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.Göttingen Universit

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

Kinetics of Bilirubin and Ammonia Elimination during Hemadsorption Therapy in Secondary Sclerosing Cholangitis Following ECMO Therapy and Severe COVID-19

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver&rsquo;s excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality

Impact of the COVID-19 Pandemic on Kidney Diseases Requiring Renal Biopsy: A Single Center Observational Study

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.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

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

Open-Access-Publikationsfonds 202

Systematic Scoring of Tubular Injury Patterns Reveals Interplay between Distinct Tubular and Glomerular Lesions in ANCA-Associated Glomerulonephritis

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Acute tubular injury with the presence of tubulitis was previously reported to be of prognostic value in ANCA glomerulonephritis (GN). In particular, distinct tubular injury lesions were associated with the deterioration of kidney function at AAV disease onset, as well as renal resistance to treatment, and higher risk of progression to composite outcome in patients with AAV. To expand our knowledge regarding distinct tubular lesions in AAV, we aimed to describe acute tubular injury patterns in association with glomerular lesions in ANCA GN by systematic histological scoring. Methods: A total number of 48 renal biopsies with confirmed renal involvement of AAV admitted to the University Medical Center Göttingen from 2015 to 2020 were retrospectively examined. By systematic scoring of tubular injury lesions, the association between clinical parameters, laboratory markers, and histopathological findings was explored. Results: We have shown that cellular casts in renal biopsies were frequently observed in the majority of cases with ANCA GN. Furthermore, we showed that tubular epithelial simplification with dilatation correlated with MPA and MPO subtypes, C3c hypocomplementemia, severe renal involvement, and uACR. Red blood cell (RBC) casts were associated with increased levels of C-reactive protein (CRP), leukocyturia, and hematuria. Finally, we found that hyaline casts were associated with an increased fraction of glomeruli with global glomerular sclerosis. Conclusions: Acute tubular injury patterns were correlated with active ANCA GN, whereas tubular injury lesions reflecting the later stages of kidney disease correlated with chronic glomerular lesions. These results suggest an interplay between different renal compartments

Consideration of Therapeutic Plasma Exchange in Association With Inflammatory Lesions in ANCA-Associated Glomerulonephritis: A Real-World Retrospective Study From a Single Center

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Pathogenic ANCAs trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN). Standard therapeutical regimens include aggressive immunosuppressive therapy. Since some patients require renal replacement therapy (RRT) despite intensive immunosuppressive therapy, additional therapeutic plasma exchange (PEX) to deplete pathogenic ANCAs has been recommended but its value has recently been questioned. Because therapeutic decision making is crucial in these critically ill patients, we here aimed to identify inflammatory lesions in association with PEX consideration in a retrospective study from a single center tertiary hospital in a real-world population of 46 patients with severe AAV requiring intensive care treatment. The decision to consider PEX was more likely in patients with need for intensive care treatment and severe renal dysfunction. In contrast, short-term outcomes did not depend on clinical, or laboratory characteristics assessed at admission. Histopathological analysis confirmed active disease reflected by increased glomerular necrosis and crescents, but these histopathological findings did not associate with short-term outcome either. Interestingly, only increased global glomerular sclerosis in renal biopsies associated with a detrimental short-term outcome. In conclusion, our study investigated determinants for the consideration of therapeutic PEX in patients with severe AAV requiring intensive care treatment. This aspect underscores the need for renal biopsy and requires further investigation in a prospective controlled setting for therapeutic decision making especially in patients with severe AAV requiring intensive care treatment, especially important for treating intensivists.Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Pathogenic ANCAs trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN). Standard therapeutical regimens include aggressive immunosuppressive therapy. Since some patients require renal replacement therapy (RRT) despite intensive immunosuppressive therapy, additional therapeutic plasma exchange (PEX) to deplete pathogenic ANCAs has been recommended but its value has recently been questioned. Because therapeutic decision making is crucial in these critically ill patients, we here aimed to identify inflammatory lesions in association with PEX consideration in a retrospective study from a single center tertiary hospital in a real-world population of 46 patients with severe AAV requiring intensive care treatment. The decision to consider PEX was more likely in patients with need for intensive care treatment and severe renal dysfunction. In contrast, short-term outcomes did not depend on clinical, or laboratory characteristics assessed at admission. Histopathological analysis confirmed active disease reflected by increased glomerular necrosis and crescents, but these histopathological findings did not associate with short-term outcome either. Interestingly, only increased global glomerular sclerosis in renal biopsies associated with a detrimental short-term outcome. In conclusion, our study investigated determinants for the consideration of therapeutic PEX in patients with severe AAV requiring intensive care treatment. This aspect underscores the need for renal biopsy and requires further investigation in a prospective controlled setting for therapeutic decision making especially in patients with severe AAV requiring intensive care treatment, especially important for treating intensivists

Kinetics of Bilirubin and Ammonia Elimination during Hemadsorption Therapy in Secondary Sclerosing Cholangitis Following ECMO Therapy and Severe COVID-19

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver’s excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality

Different Patterns of Kidney Fibrosis Are Indicative of Injury to Distinct Renal Compartments

Kidney fibrosis is a common manifestation and hallmark of a wide variety of chronic kidney disease (CKD) that appears in different morphological patterns, suggesting distinct pathogenic causes. Broad macroscopically visible scars are the sequelae of severe focal injury and complete parenchymal destruction, reflecting a wound healing response as a consequence of infarction. In the kidney, chronic glomerular injury leads to atrophy of the corresponding tubule, degeneration of this specific nephron, and finally interstitial fibrosis/tubular atrophy (IF/TA). Compared to this glomerulus-induced focal replacement scar, diffuse fibrosis independent of tubular atrophy appears to be a different pathogenic process. Kidney fibrosis appears to develop in a compartment-specific manner, but whether focal and diffuse fibrosis has distinct characteristics associated with other glomerular or tubulointerstitial lesions remains elusive. In the present study, we aimed to analyze renal fibrotic patterns related to renal lesions, which directly contribute to renal fibrogenesis, to unravel fibrotic patterns and manifestations upon damage to distinct renal compartments. Patterns of kidney fibrosis were analyzed in experimental models of CKD and various renal pathologies in correlation with histopathological and ultrastructural findings. After the induction of isolated crescentic glomerulonephritis (GN) in nephrotoxic serum-nephritis (NTN), chronic glomerular damage resulted in predominantly focal fibrosis adjacent to atrophic tubules. By contrast, using unilateral ureteral obstruction (UUO) as a model of primary injury to the tubulointerstitial compartment revealed diffuse fibrosis as the predominant pattern of chronic lesions. Finally, folic acid-induced nephropathy (FAN) as a model of primary tubular injury with consecutive tubular atrophy independent of chronic glomerular damage equally induced predominant focal IF/TA. By analyzing several renal pathologies, our data also suggest that focal and diffuse fibrosis appear to contribute as chronic lesions in the majority of human renal disease, mainly being present in antineutrophil cytoplasmic antibody (ANCA)-associated GN, lupus nephritis, and IgA nephropathy (IgAN). Focal IF/TA correlated with glomerular damage and irreversible injury to nephrons, whereas diffuse fibrosis in ANCA GN was associated explicitly with interstitial inflammation independent of glomerular damage and nephron loss. Ultrastructural analysis of focal IF/TA versus diffuse fibrosis revealed distinct matrix compositions, further supported by different collagen signatures in transcriptome datasets. With regard to long-term renal outcome, only the extent of focal IF/TA correlated with the development of end-stage kidney disease (ESKD) in ANCA GN. In contrast, diffuse kidney fibrosis did not associate with the long-term renal outcome. In conclusion, we here provide evidence that a focal pattern of kidney fibrosis seems to be associated with nephron loss and replacement scarring. In contrast, a diffuse pattern of kidney fibrosis appears to result from primary interstitial inflammation and injury