CLINICOPATHOLOGIC CONFERENCE
Pulmonary Hemorrhage and Renal Failure
Stenographic reports, edited by Philip E. Cryer, M.D. and John Kissane, M.D., of weekly clinicopathdogic conferences held in Barnes and Wohl Hospttals, are p<shed iti each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine and Pathology of Washington University School of Medicine. A 61 year old man was admitted to Barnes Hospital on August 27, 1975, because of hemoptysis and progressive renal failure. He died 19 days later. Hypertension and intermittent epistaxis were dated from 1970. Fatigue, nausea, nocturia, exertional dyspnea and ankle edema developed in mid-1974. A several week history of hemoptysis led to his first admission to Barnes Hospital in October 1974. The history also included industrial exposure to silicon and asbestos, and chronic cigarette smoking. The’ patient appeared chronically ill. The blood pressure was 180/l 10 mm Hg, the pulse rate 90/min, the respiratory rate 30/min, the temperature 37.8’C and the weight 145 pounds. There was severe arteriolar narrowing in the optic fundi with arteriovenous nicking, hemorrhages and exudates. Jugular venous distention, bilateral basilar pulmonary rales, cardiomegaly and marked peripheral edema were noted. The hemoglobin level was 7.9 g/100 ml; bone marrow examination revealed only diminished iron stores. The white blood cell count was 10,200/ mm3. The serum urea nitrogen was 50 mg/lOO ml and the serum creatinine 3.7 mg/lOO ml. The urine sediment revealed only 1 white blood cell/hpf, but there was 4+ proteinuria. The endogenous creatinine clearance was 25 ml/min and a 24 hour urine contained 2.5 g of protein. Intravenous urograms demonstrated a defect in the left kidney, believed to be a cyst, and normal size kidneys. Additional serum values included an albumin of 1.8 g/100 ml with total proteins of 4.8 g/100 ml, a cholesterol of 190 mg/lOO ml, a lactic dehydrogenase (LDH) of 328 mlU/ml and a creatinine phosphokinase (CPK) of 213 mllJ/ml. The arterial pH was 7.50, the oxygen tension (pop) 65 mm Hg and the carbon dioxide tension (pCO*) 21 mm Hg. Chest films demonstrated mild cardiomegaly and extensive bilateral perihilar infiltrates. The carbon monoxide diffusing capacity was markedly diminished. The erythrocyte sedimentation rate was 86 mm/hour. Serum complement levels were not depressed; a test for antinuclear antibodies demonstrated i-lnuclear fluorescence.
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Diuretic therapy and digitalization led to a discharge weight of 128 pounds. The pulmonary infiltrates were unchanged at the time of discharge. However, the infiltrates were not present on chest films obtained in March 1975 when the patient was admitted to Barnes Hospital for colonoscopy and subsequent removal of adenomatous colonic polyps. Despite the administration of hydralazine (100 mg four times daily), methyldopa (500 mg four times daily) and clonidine (0.2 mg four times daily), the blood pressure was not well controlled. Diastolic blood pressure levels were generally in the range of 105 to 110 mm Hg. In May the serum creatinine was 5.0 mg/lOO ml; on August 22 the value was 8.5 mg/lOO ml with a serum urea nitrogen of 110 mg/ 100 ml. The weight remained 129 pounds. However, the patient had noted increasing shortness of breath over the preceding week and this, plus recurrent epistaxis and hemoptysis, prompted his third admission to Barnes Hospital one week later. At that time he appeared both chronically and acutely ill with a prominent stare and frequent involuntary movements. The blood pressure was 200/120 mm Hg, the pulse rate BO/min, the respiratory rate 24/min, the temperature 37.0°C and the weight 129 pounds. There was no anterior bleeding from the nose, and no ulcerations were noted, but blood was noted in the pharynx. There was marked obliteration of the arterioles as well as hemorrhages in the fundi. Jugular venous distention, bilateral basilar pulmonary rales and cardiomegaly were again noted but there was no peripheral edema. An audible fourth heart sound and a left parasternal lift were described. The stool yas guaiac negative. Asterixis was present. The hemoglobin level was 7.2 g/100 ml. and burr cells were noted on the peripheral smear. The white blood cell count was 8,700/mm3 with a normal differential count: the platelet count was 300,000/mm3. The serum creatinine was 10.2 mg/lOO ml; the urine sediment revealed 5 to 10 red blood cells/high power field; no casts were seen. The 24-hour urine protein was 2.8 g. The serum albumin was 3.1 g/100 ml. The erythrocyte sedimentation rate was 60 mm/ hour, the LDH level was 371 mlU/ml and the CPK level 415 mlU/ml, but the serum glutamic-oxaloacetic transaminase, alkaline phosphatase and total bilirubin levels were normal as were the prothrombin and partial thromboplastin times. There were clots of blood in the sputum. The arterial pH was 7.43, the ~0s 52 mm Hg and the pCOz 29 mm Hg. Chest films demonstrated reappearance of the bilateral perihilar infiltrates and moderate cardiomegaly. No pathogens were isolated from cultures of the sputum, and blood cultures were negative. Furosemide and intravenous diazoxide therapy
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lowered the blood pressure to 192/104 mm Hg, but there was no symptomatic improvement. The following day hemodialysis lowered the serum creatinine to 6.4 mg/lOO ml. The blood pressure after dialysis was 160/ 100 mm Hg. Therapy with hydralazine, methyldopa, clonidine and digoxin was continued. Vomiting and an episode of hypotension were associated with the patient’s second hemodialysis on September 3. Two units of packed red blood cells were administered. Despite a 4 pound weight loss during dialysis, the patient subsequently became acutely dyspneic and cyanotic. The arterial pH was 7.52, the ~0s 44 mm Hg and the pC02 27 mm Hg. A Swan-Ganz catheter was inserted. The mean pulmonary artery pressure was 46 mm Hg, and the wedge pressure was 27 mm Hg. Phlebotomy, with the return of 3 units of packed red blood cells, and oxygen by mask led to a decrease in the patient’s respiratory distress. However, this recurred during hemodialysis on the following day. Inverted T-waves in leads V, through Vs on the electrocardiogram were noted, but subsequent serum myocardial band-CPK determinations were negative. The blood pressure was not adequately controlled with oral medications, and nitroprusside was administered. No evidence of thrombus was seen on an inferior vena cavogram on September 5. Methylprednisolone administration was begun. Fever developed on September 9. Cultures were obtained and ampicillin was administered. Melena and a decrease in hematocrit values to 16 per cent, with no evidence of upper gastrointestinal bleeding on nasogastric suction, developed on September 10. The administration of methylprednisolone was discontinued, and transfusions were given. The hematocrit value rose to 22 per cent. On September 12 gram-negative rods were reported to be growing from the earlier blood cultures. Gentamicin therapy was added. Gastrointestinal bleeding continued. Aortography with selective celiac and renal artery injections was performed on September 13. Active gastric and duodenal bleeding was demonstrated and treated with infusions of vasopressin into the celiac artery. Renal arteriograms demonstrated arterial changes consistent with nephrosclerosis. Gastrointestinal bleeding and hemoptysis continued, and on September 15 the patient suffered what was believed to be a massive intracranial hemorrhage and died.
CLINICAL DISCUSSION Dr. Saulo Klahr: Two major organs, the lung and the kidney, were primaiily involved in this patient. The lung disease was characterized by the presence of diffuse pulmonary infiltrates and moderately severe
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hypoxia (his arterial pop was 65 mm Hg and his pCOn was 21 mm Hg on his first admission in October 1974). His renal disease, on the other hand, was characterized by progressive nephron destruction with marked renal insufficiency and abnDrmal permeability of his glomerular capillaries to macromolecules. His urinary protein excretion was on the order of 2 to 3 g in 24 hours. Because of a history of hypertension, elevated blood pressure readings and fundic changes compatible with hypertensive retinopathy, coupled with a serum urea nitrogen of 50 mg/ 100 ml and a serum creatinine of 3.7 mg/ 100 ml, a diagnosis of nephrosclerosis was made on his first admission in CCtDber 1974. His pulmonary infiltrates were attributed to pneumoconiosis, more specifically silicosis. I would like to first address my attention to the pulmonary problem to see if we can gain some further insight into the process that was taking place in the lungs. Let me review briefly the major categories of diffuse pulmonary infiltrates before I ask the radiologist to show us the chest films to see whether or not they would help us in the differential diagnosis. These categories include the following: (1) Infection, including bacterial, mycotic, viral and parasitic infections. (2) Disorders of unknown cause including acute interstitial fibrosis, pulmonary alveolar proteinDsis and desquamative interstitial pneumonia. (3) Pneumoconiosis, including asbestosis and silicosis. (4) Systemic diseases, including systemic lupus erythematosus, polyarteritis, scleroderma, Wegener’s
granulomatosis and Goodpasture’s syndrome. I have also included idiopathic pulmonary hemosiderosis and amyloidosis in this category. (5) Allergic entities which include reaction to drugs, eosinophilic pneumonia, serum sickness, etc. (6) Congenital causes of pulmonary infiltrates. (7) Inhalational diseases such as Farmer’s lung, Silo-Filler’s lung and perhaps an acute reaction to silicon. (8) Metabolic causes such as uremic pneumonitis and hyperparathyroidism. (9) Neoplastic disorders including alveolar carcinoma, leukemia, lymphomas, hematogenous metastatic malignancies and (10) circulatory causes such as congestive heart failure, pulmonary embolization and mitral stenosis. At this point, Dr. Reiter will show us the chest films. Dr. Frederic0 Reiter: The chest film obtained on October 14, 1974, demonstrated extensive air space consolidation, involving the perihilar and central portions of both lungs. The margins of the consolidated lung were rather sharply defined. Bilateral small pleural effusions were present, and the cardiac size was within normal limits. The next chest film was obtained one week later and showed no significant interval change. Five months later, a follow-up chest film was obtained. The film was slightly overpenetrated, but it showed complete interval clearing of the infiltrates (Figure 1). The admission chest film in August 1975 demonstrated again bilateral air space consolidation, somewhat more extensive on the left side, with moderate cardiac enlargement and small bilateral pleural effusions (Figure 2). One week later, the infiltrates were
Figure 1. Chest roentgenogram from March 1975,. five months after the patient’s first Barnes Hospital admission, demonstrates interval clearing of the pulmonary infiltrates.
Figure 2. Chest roentgenogram from August 1975 den+ onstrates re-appearance of bilateral air space consolidation.
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much more extensive especially on the right side. Our last film of the chest, obtained 10 days before death, revealed moderate improvement, with persistent consolidation in the central portion of both lungs. Dr. Klahr: Thank you. One of the important questions here is whether to take the report of the chest film obtained in March 1975 at face value. When I reviewed the films with Drs. Reiter and Senior, I raised the question of overpenetration of this particular film and whether, because of this, some pathology present in the lung could have been masked. Was there indeed a disappearance of the infiltrates on the chest film obtained in March? This becomes an important point in terms of the differential diagnosis among some of the entities already listed. Both Dr. Reiter and Dr. Senior assured me that despite overpenetration there was marked improvement in the pulmonary infiltrates. I would like to ask Dr. Senior to comment on the pathophysiology of the pulmonary disease in this patient and to try to eliminate from further consideration some of the entities we have listed. Dr. Robert Senior: When this patient was first seen he had a diffuse infiltrative lung process, hypoxemia, alveolar hyperventilation and a low diffusing capacity. block” was a term Historically, “alveolar-capillary often used in this setting. We seldom use this label now because we think it is misleading as to the pathophysiology of the problem. Hypoxemia, in disorders producing the so-called alveolar-capillary block syndrome, often derives from disturbances in the relationship between ventilation and perfusion or the distribution of diffusion, rather than qualitative and quantitive changes in the air-blood interface [ 11. In trying to make a decision as to the etiology of the patient’s diffuse lung process, two facts stand out. One is that hemoptysis was a prominent feature of the illness. The other is that the chest film showed clearing after the first hospitalization. With the starting points of hemoptysis and reversibility, I think neoplasm and pneumoconiosis can be excluded immediately. Infection deserves mention, but I would exclude it as a category also because fever was never present and hemoptysis was such a striking feature. Certainly, hemoptysis occurs in association with pulmonary infections, however, it is uncommon in the absence of cavitation or bronchiectasis. Hemoptysis would also be an unusual feature of the interstitial pneumonias and pulmonary problems that are drugrelated. I think we are left with two categories in your outline, Dr. Klahr, systemic and circulatory. To help sort between these two categories it would have been most helpful, during the first hospitalization, to have had measurements of the pulmonary artery and pulmonary capillary wedge pressures. The measure-
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ments are easily obtained by balloon flotation (SwanGanz) catheter [2]. Normal wedge pressure would point away from pulmonary edema due to heart failure, and normal pulmonary artery pressure would be against extensive pulmonary vascular occulsion. My own bias as to the nature of the patient’s infiltrates is that they were most, if not all, due to bleeding within the substance of his lung. I think this way because he had a great deal of hemoptysis and his anemia, when he was first seen, was far out of proportion to the severity of his uremia. Dr. Klahr: Yes, I would tend to agree with your last statement. I was quite impressed with this patient’s pulmonary infiltrates on his first admission to Barnes. Despite the fact that he lost about 16 pounds in weight and that most of his peripheral edema disappeared between October 14 and October 2 1, his pulmonary infiltrates persisted. It would seem unlikely that uremic pneumonitis or pulmonary edema was the cause, at least initially, of the infiltrates. I agree that the degree of anemia, coupled with iron deficiency, would suggest that this man had bleeding into his lung. Can you get a picture like this after overwhelming exposure to silica? Could we be dealing in this patient not with a typical case of silicosis with pulmonary fibrosis but with an “allergic type” of reaction to silica? Dr. Senior: As you are implying, a fatal respiratory syndrome has been observed in people, such as sandblasters, who have had an intense exposure to high density of silica particles [3]. The picture is one of diffuse lung infiltrates with rapidly progressive, severe shortness of breath. Histologically, the lung has alveolar filling resembling alveolar proteinosis; silicotic nodules are not prominent. I do not think this syndrome fits the present case for several reasons: (1) the history is not suggestive of recent intense silica exposure: (2) hemorrhage would be an unusual expression of this type of lung disease: and (3) resolution of the infiltrates would be surprising. Dr. Klahr: Taking into consideration that this man also had renal disease, let me try to eliminate other entities. Idiopathic pulmonary hemosiderosis is seen in younger people, usually below the age of 20. Very seldom, although a few cases have been described, is renal disease associated with it, and usually survival of patients with pulmonary hemosiderosis is much longer than that seen in this particular person. Amyloidosis will very seldom give a picture like this on chest film. The course of this patient’s renal disease is also difficult to explain in terms of a diagnosis of amyloidosis. Dr. Senior, should we consider acute interstitial fibrosis or pulmonary alveolar proteinosis any further at this point in time? Dr. Senior: As I mentioned earlier, pulmonary hem-
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orrhage is not a feature of those disorders. Also wide, spontaneous fluctuations, evident on the chest films, from very abnormal to near normal and then recurrence of abnormality are not typical of that collection of diseases. Dr. Klahr: This man was 61 years old so that congenital causes of pulmonary infiltrates can be excluded. There is nothing to suggest that we are dealing with an allergic reaction. So we are left really with three major categories to explain his pulmonary infiltrates: (1) systemic diseases, namely, collagen vascular disorders, (2) metabolic disorders, and here we can eliminate hyperparathyroidism which may present with pulmonary infiltrates, usually characterized by deposition of calcium within the lung, and (3) circulatory causes. Now let me turn our attention to the kidney. Dr. Hatter, would you comment on the nature of this patient’s renal disease? Initially, Dr. Harter, his kidney disease was characterized by progressive nephron destruction and abnormal permeability of the glomerular capillaries to protein. Hence, I think we can safely assume that we are dealing with an entity that involves either the small vessels or the glomerular capillaries of the kidney. My question is this. Could the renal picture be explained on the basis of neophrosclerosis alone? Dr. Herschel Harter: The rapidity with which the glomerular filtration rate fell in this patient could be explained by glomerular destruction secondary to inadequate blood pressure control. A patient who presents with between 2 and 4 g of protein in the urine and inadequate blood pressure control may, in fact, have accelerated or malignant nephrosclerosis. Although the nephrotic syndrome is rare in hypertensive renal disease, increased proteinuria may be a heralding sign of malignant nephrosclerosis. Dr. Klahr: We will come back to this point at the end. Dr. Reiter will now show us the intravenous urogram and the arteriograms. Dr. Meter: In October 1974 a nephrotomogram was performed. The kidneys were normal in size and the collecting systems were faintly visualized. The cortex was of normal thickness, and there was no evidence to suggest hydronephrosis. On the upper lateral margin of the left kidney, a 3 cm mass lesion was seen. There was sharp contrast between the normal nephrographic density of the surrounding normal kidney tissue and the density of the lesion, suggesting a hypovascular or avascular mass. Five months later, an intravenous urogram gave us the same results. On September 13, 1975, an emergency abdominal angiogram for massive gastrointestinal bleeding was performed, and simultaneously a right renal angiogram was obtained. The intrarenal arteries were
very abnormal with irregularities of the arterial wall, areas of stenosis and small aneurysmal dilatations (Figure 3). The flow through the renal cortex was minimal and the cortical medullary junction was not well seen. This picture was considered to be consistent with active arteritis, probably related to malignant nephrosclerosis. Dr. Klahr: Thank you very much. The renal-pulmonary syndromes that should be considered in this particular patient can be divided in two major categories: (1) renal and pulmonary diseases which share a common etiologic basis, including renal vein thrombosis with pulmonary embolization and collagen vascular disorders (polyarteritis, hypersensitivity angiitis, Wegener’s granulomatosis and Goodpasture’s syndrome), and (2) renal and pulmonary diseases which do not share the same etiologic cause, including nephrosclerosis and pneumoconiosis, nephrosclerosis and pulmonary edema and/or uremic lung, nephrosclerosis, glomerulonephritis, pneumoconiosis and pulmonary edema and nephrosclerosis, pulmonary edema and pulmonary hemorrhage. Initially renal vein thrombosis with pulmonary embolization was suspected. In this regard it should be pointed out that pulmonary embolization was suspected but not documented. No studies were conducted to determine whether or not this patient indeed had pulmonary emboli. However, studies to locate a possible source of embolization were performed. An inferior vena cavogram was negative.
Right renal arteriogram demonstrates abnormal intrarenal arteries with irregularities of the arterial wall, areas of stenosis and small aneurysmal dilatations.
Figure 3.
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This, of course, does not exclude the possibility that emboli may be found in this man’s pulmonary arteries at postmortem. But, this seems unlikely in view of the roentgenographic studies. So, we are left with a differential diagnosis between collagen vascular disorders and ordinary nephrosclerosis with severe lung complications that may be related to the consequences of hypertension. Dr. Harter, would you address yourself to the differential diagnosis of collagen vascular disorders in this patient? Dr. Hatter: Polyarteritis is a possibility in this patient. lt is a disease that predominantly involves mediumsized vessels, but there may be small vessel involvement. Small vessel polyarteritis produces a glomerulitis and is usually seen in the older population: it is infrequently associated with hypertension. On the other hand, medium-sized vessel involvement occurs in younger subjects, and hypertension is a predominant feature while glomerulitis is rare. Although the patient presented with what appeared to be a glomerulitis, he had significant hypertension, thus the diagnosis of polyarteritis is somewhat difficult to make. Pulmonary involvement with polyarteritis has been documented. In a large series of patients described by Rose and Spencer [4], fully one-third had pulmonary involvement, but whether they had hemoptysis is not entirely clear. The patients typically had evanescent diffuse pulmonary infiltrates. Of interest, pulmonary involvement was documented in 39 of 252 autopsies of patients with glomerulonephritis [6]. It was typified most commonly by hemosiderosis, which would imply pulmonary hemorrhage. I doubt that these cases could be called Goodpasture’s syndrome. They do attest, however, to the extremely high incidence of pulmonary involvement in patients with differing glomerulopathic disorders. Another possible diagnosis in this patient is Wegener’s granulomatosis [ 61. It is a disease that can affect a person of almost any age, although it is predominantly seen in people in the 40’s and 50’s. There is male predominance. The disease most closely represents, clinically, an allergic vasculitis, with rapid renal failure progressing over 12 months. Pathologically, however, it is a necrotizing granulomatous disease. Pulmonary infiltrates may occur in this disorder, but they are usually discrete and nodular rather than diffuse. They may be evanescent, however. Because of the duration of the disease of this patient, as well as the clinical picture, I believe this diagnosis is unlikely. Another possibility is Goodpasture’s syndrome [ 71. It is a disease involving primarily males in the early third decade. Typbally, the disease will present with pulmonary involvement associated with frank hemoptysis. The renal involvement will usually manifest itself somewhat later, but it may occur prior to the
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onset of pulmonary disease. The clinical picture is again one of rapidly progressive glomerulonephritis with hematuria, red cell casts and moderate to severe proteinuria. The disease is typified by circulating antibodies to both glomerular and pulmonary basement membrane. The usual course of the disease is rapid, with pulmonary failure. Because of the chronicity of the disease in this patient, as well as the patient’s age, I do not believe that Goodpasture’s syndrome is likely. Thus, of those diagnoses listed, polyarterttis is the only one that would seem likely. Dr. Klahr: Let me ask you another question that relates to the episodes of acute respiratory distress which occurred during and immediately after dialysis. There are three distinct possibilities as far as I can see. Either we are dealing with pulmonary edema, intra-alveolar hemorrhage or embolization. Both times that this patient had acute respiratory insufficiency after dialysis, he lost weight. Does this rule out pulmonary edema? Dr. Harter: This patient had a relatively severe pulmonary compromise during his hemodialysis. It is important to remember that, frequently with hemodialysis, patients receive plasma expanders during the procedure, either to maintain their blood pressure, to raise their hematocrit value or to afford a more efficient removal of extracellular fluid. Since the typical dialysis coil will contain somewhere between 150 and 200 ml of blood, as the dialysis is terminated the infusion of this fluid to the patient may precipitate congestive heart failure. I think that on at least one occasion this occurred in this patient. Another possibility leading to this clinical picture is severe myocardial ischemia. This may occur during hemodialysis due to an increased cardiac output, or to hyperor hypotension, induced by either reflex vasospasm or excessive fluid removal during dialysis. With severe myocardial ischemia and decreasing cardiac output, congestive heart failure may again occur. We recently have described a series of patients with subcutaneous arteriovenous fistulas, in whom high output cardiac failure developed [6]. In a patient with severe cardiac disease, the added workload of an arteriovenous shunt may be enough to precipitate congestive heart failure, although this possibility seems unlikely. Finally, the development of severe acidosis secondary to poor metabolism of either lactate or acetate, leading to further cardiac decompensation may occur. The second possibility for these episodes on hemodialysis may relate to the patient’s pulmonary disease. Certainly, pulmonary emboli in patients receiving femoral venous catheterizations must be considered. Also, pulmonary hemorrhage in someone with diffuse vasculitis may occur because of heparinization required during the procedure. However, we
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have no evidence for this. As an explanation for the pulmonary decompensation in this patient, I favor cardiac failure due to increased cardiac workload and volume overload in a patient with already severely compromised cardiac function. Dr. Hoffsten, would the complement Dr. Klahr: values that were obtained, and I realize that there was only a single set of values, help us at all in the differential diagnosis of this patient’s renal disease? Secondly, why wasn’t a renal biopsy specimen obtained in this gentleman? Dr. Philip Hoffsten: The complement values available were obtained a year before the final episode; I do not think they would be of help in making a diagnosis. The values were actually higher than normal, which is not diagnostic in regard to his renal disease. The serum concentration for the third component of complement (C-3) is commonly decreased in socalled hypocomplement chronic glomerulonephritis or in acute glomerulonephritis via activation of the alternate complement pathway. Sometimes complement values are low in systemic lupus erythematosus when the classic pathway is activated. In a series of cases of Goodpasture’s syndrome [ 91, serum C-3 concentrations were depressed in only two of 19 cases. In regard to considering a renal biopsy, this gentleman had a clinical course which ran at least a year and probably much longer than that. During the year before his death, his renal failure was slowly progressive, but there was a marked increase in the month prior to his admission. The diagnostic value of a renal biopsy would be in detecting a reversible renal lesion. Chronic progressive renal disease with a glomerular filtration rate less than 25 per cent of normal is rarely reversed by any form of therapy regardless of the etiology of the disease. Sometimes patients, with diseases such as rapidly progressive glomerulonephritis, in whom the glomerular filtration has decreased to low values in a short period of time can be treated effectively and renal function can be recovered. These patients should undergo a renal biopsy, the results of which can serve as a guide in selecting therapy. However I do not believe this patient qualified in that regard. My belief in this patient was that he had a slowly progressive renal disease and that, even with a tissue diagnosis, the likelihood that we could reverse anything was very small. That coupled with the extreme risk of a renal biopsy in this patient with severe pulmonary insufficiency mitigated strongly against the procedure. Dr. Klahr: Thank you Dr. Hoffsten. I would tend to agree with Dr. Harter in terms of Wegener’s granulomatosis. In an article published recently [IO], 21 cases of Wegener’s granulomatosis were reviewed. In 95 per cent of these cases, there were mucosal
ulcerations of the nasopharynx and the paranasal sinuses. In this gentleman we are told that there was no nose ulceration. This negative finding would speak strongly against the diagnosis of classic Wegener’s granulomosis in our patient. In terms of Goodpasture’s syndrome, the clinical course is compatible. There are a few things, however, that do not fit with the diagnosis of Goodpasture’s syndrome. First, there is a low incidence of hypertension in Goodpasture’s syndrome. Only six patients in a series of 45 patients had diastolic readings above 90 mm Hg [7]. In this man, of course, one could postulate that he had underlying hypertension and that then Goodpasture’s syndrome developed. The lack of a very active urine sediment also is somewhat against this diagnosis. The patient’s renal function, although decreased, was stable up until six weeks before his death; then it deteriorated suddenly. This, again, is not typical of Goodpasture’s syndrome. How about polyarteritis? It could not be classic polyarteritis, as described by Meier and Kussmaul, since in this entity the lung is not at all involved. So medium-sized or large artery involvement seems somewhat unlikely in terms of explaining the lung lesions. If we are going to explain the lung lesions and the renal lesions on the same basis, we should consider hypersensitivity angiitis. But then there are several things which do not fit with that diagnosis. There was no fever, except for a single reading of 37.8’C. There was no eosinophilia. Sixty-nine per cent of the patients of Rose [ 1 I] with lung involvement due to hypersensitivity angiiiis had eosinophilia. No leukocytosis was present at all during the course of disease in this man. All this makes me doubt that this man had hypersensitivity angiitis. I am left with the fact that this man had long-standing hypertension and that perhaps necrotizing arteritis developed despite the fact that his blood pressure levels were not as high as one would like to see to make this diagnosis. I believe that, indeed, he had congestive heart failure, cardiomegaly and advanced nephrosclerosis. The deterioration in renal function could be due to accelerated nephrosclerosis or to superimposed glomerulonephritis. Pulmonary edema and hemorrhage were probably responsible for the lung findings. There will be ulceration of the upper gastrointestinal tract, and the pathologist is going to tell us that the patient had a cyst in the left kidney. Instead of making a diagnosis of a somewhat rare entity I am going to say that this man had malignant hypertension. Are there any comments from the panel? Dr. Harter: There may be pulmonary involvement with silica or some other form of pneumoconosis. Dr. Klahr: I suspect the pathologist is going to show some silica in the lungs, but I do not think it will be significant from the pathologic point of view.
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Dr. Senior: I am sure he will have silica in his lungs, but I think it is of no importance. I want to re-emphasize the significance of severe hemoptysis and diffuse infiltrates which I believe indicate a pulmonary vascular problem of some sort, probably vasculitis. I wish to add one point to Dr. Harter’s comments. The respiratory problem with dialysis was almost certainly pulmonary edema due to heart failure, since left atrial pressure was quite high as measured by the SwanGanz catheter and improvement occurred with plasmaphoresis. PATHOLOGIC
DISCUSSION
The pathology was that of a very Dr. Dan McKeel: classic case of malignant nephrosclerosis. I want to take you through the autopsy findings, then explain the pulmonary lesion and, finally, provide one plausible explanation of all that was happening. The immediate cause of death was massive acute intracranial hemorrhage (Figure 4). A multifocal corpus striatal
hemorrhage destroyed most of the cerebral hemisphere, then dissected into the third ventricle, both lateral ventricles, the fourth ventricle, and the tegmentum of the pons. The kidneys, as is often the case in end-stage nephrosclerosis, were not reduced in weight; one weighed 139 g and the other 142 g. A 4 by 4 cm left renal cyst and multiple other cysts were evident in both kidneys. The largest one on the left contained blood and a small yellow nodule, which histologically was an area of intense tubular hyperplasia rather than cancer. Other studies have shown that one-third of blood-containing renal cysts contain neoplasms probably derived from tubular cells. Tubular regeneration and proliferation coexisted with some of the more classic changes of nephrosclerosis. On cut section the renal cortical width was normal and the arteries were prominent. Microscopically (Figure 5), the kidney was much more dramatic than the gross picture. The cortical architecture was greatly altered.
Figure 4. Coronal sections of fixed brain with massive intracerebral hemorrhage extending into the ventricles and pons.
Figure 5. Photomicrograph of the kidney shows two well preserved glomeruli, one partly sclerotic giomeruus (far left), ttibuiar dilatation and casts, and atrophic and regenerating tubules (upper leff). Hematoxyin and eosin stain; original magnifjcation X 40, reduced by 30 per cent.
Figure 6. Photomicrograph illustrates acute hemorrhage surrounding a damaged glomerulus. Periodic acid-SchiffGiemsa stain; orjgk?ai magnification X 10, reduced by 30 per cent.
Figure 7. Photomicrograph of renal artery with “onionskin” intimal hyperplasia typical of malignant nephrosclerotic vascular disease. Verhoeff-Van Gieson stain; origjnal magnification X 100, reduced by 30 per cent.
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A representative section showed a hemorrhagic, necrotic glomerulus with hemorrhage surrounding it and many flattened dilated tubules, some with eosinophilic casts, a classic finding of malignant nephrosclerosis. Widespread drop out of tubules with dilatation of remaining ones was evident, associated with interstitial fibrosis. Typically, a third or half of the glomeruli appeared almost normal. Many highly abnormal ones were also present. Some abnormal glomeruli exhibited hyalinization and shrinkage of the tufts, thickening of Bowman’s capsule and collagenization internal to the capsule, alterations that can also be seen in ordinary essential hypertension; thus many people believe that malignant nephrosclerosis is an exaggerated phase of chronic vascular disease of the kidneys. However, other areas showed focal glomerular necrosis with hemorrhage suggesting acute damage (Figure 6). Large numbers of completely sclerotic glomeruli, scattered foci of chronic inflammatory cells in the interstitium, and areas of marked fibrosis and atrophy of the tubules were also seen. Vascular changes in the kidneys were striking. lntralobular arteries showed the classic changes of malignant ne-
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phrosclerosis: marked concentric intimal hyperplasia causing an almost pinpoint lumen (Figure 7). Onionskin concentric layering of the intima is a hallmark of this disease. Thus, there is a beautiful correlation of the renal arteriogram and the postmortem renal vascular morphology. The adrenal glands showed bilateral cortical hyperplasia with focal nodularity, mainly of the zona fasciculata, demonstrating the typical hyperplastic cell morphology that is common in patients with malignant hypertension. In a healthy person, the combined true adrenal weight ought not to exceed 6 g. The combined weight of the patient’s hyperplastic adrenals was 22 g. Malignant hybertension, of course, affects vessels throughout the body; these lesions are shown in a series of small arterioles and arteries in the periadrenal tissues (Figure 8). The typical lesions included (1) intimal hyperplasia very similar to what was present in the kidney: (2) vessels with definite intimal hyperplasia, which also showed smudging and fibroid necrosis of portions of the wall; (3) other arteries showed myxoid intimal thickening .as weli as marked hyalini-
Figure 8. Photomicrographs of periadrenal arterioles showing various stages of hypertensive vascular damage. A, concentric intimat hyperpiasia. 8. intimal hyperpiasia with focal mural hyalinization. C, concentric and myxoid hyperpfasia. 0, total mural hyalinization (fibrinoid necrosis). All hematoxylin and eosin stains; original magnification X 200, reduced by 27 per cent. March 1976
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_ Survey photomicrograph of the lung shows difFigure fi. fuse intraalveoiar fibrin deposition and cellularity with central foci of hemorrhage. Hematoxylin and eosin stain; original magnification X 40, reduced by 30 per cent.
zation and fibrinoid change in the arterial wall; and (4) vessels with marked fibroid necrosis and narrowing of the lumen. Elastic tissue stains demonstrated that in addition to fibroblastic intimal proliferation, some larger arteries exhibited reduplication and splitting of the internal elastic lamina. The lungs at autopsy were extremely heavy, having a combined weight of approximately 2,500 g or four times over normal. The cut surfaces showed beefy red consolidation with a glassy sheen. Patchy anthracotic pigmentation and areas of mild emphysematous change were appreciated. The gross appearance was not that of a severe case of pneumoconiosis. Microscopically, a fibrin layer adhered to the pleural surface. Anthracotic pigment was throughout the lung, but there was no dramatic silica nodule or fibrosis. Portions of the lung were digested, and asbestos bodies were isolated; they were not increased in number over what is commonly seen at autopsy. Thus, we did not find microscopic evidence of pneumoconiosis or, in fact, of most of the entities entertained in the clinical differential diagnosis, except abundant evidence of pulmonary hemorrhage. Low power survey micrographs illustrated marked consolidation of the air spaces with small and large focal areas of hemorrhage (Figure 9). Higher magnification microscopy revealed a variety of cell types, mixed with red cells among masses of fibrin. The cellular composition in the alveolar spaces was very pleomorphous and included large macrophages, neutrophils and chronic inflammatory cells. Many foci in both lungs had a predominant infiltrate of polymorphonuclear leukocytes associated with demonstrable intracellular gram-negative rods, which constituted evidence of a confluent bronchopneumonia as one primary pathologic process. Postmortem blood cul-
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Figure 10. Photomicrograph of autopsy kidney section stained for fibrin. The upper capillary loops are filled with compact and fibriliar fibrin and globular fibrinogenfibrin forms. Note a fibrin thrombus partly filling the afferent arteriole at lower right. Periodic acid-Schiff-Giemsa stain; original magnification X 400, reduced by 30 per cent.
tures yielded Citrobacter and Klebsiella organisms compatible with this histologic type of fairly acute pneumonitis. In addition, there was evidence of a second more chronic pathologic process. I have already mentioned the chronic nature of much of the alveolar inflammatory infiltrate. The edema was in the form of fibrin, shown by the phosphotungstic acid hematoxylin (PTAH) stain which selectively stains fibrin strands blue. I believe these three processes, that is, hemorrhage, fibrinous edema and bronchopneumonia satisfactorily explain the roentgenographic findings in the lung. I believe that since many of the macrophages had hemosiderin, fibrin and red cells, the hemorrhages were probably episodic and recurrent. How can the renal and pulmonary pathology be tied together? By an intermediate mechanism, disseminated intravascular coagulation (DIC), manifested anatomically in several ways. Direct immunofluorescence was performed on the kidneys and the lungs by Dr. Mancilla. The lung findings were completely negative for immunoglobulin, fibrin and complement, and the consultant believed that this effectively ruled out Goodpasture’s syndrome. Fibrin and thrombi strands were appreciated in many renal glomeruli stained by phosphotungstic acid hematoxylin or periodic acid-Schiff-Giemsa (Figure 10). The immunofluorescence pattern showed a very dramatic deposition of fibrin in the glomerular capillaries. I reviewed the record searching for additional evidence that DIC might have occurred. One was the mention of “burr” cells present on the admission blood smear; “burr” cells or schistocytes are morphologic sign posts of microangiopathic hemolytic anemia,
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marrow is often hyperplasic. If the DIC has been present for a long time, megakaryocytic hyperplasia is even more remarkable. That is what I found in this case. Many small immature megakaryocytes with single lobed nuclei as well as mature megakaryocytes were present in the marrow sections (Figure 11). Summarizing, this man had nephrosclerosis which may have been present for many years. The nephrosclerosis entered an accelerated phase for unknown reasons. There was no evidence of a progressive glomerulonephritis or pyelonephritis. I suggest that he probably had for a long time, associated with his hypertension, a chronic type of disseminated intravasFigure 1 I. Photomicrograph of autopsy bone marrow section demonstrating hyperplasia especially marked in the megakaryocytic series. Hematoxylin and eosin stain; original magnification X 200, reduced by 30 per cent.
cular coagulation as discussed by McKay [ 121 and with maligby Edson [ 131. This type is associated nancies, chronic vasculitis and repetitive vascular endothelial damage resulting in a chronic hypercoagulable state. I hypothesize that this might be an explanation of the postulated episodic pulmonary hemor-
which I speculate this patient might have had. Two days before the patient’s death, laboratory findings included
a platelet
count of 23,000/mm3,
rhages and edema. Terminally, gram-negative septicemia developed, probably arising from the pulmonary infection, which caused an acute DIG syndrome with marked thrombocytopenia, that is, consumptive
slightly pro-
longed prothrombin and partial prothrombin times, and fibrin split product elevation of very mild degree, 8 pg/ml, the upper normal range being 4 pg/ml. I found more evidence of DIC in the rest of the autopsy, for example, microthrombi composed mostly of platelets intermixed with fibrin scattered throughout
coagulopathy, causing a fatal intracerebral hemorrhage. Some medical investigators believe very strongly that DIC is an integral part of the expression of malignant hypertension, but others believe the two
the gastrointestinal tract, spleen and pancreas. Fibrin microthrombosis is one of the hallmarks of DIC at autopsy: the other, of course, is the presence of bleeding in various sites. We have already seen that there was a massive terminal intracranial hemorrhage. But clinically there were also problems with gastrointestinal bleeding. Several very small gastrointestinal ul-
conditions are causally unrelated diseases. Dr. Stanley Robbins, in the latest edition of his text “Pathologic Basis of Disease,” asserts that DIC may be the “fundamental mediator” of the disease, malignant
cers were formed, two in the antrum of the stomach and one in the duodenum. A long segment of the small bowel was filled with recently clotted blood: thus I must assume there was significant oozing. The final evidence supporting DIC was the bone marrow, in which it is important to differentiate thrombocytopenia on the basis of marrow failure from thrombocytopenia associated with DIC in which the bone
lesions predisposed to this chronic coagulopathy may serve to explain the episodic pulmonary hemorrhages. We certainly know from the publications of [ 14,151 that massive Minna, Robboy and Colman pulmonary hemorrhage is definitely associated with severe DIC, and I hope this association will receive
hypertension. That is one view point, close to my own, but other people will certainly disagree. Acceptance of the concept that the widespread vascular
more
clinical,
laboratory
and pathologic
study in the
future.
REFERENCES 1.
2.
3. 4.
Arndt H, King TKC, Briscoe WA: Diffusing capacities and ventilation: Perfusion ratios in oatients with the clinical syndrome of alveolar capillary’block. J Clin Invest 49: 408, 1970. Swan HJC: Balloon flotation catheters-Their use in Hemodynamic monitoring in clinical practice. JAMA 233: 865. 1975. Buechner HA, Ansari A: Acute Silica-Proteinosis. Dis Chest 55: 274, 1969. Rose GA and Spencer H: Polyarteritis nodosa. Q J Med 26: 43, 1957.
5. 6.
7.
8.
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McCaughey WT, Thomas BJ: Pulmonary hemorrhage and olomeruloneohritis. Am J Clin Pathol 38: 577, 1962. Fa&i AS, Wolff SM: Wegener’s granulomatosis: studies in 18 patients and a review of the literature. Medicine (Baltimore) 52: 535. 1973. Proskey AJ, Weatherbe L. Easterling RE, Greene JA, Weller JM: Goodpasture’s syndrome: a report of five cases and a review of the literature. Am J Med 48: 162, 1970. Anderson CB, Codd JF, Graff RA, Grace MA. Hatter HR: Cardiac failure in upper extremity arterial-venous dialysis fistulas: case reports and a review of the literature. Arch
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9.
10. 11. 12.
408
Intern bled (in press). Wilson CB, Dixon FJ: Antiglomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 3: 74, 1973. Wolff SM, Fauci AS, Horn RG, Dale DC: Wegener’s granulomatosis. Ann Intern Med 81: 513, 1974. Rose TM: The natural history of polyarteritis. Br Med J 2: 1148, 1957. McKay DG: Intravascular coagulation-acute and chronicdisseminated and local. Proc lnst Med ‘Chic 29: 159,
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13. 14.
15.
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1972. Edson JR: Mechanisms and dynamics of intravascular coagulation. Geriatrics 74: 65, 1974. Minna JD, Robboy Coleman RW: Disseminated Intravascular Coagulation in Man. Springfield, Ill., Charles C Thomas, 1974, p 78. Robboy SJ, Minna JD, Colman RW. Birndorf NI, Lopas H: Pulmonary hemorrhage syndrome as a manifestation of disseminated intravascular coagulation. Analysis of 10 cases. Chest 63: 718, 1973.
Pulmonary Hemorrhage and Renal Failure
Stenographic reports, edited by Philip E. Cryer, M.D. and John Kissane, M.D., of weekly clinicopathdogic conferences held in Barnes and Wohl Hospttals, are p<shed iti each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine and Pathology of Washington University School of Medicine. A 61 year old man was admitted to Barnes Hospital on August 27, 1975, because of hemoptysis and progressive renal failure. He died 19 days later. Hypertension and intermittent epistaxis were dated from 1970. Fatigue, nausea, nocturia, exertional dyspnea and ankle edema developed in mid-1974. A several week history of hemoptysis led to his first admission to Barnes Hospital in October 1974. The history also included industrial exposure to silicon and asbestos, and chronic cigarette smoking. The’ patient appeared chronically ill. The blood pressure was 180/l 10 mm Hg, the pulse rate 90/min, the respiratory rate 30/min, the temperature 37.8’C and the weight 145 pounds. There was severe arteriolar narrowing in the optic fundi with arteriovenous nicking, hemorrhages and exudates. Jugular venous distention, bilateral basilar pulmonary rales, cardiomegaly and marked peripheral edema were noted. The hemoglobin level was 7.9 g/100 ml; bone marrow examination revealed only diminished iron stores. The white blood cell count was 10,200/ mm3. The serum urea nitrogen was 50 mg/lOO ml and the serum creatinine 3.7 mg/lOO ml. The urine sediment revealed only 1 white blood cell/hpf, but there was 4+ proteinuria. The endogenous creatinine clearance was 25 ml/min and a 24 hour urine contained 2.5 g of protein. Intravenous urograms demonstrated a defect in the left kidney, believed to be a cyst, and normal size kidneys. Additional serum values included an albumin of 1.8 g/100 ml with total proteins of 4.8 g/100 ml, a cholesterol of 190 mg/lOO ml, a lactic dehydrogenase (LDH) of 328 mlU/ml and a creatinine phosphokinase (CPK) of 213 mllJ/ml. The arterial pH was 7.50, the oxygen tension (pop) 65 mm Hg and the carbon dioxide tension (pCO*) 21 mm Hg. Chest films demonstrated mild cardiomegaly and extensive bilateral perihilar infiltrates. The carbon monoxide diffusing capacity was markedly diminished. The erythrocyte sedimentation rate was 86 mm/hour. Serum complement levels were not depressed; a test for antinuclear antibodies demonstrated i-lnuclear fluorescence.
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Diuretic therapy and digitalization led to a discharge weight of 128 pounds. The pulmonary infiltrates were unchanged at the time of discharge. However, the infiltrates were not present on chest films obtained in March 1975 when the patient was admitted to Barnes Hospital for colonoscopy and subsequent removal of adenomatous colonic polyps. Despite the administration of hydralazine (100 mg four times daily), methyldopa (500 mg four times daily) and clonidine (0.2 mg four times daily), the blood pressure was not well controlled. Diastolic blood pressure levels were generally in the range of 105 to 110 mm Hg. In May the serum creatinine was 5.0 mg/lOO ml; on August 22 the value was 8.5 mg/lOO ml with a serum urea nitrogen of 110 mg/ 100 ml. The weight remained 129 pounds. However, the patient had noted increasing shortness of breath over the preceding week and this, plus recurrent epistaxis and hemoptysis, prompted his third admission to Barnes Hospital one week later. At that time he appeared both chronically and acutely ill with a prominent stare and frequent involuntary movements. The blood pressure was 200/120 mm Hg, the pulse rate BO/min, the respiratory rate 24/min, the temperature 37.0°C and the weight 129 pounds. There was no anterior bleeding from the nose, and no ulcerations were noted, but blood was noted in the pharynx. There was marked obliteration of the arterioles as well as hemorrhages in the fundi. Jugular venous distention, bilateral basilar pulmonary rales and cardiomegaly were again noted but there was no peripheral edema. An audible fourth heart sound and a left parasternal lift were described. The stool yas guaiac negative. Asterixis was present. The hemoglobin level was 7.2 g/100 ml. and burr cells were noted on the peripheral smear. The white blood cell count was 8,700/mm3 with a normal differential count: the platelet count was 300,000/mm3. The serum creatinine was 10.2 mg/lOO ml; the urine sediment revealed 5 to 10 red blood cells/high power field; no casts were seen. The 24-hour urine protein was 2.8 g. The serum albumin was 3.1 g/100 ml. The erythrocyte sedimentation rate was 60 mm/ hour, the LDH level was 371 mlU/ml and the CPK level 415 mlU/ml, but the serum glutamic-oxaloacetic transaminase, alkaline phosphatase and total bilirubin levels were normal as were the prothrombin and partial thromboplastin times. There were clots of blood in the sputum. The arterial pH was 7.43, the ~0s 52 mm Hg and the pCOz 29 mm Hg. Chest films demonstrated reappearance of the bilateral perihilar infiltrates and moderate cardiomegaly. No pathogens were isolated from cultures of the sputum, and blood cultures were negative. Furosemide and intravenous diazoxide therapy
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lowered the blood pressure to 192/104 mm Hg, but there was no symptomatic improvement. The following day hemodialysis lowered the serum creatinine to 6.4 mg/lOO ml. The blood pressure after dialysis was 160/ 100 mm Hg. Therapy with hydralazine, methyldopa, clonidine and digoxin was continued. Vomiting and an episode of hypotension were associated with the patient’s second hemodialysis on September 3. Two units of packed red blood cells were administered. Despite a 4 pound weight loss during dialysis, the patient subsequently became acutely dyspneic and cyanotic. The arterial pH was 7.52, the ~0s 44 mm Hg and the pC02 27 mm Hg. A Swan-Ganz catheter was inserted. The mean pulmonary artery pressure was 46 mm Hg, and the wedge pressure was 27 mm Hg. Phlebotomy, with the return of 3 units of packed red blood cells, and oxygen by mask led to a decrease in the patient’s respiratory distress. However, this recurred during hemodialysis on the following day. Inverted T-waves in leads V, through Vs on the electrocardiogram were noted, but subsequent serum myocardial band-CPK determinations were negative. The blood pressure was not adequately controlled with oral medications, and nitroprusside was administered. No evidence of thrombus was seen on an inferior vena cavogram on September 5. Methylprednisolone administration was begun. Fever developed on September 9. Cultures were obtained and ampicillin was administered. Melena and a decrease in hematocrit values to 16 per cent, with no evidence of upper gastrointestinal bleeding on nasogastric suction, developed on September 10. The administration of methylprednisolone was discontinued, and transfusions were given. The hematocrit value rose to 22 per cent. On September 12 gram-negative rods were reported to be growing from the earlier blood cultures. Gentamicin therapy was added. Gastrointestinal bleeding continued. Aortography with selective celiac and renal artery injections was performed on September 13. Active gastric and duodenal bleeding was demonstrated and treated with infusions of vasopressin into the celiac artery. Renal arteriograms demonstrated arterial changes consistent with nephrosclerosis. Gastrointestinal bleeding and hemoptysis continued, and on September 15 the patient suffered what was believed to be a massive intracranial hemorrhage and died.
CLINICAL DISCUSSION Dr. Saulo Klahr: Two major organs, the lung and the kidney, were primaiily involved in this patient. The lung disease was characterized by the presence of diffuse pulmonary infiltrates and moderately severe
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hypoxia (his arterial pop was 65 mm Hg and his pCOn was 21 mm Hg on his first admission in October 1974). His renal disease, on the other hand, was characterized by progressive nephron destruction with marked renal insufficiency and abnDrmal permeability of his glomerular capillaries to macromolecules. His urinary protein excretion was on the order of 2 to 3 g in 24 hours. Because of a history of hypertension, elevated blood pressure readings and fundic changes compatible with hypertensive retinopathy, coupled with a serum urea nitrogen of 50 mg/ 100 ml and a serum creatinine of 3.7 mg/ 100 ml, a diagnosis of nephrosclerosis was made on his first admission in CCtDber 1974. His pulmonary infiltrates were attributed to pneumoconiosis, more specifically silicosis. I would like to first address my attention to the pulmonary problem to see if we can gain some further insight into the process that was taking place in the lungs. Let me review briefly the major categories of diffuse pulmonary infiltrates before I ask the radiologist to show us the chest films to see whether or not they would help us in the differential diagnosis. These categories include the following: (1) Infection, including bacterial, mycotic, viral and parasitic infections. (2) Disorders of unknown cause including acute interstitial fibrosis, pulmonary alveolar proteinDsis and desquamative interstitial pneumonia. (3) Pneumoconiosis, including asbestosis and silicosis. (4) Systemic diseases, including systemic lupus erythematosus, polyarteritis, scleroderma, Wegener’s
granulomatosis and Goodpasture’s syndrome. I have also included idiopathic pulmonary hemosiderosis and amyloidosis in this category. (5) Allergic entities which include reaction to drugs, eosinophilic pneumonia, serum sickness, etc. (6) Congenital causes of pulmonary infiltrates. (7) Inhalational diseases such as Farmer’s lung, Silo-Filler’s lung and perhaps an acute reaction to silicon. (8) Metabolic causes such as uremic pneumonitis and hyperparathyroidism. (9) Neoplastic disorders including alveolar carcinoma, leukemia, lymphomas, hematogenous metastatic malignancies and (10) circulatory causes such as congestive heart failure, pulmonary embolization and mitral stenosis. At this point, Dr. Reiter will show us the chest films. Dr. Frederic0 Reiter: The chest film obtained on October 14, 1974, demonstrated extensive air space consolidation, involving the perihilar and central portions of both lungs. The margins of the consolidated lung were rather sharply defined. Bilateral small pleural effusions were present, and the cardiac size was within normal limits. The next chest film was obtained one week later and showed no significant interval change. Five months later, a follow-up chest film was obtained. The film was slightly overpenetrated, but it showed complete interval clearing of the infiltrates (Figure 1). The admission chest film in August 1975 demonstrated again bilateral air space consolidation, somewhat more extensive on the left side, with moderate cardiac enlargement and small bilateral pleural effusions (Figure 2). One week later, the infiltrates were
Figure 1. Chest roentgenogram from March 1975,. five months after the patient’s first Barnes Hospital admission, demonstrates interval clearing of the pulmonary infiltrates.
Figure 2. Chest roentgenogram from August 1975 den+ onstrates re-appearance of bilateral air space consolidation.
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much more extensive especially on the right side. Our last film of the chest, obtained 10 days before death, revealed moderate improvement, with persistent consolidation in the central portion of both lungs. Dr. Klahr: Thank you. One of the important questions here is whether to take the report of the chest film obtained in March 1975 at face value. When I reviewed the films with Drs. Reiter and Senior, I raised the question of overpenetration of this particular film and whether, because of this, some pathology present in the lung could have been masked. Was there indeed a disappearance of the infiltrates on the chest film obtained in March? This becomes an important point in terms of the differential diagnosis among some of the entities already listed. Both Dr. Reiter and Dr. Senior assured me that despite overpenetration there was marked improvement in the pulmonary infiltrates. I would like to ask Dr. Senior to comment on the pathophysiology of the pulmonary disease in this patient and to try to eliminate from further consideration some of the entities we have listed. Dr. Robert Senior: When this patient was first seen he had a diffuse infiltrative lung process, hypoxemia, alveolar hyperventilation and a low diffusing capacity. block” was a term Historically, “alveolar-capillary often used in this setting. We seldom use this label now because we think it is misleading as to the pathophysiology of the problem. Hypoxemia, in disorders producing the so-called alveolar-capillary block syndrome, often derives from disturbances in the relationship between ventilation and perfusion or the distribution of diffusion, rather than qualitative and quantitive changes in the air-blood interface [ 11. In trying to make a decision as to the etiology of the patient’s diffuse lung process, two facts stand out. One is that hemoptysis was a prominent feature of the illness. The other is that the chest film showed clearing after the first hospitalization. With the starting points of hemoptysis and reversibility, I think neoplasm and pneumoconiosis can be excluded immediately. Infection deserves mention, but I would exclude it as a category also because fever was never present and hemoptysis was such a striking feature. Certainly, hemoptysis occurs in association with pulmonary infections, however, it is uncommon in the absence of cavitation or bronchiectasis. Hemoptysis would also be an unusual feature of the interstitial pneumonias and pulmonary problems that are drugrelated. I think we are left with two categories in your outline, Dr. Klahr, systemic and circulatory. To help sort between these two categories it would have been most helpful, during the first hospitalization, to have had measurements of the pulmonary artery and pulmonary capillary wedge pressures. The measure-
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ments are easily obtained by balloon flotation (SwanGanz) catheter [2]. Normal wedge pressure would point away from pulmonary edema due to heart failure, and normal pulmonary artery pressure would be against extensive pulmonary vascular occulsion. My own bias as to the nature of the patient’s infiltrates is that they were most, if not all, due to bleeding within the substance of his lung. I think this way because he had a great deal of hemoptysis and his anemia, when he was first seen, was far out of proportion to the severity of his uremia. Dr. Klahr: Yes, I would tend to agree with your last statement. I was quite impressed with this patient’s pulmonary infiltrates on his first admission to Barnes. Despite the fact that he lost about 16 pounds in weight and that most of his peripheral edema disappeared between October 14 and October 2 1, his pulmonary infiltrates persisted. It would seem unlikely that uremic pneumonitis or pulmonary edema was the cause, at least initially, of the infiltrates. I agree that the degree of anemia, coupled with iron deficiency, would suggest that this man had bleeding into his lung. Can you get a picture like this after overwhelming exposure to silica? Could we be dealing in this patient not with a typical case of silicosis with pulmonary fibrosis but with an “allergic type” of reaction to silica? Dr. Senior: As you are implying, a fatal respiratory syndrome has been observed in people, such as sandblasters, who have had an intense exposure to high density of silica particles [3]. The picture is one of diffuse lung infiltrates with rapidly progressive, severe shortness of breath. Histologically, the lung has alveolar filling resembling alveolar proteinosis; silicotic nodules are not prominent. I do not think this syndrome fits the present case for several reasons: (1) the history is not suggestive of recent intense silica exposure: (2) hemorrhage would be an unusual expression of this type of lung disease: and (3) resolution of the infiltrates would be surprising. Dr. Klahr: Taking into consideration that this man also had renal disease, let me try to eliminate other entities. Idiopathic pulmonary hemosiderosis is seen in younger people, usually below the age of 20. Very seldom, although a few cases have been described, is renal disease associated with it, and usually survival of patients with pulmonary hemosiderosis is much longer than that seen in this particular person. Amyloidosis will very seldom give a picture like this on chest film. The course of this patient’s renal disease is also difficult to explain in terms of a diagnosis of amyloidosis. Dr. Senior, should we consider acute interstitial fibrosis or pulmonary alveolar proteinosis any further at this point in time? Dr. Senior: As I mentioned earlier, pulmonary hem-
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orrhage is not a feature of those disorders. Also wide, spontaneous fluctuations, evident on the chest films, from very abnormal to near normal and then recurrence of abnormality are not typical of that collection of diseases. Dr. Klahr: This man was 61 years old so that congenital causes of pulmonary infiltrates can be excluded. There is nothing to suggest that we are dealing with an allergic reaction. So we are left really with three major categories to explain his pulmonary infiltrates: (1) systemic diseases, namely, collagen vascular disorders, (2) metabolic disorders, and here we can eliminate hyperparathyroidism which may present with pulmonary infiltrates, usually characterized by deposition of calcium within the lung, and (3) circulatory causes. Now let me turn our attention to the kidney. Dr. Hatter, would you comment on the nature of this patient’s renal disease? Initially, Dr. Harter, his kidney disease was characterized by progressive nephron destruction and abnormal permeability of the glomerular capillaries to protein. Hence, I think we can safely assume that we are dealing with an entity that involves either the small vessels or the glomerular capillaries of the kidney. My question is this. Could the renal picture be explained on the basis of neophrosclerosis alone? Dr. Herschel Harter: The rapidity with which the glomerular filtration rate fell in this patient could be explained by glomerular destruction secondary to inadequate blood pressure control. A patient who presents with between 2 and 4 g of protein in the urine and inadequate blood pressure control may, in fact, have accelerated or malignant nephrosclerosis. Although the nephrotic syndrome is rare in hypertensive renal disease, increased proteinuria may be a heralding sign of malignant nephrosclerosis. Dr. Klahr: We will come back to this point at the end. Dr. Reiter will now show us the intravenous urogram and the arteriograms. Dr. Meter: In October 1974 a nephrotomogram was performed. The kidneys were normal in size and the collecting systems were faintly visualized. The cortex was of normal thickness, and there was no evidence to suggest hydronephrosis. On the upper lateral margin of the left kidney, a 3 cm mass lesion was seen. There was sharp contrast between the normal nephrographic density of the surrounding normal kidney tissue and the density of the lesion, suggesting a hypovascular or avascular mass. Five months later, an intravenous urogram gave us the same results. On September 13, 1975, an emergency abdominal angiogram for massive gastrointestinal bleeding was performed, and simultaneously a right renal angiogram was obtained. The intrarenal arteries were
very abnormal with irregularities of the arterial wall, areas of stenosis and small aneurysmal dilatations (Figure 3). The flow through the renal cortex was minimal and the cortical medullary junction was not well seen. This picture was considered to be consistent with active arteritis, probably related to malignant nephrosclerosis. Dr. Klahr: Thank you very much. The renal-pulmonary syndromes that should be considered in this particular patient can be divided in two major categories: (1) renal and pulmonary diseases which share a common etiologic basis, including renal vein thrombosis with pulmonary embolization and collagen vascular disorders (polyarteritis, hypersensitivity angiitis, Wegener’s granulomatosis and Goodpasture’s syndrome), and (2) renal and pulmonary diseases which do not share the same etiologic cause, including nephrosclerosis and pneumoconiosis, nephrosclerosis and pulmonary edema and/or uremic lung, nephrosclerosis, glomerulonephritis, pneumoconiosis and pulmonary edema and nephrosclerosis, pulmonary edema and pulmonary hemorrhage. Initially renal vein thrombosis with pulmonary embolization was suspected. In this regard it should be pointed out that pulmonary embolization was suspected but not documented. No studies were conducted to determine whether or not this patient indeed had pulmonary emboli. However, studies to locate a possible source of embolization were performed. An inferior vena cavogram was negative.
Right renal arteriogram demonstrates abnormal intrarenal arteries with irregularities of the arterial wall, areas of stenosis and small aneurysmal dilatations.
Figure 3.
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This, of course, does not exclude the possibility that emboli may be found in this man’s pulmonary arteries at postmortem. But, this seems unlikely in view of the roentgenographic studies. So, we are left with a differential diagnosis between collagen vascular disorders and ordinary nephrosclerosis with severe lung complications that may be related to the consequences of hypertension. Dr. Harter, would you address yourself to the differential diagnosis of collagen vascular disorders in this patient? Dr. Hatter: Polyarteritis is a possibility in this patient. lt is a disease that predominantly involves mediumsized vessels, but there may be small vessel involvement. Small vessel polyarteritis produces a glomerulitis and is usually seen in the older population: it is infrequently associated with hypertension. On the other hand, medium-sized vessel involvement occurs in younger subjects, and hypertension is a predominant feature while glomerulitis is rare. Although the patient presented with what appeared to be a glomerulitis, he had significant hypertension, thus the diagnosis of polyarteritis is somewhat difficult to make. Pulmonary involvement with polyarteritis has been documented. In a large series of patients described by Rose and Spencer [4], fully one-third had pulmonary involvement, but whether they had hemoptysis is not entirely clear. The patients typically had evanescent diffuse pulmonary infiltrates. Of interest, pulmonary involvement was documented in 39 of 252 autopsies of patients with glomerulonephritis [6]. It was typified most commonly by hemosiderosis, which would imply pulmonary hemorrhage. I doubt that these cases could be called Goodpasture’s syndrome. They do attest, however, to the extremely high incidence of pulmonary involvement in patients with differing glomerulopathic disorders. Another possible diagnosis in this patient is Wegener’s granulomatosis [ 61. It is a disease that can affect a person of almost any age, although it is predominantly seen in people in the 40’s and 50’s. There is male predominance. The disease most closely represents, clinically, an allergic vasculitis, with rapid renal failure progressing over 12 months. Pathologically, however, it is a necrotizing granulomatous disease. Pulmonary infiltrates may occur in this disorder, but they are usually discrete and nodular rather than diffuse. They may be evanescent, however. Because of the duration of the disease of this patient, as well as the clinical picture, I believe this diagnosis is unlikely. Another possibility is Goodpasture’s syndrome [ 71. It is a disease involving primarily males in the early third decade. Typbally, the disease will present with pulmonary involvement associated with frank hemoptysis. The renal involvement will usually manifest itself somewhat later, but it may occur prior to the
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onset of pulmonary disease. The clinical picture is again one of rapidly progressive glomerulonephritis with hematuria, red cell casts and moderate to severe proteinuria. The disease is typified by circulating antibodies to both glomerular and pulmonary basement membrane. The usual course of the disease is rapid, with pulmonary failure. Because of the chronicity of the disease in this patient, as well as the patient’s age, I do not believe that Goodpasture’s syndrome is likely. Thus, of those diagnoses listed, polyarterttis is the only one that would seem likely. Dr. Klahr: Let me ask you another question that relates to the episodes of acute respiratory distress which occurred during and immediately after dialysis. There are three distinct possibilities as far as I can see. Either we are dealing with pulmonary edema, intra-alveolar hemorrhage or embolization. Both times that this patient had acute respiratory insufficiency after dialysis, he lost weight. Does this rule out pulmonary edema? Dr. Harter: This patient had a relatively severe pulmonary compromise during his hemodialysis. It is important to remember that, frequently with hemodialysis, patients receive plasma expanders during the procedure, either to maintain their blood pressure, to raise their hematocrit value or to afford a more efficient removal of extracellular fluid. Since the typical dialysis coil will contain somewhere between 150 and 200 ml of blood, as the dialysis is terminated the infusion of this fluid to the patient may precipitate congestive heart failure. I think that on at least one occasion this occurred in this patient. Another possibility leading to this clinical picture is severe myocardial ischemia. This may occur during hemodialysis due to an increased cardiac output, or to hyperor hypotension, induced by either reflex vasospasm or excessive fluid removal during dialysis. With severe myocardial ischemia and decreasing cardiac output, congestive heart failure may again occur. We recently have described a series of patients with subcutaneous arteriovenous fistulas, in whom high output cardiac failure developed [6]. In a patient with severe cardiac disease, the added workload of an arteriovenous shunt may be enough to precipitate congestive heart failure, although this possibility seems unlikely. Finally, the development of severe acidosis secondary to poor metabolism of either lactate or acetate, leading to further cardiac decompensation may occur. The second possibility for these episodes on hemodialysis may relate to the patient’s pulmonary disease. Certainly, pulmonary emboli in patients receiving femoral venous catheterizations must be considered. Also, pulmonary hemorrhage in someone with diffuse vasculitis may occur because of heparinization required during the procedure. However, we
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have no evidence for this. As an explanation for the pulmonary decompensation in this patient, I favor cardiac failure due to increased cardiac workload and volume overload in a patient with already severely compromised cardiac function. Dr. Hoffsten, would the complement Dr. Klahr: values that were obtained, and I realize that there was only a single set of values, help us at all in the differential diagnosis of this patient’s renal disease? Secondly, why wasn’t a renal biopsy specimen obtained in this gentleman? Dr. Philip Hoffsten: The complement values available were obtained a year before the final episode; I do not think they would be of help in making a diagnosis. The values were actually higher than normal, which is not diagnostic in regard to his renal disease. The serum concentration for the third component of complement (C-3) is commonly decreased in socalled hypocomplement chronic glomerulonephritis or in acute glomerulonephritis via activation of the alternate complement pathway. Sometimes complement values are low in systemic lupus erythematosus when the classic pathway is activated. In a series of cases of Goodpasture’s syndrome [ 91, serum C-3 concentrations were depressed in only two of 19 cases. In regard to considering a renal biopsy, this gentleman had a clinical course which ran at least a year and probably much longer than that. During the year before his death, his renal failure was slowly progressive, but there was a marked increase in the month prior to his admission. The diagnostic value of a renal biopsy would be in detecting a reversible renal lesion. Chronic progressive renal disease with a glomerular filtration rate less than 25 per cent of normal is rarely reversed by any form of therapy regardless of the etiology of the disease. Sometimes patients, with diseases such as rapidly progressive glomerulonephritis, in whom the glomerular filtration has decreased to low values in a short period of time can be treated effectively and renal function can be recovered. These patients should undergo a renal biopsy, the results of which can serve as a guide in selecting therapy. However I do not believe this patient qualified in that regard. My belief in this patient was that he had a slowly progressive renal disease and that, even with a tissue diagnosis, the likelihood that we could reverse anything was very small. That coupled with the extreme risk of a renal biopsy in this patient with severe pulmonary insufficiency mitigated strongly against the procedure. Dr. Klahr: Thank you Dr. Hoffsten. I would tend to agree with Dr. Harter in terms of Wegener’s granulomatosis. In an article published recently [IO], 21 cases of Wegener’s granulomatosis were reviewed. In 95 per cent of these cases, there were mucosal
ulcerations of the nasopharynx and the paranasal sinuses. In this gentleman we are told that there was no nose ulceration. This negative finding would speak strongly against the diagnosis of classic Wegener’s granulomosis in our patient. In terms of Goodpasture’s syndrome, the clinical course is compatible. There are a few things, however, that do not fit with the diagnosis of Goodpasture’s syndrome. First, there is a low incidence of hypertension in Goodpasture’s syndrome. Only six patients in a series of 45 patients had diastolic readings above 90 mm Hg [7]. In this man, of course, one could postulate that he had underlying hypertension and that then Goodpasture’s syndrome developed. The lack of a very active urine sediment also is somewhat against this diagnosis. The patient’s renal function, although decreased, was stable up until six weeks before his death; then it deteriorated suddenly. This, again, is not typical of Goodpasture’s syndrome. How about polyarteritis? It could not be classic polyarteritis, as described by Meier and Kussmaul, since in this entity the lung is not at all involved. So medium-sized or large artery involvement seems somewhat unlikely in terms of explaining the lung lesions. If we are going to explain the lung lesions and the renal lesions on the same basis, we should consider hypersensitivity angiitis. But then there are several things which do not fit with that diagnosis. There was no fever, except for a single reading of 37.8’C. There was no eosinophilia. Sixty-nine per cent of the patients of Rose [ 1 I] with lung involvement due to hypersensitivity angiiiis had eosinophilia. No leukocytosis was present at all during the course of disease in this man. All this makes me doubt that this man had hypersensitivity angiitis. I am left with the fact that this man had long-standing hypertension and that perhaps necrotizing arteritis developed despite the fact that his blood pressure levels were not as high as one would like to see to make this diagnosis. I believe that, indeed, he had congestive heart failure, cardiomegaly and advanced nephrosclerosis. The deterioration in renal function could be due to accelerated nephrosclerosis or to superimposed glomerulonephritis. Pulmonary edema and hemorrhage were probably responsible for the lung findings. There will be ulceration of the upper gastrointestinal tract, and the pathologist is going to tell us that the patient had a cyst in the left kidney. Instead of making a diagnosis of a somewhat rare entity I am going to say that this man had malignant hypertension. Are there any comments from the panel? Dr. Harter: There may be pulmonary involvement with silica or some other form of pneumoconosis. Dr. Klahr: I suspect the pathologist is going to show some silica in the lungs, but I do not think it will be significant from the pathologic point of view.
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Dr. Senior: I am sure he will have silica in his lungs, but I think it is of no importance. I want to re-emphasize the significance of severe hemoptysis and diffuse infiltrates which I believe indicate a pulmonary vascular problem of some sort, probably vasculitis. I wish to add one point to Dr. Harter’s comments. The respiratory problem with dialysis was almost certainly pulmonary edema due to heart failure, since left atrial pressure was quite high as measured by the SwanGanz catheter and improvement occurred with plasmaphoresis. PATHOLOGIC
DISCUSSION
The pathology was that of a very Dr. Dan McKeel: classic case of malignant nephrosclerosis. I want to take you through the autopsy findings, then explain the pulmonary lesion and, finally, provide one plausible explanation of all that was happening. The immediate cause of death was massive acute intracranial hemorrhage (Figure 4). A multifocal corpus striatal
hemorrhage destroyed most of the cerebral hemisphere, then dissected into the third ventricle, both lateral ventricles, the fourth ventricle, and the tegmentum of the pons. The kidneys, as is often the case in end-stage nephrosclerosis, were not reduced in weight; one weighed 139 g and the other 142 g. A 4 by 4 cm left renal cyst and multiple other cysts were evident in both kidneys. The largest one on the left contained blood and a small yellow nodule, which histologically was an area of intense tubular hyperplasia rather than cancer. Other studies have shown that one-third of blood-containing renal cysts contain neoplasms probably derived from tubular cells. Tubular regeneration and proliferation coexisted with some of the more classic changes of nephrosclerosis. On cut section the renal cortical width was normal and the arteries were prominent. Microscopically (Figure 5), the kidney was much more dramatic than the gross picture. The cortical architecture was greatly altered.
Figure 4. Coronal sections of fixed brain with massive intracerebral hemorrhage extending into the ventricles and pons.
Figure 5. Photomicrograph of the kidney shows two well preserved glomeruli, one partly sclerotic giomeruus (far left), ttibuiar dilatation and casts, and atrophic and regenerating tubules (upper leff). Hematoxyin and eosin stain; original magnifjcation X 40, reduced by 30 per cent.
Figure 6. Photomicrograph illustrates acute hemorrhage surrounding a damaged glomerulus. Periodic acid-SchiffGiemsa stain; orjgk?ai magnification X 10, reduced by 30 per cent.
Figure 7. Photomicrograph of renal artery with “onionskin” intimal hyperplasia typical of malignant nephrosclerotic vascular disease. Verhoeff-Van Gieson stain; origjnal magnification X 100, reduced by 30 per cent.
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A representative section showed a hemorrhagic, necrotic glomerulus with hemorrhage surrounding it and many flattened dilated tubules, some with eosinophilic casts, a classic finding of malignant nephrosclerosis. Widespread drop out of tubules with dilatation of remaining ones was evident, associated with interstitial fibrosis. Typically, a third or half of the glomeruli appeared almost normal. Many highly abnormal ones were also present. Some abnormal glomeruli exhibited hyalinization and shrinkage of the tufts, thickening of Bowman’s capsule and collagenization internal to the capsule, alterations that can also be seen in ordinary essential hypertension; thus many people believe that malignant nephrosclerosis is an exaggerated phase of chronic vascular disease of the kidneys. However, other areas showed focal glomerular necrosis with hemorrhage suggesting acute damage (Figure 6). Large numbers of completely sclerotic glomeruli, scattered foci of chronic inflammatory cells in the interstitium, and areas of marked fibrosis and atrophy of the tubules were also seen. Vascular changes in the kidneys were striking. lntralobular arteries showed the classic changes of malignant ne-
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phrosclerosis: marked concentric intimal hyperplasia causing an almost pinpoint lumen (Figure 7). Onionskin concentric layering of the intima is a hallmark of this disease. Thus, there is a beautiful correlation of the renal arteriogram and the postmortem renal vascular morphology. The adrenal glands showed bilateral cortical hyperplasia with focal nodularity, mainly of the zona fasciculata, demonstrating the typical hyperplastic cell morphology that is common in patients with malignant hypertension. In a healthy person, the combined true adrenal weight ought not to exceed 6 g. The combined weight of the patient’s hyperplastic adrenals was 22 g. Malignant hybertension, of course, affects vessels throughout the body; these lesions are shown in a series of small arterioles and arteries in the periadrenal tissues (Figure 8). The typical lesions included (1) intimal hyperplasia very similar to what was present in the kidney: (2) vessels with definite intimal hyperplasia, which also showed smudging and fibroid necrosis of portions of the wall; (3) other arteries showed myxoid intimal thickening .as weli as marked hyalini-
Figure 8. Photomicrographs of periadrenal arterioles showing various stages of hypertensive vascular damage. A, concentric intimat hyperpiasia. 8. intimal hyperpiasia with focal mural hyalinization. C, concentric and myxoid hyperpfasia. 0, total mural hyalinization (fibrinoid necrosis). All hematoxylin and eosin stains; original magnification X 200, reduced by 27 per cent. March 1976
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_ Survey photomicrograph of the lung shows difFigure fi. fuse intraalveoiar fibrin deposition and cellularity with central foci of hemorrhage. Hematoxylin and eosin stain; original magnification X 40, reduced by 30 per cent.
zation and fibrinoid change in the arterial wall; and (4) vessels with marked fibroid necrosis and narrowing of the lumen. Elastic tissue stains demonstrated that in addition to fibroblastic intimal proliferation, some larger arteries exhibited reduplication and splitting of the internal elastic lamina. The lungs at autopsy were extremely heavy, having a combined weight of approximately 2,500 g or four times over normal. The cut surfaces showed beefy red consolidation with a glassy sheen. Patchy anthracotic pigmentation and areas of mild emphysematous change were appreciated. The gross appearance was not that of a severe case of pneumoconiosis. Microscopically, a fibrin layer adhered to the pleural surface. Anthracotic pigment was throughout the lung, but there was no dramatic silica nodule or fibrosis. Portions of the lung were digested, and asbestos bodies were isolated; they were not increased in number over what is commonly seen at autopsy. Thus, we did not find microscopic evidence of pneumoconiosis or, in fact, of most of the entities entertained in the clinical differential diagnosis, except abundant evidence of pulmonary hemorrhage. Low power survey micrographs illustrated marked consolidation of the air spaces with small and large focal areas of hemorrhage (Figure 9). Higher magnification microscopy revealed a variety of cell types, mixed with red cells among masses of fibrin. The cellular composition in the alveolar spaces was very pleomorphous and included large macrophages, neutrophils and chronic inflammatory cells. Many foci in both lungs had a predominant infiltrate of polymorphonuclear leukocytes associated with demonstrable intracellular gram-negative rods, which constituted evidence of a confluent bronchopneumonia as one primary pathologic process. Postmortem blood cul-
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Figure 10. Photomicrograph of autopsy kidney section stained for fibrin. The upper capillary loops are filled with compact and fibriliar fibrin and globular fibrinogenfibrin forms. Note a fibrin thrombus partly filling the afferent arteriole at lower right. Periodic acid-Schiff-Giemsa stain; original magnification X 400, reduced by 30 per cent.
tures yielded Citrobacter and Klebsiella organisms compatible with this histologic type of fairly acute pneumonitis. In addition, there was evidence of a second more chronic pathologic process. I have already mentioned the chronic nature of much of the alveolar inflammatory infiltrate. The edema was in the form of fibrin, shown by the phosphotungstic acid hematoxylin (PTAH) stain which selectively stains fibrin strands blue. I believe these three processes, that is, hemorrhage, fibrinous edema and bronchopneumonia satisfactorily explain the roentgenographic findings in the lung. I believe that since many of the macrophages had hemosiderin, fibrin and red cells, the hemorrhages were probably episodic and recurrent. How can the renal and pulmonary pathology be tied together? By an intermediate mechanism, disseminated intravascular coagulation (DIC), manifested anatomically in several ways. Direct immunofluorescence was performed on the kidneys and the lungs by Dr. Mancilla. The lung findings were completely negative for immunoglobulin, fibrin and complement, and the consultant believed that this effectively ruled out Goodpasture’s syndrome. Fibrin and thrombi strands were appreciated in many renal glomeruli stained by phosphotungstic acid hematoxylin or periodic acid-Schiff-Giemsa (Figure 10). The immunofluorescence pattern showed a very dramatic deposition of fibrin in the glomerular capillaries. I reviewed the record searching for additional evidence that DIC might have occurred. One was the mention of “burr” cells present on the admission blood smear; “burr” cells or schistocytes are morphologic sign posts of microangiopathic hemolytic anemia,
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marrow is often hyperplasic. If the DIC has been present for a long time, megakaryocytic hyperplasia is even more remarkable. That is what I found in this case. Many small immature megakaryocytes with single lobed nuclei as well as mature megakaryocytes were present in the marrow sections (Figure 11). Summarizing, this man had nephrosclerosis which may have been present for many years. The nephrosclerosis entered an accelerated phase for unknown reasons. There was no evidence of a progressive glomerulonephritis or pyelonephritis. I suggest that he probably had for a long time, associated with his hypertension, a chronic type of disseminated intravasFigure 1 I. Photomicrograph of autopsy bone marrow section demonstrating hyperplasia especially marked in the megakaryocytic series. Hematoxylin and eosin stain; original magnification X 200, reduced by 30 per cent.
cular coagulation as discussed by McKay [ 121 and with maligby Edson [ 131. This type is associated nancies, chronic vasculitis and repetitive vascular endothelial damage resulting in a chronic hypercoagulable state. I hypothesize that this might be an explanation of the postulated episodic pulmonary hemor-
which I speculate this patient might have had. Two days before the patient’s death, laboratory findings included
a platelet
count of 23,000/mm3,
rhages and edema. Terminally, gram-negative septicemia developed, probably arising from the pulmonary infection, which caused an acute DIG syndrome with marked thrombocytopenia, that is, consumptive
slightly pro-
longed prothrombin and partial prothrombin times, and fibrin split product elevation of very mild degree, 8 pg/ml, the upper normal range being 4 pg/ml. I found more evidence of DIC in the rest of the autopsy, for example, microthrombi composed mostly of platelets intermixed with fibrin scattered throughout
coagulopathy, causing a fatal intracerebral hemorrhage. Some medical investigators believe very strongly that DIC is an integral part of the expression of malignant hypertension, but others believe the two
the gastrointestinal tract, spleen and pancreas. Fibrin microthrombosis is one of the hallmarks of DIC at autopsy: the other, of course, is the presence of bleeding in various sites. We have already seen that there was a massive terminal intracranial hemorrhage. But clinically there were also problems with gastrointestinal bleeding. Several very small gastrointestinal ul-
conditions are causally unrelated diseases. Dr. Stanley Robbins, in the latest edition of his text “Pathologic Basis of Disease,” asserts that DIC may be the “fundamental mediator” of the disease, malignant
cers were formed, two in the antrum of the stomach and one in the duodenum. A long segment of the small bowel was filled with recently clotted blood: thus I must assume there was significant oozing. The final evidence supporting DIC was the bone marrow, in which it is important to differentiate thrombocytopenia on the basis of marrow failure from thrombocytopenia associated with DIC in which the bone
lesions predisposed to this chronic coagulopathy may serve to explain the episodic pulmonary hemorrhages. We certainly know from the publications of [ 14,151 that massive Minna, Robboy and Colman pulmonary hemorrhage is definitely associated with severe DIC, and I hope this association will receive
hypertension. That is one view point, close to my own, but other people will certainly disagree. Acceptance of the concept that the widespread vascular
more
clinical,
laboratory
and pathologic
study in the
future.
REFERENCES 1.
2.
3. 4.
Arndt H, King TKC, Briscoe WA: Diffusing capacities and ventilation: Perfusion ratios in oatients with the clinical syndrome of alveolar capillary’block. J Clin Invest 49: 408, 1970. Swan HJC: Balloon flotation catheters-Their use in Hemodynamic monitoring in clinical practice. JAMA 233: 865. 1975. Buechner HA, Ansari A: Acute Silica-Proteinosis. Dis Chest 55: 274, 1969. Rose GA and Spencer H: Polyarteritis nodosa. Q J Med 26: 43, 1957.
5. 6.
7.
8.
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McCaughey WT, Thomas BJ: Pulmonary hemorrhage and olomeruloneohritis. Am J Clin Pathol 38: 577, 1962. Fa&i AS, Wolff SM: Wegener’s granulomatosis: studies in 18 patients and a review of the literature. Medicine (Baltimore) 52: 535. 1973. Proskey AJ, Weatherbe L. Easterling RE, Greene JA, Weller JM: Goodpasture’s syndrome: a report of five cases and a review of the literature. Am J Med 48: 162, 1970. Anderson CB, Codd JF, Graff RA, Grace MA. Hatter HR: Cardiac failure in upper extremity arterial-venous dialysis fistulas: case reports and a review of the literature. Arch
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9.
10. 11. 12.
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Intern bled (in press). Wilson CB, Dixon FJ: Antiglomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 3: 74, 1973. Wolff SM, Fauci AS, Horn RG, Dale DC: Wegener’s granulomatosis. Ann Intern Med 81: 513, 1974. Rose TM: The natural history of polyarteritis. Br Med J 2: 1148, 1957. McKay DG: Intravascular coagulation-acute and chronicdisseminated and local. Proc lnst Med ‘Chic 29: 159,
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13. 14.
15.
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1972. Edson JR: Mechanisms and dynamics of intravascular coagulation. Geriatrics 74: 65, 1974. Minna JD, Robboy Coleman RW: Disseminated Intravascular Coagulation in Man. Springfield, Ill., Charles C Thomas, 1974, p 78. Robboy SJ, Minna JD, Colman RW. Birndorf NI, Lopas H: Pulmonary hemorrhage syndrome as a manifestation of disseminated intravascular coagulation. Analysis of 10 cases. Chest 63: 718, 1973.
