Weight loss and cystic disease progression in autosomal dominant polycystic kidney disease

Hopp, Katharina; Catenacci, Victoria A.; Dwivedi, Nidhi; Kline, Timothy L.; Wang, Wei; You, Zhiying; Nguyen, Diemmy; Bing, Kristen; Poudyal, Bhavya; Johnson, Ginger C.; Jackman, Matthew R.; Miller, Marsha; Steele, Cortney N.; Serkova, Natalie J.; MacLean, Paul S.; Nemenoff, Raphael A.; Gitomer, Berenice; Chonchol, Michel; Nowak, Kristen L.

doi:10.1016/j.isci.2021.103697

Cited by 24 publications

(31 citation statements)

References 53 publications

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“…Mice, mimicking this human mutation, are viable for at least 1 year as homozygotes and have slow progression of PKD. Due to a panel of traits close to human ADPKD (late onset, sex differences, high blood urea nitrogen (BUN), and predominant (~70%) development of cysts in the collecting ducts (CD) of mature mice, this hypomorphic model of ADPKD is widely used in preclinical studies (Hopp, Catenacci, et al, 2022; Hopp et al, 2015; Hopp, Kleczko, et al, 2022; Jamadar et al, 2021; Pastor‐Soler et al, 2022). Our studies provide the first evidence that pannexin‐1 is a specific target in the epithelium of human cysts and aim to show how probenecid inhibits cyst formation in vivo.…”

Section: Introductionmentioning

confidence: 99%

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease

Arkhipov

Potter²,

Sultanova

et al. 2023

Physiological Reports

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Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder leading to the development of multiple cysts along the nephron. Over the years, cysts grow and replace normal functional tissues, causing an increase in kidney size, tissue damage, and renal insufficiency. The majority of ADPKD cases is caused by mutations in PKD1 (in 78% of disease pedigrees) or PKD2 (in 15% of disease pedigrees). Genetic analyses report that the

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Section: Introductionmentioning

confidence: 99%

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease

Arkhipov

Potter²,

Sultanova

et al. 2023

Physiological Reports

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“…It has been suggested that these improvements involve mTOR signaling inhibition, AMPK activation, and a reduction in IGF-I supporting restoration of metabolic reprogramming. Accordingly, a clinical trial evaluating the effect of weekly caloric reduction achieved with either caloric restriction or intermittent fasting in 29 overweight/obese individuals with ADPKD was recently completed ( Hopp et al, 2021 ; https://clinicaltrials.gov/ct2/show/NCT03342742 ). The trial was designed as a weight loss intervention based on the prior epidemiological observation that ADPKD progression is faster with higher BMI ( Nowak et al, 2018 ).…”

Section: Cholesterol Reducing Agentsmentioning

confidence: 99%

“…The investigators demonstrated the feasibility of 1-year daily caloric restriction (DCR) and intermittent fasting (IMF) in a cohort of overweight or obese patients with ADPKD. Weight loss occurred with both DCR and IMF, however, weight loss was greater, and adherence and tolerability were better with caloric restriction ( Hopp et al, 2021 ). The study was a pilot and feasibility study, so the sample size was small, and a control group was not included but, according to the investigators, similar annual kidney growth in both groups was observed that was qualitatively low compared to historical controls.…”

Section: Cholesterol Reducing Agentsmentioning

confidence: 99%

Metabolism-based approaches for autosomal dominant polycystic kidney disease

Bakaj

Pocai²

2023

Front. Mol. Biosci.

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end stage kidney disease (ESKD) through the development and expansion of multiple cysts throughout the kidney parenchyma. An increase in cyclic adenosine monophosphate (cAMP) plays an important role in generating and maintaining fluid-filled cysts because cAMP activates protein kinase A (PKA) and stimulates epithelial chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). A vasopressin V2 receptor antagonist, Tolvaptan, was recently approved for the treatment of ADPKD patients at high risk of progression. However additional treatments are urgently needed due to the poor tolerability, the unfavorable safety profile, and the high cost of Tolvaptan. In ADPKD kidneys, alterations of multiple metabolic pathways termed metabolic reprogramming has been consistently reported to support the growth of rapidly proliferating cystic cells. Published data suggest that upregulated mTOR and c-Myc repress oxidative metabolism while enhancing glycolytic flux and lactic acid production. mTOR and c-Myc are activated by PKA/MEK/ERK signaling so it is possible that cAMPK/PKA signaling will be upstream regulators of metabolic reprogramming. Novel therapeutics opportunities targeting metabolic reprogramming may avoid or minimize the side effects that are dose limiting in the clinic and improve on the efficacy observed in human ADPKD with Tolvaptan.

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“…[6][7][8] Ketogenic dietary interventions (e.g., caloric restriction, intermittent fasting, and classic ketogenic diet) can activate AMPK pathways, improve cellular metabolism, and reduce cyst growth in preclinical models. [9][10][11][12] This section summarizes the rationale, benefits, and safety concerns of these interventions for ADPKD.…”

Section: Metabolic Reprogramming and Rationale Of Dietary Interventio...mentioning

confidence: 99%

Polycystic Kidney Disease Diet

Chebib,

Nowak,

Chonchol

et al. 2023

CJASN

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary interventions such as caloric restriction, intermittent fasting, and the ketogenic diet have recently emerged as potential strategies to induce metabolic reprogramming and slow ADPKD progression. We review the available evidence supporting the efficacy and safety of these interventions in ADPKD. Dietary interventions show promise in managing ADPKD by improving metabolic health and reducing oxidative stress. However, while preclinical studies have shown favorable outcomes, limited clinical evidence supports their effectiveness. Also, the long-term consequences of these dietary interventions, including their impact on adverse events in ADPKD patients, remain uncertain. To optimize ADPKD management, patients are advised to follow a dietary regimen that aims to achieve or maintain an ideal weight and includes high fluid intake, low sodium, and limited concentrated sweets. Caloric restriction appears particularly beneficial for individuals with overweight or obesity as it promotes weight loss and improves metabolic parameters. Supplementation with curcumin, ginkgolide B, saponins, vitamin E, niacinamide, or triptolide has demonstrated uncertain clinical benefit in ADPKD patients. Notably, beta-hydroxybutyrate (BHB) supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials. Therefore, the use of these supplements is not currently recommended for ADPKD patients. In summary, dietary interventions such as caloric restriction, intermittent fasting, and the ketogenic diet hold promise in ADPKD management by enhancing metabolic health. However, extensive clinical research is necessary to establish their effectiveness and long-term impacts. Adhering to personalized dietary guidelines, including weight management and specific nutritional restrictions, can contribute to optimal ADPKD management. Future research should prioritize well-designed clinical trials to determine the benefits and safety of dietary interventions and supplementation in ADPKD.

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Weight loss and cystic disease progression in autosomal dominant polycystic kidney disease

Cited by 24 publications

References 53 publications

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease

Metabolism-based approaches for autosomal dominant polycystic kidney disease

Polycystic Kidney Disease Diet

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