1268

KIDNEY BIOPSY IN SYSTEMIC LUPUS ERYTHEMATOSUS

11. Survival Analyses According to Biopsy Results

JOHN McLAUGHLIN, DAFNA D. GLADMAN, MURRAY B. UROWITZ, CLAIRE BOMBARDIER, VERNON T. FAREWELL, and EDWARD COLE

Renal biopsy specimens from 123 patients with systemic lupus erythematosus (SLE) seen between 1970 and 1984 were assessed according to the World Health Organization classification and according to the pres- ence of proliferative, active, or chronic renal lesions. Survival analysis was used to study the determinants of mortality. Survival rates were higher for patients with minimal lesions, intermediate for patients with focal or diffuse proliferative nephritis, and low for patients with glomerular sclerosis. The presence of proliferative and chronic lesions was associated with a higher risk of dying. Renal biopsy results are helpful in predicting prognosis for all-cause mortality in patients with SLE.

From the University of Toronto Rheumatic Disease Unit, the Wellesley Hospital and Women’s College Hospital, Toronto, the Departments of Statistics and Actuarial Science and Health Studies, University of Waterloo, Waterloo, and the Division of Nephrology, St. Michael’s Hospital, Toronto, Ontario, Canada.

Supported by grants from the Arthritis Society and the Ontario Ministry of Health. Dr. McLaughlin’s work was supported by a PhD Fellowship from the National Health Research and Development Program of Health and Welfare, Canada.

John McLaughlin, PhD: Assistant Professor, Department of Preventive Medicine and Biostatistics, University of Toronto: Dafna D. Gladman, MD, FRCPC: Associate Professor of Medicine, Rheumatic Disease Unit, University of Toronto, and Rheumatolo- gist, The Wellesley Hospita!: Murray B. Urowitz, MD, FRCPC: Professor of Medicine, Physician-in-Chief, The Wellesley Hospital; Claire Bombardier, MD, FRCPC: Associate Professor of Medicine, Rheumatologist, The Wellesley Hospital, and Director, Clinical Epidemiology Program, University of Toronto: Vernon T. Farewell, PhD: Professor, Department of Statistics and Actuarial Science and Department of Health Studies, University of Waterloo: Edward Cole, MD, FRCPC: Associate Professor of Medicine, University of Toronto, and Division of Nephrology, St. Michael’s Hospital.

Address reprint requests to Dafna D. Gladman, MD, FRCPC, The Wellesley Hospital, 160 Wellesley Street East, Jones Building, Room 102, Toronto, Ontario, M4Y 153, Canada.

Submitted for publication August 14, 1990: accepted in revised form May 1, 1991.

The prognostic importance of renal biopsy in systemic lupus erythematosus (SLE) remains contro- versial. Several studies have demonstrated a relation- ship between survival and light microscopy findings on renal biopsy (1-9). Cameron (10) failed to detect such an association, and others have argued that the his- tologic classification of renal morphology does not add to the predictive value of clinical information, specif- ically when predicting renal death (1 1-13). We have shown that renal morphology does not always corre- late with the clinical features of renal disease noted at the time of biopsy (14).

The aim of this study was to assess whether renal biopsy provided important information about prognosis for all-cause mortality in patients with SLE.

PATIENTS AND METHODS Sample selection. Study subjects were selected from

the University of Toronto Lupus Database. This database contains observations made prospectively during the clinical examinations of SLE patients seen at the SLE clinic of a teaching hospital since 1970. Data collection has been stan- dardized by the use of a data collection form, which guides clinicians through the observation and definition of 207 demographic, historical, physical, laboratory, and therapeu- tic variables (15). To be included in the database, each patient must be diagnosed as having SLE, either by fulfilling 4 or more of the American College of Rheumatology (ACR) (formerly, the American Rheumatism Association [ARA]) criteria for the classification of SLE (16), or by having other manifestations of SLE in addition to several of the ACR (ARA) criteria.

This study included the members of the SLE data- base who had a renal biopsy at the Wellesley Hospital from 1970 until 1984. The indication for a renal biopsy did not require the presence of clinical renal disease. During this period, patients had biopsies as part of the assessment of

Arthritis and Rheumatism, Vol. 34, No. 10 (October 1991)

SLE SURVIVAL AND RENAL BIOPSY 1269

their SLE. This period of inclusion was chosen because the classification of renal biopsies obtained during this time was standardized by means of an expert review committee, and because it allowed a minimum of 2 years of followup for each subject. These cases were followed from the time of the patient’s first renal biopsy until January I , 1987. Only those whose renal tissue was first examined by biopsy, prior to their death, were included.

Of the 148 patients whose renal biopsies were read by the committee (see below and see ref. 14), 25 were excluded from this study: 14 whose renal tissue was first examined postmortem, and 11 whose biopsies were per- formed prior to their attending the SLE clinic. Thus, 123 patients were included in the present investigation. Further details of the SLE database and the clinical setting have been previously reported (14).

Renal biopsy assessment. Renal biopsy specimens were assessed using the World Health Organization (WHO) criteria for the classification of lupus nephritis (17,18). Biop- sies were read by a committee composed of a nephrologist, 2 renal pathologists, and 2 rheumatologists (14). The WHO classes were then grouped according to the presence of proliferative lesions (classes IV and subsets of classes 111 and V, which refer to proliferative lesions). Biopsies were also classified according to the presence of chronic renal lesions (glomerular sclerosis, interstitial fibrosis) and active renal lesions (cellular proliferation, cellular crescents, leu- kocytic infiltration, karyorrhexis, fibrinoid necrosis, and interstitial mononuclear cell infiltration), as defined by the indices reported by Austin et a1 (19). Active lesions were further classified according to the number of lesions present, whether 0, 1-2, or 3-4. By pooling the chronicity and activity variables into a single variable, patients were classified as having 1) neither active nor chronic lesions, 2) active lesions alone, or 3) chronic lesions with or without active lesions. These biopsies were read prior to the availability of the semiquantitative scoring system reported by Austin et al (19). Therefore, only the presence or absence of the lesions was recorded. Further details of the procedures employed ill the review of the renal biopsy specimens have been de- scribed elsewhere (14). Observations made using immuno- fluorescence and electron microscopy techniques were not available for all patients (obtained for 53% and 63%, respec- tively). The prognostic significance of these factors is there- fore not considered in this report.

Outcome measures. The primary outcome state was death due to any cause. Survival status was determined as of January 1, 1987. End-stage renal disease (ESRD), defined as the need for chronic dialysis and/or renal transplantation, was also documented. Patients who had not been seen at the SLE clinic for 1 year prior to the end-point date were traced to verify their final outcome status.

Statistical analysis. Survival analysis was used to study the determinants of mortality. Survival time was defined as the interval from the time of biopsy until death or until January 1, 1987, at which time living patients were “censored.” Nonparametric life-table methods were used to calculate the Kaplan-Meier estimates of survival probabili- ties (20), and survival curves were plotted. The null hypoth- esis of no difference in survival rates of patient subgroups was tested by a log-rank test (see chapter 6, ref. 21).

Table 1.

Number of subjects 123 Duration of followup, median years

(minimum, maximum) Number of assessments, median (minimum,

maximum) Duration of SLE before biopsy, median

years (minimum, maximum) Age, mean (standard deviation) Femalehale, number 91 1 Corticosteroid usage, number (%) Immunosuppressive agent usage, number (46) WHO biopsy class, number (%)

Features of the study sample at the time of biopsy*

4.7 (0, 15.9)

16 ( I , 71)

0.8 (0, 26)

33.9 (12.6)

96 (78) 13 (11)

Class I 8 (7) Class I1 52 (42) Class 111 20 (16) Class IV 32 (26) Class V 7 (6) Class V1 4 (3)

(minimum, maximum) Serum creatinine, median pmoles/liter

* See Patients and Methods for descriptions of the World Health Organization (WHO) biopsy classification system. SLE = systemic lupus erythematosus.

79.6 (44, 442)

Proportional hazards models (chapter 4, ref. 21) were used to estimate relative risk (RR). Relative risk was estimated as the antilogarithm of the regression coefficient for each cova- riate. Significance tests for individual parameters and 95% confidence intervals were obtained, based on the asymptotic normality of the parameter estimates. For ordinal variables, a trend test was performed to test for a general pattern of increasing (or decreasing) risk. The SAS (Statistical Analysis System) software program (22) was used for the statistical analysis.

RESULTS Patient characteristics. The features of the 123

subjects who were selected for this study are summa- rized in Table 1. T h e duration of SLE before biopsy was quite short , with a median of 0.8 years, whereas the length of followup after biopsy w a s long, with a median of 4.7 years and a total of 886.8 person-years of observation. The age and sex distributions are similar to those usually reported for SLE: patients seen in rheumatology clinics. T h e subjecl s were predomi- nantly women in their child-bearing years.

The median serum creatinine level was normal, at 79.6 pmoleslliter, with a range of 44-442 pmoles/ liter; 13 patients had an elevated serum creatinine level (> 120 pmoleslliter). Forty-nine percent of the patients had normal findings o n biopsies or had mesangial lesions only, while 42% had proliferative lesions (Ta- ble 1). Regarding treatment, 78% of the patients took corticosteroids, whereas only 1 1% took immunosup-

1270 McLAUGHLIN ET AL

pressive medications (azathioprine). The ACR (ARA) criteria for the classification of SLE (16) were met by 98% of the patients (120 of the 123) at the time of biopsy. For the remaining 3 patients, the diagnosis of SLE was made on the basis of the presence of 3 ACR (ARA) criteria plus other features of SLE.

Twenty-eight patients (23%) died during the study period. Five of them had ESRD (need for chronic dialysis and/or renal transplantation). Only 1 patient who survived developed ESRD. Due to the rarity of ESRD, it was not further analyzed as a study outcome.

Renal biopsy findings. Figure 1 presents the survival curves for patients classified by the WHO criteria. Differences can be noted in the survival rates among the 6 WHO classes. Patients with normal histologic features or mild lesions (classes I and 11) had higher survival rates than did patients with prolifera- tive or sclerosing lesions (classes 111, IV, or VI). The log-rank test for differences among the 6 WHO classes achieved borderline significance (2 = 10.76,5 degrees

1 .a

P

0

B

R 0.9

; 0.8 L O.’ I T 0.6 Y

0 0.5

F 0.4

U R 0.3 V I v 0.2 A L

0.1

0.0

1 IV

I VI

- No cases were observed for more than 7.9 years.

1 2 3 4 5 6 7 8 9 1 0 TIME AFTER BIOPSY (years)

Figure 1. Survival curves for the World Health Organization renal morphology classes I-VI (see Patients and Methods for details).

Table 2. Frequencies and relative risks of dying, according to the WHO renal biopsy class and according to the presence or absence of proliferative, chronic, and/or active lesions, in 123 patients with SLE*

95% No. of No. of Relative confidence cases deaths risk P interval

WHO biopsy class

Class I Class I1 Class 111 Class IV Class V Class VI

Proliferative lesions

Absent Present

Absent Present

None 1 or 2 3 or 4

Chronic lesions

Active lesions

Chronic, with or without active, lesions

None Active only Chronic with or

without active

8 52 20 32 7 4

84 39

105 18

72 36 15

70 35 18

1 1 .o 9 1.4 5 2.4

10 3.9 1 2.2 2 9.7

14 1 .o 14 3.4

19 1 .o 9 4.8

14 1 .o 8 1.2 6 3.6

13 1 .o 6 1 .o 9 4.8

- - 0.77 0.2-10.7 0.44 0.3-21.2 0.20 0.5-30.4 0.59 0.1-35.2 0.07 0.9-109.3

- - 0.002 1.6-7.2

- - <0.001 2.1-1 I .o

- - 0.63 0.5-3.0 0.02 1.2-8.2

- - 0.99 0.4-2.7

<0.001 2.0-11.7

* See Patients and Methods for descriptions of the World Health Organization (WHO) biopsy classification system. A total of 28 systemic lupus erythematosus (SLE) patients died during the study.

of freedom, P = 0.056). Figure 1 shows a general pattern of increasing risk from class I through class VI. The 5-year survival probabilities were high for classes I and 11 (86% and 94%, respectively), intermediate for classes 111 and IV (72% and 73%, respectively), and low for class VI (50%). Note that the survival rate for class V did not fit in the pattern of increasing risk with increasing WHO class. The trend test was significant (2 = 7.83, 1 degree of freedom, P = 0.005), which confirmed that, in general, risk increased from class I through to class VI.

Table 2 lists the number of cases in each biopsy class and the relative risk estimates obtained from proportional hazards models along with their associ- ated P values and 95% confidence intervals. Classify- ing the 123 subjects by a 6-level variable led to sparse data. The significant-trend test indicated that the WHO classification provided some information about

SLE SURVIVAL AND RENAL BIOPSY 1271

1 .C

P

0

B I 0.7 L I T 0.E Y

R 0.5

; 0.E

0 0.5 F

0.4

U

V I v 0.2 A L

R 0.3

0.1

0.0

- ABSENT

PRESENT

1 2 3 4 5 6 7 a 9 1 0 TIME AFTER BIOPSY (years)

Figure 2. Survival curves by presence or absence of proliferative renal lesions.

the risk of dying, and suggested that the relationship may be better represented by a classification system that uses fewer classes. The patients were therefore regrouped for further analysis.

The WHO classes were reduced to 2 categories according to the presence of proliferative renal le- sions, which included the proliferative components of classes I11 and IV. None of the class V cases had associated proliferative lesions. The sclerotic lesions (class VI) were classified with the proliferative lesions on pathophysiologic grounds, since they are thought to occur as a result of advanced proliferative disease. The survival curve for patients classified according to the presence of proliferative lesions is shown in Figure 2. The difference in survival between these 2 groups of patients was statistically significant (2 = 11.01, 1 degree of freedom, P < 0.001), with a higher risk of dying in those with proliferative lesions (RR = 3.4) (Table 2).

The presence of chronic renal lesions (glomer- ular sclerosis and interstitial fibrosis) was also signifi-

cantly associated with survival. Figure 3 shows that patients with chronic lesions have significantly lower survival rates than patients without these lesions (2 = 16.5, 1 degree of freedom, P < 0.001). The relative risk estimate shows that the risk of dying was 4.8 times greater for patients who had chronic lesions than for other patients (Table 2).

The 3-level classification of renal lesion activi- ty-no activity, 1-2 active lesions, 34 active lesions- achieved borderline significance by the log-rank test (2 = 5.70, 2 degrees of freedom, P = 0.057). The relative risk estimates (Table 2) suggested that the risk for patients with 1 or 2 active lesions was very similar to that for patients with no active lesions (RR = 1.2); however, a model which assumed an increasing risk through the active lesion classes could not be rejected (P = 0.42). For ease of interpretation in further ana- lyses, the active lesions were reclaissified as absent or present. Additional analyses (Table 2) indicated that the increased risk observed in patients with active

A B

L 0.7 I T 0.6, Y

0 0.5. F 0.4-

U R 0.3. V I v 0.2, A o.ll - No cases were obisewed

for more than 8.2 years.

0.0 1 - o 1 2 3 4 5 6 7 a 9 10

TIME AFTER BIOPSY (years) Figure 3. Survival curves by presence or ahsence of chronic renal lesions.

1272 McLAUGHLIN ET AL

renal lesions (absent, present) was limited to those who also had chronic lesions.

DISCUSSION Previous studies of the role of biopsy and

clinical and laboratory measures in the prognosis for SLE patients had a wide range of selection criteria, but in general, included only patients with definite renal disease (33-13,19,23). The sample from the Toronto SLE database had a larger proportion of patients in WHO classes I and 11, a lower average value of serum creatinine, and a smaller proportion of patients who were prescribed prednisone. The large proportion of patients in classes IV and V (86%) in the sample reported by Austin et a1 (19) was due to their inclusion of only lupus nephritis patients who were candidates for immunosuppressive therapy, which thereby ex- cluded patients with less severe renal disease.

In general, these differences suggest that in relation to the previously published series of biopsied SLE patients, the sample of 123 Toronto patients had a milder level of renal disease at the time of biopsy. It is therefore possible that this sample was more repre- sentative of the SLE patients encountered by rheuma- tologists in practice, especially with regard to the severity of renal disease.

The association between the WHO classes and mortality achieved only borderline significance when examined as 6 separate classes; however, there was a significant trend of increasing risk from class I through to class VI. The trend test indicated that the WHO classification provided some useful prognostic infor- mation, and suggested that 6 classes were not neces- sary for representing the relationship with mortality.

The finding that the WHO classification was at least a weak prognostic factor is consistent with pre- vious positive findings in univariable studies (3-6). Absolute risks were, however, considerably lower in this study than in the previous studies, which may reflect the less advanced disease in this study sample. For example, the 10-year survival rates for patients in classes 11, 111, and IV were 83%, 72%, and 63%, respectively, in this study, as compared with 66%, 34%, and 56% in a recent study by Appel et a1 (6). Previous studies have not reported survival rates for WHO class I subjects, which in this study, was 86% at 10 years. It should be noted that rates for classes I, V, and VI should be interpreted cautiously because of their imprecision due to small sample sizes (a total of 4 cases in class VI).

Proliferative lesions were detected in 32% of the sample, and were also significantly associated with mortality (univariable RR = 3.4, 95% confidence in- terval 1.6-7.2). Previous studies of the prognostic role of renal biopsy have not specifically reported risk in the presence of proliferative lesions. Since class IV lesions are among the more advanced proliferative lesions, studies that have reported mortality by WHO class can be used for comparison. Patients in WHO class IV have been repeatedly found to be at an increased risk of dying, with 5-year survival rates ranging from 30% to 79% (3-6,8,10), compared with a rate of 73% in this study.

Chronic renal lesions were present in 15% of the sample and were associated with an elevated risk of dying (univariable RR = 4.8, 95% confidence inter- val 2.1-1 1 .O). The presence of active lesions was also associated with an elevated risk; however, it did not contribute additional information beyond that pro- vided by the chronic lesion variable. The prognostic importance of chronic and active renal lesions that was demonstrated here is generally consistent with previ- ous studies. In a small study (36 patients) by Fries et a1 (24), chronic lesions were associated with mortality, but not statistically significantly. Previous studies that detected a statistically significant prognostic role for chronic and active renal lesions employed outcomes other than mortality (19,25). Other studies of mortality have employed different methods of classifying renal lesions, which allow only an indirect assessment of the role of chronic lesions (3-6,8,10).

One limitation of this study is the imprecision of estimates because of the small sample size, as indi- cated by the wide confidence intervals. For example, the sample was not large enough to fully examine the prognostic significance of the WHO classes since 3 of the classes had very few patients. However, this does not mean that the results are not valid. Additional studies of larger populations of patients who undergo renal biopsy are required in order to verify the prog- nostic significance of the full WHO classification.

The WHO classification was designed to pro- vide pathologists and clinicians with a uniform ap- proach to the description of lupus nephritis. Regroup- ing the WHO classes according to proliferative and chronic lesions adds to the predictive power of the histologic patterns. Thus, renal biopsy study results are helpful in predicting prognosis for all-cause mor- tality in patients with SLE.

SLE SURVIVAL AND RENAL BIOPSY 1273

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