidneys, brain and lungs. Most prominent was fibrinoid necrosis of the walls of the arterioles and small muscular arteries. Many of the vessels contained recent and organizing thrombi, but there was no significant leukocytic infiltration of the arteriolar wall. In the kidney, the glomeruli as well as the larger vessels were involved. Mesangial hyperplasia and occasional intracapillary thrombi were found. The arterioles showed the most striking lesions with marked fibrinoid necrosis (Figure 1).
Figure 1. Two representative glomeruli are shown. On the left there is thrombosis of the afferent arteriole and fibrinoid necrosis in the wall of the intralobular artery supplying that glomerulus (arrows). There is also mesangial hyperplasia of the glomerulus and endothelial swelling and proliferation of the artery. On the right is a glomerulus with segmental proliferation of the mesangium associated with thrombosis and fibrinoid necrosis of the supplying arteriole (arrows). Masson stain, original magnification X 250.
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Case 3. A 30 year old black woman
(F.B., YNHH No. A710-89) gravida 5, para 4, was admitted to YNHH 6 days postpartum for evaluation of headaches. None of her pregnancies were complicated by signs of toxemia. Her most recent pregnancy resulted in a normal, full-term infant. Six days postpartum, she experienced severe, bifrontal headaches and was admitted to YNHH. Physical examination showed a blood pressure of 220/i 10 mm Hg, normal fundi, no edema and 3+ deep tendon reflexes. Laboratory data included a hematocrit of 37 per cent with slight anisocytosis and poikilocytosis, and adequate platelets on peripheral smear, urine sediment with 10 to 20 red and white blood cells/hpf, 24 hour urine protein of 400 mg, and serum creatinine of 0.9 mg/lOO ml. On the day after admission, after her blood pressure fell to 140/90 mm Hg, she experrenced a grand mal seizure. She was treated with phenobarbital and magnesium sulfate, but these were withdrawn over the next 4 days. She had no more seizure activity and her diastolic pressures remained below 90 mm Hg. Three days after admission a renal biopsy was performed which demonstrated a generalized diffuse mesangial hyperplasia in the glomeruli. Putt’s modification of Lendrum’s fibrin stain did not reveal any evidence of acute fibrin thrombi within the capillaries. The arterioles showed no evidence of necrosis. Electron microscopy performed on the paraffin-embedded material sometime later revealed subendothelial fluffy granular deposits. No fibrin tactoids were seen however. Three days after the renal biopsy, the patient was discharged. No medication was prescribed. She remained asymptomatic during the next few months and had normal blood pressures and no proteinuria or hematuria. Serum creatinine remained below 1 mg/ 100 ml. Six months after the initial renal biopsy, a repeat biopsy was performed which disclosed significant resolution of the mesangial hyperplasia and widening. Many glomeruli appeared entirely normal at this time. A subsequent pregnancy 1 year later was not complicated by hypertension, seizures or renal functional abnormalities pre- or postpartum. Case
4. A 30 year old woman (A.D., YNHH No. 46-98174) with two previously uncomplicated pregnancies was admitted to YNHH in her 7th month of pregnancy. Her chief complaint was a 1 day history of severe headaches. Physical examination on admission revealed a blood pressure of 210/110 mm Hg, normal fundi, 1-F peripheral edema and 3-I reflexes. Laboratory data included a hematocrit of 35 per cent, a normal peripheral smear with adequate platelets, urine sediment with no cells, 24 hour urine protein of 600 mg, serum creatinine of 1.1 mg/lOO ml, serum glutamic oxaloacetic transaminase (SGOT) of 50 units, bilirubin of 0.8 mg and alkaline phosphatase of 99 IU. The patient responded well to treatment with magnesium sulfate, phenobarbital, Aldactonee and chlorothiazide with a return of her blood pressure to normal and disappearance of the headaches. She was discharged 6 days after admission on a regimen of chlorthiazide, 500 mg/
RENAL FAILURE-FINKEILSTEIN
ET AL.
day. She remained asymptomatic for 1 week when nausea and vomiting developed, and she was again admitted to YNHH. Physical examination revealed a blood pressure of 150190 mm Hg, normal fundi, no edema and 3+ reflexes. Laboratory data included a hematocrit of 40 per cent, normal peripheral smear and urinalysis with 2+ protein and no cells. Labor was induced on the following day with delivery of a premature, healthy infant. The blood pressure returned to normal immediately after delivery and remained in the normal range throughout the remainder of the patient’s hospital stay; no antihypertensive medications were given. On the second postpartum day, the patient’s temperature rose to 1Ol’F. Her clinical course and laboratory data indicated multisystem involvement and included mild renal insufficiency, a microangiopathic hemolytic anemia with thrombocytopenia, hepatic rupture and dermatologic changes suggestive of a vasculitis. Renal abnormalities were most striking on the second day postpartum. Serum creatinine was 2.1 mg/lOO ml, urine sediment showed numerous red and white blood cells/hpf, and a :24 hour urine collection contained 4 g of protein. The renal functional abnormalities began to resolve over the ensuing 3 weeks with the serum creatinine level falling to 1.4. mg/iOO ml, the urine sediment clearing, and the 24 hour protein falling to 1.7 g/day. Serum complement was normal; antinuclear factor was present in a titer of 1:4; lupus erythematosus preparations were negative. A brisk hemolysis developed postpartum; the hematocrit level fell to a low of 28 per cent 1 week postpartum with a marked reticulocytosis; there was no evidence of blood loss; and there were numerous fragmented red blood cells on the peripheral blood smear. The hematocrit level slowly rose over the following 3 weeks with a gradual fall in the reticulocyte count and disappearance of the ‘ragmented red blood cells. The platelet count also fell to a low of 44,000/mm3 1 week postpartum, remaining in that range for 2 l/2 weeks before rising to 100,000/mm3, 4 weeks after delivery. Prothrombin time, partial thromboplastin time, serum fibrinogen and factor 8 and 11 levels were all normal. The patient complained of pain in the right upper abdominal quadrant on the day after delivery. A diagnosis of rupture of the liver was made; liver function tests showed an SGOT of 1,420 units, alkaline phosphatase of 560 IU and a bilirubin of 1.2 mg. Liver scan demonstrated two large filling defects. The pain in the right upper quadrant subsided, and the abnormal liver function tests returned to normal over the ensuing 4 weeks. One and a half weeks postpartum, a macular rash appeared on the patient’s arms, neck, face and anterior portions of her chest, and small papules appeared on her palms and finger tips. These lesions gradually cleared over the next 2 weeks. Four weeks postpartum, the patient was discharged from the hospital on no medication with a normal temperature and a normal physical examination. Six weeks postpartum she was readmitted to YNHH for renal biopsy. At this time, physical examination was again normal. Laboratory data included a hematocrit of 33 per cent, platelet
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count of 90,000/mm3, serum creatinine of 1.5 mg/iOO ml, normal urine sediment, 24 hour urine protein of 2.4 g and normal liver function tests. The renal biopsy specimen showed a generalized diffuse mesangial widening which was due to both mesangial cellular hyperplasia and an increase in mesangial matrix. This change was prominent in a segmental pattern in some glomeruli. Ultrastructural examination revealed ischemit change of the glomeruli with some collapse in the capillary loops and some folding of the capillary wall as it approached the mesangium. There was an increase in the mesangial matrix, but no electron dense material was seen. In some peripheral capillary loops there was an irregular thickening of the basement membrane resulting from deposition of a granular subendothelial material. No fibrin or fibrin tactoids were seen (Figure 2). At follow-up 9 months postpartum the patient was asymptomatic, physical examination was within normal limits and laboratory data included a hematocrit of 35 per cent, platelet count of 120,000/mm3, normal red blood cell morphology, serum creatinine of 1.2 mg/ 100 ml and a 24 hour urine protein of 400 mg. COMMENTS Acute renal failure has been described
occurring in postpartum women as a new clinicopathologic syn-
drome with increasing frequency during the past 5 years [l-12]. The characteristic features of the illness are illustrated by our first case. In that case acute and severe renal insufficiency occurred shortly after delivery in association with a microangiopathic hemolytic anemia and thrombocytopenia. Irreversible renal failure persisted, and the patient died as a result of uremia. At autopsy the hallmark findings in the kidney included (1) organizing thrombi in glomerular capillary loops: (2) widening of the mesangium with moderate mesangial and endothelial cell hyperplasia; and (3) fibrinoid necrosis, edema and intimal hyperplasia of vessel walls. Of the 26 cases previously reported this sequence has been recorded at intervals of 1 day to 7 months postpartum. Although in our Cases 1 and 4 the patients demonstrated signs of toxemia during pregnancy, in 19 of the 26 reported cases gestation had apparently been uncomplicated. A microangiopathic hemolytic anemia has been a consistent finding in all cases, and thrombocytopenia occurred in 75 per cent of those in which platelet counts were listed. Systematic clotting studies have not been performed but have been reported as normal in the few cases examined. Although hyperten-
g segmental meiangial hyperplasia with an increase ification X 250. On the right an electron micrograph lary loops is seen. Some light granular material is present in a subendothelial location (arrow) and there is nonspecific focal thickening of the basement membrane. No fibrin or fibrin tactoids are seen.
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sion has usually gressed, normal common
at onset.
been blood
present as the illness propressure values are most
Another
clinical
feature
of interest
has been fever which often could not be related to a septic process. Generalized seizures and congestive heart failure are also common clinical manifestations. In addition to these clinical features the renal histologic changes have shown striking similarity. Involvement of interlobular and afferent arteries have includgd foci of fibrinoid necrosis, occlusion with eosinophilic thrombi, intimal hyperplasia and subendothelial deposition of electron dense material. Microscopic examination has shown occluding thrombi in glomerular capillary loops, foci of necrosis and mesangial widening. An amorphous, granular electron dense material, thought to be fibrin, can usually be demonstrated in a subendothelial location on ultrastructural examination. By immunofluorescent staining a diffuse disposition of fibrin and a variable and less intense staining for BIC and IgG has been described [ $61. Although a systematic evaluation of other organs has not been reported, scattered arteriolar necrosis and occlusive thrombi have been demonstrated in the brain and heart. The important consequence of these changes in all previously reported cases has been irreversible renal damage. Sixteen patients have died of uremia, two were treated with chronic dialysis, one died in association with a rejected transplant, two were reported to have creatinine clearances of less than 7 ml/min and five have had a significant chronic reduction in function, although clearances greater than 40 ml/min persisted. The important finding in this series of patients was the complete restoration of renal function in two of the four cases. Each of our patients demonstrated the characteristic clinical features of this syndrome. Renal injury first occurred from the time of delivery to 3 months postpartum. In three of four cases, a hemolytic anemia with fragmented red blood cells and a severe thrombocytopenia was present. Although the renal histologic changes in the first two patients, who died of renal failure, were consistent with previously reported abnormalities, quantitatively less severe changes were present in the other two. However, in ultrastructural examination revealed these two, subendothelial granular deposits in peripheral capillary walls which were similar in appearance to those usually found in the typical severe cases. It seems likely, therefore, that the mild changes in renal function exhibited in our Cases 3 and 4 reflected the limited extent of the renal injury reaction. In the hemolytic-uremic syndrome of children, a disorder very similar to postpartum renal failure, a spectrum of changes has also been reported from mild to severe
irreversible
renal
failure
RENAL FAILURE-FINKELSTEIN
[ 141. It is perhaps
prising that the initial patients
ET AL.
not sur-
with this syndrome
who
were studied were the more severely affected. There is ample evidence to show the similarity between several closely linked clinical syndromes and experimental conditions to postpartum renal failure. These conditions include hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, eclampsia, the generalized Schwartzman reaction and experimentally-induced disseminated intravascular coagulation (DIC). In each condition fibrin deposition in arteriolar and glomerular capillary walls is considered to be the basic underlying pathogenic mechanism, a process termed thrombotic microangiopathy. Among the disease processes which occur in man the constellation of clinical features are used to distinguish the separate entities. Although the hemolytic-uremic syndrome occurs most commonly in children, cases in adults unrelated to the pregnant state have been reported [ 141. Both this condition and postpartum renal failure are characterized by a microangiopathic hemolytic anemia, thrombocytopenia and similar pathologic changes confined to the kidney. The distinguishing clinical feature in postpartum renal failure, therefore, is the closely linked association with pregnancy. In thrombotic thrombocytopenic purpura, fibrin deposition occurs in many organs, in addition to the kidney, and renal failure is uncommon [ 151. The pathologic changes in the kidney in toxemia of pregnancy are also thought to be secondary to fibrin deposition [ 161. Subendothelial electron-dense deposits, endothelial and mesangial cell swelling and an increase in mesangial matrix are the most striking histologic features [ 17-201. In a few recorded cases of severe eclampsia, renal changes have been strikingly similar to those seen in postpartum renal failure in association with a microangiopathic hemolytic anemia and thrombocytopenia [ 19,2 1,221. Clinically, however, toxemia is distinguished by severe hypertension, uncommon progression to irreversible renal failure and occurrence no later than 46 hours after delivery. The renal pathologic changes of these diseases have their experimental analogy in the generalized Schwartzman reaction and experimentally-induced DIC [23,24]. The relationship of pregnancy to the generalized Schwartzman reaction and the coagulation process is of special interest. Only one injection of endotoxin can produce a typical generalized Schwartzman reaction in pregnant animals whereas two properly spaced injections are required in nonpregnant subjects [25]. Placental extracts can in’duce fibrin deposition in small vessels and glomeruli when injected into animals [ 261. The relationship to the pathogenesis of postpartum renal f
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ever unclear. Retained placental fragments with release of placental tissue thromboplastin is a possible etiology, but in only one of the reported cases (our Case 2 ) was retained placental tissue noted. Therapeutically, anticoagulants would seem to be a logical mode of treatment. Anticoagulants have been shown to significantly modify the histologic changes in the generalized Schwartzman reaction [27]. Heparin has been suggested as a useful mode of treatment in the management of severe eclampsia with a microangiopathic hemolytic anemia [22], thrombotic thrombocytopenic purpura 1281 and hemolyfic-uremic syndrome [ 141. In five of the previously reported cases of postpartum renal failure in which there was some improvement in renal function, the patients were treated with heparin (in addition to steroids in two, and steroids and azathioprine in another). However, in four other cases of postpartum renal failure, the patients were treated with anti-
coagulants but no improvement was noted our Cases 3 and 4, the patients received ment and frank renal failure did not develop. In summary, hemolytic-uremic
the present data suggest syndrome, thrombotic
[9, lo]. In no treat-
that like the thrombocy-
topenic purpura and eclampsia, postpartum renal failure incorporates a spectrum of clinical expression from severe renal failure and death to mild, transient renal insufficiency with recovery of normal renal function. Although the pathogenesis of these different syndromes seems to involve intravascular coagulation and fibrin deposition, it is unclear whether these disease processes are separate nosologic entities or the varied manifestations of one disease. The absence of an inexorable, downhill course in some untreated patients with postpartum renal failure should be recalled in studies designed to test new therapeutic modalities.
REFERENCES
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a. 9. 10.
11
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16.
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Clarkson AR, Meadows R, Lawrence JR: Post partum renal failure: the generalized Schwartzman reaction. Aust Ann Med 18: 209, 1969. Erickson DC, Lagios MD, Schoenfeld P, Cohen RJ: Effect of bilateral nephrectomy in post partum nephrosclerosis. Arch Intern Med 128: 448, 1971. Dgg CS, Cameron JS: Post partum renal failure. Lancet 1: 1317, 1969. Robson JS, Martin AM, Ruckley VA, MacDonald MK: Irreversible post partum renal failure. Q J Med 37: 423, 1968. Churg J, Koffler D, Paronetto F, Rorat E, Barnett RN: Hemolytic uremic syndrome as a cause of post partum renal failure. Am J Obstet Gynecol 108: 253, 1970. Rosenmann E, Kanter A, Bacani RA, Pirani CL, Pollak VE: Fatal late post partum intravascular coagulation with acute renal failure. Am J Med Sci 257: 259, 1969. Sheer RL, Jones DB: Malignant nephrosclerosis in women postpartum. JAMA 201: 600, 1967. Wagoner RD, Holley KE, Johnson WJ: Accelerated nephrosclerosis and post partum acute renal failure in normotensive patients. Ann Intern Med 69: 237, 1968. Eisinger AJ: Post par-turn hemolytic uremic syndrome. J Obstet Gynecol Br Commonw 79: 139, 1972. Luke RG, Talbert W, Siegel RR, Holland N: Heparin treatment for post partum renal failure with microangiopathic hemolytic anemia. Lancet 2: 750, 1970. Pointicelli C, lmbasciati E, Tarontino A, Grazliani G, Redaelli B: Post partum renal failure with microangiopathic hemolytic anemia. Nephron 9: 27, 1972. Case records of the Massachusetts General Hospital. N Engl J Med 288: 93, 1973. Putt FA: Manual of Histopathological Staining Methods, New York, John Wiley & Sons, Inc., 1972. Lieberman E: Hemolytic uremic syndrome. J Pediatr 80: 1, 1972. Amorosi EL, Ultmann JE: Thrombotic thrombocytopenic purpura: report of sixteen cases and review of the literature. Medicine 45: 139, 1966. Vasalli P, McCluskey RT: The coagulation process and glo-
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1974
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merular disease. Am J Med 39: 179, 1965. Pollak VE, Nettles JB: The kidney in toxemia of pregnancy: a clinical and pathologic study based on renal biopsies. Medicine 39: 469, 1960. Altchek A, Albright NL, Sommers SC: The renal pathology of toxemia of pregnancy. Obstet Gynecol 24: 32, 1964. McKay DG, Merrill D, Weiner AE, Hertig AT, Reid PE: The pathologic anatomy of eclampsia, bilateral renal cortical necrosis, pituitary necrosis and other fatal complications of pregnancy, and its possible relationship to the generalized Schwartzman phenomenon. Am J Obstet Gynecol 66: 507, 1953. Pirani CL, Pollak VE, Lannigan R, Folli G: The renal glomerular lesions of pre-eclampsia: electron microscopic studies. Am J Obstet Gynecol 87: 1047, 1963. Dacie JV: Hemolytic Anemias, Part Ill, New York, Grune & Stratton, Inc., 1967. Brain MC, Kwah KB, Dixon HG: Heparin treatment of hemolysis and thrombocytopenia in pre-eclampsia. J Obstet Gynecol Br Commonw 74: 702, 1967. Thomas L, Good RA: Studies on the generalized Schwartzman reaction. I. General observations concerning the phenomenon. J Exp Med 96: 605, 1952. Margaretten W, Csavossy I, McKay DG: An electron microscopic study of thrombin-induced disseminated intravascular coagulation. Blood 29: 169, 1967. Wong TC: A study on the generalized Schwartzman reaction in pregnant rats induced by bacterial endotoxin. Am J Obstet Gynecol 84: 786, 1962. lrino T, Okuda T, Grollman A: Changes induced in the glomeruli of the kidney of rats by placental extracts as observed with the electron microscope. Am J Pathol 50: 421, 1967. Good RA, Thomas L: Studies on the generalized Schwartzman reaction. IV. Prevention of the local and generalized Schwartzman reaction with heparin. J Exp Med 97: 871, 1953. Bernstock J, Hirson C: Thrombotic thrombocytopenic purpura: remission on treatment with heparin. Lancet 1: 28, 1960.
FREDRIC 0. FINKELSTEIN, M.D.’ MICHAEL KASHGARIAN, JOHN P. HAYSLETT,
M.D.+
M.D.r
New Haven, Connecticut
Four patients in whom renal functional abnormalities developed in the postpartum period are discussed. Two patients had a fulminant, fatal course, typical of most of the previously reported cases of postpartum renal failure. The other two patients, however, had only mild, transient renal abnormalities. Pathologically, all four pattents showed changes suggestive of fibrin deposition in the renal vasculature. It is suggested that postpartum renal failure includes a spectrum of disease from fulminant renal failure with extensive fibrin deposition to minor renal dysfunction with minimal fibrin deposition. The syndrome of renal failure occurring at the time of delivery or during the postpartum period has been characterized by a sudden and unexplained rapid decline in renal function in association with an apparent uncomplicated pregnancy, signs of a microangiopathic hemolytic anemia and deposition of fibrin in glomerular capillaries [l-12]. In each of the 26 reported cases [l-12] irreversible renal failure occurred, so that this complication is considered to have a universally grave prognosis. In this report four patients with postpartum renal failure with typical hematologic and renal pathologic changes are described. Two women had severe uremia; the other two had a milder clinical course with complete restoration of renal function. It seems likely, therefore, that whatever mechanism is responsible, the spectrum of severity in this syndrome correlates with the initial renal injury.
Case 1. A 21 year old white woman (L.B., YNHH No. 67-51-82), gravida 1,
From the Departments of Medicine, Pediatrics and Pathology, Yale University School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Dr. Fredric 0. Finkelstein. Department of Internal Medicine, Yale School of Medicine, 333 Cedar Street, New Haven. Connecticut. Manuscript accepted December 2!7, 1973. * Recipient of Metabolism Training Grant TR-60, Veterans Administration Hospital, West Haven, Connecticut. 7 Recipient of Research Career Development Award HE 13 683, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland. z Established Investigator, American Heart Association.
para 1, was transferred to the Yale-New Haven Hospital (YNHH) for evaluation of acute renal failure, 12 days postpartum. Her pregnancy was uncomplicated until the 7th month when hypertension (90 to 100 mm Hg, diastolic), mild dependent edema and 2-t proteinuria occurred. Treatment with bendroflumethiazide was initiated. One month later she was admitted to her local hospital because of headaches, nausea and vomiting. Hypertension (190/l 10 mm Hg) and peripheral edema were found. Laboratory studies showed an elevated blood urea nitrogen level of 23 mg/lOO ml and 4-k proteinuria. After reducing her blood pressure with reserpine, apresoline and magnesium sulfate, a cesarean section was performed on the 2nd hospital day and a healthy 1,824 g infant was delivered. Spinal anesthesia was used for delivery, and no evidence of hypotension was recorded. During the subsequent 11 days her course was complicated by severe renal failure and anemia. The blood urea nitrogen level rose from 19 to 104 mg/lOO ml, urine volume fell from 2.000 to less than 200 ml/ day and the hemoglobin level declined from 14 to 7 g/100 ml despite the administration of 3 units of blood and no evidence of blood loss. On admission to the YNHH the blood pressure was 140/8O mm Hg, the fundi were normal, and there was moderate peripheral edema. Pertinent
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1974
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ET AL
laboratory studies included a hematocrit value of 22 per cent with numerous fragmented red blood cells on blood film, a reticulocyte count of 18 per cent, platelet count of 90,000/mm3, 3-l- proteinuria and cellular casts in the urine sediment. The blood urea nitrogen was 108 mg/iOO ml, serum creatinine was 10 mg/iOO ml, and the lupus erythematosus preparation, antinuclear test and Coombs’ test were negative. Additional studies revealed a normal fibrinogen level, prothrombin time and partial thromboplastin time. Throughout the hospital course the patient was oliguric and had moderate hypertension (90 to 100 mm Hg, diastolic). Anemia persisted with hematocrit values of approximately 25 per cent and many fragmented red blood cells on blood film. Despite peritoneal dialysis and removal of necrotic placental tissue, she died on the 19th hospital day. The most prominent pathologic findings at autopsy were in the heart and kidney. The heart was enlarged with hypertrophy of the left ventricle and dilatation of all chambers. Foci of myocardial necrosis were seen microscopically. The kidneys were enlarged and pale with small petechial hemorrhages on the surface. The glomeruli contained organizing thrombi with some mesangial and endothelial hyperplasia. Some arterioles showed evidence of fibrinoid necrosis of the arteriolar wall, and the intrarenal artery showed varying degrees of intimal edema and hyperplasia. In some vessels subendothelial fibrin deposition, demonstrated by Putt’s modification of Lendrum’s fibrin stain [ 131, was prominent.
Case 2. A 21 year old white woman (A.P., YNHH No. 6705-85), gravida 1, para 1, was admitted to YNHH 3 months postpartum for evaluation of oliguria and renal failure. Her
antepartum course was not complicated by any signs of preeclampsia; her renal function remained normal; and a normal, full-term infant was delivered. She remained asymptomatic until the 3rd month postpartum, when she noticed weakness, anorexia and a decrease in her urine output. She was admitted to YNHH where physical examination showed a blood pressure of 160190 mm Hg, normal fundi and 1-t peripheral edema. Urine output was 200 cc/day. Laboratory data included a hematocrit of 23 per cent with fragmented red blood cells on peripheral blood smear, platelet count of 72,000/mm3, urinalysis with 3-fprotein and several red and white blood cells/hpf in the urinary sediment, serum creatinine of 18 mg/lOO ml and a negative lupus erythematosus preparation, antinuclear factor and Coombs’ test. Clotting studies showed a normal fibrinogen, prothrombin time and partial thromoplastin time. Weekly peritoneal dialyses were performed for the remainder of her hospital stay. Mild hypertension developed, but diastolic blood pressures were kept about 100 mm Hg with Aldomet@ therapy. The patient had several grand mal seizures which were controlled with diphenylhydantoin therapy. She died 2 months after admission. The immediate cause of death was unknown. Autopsy examination revealed vascular changes in the kidneys, brain and lungs. Most prominent was fibrinoid necrosis of the walls of the arterioles and small muscular arteries. Many of the vessels contained recent and organizing thrombi, but there was no significant leukocytic infiltration of the arteriolar wall. In the kidney, the glomeruli as well as the larger vessels were involved. Mesangial hyperplasia and occasional intracapillary thrombi were found. The arterioles showed the most striking lesions with marked fibrinoid necrosis (Figure 1).
Figure 1. Two representative glomeruli are shown. On the left there is thrombosis of the afferent arteriole and fibrinoid necrosis in the wall of the intralobular artery supplying that glomerulus (arrows). There is also mesangial hyperplasia of the glomerulus and endothelial swelling and proliferation of the artery. On the right is a glomerulus with segmental proliferation of the mesangium associated with thrombosis and fibrinoid necrosis of the supplying arteriole (arrows). Masson stain, original magnification X 250.
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Case 3. A 30 year old black woman
(F.B., YNHH No. A710-89) gravida 5, para 4, was admitted to YNHH 6 days postpartum for evaluation of headaches. None of her pregnancies were complicated by signs of toxemia. Her most recent pregnancy resulted in a normal, full-term infant. Six days postpartum, she experienced severe, bifrontal headaches and was admitted to YNHH. Physical examination showed a blood pressure of 220/i 10 mm Hg, normal fundi, no edema and 3+ deep tendon reflexes. Laboratory data included a hematocrit of 37 per cent with slight anisocytosis and poikilocytosis, and adequate platelets on peripheral smear, urine sediment with 10 to 20 red and white blood cells/hpf, 24 hour urine protein of 400 mg, and serum creatinine of 0.9 mg/lOO ml. On the day after admission, after her blood pressure fell to 140/90 mm Hg, she experrenced a grand mal seizure. She was treated with phenobarbital and magnesium sulfate, but these were withdrawn over the next 4 days. She had no more seizure activity and her diastolic pressures remained below 90 mm Hg. Three days after admission a renal biopsy was performed which demonstrated a generalized diffuse mesangial hyperplasia in the glomeruli. Putt’s modification of Lendrum’s fibrin stain did not reveal any evidence of acute fibrin thrombi within the capillaries. The arterioles showed no evidence of necrosis. Electron microscopy performed on the paraffin-embedded material sometime later revealed subendothelial fluffy granular deposits. No fibrin tactoids were seen however. Three days after the renal biopsy, the patient was discharged. No medication was prescribed. She remained asymptomatic during the next few months and had normal blood pressures and no proteinuria or hematuria. Serum creatinine remained below 1 mg/ 100 ml. Six months after the initial renal biopsy, a repeat biopsy was performed which disclosed significant resolution of the mesangial hyperplasia and widening. Many glomeruli appeared entirely normal at this time. A subsequent pregnancy 1 year later was not complicated by hypertension, seizures or renal functional abnormalities pre- or postpartum. Case
4. A 30 year old woman (A.D., YNHH No. 46-98174) with two previously uncomplicated pregnancies was admitted to YNHH in her 7th month of pregnancy. Her chief complaint was a 1 day history of severe headaches. Physical examination on admission revealed a blood pressure of 210/110 mm Hg, normal fundi, 1-F peripheral edema and 3-I reflexes. Laboratory data included a hematocrit of 35 per cent, a normal peripheral smear with adequate platelets, urine sediment with no cells, 24 hour urine protein of 600 mg, serum creatinine of 1.1 mg/lOO ml, serum glutamic oxaloacetic transaminase (SGOT) of 50 units, bilirubin of 0.8 mg and alkaline phosphatase of 99 IU. The patient responded well to treatment with magnesium sulfate, phenobarbital, Aldactonee and chlorothiazide with a return of her blood pressure to normal and disappearance of the headaches. She was discharged 6 days after admission on a regimen of chlorthiazide, 500 mg/
RENAL FAILURE-FINKEILSTEIN
ET AL.
day. She remained asymptomatic for 1 week when nausea and vomiting developed, and she was again admitted to YNHH. Physical examination revealed a blood pressure of 150190 mm Hg, normal fundi, no edema and 3+ reflexes. Laboratory data included a hematocrit of 40 per cent, normal peripheral smear and urinalysis with 2+ protein and no cells. Labor was induced on the following day with delivery of a premature, healthy infant. The blood pressure returned to normal immediately after delivery and remained in the normal range throughout the remainder of the patient’s hospital stay; no antihypertensive medications were given. On the second postpartum day, the patient’s temperature rose to 1Ol’F. Her clinical course and laboratory data indicated multisystem involvement and included mild renal insufficiency, a microangiopathic hemolytic anemia with thrombocytopenia, hepatic rupture and dermatologic changes suggestive of a vasculitis. Renal abnormalities were most striking on the second day postpartum. Serum creatinine was 2.1 mg/lOO ml, urine sediment showed numerous red and white blood cells/hpf, and a :24 hour urine collection contained 4 g of protein. The renal functional abnormalities began to resolve over the ensuing 3 weeks with the serum creatinine level falling to 1.4. mg/iOO ml, the urine sediment clearing, and the 24 hour protein falling to 1.7 g/day. Serum complement was normal; antinuclear factor was present in a titer of 1:4; lupus erythematosus preparations were negative. A brisk hemolysis developed postpartum; the hematocrit level fell to a low of 28 per cent 1 week postpartum with a marked reticulocytosis; there was no evidence of blood loss; and there were numerous fragmented red blood cells on the peripheral blood smear. The hematocrit level slowly rose over the following 3 weeks with a gradual fall in the reticulocyte count and disappearance of the ‘ragmented red blood cells. The platelet count also fell to a low of 44,000/mm3 1 week postpartum, remaining in that range for 2 l/2 weeks before rising to 100,000/mm3, 4 weeks after delivery. Prothrombin time, partial thromboplastin time, serum fibrinogen and factor 8 and 11 levels were all normal. The patient complained of pain in the right upper abdominal quadrant on the day after delivery. A diagnosis of rupture of the liver was made; liver function tests showed an SGOT of 1,420 units, alkaline phosphatase of 560 IU and a bilirubin of 1.2 mg. Liver scan demonstrated two large filling defects. The pain in the right upper quadrant subsided, and the abnormal liver function tests returned to normal over the ensuing 4 weeks. One and a half weeks postpartum, a macular rash appeared on the patient’s arms, neck, face and anterior portions of her chest, and small papules appeared on her palms and finger tips. These lesions gradually cleared over the next 2 weeks. Four weeks postpartum, the patient was discharged from the hospital on no medication with a normal temperature and a normal physical examination. Six weeks postpartum she was readmitted to YNHH for renal biopsy. At this time, physical examination was again normal. Laboratory data included a hematocrit of 33 per cent, platelet
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ET AL.
count of 90,000/mm3, serum creatinine of 1.5 mg/iOO ml, normal urine sediment, 24 hour urine protein of 2.4 g and normal liver function tests. The renal biopsy specimen showed a generalized diffuse mesangial widening which was due to both mesangial cellular hyperplasia and an increase in mesangial matrix. This change was prominent in a segmental pattern in some glomeruli. Ultrastructural examination revealed ischemit change of the glomeruli with some collapse in the capillary loops and some folding of the capillary wall as it approached the mesangium. There was an increase in the mesangial matrix, but no electron dense material was seen. In some peripheral capillary loops there was an irregular thickening of the basement membrane resulting from deposition of a granular subendothelial material. No fibrin or fibrin tactoids were seen (Figure 2). At follow-up 9 months postpartum the patient was asymptomatic, physical examination was within normal limits and laboratory data included a hematocrit of 35 per cent, platelet count of 120,000/mm3, normal red blood cell morphology, serum creatinine of 1.2 mg/ 100 ml and a 24 hour urine protein of 400 mg. COMMENTS Acute renal failure has been described
occurring in postpartum women as a new clinicopathologic syn-
drome with increasing frequency during the past 5 years [l-12]. The characteristic features of the illness are illustrated by our first case. In that case acute and severe renal insufficiency occurred shortly after delivery in association with a microangiopathic hemolytic anemia and thrombocytopenia. Irreversible renal failure persisted, and the patient died as a result of uremia. At autopsy the hallmark findings in the kidney included (1) organizing thrombi in glomerular capillary loops: (2) widening of the mesangium with moderate mesangial and endothelial cell hyperplasia; and (3) fibrinoid necrosis, edema and intimal hyperplasia of vessel walls. Of the 26 cases previously reported this sequence has been recorded at intervals of 1 day to 7 months postpartum. Although in our Cases 1 and 4 the patients demonstrated signs of toxemia during pregnancy, in 19 of the 26 reported cases gestation had apparently been uncomplicated. A microangiopathic hemolytic anemia has been a consistent finding in all cases, and thrombocytopenia occurred in 75 per cent of those in which platelet counts were listed. Systematic clotting studies have not been performed but have been reported as normal in the few cases examined. Although hyperten-
g segmental meiangial hyperplasia with an increase ification X 250. On the right an electron micrograph lary loops is seen. Some light granular material is present in a subendothelial location (arrow) and there is nonspecific focal thickening of the basement membrane. No fibrin or fibrin tactoids are seen.
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POSTPARTUM
sion has usually gressed, normal common
at onset.
been blood
present as the illness propressure values are most
Another
clinical
feature
of interest
has been fever which often could not be related to a septic process. Generalized seizures and congestive heart failure are also common clinical manifestations. In addition to these clinical features the renal histologic changes have shown striking similarity. Involvement of interlobular and afferent arteries have includgd foci of fibrinoid necrosis, occlusion with eosinophilic thrombi, intimal hyperplasia and subendothelial deposition of electron dense material. Microscopic examination has shown occluding thrombi in glomerular capillary loops, foci of necrosis and mesangial widening. An amorphous, granular electron dense material, thought to be fibrin, can usually be demonstrated in a subendothelial location on ultrastructural examination. By immunofluorescent staining a diffuse disposition of fibrin and a variable and less intense staining for BIC and IgG has been described [ $61. Although a systematic evaluation of other organs has not been reported, scattered arteriolar necrosis and occlusive thrombi have been demonstrated in the brain and heart. The important consequence of these changes in all previously reported cases has been irreversible renal damage. Sixteen patients have died of uremia, two were treated with chronic dialysis, one died in association with a rejected transplant, two were reported to have creatinine clearances of less than 7 ml/min and five have had a significant chronic reduction in function, although clearances greater than 40 ml/min persisted. The important finding in this series of patients was the complete restoration of renal function in two of the four cases. Each of our patients demonstrated the characteristic clinical features of this syndrome. Renal injury first occurred from the time of delivery to 3 months postpartum. In three of four cases, a hemolytic anemia with fragmented red blood cells and a severe thrombocytopenia was present. Although the renal histologic changes in the first two patients, who died of renal failure, were consistent with previously reported abnormalities, quantitatively less severe changes were present in the other two. However, in ultrastructural examination revealed these two, subendothelial granular deposits in peripheral capillary walls which were similar in appearance to those usually found in the typical severe cases. It seems likely, therefore, that the mild changes in renal function exhibited in our Cases 3 and 4 reflected the limited extent of the renal injury reaction. In the hemolytic-uremic syndrome of children, a disorder very similar to postpartum renal failure, a spectrum of changes has also been reported from mild to severe
irreversible
renal
failure
RENAL FAILURE-FINKELSTEIN
[ 141. It is perhaps
prising that the initial patients
ET AL.
not sur-
with this syndrome
who
were studied were the more severely affected. There is ample evidence to show the similarity between several closely linked clinical syndromes and experimental conditions to postpartum renal failure. These conditions include hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, eclampsia, the generalized Schwartzman reaction and experimentally-induced disseminated intravascular coagulation (DIC). In each condition fibrin deposition in arteriolar and glomerular capillary walls is considered to be the basic underlying pathogenic mechanism, a process termed thrombotic microangiopathy. Among the disease processes which occur in man the constellation of clinical features are used to distinguish the separate entities. Although the hemolytic-uremic syndrome occurs most commonly in children, cases in adults unrelated to the pregnant state have been reported [ 141. Both this condition and postpartum renal failure are characterized by a microangiopathic hemolytic anemia, thrombocytopenia and similar pathologic changes confined to the kidney. The distinguishing clinical feature in postpartum renal failure, therefore, is the closely linked association with pregnancy. In thrombotic thrombocytopenic purpura, fibrin deposition occurs in many organs, in addition to the kidney, and renal failure is uncommon [ 151. The pathologic changes in the kidney in toxemia of pregnancy are also thought to be secondary to fibrin deposition [ 161. Subendothelial electron-dense deposits, endothelial and mesangial cell swelling and an increase in mesangial matrix are the most striking histologic features [ 17-201. In a few recorded cases of severe eclampsia, renal changes have been strikingly similar to those seen in postpartum renal failure in association with a microangiopathic hemolytic anemia and thrombocytopenia [ 19,2 1,221. Clinically, however, toxemia is distinguished by severe hypertension, uncommon progression to irreversible renal failure and occurrence no later than 46 hours after delivery. The renal pathologic changes of these diseases have their experimental analogy in the generalized Schwartzman reaction and experimentally-induced DIC [23,24]. The relationship of pregnancy to the generalized Schwartzman reaction and the coagulation process is of special interest. Only one injection of endotoxin can produce a typical generalized Schwartzman reaction in pregnant animals whereas two properly spaced injections are required in nonpregnant subjects [25]. Placental extracts can in’duce fibrin deposition in small vessels and glomeruli when injected into animals [ 261. The relationship to the pathogenesis of postpartum renal f
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ever unclear. Retained placental fragments with release of placental tissue thromboplastin is a possible etiology, but in only one of the reported cases (our Case 2 ) was retained placental tissue noted. Therapeutically, anticoagulants would seem to be a logical mode of treatment. Anticoagulants have been shown to significantly modify the histologic changes in the generalized Schwartzman reaction [27]. Heparin has been suggested as a useful mode of treatment in the management of severe eclampsia with a microangiopathic hemolytic anemia [22], thrombotic thrombocytopenic purpura 1281 and hemolyfic-uremic syndrome [ 141. In five of the previously reported cases of postpartum renal failure in which there was some improvement in renal function, the patients were treated with heparin (in addition to steroids in two, and steroids and azathioprine in another). However, in four other cases of postpartum renal failure, the patients were treated with anti-
coagulants but no improvement was noted our Cases 3 and 4, the patients received ment and frank renal failure did not develop. In summary, hemolytic-uremic
the present data suggest syndrome, thrombotic
[9, lo]. In no treat-
that like the thrombocy-
topenic purpura and eclampsia, postpartum renal failure incorporates a spectrum of clinical expression from severe renal failure and death to mild, transient renal insufficiency with recovery of normal renal function. Although the pathogenesis of these different syndromes seems to involve intravascular coagulation and fibrin deposition, it is unclear whether these disease processes are separate nosologic entities or the varied manifestations of one disease. The absence of an inexorable, downhill course in some untreated patients with postpartum renal failure should be recalled in studies designed to test new therapeutic modalities.
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