Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Amino acid metabolism in kidney health and disease

Nature Reviews Nephrology (2024)Cite this article

Subjects

Abstract

Amino acids form peptides and proteins and are therefore considered the main building blocks of life. The kidney has an important but under-appreciated role in the synthesis, degradation, filtration, reabsorption and excretion of amino acids, acting to retain useful metabolites while excreting potentially harmful and waste products from amino acid metabolism. A complex network of kidney transporters and enzymes guides these processes and moderates the competing concentrations of various metabolites and amino acid products. Kidney amino acid metabolism contributes to gluconeogenesis, nitrogen clearance, acid–base metabolism and provision of fuel for tricarboxylic acid cycle and urea cycle intermediates, and is thus a central hub for homeostasis. Conversely, kidney disease affects the levels and metabolism of a variety of amino acids. Here, we review the metabolic role of the kidney in amino acid metabolism and describe how different diseases of the kidney lead to aberrations in amino acid metabolism. Improved understanding of the metabolic and communication routes that are affected by disease could provide new mechanistic insights into the pathogenesis of kidney diseases and potentially enable targeted dietary or pharmacological interventions.

Key points

  • The kidney has an important role in the synthesis, reabsorption, metabolism and excretion of amino acids and their products.

  • A variety of inter-organ processes are dependent on amino acid metabolism in the kidneys, including acid–base balance, gluconeogenesis and energy production.

  • Metabolic processes occur parallel to physiological processes in disease, consistent with our understanding of metabolism as a pathophysiological driver of disease.

  • Distinct pathophysiological processes contribute to the rewiring of specific metabolic pathways and the development of vulnerabilities.

  • Cross-organ communication on a metabolome level may contribute to kidney disease-associated vulnerabilities and cardiovascular disease.

  • Modulation of amino acid metabolism in kidney disease is a promising avenue for novel therapeutic strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Physiological amino acid handling and metabolism.
Fig. 2: Amino acid metabolism in ADPKD.
Fig. 3: Amino acid metabolism in diabetes.
Fig. 4: Amino acid metabolism in CKD.

Similar content being viewed by others

References

  1. Brosnan, J. T. & Brosnan, M. E. Branched-chain amino acids: enzyme and substrate regulation1, 2, 3. J. Nutr. 136, S207–S211 (2006).

    Article  Google Scholar 

  2. Neinast, M. D. et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metab. 29, 417–429.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Lian, K. et al. Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice. Diabetes 64, 49–59 (2014).

    Article  PubMed  Google Scholar 

  4. Neinast, M., Murashige, D. & Arany, Z. Branched chain amino acids. Annu. Rev. Physiol. 81, 139–164 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Claris-Appiani, A., Assael, B. M., Tirelli, A. S., Marra, G. & Cavanna, G. Lack of glomerular hemodynamic stimulation after infusion of branched-chain amino acids. Kidney Int. 33, 91–94 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Castellino, P., Levin, R., Shohat, J. & DeFronzo, R. A. Effect of specific amino acid groups on renal hemodynamics in humans. Am. J. Physiol. Renal Physiol. 258, F992–F997 (1990).

    Article  CAS  Google Scholar 

  7. Schrijvers, B. F., Rasch, R., Tilton, R. G. & Flyvbjerg, A. High protein-induced glomerular hypertrophy is vascular endothelial growth factor-dependent. Kidney Int. 61, 1600–1604 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Stipanuk, M. H. Metabolism of sulfur-containing amino acids: how the body copes with excess methionine, cysteine, and sulfide. J. Nutr. 150, 2494S–2505S (2020).

    Article  PubMed  Google Scholar 

  9. Li, J. et al. Insights into S-adenosyl-l-methionine (SAM)-dependent methyltransferase related diseases and genetic polymorphisms. Mutat. Res. Mutat. Res. 788, 108396 (2021).

    Article  CAS  Google Scholar 

  10. Stipanuk, M. H. & Ueki, I. Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J. Inherit. Metab. Dis. 34, 17–32 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Chesney, R. W., Han, X. & Patters, A. B. Taurine and the renal system. J. Biomed. Sci. 17, S4 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chesney, R. W., Gusowski, N. & Dabbagh, S. Renal cortex taurine content regulates renal adaptive response to altered dietary intake of sulfur amino acids. J. Clin. Invest. 76, 2213–2221 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Han, X., Patters, A. B., Jones, D. P., Zelikovic, I. & Chesney, R. W. The taurine transporter: mechanisms of regulation. Acta Physiol. 187, 61–73 (2006).

    Article  CAS  Google Scholar 

  14. Reymond, I., Bitoun, M., Levillain, O. & Tappaz, M. Regional expression and histological localization of cysteine sulfinate decarboxylase mRNA in the rat kidney. J. Histochem. Cytochem. J. Histochem. Soc. 48, 1461–1468 (2000).

    Article  CAS  Google Scholar 

  15. Holeček, M. Serine metabolism in health and disease and as a conditionally essential amino acid. Nutrients 14, 1987 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jang, C. et al. Metabolite exchange between mammalian organs quantified in pigs. Cell Metab. 30, 594–606.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lowry, M., Hall, D. E., Hall, M. S. & Brosnan, J. T. Renal metabolism of amino acids in vivo: studies on serine and glycine fluxes. Am. J. Physiol. Renal Physiol. 252, F304–F309 (1987).

    Article  CAS  Google Scholar 

  18. Lowry, M., Hall, D. E. & Brosnan, J. T. Serine synthesis in rat kidney: studies with perfused kidney and cortical tubules. Am. J. Physiol. Renal Physiol. 250, F649–F658 (1986).

    Article  CAS  Google Scholar 

  19. Jois, M., Hall, D. E. & Brosnan, J. T. Serine synthesis by the rat kidney. N. Asp. Ren. Ammon. Metab. 63, 136–140 (1988).

    CAS  Google Scholar 

  20. Wang, W. et al. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids 45, 463–477 (2013).

    Article  PubMed  Google Scholar 

  21. Petrossian, T. C. & Clarke, S. G. Uncovering the human methyltransferasome. Mol. Cell. Proteom. 10, M110.000976 (2011).

    Article  Google Scholar 

  22. Pitts, R. F. & MacLeod, M. B. Synthesis of serine by the dog kidney in vivo. Am. J. Physiol. 222, 394–398 (1972).

    Article  CAS  PubMed  Google Scholar 

  23. Alves, A., Bassot, A., Bulteau, A.-L., Pirola, L. & Morio, B. Glycine metabolism and its alterations in obesity and metabolic diseases. Nutrients 11, 1356 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lam, C. K. L. et al. Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production. J. Biol. Chem. 285, 21913–21921 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Razak, M. A., Begum, P. S., Viswanath, B. & Rajagopal, S. Multifarious beneficial effect of nonessential amino acid, glycine: a review. Oxid. Med. Cell. Longev. 2017, 1716701 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Meléndez-Hevia, E. & de Paz-Lugo, P. Branch-point stoichiometry can generate weak links in metabolism: the case of glycine biosynthesis. J. Biosci. 33, 771–780 (2008).

    Article  PubMed  Google Scholar 

  27. Tizianello, A., Ferrari, G. D., Garibotto, G., Gurreri, G. & Robaudo, C. Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency. J. Clin. Invest. 65, 1162–1173 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tessari, P. et al. Phenylalanine hydroxylation across the kidney in humans rapid communication. Kidney Int. 56, 2168–2172 (1999).

    CAS  PubMed  Google Scholar 

  29. Møller, N., Meek, S., Bigelow, M., Andrews, J. & Nair, K. S. The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: a metabolic role of the kidney. Proc. Natl Acad. Sci. USA 97, 1242–1246 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Boirie, Y., Albright, R., Bigelow, M. & Nair, K. S. Impairment of phenylalanine conversion to tyrosine in end-stage renal disease causing tyrosine deficiency. Kidney Int. 66, 591–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Kopple, J. D. Phenylalanine and tyrosine metabolism in chronic kidney failure. J. Nutr. 137, 1586S–1590S (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Hsu, C.-N. & Tain, Y.-L. Developmental programming and reprogramming of hypertension and kidney disease: impact of tryptophan metabolism. Int. J. Mol. Sci. 21, 8705 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Castro-Portuguez, R. & Sutphin, G. L. Kynurenine pathway, NAD+ synthesis, and mitochondrial function: targeting tryptophan metabolism to promote longevity and healthspan. Exp. Gerontol. 132, 110841 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Badawy, A. A.-B. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int. J. Tryptophan Res. 10, 1178646917691938 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tan, X. et al. Indoxyl sulfate, a valuable biomarker in chronic kidney disease and dialysis. Hemodial. Int. 21, 161–167 (2017).

    Article  PubMed  Google Scholar 

  36. Duranton, F. et al. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 23, 1258 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Holeček, M. Histidine in health and disease: metabolism, physiological importance, and use as a supplement. Nutrients 12, 848 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Liu, W., Liu, T. & Yin, M. Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury. Food Chem. Toxicol. 46, 1503–1509 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Brosnan, J. T. The 1986 Borden award lecture. The role of the kidney in amino acid metabolism and nutrition. Can. J. Physiol. Pharmacol. 65, 2355–2362 (1987).

    Article  CAS  PubMed  Google Scholar 

  40. Dhanakoti, S. N., Brosnan, J. T., Herzberg, G. R. & Brosnan, M. E. Renal arginine synthesis: studies in vitro and in vivo. Am. J. Physiol. 259, E437–E442 (1990).

    CAS  PubMed  Google Scholar 

  41. Houdijk, A. P. et al. Glutamine-enriched enteral diet increases renal arginine production. J. Parenter. Enter. Nutr. 18, 422–426 (1994).

    Article  CAS  Google Scholar 

  42. Weiner, I. D., Mitch, W. E. & Sands, J. M. Urea and ammonia metabolism and the control of renal nitrogen excretion. Clin. J. Am. Soc. Nephrol. 10, 1444–1458 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Bankir, L., Bouby, N., Trinh-Trang-Tan, M.-M., Ahloulay, M. & Promeneur, D. Direct and indirect cost of urea excretion. Kidney Int. 49, 1598–1607 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Perez, G. O., Epstein, M., Rietberg, B. & Loutzenhiser, R. Metabolism of arginine by the isolated perfused rat kidney. Am. J. Physiol. 235, F376–F380 (1978).

    CAS  PubMed  Google Scholar 

  45. Li, Z. et al. Arginase: shedding light on the mechanisms and opportunities in cardiovascular diseases. Cell Death Discov. 8, 1–14 (2022).

    Article  Google Scholar 

  46. Pernow, J. & Jung, C. The emerging role of arginase in endothelial dysfunction in diabetes. Curr. Vasc. Pharmacol. 14, 155–162 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. You, H., Gao, T., Cooper, T. K., Morris, S. M. & Awad, A. S. Arginase inhibition mediates renal tissue protection in diabetic nephropathy by a nitric oxide synthase 3-dependent mechanism. Kidney Int. 84, 1189–1197 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bachmann, S. & Mundel, P. Nitric oxide in the kidney: synthesis, localization, and function. Am. J. Kidney Dis. 24, 112–129 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Carlström, M. Nitric oxide signalling in kidney regulation and cardiometabolic health. Nat. Rev. Nephrol. 17, 575–590 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Morgan, D. M. Polyamines. An overview. Mol. Biotechnol. 11, 229–250 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Kim, J. Spermidine is protective against kidney ischemia and reperfusion injury through inhibiting DNA nitration and PARP1 activation. Anat. Cell Biol. 50, 200–206 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tsikas, D. Urinary dimethylamine (DMA) and its precursor asymmetric dimethylarginine (ADMA) in clinical medicine, in the context of nitric oxide (NO) and beyond. J. Clin. Med. 9, 1843 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Duranton, F. et al. Plasma and urinary amino acid metabolomic profiling in patients with different levels of kidney function. Clin. J. Am. Soc. Nephrol. 9, 37–45 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Huang, J., Ladeiras, D., Yu, Y., Ming, X.-F. & Yang, Z. Detrimental effects of chronic l-arginine rich food on aging kidney. Front. Pharmacol. 11, 582155 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Brosnan, J. T. & Brosnan, M. E. Glutamate: a truly functional amino acid. Amino Acids 45, 413–418 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Boron, W. F. & Boulpaep, E. L. Medical Physiology. https://shop.elsevier.com/books/medical-physiology/boron/978-1-4557-4377-3 (2016).

  57. Stumvoll, M., Perriello, G., Meyer, C. & Gerich, J. Role of glutamine in human carbohydrate metabolism in kidney and other tissues. Kidney Int. 55, 778–792 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. van de Poll, M. C. G., Soeters, P. B., Deutz, N. E. P., Fearon, K. C. H. & Dejong, C. H. C. Renal metabolism of amino acids: its role in interorgan amino acid exchange. Am. J. Clin. Nutr. 79, 185–197 (2004).

    Article  PubMed  Google Scholar 

  59. Rinschen, M. M. et al. Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension. Nat. Commun. 13, 4099 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tan, Y., Chrysopoulou, M. & Rinschen, M. M. Integrative physiology of lysine metabolites. Physiol. Genomics 55, 579–586 (2023).

    Article  CAS  PubMed  Google Scholar 

  61. Thelle, K., Christensen, E. I., Vorum, H., Ørskov, H. & Birn, H. Characterization of proteinuria and tubular protein uptake in a new model of oral L-lysine administration in rats. Kidney Int. 69, 1333–1340 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Jozi, F. et al. L-Lysine ameliorates diabetic nephropathy in rats with streptozotocin-induced diabetes mellitus. BioMed. Res. Int. 2022, 4547312 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Wang, T. J. et al. 2-Aminoadipic acid is a biomarker for diabetes risk. J. Clin. Invest. 123, 4309–4317 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. McMahon, G. M. et al. Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease. Kidney Int. 91, 1426–1435 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Nishioka, N. et al. Carnitine supplements for people with chronic kidney disease requiring dialysis. Cochrane Database Syst. Rev. 12, CD013601 (2022).

    PubMed  Google Scholar 

  66. Guder, W. G. & Schorn, T. Metabolic interactions between renal proline and glutamine metabolism. https://doi.org/10.1159/000420076 (1991).

  67. Phang, J. M., Pandhare, J. & Liu, Y. The metabolism of proline as microenvironmental stress substrate. J. Nutr. 138, 2008S–2015S (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Pandhare, J., Donald, S. P., Cooper, S. K. & Phang, J. M. Regulation and function of proline oxidase under nutrient stress. J. Cell. Biochem. 107, 759–768 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hensgens, H. E., Meijer, A. J., Williamson, J. R., Gimpel, J. A. & Tager, J. M. Prolone metabolism in isolated rat liver cells. Biochem. J. 170, 699–707 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schwörer, S. et al. Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress. EMBO J. 39, e103334 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Berg, R. A. & Prockop, D. J. The thermal transition of a non-hydroxylated form of collagen. Evidence for a role for hydroxyproline in stabilizing the triple-helix of collagen. Biochem. Biophys. Res. Commun. 52, 115–120 (1973).

    Article  CAS  PubMed  Google Scholar 

  72. Lowry, M., Hall, D. E. & Brosnan, J. T. Hydroxyproline metabolism by the rat kidney: distribution of renal enzymes of hydroxyproline catabolism and renal conversion of hydroxyproline to glycine and serine. Metabolism 34, 955–961 (1985).

    Article  CAS  PubMed  Google Scholar 

  73. Cornec-Le Gall, E., Alam, A. & Perrone, R. D. Autosomal dominant polycystic kidney disease. Lancet Lond. Engl. 393, 919–935 (2019).

    Article  Google Scholar 

  74. Rowe, I. et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 19, 488–493 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Podrini, C. et al. Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. Commun. Biol. 1, 1–14 (2018).

    Article  CAS  Google Scholar 

  76. Hwang, V. J. et al. The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate. Am. J. Physiol. Renal Physiol. 309, F492–F498 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Flowers, E. M. et al. Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. Nat. Commun. 9, 814 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Du, X. & Hu, H. The roles of 2-hydroxyglutarate. Front. Cell Dev. Biol. 9, 651317 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Lomelino, C. L., Andring, J. T., McKenna, R. & Kilberg, M. S. Asparagine synthetase: function, structure, and role in disease. J. Biol. Chem. 292, 19952–19958 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yang, C. et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol. Cell 56, 414–424 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Baliga, M. M. et al. Metabolic profiling in children and young adults with autosomal dominant polycystic kidney disease. Sci. Rep. 11, 6629 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yoo, H. C., Yu, Y. C., Sung, Y. & Han, J. M. Glutamine reliance in cell metabolism. Exp. Mol. Med. 52, 1496–1516 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Durán, R. V. & Hall, M. N. Glutaminolysis feeds mTORC1. Cell Cycle 11, 4107–4108 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Durán, R. V. et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol. Cell 47, 349–358 (2012).

    Article  PubMed  Google Scholar 

  85. Trott, J. F. et al. Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis. Am. J. Physiol. Renal Physiol. 315, F1855–F1868 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ramalingam, H. et al. A methionine-mettl3-N6-methyladenosine axis promotes polycystic kidney disease. Cell Metab. 33, 1234–1247.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Parrot, C. et al. c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis. Hum. Mol. Genet. 28, 751–763 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Takahara, T., Amemiya, Y., Sugiyama, R., Maki, M. & Shibata, H. Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes. J. Biomed. Sci. 27, 87 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Maddocks, O. D. K., Labuschagne, C. F., Adams, P. D. & Vousden, K. H. Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol. Cell 61, 210–221 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Grant, G. A. D-3-Phosphoglycerate dehydrogenase. Front. Mol. Biosci. 5, 110 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zou, K. et al. Life span extension by glucose restriction is abrogated by methionine supplementation: cross-talk between glucose and methionine and implication of methionine as a key regulator of life span. Sci. Adv. 6, eaba1306 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Torres, J. A. et al. Ketosis ameliorates renal cyst growth in polycystic kidney disease. Cell Metab. 30, 1007–1023.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Oehm, S. et al. RESET-PKD: a pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease. Nephrol. Dial. Transplant. 38, 1623–1635 (2023).

    Article  CAS  PubMed  Google Scholar 

  94. Cukoski, S. et al. Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD — a randomized controlled trial. Cell Rep. Med. 4, 101283 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Knol, M. G. E. et al. Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD. Nephrol. Dial. Transplant. 39, 838–847 (2023).

    Article  PubMed Central  Google Scholar 

  96. Anthony, J. C. et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J. Nutr. 130, 2413–2419 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Yamamoto, J. et al. Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease. Kidney Int. 92, 377–387 (2017).

    Article  CAS  PubMed  Google Scholar 

  98. Nguyen, D. T. et al. The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression. JCI Insight 8, e154773 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Klawitter, J. et al. Kynurenines in polycystic kidney disease. J. Nephrol. 36, 83–91 (2023).

    Article  CAS  PubMed  Google Scholar 

  100. Pawlak, K., Domaniewski, T., Mysliwiec, M. & Pawlak, D. Kynurenines and oxidative status are independently associated with thrombomodulin and von Willebrand factor levels in patients with end-stage renal disease. Thromb. Res. 124, 452–457 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Koye, D. N., Magliano, D. J., Nelson, R. G. & Pavkov, M. E. The global epidemiology of diabetes and kidney disease. Adv. Chronic Kidney Dis. 25, 121–132 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–986 (1993).

  103. Xie, X. et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet Lond. Engl. 387, 435–443 (2016).

    Article  Google Scholar 

  104. de Vries, A. P. J. et al. Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol. 2, 417–426 (2014).

    Article  PubMed  Google Scholar 

  105. DeFronzo, R. A., Reeves, W. B. & Awad, A. S. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat. Rev. Nephrol. 17, 319–334 (2021).

    Article  CAS  PubMed  Google Scholar 

  106. Fotheringham, A. K., Gallo, L. A., Borg, D. J. & Forbes, J. M. Advanced glycation end products (AGEs) and chronic kidney disease: does the modern diet AGE the kidney? Nutrients 14, 2675 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Palmer, N. D. et al. Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study. J. Clin. Endocrinol. Metab. 100, E463–E468 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Tillin, T. et al. Diabetes risk and amino acid profiles: cross-sectional and prospective analyses of ethnicity, amino acids and diabetes in a South Asian and European cohort from the SABRE (Southall And Brent REvisited) Study. Diabetologia 58, 968–979 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lotta, L. A. et al. Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a mendelian randomisation analysis. PLoS Med. 13, e1002179 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Jäger, S. et al. Mendelian randomization study on amino acid metabolism suggests tyrosine as causal trait for type 2 diabetes. Nutrients 12, 3890 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Mi, N. et al. Branched-chain amino acids attenuate early kidney injury in diabetic rats. Biochem. Biophys. Res. Commun. 466, 240–246 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Tofte, N. et al. Metabolomic assessment reveals alteration in polyols and branched chain amino acids associated with present and future renal impairment in a discovery cohort of 637 persons with type 1 diabetes. Front. Endocrinol. 10, 818 (2019).

    Article  Google Scholar 

  114. Welsh, P. et al. Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial. Diabetologia 61, 1581–1591 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhou, C. et al. Metabolomic profiling of amino acids in human plasma distinguishes diabetic kidney disease from type 2 diabetes mellitus. Front. Med. 8, 765873 (2021).

    Article  Google Scholar 

  116. Zhu, H. et al. Impaired amino acid metabolism and its correlation with diabetic kidney disease progression in type 2 diabetes mellitus. Nutrients 14, 3345 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Majumder, S. et al. Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease. J. Clin. Invest. 128, 483–499 (2018).

    Article  PubMed  Google Scholar 

  118. Komers, R. et al. Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes. Lab. Investig. J. Tech. Methods Pathol. 93, 543–552 (2013).

    Article  CAS  Google Scholar 

  119. Chen, H. et al. Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver. Nat. Commun. 13, 3835 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Handzlik, M. K. et al. Insulin-regulated serine and lipid metabolism drive peripheral neuropathy. Nature 614, 118–124 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Santos-Silva, J. C. et al. Taurine supplementation ameliorates glucose homeostasis, prevents insulin and glucagon hypersecretion, and controls β, α, and δ-cell masses in genetic obese mice. Amino Acids 47, 1533–1548 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, R. et al. Taurine supplementation reverses diabetes-induced podocytes injury via modulation of the CSE/TRPC6 axis and improvement of mitochondrial function. Nephron 144, 84–95 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Singh, P. et al. Taurine deficiency as a driver of aging. Science 380, eabn9257 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Branco, R. C. S. et al. Long-term taurine supplementation leads to enhanced hepatic steatosis, renal dysfunction and hyperglycemia in mice fed on a high-fat diet. Adv. Exp. Med. Biol. 803, 339–351 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Tao, X., Zhang, Z., Yang, Z. & Rao, B. The effects of taurine supplementation on diabetes mellitus in humans: a systematic review and meta-analysis. Food Chem. Mol. Sci. 4, 100106 (2022).

    Article  CAS  Google Scholar 

  126. Kidney Disease: Improving Global Outcomes (KDIGO), Acute Kidney Injury Work Group KDIGO clinical practice guideline for acute kidney injury. Kidney Int. Suppl. 2, 6 (2012).

  127. Ronco, C., Bellomo, R. & Kellum, J. A. Acute kidney injury. Lancet 394, 1949–1964 (2019).

    Article  CAS  PubMed  Google Scholar 

  128. Price, S. R. et al. Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism. J. Am. Soc. Nephrol. 9, 439 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Sieckmann, T. et al. Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury. Kidney Int. 104, 90–107 (2023).

    Article  CAS  PubMed  Google Scholar 

  130. Boudonck, K. J. et al. Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol. Pathol. 37, 280–292 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Oken, D. E., Sprinkel, F. M., Kirschbaum, B. B. & Landwehr, D. M. Amino acid therapy in the treatment of experimental acute renal failure in the rat. Kidney Int. 17, 14–23 (1980).

    Article  CAS  PubMed  Google Scholar 

  132. Abel, R. M. et al. Improved survival from acute renal failure after treatment with intravenous essential L-amino acids and glucose. N. Engl. J. Med. 288, 695–699 (1973).

    Article  CAS  PubMed  Google Scholar 

  133. Singer, P. High-dose amino acid infusion preserves diuresis and improves nitrogen balance in non-oliguric acute renal failure. Wien. Klin. Wochenschr. 119, 218–222 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Landoni, G. et al. A randomized trial of intravenous amino acids for kidney protection. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2403769 (2024).

  135. Mitchell, J. R. et al. Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell 9, 40–53 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Koehler, F. C. et al. A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism. Transl. Res. J. Lab. Clin. Med. 244, 32–46 (2022).

    CAS  Google Scholar 

  137. Späth, M. R. et al. Organ protection by caloric restriction depends on activation of the de novo NAD+ synthesis pathway. J. Am. Soc. Nephrol. 34, 772–792 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Grundmann, F. et al. Preoperative short-term calorie restriction for prevention of acute kidney injury after cardiac surgery: a randomized, controlled, open-label, pilot trial. J. Am. Heart Assoc. 7, e008181 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Grundmann, F. et al. Dietary restriction for prevention of contrast-induced acute kidney injury in patients undergoing percutaneous coronary angiography: a randomized controlled trial. Sci. Rep. 10, 5202 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Robertson, L. T. et al. Protein and calorie restriction contribute additively to protection from renal ischemia reperfusion injury partly via leptin reduction in male mice. J. Nutr. 145, 1717–1727 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hine, C. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132–144 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Osterholt, T. et al. Preoperative short‐term restriction of sulfur‐containing amino acid intake for prevention of acute kidney injury after cardiac surgery: a randomized, controlled, double‐blind, translational trial. J. Am. Heart Assoc. 11, e025229 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Piret, S. E. et al. Krüppel-like factor 6–mediated loss of BCAA catabolism contributes to kidney injury in mice and humans. Proc. Natl Acad. Sci. USA 118, e2024414118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Nagata, S. et al. Regular exercise and branched-chain amino acids prevent ischemic acute kidney injury-related muscle wasting in mice. Physiol. Rep. 8, e14557 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Navarro Garrido, A. et al. Aristolochic acid-induced nephropathy is attenuated in mice lacking the neutral amino acid transporter B0AT1 (Slc6a19). Am. J. Physiol. Renal Physiol. 323, F455–F467 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Nakade, Y. et al. Gut microbiota-derived D-serine protects against acute kidney injury. JCI Insight 3, e97957 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Sasabe, J. et al. Interplay between microbial D-amino acids and host D-amino acid oxidase modifies murine mucosal defence and gut microbiota. Nat. Microbiol. 1, 1–7 (2016).

    Article  Google Scholar 

  148. Meyer, T., Ichikawa, I., Zatz, R. & Brenner, B. The renal hemodynamic response to amino acid infusion in the rat. Trans. Assoc. Am. Physicians 96, 76–83 (1983).

    CAS  PubMed  Google Scholar 

  149. Seney, F. D. Jr, Persson, E. G. & Wright, F. S. Modification of tubuloglomerular feedback signal by dietary protein. Am. J. Physiol. Renal Physiol. 252, F83–F90 (1987).

    Article  Google Scholar 

  150. Yao, B., Xu, J., Qi, Z., Harris, R. C. & Zhang, M.-Z. Role of renal cortical cyclooxygenase-2 expression in hyperfiltration in rats with high-protein intake. Am. J. Physiol. Renal Physiol. 291, F368–F374 (2006).

    Article  CAS  PubMed  Google Scholar 

  151. Sekine, Y. et al. Amino acid transporter LAT3 is required for podocyte development and function. J. Am. Soc. Nephrol. 20, 1586–1596 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kurayama, R. et al. Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis. Lab. Invest. 91, 992–1006 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Tian, Z. & Liang, M. Renal metabolism and hypertension. Nat. Commun. 12, 963 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Cheng, Y. et al. Urinary metabolites associated with blood pressure on a low- or high-sodium diet. Theranostics 8, 1468–1480 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Rinschen, M. M. et al. Metabolic rewiring of the hypertensive kidney. Sci. Signal. 12, (2019).

  156. Shah, V. O. et al. Plasma metabolomic profiles in different stages of CKD. Clin. J. Am. Soc. Nephrol. 8, 363–370 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. Jia, Y. et al. Long-term high intake of whole proteins results in renal damage in pigs. J. Nutr. 140, 1646–1652 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Obeid, W., Hiremath, S. & Topf, J. M. Protein restriction for CKD: time to move on. Kidney360 3, 1611–1615 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Koppe, L., Fouque, D. & Soulage, C. O. The role of gut microbiota and diet on uremic retention solutes production in the context of chronic kidney disease. Toxins 10, 155 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Vanholder, R., Schepers, E., Pletinck, A., Nagler, E. V. & Glorieux, G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J. Am. Soc. Nephrol. 25, 1897 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Barreto, F. C. et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 4, 1551 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Yang, Y., Mihajlovic, M., Janssen, M. J. & Masereeuw, R. The uremic toxin indoxyl sulfate accelerates senescence in kidney proximal tubule cells. Toxins 15, 242 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Sun, C.-Y., Chang, S.-C. & Wu, M.-S. Uremic toxins induce kidney fibrosis by activating intrarenal renin–angiotensin–aldosterone system associated epithelial-to-mesenchymal transition. PLoS One 7, e34026 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Owada, S. et al. Indoxyl sulfate reduces superoxide scavenging activity in the kidneys of normal and uremic rats. Am. J. Nephrol. 28, 446–454 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  166. Dou, L. et al. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int. 93, 986–999 (2018).

    Article  CAS  PubMed  Google Scholar 

  167. Kolachalama, V. B. et al. Uremic solute-aryl hydrocarbon receptor-tissue factor axis associates with thrombosis after vascular injury in humans. J. Am. Soc. Nephrol. 29, 1063–1072 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Patel, K. P., Luo, F. J.-G., Plummer, N. S., Hostetter, T. H. & Meyer, T. W. The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. Clin. J. Am. Soc. Nephrol. 7, 982–988 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Cheng, Y. et al. The relationship between blood metabolites of the tryptophan pathway and kidney function: a bidirectional Mendelian randomization analysis. Sci. Rep. 10, 12675 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Fernstrom, J. D. & Fernstrom, M. H. Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J. Nutr. 137, 1539S–1547S (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Meijers, B. K. I. et al. p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin. J. Am. Soc. Nephrol. 5, 1182–1189 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Fernandes, A. L. F. et al. Dietary intake of tyrosine and phenylalanine, and p-cresyl sulfate plasma levels in non-dialyzed patients with chronic kidney disease. J. Bras. Nefrol. 42, 307–314 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Barba, C. et al. A low aromatic amino-acid diet improves renal function and prevent kidney fibrosis in mice with chronic kidney disease. Sci. Rep. 11, 19184 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Billing, A. M. et al. Metabolic communication by SGLT2 inhibition. Circulation 149, 860–884 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Pillai, S. M. et al. Differential impact of dietary branched chain and aromatic amino acids on chronic kidney disease progression in rats. Front. Physiol. 10, 1460 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Newgard, C. B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Wilcken, D. E. & Wilcken, B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J. Clin. Invest. 57, 1079–1082 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Jamison, R. L. et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease a randomized controlled trial. JAMA 298, 1163–1170 (2007).

    Article  CAS  PubMed  Google Scholar 

  179. Martí-Carvajal, A. J., Solà, I., Lathyris, D. & Dayer, M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst. Rev. 8, CD006612 (2017).

    PubMed  Google Scholar 

  180. Xiao, Y. et al. Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism. Int. J. Biochem. Cell Biol. 67, 158–166 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Green, T. J. et al. Homocysteine-lowering vitamins do not lower plasma S-adenosylhomocysteine in older people with elevated homocysteine concentrations. Br. J. Nutr. 103, 1629–1634 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Stam, F. et al. Homocysteine clearance and methylation flux rates in health and end-stage renal disease: association with S-adenosylhomocysteine. Am. J. Physiol. Renal Physiol. 287, F215–F223 (2004).

    Article  CAS  PubMed  Google Scholar 

  183. Ingrosso, D. et al. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 361, 1693–1699 (2003).

    Article  CAS  PubMed  Google Scholar 

  184. Garibotto, G. et al. The kidney is the major site of S-adenosylhomocysteine disposal in humans. Kidney Int. 76, 293–296 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Schievink, B. et al. Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes. Diabetes Obes. Metab. 18, 64–71 (2016).

    Article  CAS  PubMed  Google Scholar 

  186. Hesaka, A. et al. D-Serine reflects kidney function and diseases. Sci. Rep. 9, 5104 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Lee, H., Jang, H. B., Yoo, M.-G., Park, S. I. & Lee, H.-J. Amino acid metabolites associated with chronic kidney disease: an eight-year follow-up Korean epidemiology study. Biomedicines 8, 222 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Dahabiyeh, L. A. et al. Metabolomics profiling distinctively identified end-stage renal disease patients from chronic kidney disease patients. Sci. Rep. 13, 6161 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Rhee, E. P. et al. A combined epidemiologic and metabolomic approach improves CKD prediction. J. Am. Soc. Nephrol. 24, 1330–1338 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Bello, A. K. et al. Epidemiology of haemodialysis outcomes. Nat. Rev. Nephrol. 18, 378–395 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Post, A. et al. Amino acid homeostasis and fatigue in chronic hemodialysis patients. Nutrients 14, 2810 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Ikizler, T. A. et al. Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation. Am. J. Physiol. Endocrinol. Metab. 282, E107–E116 (2002).

    Article  CAS  PubMed  Google Scholar 

  193. Hendriks, F. K. et al. Branched-chain ketoacid co-ingestion with protein lowers amino acid oxidation during hemodialysis: a randomized controlled cross-over trial. Clin. Nutr. 42, 1436–1444 (2023).

    Article  CAS  PubMed  Google Scholar 

  194. Koppe, L., Cassani de Oliveira, M. & Fouque, D. Ketoacid analogues supplementation in chronic kidney disease and future perspectives. Nutrients 11, 2071 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Thiele, I. et al. Personalized whole-body models integrate metabolism, physiology, and the gut microbiome. Mol. Syst. Biol. 16, e8982 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Harris, A. N. & Weiner, I. D. Sex differences in renal ammonia metabolism. Am. J. Physiol. Renal Physiol. 320, F55–F60 (2021).

    Article  CAS  PubMed  Google Scholar 

  197. Li, Q., McDonough, A. A., Layton, H. E. & Layton, A. T. Functional implications of sexual dimorphism of transporter patterns along the rat proximal tubule: modeling and analysis. Am. J. Physiol. Renal Physiol. 315, F692–F700 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Yahyaoui, R. & Pérez-Frías, J. Amino acid transport defects in human inherited metabolic disorders. Int. J. Mol. Sci. 21, 119 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  199. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Online Mendelian Inheritance in Man, OMIM https://omim.org/ (2023).

  200. Bröer, S. & Bröer, A. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem. J. 474, 1935–1963 (2017).

    Article  PubMed  Google Scholar 

  201. Camargo, S. M., Poncet, N. & Verrey, F. in Studies of Epithelial Transporters and Ion Channels: Ion Channels and Transporters of Epithelia in Health and Disease Vol. 3 (eds Hamilton, K. L. & Devor, D. C.) 255–323 (Springer International Publishing, 2020).

  202. Hediger, Matthias. A. SLCtables. http://slc.bioparadigms.org/ (2019).

  203. Grewer, C., Gameiro, A. & Rauen, T. SLC1 glutamate transporters. Pflugers Arch. 466, 3–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  204. Scopelliti, A. J., Heinzelmann, G., Kuyucak, S., Ryan, R. M. & Vandenberg, R. J. Na+ interactions with the neutral amino acid transporter ASCT1. J. Biol. Chem. 289, 17468–17479 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Zerangue, N. & Kavanaugh, M. P. ASCT-1 is a neutral amino acid exchanger with chloride channel activity. J. Biol. Chem. 271, 27991–27994 (1996).

    Article  CAS  PubMed  Google Scholar 

  206. Bhutia, Y. D. & Ganapathy, V. Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochim. Biophys. Acta 1863, 2531–2539 (2016).

    Article  CAS  PubMed  Google Scholar 

  207. Fotiadis, D., Kanai, Y. & Palacín, M. The SLC3 and SLC7 families of amino acid transporters. Mol. Asp. Med. 34, 139–158 (2013).

    Article  CAS  Google Scholar 

  208. Rasola, A., Galietta, L. J. V., Barone, V., Romeo, G. & Bagnasco, S. Molecular cloning and functional characterization of a GABA/betaine transporter from human kidney. FEBS Lett. 373, 229–233 (1995).

    Article  CAS  PubMed  Google Scholar 

  209. Bröer, S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol. Rev. 88, 249–286 (2008).

    Article  PubMed  Google Scholar 

  210. Bröer, A. et al. The orphan transporter v7-3 (slc6a15) is a Na+-dependent neutral amino acid transporter (B0AT2). Biochem. J. 393, 421–430 (2006).

    Article  PubMed  Google Scholar 

  211. Bröer, S. & Gether, U. The solute carrier 6 family of transporters. Br. J. Pharmacol. 167, 256–278 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Nagamori, S. et al. Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1. Proc. Natl Acad. Sci. USA 113, 775–780 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Thwaites, D. T. & Anderson, C. M. The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br. J. Pharmacol. 164, 1802–1816 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Roshanbin, S. et al. Histological characterization of orphan transporter MCT14 (SLC16A14) shows abundant expression in mouse CNS and kidney. BMC Neurosci. 17, 43 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Ramadan, T. et al. Basolateral aromatic amino acid transporter TAT1 (Slc16a10) functions as an efflux pathway. J. Cell. Physiol. 206, 771–779 (2006).

    Article  CAS  PubMed  Google Scholar 

  216. Zhou, Y. et al. Deletion of the γ-aminobutyric acid transporter 2 (GAT2 and SLC6A13) gene in mice leads to changes in liver and brain taurine contents. J. Biol. Chem. 287, 35733–35746 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Pillai, S. M. & Meredith, D. SLC36A4 (hPAT4) is a high affinity amino acid transporter when expressed in xenopus laevis oocytes. J. Biol. Chem. 286, 2455–2460 (2011).

    Article  CAS  PubMed  Google Scholar 

  218. Bodoy, S., Fotiadis, D., Stoeger, C., Kanai, Y. & Palacín, M. The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol. Asp. Med. 34, 638–645 (2013).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Martine G. E. Knol, Vera C. Wulfmeyer & Markus M. Rinschen

  2. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    Martine G. E. Knol

  3. Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

    Roman-Ulrich Müller

  4. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany

    Roman-Ulrich Müller

  5. III Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

    Markus M. Rinschen

  6. Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark

    Markus M. Rinschen

  7. Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Markus M. Rinschen

Authors
  1. Martine G. E. Knol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vera C. Wulfmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roman-Ulrich Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Markus M. Rinschen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Markus M. Rinschen.

Ethics declarations

Competing interests

R.U.M. is a member of the scientific advisory board of Santa Barbara Nutrients and chair of the working group Genes&Kidney of the European Renal Association. M.M.R. reports research funding from Novo Nordisk A/S. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Nephrology thanks Ling Zheng, Sarantos Kostidis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Knol, M.G.E., Wulfmeyer, V.C., Müller, RU. et al. Amino acid metabolism in kidney health and disease. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00872-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41581-024-00872-8

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing