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.

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.

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.

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.

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.

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.

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.

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.

Implication of platelets and complement C3 as link between innate immunity and tubulointerstitial injury in renal vasculitis with MPO-ANCA seropositivity.

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.

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.

Case report: Kinetics of human leukocyte antigen receptor HLA-DR during liver injury induced by potassium para-aminobenzoate as assessed for causality using the updated RUCAM.

Potassium para-aminobenzoate (POTABA) is used to treat Peyronie's disease by decreasing fibrosis and plaque size progression. Among potential side effects, drug-induced liver injury (DILI) attributed to POTABA administration has been reported in a few cases and inferred to immune hypersensitivity. In the present case, we investigated clinical, biochemical, and serological features as well as searched for non-drug-related causes, and applied the updated Roussel Uclaf Causality Assessment Method (RUCAM) confirming a highly probable causality of POTABA-induced liver injury. Moreover, we here observed specific activated CD3+ T lymphocytes during the acute phase of liver injury by monitoring of human leukocyte antigen receptor (HLA-DR) expression. Furthermore, improvement of biochemical markers of liver injury after POTABA withdrawal was associated with a rapid decline of CD3+ HLA-DR+ immune cells. In contrast, CD14+ monocytes expressing HLA-DR remained stable during recovery from liver injury. These observations implicate a specific involvement of activated T lymphocytes in liver injury mediated by POTABA. Clinicians should be aware of POTABA-induced liver injury, and measurement of activated immune cells by assessment of HLA-DR could provide pathomechanistic insights enabling biomonitoring of recovery from DILI.

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.

Oncogenic collagen I homotrimers from cancer cells bind to α3ß1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer.

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 α3ß1 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-α3ß1 integrin signaling axis as a cancer-specific therapeutic target.

Compartmentalization of Intrarenal Programmed Cell Death Protein 1-Ligand 1 and Its Receptor in Kidney Injury Related to Immune Checkpoint Inhibitor Nephrotoxicity.

Background: Due to advances in cancer therapy, immune checkpoint inhibitors (ICIs) are new classes of drugs targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor (PD-1) used in many cancer therapies. Acute interstitial nephritis (AIN) is a potential and deleterious immune-related adverse events (irAE) and the most common biopsy-proven diagnosis in ICI-related nephrotoxicity. AIN in patients receiving ICIs is was only seen in cases with tubular PD-L1 positivity, while PD-1 expression is limited to inflammatory cells and also observed in injured kidneys independent of ICI therapy. We have previously described that PD-L1 positivity can also be detected in glomerular and endothelial compartments. We here aimed to describe compartmentalization of renal PD-L1 expression specifically in injured kidneys with confirmed nephrotoxicity related to ICIs, its association with presence of PD-1, and clinical findings. Methods: We included human kidney samples with AIN related to ICI therapy to describe PD-L1 and PD-1 expression localized to different renal compartments in association with clinical and laboratory parameters. Results: We herein report compartmentalization of PD-L1 with tubular positivity in all cases, partially overlapping with glomerular and endothelial PD-L1 positivity. Furthermore, we provide evidence that tubular PD-L1 in ICI-related nephrotoxicity correlates with levels of C-reactive protein (CRP), while glomerular and endothelial PD-L1 positivity with lower serum levels of complement component C4. Interestingly, glomerular PD-L1 correlated with kidney function, while interstitial cell PD-1 positivity specifically with severity of kidney injury. Finally, we provide evidence for signaling pathways associated with intrarenal PD-L1/PD-1 expression. Conclusion: Our findings implicate that that AIN related to ICI therapy requires presence of interstitial cells positive for PD-1, and that blocking PD-L1/PD-1 signaling may contribute to nephrotoxicity specifically related to these agents.

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.

Calreticulin Shortage Results in Disturbance of Calcium Storage, Mitochondrial Disease, and Kidney Injury.

Renal Ca2+ reabsorption plays a central role in the fine-tuning of whole-body Ca2+ homeostasis. Here, we identified calreticulin (Calr) as a missing link in Ca2+ handling in the kidney and showed that a shortage of Calr results in mitochondrial disease and kidney pathogenesis. We demonstrated that Calr+/- mice displayed a chronic physiological low level of Calr and that this was associated with progressive renal injury manifested in glomerulosclerosis and tubulointerstitial damage. We found that Calr+/- kidney cells suffer from a disturbance in functionally active calcium stores and decrease in Ca2+ storage capacity. Consequently, the kidney cells displayed an abnormal activation of Ca2+ signaling and NF-κB pathways, resulting in inflammation and wide progressive kidney injury. Interestingly, the disturbance in the Ca2+ homeostasis and signaling in Calr+/- kidney mice cells triggered severe mitochondrial disease and aberrant mitophagy, resulting in a high level of oxidative stress and energy shortage. These findings provide novel mechanistic insight into the role of Calr in kidney calcium handling, function, and pathogenesis.

Kinetics of human leukocyte antigen receptor HLA-DR+ monocytes and T lymphocytes during remission induction therapy in ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by small vessel inflammation and the presence of autoantibodies against cytoplasmic proteases, most often proteinase-3 and myeloperoxidase. Peripheral blood monocytes are an important source of local macrophage accumulation within parenchymal organs, as evidenced by their presence in early lesions in ANCA-associated glomerulonephritis. Major histocompatibility complex (MHC) II cell surface receptor human leukocyte antigen receptor (HLA-DR) allows antigen presentation to T cells and is crucial for the initiation of an immune response. We herein report HLA-DR abundance in AAV and the kinetics of HLA-DR+ monocytes and T lymphocytes during remission induction therapy in AAV. Life-threatening AAV with pulmonary hemorrhage and renal involvement was associated with the presence of HLA-DR in a considerable population of peripheral blood monocytes and T lymphocytes, and relapsing disease manifested despite persistent B cell depletion after remission induction with rituximab. Moreover, remission induction in AAV with steroids, plasma exchange and intravenous cyclophosphamide, and improvement of clinical symptoms were associated with a decrease in HLA-DR+ differing between monocytes and T lymphocytes. Particularly, persistent suppression of HLA-DR+ monocytes was observed during remission induction, while an initial decrease in HLA-DR+ T lymphocytes was followed by recovery of this population during the further course. Detailed insights into HLA-DR kinetics could pave the way towards an increased understanding of immunopathology and identify patients that could mostly benefit from distinct remission induction regimens.