value of renal biopsy in the nephrotic syndrome in adults. Only one patient had a possible associated condition (mild

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1 31 ay 1969 Nehrotic Syndrome-Sharstone et al. BRITISH 535 Another suggestion to exlain the discreancy is that some atients in the resent series with mild membranous nehroathy have been included in the minimal change grou. This is very unlikely in view of the clinical resentation and course of the 15 atients allocated to the minimal change grou. All had highly selective differential rotein clearances (Cameron and Blandford, 1966) and normal renal function. Ten of these atients subsequently lost their roteinuria, either sontaneously or as the result of theray in the associated trial (Sharstone et al., 1969), and a further four showed great reduction in roteinuria with clinical imrovement; only one atient failed to resond to steroids at all. The ossibility remains, however, that there may be geograhical variations in the incidence of membranous nehroathy, and a number of clinicians have the imression from exerience on either side of the Atlantic that the condition is commoner in the United States than in England. Sex Incidence Even allowing for the difficulty in assessing renal histology just discussed, the sex ratios found in this survey were surrising. In children, a grou largely consisting of atients with minimal change histology, a rather constant male: female ratio of 2: 1 is found (Rothenberg and Heymann, 1957 Arneil, 1961). ost revious series of adult nehrotics have shown either equal sex incidence or a reonderance of males (Hetinstall, 1966;, though Pearl et al. (1963) also reorted an excess of females in their series, which consisted of 53 adults and children. Renal Amyloidosis Although the trial rotocol secifically excluded atients with evidence of multi-systern disease, it is of interest that six atients ( 7% of total) fulfilling the clinical and biochemical criteria for entry were found on renal biosy to have amyloidosis. This is in line with the incidence of 11 to 12% in other series of nehrotic atients (Berman and Schreiner, 1958; Blainey et al., 1960; axwell et al., 1964) and emhasizes the value of renal biosy in the nehrotic syndrome in adults. Only one atient had a ossible associated condition (mild bronchiectasis), but during the eriod of the survey biosy was carried out in a further three atients with amyloidosis, rheumatoid arthritis, and the nehrotic syndrome. This is in keeing with the finding of Brandt et al. (1968) of an equal incidence of the nehrotic syndrome in both rimary and secondary amyloidosis. This was a collaborative study, and the interest and work of large numbers of eole made it ossible. The consultant hysicians of the South-east etroolitan Region referred their atients to us and to them our thanks are due. Dr. J. S. S. Fairley of the Southeast etroolitan Regional Hosital Board and his colleagues gave us every facility and a financial grant to hel the survey. Dr. F. S. Goldby erformed some of the biosies, and r. J. Kaye And r. Gabriel Bankole carried out the biochemical estimations. The histological secimens were exertly rocessed by r. D. J. Ware, r. J. Osborne, and r. R. Francis. REFERENCES Arneil, G. C. (1961). Lancet, 2, 13. Berger, J., de ontera, H., and Galle, P. (1961). Archives d'anatomie Pathologique, 9, 313. Berman, L. B., and Schreiner, G. E. (1958). American Journal of edicine, 24, 249. Blainey, J. D., Brewer, D. B., Hardwicke, J., and Soothill, J. F. (1960). Quarterly Journal of edicine, 29, 235. Brandt, K., Cathcart, E. S., and Cohen, A. S. (1968). American Journal of edicine, 44, 955. Cameron, J. S. (1968). British edical Yournal, 4, 352. Cameron, J. S., and Blandford, G. (1966). Lancet, 2, 242. Hetinstall, R. H. (1966). Pathology of the Kidney, London. Hiller, A., cintosh, J. F., and Van Slyke, D. D. (1927). Journal of Clinical Investigation, 4, 235. Kark, R.., and uehrcke, R. C. (1954). Lancet, 1, 47. cgovern, V. J. (1964). Australasian Annals of edicine, 13, 306. axwell,. H., Adams, D. A., and Goldman, R. (1964). Annals of Internal edicine, 60, 539. Ogg, C. S., Cameron, J. S., and White, R. H. R. (1968). Lancet, 2, 78. Pearl,. A., Burch, R. R., Carvajal, E., ccracken, B. H., Woody, H. B., and Sternberg, W. H. (1963). Archives of Internal edicine, 112, 716. Robson, J. S. (1967). In Renal Disease, 2nd ed., edited by D. A. K. Black, Oxford. Rothenberg,. B., and Heymann, W. (1957). Pediatrics, 19, 446. Sharstone, P., Ogg, C. S., and Camaron, J. S. (1969). British edical Journal, 2, 535. Nehrotic Syndrome Due to Primary Renal Disease in Adults: II. A Controlled Trial of Prednisolone and Azathiorine P. SHARPSTONE,*.B.,.R.C.P.; C. S. OGG,t.D., B.SC.,.R.C.P.; J. S. CAERONt.D., B.SC.,.R.C.P. British edical Jozurnal, 1969, 2, Summary: A controlled trial in 20 adult atients with the nehrotic syndrome due to roliferative glomerulonehritis comared the effects of consecutive eight-week courses of treatment with rednisolone in conventional dosage and a low-dose azathiorine-rednisolone combination. Though the azathiorine regimen avoided serious toxicity and roduced a statistically significant imrovement in creatinine clearance and urine rotein excretion, the results were not significantly better than with rednisolone itself and overall were not of great clinical value. Prolongation of the azathiorine-redniso- *Lecturer in edicine, King's College Hosital edical School, London S.E.5. t Renal Physician, Guy's Hosital, London S.E.1. *Renal Physician and Senior Lecturer, Deartment of edicine, Guy's Hosital, London S.E.I. lone treatment to one year was associated with some small imrovement in the results. The effectiveness of rednisolone in the nehrotic syndrome of adults with minimal renal histological abnormality was confirmed by a comlete loss of roteinuria within eight weeks in six out of eight atients and substantial reduction in the other two. These two atients subsequently received azathiorine as well but with equivocal results. Introduction The value of corticosteroids in the treatment of adult atients with the nehrotic syndrome is small because this is largely confined to those with mild or minimal lesions of the glomeruli

2 ay 1969 Nehrotic Syndrome-Sharstone et al. (Blainey et al., 1960 ; Nesson et al., 1963 ; Pearl et al., 1963; Jensen and Jensen, 1967; Cameron, 1968). The demonstration of some benefit from the use of cytotoxic and antimetabolite drugs in some atients with corticosteroid-resistant disease (White et al., 1966 ; Adams et al., 1967 ; ichael et al., 1967) is thus of great interest. The results of these investigations, though encouraging, were variable, the atients were selected according to varying criteria, and different drug regimens were used. Evaluation of the significance of these findings is difficult and the need for a controlled trial with statistical assessment of the results is clear (British edical fournal, 1966; New England 7ournal of edicine, 1967). The resent trial was designed to comare the short-term effect of rednisolone given in conventional dosage with that of rednisolone in lower dosage in combination with azathiorine in adult atients with the nehrotic syndrome due to rimary renal disease. Each atient received both treatments and thus acted as his own control. Relatively low dosage of azathiorine was used to minimize toxic effects and to test the ossibility of obtaining a useful result with a regimen suitable for outatient use. Azathiorine was chosen for initial trial because of greater revious exerience of its use in glomerulonehritis and in the field of translantation. Prednisolone in moderate dosage was given concurrently because of the ossibility of a synergistic action with azathiorine (ichael et al., 1967) and also for its ossible rotective effect against leucoenia (John, 1966). BRITISH EDICAL JOURNAL standardize other theraeutic measures such as duration of stay in hosital, diet, diuretics, or antihyertensive drugs. Assessment New atients were visited by one of us at the referring hosital, a note was made of the history and initial clinical and laboratory findings, and aliquots of three measured 24-hour urine collections and a lasma samle were taken. Renal biosy was carried out by the technique of Kark and uehrcke (1954). Classification of the renal histology was as described in the revious aer (Sharstone et al., 1969), and on notification of the result of this to the referring hysician the allocated treatment regimen was started. At the end of each of the three treatment eriods further lasma samles and aliquots of three 24-hour urine collections were requested. Chemical estimations were carried out centrally and results obtained for 24- hour creatinine clearance, urea clearance, and rotein excretion, all averaged over three days. In addition lasma 1,7globulin concentration and the selectivity of differential urine rotein clearances were measured on the initial samles. A note of the results of clinical assessment, serum roteins, urine rotein excretion, blood urea, and white blood count was made at twoweekly intervals for the first 16 weeks and two-monthly thereafter by the referring hysician on a form which was returned at the end of the trial. Design of the Trial For the urose of this trial the nehrotic syndrome was defined as roteinuria greater than 3 g./24 hours, serum albumin less than 3 g./0 ml., and oedema at the time of starting treatment or within two weeks of this. The other criteria for entering were: age over 14 years, absence of clinical or laboratory evidence of any multisystem disease with which the nehrotic syndrome may be associated (excet Henoch- Schonlein syndrome), and the absence of revious treatment with corticosteroid or other immunosuressive drug. Thirty-four atients satisfied the criteria for the trial and comrised the first 32 consecutive atients seen in a survey of the nehrotic syndrome in adults in the South-east etroolitan Region of England (Sharstone et al., 1969), lus two atients referred from outside this region. In three cases ermission for entry to the trial was withheld by the referring hysician and two atients did not receive the scheduled drug dosage. These five atients (all of whom had minimal change renal histology) are not considered further. Treatment Each atient was given consecutive eight-week courses of treatment with (1) rednisolone in conventional dosage and (2) lower dose of rednisolone in conjunction with azathiorine. Regimen 1 comrised rednisolone 60 mg. daily for three days, 45 mg. daily for seven days, then 20 mg. daily to eight weeks; and regimen 2 comrised rednisolone 20 mg. daily lus azathiorine 150 mg. daily for eight weeks. The order of treatments was randomized for atients allocated after renal biosy as roliferative glomerulonehritis or membranous nehroathy. Patients with minimal change lesions all receivcd rednisolone in the first instance. Patients whose urine became rotein-free-that is, negative or trace to Albustix on three consecutive days-at any stage left the trial (" cure "). After comletion of 16 weeks' treatment atients with ersisting roteinuria were treated for a further eight months with regimen 3, azathiorine 150 mg. daily in combination with a slightly lower dose of rednisolone-15 mg. daily. The atients remained under the care of the referring hysiciar s at their own hositals, and no attemt was made to Chemical ethods Creatinine was measured as dialysable JaflX--ositive chromogens by the standard AutoAnalyzer technique. Urea was measured by the diacetyl monoxime method by means of an AutoAnalyzer. Urine roteins were measured by the biuret method of Hiller et al. (1927). Serum albumin was measured on an AutoAnalyzer by the biuret method. C'3 comonent of comlement (/ 1,-globulin) was measured as /lk-globulin in aged sera or lasmas, the method of Ogg et al. (1968) being used. Differential rotein clearances were measured by the method of Cameron and Blandford (1966) and exressed as the ratio urinary Cig. /C transferrin. Results Twenty-nine atients entered the trial; 20 had roliferative glomerulonehritis of varying degrees of severity, eight had no or minimal histological abnormality, and one had membranous nehroathy. The renal biosy findings and initial features for the first two grous are given in Tables I and II, while the single atient with membranous nehroathy is not considered further. Proliferative Glornerulonehritis: Results after 8 and 16 Weeks Deaths.-Three atients died within 16 weeks of starting treatment. Case 4 entered the trial with chronic renal failure (blood urea 246 mg./0 ml., creatinine clearance 6 ml./min.) and died of uraemia two weeks later while on rednisolone. Case 6, known reviously to have had roteinuria, develoed the nehrotic syndrome after artial gastrectomy for duodenal ulcer; raidly reaccumulating ascites required eritoneal drainage, and he died while on rednisolone, two weeks after admission, from hyovolaemia in site of massive infusions of lasma exanders. Case 8 initially had severely imaired renal function and hyertension. Raid deterioration occurred during eight weeks on the azathiorine regimen, and she died after six weeks on rednisolone.

3 31 ay 1969 Nehrotic Syndrome-Sharstone et al. BRITIsH EDICAL JOURNAL TABLE I.-Initial Clinical and Laboratory Findings in 20 Patients with Proliferative Glomerulonehritis 537 Case No. - l l 1 F * ,, severe Renal Histology some crescents with sclerosis, acute exudative, severe; scarring and caillary wall thickening, acute exudative, resolving, severe, some crescents, severe with glomerulosclerosis, severe with glomerulosclerosis, severe, caillary wall thickening (membranoroliferative) =Proliferative glomerulonehritis. B.P. (mm. Hg) I Transferrin) -1~ 170/ / / / / /0 160/5 2/ /80 200/ /120 /1 190/ /90 130/90 140/80 140/90 190/90 190/90 /0 Toxic Withdrawal.-Case 14 was withdrawn from the trial after 13 weeks because of vomiting roduced by azathiorine. There had been no objective evidence of imrovement in his renal function on either of the regimens. No other significant side-effect of treatment occurred during this art of the trial. In most atients the white blood count remained within normal limits throughout, and in no case did the white blood count fall to below 5,000/cu. mm. TABLE II.-Initial Clinical and Laboratory Findings in Eight Patients with No or inimal Histological Abnormality Selectivity Plasma of Plasma Plasma Blood Choles- Case Sexe B.P. Proteinuria C'3 Albumin Urea terol No. g (mm. Hg) (CI2G/C (mg./ (g./ (mg./ (mg./ Trans- 0 ml.) 0 ml.) 0 ml.) 0 ml.) ferrin) / / / F / / / / F / " Cures."-The urine of two atients became rotein free. Case 5 had the histological icture of acute diffuse exudative glomerulonehritis (though oedema had been first noticed six months reviously) and lost his roteinuria within six weeks of entry to the trial while on the azathiorine regimen. Case 20, with a mild roliferative lesion, also started treatment with the TABLE III.-Results of Initial Renal Function Tests and Results with Proliferative Selectivity of Proteinuria (C I 2G/C Plasma C'3 (mg./0 ml.) Plasma Blood 1 Albumin Jrea Cholesterol (g./0 l.) (g/0 ml.) (mg./0 ml.) li..i * Nehrotic syndrome associated with anahylactoid urura. Plasma azathiorine combination and lost his roteinuria within six weeks. The results of investigations at the start and finish of each of the treatment eriods are given in Table III. Of the 14 atients who comleted both courses of treatment equal numbers received steroid alone as the first treatment as received the combined regimen first. The mean results before treatment and the mean changes after eight weeks on each of the treatment regimens are given in Table IV for the 14 comleted courses of rednisolone and for the 16 comleted courses of the combined treatment. The mean results of each investigation at the start of each of the treatment eriods did not differ significantly. A significant reduction in roteinuria occurred during both treatments, with a greater fall during azathiorine, but the difference between the effects of the two treatments was not statistically significant. Only azathiorine in combination with redni- 'solone resulted in a significant increase in creatinine clearance, which did, however, increase to a lesser extent with the steroid regimen. When the two treatments were comared no significant difference was found between them. Exclusion from analysis of the two atients whose urine became free from rotein resulted in loss of significance (P>0-05) of both the mean reduction of roteinuria (2-86 g./24 hours) and the increase in creatinine clearance (15-3 ml./min.) with the azathiorine-rednisolone combination. The mean urea clearances of the atients for whom this investigation was available did not change significantly with either treatment. after 8 Weeks', 16 Weeks', and 1 Year's Treatment in 20 Patients Glomerulonehritis Case Order of Initial Resultst Results at 8 Weekst Results at16 Weekst- Results at 1 Yeart No. Treatments* Proteinuria, Creatinine Ure-a Proein. Creatinine i Urea, Prtiu. Creatinine Clearance Clearance rotemuria Clearance Clearance Proteinursa Urea Poenra Creatinine (g./24 hr.) Clearance Clearance Poteir arance (ml./min.) (ml./min.) (g./24hr.) (mi./min.) (ml./min.) (g./24hr.) (l./min.) (ml./mln.) (g./24 hr.) (ml./min.) 1 Pred Pred * * Aza Prod Died after 2 Aza wee-s "Cured" Pred Aza. Died after 2 weeks Aza "Cured" at 4 months 9 Aza Died after 14 weeks 40 Pred Aza S Pred Prod Pred Toxic withdrawal at 13 weeks Aza Pred "CCured "at 8 montlh 17 Aza Prod Aza Toxic withdrawal at 6 months ao Aza "Cured " Pred. First eight weeks = on high dose rednisolone, second eight weeks on rednisolone lus azathiorine. Aza. =Treatments in reverse order. tean of three 24-hour urine collections. B Sex F F Age i 1.. I

4 ay 1969 Nehrotic Syndrome-Sharstone et al. Creatinine clearance (ml./min.) TABLE IV.-ean Pretreatment Results and ean Changes after Two Treatment Regimens in Patients with Proliferative Glomerukmoehritis Urine rotein excretion (g./24 hr.) Urea clearance (ml./mm.) High-dose Prednisolone Prednisolone + Azathiorine No. of Cases ean ± S.E. No. of Cases ean ± S.E. II i~ _ ± ± ± ± >P> ± ± >P>O ± ± ± ± >P>O ±6-6 S.E. = Standard error. P based on t test alied to aired differences between before and after treatment results in each atient. = P > Results at One Year The results after a further eight months' treatment with azathiorine and rednisolone are shown in Table III. By this time two further atients (Cases 7 and 16) had lost their roteinuria. Case 19 was withdrawn from the trial at six months because of cellulitis of the legs and buccal ulceration, but her white blood count at this time was 20,000/cu. mm. and robably these comlications were the result of her disease rather than the treatment. For the remaining 11 atients the mean aired change in creatinine clearance between 16 weeks and one year was ±-8 ml./min. (P>0-1) and the change in roteinuria was -2-6±0 95 g./24 hours (0-05>P>0-02). inimal Change Histology The urine of six of the eight atients in this grou became free from rotein within eight weeks of starting oft rednisolone, and in the other two cases there was a definite reduction (Table V). These two atients subsequently received azothiorine in addition, with a decrease in roteinuria in one and an increase in the other. Case 1 subsequently lost his roteinuria on continued treatment with the two drugs, while in Case 3 heavy roteinuria ersisted. Three of the remaining atients remained in remission to one year without further treatment, while the other three relased after stoing rednisolone and required further steroid treatment. TABLE V.-Results of Initial Renal Function Tests and Results at Eight Weeks, 16 Weeks, and Ofte Year in the Eight Patients with No or inimal Histological Abnormality Case No. i ean Remission in 4 weeks 16-8 Remission in 4 weeks Remission in 8 weeks Remission in 2 weeks Remission in 2 weeks Remission in 6 weeks Iean of three 24-hour urine collections. Lost roteinuria at 24 weeks Proteinuria 8-5 g./ 24 hr. at 1 year Relase Relase Relase Discssion Proliferative Glomerulonehritis Evidence had reviously been obtained In small numbers of atients of the ability of azathiorine, cyclohoshamide, and related drugs to influence the course of some atients with the BRITISH EDICAL JOURNAL Difference between the Two Regimens nehrotic syndrome due to roliferative glomerulonehritis. The results of earlier investigations were summarized by White et al. (1966), who themselves found a favourable resonse to azathiorine or cyclohoshamide, usually in combination with rednisolone, in 12 out of 18 atients, most of whom were children. Adams et al. (1967) and ichael et al. (196V), however, did not roduce imrovement with azathiorine and rednisolone in a total of six adult atients, though in some atients with glomerulonehritis unaccomanied by the nehrotic syndrome both grous obtained more encouraging results. The dosage of immunosuressive drugs used in all these studies was such as to cause serious toxic effects such as anaemia, leucoenia, gastrointestinal disturbances, and aloecia in a high roortion of cases. The dose of azathiorine used in the resent trial succeeded in avoiding these consequences in all but one atient. We have, however, seen serious leucoenia in another atient, not included in this trial, who had severely imaired renal function and was treated similarly. Another ossible longer-term side-effect of the immunosuressive treatment was the develoment of lymhosarcoma in Case 2. He died of heart failure due to endomyocardial fibrosis of the left ventricle eight months after finishing one year of treatment in the trial. Dysnoea and cardiac enlargement antedated the start of rednisolone and azathiorine, suggesting that the cardiac lesion was not a comlication of the treatment. Shortly before his death, however, inguinal lymh node enlargement was noted, and necrosy showed lymhosarcoma of inguinal and iliac lymh nodes. Though the develoment of a lymhoma after immunosuressive treatment may have been fortuitous in this atient, this association has been noted reviously. Reticulum-cell sarcomas have been reorted in three atients receiving azathiorine as well as other immunosuressive drugs after renal translantation (Doak et al., 1968; Woodruff, 1969), and in the exerimental field NZB and NZB/NZW mice have been shown to develo thymic lymhomas after the administration of azathiorine alone (Casey, 1968a, 1968b). The resent findings show a statistically significant mean increase in creatinine clearance and decrease in roteinuria in 16 atients with the nehrotic syndrome due to roliferative glomerulonehritis after eight weeks' treatment with azathiorine 150 mg. daily and rednisolone 20 mg. daily. With rednisolone by itself in a dose of 60 mg. daily reducing to 20 mg. daily over eight weeks the urine rotein excretion decreased significantly, but the increase in creatinine clearance was not significant, Though the results with the combined regimen were more favourable than with steroid alone, comarison of the two forms of treatment showed that this advantage was not significant. The.R.C. trial of corticosteroid theray in the nehrotic syndrome (Rose and Black, 1967) showed that some decrease in the quantity of roteinuria was foumd in adults with roliferative glomerulonehritis, equally in those who received corticosteroids and those who did not. In this situation of the resent trial, where both regimens aarently show an effect and no untreated grou is included, ! Il

5 31 ay 1969 Nehrotic Syndrome-Sharstone et al. BDImsH 539 the assumtion must be made that most or all of the imrovement is art of the natural history of the condition. Though our findings suggest that azathiorine for eight weeks in the dose used may have some slight favourable influence on the course of the disease, the clinical benefit to the atients was small, most of the atients still falling within our definition of the nehrotic syndrome after treatment. Of the two " cured " atients, one had the histological icture of acute glomerulonehritis and the other a mild glomerular lesion, and in both cases the ossibility of a remission occurring with steroid alone or without any treatment cannot be excluded. Investigation of a larger number of atients might imrove the statistical significance of the results, but it seems likely that our original hoe of roducing substantial benefit in the short term with relatively non-toxic doses of azathiorine and rednisolone will not be realized. The significance of the results of a further 36 weeks' treatment with the combined drugs is limited, since no controls were available for this eriod. Proteinuria was lost in two further atients and significantly reduced in the others. The mean fall in creatinine clearance during this time was not statistically significant, but ossibly deteriorating renal function accounted in art for the diminished roteinuria in the latter atients. Nevertheless, these results do erhas indicate that in future trials treatment eriods of longer than eight weeks' duration should be assessed. We cannot conclude from this study that imnmunosuressive or cytotoxic agents are without value in nehrotics with roliferative glomerulonehritis. Proliferative glomerulonehritis may comrise a variety of different conditions. The ossibility remains that the low-dose azathiorine treatment may be of value in some of the atients, such as those with mild lesions. Because of the small numbers in the resent trial, further subdivision of the atients was imossible, but this question may be answered by larger collaborative trials such as that currently being sonsored by the edical Research Council. A second ossibility is that larger doses of azathiorine may be effective. Our revious exerience (White et al., 1966) of the toxic effects of these higher doses renders this aroach too dangerous to be useful. Finally, a third ossibility is that another cytotoxic agent, such as cyclohoshamide or chlorambucil, might be effective. It is by no means certain that any of these agents act via their immunosuressive activity, and their success in this minimal change grou, where there is no evidence as yet of any immune disturbance, suorts this suggestion. At resent we are investigating the value of cyclohoshamide and chlorambucil in the grou of atients discussed in this aer. inimal Change Lesion Corticosteroid theray alone roduces remission of roteir.- uria in most children with the nehrotic syndrome and normal or minimal change renal histology (White, 1967; Cameron, 1968), and similar results have been obtained in the smaller number of adults investigated (Blainey et al., 1960; Nesson et al., 1963 Pearl et al., 1963; Jensen and Jensen, 1967; Cameron, 1968). Our results confirm that the overall oorer resonse to corticosteroid theray of the nehrotic syndrome in adults is due to the higher roortion of atients with severe glomerular disease in this age grou rather than to any difference in the resonse to corticosteroids between adults and children who have minimal lesions. The main roblems in the management of these atients are the grous who require unaccetably high doses of steroid for control (steroid resistant) or who relase frequently between course of treatment (steroid deendent). Cytotoxic drugs have been strikingly successful in children in this situation (White, 1967; Lagrue et al., 1967; oncrieff st al., 1969; Soothill of al., 1969). In most instances cyclohoshamide or chlorambucil was used. In adults little information is available for any cytotoxic agent in this grou. Whereas Adams et al. (1967) roduced remission in the two atients they treated with azathiorine and rednisolone, ichael et al. (1967) had a favourable resonse in only one out of three such atients. In the two atients in the resent trial who failed to lose roteinuria on rednisolone the addition of azathiorine for eight weeks was associated with a reduction in roteinuria in one and an increase in the other. This was a collaborative study, and the interest and work of large numbers of eole made it ossible. The consultant hysicians of the South-east etroolitan Region referred their atients to us, and to them our thanks are due. Dr. J. S. S. Fairley, of the South-east etroolitan Regional Hosital Board, and his colleagues gave us every facility and a financial grant. Dr. F. S. Goldby erformed some of the biosies, and r. J. Kaye and r. Gabriel Bankole carried out the biochemical estimations. The histological secimens were exertly rocessed by r. D. J. Ware, r. J. Osborne, and r. R. Francis REFERENCES Adams, D. A., Gordon, A., and axwell,. H. (1967). Yournal of the American edical Association, 199, 459. Blainey, J. D., Brewer, D. B., Hardwlcke, J., and Soothill, J. F. (1960). Quarterly Yournal of edicine, 29, 235. British edical Yournal, 1966, 2, 842. Cameron, J. S. (1968). British edical Yournai, 4, 352. Cameron, J. S., and Blandford, G. (1966). Lascet, 2, 242. Casey, T. P. (1968a). Clinical and Exerimental Immunology, 3, 305. Casey, T. P. (1968b). Blood, 31, 396. Doak, P. B., ontgomerle, J. Z., North, J. D. K., and Smith, F. (1968). British edical Yournal, 4, 746. iller, A., ackintosh, J. F., and Van Slyke, D. D. (1927). 7ournal of Clinical Investigation, 4, 235. Jensen, H., and Jensen, B. (1967). Acta edica Scandinavica, 182, 741. John, T. J. (1966). American Yournal of Diseases of Children, 111, 68. Kark, R.., and uehrcke, R. C. (1954). Lancet, 1, 47. Lagrue, G., Barity, J., Canlorbe, P., Vassal, J., and illiez, P. (1967). Presse idicale, 7S, ichael, A. F., et al. (1967). New England 7ournal of edicine, 276, 817. oncrieff,. W., White, R. H. R., Ogg, C S., and Cameron, J. S. (1969). British edical Yournaf, 1, 666. Nesson, H. R., Sroul, L. B., jun., Relman, A. S., and Schwartz, W. B. (1963). Annals of Internal edicine, 58, 268. New England Yournal of edicine, 1967, 276, 868. Ogg, C. S., Cameron, J. S., and White, R. H. R. (1968). Lancet, 2, 78. Pearl,. A., Burch, R. R. Carajal, E., ccracken, B. H., Woody, H. B., and Steinberg, W. H. (1963). Archives of Internal edicine, 112, 716. Rose, G., and Black, D. A. K. (1967). Quarterly 7ournal of edicine, 36, 607 (Abstract). Sharstone, P., Ogg, C. S., and Cameron, J. S. (1969). British edical Yournal, 2, Soothill, J. F., claine, P. N., Cottom, D. G., and Wolff, 0. H. (1969). Nehron (Abstract). In ress. White, R. H. R. (1967). Proceedings of the Royal Society of edicine, 60, White, R. H. R., Cameron, J. S., and Trounce, J. R. (1966). British edical Yournal, 2, 853. Woodruff,. F. A. (1969). Antibiotica et Chemotheraia. In ress.