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  • Review Article
  • Published:

The next generation of therapeutics for chronic kidney disease

Nature Reviews Drug Discovery volume 15, pages 568–588 (2016)Cite this article

Subjects

Key Points

  • Approximately 20 million people in the United States are currently affected by CKD, with half a million of these presenting with the most severe form: end-stage renal disease (ESRD). The only treatments for ESRD are dialysis or transplantation. The yearly mortality of patients on dialysis can be as high as 20%, and transplantation is limited by organ shortage.

  • Current treatment strategies are almost exclusively based on blocking the renin–angiotensin–aldosterone system. Inhibitors of this system decrease systemic blood pressure and glomerular hyperfiltration leading to subsequent reduction in proteinuria and prevention of functional decline.

  • Diabetic nephropathy remains the leading cause of CKD. Early metabolic dysregulation seems to be a key disease driver. Early targeting of metabolic pathways has shown therapeutic benefit in early-stage clinical trials.

  • Glomerular epithelial cells or podocytes are a key component of the glomerular filtration barrier that prevents albumin leakage into the urine. They are terminally differentiated with limited (if any) renewal capacity. Podocyte-targeted therapeutics could protect from albuminuria and glomerulosclerosis development.

  • Several drugs in current trials target inflammatory pathways, including specific cytokines (such as CC-chemokine ligand 2 (CCL2)) or signalling molecules (such as Janus kinase (JAK)). Such drugs might provide therapeutic benefit at later disease stages in which inflammation is a prominent feature of the disease.

  • Precision medicine approaches that are based on specific genetic or protein biomarkers have the potential to help the development of novel CKD therapeutics and enrich for patients that will respond to specific drugs.

Abstract

Chronic kidney disease (CKD) represents a leading cause of death in the United States. There is no cure for this disease, with current treatment strategies relying on blood pressure control through blockade of the renin–angiotensin system. Such approaches only delay the development of end-stage kidney disease and can be associated with serious side effects. Recent identification of several novel mechanisms contributing to CKD development — including vascular changes, loss of podocytes and renal epithelial cells, matrix deposition, inflammation and metabolic dysregulation — has revealed new potential therapeutic approaches for CKD. This Review assesses emerging strategies and agents for CKD treatment, highlighting the associated challenges in their clinical development.

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Figure 1: Targeting the renin–angiotensin–aldosterone system.
Figure 2: Targeting the glomerulus in the treatment of CKD.
Figure 3: Targeting tubulointerstitial fibrosis in the treatment of CKD.
Figure 4: Metabolic alterations in CKD.

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Acknowledgements

The work was supported by grants from the US National Institutes of Health (NIH) R01 DK076077, DK087635 DK105821 and DP3 108220 to K.S.

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Authors and Affiliations

  1. Biotechnology Discovery Research, Eli Lilly and Company, Indianapolis, 46285, Indiana, USA

    Matthew D. Breyer

  2. Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Katalin Susztak

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Correspondence to Katalin Susztak.

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M.D.B. is a full-time paid employee of Eli Lilly and Company. The laboratory of K.S. receives research support from Biogen, Boehringer Ingelheim and ONO Pharma.

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Glossary

Chronic kidney disease

A disease in which a gradually progressive decrease of greater than 40% decline in the kidney's filtering function or abnormal leakiness to plasma proteins (mostly albumin) is seen.

Polycystic kidney disease

A disease caused by mutations in PKD1 or PKD2 that result in excessive cyst accumulation and renal failure.

Fibrosis

The histological manifestation of chronic kidney disease: loss of epithelial cells and vascular supply as well as accumulation of inflammatory cells, matrix and myofibroblasts.

Podocytes

Terminally differentiated glomerular epithelial cells. Podocytes have a key role in maintaining the filtration barrier.

Diabetic kidney disease

A clinical diagnosis established based on the presence of proteinuria and decreased filtration in patients with diabetes. The most common cause of chronic kidney disease in the western world.

APOL1-associated kidney disease

Kidney disease caused by genetic variants (G1 and G2) in the apolipoprotein L1 gene that are present in close to one-third of African Americans. These mutations are associated with a several-fold increase in chronic kidney disease and end-stage renal disease but protect from African sleeping sickness.

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Breyer, M., Susztak, K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov 15, 568–588 (2016). https://doi.org/10.1038/nrd.2016.67

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