The next generation of therapeutics for chronic kidney disease

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Abstract
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.

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