Impaired Na⁺−K⁺-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury

Hyperuricemia contributes to renal inflammation. We aimed to investigate the role of Na⁺–K⁺–ATPase (NKA) in hyperuricemia-induced renal tubular injury. Human primary proximal tubular epithelial cells (PTECs) were incubated with uric acid (UA) at increasing doses or for increasing lengths of time. PTECs were then stimulated by pre-incubation with an NKA α1 expression vector or small interfering RNA before UA (100 μg ml⁻¹, 48 h) stimulation. Hyperuricemic rats were induced by gastric oxonic acid and treated with febuxostat (Feb). ATP levels, the activity of NKA and expression of its α1 subunit, Src, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and interleukin 1β (IL-1β) were measured both in vitro and in vivo. Beginning at concentrations of 100 μg ml−1, UA started to dose-dependently reduce NKA activity. UA at a concentration of 100 μg ml⁻¹ time-dependently affected the NKA activity, with the maximal increased NKA activity at 24 h, but the activity started to decrease after 48 h. This inhibitory effect of UA on NKA activity at 48 h was in addition to a decrease in NKA α1 expression in the cell membrane, but an increase in lysosomes. This process also involved the subsequent activation of Src kinase and NLRP3, promoting IL-1β processing. In hyperuricemic rats, renal cortex NKA activity and its α1 expression were upregulated at the 7th week and both decreased at the 10th week, accompanied with increased renal cortex expression of Src, NLRP3 and IL-1β. The UA levels were reduced and renal tubular injuries in hyperuricemic rats were alleviated in the Feb group. Our data suggested that the impairment of NKA and its consequent regulation of Src, NLRP3 and IL-1β in the renal proximal tubule contributed to hyperuricemia-induced renal tubular injury.

Hypoxia inducible factor-1α gene silencing aggravates growth inhibition and necrosis of human proximal renal tubular epithelial cell under hypoxia / 中华肾脏病杂志

Objective To explore the effect of hypoxia inducible factor-1α silencing by siRNA on proliferation, apoptosis and necrosis of human renal proximal epithelial cell ( HK-2 )under hypoxia. Methods CoCl2 was used to mimic hypoxia, and siRNA technique was used to silence HIF-1α. HK-2 cells were divided into five groups, including normal culture group,hypoxia culture group, transfection reagent group, negative control group and HIF-1α siRNA group.MTT assay was used to detect the growth inhibition ratio of cells. TUNEL and caspase-3 quantity was used to detect apoptosis. LDH activity in supernatant was detected to evaluate cell necrosis.Real-time PCR and Western blotting were used to detect mRNA and protein of HIF-1α, HIF-2α,glucose transporter 1(Glut-1) and vascular endothelial growth factor (VEGF). Results (1) The transfection efficiency of siRNA was 95%-100%. Under normoxia, the efficiency of siRNA silencing HIF-1α gene reached to 70%, while under hypoxia, it was 97%. (2) The growth inhibition ratio of cells in HIF-1α siRNA group was significantly higher than that of other groups including hypoxia culture group, transfection reagent group and negative control group (all P＜0.05). No significant difference was found in apoptotic ratio of the other four groups except normal culture group (P＞0.05). The LDH level in HIF-1α siRNA group was significantly higher than that of hypoxia culture group, transfection reagent group and negative control group (P＜0.05). (3) The expression of HIF1α, Glut-1, VEGF mRNA and protein in HIF-1α siRNA group was significantly lower than that of hypoxia culture group, transfection reagent group and negative control group (P＜0.05). No significant difference was observed on the level of HIF-2α mRNA and protein in the other four groups except normal culture group (P＞0.05). Conclusion HIF-1α gene silencing can inhibit the mRNA and protein expression of Glut-1 and VEGF, and can aggravate growth inhibition and necrosis of HK-2 cells under hypoxia.

Clinicopathological analysis of IgA nephropathy patients with mild proteinuria and/or hematuria / 中华肾脏病杂志

Objective To clarify the relationship between clinical manifestation and pathological features of IgA nephropathy (IgAN) patients with mild proteinuria and/or hematuria.Methods Clinicopathological data from 316 biopsy-proven IgAN cases (proteinuria＜1 g/24 h and/or hematuria, and Scr＜133 μmol/L) from our hospital between January 1993 and October 2009 were studied retrospectively. The renal histopathology was quantified according to Lee's grading and Katafuchi's semi-quantitative standard, and the risk factors for renal pathological lesions were evaluated using multifactor logistic regression analysis. Results Among these 316 patients, 123 were male and 193 patients were female. The mean age at the time of renal biopsy was (33.10±10.69) years old. Clinical features were found as follows: hematuria with proteinuria was found in 267 patients (84.5%), isolated hematuria in 24 patients (7.6%), and isolated proteinuria in 25 patients (7.9%). 16.5% of patients had hypertension. The percentages of CKD stage Ⅰ, Ⅱ, Ⅲ were 76.9%, 20.9% and 2.2%, respectively. 31.3% of patients presented Lee's grade Ⅲ or more severe.52.8% of patients had various degrees of glomerulosclerosis. Crescent formation was observed in 20.3% of patients. 22.5% of patients showed tubular atrophy;16.8% showed interstitial fibrosis and 24.7% also had renal vascular lesions. The extent of glomerulosclerosis was negatively correlated with eGFR levels, but positively correlated with the amount of proteinuria and mean arterial pressure (MAP) level (P＜0.05). The score of tubulointerstitial lesion was positively correlated with the amount of proteinuria and negatively correlated with eGFR and hemoglobin (Hb)level (P＜0.05). The degree of renal vascular lesion was also correlated to MAP level positively and eGFR level negatively (P＜0.05). Multifactor logistic regression analysis revealed that proteinuria, Scr and Hb at the time of renal biopsy were independent risk factors for severe renal pathological lesions (Lee's grade Ⅲ or more severe) with odds ratio of 8.564, 1.031 and 0.975 respectively (all P＜0.01). Conclusions Severe renal histological lesions and decrease of renal function may be seen in some IgAN patients with mild proteinuria and/or hematuria. The levels of proteinuria,Scr and Hb are the independent risk factors for severe renal pathological lesions. Renal biopsy is important in these patients in order to make diagnosis and individual treatment.

Efficacy of low-dose daytime ambulatory peritoneal dialysis in diabetic end-stage renal disease patients with better residual renal function / 中华肾脏病杂志

Objective To study the efficacy of low-dose daytime ambulatory peritoneal dialysis (DAPD) and low-dose CAPD in diabetic end-stage renal disease (ESRD) patients with better residual renal function (RRF). Methods Forty stable diabetic ESRD patients with better RRF (rGFR ≥ 5 ml/min and urine volume ≥ 750 ml/d) were enrolled. They were randomly divided into two groups: low-dose DAPD group (n=20) and low-dose CAPD group (n=20). DAPD group received three 1.5 L to 2 L daily exchanges with a nocturnal empty belly, dwelling for 3 to 4 hours. CAPD group received three 1.5 L to 2 L daily exchange or four 1.5 L daily exchange regimens and dwelled during the night. At the beginning of the study and 6 months later, total weekly Kt/V and Ccr (peritoneal+renal), rGFR were calculated. Meanwhile 24-hour urinary protein,serum albumin (Alb), hemoglobin (Hb), fasting plasma glucose, glycosylated hemoglobin and insulin dosage were measured. Nutritional status was assessed by SGA. Results Thirty-five patients fulfilled the study. There were no significant differences between two groups in age, gender, BMI,PD time, D/Pcr, etc. At the end of the 6th month, the insulin dose[(33.6±10.9) U/d] and 24-hour dialysate protein [(11.13t4.95) g] in CAPD group were significantly higher as compared to DAPD group [(20.6±6.2) U/d, P＜0.05 and (5.66±2.88) g, P＜0.01 respectively]. Alb in CAPD group [(29.7±4.2) g/L] was significantly lower than that in DAPD group [(36.5 ±3.9) g/L, P＜0.05].While the net ultrafiltration [(554±187) ml vs (309±177) ml], 24-hour urine volume [(1090±361)ml vs (750±258) ml] and rGFR [(8.21±2.40) ml/min vs (4.88±2.11) ml/min] in DAPD group were all significantly higher than those in CAPD group (all P＜0.05). Conclusion For the diabetic ESRD patients with better RRF, the low-dose DAPD regimen is more effective to control plasma glucose, improve nutritional status and protect RRF than the low-dose CAPD.

Cross-sectional study on hypertension in patients with chronic kidney disease / 中华肾脏病杂志

Objective To investigate the situation of prevalence,treatment and control of hypertension in patients with chronic kidney disease(CKD)by CROSS-sectional study. Methods Nine hundred out-patients with CKD in our department from November 2006 to March 2007 were enrolled in the study,including 480 male and 420 female.Among 900 CKD cases,354 patients underwent maintenance dialysis,including 228 on hemodialysis and 126 on peritoneal dialysis.Results The prevalence of hypertension in CKD patients was 80.2%(nude 83.5%vs female 76.4%,P<0.01).The prevalence of hypertension in patients on dialysis was significantly higher than that in non-dialysis patients(90.1%vs 73.8%,P<0.01),but there was no significant difference between hemodialysis and peritoneal dialysis cases.Antihypertensive treatment rate was 92.4%in CKD patients with hypertension.and was significantly higher in patients on dialysis than that in non-dialysis patients(95.6%vs 89.8%.P<0.01).The control rate according to current recommendations for CKD patients (BP<130/80 mm Hg) was very low. Control of both SBP and DBP was only achieved in 20.4% of non- dialysis patients. The control rate of hypertension (BP< 125/75 mm Hg) in patients with proteinuria >1 g/24 h was 8.4%. The proportion of dialysis patients with BP<140/90 mm Hg was significantly lower than that of non-dialysis patients (45.2% vs 55.5%, P<0.01). The percentage of hemodialysis patients with BP < 140/90 mm Hg was significantly higher than that of peritoneal dialysis patients (49.8% vs 36.5%, P<0.05). The prevalence of hypertension was associated with the decrease of renal function and the increase of age. The prevalence of hypertension in diabetic nephropathy was higher than that in primary glomerular diseases. Patients received 1, 2, 3 and 4 or more kinds of antihypertensive drugs accounted for 37.2%, 37.5%, 19.3% and 5.9% respectively. The combination of calcium channel blocker (CCB) and renin-angiotensin-aldosterone system (RAAS) inhibitors was more frequently used in CKD patients. The CCB was the most frequently prescribed drug (74.1% ), followed by angiotensin Ⅱ receptor blockers (ARB) (48.4%), angiotensin-converting enzyme inhibitors (ACEI) (25.6%) and alpha, beta-blockers (24.7%). Conclusions The prevalence of hypertension in CKD patients is quite high, which is associated with the progression of renal function, increase of age, the type of underlying kidney disease, obesity and diabetes mellitus. The control of hypertension is unsatisfied in CKD patients, especially in dialysis patients and those with overt proteinuria.

Comparison of two antibiotic prophylaxis schemes for the prevention of recurrent urinary tract infection in postmenopausal women / 中华肾脏病杂志

ObjectiveTo compare the efficacy and safety of intermittent patient-initiated single-dose antibiotic prophylaxis and continuous antibiotic prophylaxis for the prevention of recurrent urinary tract infection (UTI) in postmenopausal women. MethodsA randomized controlled clinical trial was conducted for the prevention of recurrent urinary tract infection. Single dose of antibiotic was given every night in continuous antibiotic prophylaxis group and every time after exposure to conditions predisposed to UTI in intermittent antibiotic prophylaxis group. The duration of prevention was 12 months in both groups. ResultsThe effective rates of intermittent antibiotic prophylaxis and continuous antibiotic prophylaxis were 71.0% and 81.8% respectively (P＞0.05). The incidence of gastrointestinal adverse reaction in intermittent antibiotic prophylaxis group was significantly lower than that in continuous antibiotic prophylaxis group (7.7% vs 28.6%,P＜0.05). ConclusionsCompared with continuous antibiotic prophylaxis, intermittent patient-initiated single-dose antibiotic prophylaxis is a better prophylaxis with less gastrointestinal adverse reactions for the prevention of recurrent urinary tract infection in postmenopausal women.