Preclinical and clinical trials for identifying treatments for polycystic kidney disease

2013 ◽  
pp. 176-186
Author(s):  
Vincent H Gattone ◽  
Robert L Bacallao
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Polycystic Kidney

scholarly journals An Empirical Biomarker-based Calculator for Autosomal Recessive Polycystic Kidney Disease The Nieto-Narayan Formula

2016 ◽  
Author(s):  
Jake A Nieto ◽  
Michael A Yamin ◽  
Itzhak D. Goldberg ◽  
Prakash Narayan
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Imaging Modality ◽  
Pediatric Population ◽  
Polycystic Kidney ◽  
Drug Candidates ◽  
Serial Determination ◽  
Stage Renal Disease

Autosomal polycystic kidney disease (ARPKD) is associated with progressive enlargement of the kidneys fuelled by the formation and expansion of fluid-filled cysts. The disease is congenital and children that do not succumb to it during the neonatal period will, by age 10 years, more often than not, require nephrectomy+renal replacement therapy for management of both pain and renal insufficiency. Since increasing cystic index (CI; percent of kidney occupied by cysts) drives both renal expansion and organ dysfunction, management of these patients, including decisions such as elective nephrectomy and prioritization on the transplant waitlist, could clearly benefit from serial determination of CI. So also, clinical trials in ARPKD evaluating efficacy of novel drug candidates could benefit from serial determination of CI. Although ultrasound is currently the imaging modality of choice for diagnosis of ARPKD, its utilization for assessing disease progression is highly limited. Magnetic resonance imaging or computed tomography, although more reliable for determination of CI, are expensive, time-consuming and somewhat impractical in the pediatric population. Using a well-established mammalian model of ARPKD, we undertook a big data-like analysis of minimally- or non-invasive serum and urine biomarkers of renal injury/dysfunction to derive a family of equations for estimating CI. We then applied a signal averaging protocol to distil these equations to a single empirical formula for calculation of CI. Such a formula will eventually find use in identifying and monitoring patients at high risk for progressing to end-stage renal disease and aid in the conduct of clinical trials.

scholarly journals Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

2020 ◽  
Vol 15 (4) ◽  
pp. 577-584 ◽  
Author(s):  
Kristen L. Nowak ◽  
Katharina Hopp
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Intermittent Fasting ◽  
Metabolic Demand ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease is characterized by progressive development and enlargement of kidney cysts, leading to ESKD. Because the kidneys are under high metabolic demand, it is not surprising that mounting evidence suggests that a metabolic defect exists in in vitro and animal models of autosomal dominant polycystic kidney disease, which likely contributes to cystic epithelial proliferation and subsequent cyst growth. Alterations include defective glucose metabolism (reprogramming to favor aerobic glycolysis), dysregulated lipid and amino acid metabolism, impaired autophagy, and mitochondrial dysfunction. Limited evidence supports that cellular kidney metabolism is also dysregulated in humans with autosomal dominant polycystic kidney disease. There are notable overlapping features and pathways among metabolism, obesity, and/or autosomal dominant polycystic kidney disease. Both dietary and pharmacologic-based strategies targeting metabolic abnormalities are being considered as therapies to slow autosomal dominant polycystic kidney disease progression and are attractive, particularly given the slowly progressive nature of the disease. Dietary strategies include daily caloric restriction, intermittent fasting, time-restricted feeding, a ketogenic diet, and 2-deoxy-glucose as well as alterations to nutrient availability. Pharmacologic-based strategies include AMP-activated kinase activators, sodium glucose cotransporter-2 inhibitors, niacinamide, and thiazolidenediones. The results from initial clinical trials targeting metabolism are upcoming and anxiously awaited within the scientific and polycystic kidney disease communities. There continues to be a need for additional mechanistic studies to better understand the role of dysregulated metabolism in autosomal dominant polycystic kidney disease and for subsequent translation to clinical trials. Beyond single-intervention trials focused on metabolic reprograming in autosomal dominant polycystic kidney disease, great potential also exists by combining metabolic-focused therapeutic approaches with compounds targeting other signaling cascades altered in autosomal dominant polycystic kidney disease, such as tolvaptan.

scholarly journals The cellular pathways and potential therapeutics of Polycystic Kidney Disease

2021 ◽  
Author(s):  
Taylor Richards ◽  
Kavindiya Modarage ◽  
Soniya A. Malik ◽  
Paraskevi Goggolidou
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cellular Proliferation ◽  
Cyst Formation ◽  
Great Promise ◽  
Polycystic Kidney ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Stage Renal Disease

Polycystic Kidney Disease (PKD) refers to a group of disorders, driven by the formation of cysts in renal tubular cells and is currently one of the leading causes of end-stage renal disease. The range of symptoms observed in PKD is due to mutations in cilia-localising genes, resulting in changes in cellular signalling. As such, compounds that are currently in preclinical and clinical trials target some of these signalling pathways that are dysregulated in PKD. In this review, we highlight these pathways including cAMP, EGF and AMPK signalling and drugs that target them and may show promise in lessening the disease burden of PKD patients. At present, tolvaptan is the only approved therapy for ADPKD, however, it carries several adverse side effects whilst comparatively, no pharmacological drug is approved for ARPKD treatment. Aside from this, drugs that have been the subject of multiple clinical trials such as metformin, which targets AMPK signalling and somatostatins, which target cAMP signalling have shown great promise in reducing cyst formation and cellular proliferation. This review also discusses other potential and novel targets that can be used for future interventions, such as β-catenin and TAZ, where research has shown that a reduction in the overexpression of these signalling components results in amelioration of disease phenotype. Thus, it becomes apparent that well-designed preclinical investigations and future clinical trials into these pathways and other potential signalling targets are crucial in bettering disease prognosis for PKD patients and could lead to personalised therapy approaches.

Clinical Trials in Autosomal Dominant Polycystic Kidney Disease

2015 ◽  
pp. 109-135 ◽  
Author(s):  
Alan S.L. Yu ◽  
◽  
Mireille El-Ters ◽  
Franz T. Winklhofer ◽  
◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney
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