Fetal growth restriction followed by very preterm birth is associated with smaller kidneys but preserved kidney function in adolescence.

BACKGROUND: Preterm birth and fetal growth restriction (FGR) are associated with structural and functional kidney changes, increasing long-term risk for chronic kidney disease and hypertension. However, recent studies in preterm children are conflicting, indicating structural changes but normal kidney function. This study therefore assessed kidney structure and function in a cohort of adolescents born very preterm with and without verified FGR. METHODS: Adolescents born very preterm with FGR and two groups with appropriate birthweight (AGA) were included; one matched for gestational week at birth and one born at term. Cortical and medullary kidney volumes and T1 and T2* mapping values were assessed by magnetic resonance imaging. Biochemical markers of kidney function and renin-angiotensin-aldosterone system (RAAS) activation were analyzed. RESULTS: Sixty-four adolescents were included (13-16 years; 48% girls). Very preterm birth with FGR showed smaller total (66 vs. 75 ml/m2; p = 0.01) and medullary volume (19 vs. 24 ml/m2; p < 0.0001) compared to term AGA. Corticomedullary volume ratio decreased from preterm FGR (2.4) to preterm AGA (2.2) to term AGA (1.9; p = 0.004). There were no differences in T1 or T2* values (all p ≥ 0.34) or in biochemical markers (all p ≥ 0.12) between groups. CONCLUSIONS: FGR with abnormal fetal blood flow followed by very preterm birth is associated with smaller total kidney and medullary kidney volumes, but not with markers of kidney dysfunction or RAAS activation in adolescence. Decreased total kidney and medullary volumes may still precede a long-term decrease in kidney function, and potentially be used as a prognostic marker. A higher resolution version of the Graphical abstract is available as Supplementary information.

[Lung ultrasound promising method for assessing acute dyspnea and monitoring decompensated heart failure]. / Lungultraljud ­ en uppseglande metod vid dyspné och hjärtsvikt.

Ultrasound plays an important role in several medical fields. The heart was the first organ for which ultrasound gained clinical utility, followed by obstetric and gynecological applications. Shortly thereafter, abdominal organs and blood vessels became targets for ultrasound examination. The lung was long considered inaccessible for ultrasound due to its high air content. Work since the 1990s has however established a role for lung ultrasound, in leveraging several technical artefacts generated in the normal lung and in conditions with reduced air content, to allow rapid diagnosis of interstitial fluid accumulation, pneumothorax, pneumonia among others. In this article, we provide an overview of the potential of lung ultrasound, particularly as a promising method for assessment of patients presenting with acute dyspnea in the emergency department and for monitoring residual fluid in patients with decompensated heart failure. We also discuss limitations and caveats of the method.

Carotid Plaque Morphology is Similar in Patients with Reduced and Normal Renal Function.

BACKGROUND: Chronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP). METHODS: Patients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin. RESULTS: Carotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m2. Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking). CONCLUSIONS: The higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought.

Malignancies in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis: A Population-based Cohort Study.

OBJECTIVE: Patients with ANCA-associated vasculitides (AAV) exhibit higher rates of malignancy than the general population. We assessed whether the cancer risk is increased in a well-characterized population-based cohort of AAV in southern Sweden, followed for a median time of 8 years. METHODS: With case record review, the outcomes and malignancy development in a cohort of 195 patients with AAV [granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA] diagnosed between 1997 and 2010 were assessed. The patients were followed until death or December 31, 2015. The age- and sex-standardized incidence ratios (SIR) were estimated using the Swedish population data as a reference. RESULTS: During the observation period of about 1500 person-years, we found 60 cancers in 52 of the 195 patients. SIR (95% CI) was 2.8 (2.1-3.6) for cancers at all sites, 1.8 (1.3-2.5) for all cancers excluding squamous cell carcinoma (SCC), 12.9 (8.4-18.8) for SCC, 4.3 (1.4-10.0) for bladder cancer, and 7.0 (1.4-20.5) for pancreatic cancer. Cumulative doses of cyclophosphamide (CYC) < 10 g were not associated with higher incidence of cancers other than SCC (SIR 1.63, 95% CI 0.8-2.9). CONCLUSION: In contrast to previous publications assessing malignancy risk in patients with AAV, we show in this population-based cohort of patients a persistent increased risk for overall malignancy, bladder cancer, and pancreatic cancer as well as a markedly increased risk for SCC. There was no increase in incidence of cancers other than SCC for those treated with < 10 g CYC.

Long-term patient survival in a Swedish population-based cohort of patients with ANCA-associated vasculitis.

OBJECTIVES: Patients with antineutrophil cytoplasmatic antibodies-associated vasculitides (AAV) exhibit higher mortality than the general population. In the current study, we assessed whether cluster affiliation based on clinical presentation might predict mortality. METHODS: With case record review, the outcomes for a population-based cohort of patients diagnosed with AAV in southern Sweden (catchment area of 0.7 million inhabitants) between 1997 and 2010 were assessed. Based on organ involvement at presentation, the cohort was stratified into the following clusters: gastrointestinal, cardiovascular, non-renal, renal with proteinase 3 (PR3) and renal without PR3. Cluster affiliation, demographics, clinical and laboratory values at entry were tested as prognostic factors for survival in multivariable models. RESULTS: 195 patients (98 female) with a median age of 69 years (IQR 55-77) at diagnosis were included in the cohort. The median time of follow-up was 4 years for the 98 patients (50%) who died during follow-up and 11 years for those alive at end of follow-up. The 1-year, 2-year, 5-year and 10-year survival was 87%, 82%, 70% and 55%, respectively. Prognostic factors for survival were sex, age, renal function and cluster affiliation. The mortality of patients with AAV was significantly increased compared with the general population except in the non-renal cluster. The cardiovascular and gastrointestinal clusters showed the highest mortality. CONCLUSION: Even though the mortality in patients with AAV is increased compared with the general population this does not apply to patients without gastrointestinal, cardiovascular or renal involvement at diagnosis. We suggest that the initial clinical presentation is an important predictor for survival.

C1-Inhibitor Decreases the Release of Vasculitis-Like Chemotactic Endothelial Microvesicles.

The kinin system is activated during vasculitis and may contribute to chronic inflammation. C1-inhibitor is the main inhibitor of the kinin system. In this study, we investigated the presence of the kinin B1 receptor on endothelial microvesicles and its contribution to the inflammatory process. Compared with controls (n=15), patients with acute vasculitis (n=12) had markedly higher levels of circulating endothelial microvesicles, identified by flow cytometry analysis, and significantly more microvesicles that were positive for the kinin B1 receptor (P<0.001). Compared with microvesicles from wild-type cells, B1 receptor-positive microvesicles derived from transfected human embryonic kidney cells induced a significant neutrophil chemotactic effect, and a B1 receptor antagonist blocked this effect. Likewise, patient plasma induced neutrophil chemotaxis, an effect decreased by reduction of microvesicle levels and by blocking the B1 receptor. We used a perfusion system to study the effect of patient plasma (n=6) and control plasma (n=6) on the release of microvesicles from glomerular endothelial cells. Patient samples induced the release of significantly more B1 receptor-positive endothelial microvesicles than control samples, an effect abrogated by reduction of the microvesicles in the perfused samples. Perfusion of C1-inhibitor-depleted plasma over glomerular endothelial cells promoted excessive release of B1 receptor-positive endothelial microvesicles compared with normal plasma, an effect significantly decreased by addition of C1-inhibitor or B1 receptor-antagonist. Thus, B1 receptor-positive endothelial microvesicles may contribute to chronic inflammation by inducing neutrophil chemotaxis, and the reduction of these microvesicles by C1-inhibitor should be explored as a potential treatment for neutrophil-induced inflammation.

Microvesicle transfer of kinin B1-receptors is a novel inflammatory mechanism in vasculitis.

During vasculitis, activation of the kinin system induces inflammation, whereby the kinin B1-receptor is expressed and activated after ligand binding. Additionally, activated blood cells release microvesicles into the circulation. Here we determined whether leukocyte-derived microvesicles bear B1-kinin receptors during vasculitis, and if microvesicles transfer functional B1-receptors to recipient cells, thus promoting inflammation. By flow cytometry, plasma from patients with vasculitis were found to contain high levels of leukocyte-derived microvesicles bearing B1-receptors. Importantly, renal biopsies from two patients with vasculitis showed leukocyte-derived microvesicles bearing B1-receptors docking on glomerular endothelial cells providing in vivo relevance. Microvesicles derived from B1-receptor-transfected human embryonic kidney cells transferred B1-receptors to wild-type human embryonic kidney cells, lacking the receptor, and to glomerular endothelial cells. The transferred B1-receptors induced calcium influx after B1-receptor agonist stimulation: a response abrogated by a specific B1-receptor antagonist. Microvesicles derived from neutrophils also transferred B1-receptors to wild-type human embryonic kidney cells and induced calcium influx after stimulation. Thus, we found a novel mechanism by which microvesicles transfer functional receptors and promote kinin-associated inflammation.

ANCA-associated vasculitis and malignancy: current evidence for cause and consequence relationships.

In this review, we summarise the current understanding of the potential link between cancer and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (Wegener's; GPA) and microscopic polyangiitis (MPA). As is true for many autoimmune or inflammatory rheumatic diseases, AAV diagnosis and therapy are associated with an increased risk of de novo cancer development, likely as a result of impaired immunosurveillance, direct oncogenicity of immunosuppressive agents and perhaps malignant degeneration of tissues undergoing chronic immune stimulation. Data from several studies suggest a standardised incidence ratio of cancer in AAV of 1.6-2.0 compared to the general population and a possibly higher risk in GPA than in MPA. The most prominent cancers observed in AAV include urinary tract cancer, leukaemia and non-melanoma skin cancer. The effect of individual therapeutic agents is difficult to dissect, but cyclophosphamide has emerged as a major contributor to cancer development because of its direct carcinogenic properties. Awareness of cancer risk in AAV calls for increased implementation of measures to prevent or screen for cancer and development of less carcinogenic therapies. Cancer has also been suggested as a potential trigger or cause of AAV. Although some studies found that prior or concomitant history of cancer increases the risk of AAV, available data are inconsistent and suggest that the fraction of AAV that might be attributable to cancer is at best small.

Long-term patient survival in ANCA-associated vasculitis.

BACKGROUND: Wegener's granulomatosis and microscopic polyangiitis are antineutrophil cytoplasm antibodies (ANCA)-associated vasculitides with significant morbidity and mortality. The long-term survival of patients with ANCA associated vasculitis treated with current regimens is uncertain. OBJECTIVE: To describe the long-term patient survival and possible prognostic factors at presentation in an international, multicentre, prospectively recruited representative patient cohort who were treated according to strictly defined protocols at presentation and included the full spectrum of ANCA-associated vasculitis disease. METHODS: Outcome data were collected for 535 patients who had been recruited at the time of diagnosis to four randomised controlled trials between 1995 and 2002. Trial eligibility was defined by disease severity and extent, covered the spectrum of severity of ANCA-associated vasculitis and used consistent diagnostic criteria. Demographic, clinical and laboratory parameters at trial entry were tested as potential prognostic factors in multivariable models. RESULTS: The median duration of follow-up was 5.2 years and 133 (25%) deaths were recorded. Compared with an age- and sex-matched general population there was a mortality ratio of 2.6 (95% CI 2.2 to 3.1). Main causes of death within the first year were infection (48%) and active vasculitis (19%). After the first year the major causes of death were cardiovascular disease (26%), malignancy (22%) and infection (20%). Multivariable analysis showed an estimated glomerular filtration rate <15 ml/min, advancing age, higher Birmingham Vasculitis Activity Score, lower haemoglobin and higher white cell count were significant negative prognostic factors for patient survival. CONCLUSION: Patients with ANCA-associated vasculitis treated with conventional regimens are at increased risk of death compared with an age- and sex-matched population.