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The Children's Hospital Medical Center, Boston, Mass.
CLINICAL
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M.D., Editor Gordon F. Vawter, M.D., Assistant Editor
A
2L~12-YEAR-OLD
G I R L was admitted
for the second time with intermittent pain in the left flank and fever which had been present one month. The child had been well, although slow in social development, until 18 months of age when she had coryza, sore throat, and a temperature of 101 to 102 ~ F. which was treated with penicillin for three days. Two weeks later fever recurred (100 ~ F.) accompanied by urinary frequency, dysuria, and pink urine on several occasions. The following studies were recorded: Blood pressure was 110/72 mm. Hg; hematocrit, 26 per cent; blood leukocytes, 4,400 per cubic millimeter; and urinalysis demonstrated specific gravity 1.005 to 1.012, proteinuria 10 to 70 rag. per cent, with many leukocytes on two occasions in the spun sediment with more than 100,000 colonies of Escherichia coli growing per milliliter of urine. Intravenous pyelogram suggested bilateral hydronephrosis, severe on the left and minimal on the right. The child improved on Gantrisin (4 teaspoonfuls per day) pending transfer to the Children's Hospital Medical Center where she'entered for the first time at 19 months of age. Vital signs were: pulse rate, 100 per minute; respirations, 18 per minute; and temperature, 99 ~ F. Studies of blood revealed Vol. 70, No. 6, pp. 1000-1008
a hematocrit of 37 per cent, 4,800 leukocytes per cubic millimeter, and a blood-ureanitrogen (BUN) value of 14 rag. per cent. Urine contained 0 to 500 rag. per cent of protein, 50 leukocytes per high-power field (later falling to 3 to 6), and no growth on bacterial culture. Cystoscopy revealed a normal bladder. Left retrograde pyelogram showed severe hydronephrosis and a short ureteral pelvic stricture. A Y-V plasty was made on the stricture. Biochemical studies of blood obtained postoperatively were: carbon dioxide, 16.4 mEq. per liter; sodium, 126 mEq. per liter; potassium, 4.6 mEq. per liter; and chloride, 85 mEq. per liter. The child did well, except for a fever of 102 ~ F. which was recorded following removal of the nephrostomy tube on the tenth day in the hospital. E. coli was cultured from urine, and therapy with chloramphenicol was begun. During this period, serum contained sodium, 138 mEq. per liter and chloride, 96 mEq. per liter. The intravenous pyelogram revealed continuing severe hydronephrosis and some delay in emptying of the left pelvis. After one month she was discharged receiving Gantrisin and was closely followed in the genitourinary clinic. One month later, urinalysis demonstrated proteinuria, pyuria (10 to 20 leukocytes), and bacilluria (over 100,000
Volume 70 Number 6
colonies of Klebsiella). Furadantin and Gantrisin were administered, and subsequent cultures of urine were negative. On the second admission physical findings included: pulse rate, 108 per minute; temperature, 100 ~ F.; blood pressure, 172/78 mm. Hg; pallor, and moderate tenderness over the left costovertebral area. Neither kidney was palpable. Laboratory studies demonstrated: hematocrit, 38 per cent; blood leukocytes, 7,600 per cubic millimeter; p H urine, 5; pro teinuria (59 mg. per cent); bacteriologically sterile urine, 10 to 20 erythrocytes and rare leukocytes in the centrifuged urinary sediment; and BUN, 12 mg. per cent. Therapy with Gantrisin was continued in the hospital. Maximal fevers of 100 to 101.5 ~ F. occurred daily whereas the cardiac rate averaged between 110 and 140 per minute. Cystoscopy and left retrograde pyelogram on the second day revealed severe hydronephrosis and some ureteropelvic obstruction. On the fifth day, therapy with Achromycin (500 mg., 6 hourly) was begun. The next day the left kidney was operated on: adhesions binding the upper ureter to the pelvis were freed; nephro.stomy and proximal catheter ureterostomy were made, since further plastic repair was not feasible. Postoperatively, the patient was maintained on 500 ml. each of 5 per cent glucose in water and normal saline intravenously and she did well, except that she refused oral intake and had small vomits occasionally. On the fourth postoperative day, she was lethargic and temperature fell to 94 ~ F., rectally, and nephrostomy drainage had fallen from 315 to 83 ml. per day. Extremities were cold and blue. Blood pressure was 80 mm. H g systolic. Therapy was begun with ampicillin, Chloromycetin (500 mg. per day) and hydrocortisone (75 rag.). Blood sugar was 616 mg. per cent (glucosuria 2+, acetone 0). Other studies of blood demonstrated a nonprotein nitrogen (NPN) value of 100 mg. per cent; carbon dioxide, 7.7 mEq. per liter; sodium, 112 mEq. per liter; potassium, 6.4 mEq. per liter; chloride, 80 mEq. per liter, and leukocytes, 39,000 per cubic millimeter.
Clinical pathological conference
1 00 1
Roentgenological studies of the chest and abdomen demonstrated only microcardia. Plasma, saline, and sodium bicarbonate solution were given intravenously, and some improvement resulted. Next day, while the patient was lying on a warming blanket, her temperature was 98.6 ~ F. and systolic blood pressure was 104 mm. Hg. A leukocyte count was 8,400 per cubic millimeter, and hemoglobin, 11.5 Gm. per cent. Blood contained: carbon dioxide, 5.5 mEq. per liter (later rising to 18.3 mEq. per liter); sodium, 125 mEq. per liter; potassium, 4.2 mEq. per liter; chloride, 82 to 84 mEq. per liter, and calcium, 8.5 mg. per cent. Urine contained 8.8 mEq. per liter of sodium and 1.2 mEq. per liter of potassium, whereas nephrostomy urine contained 9.4 mEq. per liter of sodium and 1.1 mEq. per liter of potassium. Therapy with Achromycin was discontinued. Coffee-ground material was obtained in gastric aspirate. She seemed improved after a transfusion of whole blood, but no clear benefit was observed following administration of Tris buffer. Two days later she recovered from cardiac arrest after treatment with additional sodium bicarbonate, calcium chloride, and intubation. She died later in the day after several further cardiac arrests. DR. ROBERT FILLER.@ This is a case of a 2year-old girt who had infection of the urinary tract, associated with a potentially correctable surgical lesion. An operation was performed but could not be termed a success. A second operation was necessary, shortly followed by a whole series of catastrophic events ending in death. I would like to divide the discussion into two parts; first, a discussion of the basic urinary abnormality together with the basic pathology in the kidney, and second, an analysis of the fatal outcome. Eighteen months is, perhaps, a common age for the occurrence of renal infection associated with an underlying renal anomaly, but frequently pyelonephritis is found even earlier in life. We now know that renal infections are often misdiagnosed as upper respiratory infections or other viral diseases in the very young. However, two ~Dr. Filler is Assistant in Surgery, Children's Hospital Medical Center, Boston, Mass.
1 002
Clinical pathological conference
weeks after onset of fever, this patient developed symptoms of frequency, dysuria, and episodes of presumptive hematuria, clearly indicating urinary tract involvement. These symptoms, of course, are not specific for any particular renal anomaly and could reflect infection of the lower urinary tract as well as infection of the upper urinary tract. These original symptoms give us no clue to the exact location of the basic pathology. One important point in the original and subsequent physical examinations was the blood pressure of 110/72, which, for a child of this age, would be abnormally high. This perhaps gives us some inkling that this girl probably has relatively severe renal disease, even at this age. The urinalyses indicate a significant urinary tract infection associated with E. coli but do not allow us to localize the process further. The normal N P N value is noteworthy, but we must remember that she need have no more than 20 per cent of her nephrons functioning to maintain this value. The patient had x-rays and eventually a retrograde pyelogram at the time of cystoscopy. Perhaps Dr. Wittenborg can review these since the protocol does not give a complete picture of the results. DR. MARTIN WITTENBORG. I have selected only representative examples of the many films available. The first set of films shows an intravenous urogram. The liver and splenic shadows, gastrointestinal tract, lumbar spine, and pelvis are normal. Five minutes after the injection of the opaque medium, the appearance time of dye, on the right, is good, but there is marked delay on the left, with only little, rounded globules filling up what appear to be dilated collecting structures. I think the protocol is a little bit amiss in this description. In fact this is not really bilateral hydronephrosis. The right kidney looks remarkably normal compared to the left, although there is only slight blunting of the upper calyces. And we will see later that there is only a right pelvic ectasia. Three and one half hours after the dye has been injected, the right kidney is essentially drained. The bladder has good content of dye, and on the left you see gross hydronephrosis with calyces dilated and blunted, and there is no suggestion that the left ureter is enlarged. Cystogram on the next day shows that the bladder has normal capacity with no ureteral reflux on either side. Voiding cystogram was normal. Left retrograde pyelography confirms the marked dilatation of the renal pelvis and also
The Journal of Pediatrics June 1967
suggests a slight extravasation of dye into renal tissue. In a later film, there is a distinct, localized obstruction at the pelvic ureteral junction with a perfectly normal ureter. DR. FILLER. Do you think that any of the findings on the right side could be interpreted as secondary to infection? DR. WITTENBORO. The calyceal structures are blunted, what we call ectasia, a mild dilatation which can be secondary either to pyelonephritis, to a low-grade outflow obstruction, or to a combination of both. The fact that the pelvis is perfectly normal in size at this age is not too helpful. As a rule, if ectasia is on an obstructive basis, we would see comparable dilatation on both sides. I would suspect that here it is infection, DR. FILLER. This set of findings fits into a group of hydronephroses characterized by ureteropelvic obstruction, the point of obstruction being at the ureteric origin from the pelvis. In such specimens the typical morphological findings include a large, rounded, renal pelvis to which is attached a ureter of normal caliber. The pelvis dilates medially and is quite distinct from renal parenchyma. Associated with the dilatation are all degrees of renal parenchymal atrophy. In cases which are less severe and of shorter duration there is more renal tissue than in those with long-standing obstruction. In cases with severe obstruction, the dilated pelvis is merely a sac of pus and stagnant urine. Several different anatomic abnormalities can be associated with ureteropelvic obstruction. Aberrant renal vessels to the lower pole of the kidney can kink and obstruct the ureter and in these cases intrinsic ureteral defects or strictures often coexist. The surgical lesson here is that, after the division of an aberrant renal vessel, the inside of the ureter must be inspected to avoid missing an intrinsic obstruction. Strictures at the ureteropelvic junction can exist in the absence of aberrant vessels as can intrinsic valvelike obstructions. Adhesions of unknown etiology with kinking and obstruction of the upper ureter have been seen to cause ureteropelvic obstruction. Localized developmental defects of the ureter resulting in malformations in which multiple tight convolutions obstruct the upper ureter have also been noted in these patients. Perhaps the rarest lesion seen in these cases is a defect in the muscular wall of the ureter which causes the ureter to dilate and become aperistaltic, resulting in a functional block to urine flow.
Volume 70 Number 6
A Y-V plasty was done in the patient. This is the usual operation to correct most of these defects. There are some instances, however, when a portion of the ureter has to be resected and continuity restored by anastomosis between the pelvis and the lower ureter. There are others with other variations of the stricture, in which some other type of plastic procedure can be carried out to relieve the obstruction. The protocol does not describe the exact lesion in this particular case. Perhaps someone can tell us a little more about that. At any rate, on the basis of frequency of lesions, I assume that either an aberrant renal vessel or a ureteropelvic stricture was present in this little girl. In terms of surgery, there are several possibilities when one sees a case such as this. One is to carry out some kind of reparative procedure, and the other is to perform a nephrectomy. This is the major decision that has to be made at the operating table after the kidney is exposed, since it often cannot be made preoperatively. There are several facts that would lead one to refrain from removing the kidney. In the presence of bilateral disease with bilateral hydronephrosis and an already significant decrease in renal tissue, then one would try to do everything in his power to save the kidney. On the other hand, if the renal parenchyma is so highly thinned out that, despite adequate correction of the obstruction, there is little likelihood of return of renal function, then nephrectomy would be wiser, especially since such a kidney can still be the site of persistent serious infection. The decision can be made only by the surgeon when he has the kidney in his hands. This particular child had some abnormality in the opposite kidney according to the protocol. Ureteropelvic disease is usually unilateral, but about 10 per cent of patients have bilateral lesions. In general, one would attempt to repair both sides. So far as results are concerned, most of the series in the literature show that about 75 per cent of these children have what can be termed good or excellent results. By that is meant a relief of symptoms and freedom from infection. So far as improvement in the pyelogram is concerned, approximately 50 per cent show reasonable improvement, with decrease in size of the renal pelvis and increased function on the affected side. About 25 per cent of cases could be classified as failures with recurrent infections and persistent symptoms. These failures of course are the cases which require further surgical therapy.
Clinical pathological con[erence
1 O0 3
Most of the failures occur in the most severely affected kidneys. In this particular girl, after first operation, there were no significant complications. She did have a fever when the nephrostomy tube was removed. Such a transient fever is very common and probably represents a transient bacteremia due to bacteria which are invariably present about these tubes. After a successful operation we generally do not see radiographic improvement in the hydronephrosis for the first few months, but in about four to six months improvement should be seen. This girl was followed for approximately six months after the first operation and during that time she had recurrent infection, and further x-ray studies. DR. WITTENBORG. An intravenous pyelogram was taken about 30 days after the Y-V-plasty procedure. The pelvic dilatation still persists on the left, which is not particularly disturbing, since it takes time for this to diminish. On the other hand, there is very poor visualization of the ureter on the entire set of films. The right renal cortex seems to be a little narrower and the calyces seem to be a little blunter than they were before without evidence of obstruction. There might be an active pyelonephritis on the right side. Now let us take a look at the film taken six months after the operation. The left kidney shows persistent hydronephrosis with poor visualization of the ureter. Let us see the films taken a month later. On the left, the urinary drainage system shows dilated calyces. Because the ureter is not visualized, we take a film some hours later after the child had been upright. This is a two- or three-hour follow-up drainage film showing accumulation of opaque medium in the left renal drainage system and a very, very narrow ureter. DR. FILTER. O n the basis of these further studies and the recurrent infection, it was decided that something further had to be done with this kidney. At the time of the second operation, adhesions were found about the ureter. They were divided and the kidney pelvis was drained by nephrostomy, probably the most reasonable approach until such time as the kidney could recover as much function as possible. I am sure there was some thought that perhaps something further, even nephrectomy, would have to be done in the future. On the fourth postoperative day, something happened. One has the impression, on first look, that something occurred suddenly. We now have
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Clinical pathological conference
a patient who can be classified as being in shock. As surgeons, we think immediately of hypovolemia. We have no evidence from the protocol that any bleeding was occurring, either into the urine, into the wound, or elsewhere. Hemorrhage. therefore seems unlikely. On the other hand, there are other causes of severe, rapid fluid loss which lead to a reduction in blood volume and shock. Generally, these processes are associated with some type of peritoneal insult or vomiting and diarrhea with massive fluid losses. We have no evidence for either one of these hypotheses. In a child with renal disease and recurrent infections in her urinary tract, one must consider the possibility of septic shock. Exactly what a septic shock is, of course, is another question. Much of the evidence today seems to suggest that it is shock secondary to a release of endotoxin into the bloodstream, since some of these signs can be reproduced by injections of bacterial endotoxin intravenously into animals. The endotoxin theory has certainly not been proved in man. At any rate, there is no question that, associated with infection, there can be severe hypotension and death, with varying degrees of bowel necrosis and eventually renal shutdown. The problem here is that Dr. Vawter told me that bacteriological studies of her urine at this. time were negative. Although this girl must have had some microorganisms in her renal parenchyma, whose growth was suppressed by antibiotics, I would still expect to find bacteria in the urine if the child's problems were caused by septic shock. One sees septic shock much more commonly in situations when there is much more evidence of an acute infection going on than seen here. In adults, one thinks of coronary occlusions or pulmonary embolism as causes of sudden onset of shock, but I think that, in this child, we can dismiss these possibilities. In spite of the fact that the protocol leads one to believe this was a sudden catastrophe, I have the feeling that perhaps it was a little more gradual in development. Usually, after operations on the urinary tract, children are well soon afterwards. Postoperatively this girl did not eat very much and had occasional vomiting episodes for four days. To have the electrolyte levels that were obtained on the fourth postoperative day is strong indication that something had to have been wrong for several days. This girl had a
The lour~zal o[ Pediatrics June 1967
severe biochemical lesion and the question is, why? One of the possibilities that comes to mind immediately is adrenal insufficiency. The etiology of such might be a bit obscure, but it could be conceivably related to hemorrhage into the adrenal glands, perhaps on the basis of infection in her kidneys. Adrenal hemorrhage is associated with meningococcal infection, but it occurs frequently with other types of infections. Persons with Addisonian crisis are usually hyperthermic, but they can be hypothermic when severely ill, as was this girl. She was given steroids during this period of time, but without much benefit from this or any of the other measures taken to help her. The fact that she did not benefit from the treatment which would be adequate for adrenal insufficiency is perhaps against the diagnosis. The second possibility which I would like to discuss is related to the biochemical lesion that is likely to occur with bilateral kidney disease with superimposed obstructive uropathy. In obstruction and in pyelonephritis there is severe thinning of the renal parenchyma, with a basic defect-in the renal tubules in that they selectively lose sodium and other solutes. The tubules. cannot acidify the urine properly and they retain acid and usually chloride leading to a hyperchloremic acidosis. This girl was acidotic, to be sure, but the chloride levels were somewhat low rather than high, perhaps in relation to vomiting. At any rate in obstructive uropathy, when the obstruction is relieved, the kidney is then subjected to a solute diuresis. Nonprotein nitrogen plus other wastes and acid radicals require excretion, all of which increase the solute load to the kidneys. An obligatory water loss accompanies the excreted solute, and, in spite of antidiuretic hormones and other hormonal effects, these kidneys cannot conserve water. Therefore, after relief of obstructions, it is not unusual to see a massive diuresis. In adults, urine outputs often are as high as 12,000 c.e. per day and associated with the water loss is a sodium loss as well. This girl demonstrates several findings which lead us to wonder if an unsuspected solute diuresis in the immediate postoperative period tipped the scales. If we refer to her first admission we see that postoperatively the sodium was a little bit tow and she was acidotic. I do not know how much relief of obstruction she had taken then but these two findings, acidosis and
Volume 70 Number 6
low sodium, would lead one to suspect that a period of diuresis might have occurred, following her first operation after the first admission. After the second operation we really do not know how much urine she lost and I am glad that data were not included, since they might ruin the hypothesis, but we do know that the nephrostomy drainage was 315 ml. on one day, but, when she was in shock, fell to 83 ml. At any rate, I think that a solute diuresis may have been the basic lesion underlying most of this girl's problems. The nephrostomy urine and the urine obtained from the bladder had similar sodium and potassium concentrations, indicating that both kidneys were putting out the same kind of urine. In other words, both kidneys were severely affected. If one had an obstructive and infected lesion on one side, with a normal kidney on the opposite side, one would not expect to see such derangements of serum electrolytes. The x-ray evidence of bilateral renal disease is therefore very important in that it establishes the proper background for this postulated biochemical abnormality. The pathophysiology leading to the final fatal outcome would be as follows: As these unreplaced fluid electrolyte losses continued with further diuresis, hypovolemia and severe ,electrolyte imbalance resulted. The decreased blood volume eventually manifested itself as hypotension. Hypotension caused further decrease in renal blood flow and in a damaged kidney, '.already highly susceptible, acute tubular necrosis occurred. Death was due to the resulting bio,chemical lesion. Other causes of acute renal failure must not be forgotten. Aside from the usual lesion of tubular necrosis we must consider the possibility of bilateral cortical necrosis, a very unusual lesion. From 40 to 50 per cent of such cases occur in pregnant women, but cortical necrosis has been ,described in children with severe sah-wasting states, mainly gastrointestinal in origin. Another lesion which can cause renal failure is renal vein thrombosis. Generally this occurs in young children who have severe water and electrolyte loss resulting from severe vomiting and diarrhea. I do not think that this patient falls into either of these two categories, but I think that they are the other possibilities. In addition to the possibility of the development of resistant bacterial infections, we are concerned with another complication in patients who ]have been on multiple antibiotics and who have
Clinical pathological conference
10 0 5
renal lesions--the development of superimposed moniliaI infections. We have seen serious monilial infections in the urine several times under these circumstances. Furthermore, Candida also has an endotoxin which can produce a septic shocklike picture just like that associated with bacterial infections. However, Candida is easily cultured on the usual bacteriological laboratory media and probably would have been recognized had it been present. DR. ANOELO ERAKLIS. The basic fault here, I think, is failure to appreciate the degree of preexisting renal disease on the right side as well as on the left. I think that the series of intravenous pyelograms indicated the severity and the rate of progression of the interstitial nephritis and destructive changes in the renal parenchyma on the better side of the two kidneys. The BUN prior to surgery was perfectly normal. The degree of electrolyte difficulties that we encountered postoperatively were not suspected beforehand. It was well known that the child was not thriving between the first and second operations. O n reviewing the chart in terms of diet, activity, and recurrent infections that were well known and actively treated in the outpatient department, it was felt that the child's prognosis was probably grim unless the left kidney was decompressed. As to what might have gone wrong with the first operation, I think this has been a problem of concern for some time to people who deal in this area. The number of ureteropelvic strictures that we see is relatively small. Probably 15 to 20 per cent do not do well with a Y-V plasty. This depends upon two things: First, how much hydronephrosis is there behind the obstruction in the first place? A very large, baggy, nonperistaltic type of pelvis does not empty rapidly and efficiently; hence, a reservoir of urine which is likely to become infected and cause progressive difficulty in this regard. Second, stricture, which is no reflection on the person or the technique that is used in doing the operation, is caused by the amount of leakage of infected urine around the kidney and around the anastomosis that is created. If there is such leakage, the scarring and the healing that take place encompass the ureter, drags it up in scar tissue, and yon get a recurrence of the stricture. This is what had occurred in this girl, the Y-V plasty being intact. In fact, when this child was operated on the second time, not only was a nephrostomy done to decompress the ureter, but a corrective procedure was tried,
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Clinical pathological conference
namely, a Davis intubated ureterostomy, whereby the ureter is opened longitudinally, a catheter is placed in the ureter over which the ureteral epithelium will grow, and a wider opening will thereby ensue when the catheter is removed. I think the lesson in this case is that these children who have chronic infection and an anatomical lesion should have a more thorough evaluation of their renal capacity and renal reserve. Function which seems to be adequate prior to surgery becomes inadequate with the added stress of surgery and the requirements of the metabolic situation postoperatively. There probably was more disease on the right side than we anticipated. Whereas a left nephrectomy originally might be considered, I think the course of events here suggests that we were correct in trying to save as much kidney as we could. DR. SIDNEY FARBER. Have you any note concerning the heart, Dr. Eraklis? DR. ERAKEIS. Our initial clinical examinations gave no hint of either cardiac abnormality or underlying adrenal insufficiency. DR. FARBER. DO you feel physical examination is enough, Dr. Berenberg, to exclude cardiomegaly? DR. WILLIAM BERENBERG. I think that it is apt to be more helpful in excluding eardiomegaly than excluding microcardia. DR. FARBER. I have greater faith in percussion or the stethoscope than that. DR. BERENBERO. I have a feeling, in a 2-yearold child, the point of maximal cardiac impulse probably is a little more reliable in terms of cardiac size. The sodium during the first admission might have prompted concern about adrenal function. I still have concern about the adrenal in light of the chemical results. The other provocative question is the comment about the slow social development. We begin to get more and more sensitive about individuals who are retarded; generally, those who are prehaps slow both in motor and social patterns, and particularly, those that have this in combination with low-set ears and renal problems and perhaps multiple difficulties. One might even say, noticing the combination of slow motor development and renal anomalies, that maybe there was something wrong in the brain itself that might have had some relationship to the type of aldosterone response you got in the face of surgery. There is one other point, just as a matter of caution. This baby received fairly stiff doses of
The Journal of Pediatrics June 1967
tetracycline (500 mg. every 6 hours) for a small baby. Dr. Fellers and I have become very sensitive to renal tubular abnormalities which occur when you are faced with degraded tetracycline. I would hope that in the Children's Hospital we don't have tetracycline sitting on anyone's shelf for a period of a year or two. However, while other clinical features are compatible, the level of potassium, perhaps, rules against the effect of degraded tetracycline. DR. SHERWlN KEVY. Frankly, I do not believe the child had any evidence of adrenal insufficiency, especially with such a low- potassium value. But, needed here was a measurement of blood volume. I am quite sure that Dr. Filler's point about these children losing a lot more in the way of fluids than people realize is certainly the truth. I would think that this is a problem primarily of a child who is really dehydrated, with microcardia and shock. Dm FARBER. What is evidence of microcardia? DR. KEvY. One of the very last x-rays taken was reported as showing microcardia. DR. VAWTER. In a dissection of the entire urinary tract in continuity it can be observed that the urinary bladder and both ureters are essentially normal. Despite the history of recurrent bacteriuria, there is only the most meager evidence of inflammation in the urinary bladder, the process consisting essentially of only a few widely scattered lymphocytes. The right kidney, which is of normal size, is involved by a moderate hydronephrosis. Whereas the renal cortex is quite pale or anemic, there is no sign of scar or abscess. The right ureter is narrowest at its junction with the pelvis, suffi-~ ciently marked to represent a moderate ureteropelvic stenosis. As the radiological studies predicted, the left kidney is the site of marked hydronephrosis with severe thinning and atrophy of parenchyma which is, in many areas, well under 3 mm. in width. Pelvic tissues are thickened, scarred, and focally congested. In this arc of the lower pole, where the nephrostomy sump lay, there is a grumous, bloody coagulation partly reflecting necrosis of the residual tips of the renal papillae as well as limited yellow areas of renal infarction apparently related entirely to the surgical introduction of the nephrostomy and ureterostomy tubes. The whole left kidney lies surrounded by a rim of bloody and friable inflammatory tissue. The ureter is congested and locally hemorrhagic. The
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lumen was blocked, as planned surgically, by the ureterostomy tube, so that one must conclude that the urine obtained from the Madder reflects entirely the functional state of the opposite right kidney. Microscopic study confirms the differing degrees of renal atrophy and hydronephrosis, between the two kidneys. Remarkably enough, there is virtually no active or chronic pyelonephritis in either kidney, although there is well marked chronic inflammation confined to the wall of the pelvis of the left kidney. The dominant impression is that of hydronephrotic atrophy. As predicted by Dr. Filler, there is degeneration of renal tubules, but only rarely is this associated with frank necrosis or cast formation, principally in the left kidney. Extensive fatty degeneration can be most easily demonstrated in the proximal convoluted tubules and thick limbs of the ascending loops of Henle. Microscopic ultraviolet fluorescent studies demonstrate a bright yellow fluorescence similar to that found when tetracyclines are present in renal tubular epithelium in high concentration. This is a touchy point because the tetracyclines will attach themselves to necrotic tissue elements or almost any inert protein which may be present. However, one might consider that a patient with failing renal function, in the presence of the doses of tetracyclines administered to this girl, may have presented the kidneys with higher concentrations of tetracyclines than we know. Even in the absence of the degradation products mentioned by Dr. Berenberg, tetracyclines have the capacity to produce at least transient damage to mitochondria with uncoupling of the processes of oxidative phosphorylation, which theoretically would be quite capable of leading to the fatty degeneration of renal tubules. This could equally contribute to the extensive, fine, fatty degeneration which was observed in this gM's liver. These observations are, however, not intended to change the emphasis of Dr. Filler's analysis, with which I am in general agreement. While the total adrenal mass was sIightly below that expected for her age, this is far from frank atrophy. Since the zona fasciculata is depleted of lipid we might infer that the patient was capable of secreting ACTH. In addition there is hypertrophy of the zona glomerulosa as we might expect if the patient were capable of sustaining an aldosterone response such as might be expected in the light of the observed severe
Clinical pathological con[erence
1 O0 7
hyponatremia. It appears that the adrenal cortex is doing the best it can under adverse circumstances, but the picture of acute exhaustion is of interest in view of the clinical therapy with corticosteroids. Finally, there was evidence of infection with both Staphylococcus aureus and Monilia (Candida) cultured both from hearts' blood and necrotic left renal tissue. Superficial monilial esophagitis, gastritis (with focal hemorrhage), patchy enteritis, and laryngotracheitis were recognized grossly and microscopically. Monilial tracheitis is an uncommon and unusual lesion despite considerable personal experience with monilial lesions generally. It appears that most commonly monilial involvement of the respiratory tract is confined to squamous epithelium as found in the vocal cords of the larynx. Whether steroid therapy influenced the development of this unusual lesion, is difficult to determine but experimentally it is easily shown that Monilia are more "toxic" when steroids are present in high concentrations. Apart from the lesions mentioned there was no other anomaly and no other site of hemorrhage. No hidden or internal sites of marked fluid loss were observed beyond the moderate edema of upper abdominal viscera and mesentery so common in shock.
Clinical diagnoses were: 1. Left ureteropelvic stricture with hydronephrosis. 2. Bilateral pyelonephritis. 2. Probable posturinary decompression syndrome with diuresis and sodium loss. 4. Hypovolemia and shock, secondary to 3. 5. ? Septic shock. 6. ? Acute renal tubular necrosis. 7. ? Secondary moniliasis.
Pathologic diagnoses were: 1. Bilateral ureteropelvic stenosis, severe on left with postoperative left periureteral fibrosis. 2. Bilateral hydronephrosis, severe on left with chronic left pyelitis. 3. Postoperative status with hemorrhagic left perinephritis, local infarction, and papillary necrosis of left kidney, left nephrostomy, and ureterostomy.
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Clinical pathological conference
4. Staphylococcal and monilial sepsis with superficial acute esophagitis, gastritis, enteritis, laryngotracheitis, and local renal papillary necrosis.
The Journal o[ Pediatrics June 1967
5. Posturinary decompression syndrome (clinical). 6. Fatty degeneration of renal tubules and liver with tetracycline fluorescence of renal tubules.
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M.D., Editor Gordon F. Vawter, M.D., Assistant Editor
A
2L~12-YEAR-OLD
G I R L was admitted
for the second time with intermittent pain in the left flank and fever which had been present one month. The child had been well, although slow in social development, until 18 months of age when she had coryza, sore throat, and a temperature of 101 to 102 ~ F. which was treated with penicillin for three days. Two weeks later fever recurred (100 ~ F.) accompanied by urinary frequency, dysuria, and pink urine on several occasions. The following studies were recorded: Blood pressure was 110/72 mm. Hg; hematocrit, 26 per cent; blood leukocytes, 4,400 per cubic millimeter; and urinalysis demonstrated specific gravity 1.005 to 1.012, proteinuria 10 to 70 rag. per cent, with many leukocytes on two occasions in the spun sediment with more than 100,000 colonies of Escherichia coli growing per milliliter of urine. Intravenous pyelogram suggested bilateral hydronephrosis, severe on the left and minimal on the right. The child improved on Gantrisin (4 teaspoonfuls per day) pending transfer to the Children's Hospital Medical Center where she'entered for the first time at 19 months of age. Vital signs were: pulse rate, 100 per minute; respirations, 18 per minute; and temperature, 99 ~ F. Studies of blood revealed Vol. 70, No. 6, pp. 1000-1008
a hematocrit of 37 per cent, 4,800 leukocytes per cubic millimeter, and a blood-ureanitrogen (BUN) value of 14 rag. per cent. Urine contained 0 to 500 rag. per cent of protein, 50 leukocytes per high-power field (later falling to 3 to 6), and no growth on bacterial culture. Cystoscopy revealed a normal bladder. Left retrograde pyelogram showed severe hydronephrosis and a short ureteral pelvic stricture. A Y-V plasty was made on the stricture. Biochemical studies of blood obtained postoperatively were: carbon dioxide, 16.4 mEq. per liter; sodium, 126 mEq. per liter; potassium, 4.6 mEq. per liter; and chloride, 85 mEq. per liter. The child did well, except for a fever of 102 ~ F. which was recorded following removal of the nephrostomy tube on the tenth day in the hospital. E. coli was cultured from urine, and therapy with chloramphenicol was begun. During this period, serum contained sodium, 138 mEq. per liter and chloride, 96 mEq. per liter. The intravenous pyelogram revealed continuing severe hydronephrosis and some delay in emptying of the left pelvis. After one month she was discharged receiving Gantrisin and was closely followed in the genitourinary clinic. One month later, urinalysis demonstrated proteinuria, pyuria (10 to 20 leukocytes), and bacilluria (over 100,000
Volume 70 Number 6
colonies of Klebsiella). Furadantin and Gantrisin were administered, and subsequent cultures of urine were negative. On the second admission physical findings included: pulse rate, 108 per minute; temperature, 100 ~ F.; blood pressure, 172/78 mm. Hg; pallor, and moderate tenderness over the left costovertebral area. Neither kidney was palpable. Laboratory studies demonstrated: hematocrit, 38 per cent; blood leukocytes, 7,600 per cubic millimeter; p H urine, 5; pro teinuria (59 mg. per cent); bacteriologically sterile urine, 10 to 20 erythrocytes and rare leukocytes in the centrifuged urinary sediment; and BUN, 12 mg. per cent. Therapy with Gantrisin was continued in the hospital. Maximal fevers of 100 to 101.5 ~ F. occurred daily whereas the cardiac rate averaged between 110 and 140 per minute. Cystoscopy and left retrograde pyelogram on the second day revealed severe hydronephrosis and some ureteropelvic obstruction. On the fifth day, therapy with Achromycin (500 mg., 6 hourly) was begun. The next day the left kidney was operated on: adhesions binding the upper ureter to the pelvis were freed; nephro.stomy and proximal catheter ureterostomy were made, since further plastic repair was not feasible. Postoperatively, the patient was maintained on 500 ml. each of 5 per cent glucose in water and normal saline intravenously and she did well, except that she refused oral intake and had small vomits occasionally. On the fourth postoperative day, she was lethargic and temperature fell to 94 ~ F., rectally, and nephrostomy drainage had fallen from 315 to 83 ml. per day. Extremities were cold and blue. Blood pressure was 80 mm. H g systolic. Therapy was begun with ampicillin, Chloromycetin (500 mg. per day) and hydrocortisone (75 rag.). Blood sugar was 616 mg. per cent (glucosuria 2+, acetone 0). Other studies of blood demonstrated a nonprotein nitrogen (NPN) value of 100 mg. per cent; carbon dioxide, 7.7 mEq. per liter; sodium, 112 mEq. per liter; potassium, 6.4 mEq. per liter; chloride, 80 mEq. per liter, and leukocytes, 39,000 per cubic millimeter.
Clinical pathological conference
1 00 1
Roentgenological studies of the chest and abdomen demonstrated only microcardia. Plasma, saline, and sodium bicarbonate solution were given intravenously, and some improvement resulted. Next day, while the patient was lying on a warming blanket, her temperature was 98.6 ~ F. and systolic blood pressure was 104 mm. Hg. A leukocyte count was 8,400 per cubic millimeter, and hemoglobin, 11.5 Gm. per cent. Blood contained: carbon dioxide, 5.5 mEq. per liter (later rising to 18.3 mEq. per liter); sodium, 125 mEq. per liter; potassium, 4.2 mEq. per liter; chloride, 82 to 84 mEq. per liter, and calcium, 8.5 mg. per cent. Urine contained 8.8 mEq. per liter of sodium and 1.2 mEq. per liter of potassium, whereas nephrostomy urine contained 9.4 mEq. per liter of sodium and 1.1 mEq. per liter of potassium. Therapy with Achromycin was discontinued. Coffee-ground material was obtained in gastric aspirate. She seemed improved after a transfusion of whole blood, but no clear benefit was observed following administration of Tris buffer. Two days later she recovered from cardiac arrest after treatment with additional sodium bicarbonate, calcium chloride, and intubation. She died later in the day after several further cardiac arrests. DR. ROBERT FILLER.@ This is a case of a 2year-old girt who had infection of the urinary tract, associated with a potentially correctable surgical lesion. An operation was performed but could not be termed a success. A second operation was necessary, shortly followed by a whole series of catastrophic events ending in death. I would like to divide the discussion into two parts; first, a discussion of the basic urinary abnormality together with the basic pathology in the kidney, and second, an analysis of the fatal outcome. Eighteen months is, perhaps, a common age for the occurrence of renal infection associated with an underlying renal anomaly, but frequently pyelonephritis is found even earlier in life. We now know that renal infections are often misdiagnosed as upper respiratory infections or other viral diseases in the very young. However, two ~Dr. Filler is Assistant in Surgery, Children's Hospital Medical Center, Boston, Mass.
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Clinical pathological conference
weeks after onset of fever, this patient developed symptoms of frequency, dysuria, and episodes of presumptive hematuria, clearly indicating urinary tract involvement. These symptoms, of course, are not specific for any particular renal anomaly and could reflect infection of the lower urinary tract as well as infection of the upper urinary tract. These original symptoms give us no clue to the exact location of the basic pathology. One important point in the original and subsequent physical examinations was the blood pressure of 110/72, which, for a child of this age, would be abnormally high. This perhaps gives us some inkling that this girl probably has relatively severe renal disease, even at this age. The urinalyses indicate a significant urinary tract infection associated with E. coli but do not allow us to localize the process further. The normal N P N value is noteworthy, but we must remember that she need have no more than 20 per cent of her nephrons functioning to maintain this value. The patient had x-rays and eventually a retrograde pyelogram at the time of cystoscopy. Perhaps Dr. Wittenborg can review these since the protocol does not give a complete picture of the results. DR. MARTIN WITTENBORG. I have selected only representative examples of the many films available. The first set of films shows an intravenous urogram. The liver and splenic shadows, gastrointestinal tract, lumbar spine, and pelvis are normal. Five minutes after the injection of the opaque medium, the appearance time of dye, on the right, is good, but there is marked delay on the left, with only little, rounded globules filling up what appear to be dilated collecting structures. I think the protocol is a little bit amiss in this description. In fact this is not really bilateral hydronephrosis. The right kidney looks remarkably normal compared to the left, although there is only slight blunting of the upper calyces. And we will see later that there is only a right pelvic ectasia. Three and one half hours after the dye has been injected, the right kidney is essentially drained. The bladder has good content of dye, and on the left you see gross hydronephrosis with calyces dilated and blunted, and there is no suggestion that the left ureter is enlarged. Cystogram on the next day shows that the bladder has normal capacity with no ureteral reflux on either side. Voiding cystogram was normal. Left retrograde pyelography confirms the marked dilatation of the renal pelvis and also
The Journal of Pediatrics June 1967
suggests a slight extravasation of dye into renal tissue. In a later film, there is a distinct, localized obstruction at the pelvic ureteral junction with a perfectly normal ureter. DR. FILLER. Do you think that any of the findings on the right side could be interpreted as secondary to infection? DR. WITTENBORO. The calyceal structures are blunted, what we call ectasia, a mild dilatation which can be secondary either to pyelonephritis, to a low-grade outflow obstruction, or to a combination of both. The fact that the pelvis is perfectly normal in size at this age is not too helpful. As a rule, if ectasia is on an obstructive basis, we would see comparable dilatation on both sides. I would suspect that here it is infection, DR. FILLER. This set of findings fits into a group of hydronephroses characterized by ureteropelvic obstruction, the point of obstruction being at the ureteric origin from the pelvis. In such specimens the typical morphological findings include a large, rounded, renal pelvis to which is attached a ureter of normal caliber. The pelvis dilates medially and is quite distinct from renal parenchyma. Associated with the dilatation are all degrees of renal parenchymal atrophy. In cases which are less severe and of shorter duration there is more renal tissue than in those with long-standing obstruction. In cases with severe obstruction, the dilated pelvis is merely a sac of pus and stagnant urine. Several different anatomic abnormalities can be associated with ureteropelvic obstruction. Aberrant renal vessels to the lower pole of the kidney can kink and obstruct the ureter and in these cases intrinsic ureteral defects or strictures often coexist. The surgical lesson here is that, after the division of an aberrant renal vessel, the inside of the ureter must be inspected to avoid missing an intrinsic obstruction. Strictures at the ureteropelvic junction can exist in the absence of aberrant vessels as can intrinsic valvelike obstructions. Adhesions of unknown etiology with kinking and obstruction of the upper ureter have been seen to cause ureteropelvic obstruction. Localized developmental defects of the ureter resulting in malformations in which multiple tight convolutions obstruct the upper ureter have also been noted in these patients. Perhaps the rarest lesion seen in these cases is a defect in the muscular wall of the ureter which causes the ureter to dilate and become aperistaltic, resulting in a functional block to urine flow.
Volume 70 Number 6
A Y-V plasty was done in the patient. This is the usual operation to correct most of these defects. There are some instances, however, when a portion of the ureter has to be resected and continuity restored by anastomosis between the pelvis and the lower ureter. There are others with other variations of the stricture, in which some other type of plastic procedure can be carried out to relieve the obstruction. The protocol does not describe the exact lesion in this particular case. Perhaps someone can tell us a little more about that. At any rate, on the basis of frequency of lesions, I assume that either an aberrant renal vessel or a ureteropelvic stricture was present in this little girl. In terms of surgery, there are several possibilities when one sees a case such as this. One is to carry out some kind of reparative procedure, and the other is to perform a nephrectomy. This is the major decision that has to be made at the operating table after the kidney is exposed, since it often cannot be made preoperatively. There are several facts that would lead one to refrain from removing the kidney. In the presence of bilateral disease with bilateral hydronephrosis and an already significant decrease in renal tissue, then one would try to do everything in his power to save the kidney. On the other hand, if the renal parenchyma is so highly thinned out that, despite adequate correction of the obstruction, there is little likelihood of return of renal function, then nephrectomy would be wiser, especially since such a kidney can still be the site of persistent serious infection. The decision can be made only by the surgeon when he has the kidney in his hands. This particular child had some abnormality in the opposite kidney according to the protocol. Ureteropelvic disease is usually unilateral, but about 10 per cent of patients have bilateral lesions. In general, one would attempt to repair both sides. So far as results are concerned, most of the series in the literature show that about 75 per cent of these children have what can be termed good or excellent results. By that is meant a relief of symptoms and freedom from infection. So far as improvement in the pyelogram is concerned, approximately 50 per cent show reasonable improvement, with decrease in size of the renal pelvis and increased function on the affected side. About 25 per cent of cases could be classified as failures with recurrent infections and persistent symptoms. These failures of course are the cases which require further surgical therapy.
Clinical pathological con[erence
1 O0 3
Most of the failures occur in the most severely affected kidneys. In this particular girl, after first operation, there were no significant complications. She did have a fever when the nephrostomy tube was removed. Such a transient fever is very common and probably represents a transient bacteremia due to bacteria which are invariably present about these tubes. After a successful operation we generally do not see radiographic improvement in the hydronephrosis for the first few months, but in about four to six months improvement should be seen. This girl was followed for approximately six months after the first operation and during that time she had recurrent infection, and further x-ray studies. DR. WITTENBORG. An intravenous pyelogram was taken about 30 days after the Y-V-plasty procedure. The pelvic dilatation still persists on the left, which is not particularly disturbing, since it takes time for this to diminish. On the other hand, there is very poor visualization of the ureter on the entire set of films. The right renal cortex seems to be a little narrower and the calyces seem to be a little blunter than they were before without evidence of obstruction. There might be an active pyelonephritis on the right side. Now let us take a look at the film taken six months after the operation. The left kidney shows persistent hydronephrosis with poor visualization of the ureter. Let us see the films taken a month later. On the left, the urinary drainage system shows dilated calyces. Because the ureter is not visualized, we take a film some hours later after the child had been upright. This is a two- or three-hour follow-up drainage film showing accumulation of opaque medium in the left renal drainage system and a very, very narrow ureter. DR. FILTER. O n the basis of these further studies and the recurrent infection, it was decided that something further had to be done with this kidney. At the time of the second operation, adhesions were found about the ureter. They were divided and the kidney pelvis was drained by nephrostomy, probably the most reasonable approach until such time as the kidney could recover as much function as possible. I am sure there was some thought that perhaps something further, even nephrectomy, would have to be done in the future. On the fourth postoperative day, something happened. One has the impression, on first look, that something occurred suddenly. We now have
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Clinical pathological conference
a patient who can be classified as being in shock. As surgeons, we think immediately of hypovolemia. We have no evidence from the protocol that any bleeding was occurring, either into the urine, into the wound, or elsewhere. Hemorrhage. therefore seems unlikely. On the other hand, there are other causes of severe, rapid fluid loss which lead to a reduction in blood volume and shock. Generally, these processes are associated with some type of peritoneal insult or vomiting and diarrhea with massive fluid losses. We have no evidence for either one of these hypotheses. In a child with renal disease and recurrent infections in her urinary tract, one must consider the possibility of septic shock. Exactly what a septic shock is, of course, is another question. Much of the evidence today seems to suggest that it is shock secondary to a release of endotoxin into the bloodstream, since some of these signs can be reproduced by injections of bacterial endotoxin intravenously into animals. The endotoxin theory has certainly not been proved in man. At any rate, there is no question that, associated with infection, there can be severe hypotension and death, with varying degrees of bowel necrosis and eventually renal shutdown. The problem here is that Dr. Vawter told me that bacteriological studies of her urine at this. time were negative. Although this girl must have had some microorganisms in her renal parenchyma, whose growth was suppressed by antibiotics, I would still expect to find bacteria in the urine if the child's problems were caused by septic shock. One sees septic shock much more commonly in situations when there is much more evidence of an acute infection going on than seen here. In adults, one thinks of coronary occlusions or pulmonary embolism as causes of sudden onset of shock, but I think that, in this child, we can dismiss these possibilities. In spite of the fact that the protocol leads one to believe this was a sudden catastrophe, I have the feeling that perhaps it was a little more gradual in development. Usually, after operations on the urinary tract, children are well soon afterwards. Postoperatively this girl did not eat very much and had occasional vomiting episodes for four days. To have the electrolyte levels that were obtained on the fourth postoperative day is strong indication that something had to have been wrong for several days. This girl had a
The lour~zal o[ Pediatrics June 1967
severe biochemical lesion and the question is, why? One of the possibilities that comes to mind immediately is adrenal insufficiency. The etiology of such might be a bit obscure, but it could be conceivably related to hemorrhage into the adrenal glands, perhaps on the basis of infection in her kidneys. Adrenal hemorrhage is associated with meningococcal infection, but it occurs frequently with other types of infections. Persons with Addisonian crisis are usually hyperthermic, but they can be hypothermic when severely ill, as was this girl. She was given steroids during this period of time, but without much benefit from this or any of the other measures taken to help her. The fact that she did not benefit from the treatment which would be adequate for adrenal insufficiency is perhaps against the diagnosis. The second possibility which I would like to discuss is related to the biochemical lesion that is likely to occur with bilateral kidney disease with superimposed obstructive uropathy. In obstruction and in pyelonephritis there is severe thinning of the renal parenchyma, with a basic defect-in the renal tubules in that they selectively lose sodium and other solutes. The tubules. cannot acidify the urine properly and they retain acid and usually chloride leading to a hyperchloremic acidosis. This girl was acidotic, to be sure, but the chloride levels were somewhat low rather than high, perhaps in relation to vomiting. At any rate in obstructive uropathy, when the obstruction is relieved, the kidney is then subjected to a solute diuresis. Nonprotein nitrogen plus other wastes and acid radicals require excretion, all of which increase the solute load to the kidneys. An obligatory water loss accompanies the excreted solute, and, in spite of antidiuretic hormones and other hormonal effects, these kidneys cannot conserve water. Therefore, after relief of obstructions, it is not unusual to see a massive diuresis. In adults, urine outputs often are as high as 12,000 c.e. per day and associated with the water loss is a sodium loss as well. This girl demonstrates several findings which lead us to wonder if an unsuspected solute diuresis in the immediate postoperative period tipped the scales. If we refer to her first admission we see that postoperatively the sodium was a little bit tow and she was acidotic. I do not know how much relief of obstruction she had taken then but these two findings, acidosis and
Volume 70 Number 6
low sodium, would lead one to suspect that a period of diuresis might have occurred, following her first operation after the first admission. After the second operation we really do not know how much urine she lost and I am glad that data were not included, since they might ruin the hypothesis, but we do know that the nephrostomy drainage was 315 ml. on one day, but, when she was in shock, fell to 83 ml. At any rate, I think that a solute diuresis may have been the basic lesion underlying most of this girl's problems. The nephrostomy urine and the urine obtained from the bladder had similar sodium and potassium concentrations, indicating that both kidneys were putting out the same kind of urine. In other words, both kidneys were severely affected. If one had an obstructive and infected lesion on one side, with a normal kidney on the opposite side, one would not expect to see such derangements of serum electrolytes. The x-ray evidence of bilateral renal disease is therefore very important in that it establishes the proper background for this postulated biochemical abnormality. The pathophysiology leading to the final fatal outcome would be as follows: As these unreplaced fluid electrolyte losses continued with further diuresis, hypovolemia and severe ,electrolyte imbalance resulted. The decreased blood volume eventually manifested itself as hypotension. Hypotension caused further decrease in renal blood flow and in a damaged kidney, '.already highly susceptible, acute tubular necrosis occurred. Death was due to the resulting bio,chemical lesion. Other causes of acute renal failure must not be forgotten. Aside from the usual lesion of tubular necrosis we must consider the possibility of bilateral cortical necrosis, a very unusual lesion. From 40 to 50 per cent of such cases occur in pregnant women, but cortical necrosis has been ,described in children with severe sah-wasting states, mainly gastrointestinal in origin. Another lesion which can cause renal failure is renal vein thrombosis. Generally this occurs in young children who have severe water and electrolyte loss resulting from severe vomiting and diarrhea. I do not think that this patient falls into either of these two categories, but I think that they are the other possibilities. In addition to the possibility of the development of resistant bacterial infections, we are concerned with another complication in patients who ]have been on multiple antibiotics and who have
Clinical pathological conference
10 0 5
renal lesions--the development of superimposed moniliaI infections. We have seen serious monilial infections in the urine several times under these circumstances. Furthermore, Candida also has an endotoxin which can produce a septic shocklike picture just like that associated with bacterial infections. However, Candida is easily cultured on the usual bacteriological laboratory media and probably would have been recognized had it been present. DR. ANOELO ERAKLIS. The basic fault here, I think, is failure to appreciate the degree of preexisting renal disease on the right side as well as on the left. I think that the series of intravenous pyelograms indicated the severity and the rate of progression of the interstitial nephritis and destructive changes in the renal parenchyma on the better side of the two kidneys. The BUN prior to surgery was perfectly normal. The degree of electrolyte difficulties that we encountered postoperatively were not suspected beforehand. It was well known that the child was not thriving between the first and second operations. O n reviewing the chart in terms of diet, activity, and recurrent infections that were well known and actively treated in the outpatient department, it was felt that the child's prognosis was probably grim unless the left kidney was decompressed. As to what might have gone wrong with the first operation, I think this has been a problem of concern for some time to people who deal in this area. The number of ureteropelvic strictures that we see is relatively small. Probably 15 to 20 per cent do not do well with a Y-V plasty. This depends upon two things: First, how much hydronephrosis is there behind the obstruction in the first place? A very large, baggy, nonperistaltic type of pelvis does not empty rapidly and efficiently; hence, a reservoir of urine which is likely to become infected and cause progressive difficulty in this regard. Second, stricture, which is no reflection on the person or the technique that is used in doing the operation, is caused by the amount of leakage of infected urine around the kidney and around the anastomosis that is created. If there is such leakage, the scarring and the healing that take place encompass the ureter, drags it up in scar tissue, and yon get a recurrence of the stricture. This is what had occurred in this girl, the Y-V plasty being intact. In fact, when this child was operated on the second time, not only was a nephrostomy done to decompress the ureter, but a corrective procedure was tried,
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Clinical pathological conference
namely, a Davis intubated ureterostomy, whereby the ureter is opened longitudinally, a catheter is placed in the ureter over which the ureteral epithelium will grow, and a wider opening will thereby ensue when the catheter is removed. I think the lesson in this case is that these children who have chronic infection and an anatomical lesion should have a more thorough evaluation of their renal capacity and renal reserve. Function which seems to be adequate prior to surgery becomes inadequate with the added stress of surgery and the requirements of the metabolic situation postoperatively. There probably was more disease on the right side than we anticipated. Whereas a left nephrectomy originally might be considered, I think the course of events here suggests that we were correct in trying to save as much kidney as we could. DR. SIDNEY FARBER. Have you any note concerning the heart, Dr. Eraklis? DR. ERAKEIS. Our initial clinical examinations gave no hint of either cardiac abnormality or underlying adrenal insufficiency. DR. FARBER. DO you feel physical examination is enough, Dr. Berenberg, to exclude cardiomegaly? DR. WILLIAM BERENBERG. I think that it is apt to be more helpful in excluding eardiomegaly than excluding microcardia. DR. FARBER. I have greater faith in percussion or the stethoscope than that. DR. BERENBERO. I have a feeling, in a 2-yearold child, the point of maximal cardiac impulse probably is a little more reliable in terms of cardiac size. The sodium during the first admission might have prompted concern about adrenal function. I still have concern about the adrenal in light of the chemical results. The other provocative question is the comment about the slow social development. We begin to get more and more sensitive about individuals who are retarded; generally, those who are prehaps slow both in motor and social patterns, and particularly, those that have this in combination with low-set ears and renal problems and perhaps multiple difficulties. One might even say, noticing the combination of slow motor development and renal anomalies, that maybe there was something wrong in the brain itself that might have had some relationship to the type of aldosterone response you got in the face of surgery. There is one other point, just as a matter of caution. This baby received fairly stiff doses of
The Journal of Pediatrics June 1967
tetracycline (500 mg. every 6 hours) for a small baby. Dr. Fellers and I have become very sensitive to renal tubular abnormalities which occur when you are faced with degraded tetracycline. I would hope that in the Children's Hospital we don't have tetracycline sitting on anyone's shelf for a period of a year or two. However, while other clinical features are compatible, the level of potassium, perhaps, rules against the effect of degraded tetracycline. DR. SHERWlN KEVY. Frankly, I do not believe the child had any evidence of adrenal insufficiency, especially with such a low- potassium value. But, needed here was a measurement of blood volume. I am quite sure that Dr. Filler's point about these children losing a lot more in the way of fluids than people realize is certainly the truth. I would think that this is a problem primarily of a child who is really dehydrated, with microcardia and shock. Dm FARBER. What is evidence of microcardia? DR. KEvY. One of the very last x-rays taken was reported as showing microcardia. DR. VAWTER. In a dissection of the entire urinary tract in continuity it can be observed that the urinary bladder and both ureters are essentially normal. Despite the history of recurrent bacteriuria, there is only the most meager evidence of inflammation in the urinary bladder, the process consisting essentially of only a few widely scattered lymphocytes. The right kidney, which is of normal size, is involved by a moderate hydronephrosis. Whereas the renal cortex is quite pale or anemic, there is no sign of scar or abscess. The right ureter is narrowest at its junction with the pelvis, suffi-~ ciently marked to represent a moderate ureteropelvic stenosis. As the radiological studies predicted, the left kidney is the site of marked hydronephrosis with severe thinning and atrophy of parenchyma which is, in many areas, well under 3 mm. in width. Pelvic tissues are thickened, scarred, and focally congested. In this arc of the lower pole, where the nephrostomy sump lay, there is a grumous, bloody coagulation partly reflecting necrosis of the residual tips of the renal papillae as well as limited yellow areas of renal infarction apparently related entirely to the surgical introduction of the nephrostomy and ureterostomy tubes. The whole left kidney lies surrounded by a rim of bloody and friable inflammatory tissue. The ureter is congested and locally hemorrhagic. The
Volume 70 Number 6
lumen was blocked, as planned surgically, by the ureterostomy tube, so that one must conclude that the urine obtained from the Madder reflects entirely the functional state of the opposite right kidney. Microscopic study confirms the differing degrees of renal atrophy and hydronephrosis, between the two kidneys. Remarkably enough, there is virtually no active or chronic pyelonephritis in either kidney, although there is well marked chronic inflammation confined to the wall of the pelvis of the left kidney. The dominant impression is that of hydronephrotic atrophy. As predicted by Dr. Filler, there is degeneration of renal tubules, but only rarely is this associated with frank necrosis or cast formation, principally in the left kidney. Extensive fatty degeneration can be most easily demonstrated in the proximal convoluted tubules and thick limbs of the ascending loops of Henle. Microscopic ultraviolet fluorescent studies demonstrate a bright yellow fluorescence similar to that found when tetracyclines are present in renal tubular epithelium in high concentration. This is a touchy point because the tetracyclines will attach themselves to necrotic tissue elements or almost any inert protein which may be present. However, one might consider that a patient with failing renal function, in the presence of the doses of tetracyclines administered to this girl, may have presented the kidneys with higher concentrations of tetracyclines than we know. Even in the absence of the degradation products mentioned by Dr. Berenberg, tetracyclines have the capacity to produce at least transient damage to mitochondria with uncoupling of the processes of oxidative phosphorylation, which theoretically would be quite capable of leading to the fatty degeneration of renal tubules. This could equally contribute to the extensive, fine, fatty degeneration which was observed in this gM's liver. These observations are, however, not intended to change the emphasis of Dr. Filler's analysis, with which I am in general agreement. While the total adrenal mass was sIightly below that expected for her age, this is far from frank atrophy. Since the zona fasciculata is depleted of lipid we might infer that the patient was capable of secreting ACTH. In addition there is hypertrophy of the zona glomerulosa as we might expect if the patient were capable of sustaining an aldosterone response such as might be expected in the light of the observed severe
Clinical pathological con[erence
1 O0 7
hyponatremia. It appears that the adrenal cortex is doing the best it can under adverse circumstances, but the picture of acute exhaustion is of interest in view of the clinical therapy with corticosteroids. Finally, there was evidence of infection with both Staphylococcus aureus and Monilia (Candida) cultured both from hearts' blood and necrotic left renal tissue. Superficial monilial esophagitis, gastritis (with focal hemorrhage), patchy enteritis, and laryngotracheitis were recognized grossly and microscopically. Monilial tracheitis is an uncommon and unusual lesion despite considerable personal experience with monilial lesions generally. It appears that most commonly monilial involvement of the respiratory tract is confined to squamous epithelium as found in the vocal cords of the larynx. Whether steroid therapy influenced the development of this unusual lesion, is difficult to determine but experimentally it is easily shown that Monilia are more "toxic" when steroids are present in high concentrations. Apart from the lesions mentioned there was no other anomaly and no other site of hemorrhage. No hidden or internal sites of marked fluid loss were observed beyond the moderate edema of upper abdominal viscera and mesentery so common in shock.
Clinical diagnoses were: 1. Left ureteropelvic stricture with hydronephrosis. 2. Bilateral pyelonephritis. 2. Probable posturinary decompression syndrome with diuresis and sodium loss. 4. Hypovolemia and shock, secondary to 3. 5. ? Septic shock. 6. ? Acute renal tubular necrosis. 7. ? Secondary moniliasis.
Pathologic diagnoses were: 1. Bilateral ureteropelvic stenosis, severe on left with postoperative left periureteral fibrosis. 2. Bilateral hydronephrosis, severe on left with chronic left pyelitis. 3. Postoperative status with hemorrhagic left perinephritis, local infarction, and papillary necrosis of left kidney, left nephrostomy, and ureterostomy.
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Clinical pathological conference
4. Staphylococcal and monilial sepsis with superficial acute esophagitis, gastritis, enteritis, laryngotracheitis, and local renal papillary necrosis.
The Journal o[ Pediatrics June 1967
5. Posturinary decompression syndrome (clinical). 6. Fatty degeneration of renal tubules and liver with tetracycline fluorescence of renal tubules.