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 SLE patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti-CD45 antibody staining and standard histochemical staining. Follow-up data was obtained and survival analysis carried out to determine which histologic features were predictive of subsequent renal failure. Results By CD45 staining TI was a common pathological finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with dsDNA 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 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 (HR 2.2, 95% C.I. 1.3, 3.6, p=0.002 vs. HR 1.0, 95% C.I. 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 immunological mechanisms underlying TI may provide novel targets for therapeutic intervention.

Long‐term outcome of lupus nephritis in Asian Indians

“…A possible explanation could be the improved outcomes in class IV (and class III) with current cytotoxic regimens (1). Also, tubulointerstitial inflammation rather than glomerular pathology may be an important determinant of prognosis, which we did not study (32). However, there may have been a true difference in outcomes that our study may not have detected due to smaller numbers in the nonproliferative classes.…”

“…Indeed, many studies have found proliferative lesions on biopsy or class IV to have a worse prognosis (2,8,10,30,31). However, there have been some studies that also did not find any differences in outcomes by class of nephritis (11,21,32). A possible explanation could be the improved outcomes in class IV (and class III) with current cytotoxic regimens (1).…”

Population pharmacokinetic and pharmacodynamic analysis of BIIB023, an anti‐TNF‐like weak inducer of apoptosis (anti‐TWEAK) monoclonal antibody

“…The progression of LN from a mild condition to a more severe form and possible renal failure involves multiple pathways within the kidney; therefore, a treatment that targets common underlying pathologies would be advantageous [9,35,36]. Involvement of the TWEAK/Fn14 axis in both glomerular and tubular damage positions this pathway as an attractive therapeutic target for the treatment of patients with LN, many of whom currently rely on broadly immunosuppressive agents [9].…”

“…Baseline assessments were performed prior to dosing on Day 1. Follow-up occurred through the final study visit on Day 71, with assessments on Days 3, 4, 6 (±6 hours), and on Days 8,11,15,22,29,35,43, 57 and 71 (±2 days).…”

“…Blood samples were collected for the determination of BIIB023 serum concentrations on Day 1 (predose and 5 minutes, 2 hours and 8 hours after the end of the 1 hour infusion), Day 2 (24 hours postdose), Day 3 (48 hours postdose), Day 4 (72 hours postdose), Day 6 (120 hours postdose), Days 8,11,15,22,29,35,43,57 and Day 71 (final study visit or early withdrawal from the study visit). All BIIB023 concentrations reported as below the limit of quantification (BLQ; <0.1 μg ml À1 ) were set equal to zero (i.e., they were not treated as 'missing').…”