Li Chun Ho

Sleep apnea and the risk of chronic kidney disease: A nationwide population-based cohort study

STUDY OBJECTIVES Sleep apnea (SA) is characterized by apnea during sleep and is associated with cardiovascular diseases and an increase in all-cause mortality. Chronic kidney disease (CKD) is a global health problem that has placed a substantial burden on healthcare resources. However, the relationship between SA and the incidence of CKD is not clear. This study aimed to determine whether SA is an independent risk factor for the development of CKD. DESIGN Retrospective cohort study. SETTING National Health Insurance Research Database (NHIRD) of Taiwan. PATIENTS OR PARTICIPANTS A total of 4,674 adult patients (age ≥ 30 y) in whom SA was newly diagnosed from 2000 to 2010 were included, together with 23,370 non-SA patients as the comparison group. The two groups were frequency-matched for sex, age, and year of receiving medical service. Each individual was followed until 2011. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS These two groups were monitored and observed for the occurrence of CKD. Patients with SA experienced a 1.94-fold increase (95% confidence interval [CI], 1.52-2.46; P < 0.001) in the incidence of CKD, which was independent of sex, age, and comorbid medical conditions. Additionally, they showed a 2.2-fold increase (95% CI, 1.31-3.69; P < 0.01) in the incidence of end-stage renal disease (ESRD). CONCLUSIONS Patients with sleep apnea are at increased risk for chronic kidney disease and end-stage renal disease compared with the general population. As such, screening renal function and treatment of chronic kidney disease is an important issue in patients with sleep apnea.

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.

Egr-1 deficiency protects from renal inflammation and fibrosis

NF-κB and TGFβ play critical roles in renal inflammation and fibrosis, and their regulation in the kidney is thus of great interest. Early growth response-1 (Egr-1), a transcription factor belonging to the immediate early gene family, has been found to regulate inflammation and fibrosis in non-kidney tissues, but its role in renal failure has not been clear. In this study, wild-type and Egr1−/− mice were fed with an adenine-enriched diet to induce tubulointerstitial nephritis (TIN), and primary tubular epithelial cells (PTECs) were treated with pro-inflammatory and pro-fibrotic cytokines. Kidney tissues from patients with or without renal failure were stained for Egr-1. Our results showed that Egr-1 expression was upregulated in the kidney with TIN, and the tubular epithelial cell is the primary site for Egr-1 upregulation and nuclear translocation. Egr1−/− mice were protected from renal failure, reflected by low levels of serum urea and creatinine. The protective effect was related to an attenuation of tubular injury, immune cell infiltration, NF-κB activity, and cytokine/chemokine expressions in the kidney. Renal fibrotic area and TGFβ signaling were also reduced in Egr1−/− mice. In vitro study showed that Egr-1 deficiency attenuated the ordinary responses of PTECs to TNFα and TGFβ. Importantly, Egr-1 is of clinical significance since the activity of Egr-1 in renal tubular cells was upregulated in renal failure patients. Our study highlights the integrative role of Egr-1 in renal inflammation and fibrosis. Thus, Egr-1 may serve as a therapeutic target for human kidney diseases.Key messagesRenal failure activates Egr-1 in human and mouse tubular cells.Egr-1 deficiency attenuates NF-κB and TGFβ-mediated renal inflammation/fibrosis.Egr1−/− PTECs respond weakly to pro-inflammatory or pro-fibrotic stimulation.

Different Risk of Common Gastrointestinal Disease Between Groups Undergoing Hemodialysis or Peritoneal Dialysis or With Non-End Stage Renal Disease: A Nationwide Population-Based Cohort Study.

AbstractPeritoneal dialysis (PD) is one type of renal replacement therapy, but potential peritoneal damage and gastrointestinal (GI) tract adverse effects during long-term exposure to bio-incompatible dialysate remain a concern. Although GI disease frequently occurs in dialysis patients, whether the risk of GI diseases differs among PD and hemodialysis (HD) or non-uremic groups is still uncertain.In this retrospective cohort study, data were obtained from the National Health Insurance Research Database, which includes almost all dialysis patients in Taiwan. Between 2000 and 2009, a total of 1791 PD and 8955 HD incident patients were enrolled and matched for age and sex or for propensity score. In addition, a comparison cohort of 8955 non-uremic patients was also selected. Individuals were monitored for the occurrence of common GI diseases until 2010, and data were analyzed using several different models.Generally speaking, the results showed that the risk of gastroesophageal reflux, intestinal obstruction or adhesions, and abdominal hernia was significantly higher in the PD group, whereas the risk of peptic ulcer disease and lower GI diverticula and bleeding was significantly greater in the HD group. Meanwhile, the risk of mesenteric ischemia, liver cirrhosis, and acute pancreatitis was higher in dialysis patients, but was not significantly different between the PD and HD groups; moreover, the risk of appendicitis in the PD group appeared to be lower than that in the HD group.In conclusion, dialysis patients have a higher risk of most common GI diseases, and PD and HD modalities are associated with different GI diseases.

Parathyroidectomy Associates with Reduced Mortality in Taiwanese Dialysis Patients with Hyperparathyroidism: Evidence for the Controversy of Current Guidelines

Parathyroidectomy is recommended by the clinical guidelines for dialysis patients with unremitting secondary hyperparathyroidism (SHPT). However, the survival advantage of parathyroidectomy is debated because of the selection bias in previous studies. To minimize potential bias in the present nationwide cohort study, we enrolled only dialysis patients who had undergone radionuclide parathyroid scanning to ensure all patients had severe SHPT. The parathyroidectomized patients were matched with the controls based on propensity score for parathyroidectomy. Mortality hazard was estimated using multivariate Cox proportional hazard models adjusting for comorbidities before scanning (model 1) or over the whole study period (model 2). Our results showed that among the 2786 enrolled patients, 1707 underwent parathyroidectomy, and the other 1079 were controls. The crude mortality rates were lower in the parathyroidectomized patients than in the controls. In adjusted analyses for the population matched on propensity score, parathyroidectomy was associated with a significant 20% to 25% lower risk for all-cause mortality (model 1: hazard ratio 0.76, 95% confidence interval 0.61 to 0.94; model 2: hazard ratio 0.80, 95% confidence internal 0.64 to 0.98). We concluded that parathyroidectomy was associated with a reduced long-term mortality risk in dialysis patients with severe SHPT.

Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis

Pancreatic β-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how β-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue β-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic β-cells to translate fatty acid stimuli into a cellular adaptation mechanism.Key MessagePA stimulates Egr-1 expression via a calcium influx-MEK1/2-ERK1/2-Elk-1 cascade.Egr-1 attenuates PA-induced ER stress and apoptosis.Egr-1 maintains Akt survival pathway to protect β-cells from PA-induced apoptosis.Egr-1-deficient islets are prone to ex vivo stimuli of apoptosis.Human EGR1 expression correlates with genes for ER stress and anti-apoptosis.

Diuretics Prevent Thiazolidinedione-Induced Cardiac Hypertrophy without Compromising Insulin-Sensitizing Effects in Mice

Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg(+/-)) mice, but not in mice defective for ligand binding (Pparg(P465L/+)). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity.

Cystatin C as a predictor for outcomes in patients with negligible renal function

Background: High serum cystatin C (CysC) has been associated with clinical risks independently of the glomerular filtration rate (GFR). This study aims to investigate the predictive power of CysC in patients with a negligible GFR. Methods: Patients on chronic hemodialysis or peritoneal dialysis were enrolled for measurement of CysC levels and were followed up for one year. A daily urine amount <100 ml was considered negligible residual renal function (RRF). Results: CysC results were available in 183 dialysis patients. Of these, 131 patients had a negligible RRF. The multivariate Cox proportional hazards model showed that CysC was an independent predictor of fatal and nonfatal cardiovascular and infection events in all dialysis patients and in dialysis patients with a negligible RRF. Conclusion: CysC maintained its predictive power for adverse outcomes in patients with no meaningful GFR, indicating that the prognostic value of CysC is independent of the GFR. i 2014 S. Karger AG, Basel