Development of gene silencer pyrrole-imidazole polyamides targeting GSK3ß for treatment of polycystic kidney diseases.

The cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB)-glycogen synthase kinase 3ß (GSK3ß) signaling pathway was reported to be involved in the progression of autosomal dominant polycystic kidney diseases (ADPKD). We designed and synthesized pyrrole-imidazole (PI) polyamides as novel gene-silencers to prevent binding of CREB on the GSK3ß gene promoter and examined the effects of the PI polyamides on proliferation and cyst formation of mouse collecting duct M1 cells. The GSK3ß PI polyamides significantly inhibited expression of GSK3ß mRNA in M1 cells with forskolin. To obtain cells as collecting ducts from ADPKD, the PKD1 gene was knocked down by shRNA. Lower concentrations of forskolin significantly stimulated proliferation of PKD1 knock-down M1 cells, whereas GSK3ß PI polyamide significantly inhibited proliferation of PKD1 knock-down M1 cells with forskolin. Stimulation with forskolin for 5 days induced enlargement of cysts from PKD1 knock-down M1 cells. GSK3ß PI polyamides significantly suppressed the enlargement of cysts with forskolin stimulation in PKD1 knock-down M1 cells. Thus, the present study showed that transcriptional suppression of the GSK3ß gene by PI polyamides targeting the binding of CREB inhibited the proliferation and cyst formation of PKD1 knock-down M1 cells. The GSK3ß PI polyamides may potentially be novel medicines for ADPKD.

Randomized trial of frequent low-efficiency and short hemodialysis/hemofiltration in hemodialysis patients with acute brain injury.

PURPOSE: The aim of the study was to compare effects of frequent low-efficiency and short hemodialysis (FLESHD) and frequent low-efficiency and short hemofiltration (FLESHF) in hemodialysis (HD) patients with acute brain injury (ABI).
 METHODS: We randomly divided 13 HD patients with ABI into FLESHD (n = 6) or FLESHF (n = 7) groups. Conditions for the first to third sessions were as follows. FLESHD: intravenous administration of glycerol 400 ml/session, blood flow rate (QB) 100 ml/min, dialysate flow rate 300 ml/min, and treatment duration 2 h (HD-1). FLESHF: intravenous administration of glycerol 400 ml/session, QB 150 ml/min, substitution flow rate 10 l/session, and treatment duration 4 h (HF-1). After the fourth session, we gradually changed the conditions and stopped glycerol administration (HD-2 and HF-2).
 RESULTS: There were no significant differences in survival rate, consciousness level, or adverse effects during hospitalization in either group. In mixed model analysis, the level of HCO3- post FLESHF was significantly (p<0.0001) increased compared with the level post FLESHD. However, no significant differences were seen in the levels of osmolality, in blood pressure before and after either dialysis method, or in the level of HCO3- pre dialysis. The variation in the relative ratio of BUN before FLESHF was significantly higher (p<0.05) than the relative ratio before FLESHD in the sixth session. In the FLESHD groups, serum sodium was higher and serum potassium was lower than in the FLESHF groups.
 CONCLUSIONS: FLESHD with glycerol under these conditions may be a better therapeutic option for managing patients with ABI, although the short-term survival rate is similar.

Successful treatment of pheochromocytoma in a patient with hemodialysis: a case report and review of the literature.

Pheochromocytoma in a patient with end-stage renal disease is considered rare. A 40-year-old man who had undergone renal transplantation in childhood and had been on hemodialysis (HD) for the last 6 years suddenly developed paroxysmal palpitations and hypertension. His plasma catecholamine (CA) level was increased and a right adrenal mass was found on magnetic resonance imaging. He was diagnosed with pheochromocytoma, and right adrenalectomy was conducted after pretreatment with CA blockade and volume expansion. The surgery was conducted safely, his symptoms resolved, and his plasma CA level decreased to the normal range. Since paroxysmal hypertension is a common symptom in patients with HD, careful attention is needed to diagnose pheochromocytoma.

Efficacy analysis of the renoprotective effects of aliskiren in hypertensive patients with chronic kidney disease.

We aimed to assess the effect of aliskiren treatment on blood pressure, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label study of 67 patients with CKD who were already being treated with other antihypertensives. Inclusion criteria were blood pressure (BP) ≥130/80 mmHg, albuminuria ≥30 mg/g, and estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2). Subjects were treated with 150 mg/day aliskiren, which was increased to 300 mg/day for the 24-week study period. Aliskiren effectively reduced both systolic and diastolic BP, plasma renin activity (PRA), serum aldosterone concentration, albuminuria, urinary N-acetyl-glucosaminidase, and urinary ß2-microglobulin levels. Although eGFR was significantly decreased after 4 weeks of aliskiren treatment, it recovered to a pretreatment level within 12 weeks of treatment initiation. There were no significant differences in the percent reduction of albuminuria or changes of eGFR levels when the subjects were divided into three groups on the basis of baseline eGFR (stages 1/2, 3, and 4) and the presence or absence of diabetes mellitus (DM group and non-DM group). Furthermore, in patients not treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors, including angiotensin receptor blockers or angiotensin-converting enzyme inhibitors at baseline, changes in eGFR were significantly increased compared with those already treated with RAAS inhibitors at baseline. Aliskiren administration reduced BP, PRA, serum aldosterone levels, and albuminuria, while maintaining eGFR, regardless of the presence or absence of DM or the degree of eGFR.

Aliskiren reduces home blood pressure and albuminuria in patients with hypertensive nephrosclerosis.

BACKGROUND: The aim of this study was to investigate the antialbuminuric and antihypertensive effects of aliskiren by monitoring home blood pressure (BP) in comparison with the effects of the angiotensin receptor blocker (ARB) valsartan in patients with hypertensive nephrosclerosis and albuminuria. METHODS: We conducted an open-label, randomized trial to compare the effects of aliskiren with those of valsartan. Patients with BP <150/90 mmHg, an estimated glomerular filtration rate of 90-30 mL/min/1.73 m(2), and albuminuria >30 mg/g, despite treatment with a 160 mg daily dose of valsartan, were randomly assigned to the following two groups: the aliskiren group, who switched from 160 mg/day valsartan to 150 mg/day aliskiren, which was later increased to 300 mg/day (n = 20); and the valsartan group, who continued with 160 mg/day valsartan (n = 20). RESULTS: After 12 weeks of treatment, although there was no significant difference in clinic BP between groups, a significant reduction in morning and evening systolic BP was observed in the aliskiren group. The decrease in albuminuria in the aliskiren group was significantly better than that in the valsartan group, and a significant correlation was noted between the change in morning systolic BP and the change in albuminuria in the aliskiren group (r = 0.564, P = 0.0084). CONCLUSION: We showed that aliskiren treatment leads to a greater reduction in albuminuria and home systolic BP values than valsartan in patients with nephrosclerosis. We propose that aliskiren therapy should be considered as a therapeutic modality to complement ARBs in hypertensive patients with nephrosclerosis.