- Email: [email protected]
The management of childhood nephrosis
Annotations
alterations in pattern, and represented muscle injury or muscle death. This was in patients who already had heart disease with some limitation of cardiac reserve, and who were least able to afford further myocardial damage. The damage suffered by these patients gave rise to no symptoms or signs and would not have been detected but for the study which was being made at the time. Even the 3 cases of probable myocardial infarction were asymptomatic-, doubtless because they occurred under anesthesia and under the influence of postoperative analgesic drugs. The occurrence of myocardial infarction during or after operation was stressed by Mendelsohn and Monheit,’ who suggested that the incidence of this condition was considerably higher than was generally suspected. Driscoll and associates* arrived at a similar conclusion. It is not difficult to enumerate the factors associated with surgery under general anesthesia which may be particularly hazardous to the patient with ischemic heart disease. Anesthesia can be responsible for anosia due to laryngeal spasm, hypoventilation, and ventilation-perfusion inequality, and also for falls in cardiac output due to positive pressure myocardial depression, and cardiac respiration, arrhythmias. Surgery carries its own dangers from shock, and perhaps from reflex falls in cardiac output and coronary vasoconstriction evoked by manipulation of the peritoneum and viscera. In the postoperative phase, pain and analgesic drugs may cause hypoventilation, and ventilation-perfusion inequality can persist as an additional cause of lowered arterial oxygen saturation. Further research may well be directed to defining more precisely the relative importance of these factors so that suitable measures may be taken to avoid those which most frequently increase myocardial ischemia. Greater emphasis needs to be placed on the identification of patients who are at risk; preoperative ECGs should be taken on all elderly patients, as well as on those with symptoms and signs suggestive of arterial disease.
The management
There would be no complacency about the risk faced by patients with ischemic heart disease undergoing surgery if the cardiac damage they had suffered were readily apparent. The fact that it can so frequently remain undetected places a special responsibility on the anesthetist and surgeon and calls for a high degree of technical skill and clinical judgment. D. d. Chamberlain, M.B., M.R.C.P. Department of Cardiology J. Edmonds-Seal, M.B., F.F.A., R.C.S. Department of Anesthesia St. Bartholomew’s Hospital London, E.C. 1, England REFERENCES 1. Nachlas, M. M., A4brams, S. J., and Golberg, M. M.: The influence of arteriosclerotic heart disease on surgical risk, Am. J. Surg. 101:447, 1961. 2. Driscoll, A. C., Hobika, J. H., Etsten, B. E., and Proger, S.: Clinically unrecognised myocardial infarction following surgery, New England J. Med. 264:633, 1961. 3. Chamberlain, D. A., and Edmonds-Seal, J.: Effects of surgery under general anaesthesia on the electrocardiogram in ischaemic heart disease and hypertension, Brit. M. J. 2:784, 1964. 4. Hannigan, C. A., Wroblewski, F., Lewis, W. H., and LaDue, J. S.: Major surgery in patients with healed myocardial infarction, Am. J. M. SC. 222:628, 1951. 5. Master, A. M., Dack, S., and Jaffe, H. L.: Postoperative coronary artery occlusion, J.A.M.A. 110:1415, 1938. 6. Wasserman, F., Bellet, S., and Saichek, R. P.: Postoperative myocardial infarction, New England J. Med. 252:967, 1955. 7. Mendelsohn, D., and Monheit, R.: Electrocardiographic and blood-pressure changes during and after biliary-tract surgery, New England J. Med. 254:307, 1956.
of childhood
With the advent of prolonged corticosteroid therapy, the last decade has witnessed a major breakthrough in the management of the nephrotic child and a marked improvement in his immediate prognosis. The same degree of optimism has not been justified with respect to the long-term outcome, particularly the ultimate mortality from renal failure.132 A recent review of our experience with children suffering from “nephrosis” during the three therapeutic eras-preantibiotic, antibiotic, and steroid-
835
nephrosis
makes us believe, however, that late prognosis can also be significantly improved with adequate steroid treatment.3 The term “nephrosis” in the present context is used to connote the usually idiopathic childhood syndrome of massive proteinuria, hypoproteinemia, hyperlipemia, and edema, without, at least in the early stages of the disease, persistent hematuria, hypertension, or renal failure. Typical “foot process and basement-membrane changes seen by electron-
836
Am. Hart .I. December, 1965
Annotations
microscopy characterize the condition histologically. Spontaneous recovery of 40 to 50 per cent of the patients within 2 to 3 years of onset has been the rule, provided that the child does not succumb to infection.1*4,6 This tendency of the disease was brought into sharp focus by the advent of effective antibacterial agents which so curtailed mortality due to pneumococcal peritonitis. As used initially for short treatment periods, steroids and ACTH did little to change the course of the disease; their particularly favorable influence was noted when prolonged maintenance therapy was introduced.6 Although relapses are still common today, and a certain proportion of the patients develops progressive renal failure and dies, the clinical course of the disease has been altered beyond recognition. Modern treatment has decreased morbidity to such an extent that the average child can look forward to leading a reasonably normal life, except during periods of acute exacerbation. Mortality from infections has been almost eliminated, and that from renal failure, diminished. Life has been prolonged even in the group of children with renal failure who finally die of uremia and hypertension. Supportive therapy is of the utmost importance in the management of nephrosis. The details have been discussed in several recent articles.3*7*8 These include the control of edema with the use of infusions of albumin, diuretics, and, rarely, paracentesis; maintenance of adequate nutrition; prevention and control of infection; and management of hypertension and renal failure. The greatest ingenuity may be required to deal effectively with the emotional impact of this chronic disease on the young child. The different preparations of steroids and various schedules of dosage have failed to show a significant superiority of one over the others. As soon as the diagnosis has been established, we begin treatment with cortisone, 300 mg. per square meter per day, or prednisone in an equivalent dose. The amount of drug is reduced to 200 mg. per square meter per day after 6 weeks of therapy, or when remission has occurred, whichever is earlier. (A remission is taken to mean disappearance of edema and proteinuria, elevation of serum protein to 6 Gm. per cent or over, and reduction of serum cholesterol to 200 mg. per cent or less.) Steroids are continued at this dose level for 3 months of uninterrupted remission. Relapses are treated promptly in a fashion similar to that used for the initial episode. Most patients require therapy for 135 to 2 years before achieving prolonged remission. Even then, the risk of late relapses persists.9 Side effects of steroid therapy are frequent and occasionally serious. In an attempt to reduce these, we have recently treated with steroids on an alternate-day schedule 20 patients representing a wide spectrum of the problems of childhood nephrosis. The total amount of drug for 2 days has been given in a single morning dose every 48 hours,‘0 as suggested by Harter and associates1 The effectiveness of this schedule over the still relatively short period of follow-up extending from 3 to 20 months has been similar to that of the usual S-hourly dosage regimen. Except for mild rounding of the face, there has been a remarkable freedom from Cushingoid changes, electrolyte or growth disturbances,
hypertension, convulsions, and other side effects associated with steroid therapy of conventional schedule. Fasting plasma cortisol levels in 3 patients have failed to show any evidence of adrenocortical suppression. A small percentage of nephrotic patients fails to respond to steroid therapy. Several studies have pointed out correlation of such refractoriness with functional’2 or histologic’3-16 severity of the glomerular lesion, age of the patient,14,‘6n” the duration of disease before treatment is begun’* and, more recently, immunopathologic findings in the kidneys.19 These patients present a formidable therapeutic problem. Antimetabolite or immunosuppressive drugs, including nitrogen mustard, 6-thioguanine, 6-mercaptopurine, cyclophosphamide, and azathioprine, have proved to be of some value in their management.20.26 We obtained complete or partial remission after 10 of 13 courses of treatment with nitrogen mustard or cyclophosphamide. In another steroid-resistant patient, azathioprine (Imuran) was used twice with success. Meanwhile, steroids were continued in the usual dose. On the basis of this experience, we believe that immunosuppressive drugs have a definite place in the treatment of nephrosis. Although early and prolonged steroid therapy with judicious use of various supportive measures leads to recovery in the majority of patients, the management of nephrosis is by no means easy. The unpredictable, long, and fluctuating course of the disease challenges the equanimity and patience of the physician and the parents alike. Efforts directed at further sophistication of steroid therapy, esploration of the role of antimetabolites in resistant cases, and that of gammaglobulin in prevention of relapses due to infection hold promise of even greater therapeutic dividends. Krishna M. Saxena, M.D. John D. Crawford, M.D. Children’s Service The Massachusetts General Hospital Boston, Mass., 02114
REFERENCES 1. Lawson, D., Moncrieff, A., and Payne, W. W.: Forty years of nephrosis in childhood, Arch. Dis. Child. 35:115, 1960. 2. Merrill, A. J.: Management of the nephrotic syndrome, AM. HEART J. 61:719, 1961. 3. Saxena, K. M., and Crawford, J. D.: The treatment of nephrosis, New England J. Med. 272:522, 1965. 4. Rarness, L. A., Moll, G. H., and Janeway, C. A.: Nephrotic syndrome. 1. Natural history of the disease, Pediatrics 5:486, 1950. 5. Arneil, G. C.: 164 Children with nephrosis, Lancet 2:1103, 1961. 6. Riley, C. M., and Scaglione, P. R.: Current management of nephrosis; statistical evaluation and a proposed approach to therapy, Pediatrics 23:.561, 1959. 7. Williams, G. F.: Nephrotic syndrome in children, Postgrad. Med. 33:514, 1963. 8. Arneil, G. C.: The syndrome of proteinuria.
Volume 70 h’umber
Annotations
6
The nephrotic syndrome, AM. HEART J. 65:723, 1963. 9. Worthen, H. G., Michael, A. F., Vernier, R. L., and Good, R. A.: Late recurrences of the nephrotic syndrome: Recurrence after prolonged remissions induced by adrenal steroids, Am. J. Dis. Child. 103:794, 1962. 10. Soyka, L. F., and Saxena, K. M. Alternate day steroid therapy for nephrotic children, J.A.M.A. 192:125, 1965. 11. Harter, J. G., Reddy, W. J., and Thorn, G. W.: Studies on intermittent corticosteroid dosage regimen, New England J. Med. 269:591, 1963. 12. McCrory, W. W., Rapaport, M., and Fleisher, D. S.: Estimation of severity of nephrotic syndrome as a guide to therapy and prognosis, Pediatrics 23:861, 1959. 13. Vernier, R. L., Worthen, H. G., and Good, R. A.: The pathology of the nephrotic syndrome, J. Pediat. 58:446, 1961. 14. Pearl, M. A., Burch, R. R., Carvajal, E., McCracken, B. H., Woody, H. B., and Sternberg, W. H.: Nephrotic syndrome. A clinical and pathological study, Arch. Int. Med. 112:716, 1963. 1.5. Nesson, H. R., Sproul, L. E., Relman, A. S., and Schwartz, W. B.: Adrenal steroids in the treatment of idiopathic nephrotic syndrome in adults, Ann. Int. Med. 58:268, 1963. 16. Adams, D. A., Maxwell, M. H., and Bernstein, D. : Corticosteroid therapy of glomerulonephritis and the nephrotic syndrome: A review, J. Chron. Dis. 15:29, 1962. 17. Parker, R. A., and Piel, C. F.: The nephrotic
On the mechanism of exaggerated natriuresis
The mechanism of the augmented natriuretic response to sodium loading which occurs in hypertensive subjects is unknown. The recent suggestion in these pages that this exaggerated natriuresis may result from a chronically enhanced concentration of medullary sodium’ is of interest because it stimulates new thinking about the phenomenon and invites consideration of indirect data, presently available, which appear to argue against this suggestion. If the medulla of hypertensive man has indeed an abnormally high concentration of sodium, then an enhanced capacity to concentrate the urine might be expected in such subjects. In fact, however, essential hypertension does not appear to augment concentrating capacity in man.2 During water diuresis, sodium is washed out of
83 7
syndrome in the first year of life, Pediatrics 25:967, 1960. 18. Heyman, W., and Hunter, J. L. P.: Importance of early treatment of the nephrotic syndrome, J.A.M.A. 175:563, 1961. 19. Drummond, K. N., Michael, A. F., Good, R. A., and Vernier, R. L.: Immunopathologic studies in the nephrotic syndrome, (Abstract) J. Pediat. 65:1114, 1964. 20. Kelley, V. C., and Panos, T. C.: The nephrotic syndrome in children. 1. Clinical response to nitrogen mustard therapy, J. Pediatrics 41:505, 1952. 21. West, C. D.: Use of combined hormone and mechlorethamine (nitrogen mustard) therapy in lipoid nephrosis, Am. J. Dis. Child. 95:498, 1958. 22. Talamo, R. C., and Crawford, J. D.: Trimethadione nephrosis treated with cortisone and nitrogen mustard, New England J. Med. 269:15, 1963. 23. Goodman, H. C., Wolff, S. M., Carpenter, R. R., Andersen, B. R., and Brandriss, M. W.: Current studies on the effect of antimetabolites in nephrosis, other non-neoplastic diseases, and experimental animals, Ann. Int. Med. 59:388, 1963. 24. Lagrue, G., et al.: R&&tats de la chit&otherapie prolong6 au tours de certains syndromes nephrotiques, J. d’Uro1. 70:156, 1964. 2.5. Coldbeck, J. H.: Experience with alkylating agents in the treatment of children with the nephrotic syndrome, M. J. Australia 2:987, 1964.
in hypertensive
man
the renal medulla.3 The fact that a hypertensive subject may exhibit exaggerated natriuresis during maximal water diuresis4 therefore indicates that exaggerated natriuresis can still occur even when the concentration of medullary sodium is decreased. The fact that clearance of free water increased normally in this study with increasing delivery of sodium to the diluting segment further shows that limited tubular capacity to reabsorb sodium could not be demonstrated.4 In fact, it appears that exaggerated natriuresis is not the result of a limited tubular capacity for reabsorption of sodium, since it may occur with decreasing glomerular filtration rate6 or decreasing concentration of serum sodium,6 and even without the infusion of saline.T Thus, an overflow natriuresis
alterations in pattern, and represented muscle injury or muscle death. This was in patients who already had heart disease with some limitation of cardiac reserve, and who were least able to afford further myocardial damage. The damage suffered by these patients gave rise to no symptoms or signs and would not have been detected but for the study which was being made at the time. Even the 3 cases of probable myocardial infarction were asymptomatic-, doubtless because they occurred under anesthesia and under the influence of postoperative analgesic drugs. The occurrence of myocardial infarction during or after operation was stressed by Mendelsohn and Monheit,’ who suggested that the incidence of this condition was considerably higher than was generally suspected. Driscoll and associates* arrived at a similar conclusion. It is not difficult to enumerate the factors associated with surgery under general anesthesia which may be particularly hazardous to the patient with ischemic heart disease. Anesthesia can be responsible for anosia due to laryngeal spasm, hypoventilation, and ventilation-perfusion inequality, and also for falls in cardiac output due to positive pressure myocardial depression, and cardiac respiration, arrhythmias. Surgery carries its own dangers from shock, and perhaps from reflex falls in cardiac output and coronary vasoconstriction evoked by manipulation of the peritoneum and viscera. In the postoperative phase, pain and analgesic drugs may cause hypoventilation, and ventilation-perfusion inequality can persist as an additional cause of lowered arterial oxygen saturation. Further research may well be directed to defining more precisely the relative importance of these factors so that suitable measures may be taken to avoid those which most frequently increase myocardial ischemia. Greater emphasis needs to be placed on the identification of patients who are at risk; preoperative ECGs should be taken on all elderly patients, as well as on those with symptoms and signs suggestive of arterial disease.
The management
There would be no complacency about the risk faced by patients with ischemic heart disease undergoing surgery if the cardiac damage they had suffered were readily apparent. The fact that it can so frequently remain undetected places a special responsibility on the anesthetist and surgeon and calls for a high degree of technical skill and clinical judgment. D. d. Chamberlain, M.B., M.R.C.P. Department of Cardiology J. Edmonds-Seal, M.B., F.F.A., R.C.S. Department of Anesthesia St. Bartholomew’s Hospital London, E.C. 1, England REFERENCES 1. Nachlas, M. M., A4brams, S. J., and Golberg, M. M.: The influence of arteriosclerotic heart disease on surgical risk, Am. J. Surg. 101:447, 1961. 2. Driscoll, A. C., Hobika, J. H., Etsten, B. E., and Proger, S.: Clinically unrecognised myocardial infarction following surgery, New England J. Med. 264:633, 1961. 3. Chamberlain, D. A., and Edmonds-Seal, J.: Effects of surgery under general anaesthesia on the electrocardiogram in ischaemic heart disease and hypertension, Brit. M. J. 2:784, 1964. 4. Hannigan, C. A., Wroblewski, F., Lewis, W. H., and LaDue, J. S.: Major surgery in patients with healed myocardial infarction, Am. J. M. SC. 222:628, 1951. 5. Master, A. M., Dack, S., and Jaffe, H. L.: Postoperative coronary artery occlusion, J.A.M.A. 110:1415, 1938. 6. Wasserman, F., Bellet, S., and Saichek, R. P.: Postoperative myocardial infarction, New England J. Med. 252:967, 1955. 7. Mendelsohn, D., and Monheit, R.: Electrocardiographic and blood-pressure changes during and after biliary-tract surgery, New England J. Med. 254:307, 1956.
of childhood
With the advent of prolonged corticosteroid therapy, the last decade has witnessed a major breakthrough in the management of the nephrotic child and a marked improvement in his immediate prognosis. The same degree of optimism has not been justified with respect to the long-term outcome, particularly the ultimate mortality from renal failure.132 A recent review of our experience with children suffering from “nephrosis” during the three therapeutic eras-preantibiotic, antibiotic, and steroid-
835
nephrosis
makes us believe, however, that late prognosis can also be significantly improved with adequate steroid treatment.3 The term “nephrosis” in the present context is used to connote the usually idiopathic childhood syndrome of massive proteinuria, hypoproteinemia, hyperlipemia, and edema, without, at least in the early stages of the disease, persistent hematuria, hypertension, or renal failure. Typical “foot process and basement-membrane changes seen by electron-
836
Am. Hart .I. December, 1965
Annotations
microscopy characterize the condition histologically. Spontaneous recovery of 40 to 50 per cent of the patients within 2 to 3 years of onset has been the rule, provided that the child does not succumb to infection.1*4,6 This tendency of the disease was brought into sharp focus by the advent of effective antibacterial agents which so curtailed mortality due to pneumococcal peritonitis. As used initially for short treatment periods, steroids and ACTH did little to change the course of the disease; their particularly favorable influence was noted when prolonged maintenance therapy was introduced.6 Although relapses are still common today, and a certain proportion of the patients develops progressive renal failure and dies, the clinical course of the disease has been altered beyond recognition. Modern treatment has decreased morbidity to such an extent that the average child can look forward to leading a reasonably normal life, except during periods of acute exacerbation. Mortality from infections has been almost eliminated, and that from renal failure, diminished. Life has been prolonged even in the group of children with renal failure who finally die of uremia and hypertension. Supportive therapy is of the utmost importance in the management of nephrosis. The details have been discussed in several recent articles.3*7*8 These include the control of edema with the use of infusions of albumin, diuretics, and, rarely, paracentesis; maintenance of adequate nutrition; prevention and control of infection; and management of hypertension and renal failure. The greatest ingenuity may be required to deal effectively with the emotional impact of this chronic disease on the young child. The different preparations of steroids and various schedules of dosage have failed to show a significant superiority of one over the others. As soon as the diagnosis has been established, we begin treatment with cortisone, 300 mg. per square meter per day, or prednisone in an equivalent dose. The amount of drug is reduced to 200 mg. per square meter per day after 6 weeks of therapy, or when remission has occurred, whichever is earlier. (A remission is taken to mean disappearance of edema and proteinuria, elevation of serum protein to 6 Gm. per cent or over, and reduction of serum cholesterol to 200 mg. per cent or less.) Steroids are continued at this dose level for 3 months of uninterrupted remission. Relapses are treated promptly in a fashion similar to that used for the initial episode. Most patients require therapy for 135 to 2 years before achieving prolonged remission. Even then, the risk of late relapses persists.9 Side effects of steroid therapy are frequent and occasionally serious. In an attempt to reduce these, we have recently treated with steroids on an alternate-day schedule 20 patients representing a wide spectrum of the problems of childhood nephrosis. The total amount of drug for 2 days has been given in a single morning dose every 48 hours,‘0 as suggested by Harter and associates1 The effectiveness of this schedule over the still relatively short period of follow-up extending from 3 to 20 months has been similar to that of the usual S-hourly dosage regimen. Except for mild rounding of the face, there has been a remarkable freedom from Cushingoid changes, electrolyte or growth disturbances,
hypertension, convulsions, and other side effects associated with steroid therapy of conventional schedule. Fasting plasma cortisol levels in 3 patients have failed to show any evidence of adrenocortical suppression. A small percentage of nephrotic patients fails to respond to steroid therapy. Several studies have pointed out correlation of such refractoriness with functional’2 or histologic’3-16 severity of the glomerular lesion, age of the patient,14,‘6n” the duration of disease before treatment is begun’* and, more recently, immunopathologic findings in the kidneys.19 These patients present a formidable therapeutic problem. Antimetabolite or immunosuppressive drugs, including nitrogen mustard, 6-thioguanine, 6-mercaptopurine, cyclophosphamide, and azathioprine, have proved to be of some value in their management.20.26 We obtained complete or partial remission after 10 of 13 courses of treatment with nitrogen mustard or cyclophosphamide. In another steroid-resistant patient, azathioprine (Imuran) was used twice with success. Meanwhile, steroids were continued in the usual dose. On the basis of this experience, we believe that immunosuppressive drugs have a definite place in the treatment of nephrosis. Although early and prolonged steroid therapy with judicious use of various supportive measures leads to recovery in the majority of patients, the management of nephrosis is by no means easy. The unpredictable, long, and fluctuating course of the disease challenges the equanimity and patience of the physician and the parents alike. Efforts directed at further sophistication of steroid therapy, esploration of the role of antimetabolites in resistant cases, and that of gammaglobulin in prevention of relapses due to infection hold promise of even greater therapeutic dividends. Krishna M. Saxena, M.D. John D. Crawford, M.D. Children’s Service The Massachusetts General Hospital Boston, Mass., 02114
REFERENCES 1. Lawson, D., Moncrieff, A., and Payne, W. W.: Forty years of nephrosis in childhood, Arch. Dis. Child. 35:115, 1960. 2. Merrill, A. J.: Management of the nephrotic syndrome, AM. HEART J. 61:719, 1961. 3. Saxena, K. M., and Crawford, J. D.: The treatment of nephrosis, New England J. Med. 272:522, 1965. 4. Rarness, L. A., Moll, G. H., and Janeway, C. A.: Nephrotic syndrome. 1. Natural history of the disease, Pediatrics 5:486, 1950. 5. Arneil, G. C.: 164 Children with nephrosis, Lancet 2:1103, 1961. 6. Riley, C. M., and Scaglione, P. R.: Current management of nephrosis; statistical evaluation and a proposed approach to therapy, Pediatrics 23:.561, 1959. 7. Williams, G. F.: Nephrotic syndrome in children, Postgrad. Med. 33:514, 1963. 8. Arneil, G. C.: The syndrome of proteinuria.
Volume 70 h’umber
Annotations
6
The nephrotic syndrome, AM. HEART J. 65:723, 1963. 9. Worthen, H. G., Michael, A. F., Vernier, R. L., and Good, R. A.: Late recurrences of the nephrotic syndrome: Recurrence after prolonged remissions induced by adrenal steroids, Am. J. Dis. Child. 103:794, 1962. 10. Soyka, L. F., and Saxena, K. M. Alternate day steroid therapy for nephrotic children, J.A.M.A. 192:125, 1965. 11. Harter, J. G., Reddy, W. J., and Thorn, G. W.: Studies on intermittent corticosteroid dosage regimen, New England J. Med. 269:591, 1963. 12. McCrory, W. W., Rapaport, M., and Fleisher, D. S.: Estimation of severity of nephrotic syndrome as a guide to therapy and prognosis, Pediatrics 23:861, 1959. 13. Vernier, R. L., Worthen, H. G., and Good, R. A.: The pathology of the nephrotic syndrome, J. Pediat. 58:446, 1961. 14. Pearl, M. A., Burch, R. R., Carvajal, E., McCracken, B. H., Woody, H. B., and Sternberg, W. H.: Nephrotic syndrome. A clinical and pathological study, Arch. Int. Med. 112:716, 1963. 1.5. Nesson, H. R., Sproul, L. E., Relman, A. S., and Schwartz, W. B.: Adrenal steroids in the treatment of idiopathic nephrotic syndrome in adults, Ann. Int. Med. 58:268, 1963. 16. Adams, D. A., Maxwell, M. H., and Bernstein, D. : Corticosteroid therapy of glomerulonephritis and the nephrotic syndrome: A review, J. Chron. Dis. 15:29, 1962. 17. Parker, R. A., and Piel, C. F.: The nephrotic
On the mechanism of exaggerated natriuresis
The mechanism of the augmented natriuretic response to sodium loading which occurs in hypertensive subjects is unknown. The recent suggestion in these pages that this exaggerated natriuresis may result from a chronically enhanced concentration of medullary sodium’ is of interest because it stimulates new thinking about the phenomenon and invites consideration of indirect data, presently available, which appear to argue against this suggestion. If the medulla of hypertensive man has indeed an abnormally high concentration of sodium, then an enhanced capacity to concentrate the urine might be expected in such subjects. In fact, however, essential hypertension does not appear to augment concentrating capacity in man.2 During water diuresis, sodium is washed out of
83 7
syndrome in the first year of life, Pediatrics 25:967, 1960. 18. Heyman, W., and Hunter, J. L. P.: Importance of early treatment of the nephrotic syndrome, J.A.M.A. 175:563, 1961. 19. Drummond, K. N., Michael, A. F., Good, R. A., and Vernier, R. L.: Immunopathologic studies in the nephrotic syndrome, (Abstract) J. Pediat. 65:1114, 1964. 20. Kelley, V. C., and Panos, T. C.: The nephrotic syndrome in children. 1. Clinical response to nitrogen mustard therapy, J. Pediatrics 41:505, 1952. 21. West, C. D.: Use of combined hormone and mechlorethamine (nitrogen mustard) therapy in lipoid nephrosis, Am. J. Dis. Child. 95:498, 1958. 22. Talamo, R. C., and Crawford, J. D.: Trimethadione nephrosis treated with cortisone and nitrogen mustard, New England J. Med. 269:15, 1963. 23. Goodman, H. C., Wolff, S. M., Carpenter, R. R., Andersen, B. R., and Brandriss, M. W.: Current studies on the effect of antimetabolites in nephrosis, other non-neoplastic diseases, and experimental animals, Ann. Int. Med. 59:388, 1963. 24. Lagrue, G., et al.: R&&tats de la chit&otherapie prolong6 au tours de certains syndromes nephrotiques, J. d’Uro1. 70:156, 1964. 2.5. Coldbeck, J. H.: Experience with alkylating agents in the treatment of children with the nephrotic syndrome, M. J. Australia 2:987, 1964.
in hypertensive
man
the renal medulla.3 The fact that a hypertensive subject may exhibit exaggerated natriuresis during maximal water diuresis4 therefore indicates that exaggerated natriuresis can still occur even when the concentration of medullary sodium is decreased. The fact that clearance of free water increased normally in this study with increasing delivery of sodium to the diluting segment further shows that limited tubular capacity to reabsorb sodium could not be demonstrated.4 In fact, it appears that exaggerated natriuresis is not the result of a limited tubular capacity for reabsorption of sodium, since it may occur with decreasing glomerular filtration rate6 or decreasing concentration of serum sodium,6 and even without the infusion of saline.T Thus, an overflow natriuresis