Yun Kyu Oh

Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney

BACKGROUND Chronic hypoxia in the kidney has been suggested as a final common pathway to end-stage renal disease. Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses, and it is a promising target with therapeutic potential in various kidney disease models. In this study, we investigated whether HIF activation could attenuate renal injury in the rat remnant kidney model. METHODS Two weeks after a subtotal nephrectomy, rats received a continuous infusion of dimethyloxalylglycine (DMOG) for 4 weeks to activate HIF. RESULTS The DMOG infusion halted the progression of proteinuria. A histological evaluation revealed that the glomerulosclerosis and tubulointerstitial injury were significantly decreased by DMOG treatment. DMOG increased renal HIF-1alpha protein. The expression of glucose transporter-1 (GLUT-1) and prolyl hydroxylase 3 (PHD3) and the immunostaining of vascular endothelial growth factor (VEGF) were increased by DMOG. DMOG-treated rats showed less podocyte injury manifested by decreased immunostaining of desmin and the restoration of podoplanin staining. Furthermore, plasma malondialdehyde (MDA), a marker of oxidative stress, showed a tendency to decrease, and the renal expression of catalase, an antioxidant, was significantly increased by DMOG. The DMOG treatment decreased macrophage infiltration and reduced fibrosis, as manifested by decreased type IV collagen and osteopontin expression. CONCLUSIONS Activation of HIF by DMOG halted the progression of proteinuria and attenuated structural damage by preventing podocyte injury in the remnant kidney model. This renoprotection was accompanied by a reduction of oxidative stress, inflammation and fibrosis.

Antidiuretic Effect of Hydrochlorothiazide in Lithium-Induced Nephrogenic Diabetes Insipidus Is Associated with Upregulation of Aquaporin-2, Na-Cl Co-transporter, and Epithelial Sodium Channel

Thiazides have been used in patients with nephrogenic diabetes insipidus (NDI) to decrease urine volume, but the mechanism by which it produces the paradoxic antidiuretic effect remains unclear. Previous studies have reported that downregulation of aquaporin-2 (AQP2) is important for the development of lithium-induced (Li-induced) polyuria and that hydrochlorothiazide (HCTZ) increases renal papillary osmolality and Na(+) concentration in Brattleboro rats. For elucidating the molecular basis of the antidiuretic action of HCTZ in diabetes insipidus, whether administration of HCTZ may affect the expression of AQP2 and major renal Na(+) transporters in Li-induced NDI rats was investigated, using semiquantitative immunoblotting and immunohistochemistry. After feeding male Sprague-Dawley rats Li chloride-containing rat diet for 4 wk, HCTZ or vehicle was infused subcutaneously via osmotic minipump. Urine output was significantly decreased by HCTZ treatment, whereas it was not changed in vehicle-treated rats. Urine osmolality was also higher in HCTZ-treated rats than in vehicle-treated rats. Semiquantitative immunoblotting using whole-kidney homogenates revealed that HCTZ treatment caused a significant partial recovery in AQP2 abundance from Li-induced downregulation. AQP2 immunohistochemistry showed compatible findings with the immunoblot results in both cortex and medulla. The abundances of thiazide-sensitive NaCl co-transporter and alpha-epithelial sodium channel were increased by HCTZ treatment. Notably, HCTZ treatment induced a shift in molecular weight of gamma-epithelial sodium channel from 85 to 70 kD, consistent with previously demonstrated aldosterone stimulation. The upregulation of AQP2 and distal renal Na(+) transporters in response to HCTZ treatment may account for the antidiuretic action of HCTZ in NDI.

Depression and health-related quality of life in maintenance hemodialysis patients.

BACKGROUND This study was designed to determine the prevalence of depression among hemodialysis (HD) patients from urban hospitals in Korea, to illustrate demographic factors and biomarkers associated with depression and health-related quality of life (HRQOL), and to demonstrate association between depression and HRQOL. PATIENTS AND METHODS For this multicenter, cross-sectional study, 160 HD patients from 3 university teaching hospitals and 3 local dialysis units in Korea were enrolled. Korean Becks depression inventory and Korean version of Kidney Disease Quality of Life short form, version 1.3 (KDQOL-SFTM 1.3) were used to evaluate depression and quality of life, respectively. RESULTS Depression was found in 51 out of 160 (31.9%) patients. Old age (> 60 years old), low hemoglobin level (< 10 g/dl), and low economic status were associated with depression, and old age (OR 6.138, p = 0.001) was the most important risk factor among them. Old age, female gender, presence of diabetes mellitus, high comorbidity index score (modified Charlson comorbidity index > or = 6), hypoalbuminemia (< 4.0 g/dl), and high CRP (> 0.5 mg/dl) were common factors associated with decreased HRQOL. Depression and HRQOL showed inverse linear relationship. CONCLUSIONS Moderate to severe depression was common in maintenance HD patients in Korea. Among factors associated with depression and decreased HRQOL, some characteristics are potentially modifiable by social and medical intervention. Further prospective studies are warranted to see whether depression and HRQOL can be improved by modifying these factors.

Effect of multidisciplinary pre-dialysis education in advanced chronic kidney disease: Propensity score matched cohort analysis.

Aim:  The mortality and morbidity of end‐stage renal failure patients remains high despite recent advances in pre‐dialysis care. Previous studies suggesting a positive effect of pre‐dialysis education were limited by unmatched comparisons between the recipients and non‐recipients of education. The present study aimed to clarify the roles of the multidisciplinary pre‐dialysis education (MPE) in chronic kidney disease patients.

Prevalence of Vitamin D Deficiency and Effects of Supplementation With Cholecalciferol in Patients With Chronic Kidney Disease

OBJECTIVE We aimed to evaluate the vitamin D status, the effect of cholecalciferol supplementation, and the factors associated with vitamin D restoration in nondialytic patients with chronic kidney disease (CKD). DESIGN The present study was a prospective open-label trial. SETTING This study took place at the Seoul National University Boramae Medical Center. SUBJECTS Patients with nondialytic CKD (estimated glomerular filtration rate [eGFR] 10-59 mL/min per 1.73 m(2)) participated in this study. INTERVENTION Vitamin D status in 210 CKD patients was assessed and the patients with vitamin D deficiency (<30 ng/mL) were administered cholecalciferol (1,000 IU/day) for 6 months. MAIN OUTCOME MEASURE The restoration rate of vitamin D deficiency at 3 and 6 months and the response-related factors were analyzed. RESULTS The prevalence of vitamin D deficiency was 40.7% in CKD Stage 3, 61.5% in Stage 4, and 85.7% in Stage 5. The subgroup with vitamin D deficiency had a greater proportion of patients with diabetes, lower eGFR, and higher proteinuria. With the supplementation, 52 patients (76.5%) reached levels of 25-hydroxy vitamin D (25(OH)D) of 30 ng/mL or greater at 3 months, and the restoration of vitamin D was observed in 61 patients (89.7%) at 6 months. Lower levels of 25(OH)D and a higher amount of proteinuria at baseline were the factors associated with lower response to vitamin D supplementation. CONCLUSION Vitamin D deficiency rate was high in nondialytic CKD patients, and the proportion increased as renal function decreased. A higher amount of proteinuria was the independent risk factor of nonresponse with supplementation. Vitamin D was replenished in most patients with cholecalciferol supplementation without any significant adverse effects.

Urinary N-acetyl-β-D glucosaminidase as a surrogate marker for renal function in autosomal dominant polycystic kidney disease: 1 year prospective cohort study

BackgroundRenal failure is one of the most serious complications associated with autosomal dominant polycystic kidney disease (ADPKD). To date, early markers have failed to predict renal function deterioration at the early stages. This 1-year prospective study evaluated N-acetyl-β-D-glucosaminidase (NAG) as a new surrogate marker for renal function in ADPKD.MethodsA total of 270 patients were enrolled in the study, and we measured urinary NAG, β2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) prospectively for 1 year to compare their predictive values for renal function.ResultsBaseline urinary NAG/Cr was negatively correlated with estimated glomerular filtration rate (GFR) (r2 = 0.153, P < 0.001) and positively correlated with total kidney volume (TKV) (r2 = 0.113, P < 0.001). Among other biomarkers, urinary NAG/Cr better discriminated patients with decreased renal function from those with conserved renal function, showing the largest area under the curve (AUC 0.794). Immunohistochemical study revealed strong staining along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells. However, both single and repeated measurements of urinary NAG/Cr failed to predict renal function decline in 1 year.ConclusionsUrinary NAG/Cr may be a useful surrogate marker for renal function in ADPKD patients.

Blood Pressure-Related Genes and the Progression of IgA Nephropathy

Background/Aims: Hypertension is one of the most significant prognostic factors of immunoglobulin A nephropathy (IgAN). We investigated the role of polymorphisms of hypertension-related genes in the clinical impact of IgAN. Methods: A total of 238 IgAN and 300 healthy cohorts were studied. The polymorphisms of angiotensinogen (AGT M235T), the angiotensin II type 1 receptor (A1166C), aldosterone synthase (C-344T), α-adducin (G460W) and endothelin-1 (K198N and 3A/4A) were determined. Results: The genotype distributions of the polymorphisms were similar between patients and controls. The individual genotypes taken alone were not associated with the development of hypertension or progression of renal dysfunction. Although AGT M235T was not associated with the development of hypertension in either sex, men with M235T TT were found to be at an increased risk of IgAN progression compared to those with the other genotypes (p = 0.019). In the Cox regression model with adjustment for clinical risk factors, including age at diagnosis, hypertension, serum creatinine and urinary protein excretion at renal biopsy, AGT M235T TT variant was an independent risk factor only for male patients (hazard ratio 5.848; p = 0.005). Conclusion: Our results suggest that the AGT M235T polymorphism is associated with the progression of IgAN in Korean male patients.

Clinical outcomes of patients with hepatorenal syndrome after living donor liver transplantation

Liver transplantation (LT) is the treatment of choice for hepatorenal syndrome (HRS). However, the clinical benefits of living donor liver transplantation (LDLT) are not yet well established. We, therefore, investigated the outcomes of patients with HRS who underwent LDLT and patients with HRS who received transplants from deceased donors. This study focused on 71 patients with HRS out of a total of 726 consecutive adult Korean patients who underwent LT at a single Asian center. We compared 48 patients who underwent LDLT with 23 patients who underwent deceased donor liver transplantation (DDLT). Patients with HRS showed poorer survival than patients without HRS (P = 0.01). Poorer survival was associated with higher in‐hospital mortality for patients with HRS (18.3% versus 5.2%, P < 0.001). In comparison with DDLT, LDLT was associated with younger donors and shorter ischemic times. The survival rate with LDLT was significantly higher than the survival rate with DDLT (P = 0.02). Among patients with high Model for End‐Stage Liver Disease scores (≥30) or type 1 HRS, the survival rates for the LDLT group were not inferior to those for the DDLT group. LDLT significantly improved recipient survival after adjustments for several risk factors (hazard ratio = 0.20, 95% confidence interval = 0.05‐0.85, P = 0.03). Kidney function was significantly improved after LT, and there was no difference between LDLT and DDLT. No patients in the HRS cohort required maintenance renal replacement therapy. In conclusion, LDLT may be a beneficial option for patients with HRS. Liver Transpl 18:1237–1244, 2012.

Lower Residual Renal Function is a Risk Factor for Depression and Impaired Health-Related Quality of Life in Korean Peritoneal Dialysis Patients

We retrospectively evaluated demographic and biochemical parameters associated with depression and health-related quality of life (HRQOL) in maintenance peritoneal dialysis (PD) patients. This study included 105 patients maintaining PD at Seoul National University Hospital. Data were collected from electronic medical record. Korean Becks Depression Inventory and Korean version of Kidney Disease Quality of Life short form, version 1.3 were used to evaluate depression and HRQOL, respectively. Moderate to severe depression was found in 24.8% of patients. Patients with lower normalized protein equivalent of nitrogen appearance (nPNA) (< 1.2 g/kg/day), lower weekly renal Kt/Vurea (< 0.2), and lower serum albumin level (≤ 4.0 g/dL) were associated with depression (P < 0.05). Among them, lower weekly renal Kt/Vurea was the only independent risk factor associated with depression (OR = 3.1, P = 0.007). Depressed patients showed significantly lower scores in every dimension of HRQOL (P < 0.001). Lower weekly renal Kt/Vurea (β = 0.24, P = 0.005) and lower nPNA (β = 0.15, P = 0.03) were the independent risk factors associated with lower kidney dialysis component summary, whereas lower plasma hemoglobin level was the consistent risk factor for lower physical component summary (β = 0.22, P = 0.03) and mental component summary (β = 0.22, P = 0.01). Depression is a prevalent psychological problem in PD population. Residual renal function is the most important factor associated with depression and impaired HRQOL in PD patients.

Effects of potassium on expression of renal sodium transporters in salt-sensitive hypertensive rats induced by uninephrectomy

Dietary potassium is an important modulator of systemic blood pressure (BP). The purpose of this study was to determine whether dietary potassium is associated with an altered abundance of major renal sodium transporters that may contribute to the modulation of systemic BP. A unilateral nephrectomy (uNx) was performed in male Sprague-Dawley rats, and the rats were fed a normal-salt diet (0.3% NaCl) for 4 wk. Thereafter, the rats were fed a high-salt (HS) diet (3% NaCl) for the entire experimental period. The potassium-repleted (HS+KCl) group was given a mixed solution of 1% KCl as a substitute for drinking water. We examined the changes in the abundance of major renal sodium transporters and the expression of mRNA of With-No-Lysine (WNK) kinases sequentially at 1 and 3 wk. The systolic BP of the HS+KCl group was decreased compared with the HS group (140.3 ± 2.97 vs. 150.9 ± 4.04 mmHg at 1 wk; 180.3 ± 1.76 vs. 207.7 ± 6.21 mmHg at 3 wk). The protein abundances of type 3 Na(+)/H(+) exchanger (NHE3) and Na(+)-Cl(-) cotransporter (NCC) in the HS+KCl group were significantly decreased (53 and 45% of the HS group at 1 wk, respectively; 19 and 8% of HS group at 3 wk). WNK4 mRNA expression was significantly increased in the HS+KCl group (1.4-fold of control at 1 wk and 1.9-fold of control at 3 wk). The downregulation of NHE3 and NCC may contribute to the BP-attenuating effect of dietary potassium associated with increased urinary sodium excretion.