Junne Ming Sung

Transforming Growth Factor-β1 Induces Smad3-Dependent β1 Integrin Gene Expression in Epithelial-to-Mesenchymal Transition during Chronic Tubulointerstitial Fibrosis

Transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-β1 enhances β(1) integrin levels in NMuMG cells, the detailed molecular mechanisms underlying TGF-β1-induced β(1) integrin gene expression and the role of β(1) integrin during EMT in the renal system are still unclear. In this study, we examined the role of β(1) integrin in TGF-β1-induced EMT both in vitro and in vivo. TGF-β1-induced augmentation of β(1) integrin expression was required for EMT in several epithelial cell lines, and knockdown of Smad3 inhibited TGF-β1-induced augmentation of β(1) integrin. TGF-β1 triggered β(1) integrin gene promoter activity as assessed by luciferase activity assay. Both knockdown of Smad3 and mutation of the Smad-binding element to block binding to the β(1) integrin promoter markedly reduced TGF-β1-induced β(1) integrin promoter activity. Chromatin immunoprecipitation assay showed that TGF-β1 enhanced Smad3 binding to the β(1) integrin promoter. Furthermore, induction of unilateral ureteral obstruction triggered increases of β(1) integrin in both renal epithelial and interstitial cells. In human kidney with chronic tubulointerstitial fibrosis, we also found a concomitant increase of β(1) integrin and α-smooth muscle actin in tubule epithelia. Blockade of β(1) integrin signaling dampened the progression of fibrosis. Taken together, β(1) integrin mediates EMT and subsequent tubulointerstitutial fibrosis, suggesting that inhibition of β(1) integrin is a possible therapeutic target for prevention of renal fibrosis.

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.

Scrub Typhus Associated with Multiorgan Failure: a Case Report

The spectrum of clinical severity for scrub typhus ranges from inapparent, mild, to severe or fatal. The pathologic changes are focal or disseminated multiorgan vasculitis of the small blood vessels, a fact that helps explain the great diversity of clinical manifestations that can be encountered. We reported a case of scrub typhus with unusual and serious multiorgan involvement, including tubulointerstitial nephritis (TIN) with acute renal failure (ARF), interstitial pneumonitis with adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), liver function impairment, upper gastrointestinal bleeding, prolonged hyperamylasaemia and hyperlipasaemia. Chloramphenicol administration rapidly altered the clinical course, but with sequelae of renal impairment and prolonged hyperamylasaemia and hyperlipasaemia for 10 months.

Association of Left Ventricular Longitudinal Strain with Mortality among Stable Hemodialysis Patients with Preserved Left Ventricular Ejection Fraction

BACKGROUND AND OBJECTIVES Little is known about the optimal echocardiographic parameters for risk stratification in stable dialysis patients with preserved left ventricular ejection fraction (LVEF) (ejection fraction ≥ 50%). Left ventricular (LV) global peak systolic longitudinal strain (GLS) is the ratio of the maximal change in myocardial longitudinal length in systole to the original length and reliably and accurately assesses LV function. During systole, LV myocardium in the longitudinal direction shortens and GLS is represented by a negative value. The more negative value of GLS, the better the LV function is. This study hypothesized that subtle abnormalities of GLS are associated with an adverse prognosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective study collected clinical and echocardiographic data (including GLS) from 88 stable hemodialysis patients (mean age 67.0 ± 11.2 years; 35% men) with preserved LVEF. These patients were enrolled from December 2008 to January 2009 and were followed-up for 25.6 ± 9.9 months. The primary outcome was all-cause mortality. Multivariate Cox regression analysis was used to investigate risk factors for mortality. RESULTS The mortality group (n=24) had lower albumin levels, less negative GLS, and higher prevalence of coronary artery disease and diabetes mellitus than the survival group. Using a GLS cutoff value of -15%, the less negative GLS group (GLS ≥-15%) had a higher mortality rate. Cox regression analyses revealed that lower albumin level (hazard ratio, 0.16; 95% confidence interval, 0.05 to 0.53; P=0.003) and less negative GLS (hazard ratio, 3.57; 95% confidence interval, 1.41 to 9.04; P=0.01) were independent predictors of all-cause mortality. Furthermore, less negative GLS was associated with a higher cardiovascular death rate. CONCLUSIONS Less negative GLS is predictive of poor prognosis among stable hemodialysis patients with preserved LVEF.

Adult-onset minimal change disease among Taiwanese: clinical features, therapeutic response, and prognosis.

There are some racial differences in the prevalence and prognosis of idiopathic nephrotic syndrome; however, reports about minimal change disease (MCD) in Chinese were rare. We retrospectively analyzed 123 Chinese adults with idiopathic nephrotic syndrome, who received percutaneous renal biopsy in our institution within the last 10 years. In total, 46 patients (37.4%) were compatible with the pathological diagnosis of MCD. The male to female ratio was 1.2:1. The mean age of onset was 30.9 years, and 80% of the patients with MCD were less than 40 years. The mean daily proteinuria was 10.2 g, and serum albumin was 1.8 mg/dl. Azotemia occurred in 16 (35%) of 46 cases; hypertension, 13%; and microscopic hematuria, 13%. High selectivity index for proteinuria (SI <0.1) was noted in 12 (39%) of 31 cases; and high IgE level was found in 83.7% of the study subjects, although only one case had allergic history. Complete remission in 36 MCD patients treated with corticosteroid was achieved by 42% (15/36), 80% (29/36), and 94% (34/36) within 4, 8, and 12 weeks, respectively. The time interval to remission was similar between the younger group (<40 years old, 1.7 months) and older group (>40 years old, 1.6 months). Nineteen (56%) of 34 cases with steroid response did not relapse, and the other cases (44%) had a mean relapse rate of 1.5 times per patient within a period of 45 months. The age of onset in MCD cases was not significantly correlated with steroid-responsive rate, and the time interval to remission. However, a tendency existed between the onset in the young age and the sequentially relapsing rate (p = 0.06). Two cases with primary steroid resistance and 5 cases with frequent relapse or steroid dependence responded well to intravenous pulse therapy of cyclophosphamide, except one refractory case. No thrombotic episode was ever noted in our group. Regarding infectious complications, primary peritonitis occurred in one, pneumonia in one, and cellulitis in 6 cases during active nephrotic stage. Two mortality cases, one with E. coli-related necrotizing fasciitis and one from pneumonia, were noted. In brief, compared with children, adult patients with MCD had lesser high selectivity index for proteinuria, the same steroid-responsive rate (94%), but slower response, and significantly lesser relapsing rate. The intravenous pulse therapy of cyclophosphamide may be an alternative regimen for adult patients with steroid resistance or dependency. In addition, the Asian adult-onset MCD had younger age, male predominance, and lesser relapsing rate in comparison to those of the Western population.

Diabetes and End-Stage Renal Disease Synergistically Contribute to Increased Incidence of Cardiovascular Events: A Nationwide Follow-up Study During 1998–2009

OBJECTIVE This study aimed to investigate the effect of interaction of diabetes and end-stage renal disease (ESRD) on the risks of cardiovascular (CV) events. RESEARCH DESIGN AND METHODS By using two representative national cohorts, we determined the age- and sex-specific incidences and 20-year risks of incident CV events, including acute myocardial infarction (AMI), stroke, and congestive heart failure (CHF), stratified by the presence of diabetes, de novo diabetes after ESRD, or ESRD. Individuals were excluded if age <18 years or if previous CV events or malignancies were present before enrollment. Cox proportional hazards models were also constructed with adjustments for competing risk of mortality. RESULTS A total 648,851 non-ESRD individuals and 71,397 ESRD patients, including 53,342 and 34,754 diabetic patients, respectively, were followed up during 1998–2009. A monotonic risk pattern of CV-related incidences was noted with the presence of diabetes, ESRD, or both, respectively, after stratification by age and sex. De novo diabetes showed similar increased risks for CV incidences, especially AMI and stroke. There is a multiplicatively synergistic effect of diabetes and ESRD for CV-related risks, especially for AMI and stroke, of which the adjusted hazard ratios (aHRs) were 5.24 (95% CI 4.83–5.68) and 2.43 (2.32–2.55), respectively, in comparison with people without diabetes or ESRD; de novo diabetes after ESRD had similar effects with aHRs of 4.12 (3.49–4.87) and 1.75 (1.57–1.95), respectively. CONCLUSIONS Diabetes and ESRD synergistically increase risks of CV events. Proactive screening and control for diabetes in patients with ESRD should be built into our daily practice.

Decreased Salivary Flow Rate as a Dipsogenic Factor in Hemodialysis Patients: Evidence from an Observational Study and a Pilocarpine Clinical Trial

Decreased salivary flow rate causes xerostomia (symptoms of oral dryness) in patients who undergo hemodialysis (HD); however, whether it thus contributes to thirst and excess interdialytic weight gain (IDWG) remains undetermined. In the observational study, 3 mo of data of 90 stable HD patients were collected, and sensations of thirst and xerostomia were assessed by 100-mm visual analog scales (VAS). Multivariate analyses revealed that the VAS oral dryness score was an independent determinant for thirst, daily IDWG, and IDWG%. Unstimulated whole salivary flow rate (UWS) was measured in 45 participants and was negatively correlated with VAS oral dryness score (r = -0.690, P <or= 0.001), daily IDWG (r = -0.361, P = 0.016), and daily IDWG% (r = -0.302, P = 0.045). In the interventional trial, the test drug was 5 mg of oral pilocarpine solution or placebo. Sixty hyperdipsic HD patients (IDWG% > 2%/d) were randomly assigned to either the sequence pilocarpine (2 wk)-washout (3 wk)-placebo (2 wk)-washout (2 mo)-placebo (3 mo) or placebo (2 wk)-washout (3 wk)-pilocarpine (2 wk)-washout (2 mo)-pilocarpine (3 mo) with 35 participants completing the trial. During the 2-wk crossover period (the first to seventh weeks), pilocarpine increased UWS and decreased xerostomia and thirst. The IDWG(2d) decreased (by approximately 0.2 kg; P = 0.013) but not IDWG(3d). During the 3-mo interventional period, pilocarpine increased UWS but decreased both IDWG(2d) (by 0.76 kg; P = 0.021) and IDWG(3d) (by 1.07 kg; P = 0.007). It also modestly increased serum albumin and decreased mean BP. Pilocarpine-related adverse effects were generally mild. In conclusion, decreased salivary flow is a dipsogenic factor in HD patients, and pilocarpine can alleviate it.

Generalized argyria in two chronic hemodialysis patients

Silver can be absorbed through ingestion, topical administration, or inhalation. Generalized argyria results from deposition of silver in the skin, nails, mucous membranes, and internal organs and is characterized by a diffuse bluish-gray discoloration in sun-exposed areas. We report two cases of generalized argyria in patients on maintenance hemodialysis (HD) therapy for more than 15 years. They presented with diffuse hyperpigmentation of the face that was mistaken to be related to uremia and bluish-gray discoloration of all nails believed to be cyanosis. Histopathologic examination of skin biopsy specimens showed characteristic findings of argyria, which was further confirmed by radiograph microanalysis. Their serum silver levels were also elevated. No definite silver source could be determined. However, their argyria might be related to their long-term HD therapy because (1) they had been on HD therapy for more than 15 years and the discoloration appeared several years afterward, and (2) the water used for HD was not well processed in the early 1980s in TAIWAN: Argyria should be suspected in chronic HD patients presenting with a diffuse bluish-gray discoloration of the skin and nails and evaluated carefully by skin biopsy.

Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy

ABSTRACT Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4−/− mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN. Summary: Activation of the HSP70-TLR4 axis by albumin in the tubular cell induces tubular inflammation and injury.

Interleukin-20 targets renal cells and is associated with chronic kidney disease

Interleukin (IL)-10 is an anti-inflammatory factor that suppresses renal fibrosis and improves renal function in CKD rats. IL-20 belongs to the IL-10 family; therefore, we sought to determine whether IL-20 is involved in CKD. CKD patients at stage five expressed significantly higher IL-20 in serum than controls. Immunohistochemical staining demonstrated that more IL-20 protein was expressed in the kidney tubular-epithelial cells, mesangial cells, and immune cells of CKD rats with a 5/6 nephrectomy. The lung, liver, and heart tissue of CKD rats also overexpressed IL-20. Thus, we treated two tubular epithelial cells, TKPTS and M-1 cells, with IL-20 to study its effects on CKD. IL-20 treatment induced apoptosis in these cells via caspase-3 activation. Incubating IL-20 with rat interstitial fibroblasts, NRK-49F cells, upregulated TGF-beta1 production, one key inducer for renal fibrogenesis. Therefore, IL-20 injured renal epithelial cells and induced fibroblasts to produce TGF-beta1 that hastened the progression of CKD.