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Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

Key Points

  • Biomimetic studies of non-laboratory wild animals are useful for identifying mechanisms that protect or increase susceptibility to disease

  • Domestic and captive felids are vulnerable to chronic kidney disease (CKD), supporting the hypothesis that high protein intake — particularly from red meats and in combination with dehydration — is nephrotoxic

  • Extreme models of ageing, such as Hutchinson–Gilford progeria syndrome and the naked mole rat, can be used to investigate the mechanisms of vascular progeric processes in CKD

  • Current evidence suggests that elevated serum phosphate levels promote ageing and cellular senescence

  • The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) may offer protection against diseases in extreme environmental conditions and may promote longevity in the animal kingdom; NRF2 agonists (such as resveratrol and sulforaphane) might improve the uraemic complications of CKD

  • Lipid composition of membranes has a role in seasonal acclimatization of metabolic activities in the animal kingdom

  • Hibernating wild bears with anuria are protected against many of the complications observed in humans with CKD, such as muscle wasting, osteoporosis and azotaemia; future studies should investigate the mechanisms behind these protective effects

Abstract

Many of the >2 million animal species that inhabit Earth have developed survival mechanisms that aid in the prevention of obesity, kidney disease, starvation, dehydration and vascular ageing; however, some animals remain susceptible to these complications. Domestic and captive wild felids, for example, show susceptibility to chronic kidney disease (CKD), potentially linked to the high protein intake of these animals. By contrast, naked mole rats are a model of longevity and are protected from extreme environmental conditions through mechanisms that provide resistance to oxidative stress. Biomimetic studies suggest that the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) offers protection in extreme environmental conditions and promotes longevity in the animal kingdom. Similarly, during months of fasting, immobilization and anuria, hibernating bears are protected from muscle wasting, azotaemia, thrombotic complications, organ damage and osteoporosis — features that are often associated with CKD. Improved understanding of the susceptibility and protective mechanisms of these animals and others could provide insights into novel strategies to prevent and treat several human diseases, such as CKD and ageing-associated complications. An integrated collaboration between nephrologists and experts from other fields, such as veterinarians, zoologists, biologists, anthropologists and ecologists, could introduce a novel approach for improving human health and help nephrologists to find novel treatment strategies for CKD.

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Figure 1: Novel insight into treatment strategies of CKD from studies of wild animals.
Figure 2: Effect of red meat intake on kidney functions.
Figure 3: Extreme models of ageing with a marked discrepancy between chronological and biological age can be used to learn more about progeric processes in CKD.
Figure 4: The role of phosphate in ageing.
Figure 5: Strategies to increase lifespan, protect organs and avoid renal ischaemia–reperfusion injury.
Figure 6: Nitrogen metabolism in hibernating bears.

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Acknowledgements

The authors thank the Scandinavian Brown Bear Project (in particular, O. Fröbert, J. E. Swenson, S. Brunberg, J. M. Arnemo and A. Zedrosser). P.S.'s research benefits from support from the Swedish Medical Research Council, the Heart and Lung Foundation, Njurfonden and EU-funded INTRICARE projects. R.J.J. and M.L. benefit from research support from the Veterans Administration (BX002586), Department of Defense (PR130106), US National Institutes of Health (NIH) (DK108859 and DK109408), La Isla Foundation, Solidaridad and the Danone Research Foundation. M.K. is supported by the Japan Agency for Medical Research and Development (AMED) Core Research for Evolutionary Medical Science and Technology (CREST), AMED, and the Japan Society for the Promotion of Science (16H05302, 16K15470). W.A.'s research has benefited from the grant 'Polyunsaturated fatty acids and seasonal acclimatization' (30061-B25).

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Contributions

P.S. and R.J.J. launched the idea of studying renal biomimetics. P.S., J.P., M.K., M.L., W.A., T.R., P.G.S. and R.J.J. researched the literature, discussed the content of the article and wrote the text. All authors reviewed or edited the article before submission.

Corresponding author

Correspondence to Peter Stenvinkel.

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Competing interests

P. S. received grants and honoraria from Baxter, Bayer, Astra Zeneca, Bristol-Myers Squibb, Pfizer, Akeiba and Corvidia. M.K. has received grants and honoraria from Bayer, Astellas, Bristol-Myers Squibb and Kissei Pharmaceuticals. R.J.J. has grants from the US National Institutes of Health (NIH), Department of Defense and the Veteran's Administration. He is also a member of Colorado Research Partners, LLC, which is developing inhibitors of fructose metabolism. The other authors declare no competing interests.

Supplementary information

Supplementary information tables

Supplementary information S1–S5 (table) (PDF 409 kb)

PowerPoint slides

Glossary

Uraemic phenotype

Phenotype that includes several physical characteristics, such as vascular stiffness, sarcopenia, frailty, osteoporosis and left ventricular hypertrophy.

Chronic tubulointerstitial fibrosis

Diseases that affect the physiology of non-glomerular structures (tubules and/or the interstitium) in the kidney.

Glomerular haemodynamics

The regulation of efferent and afferent glomerular arteriolar resistance required to maintain a stable glomerular filtration rate.

Urinary specific gravity

Test that compares the density of urine to that of water.

N-Nitroso compounds

Compounds found in processed meat that are formed endogenously from the intake of nitrite and nitrate.

Nutrigenomic compounds

Bioactive nutrients that have an effect on or interact with the genome. Nutrigenomics also encompasses the effect of genetic variations on the absorption, metabolism, elimination or biological effects of various nutrients.

Telomere attrition

Telomeres are the protective endcaps of chromosomes. Attrition, or shortening, of telomeres is a form of tumour suppression and may be due to inflammation and oxidative stress as well as exposure to infectious agents, resulting in limited stem cell function, regeneration and organ maintenance during ageing.

Uraemic milieu

Toxic internal milieu in patients with uraemia that is characterized by accumulation of uraemic toxins and waste products that promote inflammation, oxidative stress, carbonylation, calcification and endothelial dysfunction.

Senescent cells

Cellular senescence is an irreversible cell cycle arrest mechanism that acts to protect against cancer. Senescent cells also have a role in complex biological processes, such as development, tissue repair and age-related disorders.

Hypercapnia

Abnormally elevated carbon dioxide (CO2) levels in the blood.

High-molecular-weight hyaluronan

A high-molecular-weight polysaccharide found in the extracellular matrix, especially in soft connective tissues.

Antagonistic pleiotropy

Scenarios in which one gene contributes to multiple traits, whereby at least one of these traits is beneficial and at least one is detrimental to the organism's health.

Phosphate appetite

A well-documented behaviour in animals that is induced by phosphate deficiency, which is especially common among herbivores.

Protein–energy wasting

A process characterized by a decline in body protein mass and energy reserves, including muscle and fat wasting and loss of visceral proteins. Protein energy wasting is often associated with inflammation and is a strong predictor of mortality.

Caloric restriction

A reduction in calorie intake without incurring malnutrition or a reduction in essential nutrients. In a variety of species, such yeast, fish, rodents and dogs, calorie restriction has been shown to slow the biological ageing process.

Sirtuin

Sirtuins (or NAD+-dependent histone deacetylases) are a class of proteins that possess deacylase activity and regulate important biological pathways and cellular processes, including ageing, inflammation, transcription and apoptosis. Sirtuin agonists include pterostilbene and resveratrol.

Trans-sulfuration pathway

A metabolic pathway that involves the interconversion of homocysteine and cysteine via the intermediate cystathionine.

S-Sulfhydration

A post-translational modification that increases the catalytic activity of proteins. Physiological actions of sulfhydration include the regulation of endoplasmic reticulum stress signalling, inflammation and vascular tension.

One-carbon methyl donor units

DNA methylation influences the expression of some genes and depends upon the availability of methyl groups. Dietary methyl groups are derived from food sources that contain methionine, one-carbon units, choline or betaine (a choline metabolite).

Torpor

A state of reduced body temperature and metabolic rate in animals that enables them to survive periods of reduced food availability.

Circadian clock

The circadian clock regulates the internal and external activities of organisms, such as sleep and changes in metabolism, based on the day–night cycle.

Chronotherapy

The science of timing drugs according to the circadian clock. This approach is used in various clinical conditions, such as cancer, hypertension, seasonal affective disorder and bipolar disorder.

Renal lobulation

Carnivores and most small mammals have smooth-surfaced and uni-pyramidal kidneys, whereas primates and Suidae (hogs and pigs) have a smooth-surfaced and multi-pyramidal kidney system. Large terrestrial mammals have multi-lobulated and multi-pyramidal kidneys to keep the proximal convoluted tubules short. Most marine mammals and bears have each lobe separated into renules (reniculated kidney system).

Therapeutic hypothermia

(also known as targeted temperature management). The induction of mild hypothermia (32–35 °C) after cardiac arrest for neuroprotection.

Sedentary behaviour

A type of behaviour that is characterized by an energy expenditure ≤1.5 metabolic equivalents while in a lying, reclining or sitting posture. Typical sedentary behaviours include watching TV, computer work, driving and reading.

Denervation

Loss of nerve supply to a part of the body, which can be due to multiple causes, such as surgery, physical injury, chemical toxicity or diseases.

Disuse atrophy

A type of muscle atrophy that occurs when a muscle is less active than usual. Disuse atrophy is a common feature in chronic debilitating diseases and immobility.

Mechanical unloading

A mechanical manoeuvre or therapy that decreases tissue growth and regeneration. Whereas mechanical loading of mammalian tissues is a potent promoter of tissue growth and regeneration, mechanical unloading in microgravity causes reduced tissue regeneration via stem cell tissue progenitors.

Eucalcaemia

The maintenance of normal and constant serum calcium levels.

Blueberries

Blueberries comprise all blue-coloured berries of the Vaccinium genus, of which the most common is bilberries. Blueberries have a low glycaemic index and are a rich source of fibres, vitamin K, manganese, >15 different anthocyanins (especially delphinidin and malvidin), quercetin, myricetin and resveratrol.

Anthocyanins

Anthocyanins (>600 molecular structures) belong to a class of molecules called flavonoids that are universal plant colourants responsible for the red, purple and blue colours in many fruits, berries, vegetables and flowers. Due to their contribution in multiple physiological activities, the consumption of these molecules is believed to have a substantial role in preventing lifestyle-related diseases.

Senolytic effects

Senolytic compounds selectively induce the death of senescent cells.

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Stenvinkel, P., Painer, J., Kuro-o, M. et al. Novel treatment strategies for chronic kidney disease: insights from the animal kingdom. Nat Rev Nephrol 14, 265–284 (2018). https://doi.org/10.1038/nrneph.2017.169

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