Predictive value of renal pathology in diffuse proliferative lupus glomerulonephritis

Kidney International, Vol. 36 (1989), pp. 891—896

Predictive value of renal pathology in diffuse proliferative lupus glomerulonephritis MELVIN M. SCHWARTZ, JAY BERNSTEIN, GARY S. HILL, KEITH HOLLEY, ELIZABETH A. PHILLIPS, and THE Luus NEPHRITIS COLLABORATIVE STUDY GROUP The Lupus Nephritis Collaborative Study Group: Clinical Coordinating Center: Edmund J. Lewis, Principal Investigator, B.S. Kasinath, Coprincipal Investigator, Anil K. Bidani, Director, Central Immunology Laboratory, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois. Biostatistics Coordinating Center: John Lachin, Shu-ping Lan, Elizabeth A. Phillips, George Washington University, Bethesda, Maryland. Pathology Reading Committee: Melvin M. Schwartz, Chairman and Director of the Central Pathology Laboratory, RushPresbyterian-St. Luke's Medical Center, Chicago, Illinois; Jay Bernstein, William Beaumont Hospital, Royal Oak, Michigan; Gary S. Hill, Francis Scott Key Medical Center, Baltimore, Maryland; Keith Holley, Mayo Clinic, Rochester, Minnesota. Clinics: Marc A. PohI, John Clough, Gordon Gephardt, Cleveland Clinic, Cleveland, Ohio; Tomas Berl, University of Colorado, Denver, Colorado; Nathan Levin, Henry Ford Hospital, Detroit, Michigan; Lawrence G. Hunsicker, Stephen Bonsib, University of Iowa, Iowa City, Iowa; Norman Simon, Hartmann Friederici, Evanston Hospital, Evanston, Illinois; Francesco del Greco, Frank A. Carone, Northwestern University, Chicago, Illinois; Lee Hebert, Han M. Sharma, Ohio State University, Columbus, Ohio; Eric Neilson, John Tomazewski, University of Pennsylvania, Philadelphia, Pennsylvania; Howard L. Corwin, Melvin M. Schwartz, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois; Andrew Levey, Angelo Ucci, Tufts-New England Medical Center, Boston, Massachusetts; Howard Shapiro, Barbara F. Rosenberg, William Beaumont Hospital, Royal Oak, Michigan; Jacob Lemann, John Garancis, Medical College of Wisconsin, Milwaukee, Wisconsin; Kenneth Shapiro, Praveen Chander, New York Medical College, Valhalla, New York; Fred Whittier, John W. Graves, Joan Bathon, Roger Riley, West Virginia University, Morgantown, West Virginia, USA

Predictive value of renal pathology in diffuse proliferative lupus gbmerulonephritis. We tested the value of the activity (A!) and chronicity (CI) indices devised by Austin et alE!, 21 as predictors of outcome in lupus patients with diffuse proliferative glomerulonephntis (DPGN). Four renal pathologists independently scored the Al and CI on 84 renal biopsy specimens from patients with lupus DPGN followed for 109 74

weeks (mean

that the degree of inflammation required for the diagnosis of DPON is

alone predictive of outcome. Since the histological indices did not improve the predictive value of the standard histological classification (ISKDC/WHO) in this group of patients with DPGN, we recommend holding in abeyance therapeutic decisions based upon the CI until its predictive value is independently confirmed.

SD), and the mean score was compared to the

development of renal failure and to adverse outcome (combined data for

renal failure, death and predefined clinical stop points). Receiver operator characteristic curves were derived from a series of 2 x 2 tables

Glomerular pathology has been demonstrated to be an indicator of prognosis in the patient with systemic lupus erythematosus (SLE) [2—7]. Although patients falling within the category of diffuse proliferative glomerulonephritis (DPGN) have the

in which one variable was renal failure or adverse outcome and the other variable was Al or Cl dichotomized by a cut-off point. Over the

entire range (0 to 10) of the CI there was no value that separated patients who developed renal failure from those who did not. The ROC curve analysis indicated that the sensitivity and specificity of the CI

worst prognosis among those with lupus nephritis, there is

were too low to allow it to function as a good test. Once patients entering renal failure were identified, the mean CI approached but did not reach a significant difference when compared to the mean CI of those who did not go into renal failure (4,38 0.42, mean SE vs. 3.19

marked variability in the clinical course. Because of this, efforts

and in revised form May 30, 1989 Accepted for publication June 18, 1989

International Study of Kidney Disease in Children/World

© 1989 by the International Society of Nephrology

the efficacy of the Al/Cl as predictors of outcome in patients

have been made to define the histological features associated with a poor renal prognosis. Austin et al [1, 2] have reported 0.23, P = 0.0620). The Cl did not predict the adverse clinical that a semiquantitative index of glomerular sclerosis, fibrous outcomes, There was no cut-off value of the CI which separated glomerular crescents, tubular atrophy, and interstitial fibrosis patients who had an adverse outcome from those who did not, and this result was confirmed by ROC analysis. As a group, the patients who (Chronicity Index, CI) is a better indicator of renal failure than reached an adverse outcome had a higher CI (4.12 0.37, mean SE) is either a conventional histological classification system based than those who did not (3.2 0.24), but this difference was not upon the extent and nature of the glomerular abnormality or an significant (P = 0.3944). In this population of patients with the his- index based upon the quantitation of active histological signs of tologic diagnosis of DPGN, there was no value for the Al over its entire range (4 to 22) that predicted either renal failure or adverse outcome. acute inflammation (Activity Index, Al). Because of the broad The mean Al was not different either for those who developed renal prognostic and therapeutic implications of these studies, others failure and those who did not (11.24 0.48, mean SE vs. 11.35 0.47, [8, 9] have attempted to duplicate their findings with conflicting P = 0.7257) or for those with and without an adverse outcome (11.41 results. 0.44, mean SE vs. 11.27 0.50, P = 0.7061). This finding indicates As part of a multicenter, prospective, randomized trial of the effect of plasmapheresis on outcome in severe SLE glomerulonephntis (GN), we have biopsied and studied a large number of patients with histologic diagnosis of DPGN as defined by the Received for publication August 19, 1988 Health Organization (ISKDC/WHO) Classification [10]. To test

891

892

Schwartz et a!: Pathology of lupus glomerulonephritis

Table 1. Patient characteristics at baseline Number of patients Age Male/female Caucasian Black Hispanic Other Renal involvement to biopsy Diastolic blood pressure Serum creatinine Serum C3

Urine protein excretion Azathioprine within 3 months of biopsy Alkylating agent within 3 months of biopsy Prednisone therapy at time of biopsy a Mean SD

84 32.1 12.5 yearsa 14/70 60% 22% 7% 11% 27.22 monthsa 13.40 13 mm Hga 88 2 1.30 mg/dla 57 29 mgldla

5.5

Table 2. Exclusion critera

A. Less than 16 years old. B. Currently pregnant. C. Serum creatinine greater than 6 mg/dl. D. Ever received plasmapheresis. E. Has a history of primary myocardial disease. F. Has a history of neoplasia within past 5 years. G. Has a history of prednisone associated psychosis. H. Has a history of peptic ulceration documental by radiology or endoscopy within the past 3 years.

I. Has evidence of primary active liver disease. J. Physician does not agree to patient participating in the study.

4.2 g/24 hoursa

13%

7% 75%

renal lesions, the type and severity of systemic symptoms, and the therapy they received. The two treatment groups did not differ with respect to the prognosis of severe SLE GN, survival, development of renal failure, or the appearance or outcome of

severe life-threatening complications [13]. Study entry and analysis began at the time of randomization, and the length of follow-up ranged from 3 to 258 weeks with a mean of 109 74 with SLE and DPGN, we scored each biopsy for activity and weeks (mean SD). chronicity indices, and the histological indices were related to outcome. Renal pathology Pathology material. The Central Pathology Laboratory reMethods ceived the following materials from the individual clinic patholPatients ogists: (1) the set of histologic slides stained with hematoxylin The present analysis is based upon the 84 patients from whom and eosin, Masson's trichrome, periodic acid-Schiff (PAS), and prerandornization renal biopsy specimens were available in the PAS-silver methenamine that had been used in the clinic to Study of Plasmapheresis In Severe Lupus Nephritis undertaken establish the histologic diagnosis and to determine eligibility; (2) by the Lupus Nephritis Collaborative Study Group (LNCSG). photomicrographs documenting immunofluorescence staining The detailed pathologic description of the biopsies [11] has been with anti-IgG and anti-fibrin; and (3) copies of the electron reported elsewhere, The patients' clinical and laboratory values micrographs. Methodological details have been previously reare given in Table 1. Admission criteria included: (a) a diagnosis of SLE conforming to the criteria of the American Rheumatism Association [14]; (b) clinical evidence of' renal disease; (c) the absence of defined exclusion criteria (Table 2); and (d) biopsy diagnosis of DPGN obtained within three weeks of randomiza-

ported [13]. The morphological material was coded in the Central Pathology Laboratory so the pathologists scoring the biopsies would not have direct knowledge of the clinic laboratories or of their pathologic diagnosis. Definition of DPGN as an entry criterion. The biopsies were

tion. The 85 patients who met the admission criteria were classified according to a modification of the ISKDC/WHO randomized to either standard treatment or standard treatment classification of SLE ON [10]. DPGN, as described in the plus plasmapheresis to assess the clinical effect of plasmapher-

literature [3—7], includes a heterogenous group of lesions that

esis in severe lupus GN. All patients received 60 mg/day are separated from less severe forms of lupus ON by signs of "severe" inflammation in the majority of the glomeruli. For the purpose of this report the diagnosis of DPGN was established weeks, after which they were reevaluated and either continued either by: (1) involvement of all or nearly all (more than 80%) of or entered into a regimen with tapering dosage. They also glomeruli by severe cellular proliferation and infiltration in a received cyclophosphamide, 2 mg/kg/day, for five weeks, fol- global endocapillary, mesangiocapillary or crescentic pattern or lowed by 1 mg/kg/day for 2 weeks. Cyclophosphamide was then by prominent subendothelial deposits; or (2) severe segmental discontinued [12]. The validity of the therapeutic trial depended UN with active histological evidence of inflammation in more upon the homogeneity of the patients in the different treatment than 50% of the glomeruli [7, 15]. Patients with extensive groups. A total of 45 demographic features, historical and epimembranous immune deposits who also had severe prolifertherapeutic details, physical findings, and laboratory data were ative changes in more than 50% of glomeruli qualified to enter compared for the standard and the standard plus plasmaphere- this study. These forms of lupus GN are the most severe end of sis groups, and they were similar in all respects [11]. The ARA the morphologic spectrum of the ISKDC/WHO categories. A criteria gave us a standard for the diagnosis of systemic lupus minimum of ten glomeruli were required for classification, and erythematosus; the exclusion criteria assured us that the pa- the 84 biopsies contained 19.4 10 glomeruli (mean SD). tients were able to tolerate either therapeutic regimen and that One-third of the biopsies had no hyalinized glomeruli, and those they did not have end-stage kidney disease; the renal biopsy with obscolescent glomeruli had 2.9 0.6 glomeruli (mean prednisone if they weighed less than 80 kg and 80 mg/day if they

weighed more than 80 kg. They received this dose for four

documented the presence of "active" inflammation and/or SD) involved. Activity and chronicity indices (Al/Cl). The published criteria necrosis in fifty percent or more of the glomeruli. Thus, the patients were homogeneous with respect to the severity of their for scoring the Al/Cl were followed [1, 2]. The following

893

Schwartz et a!: Pathology of lupus glomerulonephritis

features were scored on the basis of the percentage of total glomeruli involved (less than 25 percent—i +, 25 to 50 per-

Table 3. Chronicity index (CI) summarized by outcomes (Austin et al [2] definition of chronicity cut offs)

cent—2+, and >50 percent—3 +): glomerular cell proliferation, karyorrhexis and fibrinoid necrosis, cellular crescents, hyaline deposits (wire loops and hyaline thrombi), glomerular sclerosis, Renal failurea CIl and fibrous crescents. Leukocyte exudation was scored on the CI=2,3 number of neutrophils/glomerulus, (2/glomerulus—i +, 3/gbCI4 merulus—2 +, 3 or more/glornerulus—3 +). Interstitial inflammation, tubular atrophy, and interstitial fibrosis were scored as = 4.86

mild (<20 percent—l+), moderate (20 to 40%) or severe

(>40%) based on the proportion of cortical tissue involved. The Al/Cl were the sum of the scores of the individual pathological featLres except for karyorrhexis/fibrinoid necrosis and cellular

Present

Not present

Totals

2a

11

5

24 26

13 29 42

Adverse outcome

CI1 CI=2,3 CI4

N

16

N

T

2 8

11 21

18

24

-

N

4 13

29 42

4

crescents which were weighted (score x 2). The Al was thus x2 = 403b defined as the sum of the scores for glomerular proliferation, a Defined in text leukocyte exudation, karyorrhexis and fibrinoid necrosis (x2), b None of the above statistics reach the 5% significance level, the cellular crescents (x2), hyaline deposits and interstitial inflamcritical values for the chi-square distribution being 5.99 for 2 degrees of mation. The maximum score for the AT was 24 points. The CI freedom (chronicity). was the sum of glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The maximum score for the CI was 12 points.

Pathology Reading Committee (PRC) The eligibility of the patient for entry into the study, based on the renal pathology, was determined by the individual clinic pathologists, but histologic stratification and scoring of the A! and CI were accomplished by the PRC. As cases accrued, the PRC met at six month intervals and reached a consensus on histologic diagnosis and patient eligibility in each case after examining all the pathology materials and filling out a detailed worksheet. The worksheet was sent to the LNCSG Biostatisti-

cal Coordinating Center (BCC) in Bethesda, Maryland for

and sensitivity of each test value are plotted (ordinate = sensitivity and abscissa =

1— specificity), the resulting receiver operator characteristics (ROC) curve describes the diagnostic efficacy of the test [17, 181. For example, in a test that has both high sensitivity and specificity the ROC curve will be shifted up and to the left. The point where the rapidly rising curve shifts to a plateau will be the value separating the true positives from the true negatives. In contrast a curve with low sensitivity and specificity will be a straight line midway between the axes. For each outcome, a Wilcoxon Rank Sum Test was carried out for both Activity and Chronicity, within each Pathology Category. The tests, appropriately weighted, were combined over these strata and (applying the normal approximation) yielded Pvalues quoted in the text [19].

analysis. At the end of the Clinical Trial, the Chairman of the PRC (MMS) abstracted the criteria for the Al and CI, and, after consultation with the other members, a second worksheet was constructed. Each member independently scored each biopsy Results for Al and CI. The worksheets containing each member's score for the Al and C! were sent to the BCC for analysis. Evaluation Relationship of the CI to the specific outcome of renal failure of Al/Cl in relation to outcome and pathologic diagnosis are The CI did not predict renal failure as a specific outcome. The based upon the mean score of the four observers. entire range (range = 0 to 10) of CI scores was evaluated for Outcomes

predictive efficacy, and there was no value of the CI that separated patients who developed renal failure from those who

Three endpoints were organized in the clinical trial: death did not develop renal failure (data not shown). For example, (due to renal and non-renal causes), chronic renal failure (serum when the cutoff points, previously reported to have graded creatinine 6.0 mgldl or a rise in serum creatinine of >3.0 predictive values, were tested [2] (Table 3), they failed to mg/dl), or defined clinical stop points that indicated serious separate patients with and without renal failure. The same data

complications due to SLE, the therapeutic program or an were used in the ROC analysis (Fig. 1), and the data revealed a intercurrent disease process [12]. For this presentation only straight line relationship. That is, for any value of the CI the renal failure and adverse outcome, the latter comprising all patient had a 50% chance of reaching the renal failure endpoint, three study endpoints, will be analyzed in relationship to the CI and as a test, the C! did not predict the occurrence of renal and the A!.

failure for individuals. While not prospectively predictive, the mean CI of patients who developed renal failure was higher Statistics than those who did not reach renal failure, but this analysis of Sensitivity and specificity were determined from a series of 2 retrospective difference did not reach statistical significance x 2 tables in which the binary outcome variable (renal failure/ (4.38 0.42, mean SE vs. 3.19 0.23, P = 0.0620). no renal failure; adverse outcome/no adverse outcome) is one Relationship of the CI to the combined study outcomes classification and activity or chronicity dichotomized by a cutoff point is the second classification. In this type of analysis The CI was tested against the combined study outcomes the 2 x 2 tables for each value of the test (CI or Al) allows the (death, renal failure, and clinical stop points), and it did not calculation of a chi-square statistic [16]. When the specificity predict an adverse result. There was no value of the CI which

894

Schwartz a al: Pathology of lupus glomerulonephritis *

1.0 a

Table 4. Activity index (Al) summarized by outcomes (Austin et al [21 definition of activity cut offs) Present

0.8

> 1 C

Totals

Not present

N

N

N

Renal failurea

0.6

AI<12

iia

30

41

12

31

43

13 15

28

41

28

43

AI12

T

= 0.0I2

0.4

Adverse outcomea

AI<12

a

0.2

AI12 =

0.0

0.2

0.0

0.4

0.6

0.8

a Defined

1.0

1 - Specificity

in text

b None of the above statistics reach the 5% significance level, the

critical values for the chi-square distribution being 3.84 for 1 degree of

Fig. 1. ROC curve using CI as a test for renal failure. The curve freedom (activity). indicates that CI does not differentiate patients who develop renal failure from those who do not. 1.0

1.0

*

* 0.8

0.8

*

0.6 >

*

0.6

*

*

a,

C

Cl,

0.4

C

(0 0.4

*

* 0.2

—'

0.0

0.0

*

0.2

*

0.2

0.4

0.6

0.8

1.0

1 - Soecificity

0.0 0.0

*

0.2

0.4

0.6

0.8

1.0

1 - Specificity

Fig. 2. ROC curve using CI as a test for the study endpoints (renal

Fig. 3. ROC curve using Al as a test for the study endpoints (renal

failure, death and clinical stop points). The curve indicates that CI does not distinguish patients who reach a study endpoint (adverse outcome) from those who do not.

failure, death and clinical stop points). The curve indicates that the Al

does not distinguish patients who reach a study endpoint (adverse outcome) from those who do not.

separated patients who reached an adverse outcome from those not predict renal failure or adverse outcome in our individual who did not (data not shown), and the selected values of the CI patients with DPGN. When the mean AT for the group of [2] illustrated in Table 3 did not reach significance. The ROC patients who developed renal failure (11.24 0.48) was comanalysis based upon these data (Fig. 2) graphically demon- pared with the mean AT for the group of patients who did not strates the predictive failure of the CI. As a group, the patients develop renal failure (11.35 0.47), there was no difference (P who reached an adverse outcome had a higher CI (4.12 0.37, = 0.7257). The mean Al was also tested for all the study mean SE) than those who did not reach an adverse outcome endpoints, and there was no difference between the group with SE) and without 0.44, mean (3.2 0.24), but the difference was not significant (P = 0.14). adverse outcome (11.41 adverse outcome (11.27 0.50, P = 0.385). Relationship of the Al to the spec j/ic outcome of renal failure Discussion and to the combined study endpoints (adverse outcome) The glomerular lesion of DPGN has been considered to carry There was no predictive value for the Al over its entire range (range 4 to 22). When the patients were arbitrarily divided at a a poor prognosis in lupus patients [2—7, 15], and it appears to score of 12 (12 < Al 12) [2], there was no predictive value for reflect a degree of systemic disease activity that places the either renal failure or adverse outcome (Table 4). When the data patient at increased risk of both renal and non-renal complicain the 2 X 2 tables was used to determine specificity and tions of SLE [2—7, 15]. In this study of a clinically well-defined

sensitivity, ROC curves for renal failure (not shown) and group of patients with lupus DPGN who had been treated adverse outcome (Fig. 3) were straight lines. Thus, the Al did according to defined therapeutic protocols, neither the Al nor

895

Schwartz et a!: Pathology of lupus glomerulonephrizis

the CI identified the individuals who would develop adverse outcomes or renal failure over a mean follow-up of 109 74 (mean SD) weeks. There were no significant differences in the CI between groups of patients who did well and those who did poorly, and the lack of a discriminating value for either the Al or the CI markedly reduces their prognostic value in individual patients. Thus, the histological indices of glomerular injury proposed by Austin et all 1, 2] failed to augment information available from standard histopathologic evaluation. Patients with an elevated CI, analyzed as a group, may be at greater risk of developing renal failure than individuals with comparable "active" glomerular lesions and no morphological evidence of chronicity. Austin et al reported that an elevated CI identifies a group of patients at risk of developing renal failure when they are followed for four [1] and five [2] years. Rush et al [8] studied 20 children with diffuse proliferative lupus GN. Using an index of clinical outcome based on urinalysis, serum creatinine, need for dialysis/transplantation, and death from end-stage renal failure, they found that CI was predictive of renal outcome but the A! was not. However, the significance of these observations may be questioned. The presence of both an

that the CI is an independent therapeutic guide should be discouraged. Technical issues regarding accurate quantitation and reproducibility of a histologic index must be taken into consideration

if we are to evaluate the potential benefit of this parameter. Histopathologic grading systems, such as the activity and chronicity indices, are based upon a series of subjective interpretations. Differences among pathologists or between tempo-

rally separate observations by a single pathologist are frequently a function of observer variation rather than real differences in pathology [21—23]. Even assuming that the his-

tologic indices are reproducible, a minor amount of chronic disease may significantly elevate the CI. Glomerular sclerosis involving less than 25% of the glomeruli and concomitant tubular atrophy and interstitial fibrosis can result in the calculation of a CI of 2 or higher, and Austin et al report that patients

with even this level of chronicity had a significantly worse course than those with a CI of I or 0. However, analysis of their published reports [1, 2] reveals 30 patients who did not develop renal failure who had glomerular lesions other than DPGN and a chronicity index of two or higher [24]. If the chronicity index only predicts renal failure in patients with DPGN, its usefulness

elevated CI and DPGN in a renal biopsy implies not only irreversible damage but the potential of further glomerular is considerably diminished in lupus, a disease with notorious destruction and loss of renal function. It is logical to reason that a patient with lupus nephritis who has travelled a portion of the

variability in its rate of progression and a significant proportion of initially benign forms of glomerulonephritis that transform to road to renal failure will develop renal insufficiency more more aggressive lesions. The issues raised by Austin et al [1, 2, quickly than a patient with comparable glomerular inflammation 25, 26] in the histologic assessment of the renal biopsy in lupus who has not yet suffered irreversible nephron loss. The problem are important. However, the lack of predictive value of the CI with this tautological approach is that most patients with an in our large group of patients with DPGN and in lupus patients elevated CI do not develop renal failure (Table 3). In fact, an with glomerular lesions other than DPGN raises doubt regardelevated CI did not help us to identify the individual patient who ing the clinical value of this measurement. We recommend developed renal failure after a mean follow-up of 109 weeks. holding in abeyance therapeutic decisions based upon the CI The reason that some patients with an elevated CI eventually until its value is independently confirmed.

develop renal failure may be related to non-immunological factors in the progression of chronic renal disease. A less speculative interpretation of the data, based upon our current understanding of the pathogenesis of glomerular scarring and nephron loss in lupus nephritis, is that patients with an elevated CI exhibit the sequelae of a protracted course and have a more advanced renal lesion at the time of biopsy.

The pathology seen on renal biopsy is frequently used as a therapeutic guide in addition to its role as a prognostic indicator [2, 7, 15]. The effectiveness of standard treatment and the lack

Acknowledgments This work was supported by United States Public Health Service research award AM 27770. We thank Christine Spano for assistance in preparing the manuscript.

Reprint requests to Melvin M. Schwartz, M.D., Department of Pathology, Rush-Presbyterian-St. Luke's Medical Center, 1653 W. Congress Parkway, Chicago, Illinois 60612, USA.

of correlation between the activity index and outcome is attributed, at least in part, to the response to therapy of the "active" signs of inflammation that form the basis for the ISKDC/WHO classification [20]. In contrast, Magil et al [9] found that the AT but not the CI predicted renal insufficiency (established Se,. = 2.0 mg/dl). General experience with lupus nephritis dating from the first renal biopsy study [3] indicates that patients with DPGN should be treated whether or not the glomerular lesion is accompanied by chronic parenchymal damage. The CI indicates a level of chronic renal damage, and the glomerular scars, tubular atrophy and interstitial fibrosis that constitute the CI are thought to be irreversible and therapeutically unresponsive. In drawing a distinction between chronic parenchymal damage and glomerular "activity," the CI has focused attention on untreatable abnormalities. The rational therapy of lupus nephritis is directed at reducing the destructive

effect of the active inflammatory lesion, and any implication

References I. AUSTIN HA III, MUENZ LR, JOYCE KM, ANTONOVYCH T, KULLICK ME, KLIPPEL JH, DECKER JL, BALOW JE: Prognostic factors

in Lupus Nephritis. Contribution of renal histologic data. Am J Med 75:382—391, 1983 2. AUSTIN HA III, MUENZ LR, JOYCE KM, ANTONOVYCH T, BALOW

JE: Diffuse proliferative lupus nephritis: Identification of specific pathologic features affecting renal outcome. Kidney liii 25:689—695, 1984

3. MUEHRCKE RC, KARK RM, PI1NI CL, POLLAK VE: Lupus Nephritis. A clinical and pathologic study based on renal biopsies. Medicine 36: 1—146, 1957 4. POLLAK yE, PI1LANI CL, SCHWARTZ FD: The natural history of the

renal manifestations of systemic lupus erythematosus. J Lab Clin Med 63:537—550, 1964 5. BALDWIN DS, LOWENSTEIN J, ROTHFIELD NF, GALLO U, MC-

CLUSKEY RT: The clinical course of the proliferative and membranous forms of lupus nephritis. An mt Med 73:929—942, 1970

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Schwartz et a!: Pathology of lupus glomerulonephritis

6. BALDWIN DS, GLUCK MC, LOWENSTEIN J, GALLO GR: Lupus nephritis. Clinical course as related to morphologic forms and their transitions. Am J Med 62:12—30, 1977 7. APPEL GB, SILVA FG, PIRANI CL, MELTZER JI, ESTES D: Renal involvement in systemic lupus erythematosus (SLE): A study of 56 patients emphasizing histologic classification. Medicine (Baltimore) 57:371—410, 1978

8. RUSH PJ, BAUMAL R, SHORE A, BALFE JW, SCHREIBER M: Correlation of renal histology with outcome in children with lupus nephritis. Kidney In! 29:1066—1071, 1986 9. MAGIL AB, PUTERMAN ML, BALLON HS, CHAN V, LIRENMAN DS, RAE A, SUTTON RAL: Prognostic factors in diffuse proliferative lupus glomerulonephritis. Kidney mt 34:511—517, 1988 10. CHURO J, SOBIN LH: Renal disease. Classification and Atlas of Glomerular Disease. New York, Igaku-Shoin, 1982, pp. 127—149 Ii. SCHWARTZ MM, LAN S-P, THE Lueus NEPHRITIS COLLABORATIVE STUDY GROUP: Clinical outcome of 3 discrete glomerular lesions in severe lupus glomerulonephritis (LGN). Am J Kid Dis 13:273—283, 1989

12. HEBERT L, NEILSON E, POHL M, LACHIN J, HUNSICKER L, LEWIS EJ, THE LuPus NEPHRITIS COLLABORATIVE STUDY GROUP: Clin-

ical course of severe lupus nephritis during the controlled clinical trial of plasmapheresis therapy. (abstract) Kidney In! 31:201, 1987 13. LEWIS EJ, LACHIN J, THE LuPus NEPHRITIS COLLABORATIVE STUDY GROUP: Primary outcomes in the controlled trial of plasma-

pheresis therapy. (abstract) Kidney mt 31:208, 1987

16. FLEIS JL: Statistical Methods. New York, John Wiley and Sons, 1981

17. SWETS JA, PICKETT RM, WHITEHEAD SF, GErrY DJ, SCHNUR JA,

SWETS JB, FREEMAN BA: Assessment of diagnostic technologies.

Advanced measurement methods are illustrated in a study of computed tomography of the brain. Science 205:753—759, 1979 18. LANGLEY FA, BUCKLEY CH, TASKER M: The use of ROC curves in

histopathologic decision making. Anal Quant Cytol Histol 7:167— 173, 1985

19. LEHMANN EL: Nonparametrics: Statistical Method Based on Ranks. New York, Holden-Day, 1975 20. CAMERON JS, TURNER DR, Ooo CS, WILLIAMS DG, LESSOF MH,

CHANTLER C, LEIBOWITZ S: Systemic lupus with nephritis: A long-term study. Q J Med 48:1—24, 1979 21. SissoNs HA: Agreement and disagreement between pathologists in histological diagnosis. Postgrad Med J 51:685—689, 1975 22. SILCOCKS PBS: Measuring repeatability and validity of histological diagnosis—A brief review with some practical examples. J Clin Pathol 36:1269—1275, 1983 23. REID B, HAGGITT RC, RUBIN EE, ROTH G, SUROWICZ CM, VAN BELLE G, LEWIN K, WEINSTEIN WM, ANTONIOLI DA, GOLDMAN H, MACDONALD W, OWEN D: Observer variation in the diagnosis

of dysplasia in Barrett's esophagus. Hum Pathol 19:166—178, 1988 24. LEWIS EJ, KAWALA K, SCHWARTZ MM: Histologic features that

correlate with the prognosis of patients with lupus nephritis. Am J Kidney Dis 10:192—197, 1987

25. BALOW JE, AUSTIN HA III, MUENZ LR, JOYCE KM, AN-

14. TAN EM, COHEN AS, FRIES JF, MASt AT, MCSHANE DJ, ROTHFIELD NF, SCHALLER JG, TALAL N, WINCHESTER RJ: The 1982

TONOVYCH TT, KLIPPEL JH, STEINBERG AD, PLATZ PH, DECKER

revised criteria for the classification of systemic lupus erythemato-

lupus nephritis. N EnglJ Med 311:491—495, 1984 26. AUSTIN HA III, KLIPPEL JH, BALOW JE, LERICHE NGH, STEIN-

sus. Arthr Rheurn 25:1271—1277, 1982

15. SCHWARTZ MM, KAWALA KS, CORWIN HL, LEWIS EJ: The

JL: Effect of treatment on the evolution of renal abnormalities in

prognosis of segmental glomerulonephritis in systemic lupus

BERG AD, PLATZ PH, DECKER JL: Therapy of lupus nephritis: Controlled trial of prednisone and cytotoxic drugs. N Engi J Med

erythematosus. Kidney mt 32:274—279, 1987

314:614—619, 1986