Clinical and Pathological Features of Plasma Cell-Rich Acute Rejection After Kidney Transplantation

Hasegawa, Jumpei; Honda, Kazuho; Omoto, Kazuya; Wakai, Sachiko; Shirakawa, Hiroki; Okumi, Masayoshi; Ishida, Hideyuki; Fuchinoue, Shohei; Hattori, Motoshi; Tanabe, Kazunari

doi:10.1097/tp.0000000000002041

Cited by 17 publications

(19 citation statements)

References 20 publications

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“…We investigated the presence of plasma cells within allografts in our model. Although the exact effector function of intra-renal plasma cells and their role in allograft rejection is not fully understood, intra-renal plasma cells have been associated with chronic allograft rejection and poor prognosis [24,[33][34][35][36]. Although we have previously shown that anti-BAFF therapy reduced the number of splenic plasma cells [23], the difference in intra-renal plasma cells between groups was not statistically significant in this study.…”

Section: Discussioncontrasting

confidence: 77%

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B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats

Steines

Poth

Herrmann

et al. 2020

IJMS

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Intra-renal tertiary lymphoid organs (TLOs) are associated with worsened outcome in kidney transplantation (Ktx). We used an anti-BAFF (B cell activating factor) intervention to investigate whether BAFF is required for TLO formation in a full MHC-mismatch Ktx model in rats. Rats received either therapeutic immunosuppression (no rejection, NR) or subtherapeutic immunosuppression (chronic rejection, CR) and were sacrificed on d56. One group additionally received an anti-BAFF antibody (CR + AB). Intra-renal T (CD3+) and B (CD20+) cells, their proliferation (Ki67+), and IgG+ plasma cells were analyzed by immunofluorescence microscopy. Formation of T and B cell zones and TLOs was assessed. Intra-renal expression of TLO-promoting factors, molecules of T:B crosstalk, and B cell differentiation was analyzed by qPCR. Intra-renal B and T cell zones and TLOs were detected in CR and were associated with elevated intra-renal mRNA expression of TLO-promoting factors, including CXCL13, CCL19, lymphotoxin-β, and BAFF. Intra-renal plasma cells were also elevated in CR. Anti-BAFF treatment significantly decreased intra-renal B cell zones and TLO, as well as intra-renal B cell-derived TLO-promoting factors and B cell differentiation markers. We conclude that BAFF-dependent intra-renal B cells promote TLO formation and advance local adaptive alloimmune responses in chronic rejection.

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Section: Discussioncontrasting

confidence: 77%

“…Plasma cells are antibody-producing cells derived from B cells and have been found within kidney allograft infiltrates [24]. We therefore determined the amount of intra-renal plasma cells by staining for IgG + elliptical cells, as previously described [23].…”

Section: Effect Of Anti-baff Treatment On Intra-renal Plasma Cellsmentioning

confidence: 99%

B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats

Steines

Poth

Herrmann

et al. 2020

IJMS

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“…Not only are suppression of NLR and PLR associated with ACR, but the underlying mechanism is from a relative increase in the lymphocyte count, which is expected given the pathogenesis of rejection. While flow cytometric detection of early T cell activation, CD69 expression has yielded mixed results [ 4 , 18 ], quantitative competitive RT-PCR assays measuring mRNA for cytotoxic effector molecule expression by PBMCs in renal transplant recipients have yielded more favorable results [ 4 , 17 , 19 , 20 ]. Compared to these techniques, a routinely obtained CBC with differential easily captures the inflammatory signature that precedes detection of allograft dysfunction and allows integration of this information with ongoing allograft and urinary immune biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Predict Acute Cellular Rejection in the Kidney Allograft

et al. 2018

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BackgroundKidney transplantation is the treatment of choice for end stage kidney disease, but acute rejection remains a limiting factor in optimizing allograft and patient survival. Needle biopsy is the current standard of care for this diagnosis. The potential for complications with repeat biopsies limits the ability to obtain temporal immune surveillance of the allograft. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be strong predictors of inflammation and of worse prognosis in a variety of conditions.Material/MethodsThis is a single center retrospective case control study which included all patients who underwent a “for -cause biopsy” of a transplanted kidney. NLR and PLR were calculated 1 month prior, at the time, and 6 months and 1 year after the biopsy.ResultsA total of 159 biopsies were reviewed; 127 (79.9%) of these satisfied all inclusion and exclusion criteria, and 63.0% of the sample cohort (n=80) demonstrated acute cellular rejection (ACR). Patients without evidence of ACR had an average NLR of 26.8, which was approximately 7-fold greater than those patients with findings of ACR (P<0.01). A similar trend was found for PLR, where patients without ACR had a 5.5-fold greater PLR compared to those with rejection (P<0.01). The ROC showed AUC of 0.715 and 0.716 respectively. The NLR cutoff of 9.5 had a positive predictive value (PPV) of 80% and a negative predictive value (NPV) of 77.8%; the PLR cutoff of 380 had a PPV of 75% and a NPV of 100%.ConclusionsThis study showed that NLR and PLR are easily obtainable and reproducible predictors of ACR in the kidney allograft. Serial monitoring of these ratios will help identify subclinical inflammation before evidence of allograft dysfunction.

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“…The majority (about 90%) of acute rejections, especially in the first year after ktx, are T cell-mediated [3]. However, emerging evidence has revealed that intra-graft B-cell accumulation plays an important role in T cell-mediated rejection as well and correlates with a worse outcome [4,5,6]. However, the mechanistic details are not completely resolved.…”

Section: Introductionmentioning

confidence: 99%

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection

Schiffer

Wiehler

Bräsen

et al. 2019

IJMS

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The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.

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Clinical and Pathological Features of Plasma Cell-Rich Acute Rejection After Kidney Transplantation

Abstract: The results indicated that PCAR was an independent risk factor for allograft loss. PCAR presented with all types of rejection in the Banff 2015 criteria, and AMR/sAMR was associated with poor allograft survival.

Cited by 17 publications

References 20 publications

B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats

B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Predict Acute Cellular Rejection in the Kidney Allograft

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection

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