Aortitis: recent advances, current concepts and future possibilities

Broadly defined, aortitis refers to inflammation of the aorta and incorporates both infectious and non-infectious aetiologies. As advanced imaging modalities are increasingly incorporated into clinical practice, the phenotypic spectrum associated with aortitis has widened. The primary large vessel vasculitides, giant cell arteritis and Takayasu arteritis, are the most common causes of non-infectious aortitis. Aortitis without systemic disease or involvement of other vascular territories is classified as clinically isolated aortitis. Periaortitis, where inflammation spreads beyond the aortic wall, is an important disease subset with a distinct group of aetiologies. Infectious aortitis can involve bacterial, viral or fungal pathogens and, while uncommon, can be devastating. Importantly, optimal management strategies and patient outcomes differ between aortitis subgroups highlighting the need for a thorough diagnostic workup. Monitoring disease activity over time is also challenging as normal inflammatory markers do not exclude significant vascular inflammation, particularly after starting treatment. Additional areas of unmet clinical need include clear disease classifications and improved short-term and long-term management strategies. Some of these calls are now being answered, particularly with regard to large vessel vasculitis where our understanding has advanced significantly in recent years. Work extrapolated from temporal artery histology has paved the way for targeted biological agents and, although glucocorticoids remain central to the management of non-infectious aortitis, these may allow reduced glucocorticoid reliance. Future work should seek to clarify disease definitions, improve diagnostic pathways and ultimately allow a more stratified approach to patient management

Mutational heterogeneity in cancer and the search for new cancer genes

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention

Combination Cyclophosphamide and Rituximab to Minimize Glucocorticoid Use in Antineutrophil Cytoplasm Antibody–Associated Vasculitis

IntroductionThe optimal duration of immunosuppressive therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is uncertain. Glucocorticoids are a mainstay of treatment but are associated with significant morbidity. Here, we describe outcomes of a cohort of patients treated with combination cyclophosphamide and rituximab induction alongside a rapidly tapering oral-only glucocorticoid regimen.MethodsIn this retrospective, observational, cohort study, we identified patients presenting with AAV between 2011 and 2023 treated with combination cyclophosphamide and rituximab induction therapy. We analyzed biochemical, histologic, and outcome data, including time-to-remission and relapse rate. A subgroup analysis compared outcomes based on glucocorticoid duration.ResultsA total of 112 patients with active AAV treated with combination cyclophosphamide and rituximab were identified (median age: 67 years; 85% kidney involvement; baseline estimated glomerular filtration rate [eGFR] 24 ml/min per 1.73 m2). Of the patients, 96% achieved remission; median time-to-remission was 77 (interquartile range [IQR]: 64–92) days. All patients demonstrated biochemical and histologic improvement following treatment. Five patients (5%) experienced a disease relapse over 2.9 (IQR: 1.7–4.3) years follow-up. The cumulative glucocorticoid dose was 1780 (IQR: 1141–2935) mg with median duration of 12.5 (IQR: 8.0–39.0) weeks. Patients treated with oral glucocorticoids for > 12 weeks received a higher cumulative dose (2935 vs. 1133 mg; P < 0.001) with a trend toward more serious infections (21% vs. 7%; P = 0.06) than those treated for ≤ 12 weeks with no differences in disease remission (100% vs. 91%; P = 0.07) or relapse (9% vs. 0%; P = 0.07) rates.ConclusionEarly withdrawal of oral glucocorticoid therapy in patients with severe AAV treated with combination cyclophosphamide and rituximab induction immunosuppression is safe and effective and may reduce morbidity, in particular serious infections

Corrigendum to "Novel retinal vascular phenotypes for the potential assessment of long-term risk in living kidney donors." Kidney Int. 2022;102:661-665

DOI of original article: https://doi.org/10.1016/j.kint.2022.06.019 The authors regret that Supplementary Tables S1–S3 and Supplementary Figures S1 and S2 were inadvertently not included with the published Supplementary Material. The authors would like to apologize for any inconvenience caused.</p

Cardiovascular outcomes in patients with chronic kidney disease and COVID-19:a multi-regional data-linkage study

BACKGROUND: Data describing cardiovascular outcomes in patients with COVID-19 and chronic kidney disease (CKD) are lacking. We compared cardiovascular outcomes of patients with and without COVID-19, stratified by CKD status. METHODS: This retrospective, multi-regional data-linkage study utilised individual patient-level data from two Scottish cohorts. All patients tested for SARS-CoV-2 in Cohort 1 between 01/02/2020 and 31/03/2021, and in Cohort 2 between 28/02/2020 and 08/02/2021, were included. RESULTS: Overall, 86 964 patients were tested for SARS-CoV-2. There were 36 904 patients (61±21 years, 58.1% women, 15.9% CKD, 10.1% COVID-19 positive) in Cohort 1 and 50 060 patients (63±20 years, 62.0% women, 16.4% CKD, 9.1% COVID-19 positive) in Cohort 2. In CKD patients, COVID-19 increased the risk of cardiovascular death by more than two-fold within 30 days (cause-specific hazard ratio [csHR] meta-estimate 2.34, 95% confidence interval [CI] 1.83–2.99), and by 57% at the end of follow-up (csHR meta-estimate 1.57, 95% CI 1.31–1.89). Similarly, the risk of all-cause death in COVID-19 positive versus negative CKD patients was greatest within 30 days (HR 4.53, 95% CI 3.97–5.16). Compared to patients without CKD, those with CKD had a higher risk of testing positive (11.5% versus 9.3%). Following a positive test, CKD patients had higher rates of cardiovascular death (11.1% versus 2.7%), cardiovascular complications, and cardiovascular hospitalisations (7.1% versus 3.3%) than those without CKD. CONCLUSIONS: COVID-19 increases the risk of cardiovascular and all-cause death in CKD patients, especially in the short-term. CKD patients with COVID-19 are also at a disproportionate risk of cardiovascular complications than those without CKD

Utility of interval kidney biopsy in ANCA-associated vasculitis

OBJECTIVES: ANCA-associated vasculitis (AAV) is a rare autoimmune disorder that commonly involves the kidney. Early identification of kidney involvement, assessing treatment-response and predicting outcome are important clinical challenges. Here, we assessed the potential utility of interval kidney biopsy in AAV. METHODS: In a tertiary referral centre with a dedicated vasculitis service, we identified patients with AAV who had undergone interval kidney biopsy, defined as a repeat kidney biopsy (following an initial biopsy showing active AAV) undertaken to determine the histological response in the kidney following induction immunosuppression. We analysed biochemical, histological and outcome data, including times to kidney failure and death for all patients. RESULTS: We identified 57 patients with AAV who underwent at least one interval kidney biopsy (59 interval biopsies in total; median time to interval biopsy ∼130 days). Of the 59 interval biopsies performed, 24 (41%) patients had clinically suspected active disease at time of biopsy which was confirmed histologically in only 42% of cases; 35 (59%) patients were in clinical disease-remission, and this was correct in 97% of cases. The clinician’s impression was incorrect in one in four patients. Hematuria at interval biopsy did not correlate with histological activity. Interval biopsy showed fewer acute lesions and more chronic damage compared with initial biopsy and led to immunosuppressive treatment-change in 75% (44/59) of patients. Clinical risk prediction tools tended to operate better using interval biopsy data. CONCLUSION: Interval kidney biopsy is useful for determining treatment-response and subsequent disease management in AAV. It may provide better prognostic information than initial kidney biopsy and should be considered for inclusion into future clinical trials and treatment protocols for patients with AAV

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]