RAISED COMPLEMENT IN NEPHRITIS: PROGNOSTIC SIGNIFICANCE

55 RAISED COMPLEMENT IN NEPHRITIS: PROGNOSTIC SIGNIFICANCE

cholesterol, a substance under trial as a cholesterollowering agent. Alternatively, an endocrine disturbance, corresponding to the gonadal failure with elevated gonadotrophins that is seen in affected males, might be responsible. The action of intrauterine environmental factors in disorder normally determined by simple mendelian inheritance has already been established in maternal phenylketonuria, 10. 11 and transitory effects of a maternal disorder are seen in the infants born to mothers with non-mendelian disorders such as myasthenia gravis. Neither example, however, is precisely similar to the situation in dystrophia myotonica, for in the present series apparently unaffected sibs of the earlyonset cases were observed, in addition to others showing the more typical form of the disease. This suggests that, unlike the situation in maternal phenylketonuria, only those individuals that are genotypically affected with dystrophia myotonica are susceptible to the maternal influence. Further confirmation of this hypothesis must await biochemical studies of early-onset cases of dystrophia myotonica and their mothers, with the aim of identifying the presumed maternal factor. It is possible that this may throw light not only on the early-onset form, but also on the more general xtiology of the disease in other age-groups. This work was performed during the tenure by one of us (P. S. H.) of a research fellowship in the Division of Medical Genetics, Johns Hopkins Hospital, under Dr. Victor A. McKusick, whose help is gratefully acknowledged. We should also like to thank Dr. Marian Rivas for her participation in the study. This work was supported by Muscular Dystrophy Associations of

ROGER GABRIEL* A. A. GLYNN A. M. JOEKES

Hospitals, London W.C.2, and the Wright-Fleming Institute, London W.2

St. Peter’s

a

America. REFERENCES

1. Vanier, T. M. Br. med. J. 1960, ii, 1284. 2. Dodge, P. R., Gamsdorp, I., Byers, R. K., Russell, P. Pediatrics, Springfield, 1965, 35, 3. 3. Dyken, P. R., Buchanan, D. N. Proc. Inst. Med. Chicago, 1965,

25, 301. Pruzanski, W. Brain, 1966, 89, 563. Watters, G. V., Williams, T. W. Archs Neurol., Chicago, 1967, 17, 137. 6. Gordon, N., Hilson, D. Br. J. clin. Pract. 1967, 21, 537. 7. Harper, P. S. D.M. thesis, Oxford University, 1971. 8. Harper, P. S., Rivas, M., Bias, W. B., Hutchinson, J. R., Dyken, P. R., McKusick, V. A. Am. J. hum. Genet. (in the press). 9. Krull, G., Leijnse, B., de Vlieger, M., Vietor, W. P. J., Ter Braak, J. W. G. Lancet, 1966, ii, 668. 10. Winer, N., Klachko, D. M., Baer, R. D., Langley, P. L., Burns, T. W. Science, 1966, 153, 312. 11. Fisch, R. O., Walter, W. A., Anderson, J. A. Pediatrics, Springfield, 1966, 37, 979. 12. Stevenson, R. E., Huntley, C. C. ibid. 1967, 40, 33. 4. 5.

" ... the rearing of children is a stressful task. It has been rendered more difficult by certain features of modern society. True, life not so long ago was more precarious: women often died in childbirth; children died in such numbers that the coffin was as familiar as the cradle. But child-rearing was less stressful when there was rarely change; when families lived for generations in the same place; when there was a generally accepted religious framework to life. How different it all is now. The old certitudes have gone. The beliefs and the sanctions which accompanied the beliefs have dwindled. The support of a stable community has mostly gone. The parents and children are on their own in a small family unit. The unit has to bear a burden of child-rearing which used to be shared by relatives and neighbours. Early marriage, accompanied by higher breakdown rates; inadequate housing; the severe social restriction and loneliness often suffered by isolated young mothers-all these produce strain upon the family system. "-Sir KEITH JOSEPH, speaking in London on

June

29.

Total hæmolytic

complement activity (C.H.) and the concentration of the third component of complement (C3) were measured in 134 patients with glomerulonephritis. 21 patients were found to have increased C.H. activity. 13 of Summary

these and 37 others had a raised serum-C3 concentration. Four years later a much-increased mortality was noted in those patients who had had a raised C.H. It is emphasised that a raised C.H. has (P<0·01). been defined as above two standard deviations from the mean normal control values. Increase in the serum-C3 concentration had no apparent prognostic

significance. Introduction

THERE is considerable evidence for an immunopathological basis for many forms of glomerulonephritis.1 The fall in serum hsemolytic activity which may occur in an acute nephritis and the observation of altered forms of the complement component C3 on analysis of sera from such patients 2 suggest the participation of complement in the immunological reaction. Since Lange et al.noted persistent reduction in the levels of hxmolytic complement in a group of patients with nephritis and showed that these subjects had a poor prognosis, attention has been focused upon hypocomplementaemia in nephritis. Reduced serumcomplement is characteristically associated with acute post-streptococcal nephritis,* acute exacerbation of lupus nephritis,5 and membranoproliferative nephritis.g However, normal serum levels of the third component of complement have been recorded in some cases of acute nephritis 7; these observations were within a few days of onset of the renal lesion and do not appear to reflect the transient depression usually found in this condition. Not all patients with membranoproliferative nephritis and initial hypocomplementxmia remain hypocomplernentaemic.8* No comment has been made on the finding of raised levels of serum-complement in patients with nephritis. We discuss here our findings from 134 glomerulonephritics, studied first between June, 1967, and April, 1968, and again between December, 1971, and January, 1972. Many of our patients were found to have raised levels of haemolytic complement or the third component of complement, or both. Materials and Methods

Controls

Blood-samples from 57 healthy hospital and laboratory staff, aged 17-67 years, were used to define normal concentrations of both hxmolytic complement and the third component of complement. Blood was also taken from 12 patients with polycystic renal disease. *

Present address: Medical Unit, Westminster Hospital, London S.W.1.

56 Patients 134 nephritic patients seen in the outpatient clinic or wards were sampled without selection. All patients had percutaneous renal biopsies performed. In all patients complement was measured by the following methods: 1. Total hcemolytic complement (C.H.).-Blood was allowed to clot at 37 °C. It was then centrifuged, and aliquots of serum were frozen in solid carbon dioxide and stored at -60°C until assay. The haemolytic complement was measured by the method of Mayerand expressed as 50% hasmolytic units (c.H. so). 2. Third component of complement (C3).-Serum was stored at - 20°C and before assay allowed to stand at room temperature for six to ten hours. C3 was measured by the single radial diffusion method,lo each sample being assayed in quadruplicate and the mean value taken. * Immunoplates ’ (Baxter Laboratories) were used. All sera were assayed within four months of collection.

Results

Control Values of Serum-complement The mean total haemolytic complement for all the normal subjects was 44 C.H. 50 units per ml. For the male controls the value was 46 C.H.5o units per ml. and for the females 41 C.H’5ounits per ml. The range ±2 S.D. for all the controls was 25-63 units. The mean value for the third component of complement was 140 mg. per 100 ml.; the range ±2 S.D. was 100180 mg. per 100 ml. The levels obtained from patients’ sera outside the second standard deviation values were taken as pathological. The results for c.H. and C3 in the serum taken from the 12 patients with polycystic renal disease fell within the normal range. The plasma-creatinine of these patients lay between 1-7 and 22-0 mg. per 100 ml. One of these patients was being treated by chronic

dialysis. Complement Values in Patients at Original Sampling Of the 134 patients with glomerulonephritis sampled between July, 1967, and April, 1968, 75 had normal c.H. and C3 concentrations, 58 had raised c.H. or C3 or both, and 1 had no detectable c.H. activity in his serum, the serum C3 concentration being 28 mg. per

PROGRESSIVE-RENAL-FAILURE DEATHS IN 134 PATIENTS GROUPED ACCORDING TO C.H. AND c3 CONCENTRATIONS IN 1967-68

in whom c.H. and C3 concentrations were normal, 22 had died. 15 of these 22 deaths were due to renal failure. The renal function, judged by plasma-creatinine, of the remaining 53 patients had deteriorated in 5, improved in 1, and remained normal in 43 (fig. 1). In 4 patients follow-up has not been possible. Of the 21 patients in whom c.H. was raised, 15 had died-13 of them from renal failure. Of the remaining patients, kidney function had remained normal in 1 and had deteriorated in 1; and 1 was lost to follow-up. Of the 37 patients with an elevated C3 alone, 5 had died-3 from renal failure. 2 of the remaining 37 patients had improved, their plasma-creatinine now being within normal limits. In the remaining patients in this group renal function had continued to be normal. In the 13 patients in whom both c.H. and C3 were raised, 9 had died-8 from renal insufficiency. Of the remaining 4, 1 had developed advanced renal failure. The accompanying table shows the deaths from renal failure of the patients grouped according to their c.H. and C3 concentrations in 1967-68. Fig. 2 shows the plasma-creatinine measured in 1967-68 and again in 1971-72 in those patients who had raised c.H. or C3 or both when first sampled.

100 ml. Of the 58 patients with increased c.H. or C3, 21 had an increase in c.H. and 50 had an increased C3. In 13 of the 58 patients both c.H. and C3 were increased.

Mortality of Patients 4-4! Years after Initial Sampling After four to four-and-a-half years, of the 75 patients

Fig. 1-Plasma-creatinine in 1967-68 and in 1971-72 in those patients in whom both C.H. and C3 were normal in 1967-68.

Fig. 2-Plasma-creatinine in 1967-88 and in 1971-72 in those patients in whom either C.H. or C3 or both were raised in 1967-68.

57 The

one

hypocomplementasmic patient is being

treated by chronic dialysis. The difference between patients with normal c.H. levels (mortality-rate 20%) and those with a raised c.H.

(mortality-rate 63%) is statistically significant: test using the 4-fold table for small

p<0’01 by the x2 numbers.

Re-measurement of C.H. and C3 at End of Follow-up Period In 52 patients c.H. and C3 were re-estimated during the period December, 1971, to January, 1972. In 4 patients C3 was found to be raised, and in 3 of these patients C3 had been raised in 1967-68. In none of the 52 patients was C.H. raised.

Histological Findings The microscopic

appearance of the kidney was assessed in all cases. 13 patients had no abnormality of the glomeruli; the other 121 had various forms of proliferative glomerular lesions. Within this group 7 biopsy specimens were identified as showing the histological changes which have been described as 11

hypocomplementasmic persistent glomerulonephritis or membranoproliferative glomerulonephritis.6 Only 1 of these patients had hypocomplementaemia, 1 had raised C.H. and C3; and 3 others had isolated raised C3. No constant relationship was found between the histological type of glomerulonephritis and the c.H. and C3 levels. Discussion

In contrast to the previous interest in low complelevels in glomerulonephritics, we have found raised c.H. or C3 or both in a considerable proportion of patients with glomerulonephritis. A raised c.H. has been found to be of serious prognostic signifiWe suggest that an increased c.H. or C3 cance. concentration follows immune involvement of the kidneys. It is known that after a period of increased complement consumption in vivo, the synthesis of protein for the complement cascade can be accelerated 12a and a state of overproduction may develop. Possibly such overproduction may persist as suggested by our findings of increased C3 concentration in some subjects upon two occasions separated by four to fourand-a-half years. The increased mortality in our patients with a high C.H. compared with those in whom the c.H. was normal is statistically significant. Taken simply as an empirical finding, this may be useful as a guide to prognosis. If therapeutic measures to reduce complement levels over a long period can be found, their ability to improve the outlook in these patients could be determined by a long-term trial. It would be easier to plan such a trial and to assess its likelihood of success if more were known about the mechanisms leading to a ment

high c.H. A complement-inhibiting factor in the serum of some patients with acute post-streptococcal and some forms of chronic nephritis has been described. 13 Probably the same factor is that acting on C3 described by Spitzer et al.14 in the serum of patients with hypocomplementaemic glomerulonephritis. It is not known

whether the effect on C3 activates the remaining complement components, so allowing further renal damage to occur, or whether by destroying C3 the factor prevents complement activity. If the factor were a protective response, its absence could explain the relation between high C.H. and high mortality in our series. This point needs further investigation. There is some suggestion from the figures that patients with a raised C3 do better than those without, but that this effect is swamped by the adverse influence of a raised c.H. Because of the small numbers involved it is probably best to assume for the present that raised C3 levels have no prognostic value and to reconsider the problem when more data are available. The striking finding of the serious prognostic significance of a raised serum-c.H. concentration is no longer evident if the limits of normality are reduced to one standard deviation from the mean. Possibly our stringent criterion of raised c.H. accounts for the failure of other workers to remark on this finding. REFERENCES

1. Unanue, E. R., Dixon, F. J. Adv. Immun. 1967, 6, 1. 2. Soothill, J. F. Clin. exp. Immun. 1967, 2, 83. 3. Lange, K., Wasserman, E., Slobody, L. B. Ann. intern. Med. 1960, 53, 636. 4. Gotoff, S. P., Fellers, F. X., Vawter, G. F., Janeway, C. A., Rosen, F. S. New Engl. J. Med. 1965, 273, 524. 5. Gotoff, S. P., Isaacs, E. W., Muehrcke, R. C., Smith, R. D. Ann. intern. Med. 1969, 71, 327. 6. Cameron, J. S., Glasgow, E. F., Ogg, C. S., White, R. H. R. Br. med. J. 1970, iv, 7. 7. Tina, L. U., D’Albora, J. B., Antonovych, T. T., Bellanti, J. A., Calcagno, P. L. Am. J. Dis. Child. 1968, 115, 29. 8. West, C. D., McAdams, A. J. Nephron, 1970, 7, 193. 9. Mayer, M. M. in Experimental Immunochemistry (edited by E. A. Kabat and M. M. Mayer). Springfield, Ill., 1961. 10. Mancini, G., Carbonara, A. O., Hermans, J. F. Immunochemistry, 1965, 2, 235. 11. West, C. D., McAdams, A. J., McConville, J. M., Davis, N. C., Holland, N. H. J. Pediat. 1965, 67, 1089. 12. Petz, L. D., Fink, D. J., Letsky, E. A., Fudenberg, H. H., MullerEberhard, H. J. J. clin. Invest. 1968, 47, 2469. 13. Pickering, R. J., Gewurz, H., Good, R. A. J. Lab. clin. Med. 1968,

72, 298. 14. Spitzer, R. E., Vallota, E. H., Forristal, J., Sudora, E., Stitzel, A., Davis, C. D., West, C. D. Science, 1969, 164, 436.

EARLY MOBILISATION AND DISCHARGE OF PATIENTS WITH ACUTE MYOCARDIAL INFARCTTON D. MCC. BOYLE M. BARBER M. J. WALSH J. N. C. CHATURVEDI G. SHIVALINGAPPA Cardiac Department, Ulster

Hospital, Dundonald, Belfast

of a mobile coronaryunit in addition to a hospital coronary-care unit (C.C.U.) increases the demand for monitoring facilities and convalescent beds. Early mobilisation and early discharge of patients not at risk is therefore important. The results of such a policy in patients with acute myocardial infarction admitted to a C.C.U. are reported. 18% of patients were discharged by the seventh day, and 62% spent ten

Summary

The

operation

care

days or less in hospital. The subsequent mortality and readmission-rate suggest that early discharge was not harmful. Factors which predicted the risk of dying