Novel Treatments of Autosomal Dominant Polycystic Kidney Disease

Mahnensmith, Rex L.

doi:10.2215/cjn.02480314

Cited by 10 publications

(4 citation statements)

References 44 publications

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“…Specific therapies targeted to prevent or delay progression of polycystic kidney disease are under investigation. Novel therapies with strong molecular rationales have entered into preclinical and/or clinical trials as potentially modifying ADPKD: vasopressin‐receptor inhibitors, mammalian target of rapamycin inhibitors, somatostatin analogs, statins, and EGFR activity using tyrosine kinase inhibitors . EGFR activity inhibition reduces cyst formation in different animal models of polycystic kidney disease …”

Section: Discussionmentioning

confidence: 99%

“…Novel therapies with strong molecular rationales have entered into preclinical and/or clinical trials as potentially modifying ADPKD: vasopressin-receptor inhibitors, mammalian target of rapamycin inhibitors, somatostatin analogs, statins, and EGFR activity using tyrosine kinase inhibitors. 30,38,39 EGFR activity inhibition reduces cyst formation in different animal models of polycystic kidney disease. 34,[40][41][42][43] The nimotuzumab competitively inhibits the binding of the EGF ligand to the extracellular domain of the HER1 protein, leading to a further inhibition of the homodimerization or heterodimerization of this receptor and subsequent autophosphorylation of its tyrosine residues, the activation of the different ligandinduced signal transduction pathways (Ras-Raf-MEK-MAPKS cascade; PI3K) will be inhibited as well.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

Castro-Suárez

Rodríguez-Vera

Villegas

et al. 2019

The Journal of Clinical Pharma

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression and mislocalization of epidermal growth factor receptor (EGFR) to the apical membranes of cystic epithelial cells. Nimotuzumab is a humanized antibody that recognizes an extracellular domain III of human EGFR. The aim of this study was to assess the pharmacokinetic behavior of nimotuzumab in patients with ADPKD given as a single dose. A phase I, single‐center, and noncontrolled open clinical study was conducted. Five patients were enrolled at each of the following fixed‐dose levels: 50, 100, 200, and 400 mg. Intravenous continuous infusions of nimotuzumab were administered every 14 days during a year, except the first administration, when blood samples were drawn during 28 days for pharmacokinetic assessments. Subjects were closely monitored during the trial and at completion of the administration of nimotuzumab, including the anti‐idiotypic response. For the first time, nimotuzumab was used for treating a nononcological disease. The administration of nimotuzumab showed dose‐dependent kinetics. Nimotuzumab does not develop anti‐idiotypic response against the murine portion present in the hypervariable region of the antibody present in the serum of the patients treated. No significant differences were found in the systemic clearance between the 100‐ and 400‐mg dose, which indicates that the optimal biological dose is in this range of dose.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

Castro-Suárez

Rodríguez-Vera

Villegas

et al. 2019

The Journal of Clinical Pharma

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“…Thus, there is a critical need for safe, inexpensive treatments that can delay the progression of cyst enlargement and the accompanying destruction of the renal parenchyma that can lead to renal failure. Several drugs, such as the V2 receptor agonist tolvaptan as well as immunosuppressive and chemotherapeutic agents, have entered or, in the case of tolvaptan, completed clinical trials [22][23][24] . However, these drugs have side effects that may limit patient compliance as well as safety of long-term use.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptor γ agonists

Flaig

Gattone

Blazer‐Yost

2016

Journal of Translational Internal Medicine

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Background and Objectives:The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD). Materials and Methods: The PCK rat is a slowly progressing cystic model while the Wpk -/-rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4-28). Wpk -/-rats were fed with pharmacological (2.0 mg/kg BW) and sub-pharmacologic (0.2 mg/kg BW) doses of pioglitazone from day 5 to 18. At termination, kidney weights of treated versus untreated cystic animals were used to determine efficacy. The current studies were also compared with previous studies containing higher doses of PPARγ agonists. The concentrations used in the animals were calculated with reference to equivalent human doses for both drugs. Results:The current studies demonstrate: 1) that low, pharmacologically relevant, doses of the PPARγ agonists effectively inhibit cyst growth; 2) there is a class action of the drugs with both commercially available PPARγ agonists, rosiglitazone, and pioglitazone, inhibiting cyst growth; 3) the drugs showed efficacy in two different preclinical cystic models. In the PCK rat, animals fed with a sub-pharmacological dose of rosiglitazone for 24 weeks had significantly lower kidney weights than untreated animals (3.68 ± 0.13 g vs. 4.17 ± 0. 11 g, respectively, P < 0.01) while treatment with a pharmacologic dose had no significant effect on kidney weight. The rapidly progressing Wpk -/-rats were fed with pharmacological and sub-pharmacologic doses of pioglitazone from day 5 to 18 and the kidneys were compared with non-treated, cystic animals. Kidney weights on the pharmacologic dose were not statistically lower than the untreated animals while rats fed a sub-pharmacologic dose showed a significant decrease compared with untreated animals (3.35 ± 0.15 g vs. 4.55 ± 0.46 g, respectively, P = 0.045). Conclusion: Concentrations of PPARγ agonists below the human equivalent diabetic doses are effective in slowing cyst growth in two rodent models of PKD.

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“…Over time, these mechanisms are overwhelmed due to ongoing cyst growth causing compression, fibrosis and inflammation. This results in progressive renal impairment [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Patient Survey of current water Intake practices in autosomal dominant Polycystic kidney disease: the SIPs survey

El-Damanawi¹,

Harris²,

Sandford

et al. 2017

Clinical Kidney Journal

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Background: Autosomal dominant polycystic kidney disease (ADPKD) affects 12.5 million worldwide. Vasopressin drives cysts growth and in animal models can be suppressed through high water intake. A randomized controlled trial of ‘high’ versus ‘standard’ water intake in ADPKD is essential to determine if this intervention is beneficial. We conducted an ADPKD patient survey to gain an understanding of current fluid intake practices and the design challenges of a randomized water intake trial. Methods: In collaboration with the PKD Charity, we developed and distributed an online survey to ADPKD patients over age 16 years and not on renal replacement therapy. Results: Of the 2377 invited, 89 ADPKD patients completed the Survey of current water Intake practices in autosomal dominant Polycystic kidney disease (SIPs) online questionnaire. Most were female (65, 73%) and white (84, 94%), with a median age group of 45–49 years. The risk of contamination between treatment arms was highlighted by the survey as the majority (70, 79%) routinely discussed ADPKD management with family despite only 17% sharing the same household. More participants reported drinking beyond thirst (65, 73%) than those actually indicating a daily fluid intake of >2 L (54, 61%). This discrepancy emphasizes inaccuracies of fluid intake estimates and the requirement for objective methods of measuring water intake. Overall, only 51% believed high water intake was beneficial, while 91% were willing to participate in research evaluating this. Conclusion: ADPKD poses unique design challenges to a randomized water intake trial. However, the trial is likely to be supported by the ADPKD community and could impact significantly on PKD management and associated healthcare costs.

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Novel Treatments of Autosomal Dominant Polycystic Kidney Disease

Cited by 10 publications

References 44 publications

Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptor γ agonists

Patient Survey of current water Intake practices in autosomal dominant Polycystic kidney disease: the SIPs survey

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