Precision Nephrology: Understanding Kidney Injury To Bring The Right Drug To The Right Person
Another kidney disease that is likely to benefit early from human kidney organoid models is polycystic kidney disease (PKD). Kidney organoids from individuals with PKD develop large cysts that mimic kidney cysts seen in people with PKD, indicating that such organoids may be the ideal tool for drug discovery.13,14
Precision medicine, however, did not yield SGLT-2i, which has dramatically improved CKD management Therefore, why advocate for this cumbersome, costly approach? Because unlike in oncology, where precision medicine frequently guides drug discovery, the success rate of drug discovery in nephrology
is abysmal. There has been over a 30-year gap between the approval of ACE inhibitors and recent approval of SGLT-2i for slowing CKD progression. At this rate, the next breakthrough kidney drug will be approved in 2050, after three million new people will have reached dialysis in the US alone.
Patient-derived kidney organoids may help accelerate the discovery of therapeutic targets and more efficiently identify potential toxicities of candidate drugs. Nephrology writ large is being transformed by a deeper understanding of biology, genetics, and novel technologies, all poised to set the stage for improving the understanding and treatment of kidney injury.
Meet The Experts
- KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012 Mar;2(1):1-138. doi:10.1038/kisup.2012.1.
- KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013 Jan;3(1). https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf.
- Abrahams E. Right drug—right patient—right time: personalized medicine coalition. Clin Transl Sci 2008 May;1(1):11-12. doi: 10.1111/j.1752-8062.2008.00003.x.
- Hodgin JB, Nair V, Zhang H, et al. Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli. Diabetes 2013 Jan;62(1):299-308. doi: 10.2337/db11-1667.
- Zhang H, Nair V, Saha J, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int 2017 Oct;92(4):909-21. doi: 10.1016/j. kint.2017.03.027.
- Tuttle KR, Brosius FC, Adler SG, et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. Nephrol Dial Transplant 2018 Nov;33(11):1950-59. doi: 10.1093/ndt/gfx377.
- Wilson PC, Wu H, Kirita Y, et al. The single-cell transcriptomic landscape of early uman diabetic nephropathy. Proc Natl Acad Sci USA 2019 Sep 24;116(39):19619-25. doi: 10.1073/pnas.1908706116.
- He B, Chen P, Zambrano S, et al. Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes. Nat Commun 2021 Apr 9;12(1):2141. doi: 10.1038/s41467-021-22331-9.
- Kopp JB, Nelson GW, Sampath K, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 2011 Nov;22(11):2129-37. doi: 10.1681/ASN.2011040388.
- Larsen CP, Beggs ML, Saeed M, Walker PD. Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol 2013 Apr;24(5):722-5. doi: 10.1681/ASN.2012121180.
- Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010 Aug 13;329(5993):841-5. doi: 10.1126/science.1193032.
- Wu H, Larsen CP, Hernandez-Arroyo CF, et al. AKI and collapsing glomerulopathy associated with COVID-19 and APOL 1 high-risk genotype. J Am Soc Nephrol 2020 Aug;31(8):1688-95. doi: 10.1681/ASN.2020050558.
- Freedman BS, Brooks CR, Lam AQ, et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 2015 Oct 23;6:8715. doi: 10.1038/ncomms9715.
- Kuraoka S, Tanigawa S, Taguchi A, et al. PKD1-dependent renal cystogenesis in human induced pluripotent stem cell-derived ureteric bud/collecting duct organoids. J Am Soc Nephrol 2020 Oct;31(10):2355-71. doi: 10.1681/ASN.2020030378.