Variable Expression of Programmed Cell Death Protein 1-Ligand 1 in Kidneys Independent of Immune Checkpoint Inhibition

Hakroush, Samy; Kopp, Sarah Birgit; Tampe, Désirée; Gersmann, Ann-Kathrin; Korsten, Peter; Zeisberg, Michael; Tampe, Björn

doi:10.3389/fimmu.2020.624547

Cited by 19 publications

(29 citation statements)

References 14 publications

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“…A total number of 148 kidney biopsies with various intrarenal renal pathologies including 53 cases with ANCA GN at the University Medical Center Göttingen were retrospectively included between 2015 and 2020, the patient cohort has previously been described [ 45 , 61 , 62 , 63 ]. While no formal approval was required for the use of routine clinical data, a favorable ethical opinion was granted by the local Ethics committee (protocol codes: 22/2/14, approval date 22 September 2014 and 28/09/17, approval date 17 November 2017).…”

Section: Methodsmentioning

confidence: 99%

Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

Hakroush

Tampe

Korsten

et al. 2021

IJMS

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Background: Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic kidney disease (CKD), end-stage renal disease (ESRD) or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN), a common manifestation of glomerular injury in AAV. However, there is growing evidence that activation of the complement pathway contributes to the pathogenesis and progression of AAV. We here aimed to compare glomerular and tubulointerstitial lesions in ANCA GN and extrarenal manifestation of AAV in association with levels of circulating complement components C3c and C4. Methods: Plasma levels of C3c and C4 in a total number of 53 kidney biopsies with ANCA GN were retrospectively included between 2015 and 2020. Glomerular and tubulointerstitial lesions were evaluated according to established scoring systems for ANCA GN and analogous to the Banff classification. Results: We here show that circulating levels of C3c and C4 in ANCA GN were comparable to the majority of other renal pathologies. Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation. By systematic scoring of glomerular and tubulointerstitial lesions, we provide evidence that low levels of circulating C3c and C4 correlated with vasculitis manifestations to distinct renal compartments in ANCA GN. Conclusions: We here expand our current knowledge about distinct complement components in association with vasculitis manifestations to different renal compartments in ANCA GN. While low levels of C4 correlated with glomerulitis, our observation that low levels of circulating complement component C3c is associated with interstitial vasculitis manifestation reflected by intimal arteritis implicates that C3c contributes to tubulointerstitial injury in ANCA GN.

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Section: Methodsmentioning

confidence: 99%

Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

Hakroush

Tampe

Korsten

et al. 2021

IJMS

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“…A total number of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively included between 2015 till 2020; the patient cohort has previously been described (16)(17)(18)(19)(20)(21). While no formal approval was required for the use of routine clinical data, a favorable ethical opinion was granted by the local Ethics committee (no.…”

Section: Study Populationmentioning

confidence: 99%

Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

et al. 2021

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BackgroundAcute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN.MethodsA total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation.ResultsNeutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes.ConclusionOur observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

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“…A total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively included between 2015 and 2020, the patient cohort was previously described (19)(20)(21)(22)(23)(24)(25). While no formal approval was required to use routine clinical data, a favorable ethical opinion was granted by the local Ethics committee (protocol no.…”

Section: Study Populationmentioning

confidence: 99%

“…(15-20.5). The median (IQR) SAPS II at admission was 24(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), and 24/53 (45.3%) of patients required ICU supportive care. There were 44/53 patients (83%) with some extrarenal manifestation of AAV (31 with lung, 9 with sinus, 12 with joint, 4 with ear, 3 with eye, 6 with peripheral nerve, and 9 with skin involvement), and 7/53(13.2%) had alveolar hemorrhage.…”

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confidence: 99%

Comprehensive Analysis of Sex Differences at Disease Manifestation in ANCA-Associated Glomerulonephritis

et al. 2021

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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems, including the kidney. Besides investigations focusing on renal outcomes, sex differences associated with distinct clinical and histopathological findings in ANCA glomerulonephritis (GN) have not been systematically investigated. Therefore, we here aimed to systematically analyze sex differences in patients with AAV and biopsy-proven ANCA GN. We provide a comprehensive analysis of 53 kidney biopsies with ANCA GN retrospectively included between 2015 and 2020 and identified specific sex differences in ANCA GN concerning laboratory parameters and systematic scoring of renal histopathology glomerular and tubulointerstitial lesions, and extrarenal manifestations of AAV. We did not observe any correlation between sex and short-term clinical AAV course or disease severity by comparing general AAV parameters. AAV manifestations in females occurred at an older age with more joint involvement. Regarding histopathological findings, we, again, observed no sex difference among ANCA GN classification, but a significant correlation between females and distinct histopathological findings with less tubulointerstitial inflammation and vasculitis of peritubular capillaries. Finally, we here identified fewer associations between clusters of clinical, laboratory parameters, and histopathological findings in females as compared to males. These findings are of great relevance and further improve our understanding of sex differences in the pathogenesis of ANCA GN. While future studies about specific sex differences and conclusions in these clusters are crucial, our observations further support that sex differences are relevant, affect distinct parameters, and influence clinical, laboratory parameters, and histopathological findings in AAV, particularly ANCA GN.

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Variable Expression of Programmed Cell Death Protein 1-Ligand 1 in Kidneys Independent of Immune Checkpoint Inhibition

Cited by 19 publications

References 14 publications

Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

Comprehensive Analysis of Sex Differences at Disease Manifestation in ANCA-Associated Glomerulonephritis

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