Novel Treatments for Polycystic Kidney Disease

Patil, Ameya; Sweeney, William E.; Pan, Cynthia G.; Avner, Ellis D.

doi:10.3233/trd-190040

Cited by 2 publications

(3 citation statements)

References 79 publications

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“…There are multiple pathways and signaling molecules that cause phenotypic changes in renal epithelial cells, which ultimately lead to cyst formation. How malfunctioning PKD proteins affect these pathways is not yet fully understood [ 6 ]. For the implementation of novel treatment targets and strategies to preserve renal function in patients suffering from ADPKD, it is crucial to identify the cellular mechanisms and understand the pathophysiological cascade involved in the formation and growth of renal cysts in ADPKD.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, there is a broad consensus regarding the important roles that fluid secretion and cell proliferation play in the multidimensional cyst development and enlargement process [ 6 , 9 ]. Enhanced fluid secretion is supposed to be mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), which facilitates cAMP-stimulated chloride secretion in ADPKD cysts [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Enhanced fluid secretion is supposed to be mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), which facilitates cAMP-stimulated chloride secretion in ADPKD cysts [ 10 , 11 ]. The involvement of CFTR in the progression of ADPKD is supported by the increased intracellular cAMP levels in ADPKD cysts that have been identified as a common pathogenic mechanism of the disease [ 6 ]. The only medication that has been approved for the treatment of ADPKD so far is tolvaptan ® , a vasopressin V 2 receptor antagonist which targets the antidiuretic hormone arginine vasopressin (AVP)-stimulated cAMP production.…”

Section: Introductionmentioning

confidence: 99%

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A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices

Bichlmayer

Mahl

Hesse

et al. 2022

Cells

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(1) Background: Autosomal dominant polycystic kidney disease (ADPKD) is a frequent monogenic disorder that leads to progressive renal cyst growth and renal failure. Strategies to inhibit cyst growth in non-human cyst models have often failed in clinical trials. There is a significant need for models that enable studies of human cyst growth and drug trials. (2) Methods: Renal tissue from ADPKD patients who received a nephrectomy as well as adult mouse kidney slices were cultured on a chorioallantoic membrane (CAM) for one week. The cyst volume was monitored by microscopic and CT-based applications. The weight and angiogenesis were quantified. Morphometric and histological analyses were performed after the removal of the tissues from the CAM. (3) Results: The mouse and human renal tissue mostly remained vital for about one week on the CAM. The growth of cystic tissue was evaluated using microscopic and CT-based volume measurements, which correlated with weight and an increase in angiogenesis, and was accompanied by cyst cell proliferation. (4) Conclusions: The CAM model might bridge the gap between animal studies and clinical trials of human cyst growth, and provide a drug-testing platform for the inhibition of cyst enlargement. Real-time analyses of mouse kidney tissue may provide insights into renal physiology and reduce the need for animal experiments.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices

Bichlmayer

Mahl

Hesse

et al. 2022

Cells

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Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease

Castro-Suárez

Trame²,

Ramos-Suzarte

et al. 2020

Pharmaceutics

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM®. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas.

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Novel Treatments for Polycystic Kidney Disease

Cited by 2 publications

References 79 publications

A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices

A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices

Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease

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