Daw-Yang Hwang

ITPKC single nucleotide polymorphism associated with the Kawasaki disease in a Taiwanese population.

Kawasaki disease (KD) is characterized by systemic vasculitis with unknown etiology. Previous studies from Japan indicated that a gene polymorphism of ITPKC (rs28493229) is responsible for susceptibility to KD. We collected DNA samples from 1,531 Taiwanese subjects (341 KD patients and 1,190 controls) for genotyping ITPKC. In this study, no significant association was noted for the ITPKC polymorphism (rs28493229) between the controls and KD patients, although the CC genotype was overrepresented. We further combined our data with previously published case/control KD studies in the Taiwanese population and performed a meta-analysis. A significant association between rs28493229 and KD was found (Odds Ratio:1.36, 95% Confidence Interval 1.12–1.66). Importantly, a significant association was obtained between rs28493229 and KD patients with aneurysm formation (P = 0.001, under the recessive model). Taken together, our results indicated that C-allele of ITPKC SNP rs28493229 is associated with the susceptibility and aneurysm formation in KD patients in a Taiwanese population.

Urinary neutrophil gelatinase-associated lipocalin levels predict cisplatin-induced acute kidney injury better than albuminuria or urinary cystatin C levels

Cisplatin‐induced acute kidney injury (AKI) is a major concern among clinicians in prescribing cisplatin‐based chemotherapy. This study evaluated and compared the ability of urinary biomarkers, including urinary neutrophil gelatinase‐associated lipocalin (NGAL), cystatin C, and the urinary albumin to creatinine ratio (ACR) to predict cisplatin‐induced AKI. Thirty‐three cancer patients receiving cisplatin‐based chemotherapy were prospectively studied, including 10 (30%) who developed AKI (the study group). Changes of urinary biomarkers were compared at 4 hours, 8 hours, and 12 hours, and 1 day, 2 days, 3 days, and 4 days after cisplatin intravenous infusions (75 mg/m2) versus the baseline. There was a significant increase in urinary NGAL levels from 12 hours to 4 days (p < 0.05) compared to baseline after cisplatin infusion in the AKI group. The magnitude of these changes over time differed significantly by group (p < 0.001). The area under the receiver operating curve describing the relationship between urinary NGAL levels and AKI within 12 hours was 0.865 (95% confidence interval = 0.691–1.000). Urinary NGAL levels independently predicted AKI 12 hours after cisplatin (p = 0.045) after adjustments for age, gender, body mass index, baseline serum creatinine, and urinary total protein. Urinary NGAL levels may be an early biomarker of AKI in patients receiving cisplatin‐based treatment.

Hypokalemia, Its Contributing Factors and Renal Outcomes in Patients with Chronic Kidney Disease

Background In the chronic kidney disease (CKD) population, the impact of serum potassium (sK) on renal outcomes has been controversial. Moreover, the reasons for the potential prognostic value of hypokalemia have not been elucidated. Design, Participants & Measurements 2500 participants with CKD stage 1–4 in the Integrated CKD care program Kaohsiung for delaying Dialysis (ICKD) prospective observational study were analyzed and followed up for 2.7 years. Generalized additive model was fitted to determine the cutpoints and the U-shape association between sK and end-stage renal disease (ESRD). sK was classified into five groups with the cutpoints of 3.5, 4, 4.5 and 5 mEq/L. Cox proportional hazard regression models predicting the outcomes were used. Results The mean age was 62.4 years, mean sK level was 4.2±0.5 mEq/L and average eGFR was 40.6 ml/min per 1.73 m2. Female vs male, diuretic use vs. non-use, hypertension, higher eGFR, bicarbonate, CRP and hemoglobin levels significantly correlated with hypokalemia. In patients with lower sK, nephrotic range proteinuria, and hypoalbuminemia were more prevalent but the use of RAS (renin-angiotensin system) inhibitors was less frequent. Hypokalemia was significantly associated with ESRD with hazard ratios (HRs) of 1.82 (95% CI, 1.03–3.22) in sK <3.5mEq/L and 1.67 (95% CI,1.19–2.35) in sK = 3.5–4 mEq/L, respectively, compared with sK = 4.5–5 mEq/L. Hyperkalemia defined as sK >5 mEq/L conferred 1.6-fold (95% CI,1.09–2.34) increased risk of ESRD compared with sK = 4.5–5 mEq/L. Hypokalemia was also associated with rapid decline of renal function defined as eGFR slope below 20% of the distribution range. Conclusion In conclusion, both hypokalemia and hyperkalemia are associated with increased risk of ESRD in CKD population. Hypokalemia is related to increased use of diuretics, decreased use of RAS blockade and malnutrition, all of which may impose additive deleterious effects on renal outcomes.

The rs1014290 Polymorphism of the SLC2A9 Gene Is Associated with Type 2 Diabetes Mellitus in Han Chinese

Aims. The SLC2A9 gene encodes the glucose transporter 9, with the abilities of transporting both glucose and uric acid and is involved in the pancreatic glucose-stimulated insulin secretion. The single nucleotide polymorphisms (SNPs) of SLC2A9 accounted for 5% variance of serum uric acid (UA). UA was identified as a risk factor for type 2 diabetes mellitus (DM). We investigated whether the SLC2A9 gene variations are associated with type 2 DM in Han Chinese. Methods. Three common SNPs of the SLC2A9, rs1014290, rs2280205, and rs3733591, were genotyped in 1003 Han Chinese randomly selected from Kaohsiung, Taiwan. Results. The variant SNP rs1014290 is associated with decreased 0.12-fold risk of type 2 DM (P = .002). Per-copy increase in the minor C-allele results in 0.13 mmol/L (P = .037) and 10.03 μmol/L (P = .016) decrease in serum glucose and UA, respectively. Conclusions. The SNP rs1014290 within the SLC2A9 gene is associated with type 2 DM in Han Chinese.

Glycated Hemoglobin and Outcomes in Patients with Advanced Diabetic Chronic Kidney Disease.

Diabetes is the major risk factor for end-stage renal disease (ESRD) worldwide. In advanced chronic kidney disease (CKD), less is known about the predictive value of HbA1c. We enrolled 2401 diabetic patients with stage 3–4 and stage 5 CKD, who were classified into 4 groups according to their baseline HbA1c values (<6%, 6%–7%, 7%–9%, and >9%). During the median follow-up of 3 years, 895 patients developed ESRD, and 530 died. In linear regression analysis, higher HbA1c correlated with higher eGFR in patients with stage 5 CKD but not in stage 3–4 CKD. In Cox regression analysis, a trend toward worse clinical outcomes existed when the HbA1c level exceeded 6% in stage 3–4 CKD, but the significance was only observed for >9%. The hazard ratios (HRs) for ESRD, all-cause mortality and combined CV events with mortality in the group of HbA1c >9% were 1.6 (95% CI, 1.07 to 2.38), 1.52 (95% CI, 0.97 to 2.38) and 1.46 (95% CI, 1.02 to 2.09), respectively. This study demonstrates that the higher HbA1c level is associated higher risks for clinical outcomes in diabetic patients with stage 3–4 CKD but not in stage 5 CKD.

Microscopic Haematuria and Clinical Outcomes in Patients With Stage 3-5 Nondiabetic Chronic Kidney Disease.

Microscopic haematuria is proposed as a prognostic factor for renal outcomes in patients with glomerulonephritis. However, the role of haematuria in patients with advanced chronic kidney disease (CKD) or heavy proteinuria has not been investigated. We divided 1799 patients with stage 3–5 nondiabetic CKD into 3 groups according to the results from 3 urinalyses: no haematuria (0–2 red blood cells [RBCs]/hpf ≥2 times), mild haematuria (2–5 RBCs/hpf ≥2 times) and moderate haematuria (≥5–10 RBCs/hpf ≥2 times). The estimated glomerular filtration rate was 25.4 mL/min/1.73 m2, with a urine protein-to-creatinine ratio (UPCR) of 881 mg/g. The hazard ratios (HRs) of mild and moderate haematuria for end-stage renal disease (ESRD) were 1.28 (95% confidence interval [CI]: 1.05–1.56, P = 0.024) and 1.34 (95% CI: 1.03–1.74, P = 0.030), respectively. The HR of moderate haematuria for mortality was 1.56 (95% CI: 1.11–2.20, P = 0.011). According to subgroup analysis, the HR of moderate haematuria for ESRD in patients with a UPCR of <500 mg/g was more prominent than that in patients with a UPCR of ≥500 mg/g. Microscopic haematuria in patients with stage 3–5 nondiabetic CKD is associated with increased risks of ESRD and mortality.

Urinary neutrophil gelatinase-associated lipocalin and clinical outcomes in chronic kidney disease patients.

Abstract Background: Tubulointerstitial damage is a final common pathway of most renal diseases. Whether urinary neutrophil gelatinase-associated lipocalin (uNGAL), a biomarker for renal tubular damage, is of prognostic value for clinical outcomes in chronic kidney disease (CKD) patients has not been well investigated. Methods: The uNGAL and proteinuria levels were measured among a cohort of 473 advanced CKD patients of various etiologies recruited during 2002–2009. Results: The estimated glomerular filtration rate (eGFR) was 32.3±22.0 mL/min/1.73 m2 with a urine protein-to-creatinine ratio (UPCR) 680 (255–1248) mg/g and 132 (27.9%) participants had diabetes. The baseline uNGAL level was significantly associated with male gender, eGFR, UPCR, and hemoglobin. The hazard ratio (HR) of the highest uNGAL tertile for end-stage renal disease (ESRD) was 3.44 (95% CI 1.47–8.06, p=0.004). With the adjustment of urine creatinine and urine protein, HR of the highest urine NGAL-to-creatinine ratio (UNCR) tertile and the highest urine NGAL-to-protein ratio (UNPR) tertile was 3.06 (95% CI 1.19–7.90, p=0.02) and 2.10 (95% CI 1.13–3.89, p=0.02), respectively. UNPR increased the prediction of survival model for ESRD. HR of the highest UNCR tertile and UNPR tertile for cardiovascular (CV) events was 2.21 (95% CI 0.81–5.98, p=0.08) and 2.79 (95% CI 1.25–6.26, p=0.01), respectively. None of these were associated with all-cause mortality. Conclusions: Elevated uNGAL in CKD patients is associated with risks for ESRD and probably CV events. UNPR could improve the prediction for ESRD.

B7-1 expression regulates the hypoxia-driven cytoskeleton rearrangement in glomerular podocytes

Chronic hypoxia has been recognized as a common mechanism driving the progression of many glomerular diseases. Glomerular cells, although susceptible to hypoxic injuries, are less studied to unravel the hypoxia-related influences. In the present study, we showed that both lipopolysaccharide (LPS) and hypoxia induced B7-1 and hypoxia-inducible factor (HIF)-1α expression in podocytes. B7-1, an essential player in the regulation of podocyte stress fibers, interacted directly with the NH(2)-terminal oxygenation domain of HIF-1α protein and, therefore, might interfere with the HIF-related oxidative events. The suggestion was supported by the changes in the expression of inducible nitric oxide synthase and nitric oxide. The orderly arranged stress fibers in differentiated podocytes were disrupted by either LPS or hypoxic stimulation, and the disruption could be rescued if they were brought back to normal oxygen tension. Cell motility increased with the stimulation by LPS and hypoxia, most probably mediated by the induction of B7-1 and HIF-1α, respectively. We generated a B7-1 knockdown podocyte cell line using the lentiviral small interfering RNA system. The LPS- and hypoxia-induced stress fiber disruption was largely prevented in the B7-1 knockdown podocytes. The increased cell motility by LPS and hypoxia stimulations was also ameliorated in the B7-knockdown podocytes. In summary, we found that both B7-1 and HIF were upregulated by LPS and hypoxic stimulations in podocytes and they interacted with each other. Hypoxia disrupted the abundant stress fibers and increased cell motility. These hypoxia-induced changes were prevented in B7-knockdown podocytes, and they highlighted the importance of B7-1 expression in the hypoxia-related podocyte injuries.

Mutations in Pseudohypoparathyroidism 1a and Pseudopseudohypoparathyroidism in Ethnic Chinese

An inactivating mutation in the GNAS gene causes either pseudohypoparathyroidism 1a (PHP1A) when it is maternally inherited or pseudopseudohypoparathyroidism (PPHP) when it is paternally inherited. We investigated clinical manifestations and mutations of the GNAS gene in ethnic Chinese patients with PHP1A or PPHP. Seven patients from 5 families including 4 girls and 2 boys with PHP1A and 1 girl with PPHP were studied. All PHP1A patients had mental retardation. They were treated with calcitriol and CaCO3 with regular monitoring of serum Ca levels, urinary Ca/Cr ratios, and renal sonography. Among them, 5 patients also had primary hypothyroidism suggesting TSH resistance. One female patient had a renal stone which was treated with extracorporeal shockwave lithotripsy. She had an increased urinary Ca/Cr ratio of 0.481 mg/mg when the stone was detected. We detected mutations using PCR and sequencing as well as analysed a splice acceptor site mutation using RT-PCR, sequencing, and minigene construct. We detected 5 mutations: c.85C>T (Q29*), c.103C>T (Q35*), c.840-2A>G (R280Sfs*21), c.1027_1028delGA (D343*), and c.1174G>A (E392K). Mutations c.840-2A>G and c.1027_1028delGA were novel. The c.840-2A>G mutation at the splice acceptor site of intron 10 caused retention of intron 10 in the minigene construct but skipping of exon 11 in the peripheral blood cells. The latter was the most probable mechanism which caused a frameshift, changing Arg to Ser at residue 280 and invoking a premature termination of translation at codon 300 (R280Sfs*21). Five GNAS mutations in ethnic Chinese with PHP1A and PPHP were reported. Two of them were novel. Mutation c.840-2A>G destroyed a spice acceptor site and caused exon skipping. Regular monitoring and adjustment in therapy are mandatory to achieve optimal therapeutic effects and avoid nephrolithiasis in patients with PHP1A.

Atypical X-linked agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin M deficiency patient.

BackgroundX-linked agammaglobulinaemia (XLA) is the most common inherited humoural immunodeficiency disorder. Mutations in the gene coding for Bruton’s tyrosine kinase (BTK) have been identified as the cause of XLA. Most affected patients exhibit a marked reduction of serum immunoglobulins, mature B cells, and an increased susceptibility to recurrent bacterial infections. However, the diagnosis of XLA can be a challenge in certain patients who have near-normal levels of serum immunoglobulin. Furthermore, reports on XLA with renal involvement are scant.Case presentationWe report an atypical XLA patient who presented with selective immunoglobulin M (IgM) immunodeficiency and nephropathy. He was diagnosed with selective IgM immunodeficiency, based on his normal serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels but undetectable serum IgM level. Intravenous immunoglobulin was initiated due to increased infections and persistent proteinuria but no improvement in proteinuria was found. A lupus-like nephritis was detected in his kidney biopsy and the proteinuria subsided after receiving a mycophenolate mofetil regimen. Although he had a history of recurrent bacterial infections since childhood, XLA was not diagnosed until B-lymphocyte surface antigen studies and a genetic analysis were conducted.ConclusionsWe suggest that B-lymphocyte surface antigen studies and a BTK mutation analysis should be performed in familial patients with selective IgM deficiency to rule out atypical XLA.