aliskiren and Polycystic-Kidney--Autosomal-Dominant

The intrarenal renin angiotensin system (RAS) is activated in polycystic kidney disease. We have recently shown in the Pkd1 mouse that Gen 2 antisense oligonucleotide (ASO), which suppresses angiotensinogen (Agt) synthesis, is efficacious in slowing kidney cyst formation compared with lisinopril. The aim of this current study was to determine 1) if unilateral nephrectomy accelerates cystogenesis in Pkd1 mice (as previously shown in cilia knockout mice) and 2) whether Agt ASO can slow the progression in this accelerated cystic mouse model. Adult Pkd1 conditional floxed allele mice expressing cre were administered tamoxifen, resulting in global knockout of Pkd1. Three weeks after tamoxifen injection, mice underwent left unilateral nephrectomy. Mice were then treated with Agt ASO (75 mg/kg per week) or aliskiren (20 mg/kg per day)+Agt ASO or control for 8 wk. Unilateral nephrectomy accelerated kidney cyst formation compared with nonnephrectomized mice. Both Agt ASO and Aliskiren+Agt ASO treatments significantly reduced plasma and urinary Agt levels. Blood pressure was lowest in Aliskiren+Agt ASO mice among all treatment groups, and the control group had the highest blood pressure. All mice developed significant kidney cysts at 8 wk after nephrectomy, but Agt ASO and Aliskiren+Agt ASO groups had fewer kidney cysts than controls. Renal pAkt, pS6 levels, and apoptosis were significantly suppressed in those receiving Agt ASO compared with controls. These results indicate that suppressing Agt using an ASO slowed the progression of accelerated cystic kidney disease induced by unilateral nephrectomy in Pkd1 mice by suppressing intrarenal RAS, mammalian target of rapamycin pathway, and cell proliferation.

Topics: Amides; Angiotensinogen; Animals; Apoptosis; Cell Proliferation; Disease Models, Animal; Disease Progression; ErbB Receptors; Female; Fumarates; Genetic Predisposition to Disease; Kidney; Male; Mice, Knockout; Nephrectomy; Oligonucleotides, Antisense; Phenotype; Polycystic Kidney, Autosomal Dominant; Renin; Renin-Angiotensin System; Time Factors; TOR Serine-Threonine Kinases; TRPP Cation Channels

Hypokalemic hypertension is a common condition leading to the diagnosis of secondary hypertension. We report the case of a 60-year-old woman for whom the diagnosis of autosomal dominant polycystic kidney disease arose during the investigation of possible hyperaldosteronism. Activation of the renin system, as supported by recent studies, can explain the mechanism of hypokalemia and hypertension in this inherited cystic kidney disorder. Clinicians should be aware of this relatively uncommon clinical phenomenon of secondary hypertension in polycystic kidney disease. Increased understanding of the disorder's underlying mechanism should lay the foundation for better appreciation of potentially effective blood pressure treatments. The availability of a direct renin inhibitor may redirect research toward finding a remedy for this troublesome disease.

Topics: Amides; Female; Fumarates; Humans; Hypertension; Hypokalemia; Middle Aged; Polycystic Kidney, Autosomal Dominant; Potassium Chloride; Renin; Treatment Outcome

A 47-year-old woman with family history of autosomal-dominant polycystic kidney disease (ADPKD), who underwent living-donor kidney transplantation in 2000, presented with recurrent edema, hyperreninemia, and hyperaldosteronism. Since 2002, her antihypertensive therapy comprised ramipril and spironolactone. The post-transplantation kidney function was stable. Based on the clinical picture and reports of renin secretion by renal cysts in ADPKD, we performed a trial of aliskiren therapy (300 mg/day). The patient showed excellent blood pressure control and reduction of edema, with aldosterone levels normalizing within 2 months. This is a novel report of aliskiren therapy for treatment of edema, hyperreninemia, and hyperaldosteronism in ADPKD.

Topics: Amides; Female; Fumarates; Humans; Hyperaldosteronism; Middle Aged; Polycystic Kidney, Autosomal Dominant; Recurrence; Remission Induction; Renin