Background/Purpose:     Current classification criteria of lupus nephritis (LN) emphasize glomerular pathology, however tubular atrophy and interstitial fibrosis (TAIF) are better predictors of poor renal outcomes.¹ In this work, we evaluate tubulointerstitial inflammation (TII) as a risk factor for TAIF and renal failure.

Methods:     The subset of LN patients that underwent ≥2 renal biopsies, because of persistent or recurrent LN, at Columbia University Medical Center (CUMC) from 1994-2018 were identified. All renal biopsies were interpreted by nephropathologists at the CUMC Department of Pathology and classified using the ISN/RPS LN classification criteria. OPAL multiplex immunohistochemistry staining to identify CD3, CD4, CD8, CD19 and CD68 expression in the kidney tissue was performed.

Results:     104 LN patients (84% female, 25±12 years old at diagnosis, 14% White, 40% Black, 35% Hispanic) requiring sequential renal biopsies with a median follow-up of 11 [6-16] years were identified. On initial biopsy, 94/104 (90%) had class III or IV proliferative LN with or without class V.  Forty-seven (51%) patients developed ESRD. Nine patients died and 14 were lost to follow-up.
    Multivariable modeling of histopathological findings on biopsy 1 identified the presence of crescents to be associated with progression to ESRD (OR 3.14 95% CI 1.22, 8.08), while the presence of wire-loop lesions was protective (OR 0.28 98% CI 0.09, 0.85). On biopsy 2, the presence of TAIF≥25% (OR 4.50, 95% CI 1.30, 15.55) and glomerulosclerosis in >25% of glomeruli (OR 3.78, 95% CI 1.15, 0.03) were the only independent predictors of ESRD.
    There was a sequential increase in TAIF severity on successive biopsy samples (10%, 26%, 34%, and 46% TAIF on biopsy 1 through 4, respectively).  On univariable analysis, TAIF≥25% biopsy 2-4 predicted progression to ESRD (p< 0.01). The severity of TII on biopsy 1 was associated with increased risk of more advanced TAIF on biopsy 2, while TII on biopsy 2 predicted TAIF on biopsy 3, (Fig 1). Interestingly, in the 78 patients with < 25% TAIF and < 25% sclerotic glomerular involvement, moderate-severe TII significantly predicted ESRD (OR 4.76 95% CI 1.68, 13.50), (Fig 2).
    Multiplex immunohistochemistry staining of kidney biopsy samples revealed that TII could be detected as organized immune infiltrate of T cell rich and B cell rich areas reminiscent of tertiary lymphoid structures (Fig 3, left) or as tubulitis mediated by CD3 T cells, often CD4^neg and CD8^neg (Fig 3, right).  

Conclusion:     TII predicts the development and extent of TAIF in lupus nephritis and is associated with a higher risk of progression to ESRD.

ACKNOWLEDGEMENT: The authors gratefully acknowledge the support of Dr. Anca D. Askanase and Dr. Adam Mor in this work.

1. Hsieh C et al.  Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken). 2011 Jun;63(6):865-74.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tubulointerstitial-inflammation-predicts-tubular-atrophy-fibrosis-and-renal-function-loss-in-lupus-nephritis/