Health At A Glance

The majority of patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) have antineu-trophil cytoplasmic antibodies (ANCA) in their serum. This is particularly true of patients with “disseminated” disease, the great majority of whom are ANCA positive. WG and MPA are often termed “ANCA-associated vasculitides” (AAV), even though not all patients with these conditions have ANCA. The Churg—Strauss syndrome, another disorder classified as an AAV, is discussed in Chap. 23. Multiple antibodies may lead to positive immunofluores-cence testing for ANCA in either perinuclear (P-ANCA) or cytoplasmic (C-ANCA) patterns. However, only antibodies to myeloperoxidase (MPO) and proteinase-3 (PR3) are associated with the A AV. Antibodies directed against PR3 and MPO are termed PR3-ANCA and MPO-ANCA, respectively. WG may be associated with destructive upper respiratory tract disease, including saddle-nose deformity, erosive sinusitis, and subglottic stenosis. A host of ocular lesions may occur in the A AV, including episcleritis, scleritis, peripheral ulcerative keratitis, and orbital pseudotumor. Most of these lesions are more common in WG than in MPA. Lung disease in the AAV ranges from nodular lesions with a tendency to cavitate (in WG), to interstitial lung disease (MPA), and to alveolar hemorrhage (both WG and MPA). Segmental, necrotizing glomerulonephritis commonly accompanies the AAV. Because of the paucity of immunoreactants such as immunoglobulins and complement components in kidney biopsies relative to the biopsies from patients with immune complex-mediated glomerulonephritis, the glomerulonephritis of the A AV is termed “pauci-immune.”

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ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease.

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Pathogenesis and therapeutic interventions for ANCA-associated vasculitis

Background and objectives Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related complications are not uncommon. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases–sponsored Kidney Precision Medicine Project requires that all participants undergo a kidney biopsy; therefore, the objective of this analysis was to study complication rates of native kidney biopsies performed using automated devices under kidney imaging. Design, setting, participants, & measurements This is a systematic review and meta-analysis of the literature published from January 1983 to March 2018. The initial PubMed search yielded 1139 manuscripts. Using predetermined selection criteria, 87 manuscripts were included in the final analysis. A random effects meta-analysis for proportions was used to obtain combined estimates of complication rates. Freeman–Tukey double-arcsine transformations were used to stabilize variance as complications were rare. Results A total of 118,064 biopsies were included in this study. Patient age ranged from 30 to 79 years, and 45% of patients were women. On the basis of our meta-analysis, pain at the site of biopsy is estimated to occur in 4.3% of biopsied patients, hematomas are estimated to occur in 11%, macroscopic hematuria is estimated to occur in 3.5%, bleeding requiring blood transfusions is estimated to occur in 1.6%, and interventions to stop bleeding are estimated to occur in only 0.3%. Death attributed to native kidney biopsy was a rare event, occurring only in an estimated 0.06% of all biopsies but only 0.03% of outpatient biopsies. Complication rates were higher in hospitalized patients and in those with acute kidney disease. The reported complications varied on the basis of study type and geographic location. Conclusions Although the native kidney biopsy is an invasive diagnostic procedure, the rates of bleeding complications are low. Albeit rare, death can occur postbiopsy. Complications are more frequently seen after kidney biopsies of hospitalized patients with AKI.

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Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications.

Classification of the vasculitides has been traditionally based on vessel size. The American College of Rheumatology (ACR) criteria were developed in the 1980s and published in 1990 before the development of ANCA testing and modern imaging techniques such as MRI and PET scanning, and therefore, these criteria are not fit for use in 2010s. The Chapel Hill Consensus Conference provided a framework for defining various types of vasculitis. In the next two years, new classification criteria will be published from the DCVAS study, which will provide a modern system for the classification of vasculitis for clinical studies. The epidemiology of vasculitides is increasingly well studied; however, there remain gaps in our knowledge of the occurrence of vasculitis in many populations, especially from the third world or those with health care systems that do not permit ready collection of accurate epidemiological data. Giant cell arteritis presents in the elderly and those of Northern European ancestry; ANCA-associated vasculitis appears to have a consistent overall occurrence, but there are differences in the occurrence of MPO and PR3 vasculitis between populations. Kawasaki disease occurs most commonly in Asian populations, especially Japanese, and in those aged less than 5 years. It is currently the most common cause of acquired cardiac disease in those populations.

Introduction, epidemiology and classification of vasculitis

The prevalence of acute renal infarction (ARI) in Japan remains unclear. We describe the clinical features and renal prognosis of ARI in Japanese patients. This single-center, retrospective, observational study included 33 patients with newly diagnosed ARI (2009–2013). Their clinical features and long-term renal outcomes were evaluated. The prevalence of ARI among emergency room patients was 0.013 %. The incidence of ARI among in-patients was 0.003 % (mean age 71.9 ± 13.4 years; men 63 %). Enhanced computed tomography or renal isotope scans were obtained to diagnose ARI. ARI involved the left kidney in 70 %, right kidney in 18 %, and both kidneys in 12 % of patients. Four cases had splenic infarction, and 70 % of patients had atrial fibrillation. We noted abdominal or flank pain in 66 %, fever (>37.6 °C) in 36 %, and nausea/vomiting in 6 % of patients. The white blood cell count, and levels of lactate dehydrogenase and C-reactive protein peaked at 2–4 days after onset. Acute kidney injury due to ARI occurred in 76 % of patients. The estimated glomerular filtration rate decreased to ~70 % and recovered to ~80 % of the original value after 1 year. The mortality rates were 9 and 15 % at 1 month and 1 year, respectively. We determined the prevalence of ARI among emergency room patients, its incidence among in-patients, and short-term and long-term mortality. The majority of ARI cases were of cardiac origin, and the others were due to trauma or systemic thrombotic disease. Clinicians should recognize ARI as a fatal arterial thrombotic disease.

A case series of acute renal infarction at a single center in Japan

Background Antineutrophil cytoplasmic antibody-associated vasculitis is triggered by environmental factors, including silica dust exposure. Repeated tsunami waves brought a large volume of silica-containing sludge inland after the Great East Japan earthquake in 2011. We aimed to determine if the serious disaster influenced the clinical features of the microscopic polyangiitis. Methods This is an observational retrospective study conducted in a single institute. A total of 43 patients were included based on the CHCC2012 criteria for microscopic polyangiitis from 2007 to 2015. We used the Poisson regression model to determine the incidence of microscopic polyangiitis within the annual population of the medical district. The participants were selected during a 3-year period from before (N = 13) to after the disaster (N = 20). The differences of parameters and the overall survival between the groups were analyzed. Results The incidence of microscopic polyangiitis increased after the disaster (λ = 17.4/million/year [95%CI: 7.66-39.6] before the disaster and λ = 33.1/million/year [17.7-61.7] after the disaster, P = 0.044). A high Birmingham Activity Score was associated with a high incidence of microscopic polyangiitis after the disaster. The overall survival of the patients with microscopic polyangiitis declined significantly after the disaster. Conclusions The Great East Japan earthquake influenced the development of the microscopic polyangiitis in our restricted area. The patients who developed after the disaster had severe symptoms and a high mortality rate.

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The influence of the Great East Japan earthquake on microscopic polyangiitis: A retrospective observational study.

Purpose Pyelonephritis, an upper urinary tract infection, is a serious infection that often requires hospitalization. However, the accurate diagnosis of acute pyelonephritis can be difficult, especially among older individuals who can present with unusual symptoms. Imaging with computed tomography (CT) is not unusual in the diagnosis of pyelonephritis, with some clinicians regarding perirenal fat stranding (PFS) as a characteristic finding. However, the sensitivity and specificity of PFS in diagnosing pyelonephritis are currently unknown. We therefore sought to clarify the relevance of PFS in diagnosing acute pyelonephritis. Patients and methods We conducted a case-controlled retrospective analysis of medical records. The pyelonephritis group included 89 patients who had been diagnosed with acute pyelonephritis, while the control group included 319 patients who had undergone percutaneous renal biopsy. CT findings were available for both groups. The frequency of PFS and its sensitivity and specificity for the diagnosis of acute pyelonephritis were investigated. Results The mean ages of the pyelonephritis and control groups were 74±15 years and 63±16 years, respectively. A total of 28% of men were in the pyelonephritis group vs 61% of men in the control group. The frequency of PFS was 72% in the pyelonephritis group vs 39% in the control group. Age and renal dysfunction were associated with an increased frequency of PFS. After adjusting for age, sex, and renal function using a propensity score analysis, the sensitivity, specificity, and positive likelihood ratio of PFS for diagnosing acute pyelonephritis were 72%, 58%, and 1.7, respectively. Conclusion The presence of PFS was not useful in diagnosing acute pyelonephritis.

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Perirenal fat stranding is not a powerful diagnostic tool for acute pyelonephritis

Background/aim Cardiovascular disease is the most serious cause of death in patients on hemodialysis. Low serum magnesium (Mg) and high serum calcium (Ca) levels have been associated with poor outcome and cardiovascular mortality in patients on maintenance and initiation dialysis. As a more accurate marker is warranted, we evaluated the efficacy of a novel serum Ca-Mg marker of all-cause and cardiovascular mortality that indicates vessel calcification. Methods We recruited 378 consecutive patients with end-stage renal disease who started dialysis between January 2009 and December 2015 at the Japanese Red Cross Ishinomaki Hospital. We collected data of patients' demographic characteristics and comorbidities from their electronic medical records. We retrospectively examined the association of the serum Ca-Mg ratio with all-cause and cardiovascular mortality using the Cox proportional hazard model, and determined the value that predicted cardiovascular death using the receiver operating characteristic (ROC) curve. Results Overall, 253 patients with serum Mg and Ca data were analyzed. The 3-year survival rate of this group was 0.70 (95% confidence interval [CI] 0.55-0.80), and the hazard ratio for the risk of death was 3.94 (95% CI 1.37-11.31). The 3-year cardiovascular mortality rate was 0.12 (95% CI 0.05-0.23), which was significantly higher than that of the other groups. The ROC curve of cardiovascular mortality with the Ca-Mg ratio was greater than that of Mg (area under the curve 0.75 vs. 0.69, p = 0.037). Conclusion A high Ca-Mg ratio was significantly associated with all-cause and cardiovascular mortality, and it was more accurate than serum Mg.

Evaluation of the Predictive Value of the Serum Calcium-Magnesium Ratio for All-Cause and Cardiovascular Mortality in Incident Dialysis Patients.

Summary Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg-Lepob/J (ob/ob) mice. Vaccination with the E3 (32EPKSRFAMLD41) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in ob/ob mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in ob/ob mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc-Apoeshl mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases.

Hirotaka Fukami

Papers

A case series of acute renal infarction at a single center in Japan

The influence of the Great East Japan earthquake on microscopic polyangiitis: A retrospective observational study.

Perirenal fat stranding is not a powerful diagnostic tool for acute pyelonephritis

Evaluation of the Predictive Value of the Serum Calcium-Magnesium Ratio for All-Cause and Cardiovascular Mortality in Incident Dialysis Patients.

Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia.