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Nephron overload as a therapeutic target to maximize kidney lifespan

Abstract

Kidney lifespan is a patient-oriented outcome that provides much needed context for understanding chronic kidney disease (CKD). Nephron endowment, age-associated decline in nephron number, kidney injury history and the intrinsic capacity of nephrons to adapt to haemodynamic and metabolic overload vary widely within the population. Defining percentiles of kidney function might therefore help to predict individual kidney lifespan and distinguish healthy ageing from progressive forms of CKD. In response to nephron loss, the remaining nephrons undergo functional and structural adaptations to meet the ongoing haemodynamic and metabolic demands of the organism. When these changes are no longer sufficient to maintain kidney cell homeostasis, remnant nephron demise occurs and CKD progression ensues. An individual’s trajectory of glomerular filtration rate and albuminuria reflects the extent of nephron loss and adaptation of the remaining nephrons. Nephron overload represents the final common pathway of CKD progression and is largely independent of upstream disease mechanisms. Thus, interventions that efficiently attenuate nephron overload in early disease stages can protect remnant kidney cells and nephrons, and delay CKD progression. This Review provides a conceptual framework for individualized diagnosis, monitoring and treatment of CKD with the goal of maximizing kidney lifespan.

Key points

  • The current chronic kidney disease (CKD) classification is useful from the perspective of epidemiology, public health care and advocacy. Kidney lifespan is a more individualized, patient-oriented outcome that takes into account linear and non-linear declines in estimated glomerular filtration rate (eGFR) for the prediction of individual prognoses.

  • Population percentiles of eGFR acknowledge its age-specific spectrum and, along with individualized eGFR slopes, could help distinguish between healthy kidney ageing and progressive CKD. Percentiles are population-specific and should help identify patients at risk of CKD, as well as improve patient prognosis and management.

  • Adaptation to haemodynamic and metabolic overload is observed in the remaining nephrons in CKD but not in physiological kidney ageing. Adaptation is first evidenced by nephron hypertrophy and later by albuminuria.

  • Haemodynamic stress promotes podocyte loss directly and metabolic stress is a key driver of loss of tubular epithelial cells. Both types of stress can lead to secondary focal segmental glomerulosclerosis, tubular atrophy and interstitial fibrosis.

  • Progressive nephron loss reduces kidney lifespan. Dual blockade of the renin–angiotensin–aldosterone system and of sodium–glucose co-transporter 2 is very potent in both alleviating mechanisms of stress and prolonging kidney lifespan, and hence CKD has become a treatable disease.

  • Prolonging kidney lifespan with novel combination therapies is effective in patients with glomerular forms of CKD. Broad implementation of this approach requires effort at all levels, including improving our ability to assess and predict individual kidney lifespan, implementing remnant nephron overload as a pathophysiological concept and a treatment target, and raising awareness that CKD is a treatable disease.

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Fig. 1: Gaussian distribution of nephron number and GFR percentiles.
Fig. 2: Adaptations to nephron overload and CKD progression.
Fig. 3: Structural adaptations of nephrons.
Fig. 4: Modulation of haemodynamic and metabolic overload, and its effect on kidney lifespan.
Fig. 5: Pathophysiological mechanisms and treatment targets in glomerular versus tubular forms of CKD.

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Acknowledgements

K.R.T. is supported by four NIDDK/NIH grants, one NCATS/NIH grant, one NIMHD/NIH grant, and a CDC contract all from the US Government, as well as research grants from Goldfinch Bio, Bayer and Travere. A.D.R. is supported by funding from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK090358). H.-J.A. is supported by the Deutsche Forschungsgemeinschaft (AN372/30-1).

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All authors researched data for the article, made substantial contributions to discussions of the content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Hans-Joachim Anders.

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P.D. has received consultancy fees from Bayer and AstraZeneca. K.R.T. has received consulting fees for diabetes and CKD from Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca, Gilead, Goldfinch Bio, Novo Nordisk and Bayer. A.G. has received consulting and lecture fees from Fresenius Medical Care. H.-J.A. has received consultancy fees from Bayer, Janssen, GSK, Novartis, Boehringer, AstraZeneca and PreviPharma. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks M. Canney, A. Levin, R. Liu, P. Rossing, J. Wei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Luyckx, V.A., Rule, A.D., Tuttle, K.R. et al. Nephron overload as a therapeutic target to maximize kidney lifespan. Nat Rev Nephrol 18, 171–183 (2022). https://doi.org/10.1038/s41581-021-00510-7

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