Adult hemolytic-uremic syndrome

Kidney International, Vol. 18 (1980), pp. /25-134

NEPHROLOGY FORUM

Adult hemolytic-uremic syndrome Principal Discussant: LILIANE MOREL-MAROGER institut National de Ia Sante ci de la Recherche Médicale, and Hôpital Tenon, Paris, France

was unremarkable except for a grade IVVI systolic ejection murmur. His oral pharynx was clear. There was no rash, costovertebral angle tenderness, pitting edema, or lymphadenopathy. The laboratory findings revealed: serum sodium 139 mEq, potassium 7.5 mEq, chloride 101 mEq, and bicarbonate 19 mEq per liter. The BUN was 207 mg/dl, and the serum creatinine was 21.9 mg/dl. Urinalysis revealed a specific gravity of 1.010, pH 6, 2+ protein, and 2+ blood. Urine sediment contained 6 to 10 white blood cells, 6 to 10 red blood cells, and occasional tubular cells and coarse granular casts per high-power field. There were no cellular casts. The hematocrit was 20%; white blood cell count 12,300 mm3; and platelet count 384,000 mm3. The reticulocyte count was 17%. Examination of the peripheral blood smear re-

The Nephrologv Forum is designed to relate the principles of basic science to clinical problems in nephrology.

Editors JORDAN J. COHEN JOHN T. HARRINOTON JEROME P. KASSIRER

vealed 3+ anisocytosis, 2+ poikilocytosis, 2+ microcytes, 2+ macrocytes, 2+ schistocytes, and 1 + polychromatophilia. Pro-

New England Medical Center Hospital Boston, Massachusetts

thrombin time: patient, 11.5 sec; control, 11.0 sec. Partial thromboplastin time: patient, 29.0 sec; control 25.0 sec. A sugar-

water test was negative. Autohemolysis was less than 1%. Plasma haptoglobin was 10 mg/dl (normal 50-200 mg/dl). An anti-

Case Presentation

nuclear antibody test was negative. Glucose-6-phosphate dehy-

A 17-year-old male was transferred to the New England Medical Center Hospital (NEMCH) for evaluation of acute renal failure following a 5-day episode of nausea and vomiting. During a

trocardiogram was remarkable only for peaked T waves. A percutaneous femoral vein catheter was placed, and the patient underwent 21/2 hours of hemodialysis against a zero-potassium bath. He received 3 additional dialysis treatments over the next 4 days. The urine output exceeded 400 cc for the first time on the fifth hospital day and gradually increased thereafter. The BUN was 25 mg/dl and the serum creatinine was 1.7 mg/dl at discharge, approximately 3 weeks after admission. One month later, the patient was doing well clinically. Random urinalysis revealed no protein. The hematocrit was 28%, the reticulocyte count was 2.4%, and the BUN and serum creatinine were nor-

drogenase and pyruvate kinase tests were normal. The elec-

routine examination 3 months earlier, his blood pressure had been 98/64 mm Hg and laboratory findings included a hematocrit of 40% and a white blood cell count of 8700 mm3 with a normal differential. Urinalysis revealed a specific gravity of 1.010, pH

6.0, and no protein or glucose. The patient received a routine diphtheria-tetanus vaccination at that time. Two weeks prior to admission, he returned from a camping trip and complained of myalgias and a temperature of 102° F for 2 to 3 days. Five days prior to admission, nausea, vomiting, and diarrhea began. One day prior to admission, he noted "puffy cheeks" and "poor color," and he went to a local hospital. Laboratory findings there revealed serum sodium 142 mEq, chloride 103 mEq, potassium 7.8 niEq, and bicarbonate 17 mEq per liter. The blood urea nitrogen (BUN) was 190 mg/dl and the serum creatinine was 21.4 mg/ dl. Urinalysis revealed a specific gravity of 1.022, pH 5, 4+ protein, and 4+ blood. Urine sediment contained 7 to 10 white blood cells, 10 to 12 red blood cells, and 4 to 6 coarse granular casts per

mal.

Discussion

DR. LILIANE MOREL-MAROGER (Maître de Re-

cherche a l'Institut National de Ia Sante et de la Recherche Médicale, Service du Professeur Richet,

Hôpital Tenon, Paris, France): Although I am a morphologist being asked to arrive at a diagnosis

high-power field. The hematocrit was 20%; anisocytosis and poikilocytosis were noted on the peripheral smear. The platelet count was 134,000 mm3. The patient was treated with glucose and insulin and was immediately transferred. The past medical history disclosed significant congenital abnormalities, including an imperforate anus and a rectourethral fistula. A colostomy was surgically formed at age 5 days. At 1 year he had an abdominal peroneal "pull-through" operation resulting in nearly normal bowel control. Because of intermittent enuresis, he was treated with Tofranil® 50 mg orally each eve-

without a renal biopsy, I will guess from the history that this patient had some form of hemolytic-uremic

syndrome. He presented with all the features of Presentation of the Forum is made possible by grants from Smith Kline & French Laboratories, Hoechst-Roussel Pharmaceuticals Inc., CIBA Pharmaceutical Company, GEIGY Pharmaceuticals, and Boehringer Ingelheim Ltd. 0085-2538/80/0018-0125 $02.00

ning.

Physical examination on admission to NEMCH revealed a

pale alert male in no acute distress. His blood pressure was 148/ 80 mm Hg, pulse 67, respirations 19. The physical examination

© 1980 by the International Society of Nephrology 125

126

Nephrology Forum

acute renal failure and some of the findings of microangiopathic anemia. In the absence of a renal biopsy, however, it is difficult for me to be specific

tient did not have macroscopic hematuria, overt edema, or hypertension; thus, I do not believe that

patient in whom the cause of renal disease is not clear. The biopsy is done as soon as possible, provided no contraindications such as hypertension, a

he had acute postinfectious glomerulonephritis. This patient was free of any personal or familial renal antecedents, and we know that three months earlier he had had a normal urinalysis. The first sign of trouble occurred when he returned from a camping trip complaining of nausea, abdominal pain, diarrhea, and fever. Although no medical data were gathered at that time, we can entertain a few possibilities: he might have had a transient bacterial infection—perhaps with a Gram-negative organism— or he might have been bitten by an insect or an animal such as a dog [5]. Also, he might have suffered from the prodromic period known to occur in the hemolytic-uremic syndrome in many children [6].

single kidney, or a coagulation disorder are present. This policy has allowed us to recognize a variety of disorders affecting the kidney that otherwise might have gone undetected [1, 2]. When admitted to the New England Medical Center Hospital, this patient had severe acute renal failure that necessitated hemodialysis. As I mentioned,

broader consideration of this interesting condition. As Kaplan and Drummond have emphasized, it is likely that the hemolytic-uremic syndrome can occur in response to various causative factors [7]. The exact triggering mechanisms, however, are still unknown. In young children, in whom the condition

about the nature of this patient's disease; nevertheless, I will review briefly the clinical findings and

then consider the possible morphologic counterparts of his acute renal failure. In Dr. Gabriel Richet's group at Hôpital Tenon, the policy in the renal intensive care unit over the last 12 years apparently has been quite different from yours. As a rule, a renal biopsy is performed in any patient with acute renal failure that is not obviously due to classic tubular necrosis, that is, in any

he also had some features suggestive of microangiopathic anemia, namely schistocytosis and reticulocytosis. The reticulocyte count was 17%; this figure is well within the range we observed in a se-

ries of patients with the hemolytic-uremic syndrome, all of whom had more than iO reticulocytes per mm3 [3, 4]. In addition, burr cells and alow haptoglobin level were present. Thus, the clinical diagnosis of hemolytic-uremic syndrome can be strongly suspected despite some atypical features includ-

ing marked qualitative proteinuria and urinary casts. Although these findings can occur in any ohguric patient, and we have found them in adult patients with a variety of lesions including tubular necrosis [2], these features are relatively uncommon

in the hemolytic-uremic syndrome. Moreover, spontaneous recovery of renal function occurred very rapidly. This course is atypical of the hemolytic-uremic syndrome in adults; recovery usually requires several weeks. Although the platelet count was normal when the patient was discharged, the minimal hematologic abnormalities that did persist could be interpreted as evidence of an underlying microangiopathic anemia, perhaps related to a lesion of the renal arteries or arterioles. That he was not hypertensive does not entirely rule out this possibility [4]. The patient himself noted puffy cheeks, again an unusual manifestation of the hemolyticuremic syndrome in adults. Although this symptom might suggest an acute nephritic syndrome, the pa-

I would like to turn now from this patient to a

was first recognized, the hemolytic-uremic syndrome is a reasonably clear-cut clinicopathologic entity. In this age group, the syndrome is characterized by microangiopathic anemia and acute renal failure, either with anuria or with an acute nephritic

syndrome. The child usually experiences a pro-

dromic phase, as did the patient who is the subject

of this Forum; the prodrome is characterized by acute transient gastrointestinal symptoms, respiratory symptoms, or generalized malaise. On pathologic examination, the renal lesions as first described by Gasser suggest cortical necrosis [8]. Habib et al, however, have described a specific lesion,

which they have named thrombotic microangiopathy [9]. This lesion is characterized by a thickening of the capillary walls due both to the deposition of a fluffy, finely fibrillar material and to

a swelling of the endothelium. Sometimes these changes occur in association with mesangial thickening; in addition, aggregated platelets and damaged erythrocytes tend to be sequestered in the capillary lumina or in the subendothehial space. Various degrees of intimal and endothehial proliferation, as well as arteriolar thrombosis can be present, especially in older children. Several subsequent reports of the pathology of this condition have appeared [3, 4, 10-14].

In adults, the hemolytic-uremic syndrome is a much more heterogeneous condition. The clinical syndrome can occur under various circumstances,

Adult heinolytic-uremic syndrome

many of which are listed in Table 1 [4, 15—33]. Between 1969 and 1977 we observed at the Hôpital Te-

127

thickened appearance [35], fibrillar widening of

non 31 adult patients with the hemolytic-uremic syndrome. Our experience with these patients clearly shows that an early renal biopsy in hemo-

mesangial areas, intact or fragmented erythrocytes in the capillary lumina, glomerular thrombosis, and diffuse glomerular congestion. This combination of lesions, when severe, markedly reduced the caliber

lytic-uremic syndrome can provide useful informa-

of the capillary lumina and frequently occluded them. The second principal lesion consisted of is-

tion. All of the 31 patients were hospitalized for acute renal failure and hemolytic anemia of the microangiopathic type" [34]. The presumptive diagnosis of hemolytic anemia was made when the hema-

tocrit rapidly fell below 30% in the absence of bleeding and the reticulocyte count was found to be greater than l0 per mm3. The diagnosis was further

strengthened by the finding of a low serum haptoglobin level in all patients in whom it was measured. Fragmented red cells were present in blood smears of most patients in whom they were sought.

Fourteen patients had ocular lesions consisting of soft exudates; one had an inflammatory retinal de-

tachment. Purpura occurred in only 3 patients. Causative factors possibly responsible for the hemolytic-uremic syndrome were present in 21 of the 31 patients: previous hypertension existed in 9, multiple systemic sclerosis in 4, pregnancy in 3, acute promyelocytic leukemia in one, and pulmonary hypertension in one; 2 used oral contraceptive pills. Elapsed time between onset of the clinical syndrome and the diagnosis by renal histology varied from 4 days to 3 months. On the initial biopsy samples, all 31 patients had

glomerular lesions; 28 patients also had conspicuous arterial and arteriolar lesions. The gbmerular lesions fell into two categories: The first were identical to the thrombotic microangiopathy described in young children with this syndrome, namely, clear fluffy subendothelial deposits, swelling of the endothelium giving the capillary wall a Table 1. Presumed causative or associated factors in the adult hemolytic-uremic syndrome

Viruses Shigellosis Lipopolysaccharides and septicemias Microtatobiotes

chemic gbomeruli, with thickening and wrinkling of the glomerular basement membrane, atrophy of the glomerular tuft with disappearance of most nuclei and partial loss of structure, and thickening of Bowman's capsule [36]. In 5 patients, thrombotic micro-

angiopathy was present alone, whereas both the thrombotic microangiopathy and the ischemic lesions were present in all the others. The proportion of both types of lesions varied widely from one patient to the next. On immunofluorescent examination, no immunoglobulins except traces of 1gM were detected in the gbomeruli. Both 1gM and C3 were found in most arterial walls, but this finding does not appear to be

significant. Sizable amounts of fibrinogen were found in the subendothelial glomerular deposits and

the glomerular thrombi, but stains for fibrin were consistently negative by light microscopy. Arteriolar thrombi also contained fibrinogen, which was present in the media and sometimes in the thickened intima of a few medium-sized arteries. Some investigators [37] have reported finding more immunogbobulins than we did, but the difference probably relates to the stage of the lesions. in a recent study of 20 adults with the hemolyticuremic syndrome, we focused on renal biopsies ob-

tained during the first 30 days after the onset of acute renal failure [4]. We found that the severity of the glomerular, tubular, and interstitial lesions did

not differ between the 4 patients who recovered good renal function and those who did not. Vascular lesions, however, especially those that could be attributed to intravascular coagulation, were less severe in patients who recovered. This finding suggests that changes in small intrarenal arteries are responsible for the irreversible renal damage (often leading to cortical necrosis) that occasionally occurs in the hemolytic-uremic syndrome. Recent studies suggest that the hemolytic-uremic syndrome in adults might be triggered by an intra-

Dog bite Snake bite Drugs (phenylbutazone) Contraceptive pills Pregnancy Radiation

vascular coagulation that can become superim-

Transplantation Scieroderma Renal vascular lesions and/or hypertension Red cell membrane phospholipid alterations Platelet lesions Addison's disease

posed on various underlying anomalies (Fig. 1). The precise pathogenesis of the hemolytic-uremic syndrome is still unknown, but it is likely to result from any event giving rise to intraglomerular coagulation

[38-42]. This assumption is strengthened by the

128

Nephro/ogy Forum Intravascular coagulation

7-

Glomerular endothelial lesions

Arterial lesions

Thrombotic microangiopathy

Accelerated nephrosclerosis

Fig. 1. Proposed pat hogenesisfrr the renal lesions characteristic

of hemolytic-uremic syndrome in adults.

multiple circumstances in which this clinical and/or histologic syndrome has been reported (see Table 1) and in which the only common denominator is the presence of some factor inducing intravascular coagulation. Unfortunately, no animal model for the

hemolytic-uremic syndrome exists, probably because no experimental condition has been devised for producing the kind of glomerular endothelial damage required for intravascular coagulation at this site 138, 41].

Evidence for the importance of intravascular coagulation in the hemolytic-uremic syndrome is pro-

vided by the combination of microangiopathic anemia [34, 39], thrombocytopenia, and the presence of fibrinogen in the glomeruli. These findings have prompted numerous therapeutic attempts using heparin or other anticoagulant drugs [42-48]. Although all of the triggering causes of the hemolyticuremic syndrome have not been identified, it is now known that multiple factors exist: (1) Some patients appear to have a defect of a plasma factor. Upshaw described a patient who suffered from several acute episodes of microangiopathic anemia that were re-

versed by administration of normal plasma [49]. This plasma defect was attributed by Remuzzi et al to the lack of a prostacyclin inhibitor [50]. They successfully treated patients who had the hemolytic-uremic syndrome with fresh plasma infusion. Whether these plasma "deficiencies" are acquired or congenital is unknown [51], but this mechanism could explain instances in which the syndrome is familial [52]. (2) Anomalies of circulating blood cells also might have a causative role in some instances. Blatter et al reported an abnormally high percentage of megathrombocytes in three siblings with the he-

molytic-uremic syndrome [53]. In a personal communication, Drummond has suggested that a modification of the red cell membrane could trigger the hemolysis. (3) Intravascular coagulation also might be induced by immunologic factors, perhaps mediated by immune complexes that have been found in some patients with the hemolytic-uremic syndrome [54]. A role for immune mechanisms in the hemo-

lytic-uremic syndrome is further supported by the presence of low levels of complement or of C3-splitting activity in several patients [54—57]. In some of these individuals, evidence for complement activation persisted after bilateral nephrectomy and transplantation; these findings led Kourilsky et alto postulate that some patients with the hemolytic-uremic syndrome have a primary abnormality of their complement system [58]. This defect and possibly oth-

ers also could explain the occurrence of the syndrome in families [52] as well as account for some epidemic forms in which a subtle 'immune deficiency" renders the individuals more susceptible to the syndrome [59, 60]. (4) It is now established that the hemolytic-uremic syndrome can be superim-

posed on underlying renal disease; examples include the hemolytic-uremic syndrome occurring in patients with scieroderma [61, 62] or primary gbmerular disease [63]. Whatever the exact mechanism triggering intraglomerular coagulation, a defect probably exists in the local fibrinolytic mechanism of the glomeruli. Experimental observations in rats indicate that infusion of thrombin leads to extensive accumulation of fibrinogen thrombi in the gbomeruli, but these thrombi are cleared from the glomeruli in one hour [64, 65].

Some investigators have advocated the use of heparin in the hemolytic-uremic syndrome, especially if the lesions on renal biopsy appear fresh and inflammatory and if the glomeruli are filled with fibrinogen-related antigens [42-47]. The beneficial effects of heparin, however, have not been confirmed

[48]. It is difficult to establish the efficacy of any treatment in the absence of controlled trials when the natural history of the disease in question is undefined [4, 6, 7, 23]. Some patients described in the literature and some in our series have seemed responsive to heparin therapy, but we cannot say that they would not have recovered spontaneously. In the patient we are discussing today, the renal recovery was clearly spontaneous. The long-term outlook of patients with the hemolytic-uremic syndrome, even after apparent recovery, is also in doubt. In our series, some patients developed hypertension and severe ocular damage after the hemolytic-uremic syndrome; this complication suggests that vascular damage might be asymptomatic initially and then progress to cause secondary hypertension. In my view, the most important point illustrated by the patient who was presented today is the usefulness of a renal biopsy. This patient had no contraindication to renal biopsy; the platelet count was above 100,000 mm3 and he was not hypertensive. Is

Adult hemoiytic-ureinic syndrome

an early biopsy warranted in "atypical acute renal failure"? My answer would be an unequivocal yes. An early renal biopsy is probably the only way to establish a definite diagnosis rapidly. It is true that from the clinical history of this patient, we probably can exclude a minor form of acute glomerulonephritis because he did not have findings typical of the nephritic syndrome. It is quite possible, however, that both his acute renal failure and his hemolytic anemia were independent manifestations of some

other process and that morphologic examination would have revealed nothing more than acute tubular necrosis. Dr. Kanfer in our group has observed three patients with tubular necrosis immediately af-

ter childbirth; these patients all had anemia with schistocytosis and they were anuric [66]. In addi-

tion to clarifying the diagnosis, an early renal

129

!'I.N.S.E.R.M., Unite 192 de Nephrologie Pediatrique, Hópital Necker —Enfants-Malades, Paris): Thank you. I would like to comment on Dr. MorelMaroger's hypothesis that intravascular coagulation is the primary event in the hemolytic-uremic syndrome. Evidence strongly suggests that this disease is not a form of disseminated intravascular coagu-

lation [6]. Local intravascular coagulation does occur, but I believe it is a secondary phenomenon. My hypothesis is that the primary event, a lesion of the endothelial cell layer, predominates in the arteries and arterioles in some instances and in the glomerular capillaries in others. DR. JOHN T. HARRLNGTON: Can one produce he-

molytic-uremic syndrome in an experimental animal by inducing intravascular coagulation? DR. MOREL-MAROGER: There is no valid experi-

mental model for the hemolytic-uremic syndrome.

biopsy often can provide important prognostic information; the experience in Dr. Richet's department is that prognosis differs considerably in patients with purely tubular renal lesions from that in patients with microangiopathy. Alternatively, a renal biopsy in this patient might have shown thrombotic microangiopathy. As I mentioned earlier, the rapidity with which his renal function recovered is

thrombi are produced in the rat, they are removed rapidly by local fibrinolytic activity [65]. Efforts to produce a model in rabbits have only succeeded in creating renal cortical necrosis [38].

surprising, as is the persistence of minor hematologic abnormalities. Nevertheless, if thrombotic microangiopathy had been found, some idea of the prognosis could have been gleaned from the presence or absence of the severe arteriolar changes I have described. To conclude, I propose two alternative morpho-

Massachusetts General Hospital, Boston): The

logic possibilities: acute tubular necrosis with a coincidental hematologic disorder, or thrombotic microangiopathy with mild arterial lesions. If the first hypothesis is true, this patient's renal lesion is

healed. If the second obtains, hemolytic-uremic syndrome might recur; we have observed this phenomenon in two patients and another has been described in the literature [67]. Finally, this patient should be monitored carefully both for recurrence of the syndrome and for the possible development of hypertension. Questions and Answers

DR. JORDAN J. COHEN: We are fortunate to have

Dr. Renée Habib with us today. Dr. Habib, you have contributed much to our understanding of the hemolytic-uremic syndrome, as acknowledged by Dr. Morel-Maroger in her numerous references to your work. I hope you will feel free to participate in the discussion. DR. RENÉE HABIB (Directeur de Recherche a

As I mentioned earlier, when intraglomerular

DR. COHEN: Dr. Herrin, first would you comment

on your experience with the hemolytic-uremic syndrome in children? Second, how do you treat these patients? DR. JOHN HERRIN (Chief, Pediatric Nephroiogy,

clinical spectrum of hemolytic-uremic syndrome is wider in the pediatric age group than in adults. In addition, in childhood there is usually a more clearcut prodrome, which often suggests a viral illness but sometimes indicates one that is bacterial in origin. Pathologic findings in the hemolytic-uremic syndrome are not necessarily confined to the blood and kidney; close review, especially of older children, reveals a more generalized syndrome, with gastrointestinal involvement often quite prominent. Perforations of the gastrointestinal tract can occur. Furthermore, considerable variation in clinical features can occur at different times, even at the same hospital. Over the past 8 years, we have treated approximately 20 children with the hemolytic-uremic syndrome; the clinical picture seems to vary from

year to year, ranging from relatively mild in one year to very severe in another. The efficacy of therapeutic modalities is difficult to assess in this heterogeneous disorder because it has such a variable natural history. Assessment is particularly difficult because aggressive supportive

treatment alone, when undertaken in the active phase of the illness, reduces the mortality rate dra-

130

Nephrolog)' Foru,n

matically [68, 69]. Thus, claims for the efficacy of heparin, streptokinase, acetylsalicylic acid, dipyridamole, and other compounds must be compared with the results of supportive care alone. Currently, 90% to 95% of children with hemolytic-uremic syndrome survive with conservative therapy without anticoagulants [70]. Our most pressing concern is to find methods for identifying in advance the 5% to

10% of patients in whom spontaneous recovery does not follow control of fluid and electrolyte balance and peritoneal dialysis; it is this group in which experimental treatments need to be evaluated. DR. HABIB: I agree that we see a wider clinical

spectrum in very young children than we do in adults. In adults the disease is almost always severe, whereas babies exhibit a mild form of the disease and have an excellent prognosis. In our experience, the dividing line is about 2 years of age; the

disease in older children behaves very much like that in adults. But the real difference in presentation is not related to age; it is related to the type of renal

involvement. In the near future we will publish a study conducted over the last 10 years of 70 children. In the 52 patients in whom we were able to obtain kidney specimens, we found 10 patients with cortical necrosis, 29 with the characteristic features of glomerular thrombotic microangiopathy, and 13 with predominant arterial involvement and ischemic glomerular changes. Most of the adult cases that

have been reported belong to the last category. In fact, 10 of the 15 children over 2 years of age in our series had predominant arterial involvement, and 9 of them developed severe hypertension that neces-

sitated bilateral nephrectomy. Another big difference in the syndrome between children and adults is that it is often manifested as a secondary disorder in adults. In most children, the hemolyticuremic syndrome is primary. DR. MANUEL MARTLNEZ-MALDONADO (Director

of Medical Services, San Juan VA Hospital, San Juan, Puerto Rico): Is it possible that the primary disorder is an affliction of the platelets? Let us assume, for example, that a virus infects the platelets and leads to release of prostacyclin, which in turn stimulates the glomeruli to synthesize thromboxane. Couldn't that stimulation cause the endothelial

lesion and explain all the pathologic and clinical manifestations of the disease? DR. MOREL-MAROGER: I believe that the hemolytic-uremic syndrome is a heterogeneous condition and that a single causative factor is not likely. Primary platelet anomalies have been described in microangiopathic anemia, but I am not aware of any patients with hemolytic-uremic syndrome in whom

the renal lesion was clearly caused by a platelet disorder. Many diseases in which thrombotic microangiopathy is not present exhibit platelet activation. Also I know of no satisfactory explanation for the accumulation of fibrin in the glomeruli. As I mentioned, if one induces intraglomerular coagulation

experimentally, as Dr. J. D. Sraer did in Hôpital Tenon [65], the local fibrinolytic activity of the glomeruli removes capillary thrombi within one hour.

DR. KENNETH SHAPIRO (Renal Fellow, NEMCH): Do you believe prostaglandins play any role in the pathogenesis of this disorder? DR. MOREL-MAROGER: The situation is so com-

plicated that it is difficult to know. The only information relevant to your question is that of Remuzzi

et al, who suggested that hemolytic-uremic syndrome is related to the absence of a plasma factor that normally stimulates prostaglandin production [50]. DR. JEROME P. KASSIRER: Given the clinical pre-

sentation of this patient and his remarkable response to supportive therapy alone, what do you think the biopsy might have shown? DR. MOREL-MAROGER: The clinical presentation

and the rapid recovery do not allow a precise classification of this patient; of the two possibilities I sug-

gested, acute tubular necrosis would be the more likely diagnosis; thrombotic microangiopathy would be my second guess.

DR. HABIB: This question reminds me of the good old days" and how we used to discuss patients who had the nephrotic syndrome. We all know that lipoid nephrosis is the most frequent cause of nephrotic syndrome in children, but we now know that several glomerular diseases can mimic lipoid nephrosis. The situation with hemolytic-uremic syndrome is analogous. Even though thrombotic microangiopathy —either with predominant glomerular involvement or with predominant arterial involvement—is the most frequent cause of the hemolytic-uremic syndrome, other conditions can mimic it. I know of many patients who appeared to have hemolytic-uremic syndrome clinically but who, at biopsy, did not show lesions consistent with either glomerular or vascu-

lar thrombotic microangiopathy. Most of the patients recovered very rapidly. The problem is even more complicated in adults because of the high incidence of secondary hemolytic-uremic syndrome. DR. KASSIRER: You alluded to the risk of renal biopsy in patients with this condition. Can you elaborate on those risks in your series?

DR. MOREL-MAROGER: In our series of 20

Adult hernolytic-uremic syndrome

biopsies, 4 were complicated by retroperitoneal hematomas [4]. Thus, the risk associated with biopsy

in patients with the hemolytic-uremic syndrome might be higher than in other groups of patients — those with nephrotic syndrome, for example. In the absence of a coagulation disorder or hypertension, however, I think the risk of biopsy is worth taking. DR. COHEN: Dr. Habib, what do you regard as

the indications for renal biopsy in children and adults suspected of having hemolytic-uremic syndrome? Does the biopsy provide therapeutic guidance or is it useful simply for estimating the prognosis? DR. HABIB: I consider renal biopsy useful for estimating the prognosis. The procedure not only allows one to distinguish among the three pathologic patterns observed, that is, cortical necrosis, thrombotic microangiopathy with predominant glomeru-

lar involvement, and thrombotic microangiopathy with predominant vascular involvement, but in the glomerular form of the disease, renal biopsy also can provide an estimate of the percentage of glomeruli affected. In our experience, most of the patients who eventually developed residual renal functional impairment had more than 50% of their glomeruli affected on the initial biopsy. From a study per-

formed in our laboratory, we know that the gbmerular damage is irreversible; in subsequent biopsies performed one year after onset of the syndrome, the percentage of sclerotic glomeruli corre-

sponded exactly to the percentage of affected gbomeruli observed on the initial biopsy [71]. Be-

cause we are dealing with a syndrome, a renal biopsy also might be helpful in establishing the correct diagnosis. The patient presented today well illustrates the problems raised in differential diagnosis when a renal biopsy has not been performed. DR. JOHN DONOHOE (Consultant Nephrologist,

Mater Misericordiae Hospital, Dublin, Ireland): Would you comment on the possible efficacy of converting enzyme inhibitor in the treatment of this condition? It is claimed that converting enzyme in-

131

considerable renal function with treatment [61, 62].

Although no studies have been reported of serial biopsies documenting the disappearance of arterial proliferation, this is probably what happens at the local level. Serum from patients with scieroderma recently has been shown to contain a factor that is toxic for endothelial cells [72]. I am not aware of an attempt to use converting enzyme inhibitor in the treatment of hemolytic-uremic syndrome unrelated to scieroderma, but it would be an interesting study, especially in adults with extensive vascular lesions. DR. BRUCE CHAN (Renal Division, Rhode Island

Hospital, Providence, Rhode Island): Would you add acute albograft rejection to the list of causes of adult hemolytic-uremic syndrome? If so, it is interesting to note that heparin therapy in the treatment

of allograft rejection has been pretty much abandoned. DR. MOREL-MAROGER: Yes, I would include re-

jection—at least from the morphologic point of view—as a cause of thrombotic microangiopathy in

adults. I agree that heparin is useless in such circumstances but I cannot imagine that any therapy would have been valuable in the few patients I have

seen. These were individuals in whom the most prominent feature was the combination of arterial lesions—very much like those of scieroderma—and ischemic glomeruli, with a few loops enlarged by fibrillar deposits. These lesions were not reversible. DR. KASSIRER: Dr. Habib, do you think heparin has any value in the treatment of the hemolytic-uremic syndrome? DR. HABIB: Our data and those of others [46] suggest that it has no value in children. We found in a retrospective study that the recovery rate was even higher in the nontreated group as compared to the treated group (Table 2). These results do not mean

much, however, because of the wide spectrum of renal involvement observed. Moreover, it is likely that we tended to treat those patients who were more severely affected. There are no controlled

hibitor is very helpful in so-called scleroderma

studies but even if such a study were done, I think it would be very difficult to interpret.

crisis, in which the vascular lesions are like those that you described in the hemolytic-uremic syndrome.

scribed in patients with hemolytic-uremic syndrome are reminiscent of some of the lesions occurring in

DR. MOREL-MAROGER: Let me first comment on

the renal lesions in scleroderma. The glomerular le-

sions are exclusively ischemic. The presence of

DR. COHEN: The pathologic lesions you de-

thrombotic thrombocytopenic purpura. Do you think any relationship exists between these two conditions? DR. HABIB: The hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura have three

fibrinogen in the glomeruli does, of course, support the suggestion that local coagulation occurs, but I do not believe that these glomerular lesions are ever

common features: microangiopathic hemolytic

of the thrombotic microangiopathic type. I admit that some patients with scieroderma crisis recover

bosis. We arbitrarily make a diagnosis of hemolytic-

anemia, thrombocytopenia, and arteriolar throm-

Nephrology Forum

132

Table 2. Primary hemolytic-uremic syndrome

No treatment Outcome

Infants

BP1 GFR1'Oj,

GFR+BP1' ESRFC+BPI

Children

Infants

N=5

N= 35

13

2

2

0

1 1

1

N= 20 Recovery Proteinuria

Heparin 0

0

Children

Total

N= 10

N=70

21

2

38

2 3 4

0

4

0

1

1

3

1

4

0 0 0 8

5

5 2 16

BP denotes blood pressure

b GFR denotes glomerular filtration rate

ESRF denotes end-stage renal failure

uremic syndrome when renal manifestations predominate; in a small percentage, central nervous system involvement is also evident. Conversely, we

diagnose thrombotic thrombocytopenic purpura when CNS involvement predominates; renal disease in these instances is mild or absent. Since we do not know the cause of either condition, two possible explanations could account for the observed overlap: (1) hemolytic-uremic syndrome and throm-

botic thrombocytopenic purpura could represent variants of the same disease process, differing only in localization of the arteriolar changes or, (2) hemolytic-uremic syndrome and thrombotic thrombo-

cytopenic purpura could be two completely different diseases that coincidentally have three com-

mon features, two of which (microangiopathic hemolytic anemia and thrombocytopenia) are likely the consequence of the third one, arteriolar thrombosis. Acknowledgments

The editors wish to thank Dr. Barrie Paster of Amesbury, Massachusetts for having referred the

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