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Nephrotic Syndrome: Treatment with ACTH and Nitrogen Mustard
Nephrotic Syndrome: Treatment with ACTH and Nitrogen Mustard ROBERT D. TAYLOR, M.D., F.A.C.P.
THE nephrotic syndrome consists of: edema, usually considerable, often amounting to anasarca; proteinuria, always impressive; hypoproteinemia, which is due to hypoalbuminemia, and hyperlipemia with hypercholesterolemia. This clinical picture complicates intercapillary glomerulosclerosis; renal amyloidosis; systemic lupus erythematosus; renal vein thrombosis; glomerulonephritis in all its phases, acute, subacute and chronic; and it is the characteristic feature of lipoid nephrosis-assuming that there is such an entity. In our limited experience, AOTH and nitrogen mustard have been of no value in treating the edema and proteinuria of intercapillary glomerulosclerosis and amyloidosis. As far as we know, they have not been used in patients with renal vein thrombosis; from the nature of the lesion, little benefit would be expected. The values of steroidal therapy and of nitrogen mustard in the management of systemic lupus erythematosus are now well established; these, however, are not pertinent to this discussion which concerns only the nephrotic syndrome as it appears in glomerulonephritis. This condition and/or nephrosis is often ameliorated by treatment with one or other or both of these agents. Subjectively, the most distressing part of the syndrome is edema. Most methods of treatment have attempted to control edema by inducing diuresis. Intravenous acacia solution was used for a number of years;1 but it was infrequently effective and the substance is sequestered in the liver with some possible, albeit undemonstrated, deleterious effects.2 Concentrated sodium-free human-albumin transfusions were nearly as disappointing and much more expensive. Diuresis was induced in an occasional patient, usually transiently; plasma albumin level was little affected; the administered albumin was rapidly excreted in the urine and, after a few days, the situation, including the edema, was unchanged. 3 In some patients the increase in plasma volume created by the hyperoncotic albumin brought on signs of heart failure and pulmonary edema during its injection. Severe restriction of sodium and administration of diuretic drugs have more or less reduced the edema but rarely bring it 995
996
Robert D. Taylor
under complete control. Attempts to elevate the plasma albumin level by dietary means have failed completely. Frequently a bout of feverof whatever origin-has been followed by remission. This was applied therapeutically by Janeway and his associates 4 who exposed nephrotic youngsters to measles. Of 12 who thus contracted the disease, eight had remissions. Since ACTH and nitrogen mustard have become available, sodium restriction is the only one of these various modes of treatment which remains in routine use. ACTH AND CORTISONE
Farnsworth5
was the first to use ACTH in patients with glomerulonephritis and the nephrotic syndrome. In some of them she noted transient diminutions of proteinuria and hematuria. The most impressive result was release of edema; this occurred most frequently after the drug had been discontinued. Since her observations, it has become common practice to use ACTH interchangeably with cortisone in the treatment of the nephrotic state. Treatment is begun in the hospital. Intake of dietary sodium is limited to 1 gram or less daily. Body weight and quantitative proteinuria are recorded daily. Serum protein and blood cholesterol levels, hemoglobin and white cell counts, urea clearance or other sensitive indices of excretory function are measured at appropriate intervals. A quanti tative 6 examination of the urinary sediment is made weekly. ACTH (0.5 mg./kg.) or cortisone (l.25 mg./kg.) is given every six hours for ten days. This treatment will bring about diuresis and some diminution of proteinuria in 75 to 80 per cent of children and 40 to 60 per cent of adults. Some few patients will stay well permanently, but at least half will have one or more relapses and some will progress to renal failure and death. This therapy has not been used for a long enough time to show whether these drugs affect life expectancy; however, it seems now well established that treatment can induce remission and, less confidently, it can be stated that the incidence of relapses can be lessened with long-term steroidal treatment. The problems of long-term treatment are to decide what patients need such treatment, when, and how long is long enough. Decisions concerning these problems must be made arbitrarily at the present time and until the studies in progress have gone further. Since some patients will stay completely well after the initial diuresis, it seems wise to reserve long-term treatment for those who show signs of relapse by the return of even slight proteinuria. Those who are freed of edema but continue to have abnormal proteinuria should also receive long-term treatment. A workable program for these patients is to give them 400 mg. of cortisone daily for the first three days of each week for a year after recovery from the most recent relapse. During the next four years, urinalysis for protein should be made every three months. After
997
Nephrotic Syndrome
five years without relapse, most observers would consider the disease cured. This schedule works well with children; however, adults tolerate large, long-term dosage with cortisone poorly. Mental changes, acne, infections, moon face and other signs of hypercorticoidism appear too frequently to justify continuom; treatment in adults, so that it is repeated only on the indication of definite relapse. NITROGEN M.USTARD
Steroidal treatment usually is simpler both for patient and for physician than is treatment with nitrogen mustard; the latter is of most value for those who cannot tolerate or do not respond to steroidal management. It first was used by Chasis, Goldring and Baldwin in 1949 7 in patients with glomerulonephritis with the hope that it would inhibit the antigen-antibody mechanism believed to underlie this disease. They noted transient diminution of proteinuria during and immediately after treatment, but no permanent improvement was observed. In some patients, who had edema, release of edema was impressive. Following their report we began using nitrogen mustard to treat patients,8 particularly adult patients with the nephrotic syndrome. There are 22 who have been traced for from three to six years. In most patients signs of disease had been present from two to eight months before treatment was begun. All of the patients were hospitalized and were studied, as were those who were treated with steroids. Nitrogen mustard, 0.1 mg./kg. of actual body weight, was given intravenously in 5 per cent glucose on each of four successive days. Each injection was followed by an infusion of 250 cc. of 5 per cent glucose in water. In those who became nauseated, 25 mg. of chlorpromazine was given intramuscularly before subsequent infusions. If diuresis did not follow the first course of nitrogen mustard, treatment was repeated as soon as the peripheral blood indicated recovery of the depressed bone marrow. In our experience, more than four courses have not been helpful. An example of a favorable result following nitrogen mustard therapy is shown in Figure 157. Nine of the 22 patients had release of edema, followed by disappearance of proteinuria and the other signs of the nephrotic syndrome. Four were adults and have had no recurrences in four to six years. Five were children: four of them had relapses; a total of eight of the group of 22 that were successfully treated with nitrogen mustard are now well for more than three years. At the time of treatment, five patients had impressive signs of advanced renal disease that had been present for an average of 10.5 months. They derived no benefit and now are dead. One child with
Roben D. Taylor
998
good renal function, but who had no diuresis, died suddenly during subsequent treatment with ACTH. Seven patients were given from two to five courses of nitrogen mustard with no changes in the nephrotic syndrome. They still are living but slow evidences of advancing renal disease. There were no clinical signs to differentiate those who did not respond well from those who did. Among nonresponders, hematuria was slightly greater, and hypoalbuminemia not quite so severe, but there was great overlapping of the 5-
43-
2-
PLASMA ALBUMIN Gm •. per 100ee.
1-
12 10 -
864-
264 -
60 -
00000 0 0 0 ° 0 0 0
56 -
0
0 0000 0 °0 0
o
52 48 -
o
BODY WEIGHT "gm •. o
44-
0 00 0
JULY
0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0
AUGUST
SEPTEMBER
DAYS OF ILLNESS
Fig. 157. The arrows indicate the days on which nitrogen mustard, 0.1 mg./kg. of body weight, was given. The drug transiently depressed urinary protein level; proteinuria persisted during subsequent injections and only slowly disappeared. The diuresis began before the plasma albumin level increased, suggesting that the diuresis was not an osmotic one. The 40 year old woman from whose record this chart was made has been well for 6 years.
two groups. These nitrogen mustard nonresponders subsequently were treated with ACTH, to which they also failed to respond. COMBINED TREATMENT WITH ACTH AND NITROGEN MUSTARD
Dr. Robert Mercer and Dr. Viola Startzman of The Department of Pediatrics of the Cleveland Clinic have traced nine children having the nephrotic syndrome who failed to respond either to ACTH or to nitrogen mustard when used separately. They have treated these children with ACTH and nitrogen mustard simultaneously. ACTH was given in 25 mg. doses intramuscularly four times daily for ten days. On each of the first four days of treatment the mustard was given intravenously 0.1 mg./kg. of ideal body weight. In eight children there ensued release of
999
Nephrotic Syndrome
edema, diminution of proteinuria; no relapses were observed in the nine months that these have been traced. One patient was not improved. PROPHYLACTIC TREATMENT
The relationship between streptococcal infection and glomerulonephritis is well established. It is an observation of long standing that infection frequently precedes relapse into the nephrotic state among . children with this syndrome. There are no extensive studies demonstrating that prophylactic treatment of these patients with sulfonamides or penicillin is of great value. However, there are many good studies dating from those of Thomas and associates in 1943 9 to those of Denny, Wannamaker, Brink, and Custer in 195210 showing that antibacterial treatment over long periods lessens the frequency of recurrence in patients with rheumatic fever-a disease also precipitated by streptococcal infections. For these reasons, we feel that it is wise to give patients who tend to relapse frequently, maintenance doses of long-acting orally active penicillin. Bicillin 2,400,000 units daily, is the dosage we have used successfully. The same compound may be more advantageously given intramuscularly in a dose of 1,200,000 units once a month. SUMMARY
The nephrotic syndrome, secondary to glomerulonephritis and socalled nephrosis, usually can be brought under control, although the mechanisms of the therapeutic effects are not understood. ACTH or cortisone, because of their simplicity and probable greater efficacy, first should be tried in all patients. In those who relapse, treatment should be reinstituted for a year after the most recent return of proteinuria and edema. These patients still may have recurrence of signs of disease for three to five years. Examination of urine specimens at three-month intervals over such a period will insure early detection of the return of proteinuria and treatment can be instituted before the syndrome becomes full-blown. In those patients who do not respond to steroidal treatment, nitrogen mustard may induce diuresis and remission of the disease. It can be used alone or in combination with ACTH or with cortisone. Relapse often is precipitated from infection by streptococci. For those patients who have repeated episodes, it cannot harm, and it may possibly benefit them, to be treated with long-acting penicillin preparations. REFERENCES 1. Hartmann, A. F., Senn. M. J. R, Nelson, M. V. and Perley, A. M.: The Use of Acacia in the Treatment of Edema. J.A.M.A. 100: 251, 1933.
2. Andersch, M. and Gibson, R. B.: Studies on the Effects of Intravenous Injections of Colloids; Deposition of Acacia in the Liver and Other Organs and Its Excretion in Urine and Bile. J. Pharmacol. & Exper. Therap. 52: 390, 1934. 3. Seegal, D. and Wertheim, A. R.: Recent Advances in Our Knowledge Concerning the Nephrotic Syndrome. Bull. New York Acad. Med. 25: 606, 1949.
1000
Robert D. Taylor
4. Janeway, C. A. and others: Diuresis in Children with Nephrosis. Comparison of Response to Injection of Normal Human Serum Albumin and to Infection, Particularly Measles. Tr. A. Am. Physicians 61: 108, 1948. 5. Farnsworth, E. B.: Studies on the Influence of Adrenocorticotropin in Acute Nephritis, in Simple Nephrosis and in Nephrosis with Azotemia. Proe. First Clinical ACTH Conference, Philadelphia, The B1akiston Co., 1950. 6. Addis, T.: A Clinical Classification of Bright's Disease. J.A.M.A. 85: 163, 1925. 7. Chasis, H., Goldring, W. and Baldwin, D. S.: Effect of Febrile Plasma, Typhoid Vaccine and Nitrogen Mustard on Renal Manifestations of Human Glomerulonephritis. Proc. Soc. Exper. BioI. & Med. 71: 565, 1949. 8. Taylor, R. D., Corcoran, A. C. and Page, 1. H.: Treatment of the Nephrotic Syndrome with Nitrogen Mustard. Proc. 23rd Annual Meeting of Central Society for Clinical Research, J. Lab. & Clin. Med. 36: 996, 1950. 9. Thomas, C. B., France, R. and Reichsl):lan, F.: The Prophylactic Use of Sulfanilamide in Patients Susceptible to Rheumatic Fever. J.A.M.A. 116: 551, 1941. 10. Denny, F. W. and others: Prevention of Rheumatic Fever. J.A.M.A. 143: 151 1950.
THE nephrotic syndrome consists of: edema, usually considerable, often amounting to anasarca; proteinuria, always impressive; hypoproteinemia, which is due to hypoalbuminemia, and hyperlipemia with hypercholesterolemia. This clinical picture complicates intercapillary glomerulosclerosis; renal amyloidosis; systemic lupus erythematosus; renal vein thrombosis; glomerulonephritis in all its phases, acute, subacute and chronic; and it is the characteristic feature of lipoid nephrosis-assuming that there is such an entity. In our limited experience, AOTH and nitrogen mustard have been of no value in treating the edema and proteinuria of intercapillary glomerulosclerosis and amyloidosis. As far as we know, they have not been used in patients with renal vein thrombosis; from the nature of the lesion, little benefit would be expected. The values of steroidal therapy and of nitrogen mustard in the management of systemic lupus erythematosus are now well established; these, however, are not pertinent to this discussion which concerns only the nephrotic syndrome as it appears in glomerulonephritis. This condition and/or nephrosis is often ameliorated by treatment with one or other or both of these agents. Subjectively, the most distressing part of the syndrome is edema. Most methods of treatment have attempted to control edema by inducing diuresis. Intravenous acacia solution was used for a number of years;1 but it was infrequently effective and the substance is sequestered in the liver with some possible, albeit undemonstrated, deleterious effects.2 Concentrated sodium-free human-albumin transfusions were nearly as disappointing and much more expensive. Diuresis was induced in an occasional patient, usually transiently; plasma albumin level was little affected; the administered albumin was rapidly excreted in the urine and, after a few days, the situation, including the edema, was unchanged. 3 In some patients the increase in plasma volume created by the hyperoncotic albumin brought on signs of heart failure and pulmonary edema during its injection. Severe restriction of sodium and administration of diuretic drugs have more or less reduced the edema but rarely bring it 995
996
Robert D. Taylor
under complete control. Attempts to elevate the plasma albumin level by dietary means have failed completely. Frequently a bout of feverof whatever origin-has been followed by remission. This was applied therapeutically by Janeway and his associates 4 who exposed nephrotic youngsters to measles. Of 12 who thus contracted the disease, eight had remissions. Since ACTH and nitrogen mustard have become available, sodium restriction is the only one of these various modes of treatment which remains in routine use. ACTH AND CORTISONE
Farnsworth5
was the first to use ACTH in patients with glomerulonephritis and the nephrotic syndrome. In some of them she noted transient diminutions of proteinuria and hematuria. The most impressive result was release of edema; this occurred most frequently after the drug had been discontinued. Since her observations, it has become common practice to use ACTH interchangeably with cortisone in the treatment of the nephrotic state. Treatment is begun in the hospital. Intake of dietary sodium is limited to 1 gram or less daily. Body weight and quantitative proteinuria are recorded daily. Serum protein and blood cholesterol levels, hemoglobin and white cell counts, urea clearance or other sensitive indices of excretory function are measured at appropriate intervals. A quanti tative 6 examination of the urinary sediment is made weekly. ACTH (0.5 mg./kg.) or cortisone (l.25 mg./kg.) is given every six hours for ten days. This treatment will bring about diuresis and some diminution of proteinuria in 75 to 80 per cent of children and 40 to 60 per cent of adults. Some few patients will stay well permanently, but at least half will have one or more relapses and some will progress to renal failure and death. This therapy has not been used for a long enough time to show whether these drugs affect life expectancy; however, it seems now well established that treatment can induce remission and, less confidently, it can be stated that the incidence of relapses can be lessened with long-term steroidal treatment. The problems of long-term treatment are to decide what patients need such treatment, when, and how long is long enough. Decisions concerning these problems must be made arbitrarily at the present time and until the studies in progress have gone further. Since some patients will stay completely well after the initial diuresis, it seems wise to reserve long-term treatment for those who show signs of relapse by the return of even slight proteinuria. Those who are freed of edema but continue to have abnormal proteinuria should also receive long-term treatment. A workable program for these patients is to give them 400 mg. of cortisone daily for the first three days of each week for a year after recovery from the most recent relapse. During the next four years, urinalysis for protein should be made every three months. After
997
Nephrotic Syndrome
five years without relapse, most observers would consider the disease cured. This schedule works well with children; however, adults tolerate large, long-term dosage with cortisone poorly. Mental changes, acne, infections, moon face and other signs of hypercorticoidism appear too frequently to justify continuom; treatment in adults, so that it is repeated only on the indication of definite relapse. NITROGEN M.USTARD
Steroidal treatment usually is simpler both for patient and for physician than is treatment with nitrogen mustard; the latter is of most value for those who cannot tolerate or do not respond to steroidal management. It first was used by Chasis, Goldring and Baldwin in 1949 7 in patients with glomerulonephritis with the hope that it would inhibit the antigen-antibody mechanism believed to underlie this disease. They noted transient diminution of proteinuria during and immediately after treatment, but no permanent improvement was observed. In some patients, who had edema, release of edema was impressive. Following their report we began using nitrogen mustard to treat patients,8 particularly adult patients with the nephrotic syndrome. There are 22 who have been traced for from three to six years. In most patients signs of disease had been present from two to eight months before treatment was begun. All of the patients were hospitalized and were studied, as were those who were treated with steroids. Nitrogen mustard, 0.1 mg./kg. of actual body weight, was given intravenously in 5 per cent glucose on each of four successive days. Each injection was followed by an infusion of 250 cc. of 5 per cent glucose in water. In those who became nauseated, 25 mg. of chlorpromazine was given intramuscularly before subsequent infusions. If diuresis did not follow the first course of nitrogen mustard, treatment was repeated as soon as the peripheral blood indicated recovery of the depressed bone marrow. In our experience, more than four courses have not been helpful. An example of a favorable result following nitrogen mustard therapy is shown in Figure 157. Nine of the 22 patients had release of edema, followed by disappearance of proteinuria and the other signs of the nephrotic syndrome. Four were adults and have had no recurrences in four to six years. Five were children: four of them had relapses; a total of eight of the group of 22 that were successfully treated with nitrogen mustard are now well for more than three years. At the time of treatment, five patients had impressive signs of advanced renal disease that had been present for an average of 10.5 months. They derived no benefit and now are dead. One child with
Roben D. Taylor
998
good renal function, but who had no diuresis, died suddenly during subsequent treatment with ACTH. Seven patients were given from two to five courses of nitrogen mustard with no changes in the nephrotic syndrome. They still are living but slow evidences of advancing renal disease. There were no clinical signs to differentiate those who did not respond well from those who did. Among nonresponders, hematuria was slightly greater, and hypoalbuminemia not quite so severe, but there was great overlapping of the 5-
43-
2-
PLASMA ALBUMIN Gm •. per 100ee.
1-
12 10 -
864-
264 -
60 -
00000 0 0 0 ° 0 0 0
56 -
0
0 0000 0 °0 0
o
52 48 -
o
BODY WEIGHT "gm •. o
44-
0 00 0
JULY
0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0
AUGUST
SEPTEMBER
DAYS OF ILLNESS
Fig. 157. The arrows indicate the days on which nitrogen mustard, 0.1 mg./kg. of body weight, was given. The drug transiently depressed urinary protein level; proteinuria persisted during subsequent injections and only slowly disappeared. The diuresis began before the plasma albumin level increased, suggesting that the diuresis was not an osmotic one. The 40 year old woman from whose record this chart was made has been well for 6 years.
two groups. These nitrogen mustard nonresponders subsequently were treated with ACTH, to which they also failed to respond. COMBINED TREATMENT WITH ACTH AND NITROGEN MUSTARD
Dr. Robert Mercer and Dr. Viola Startzman of The Department of Pediatrics of the Cleveland Clinic have traced nine children having the nephrotic syndrome who failed to respond either to ACTH or to nitrogen mustard when used separately. They have treated these children with ACTH and nitrogen mustard simultaneously. ACTH was given in 25 mg. doses intramuscularly four times daily for ten days. On each of the first four days of treatment the mustard was given intravenously 0.1 mg./kg. of ideal body weight. In eight children there ensued release of
999
Nephrotic Syndrome
edema, diminution of proteinuria; no relapses were observed in the nine months that these have been traced. One patient was not improved. PROPHYLACTIC TREATMENT
The relationship between streptococcal infection and glomerulonephritis is well established. It is an observation of long standing that infection frequently precedes relapse into the nephrotic state among . children with this syndrome. There are no extensive studies demonstrating that prophylactic treatment of these patients with sulfonamides or penicillin is of great value. However, there are many good studies dating from those of Thomas and associates in 1943 9 to those of Denny, Wannamaker, Brink, and Custer in 195210 showing that antibacterial treatment over long periods lessens the frequency of recurrence in patients with rheumatic fever-a disease also precipitated by streptococcal infections. For these reasons, we feel that it is wise to give patients who tend to relapse frequently, maintenance doses of long-acting orally active penicillin. Bicillin 2,400,000 units daily, is the dosage we have used successfully. The same compound may be more advantageously given intramuscularly in a dose of 1,200,000 units once a month. SUMMARY
The nephrotic syndrome, secondary to glomerulonephritis and socalled nephrosis, usually can be brought under control, although the mechanisms of the therapeutic effects are not understood. ACTH or cortisone, because of their simplicity and probable greater efficacy, first should be tried in all patients. In those who relapse, treatment should be reinstituted for a year after the most recent return of proteinuria and edema. These patients still may have recurrence of signs of disease for three to five years. Examination of urine specimens at three-month intervals over such a period will insure early detection of the return of proteinuria and treatment can be instituted before the syndrome becomes full-blown. In those patients who do not respond to steroidal treatment, nitrogen mustard may induce diuresis and remission of the disease. It can be used alone or in combination with ACTH or with cortisone. Relapse often is precipitated from infection by streptococci. For those patients who have repeated episodes, it cannot harm, and it may possibly benefit them, to be treated with long-acting penicillin preparations. REFERENCES 1. Hartmann, A. F., Senn. M. J. R, Nelson, M. V. and Perley, A. M.: The Use of Acacia in the Treatment of Edema. J.A.M.A. 100: 251, 1933.
2. Andersch, M. and Gibson, R. B.: Studies on the Effects of Intravenous Injections of Colloids; Deposition of Acacia in the Liver and Other Organs and Its Excretion in Urine and Bile. J. Pharmacol. & Exper. Therap. 52: 390, 1934. 3. Seegal, D. and Wertheim, A. R.: Recent Advances in Our Knowledge Concerning the Nephrotic Syndrome. Bull. New York Acad. Med. 25: 606, 1949.
1000
Robert D. Taylor
4. Janeway, C. A. and others: Diuresis in Children with Nephrosis. Comparison of Response to Injection of Normal Human Serum Albumin and to Infection, Particularly Measles. Tr. A. Am. Physicians 61: 108, 1948. 5. Farnsworth, E. B.: Studies on the Influence of Adrenocorticotropin in Acute Nephritis, in Simple Nephrosis and in Nephrosis with Azotemia. Proe. First Clinical ACTH Conference, Philadelphia, The B1akiston Co., 1950. 6. Addis, T.: A Clinical Classification of Bright's Disease. J.A.M.A. 85: 163, 1925. 7. Chasis, H., Goldring, W. and Baldwin, D. S.: Effect of Febrile Plasma, Typhoid Vaccine and Nitrogen Mustard on Renal Manifestations of Human Glomerulonephritis. Proc. Soc. Exper. BioI. & Med. 71: 565, 1949. 8. Taylor, R. D., Corcoran, A. C. and Page, 1. H.: Treatment of the Nephrotic Syndrome with Nitrogen Mustard. Proc. 23rd Annual Meeting of Central Society for Clinical Research, J. Lab. & Clin. Med. 36: 996, 1950. 9. Thomas, C. B., France, R. and Reichsl):lan, F.: The Prophylactic Use of Sulfanilamide in Patients Susceptible to Rheumatic Fever. J.A.M.A. 116: 551, 1941. 10. Denny, F. W. and others: Prevention of Rheumatic Fever. J.A.M.A. 143: 151 1950.