Epidemic hemolytic-uremic syndrome in children

Kidney International, VoL 52 (1997), pp. 1708—1 719

NEPHROLOGY FORUM

Epidemic hemolytic-uremic syndrome in children Principal discussant: Hoicio A. REPETITO Hospital Nacional Prof A. Posadas, and University of Buenos Aires School of Medicine, Buenos Aires, Argentina

140 mEq/liter; potassium, 5.2 mEq/liter; chloride, 108 mEq/liter; bicarbonate, 13.6 mEq/liter; and platelet count, less than 50,000/mm3. The peripheral blood smear showed many fragmented erythrocytes. Acute

Editors JORDAN J. COHEN JOHN T. HARR!NGTON

HUS was diagnosed. Reserpine was given intramuscularly, and peritoneal

NIcoIAos E. M.rIAs

mg/dl. Anuria persisted for eight days, during which he was dialyzed five times. He was discharged after three weeks with a blood urea of 105 mg/dl. A low-protein diet and salt restriction were prescribed, as was alphamethyldopa for his hypertension. One month after admission, his blood pressure was under control; his urea was 82 mg/dl, and his serum creatinine, 1.4 mgldl. He was followed at our hospital for six months and returned to his home province with controlled blood pressure; urea, 41 mg/dl; and serum creatinine, 1.1 mg/dl. He returned for a checkup at 5 years, 11 months of age, about five years after the acute illness. He was normotensive without medication; the urea was 36 mg/dl and the serum creatinine, 0.8 mg/dl. His

dialysis was initiated on the second day, when his blood urea was 210

Managing Editor CHERYL J. ZUSMAN

Tufts University School of Medicine

CASE PRESENTATIONS Patient 1. An 18-month-old girl presented with paleness and oliguria preceded by non-bloody diarrhea that had started five days previously. On admission, her blood pressure was 120/85 mm Hg (90th percentile, 105/68 mm Hg) and she was anuric. Her blood urea concentration was 168 mg/dl

and hematocrit 22%; a blood smear contained numerous fragmented erythrocytes. Her serum electrolytes were: sodium, 132 mEq/liter; potassium, 5.8 mEq/liter; chloride, 102 mEq/liter; and bicarbonate, 15.2 mEqI liter. A diagnosis of the acute hemolytic-uremic syndrome (HUS) was made. She received one packed red blood cell transfusion. After three days of anuria and with her blood urea level reaching 285 mgldl, peritoneal

dialysis was started. Her anuria persisted for five days and she was discharged after two weeks, normotensive with a blood urea of 68 mg/dl and a serum creatinine of 0.85 mgldl. On followup she remained normotensive; her urea was 19 mg/dl one month after the beginning of the acute disease. Her serum creatinine concentration was normal (0.6 mg/dl) at one

year followup, but she still had proteinuria of 100 mg/dl in the first morning sample. Subsequent measurements revealed decreased proteinuria, which became intermittent after four years and has remained absent since the eighth year of followup. Her last evaluation, 13 years after the acute illness, revealed a normal adolescent girl, with normal growth and

development; a blood pressure of 110/65 mm Hg; serum creatinine concentration, 0.8 mg/dl; and a normal urinalysis. Patient 2. A 7-month-old boy was admitted to the hospital because of generalized convulsions. Diarrhea and pallor had been present for three days. He had been anuric for the previous 11 hours. Despite administration of intravenous phenobarbital, the baby continued to have intermittent hypertonia, alternating with hypotonia. He appeared normohydrated, and his blood pressure was 160/80 mm Hg (90th percentile, 105/67 mm Hg). His blood chemistries showed: hematocrit, 26%; urea, 140 mg/dl; sodium,

The Nephrology Forum is funded in part by grants from Novartis Argentina, S.A.; Amgen, Incorporated; Merck & Co., Incorporated;

urine contained minimal protein. Followup measurements at his home showed persistent subnephrotic proteinuria but normal serum creatinine levels until 12 years after the acute HUS, when his serum creatinine rose to 1.2 mg/dl. The serum creatinine level slowly increased thereafter (Fig. 1). He became hypertensive 14 years after the acute HUS and returned at

16 years of age in end-stage renal failure, entering our program of hemodialysis and transplantation. Patient 3. A 17-month-old girl was admitted to the hospital because of diarrhea over five days with bloody striae over the last two days. She was pale and irritable. Her blood pressure was 127/82 mm Hg (90th percentile, 105/69 mm Hg). She had been anuric for two weeks. Her blood chemistries on admission were: hematocrit, 18%; urea, 95 mg/dl; serum creatinine, 3.6 mg/dl; sodium, 132 mEq/liter; potassium, 5.8 mEq/liter; chloride, 104 mEq/liter; bicarbonate, 15 mEqlliter; and platelet count, 86,000/mm3. The peripheral blood smear showed anisocytosis, poikilocytosis, and fragmented red cells. The diagnosis of acute HUS was made. The patient was given a packed erythrocyte transfusion, an antihypertensive medication, and she was dialyzed via the peritoneal route. She

began to urinate two weeks later, although she remained oliguric for another week. The child was followed as an outpatient, and she required propranolol to keep her blood pressure under control. She had persistent proteinuria, and her blood urea concentration remained between 80 mg/dl and 100 mgldl even with protein restriction. Her serum creatinine level remained elevated and increased slowly until 2 years and 9 months after the acute episode (Fig. 2). When she was 4 years, 4 months old, she received her mother's kidney. Immunosuppressive medication consisted of prednisone and azathioprine; she had no acute rejection. One month post transplantation, her blood pressure was 120/75 mm Hg while she was receiving propranolol, her serum creatinine was 0.4 mgldl, and her blood urea was 19 mg/dl. Five months after transplantation, her antihypertensive medication was withdrawn. She remained in good health, growing adequately and leading a normal life. At last followup, 12 years and 10 months after transplantation, this 17-year-old girl's height is 151 cm and her blood pressure is 120/75 mm Hg without antihypertensive medication. Her serum creatinine level is 0.92 mg/dl, with an estimated creatinine clearance of 90 ml/min/1.73 m2.

Marion Merrell Dow, Incorporated; Dialysis Clinic, Incorporated; and R & D Laboratories, Incorporated.

DISCUSSION

© 1997 by the International Society of Nephrology

Nacional Prof A. Posadas, Professor of Pediatrics, University Bs.As.

DR. Hoicio A. REPETrO (Chief Service of Pediatrics, Hospital

1708

1709

Nephrolo Fonsm: HUS in children Table 1. Pathogenesis of HUS

2.0

Associoted with infection Bacterial cytotoxin (E. coli, Shigella, Salmonella)

Hypertension

1.5 C) Cl)

HD

1.0

0.5

Associated with systemic conditions

0.2

0

1 2 3 4 5 6 11 12 13 14 15 16

Time, years after acute stage Fig. 1. Patient Two. Evolution of serum creatinine.

Exposure to toxins Cyclosporine Mitomycin

Radiation

infection does not have diarrhea at presentation and may be

1.5 C)

Cancer Pregnancy Malignant hypertension Transplant rejection Glomerulonephritis

different endothelial functions that protect the microvasculature from thrombosis is the generally accepted hypothesis for the latter [6]. The definition generally used for its diagnosis requires the absence of gastrointestinal symptoms in the prodromic phase [7]. As we will see when I speak of epidemiology, a small group of children with evidence of verotoxin-producing E. coli (VTEC)

2.0

Cl)

Pneumococcal neuraminidasc Viral idiopathic or "atypical" Sporadic Recurrent Hereditary

1.0 0.5

0.2 0

1

2

3

Time, years after acute stage Fig. 2. Patient Three. Evolution of serum creatinine.

erroneously classified as "atypical." One subgroup encompasses children who suffer one or more recurrences [8]. These children have a higher incidence of affected siblings, a high mortality rate, and a high chance of recurrence in the transplanted kidney [9]. In some of these patients, hypocomplementemia characterized the recurrence [10, 11]. Finally, an extensive analysis of the familial forms can be found in a chapter by Kaplan [12]. Some of these children have the HUS associated with verotoxin due to home

contact. Others have hereditary forms; in these cases disease recurrence, hypocomplementemia, or recurrence in the renal graft is common, and they are included within the idiopathic HUS. For the purposes of this Forum, I will limit our discussion to the classic epidemic form.

When I was a resident in pediatrics in Argentina at the Medical School, Buenos Aires, Argentina): The hemolytic-uremic beginning of the 1960s, we interpreted the clinical picture in these syndrome was first described by Gasser et al more than 40 years infants as due to sepsis of gastrointestinal origin. We believed the ago [I]. Since then, several studies have established the multisys- anemia and thrombocytopenia to be part of the disseminated temic character of the thrombotic microangiopathy that consti- intravascular coagulation and the renal insufficiency to be due to tutes the basic anatomic lesion of HUS [2—4]. In 1978, Kaplan and acute tubular necrosis. The syndrome had been described in 1955

Drummond emphasized the different clinical entities that can present as this syndrome [5]: idiopathic sporadic or epidemic forms, syndromes occurring post pregnancy or oral contraceptive

use, a lesion associated with infection, a familial or hereditary syndrome, and post-renal-transplantation HUS. With our current knowledge, I believe that these entities can be classified as (1) HUS associated with infections, including the "classic" epidemic (enteropathic) form with its high prevalence in children; (2) idiopathic HUS, which can be hereditary or sporadic, and probably is related to primary endothelial dysfunction; (3) HUS associated with systemic diseases or other precipitating factors; (4) and HUS resulting from exposure to toxins (drugs or radiation) (Table 1). In children, the epidemic form can be difficult to differentiate from the "atypical" or idiopathic form. An intrinsic defect in the

in a Swiss journal [1], but not until 1962 was the Argentine experience with HUS presented in a paper on acute renal failure (ARF) [13]. Gianantonio, to whom we are paying homage in this Forum, and his coworkers from the Children's Hospital of Buenos

Aires, published the first complete description of the clinical features and evolution of the syndrome in more than 50 children with HUS two years later [14]. As knowledge accumulated about

the different nosologic entities presenting as HUS and the epidemiologic characteristics of the syndrome, we became aware that in our country, diarrhea accompanied the other symptoms in at least 90% of affected children. In 1981, we reviewed 95 children

with HUS; gastrointestinal symptoms in the prodromic phase were present in 93% (unpublished data). We can speculate retrospectively that these patients' disease probably was related to cytotoxins of enterobacteriae [15], Thirty years later, we still have

1710

Nephrology Fonm: HUS in children

Diarrhea

11110 76° b

Bloody

U 71°c

Vomiting Fever

58%

Edema Arterial hypertension

52%

Anuria

52%

51%

Upper resp. illness

______25%

Major neurologic signs Purpura

'H

:jP

•• -- •,_--__a-_. iS-—s1-:

-.

Fig. 3. Prevalence of prodromal signs and symptoms.

Seizures

no useful treatment, other than supportive measures, in this "classic" form of the syndrome [16—21].

Cardiac failure Fig. 4. Prevalence of signs and symptoms in acute stage.

Epidemiology Let me begin by presenting an overview of the natural history of

enteropathic, or diarrhea-associated, HUS. In the areas where admitted for ARF to our service. Another distinct feature of the HUS in children is endemic, the strong association with diarrhea acute form of HUS is the high incidence of neurologic involveprompted a search for an infectious agent in the stool. The ment. Central nervous system (CNS) sequelae [3, 32—40] are sophisticated analysis by Chesney and Kaplan [22] on the patient infrequent. Hematologic changes occur only during the acute discussed by Ullis and Rosenblatt [23] as having disseminated phase. The literature contains only occasional reports of persisintravascular coagulation, and the epidemics of shigellosis com- tent lesions in the liver [41], pancreas [42—45], colon [46], or other plicated by HUS in Bangladesh [24] disclosed a close link between enterobacteriae and HUS. In 1983, Karmali et at demonstrated a causal association between VTEC and HUS [25]. This finding was unequivocally confirmed two years later [26]. Between 1986 and 1989, three reports from Argentina suggested that the verotoxin-

producing bacterium E. coli was the major cause of classic, epidemic HUS in this geographic area [27—29]. Lopez et al also showed that the E. coli serotype prevalent in other parts of the world, namely 0157:H7, was present in fewer than 5% of Argen-

tine children with HUS, but that 48% of them had evidence of free fecal toxin; this finding strongly suggested the presence of different strains of the bacterium in Argentina [29]. On the other hand, the frequency of cytotoxin-associated gastroenteritis in Argentina is approximately 23%, much higher than the 0.6% to 2.4% in other parts of the world [30]. Clinical picture The clinical picture of the acute phase of HUS in the three patients discussed today is typical of the epidemic form of the disease. For a few days preceding the sudden Onset of pallor and central nervous system involvement, they all had diarrhea. initial laboratory data showed a decreased hematocrit with fragmented erythrocytes in the peripheral blood smear and a low platelet count, characteristic of microangiopathic hemolytic anemia. The blood urea level was elevated, and all three patients were anuric on admission. The rest of the laboratory studies reflected alterations due to ARF. Diarrhea and vomiting are the most frequent of the prodromal signs and symptoms that occur in HUS. Figure 3 presents the prevalence of these prodromal signs and symptoms in 274 children admitted to two hospitals in Argentina whom we

organs [38]. Fortunately, more than 95% of patients recover from the acute

phase of the illness [31, 32]. The mortality rate is less than 5% (range, 0.5% to 4.5% between 1978 and 1993 in Argentina; data from the registry of the Nephrology Committee of the Argentine Society of Pediatrics). The three patients presented today illustrate different courses of the renal lesion of the HUS. The first patient seems to have

been cured after 13 years of followup. The second patient experienced a moderately severe acute stage and recovered from

the ARF; his creatinine clearance (Ccr) eventually returned to normal. But he had persistent proteinuria and many years later developed hypertension, which then progressed to end-stage renal failure (ESRF). The third child had a very severe acute phase and arrived at ESRF without ever recovering acceptable renal function. She received a successful renal transplant.

After recovery from the ARF of HUS, renal function follows

one of two patterns. In a few patients, the serum creatinine concentration does not totally return to the normal range, and ESRF develops relatively rapidly, an average of 4 years after the acute illness [47], as in Patient 3. We observed this course in 6 of

14 children who received renal transplants for HUS. In the second, more common pattern, the vast majority of patients recover normal renal function, at least as measured by Ccr or serum creatinine concentration. One year after the acute episode, one-half of them have a normal serum creatinine concentration

and no proteinuria (by spot sample testing). In 6%, the Ccr is normal but proteinuria (rarely in the ncphrotic range) is present.

The remaining 45% have a reduced Ccr with proteinuria. Patients in the last two groups also can he hypertensive (Fig. 5). In our own studied [31]. The acute stage of the disease was marked by study of patients after three years of followup, the proportion of hypertension, edema, hematologic abnormalities, and anuria; patients with normal Ccr and no proteinuria increased to 62%; the Figure 4 illustrates the prevalence of these and other findings in group with normal Ccr but with proteinuria increased to 14%; and the acute stage [31]. The most frequent cause of ARF in Argen- those with a diminished Ccr fell to 24%. Thus, some patients tine children, HUS was diagnosed in 65% of 237 children continue to recover from the acute insult even after the first year

1711

Nephrologt Fomm: HUS in children

-j

P<0.025 —

E

(45°c)

C

p 0

150

(63%)

(62%)

(49%)

-l

P.cO.025 —

a)

Ix

(24%)

(18%) (19°o)

1 4°of"

> 10 years follow-up 3 years year Fig. 5. Renal status at one, three, and >10 years of follow-up after the acute HUS [31, 48]. Hatched bar: normal Ccr, no proteinuria; vertical1

0

a —

0

______

—w 100

a)

50

—

Basal

C1X 59.5 102.7

Peak 84.9

154.7

striped bar: normal Ccr, proteinuria; open bar: decreased Ccr, proteinuria. Fig. 6. Mean CIN before and 2 hrs after a protein load in HUS patients at follow-up. Cross-hatched bar: HUS; horizontal-hatched bars: controls.

Table 2. Long-term course of renal involvement in HUS

Prot or HBP + Number of "Normal"" % patients 50 56 28 64 47 62 61

61

80

65

124 128

40 62 63

normal Ccr"

. Ccr Followup %

years

Reference

2—5

7 28 11 26 19 14

32 21 6 28 9 41 24

5—10

54 54

2—7

50

5—18

51

3

3 31

18

19

10—19

48

% 10

10 5—13

53

(measured by serum creatinine levels or Ccr) [57] did so because of hyperifitration injury to the remaining nephrons [58, 59]. These patients almost always had associated proteinuria and also often

had hypertension. Three lines of research have produced data compatible with that hypothesis. In our study [57], 4 of 12 patients with normal Ccr many years after the acute stage of their disease

were unable to increase their inulin clearance when challenged with protein loads [60]. One possible interpretation of this finding a Normal: no hypertension, no proteinuria, and normal creatinine is that these children are utilizing their "functional reserve" (prior clearance to the protein load) in the presence of a reduced nephron mass b Prot: proteinuria; HBP: hypertension; Ccr: creatinine clearance 118

[60]. Bosch's recent review suggests that the best way to quantitate

of followup [31]. Spizzirri et a! reviewed patients from the same cohort followed for more than 10 years and found that 63% still had normal Ccr and no proteinuria; 18% had normal Ccr with

persistent proteinuria; only 16% now had a reduced Ccr; and 3.4% were in ESRF (Fig. 5) [48]. One patient developed ESRF 20 years after the acute episode. We also have known of occasional patients who began chronic dialysis as long as 22 years after their acute illness: among our 14 patients with HUS who received renal transplants, this slow course of progression was observed in 8 children, This group required a renal graft in an average of 9.8

years after onset of the acute disease [47]. Analysis of these clinical data shows that children who are doing well after three years of followup are highly likely to continue to do well for many

years thereafter; only few patients develop proteinuria after having normal findings for many years. Studies from around the world have shown a similar proportion of patients with a classic HUS following the same course (Table 2) [3, 31, 48, 50—54]. We believe that in comparing outcomes in

patients with HUS, one should select those with most patients having the diarrheal form of the disease. The outcome generally is worse in patients with the atypical forms of HUS [7, 55, 56].

Pathogenesis Several years ago, we suggested that patients with HUS whose

renal function deteriorated after a period of normal function

this diminished mass is determination of the maximal filtration capacity [61], namely, the maximum GFR achieved after a standardized protein load, and comparison of that determination with normal values for age. The mean peak inulin clearance after the protein load in the 12 HUS patients we studied was 84.9 ml!min/ 1.73 m2, significantly lower than that in normal children (154.7 ml/min/1.73 m2) (P < 0.025) (Fig. 6) [57]. Not too surprisingly, the relation between creatinine clearance and inulin clearance was disproportionally high in some of the 12 children; tubular creatinine oversecretion probably maintained the normal serum creatmine levels. The second line of research implicating hyperfiltration injury comes from Perelstein et al, who showed that some children who had completely normal clinical and laboratory findings years after an acute episode could develop microalbuminuria [62]. The authors speculated that increased filtration of albumin, implicated as the predictor of progressive lesions in other renal diseases [63], might cause the subsequent loss of renal function. A third line of inquiry was reported by Habib and coworkers, who, studying sequential pathologic specimens, established that the proportion of glomeruli involved in the acute insult was the same as the proportion of scarred glomeruli later [4]. Histologic changes in biopsy specimens from patients with chronic 1-IUS [3, 64] show focal and segmental sclerosis and mesangial expansion in

the glomeruli. These observations also suggest a hemodynamic mechanism as the cause of progressive scarring and progressive loss of renal function.

1712

IVephrology Forum: HUS in children

Many studies have searched for findings in the acute stage of become a routine treatment for children with HUS who progress HUS that would precisely predict the late course of the illness. to ESRF. Although scattered case reports describe recurrence of The presence of diarrhea and the characteristics of classic, HUS in the graft [9, 76—82], several groups have found no epidemic HUS are associated with a better prognosis; the vari- recurrence of HUS in a substantial number of patients [47, ables pointing to a poor prognosis are those associated with the 83—87]. In addition, Gagnadoux and colleagues, although not initial destruction of a larger number of nephrons. Not too observing recurrences in the epidemic form, reported that pasurprisingly, the presence of anuria and its duration as well as the tients who received renal grafts because of HUS had a worse need for, and duration of, dialysis are the variables commonly long-term prognosis than did children whose original renal disreported to predict late outcome [48—54]. As 1 mentioned earlier, ease was not HUS [86]. studies of the pathologic features in the acute phase have shown Three problems complicate an analysis of the risk of recurrence that the percentage of compromised glomeruli can predict the late of HUS in a transplanted kidney: (1) Thrombotic microangiogracourse [4, 50]. Persistent hypertension also increases the risk for phy can be the pathologic pattern of acute immunologic rejection chronic sequelae [3, 31, 48—54]. Severe extrarenal manifestations [79]. (2) Thrombotic microangiopathy has been seen in renal

[65], such as marked CNS symptoms [51, 54] and bloody diarrhea or rectal prolapse [66], also are associated with a poor long-term

allografts in patients receiving cyclosporine whose original disease

outlook. These signs probably simply reflect a more severe was not HUS [88—90] and in patients with bone marrow [91, 92] or liver transplantation [93]. (3) Recurrence has been reported disseminated microangiopathic process. Recently, Renaud and coworkers concluded that age at onset, long considered of prognostic significance, is not. They demonstrated that the difference in outcome between infants and older children is simply due to the higher frequency of the atypical subset of HUS (with its known poorer outcome) in older children [56].

predominantly in older children and in adults, and in patients who had recurrent or non-epidemic familial types of HUS [9, 76—81]. When we first reviewed our own experience with transplantation in children with HUS, we found that the only patient who had a

Management of chronic renal disease following acute HUS

acute HUS not preceded by gastrointestinal symptoms. He did not

Children who have normal creatinine clearance but persistent proteinuria one year after an acute episode of HUS are at risk of developing progressive renal failure [31, 48]. Persistent hypertension also is a predictor of a poor outcome. However, even patients with a normal Ccr, no proteinuria, and normal blood pressure can develop progressive renal insufficiency. Our approach is to start treatment if the patient has persistent proteinuria of any degree one year after the acute episode. First, we limit the protein in the diet to the recommended dietary allowance [67]'; most middle class children in our country consume amounts exceeding it. Next, we try to reduce blood pressure to average or low-normal values with ACE inhibitors. Third, even if the patient has normal blood

pressure, we administer angiotensin-converting-enzyme (ACE)

blockers. Although there is no conclusive evidence that this treatment program prevents the progression of HUS, studies in experimental animals [68, 69] and in other human renal diseases in which a similar mechanism might be present [70—72] have demonstrated a reduction in proteinuria and a diminution in the rate of functional deterioration. Briones and colleagues from the Pediatric Hospital of Buenos Aires have reported in abstract that administration of ACE inhibitors decreased proteinuria from 63.5 11.2 mg/m2/hr to 9.8 2.0 mg/m2/hr in 25 children with renal sequelae post HUS [73]. A long-term, prospective multicenter study of a larger number of patients will he needed to provide definitive conclusions regarding the efficacy of a lowprotein diet or ACE inhibition in patients with renal sequelae following HUS.

Hemolytic-uremic syndrome accounts for about 20% of chil-

recurrence that led to the loss of his graft (two months post transplantation) was an 8-year-old boy who had had a severe, recover from the acute failure and required hemodialysis until transplantation. His brother had had non-diarrheal HUS, equally severe, 5 years previously [47]. Since then, we have transplanted kidneys into 4 other children with atypical HUS, and we have not

observed another recurrence. More recently, we reviewed the course of 23 renal transplants in 20 children whose original disease had been HUS [94]. Hemolytic-uremic syndrome had been preceded by diarrhea in 16 patients who had presented with

the classic epidemic type; this group received 19 grafts. The survival of these 19 grafts, maintenance of stable renal function, incidence of acute rejection, and prevalence of proteinuria and hypertension were compared with the same measures in a randomly selected group of 19 children who received renal trans-

plants because of ESRF not due to HUS ("controls"). Mean followup in both groups was 5 years, with a range of ito 11 years.

Actuarial survival of the grafts (in patients with or without preceding HUS) and of the grafts with normal serum creatinine was similar in the two groups (P = 0.73 and 0.27, respectively, log-rank test) (Figs. 7, 8). Mean survival of the grafts was 7.16 years in the HUS patients versus 8.53 years in the controls (P, NS).

Mean survival with a normal serum creatinine was 2.07 (HUS) versus 2.71 years (controls) (P, NS). There were 14 acute rejections in the HUS patients versus 8 episodes in the control group (P, NS). Prevalence of proteinuria and hypertension at 1 and 5

years post transplantation was similar for the two groups. No evidence of thrombotic microangiopathy was seen in the 6 trans-

planted kidneys surigically removed or in the 6 biopsies performed for other diagnostic purposes. We conclude that patients

dren who enter ESRF programs in Argentina [74]. Since the who receive renal transplants for classic epidemic HUS have a report from Cerilli et a! in 1972 [75], renal transplantation has very low risk of disease recurrence and that the long-term outcome of the grafts in these patients is not different from that in patients with ESRF from other causes. Moreover, in patients One has to be cautious in reducing dietary protein, since you can cause

whose original disease was classic HUS, the use of cyclosporine A

other essential components (calcium, zinc, iron) to fall below their

in 12 of the 19 grafts did not seem to increase the risk of

recommended dietary allowances [67].

recurrence.

1713

Nephrology Forum: HUS in children

88.2 74.1

74.1

61.1

68.9 ci

0 1) a-

C)

a-

47.1

32.6

HI 1st year

5th year

1St year

8th year

Fig. 7. Actuarial survival of grafts in patients with HUS () and without HUS (E).

t3. 5th year

Fig. 8. Actuarial survival of grafts with normal SCr (HUS,

non-

HUS, LI).

Conclusion

QUESTIONS AND ANSWERS

In the classic, epidemic form of FIUS in children, mortality in the acute stage now is lower than 5%. Children usually die due to intercurrent infection or severe neurologic, intestinal, or myocardial complications associated with the more severe patterns of the

DR. JOHN T. HARRINUTON (Dean, Tufts University School of Medicine, Boston, Massachusetts, USA): Dr. Repetto, you said that

few patients over the age of three develop "classic" HUS. What accounts for this immunity in children older than three? Do we acute disease. Treatment in the acute phase is supportive. With know what specific antibodies are responsible? DR. REPETITO: This is a very interesting question. I know of no modern methods of management of fluid and electrolyte disorders and of hypertension, no patient should die of the complications of data based on specific studies to answer it, but one can speculate. ARF. Of the 95% who survive, approximately one-third are at risk In Argentina, these children appear to be in contact with the of having chronic sequelae. The chronic course is characterized verotoxin in the second half of the first year of age, when most of predominantly by the hemodynamic sequelae of the renal lesion them stop being breast-fed and start incorporating meat and produced during the acute stage. Motor, sensory, or intellectual unpasteurized milk into their diet. Due the high prevalence of deficits; diabetes; myocardial infarctions; or intestinal strictures VTEC in our country, susceptible children would develop HUS are infrequent. We believe that enough evidence supports the then. There seems to be some kind of immunity either to the hypothesis that the progressive renal failure of HUS is due to the VTEC or to the toxin; there have been no reports of wellglomerular and tubulo-interstitial scarring related to the initial documented recurrences in this type of HUS, although no specific decrease of the nephron mass by the acute microangiopathic immunity has been found. Children over three years could have process, and not to persistence or recurrence of the original the same kind of protection if they are among those who had VTEC infection without developing HUS. In the group studied by disease. Three courses of progression to ESRF have been described. Lopez et al, 19% of children with diarrhea not developing 1-TUS Children with the most severe forms do not recover from the ARF had either VTEC in the stools, production of verotoxin from the and enter directly into a dialysis and transplantation program. A stool culture, or serum antibodies against verotoxin [29, 30]. The second group recovers renal function partially but with persistent possibility also exists that verotoxin receptors are differently proteinuria and hypertension; subsequent progression to ESRF expressed at different ages. We have seen patients who developed occurs in two to five years. The third group, the majority of those HUS shortly after their arrival from other countries. Some of their who progress to renal failure, ultimately initially recover normal older siblings presented bloody diarrhea, but we could not find serum creatinine and creatininc clearance levels; some of these any laboratory evidence of even subclinical HUS. DR. MANUEL MARTINEZ-MALDONADO (Professor and Vice-chair, patients do, however, develop proteinuria and/or hypertension. These children progress to ESRF after more than five years, at Department of Medicine, Emory University School of Medicine, times as late as 20 years after the acute disease. Treatment in the Atlanta, Georgia, USA): Have any attempts been made to biopsy later years seeks to prevent the progression of chronic renal the kidneys of the patients in whom proteinuria, hypertension, or insufficiency. Transplantation is indicated in this form of HUS, as both occur one year or more after acute HUS? If so, what lesion there is little, if any, risk of recurrence, and the prognosis is similar is found? Thrombotic microangiopathy is mostly part of the acute to that of patients who receive renal transplants for other diseases. response. If later lesions are also thrombotic microangiopathy, are

1714

Nephrology Fonim: HUS in children

these re-exposure to toxin from shiga-like E. coli 0157:H7 or "memory of cells" to other stimuli? DR. REPETTO: Habib et a! reported the histologic findings in sequential biopsies obtained during the acute period and one year

intravenous gamma globulin. Unfortunately, results generally have been discouraging. Three carefully designed studies in populations in which most children had the diarrhea! form were prospective and controlled. One was performed by Drs. Vitacco

later [4]. When they correlated the clinical data with the late and coworkers in Buenos Aires many years ago [171. At that time, biopsy results, they found that the patients who had hypertension, proteinuria, and/or any decrease of creatinine clearance showed

because intravascular coagulation was believed to be responsible

the typical findings associated with the chronic renal sequelae, namely, expansion of the mesangium, increased mesangial cellularity, interstitial infiltrates, tubular atrophy, and focal glomerular sclerosis. This has also been the experience of Gallo and his team

authors studied children with the most severe forms of epidemic

[3, 64]. DR. MARTINEZ-MALDONADO: Was thrombotic microangiopathy

present in the followup? DR. REPETFO: No. Dr. Habib was very careful in looking for that

feature, and she could not find any sign of acute thrombotic microangiopathy. DR. MARTINEZ-MALDONADO: Let me return to Dr. Harrington's

question. In Argentina, if lesions of thrombotic microangiopathy

for HUS, some groups advocated the use of heparin. These HUS, comparing heparin versus conventional treatment in a randomly selected control group. Not only they did not find any benefit of heparin treatment, but they noticed an increased risk of intracranial hemorrhage. Two other more recent, multicentric, prospective, and controlled studies came from Italy and France [20, 95]. Because plasma infusion or plasmapheresis had been

reported as effective in the control of the acute phase of the atypical forms of HUS—possibly because of the altered metabolism of the vascular endothelial products that prevent the microthrombosis—these investigators studied a total of 56 children,

presented later, it could mean one of two things: either a about 80% of whom had associated gastroenteritis. Patients re-exposure to the verotoxin or "memory" of the kidney in its reponse to other stimuli, but the response is the same. I wonder what you think about that. DR. REPETFO: We have never seen recurrences of HUS in children who present with the typical epidemic form. Nor have I recalled this fact in my talks with other pediatric nephrologists in Argentina. The lack of recurrences probably is due to some kind of immunity against the VTEC prevalent in our country or to the toxin, but I don't think that this has anything to do with the kidney itself. We usually tell the parents of these children, if we are sure that we are dealing with the epidemic diarrheal form, that with our experience gathered over four decades, the disease is highly

treated with plasma infusion for two to three weeks had no better outcome than did those control patients treated supportively, both

in the acute phase and during a mean followup of 16 and 12 months. My own belief is that epidemic HUS is a one-shot disease

and that by the time the patients get to us, the thrombotic microangiopathy is already established. I believe that all efforts should be directed towards preventing intestinal infection or the effect of the verotoxin. DR. Luis SALINAS-MADRIGAL (Professor of Pathology, Internal Medicine and Pediatrics, St. Louis University Cell Sciences Center, St. Louis, Missouri, USA): Horacio, I was very much interested in

the fact that cyclosporine does not influence the incidence of unlikely to recur. Patients who do develop recurrences clearly recurrence of the disease in the epidemic form. We have transhave atypical forms of HUS, and most of them have more than planted kidneys into three adults with idiopathic HUS and one one recurrence, at times associated with hypocomplementemia patient with mitomycin-induced HUS. In those four patients, [551. cyclosporine seemingly produced early recurrence of the thromDR. NIcoLAos E. MADIAS (Chief Division of Nephrology, New botic process in the graft. Does this mean that we are talking England Medical Center, Boston): First, I would like to make a about different entities when we discuss the idiopathic versus the comment. Regarding the increased susceptibility of young chil- epidemic form? Might this explain many of the differences in the dren to epidemic HUS, the shiga-toxin receptor is now well response to treatment? You just mentioned plasma infusion as

characterized. It would be of interest to look for different being more effective in the idiopathic forms as compared with the

expression of the receptor in young children versus older age epidemic form; this is a fascinating difference, I think. groups. It is possible that this could differ as a function of age. DR. REPETFO: We have transplanted kidneys into five children My question relates to your comment that only supportive care with the atypical form of HUS. One had the recurrence that I is indicated in patients with epidemic HUS. Although so-called related in my discussion. The other four received triple therapy atypical HUS clearly has a worse outcome, epidemic HUS does with lower doses of cyclosporine, yet we have not seen either a not strike me as a benign disorder, given that as many as 5% of the

affected children die in the acute phase, about 5% develop CNS sequelae, some children never recover from ARF, and about 40% develop long-term renal abnormalities. How vigorously have therapies such as plasma infusion or exchange been studied in this disorder? One might make the case for using these approaches in the children who present with the most serious clinical characteristics.

DR. REPETrO: Regarding your comment, I believe that the studies of receptors comprise a new avenue for research that could yield important knowledge for the management of HUS.

Now, let me answer your question. Numerous studies have reported results of treatment in the acute phase [16—21], testing inhibitors of platelet aggregation, anticoagulants, or high-dose

hematologic or a renal recurrence. The experience in other

centers in our country [87] and in France [86] with transplantation in the epidemic enteropathic form is the same. Cyclosporine does not seem to add to the risk of recurrence, But, as you just heard, I still think that the analysis of its responsibility in recurrences is quite difficult. We are aware of the effect of cyclosporine on the

endothelium and the mesangium, but its direct participation in recurrences of HUS has yet to be proven. On the other hand, as I said, I am convinced that we are talking of different pathogenetic entities that produce the same clinical syndrome and pathologic lesion. The nosologic problem is further increased by the fact that evidence of verotoxin infection has been demonstrated in children with HUS who did not present with diarrhea.

Nephrology Forum: HUS in children

1715

DR. EXENI:

A 1994 report suggested that an absorbent agent

DR. ELVIRA ARRIZURIETA (Chief Laboratoiy of Experimental Renal Medicine, Institute of Medical Research, University of Buenos

might prevent HUS [1031. Is there any new medication that could absorb the toxin? DR. REPETFO: As you know, the Canadians are performing a prospective study with an oral absorbent that seems to be capable of absorbing the toxin. They reported preliminary results last year at the International Pediatric Nephrology Meeting in Chile, and

Aires School of Medicine, Buenos Aires): How can you make an early diagnosis of CRF in a child who had HUS? DR. REPETTO: Two methods can detect a minimal degree of renal dysfunction, which is not the same as saying that the child definitely will progress to renal failure. The first is determination of the maximum filtration capacity, which requires, as I discussed, we eagerly hope that they get good results. Also, I have been

a method for measuring GFR precisely. For routine clinical

talking with Dr. Monnens from Holland, who is working to

purposes, the determination of microalbuminuria is simpler, but we have to be careful in interpreting these very sensitive findings and in presenting that information to the parents.

itself.

DR. ARRIZURIETA: Do you treat those children with low-protein

diets or medications to slow the progression of ESRD? DR. REPETI'O: Yes, we start reducing the protein load and giving

develop vaccines against the prevalent VTEC strains or the toxin

DR. ExENI: What is the incidence of hemolytic-uremic syndrome in Argentina as compared with other countries? DR. REPETTO: Your own editorial estimates an incidence here

of 7 cases per 100,000 inhabitants against 2 per 100,000 in

countries with a supposedly high incidence [104]. At least 6000 them ACE inhibitors when proteinuria persists one year after the pediatric cases have been registered in Argentina since 1964, so I acute event. We think that we might be able to prevent progres- believe that 7 cases per 100,000 is obviously an underestimation. sion of ESRD, or at least slow it down, but we need more data to DR. ExENI: Is there a relationship between the use of antibiotics confirm this conjecture. in the diarrheal stage and evolution of the disease? DR. ARRIZURIETA: What is the VTEC type in this country?

DR. Rapnrro: This question raises an important problem for DR. REI'E'vro: Lopez and coworkers showed that 0157:H7 E. the pediatrician. The dysenteric type of diarrhea in the prodromal coli was only 2% of the verotoxin-producing E. coli isolated [29]; period mimics that of bacterial origin and prompts primary prevalence in other parts of the world ranges between 40% and physicians to give antibiotics. Pavia et al did report a higher risk of 79%. There are sporadic reports of 011, 025:H2 etc. from our HUS in children treated with antibacterial drugs [105]. On the country [96]. Both groups are conducting studies to gather more other hand, a randomized Canadian study showed that the use of information. trimethoprim-sulfamethoxazole did not affect the incidence of DR. JORGE FERRARIS (Chief of Pediatric Renal Transplantation,

Hospital Italiano, Buenos Aires): We think that the best predictor of CRF is the length of the acute phase. For example, a patient with a severe acute phase, more than 14 days of oligoanuria, has a 90% chance of developing CRF; a patient with a moderate acute phase, 7 to 14 days of oligoanuria, has a 30% chance; and a patient with a mild acute phase, less than 7 days of oligoanuria, has less than a 2% chance of developing CRF [97]. My question is, what

HUS [106]. The speculation is that more verotoxin could be liberated by the massive destruction of germs. The inoculum might be one of the determinants of the severity of the disease. Robinson and coworkers demonstrated a clear dose-dependent inhibition of mesangial cell mitogenesis by verotoxin [107]. DR. PABLO MASSARI (Chief Renal Service, Hospital-Privado-

Centro Medico de Córdoba, Córdoba, Argentina): We are always arguing with our pediatricians about patients reaching ESRF 22 to do you think about using leukocytosis in the acute phase as a 25 years after an acute HUS, after they have had a course without symptoms and laboratory abnormalities. How can you be sure that predictor of CRF [981? DR. REPETrO: We have not looked at that specifically. British the cause of this late ESRF is the much earlier episode of HUS? DR. REPETrO: I agree with you that one cannot be certain, but groups have postulated that the leukocyte elastase is a putative intermediate in triggering the lesion [99 —101], but I cannot answer at least we can rule out several other causes leading to CRF. Then HUS becomes a plausible cause. In the early years of dealing with the question based on our own experience. DR. FERRARIS: How long should the followup be in patients with these patients, we saw some children who developed nephrotic-

range proteinuria without renal insufficiency. Treating few of mild HUS? DR. REPEvm: This question reveals part of a big dilemma in these children with steroids (as if they had idiopathic nephrotic syndrome) did not result in any change in protein excretion. following these children. The predictive correlations you menDR. HARRINGTON: Is there a good experimental model of HUS tioned are, of course, statistical, and we have had patients with in which we could investigate the role of intermediate metabolites only I or 2 days of anuria who ended up in CRF. On the other or factors like cytokines, ICAMs, and all the other fancy stuff? hand, we have seen infants with anuria lasting more than 10 days DR. REPEno: No experimental model has been produced in the who appear cured after more than three years of followup. We laboratory, with the exception of a potential and not-well-defined

have to establish more exact methods for predicting the final

outcome. This is why I follow these children until the end of their growing period, that is, until they are about 20 years of age. DR. RAMOM ExENI (Chief Department of Nephroloi, San Justo

Qzildren 's Hospital, Province of Buenos Aires): Do verotoxin infections exist in the parents or siblings of affected patients? DR. REPEITO: Studies have looked for familial contagion of the

toxic model in monkeys, published in the veterinary literature [108). Interestingly, a few days ago, at an international symposium held in Buenos Aires, Dr. Mohamed Karmali reviewed data on a

spontaneous canine model of the disease. Alabama greyhounds develop a diffuse microangiopathy both pathologically and histologically similar to HUS. They start by having ulcers in the skin, which is not seen in the human disease, and renal involvement follows. The investigators are taking extreme care of the dogs,

VTEC [102]. In our country, a very recent publication reported cumulative evidence of VTEC infection in more than 30% of treating them as if they were in a spa, trying to put them in the best family members of children with diarrheal HUS [96]. situation to study them experimentally [109].

1716

Nephrology Forum: HUS in children

DR. HARRINOTON: What is the specific pathophysiologic cause

HUS and increased severity of neurologic manifestations with

of the CNS abnormalities in HUS? Is it simply hypertension, or is their use [36, 120]. there evidence of a cerebral microangiopathy as well? DR. REPETFO: Most of the CNS symptoms are present early in Reprint requests to Dr. H. Repetto, T Garcia 2369, 1426, Buenos Aires, the acute period and tend to improve with adequate management Argentina of the hypertension and the fluid and electrolyte derangements. Yet some patients develop encephalic hemorrhages documented NOTE ADDED IN PROOF by MR scan [110], and autopsy studies have shown microthrombi, significantly increased number of neutrophils within the glomeruli of infarcts, and hemorrhage in a variety of CNS regions [33, 111— D+A HUS was reported in a recent multicentric pathology study in 113].

DR. MADIAS: Low birth weight has been associated with small kidneys, decreased number of nephrons, and future development

England. INWARD CD, HOWIE Al, FITZPATRICK MM, RAFAAT F, MILF0RD DV, AND TAYLOR CM ON BEHALF OF THE BRITISH ASSOCIATION FOR PAEDIATRIC

of hypertension [114]. Also, there is experimental support for NEPHROLOGY. Renal histopathology in fatal cases of diarrhoea-associated intrauterine growth retardation resulting in hypertension and haemolytic uraemic syndrome. Paediatr Nephrol 11:556—559, 1997 renal disease in the rat [115]. Have any studies linked low birth REFERENCES weight with progression to ESRF in HUS? DR. REPETI'O: I am not aware of any study in that respect, but our own patients with HUS generally are well nourished and have very good physical development. DR. MADIAs: Since you mentioned that your current policy is to

initiate treatment in children who exhibit persistent proteinuria after one year from the acute episode of HUS, I would consider it reasonable to initiate treatment at the microalbuminuric stage. In view of the progressive nature of the renal disease and the safety profile of available therapies, I would not hesitate to intervene at the stage of microalbuminuria. DR. REPETrO: I could agree with you, and we are thinking of doing that. The problem is that no one has yet verified that the remaining nephrons are hyperfunctioning in this clinical model. If you are very critical, you might not decide to start treatment at that early stage. I believe that a prospective research study should be developed before implementing this approach as routine treatment. Let me point out that the results showing the proportion of patients arriving at ESRF came from a time when we did not aggressively treat patients in the chronic stage. We still don't know what is going to happen now that we are routinely using ACE inhibitors and reducing the dietary protein load. DR. RODOLFO S. MARTIN (Career Investigator, Institute of Medical Research, University of Buenos Aires School of Medicine): Has our new knowledge gained about shiga-like toxins (verocytotoxin)

prompted any dietary measures or vaccines for preventing the syndrome? DR. REPETFO: Yes, three areas promise hope for preventing

HUS. One is the public health area. Adequate counseling and public awareness should reduce the risk of consuming undercooked meat [116], unpasteurized cheese [117], and raw milk [118]. A group from La Plata, Province of Buenos Aires, reported that a high proportion of their patients develop HUS as a result of drinking milk obtained directly from cows [119]. I also believe that reporting of cases occurring in nursing homes or day-care centers should be mandatory [118]. A second approach is, as you mentioned, vaccines. I believe that

we do not have the necessary pharmacologic infrastructure to develop them in our country. Fortunately, efforts in Canada and in Holland are proceeding (personal communications). The third approach, as I mentioned in my answer to Dr. Exeni, is the use of orally administered toxin-binding resins, I should mention that antimotility agents are contraindicated in children with acute diarrhea. Two studies have shown an increased risk of

1. GASSER VC, GAUTIER E, STECK A, SEIBENMANN EE, OESCFILIN R:

Hämolytische-uramische syndrome: Bilaterale Nierenindennekrosen

bei akuten erworbenen hamolytischen Anemia. Schweiz Med Wochensch 85:905—909, 1955 2. ROYER F, HABIB R, MATHIEU H: La microangiopathie thrombotique

du rein chez l'enfant. Ann Pediatr (Paris) 36:572—587, 1960 3. GIANA.NTONIO CA, VITACCO M, MENDILAHARZU F, GALLO G, SoTo

ET: The hemolytic-uremic syndrome. Nephron 11:174—192, 1973 4. HABIB R, LEVY M, GAGNADOUX MF, BROYER M: Prognosis of the hemolytic uremic syndrome in children.Adv Nephrol 11:99—128, 1982 5. KAPLAN BS, DRUMMOND KN: The hemolytic uremic syndrome is a syndrome (editorial). N Engi J Med 298:964—966, 1978 6. REMUZZI G: Nephrology Forum: HUS and TTP: Variable expression of a single entity. Kidney mt 32:292—308, 1987 7. FITZPATRICK MM, WALTERS MDS, TROMPETER RS, DILLON MJ,

BARRAT TM: Atypical (non-diarrhea-associated) hemolytic-uremic syndrome in childhood. J Pediatr 122:532—537, 1993 8. KAPLAN BS: Hemolytic uremic syndrome with recurrent episodes: An important subset. Clin Nephrol 8:495—498, 1977 9. HEBERT D, SIBLEY RK, MAUER SM: Recurrence of hemolytic uremic syndrome in renal transplant recipients. Kidney mt 30:S51—S58, 1986 10. GARRERAS L, ROMER0 R, REQUESENS E, OLIVER AJ, CARRERA M, CLAVO M, ALSINA J: Familial hypocomplementemic hemolytic ure-

mic syndrome with HLA-A3, B7 haplotype. JAMA 245:602—604, 1981 11. BOGDANOVIC R, CVORIC A, NICOLIK V, SINDJIC M: Recurrent

haemolytic-uraemic syndrome with hypocomplementemia: A case report. Pediatr Nephrol 2:236—238, 1988 12. KAPLAN BS, KAPLAN P: Hemolytic uremic syndrome in families, in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, edited by KAPLAN BS, TROMPETER RS, MOAKE JL, New York, Dekker, 1992, pp 213—225 13. GIANANTONIO CA, VITACCO M, MENDILAHARZU J, MENDILAHARZU

F, RUTTY A: Acute renal failure in infancy and childhood. Clinical course and treatment of forty-one patients. J Pediatr 611:660—678, 1962 14. GIANANTONIO C, VITACCO M, MENDIAHARZU F, RUTTY A: The

hemolytic-uremic syndrome. J Pediatr 64:478—491, 1964 15. CHART H, ROWE B, VA.r.4 DER KAR N: Serologic identification of E.

coil 0157 H7 as a cause of HUS in the Netherlands (letter). Lancet 377:437, 1991 16. KAPLAN BS, KATS J, KRAWITZ S, LURIE A: An analysis of the results

of therapy in 67 cases of hemolytic-uremic syndrome. J Pediatr 78:420—425, 1971 17. VITACCO M, SANCHEZ-AVALOS J, GIANANTONIO CA: Heparin ther-

apy in the hemolytic-uremic syndrome. J Pediatr 83:271—275, 1973 18. AREN5ON EB JR, AUGUST CS: Treatment of the hemolytic-uremic syndrome with aspirin and dipyridamole. J Pediatr 86:957—961, 1975 19. O'REGAN S, CHESNEY RW, MONGEAU JG, ROBITAILLE P: Aspirin

and dipyridamole therapy in the hemolytic-uremic syndrome. J Pediatr 97:473—476, 1980

20. RIzzONI G, CLARIS-APPIANNI A, EDEFONTI A, FACCHIN F, FRANCHINI F, GUSMANS P, IMBASCIATI E, PAVANELLO L, PERFUMO F,

Nephrology Forum: HUS in children

REMUZZI G: Plasma infusion for HUS in children: results of a multicenter controlled trial. J Pediatr 112:284—290, 1988

21. RoasoN WLM, FIcK GH, JADAVJI T, LEUNG AKC: The use of intravenous gammaglobulin in the treatment of typical hemolytic uremic syndrome. Pediatr Nephrol 5:289—292, 1991 22. CHESNEY RW, KAPLAN BS: Hemolytic uremic syndrome with shigellosis. J Pediatr 84:312—313, 1974 23. ULLIS KC, ROSENBLAVF RM: Shiga bacillus dysentery complicated by

bacteremia and disseminated intravascular coagulation. J Pediatr

1717

islet cell necrosis: Association with hemolytic uremie syndrome. JPediatr 100:582—584, 1982 44. ANDREOLI SP, BERGSTEIN JM: Exocrine and endocrine pancreatic insufficiency and calcinosis after hemolytic-uremic syndrome. J Pediatr 110:816—817, 1987 45. Al HERBISCH, AL RASIIEED SA: Persistent insulin-dependent diabetes mellitus in hemolytie-uremic syndrome. Child Nephrol Urol 12:59— 61, 1992 46. SAWAF H, SHARP MJ, YOUN KJ, JWELL PA, RABBANI A: Ischemic

83:90—92, 1973 24. KOSTER F, LEVIN J, WALKER L, TUNG KSK, GILMAN RH, RAHAMAN

colitis and stricture after hemolytic-uremic syndrome. Pediatrics

MM, MAJID MA, ISLAM S, WILLIAMS RC: Hemolytic-uremic syndrome after shigellosis. N Engi J Med 298:927—933, 1978 25. KARMALI MA, STEELE BT, PETRIC M, LIM C: Sporadic cases of

47. Rn'rro HA, VAZQUEZ LA, CALVO P, PALTI C: Renal transplantation in children with idiopathic "classic" hemolytic uremie syndrome (abstract). Pediatr Nephrol 3:C185, 1989 48. SPIZZIRRI FD, RAHMAN RC, BIBIL0NI N, RusCAsso J, AMOREO 0:

haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing E. coli in stools. Lancet 1:619—620, 1983 26. KARMALI MA, PETRIC M, LIM C, FLEMING PC, ARBUS GC, LI0R H:

The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis 151:

61:315—317, 1987

Childhood hemolytic uremic syndrome in Argentina: long-term follow-up and prognostic features. Pediatr Nephrol li:156—160, 1997 49. GIANANTONLO C, VITACCO M, MENDILAHARZU F, GALLO G: The

hemolytic-uremic syndrome: renal status of 76 patients at long-term follow-up. J Pediatr 72:757—765, 1968

775—782, 1985 27. DE CRISTOFANO MG, FAYAD A, FERRARIS J, CORTINEZ C, RAMIREZ

50. LOIRAT C, S0NsINO E, VARGA MORENO A, PILLION C, MERCIER JC,

J, Ascior'm A, GIANANTONIO CA: Sindrome urémico hemolItico de la

BEAUFILS F, MATHIEU H: Hemolytic-uremic syndrome: An analysis

infancia. Su relación con Ia presencia de verotoxina libre fecal. Arch

of the natural history and prognostic features. Acta Pediatr Scand

Arg Pediatr 84:339—342, 1986 28. NoviLLo A, VOYER L, CRAVIOTO R, FREIRE MC, CASTANO G, WAINSTEIN R, BINZTEIN N: Haemolytic uremic syndrome associated

with faecal cytotoxin and verotoxin neutralizing antibodies. Pediatr Nephrol 2:288—290, 1988 29. LOPEZ EL, DIAZ M, GRINSTEIN 5, DEVOTO 5, MENDILAHARZU F, MURRAY BE, ASHKENAZI S, RUBEGLIO E, WOLOJ M, VAZQUEZ M, TURCO M, PICKERING LK, CLEARY TG: Hemolytic uremic syndrome

and diarrhea in Argentine children: the role of shiga like toxins. JlnfectDis 160:469—475, 1989 30. LOPEZ EL, GIANA.NTONIO CA, CLEARY TG: The hemolytic uremic

syndrome in Argentina, in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, edited by KAPLAN BS, TROMPETER RS, MOAKE JL, New York, Dekker, 1992, pp 89—96 31. REPEYrO HA, BIBILONI N, SPIzzIRRI F, VAZQUEZ LA, DE LA TORRE MC, RAHMAN R, OR5I MC, DEREGIBUS M: Long- term follow-up of

the renal lesion of the infantile hemolytic uremic syndrome (abstract). Pediatr Nephrol 3:C184, 1989 32. GIANANTONLO CA: Past and present of hemolytic uremic syndrome in

Argentina, in Renal Emergencies, edited by STRAUSS T, Boston, Martinus-Nijhoff M, 1984, pp 13—20 33. BALE JF JR, BRASHER C, SIEGLER RL: CNS manifestations of the hemolytic-uremic syndrome. Am J Dis Child 134:869—872, 1980 34. STEELE BT, MURPHY MB, CHUANG SH, MCGREAL D, ARBUS GS:

73:505—5 14, 1984 51. SIEGLER RL, MILLIGAN MK, BURNINGHAM TH, CHRISTOFFERSON

RD, CHANG S-Y, JORDE LB: Long-term Outcome and prognostic indicators in the hemolytic-uremic syndrome. J Pediatr 118:195—200, 1991

52. FITZPATRICK MM: Long-term outcome of hemolytic uremie syndrome in children, in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, edited by KAPLAN BS, TROMPETER RS, MOAKE JL, New York, Dekker, 1992, pp 441—451 53. KELLES A, VAN DYCK M, PROE5MANS W: Childhood haemolytic

uraemic syndrome: long-term outcome and prognostic features. Eur JPediatr 153:38—42, 1994 54. TONSHOFF B, SAMMET A, SANDEN Y, MEHLS 0, WALDHERR R, SCHARER K: Outcome and prognostic determinants in the hemolytic syndrome of children. Nephron 68:63—70, 1994 55. KAPLAN BS, PROESMANS W: The hemolytie uremic syndrome of childhood and its variants. Semin Hematol 24:148—160, 1987 56. RENAUD C, NIAUDET P, GAGNADOUX MF, BROYER M, HABIB R:

Haemolytic uraemic syndrome: prognostic factors in children over 3 years of age. Pediatr Nephrol 9:24—29, 1995 57. TUFRO A, ARRIZURIETA E, REPErFO HA: Renal functional reserve in

children with a previous episode of hemolytic uremic syndrome. Pediatr Nephrol 5:184—188, 1991 58. BRENNER BM: Nephrology Forum: Hemodynamically mediated gb-

Recovery from prolonged coma in hemolytic uremic syndrome.

merular injury and the progressive nature of kidney disease. Kidney

JPediatr 102:402—404, 1983 35. Bos AP, DONCKERWOLCKE RA, VAN VUGHT AJ: The hemolyticuremic syndrome: prognostic significance of neurological abnormalities. Helv PediatrActa 40:381—389, 1985 36. CIMOLAI N, MORRISON BJ, CARTER JE: Risk factors for the central nervous system manifestations of gastroenteritis-associated hemolytic-uremic syndrome. Pediatrics 90:616—62l, 1992

mt 83:647—655, 1983 59. NEURINGER JR, BRENNER B: Hemodynamic theory of progressive

37, FITZPATRICK MM, DILLON GI, BARRAT TM, TROMPE ER RS: Central

61. BOSCH JP: Renal reserve: A functional view of glomerular filtration

nervous involvement in diarrhea-associated haemolytic-uracmic syndrome (abstract). Pediatr Nephrol 6:C166, 1992

62. PERELSTEIN EM, GRUNF'ELD BC, SIMSOLO RB, GIMENEZ MI, GIAN-

renal disease. A 10 years update in brief review. Am J Kidney Dis 22:98—104, 1993 60. ANASTASTO P, SANTORO D, SPITATI L, CIRILLO M, DI LEO VA, D

SANTO NC: Renal functional reserve in children. Semin Nephrol 15:454—462, 1995

rate. Semin Nephrol 15:381—385, 1995

1995 41. VAN RHIJN A, DONCKERWOLCKE RA, KUYTEN RH: Liver damage in

ANTONIO CA: Renal functional reserve in haemolytic uremic syndrome and single kidney. Arch Dis Child 65:728—731, 1991 63. MOGENSEN EC: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356— 360, 1987 64. CAIETrI MG, GALLO G, GIANANTONIO CA: Development of focal segmental sclerosis and hyalinosis in hemolytic urcmic syndrome. PediairNephrol 10:687—692, 1996 65. GUY0T C, DANIEL MD, ROZE JC, RENOULT E, DUBIGEON P,

the hemolytic uremic syndrome. Helv Pediatr Acta 32:77—8 1, 1977 42. ANDREOLI SP, BERGSTEIN JM: Development of insulin-dependent

BUZELIN F: Prognostic du syndrome hemolytic et uremic chez l'enfant. Importance de b'atteinte extra-renale. Arch Fr Pediatr 43:

38. SInG LER RL, PA VIA AT, CHRISTOFFERSON RD, MILLIGAN MK: A 20

years population-based study of post-diarrheal hemolytic-uremic

syndrome in Utah. Pediatrics 94:35—40, 1994 39. SIEGLER RL: Spectrum of extrarenal involvement in postdiarrheal

hemolytic-uremic syndrome. J Pediatr 125:511—518, 1994 40. GALLO GE, GIANANTONIO CA: Extrarenal involvement in diarrheaassociated haemolytic-uraemic syndrome. Pediatr Nephrol 9:117—119,

diabetes mellitus during the hemolytic uremic syndrome. J Pediatr 100:541—545, 1982 43. BURNS JC, BERMAN ER, FAYNE JL, SHIKES RH, LUM GH: Pancreatic

253—258, 1986 66. LOPEZ EL, DEVOTO 5, FAYAD A, CANEPA C, MORROW AL, CLEARY

TG: Association between severity of gastrointestinal prodrorne and

1718

Nephrology Forum: PIUS in children

long-term prognosis in classic hemolytic-uremic syndrome. J Pediatr 120:210—215, 1992

67. RAYMOND NG, DWYER JT, NEVINS P, KURTIN P: An approach to protein restriction in children with renal insufficiency. Pediatr Nephrol 4:145—151, 1990 68. RAIJ L, CHI0U X, OWENS R, WRIGLEY B: Therapeutic implications of

88. VAN BUREN D, VAN BUREN CT, FLECHNER SM, MADDOX AM, VERANI R, KAHAN BD: Dc novo hemolytic uremic syndrome in renal

transplant recipients immunosuppressed with cyclosporine. Surgery 98:54—62, 1985

89. WOLFE JA, MCCANN RL, SANFILIPPO F: Cyclosporine associated

hypertension induced glomerular injury. Comparison of enalapril

microangiopathy in renal transplantation: A severe but potentially reversible form of early graft injury. Transplantation 41:541—544,

associated with systemic hypertension in the rat. J Gun Invest

90. GIROUX L, SMEESTERS C, CORMAN J, PAQUIN F, ALLAIRE G, ST LOUIS G, DALORE P: Hemolytic uremic syndrome in renal allografted patients treated with cyclosporine. Can J Physiol Pharmacol 65:1125— 1131, 1987

77:1993—2000, 1986

91. SHULMAN H, STRIKER G, DEEG HJ, KENNEDY M, STORB R, THOMAS

and a combination of hydralazine, reserpine and hydrochlorothiazide in an experimental model. Am J Med 79(suppl 3C):37—41, 1985 69. ANDERSON S, RENNKE HG, BRENNER BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease

70. MANN JFE, REISCI-I C, RITZ E: Use of angiotensin-converting enzyme inhibitors for the preservation of kidney function. Nephron 55(suppl 1):38—42, 1990

71. RonIclo JL, ALCAZAR JM, RUILOPE JL: Influence of converting enzyme inhibition on glomerular filtration and proteinuria. Kidney mt 38:590—594, 1990

1986

DE: Nephrotoxicity of cyclosporin A after allogeneic marrow transplantation. Glomerular thrombosis and tubular injury. NEnglJMed 305:1392—1395, 1981

92. CRAIG JI, SHEEHAN T, BELL K: The hemolytic uremic syndrome and bone marrow transplantation. Br Med J 295:887, 1987 93. BONSER RS, ADu D, FRANKLIN Y, MCMASTER P: Cyclosporin-

72. HANNEDOUCHE T, LANDAIS P, GOLFARB B, El. ESPER N, FOURNIER A, GODIN M, DURAND D, CHANARD J, MIGNON F, Suc JM, GRUN-

induced hemolytic syndrome in liver allograft recipients. Lancet

FELD JP: Randomised controlled trial of enalapril and f3 blockers in non-diabetic chronic renal failure. Br Mcdi 309:833—837, 1994 73. BRIONES L, TURCONI A, PEgALOZA J, DELGADO N: Long-term antiproteinuric effect of angiotensin converting enzyme inhibitors in children with renal sequelae following hemolytic uremic syndrome (abstract). Pediatr Nephrol 9:C39, 1995 74. REPETI-O HA: Follow-up of hemolytic uremic syndrome in Argentina, in Hemolytic Uremic Syndrome and Thrombotic Thrombocytope-

94. RODRIGUEZ-RILO L, BRANDI M, REPE1-ro HA, PALTI G, VAZQUEZ

nic Puprura, edited by KAPLAN BS, TROM PETER RS, MOAKE JL, New

York, Dekker, 1992, pp 89—96 75. CERILLI GS, NELSON C, DORFMANN L: Renal homotransplantation in

infants and children with the hemolytic-uremic syndrome. Surgery 71:66—71, 1972 76. FOLMAN R, ARBUS GS, CHURCHILL B, GAUM L, HUBER J: Recur-

rence of the hemolytic uremic syndrome in a 3½ year old child, 4 months after second renal transplantation. Clin Nephrol 10:121—127, 1978 77. LEITHNER C, SINZINGER H, POHANKA E, SCHWARTZ M, KRETSCHMER

G, SYRE G: Recurrence of haemolytic uraemic syndrome by cyclosporin A after renal transplantation. Lancet 1:1470, 1982

78. CAMERON JS: Effect of the recipient's disease on the results of transplantation (other than diabetes mellitus). Kidney mt 23:S24— S33, 1983 79. BONSIB SM, ERCOLANI L, NGHEIM D, HAMILTON HE: Recurrent

thrombotic microangiography in a renal allograft. Case report and review of the literature. Am J Med 79:520—527, 1985 80. STROM TB, MCCLUSKEY RT: Case records of the Massachusetts General Hospital. Case 15—1986. NEnglJMed 314:1032—1040, 1986 81. VAN DER BERG-WOLF MG, KOOTLE A, WEENING JJ, PAUL LC:

Recurrent hemolytic syndrome in a renal transplant recipient and

2:1337, 1984

LA: Long-term course of renal transplants in hemolytic-uremic syndrome (abstract). Pediatr Nephrol 9:C38, 1995 95. LOIRAT C, S0NsIN0 E, HINGLAIS N, JAIS JP, LANDAIS P, FERMANIAN

J: Treatment of the childhood haemolytic uraemic syndrome with plasma. A multicenter randomized controlled trial. Pediatr Nephrol 2:279—285, 1988 96. RIVAS M, VOYER LE, ToUs M, DE MENA MF, LEARDINI N, WAINSTEIN R, CAl LEJO R, QUADRI B, CORTI 5, PRADO V: Verocytotoxin-

producing Escherichia coli infection in family members of children with hemolytic uremic syndrome. Medicina (B Aires) 56:119—125, 1996

97. GIANANTONIO CA: Hemolytic uremic syndrome, in Acute Renal Failure, edited by ANDREUCCI V, Martinus Nijhoff, 1984, pp 327—329 98. WALTERS MDS, MATrHEI IV, KARR R, DILLON MJ, BARRATr TM:

The polymorphonuclear leukocyte count in childhood haemolytic uraemic syndrome. Pediatr Nephrol 3:130—134, 1989 99. KAPLAN BS, MILLS M: Elevated serum elastase and alpha-1-antitrypsin levels in hemolytic uremic syndrome. Clin Nephrol 30:193—196, 1988

100. MILFORD D, TAYLOR CM, RAFAAT F, HALLORAN E, DAWES J:

Neutrophil elastases and haemolytic uraemic syndrome. Lancet 2:1153, 1989 101. FITZPATRICK MM, SHAH V, FILLER 0, DILLON MJ, BARRATr TM:

Neutrophil activation in the haemolytic uraemic syndrome: free and complexed elastase in plasma. Pediatr Nephrol 6:50—53, 1992 102. ROWE PC, ORRBINE E, OGBORN M: Epidemic E. coli 0157:H7 gastroentcritis and hemolytic uremic syndrome in a Canadian Inuit

community: intestinal illness in family members as a risk factor.

review of the Leyden experience. Transplantation 45:248—251, 1988

JPediatr 124:21—26, 1994 103. ARMSTRONG GD, ROWE PC, ORRBINE E: Results of phase 1 study

82. SPRINGATE J, FILDER R, ANTHOINE 5, ANTHONE R, BREUTJENS J,

into the usc of Synsorb-PK for preventing hemolytic uremic syn-

O'SHEA M, FELD L: Recurrent hemolytic uremic syndrome after renal transplantation. Transplant Proc 20:559—561, 1988

drome, in Recent Advances in Verocytotoxin Producing E. coli Infections, edited by KARMALI MA, GIGLI0 AG, Bergamo, Italy, Elsevier

83. ARIAS-RODRIGUEZ M, SRAER JD, KOURISKY 0, SMITH MD, VERROUST PJ, MEYRIER A, KUNTZIGI-I& HE, KANFER A, NESSIM V, NEIJILLY G, MOREL-MAROCiER L, RICIIET 0: Renal transplantation

and immunological abnormalities in thrombotic microangiopathy of adults. Transplantation 23:360—365, 1977 84. PIRSON Y, LECLERO B, SQUIFFLET JS, ALEXANDER GPJ, VAN

Science, 1994, pp 38 1—384

104. EXENI RA: Sindrome Uremico Hemolitico. Medicina (B Aires) 56:197—198, 1996

YPERSELE DE STRIHOU C: Good prognosis of the hcmolytic uremic

105. PAVJA AT, NIchoLs CR, GREEN DP, TAUXE RV, Moi-rICE 5, GREENE KD: Hcmolytic-uremic syndrome during an outbreak of Escherichia coli 0157:H7 infections in institutions for mentally retarded persons: clinical and epidemiological observations. J Pediatr

syndrome after renal transplantation (abstract). 23rd Cong. EDTA, Budapest, 1986, p 197

106. PROULX F, TURGEON JP, DELAGE 0, LAFLEUR L, CHICOINE L:

116:544—551, 1990

85. BERDEN JHM, NETrER P, VAN LIESSUM PA, HOITSMA AJ, ASSMAN

Randomized, controlled trial of antibiotic therapy for Escherichia

KIM, MONNENS LA, KOENE RAP: Hemolytic uremic syndrome during cyclosporin immunosuppression in renal allograft recipients.

coli 0157:117 enteritis. J Pediatr 12 1:299—303, 1992 107. ROBINSON LA, HURLEY RM, LINGWOOD C, MATSELL DG: Esche-

Clin Transplant 1:246—252, 1987 86. GAGNADOUX MF, BROYER M, HABIB R: Renal transplantation in hemolytic-uremic syndrome (abstract). PediairNephrol 3:C184, 1989 87. BASSANI C, FERRARIS J, GIANANTONIO CA, RUIS 5, RAMIREZ J:

gial cells. Pediatr Nephrol 9:700—704, 1995 108. HILLYER CD, DUNCAN A, LEDFORD M, BARRET TJ, KLUMPP SA,

Renal transplantation in patients with classical hemolytic uremic syndrome. Pediatr Nephrol 5:607—611, 1991

richia coli vcrotoxin binding to human paediatric glomerular mesanANDERSON DC, MCCLURE HM, WINTON EF: Chemotherapy-induced hemolytic uremic syndrome: description of a potential animal model. J Med Prima to! 24:68—73, 1995

Nephrology Forum: HUS in children

1719

ultrastructural lesions of idiopathic cutaneous and renal glomerular

ular damage in adult rats born with mild oligoncphronia of proteindeprived mothers. JAm Soc Nephrol 1:629, 1990

vasculopathy of greyhounds. Vet Pathol 32:451—459, 1995 110. JEONG YK, KIM 10, KIM WS, HWAANG YS, CHOI Y, YEON KM:

116. BRANDT JR, FOUSER LS, WATKINS SL, ZELIKOVIC I, TARR PT, VALLE-NAZAR S, AVNER ED: Escherichia coli 0157:h7-associated

Hemolytic uremic syndrome: MR findings of CNS complications.

hemolytic-uremic syndrome after ingestion of contaminated ham-

Pediatr Radiol 24:585—586, 1994 111. ROONEY JC, ANDERSON RMcD, HOPKINS IJ: Clinical and patholog-

117. DESCI-JENES G, CASENAVE C, GRIMOUT F, DESENCLOS JC, BENOIT 5,

109. HERTZKE DM, COWAN LA, Sd-tONING P, FENWICK BM: Glomerular

ical aspects of central nervous involvement in the hemolytic uremic syndrome. Proc Aust Assoc Neurol 8:65—67, 1971 112. UPADHYAYA K, BARWICK K, FISt-tAUT M, KASHGARIAN M, SIEGEL

NJ: The importance of nonrenal involvement in hemolytic uremic syndrome. Pediatrics 65:115—120, 1980 113. ARGYLE JC, HOGG RJ, PYSHER TJ, SILVA FG, SIEGLER RL: A clinicopathological study of 24 children with hemolytic uremic syn-

drome. A report of the Southwest Pediatric Nephrology Study

burgers. J Pediatr 125:519—526, 1994 COLLIN M, BARON S, MARIANI P, GRIMOU PA, NIVET H: Cluster of

cases of hemolytic uremic syndrome due to unpasteurized cheese. Pediatr Nephrol 10:203—205, 1996 118. BOYCE TG, SWERDLOW DL, GRIFFIN PM: Escherichia coli 0157:h7

and the hemolytic-uremic syndrome. N Engi J Med 333:364—368, 1995 119. PEREZ N, RAHMAN R, ZALBA J, BIBIL0NI N, LASARTE P, SPIZZIRRI F:

Group. Pediatr Nephrol 4:52—5 8, 1990 114. MACKENZIE HS, BRENNER BM: Fewer nephrons at birth: a missing

Haemolytic uraemic syndrome and unpasteurized milk (letter). Acta Paediatr 83:142, 1994

link in the etiology of essential hypertension? Am J Kidney Dis

120. CIMOLAI N, CARTER JE, MORRISON BJ, ANDERSON JD: Risk factors

26:91—98, 1995 115. GILBERT T, LELIEVERE-PEORIER M, MERLET-BENICHOU C: Glomer-

for the progression of Escherichia coli 0157:h7 enteritis to hemolyticuremic syndrome. JPediatr 116:589—592, 1990