Selecting the right therapeutic target for kidney disease

Abstract

Kidney disease is a complex disease with several different etiologies and underlying associated pathophysiology. This is reflected by the lack of effective treatment therapies in chronic kidney disease (CKD) that stop disease progression. However, novel strategies, recent scientific breakthroughs, and technological advances have revealed new possibilities for finding novel disease drivers in CKD. This review describes some of the latest advances in the field and brings them together in a more holistic framework as applied to identification and validation of disease drivers in CKD. It uses high-resolution ‘patient-centric’ omics data sets, advanced in silico tools (systems biology, connectivity mapping, and machine learning) and ‘state-of-the-art‘ experimental systems (complex 3D systems in vitro, CRISPR gene editing, and various model biological systems in vivo). Application of such a framework is expected to increase the likelihood of successful identification of novel drug candidates based on strong human target validation and a better scientific understanding of underlying mechanisms.

Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease

“…Targeting specific signaling pathways rather than using broad antiinflammatory mechanisms is important to optimize efficacy and minimize side effects. 28 Therefore, we explored the mRNA expression of 20 mechanistically diverse proinflammatory cytokines in kidney biopsies from patients with DKD. 15 Post hoc analysis of the Karolinska Institute/Sahlgrenska University Hospital DKD patient cohort receiving angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers ( N = 19) demonstrated a significant upregulation of CCL5 , chemokine ( C-X-C motif ) ligand 1 ( CXCL1 ), and IL-33 in glomerular and tubulointerstitial compartments ( Figure 1 a).…”

Shared and Distinct Renal Transcriptome Signatures in 3 Standard Mouse Models of Chronic Kidney Disease

“…It should, however, be noted that the UUO model does not reflect the natural history of CKD. In contrast, the uIRI model is considered recapitulating human renal ischemic insults leading to acute kidney injury and thus preferred for testing drugs targeting mechanisms leading to oxidative cell damage [24][25][26].…”

“…The uIRI model, another surgically induced model, is advantageous for studying the transition from ischemic acute kidney injury to CKD [23]. Importantly, the three models are recognized for their reproducibility and robust kidney inflammatory and fibrotic responses and thus remain instrumental in preclinical target and drug discovery [20,21,[24][25][26]. Considering that the three models differ with regards to induction method, disease severity, and clinical translatability, they have individual advantages and limitations and thus different utility in preclinical target and drug discovery [27,28].…”

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

“…Nevertheless, it is widely acknowledged that the clinical development success rates for investigational drugs is low [16], which is, at least in part, due to the fact that animal experiments often fail to replicate when tested in rigorous human trials [17]. Therefore, it should remain a top priority of the scientific community to develop and implement relevant preclinical models of renal fibrosis with a high predictive value, such as human PCKS [18,19].…”