Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis often leading to critical illness by multi-organ failure. Data for patients with specifically ...ANCA-associated renal vasculitis requiring intensive care unit (ICU) supportive care are limited and have mainly focused on long-term renal and overall outcome. Particularly, data on critical illness during the initial course of disease are scarce and remain poorly determined. Therefore, the purpose of this retrospective study was to identify predictors of critical illness in a cohort of patients with ANCA-associated renal vasculitis. We retrospectively included a total number of 53 cases with confirmed ANCA-associated renal vasculitis between 2015 till 2020 in a single-center cohort study. We here identified an association between low hemoglobin levels and requirement of ICU supportive care in patients with ANCA-associated renal vasculitis. Furthermore, levels of hemoglobin below 9.8 g/dL at admission independently predicted prolonged requirement of ICU supportive care in critically ill patients with ANCA-associated renal vasculitis. These findings confirm that low levels of hemoglobin negatively affect short-term outcome and could further improve our current understanding for the role of anemia in ANCA-associated renal vasculitis.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis affecting multiple organ systems, including the kidney. Small vessels in the kidney include ...small-sized arteries, capillaries, and venules. Intrarenal C4 deposits are now increasingly recognized as a potential marker and pathogenic mechanism of autoantibody-mediated tissue damage in ANCA-associated renal vasculitis. We here describe the relevance of complement C4 deposits localized to distinct vascular compartments in a cohort of biopsy-proven ANCA-associated renal vasculitis. A cohort of 43 biopsy-proven cases of ANCA-associated renal vasculitis with myeloperoxidase (MPO) or proteinase 3 (PR3) seropositivity were retrospectively enrolled in a single-center observational study. Univariate and multivariate regression analysis was performed to identify parameters associated with intrarenal C4 deposits in ANCA-associated renal vasculitis. We here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with better short-term survival (p = 0.008), implicating that this subgroup had a superior response to remission induction therapy. Second, C4 deposits in interlobular arteries were associated with eosinophilic infiltrates in renal vasculitis with MPO-ANCA seropositivity (p = 0.021). In renal vasculitis positive for MPO-ANCA, the absence of C4 deposits in the glomerular tuft was associated with sclerotic class ANCA-associated renal vasculitis (p < 0.001), and tubular RBC casts (p = 0.024). Fourth, complement C4 in interlobular arteries is associated with tubular atrophy specifically in renal vasculitis with PR3-ANCA seropositivity (p = 0.006). Finally, complement C4 deposits in peritubular capillaries associated specifically with hyaline casts in cases positive for PR3-ANCA (p = 0.025), implicating a role in tubular injury. Interestingly, C4 deposits were localized to distinct vascular compartments independent of the systemic activation of the complement system, reflected by the consumption of respective serum complement molecules in ANCA-associated renal vasculitis. In summary, we here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with survival and distinct histopathological lesions. Considering recent advances in AAV therapy with the emergence of new therapeutics that inhibit complement activation, we here provide novel insights into complement C4 as a potential marker to identify patients who may benefit most from these drugs. Thus, our results may contribute to a more personalized treatment approach of AAV depending on the relevance of distinct intrarenal complement deposits.
Lupus nephritis is one of the most common and serious complications of systemic lupus erythematosus (SLE). Lupus nephritis is a major cause of kidney failure in patients with SLE, attributed to ...increased morbidity and mortality. The in situ deposition of intrarenal immune complexes promotes the accumulation of inflammatory cells and causes kidney injury.
We here extracted transcriptome array datasets for expression of complement molecules in human lupus nephritis. Furthermore, we performed gene set enrichment analysis to identify molecular signatures associated with follow-up kidney function in lupus nephritis.
Within the glomerular compartment, intrarenal mRNA expression levels of
(p=
) and
(p=
) correlated with treatment success reflected by kidney function recovery specifically in class III lupus nephritis, while no such association was observed in class II or class IV lupus nephritis. Interestingly, mRNA expression levels of either glomerular
or
resulted in identical gene set and signalling pathways enrichments in human lupus nephritis, including interferon signalling and signalling by interleukins. Direct comparison of
and
confirmed a strong association between glomerular mRNA expression levels of both complement receptors (r=0.8955, p<0.0001).
This study provides additional insights into signalling pathways associated with intrarenal synthesis of complement components in lupus nephritis that might be also affected by targeted therapy of the complement system. These results require confirmation but may contribute to a personalised treatment approach in distinct classes of human lupus nephritis.
Introduction
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune ...glomerulonephritis, depicting in turn a major denominator of AAV mortality. It is well established that AAV patients feature an increased risk of developing thrombotic events, and platelets are activated in AAV patients being triggered by the alternative complement pathway. Platelets guard vessels integrity and initiate thrombus formation in response to endothelial damage, further constituting a triangular interconnection with the activation of neutrophils and the complement system. We here aimed to systematically assess the relevance of platelet counts and systemic complement system activation regarding distinct histopathological lesions in ANCA-associated renal vasculitis.
Methods
A cohort of 53 biopsy-proven cases of ANCA-associated renal vasculitis were retrospectively enrolled in a single-center observational study. Univariate and multivariate regression analysis was performed to identify parameters associated with platelet counts in ANCA-associated renal vasculitis compared to disease controls. Finally, the relevance of platelets for disease course and recovery was assessed by survival analysis.
Results
Lower platelet counts correlated with markers of kidney injury including eGFR loss (
p=0.0004
) and lower complement C3 levels (
p=0.0037
). Multivariate and subgroup analysis revealed that this association was only present in the subgroup with MPO-ANCA seropositivity (eGFR loss:
p=0.0009
, lower C3:
p=0.0032
). While lower platelet counts correlated with kidney injury in the PR3-ANCA subgroup (eGFR loss:
p=0.0272
), we did not observe an independent association with complement C3 levels (
p=0.4497
). Independent of any glomerular lesion, lower platelet counts correlated with interstitial fibrosis (
p=0.0313
), tubular atrophy (
p=0.0073
), and tubulitis in areas of interstitial fibrosis and tubular atrophy (
p=0.0033
). Finally, we observed significant differences with increased requirement of kidney replacement therapy (KRT) or death in the subgroup below median platelet counts (HR: 4.1, 95% CI: 1.6-10,
p=0.0047
), associated with a lower probability of discharge and prolonged hospitalization in this subgroup (HR: 0.5, 95% CI: 0.3-0.9,
p=0.0113
).
Conclusion
Based on our observation that an association between platelets and complement system activation is only observed in the MPO-ANCA subgroup, this could implicate that platelets and complement C3 link innate immunity to tubulointerstitial injury in the presence of MPO-ANCA autoantibodies.
Background
The coronavirus disease-2019 (COVID-19) pandemic impacted healthcare services for kidney disease patients. Lockdown and social distancing were mandated worldwide, resulting in closure of ...medical services. The diagnosis of various kidney diseases may have been delayed during the COVID-19 pandemic because non-urgent tests and visits were postponed due to closure of medical services during the lockdown.
Methods
We here report the impact of the COVID-19 pandemic on a total number of 209 native kidney diseases requiring renal biopsy for diagnosis in a retrospective observational study from a tertiary hospital in Germany.
Results
The lockdown period in March and April 2020 primarily affected patients admitted to the normal medical ward with a compensatory increased rate of renal biopsies in the postlockdown phase. In addition, there was a shift toward more patients admitted with hemoglobinuria during the COVID-19 pandemic. This phenomenon of an increased number of patients with hemoglobinuria during the COVID-19 pandemic was specifically observed in a subgroup with hypertensive nephropathy requiring renal biopsy and associated with increased proteinuria, not attributed to the COVID-19 lockdown period itself.
Conclusion
To our knowledge, this is the first report of identifying a subpopulation susceptible to closure of medical services during the COVID-19 pandemic and diagnostic delay of specific kidney diseases. Therefore, the COVID-19 pandemic should be regarded as a risk factor especially in patients with diseases other than COVID-19 primarily admitted to the normal medical ward.
In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results ...from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances T cell infiltration and enables efficacy of anti-PD-1 immunotherapy. This study identifies the functional impact of Col1 homotrimers on tumor microbiome and tumor immunity, implicating Col1 homotrimer-α3β1 integrin signaling axis as a cancer-specific therapeutic target.
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•Col1 produced by pancreatic cancer cells is the oncogenic homotrimer variant•Col1 homotrimer deletion in cancer cells inhibits pancreatic tumor progression•Col1 homotrimer deletion enriches T cells and beneficial tumor microbiome•Col1 homotrimer deletion enables the efficacy of anti-PD-1 immunotherapy
Chen et al. identify that type I collagen (Col1) produced by pancreatic cancer cells is the abnormal homotrimer variant with oncogenic properties. Deletion of Col1 homotrimer in cancer cells inhibits tumor progression and reshapes the tumor microbiome. Cancer-Col1 homotrimer deletion enhances T cell infiltration and enables efficacy of anti-PD-1 immunotherapy.
Background
The activation of the complement system contributes essentially to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. We here aimed to directly ...compare levels of C3 and C4 for outcome prediction in ANCA-associated renal vasculitis.
Methods
Serum levels of complement components C3 and C4 were directly compared in association with clinical and outcome data in a retrospective cohort of ANCA-associated renal vasculitis.
Results
As compared to poor outcome prediction by low levels of complement C3 (
p
= 0.0093), low levels of complement C4 did not associate with early requirement of kidney replacement therapy (KRT) or death (
p
= 0.2396). In the subgroup that experienced KRT or death, low C3 levels identified 11/14 (78.6%,
p
= 0.0071) and C4 levels 9/14 (64.3%,
p
= 0.1786) cases. Interestingly, 2/14 (14.3%) patients that experienced KRT or death had isolated C4 lowering, and combining low C3 and/or C4 levels identified 13/14 (92.3%,
p
< 0.0001) cases in this subgroup. Non-superiority to predict poor outcome by low C3 and/or C4 as compared to C3 alone in the total cohort was attributed to 4/24 (16.7%) patients with isolated C4 lowering in the subgroup that did not experience KRT or death.
Conclusion
While low levels of complement C3 were superior in predicting poor outcome in ANCA-associated renal vasculitis, a minor fraction with poor outcome had isolated C4 lowering not captured by serum C3 measurements. Therefore, detailed knowledge of distinct complement components contributing to kidney injury could be of relevance to improve current strategies targeting the complement system in ANCA-associated renal vasculitis.
Graphical abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems, including the kidney. The activation of the complement system ...contributes essentially to its pathogenesis by autoantibody-antigen recognition directed against host cells in ANCA-associated renal vasculitis. We herein provide evidence for intrarenal synthesis of complement C3 localized to distinct vascular compartments in ANCA-associated renal vasculitis that associated with distinct inflammatory signaling pathways. Therefore, a total number of 43 kidney biopsies with ANCA-associated renal vasculitis were retrospectively included and evaluated for presence/absence of C3 deposits localized to distinct vascular compartments in association with clinicopathological biopsy findings. In addition, intrarenal C3 mRNA expression levels specifically from microdissected tubulointerstitial and glomerular compartments were extracted from transcriptome datasets. C3 deposits were present in the glomerular tuft, interlobular arteries, peritubular capillaries, and venules in ANCA-associated renal vasculitis. Most C3 deposits are localized to the glomerular tuft overlapping with peritubular capillaries. The presence of C3 deposits in the glomerular tuft correlated with impaired kidney function and overall short-term survival. Intrarenal complement C3 deposits were not associated with consumption of respective serum levels, supporting the concept of intrarenal C3 synthesis. Finally, intrarenal synthesis of complement C3 was linked to distinct inflammatory signaling pathways in the kidney that is especially relevant in ANCA-associated renal vasculitis. Considering recent advances in AAV therapy with the emergence of new therapeutics that inhibit complement activation, we here provide novel insights into intrarenal complement synthesis and associated inflammatory signaling pathways in ANCA-associated renal vasculitis.
•The activation of the complement system contributes essentially to the pathogenesis of renal vasculitis.•Most intrarenal complement C3 localized to the glomerular tuft, associated with impaired kidney function and survival.•Intrarenal synthesis of complement C3 is linked to distinct inflammatory signaling pathways in renal vasculitis.
Aryl hydrocarbon receptor nuclear translocator (ARNT) mediates anti-fibrotic activity in kidney and liver through induction of ALK3-receptor expression and subsequently increased Smad1/5/8 signaling. ...While expression of ARNT can be pharmacologically induced by sub-immunosuppressive doses of FK506 or by GPI1046, its anti-fibrotic activity is only realized when ARNT-ARNT homodimers form, as opposed to formation of ARNT-AHR or ARNT-HIF1α heterodimers. Mechanisms underlying ARNTs dimerization decision to specifically form ARNT-ARNT homodimers and possible cues to specifically induce ARNT homodimerization have been previously unknown. Here, we demonstrate that phosphorylation of the Ser77 residue is critical for ARNT-ARNT homodimer formation and stabilization. We further demonstrate that inhibition of PP2A phosphatase activity by LB100 enhances ARNT-ARNT homodimers both in vivo and in vitro (mouse tubular epithelial cells and human embryonic kidney cells). In murine models of kidney fibrosis, and also of liver fibrosis, combinations of FK506 or GPI1046 (to induce ARNT expression) with LB100 (to enhance ARNT homodimerization) elicit additive anti-fibrotic activities. Our study provides additional evidence for the anti-fibrotic activity of ARNT-ARNT homodimers and reveals Ser77 phosphorylation as a novel pharmacological target to realize the therapeutic potential of increased ARNT transactivation activity.
Background
Renal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody-(ANCA)-associated vasculitis potentially resulting in pauci-immune necrotizing and crescentic ...ANCA glomerulonephritis (GN) with rapid deterioration of kidney function, progression to end stage kidney disease or, if left untreated, lethal exitus. Analysis of the urinary sediment routinely supports clinical management of ANCA GN, but histopathological implications of aberrancies in the urinary sediment mostly remain elusive. Therefore, we aimed to systematically assess the correlation of aberrancies in the urinary sediment and clinico-pathologic findings.
Methods
A total of 42 kidney biopsies with ANCA GN were retrospectively analyzed in a single-center observational study. Laboratory and histopathological parameters were systematically analyzed and correlated with findings of the urinary sediment.
Results
In the overall ANCA GN cohort, leukocyturia and hematuria were associated among each other, and with markers for non-selective glomerular damage, respectively. Non-invasive measurement of leukocyturia indicated focal (but not extensive) Bowman’s capsule rupture (BCR) specifically in proteinase-3 (PR3)-ANCA GN, whereas hematuria correlated with extensive (but not focal) BCR. Concerning intrarenal immune cell infiltration, leukocyturia was associated with tubulointerstitial plasma cell infiltration in PR3-ANCA GN. Finally, none of these associations were detectable in myeloperoxidase-ANCA GN, implying different modes of kidney damage.
Conclusion
We herein expand our current knowledge by providing evidence that leukocyturia and hematuria enable non-invasive differentiation of BCR severity specifically in PR3-ANCA GN.
Graphical abstract
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