The next generation of therapeutics for chronic kidney disease

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.

Figure 1. Targeting the renin angiotensin aldosterone system

Schematic representation of the renin angiotensin aldosterone system. Renin converts angiotensinogen to Angiotensin I and the angiotensin converting enzyme converts angiotensin I to angiotensin II. Renin inhibitors block renin, ACEI block ACE, AT1R block angiotensin action on the receptor while mineralocorticoid antagonists inhibit aldosterone.

Figure 2. Targeting the glomerulus in the treatment of CKD

A. The left of the figure depicts the normal glomerulus with endothelial cells, glycocalyx, basement membrane and podocytes shown. The boxes illustrate the different abnormalities observed in CKD and potential therapeutic strategies and agents to target them. For endothelial cells, these include: loss of glycocalyx targeted by sulodexide, increased endothelin 1A signaling blocked by Atrasertan, decreased VEGF expression and increased B7-1 expression targeted by Abatacept. For podocytes, these include podocyte loss by detachment and apoptosis targeted by ROS inhibitors, FAK inhibitors or integrin inhibitors, increased dynamin oligomerization and cytoskeletal changes targeted by BisT23, Podocyte hypertrophy by increased mTOR and LKB1 targeted by rapamycin, and podocyte dedifferentiation by increased Wnt and Notch signaling targeted by lithium and gamma secretase inhibitors. B. PAS stained kidney sections from a patient with diabetic glomerulosclerosis. Note the increased pink matrix materials, indicative of glomerulosclerosis and the obliterated glomerular capillaries.

Figure 3. Targeting tubulointerstitial fibrosis in the treatment of CKD

A. Normal (healthy) renal tubule cross-section versus B. tubulointerstitium in CKD. Several therapeutic targets are shown including: increased TGFb signaling blocked by neutralizing antibody CAT-192, blocking latent TGFb by inhibiting alphavbeta6 with STX 100 antibody, tubule dedifferentiation and proinflammatory phenotype by increasing JAK and Notch signaling (blocked by gamma secretase inhibitor or baricitinib), increased TNFa and MCP1 levels, increased complement activation, collagen cross-linking by LoxL2, and increased GLi2 and Wnt signaling in fibroblasts leading to activated myofibroblast accumulation. B. PAS stained human kidney section from a patient with diabetic kidney disease. Note the increased interstitial matrix, the increase in myofibroblasts and inflammatory cells and tubule cell dedifferentiation.

Figure 4. Metabolic alterations in CKD

Metabolic dysregulation, particularly poor glucose control, is associated with the development of diabetic nephropathy. Key factors contributing to disease development include increased SGLT2 mediated glucose uptake and increased mitochondrial and plasma membrane ROS generation . In addition, fatty acid oxidation is decreased due to loss of nuclear receptor activity of PPARA, RXR, PPARGC1A, LXR/FXR and their upstream regulator AMPK, LKB1 and miR 21. Effects of metabolic fluctuations are long lasting as they can influence the epigenome; cytosine methylation and histone acetylation. Agents being investigated, which target many of these alterations, including: empagliflozin, dapaglifozin and canagliflozin that block SGLT1, GTK137831 that blocks NOX4, 5Aza that blocks cytosine methylation, HDAC inhibitors that block histone acyltransferases, miR21 and fibrates that activate PPARA, and GW3965 that blocks LXR/FXR, are shown in the red and green boxes.