Identical 3-year-old Twins with Disseminated Lupus ErythematosusOne with Nephrosis and One with Nephritis.код для вставкиСкачать
Identical 3-year-old Twins with Disseminated Lupus Erythematosus: One with Nephrosis and One with Nephritis By ELLINLIEBERMAN, EVAHEUSER, VIRGILHANSON, HELENKORNREICH, GEORGEN. DONNELL, AND BENJAMIN H. LANDING Sis ( SLE ) hn uncommon disorder in young children and is rarely considered as an explanation for renal disease in this age group. Although there are many reports of disseminated lupus in identical twins, none of these has concerned children.'"' The present report has a twofold purpose: the description of SLE in 3-year old identical twins with differing renal and immunologic involvement and, secondly, the description of the response of a critically ill child with lupus nephrosis to immunosuppressive therapy. YSTEMIC LUPUS ERYTHEMATOSUS CASEDESCFUPTION Patient No. 1. A 3-year old Mexican-Filipino girl had always been in good health and had not received drugs for any prolonged period. Seven months prior to admission to Childrens Hospital of Los Angeles she developed a flat, red rash on the soles of the feet and the palms of her hands. Arthritis, enlarged lymph nodes and lethargy were noted during the following months. Prednisone (15 mgm. daily) From the Departments of Pedkrtrics and Pathology, University of Southern California School of Medicine and the Childrens Hospital of Los Angeles. Supported in part b y the United States Public Health Service (FR 86) and in part b y the Las Madrinas Fund of the Childrens Hospital of Los Angeles. ELLINLIEBERMAN, M.D.: Assistant Professor of Pediatrics; Southern California School of Medicine and Associate Attending Physician, Childrens Hospital of Los Angeles. EVA HEUSER,M.D.: Assistant Professor of Pathology; C'outhern California School Olf Medicine and Associate Pathologist, Childrens 22 was given for 3 months preceding admission. Dermatologic consultation was sought because of thinning hair. Generalized edema insidiously developed, with the feet, face and abdomen particularly involved. On April 29, 1965 she was referred to Childrens Hospital of Los Angeles for further evaluation and management. Family history revealed an identical twin with evidence of disseminated lupus for the preceding two months (Patient No. 2). Six siblings, the parents and paternal grandparents had a negative history for collagen disease and normal serum protein electrophoresis, uric acid and antinuclear factor determinations ( ANF ) . A paternal great uncle died with diabetes mellitus and renal disease and another with chronic glomerulonephritis. The post mortem findings of the latter were consistent with chronic glomerulonephritis with marked foam cell involvement. Physical examination revealed a Cushingoid, dark skinned 3-year-old girl with moon facies, distended abdomen, anasarca, and an erythematous rash on the soles and palms. She was photographed at the time of admission with her twin (Fig. 1). A rash was also present on the cheeks and the bridge of the nose. Additional findings included moderately large, soft, movable cervical nodes. The physical and laboratory findHospital of Los Angeles. Vmcn. HANSON,M.D.: Associate Professor of Pediatrics; Southem California School of Medicine and Medical Director, Childrens Hospital of Los Angeles Rehabibtion Center. HELEN KOIINREICH, M.D.: Instructor qf Pediatrics, Southern California Schod of Medicine and Associate Attending Physician, ChiMrens Hospital of Los Angeles. GEORGEN . DONNELL,M.D.: ProfesEor of Pediatrics; Southern California School of Medicine and Assistant Physician-in-Chief, Childrens Hospital of Los Angeles. BENJAMINH . LANDING,M.D.: Professor of Pathology and Pediatrics; Southern California School of Medicine and Director of Laboratories and Pathologist-in-Chief, Childrens flozpital of Les Angeles. ARTHRITIS AND RHEUhIATIShf, VOL. 11. NO. 1 (February 1968) IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS 23 Fig. 1.-Patient No. 1 on the right and her twin, Patient No. 2 on the left a t the time of admission, April 29, 1965. ings of each twin at the time of admission are summarized in Table 1. A 12-hour Addis count was as follows: Total volume 48 ml. 6.0 PH Specific gravity 1.018 Protein 800 mg./100 ml. Red blood cell-total 6,528,000 White blood cell-totnl 1,824,000 Casts-total 5,128 white blood cell red blood cell 31,968 coarse granular 42,624 waxy 10,656 The results of erythrocyte blood grouping were as follows: A B C D E c e K Fy" Twin No. 1: - Twin No. 2: - - ++++--+ ++++--+ Dermatoglyphic patterns showed similarities in the finger tip couplets and palmar ridge patterns. Course in the hospital. Her clinical course is illustrated in Fig. 2, and was initially characterized by persistent and gradually increasing edema and hypertension' and constant proteinuria despite prednisone (40 mg. daily), chloroquine (200 mg. daily), diuretic and antihypertensive therapy. A renal biopsy, obtained surgically on the loth day of hospitalization, is described below. Generalized seizures occurred on the 33rd and 34th hospital days when she was still severely edematous and her blood pressure was 165/120. Subsequently, increased antihypertensive therapy ( alpha methyldopa, guanethidine and hydralazine) was required. Throughout the month she remained critically ill and massively edematous with intermittent respiratory distress. Morphologic variation of erythrocytes was noted but the Coombs' test remained 24 LIEBERMAN ET AL. Table 1.-Laboratory Patient No. I Findim Hypercorticism Anasarca Rash Facial Peripheral Lymphadenopathy Hepatosplenomegaly Arthritis Alopecia Blood pressure Hemoglobin (gm/lOO ml) Leukocyte count Sedimentation rate (mm/hr) Proteinuria Hematuria BUN (mg/100 ml) q / G ratio (gm/lOO ml) Cholesterol (mg/100 ml) LE Findings on Admission ++ ++ ++ - + (minimal) - ++ +/- 2 140/100 12 12,Ooo 41 4+ Many RBC, with casts Prep Antinuclear factor C-reactive protein Protein electrophoresis (gmJl00 ml) Total protein Albumin Alpha-I globulin Alpha-2 globulin Beta globulin Gamma globulin negative. Six weeks after admission ethacrynic acid was started. Within six hours a gradual diuresis began. One week later flaccid paralysis of the legs was noted. Although her weight had decreased moderately, she had not significantly improved despite substantial doses of prednisone for six weeks; therefore, eight weeks after admission, azathioprine (10 mg., 8 mg., and 6 mg./kg. for 2 days each, then 4 mg./kg. daily) was prescribed in addition to prednisone (100 mg./day for 7 days, then 60 mg./day for 21 days). Therapy with ethacrynic acid was continued to keep her edemafree. Gradual improvement took place over the next 2 months. After 3 months of immunosuppressive therapy a second renal biopsy (percutaneous) was obtained which is described below. Her muscle strength gradually improved and she was discharged on azathioprine, prednisone, antihypertensive therapy and ethacrynic acid. The dosage of these medications was gradually reduced and azathioprine was discontinued 6% months after discharge. Three months after discharge routine urinalysis and serum 54 1.9/1.4 745 - strongly Patient No. 2 + f 145/85 10.6 8,500 31 3+ 5-8 RBC/hpf 22 3.8/2.6 240 ++ + 3.1 1.3 0.2 6.3 3.8 0.2 0.7 06 0.5 0.6 0.4 1.1 chemistries became normal. She remained anemic. At no time has she had a positive LE cell preparation, or positive nuclear fluorescence ( ANF). Followup studies (12-18 months after admission) are compared with those of her twin in Table 2. Patient No. 2. The less severely affected twin had been well until 2 months prior to admission when the mother noted swelling behind her ears, followed by a rash on the soles and palms. Despite cortisone therapy a flat, red rash appeared over the cheeks and bridge of the nose, her knees became swollen, and her hair became markedly thinner. She was admitted with her twin sister on April 29, 1965 (Fig. 1). Physical examination revealed a well developed, well nourished dark skinned 3-year-old girl in no acute distress. The signs of hypercorticism were minimal. Her physical findings and laboratory data are summarized in Tahle 1. Course in the hospital. The patient initially was treated with 15 mg. prednisone daily until an open renal biopsy was obtained on May 7, 1965 (9th 25 IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS PREDNISONE DIURETICS -:CHLOROTHIAZ IDE n CHOLESTEROL ............,............,'................ BUN MAY Fig. 2.-Course JUNE JULY AUGUST SEPTENBER OCTOBER I NWEMBER of the nephrotic syndrome in Patient no. 1. hospital day). Postoperatively, prednisone (60 mg. daily) and chloroquine (200 mg. daily) were given for one month. The chloroquine dose was then reduced to 100 mg./day. The dose of corticosteroids was changed to alternate days and then gradually tapered to 25 mg. every other day. She was discharged after 20 hospital days and then electively readmitted to the Clinical Research Center 8 months later for repeat studies. Physical examination showed signs of hypercorticism; no signs of active lupus were present. Laboratory data revealed a normal hemogram and urinalysis, with the exception of many leucocytes per high powered field and few erythrocytes per high powered field. A 12-hour Addis count revealed a total of 5,875,000 leucocytes and 2,750,000 erythrocytes. Serum chemical studies were within normal limits. A percutaneous renal biopsy was obtained without complications and is described below. She was discharged on chloroquine, 100 mg. daily and prednisone 20 mg. every other day. Four months later she developed a recurrence of her facial rash when exposed to sunlight but there were no associated signs or symptoms of reactivation of lupus. Periodic ophthalmologic examinations have not revealed any abnormality. Her laboratory studies obtained 12-18 months after admission are summarized in Table 2. PATHOLOGY Renal Biopsy 5/8/65 - Patient No. 1 (Fig. 3 ) The specimen contained 25 abnormal glomeruli. Five glomeruli showed prominent cellular crescents. All glomeruli showed centrilobular cellularity and three resembled those of chronic hypertrophic glomerulonephritis with hyalinized balls replacing the lobules. Most of the glomeruli 26 LIEBERMAN ET AL. Table 2.-Summary of Laboratory Findings 12-18 Months After Admission Patient No. 1 Findings Hemogram: Hemoglobin (Gm/100 nil.) WBC Sedimentation rate (mm./hr.) Patient No. 2 12.8 7,400 12 Antinuclear factor:* 10.0 7,300 16 - Routine urinalysis: Specific gravity Protein WBC/hpf RBC/hpf 1.023 0 0-3 rare 1.024 0 0-2 0 Serum chemistries: BUN (mg./100 ml.) Creatinine (mg./100 ml.) Cholesterol (mg./100 ml.) 14 0.3 132 15 - 6.4 4.2 0.2 6.0 4.2 0.2 0.5 0.4 0.6 0.9 0.6 Protein electrophoresis: Total protein Albumin Alpha-1 globulin Alpha-2 globulin Beta globulin Gamma globulin - 119 0.7 *13 months after admission. showed evidence of inflammation, with neutrophils and with karyorrhexis in the glomerular tufts and with irregular but prominent fibrinoid thickening of basement membranes. The tubules were diffusely and mildly atrophic; hyaline and urate casts were present. The tubules were separated by fibrotic interstitial tissue in which focal accumulation of lymphocytes occurred. The intralobular arteries were thickened with hyaline medias but without obvious vasculitis. interstitial fibrosis and focal mononuclear round cell accumulations were present. A few very dilated tubules with hyaline casts were present; other tubules contained calcified urates and occasional red blood cell casts. A large intralobular artery was slightly dilated but cot otherwise remarkable. The increase in fibrosis and parenchymal atrophy with less evidence of active inflammation are the features which distinguish the second biopsy from the first. Renal Biopsy 517165- Patient No. 2 (Fig. 5 ) The biopsy contained 6 glomeruli and The second biopsy contained 20 glomer- consisted predominantly of medulla which uli, 5 of which were completely hyalinized. was not obviously abnormal. The glomeruli The remainder showed thickened hyaline all showed enlargement, centrilobular hyalobules with some centrilobular cellularity line thickening and cellularity with a few but without exudation. There were adhe- neutrophils and basement membrane sions but no proliferative crescents, and thickening without fibrinoid necrosis, exthick basement membranes which ap- cept for one glomerulus. There were no peared hyaline rather than fibrinoid. Focal crescents. Bowman’s spaces contained Renal Biopsy (Fig. 4 ) 1011165-Patient No. 1 27 IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS Fig. ?-Renal biopsy No. 1, 5/8/6%Patient No. 1: Initial biopsy of the renal cortex illustrates the variable extent of glomerular involvement, with both glomeruli showing largely centrilobular hypercellularity, with karyorrhexis and irregular thickening of the peripheral basement membranes. The glomerulus on the right also shows an early cellular crescent (H & E X 300). granular eosinophilic debris. There was some medial thickening of intralobular and afferent arterioles. The glomerular involvement was of similar extent and severity in all the glomeruli, although it tended to be somewhat segmental within any given glomerulus. The interstitial tissue surrounding the most severely involved glomerulus showed a minimal increase of fibrous tissue and infiltration by a few mononuclear cells. otherwise normal. The afferent arterioles and tubules were within normal limits. DIsCUssioN In 1960 Cook et al.5 described 37 patients with systemic lupus erythematosus who were all four years of age or older at the time of onset. More recently, Duboise mentioned three children between 0 and 4 years of age without giving any clinical deRenul Biopsy 11I66 -Patient No. 2 tails. Peterson et al.' included one child who was four years of age at the time of (Fig. 6 ) onset. These twins are the only patients The second biopsy contain3d 18 glomer- seen at Childrens Hospital of Los Angeles uli. All showed slight centrilobular cellu- whose illness began earlier than five years larity and thickening, and slight basement of age.s Therefore, these 3-year old twins membrane thickening. An occasional glo- represent the youngest reported patients merulus showed pericapsular fibrosis and with SLE with the exception of one newa few synechiae. The interstitium was born with congenital SLE? 28 LIEBERMAN E T AL. Fig. 4.-Renal biopsy No. 2, 10/1/65-Patient No. 1: Hyaline changes in capsule and tufts of the glomerulus at the right and some centrilobular cellularity in both. Some increase in interstitial fibrosis is also shown ( H & E X 300). The probability that these children are ial discoid and systemic lupus and kinmonozygous twins is supported by their ap- ships with an increased incidence of autopearance, their sex, by identical major and immune disease, asymptomatic hypergamminor red blood cell groups and by their maglobulinemia, positive ANF or LE cell dermatoglyphic patterns. No information preparations have been rep~rted.~':'~In Concerning the placenta was available. the relatives of these twins ( 6 siblings, 2 Skin grafting was not done. The occurrence parents and 2 paternal grandparents) none of SLE in these twins thus suggests the had a history suggestive of autoimmune possibility of a genetic influence, even disease, laboratory evidence of hypergamthough environmental factors may have maglobulinemia, or positive ANF. had a critical role. Several case reports atThe absence of antinuclear antibody in test to the frequency of concordance of Patient No. 1 raises the question as to SLE in twins and, thus, create a statistical whether she had SLE. Clinically she met bias in favor of identical t w i n ~ . l A - ~recent the criteria proposed by Bywaters15 and report, however, emphasized the occur- Dubok6 All patients seen at Childrens rence of SLE in one twin and multiple Hospital of Los Angeles with florid disease sclerosis in another.1° Data concerning had positive ANF determinations regardlupus in discordant twins is not available. less of prior therapy. The hypogammaIt is less probable that these twins were globulinemia (0.4 Gm. per cent) might dizygous and had a predisposition to SLE have resulted in antibody depletion and a because of some familial tendency. Famil- negative test for nuclear fluorescence. In 29 IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS Fig. 5.--Renal biopsy No. 1, 5/7/65-Patient No. 2: Initial biopsy of Patient No. 2 showed enlarged glomeruli with centrilobular hyaline thickening and cellularity, including a few neutrophils and karyorrhectic nuclei (H & E X 350). our experience antinuclear antibody titers Although the course of SLE has been inhave decreased as the patients improved fluenced favorably by antibiotics, antimaand, therefore, it is not surprising that this larials and steroids, the presence of clinical patient did not develop a positive ANF renal disease, especially the nephrotic syndetermination later. The course of disease drome, is generally regarded as of grave in the less severely affected twin was simi- i m ~ 0 r t . l If ~ hypertension and azotemia lar although less severe, without evidence were additional findings, most authors reof gamma globulin depletion. Both the LE garded the outlook as dismal prior to the cell preparation and ANF determination use of high dose steroid therapy. The literwere positive at the time of admission and ature most often cited refers to adult pabecame negative with clinical recovery. tients, but the few pediatric reports reflect Table 3.-Antinuclear Factor and Latex Fixation Tests Antinuclear Patient F- Date Latex Fixation Patient No. 1 1%5 : 4/30,6/29, 7/15, 8/11 1966: 6/28 (All negative) (All negative) Patient No. 2 4/30/65 5/28/65 1/14/66 6/28/66 + undiluted + undiluted 1 :32 negative negative negative nemtive negative 30 LIEBERMAN ET AL. Fig. 6.- Renal biopsy No. 2, 1/18/6&Patient No. 2: Slight centrilobular prominence and cellularity and occasional synechiae in two glomeruli. The surrounding parenchyma is normal (H & E X 350). similar conclusion^.^^^ The effect of high The patient described above (Patient dose steroid therapy in advanced renal dis- No. 1) had remained desperately ill deease with and without the nephrotic syn- spite very large doses of prednisone and drome is generally regarded as favorable therefore the decision was made to give 5,7~17 although notable exceptions exi~t.1~her a trial of immunosuppressive therapy, Pollak et al. reported that 13 of 16 patients based on the optimistic results of Kellum,20 treated with low doses of steroids died Vernier,2l Michael,= and ad am^.^^ In with renal failure, whereas only 13 of 31 this patient with “steroid resistance” (i.e., treated with high doses died with renal no response to steroid therapy in high dosfailure.ls These authors also described the age for six weeks) the achievements of imoutcome in terms of the initially observed munosuppressive therapy were dramatic. renal histology. Of 47 patients with histo- She remains in clinical and chemical relogic lupus glomerulonephritis, 26 died mission with the exception of recently with renal failure and 23 of these had the noted mild proteinuria (23 months after nephrotic syndrome. In contrast, of 23 pa- admission). This experience is not unique; tients with lupus glomerulitis only 2 died Vernier,21 G r ~ p e *and ~ KellumZ0have rewith renal failure.Is Changes in histology ported patients with extensive renal inin the first and second biopsies from both volvement, with or without the nephrotic our patients are consistent with Pollak‘s syndrome, in whom immunosuppressive findings and again illustrate the dissoci- therapy has induced a remission or marked ation of severity and activity of renal le- clinical improvement. sions. 31 IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS ACKNOWLEDGMENTS Ethacrynic acid - “Edecrin”@ was supplied by Robert Dengler, M. D. of Merck Sharp and Dohme, Inc. Azathioprine - “1muran’”B was supplied by Donald S. Searle, Ph.D., M.D. of Burroughs Wellcome. The authors are grateful to Dr. John R. Alniklov for referral of these patients, to Dr. Robert Vernier for his suggestions concerning immunosuppressive therapy and to Dr. Harold H. Edelbrock for obtaining the renal biopsies. SUMMARY Twin 3-year old girls with SLE are described. They are the youngest reported patients with SLE and the only twins with SLE in the pediatric age group. Patient No. 1 had the nephrotic syndrome, hypertension and azotemia. She was treated with immunosuppressive therapy (azathioprine and prednisone) and gradually improved. Immunologic tests for SLE remained negative throughout her illness. Two renal biopsies (with a five-month interval) are described and the dichotomy between the clinical improvement which ultimately was dramatic and severe renal scarring is described. The less severely affected twin had classical features of SLE with nephritis; her LE cell preparation and ANF determination were positive initially. Two renal biopsies (with an eight month interval) are described. Therapy consisted of chloroquine and prednisone; she has been asymptomatic .except for recurrence of facial rash on one occasion following exposure to sunlight. SUMMARIOIN INTERLINGUA Es describite un par de geninas identic de tres annos de etate con signos classic de disseminate lupus erythematose sed con dif€erente affectiones renal e immunologic. Gemina I esseva criticamente malade con nephrosis; remission clinic e chimic esseva inducite per un therapia immunisuppressive. Gemina I1 habeva constatationes clinic e histologic de nephritis. Es describite Ie tractamento, biopsias renal, e le responsa clinic. REFERENCES 1. Davis, M. W., and Gutridge, G. H.: Dis- 2. 3. 4. 5. 6. seminated lupus erythematosus in identical twin sisters associated with diabetes mellitus in one case. J. Missouri Med. Ass. 48:446, 1951. Blumenfeld, H. G., Kaplan, S. B., Mills, D. M., and Clark, G. M.: Disseminated lupus erythematosus in identical twins. J.A.M.A. 185:667, 1963. Wagenhals, C. O., and Burgeson, P. A.: Systemic lupus erythematosus in identical twins. New York J. Med. 58:98, 1958. Joseph, R. R., and Zarafonetis, C. J. D.: Fatal systemic lupus erythematosus in identical twins; case reports and review of the literature. h e r . J. Med. Sci. 249:190, 1965. Cook, C. D., Wedgwood, R. J. P., Craig, J. M., Hartmann, J. R., and Janeway, C. A.: Systemic lupus erythematosus. Description of 37 cases in children and a discussion of endocrine therapy in 32 of the cases. Pediatrics 26:570, 1980. Dubois, E. L.: Lupus erythematosus: a review of the current status of discoid and systemic lupus erythematosusand their variants. New 7. 8. 9. 10. 11. 12. 13. York, McGraw-Hill Book Company, 1966, p. 479. Peterson, R. D.A., Vernier, R. L., and Good, R. A.: Lupus erythematosus. Pediat. Clin. N. Amer. 10:941, 1963. Hanson, V. and Kornreich, H.: Systemic rheumatic disorders (“collagen disease”) in childhood: lupus erythematosus, anaphylactoid purpura, dermatomyositis, and scleroderma. Part I. Bull. Rheum. Dis. 17:435, 1967. Nice, C. M., Jr.: Congenital disseminated lupus erythematosus. h e r . J. Roentgen. 86:585, 1962. Holmes, F. F., Stubbs, D. W., and Larsen, W. E.: Systemic lupus erythematosus and multiple sclerosis in identical twins. Arch. Intern. Med. 119:302, 1967. Brunjes, S.,Zike, K., and Julian, R.: Familial systemic lupus erythematosus. Amer. J. Med. 30:529, 1961. Steagall, R. W. Jr., Ash, H. T.,and Fentanes, L. B.: Familial lupus erythematosus. Arch. Derm. 85:394, 1962. Pollak, V. E.: Antinuclear antibodies in 32 14. 15. 16. 17. 18. 19. LIEBERMAN ET AL. families of patients with systemic lupus erythematosus. New Eng. J. Med. 271:165, 1964. Leonhardt, T.: Family studies in systemic lupus erythematosus. Acta Med. Scand. Suppl, 416, 176:1, 1964. Weir, D. M., Holborrow, E. J., and Johnson, C. D.: A clinical study of serum antinuclear factor. Brit. Med. J. 1:933, 1961. Muehrcke, R. C., Kark, R. M., Pirani, C. L., and Pollak, V. E.: Lupus nephritis: a clinical and pathologic study based on renal biopsies. Medicine 36:1, 1957. Smith, F. G., Jr., Litman, N., and Latta, H.: Lupus glomerulonephritis: the effect of large doses of corticosteroids on renal function and renal lesions in two children. Amer. J. Dis. Child 110:302, 1965. Pollak. V. E., Pirani, C. L., and Schwartz, F. D.: The natural history of the renal manifestations of systemic lupus erythematosus. J. Lab. Clin. Med. 63:537, 1964. Rothfield, N. F., McCluskey, R. T., and Bald- 20. 21. 22. 23. 24. win, D. s.: Renal disease in systemic lupus erythematosus. New Eng. J. Med. 269:537, 1963. Kellum, R. E., and Haserick, J. R.: Mechlorethamine therapy for systemic lupus nephropathy. Arch. Derm. 87:289, 1963. Vernier, R. L., Tinglof, B., Urizar, R., Litman, N., and Smith, F. G., Jr.: Immunofluorescence studies in renal disease. Abstracts, International Congress of Nephrology, Washington, D.C., Sept. 25-30, 1966. Michael, A. F., Vernier, R. L., Dnunmond, K. N., Levitt, J. L., Herdman, R. C., Fish, A. J., and Good, R. A.: Immunosuppressive therapy of chronic renal disease. New Eng. J. Med. 276:817, 1967. Adams, D. A., Gordon, A., and Maxwell, M. H.: Azathioprine treatment of immunological renal disease. J.A.M.A. 199:459, 1967. Grupe, W. E., and Heymann, W.: Cytotoxic drugs in steroid resistant renal disease. A.M.A. Amer. J. Dis. Child. 112:448, 1936.