A new scoring system for coronary artery abnormalities in Kawasaki disease.

BACKGROUND: In China, coronary artery abnormalities (CAAs) secondary to Kawasaki disease (KD) tend to have an increased occurrence. We hypothesize that Chinese children with KD may possess several unique CAA risks, and the predictive efficacy of multiple scoring systems in Chinese patients are still to be further studied. METHODS: Two hundred and three KD patients were recruited. Using multivariable analysis, independent predictors of CAAs were combined into a scoring system. Subsequently, CAA risks of our patients were evaluated by the newly established scoring system and eight other published scoring systems. RESULTS: Seventeen (8.37%) KD patients were identified as CAAs. The newly established scoring system contained the following 5 independent predictors: days of illness at initial treatment ≥7, redness and swelling of extremities, hematocrit ≤33%, percentage of monocytes ≥8.89%, and procalcitonin ≥0.5 ng/mL. The AUC value of newly established scoring system was 0.685 with a sensitivity of 41.18% and a specificity of 84.41%, higher than Harada score, Egami score, Kobayashi score, Sato score, San Diego score, Formosa score, and Tang score, whereas lower than Hua score. CONCLUSIONS: Days of illness at initial treatment ≥7 and procalcitonin are unique predictors of CAAs in newly established scoring system. Taking into account different identification criteria and analytical methodologies, there is still some heterogeneity among different scoring systems. IMPACT: The newly established scoring system contains the five independent predictors. Days of illness at initial treatment ≥7 and PCT are unique predictors of CAAs in our study, compared with 8 other systems. The AUC value of newly established scoring system is 0.685, similar to Hua score. There is some heterogeneity among different scoring systems.

The downstream RAF-1 signaling of fibroblast growth factor-23 participates in the osteogenetic effect caused by C-type natriuretic peptide in vitro.

PURPOSE: Several studies have demonstrated that C-type natriuretic peptide (CNP) stimulates osteoblastic proliferation seemly via antagonizing the expression of fibroblast growth factor (FGF)-23 in vitro. The main aim of the present study is to probe whether the post-receptor pathways of FGF-23 participate in osteogenesis caused by CNP. METHODS: Osteoblasts were cultured in the absence or presence of CNP: 0, 10, and 100 â€‹pmol/L, for 24 â€‹h, 48 â€‹h and 72 â€‹h, respectively. RESULTS: The findings of the present study indicated that osteoblastic proliferation was directly promoted by exogenous CNP in a dose-dependent manner; osteoblastic FGF-23 was significantly down-regulated by CNP at 24 â€‹h post-treatment; RAF-1, extracellular signal-regulated kinases (ERK), and P38 were substantially suppressed by CNP in a dose- and time-dependent manner; and signal transducer and activator of transcription (STAT)-1 was not changed on the premise of the down-regulated FGF-23 in osteoblasts treated with CNP. CONCLUSION: CNP may promote osteogenesis via inhibiting ERK and P38, rather than STAT-1, in the downstream of FGF-23/RAF-1 pathway.

Assessment of coronary artery abnormalities and variability of Z-score calculation in the acute episode of Kawasaki disease-A retrospective study from China.

BACKGROUND: Accurate classification of coronary artery abnormalities (CAAs) is essential for clinical decision-making and long-term management in Kawasaki disease (KD) patients. To date, there are several echocardiographic criteria of CAA assessment. MATERIALS AND METHODS: The Japanese Ministry of Health (JMH) criteria and the Z-score criteria from 2004 American Heart Association guidelines were adopted and their detective efficacies for CAAs were compared in 251 Chinese patients with KD Z scores were calculated by 6 published methods. RESULTS: According to the JMH criteria, 19 (7.57%) KD patients were classified as CAAs during the acute KD episode. However, the detective number of CAAs was highest and had a 0.68-fold increase by the Dallaire et al method with a Z-score cut point of ≥2.5 as compared with the JMH criteria; in contrast, more than 78.95% of patients with CAAs identified by the JMH criteria had a coronary artery Z score ≥2.5. All 6 different Z-score methods had satisfactory accuracies with a range from 93.23% to 97.61% in screening CAAs. For the 19 patients with CAAs identified by the JMH criteria, their Z scores presented the widest variation calculated by the McCrindle et al method. CONCLUSIONS: The JMH criteria underestimate the prevalence of CAAs as compared with the Z-score criteria. Quantitative assessment of coronary artery luminal dimensions, normalized as Z scores adjusted for body surface, should be recommended. The larger coronary artery luminal dimensions vary, the more heterogeneous Z scores calculated by different methods have.

C-type natriuretic peptide stimulates osteoblastic proliferation and collagen-X expression but suppresses fibroblast growth factor-23 expression in vitro.

BACKGROUND: The effects of C-type natriuretic peptide (CNP) and fibroblast growth factor (FGF)-23 appear to oppose each other during the process of bone formation, whereas few studies exist on the interaction between CNP and FGF-23. The main objective of the present study is to probe whether CNP is directly responsible for the regulation of osteoblast or via antagonizing FGF-23. METHODS: Osteoblasts were cultured in the absence or presence of CNP (0, 10, and 100 pmol/L) for 24 h, 48 h and 72 h, respectively. RESULTS: The findings of the present study indicated that: (1) CNP significantly stimulated osteoblastic proliferation and collagen (Col)-X expression; (2) both osteoblastic (osteocalcin, procollagen type I carboxy-terminal propeptide, total alkaline phosphatase and bone-specific alkaline phosphatase) and osteolytic (tartrate-resistant acid phosphatase and cross-linked carboxyterminal telopeptide of type I collagen) bone turnover biomarkers were up-regulated by CNP in osteoblasts; (3) FGF-23 mRNA and protein were significantly down-regulated at 24 h by CNP in osteoblasts, but the expression of FGF receptor-1/Klotho had no significant change. CONCLUSIONS: CNP stimulates osteoblastic proliferation and Col-X expression via the down-regulation of FGF-23 possibly in vitro. However, the specific mechanisms of the interaction between CNP and FGF-23 in osteoblasts are still unclear according to our findings. A further study on osteoblasts cultured with CNP and FGF-23 inhibitor will be undertaken in our laboratory.

Clinical observation of noncoronary cardiac abnormalities in Chinese children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute, self-limited vasculitis. Coronary artery aneurysm (CAA) serves as a major contributor to the long-term prognosis of KD. In addition, acute KD usually also leads to several kinds of noncoronary cardiac abnormalities (NCA) involving the pericardium, myocardium and endocardium. MATERIALS AND METHODS: A total of 142 Chinese children with KD were recruited from July 2015 to April 2018. Blood samples were collected at 24 hours pre-intravenous immunoglobulin (IVIG) therapy. Several inflammatory mediators and biomarkers for acute myocardial infarction were detected. Echocardiography and electrocardiography (ECG) were performed. RESULTS: Plasma white blood cell counts (WBC) were significantly increased in patients with IVIG-nonresponsive KD when compared with their IVIG-responsive counterparts. A total of 106 children (74.65%) suffered from NCA, including 8 patients (5.63%) with pericardial effusion, 23 patients (16.20%) with acute myocarditis, 101 patients (71.13%) with valvular regurgitation and 8 patients (5.63%) with abnormal ECG. No significant differences were observed in the distribution of clinical classification and the response to IVIG therapy regardless of NCA exhibited or not. CONCLUSIONS: Noncoronary cardiac abnormalities is almost universal in acute KD and mainly manifests as valvular regurgitation. However, it has no influence on clinical classification and the response to IVIG therapy.

Hepatic dysfunction secondary to Kawasaki disease: characteristics, etiology and predictive role in coronary artery abnormalities.

Coronary artery abnormalities (CAAs) are prominent during the acute Kawasaki disease (KD) episode and represent the major contributors to the long-term prognosis. Several meta-analysis and published scoring systems have identified hepatic dysfunction as an independent predictor of CAA risks. The medical records of 210 KD children were reviewed. Blood samples were collected from all subjects at 24 h pre-therapy and 48 h post-therapy, respectively. Liver function test (LFT) and inflammatory mediators were detected. Multivariate logistic regression analysis was conducted to identify the reliable biomarkers predicting whether CAAs existed or not in KD patients. 90.95% of KD patients had at least 1 abnormal LFT. Hypoalbuminemia was the most prevalent type of hepatic dysfunction, followed by elevated aspartate aminotransferase, low TP, low A/G and hyperbilirubinemia, respectively. The elevated inflammatory mediators (procalcitonin and C-reactive protein) and moderate dose of aspirin played a synthetic role in hepatic dysfunction secondary to KD. However, LFT presented no significant differences between infectious and noninfectious conditions. By a multivariate analysis, a lower albumin/globulin ratio (A/G, OR 13.50, 95% CI 3.944-46.23) served as an independent predictor of CAAs and had a sensitivity of 56.25%, and a specificity of 61.11% at a cutoff value of < 1.48. In conclusion, hepatic dysfunction is a common complication during the acute KD episode, characterized by elevated serum liver enzymes, hypoalbuminemia and hyperbilirubinemia. Systemic inflammation and aspirin, rather than infectious agents, are both the major contributors of hepatic dysfunction secondary to KD. A lower A/G serves as an independent predictor of CAAs.

Association of the infectious triggers with childhood Henoch-Schonlein purpura in Anhui province, China.

BACKGROUND: Although the specific etiology of Henoch-Schonlein purpura (HSP) is still unknown, several kinds of infectious triggers have been proved to participate in its pathogenesis. The objectives of present study were to analyze the association of the infectious triggers with childhood HSP in Anhui province, China. METHODS: 1200 HSP children were recruited from January 2015 to December 2017. Serum antistreptolysin O titer, TORCH, Epstein-Barr virus, helicobacter pylori (HP), Mycoplasma antibodies (MP-Ab), tubercle bacillus antibody (TB-Ab), respiratory pathogens (legionella pneumophila, chlamydia pneumoniae, adenovirus, respiratory syncytial virus, influenza A virus, influenza B virus, rickettsia, parainfluenza virus) were determined. Patients' histories were obtained by interviews and questionnaires. RESULTS: The annual incidence of HSP was 8.13-9.17 per 100,000. HSP occurred more commonly in spring and winter than in summer with an obvious west-to-east gradient. On admission, several potential infections were identified in 611 cases (50.92%). The infectious agents including streptococcus, HP, MP, parainfluenza, respiratory syncytial virus, TB and toxoplasma gondii were identified in 205 cases (17.08%), 71 cases (5.92%), 58 cases (4.83%), 6 cases (0.5%), 1 case (0.08%), 1 case (0.08%) and 1 case (0.08%) respectively. 123 cases (10.25%) relapsed or recurred more than one time; the mean number was 2.92, and the mean interval was 11.4 weeks. The infection was the most frequent trigger regardless of clinical phenotypes and relapse/recurrence. Symptomatic treatment plus adjunctive anti-infectious agents could significantly improve the remission rate of purpura in the infectious cases (x2=24.60, p<0.01). CONCLUSIONS: Streptococcus is the most frequent infectious agent in HSP children regardless of clinical phenotype or relapse/recurrence. The complete elimination of infectious triggers may help relieve cutaneous purpura.

The time option of IVIG treatment is associated with therapeutic responsiveness and coronary artery abnormalities but not with clinical classification in the acute episode of Kawasaki disease.

BACKGROUND: In the last decade, incomplete Kawasaki disease (KD), intravenous immunoglobulin (IVIG) non-response and coronary artery abnormalities (CAA) have experienced the increasing trends in China. In addition, the enhancement of pediatricians' awareness may also raise the diagnostic rate of incomplete KD and stimulate more aggressive initial therapy in the acute episode of KD. Given this background, we hypothesize that the time option of IVIG treatment should be in parallel with peak time of systemic inflammation; either earlier or later IVIG treatment may affect the clinical classification, therapeutic responsiveness and CAA occurrence in KD patients. Therefore, the major objective of the present study is to identify whether the time option of IVIG treatment could be associated with the clinical classification, therapeutic responsiveness and CAA occurrence in the acute episode of KD. MATERIALS AND METHODS: A total of 153 children with KD were recruited between July 2015 and May 2018. All patients received the standard therapy of KD, including a single infusion of IVIG (2 g/kg) and aspirin (30-50 mg/kg/d). Blood samples were collected from all subjects within 24 h pre-IVIG treatment, respectively. Echocardiography was performed during the period from 2 days to 14 days after IVIG treatment. RESULTS: (1) The clinical classification presented no significant heterogenicity among different treatment time (x2 = 1.59, p > 0.05) (2) Eleven KD patients resisted to IVIG treatment and 7 of them (63.60%) received the initial IVIG dose on day 5 and 6. (3) The distribution of CAA onset was subjected to a significant difference according to timing option of IVIG treatment (x2 = 11.94, p < 0.05). CONCLUSIONS: The time option of IVIG treatment is associated with therapeutic responsiveness and CAA but not with clinical classification in the acute episode of KD.

C-type natriuretic peptide attenuates renal osteodystrophy through inhibition of FGF-23/MAPK signaling.

Renal osteodystrophy (ROD) occurs as early as chronic kidney disease (CKD) stage 2 and seems ubiquitous in almost all pediatric patients with CKD stage 5. Fibroblast growth factor (FGF)-23, a bone-derived endocrine regulator of phosphate homeostasis, is overexpressed in CKD and disturbs osteoblast differentiation and matrix mineralization. In contrast, C-type natriuretic peptide (CNP) acts as a potent positive regulator of bone growth. In the present study, we infused CNP into uremic rats and observed whether CNP could attenuate ROD through the inhibition of FGF-23 cascades. In uremic rats, CNP administration significantly alleviated renal dysfunction, calcium phosphate metabolic disorders, hypovitaminosis D, secondary hyperparathyroidism, the decrease in bone turnover markers and retarded bone pathological progression. More importantly, within FGF-23/mitogen-activated protein kinase (MAPK) signaling, the fibroblast growth factor receptor-1, Klotho and alternative (STAT-1/phospho-STAT-1) elements were upregulated by CNP, whereas FGF-23, RAF-1/phospho-RAF-1, and downstream (ERK/phospho-ERK and P38/phospho-P38) elements were paradoxically underexpressed in bone tissue. Therefore, CNP exerts a therapeutic effect on ROD through inhibition of FGF-23/MAPK signaling at the RAF-1 level.

Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm.

Kawasaki disease (KD) is an acute, systemic vasculitis and occurs mainly in childhood. Interleukin-6 (IL-6) is a pleiotropic cytokine synthesized predominantly by neutrophils and monocytes/macrophages and plays an important role in systemic inflammatory disease. However, a little information is currently available on the relationship of serum IL-6 with conventional inflammatory mediators, clinical classification, IVIG response and coronary artery aneurysm (CAA). 165 Chinese children with KD were enrolled and divided into six subgroups, including complete KD, incomplete KD, IVIG-responsive KD, IVIG-nonresponsive KD, coronary artery noninvolvement KD and coronary artery involvement KD. Blood samples were collected from all subjects within 24-h pre- and 48-h post-IVIG therapy, respectively. Serum IL-6 and conventional inflammatory mediators were detected. (1) Serum IL-6 markedly increased in the acute phase of KD, whereas declined to normal after IVIG therapy; it was positively correlated with C-reactive protein and erythrocyte sedimentation rate. (2) Serum IL-6 was significantly elevated in patients with incomplete KD when compared with their complete counterparts. The area under receiver operating characteristic curve (AUC) value for serum IL-6 in prediction of incomplete KD was 0.596, and the estimated sensitivity and specificity were 77.80% and 54.40% with a cutoff of IL-6 > 13.25 pg/ml, respectively. (3) Serum IL-6 was significantly elevated in patients with IVIG-nonresponsive KD when compared with their IVIG-responsive counterparts; the AUC value for serum IL-6 in prediction of IVIG-nonresponsive KD was 0.580, and the estimated sensitivity and specificity were 60.00% and 66.30% with a cutoff of IL-6 > 26.40 pg/ml, respectively. (4) No significant differences in IL-6 were found between KD patients with and without CAA. IL-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive KD rather than CAA.

Fibroblast growth factor-23 may serve as a novel biomarker for renal osteodystrophy progression.

The purpose of the present study was to determine whether fibroblast growth factor (FGF)­23 could serve as a novel biomarker for renal osteodystrophy (ROD) progression. A rat model of ROD was induced by left nephrectomy plus intravenous injection of Adriamycin. Serum FGF­23 was determined using an enzyme­linked immunosorbent assay. Serum level and bone expression of FGF­23 were both significantly elevated in the ROD group at 24 h post­surgery. Serum FGF­23 was negatively correlated with calcium, phosphate, 25­hydroxyvitamin D, conventional bone biomarkers and bone collagen X. More importantly, serum FGF­23 was significantly associated with abnormalities in bone formation rate, osteoblasts, osteoclasts, trabecular volume thickness and osteoid volume. Therefore, FGF­23 may serve as a novel biomarker for ROD.

Predisposing factors of childhood Henoch-Schönlein purpura in Anhui province, China.

Henoch-Schönlein purpura (HSP) is a common autoimmune vasculitis in childhood. The detailed pathogenesis of HSP is still unclear, whereas several types of predisposing factors have been proved to be the initial step. The objectives of present study were to analyze the distribution of predisposing factors, association of the predisposing factors with clinical manifestations and HSP relapse/recurrence. 1200 children with HSP were recruited between January 2015 and December 2017. We reviewed their laboratory tests and medical histories associated with HSP onset. The annual incidence of HSP was 8.13-9.17 per 100 000 in Anhui province. HSP occurred more commonly in spring and winter than in summer with an obvious west-to-east gradient. Cutaneous purpura was the most prevalent manifestation (100%), followed by arthritis/arthralgias (43.67%), abdominal pain (40.17%) and renal involvement (18.17%). On admission, series of potential infections were identified in 611 patients (50.92%). The histories of allergy, injury, surgery, vaccination and tick bite were declared by 231 patients (19.25%), 15 patients (1.25%), 12 patients (1.00%), 4 patients (0.33%) and 3 patients (0.25%), respectively. However, predisposing factors could not be identified in 521 children with HSP (43.42%) yet. 123 cases (10.25%) relapsed or recurred more than one time; the mean number was 2.92, and the mean interval was 11.4 weeks. The infection is the most frequent predisposing factor regardless of clinical phenotypes and relapse/recurrence, whereas the clinical manifestations exhibit an obvious heterogenicity according to different predisposing factors.

Acute Kidney Injury Secondary to Severe Hand, Foot and Mouth Disease Caused by Enterovirus-A71: Hypertension Is a Common.

Hand, foot and mouth disease (HFMD) is a common infectious disease among children, caused primarily by human enterovirus-A71 (EV-A71) and coxsackievirus-A16 (CV-A16). To date, only two case reports mention that renal involvement can be secondary to or coexisting with CV-A16-associated HFMD. In the present report, we describe a 10-year-old girl who was infected with EV-A71 and subsequently developed a definite acute kidney injury (AKI), mainly based on the characteristic rash, virus isolation, eyelid edema, hypertension, decreased urine output, mild proteinuria and impaired renal function. She was treated with intravenous ribavirin, immunoglobulin, oral administration of nifedipine and ramipril. After 7 days of intensive observations, she recovered fully. Hypertension is a common feature in both HFMD and AKI. On one hand, hypertension serves as a risk factor for severe HFMD; on the other hand, hypertension induces AKI onset and is also deteriorated by AKI.

C-Type Natriuretic Peptide Dampens Fibroblast Growth Factor-23 Expression Through MAPK Signaling Pathway in Human Mesangial Cells.

C-type natriuretic peptide (CNP) is believed to be produced locally in the kidneys and possess several renoprotective properties. In contrast, fibroblast growth factor (FGF) -23 elevates in the early stage of chronic kidney disease and predicts its outcomes. Currently, several studies have demonstrated that CNP and FGF-23 act through a close pathway, and moreover, FGF-23/mitogen-activated protein kinase (MAPK) can be obviously suppressed by CNP. In the present study, human mesangial cells (MCs) were incubated in serum-containing medium in the absence or presence of CNP (0, 10 and 100 pM) for 24, 48 and 72 h, respectively. CNP administration significantly suppresses MCs proliferation in a time- and dose-dependent manner. As a down-stream signaling of CNP activation, the expressions of natriuretic peptide receptor (NPR)-B, cyclic guanosine monophosphate-dependent protein kinases II and NPR-C were obviously augmented, whereas neutral endopeptidase expression was significantly decreased after CNP treatment in MCs. FGF-23, FGF receptor-1 and RAF-1 experienced a pronounced down-regulation in MCs with different doses of CNP throughout the whole observational period. CNP may dampen FGF-23 expression via MAPK signaling pathway in MCs.

Receptor signaling and neutral endopeptidase are involved in the resistance of C-type natriuretic peptide to human mesangial proliferation and collagen-IV expression.

C-type natriuretic peptide (CNP) is regarded as a local, paracrine hormone to regulate vascular tone and cell proliferation. Although several in vivo studies have documented that CNP exerts the inhibitory effects on mesangial cells (MCs) proliferation and collagen production, a limited number of studies exist about the resistance of CNP to MCs proliferation in vitro. Besides, whether its receptor signaling and neutral endopeptidase (NEP) are involved remains unclear. In the present study, human MCs were incubated in serum-containing medium in the absence or presence of CNP (0, 10 and 100 pM) for 24, 48 and 72 hours, respectively. CNP administration significantly suppresses MCs proliferation and collagen-IV (Col-IV) expression in a time-dependent and dose-dependent manner. As a down-stream signal molecule of CNP activation, the expressions of natriuretic peptide receptor (NPR)-B, cyclic guanosine monophosphate-dependent protein kinases II and NPR-C were obviously augmented, whereas NEP expression was significantly decreased after CNP treatment. In conclusion, receptor signaling and NEP are involved in the resistance of CNP to human mesangial proliferation and Col-IV expression.