Lupus nephritis

CLINICAL STUDIES

LupusNephritis Clinical Course as Related to Morphologic Forms and Their Transitions

DAVID

S. BALDWIN,

M.D.

MELVIN C. GLUCK, M.D. JEROME LOWENSTEIN,

M.D.

GLORIA R. GALLO, M.D. New York. New York

From the Hypertension and Renal Disease Section, Departments of Medicine and pathology, New York University School of Medicine, New York, New York. Requests for reprints should be addressed to David S. Baldwin, M.D., New York University School of Medicine, New York. New York 10016. Manuscript accepted April 5, 1976.

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January 1977

An intensive study of the course of lupus nephritis has been undertaken in 88 patients in whom strict morphologic crtteria were utilized in classification. Ail were treated with steroid, and 17 received cytotoxic drugs in addftton. Focal proliferative lupus nephrttts generally follows a benign course except in the occasional tnstances when transition to the diffuse proliferative or membranous forms occurs. Membranous lupus nephritis, when characterized by persistent nephrotic syndrome, leads stowty to renal failure, but this progression is aborted in the one-third in whom remission of the nephrotic syndrome can be achieved. A fatal outcome occurs within flve years in the majority of those with diffuse proiiferattve lupus nephritis and the nephrotic syndrome, often in association wtth necrotizing renal vascuiitis, severe hypertenston and accelerated renal failure. A small number with the dtffuse proltferative form have a rem&ton and then show only mesangial abnormalities, usually, however, with the appearance of glomerular sclerosis. Progresstve glomerular sclerosis is observed in some patients and may be a sequel of the remission of the diffuse or focal proliferative lesions, or it may represent still another form of lupus nephrttis. Mesangiai immune deposits with or without proliferation, at times in the absence of clinical renal disease, are observed early in the course of systemic lupus erythematosus (SLE) and may proceed to the diffuse proltferative or membranous forms. The present observations serve to emphasize the importance of strict morphologic classification in the comparison of different treatment regimens for lupus nephrttis. In view of the grave progrWs of established diffuse proliferative lupus nephritis, which probably evolves from a mesangtal involvement common to ail patients with SLE from its onset, early therapy may be the key to the management of lupus nephritis. In 1970, we proposed a histologic classification of lupus nephritis on the basis of our observations in 52 patients with clinical evidence of renal disease [ 11. Three fakly distinct forms with rather typical clinical features were identified: focal proliferative, diffuse proliferative and membranous lupus nephritis. Continued studies in an increased number of patients have enlarged our experience with the nature and course of lupus nephritis. Transitions between the different forms and progression to glomerular sclerosis have been noted, necrotizing vasculitis and rapidly progressive renal failure have been observed in the course of diffuse proliferative lupus nephritis, and a new

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pathologic form, mesangial lupus nephritis, has been recognized. In this report we describe the pathologic features, clinical course, and response to steroid and cytotoxic therapy in 88 patients with lupus nephritis. METHODS The diagnosis of systemic lupus erythematosus (SLE) was based on typical clinical features and was confirmed by the presence of either a positive lupus etythematosus preparation or antinuclear antibodies. Lupus nephritis was diagnosed clinically by the finding, minimally, of unequivocal urinary abnormalities; three patients with glomerular abnormalities are included despite the absence of clinical renal disease. The onset of lupus nephritis was dated from the discovery of urinary abnormalities and, except for three patients with active SLE and normal urinalyses, initial renal biopsies were performed only when clinical features of renal disease were present. It is possible that morphologic changes in the kidney often antedate the urinary abnormalities, but the design of the present studydoes not permit an examination of this question. Patients were studied on the Medical or Pediatric In-Patient Services of Bellevue Hospital and University Hospital, and in the Hypertension and Nephritis Clinic of Bellevue Hospital. Most of them were referred to the Renal Section because of the severity of their renal involvement. All patients were treated with steroids, in doses which varied depending on the severity of the renal disease and the requirements for control of the other features of their SLE. Prednisone dosage of 40 mg/day or more will be referred to as “large dose.” On the basis of 24-hour urinary excretion rates, proteinuria was assigned to one of four categories: none, up to 1 g, between 1 and 3 g, and exceeding 3 g. Reduction in proteinuria was defined as a decrease in a 24-hour excretion of at least 1.5 g and a shift into a lower category. One hundred thirty-five specimens of renal tissue were obtained at renal biopsy or postmortem examination in 88 patients. The majority of biopsy specimens, which were prepared for light microscopy, contained IO or more glomeruli. Twelve specimens contained 6 or less glomeruli, but generally these were supplemented by frozen sections prepared for immunofluorescence. Renal tissue was studied by light microscopy in 2 to 3 p sections utilizing hematoxylin and eosin, periodic acid-Schiff, periodic acid and silver methenamine counterstained with hematoxylin and eosin, and azancarmine stains. lmmunofluorescence microscopy using fluorescein-conjugated antiserums against whole globulin, immunoglobulins G (IgG), A (IgA) and M (IgM), betalC/betalA globulin (C3), and fibrin was performed as previously described [2]. Tissue processed for electron microscopy was fixed in glutaraktehyde,postfixed in osmic acid and embedded in Epone. Serial pathologic observations were made in 31 patients. In 16 patients, transition from one form of lupus nephritis to another was observed. It is recognized that additional transitions might have occurred in some patients prior to obtaining their initial biopsy specimen. From the time of documented transition, the course has been described under the newly acquired form except in the six instances in which there was a remission from diffuse proliferative lupus ne-

ET AL.

phritis to mesangial lupus nephritis. Thus, the natural history of 98 examples of lupus nephritis in 88 patients provides the basis for the present report. l

RESULTS On the basis of morphologic features, the renal lesions were categorized as follows: focal proliferative lupus nephritis 12, diffuse proliferative lupus nephritis 44, membranous lupus nephritis 24, mesangial lupus nephritis 12 and glomerular sclerosis six. The classification could usually be accomplished without difficulty. Occasionally, an arbitrary decision was required in determining whether widespread segmental lesions were to be assigned to the focal or diffuse proliferative category or whether a lesion was strictly mesangial or mildly diffuse. FOCAL PROLIFERATIVE LUPUS NEPHRITIS Morphology. Lighl microscopy: In 12 patients with focal proliferative lupus nephritis, glomerular involvement was characterized by sharply delineated segmental proliferation of some tufts, involving from 12 to 55 per cent of the glomeruli, although in one patient 80 per cent of the glomeruli were involved. Segmental lesions were frequently adherent to small epithelial crescents and showed tuft necrosis. Mild widening of mesangial areas by increased cells was present in about one-third of the cases. Peripheral capillary walls appeared normal. In one-half, from 8 to 17 per cent of the glomeruli were sclerotic. The sclerosis in some was segmental, in some global, and in one instance both segmental and global. Immunofluorescence: All specimens showed granular deposits of IgG with predominant localization in mesangial regions and scattered deposits in peripheral capillary walls of all glomeruli; in some, focal dense nodular accumulations in a few lobules appeared to correspond to sites of segmental proliferation. The same was generally true for C3. Staining for IgA and IgM was less constant and generally more scanty in distribution and amount. Fibrin, when present, was seen as small focal strands in tufts or at the periphery of lobules and adjacent capsule; it was never as abundant as immunoglobulins or C3. Electron microscopy: Electron-dense deposits were seen in all, mostly in mesangial sites and occasionally in subendothelial, subepithelial and intramembranous sites. Serial biopsies were performed in two patients (F3 and F8) (Figure 1). The lesion remained segmental with decreasing proliferation and increasing sclerosis over The pathologic material described in our earlier repot-l [l] was reviewed and in a few instances patients were reclassified. A detailed report of the light microscopic, immunopathologic and ultrastructural findings will be presented in a separate publication. l

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ET AL.

Fl F2 F3 F4 F5 F6 F7 @id

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Figure 1. Clinical course of focal proliferative lupus nephritis in 72 patients (F 1 through F 12). For Figures I, 2, 3, 4 and 5, proteinuria is represented by the following symbols: open bar = none; right stippled bar = less than 1 g; heavy stippled bar = 1 to 3 g; solid bar = greater than 3 g (nephrotic syndrome); solid line = proteinuria, not quantitated; broken line = data on proteinuria not available. The time of tissue examination and the morphologic form are indicated by the letters above each bar: F = focal proliferative lupus nephritis, D = diffuse proliferative Iupus nephritis, M = membranous lupus nephritis, Mes = mesangial lupus nephritis, S = glomen/jarsclerosis alone. when transitions occur&, reference numbers are given for ick3ntification of such patients in the other Figures. Serum creatinine concentration (mg/lOO ml) at latest observation is shown at the end of each bar. 7 = death.

two and 11 month intervals: immunofluorescence findings were unchanged, but there were possibly fewer electrondense deposits on follow-up biopsy. Clinical Features (Tables I and II, and Figure 1). Eleven of the 12 patients were female, and all but one were under 40 years of age at the onset of SLE. Urinary abnormalities, which were present in all. appeared within one year of the onset of SLE in five patients, between one and three years from the onset in four patients, and later than three years in 3 patients. The diagnosis of focal proliferative lupus nephritis was established histologically within one year of the appearance of urinary abnormalities in nine patients, after two years and seven months in one patient (F 12), after three years in another patient (F2), and after nine years in still another patient (Fl). The assumption was made that focal proliferative lupus nephritis was present from the time that urinary abnormalities appeared, even during the long intervals preceding tissue diagnosis in the latter three patients (F12, F2 and Fl), since the minimal clinical features of renal disease prior to biopsy in these patients were typical of this form. It is possible, however, that the diffuse mesangial abnormalities alone were present for some portion of the period preceding the documentation of focal proliferative lupus nephritis. Proteinuria was present in all patients with focal

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proliferative lupus nephritis at the onset of renal disease and hematuria in seven of 12. Urinary abnormalities were the sole clinical feature of renal disease in 10; mild renal insufficiency was present, in addition, in the other two. In one (F8), the nephrotic syndrome was present at the onset of renal disease and persisted for four months until her death from sepsis. Hypertension was not observed. All patients were treated intermittently with steroids in doses which were determined solely by the requirement for control of the other features of SLE. Three (F3, F9 and F2) experienced a reduction in proteinuria after steroid therapy for periods ranging between two and 16 months; in one, complete remission occurred, and in two, proteinuria decreased to less than 1 g/24 hours. Two patients (F3 and F9) have remained in remission for periods of four and one months during continued steroid therapy. Steroid therapy was discontinued after remission in one (F2); this patient had a relapse after one month and remission failed to ensue after three months of a subsequent steroid course. Seven patients (F 1, F4 through F8 and F 11) failed to undergo remission after one to nine months of steroid therapy, which was given in a “large dose” in four. Two other patients (F 10 and F 12) are also considered steroid-failures, since their remissions, which occurred only after four and five years of therapy, more likely were spontaneous. This

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TABLE

I

Lupus Nephritis--General

Features

No. Female Age at onset of SLE Under 20 years 20-40 years Over 40 years Interval between onset of SLE and discovery of renal disease Under 1 year 1 to3years Over 3 years Interval between discovery of renal disease and classification Under 1 year 1 to 3 years Over 3 years

TABLE

II

Lupus Nephritis-Clinical

Features

Focal Proliferative Lupus Nephritis

TABLE

III

Transitions

Focal Proliferative Lupus Nephritis

Diffuse Proliferative Lupus Nephritis

Membranous Lupus Nephritis

Mesangial Lupus Nephritis

12 11

44 35

24 22

12 9

3 8 1

19 20 5

10 9 5

4 4 4

5 4 3

27 8 9

11 6 7

9 2 1

12 0 0

29

15 2 7

12 0 0

9 6

at Onset and at Latest Observation

Diffuse Proliferative Lupus Nephritis

Membranous Lupus Nephritis

Mesangial Lupus Nephritis

Initial

Latest

Initial

Latest

Initial

Latest

Initial

12 12 1 0 2 0

12 11 1 5 1 1

44 44 41 24 36 0

44 43 31 29 35 1

24 23 16 8 6 1

24 23 16 13 12 1

12 8 0 2 2 3

No. of patients Proteinuria Nephrotic syndrome Hypertension Renal insufficiency No urinary abnormality Years of observation Uhder 2 yr 2 to 5 yr Over 5 yr Alive Dead Uremic death Time from onset Under 2 yr 2 to 5 yr Over 5 yr

ET AL.

8 1 3 9 3 0

0 0 0

Latest 12 7 1 3 3 3

32

15

9 3 16 28 18

3 6 15 9 1

8 4 0 12 0 0

14 4 0

0 0 1

0 0 0

in Lupus Nephritis

Transitions to

initial Form Focal proliferative lupus nephritis Diffuse proliferative lupus nephritis Membranous lupus nephritis Mesangial lupus nephritis

No. 12 44 24 12

Focal Proliferative Lupus Nephritis

Diffuse Proliferative Lupus Nephritis 2

0 0 0

January 1977

1 3

Membranous Lupus Nephritis

Mesangial Lupus Nephritis

1 2

0 6 0

1

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experience suggests that steroids may induce remission of proteinuria in about one-fourth of those with focal proliferative lupus nephritis. Eight patients have been observed for periods of less than two years, one for three years, and three for six to nine years. At the latest observation, one (F3) had no urinary abnormalities, whereas the other 11 had proteinuria. Hypertension appeared during the course of SLE in five patients, all of whom were receiving steroids. Mild renal insufficiency was present in one (F5) at the latest observation. Three patients (F2, F8 and F12) died of sepsis, and one (FlO) died of uremia after the transition to diffuse proliferative lupus nephritis. Transition to the diffuse proliferative form occurred in two patients (Fl 1 and FlO), and to the membranous form in one (F12) (Table Ill). The subsequent courses of these patients are included under the descriptions of the natural history of diffuse proliferative lupus nephritis and membranous lupus nephritis from the time that the transitions occurred. Renal biopsy in one patient (Fl 1) showed focal proliferative lupus nephritis two months after the onset of renal disease. The nephrotic syndrome appeared one month later. Repeat biopsy after a six month interval showed mild diffuse proliferative lupus nephritis, more electron-dense deposits in mesangial and subendothelial locations, and increased deposition of IgG and C3. In one patient (FlO), focal proliferative lupus nephritis was demonstrated six months after the clinical onset of renal disease. An 11’/2 year period of urinary abnormalities alone was followed by the appearance of the nephrotic syndrome and renal failure which progressed to terminal uremia in six months. Postmortem examination revealed transition to diffuse proliferative lupus nephritis with advanced global sclerosis of most glomeruli. In another patient (F 12) persistent proteinuria developed after seven years of deforming rheumatoid arthritis, and a diagnosis of SLE was established. Renal biopsy, two and a half years later, revealed focal proliferative lupus nephritis. Proteinuria, without the nephrotic syndrome, persisted despite continued steroid therapy except for a brief remission; the patient died with sepsis after six years. At postmortem examination, an unusual combination of stage II membranous lupus nephritis and segmental proliferation accompanied by sclerosis of both global and segmental types was seen. The presence of subtle “stippled” lesions, visualized on silver stain in glomerular basement membranes in the initial biopsy specimen, suggests that the initial lesion was a combination of membranous lupus nephritis and focal proliferative lupus nephritis. However, neither ultrastructural nor immunopathologic studies of the first biopsy specimen were available for confirmation. Life survival analysis [3] shows a five year mortality of 30 per cent in patients with focal proliferative lupus

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nephritis, not significantly mortality of SLE [4].

different from the over-all

DIFFUSE PROLIFERATIVE LUPUS NEPHRITIS Light microscopy: Proliferation was Morphology. global in all or most glomeruli, and varied in severity among patients. When proliferation was severe, epithelial crescents involving 30 per cent or more of the glomeruli were observed, and generally more than 25 per cent of the glomeruli were sclerotic. In eight patients, vascular lesions were a prominent feature, characterized by edema and acellular necrosis of arterioles and interlobular arteries, sometimes associated with mural hemorrhage and luminal occlusion. In four of the eight, intimal fibroplasia of interlobular and arcuate arteries was observed as well. Immunofluorescence: All specimens showed diffuse granular staining for IgG and IgM, and most for C3; IgA was less frequently demonstrated. Both IgA and IgM, and sometimes C3, were more scanty in amount and distribution than IgG. Fibrin, never as abundant as other proteins, was seen in scattered strands in random tufts, crescents and capsule. Immune deposits tended to be more abundant and coarsely granular in more severe proliferative disease. Electron microscopy: In moderate and severediffuse proliferative lupus nephritis, electron-dense deposits were larger and more numerous than in focal proliferative lupus nephritis in all sites, especially subendothelial and mesangial. In those with mild diffuse proliferative lupus nephritis, deposits tended to correspond in size, number and distribution with those in focal proliferative lupus nephritis. On serial biopsy in 14 patients, proliferation remained essentially unchanged in eight; progression of sclerosis was observed occasionally in patients whose disease followed a more protracted course. In six patients who underwent clinical remission, the lesion of diffuse proliferative lupus nephritis became predominantly mesangial with mild increase in cells and matrix; in all but one, associated global sclerosis of approximately 50 per cent of the glomeruli had developed. In these patients with remission, strikingly fewer deposits were observed both by immunofluorescence and electron microscopy. Instead, mottled rarified lesions in glomerular basement membranes and subepithelial deposits were present. Clinical Features (Tables I and II; Figure 2). Nine of the 44 patients were male and all but five were under 40 years of age. The interval between the onset of SLE and the discovery of renal disease was less than one year in 27 patients, between one and three years in eight, and greater than three years in nine. In 26 patients (Dl through D26) in whom the nephrotic syndrome was the initial manifestation of renal

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Figure 2. Clinical course of diffuse proliferative lupus nephritis in 44 patients (D 1 through 044). See Figure 1 for explanation of symbols. l = necrotizing vasculitis.

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disease, the onset of diffuse proliferative lupus nephritis was dated on this basis, even though histologic documentation in some was not available until later in the course. In the remaining 18 patients (D27 through D44), a period of urinary abnormalities without the nephrotic syndrome elapsed before the diagnosis of diffuse proliferative lupus nephritis was made either on the basis of a renal biopsy or the development of the nephrotic syndrome. Renal biopsy was performed during the period of proteinuria in nine of these 18 patients who were ultimately proved to have diffuse profiferative lupus nephritis. In three (D27,028 and D29), mesangial lupus nephritis was present; the onset of diffuse proliferative lupus nephritis was dated by the appearance of the nephrotic syndrome two years, and four years and five months after the onset of mesangial lupus nephritis in two patients (D27 and D28), and diffuse proliferative lupus nephritis was found to be present at autopsy at two and a half years in one (D29). In two others (030 and 031) focal proliferative lupus nephritis was present; the nephrotic syndrome and diffuse proliferative lupus nephritis were documented a half year and 11 ‘/z years after the onset of focal proliferative lupus nephritis. In one (D32), membranous lupus nephritis was present: diffuse proliferative lupus nephritis with nephrotic syndrome occurred one year and nine months after the onset of urinary abnormalities. In three (D42, D43 and 044). diffuse proliferative lupus nephritis was present: the nephrotic syndrome did not develop during periods of observation of one month, one year and four months, and nine years and 10 months after the documentation of diffuse proliferative lupus nephritis. In the remaining nine patients (D33 through D41), renal biopsy was not performed during the interval (two months to eight years) of proteinuria which preceded the appearance of the nephrotic syndrome and documentation of diffuse proliferative lupus nephritis. Since it is not known whether these patients had diffuse proliferative lupus nephritis or another form of lupus nephritis during the period before the appearance of the nephrotic syndrome, we have chosen not to date the onset of diffuse proliferative lupus nephritis with the appearance of urinary abnormalities, but with the development of the nephrotic syndrome or, in its absence, when histologic classification could be made. Proteinuria was present in all patients at the onset of diffuse proliferative lupus nephritis, and hematuria was present in 39. Using the criteria described for dating the onset of diffuse proliferative lupus nephritis, the nephrotic syndrome was considered an initial feature in 41 of the 44 patients. Renal insufficiency (defined as serum creatinine in excess of 1 mg/lOb ml) was present in 36, 17 of whom had serum creatinine levels exceeding 2 mg/ 100 ml. Twenty-four were hypertensive

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at the onset of disease, although 11 were already receiving steroid therapy for management of other features of SLE. In three patients with diffuse proliferative lupus nephritis the nephrotic syndrome never developed. One patient (D42) had persistent protelnuia and ncrmal renal function for 10 years. Repeat renal biopsy at four years and eight months showed a significant decrease in the diffuse glomerular proliferation and development of segmental glomerular sclerosis. This patient died with central nervous system involvement, and at postmortem the kidneys revealed stage II membranous lupus nephritis. In another patient (D43), after 15 months of lupus nephritis characterized by urinary abnormalities alone, severe hypertension and oligrric renal failure developed in association with active SLE and the patient died in one month. Necropsy demonstrated diffuse proliferative lupus nephritis with glomerular sclerosis, necrotizing arteritis and arteriolitis. Another patient (D44) was observed for only one month, during which time partial remission of proteinuria occurred spontaneously. Remission was observed in 13 of the 41 patients with the nephrotic syndrome. In 12, *remission occurred during the first year of treatment. Ten have remained in remission during observation for periods ranging from one to 15 years in seven, and for less then six months in three. Renal failure has not developed in any of the 10 patients during sustained remission of the nephrotic syndrome, and all have survived. Renal biopsies performed during clinical remission in six disclosed mesangial proliferation in five, in four of whom glomerular sclerosis had developed. The sixth patient had no previous biopsy specimen for comparison but showed mild diffuse proliferative lupus nephritis during remission. The other two patients who had a remission during the first year (D37 and Dl 1)had a relapse within six months. One (D37) was then persistently nephrotic and died after 28 months with active SLE, renal failure and infection. The other (Dl 1) died two months after relapse with central nervous system involvement. One patient (D2) did not have a remission until three and a half years of treatment; renal biopsy two years priorto the remission had already demonstrated subsidence of diffuse proliferative lupus nephritis and showed mesangial proliferation only with advanced glomerular sclerosis. This patient had a relapse within six months, remained nephrotic for an additional two years, progressed to uremia, and died with sepsis. It appears that remission is not likely to occur in diffuse proliferative lupus nephritis after persistence of the nephrotic syndrome beyond one year. When sustained remission of the nephrotic syndrome could be induced, as occurred in 10 of 4 1 patients (or approximately 25 per cent), renal failure did not develop. The six patients with diffuse proliferative lupus ne-

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phritis (02 through 06 and D 17) who showed remission to a mesangial lesion are listed in Table Ill as examples of transitions. Morphologically, however, features other than mesangial proliferation and deposits were present in the form of subepithelial deposits, mottling of the glomerular basement membrane and glomerular sclerosis. Twenty-eight of the 41 patients with the nephrotic syndrome and diffuse proliferative lupus nephritis never underwent remission. In 15 the condition progressed to uremia, within the first year in nine and in the second year in six. Of the 13 patients who did not show progression to uremia, 12 were observed for periods of less than one year with persistent nephrotic syndrome; seven died during this period of active SLE, often with infection. The 13th patient (D9) died after two years with active SLE and pancreatitis. In summary, persistent nephrotic syndrome in diffuse proliferative lupus nephritis is often associated with progressive renal failure within two years. When uremia does not develop, death is likely to occur in any case within two years under circumstances resembling those which contributed to the uremic deaths. The patients without a remission, whether uremic or not, were under treatment with large doses of steroids and immunosuppressives, and inanition and susceptibility to infection played prominent roles in their death. The role of active SLE itself in this setting often cannot be assessed . All patients with diffuse proliferative lupus nephritis were treated with steroids throughout their course, and in most instances they received large doses for many months. During recent years, 12 have received, in addition, an immunosuppressive agent (arathioprine, cyclophosphamide or 6-mercaptopurine). Although the number of patients treated with the combination is small compared to the number treated with steroids alone, and use of the combination represents more recent experience, our observations suggest that the course and outcome have been favorably affected by the addition of a cytotoxic drug. Remissions of the nephrotic syndrome were observed in six of 12 patients who received combination therapy, whereas remission occurred in only 10 of 33 patients who received steroid therapy alone. Within six months, one of the six patients in whom remission was induced by combination therapy and two of the 10 who had a remission after steroid therapy had a relapse. The difference in remission rates between patients receiving steroid therapy alone as compared to those receiving combination therapy was examined with regard to the level of renal function when therapy was instituted. Of 14 patients treated with steroid alone when serum creatinine was under 2 mg/ 100 ml, remission was induced in six (43 per cent); of seven treated with combination therapy, remission occurred

ET AL.

in four (57 per cent). When renal function was impaired, such that serum creatinine exceeded 2 mg/lOO ml, remission could not be induced with steroid atone in any of eight patients, whereas in two of four receiving combination therapy, remission occurred. Further, among 29 patients with no remission after three months of steroid therapy, the addition of immunosuppressives to four resulted in three remissions; with continuation of corticosteroid therapy alone, remissions ensued in only seven of the other 25. The mortality rate in patients treated since 1968, eight of 19 (42 per cent), is lower than that observed in our earlier series, 20 of 25 (80 per cent). In part, this may be attributable to the use of immunosuppressives, since, as stated, we have observed a higher incidence of sustained remissions and a more favorable course in patients with remission during combination therapy. However, the mortality, four of 10 (40 per cent), in patients treated with corticosteroid alone is also lower since 1968 than during the earlier years, possibly reflecting the more aggressive, yet judicious, use of steroid and the availability of more effective antibiotics. In 18 of the 44 patients with diffuse proliferative lupus nephritis, the condition has progressed to terminal uremia. Ten have died of other causes related to active SLE or its treatment. Life survival analysis from the onset of documented diffuse proliferative lupus nephritis shows a two year mortality of 53 per cent and a five year mortality of 71 per cent. An analysis based on the assumption that diffuse proliferative lupus nephritis was already present at the first clinical evidence of renal disease shows a two year mortality of 41 per cent and a five year mortality of 67 per cent. However, it is possible that other milder forms of lupus nephritis were present at first evidence of renal disease and that transition to diffuse proliferative lupus nephritis occurred later; this was documented in six of the 44 patients. MEMBRANOUS LUPUS NEPHRITIS Morphology. Light microscopy: In membranous lupus nephritis, histologic features were similar to those described in the idiopathic form of membranous glomerulonephritis [ 51. Capillary wall changes were classified as stage I in five patients, and stage II in 19 patients. Mesangial widening due to increased cells was seen in about half of those with stage II lesions, whereas equivocal or no widening was seen in the remaining specimens. Sclerotic glomeruli were seen in two-thirds of those with stage II lesions. Although no epithelial crescents were found, minor small foci of parietal epithelial cell swelling were seen in two cases. Immunofluorescence: In all but one of the specimens, finely granular deposits of IgG uniformly outlined capillary walls. In one, the pattern appeared as mixed granular and focally linear; ultrastructurally, some loops

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ET AL.

showed coalescence of electron-dense subepithelial deposits which may account for the focal linear appearance on immunofluorescence microscopy. Staining for C3 was positive in most, usually less intense and more patchy than IgG, whereas staining for IgA was usually absent. IgM when present was always more focal in distribution. Fibrin was usually absent or present only focally in occasional strands. Electron microscopy: Subepithelial deposits were smaller and more scattered in stage I as compared to stage II lesions, and in five of eight specimens, mesangial deposits were present. Serial morphologic observations in seven patients with membranous lupus nephritis showed progression from stage I to stage II in six months in one patient (M20), persistence of stage II (over one to three years) in three patients (M6, M22 and M23) and progression from stage II to stage Ill in eight years in one patient (M2). Histoldgic remission from stage II to stage 0 over eight and three-fourths years in one patient (M5), was confirmed by negative immunofluorescence. Transition to severe diffuse proliferative lupus nephritis with crescent formation occurred in one patient (M7) in association with increased immune deposits diffusely present in peripheral loops and mesangium, and with fibrin deposits in crescents. Two patients (M2 and M22) showed increased sclerosis over periods of two and a half and eight years. All but Clinical Features (Tables I and II; Figure 3). two of the 24 patients were female, and 19 were under the age of 40 years. The interval between the onset of SLE and the discovery of renal disease was less than one year in 11 patients, between one and three years in six patients and more than three years in seven patients. The renal lesion was eventually classified as membranous in all of these patients on the basis of typical morphologic features, but the onset of membranous lupus nephritis was dated with the appearance of the nephrotic syndrome in some, even though documentation of the membranous lesion on renal biopsy was not accomplished until a later date. Utilizing either morphologic or clinical criteria, the renal lesion could be classified as membranous within one year of onset of urinary abnormalities in 13 of the 24 patients. In nine patients, periods of one year and two months to four years of proteinuria preceded the development of the nephrotic syndrome and/or the performance of a renal biopsy showing membranous lupus nephritis. It is possible that the membranous lesion was present for some time during the preceding years of proteinuria, and, in fact, membranous lupus nephritis was documented histologically in five patients of this series after periods ranging up to four and a half years without the nephrotic syndrome. Proteinuria was present at the time of classification

20

January 1977

The American Journal of Mecflcine

in 23 patients, 16 of whom had the nephrotic syndrome. The nephrotic syndrome appeared later in the course in an additional three patients; thus, 79 per cent of the patients with membranous lupus nephritis manifested the nephrotic syndrome at some time. In the single patient (M8) with a negative urinalysis at the time of tissue diagnosis, minimal proteinuria developed one year later. Hematuria was present in 10 patients. Hypertension was observed in eight patients and renal insufficiency in six patients, all of whom also had the nephrotic syndrome with one exception (M7). In no instance did the blood urea nitrogen exceed 40 mg/lOO ml or the serum creatinine exceed 2.0 mg/lOO ml at the time of classification. Remissions occurred in seven patients (Ml through M7) after steroid therapy, ranging in duration from one to 16 months. Six of these remissions occurred in patients (Ml through M6) with the nephrotic syndrome; four remissions were partial (Ml through M4) and in two patients (M5 and M6) remission occurred to a negative urine (complete remission). Relapse occurred after nine months in one patient (Ml) as steroid dosage was being tapered, and remission was induced again with an increased dosage of steroid. One patient (M2) remained in partial remission for six years and 11 months without steroid therapy, then had a relapse with the nephrotic syndrome. Steroid therapy was reinstituted after six years and nine months of partial remission in one patient (M5) and resulted in complete remission one and a half years later. After four years of partial remission with small dose steroid therapy, one patient (M6) underwent complete remission which was sustained for nine months. Relapse then occurred which was unresponsive to “large” dose steroid therapy for two years and two months until death from sepsis. Two patients (M3 and M4) remain in partial remission with steroid therapy for periods of observation of less than one year. The seventh patient (M7) had a brief remission from minimal proteinuria and then a relapse to heavier proteinuria without the nephrotic syndrome despite the continued administration of steroids. The four patients (Ml, M3, M4 and M5) who remain in remission have had normal or minimally impaired renal function for periods up to one year. Two patients (M2 and M6) who had a relapse, were persistently nephrotic for two and three years, respectively, and moderate renal insufficiency developed. In one (M7), a transition to diffuse proliferative lupus nephritis occurred, and the patient died with the nephrotic syndrome and advanced renal failure. That portion of her course after transition is described under the natural history of diffuse proliferative lupus nephritis (as 032). Remission failed to occur in 17 of the patients with membranous lupus nephritis (M8 through M24). Four (M8 through Ml 1) were not nephrotic and had minimal

Volume 92

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LUPUS NEPHRITIS-BALDWIN

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proteinuria which was not affected by steroid therapy. The other 13 patients (Ml2 through M24) remained nephrotic throughout their course despite long periods of high dose steroid therapy in 10; azathioprine was given in addition to three (M22, M23 and M24). Renal function has remained normal in 11 patients with no remission for periods of observation extending up to seven months. Moderate renal insufficiency has developed in five patients (M13, M15, M18, M23 and M24) in a half to five and a half years. A single patient (M12) died of uremia after six years and nine months of persistent nephrotic syndrome. Life survival analyses show a five year mortality of 2 1 per cent from the onset of proteinuria and of 30 per cent from the time the renal lesion was classified as membranous lupus nephritis according to the criteria stated previously. These mortality rates do not differ significantly from the over-all five year experience in SLE [4]. MESANGIAL LUPUS NEPHRITIS Morphology. Light microscopy: About one half of the biopsy specimens from 12 patients classified as having mesangial lupus nephritis, were normal or showed equivocal mesangial widening, whereas the others showed definite although mild mesangial hypercellularity, associated in some with a mild increase in mesangial matrix. In four patients, up to 10 per cent of the glomeruli showed some sclerosis.

22

January 1977

Immunofluorescence: IgG, frequently C3, and sometimes IgA and IgM deposits predominated in mesangial regions in all but one of those classified as having mesangial lupus nephritis; this was true whether or not mesangial proliferation by light microscopy was equivocal or definite. Electron microscopy: Electron-dense deposits were present in all instances of mesangial lupus nephritis and were located mostly in mesangial sites and occasionally in relation to the basement membrane. Clinical Features (Tables I and II, and Figure 4). The diagnosis of mesangial lupus nephritis was made in 12 patients, three of whom had no urinary abnormalities. Nine were female. Four were under 20 years of age, four were between 20 and 40 years of age and four were over the age of 40 years. In nine patients, urinary abnormalities appeared within one year of the onset of SLE, and the histologic diagnosis was made after a few months. The other three (Mesl , Mes2 and Mes3) without urinary abnormalities, were found to have mesangial lupus nephritis on renal biopsy at one, two and four years after the onset of SLE. Five patients had both proteinuria and microhematuria, three had proteinuria alone, and one microhematuria without proteinuria (Mes4). Protein excretion was usually less than 1 g/24 hours, but two patients (Mes6 and Mes8) excreted between 1.5 and 2.5 g at the onset. In one patient (Mesl 0). the nephrotic syndrome developed one year after the onset of renal disease with the biopsy specimen still showing mesangial lupus nephritis: he subsequently showed the transition to diffuse proliferative lupus nephritis, which was found at postmortem 13 months after the second biopsy. Hypertension was seen in only two patients, one of whom was receiving steroid therapy. Minimal renal insufficiency was present in two (Mes8 and Mes 11). Eight patients have been under observation for less than two years, four for periods of two to five years. At latest observation, seven had persistence of proteinuria, one had complete remission of proteinuria but persistently microhematuria, and one continued with microhematuria alone. In the three patients who had no urinary abnormalities at the time of histologic diagnosis urinalyses were still within normal limits after one, 13 and 19 months of observation. Hypertension was present in three patients at the latest observation, all of them receiving steroids. Minimal renal insufficiency was present in three (Mes7, Mes8 and MeslO). During the period of observation, transition to another histologic form occurred in four patients (Table Ill). In one (MeslO) the nephrotic syndrome developed, still with the mesangial lesion, and progressed to terminal renal failure, showing diffuse proliferative lupus nephritis at necropsy 13 months later. In another (Mes9)

The American Journal of Medicine Volume 62

LUPUS NEPHRITIS--BALDWIN

s HD

ET AL.

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the nephrotic syndrome developed four years and five months after the histologic diagnosis of mesangial lupus nephritis was made; this patient died with renal failure and active SLE six months later, showing diffuse proliferative lupus nephritis at necropsy. In still another patient (Mesl 1)the nephrotic syndrome and moderate renal insufficiency developed after two years of persistent proteinuria, and renal biopsy then revealed diffuse proliferative lupus nephritis. One patient (Mes12), in whom the nephrotic syndrome developed at three years and one month, was found to have membranous lupus nephritis on biopsy seven months later; this patient died of sepsis after nine months. The remaining eight patients have shown no clinical evidence of progressive renal disease. GLOMERULAR

SCLEROSIS

IN LUPUS NEPHRITIS

As noted previously, sclerosis of some glomeruli was observed in each of the forms of lupus nephritis. In focal proliferative lupus nephritis and mesangial lupus nephritis, the incidence of glomerular sclerosis was less than 50 per cent and, when present, affected less than one fourth of the glomeruli; on serial biopsies, the extent of sclerosis increased. In mild or moderate diffuse proliferative lupus nephritis, the incidence and severity of glomerular sclerosis was similar to that observed in focal proliferative lupus nephritis and mesangial lupus nephritis. When diffuse proliferative lupus nephritis was classified as severe, the majority of specimens showed sclerosis, generally involving more than one fourth of the glomeruli. Serial biopsies in diffuse proliferative lupus nephritis, which were usually performed in those with more protracted courses, consistently demonstrated increased sclerosis, even in patients who had shown a clinical and morphological remission. Sclerotic glomeruli were not seen in stage I membranous lupus nephritis, but were present in the majority of those with stage II; advanced sclerosis, still with typical membranous changes, occurred in one patient (M12) who

died with severe hypertension and uremia after a seven year course. In six patients, whose courses are summarized in Figure 5, sclerosis was the only glomerular abnormality observed on renal biopsies which were performed at intervals ranging from two to 12 years from the onset of renal disease. Two of them (S 1 and S6) presented at the onset of disease with the nephrotic syndrome and renal insufficiency. In one (S6), the nephrotic syndrome and renal insufficiency subsided after two years and were followed by 10 years of little or no proteinuria. At 12 years from onset, a renal biopsy specimen showed segmental glomerular sclerosis, and renal function was only equivocally impaired. In the other patient (S 1) the nephrotic syndrome remitted at two and a half years, when renal function had returned to normal. At this time a renal biopsy specimen showed diffuse glomerular sclerosis. During the succeeding years, proteinuria became minimal, hypertension developed and progressive renal failure ensued, for which the patient required hemodialysis at nine years and two months from onset. In the other four patients (S2 through S5), glomerular sclerosis alone was found on renal biopsies performed after periods of three, five, and six and 11 years of proteinuria without the nephrotic syndrome. Moderate impairment of renal function was present in these patients at the time of renal biopsy, which showed glomerular sclerosis without proliferation or membranous changes. NECROTlZlNG VASCULITIS (TABLE IV AND FIGURE 2)

In nine patients, necrotizing vasculitis involving arterioles in all and interlobular arteries in five was observed in the kidney. The lesions were characterized by acellular necrosis of the vessles, frequently with proteinaceous thrombi occluding the lumens, with little or no associated leukocytic infiltration of the walls. lntimal fibromyxoid proliferation and mural hemorrhage of interlobular or arcuate arteries was present in four. Im-

January 1977

The American Journal of Medicine

Volume 62

23

LUPUS NEPHRITIS-BALDWIN

ET AL.

munofluorescence staining was performed in five. Discrete granular deposits of IgG and C3 in vessel walls, suggesting the presence of immune complexes, were found in three. Homogeneous deposition of serum proteins including fibrin was observed in vessel walls and lumens once and suggested plasmatic insudation. In one patient, the immunofluorescence was negative. Eight of the nine patients (identified in Table IV by the notations which are used in Figure 2) had antecedent diffuse proliferative lupus nephritis which was present for periods ranging from three to 96 months prior to the onset of severe hypertension and rapidly progressive renal failure. In the remaining patient, proteinuria was present for four months prior to the development of hypertension, but at postmortem the glomeruli were normal, and it must be presumed that the initial proteinuria was an early manifestation of vasculitis. In the patients with previous clinical data, the blood urea nitrogen ranged from 24 to 67 mg/lOO ml and serum creatinine was under 2 mg/lOO ml when the change in their clinical course occurred. Death with uremia ensued in less than six weeks in six patients, and after four to 14 months in the remaining three. Except for one (D34), all manifested heart failure and/or hypertensive encephalopathy. Severe retinopathy was present in five patients. COMMENTS The present report describing the morphologic and clinical manifestations of renal involvement in 88 patients with SLE extends our previous observations [ 1,6,7]. The clinical manifestations and course of the three previously recognized forms of lupus nephritis, namely, focal proliferative, diffuse proliferative and membranous, and of a fourth morphologic manifestation of SLE in the kidney, here designated mesangial lupus nephritis, are summarized in Table V. The recent identification of the mesangial lesion in SLE [ 8- 111 can be attributed to the increased number of renal biopsies which are being performed in patients with minimal or no urinary abnormalities, as well as to improved histologic technics, wider application of immunopathologic and ultrastructual studies, and increased awareness among nephrologists of the importance of the mesangium in the handling of circulating immune complexes. It is likely that most biopsy specimens showing this abnormality were previously classified as normal, especially in the absence of immunofluorescent or ultramicroscopic examination [6,12,13], or were referred to as glomerulitis [14], mild diffuse proliferative glomerulonephritis [ 11, lupus nephritis [ 151, mild proliferative lupus nephritis [ 161, mild diffuse proliferative lupus nephritis [ 171, minimal changes in SLE [ 18,191 and mild lupus glomerulonephritis [20,21].

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January 1977

The American Journal ol Medicine

Volume 62

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Lupus Nephritis

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Remission of proteinuria in about one-half, at times complete

Proteinuria in all, hematuria often; nephrotic syndrome rare; occasional mild renal insufficiency; hypertension absent

Focal Proliferative

Nephritis-Summary

Clinical manifestations

Lupus

Onset during 1st year of SLE in about one-half

V

Onset

TABLE

Course

Proliferative Nephritis

and Lupus

Remission of ‘nephrotic syndrome during 1st year in one-fourth, usually sustained Transition to mesangial lupus nephritis (with some glomerular sclerosis) or membranous lupus nepnritis may occur in association with remission Progression to death within two years in one-half of those without remission; death due to uremia or active SLE, often with infection; no progressive renal insufficiency during remission Two year mortality 53 per cent, five year mortality 71 per cent

Onset during 1st year of SLE in the majority; one-fifth males, as compared to one-tenth in other forms Proteinuria and hematuria in all; nephrotic syndrome at onset in over one-half, eventually in almost all; renal insufficiency at onset in most, occasionally severe; hypertension not uncommon

Lliffuse

Features

Five year mortality

30 per cent

Slowly progressive renal insufficiency during persistent nephrotic syndrome; no progressive renal insufficiency during remission

Rare transition to diffuse proliferative lupus nephritis

urinary

abnormalities;

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No progression unless transition occurs; subsequent course then determined by the form of lupus nephritis which develops

Development of nephrotic syndrome with transi tion to diffuse proliferative lupus nephritis or membranous lupus nephritis not infrequent

Minimal occur

of all SLE from onset

Lupus Nephritis ~___~.

No clinical features of renal disease in some;minimal proteinuria and/or hematuria in others; occasional mild renal insufficiency; hypertension absent

Mesangial

Proteinuria in all at onset with rare exceptions; nephrotic syndrome at onset in onehalf, eventually in four-fifths; microscopic hematuria in one-half; occasional hypertension and minimal renal insufficiency at onset Remission of nephrotic syndrome in one-third; relapse common

.Perhaps characteristic

Lupus Nephritis

Onset during 1 st year of SLE in one-half

Membranous

_._~____

LUPUS NEPHRITIS-6ALDWIN

ET AL.

The precise significance of mesangial disease is difficult to define since some mesangial abnormality probably is present In all patients with SLE, and no correlation can be found in our own material between the extent of mesangial abnormalities and the presence or absence of clinical evidence of renal disease. The possibly ubiquitous presence of mesangial abnormalities in SLE raises some question as to the justification for considering this a form of lupus nephritis and suggests that this lesion may represent one of the histologic hallmarks of SLE. Alternatively, almost semantically, one might conclude that all patients with SLE have some renal disease. Although only scant material is available for evaluation of the kidney in patients without clinical evidence of renal disease, and the material has rarely been studied by all modalities, i.e., light, immunofluorescence and electron microscopy, the reports of Koffler [ 81, Cheatum [ 91, Grishman [ lo] and Morel-Maroger [22] and their associates indicate that immune deposits, often with increased matrix and proliferation of cells, are consistently found in the mesangium in such patients. On electron microscopy, dense deposits confined to the mesangial and paramesangial regions, rarely in other sites, are found to correlate with the presence of IgG and C3 in SLE patients without clinical renal disease. Similar pathologic findings, i.e., mesangial proliferation and increased matrix and mesangial localization of immune deposits, are also observed in a certain number of patients with minimal urinary abnormalities but usually not much other clinical evidence of renal disease. Cheatum et al. [ 91 described this lesion in four of 25 patients with lupus nephritis, Ginzler et al. [ 1 l] described it in nine of 89 patients, and in the present series mesangial abnormalities alone have been found on initial biopsy in about 10 per cent of the patients with clinical evidence of lupus nephritis and in three patients in whom biopsies were performed in tha absence of any clinical evidence of renal disease. A number of observers, including ourselves, have reported the regression of diffuse proliferative lupus nephritis to the mesangial form in association with clinical remission, usually following combined steroid and cytotoxic drug therapy, [ 14,15,19]. Progression from the mesangial lesion to the diffuse proliferative form has been described by Griihman et al. [ lo], Ginzler et al. [ 111 and Zimmerman et al. [23], and we, ourselves, have observed this transition in three of our 12 patients, and the transition to membranous lupus nephritis in one. It seems likely that mesangial immune deposits are typical of all patients with SLE. The additional presence of mesangial proliferation or the occurrence of urinary abnormalities may reflect quantitatively more immune complex deposition with the production of glomerular injury. However, the extent of mesangial change and clinical

26

January 1677

The American Journal ol Medlclne

abnormalities correlate poorly. In some patients, the process may never progress any further, whereas in other patients this minimal lesion may be followed by one of the other forms of lupus nephritis. The extension of dense deposits beyond the mesangium to a paramesangial orsubendothelialdistribution appears to be an early phenomenon in the evolution of mesangial lupus nephritis to diffuse proliferative lupus nephritis [ 10,241. In the present series, mesangial lupus nephritis was characterized by mild clinical evidence of renal disease, usually proteinuria and microhematuria combined, occasionally by microhematuria alone. The lesion may exist without any urinary abnormalities. Mild hypertension and minimal impairment of renal function were found on rare occasions. The clinical evidence of renal disease usually appeared within one year of the onset of SLE. Rarely, proteinuria reached the range of 1.5 to 2.5 g/24 hours. In one patient the nephrotic syndrome developed when the renal biopsy specimen still showed only mesangial changes and shortly went on to diffuse proliferative lupus nephritis which progressed to renal failure. One may presume that the long-term course in most patients witi mesangial lupus nephritis is benign judging by the relatively good prognosis in earlier series of patients with “mild” proliferative lupus nephritis (which probably included those now designated as mesangial) and by the experience developing currently, now that this form of lupus nephritis is being specifically identified by most observers. The patients generally continua with minimal urinary abnormalities and progressive renal failure fails to develop. The distinction between the “kidney of SLE” with immune mesangial deposits and a lesion with sufficient mesangial proliferation and matrix to be termed mesangial lupus nephritis is at present an arbitrary one. Identification of the clinical, immunologic and morphologic features which characterize those in whom the condition is destined to progress to the clinically more significant forms of lupus nephritis may provide a basis for the application of preventive therapy. Although some observations were made on levels of serum complement and DNA antibodies in the present study, the data were not sufficient to permit a systematic examination of possible correlations between these immunologic parameters and the clinical course. In our previous report [ 11, we noted that transition from one form of lupus nephritis to another was uncommon. “Progression” from the mesangial form of lupus nephritis to diffuse proliferative lupus nephritis, which has been described by others [ 10,11,23] and which occurred in three of our patients, may actually represent the development of lupus nephritis in patients in whom an earlier biopsy specimen fortuitously was

Volume 62

LUPUS NEPHRITIS--BALDWIN

available to document the presence of mesangial immune deposits which are probably typical of all patients with SLE. Similarly, the appearance of membranous lupus nephritis in a single patient in our group with mesangial lupus nephritis, should perhaps be interpreted as the onset of lupus nephritis rather than as a “transition.” Transitions from focal proliferative lupus nephritis to diffuse proliferative lupus nephritis have been documented by a number of observers [ 11,13,19,25]. In the present series, this transition was observed in two of 12 patients, after almost 12 years of observation in one, and after only six months of observation in the other. In the latter patient, it seems reasonable to speculate that the apparent “transition” represents a quantitative difference in the degree of glomerular involvement in the course of a developing diffuse lesion. In one patient diffuse proliferative lupus nephritis was observed to develop after documented membranous lupus nephritis. Membranous lupus nephritis was observed after previous documentation of focal proliferative lupus nephritis in one patient and of diffuse proliferative lupus nephritis in two. The appearance of membranous lupus nephritis with epimembranous and intramembranous electron-dense deposits has been described by Hayslett et al. [21] in patients with diffuse proliferative lupus nephritis undergoing remission during treatment with azathioprine and steroids. They speculated that the change in localization of immune deposits might reflect decreased antibody production with consequent relative antigen excess and formation of small soluble circulating complexes. Although the transition to membranous lupus nephritis was made in two of our patients upon remission from diffuse proliferative lupus nephritis during steroid therapy, membrahous lupus nephritis was not observed in six other patients in whom remission from diffuse proliferative lupus nephritis was induced by steroids alone or in combination with immunosuppressive agents. The course of diffuse proliferative lupus nephritis changed abruptly in about one-fifth of the patients in the present series on the occurrence of necrotizing arteritis and arteriolitis in the kidney. In these patients severe hypertension and rapidly progressive renal failure developed leading to death, usually in weeks to months, occasionally after one year. frequently retinopathy. heart failure or encephalopathy was an associated finding. The fact that vasculitis was found almost exclusively at necropsy in patients following the course just described and rarely in renal biopsy material obtained earlier in the course of diffuse proliferative lupus nephritis indicates that the development of vasculitis carries an ominous prognosis. Several features in these patients suggest that the renal vasculitis represents an immunologic event in the course of SLE rather than the

ET AL.

appearance of malignant hypertension as a complication of their nephritis, as may be seen in other glomerular diseases. Its occurrence only in patients with diffuse proliferative lupus nephritis in whom immunologically mediated glomerular and interstitial disease is severe, favors such an hypothesis. Furthermore, immune deposits of IgG and C3 have been found in the walls of the involved vessels. The infrequent presence of severe retinopathy and the extremely rapid progression to uremic death within eight weeks in seven of the nine patients in our series would be atypical for the course of malignant hypertension complicating glomerulonephritis. Finally, the absence of antecedent lupus nephritis in one of our patients constitutes convincing evidence that necrotizing vasculitis may develop de novo as an immunologic disorder of the kidney in SLE. Glomerular sclerosis has been observed in about one-half of our patients with diffuse proliferative lupus nephritis, and to a lesser extent in those with focal proliferative lupus nephritis or membranous lupus nephritis. Sclerosis progressed in diffuse proliferative lupus nephritis primarily in patients who succumbed to uremia only after periods exceeding three years, a more protracted course than the usual one in our series. This suggests that glomerular sclerosis may be the histologic evidence of a lower level of glomerular damage in diffuse proliferative lupus nephritis, or that sclerosis may become manifest only when the disease severity is such that the patient survives for a longer period. Usually glomerular sclerosis accompanied clinical and histologic evidence of subsidence of diffuse proliferation. Whether sclerosis under such circumstances represents the end-result of the antecedent severe glomerular damage or will prove to be a progressive process in the absence of subsequent proliferation remains to be seen. In six patients whose initial renal biopsy specimens were obtained from two to 12 years after onset of renal disease, sclerosis was the only glomerular abnormality. The onset with the nephrotic syndrome in two of them suggests that a diffuse proliferative lesion probably preceded the development of sclerosis, although some proliferation was still evident when glomerular sclerosis appeared in the course of others with previously documented diffuse proliferative lesions. The membranous form, which is also commonly manifested by the nephrotic syndrome, is much less likely to have been the lesion which antedated the finding of sclerosis alone, since “membranous abnormalities” were still demonstrable in the single patient with documented membranous lupus nephritis which progressed to advanced sclerosis and uremia. On first consideration, it might be presumed that earlier biopsies in the other four patients with sclerosis alone probably would have shown diffuse proliferative lupus nephritis or mem-

January 1977

The American Journal of Medicine

Volume 62

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LUPUS NEPHRITIS-BALDWIN

ET AL.

branous lupus nephritis, the more severe forms of lupus nephritis. However, our knowledge of the natural history of these forms fails to lend strong support to this proposition, since the nephrotic syndrome, a typical feature of membranous lupus nephritis and diffuse proliferative lupus nephritis, was never present in these patients. Furthermore, the more typical histologic changes would be expected to be in evidence in addition to sclerosis, particularly since in these patients the condition had progressed to renal insufficiency. The development of sclerosis in our patients with previously documented diffuse proliferative lupus nephritis was always associated still with some proliferation, albeit mild and confined to the mesangium in some. As to focal proliferative lupus nephritis, sclerosis has developed occasionally in the course of this form, but here also proliferation continued to be evident, and in no instance have we observed progression to moderately advanced renal insufficiency as was the case in the four patients presently under discussion. We have no longterm experience with the clinical and pathologic course of the mesangial lesion and cannot exclude the possibility that glomerular sclerosis may slowly develop in the course of this form of lupus nephritis. Choosing among the known forms of lupus nephritis, it seems most likely that mild diffuse proliferative lupus nephritis without the nephrotic syndrome, or remitted diffuse proliferative lupus nephritis, or perhaps recurrent focal proliferative lupus nephritis preceded the development of glomerular sclerosis in these patients. However, an alternative hypothesis, that the glomerular sclerosis in these patients did not result from any of the known pathologic forms of lupus nephritis, warrants consideration. The possibility exists that there is a mechanism for glomerular damage in SLE which is characterized not by proliferation but by glomerular sclerosis alone. The generally grave prognosis of diffuse proliferative lupus nephritis, even with long-term administration of large dosage steroid, has naturally fostered an interest in an alternate or supplementary form of treatment. Following the reports by Chasis [26] and Baldwin [27] and their associates on the use of nitrogen mustard in glomerulonephritis, Dubois [28], in 1954, was the first to describe remissions with this drug in almost one-half of a small group of patients with lupus nephritis. There was little interest in the use of cytotoxic drugs for SLE during the next 15 years as the newly developed steroids were exploited and their undoubted value demonstrated in control of the nonrenal manifestations of the disease. As it became clear that the majority of patients with the severe forms of lupus nephritis did not fare well, and that persistent large dose steroid therapy was undoubtedlycontributing to morbidity and mortality, interest appeared anew in the possible value of cyto-

28

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toxic drugs. During the past five years Bardana [29]. Drinkard [30], Cameron [31], Steinberg [32], Sztejmbok [33], Shelp [14], Hayslett [21], Cade [3~], Dillard [35], and Steinberg [36] and their associates have reported favorable results using cyclophosphamide, azathioprine or nitrogen mustard in patients with diffuse proliferative lupus nephritis of varying severity. The effectiveness of these agents in some patients appears to be established. The frequency with which remission of the nephrotic syndrome has been obtained suggests that therapy with cytotoxic drugs may even be more effective than large dose steroid therapy, but definite superiority of cytotoxics over aggressively administered steroid remains still to be established [ 19,371. In well-controlled short-term studies, Steinberg and associates [36] have shown that cytotoxic drugs may be combined with smaller doses of steroids to achieve at least as effective control or remission of lupus nephritis as can be anticipated with large dose steroid therapy alone. However, in a more recent report dealing with patients followed for over two years, the same investigators [38] concluded that cytotoxic drugs add only marginally to the control of lupus nephritis. Although deterioration of renal function occurred more frequently with prednisone therapy alone, deaths due to infection in patients receiving cytotoxic therapy equalized the incidence of unfavorable outcomes on the different treatment regimens. Similar conclusions have been reached by Hahn et al. [39] who compared azathioprine therapy with and without prednisone in a small group of patients with “severe” lupus nephritis and found no steroid-sparing effect or favorable influence on the course of those treated with the addition of cytotoxic drug. Our own experience in 12 patients with diffuse proliferative lupus nephritis who received a cytotoxic agent in addition to prednisone suggests that the course has been favorably altered when compared to the 32 patients who were given steroid alone. Remission in the nephrotic syndrome could be induced more frequently; moderate renal insufficiency did not preclude remission, as it did with steroid therapy alone; and remission was induced by the addition of a cytotoxic drug after no response had occurred during at least three months of steroid therapy. The observations reported here on the course of lupus nephritis in a large group of patients serve to emphasize once again the distinctive clinical features of the different morphologic forms and yet the variety of courses which may be pursued among patients with the same form. Thus, the nature of lupus nephritis makes evaluation of treatment regimens exceedingly difficult. Clearly, strict classification of patients by all available morphologic criteria is critical in any study attempting to compare the immediate and long-term

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effects of different therapies. Furthermore, the variable courses which may be followed within a particular classification, particularly in patients with diffuse proliferative lupus nephritis, require observations in large numbers of patients over long periods before any conclusion can be reached concerning the benefit of new therapeutic regimens as compared to treatment with steroid alone. We have noted a high incidence (93 per cent) of the nephrotic syndrome in patients whom we have classified as having diffuse proliferative lupus nephritis, a close correlation between persistent nephrotic syndrome and progressive renal failure, and a generally poor prognosis, 53 per cent mortality in two years. It would seem that efficacy of treatment would be best tested in a sharply defined group of patients such as these with diffuse proliferative lupus nephritis. The lower incidence of nephrotic syndrome and better prognosis in diffuse proliferative lupus nephritis reported by others suggest to us that the morphologic criteria utilized in classification must not be uniform among different observers. In any case, our experience leads us to conclude that the key to effective management of lupus nephritis will probably prove to reside in early treatment, guided by certain prognostic morphologic and serologic criteria, rather than in attempts to obtain remission in patients with well-established diffuse proliferative lupus nephritis with the nephrotic syndrome. Our present knowledge concerning the clinical, pathologic and immunologic features of renal involvement in SLE permits the following hypothesis regarding the natural history of lupus nephritis. Mesangial immune deposits, at times with mesangial histologic abnormalities, are probably common to all patients with SLE. Minimal clinical evidence of renal disease may or may not be associated with the mesangial changes. Certain specific immunologic events are responsible for focal proliferative, diffuse proliferative and membranous lupus nephritis. During the first year or so of systemic lupus, focal proliferative lupus nephritis, diffuse pro-

liferative lupus nephritis or membranous lupus nephritis develops in approximately two of three patients; the remaining one-third continue with the mesangial hallmark of SLE. Once having been established, the particular form of lupus nephritis generally remains typical for a given patient, and the renal lesion varies usually only in severity, presumably reflecting spontaneous or treatment-induced quantitative changes in circulating immune complexes. Although complete remission may occur, progressive glomerular damage commonly takes place in diffuse proliferative lupus nephritis and membranous lupus nephritis. Occasionally, the immunologic events required for initiation of one of the three distinctive forms do not occur until later in the course of SLE, thus accounting for apparent “transitions” from mesangial involvement to focal proliferative lupus nephritis, diffuse proliferative lupus nephritis or membranous lupus nephritis. Even less commonly, in a patient with an established form of lupus nephritis, the immunologic basis and morphologic features of a different form may develop later. The concept of lupus nephritis as a “continuum” is tenable only if one chooses to use this term to describe the invariable presence of mesangial changes prior to the development of one of the other three forms of lupus nephritis or the occasional appearance of focal disease transiently in the course of a developing diffuse lesion. As the more severe forms of lupus nephritis, once established, rapidly produce irreversible glomerular damage and are resistant to treatment, a prophylactic approach to the problem of lupus nephritis, based on an arbitrary period of therapy early in the course of all patients with SLE, warrants serious consideration and investigation. ACKNOWLEDGMENT We gratefully acknowledge the nursing, technical and artistic contribution of Patricia Egan, R.N., Barbara de Leo, George R. Obiedzinski, Susan Schechter, Mary Wagner, Joy Pena and Pamela Hecht.

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systemic lupus erythematosus. N Engl J Med 269: 537, 1963. Baldwin DS. McCluskey RT: Renal involvement in systemic lupus erythematosus. periarteritis nodosa, scleroderma, and cryoglobulinemia, chap 12. Structural Basis of Renal Disease (Becker EL, ed), New York, Hoeber Medical Division. Harper 8 Row, 1968. Koffler D, Schur PH,Kunkel HG: Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126: 607, 1067. Cheatum DE, Hurd ER, Strunk SW, et al.: Renal histology and clinical course of systemic lupus erythematosus. A prospective study. Arthritis Rheum 16: 670, 1973. Grishman E. Porush JG. Lee SL, et al.: Renal biopsies in lupus nephritis. Correlation of electron microscopic findings with

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