Refer to: Mendoza SA, Mendoza G: Hemolytic-uremic syndromc -Pediatric Grar* Rounds, University of California, San Dicgo, and Un rsity Hospital, San Dicgo (Specialty Conference) . West J Med 123:459-466, Dcc 1975

Specialty Conference Participants STANLEY A. MENDOZA, MD GUILLERMO MENDOZA. MD

e

Taken from the weekly Pediatric Grand Rounds held at the University Hospital, University of California, San Diego, Medical Center, San Diego.

GUILLERMO MENDOZA: * The patient for discussion this morning is a 6-year-old white boy who presented with a history of six days of mild gastroenteritis that progressed to vomiting with abdominal pain and finally bloody diarrhea. Three days before admission to University Hospital, the patient was admitted to Mercy Hospital with this pattern of evolving symptoms. One day before admission here gross hematuria developed and appropriate studies were done again at that time to establish a diagnosis. A smear taken that evening showed definite microangiopathic changes which were not present on admission. Because of the presumed diagnosis of hemolytic-uremic syndrome the child was transferred to this hospital for dialysis. During the three days at Mercy Hospital, hematocrit fell from 42 to 23 percent. Platelets were originally adequate on smear, but dropped to 42,000 per cu mm. Blood urea nitrogen (BUN) climbed from 15 to 55 mg per 100 ml over the. three days. The creatinine jumped from normal to 5.3 mg per 100 ml. The serum sodium concentration fell from 138 to 128 mEq per liter before hydration was adjusted. Leukocyte count when admitted to University Hospital was 19,000 per cu mm with 40 percent segmented cells and 40 percent band cells and a reticulocyte count of 4.2 percent. On physical examination the heart rate was 136 and the respiratory rate was 24 with minimal distress. The patient was found to be pale, weak and mildly irritable. A Grade III/VI systolic murmur wvas

heard at the left sternal border without radia-

Resident in Pediatrics.

Reprint requests to: Stanley A. Mendoza, MD, Chief, Division of Pediatric Nephrology, Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093.

molytic - Uremic ndrome tion. The liver was 2 cm and spleen tip palpable. Neurologically, deep tendon reflexes were brisk symmetrically. The patient was light-headed and too weak to walk. By the time of transfer, he had been anuric for almost two days. We delayed peritoneal dialysis until the BUN reached 140 mg per 100 ml with a creatinine concentration of 8.6 mg per 100 ml. At that point the patient was moderately irritable, though his condition was otherwise unchanged from admission. Transfusion was carried out to a hematocrit of 28 percent. Dialysis was done initially for three days. The major difficulties during this time were hemolysis and thrombocytopenia without bleeding. Having been anuric for 10 days, the patient began urinating on the eighth day in hospital. At that time, platelet count went from 14,000 to 48,000 per cu mm within one day. From this point on, the platelets made a very steady rise and renal function improved steadily. The patient was discharged two weeks after admission on a 20 gram protein diet. On follow-up five weeks later, BUN was 18 mg per 100 ml with a serum creatinine concentration of 0.7 mg per 100 ml. In summary, we have a six-year-old boy with hemolyticuremic syndrome who was anuric for ten days and who appears to have achieved complete recovery. STANLEY A. MENDOZA:t The case presented this morning is in some ways a typical case of the hemolytic-uremic syndrome (HUS). Before going further, however, it is necessary to modify that remark because the hemolytic-uremic syndrome does not seem to be a single entity. There is a clear difference in the hemolytic-uremic syndrome tAssociate Professor of Pediatrics.

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HEMOLYTIC-UREMIC SYNDROME ABBREVIATIONS U&D IN TEXT BUN=blood urea nitrogen GFR = glomerular filtration rate HUS = hemolytic-uremic syndrome

as seen in different parts of the world. Very little is understood about the pathogenesis of the hemolytic-uremic syndrome. In the absence of such basic information, it is probably premature to talk about a typical case of the hemolyticuremic syndrome. Nevertheless, this case is typical of the hemolytic-uremic syndrome as it is seen in California. The disease occurs here frequently and has been reported in detail by Tune, Lieberman, Piel and their co-workers.`-4 The major locale mentioned in discussions of HUS is Argentina. HUS appears to be about ten times as common in Buenos Aires as in other places in the world. In general, nephrologists will see 2 or 3 cases of HUS a year in the United States, while in Argentina there are 30 or more cases annually.- One significant difference between HUS in Argentina and in California is the age at which the disease occurs. In the series from Buenos Aires, the oldest child with HUS was 37 months of age and the mean age was 13 months. In Argentina, therefore, HUS is a disease of infancy. In the series from Stanford, the mean age was 4½/2 years. There were only two patients at Stanford who were as young as the mean age of the patients from Argentina and, conversely, in the series from Argentina the oldest child was younger than the mean age of the patients from Stanford. In California, therefore, HUS is a disease of young children, but usually not of infants. The patients we have seen in San Diego have been mostly in the age range of four to eight years. Patients with hemolytic-uremic syndrome usually have a prodromal illness. Virtually all of the patients in California with the syndrome present with gastrointestinal symptoms. In Argentina or in Europe, about 50 percent of the patients presenit with upper respiratory symptoms. The prodromal gastrointestinal symptoms are more severe in California than in other parts of the world. It is common for the children to be admitted to hospital because of the severity of diarrhea. The patient presented this morning was, for example, admitted to hospital because of diarrhea. In the Stanford series of 28 patients, laparotomy was carried out in two during prodromal illness. In addition, there are several re460

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ports of patients diagnosed as having ulcerative colitis during the prodromal illness.89 We have seen this recently as well. The prodrome is not only more severe in California, but also tends to be longer than in Argentina. In Argentina, the acute renal failure was coincident with the onset of the prodromal illness in over 50 percent of the cases. In the Stanford series, the prodrome started an average of seven days before the hemolytic and uremic components of the disease. Because most of these children present with a prodromal illness which appears infectious in nature, there has been an intensive search for a causative organism. In addition to the fact that the children have a relatively uniform gastrointestinal prodrome, other things suggest an infectious cause for HUS. The disease is endemic in California. However, there have been several clearly defined epidemics as well. The most striking of these was in Wales, where the syndrome developed in ten patients within a few months in a small geographic area.'0 A variety of organisms have been isolated from patients with HUS. In particular, it is worth mentioning the isolation of a microtatobiote by Mettler" from two patients with HUS and one patient with thrombotic thrombocytopenic purpura. A microtatobiote is an organism similar to a rickettsia. Although this report caused considerable interest at the time, there have been no subsequent reports of the isolation of this organism in children with HUS. Viruses such as Coxsackie, ECHO 29 and arbovirus have been isolated from children with HUS. The arbovirus was isolated in Argentina. There is a disease called Argentinian hemorrhagic fever which is associated with this virus. A sizable number of patients with HUS in Buenos Aires have either had the virus or a rising antibody titer to it.6 As far as I know, this virus has not been isolated in the United States. Further evidence that HUS results from an environmental causative factor was obtained in a prospective collaborative study done- at Stanford and the University of California, San Diego. In this study the siblings of 13 patients with HUS were tested for signs of the syndrome. Three siblings were observed with subclinical manifestations of HUS.12 The presenting complaints of patients with this illness are varied. As I mentioned, the prodromal symptoms are frequently so severe that the patient is admitted because of abdominal pain, diarrhea and weight loss. Other presenting complaints

HEMOLYTIC-UREMIC SYNDROME

are neurological symptoms such as seizures or coma, or symptoms of fluid overload, such as edema, hypertension or congestive heart failure. Occasionally there is a history of infrequent urination, but this is an unusual presenting complaint. On the other hand, pallor is a relatively common presenting complaint. I have seen a number of children with HUS who have had several days of vomiting or diarrhea. Then one morning the parents come into the child's room and find him spectacularly pale. These children are taken to a physician and hemoglobin concentrations are found to be in the range of 4 to 5 grams per 100 ml.

Manifestations of Hemolytic-Uremic Syndrome What are the manifestations of the hemolyticuremic syndrome? First, as we have already mentioned, there is a prodromal illness which is usually gastrointestinal. Second, there is a hemolytic anemia with microangiopathic changes of the red blood cells. Occasionally, there is evidence of hemolysis without actual anemia. In other words, in some patients there will be hemoglobin concentrations in the range of 10 to 12 grams per 100 ml with a high reticulocyte count and red blood cells with microangiopathic changes. The peripheral smear contains helmet cells, burr cells and a sizable proportion of abnormal fragmented-appearing red blood cells. The smear is so characteristic that it should be examined in any child with acute renal failure. In this way, it is possible to make a presumptive diagnosis of hemolytic-uremic syndrome very rapidly. This is the manner in which the diagnosis was confirmed in the child presented this morning. If findings on the smear are normal, the diagnosis of hemolyticuremic syndrome becomes less likely. We have seen several children, however, in whom findings on first smears were essentially normal but in whom a typical microangiopathic smear was seen one or two days later. Most of the children with HUS are also thrombocytopenic but this is not invariable. About two thirds of patients with HUs have oliguria. There seems to be some correlation between the severity of the oliguria and the eventual outcome for the patient. However, I cared for a child in Chicago who was not oliguric until four weeks into the illness when severe central nervous system symptoms developed and he died. Patients with HUS have hematuria and protein-

uria. The BUN iS often quite high and tends to rise very rapidly because in these patients large numbers of red blood cells are breaking down and therefore more protein is being metabolized and more urea is being produced than in a normal patient. In an anephric patient on dialysis there usually is a sUN rise of about 20 mg per 100 ml per day. The increase in BUN in patients with hemolytic-uremic syndrome is often as great as 50 to 100 mg per 100 ml per day. About half of the children with HUS are hypertensive. In a sizable number there are neurological findings such as coma or stupor. It is unclear whether the neurological findings result from a primary central nervous system vasculitis or are a secondary reaction to the fluid overload, azotemia and hypertension. Our experience in California has been more compatible with the latter explanation since the neurological symptoms usually improve quickly after dialysis and administration of antihypertensive drugs. This experience is notably different from the experience in Argentina or in Europe, where a much greater proportion of the patients appear to have primary central nervous system involvement. We have had one patient who was comatose on admission and in whom there were severe central nervous system residua after the renal failure cleared. We assume that central nervous system vasculitis was present in this patient. The renal histopathology of hemolytic-uremic syndrome is extremely varied. The most typical finding is thrombotic microangiopathy, that is, abnormalities of the small arterioles in the glomerulus. On the other hand, occasionally patients will present with bilateral renal cortical necrosis, with findings of acute tubular necrosis and relatively normal glomeruli, or with proliferative nephritis that in another setting one might call chronic glomerulonephritis.13 The heterogeneous histopathology may be another reflection of our ignorance about the syndrome. As mentioned earlier, we tend to talk about hemolytic-uremic syndrome as if it is an entity; however, it probably has a number of different causes and these may be related to the different pathologic findings and prognoses.

Prognosis I would like to comment next on prognosis. In the Stanford series, there were 28 cases of the hemolytic-uremic syndrome in 27 patients. One child had two episodes of HUs separated by one THE WESTERN JOURNAL OF MEDICINE

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year during which he seemed to have recovered completely. All of the patients were treated with conservative management of the acute renal failure. Of the 27 patients, there were three deaths, which is an 11 percent mortality rate. It is important to note that two of the three deaths occurred in the five patients seen before peritoneal dialysis was available at Stanford. Thus, of the last 22 patients seen, there was only one death, which is a mortality rate of less than 5 percent. Of the 21 patients who were available for follow-up, 19 were completely well one to eight years after the original episode of hemolyticuremic syndrome. In two children there was renal insufficiency; in one a transplant was required and in the other there was stable renal insufficiency over a period of a number of years. Our experience in San Diego has been similar. Of the 13 patients we have seen in the past three years, there have been no deaths. In 11 of the children renal function is now normal. In two, BUN levels are mildly elevated and creatinine clearances are diminished. As mentioned earlier, there is residual central nervous system damage in one. The point is that these patients are terribly ill. They have severe renal failure and without good management would probably die. If they are managed through the acute episode, however, one can expect about 95 percent of the children to survive and 80 to 90 percent to recover completely. The lesson of this is that the management of the acute renal failure of the hemolytic-uremic syndrome is extremely important, because it makes a difference between a dead child and a child with a little or no residual disease. The patient presented today is apparently totally well at the present time. The hematologic features are normal, as are serum creatinine concentration and creatinine clearance. Findings on urinalysis are normal. It is reasonable to expect he will have a perfectly normal life. I repeat, therefore, it is essential that the management of these children during acute renal failure be excellent because of the high probability that good management will provide them with a normal life expectancy.

Management of Acute Renal Failure It is important then to focus on the management of acute renal failure. In general, there is no specific therapy which will hasten the recovery of renal function in children with acute renal failure. This appears to be true of the hemolyticuremic syndrome, although we will return to this 462

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TABLE 1.-Causes of Death in Acute Renal Failure 1. Circulatory overload 2. Hypertension 3. Electrolyte imbalance, especially hyperkalemia 4. Uremia 5. Infection

question later. It is equally true of acute poststreptococcal glomerulonephritis. Therefore, the goal of treatment is to provide the patient time to heal his own kidneys. My approach to this particular problem is utilitarian. By this I mean my therapy is designed to prevent the patients from dying. Table 1 lists the causes of death in children with acute renal failure. The pathogenesis, prevention and therapy of these potentially lethal complications of acute renal failure will be discussed. The first cause of death to be discussed is circulatory overload resulting in pulmonary edema, peripheral edema, tachycardia and hepatomegaly. The cause of this problem in patients with acute renal failure is salt and water overload resulting from the inability of the kidney to maintain normal body fluid volume and composition. This complication can be prevented by careful regulation of salt and water intake to prevent fluid overload. The treatment of existent circulatory overload is more difficult. The classical forms of therapy for congestive heart failure can be tried. These include phlebotomy, rotating tourniquets, oxygen, bed rest and administration of morphine. I would like to stress the point that digitalis is contraindicated in patients with acute renal failure. There are two reasons for this. First, in a patient with acute renal failure signs of circulatory overload develop because the heart has been unable to keep up with the excessive load of salt and water and not because there is intrinsic cardiac disease. The heart has increased its stroke volume maximally in an attempt to handle the salt and water overload and this increase has been insufficient to maintain circulatory balance. Digitalis acts primarily by increasing the contractility of the heart. Since patients with acute renal failure have notably increased cardiac contractility, the administration of digitalis is essentially like beating a dead horse. This reasoning would suggest that digitalis is ineffective in patients with acute renal failure, and this is what has been observed clinically. In addition, however, digitalis is highly dangerous in patients with acute renal failure, because it is very easy to induce digitalis intoxica-

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tion. Digitalis is excreted by the kidney. Patients with acute renal failure can easily be overdosed with digitalis. This presents a therapeutic dilemma. First, digitalis is poorly dialysable so that it cannot be removed easily. Second, digitalis intoxication is usually treated with intravenously giveni potassium and this is obviously extremely dangerous therapy for a patient without functioning kidneys. Since digitalis is unlikely to have a positive effect and is very dangerous, it is contraindicated in patients with acute renal failure and no evidence of intrinsic cardiac disease. What about diuretics? They often do not work in patients with acute renal failure. The reason for this is that diuretics act by decreasing reabsorption of sodium, chloride and water by the nephron. In patients with severe acute renal failure, the glomerular filtration rate (GFR) iS often very low. If the GFR iS sufficiently low, blocking tubular reabsorption will still not result in urine formation. Thus, diuretics work best in patients with mild acute renal failure and a moderately decreased GFR and least well in patients with severe acute renal failure and essentially no GFR. Nevertheless, in some patients with severe renal failure, diuresis will occur following the administration of a powerful diuretic such as furosemide or ethacrynic acid. A small increase in salt and water excretion can be lifesaving in a patient with severe circulatory overload due to acute renal failure. In addition, powerful diuretics such as ethacrynic acid or furosemide have relatively few side effects. The major reported complication of treatment with these drugs is electrolyte imbalance resulting from an excessive diuresis. This complication would represent a therapeutic triumph in a patient with circulatory overload and acute renal failure. Hearing loss has been reported with both diuretics but this is almost always transient. Since they occasionally work and are relatively safe, I feel the use of diuretics is indicated in patients with circulatory overload due to acute renal failure. Nevertheless, one should not rely upon them to be effective. The ultimate treatment for patients with acute renal failure and circulatory overload is dialysis (either peritoneal dialysis or hemodialysis). It is worth making a practical point at this time. In general, it takes at least one or two hours to begin a peritoneal dialysis or to organized a hemodialysis. Therefore, when faced with a patient with acute renal failure and circulatory overload, I use oxygen, rotating tourniquets, diuretics and mor-

phine. At the same time, I begin gathering the materials necessary to begin dialysis. By the time it is feasible to institute dialysis, the patient will have either responded to the conservative therapy or not. If not, it is possible to begin dialysis without further delay. We will discuss more about the indications and complications of dialysis in a few moments.

Hypertension in Acute Renal Failure Next, let us consider the question of the management of hypertension in acute renal failure. About half of the patients with HUS are hypertensive. Hypertension can result in coma, convulsions, encephalopathy and death in these patients. In addition, it can increase the tendency toward circulatory overload by increasing cardiac work. There are several causes of hypertension in patients with HUS. First, in patients with HUS there often are microangiopathic changes of the renal arterioles. Plasma renin activity was measured in five hypertensive patients with HUS and was notably elevated in all five.14 It seems likely that the renal vascular disease with elevated renin levels can play a significant role in causing hypertension. In addition, the patients have salt and water overload with an increase in extracellular fluid volume which predisposes to hypertension. The prevention of hypertension can be attempted by restriction of salt and water intake. Antihypertensive drugs should be used. Since it is desirable to bring the blood pressure down relatively' rapidly, drugs with a rapid onset of action are desirable. In general, I begin therapy with intravenously administered hydralazine but any number of drugs may be used. Propranolol appears to decrease* renin secretion and therefore may be useful in these patients. However, the drug has significant cardiac effects and should be used with extreme caution in patients with circulatory overload. Dialysis is an effective way of decreasing the blood pressure because salt and water can be removed, correcting the volume overload. A third cause of death in patients with acute renal failure is electrolyte imbalance, the most dangerous being hyperkalemia. There are at least three causes of hyperkalemia in patients with acute renal failure: dietary intake of potassium, tissue breakdown and administration of blood. Hyperkalemia can be a particular problem in patients with hemolytic-uremic syndrome. In these patients there is a sizable amount of cellular breakdown in the form of hemolysis. Since the THE WESTERN JOURNAL OF MEDICINE

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HEMOLYTIC-UREMIC SYNDROME TABLE 2.-Treatment of Hyperkalemia Agent

Onset of Effect

Minutes Minutes 20-30 minutes 1-2 hours

Calcium gluconate .... Sodium bicarbonate ... Insulin and glucose ... Kayexalate .... .. ... Variable Dialysis ...

Duration of Effect

30-60 minutes 1-2 hours 2-4 hours 4-6 hours

Variable

intracellular concentration of potassium is about 150 mEq per liter, the breakdown of blood releases a sizable load of potassium into the plasma. In addition, the hemolysis is frequently so severe that blood transfusions which tend to exacerbate the hyperkalemia are required.

Preventing Hyperkalemia The occurrence of hyperkalemia can be prevented in several ways: The dietary intake of potassium should be minimal. A patient should be given at least 20 to 25 percent of his estimated caloric requirement. This has the effect of decreasing protein catabolism, thereby decreasing the breakdown of cells and the release of potassium. Only fresh blood should be used to transfuse children with acute renal failure because the serum potassium concentration rises with the storage of banked blood. The risks of transfusion can be diminished further by using packed red cells rather than whole blood, thereby decreasing the volume of potassium-containing plasma administered. This is also desirable since it diminishes the volume of transfused blood thereby decreasing the risk of circulatory overload. In fact, we often do a partial exchange transfusion in these children. This procedure is done by giving one or two units of packed cells and removing a slight excess of the patient's blood. This procedure will produce a small volume deficit which will tend to decrease the blood pressure and the risk of circulatory overload, while at the same time the number of circulating red blood cells is increased. One should only transfuse these patients with buffy coat poor, washed or frozen red blood cells to diminish the risk of sensitization to tissue antigens in case the patient requires a renal transplant. In Table 2, the various forms of therapy for hyperkalemia are listed in order of their onset and duration of action. If the patient is severely hyperkalemic with pronounced changes noted on electrocardiograms, the drugs of choice are calcium and sodium bicarbonate. These can reverse electrocardiographic (EKG) abnormalities within

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one to three minutes, but the effect is short-lived. Calcium acts by antagonizing the effect of potassium on cardiac muscle. Sodium bicarbonate administration causes release of hydrogen ions from the cells in exchange for potassium ions. If the hyperkalemia is less severe or an emergency s4tuation has been temporarily alleviated by calcium and sodium bicarbonate administration, the next form of therapy is insulin and glucose. Insulin increases the uptake of glucose by cells and potassium is taken up with the glucose. It is essential that glucose be given to cover the insulin infused or the patient can become symptomatically hypoglycemic. It is said that insulin and glucose begin to act in 20 to 30 minutes, but I have seen EKG changes sooner. The effect lasts only a few hours. Calcium, sodium bicarbonate, and insulin and glucose do not remove potassium from the body. Therefore, hyperkalemia tends to recur relatively rapidly. There are two forms of therapy that do remove potassium from the body. The first is the ion exchange resin sodium polystyrene sulfonate (Kayexalate®), which is given in the sodium form either orally or rectally. The resin exchanges sodium for potassium and the potassium loaded resin is excreted in the stools. This has the disadvantage that patients with acute renal failure can get an excessive load of sodium by the use of Kayexalate. A second method for removing potassium is peritoneal dialysis or hemodialysis.

Uremia and Infection A fourth cause of death in acute renal failure is uremia. A number of problems fall into this category, but the primary life threatening aspects are neurologic symptoms, including coma, stupor and convulsions. These symptoms can also be caused by hypertension or by central nervous system vasculitis. There are a variety of nitrogenous products which build up in the blood stream of patients with acute renal failure. Although the correlation between the concentration of any of these products and the occurrence of neurologic symptoms is poor, it is generally assumed that some product (or products) of protein metabolism is responsible for the neurologic symptoms. The onset of neurologic symptoms and the rise in the concentrations of urea and creatinine can be slowed by giving enough calories to diminish protein catabolism. The symptoms of uremia can often be treated or prevented by dialysis. As I mentioned earlier, the BUN level can rise at an extremely rapid rate in patients with hemolytic-

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uremic syndrome because of the massive red blood cell breakdown. Therefore, in patients with HUS dialysis should be done relatively early in order to avoid extremely elevated blood levels of urea and other protein breakdown products. The fifth cause of death in acute renal failure is infection. Several things tend to make a patient with acute renal failure more susceptible to infectio`n. First, patients with uremia appear to have a decreased resistance to infection. Second, these patients are frequently immobile and therefore there is a tendency for hypostatic pneumonia and decubiti to develop. Third, it is a common practice to monitor urine output of these patients by the use of indwelling catheters. The risk of infection can be decreased by careful nursing, including strict attention to such things as turning, coughing and deep breathing. In addition, the use of indwelling bladder catheters is unwarranted. The only information which a catheter provides is an hour by hour measurement of the urine output. This information is essentially worthless. Therapeutically it is important to know whether a small or a large volume of urine is being produced. This information becomes available quickly because the patient either voids or an enlarged bladder develops if the urine volume is high. An indwelling catheter in a patient with a low urine output and decreased resistance to infection is an invitation to infection. The treatment of infection in patients with acute renal failure is similar to that of other patients, namely the use of the appropriate antibiotics. Of course, some antibiotics must be given in reduced doses to patients with impaired renal function. It is important to recognize that in many series, 50 percent of the deaths in acute renal failure are from infection, and therefore one must have a very high index of suspicion. The indications for dialysis in a patient with acute renal failure are circulatory overload, severe hypertension, severe electrolyte imbalance and symptoms of uremia. These indications are virtually identical with the causes of death in acute renal failure. The implication of this is that dialysis should be done promptly in every patient with acute renal failure who responds poorly to conservative measures. Dialysis, whether peritoneal dialysis or hemodialysis, is a relatively benign procedure and is frequently lifesaving in patients with acute renal failure. The choice between peritoneal dialysis and hemodialysis depends more on the experience of the physician

doing the procedure and the available equipment than on any advantage of one over the other. One possible complication of hemodialysis is probably worthy of mention. This is the dialysis dysequilibrium syndrome. This syndrome can occur if the serum osmolality is lowered too rapidly. This tends to occur in patients in whom BUN is notably elevated before dialysis. The complication can be prevented by increasing the osmolality of the dialysis bath, thereby decreasing the rate of fall of the serum osmolality.

Use of Anticoagulants No discussion of the hemolytic-uremic syndrome would be complete without mention of the use of anticoagulants, particularly heparin. A number of uncontrolled studies have suggested that heparin is valuable in the treatment of the hemolytic-uremic syndrome.2-4 These observations were made in California, and the conclusion was reached by comparing the results obtained with those obtained without heparin in Argentina. When heparin treated patients are compared with the patients from Stanford who received no heparin, no difference is seen.' In addition, a recent controlled study of the use of heparin in Argentina indicated that there was no improvement in the prognosis following the use of heparin.'5 In general, it would appear that the prognosis of patients with the hemolytic-uremic syndrome in California treated conservatively is so good that it is difficult to justify a therapeutic trial of a potentially dangerous drug such as heparin. This opinion is not universally held, and a recent report suggests that heparin may have increased the world-wide survival rate of patients with HUS. This report suggests an international collaborative study to answer the question.'6 More recently, the use of streptokinase has been proposed.'7-20 The rationale of this therapy is that thrombi can be seen in the small vessels of patients with hemolytic-uremic syndrome. It is felt that streptokinase might hasten the removal of these thrombi and therefore improve the prognosis. Once again, however, this is proposing the use of a potentially dangerous drug in a group of patients whose prognosis is excellent without the drug. In conclusion, the hemolytic-uremic syndrome in California appears to be significantly different from the syndrome described in Argentina and Europe. In California, the illness is characterized by a severe gastrointestinal prodrome which is THE WESTERN JOURNAL OF MEDICINE

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followed by acute renal failure and hemolytic anemia. The prognosis is excellent with 95 percent of the patients surviving the acute illness and about 90 percent recovering normal renal function. For this reason, intensive medical management of the acute renal failure is mandatory. REFERENCES 1. Tune BM, Leavitt TJ, Gribble TJ: The hemolytic-uremic syndrome in California-A review of 28 nonheparinized cases with long-term follow-up. J Pediatr 82:304-310, Feb 1973 2. Lieberman E, Heuser E, Donnell GN, et al: Hemolyticuremic syndrome. N Engl J Med 275:227-236, Aug 4, 1966 3. Lieberman E: Hemolytic-uremic syndrome. J Pediatr 80:1-16, Jan 1972 4. Piel CF, Phibbs RH: The hemolytic-uremic syndrome. Pediatr Clin North Am 13:295-314, May 1966 5. Gianantonio C, Vitacco M, Mendilaharzu F, et al: The hemolytic-uremic syndrome. J Pediatr 64:478-491, Apr 1964 6. Gianantonio CA, Vitacco M, Mendilaharzu F: The hemolytic-uremnic syndrome. Proc 3rd Internat Congr Nephrol, Washington 1966, Basel/New York 1967, S Karger AG, Vol 3, pp 24-36 7. Gianantonio CA, Vitacco M, Mendilaharzu F, et al: The hemolytic-uremic syndrome-Renal status of 76 patients at longterm follow-up. J Pediatr 72:757-765, Jun 1968 8. Berman W: The hemolytic-uremic syndrome: Initial clinical presentation mimicking ulcerative colitis. J Pediatr 81:275-278, Aug 1972 9. Bar-Ziv J, Ayoub JIG, Fletcher BD: Hemolytic-uremic syn-

drome: A case presenting with acute colitis. Pediatr Radiol 2: 203-206, Aug 1974 10. McLean MM, Jones CH, Sutherland DA: Haemolyticuraemic syndrome. A report of an outbreak. Arch Dis Child 41: 76-81, Feb 1966 11. Mettler NE: Isolation of a microtatobiote from patients with hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura and from mites in the United States. N.Engl J Med 281: 1023-1027, Nov 6, 1969 12. Tune BM, Groshong T, Plumer LB, et al: The hemolyticuremic syndrome in siblings-A prospective survey. J Pediatr 85: 682-683, Nov 1974 13. Aschinberg LC, Bennett B, Edelmann CM, et al: The heterogeneous pathology of the hemolytic-uremic syndrome. Pediatr Res 7:408, Apr 1973 14. Powell HR, Rotenberg E, Williams AL, et al: Plasma renin activity in acute poststreptococcal glomerulonephritis and the haemolytic-uraemic syndrome. Arch Dis Child 49:802-807, Oct 1974 15. Vitacco M, Avalos JS, Gianantonio CA: Heparin therapy in the hemolytic-uremic syndrome. J Pediatr 83:271-275, Aug 1973 16. Proesmans W, Eeckels R: Has heparin changed the prognosis of the hemolytic-uremic syndrome? Clin Nephrol 2:169-173, Sep/Oct 1974 17. Bergstein JM, Edson JR, Michael AF: Fibrinolytic treatment of the haemolytic-uraemic syndrome. Lancet 7:448-449, Feb 19, 1972 18. Monnens L, Kleynen F, van Munster P, et al: Coagulaticn studies and streptokinase therapy in the haemolytic-uraemic syndrome. Helv Paediat Acta 27:45-54, Apr 1972 19. Winterborn MH, White RHR, Stuart J: Fibrinolytic treatment of the haemolytic-uraemic syndrome. Lancet 1:1071, May 13, 1972 20. Van Wieringen P, Monnens L, de Jong M: Follow-up of 62 children with hemolytic-uremic syndrome treated by streptokinase. (Abstract) Kidney Internat 7:363-364, May 1975

Adolescent Menstrual Disorders I want to know whether there is an important abnormality here or not. If there is not, I am confident that I can pinpoint the emotional precipitating cause for hypothalamic pituitary suppression. I do nothing and, when I say nothing, I do not mean absolutely nothing. I sit down and talk to this patient for some time, explaining to her that, in my view, not menstruating is not, per se, doing her any harm. I believe that most patients who are amenorrheic for this reason are not at risk simply because they are not menstruating. I seldom find it necessary to produce any kind of withdrawal bleeding to raise their morale. It is my experience that patients accept an explanation of this kind. They come because they want to know if something is the matter with them; and I generally do nothing except give them this kind of explanation. Now, I do not lose track of them completely; I see them at intervals. I might even begin by bringing them back in six months, but I will probably see them yearly after that because, otherwise, I think they lose faith in what you have told them. They say, "Well, 1 wonder if he really understood what he was talking about," and they go off to another department and do the whole thing again-which is, generally speaking, unnecessary. -C. J. DEWHURST, MD, London Extracted from Audio-Digest Obstetrics and Gynecology, Vol. 22, No. 2, in the Audio-Digest Foundation's subscription series of tape-recorded programs. For subscription information: 1930 Wilshire Blvd., Suite 700, Los Angeles, CA 90057.

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DECEMBER 1975 * 123 * 6

Specialty conference: Hemolytic-uremic syndrome.

Refer to: Mendoza SA, Mendoza G: Hemolytic-uremic syndromc -Pediatric Grar* Rounds, University of California, San Dicgo, and Un rsity Hospital, San Di...
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