Clinical Trials and a View Toward the Future of ADPKD

Kim, Hyunsuk; Hwang, Young Hwan

doi:10.1007/978-981-10-2041-4_9

Cited by 3 publications

(3 citation statements)

References 74 publications

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“…In ADPKD, as multiple cysts grow from kidney tubules, they compress renal tissue and vascular structures, and renal ischemia and inflammation eventually result in kidney failure [ 2 ]. Recently, novel drugs including the vasopressin receptor antagonist have been introduced to attenuate cyst growth and renal function decline for ADPKD patients [ 3 ]. Since renal function remains stable in the early stage of ADPKD and starts to decline only after cysts substitute normal renal tissues, identifying rapid progressors among ADPKD patients for whom novel drugs may be beneficial is useful [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Mayo imaging classification is a good predictor of rapid progress among Korean patients with autosomal dominant polycystic kidney disease: results from the KNOW-CKD study

Park

Hong

Yeon

et al. 2022

Kidney Res Clin Pract

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Background: Mayo imaging classification (MIC) is a useful biomarker to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study was performed to validate MIC in the prediction of renal outcome in a prospective Korean AD-PKD cohort and evaluate clinical parameters associated with rapid disease progression. Methods: A total of 178 ADPKD patients were enrolled and prospectively observed for an average duration of 6.2 ± 1.9 years. Rapid progressor was defined as MIC 1C through 1E while slow progressor was defined as 1A through 1B. Renal composite outcome (doubling of serum creatinine, 50% decline of estimated glomerular filtration rate [eGFR], or initiation of renal replacement therapy) as well as the annual percent change of height-adjusted total kidney volume (mHTKV-α), and eGFR decline (mGFR-α) were compared between groups. Results: A total of 110 patients (61.8%) were classified as rapid progressors. These patients were younger and showed a higher proportion of male patients. Rapid progressor was an independent predictor for renal outcome (hazard ratio, 4.09; 95% confidence interval, 1.23-13.54; p = 0.02). The mGFR-α was greater in rapid progressors (-3.58 mL/min per year in 1C, -3.7 in 1D, and -4.52 in 1E) compared with that in slow progressors (-1.54 in 1A and -2.06 in 1B). The mHTKV-α was faster in rapid progressors (5.3% per year in 1C, 9.4% in 1D, and 11.7% in 1E) compared with that in slow progressors (1.2% in 1A and 3.8% in 1B). Conclusion: MIC is a good predictive tool to define rapid progressors in Korean ADPKD patients.

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Section: Introductionmentioning

confidence: 99%

Mayo imaging classification is a good predictor of rapid progress among Korean patients with autosomal dominant polycystic kidney disease: results from the KNOW-CKD study

Park

Hong

Yeon

et al. 2022

Kidney Res Clin Pract

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“…However, two large-scale randomized clinical trials have failed to confirm the efficacy of this approach (20). Tolvaptan, a selective arginine vasopressin receptor 2 (AVPR2) antagonist that inhibits cAMP production in response to AVP, is presently the only drug approved for the treatment of ADPKD.…”

Section: Introductionmentioning

confidence: 99%

“…The interplay between mTOR activity and the primary cilium in this process has been extensively studied, and inhibition of mTOR activity is a potential therapeutic tactic for the treatment of ADPKD. However, 2 large-scale, randomized clinical trials have failed to confirm the efficacy of this approach ( 20 ). Tolvaptan, a selective arginine vasopressin receptor 2 (AVPR2) antagonist that inhibits cAMP production in response to AVP, is presently the only drug approved for the treatment of ADPKD.…”

Section: Introductionmentioning

confidence: 99%

SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis

Panda¹,

Xiu-juan²,

Zhang³

et al. 2022

Journal of Clinical Investigation

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The Hippo pathway nuclear effector Yes-associated protein 1 (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1) driven by ERK1/2 and PI3K/AKT cascades induced endoplasmic reticulum (ER) proteotoxic stress. To reduce it by reprogramming translation, the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF-S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α-phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress-ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan, impeded these processes. Restoring ER homeostasis, and/or interfering with the SKP2-YAP interaction represent novel potential therapeutic avenues for stemming the progression of renal cystogenesis.

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HL156A, an AMP-Activated Protein Kinase Activator, Inhibits Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Seo,

Kim,

Hwang

et al. 2024

Biomolecules

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Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder. While metformin has demonstrated the ability to inhibit cyst growth in animal models of ADPKD via activation of adenosine monophosphate-activated protein kinase (AMPK), its effectiveness in humans is limited due to its low potency. This study explored the impact of HL156A, a new and more potent AMPK activator, in a mouse model of ADPKD. Methods: To investigate whether HL156A inhibits the proliferation of renal cyst cells in ADPKD in vitro, exogenous human telomerase reverse transcriptase (hTERT)-immortalized renal cyst cells from ADPKD patients were treated with HL156A, and an MTT (dimethylthiazol-diphenyltetrazolium bromide) assay was performed. To assess the cyst-inhibitory effect of HL156A in vivo, we generated Pkd1 conditional knockout (KO) mice with aquaporin 2 (AQP2)-Cre, which selectively expresses Cre recombinase in the collecting duct. The effectiveness of HL156A in inhibiting cyst growth and improving renal function was confirmed by measuring the number of cysts and blood urea nitrogen (BUN) levels in the collecting duct-specific Pkd1 KO mice. Results: When cyst cells were treated with up to 20 µM of metformin or HL156A, HL156A reduced cell viability by 25% starting at a concentration of 5 µM, whereas metformin showed no effect. When AQP2-Cre male mice were crossed with Pkd1flox/flox female mice, and when AQP2-Cre female mice were crossed with Pkd1flox/flox male mice, the number of litters produced by both groups was comparable. In collecting duct-specific Pkd1 KO mice, HL156A was found to inhibit cyst growth, reducing both the number and size of cysts. Furthermore, it was confirmed that kidney function improved as HL156A treatment led to a reduction in elevated BUN levels. Lastly, it was observed that the increase in AMPK phosphorylation induced by HL156A decreased ERK phosphorylation and α-SMA expression. Conclusion: HL156A has potential as a drug that can restore kidney function in ADPKD patients by inhibiting cyst growth.

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Clinical Trials and a View Toward the Future of ADPKD

Cited by 3 publications

References 74 publications

Mayo imaging classification is a good predictor of rapid progress among Korean patients with autosomal dominant polycystic kidney disease: results from the KNOW-CKD study

Mayo imaging classification is a good predictor of rapid progress among Korean patients with autosomal dominant polycystic kidney disease: results from the KNOW-CKD study

SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis

HL156A, an AMP-Activated Protein Kinase Activator, Inhibits Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

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