Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Outcomes for clinical trials involving adults with chronic kidney disease: a multinational Delphi survey involving patients, caregivers and health professionals.

BACKGROUND: Many outcomes of high priority to patients and clinicians are infrequently and inconsistently reported across trials in chronic kidney disease (CKD), which generates research waste and limits evidence-informed decision making. We aimed to generate consensus among patients/caregivers and health professionals on critically important outcomes for trials in CKD prior to kidney failure and the need for kidney replacement therapy, and to describe the reasons for their choices. METHODS: This was an online two-round international Delphi survey. Adult patients with CKD (all stages and diagnoses), caregivers and health professionals who could read English, Spanish or French were eligible. Participants rated the importance of outcomes using a Likert scale (7-9 indicating critical importance) and a Best-Worst Scale. The scores for the two groups were assessed to determine absolute and relative importance. Comments were analysed thematically. RESULTS: In total, 1399 participants from 73 countries completed Round 1 of the Delphi survey, including 628 (45%) patients/caregivers and 771 (55%) health professionals. In Round 2, 790 participants (56% response rate) from 63 countries completed the survey including 383 (48%) patients/caregivers and 407 (52%) health professionals. The overall top five outcomes were: kidney function, need for dialysis/transplant, life participation, cardiovascular disease and death. In the final round, patients/caregivers indicated higher scores for most outcomes (17/22 outcomes), and health professionals gave higher priority to mortality, hospitalization and cardiovascular disease (mean difference >0.3). Consensus was based upon the two groups yielding median scores of ≥7 and mean scores >7, and the proportions of both groups rating the outcome as 'critically important' being >50%. Four themes reflected the reasons for their priorities: imminent threat of a health catastrophe, signifying diminishing capacities, ability to self-manage and cope, and tangible and direct consequences. CONCLUSION: Across trials in CKD, the outcomes of highest priority to patients, caregivers and health professionals were kidney function, need for dialysis/transplant, life participation, cardiovascular disease and death.

Nonalbuminuric Diabetic Kidney Disease and Risk of All-Cause Mortality and Cardiovascular and Kidney Outcomes in Type 2 Diabetes: Findings From the Hong Kong Diabetes Biobank.

RATIONALE & OBJECTIVE: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing DKD phenotype. We compared the risks of adverse outcomes among patients with this phenotype compared with other DKD phenotypes. STUDY DESIGN: Multicenter prospective cohort study. SETTINGS & PARTICIPANTS: 19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank. EXPOSURES: DKD phenotypes defined by baseline estimated glomerular filtration rate (eGFR) and albuminuria: no DKD (no decreased eGFR or albuminuria), albuminuria without decreased eGFR, decreased eGFR without albuminuria, and albuminuria with decreased eGFR. OUTCOMES: All-cause mortality, cardiovascular disease (CVD) events, hospitalization for heart failure (HF), and chronic kidney disease (CKD) progression (incident kidney failure or sustained eGFR reduction ≥40%). ANALYTICAL APPROACH: Multivariable Cox proportional or cause-specific hazards models to estimate the relative risks of death, CVD, hospitalization for HF, and CKD progression. Multiple imputation was used for missing covariates. RESULTS: Mean participant age was 61.1 years, 58.3% were male, and mean diabetes duration was 11.1 years. During 54,260 person-years of follow-up, 438 deaths, 1,076 CVD events, 298 hospitalizations for HF, and 1,161 episodes of CKD progression occurred. Compared with the no-DKD subgroup, the subgroup with decreased eGFR without albuminuria had higher risks of all-cause mortality (hazard ratio [HR], 1.59 [95% CI, 1.04-2.44]), hospitalization for HF (HR, 3.08 [95% CI, 1.82-5.21]), and CKD progression (HR, 2.37 [95% CI, 1.63-3.43]), but the risk of CVD was not significantly greater (HR, 1.14 [95% CI, 0.88-1.48]). The risks of death, CVD, hospitalization for HF, and CKD progression were higher in the setting of albuminuria with or without decreased eGFR. A sensitivity analysis that excluded participants with baseline eGFR <30 mL/min/1.73 m2 yielded similar findings. LIMITATIONS: Potential misclassification because of drug use. CONCLUSIONS: Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Clinical features and outcomes of renal amyloidosis in Hong Kong.

AIM: Early symptoms of primary (AL) amyloidosis are non-specific. Any delay in diagnosis and treatment results in poor outcome despite increasing treatment options. We aimed to determine baseline risk factors that identify patients with poor kidney outcomes and overall survivals. METHODS: We recruited all patients aged 18 years or above with biopsy-proven renal amyloidosis between years 2000 and 2019 in three Hong Kong regional hospitals. Patients' clinical and pathological parameters, treatment response, kidney outcomes and overall survivals were recorded and analysed. RESULTS: Thirty-six cases of renal amyloidosis were recruited. Four cases were diagnosed to have multiple myeloma. Edema was the most common presenting symptom. The mean estimated glomerular filtration rate (eGFR) was 98.8 ml/min/1.73 m2 at presentation. Autologous stem cell transplant conferred the best renal outcomes as well as patients' survival. Twenty-two patients had 50% decrease in eGFR, 12 patients developed end-stage kidney disease (ESKD) and 22 patients died. Hypertension, diabetes mellitus, proteinuria and low eGFR were identified as independent baseline risk factors for ESKD. Proteinuria, hyperlipidemia, and cardiac involvement were independent baseline risk factors for death. CONCLUSION: Amyloidosis, a rare disease with poor prognosis without treatment. Hypertension, diabetes mellitus, heavy proteinuria and low eGFR at diagnosis were associated with poor kidney outcome.

SOX2 Regulates Neuronal Differentiation of the Suprachiasmatic Nucleus.

In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.

Obesity, clinical, and genetic predictors for glycemic progression in Chinese patients with type 2 diabetes: A cohort study using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank.

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. METHODS AND FINDINGS: In 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1-9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03-1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06-1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10-8) but not glycemic progression (HR: 1.01 [95% CI 0.96-1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. CONCLUSIONS: Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.

Meaning of empowerment in peritoneal dialysis: focus groups with patients and caregivers.

BACKGROUND: While peritoneal dialysis (PD) can offer patients more independence and flexibility compared with in-center hemodialysis, managing the ongoing and technically demanding regimen can impose a burden on patients and caregivers. Patient empowerment can strengthen capacity for self-management and improve treatment outcomes. We aimed to describe patients' and caregivers' perspectives on the meaning and role of patient empowerment in PD. METHODS: Adult patients receiving PD (n = 81) and their caregivers (n = 45), purposively sampled from nine dialysis units in Australia, Hong Kong and the USA, participated in 14 focus groups. Transcripts were thematically analyzed. RESULTS: We identified six themes: lacking clarity for self-management (limited understanding of rationale behind necessary restrictions, muddled by conflicting information); PD regimen restricting flexibility and freedom (burden in budgeting time, confined to be close to home); strength with supportive relationships (gaining reassurance with practical assistance, comforted by considerate health professionals, supported by family and friends); defying constraints (reclaiming the day, undeterred by treatment, refusing to be defined by illness); regaining lost vitality (enabling physical functioning, restoring energy for life participation); and personal growth through adjustment (building resilience and enabling positive outlook, accepting the dialysis regimen). CONCLUSIONS: Understanding the rationale behind lifestyle restrictions, practical assistance and family support in managing PD promoted patient empowerment, whereas being constrained in time and capacity for life participation outside the home undermined it. Education, counseling and strategies to minimize the disruption and burden of PD may enhance satisfaction and outcomes in patients requiring PD.

Lifetime cost-effectiveness analysis of first-line dialysis modalities for patients with end-stage renal disease under peritoneal dialysis first policy.

BACKGROUND: This study aimed to determine the lifetime cost-effectiveness of first-line dialysis modalities for end-stage renal disease (ESRD) patients under the "Peritoneal Dialysis First" policy. METHODS: Lifetime cost-effectiveness analyses from both healthcare provider and societal perspectives were performed using Markov modelling by simulating at age 60. Empirical data on costs and health utility scores collected from our studies were combined with published data on health state transitions and survival data to estimate the lifetime cost, quality-adjusted life-years (QALYs) and cost-effectiveness of three competing dialysis modalities: peritoneal dialysis (PD), hospital-based haemodialysis (HD) and nocturnal home HD. RESULTS: For cost-effectiveness analysis over a lifetime horizon from the perspective of healthcare provider, hospital-based HD group (lifetime cost USD$142,389; 6.58 QALYs) was dominated by the PD group (USD$76,915; 7.13 QALYs). Home-based HD had the highest effectiveness (8.37 QALYs) but with higher cost (USD$97,917) than the PD group. The incremental cost-effectiveness ratio (ICER) was USD$16,934 per QALY gained for home-based HD over PD. From the societal perspective, the results were similar and the ICER was USD$1195 per QALY gained for home-based HD over PD. Both ICERs fell within the acceptable thresholds. Changes in model parameters via sensitivity analyses had a minimal impact on ICER values. CONCLUSIONS: This study assessed the cost-effectiveness of dialysis modalities and service delivery models for ESRD patients under "Peritoneal Dialysis First" policy. For both healthcare provider and societal perspectives, PD as first-line dialysis modality was cost-saving relative to hospital-based HD, supporting the existing PD First or favoured policy. When compared with PD, Nocturnal home Home-based HD was considered a cost-effective first-line dialysis modality for ESRD patients.

Direct and indirect costs of end-stage renal disease patients in the first and second years after initiation of nocturnal home haemodialysis, hospital haemodialysis and peritoneal dialysis.

PURPOSE: To estimate the direct and indirect costs of end-stage renal disease (ESRD) patients in the first and second years of initiating peritoneal dialysis (PD), hospital-based haemodialysis (HD) and nocturnal home HD. METHODS: A cost analysis was performed to estimate the annual costs of PD, hospital-based HD and nocturnal home HD for ESRD patients from both the health service provider's and societal perspectives. Empirical data on healthcare resource use, patients' out-of-pocket costs, time spent on transportation and dialysis by ESRD patients and time spent by caregivers were analysed. All costs were expressed in Hong Kong year 2017 dollars. RESULTS: Analysis was based on 402 ESRD patients on maintenance dialysis (PD: 189; hospital-based HD: 170; and nocturnal home HD: 43). From the perspective of the healthcare provider, hospital-based HD had the highest total annual direct medical costs in the initial year (mean ± SD) (hospital-based HD = $400 057 ± 62 822; PD = $118 467 ± 15 559; nocturnal home HD = $223 358 ± 18 055; P < 0.001) and second year (hospital-based HD = $360 924 ± 63 014; PD = $80 796 ± 15 820; nocturnal home HD = $87 028 ± 9059; P < 0.001). From the societal perspective, hospital-based HD had the highest total annual costs in the initial year (hospital-based HD = $452 151 ± 73 327; PD = $189 191 ± 61 735; nocturnal home HD = $242 038 ± 28 281; P < 0.001) and second year (hospital-based HD = $413 017 ± 73 501; PD = $151 520 ± 60 353; nocturnal home HD = $105 708 ± 23 853; P < 0.001). CONCLUSIONS: This study quantified the economic burden of ESRD patients, and assessed the annual healthcare and societal costs in the initial and second years of PD, hospital-based HD and nocturnal home HD in Hong Kong. From both perspectives, PD is cost-saving relative to hospital-based HD and nocturnal home HD, except that nocturnal home HD has the lowest cost in the second year of treatment from the societal perspective. Results from this cost analysis facilitate economic evaluation in Hong Kong for health services and management targeted at ESRD patients.

Health-related quality of life and health utility of Chinese patients undergoing nocturnal home haemodialysis in comparison with other modes of dialysis.

BACKGROUND: To compare the health-related quality of life (HRQOL) and health utility of Chinese patients with end-stage renal disease (ESRD) undergoing nocturnal home haemodialysis (Home HD) against those patients undergoing other modes of dialysis. METHODS: Chinese ESRD patients undergoing Home HD were recruited in renal specialist outpatient clinics at three public hospitals in Hong Kong. SF-12 Health Survey (SF-12) was used to measure HRQOL and generate the SF-6D heath utility score. Mean scores of SF-12 domains, physical and mental component summary and SF-6D health utility of 41 patients undergoing Home HD were compared with available scores of patients receiving other forms of dialysis, namely, peritoneal dialysis (PD) (n = 103), hospital in-centre HD (n = 135) or community in-centre HD (n = 118). Adjusted linear regression models were used to examine the impact of mode of dialysis on the HRQOL and health utility scores, accounting for the sociodemographic and clinical characteristics. RESULTS: ESRD patients undergoing PD and community in-centre HD had better health utility, physical and mental component summary scores than the hospital in-centre HD. Adjusted analysis showed that hospital in-centre HD reported worse physical component summary and health utility scores when compared with PD and community in-centre HD. CONCLUSION: HRQOL and health utility scores of patients undergoing Home HD were similar to those undergoing PD and community in-centre HD. Better physical aspects of HRQOL and health utility was observed in PD and community-based HD than hospital in-centre HD, providing evidence for the increase in capacity of non-hospital-based HD, which provided flexibility as well as patient centredness and empowerment in Hong Kong.

Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.

Relatives in silent kidney disease screening (RISKS) study: A Chinese cohort study.

AIM: Family members of patients with end-stage renal disease (ESRD) have higher risk for chronic kidney disease (CKD). Limited study has examined the risk of developing CKD in relatives of patients in earlier stages of CKD. METHODS: From January 2008 to June 2009, the Hong Kong Society of Nephrology studied first-degree relatives of stage 1-5 CKD patients from 11 local hospitals. A total of 844 relatives of 466 index CKD patients (stages 1-2: 29.6%; stage 3: 16.7%; stage 4: 10.9%; stage 5: 42.7%) were reviewed for various risk factors of CKD. We also defined a composite marker of kidney damage by the presence of one or more following features: (i) positive urine protein, (ii) spot urine protein-to-creatinine ratio ≥0.15 mg/mg, (iii) hypertension and (iv) estimated glomerular filtration rate (eGFR) ≤60 mL/min per 1.73 m2 and determine its association with participant and index patient factors. RESULTS: Among these 844 relatives, 23.1%, 25.9% and 4.4% of them had proteinuria (urine protein ≥1+), haematuria (urine red blood cell ≥1+) and glycosuria (urine glucose ≥1+), respectively. Proteinuria (P = 0.10) or glycosuria (P = 0.43), however, was not associated with stages of CKD of index patients. Smoking participants had a significantly lower eGFR (102.7 vs. 107.1 mL/min per 1.73 m2 ) and a higher prevalence of proteinuria (33.6% vs. 21.4%). Multivariate analysis showed that older age, male gender, obesity, being parents of index patients and being the relatives of a female index patient were independently associated with a positive composite marker. CONCLUSION: First-degree relatives of all stages of CKD are at risk of developing CKD and deserve screening. Parents, the elderly, obese and male relatives were more likely to develop markers of kidney damage.

Long-term outcomes following H-type tracheoesophageal fistula repair in infants.

PURPOSE: To evaluate outcomes following repair of H-type tracheoesophageal fistula (TEF). METHODS: Retrospective chart review of infants with H-type TEF treated at our institution between 2000 and 2014. Patient demographics, surgical management, and postoperative function were evaluated. RESULTS: Of the 268 patients with esophageal atresia/TEF treated at our center, 16 (6%) had an H-type TEF (10 males). Thirteen (81%) had associated anomalies. All patients were symptomatic: choking and sputtering were the most common presentation (n = 10, 63%). Diagnosis Age at diagnosis was 8 days (1 day-34 months). All patients were diagnosed based on a single esophagogram. Prior to surgery, 12 (75%) patients underwent bronchoscopy and 11 underwent cannulation of the TEF tract. Surgery All patients underwent open repair. One was started thoracoscopically but converted to open due to esophageal sero-muscular injury. Repair was achieved in all patients via a transcervical approach (right-sided incision in 15). One patient had an unsuccessful prior attempt at repair using tissue glue. Following TEF division, 11 patients had tissue interposition grafts placed (9 muscle, 2 fat). Postoperative course Eight (50%) patients had postoperative vocal cord paresis (6 right-sided, 2 bilateral). A patient developed recurrent TEF 78 days postoperatively that was subsequently repaired. Follow-up At 41 months (8-143), there were no mortalities, all patients with vocal cord paresis were asymptomatic despite the fact that only 3 of 8 (38%) regained function, and nine (56%) patients had gastro-esophageal reflux requiring treatment. CONCLUSIONS: This large, single-center series demonstrates that H-type TEF can be diagnosed with esophagogram at an early age. Postoperative recurrent laryngeal nerve paresis and gastro-esophageal reflux disease are common following repair. Although most patients with vocal cord paresis eventually become asymptomatic, two-thirds do not regain vocal cord function. This reinforces the importance of routine examination of vocal cord movement following H-type TEF repair.

Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians.

Systemic lupus erythematosus (SLE) has a complex etiology and is affected by both genetic and environmental factors. Although more than 40 loci have shown robust association with SLE, the details of these loci, such as the independent contributors and the genes involved, are still unclear. In this study, we performed meta-analysis of two existing genome-wide association studies (GWASs) on Chinese Han populations from Hong Kong and Anhui, China, and followed the findings by further replication on three additional Chinese and Thailand cohorts with a total of 4254 cases and 6262 controls matched geographically and ethnically. We discovered multiple susceptibility variants for SLE in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023, P(_combined) = 1.25E-08, OR = 1.20), DDX6 (rs638893, P(_combined) = 5.19E-07, OR = 1.22) and CXCR5 (rs10892301, P(_combined) = 2.51E-08, OR = 0.85). Genetic contributions from the newly identified variants were all independent of SNP rs4639966, whose association was reported from the previous GWAS. In addition, the three newly identified variants all showed independent association with the disease through modeling by both stepwise and conditional logistic regression. The presence of multiple independent variants in this region emphasizes its role in SLE susceptibility, and also hints the possibility that distinct biological mechanisms might be involved in the disease involving this genomic region.

Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.

OBJECTIVES: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. METHODS: The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. RESULTS: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. CONCLUSIONS: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.

Screening Algorithm for BK Virus-Associated Nephropathy Using Sequential Testing of Urinary Cytology: A Probabilistic Model Analysis.

BACKGROUND: Incorporating urinary cytology in BK virus (BKV) screening algorithm potentially reduces the screening cost for BK viral nephropathy. We aimed to evaluate the test performances and screening cost of sequential 2-stage screening consisting of urine cytology followed by BKV serum quantitative polymerase chain reaction (PCR). METHODS: Ninety-five kidney transplant recipients who had BKV serum quantitative PCR/urine cytology tested and verified with histopathology (the reference gold standard) were included. A probabilistic model was constructed to evaluate the test performance and screening cost of 2-stage screening, and was compared with screening with urine cytology or serum viral load alone. RESULTS: At a viral load threshold of ≥104 copies/ml, the sensitivity and specificity of quantitative PCR alone were 83% (95% CI 69-96) and 91% (95% CI 83-97), respectively. The sensitivity and specificity of urine cytology alone were 91% (95% CI 79-100) and 74% (95% CI 60-91), respectively. Sequential 2-stage screening resulted in loss in sensitivity but a net gain in specificity (viral load threshold ≥104 copies/ml - sensitivity, 75% (95% CI 60-91); specificity, 98% (95% CI 95-99)). Two-stage screening also had superior positive predictive value and is cost effective when BKV-associated nephropathy prevalence is below 94%. CONCLUSIONS: Our study had demonstrated a favorable test performance and cost efficiency of 2-stage BKV screening.

Relationship between autoantibody clustering and clinical subsets in SLE: cluster and association analyses in Hong Kong Chinese.

OBJECTIVE: This study aims to identify the existence of, and relationship between autoantibody clusters and clinical subsets in Chinese SLE patients. METHODS: Data from 1928 SLE patients from Hong Kong were analysed. Using cluster analysis, patients were grouped by autoantibodies into clusters. The frequencies of various clinical manifestations were then compared between each cluster. Separate association analyses between individual autoantibodies and clinical manifestations as well as between clinical manifestations were also performed without any prior clustering. RESULTS: Three separate autoantibody clusters were identified, each with significantly different clinical manifestations. Cluster 1 was characterized by anti-dsDNA and the greatest prevalence of renal disorder but the lowest frequencies of other clinical manifestations. Cluster 2 was represented by the predominance of anti-Smith, anti-RNP and aPL, with greater prevalence of malar rash, oral ulcers, arthritis and serositis. Cluster 3 was characterized by anti-Ro and anti-La with greater prevalence of discoid rash, photosensitivity and haematological involvement. Individual association analysis also revealed similar findings. Patients of clusters 2 and 3 were more closely related, while cluster 1 was more distinct, associated with renal disorder only and negatively associated or not associated with other manifestations. CONCLUSION: We conclude that autoantibody clustering and clinical subsets exist in SLE patients of our locality. These clusters may be viewed as a bipolar spectrum of related autoantibody and clinical manifestations. At one end are patients with over-representation of anti-dsDNA and renal disorder, while at the other end are two distinct autoantibody clusters (anti-Sm/anti-RNP/aPL and anti-Ro/anti-La) with overlapping of other clinical manifestations.

Minimal change disease caused by exposure to mercury-containing skin lightening cream: a report of 4 cases.

Mercury is a known cause of nephrotic syndrome and the underlying renal pathology in most of the reported cases was membranous nephropathy. We describe here 4 cases of minimal change disease following exposure to mercury-containing skin lightening cream for 2 - 6 months. The mercury content of the facial creams was very high (7,420 - 30,000 parts per million). All patients were female and presented with nephrotic syndrome and heavy proteinuria (8.35 - 20.69 g/d). The blood and urine mercury levels were 26 - 129 nmol/l and 316 - 2,521 nmol/d, respectively. Renal biopsy revealed minimal change disease (MCD) in all patients. The use of cosmetic cream was stopped and chelation therapy with D-penicillamine was given. Two patients were also given steroids. The time for blood mercury level to normalize was 1 - 7 months, whereas it took longer for urine mercury level to normalize (9 - 16 months). All patients had complete remission of proteinuria and the time to normalization of proteinuria was 1 - 9 months. Mercury-containing skin lightening cream is hazardous because skin absorption of mercury can cause minimal change disease. The public should be warned of the danger of using such products. In patients presenting with nephrotic syndrome, a detailed history should be taken, including the use of skin lightening cream. With regard to renal pathology, apart from membranous nephropathy, minimal change disease should be included as another pathological entity caused by mercury exposure or intoxication.