Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring

Abstract

Objective: In lupus nephritis, glomerular injury correlates poorly with progression to renal failure. While the tubulointerstitium is also commonly involved, the importance of such involvement is not well defined. Therefore, we developed a simple method to assess the prognostic utility of measuring tubulointerstitial inflammation (TI).

Methods: Sixty-eight systemic lupus erythematosus patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti-CD45 antibody staining and standard histochemical staining. Followup data were obtained and survival analysis was carried out to determine which histologic features were predictive of subsequent renal failure.

Results: By CD45 staining, TI was a common pathologic finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with double-stranded DNA antibodies, serum C3, or glomerular inflammation. TI severity, but not glomerular injury, identified patients at greater risk for renal failure (P = 0.02). A high National Institutes of Health (NIH) chronicity index also identified patients at risk for renal failure. However, when the glomerular and tubulointerstitial subcomponents of the NIH chronicity index were separated in a bivariate model, only tubulointerstitial chronicity provided prognostic information (hazard ratio [HR] 2.2, 95% confidence interval [95% CI] 1.3-3.6; P = 0.002 versus HR 1.0, 95% CI 0.7-1.5; P = 0.97 for glomerular chronicity).

Conclusion: TI identifies lupus nephritis patients at greatest risk for progression to renal failure. The immunologic mechanisms underlying TI may provide novel targets for therapeutic intervention.

Figure 1. Interstitial nephritis severity predicts subsequent renal survival

1A. Kaplan-Meier curves demonstrating renal survival in severe (grade 3-4) versus mild (grade 1-2) interstitial inflammation* by anti-CD45. 1B. Kaplan-Meier curves demonstrating renal survival in a 5 tier measure of interstitial inflammation* by anti-CD45 antibody. Of note, no subjects fell into grade 0; thus 4 tiers are present. 1C. Kaplan-Meier curves demonstrating renal survival in a 5 tier measure of interstitial inflammation* by modified conventional light microscopy (MLM) using H&E and PAS stain. The number of patients available for analysis in each subgroup over time is provided for Figure 1A, while the total numbers of subjects over time is provided below Figures 1B and 1C. Detailed subgroup numbers for Figure 1B and 1C are provided in Tables S1 and S2. P values were derived using either a log rank test (A) or a log rank trend test (B, C). *5 tier measure: none/grade 0=0%; minimal/grade 1= <10%, mild/grade 2= 10-25%, moderate/grade 3=26-50%; or severe/grade 4= >50%.

Figure 2. ISN/RPS nephritis class and NIH activity index do not predict subsequent renal survival

2A. Kaplan-Meier curves demonstrating subsequent renal survival in those with proliferative (III+IV) or non-proliferative (II+V) nephritis class on renal biopsy. 2B. Kaplan-Meier curves demonstrating renal survival in those with an activity index of > 6 or ≤ 6. The number of patients available for analysis at each time point is provided below each figure. P values were derived using a log rank test.

Figure 3. The interstitial components of the NIH chronicity index predicts renal survival

3A. Kaplan-Meier curves demonstrating renal survival in those with a NIH chronicity index (CI) of ≤3 or >3. The NIH activity index was then divided into the glomerular (GCI) and tubulointerstitial (TCI) components and Kaplan-Meier curves were then used to examine the association of each index with subsequent renal survival. The number of patients available for analysis at each time point is provided below each figure. P values were derived using a log rank test.