Intrarenal synthesis of complement C3 localized to distinct vascular compartments 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. 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.

Relevance of Complement C4 Deposits Localized to Distinct Vascular Compartments 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.

Bowman's capsule rupture links glomerular damage to tubulointerstitial inflammation in ANCA-associated glomerulonephritis.

OBJECTIVES: We have recently described the frequency of Bowman's capsule (BC) rupture in a considerable subset of patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). Interestingly, recent reports established a better performance of glomerulocentric ANCA scoring systems after adding BC rupture to these classification systems, suggesting that characteristics of this lesion are independent from glomerular lesions. Since BC rupture may link glomerular damage to tubulointerstitial lesions via direct interaction with the surrounding interstitium, we here aimed to expand our current knowledge of this distinct lesion by a systematic description of tubulointerstitial lesions analogous to the Banff classification in association with the presence of BC rupture in ANCA GN. METHODS: A total number of 44 kidney biopsies with confirmed renal involvement of ANCA GN were retrospectively included between 2015 till 2020 in a single-centre observational study. RESULTS: We here show that presence of BC rupture was associated with severe deterioration of kidney function at disease onset, similar to previous findings regarding long-term renal survival. Furthermore, BC rupture in ANCA GN was associated with tubulointerstitial inflammation and ultrastructural analysis revealed direct cellular exchange between Bowman's space and the interstitium, potentially contributing to the observed deterioration of kidney function and worse renal outcome in ANCA GN. CONCLUSIONS: BC rupture is associated with renal outcome in ANCA GN, therefore underscoring the need for further studies with regard to the glomerular-tubulointerstitial interaction in this disease.

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

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.

Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression.

Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure-lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure-lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.

Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure.

Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level-matched Col4a3 KO mice. Although kidneys of both Col4a3 KO and Col4a3;Tsp1 DKO mice exhibited a widened tubulointerstitium, predominant lesions in Col4a3 KO kidneys were collagen deposition and fibroblast accumulation, whereas in Col4a3;Tsp1 DKO kidney inflammation was predominant, with less collagen deposition. Altered disease progression correlated with impaired activation of transforming growth factor-ß1 (TGF-ß1) in vivo and in vitro in the absence of TSP1. In summary, our findings suggest that TSP1 contributes to progression of chronic kidney disease by catalyzing activation of latent TGF-ß1, resulting in promotion of a fibroproliferative response over an inflammatory response. Furthermore, the findings suggest that fibroproliferative and inflammatory lesions are independent entities, both of which contribute to decline of renal function.

Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis.

Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis.

Comparative analysis of complement C3 and C4 serum levels for outcome prediction in ANCA-associated renal vasculitis.

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.

The rapid atrial swirl sign for ultrasound-guided tip positioning of antegrade-tunneled hemodialysis catheters: A cross-sectional pilot study.

BACKGROUND: We have previously reported that the rapid atrial swirl sign (RASS) is an accurate and safe procedure for ultrasound (US)-guided tip positioning of retrograde-tunneled hemodialysis catheters (HDCs). However, application of RASS for placement of antegrade HDCs has not been investigated yet. Therefore, we here report our first experience of applying RASS for US-guided tip positioning of antegrade-tunneled HDCs. METHODS: We performed a cross-sectional study to assess the feasibility of applying the RASS for US-guided tip positioning of antegrade-tunneled HDCs. We included a total number of 15 antegrade-tunneled HDC insertions in 13 patients requiring placement of a HDC for the temporary or permanent treatment of ESKD in a single-center, cross-sectional pilot study. RESULTS: The overall success rate of applying the RASS for US-guided tip positioning of antegrade-tunneled HDCs was 15/15 (100%) confirmed by portable anterior-posterior chest radiography, with no major adverse events after HDC insertions. In addition, this insertion technique demonstrated optimal HDC flow without any observed malfunction. CONCLUSION: This study investigated the efficacy of the RASS for US-guided tip positioning of antegrade-tunneled HDCs in patients with ESKD. Application of the RASS for US-guided tip positioning is an accurate and safe procedure for proper placement of antegrade-tunneled HDCs.

Serum sodium levels associate with recovery of kidney function in immune checkpoint inhibitor nephrotoxicity.

Background: Immune checkpoint inhibitors (ICIs) are novel drugs targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor (PD-1). Enhancing the immune system has also been associated with a wide range of immune-related adverse events (irAE). Among them, acute interstitial nephritis (AIN) is a rare but deleterious irAE in the kidney. However, determinants of recovery and long-term kidney function after ICI withdrawal and steroid therapy thereafter remain elusive. Therefore, we here aimed to identify parameters associated with recovery of kidney function in this previous established cohort of AIN in the context of ICI therapy. Methods: We here monitored kidney function over a mean follow-up time of 812 days in comparison with clinical, histopathological and laboratory parameters associated with recovery of kidney function after AIN related to ICI nephrotoxicity. Results: Abundance of intrarenal PD-L1/PD-1 did not correlate with recovery of kidney function. Furthermore, cumulative steroid dose that was initiated for treatment of AIN related to ICI nephrotoxicity was also not associated with improvement of kidney function. Finally, chronic lesions in the kidney including glomerular sclerosis and interstitial fibrosis/tubular atrophy (IF/TA) did not correlate with eGFR change during the follow-up time. However, we here identified that lower levels of serum sodium at time of kidney biopsy were the strongest independent predictor of renal recovery in ICI-related nephrotoxicity. Conclusion: Because low serum sodium levels associated with better improvement of kidney function, these observations might contribute to novel approaches to enhance recovery after AIN related to ICI nephrotoxicity.

Leukocyturia and hematuria enable non-invasive differentiation of Bowman's capsule rupture severity in PR3-ANCA glomerulonephritis.

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.

Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8+ T cells.

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows a lower proportion of CD8+ T cells and demonstrates shorter survival compared with tumors with low KRAS expression. This study highlights the role of CD8+ T cells in the eradication of PDAC following KRAS∗ elimination and provides a rationale for the combination of KRAS∗ targeting with immunotherapy to control PDAC.

Immunoadsorption therapy in patients with multiple sclerosis with steroid-refractory optical neuritis.

BACKGROUND: In multiple sclerosis relapses refractory to intravenous corticosteroid therapy, plasma exchange is recommended. Immunoadsorption (IA) is regarded as an alternative therapy, but its efficacy and putative mechanism of action still needs to be established. METHODS: We prospectively treated 11 patients with multiple sclerosis who had optical neuritis and fulfilled the indications for apheresis therapy (Trial registration DE/CA25/00007080-00). In total, five IA treatments were performed using tryptophan-IA. Clinical activity (visual acuity, Expanded Disability Status Scale, Incapacity Status Scale), laboratory values and visual evoked potentials were measured before, during and after IA, with a follow-up of six months. Moreover, proteomic analyses were performed to analyze column-bound proteins as well as corresponding changes in patients' sera. RESULTS: After the third IA, we detected an improvement of vision in eight of eleven patients, whom we termed responders. Amongst these, the mean visual acuity improved from 0.15 ± 0.12 at baseline to 0.47 ± 0.32 after the third IA (P = 0.0252) up to 0.89 ± 0.15 (P < 0.0001) at day 180 ± 10 after IA. Soluble interleukin-2 receptor decreased in responders (P = 0.03), whereas in non-responders it did not. Proteomic analyses of proteins adsorbed to IA columns revealed that several significant immunological proteins as well as central nervous system protein fragments, including myelin basic protein, had been removed by IA. CONCLUSIONS: IA was effective in the treatment of corticosteroid-refractory optic neuritis. IA influenced the humoral immune response. Strikingly, however, we found strong evidence that demyelination products and immunological mediators were also cleared from plasma by IA.

Determinants of Tunneled Hemodialysis Catheter Implantation Time by Ultrasound Guidance: A Single-Center Cross-Sectional Study.

BACKGROUND: We have previously reported that the ultrasound (US)-guided tip positioning is an accurate and safe procedure for placement of retrograde- and antegrade-tunneled hemodialysis catheters (HDCs). However, determinants of tunneled hemodialysis catheter implantation time by using US guidance have not been described yet. Therefore, we here report a comparative analysis to identify determinants of implantation time for retrograde- and antegrade-tunneled HDCs placement by US guidance. METHODS: We performed a cross-sectional study to compare implantation time for US-guided tip positioning of retrograde- and antegrade-tunneled HDCs. We included a total number of 47 tunneled HDC insertions, including 23 retrograde tunneled and 24 antegrade-tunneled HDCs in patients requiring placement of an HDC for the temporary or permanent treatment of end-stage kidney disease (ESKD) in a single-center, cross-sectional pilot study. RESULTS: We show that clinical and laboratory parameters did not differ between retrograde- and antegrade-tunneled HDC implantations. There was a tendency for shorter implantation time in antegrade-tunneled HDCs, although not statistically significant. Finally, we identified an independent inverse association between body weight (BW) and platelet counts with HDC implantation time specifically in antegrade-tunneled HDCs. CONCLUSION: In this study, we identified determinants for tunneled HDC implantation time that might be relevant for patients and interventionists.

Molecular signatures of intrarenal complement receptors C3AR1 and C5AR1 correlate with renal outcome in human lupus nephritis.

OBJECTIVE: 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. METHODS: 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. RESULTS: Within the glomerular compartment, intrarenal mRNA expression levels of C3AR1 (p=0.0333) and C5AR1 (p=0.0167) 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 C3AR1 or C5AR1 resulted in identical gene set and signalling pathways enrichments in human lupus nephritis, including interferon signalling and signalling by interleukins. Direct comparison of C3AR1 and C5AR1 confirmed a strong association between glomerular mRNA expression levels of both complement receptors (r=0.8955, p<0.0001). CONCLUSIONS: 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.

Low levels of hemoglobin associate with critical illness and predict disease course in patients with ANCA-associated renal vasculitis.

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.

Dissecting signalling pathways associated with intrarenal synthesis of complement components in lupus nephritis.

Lupus nephritis is one of the most common and serious complications of systemic lupus erythematosus, attributed to increased morbidity and mortality. The in situ deposition of intrarenal immune complexes promote the accumulation of inflammatory cells and cause kidney injury in lupus nephritis. Among potential sources of intrarenal complement deposits, the concept of intrarenal complement synthesis has been described more than three decades ago in experimental lupus nephritis. By using transcriptome datasets, we here identified accelerated intrarenal synthesis of distinct classical and alternative complement pathway components, most associated with impaired kidney function. Contrasting to this, no such induction of intrarenal complement synthesis was observed in disease controls, further supporting relevance of intrarenal complement synthesis especially in human lupus nephritis. Gene set enrichment identified that glomerular complement synthesis predominantly associated with interferon signalling and signalling by interleukins in human lupus nephritis, whereas tubulointerstitial complement synthesis with aberrant T-cell receptor signalling. Because the pathomechanistic involvement of complement system activation contributed to recent advances in targeted therapy in lupus nephritis, 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.