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Prevalence of any renal arteriosclerosis by age group in patients with lupus nephritis (LN) on biopsy reports (black bars) compared to the published prevalence of any arteriosclerosis in healthy donors by age groups. NR = not reported; * = the comparator group started at age 18–29 years (yo) (26).
Source publication
Objective
Cardiovascular disease (CVD) is accelerated in patients with systemic lupus erythematosus and lupus nephritis (LN). Despite the literature suggesting that renal arteriosclerosis predicts CVD in other glomerulonephritis diseases, arteriosclerosis grading and reporting might be particularly overlooked in LN biopsies. Our objective was to ex...
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Citations
... Renal arteriosclerosis has been shown as an early indication of incident CVD events in LN as well as IgA nephropathy [53,54]. Garg et al. examined the renal arteriosclerotic burden in individuals with LN and reported that patients with LN displayed two decades acceleration of renal arteriosclerosis in comparison to their healthy counterparts [55]. In addition, they found that LN chronicity by pathology findings had 4-fold higher odds of renal arteriosclerosis. ...
... In addition, they found that LN chronicity by pathology findings had 4-fold higher odds of renal arteriosclerosis. Thus, the renal arteriosclerosis could be an early indicator of CVD in LN subjects [55]. ...
Systemic lupus erythematosus (SLE) is associated with a significant risk of cardiovascular disease (CVD), which substantially increases disease mortality and morbidity. The overall mechanisms associated with the development of premature atherosclerosis and CVD in SLE remain unclear, but has been considered as a result of an intricate interplay between the profound immune dysregulation and traditional CVD risk factors. Aberrant systemic inflammation in SLE may lead to an abnormal lipid profile and dysfunction, which can further fuel the pro-atherosclerotic environment. The existence of a strong imbalance between endothelial damage and vascular repair/angiogenesis promotes vascular injury, which is the early step in the progression of atherosclerotic CVD. Profound innate and adaptive immune dysregulation, characterized by excessive type I interferon burden, aberrant macrophage, platelet and complements activation, neutrophil dysregulation and neutrophil extracellular traps formation, uncontrolled T cell activation, and excessive autoantibody production and immune complex formation, have been proposed to promote accelerated CVD in SLE. While designing targeted therapies to correct the dysregulated immune activation may be beneficial in the treatment of SLE-related CVD, much additional work is needed to determine how to translate these findings into clinical practice. Additionally, a number of biomarkers display diagnostic potentials in improving CVD risk stratification in SLE, further prospective studies will help understand which biomarker(s) will be the most impactful one(s) in assessing SLE-linked CVD. Continued efforts to identify novel mechanisms and to establish criteria for assessing CVD risk as well as predicting CVD progression are in great need to improve CVD outcomes in SLE.
... Yet, a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence (15,16). We previously reported an accelerated and higher burden of moderate-severe r-ASCL in LN patients, at the time of LN diagnosis, compared to healthy peers (17). Furthermore, we reported an 80% positive predicted value of reported r-ASCL that indicated the accurate grading and reporting of r-ASCL by a pathologist when r-ASCL was present. ...
... Renal biopsy was performed for clinical indication (edema, increase in serum creatinine, hematuria, and/or proteinuria), and pathologic assessments were performed using the 2003 ISN/RPS classification for LN. We abstracted the following data from renal pathology reports: 1) LN class (I-VI), which was further categorized into proliferative or nonproliferative LN, and 2) reported r-ASCL data were abstracted from renal pathology reports and were classified into the Banff r-ASCL grading categories as described in our previous manuscript (17). ...
... We used similar methods as published in our recent paper: we analyzed key cutoffs for age and SLE duration before LN diagnosis and examined associations between ASCVD and a composite of reported and overread r-ASCL (17). Along with basic sociodemographic data, variables with a P value of <0.1 in univariable models and LN proliferative class were included in multivariable analyses. ...
Objective
Lupus nephritis (LN) predicts a 9‐fold higher atherosclerosis cardiovascular disease (ASCVD) risk, highlighting the urgent need to target ASCVD prevention. Studies in IgA nephropathy reported that severe renal arteriosclerosis (r‐ASCL) in diagnostic biopsies strongly predicted ASCVD risk. We recently found that 50% of LN pathology reports overlooked r‐ASCL reporting, which could explain prior negative LN ASCVD risk studies. The present study was undertaken to examine associations between a composite of reported and overread r‐ASCL and ASCVD events in LN.
Methods
Data were abstracted from all LN patients who underwent diagnostic biopsy between 1994 and 2017, including demographic information, ASCVD risk factors, and pathology reports at the time of LN diagnosis. We manually validated all incident ASCVD events. We overread 25% of the biopsies to grade r‐ASCL using the Banff criteria. We supplemented the overread r‐ASCL grade, when available, to determine the composite of reported and overread r‐ASCL grade.
Results
Among 189 incident LN patients, 78% were female, 73% White, and the median age was 25 years. Overall, 31% had any reported r‐ASCL, and 7% had moderate‐to‐severe r‐ASCL. After incorporating systematically re‐examined r‐ASCL grade, the prevalence of any and moderate‐to‐severe r‐ASCL increased to 39% and 12%, respectively. We found 22 incident ASCVD events over 11 years of follow‐up. Using a composite of reported and overread r‐ASCL grade, we found that severe r‐ASCL in diagnostic LN biopsies was associated with 9‐fold higher odds of ASCVD.
Conclusion
Severe r‐ASCL can predict ASCVD in LN; therefore, larger studies are required to systematically report r‐ASCL and examine ASCVD associations.
Abstract Background Rheumatology researchers often categorize continuous predictor variables. We aimed to show how this practice may alter results from observational studies in rheumatology. Methods We conducted and compared the results of two analyses of the association between our predictor variable (percentage change in body mass index [BMI] from baseline to four years) and two outcome variable domains of structure and pain in knee and hip osteoarthritis. These two outcome variable domains covered 26 different outcomes for knee and hip combined. In the first analysis (categorical analysis), percentage change in BMI was categorized as ≥ 5% decrease in BMI
Zusammenfassung 1. Hintergrund und Ziele Es ist bekannt, dass chronische Nierenerkrankungen beim Menschen eine Atherosklerose verschlimmern. Allerdings sind die Mechanismen, die dieser Tatsache zugrunde liegen, noch nicht ganz geklärt. Um diese besser zu verstehen, wurde ein Tierversuch durchgeführt, in dem das klassische Mausmodell für Atherosklerose (APO E Knockout) mit einem Mausmodell für Lupusnephritis (yaa x FcγR2b Knockout) kombiniert wurde. Im Rahmen dieser Studie wurde der Einfluss einer APO E-Defizienz auf das Überleben und die Nierenmorphologie von an Lupusnephritis erkrankten Mäusen erforscht. Zunächst wurde das Überleben von vier Tiergruppen über einen Zeitraum von 40 Wochen untersucht: 1. ya x FcγR2b-/- Mäuse (n=11) 2. yaa x FcγR2b-/- APO E+/+ Mäuse (n=115) 3. yaa x FcγR2b-/- APO E+/- Mäuse (n=19) 4. yaa x FcγR2b-/- APO E-/- Mäuse (n=40). Hierbei fiel eine deutlich erhöhte Mortalität der Doppelknockout-Mäuse auf. Die vorliegende Arbeit soll der Frage nach der Ursache dieser erhöhten Sterblichkeit nachgehen: Besteht die Ursache des frühzeitigen Todes der Doppelknockout-Mäuse in einer erhöhten Schädigung der Nieren? 2. Material und Methoden Wir untersuchten Nierengewebe der folgenden vier Tiergruppen: 1. yaa x FcγR2b-/- APO E+/+ Mäuse (n=12) 2. yaa x FcγR2b-/- APO E+/- Mäuse (n=14) 3. yaa x FcγR2b-/- APO E-/- Mäuse (n=14) 4. ya x FcγR2b+/+APO E-/- Mäuse (n=9) als Kontrollgruppe. Die Tiere wurden unter Standardbedingungen gehalten und nach 17 bis maximal 42 Wochen mittels Perfusionsfixierung getötet. Im Anschluss wurden Paraffinschnitte des Nierengewebes hergestellt und HE-, PAS- und Sirius-Rot-Färbungen durchgeführt. Anhand der derart gefärbten Schnitte wurde mit Hilfe von quantitativen (Morphometrie) und semiquantitativen Untersuchungsmethoden (Glomeruloskleroseindex, Mesangialer Schädigungsindex, Tubulointerstitieller Schädigungsindex, Vaskulärer Schädigungsindex, Aktivitäts- und Chronizitätsindex nach Austin) lichtmikroskopisch die Nierenmorphologie analysiert. 3. Ergebnisse und Beobachtungen Die yaa x FcγR2b-/- APO E-/- Tiere zeigten tendenziell höhere Werte in Glomeruloskleroseindex, Tubulointerstitiellem Schädigungsindex und Aktivitätsindex nach Austin als die yaa x FcγR2b-/- APO E+/- und die yaa x FcγR2b-/- APO E+/+ Mäuse. Mit zunehmendem Mangel an APO E wurde ein – allerdings nicht signifikanter – Anstieg der jeweiligen Werte von den APO E+/+ über die APO E+/- bis hin zu den APO E-/- Mäusen mit Lupusnephritis beobachtet. Des Weiteren waren bei den Doppelknockout-Tieren das totale glomeruläre Volumen und die Anzahl der Glomeruli pro Niere tendenziell höher als bei den anderen an Lupusnephritis erkrankten Tiergruppen. Die vaskuläre Schädigung – erfasst durch den Vaskulären Schädigungsindex – war bei den Doppelknockout-Mäusen signifikant höher als bei den yaa x FcγR2b-/- APO E+/+ und den ya x FcγR2b+/+APO E-/- Tieren. 4. Schlussfolgerungen Trotz tendenziell schwerer ausgeprägter Nierenschädigungen ist die Ursache für den vorzeitigen Tod der Doppelknockout-Mäuse wohl in einer verstärkten Atheroskleroseentwicklung zu finden. APO E-Defizienz und Lupusnephritis gemeinsam führen zu einer signifikant stärkeren Gefäßschädigung als jede Ursache einzeln betrachtet. Weiterhin trägt offenbar die APO E-Defizienz zu einer stärkeren Nierenschädigung bei, so dass auf einen protektiven Einfluss des APO E auf die Niere geschlossen werden kann.
