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Targeting the progression of chronic kidney disease

Nature Reviews Nephrology volume 16, pages 269–288 (2020)Cite this article

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Abstract

Chronic kidney disease (CKD) is a devastating condition that is reaching epidemic levels owing to the increasing prevalence of diabetes mellitus, hypertension and obesity, as well as ageing of the population. Regardless of the underlying aetiology, CKD is slowly progressive and leads to irreversible nephron loss, end-stage renal disease and/or premature death. Factors that contribute to CKD progression include parenchymal cell loss, chronic inflammation, fibrosis and reduced regenerative capacity of the kidney. Current therapies have limited effectiveness and only delay disease progression, underscoring the need to develop novel therapeutic approaches to either stop or reverse progression. Preclinical studies have identified several approaches that reduce fibrosis in experimental models, including targeting cytokines, transcription factors, developmental and signalling pathways and epigenetic modulators, particularly microRNAs. Some of these nephroprotective strategies are now being tested in clinical trials. Lessons learned from the failure of clinical studies of transforming growth factor β1 (TGFβ1) blockade underscore the need for alternative approaches to CKD therapy, as strategies that target a single pathogenic process may result in unexpected negative effects on simultaneously occurring processes. Additional promising avenues include preventing tubular cell injury and anti-fibrotic therapies that target activated myofibroblasts, the main collagen-producing cells.

Key points

  • Current therapies for chronic kidney disease (CKD) target multiple pathogenic pathways, but only retard disease progression; an improved understanding of CKD pathogenesis is needed to optimize treatment.

  • In experimental models, partial epithelial–mesenchymal transition contributes to renal fibrosis through epithelial G2/M cell cycle arrest and induction of a senescence-related phenotype; these processes are potential therapeutic targets.

  • Strategies that target activated myofibroblasts (the main collagen-producing cells) or enzymes that are involved in collagen degradation could potentially improve or even reverse renal fibrosis.

  • Kidney injury results in the reactivation of developmental pathways that contribute to CKD progression; these pathways represent additional therapeutic avenues.

  • Growth factors such as PDGF, CTGF and Gremlin promote both inflammation and fibrosis in kidney disease; these factors constitute targets for CKD.

  • Epigenetic modulators are exploitable mechanisms to prevent or reduce kidney damage; microRNA therapies and BET inhibitors are renoprotective in preclinical models and are now undergoing clinical trials with CKD end points.

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Fig. 1: Potential role of AngII in the development of kidney fibrosis.
Fig. 2: Tubular cell injury in AKI, AKI-to-CKD transition and CKD progression.
Fig. 3: Glomerular injury and fibrosis.

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Acknowledgements

The authors’ work was supported by Grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI17/00119, PI16/02057, and Red de Investigación Renal REDINREN: RD16/0009), the Ministerio de Economía y Competitividad (MINECO) SAF2015-66107-R, Comunidad de Madrid “NOVELREN” B2017/BMD3751, CIFRA2-CM B2017/BMD-3686, Sociedad Española de Nefrologia, and Fundación Renal “Iñigo Alvarez de Toledo”, all from Spain. The CBMSO receives institutional support from Fundación “Ramón Areces”. The “Juan de la Cierva de Formacion” training programme (FJCI-2016-29050; salary of SR-M) and the Jose Castillejo mobility funding programme (CAS18/00318, CAS19/00133, salary of SR-M and R.R.R-D) of the Ministerio de Ciencia, Innovacion y Universidades, Spain. We thank Verónica Miguel (CBMSO), and Macarena Orejudo and Laura Marquez-Exposito (both UAM) for help with literature searches and comments on the text before submission.

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Authors and Affiliations

  1. Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain

    Marta Ruiz-Ortega & Raul R. Rodrigues-Diez

  2. Red de Investigación Renal (REDINREN), Madrid, Spain

    Marta Ruiz-Ortega, Sandra Rayego-Mateos, Santiago Lamas, Alberto Ortiz & Raul R. Rodrigues-Diez

  3. Vascular and Renal Translational Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Madrid, Spain

    Sandra Rayego-Mateos

  4. Centro de Biología Molecular “Severo Ochoa”, Madrid, Spain

    Santiago Lamas

  5. Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Madrid, Spain

    Alberto Ortiz

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All authors researched the data, contributed to discussions of the content, wrote the text and reviewed or edited the article before submission.

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Glossary

Necroptosis

A programmed form of necrosis or inflammatory cell death.

Ferroptosis

A type of programmed cell death that is dependent on iron and characterized by the accumulation of lipid peroxides.

Senescence-associated secretory phenotype

A phenotype that enables senescent cells to release a distinct secretome consisting of profibrotic and pro-inflammatory factors.

MicroRNAs

(miRNAs). Small non-coding RNAs that repress the translation and/or induce the degradation of their mRNA targets.

Bromodomain and extra-terminal domain family proteins

(BET). ‘Reader’ proteins that recognize and bind to the acetylated lysine in histones and other proteins.

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Ruiz-Ortega, M., Rayego-Mateos, S., Lamas, S. et al. Targeting the progression of chronic kidney disease. Nat Rev Nephrol 16, 269–288 (2020). https://doi.org/10.1038/s41581-019-0248-y

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