Ann Rheum Dis: first published as 10.1136/ard.14.4.371 on 1 December 1955. Downloaded from Ann. rheum. Dis. (1955), 14, 371. HISTOLOGICAL AND CLINICAL EVOLUTION OF LUPUS NEPHRITIS*t BY ROBERT C. MUEHRCKE, ROBERT M. KARK, CONRAD L. PIRANI, VICTOR E. POLLAK, AND IRVING E. STECK From the Departments of Medicine, Presbyterian Hospital, Research and Educational Hospitals, and Cook County Hospital, Chicago, and the Department ofPathology of the University of Illinois College of Medicine (RECEIVED FOR PUBLICATION JUNE 23, 1955) In recent years, lupus nephritis has become the Methods major complication and the most pressing problem Selection of Patients.-34 patients with S.L.E. were in patients suffering from lupus erythematosus studied from the medical services of three hospitals. disseminatus. The clinical course of the disease The diagnosis was established in these patients by the was different 15 years ago, when Keith (1940) wrote characteristic findings listed in the Table. At least four not an clinical and four laboratory findings were present simul- by copyright. that "renal insufficiency does play important taneously in the same patient during the course of the role in causing death". At that time patients illness, and most of the findings listed were present at usually died of a "lupus crisis" or as a result of some stage of the illness. Hargraves's cells (Hargraves concurrent infection. However, the use of anti- and others, 1948) were found in the bone marrow or in biotics, blood transfusions, balanced water and the peripheral blood of thirty patients. In three of the electrolyte therapy, steroid hormone therapy, and four patients in whom Hargraves's cells were not found, injections of corticotropin has, apparently, pro- histological study of the skin revealed findings com- longed life in those afflicted with systemic lupus patible with L.E. of TABLE erythematosus (S.L.E.). With present methods DIAGNOSTIC CRITERIA USED IN THE SELECTION care many such patients can usually be kept free of OF PATIENTS ILL WITH SYSTEMIC http://ard.bmj.com/ symptoms for a considerable length of time, only LUPUS ERYTHEMATOSUS to succumb to a rapidly progressive renal failure. Because of the problems raised by the increased Clinical Laboratory of 1. Arthralgia and arthritis 1. Skin or renal biopsy com- incidence of lupus nephritis, a study the histo- patible with L.E. logical evolution of renal involvement in S.L.E. was 2. Fever 2. Hargraves's cells 3. Serositis 3. Leucopenia, anaemia, or begun, using serial percutaneous renal biopsies (Kark thrombocytopenia and 1954; Muehrcke and others, 1955a). 4. Dermatological lesions (face, 4. Urinary abnormalities Muehrcke, on September 24, 2021 by guest. Protected hair, nails, body surface, Histological data were correlated with changing mucous membranes) 5. Raynaud's phenomenon 5. Raised erythrocyte sedimen- clinical status, clinical laboratory data, and renal tation rate function tests in a continuing study of the patho- 6. Sensitivity to sunlight 6. Positive thymol turbidity test; other tests of liver physiology and natural history of lupus nephritis. function normal 7. Splenomegaly and/or hepato- 7. Increased serum globulin Preliminary observations have been reported else- megaly levels where (Pirani and others, 1954; Muehrcke and 8. Remissions and exacerbations 8. Positive serological tests for syphilis others, 1955b). This communication outlines some 9. Positive Coombs' test observations on 34 patients studied intensively during the past 18 months. Clinical and Laboratory Observations.-All patients * Supported in part by a grant from the United States Public were admitted to hospital for study and were followed Health Service, National Institutes of Health, Bethesda, Maryland (H-1029), and by a grant from Eli Lilly and Company, Indianapolis, in a special clinic. The following measurements were Indiana. made on admission, and these studies were repeated from t Presented at the annual general meeting of the American Rheu- matism Association, 1955. See p. 413 of this issue for discussion. time to time: 371 Ann Rheum Dis: first published as 10.1136/ard.14.4.371 on 1 December 1955. Downloaded from 372 ANNALS OF THE RHEUMATIC DISEASES Urine analysis and urinary cultures; describe this lesion because it refers to a disease Haematogram, including examination for Har- process which involves only a few glomeruli at any graves's cells; one time and never exists as a diffuse, widespread Study of bleeding and clotting mechanism; lesion involving all glomeruli. Determination of serum protein and cholesterol levels; As the patches of local hypercellularity in each X rays of kidney; glomerular tuft increased in size, the glomeruli Standard urea and creatinine clearance tests; became ischaemic, a few inflammatory cells appeared, Measurement of 15 min. excretion of phenol- and early necrotic changes and karyorrhexis were sulphonephthalein; noted in the patch of cells (Fig. 2-A). As the local Specific gravity concentration test; glomerulitis progressed, small fibrinous synechiae Measurement of 24-hr excretion of urinary protein; were seen bridging Bowman's space (Fig. 2-B) and Liver function tests, including measurement of joining the glomerular tufts to Bowman's capsule. serum cholinesterase; Later, dense fibrous adhesions replaced the syne- Measurement of blood urea nitrogen, non-protein the nitrogen, and creatinine. chiae. These histological findings simulated Discrete renal function tests were also done in a few lesions offocal embolic glomerulonephritis (Fig. 2-A). patients. As the lupus nephritis progressed, the patchy became more numerous and Percutaneous Renal Biopsies.-These were done with areas of hypercellularity the patient in a prone position. Details of the renal fused together to involve the whole glomerulus. biopsy technique have been described elsewhere (Kark More and more glomeruli became completely and Muehrcke, 1954; Muehrcke and others, 1955a). involved in the process. Eosinophilic thickening The cylinder of renal tissue was divided into two of the glomerular basement was also noted. Studies portions. The first portion-a small piece of tissue- with periodic acid fuchsin stain indicated that this was placed in beef broth culture medium which was later eosinophilic material was a mucopolysaccharide. examined for bacterial growth. The second and larger We have named the widespread involvement of portion was fixed in 10 per cent. neutral formalin in glomerular tufts in the process of endothelial saline. The sections were cut at 6 p and stained with proliferation, the "general glomerulitis" stage by copyright. of haematoxylin and eosin, periodic acid fuchsin, and Mallory stain. At times formalin fixed specimens were lupus nephritis (Fig. 3, opposite). frozen, cut, and stained with oil-red-O for lipids. In some patients, the hypercellularity was a A total of 61 percutaneous renal biopsies were done, prominent finding, while in others, fibrinoid thicken- usually when the patients were afebrile; 22 patients had ing of the glomerular basement membrane was much serial renal biopsies. No serious complications followed more striking, and endothelial cell proliferation was the biopsies. All the cultures of biopsy tissue in beef less marked. This stage of local fibrinoid thickening broth were sterile. Six patients in whom biopsies had of the glomerular capillary membrane is referred to been done died later, and autopsies were done on three as a "local membranous glomerulonephritis" (Fig. of them. 4-A, overleaf). http://ard.bmj.com/ Histological Evolution of Lupus Nephritis Baehr, Klemperer, and Schifrin (1935) originally The earliest detectable histological lesions in the described this histological picture and named it the tissue were found in the glomeruli. These con- "wire-loop" lesion. However, we agree with Allen sisted of minute foci of hypercellularity at the (1955) and Hass (1955) that the fibrinoid thickening periphery of the glomerular tufts (Fig. 1). These of the glomerular basement membrane is .more lesions were the result of endothelial cell prolifera- correctly named "membranous glomerulonephritis". tion and at times were associated with localized We wish to emphasize that the advanced "wire- on September 24, 2021 by guest. Protected fibrinoid changes in the glomerular basement loop" lesions seen in patients with florid S.L.E. membrane. At this stage of lupus nephritis the differ somewhat from the glomerular lesions seen in tubules, blood vessels, and interstitial tissue were patients diagnosed as having membranous glomerulo- usually normal. nephritis (Ellis Type II; Ellis, 1942). In lupus The early glomerular lesion was very similar in nephritis, the glomerular thickening was not appearance to the lesions described by Stickney and uniform; fibrinoid changes were common in the Keith (1940). We have named this lesion "local glomerular endothelial membrane of lupus nephritis glomerulitis" (Fig. 1). "Local"-because, initially, and rare in Ellis Type II glomerulonephritis; patchy the lesion consisted of one or two patches of pro- hypercellularity was a characteristic feature of lupus liferating endothelial cells near the periphery of the nephritis, but was usually not present in the glomeruli tuft of some glomeruli. Eventually every glomerulus of Ellis Type II glomerulonephritis. A comparison in the kidney became involved in this process. of typical examples of these two lesions is shown in The term "focal glomerulitis" was not used to Figs 4-A and 5 (overleaf). Ann Rheum Dis: first published as