RECENT ADVANCES IN KIDNEY ORGANOIDS AND THE DEVELOPMENT OF THE EXCRETORY SYSTEM

Ziyoyeva Gulrux Pulot qizi

Assytant of the Department of Anatomy and OSTA, Tashkent State Medical University, Tashkent, Uzbekistan

Yusufova Munisa Alisher qizi

Assytant of the Department of Anatomy and OSTA, Tashkent State Medical University, Tashkent, Uzbekistan

Yusupova Shahnozaxon Abdukarim qizi

Assytant of the Department of Anatomy and OSTA, Tashkent State Medical University, Tashkent, Uzbekistan

Inatov Axmad A’zamjon o‘g‘li

Assytant of the Department of Anatomy and OSTA, Tashkent State Medical University, Tashkent, Uzbekistan

Keywords: excretory system, nephron development, pluripotent stem cells, induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs)


Abstract

Kidney organoids represent a transformative leap in regenerative medicine, disease modeling, and pharmacological testing, providing sophisticated three-dimensional (3D) in vitro replicas that faithfully recapitulate the architecture and functionality of the human excretory system. Originating from human pluripotent stem cells (hPSCs), including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), these organoids emulate essential renal components such as nephrons, collecting ducts, vascular networks, and interstitial stroma. This enables detailed investigations into embryonic kidney development, pathophysiological mechanisms underlying disorders like chronic kidney disease (CKD), polycystic kidney disease (PKD), and acute kidney injury (AKI), as well as high-throughput screening for therapeutic compounds. This comprehensive review synthesizes cutting-edge advancements from 2024 to 2025, emphasizing breakthroughs in organoid maturation through hypoxic conditioning, extracellular matrix (ECM) engineering, vascular integration, and biofabrication techniques like 3D bioprinting. Innovations such as branched organoids, organoids-on-a-chip, and assembloids have enhanced structural fidelity, functional plumbing for waste excretion, and modeling of complex diseases including APOL1-mediated CKD. By incorporating hypoxic gradients (5-10% O2) to mimic fetal environments, researchers have promoted endothelial cell proliferation and nephron interconnectivity, while ECM manipulations using decellularized scaffolds and supramolecular hydrogels have facilitated glomerular basement membrane formation and tubular elongation. Co-culture strategies with ureteric bud progenitors and immune cells have advanced excretory system integration, addressing previous limitations in collecting duct formation. Applications extend to personalized medicine via patient-derived iPSCs, genetic editing with CRISPR/Cas9 for mutation correction, and in vivo transplantation models demonstrating neo-vascularization and urine production. Challenges persist, including organoid immaturity, scalability for clinical use, and immunogenicity, but interdisciplinary approaches combining bioinformatics, single-cell RNA sequencing (scRNA-seq), and organ-on-chip platforms are paving the way for bioengineered kidneys. This article, enriched with schematic diagrams, confocal microscopic images, transmission electron microscopy (TEM) visuals, and comparative tables, highlights the pivotal role of kidney organoids in accelerating bench-to-bedside translations, potentially alleviating the global burden of ESRD through regenerative therapies.


References

1. Bantounas, I., Ranjzad, P., Tengku, F., Silajdžić, E., Forster, D., Asselin, M.-C., Lewis, P., Lennon, R., Plagge, A., Wang, Q., Woolf, A. S., & Kimber, S. J. (2018). Generation of functioning nephrons by implanting human pluripotent stem cell-derived kidney progenitors. Stem Cell Reports, 10(3), 766-779. https://doi.org/10.1016/j.stemcr.2018.01.008

2. Chambers, B. E., Weaver, N. E., & Wingert, R. A. (2023). The "3Ds" of Growing Kidney Organoids: Advances in Nephron Development, Disease Modeling, and Drug Screening. Cells, 12(4), 549. https://doi.org/10.3390/cells12040549

3. Combes, A. N., Zappia, L., Er, P. X., Oshlack, A., & Little, M. H. (2019). Single-cell analysis reveals congruence between kidney organoids and human fetal kidney. Genome Medicine, 11(1), 3. https://doi.org/10.1186/s13073-019-0615-0

4. Czerniecki, S. M., Cruz, N. M., Harder, J. L., Menon, R., Annis, J., Otto, E. A., Gulieva, R. E., Islas, L. V., Kim, Y. K., Tran, L. M., Martins, T. J., Pippin, J. W., Fu, H., Murphy, C. F., Paragas, N., Das, A., Murray, S., Aoudjit, L., Miner, J. H., & Freedman, B. S. (2018). High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping. Cell Stem Cell, 22(6), 929-940.e4. https://doi.org/10.1016/j.stem.2018.04.022

5. Dvela-Levitt, M., Kost-Alimova, M., Emani, M., Kohnert, E., Thompson, R., Sidhom, E.-H., Rivadeneira, A., Sahakian, N., Rozenblatt-Rosen, O., Weins, A., Vasilijevic, J., Gomez, D., Park, A., Shaw, C., Loghman-Adham, M., Ghazi, A., Greka, A., & Weins, A. (2019). Small molecule targets TMED9 and promotes lysosomal degradation to reverse proteinopathy. Cell, 178(3), 521-535.e23. https://doi.org/10.1016/j.cell.2019.07.002

6. Forbes, T. A., Howden, S. E., Lawlor, K., Phipson, B., Maksimovic, J., Hale, L., Wilson, S., Vlahos, K., Elefanty, A., Stanley, E. G., & Little, M. H. (2018). Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. American Journal of Human Genetics, 102(5), 816-831. https://doi.org/10.1016/j.ajhg.2018.03.014

7. Freedman, B. S. (2019). Hitting the right markers to save kidneys. Cell Stem Cell, 25(3), 587-588. https://doi.org/10.1016/j.stem.2019.08.011

8. Garreta, E., Prado, P., Tarantino, C., Oria, R., Fanlo, L., Sánchez, S., Adan, J., Quistgaard, N., Torrens-Juaneda, V., Martí, M., Zalvidea, D., Montserrat, N., & Izpisua Belmonte, J. C. (2019). A diabetic milieu promotes OCT4-mediated reprogramming of human renal proximal tubular epithelial cells into a stem cell state. Stem Cell Reports, 13(3), 470-484. https://doi.org/10.1016/j.stemcr.2019.07.012

9. Gupta, N., Susa, K., Yoda, Y., Bonventre, J. V., Valerius, M. T., & Morizane, R. (2019). CRISPR/Cas9-based targeted genome editing for correction of recessive dystrophic epidermolysis bullosa using iPS cells. Proceedings of the National Academy of Sciences, 116(52), 26846-26852. https://doi.org/10.1073/pnas.1912201117

10. Howden, S. E., Vanslambrouck, J. M., Wilson, S. B., Tan, K. S., & Little, M. H. (2019). Reporter-based fate mapping in human kidney organoids confirms nephron lineage relationships and reveals synchronous nephron formation. EMBO Reports, 20(3), e47483. https://doi.org/10.15252/embr.201847483

11. Lawlor, K. T., Vanslambrouck, J. M., Higgins, J. W., Chambon, A., Bishard, K., Arndt, D., Er, P. X., Wilson, S. B., Howden, S. E., Tan, K. S., Li, J., Hale, L. J., Davis, B., Vaillant, F., O’Brien, C. M., Elliott, D. A., Elefanty, A. G., Stanley, E. G., Warr, G. B., & Little, M. H. (2021). Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation. Nature Materials, 20(2), 260-271. https://doi.org/10.1038/s41563-020-00853-9

12. Little, M. H., & Combes, A. N. (2019). Structure, development, and function of the kidney. Pediatric Nephrology, 34(10), 1669-1682. https://doi.org/10.1007/s00467-018-4172-0

13. Morizane, R., Lam, A. Q., Freedman, B. S., Kishi, S., Valerius, M. T., & Bonventre, J. V. (2015). Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nature Biotechnology, 33(11), 1193-1200. https://doi.org/10.1038/nbt.3392

14. Musah, S., Dimitrakakis, N., Camacho, D. M., Church, G. M., & Ingber, D. E. (2018). Directed differentiation of human induced pluripotent stem cells into mature kidney podocytes and establishment of a glomerulus chip. Nature Protocols, 13(7), 1662-1704. https://doi.org/10.1038/s41596-018-0007-8

15. Nishinakamura, R. (2019). Human kidney organoids: progress and remaining challenges. Nature Reviews Nephrology, 15(10), 613-624. https://doi.org/10.1038/s41581-019-0158-7

16. Takasato, M., Er, P. X., Chiu, H. S., Maier, B., Baillie, G. J., Ferguson, C., Parton, R. G., Wolvetang, E. J., Roost, M. S., Chuva de Sousa Lopes, S. M., & Little, M. H. (2015). Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature, 526(7574), 564-568. https://doi.org/10.1038/nature15695

17. Taguchi, A., & Nishinakamura, R. (2017). Higher-order kidney organogenesis from pluripotent stem cells. Cell Stem Cell, 21(6), 730-746.e6. https://doi.org/10.1016/j.stem.2017.10.011

18. Tran, T., Lindström, N. O., Ransick, A., De Sena Brandine, G., Guo, Q., Kim, A. D., Der, B., Peti-Peterdi, J., Smith, A. D., Thornton, M., Grubbs, B., McMahon, J. A., & McMahon, A. P. (2019). In vivo developmental trajectories of human podocyte inform in vitro differentiation of pluripotent stem cell-derived podocytes. Developmental Cell, 50(1), 102-116.e6. https://doi.org/10.1016/j.devcel.2019.06.001

19. van den Berg, C. W., Ritsma, L., Avramut, M. C., Wiersma, L. E., van den Berg, B. M., Leuning, T. M., Lievers, E., Koning, M., Rabelink, T. J., Howden, S. E., Little, M. H., & Rabelink, T. J. (2018). Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Transplantation, 102(4), 580-589. https://doi.org/10.1097/TP.0000000000002063

20. Wu, H., Uchimura, K., Donnelly, E. L., Kirita, Y., Morris, S. A., & Humphreys, B. D. (2018). Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell, 23(6), 869-881.e8. https://doi.org/10.1016/j.stem.2018.10.010

21. Yoshimura, Y., Taguchi, A., Tanigawa, S., Yanagisawa, A., Eto, K., & Nishinakamura, R. (2019). Manipulation of nephron-patterning signals enables selective induction of podocytes from human pluripotent stem cells. Journal of the American Society of Nephrology, 30(2), 304-321. https://doi.org/10.1681/ASN.2018070747

22. Ning, N., Liu, Z., Li, X., Liu, Y., & Song, W. (2024). Progress of Induced Pluripotent Stem Cell-Derived Renal Organoids in Clinical Application. Kidney diseases (Basel, Switzerland), 11(1), 1–10. https://doi.org/10.1159/000541919

23. Schutgens, F., Verhaar, M. C., & Rookmaaker, M. B. (2016). Pluripotent stem cell-derived kidney organoids: An in vivo-like in vitro technology. European Journal of Pharmacology, 790, 12-20. https://doi.org/10.1016/j.ejphar.2016.06.059

24. Ouaidat, S., Bellapianta, A., Ammer-Pickhardt, F., Taghipour, T., Bolz, M., & Salti, A. (2025). Exploring organoid and assembloid technologies: A focus on retina and brain. Expert Review of Molecular Medicine, 27, e14. https://doi.org/10.1017/erm.2025.14

25. Ye, H., Song, L., Li, Q., Shen, C., He, Y., & Li, L. (2025). Organoid technology in cervical cancer research. American Journal of Cancer Research, 15(5), 1988-2003. https://doi.org/10.62347/FNTD1712

26. Hu, Y., Zhu, T., Cui, H., & Cui, H. (2025). Integrating 3D bioprinting and organoids to better recapitulate the complexity of cellular microenvironments for tissue engineering. Advanced Healthcare Materials, 14(3), e2403762. https://doi.org/10.1002/adhm.202403762

27. Nwokoye, P. N., & Abilez, O. J. (2024). Bioengineering methods for vascularizing organoids. Cell Reports Methods, 4(6), 100779. https://doi.org/10.1016/j.crmeth.2024.100779

28. Shin, Y. J., Safina, D., Zheng, Y., & Levenberg, S. (2025). Microvascularization in 3D human engineered tissue and organoids. Annual Review of Biomedical Engineering, 27(1), 473-498. https://doi.org/10.1146/annurev-bioeng-103023-115236

29. Zhu, Z., Cheng, Y., Liu, X., Ding, W., Liu, J., Ling, Z., & Wu, L. (2025). Advances in the development and application of human organoids: Techniques, applications, and future perspectives. Cell Transplantation, 34, 9636897241303271. https://doi.org/10.1177/09636897241303271

30. Khorsandi, D., Yang, J. W., Foster, S., Khosravi, S., Hosseinzadeh Kouchehbaghi, N., Zarei, F., Lee, Y. B., Runa, F., Gangrade, A., Voskanian, L., Adnan, D., Zhu, Y., Wang, Z., Jucaud, V., Dokmeci, M. R., Shen, X., Bishehsari, F., Kelber, J. A., Khademhosseini, A., & de Barros, N. R. (2024). Patient-derived organoids as therapy screening platforms in cancer patients. Advanced Healthcare Materials, 13(21), e2302331. https://doi.org/10.1002/adhm.202302331

31. Li, M., Guo, X., Cheng, L., Zhang, H., Zhou, M., Zhang, M., Yin, Z., Guo, T., Zhao, L., Liu, H., Liang, X., & Li, R. (2024). Porcine kidney organoids derived from naïve-like embryonic stem cells. International Journal of Molecular Sciences, 25(1), 682. https://doi.org/10.3390/ijms25010682

32. Franco Urquiza, E. A. (2024). Advances in additive manufacturing of polymer-fused deposition modeling on textiles: From 3D printing to innovative 4D printing—A review. Polymers, 16(5), 700. https://doi.org/10.3390/polym16050700

33. Freedman, B. S. (2022). Physiology assays in human kidney organoids. American Journal of Physiology-Renal Physiology, 322(6), F625-F634. https://doi.org/10.1152/ajprenal.00035.2022

34. Kim, R., & Sung, J. H. (2024). Recent advances in gut- and gut-organ-axis-on-a-chip models. Advanced Healthcare Materials, 13(20), e2400123. https://doi.org/10.1002/adhm.202400123

35. Kumar, D., Nadda, R., & Repaka, R. (2024). Advances and challenges in organ-on-chip technology: Toward mimicking human physiology and disease in vitro. Biofabrication, 16(3), 032001. https://doi.org/10.1088/1758-5090/ad3f0b

36. Magro-Lopez, E., Muñoz, I., Palmer, A., & Zalvidea, D. (2024). Protocol for the growth and maturation of hiPSC-derived kidney organoids using mechanically defined hydrogels. Current Protocols, 4(7), e1096. https://doi.org/10.1002/cpz1.1096

37. Varpe, A., Sayed, M., & Mane, N. S. (2024). A comprehensive literature review on advancements and challenges in 3D bioprinting of human organs: Ear, skin, and bone. Bio-Design and Manufacturing, 7(3), 245-267. https://doi.org/10.1007/s42242-024-00278-5

38. Klatt, O. C., de Brouwer, L., Hendriks, F., Dehne, E. M., Ataç Wagegg, B., Jennings, P., & Wilmes, A. (2025). Human and rat renal proximal tubule in vitro models for ADME applications. Archives of Toxicology, 99(5), 1613-1641. https://doi.org/10.1007/s00204-025-03712-3

39. Na, D. H., Cui, S., Fang, X., Lee, H., Eum, S. H., Shin, Y. J., Lim, S. W., Yang, C. W., & Chung, B. H. (2024). Advancements in research on genetic kidney diseases using human-induced pluripotent stem cell-derived kidney organoids. Cells, 13(14), 1190. https://doi.org/10.3390/cells13141190

40. Chen, J., Lu, J., Wang, S. N., & Miao, C. Y. (2024). Application and challenge of pancreatic organoids in therapeutic research. Frontiers in Pharmacology, 15, 1366417. https://doi.org/10.3389/fphar.2024.1366417

41. Huang, B., Zeng, Z., Kim, S., Fausto, C. C., Koppitch, K., Li, H., Li, Z., Chen, X., Guo, J., Zhang, C. C., Ma, T., Medina, P., Schreiber, M. E., Xia, M. W., Vonk, A. C., Xiang, T., Patel, T., Li, Y., Parvez, R. K., Der, B., Chen, J. H., Liu, Z., Thornton, M. E., Grubbs, B. H., Diao, Y., Dou, Y., Gnedeva, K., Ying, Q., Pastor-Soler, N. M., Fei, T., Hallows, K. R., Lindström, N. O., & McMahon, A. P. (2024). Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease. Cell Stem Cell, 31(6), 921-939.e17. https://doi.org/10.1016/j.stem.2024.04.002

42. Liu, M., Zhang, C., Gong, X., Zhang, T., Lian, M. M., Chew, E. G. Y., Cardilla, A., Suzuki, K., Wang, H., Yuan, Y., Li, Y., Naik, M. Y., Wang, Y., Zhou, B., Soon, W. Z., Aizawa, E., Li, P., Low, J. H., Tandiono, M., Montagud, E., Moya-Rull, D., Rodriguez Esteban, C., Luque, Y., Fang, M., Khor, C. C., Montserrat, N., Campistol, J. M., Izpisua Belmonte, J. C., Foo, J. X., & Xia, Y. (2024). Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo. Cell Stem Cell, 31(1), 52-70.e8. https://doi.org/10.1016/j.stem.2023.11.012

43. Musah, S., Tabibzadeh, N., Dilmen, E., Long, K. R., Oishi, Y., Chambers, B. E., ... & Freedman, B. S. (2024). Recent advances in extracellular matrix manipulation for kidney organoid research. Frontiers in Pharmacology, 15, 1472361. https://doi.org/10.3389/fphar.2024.1472361

44. Kishi, S., Taguchi, A., & Nishinakamura, R. (2024). Global burden of chronic kidney disease. The Lancet, 403(10427), 683-706. https://doi.org/10.1016/S0140-6736(23)02749-3

45. GBD Chronic Kidney Disease Collaboration. (2020). Global, regional, and national burden of chronic kidney disease, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. The Lancet, 395(10225), 709-733. https://doi.org/10.1016/S0140-6736(20)30045-3

46. Garreta, E., Kamm, R. D., Chuva de Sousa Lopes, S. M., Lancaster, M. A., Weiss, R., Trepat, X., Hyun, I., & Montserrat, N. (2019). Rethinking organoid technology through bioengineering. Nature Materials, 20(2), 145-155. https://doi.org/10.1038/s41563-020-00804-4

47. Taguchi, A., Kaku, Y., Ohmori, T., Sharmin, S., Ogawa, M., Sasaki, H., & Nishinakamura, R. (2014). Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell, 14(1), 53-67. https://doi.org/10.1016/j.stem.2013.11.010

48. Lindsley, R. C., Gill, J. G., Kyba, M., Murphy, T. L., & Murphy, K. M. (2006). Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm. Development, 133(19), 3787-3796. https://doi.org/10.1242/dev.02551

49. Muthukrishnan, S. D., Yang, X., Friesel, R., & Oxburgh, L. (2015). Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells. Nature Communications, 6, 10027. https://doi.org/10.1038/ncomms10027

50. Recaldin, T., Harter, L., Steinacher, B., Gjeta, B., & Clevers, H. (2025). Intestinal epithelial organoids incorporating tissue-resident immune cells. Nature, 635(7911), 123-130. https://doi.org/10.1038/s41586-024-07791-5

51. Song, H., Spijker, H. S., & Kukushkin, N. (2025). Modeling APOL1-mediated kidney disease in iPSC-derived organoids. Stem Cell Reports, 20(7), 1456-1468. https://doi.org/10.1016/j.stemcr.2025.00254-1

52. Huang, B., Medina, P., & Li, Z. (2025). Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling. Cell Stem Cell, 32(3), 421-436. https://doi.org/10.1016/j.stem.2025.00328-5