Ching-Yuang Lin

p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease

Background. Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients. Methods. This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24 months. Results. Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model. Conclusions. In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.

Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor alpha among patients with Kawasaki disease*

To determine the role of cytokines in Kawasaki disease, serial measurements of serum cytokine levels were done in 60 patients treated solely with aspirin. Coronary artery aneurysms later developed in 12 of them. The results suggest that elevated serum interleukin-6 and interleukin-8 levels during the first week of illness may be associated with a higher risk of coronary aneurysm formation.

Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions

IMPORTANCE The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. OBJECTIVE To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. DESIGN, SETTING, AND PARTICIPANTS Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. MAIN OUTCOMES AND MEASURES Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. RESULTS The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. CONCLUSIONS AND RELEVANCE This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Lupus Nephritis in Children—A Review of 167 Patients

BACKGROUND Relatively few studies have been made of children with lupus nephritis. The prognosis of children with lupus nephritis is ominous for those with diffuse proliferative glomerulonephritis and active interstitial inflammation. Up to now few studies have been made on this subject. OBJECTIVES To evaluate the clinical course, histopathology, and prognosis of lupus nephritis in children, to identify the risk factors for renal failure and mortality, and to share our experience in treating lupus nephritis in children. METHODS Retrospectively, 167 children under 18 years of age with lupus nephritis at Veterans General Hospital-Taipei, Taiwan from 1979 to 1991 were studied. All patients received renal biopsy and follow-up biopsies were performed in 36 children. The clinical and serologic parameters at the time of renal biopsy were recorded. RESULTS There were 55 (33%) patients with class II, 30 (18%) with class III, 69 (41.3%) with class IV, and 13 (7.8%) with class V nephritis based on initial biopsy. The mean follow-up time was 59 months. Follow-up biopsies were histologically stationary in 29 patients, progressive in five, and regressive in two. The results revealed that those with persistent hypertension, anemia, increased serum creatinine concentration, and decreased creatinine clearance rate at initial biopsy were more prone to develop renal failure. Low titer of CH50 hemolytic assay appeared to be a poor prognostic indicator. The overall renal and patient 5-year survival rates were 93.1% (135/145) and 91.08% (143/157), respectively. They were 87.7% (50/57) and 82% (55/67), respectively, of patients with class IV proliferative glomerulonephritis. CONCLUSIONS The prognosis of children with class IV nephritis in this study was better than that reported previously. All children surviving without renal failure were maintaining their normal lives with little organ dysfunction. The improved results may be due to earlier renal biopsy for precise histopathologic definition, better supportive care, and selective use of aggressive therapy, including methylprednisolone pulse therapy, intravenous cyclophosphamide, intravenous prostaglandin E1 therapy, high-dose intravenous gammaglobulin therapy, and cyclosporin A for those with high risk factors.

Improvement of Histological and Immunological Change in Steroid and Immunosuppressive Drug-Resistant Lupus nephritis by High-Dose Intravenous Gamma Globulin

From July 1984 to December 1987, 9 patients with lupus nephritis did not respond to the administration of two courses of methylprednisolone pulse therapy and cyclophosphamide treatment for 56 days. Therefore, high-dose intravenous human gamma-globulin (IVIG) was administrated. Before IVIG therapy, renal biopsy showed class IV lupus nephritis in 5 cases, class V in 2 cases, and class IV with V in 2 cases. Immunofluorescence of the renal biopsy showed heavy IgG deposits along the glomerular capillary walls. These heavy glomerular IgG deposits were dissociated after in vitro incubation of the cryostat kidney sections with plasmin-treated, PEG-treated, sulfonated human gamma-globulin and a human Fc fragment, as evidenced by a dramatic decrease or even absence of fluorescent intensity. After high-dose IVIG treatment, 3 out of 5 cases of class IV lupus nephritis had a good response with decreased proteinuria and creatinine; serum C3, C4 levels and CH50 hemolytic activity also increased. The glomerular IgG deposits decreased in the follow-up biopsy. Pathologically, 2 of them transformed into class IIb. The capacity to synthesize immunoglobulin after pokeweed mitogen stimulation was reduced and the circulating immune complexes (CIC) lowered after high-dose IVIG treatment. In the others there was partial response. These clinical and immunological improvements after high-dose IVIG therapy are probably related to the modulation of macrophage-T cell function and enhancement of suppressor T cell function. The toxicity of high dose IVIG was minimal, but the cost is high, search for an optimal dosage is warranted.

Cystic Dilatations Within the Pelvis in Patients with Ipsilateral Renal Agenesis or Dysplasia

A total of 13 cases of cystic dilatations in the pelvis with ipsilateral renal agenesis or dysplasia was detected during renal ultrasonic mass screenings among 280,000 children within the last 2.5 years. The frequency was approximately 0.00464%. These anomalies included 7 cases of Gartners cyst and 6 of seminal vesicle cyst. Sonographically, the cystic dilatations displayed a typically cystic nature with no internal echoes. The cysts were located laterally or posteriorly to the bladder, and the cystic mass protruded into or was behind the bladder and sometimes bulged the bladder wall. The dysplastic kidney in the patients with ipsilateral cystic dilatations was not detected by sonography due to its small size and the fact that it was obscured by bowel gas or overlying tissue densities. Three cases of dilated ureter communicating with the cyst were found on sonography. Since ultrasonic examination is an excellent method to identify a fluid-filled cystic structure, ultrasonography has become an important modality in the early detection, diagnosis and followup of these cystic dilatations.

Peptidoglycan Enhances IL-6 Production in Human Synovial Fibroblasts via TLR2 Receptor, Focal Adhesion Kinase, Akt, and AP-1- Dependent Pathway

Peptidoglycan (PGN), the major component of the cell wall of Gram-positive bacteria, activates the innate immune system of the host and induces the release of cytokines and chemokines. We investigated the signaling pathway involved in IL-6 production stimulated by PGN in rheumatoid arthritis synovial fibroblasts. PGN caused concentration- and time-dependent increases in IL-6 production. PGN-mediated IL-6 production was attenuated by TLR2 small interfering RNA and nucleotide-binding oligomerization domain 2 small interfering RNA. Pretreatment with PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor, and AP-1 inhibitor (tanshinone IIA) also inhibited the potentiating action of PGN. PGN increased the focal adhesion kinase (FAK), PI3K, and Akt phosphorylation. Stimulation of rheumatoid arthritis synovial fibroblast cells with PGN increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the IL-6 promoter. PGN mediated an increase in the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to AP-1 element was inhibited by Ly294002, Akt inhibitor, and FAK mutant. Our results suggest that PGN increased IL-6 production in human synovial fibroblasts via the TLR2 receptor/FAK/PI3K/Akt and AP-1 signaling pathway.

Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats

Abstract:  Nitric oxide (NO) deficiency is associated with development of hypertension. We examined whether melatonin protects against the blood pressure increase is because of the restoration of the NO pathway. Spontaneous hypertensive rats (SHR) and control normotensive Wistar Kyoto (WKY) rats aged 4 weeks were assigned to four groups (N = 6 for each group): untreated SHR and WKY, melatonin‐treated SHR and WKY. Melatonin‐treated rats received 0.01% melatonin in drinking water for 8 wks. All rats were sacrificed at 12 wk of age. SHR had higher blood pressure than WKY, which melatonin prevented. Plasma asymmetric dimethylarginine (ADMA) levels were elevated in SHR, combined with a reduction in plasma L‐arginine to ADMA ratio (AAR). In the kidney, L‐arginine, ADMA, and AAR were not different between SHR and WKY rats, whereas L‐citrulline level was increased in SHR. Melatonin decreased plasma ADMA level and restored plasma AAR. Renal dimethylarginine dimethylaminohydrolase (DDAH, ADMA‐metabolizing enzyme) activity was lower in SHR than WKY rats, which melatonin therapy prevented. Also, melatonin elevated both L‐arginine and ADMA but reduced L‐citrulline level in the kidney in SHR, which was associated with the prevention of reduced renal argininosuccinate lyase (ASL) expression in SHR. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8‐ hydroxydeoxyguanosine (8‐OHdG) immunostaining in SHR. The observed antihypertensive effects of melatonin in young SHR are because of the restoration of the NO pathway by reduction of plasma ADMA, restoration of plasma AAR, preservation of renal L‐Arg availability, and attenuation of oxidative stress.

Der p2 activates airway smooth muscle cells in a TLR2/MyD88-dependent manner to induce an inflammatory response†

Der p2 is a major allergen from Dermatophagoides pteronyssinus, the main species of house dust mite and a major inducer of asthma, inducing harmful respiratory inflammatory responses by activating cells in the respiratory tract, leading to an unstable status. We hypothesize that Der p2 may induce local inflammatory responses by directly affecting airway smooth muscle (ASM) cells. In this study, we demonstrated that Der p2 raised nuclear factor‐kappa B (NF‐κB) and extracellular signal‐regulated kinase (ERK) 1/2 activation and induced a high level of proinflammatory cytokines expression in primary cultured ASM cells. Der p2 activated the MyD88 signaling pathway through toll‐like receptor (TLR) 2, not through TLR4. Notably, Der p2 stimulated ASM cells to increase phosphorylation of ERK1/2 and expression of c‐Fos, which were also important in the T helper type 2 (Th2) immune response. These results suggest that Der p2 induces asthma through the MyD88 signaling pathway in respiratory tissue. J. Cell. Physiol. 220: 311–318, 2009.

Handgrip strength is an independent predictor of renal outcomes in patients with chronic kidney diseases

BACKGROUND In dialysis patients, protein-energy wasting (PEW) is associated with high mortality, and some indicators of PEW, such as serum albumin value, subjective global assessment (SGA) score and handgrip strength (HGS), may predict mortality. However, whether PEW is associated with poor renal outcomes and whether the indicators of PEW can predict renal outcomes in patients with non-dialysis-dependent chronic kidney disease (CKD-ND) is still unclear. METHODS We enrolled 128 clinically stable patients with CKD-ND and followed up for 33.8 ± 9.2 months. Baseline characteristics, echocardiographic information, laboratory data, HGS, SGA scores, anthropometric parameters, bioimpedance analyses and other indicators of PEW were examined in relation to the risk of reaching renal composite end points of pre-dialysis mortality or dialysis-dependent end-stage renal disease. RESULTS Twenty-six patients reached composite renal end points. Multivariate Cox regression analyses showed that HGS was an independent predictor of renal outcome in patients with CKD-ND of Stages 1-5 [CKD(1-5), hazard ratio (HR) = 0.90, P = 0.004] or advanced CKD-ND of Stages 3b [defined as estimated glomerular filtration rate (eGFR) of 30-44 mL/min/1.73 m(2)] to 5 (CKD(3b-5), HR = 0.91, P = 0.031), but not serum albumin, SGA score or other indicators of PEW. When the cutoffs were set at 24.65 kg in men with CKD(1-5), 20.15 kg in men with CKD(3b-5) and 10.15 kg in women with CKD(1-5) or CKD(3b-5), which were deduced from receiver-operating characteristics analyses, patients with lower HGS had significantly poor renal outcomes in Kaplan-Meier survival analyses in all subgroups and higher HR for reaching renal end points in multivariate Cox regression analyses in all subgroups except for women with CKD(3b-5), whose HR had marginal significance (HR = 3.78, P = 0.068) after adjusting for age and eGFR. CONCLUSIONS This is the first study demonstrating that HGS is an independent predictor of composite renal outcomes in CKD-ND patients. HGS can be incorporated to clinical practice for assessing nutrition status and renal prognosis in patients with CKD-ND.