Targeting Cyst Initiation in ADPKD

Leuenroth, Stephanie J.; Crews, Craig M.

doi:10.1681/asn.2008101118

Cited by 10 publications

(4 citation statements)

References 23 publications

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“…The disease is caused by mutations in either PKD1 or PKD2 genes, encoding the proteins polycystin-1 and polycystin-2, responsible for 85% and 15% of ADPKD cases, respectively 4 - 6 . Presently, there is no effective treatment for ADPKD, although significant progress has been made in recent years in identifying potential treatments 7 , 8 …”

Section: Introductionmentioning

confidence: 99%

CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD

et al. 2012

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Autosomal dominant polycystic kidney disease (ADPKD) and other forms of PKD are associated with dysregulated cell cycle and proliferation. Although no effective therapy for the treatment of PKD is currently available, possible mechanism-based approaches are beginning to emerge. A therapeutic intervention targeting aberrant cilia-cell cycle connection using CDK-inhibitor R-roscovitine showed effective arrest of PKD in jck and cpk models that are not orthologous to human ADPKD. To evaluate whether CDK inhibition approach will translate into efficacy in an orthologous model of ADPKD, we tested R-roscovitine and its derivative S-CR8 in a model with a conditionally inactivated Pkd1 gene (Pkd1 cKO). Similar to ADPKD, Pkd1 cKO mice developed renal and hepatic cysts. Treatment of Pkd1 cKO mice with R-roscovitine and its more potent and selective analog S-CR8 significantly reduced renal and hepatic cystogenesis and attenuated kidney function decline. Mechanism of action studies demonstrated effective blockade of cell cycle and proliferation and reduction of apoptosis. Together, these data validate CDK inhibition as a novel and effective approach for the treatment of ADPKD.

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Section: Introductionmentioning

confidence: 99%

CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD

et al. 2012

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“…At present, no medical therapy has proven to substantially slow the growth of ADPKD-related cysts or the volumetric expansion of polycystic kidneys. However, innovative strategies to blunt renal tubular cell proliferation and fluid secretion, the processes that drive growth of cystic bodies, comprise foci of active research (8,9).…”

mentioning

confidence: 99%

Renal Function and Healthcare Costs in Patients with Polycystic Kidney Disease

Lentine

Xiao

Machnicki

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Characterizing relationships of kidney function to healthcare costs in polycystic kidney disease has applications for economic evaluations of standard and emerging therapies.Design, setting, participants, & measurements: The administrative records (2003 to 2006) of a private health insurer were examined to identify polycystic kidney disease patients (n ‫؍‬ 1913) from ICD9 diagnosis codes on billing claims. The first available diagnostic claim was assumed as an index date, and baseline estimated GFR (eGFR) was computed using closest serum creatinine value. The associations of eGFR with annualized charges were modeled by nonlinear and linear regression.Results: Medical, pharmacy, and total healthcare costs varied significantly by baseline kidney function, such that mean total annualized charges (unadjusted) were approximately 5-fold higher in patients with eGFR < 15 ml/min compared with those with eGFR > 90 ml/min. After adjustment for age and gender, total charges did not differ significantly among patients with eGFR > 30 ml/min, and but rose precipitously with eGFR < 30 ml/min. Each ml/min decline <30 ml/min predicted approximately $5435 higher adjusted annual charges. Results were similar after adjustment for baseline diabetes and cardiovascular disease as identified in claims, while significantly higher adjusted charges were detected with eGFR ‫؍‬ 31 to 60 ml/min versus >90 ml/min in a subgroup free of diabetes and cardiovascular disease.Conclusions: Healthcare charges are associated with advanced renal dysfunction in polycystic kidney disease patients. Strategies that prevent loss of renal function below 30 ml/min have the potential to generate substantial reductions in medical charges.

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“…Future specific treatments of ADPKD may also involve minimally toxic doses of combination or sequential therapy directed at precystic and then both micro-and macrocystic/cystic fluid expansion aspects of ADPKD. 48,74 Unfortunately, at the present time there is no specific FDA-approved therapy for ADPKD.…”

Section: ■ Current Management Of Adpkdmentioning

confidence: 99%