Long-term assessment of steroid treatment of idiopathic childhood nephrosis

AWL Heart J. Octobev, 1967

14.

1.5. 16.

17.

intensive care unit for acute myocardial irifarction, Mod. Concepts Cardiovas. Dis. 34:23, 1965. F’arratt, J. R., and Grayson, J.: Myocardial vascular reactivity after beta-adrenergic blockade, Lancet I :338, 1966. Redding, V. J., and Russell Rees, J.: Myocardial vascular reactivity, Lancet 1:.548, 1?66. Folle, L. E., and Aviado, D. M.: The influence of beta-blocking drugs on anoxic response of the heart, Pharmacologist 6:181, 1964. Folle, L. E., and Aviado, D. M.: Cardiovascular effects of anoxia and the influence of a new beta

long-term of idiopathic

assessment childhood

Since 19.50 when cortisone and corticotropin became available intensive study of their use in idiopathic nephrosis began on both sides of the Atlantic Ocean.‘-5 Tentative short-term therapy was the usual pattern, intended to simulate the “stress” of an acute infection, which was sometimes followed by a temporary diuresis and occasionally by recovery on withdrawal. Such diuresis occurred occasionally, unpredictably, and usually transientIy. As the content and duration of steroid dosage increased it became clear that steroid “withdrawal” was not essential to provoke diuresis and indeed was undesirable. Many varients of intensive, prolonged treatment followed the introduction of prednisolone and prednisone in 19.55 but they began to crystallize into long-term intermittent therapy,6 and continuous short-term therapy.’ Results have been confusing and understanding of the natural history of the disease is a sine qua non of proper appreciation of the impact of steroid treatment on the situation which was previously obtained. Studies of Heymann and Starzman,s Galan ( 1949),g Barness and associates (1950) I0 Barnett and associates n and Arneil,rs tackled the problems of natural hisiory. Any reasonable form of intensive steroid therapy (usually complemented by a low-sodium intake, antibiotic cover, or fluid restriction) produced diuresis in the great majority of children with idiopathic nephrosis, eliminated proteinuria in a lesser proportion, and was ineffectual in a small minority. Since the production of diuresis in the majority was not difficult, the major problem during the period of 1955 to 1965 has been the avoidance of steroid overdosage and the avoidance of relapses in the responsive cases. The minority, who lacked sensitivity to steroid, was usually treated by diuretics. Unfortunately such sophisticated techniques as percutaneous renal biopsy with light, immunofluorescent, and electron microscopy, differential protein clearances,1a-14 and beta-l-c globulin estimation@ were not available in 1955. Nevertheless,

18,

19.

20.

adrenergic receptor blocking drug, J. Pharmacol. & Exper. Tberap. 149:79, 1965. Wolfson, S., Heinle, R. A., Herman, XI. V., Harvey, G., Sullivan, M., and Gorlin, R.: Propranolol and angina pectoris, Am. J. Cardiol. 18:3&i, 1966. Gillam, P. M., and Prichard, B. N.: Use of propranoloi in angina pectoris, British M. J. 2 :331, 196.5. Clausen, J., Felsby, lM., Schgnau J&-gensen, F., Lyager Nielsen, B., Rain, J., and Strange, B.: Absence of prophylactic effect of propranolol in myocardial infarction, Lancet 2:920, 1966.

of steroid

treatment

nephrosis

a long term assessment of prednisolone therapy in 1967 must be based on the 1955 to 1960 group that was diagnosed before such refinements were available. In Glasgow, Scotland, a survey of the S-10 year results in 100 per cent of the children who presented with idiopathic nephrosis has been completed recently by Arneil and Lam.n+ The results of these studies may be summarized as follows: A total of 4.5 children with idiopathic nephrosis was admitted during the period of 19.55 to 1960. All of the children, with the exception of 1 child (who recovered spontaneously), received intensive prednisolone or similar steroid therapy which amounted to approximately 1.3 Gm. of prednisolone for a period of not less than 6 weeks. After the intensive continuous therapy, no subsequent intermittent, continuous steroid, or antibiotic therapy was given to the asymptomatic patient. A total of 93 per cent of the patients responded to intensive therapy with diuresis and reduction or elimination of proteinuria. Forty per cent of the children recovered from proteinuria and remained well, with no relapses up to 5 to IO years later without any longterm intermittent steroid therapy. This result strongly suggests that prolonged steroid and antibiotic treatment is unnecessary, undesirable, and extravagant for 40 per cent of children with idiopathic nephrosis. A total of 53 per cent of the patients responded and then relapsed once or more, sometimes with variable degrees of proteinuria between gross episodes. On the long-term basis it was found that of the 53 per cent, 22 per cent had remained well and free of proteinuria for not less than 3 years at survey, 22 per cent had persisting relapses and/or proteinuria 5 to 10 years after onset, and 9 per cent died. Three children were unresponsive to repeated courses of steroid treatment but of these, two were well and free of proteinuria 5 to 10 years later. This fact is well worth recalling when one studies claims

for ~~l~~lIU!~~~L~~~~~~SSdllt therapy as eRecti>-e in steroid resistent cases! The over-all figures that were obtained for this >urvey were that 5 years after onset 91 per cent were aiive, 69 per cent were well, and 9 per cent were dead. Very similar figures have been reported from Philaer cent of the children responded well to a short sntensive course and 40 per cent required no inter“nittent or any other steroid therapy for 5 to 10 years subsequently. Therefore, it appears unjustinable to give long-term intermittent steroid therapy zjld/or antibiotic therapy to all steroid-sensitive uephrotics if 40 per cent in fact remain well with no such treatment. It is suggested that children with steroid-responsive idiopathic nephrosis receive 6 weeks of steroid treatment. If and when relapse ocstirs, a further course of steroid should then be given and prophylactic intermittent steroid therapy begun in the knowledge that of those who relapse once! at least 75per cent will relapse again. %?th hindsight, one would wish very much to know the results of differential protein clearance by the simple and eminently praciical technique of Cameron and Blandford.1g This aDnears to be the most promising way of predicting steroid sensitivity and outcome and may well replace, rather than complement routine percutaneius renal biopsy, especially if beta-i-c globulin estimations are concu~rrentl~~ considered.’ R’ith biopsy assumed, the e:xacting task of imnlunoflorescence may yield better prognostication and indication of steroid !~xensitivity than the rather confused results of Iight and electron microscopy to date. The problem of iitilliuIlosuppressaIlt therapy is c kinant today. That “starting early” in the course
pathic nephrosis. It is usual with a ne~~v jAntried Treatment, for those with initial success f-o pub!kh their fmdings and for others with i~cowh~sive or (!epressing data to remain inartictik3tc” Recent :>aoers colleazues.20 White and col;:eag-ues,*] s bv2and[VestGrupeand a.nd HiymanS ha>,e
Barnett, H. I,., Forma& C. \S-., and &fcYamara, 13.: Effect of corticowouin :.4C’W) in children with the nephrotic sy;ldrok, J..4.M. X. 147: SiOS> 1951. .!Irneil, G. C., and L\‘ilson. I-1. l<. C.. Cart-isol:e treatment of nephrosis, k&h. Dis. Childhood ZTz322, s952. .knei!, G. C., and Wilson, i3. K. C. : .kC.T.f.Z. in nephrosis, Arch. Dis. Childhood 2S:,372, 19%” Lange, I<., Yobody, I>., and Straiic”, I<.: Prolonged intermittent ACT13 and cortisone therapy in the nephrotic syndrome: lmmu~ologic basis and results, Pediatrics !..5:156, 19.55. kneil, G. C.: Treatment of nepk-:k with

586

Am. Heart .T. 5ctober, 1967

Annotations

12.

A4rneil, G. C.: 164 Children with nephrosis, Lancet, 2:1103, 1961. 13. Blainey, J. D., Brewer, D. B., Hardwicke, J., and Soothill, J- F.: The nephrotic syndrome: Diagnosis by renal biopsy and biochemical and immunological analysis related to the response to steroid therapy, Quart. J. Med. 29:235, 1960. 14. Cameron, J. S., and White, R. H. R.: Selectivity of proteinuria in children with the nephrotic syndrome, Lancet 1:463, 196.5. 1.5. West, C. D., Northway, J. D., and Davis, N.: Serum levels of beta-l-c globulin, a complement component, in nephritides, lipoid nephrosis, and other conditions. J. Clin. Invest. 43:1507, 1964. 16. Arneil, G. C., and Lam, C. N.: Long-term assessment of steroid therapy in childhood nephrosis, Lancet Z&19, 1966. 17. Cornfield, D., and Schwartz, N. W.: Nephrosis: A long-term study of children with corticosteroids, J. Pediat. 68507, 1966. 18. Saxena, K. M., and Crawford, J. D.: The man-

Collateral

circulation,

The present interest in occlusive vascular disease and revascularization of organs and limbs renders it most important to have a physiologic understanding of the proper descriptive terminology. When the circulation to living cells becomes impaired the therapeutic objective is to improve the circulation before it becomes critically insufficient and death occurs. The process of providing circulation adequate to prevent the death of tissue should be termed Y~ZXZXU~U&~~&Z. On the other hand, when functional obstruction to flow exists blood must seek alternate routes in order to reach more distant areas; the phenomenon of detouring blood flow should be termed colZateya1 circulation. The well-known alternate pathways of flow that develop in coarctation of the aorta, portal obstruction, pulmonary arterial atresia, ligation of the inferior vena cava, etc. are thus properly considered collateral circulation. In these instances, vessels which are normally present become larger in lumina! diameter so that they then conduct larger volumes of blood around the point of obstruction whether it be arterial or venous. 5%&&g is a term which indicates a direct flow of blood through relatively large channels from one large vessel to another. It can be a normal physiologic vascular phenomenon or it can develop only in the presence of peripheral vascular disease. A-V aneurysms in limbs, artifical surgical shunts, and congenital shunts (cirsoid aneurysms) are examples of large vascular shunts. These concepts of terminology are extremely inportant in clinical medicine. When a tissue suffers from impairment of blood supply the cells must receive more blood or they will function poorly or even

19.

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21.

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23.

agement of childhood nephrosis, AM. HEART J. T-0:835, 196.5. Cameron, J. S., and BIandford, G.: The simple assessment of selectivity in heavy proteinuria, Lancet 2:242, 1966. West, C D., Hong, R., and Holland, N. H.: Effect of cyclophosphamide on lipoid nephrosis in the human and on aminonucleoside nephrosis in the rat, J. Pediat. 68516, 1966. White, R. H. R., Cameron, J* S., and Trounce, J. R.: Immunosuppressive therapy in steroidresistant proliferative glomerulonephritis accompanied by the nephrotic syndrome, British M. J. 2:853, 1966. Grupe, W. E., and Heymann, W.: Cytotoxic drugs in steroid-resistant renal disease, Am. J. Dis. Child. 112:448, 1966. Barnett, H. L,: Paediatric nephrology; scientific study of kidneys and their diseases in infants and children, Arch. Dis, Childhood

41~229, 1966.

shunting,

and

revasctilarization

die. Therefore, to be effective, therapy must provide an adequate blood supply to the cells themselves. This means there must be an adequate circuIation in the minutest of blood vessels,, the capillaries. To show clinically that the capillary? circulation is adequate within an organ is possible today only by certain indirect proce,dures. Clinical bedside methods are frequently satisfactory and practical. For example, the electrocardiogram can help in detecting myocardial ischemia. Angiograms are also useful but they provide information regarding the large vessels only. Angiograms do not measure the volume or rate of blood flow nor do they indicate what the cells are actually receiving. They reveal only the vessels that are filled with the contrast material and only those which are large enough to be seen grossly, These large vessels, however, often may be functioning either as collaterals or as shunt channels. A &s&r of shunts or collaterals may produce a very “vascular” appearance on the x-ray film but only by means of more precise measurements can the clinician know whether the cells in the diseased area are actually receiving an adequate amount of blood to maintain life and necessary function. More than conventional angiograms are required to determine whether there is sufficient organic arterial disease to impair cellular function or whether sufficient collateral vessels have developed to provide adequate blood flow to the tissue. Caution should be exercised in interpreting coronary angiograms which propose to demonstrate improved coronary circulation as a result of specific therapy. The existence of many large arteries engorged with contrast material does not necessarily