Sex and the kidneys: current understanding and research opportunities

Article metrics

Subjects

Abstract

Concerns regarding sex differences are increasingly pertinent in scientific and societal arenas. Although biological sex and socio-cultural gender are increasingly recognized as important modulators of renal function under physiological and pathophysiological conditions, gaps remain in our understanding of the mechanisms underlying sex differences in renal pathophysiology, disease development, progression and management. In this Perspectives article, we discuss specific opportunities for future research aimed at addressing these knowledge gaps. Such opportunities include the development of standardized core data elements and outcomes related to sex for use in clinical studies to establish a connection between sex hormones and renal disease development or progression, development of a knowledge portal to promote fundamental understanding of physiological differences between male and female kidneys in animal models and in humans, and the creation of new or the development of existing resources and datasets to make them more readily available for interrogation of sex differences. These ideas are intended to stimulate thought and interest among the renal research community as they consider sex as a biological variable in future research projects.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Strategies to aid understanding of sex differences in kidney health and disease.

References

  1. 1.

    National Institutes of Health. NIH guidelines on the inclusion of women and minorities as subjects in clinical research. Fed. Register 59, 14508–14513 (1994).

  2. 2.

    Scott, P. E. et al. Participation of women in clinical trials supporting fda approval of cardiovascular drugs. J. Am. Coll. Cardiol. 71, 1960–1969 (2018).

  3. 3.

    Pilote, L. & Raparelli, V. Participation of women in clinical trials: not yet time to rest on our laurels. J. Am. Coll. Cardiol. 71, 1970–1972 (2018).

  4. 4.

    Geller, S. E., Koch, A., Pellettieri, B. & Carnes, M. Inclusion, analysis, and reporting of sex and race/ethnicity in clinical trials: have we made progress? J. Womens Health 20, 315–320 (2011).

  5. 5.

    National Institutes of Health. Consideration of sex a biological variable in NIH-funded research. NIH https://grants.nih.gov/grants/guide/notice-files/not-od-15-102.html (2015).

  6. 6.

    Silbiger, S. & Neugarten, J. Gender and human chronic renal disease. Gend. Med. 5, S3–S10 (2008).

  7. 7.

    Silbiger, S. R. & Neugarten, J. The role of gender in the progression of renal disease. Adv Ren. Replace. Ther. 10, 3–14 (2003).

  8. 8.

    Neugarten, J., Acharya, A. & Silbiger, S. R. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J. Am. Soc. Nephrol. 11, 319–329 (2000).

  9. 9.

    Carrero, J. J., Hecking, M., Chesnaye, N. C. & Jager, K. J. Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Nat. Rev. Nephrol. 14, 151–164 (2018).

  10. 10.

    Cobo, G. et al. Sex and gender differences in chronic kidney disease: progression to end-stage renal disease and haemodialysis. Clin. Sci. (Lond.) 130, 1147–1163 (2016).

  11. 11.

    Ricardo, A. C. et al. Sex-related disparities in CKD progression. J. Am. Soc. Nephrol. 30, 137–146 (2018).

  12. 12.

    Tanaka, R. et al. Protective effect of 17beta-estradiol on ischemic acute kidney injury through the renal sympathetic nervous system. Eur. J. Pharmacol. 683, 270–275 (2012).

  13. 13.

    Delle, H. et al. Antifibrotic effect of tamoxifen in a model of progressive renal disease. J. Am. Soc. Nephrol. 23, 37–48 (2012).

  14. 14.

    Mankhey, R. W., Bhatti, F. & Maric, C. 17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 288, F399–F405 (2005).

  15. 15.

    Zimmerman, M. A. et al. Long- but not short-term estradiol treatment induces renal damage in midlife ovariectomized Long-Evans rats. Am. J. Physiol. Ren. Physiol. 312, F305–F311 (2017).

  16. 16.

    Institute of Medicine (US) Committee on Understanding the Biology of Sex and Gender Differences. Exploring the Biological Contributions to Human Health: Does Sex Matter? Vol. 10 (eds Wizemann, T. M. & Parde, M.-L.) 433–439 (National Academies Press, 2001).

  17. 17.

    Hill, N. R. et al. Global prevalence of chronic kidney disease — a systematic review and meta-analysis. PLOS ONE 11, e0158765 (2016).

  18. 18.

    Mills, K. T. et al. A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010. Kidney Int. 88, 950–957 (2015).

  19. 19.

    Zhang, Q. L. & Rothenbacher, D. Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health 8, 117 (2008).

  20. 20.

    Murphy, D. et al. Trends in prevalence of chronic kidney disease in the united states. Ann. Intern. Med. 165, 473–481 (2016).

  21. 21.

    United States Renal Data System. Atlas of chronic disease and end-stage renal disease in the United States. (National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. 2012).

  22. 22.

    Glassock, R. J. & Winearls, C. An epidemic of chronic kidney disease: fact or fiction? Nephrol. Dial Transpl. 23, 1117–1121 (2008).

  23. 23.

    Neugarten, J. & Golestaneh, L. Influence of sex on the progression of chronic kidney disease. Mayo Clin. Proc. 94, 1339–1356 (2019).

  24. 24.

    Silbiger, S. R. & Neugarten, J. The impact of gender on the progression of chronic renal disease. Am. J. Kidney Dis. 25, 515–533 (1995).

  25. 25.

    Gilg, J., Castledine, C. & Fogarty, D. Chapter 1 UK RRT incidence in 2010: national and centre-specific analyses. Nephron Clin. Pract. 120, c1–c27 (2012).

  26. 26.

    Hecking, M. et al. Sex-specific differences in hemodialysis prevalence and practices and the male-to-female mortality rate: the dialysis outcomes and practice patterns study (DOPPS). PLOS MED. 11, e1001750 (2014).

  27. 27.

    Iseki, K. et al. Increasing gender difference in the incidence of chronic dialysis therapy in Japan. Ther. Apher. Dial 9, 407–411 (2005).

  28. 28.

    Ricardo, A. C. et al. Sex-related disparities in CKD progression. J. Am. Soc. Nephrol. 30, 137–146 (2019).

  29. 29.

    Kattah, A. G. et al. CKD in patients with bilateral oophorectomy. Clin J. Am. Soc. Nephrol. 7, 1649–1658 (2018).

  30. 30.

    Elliot, S. J. et al. Estrogen deficiency accelerates progression of glomerulosclerosis in susceptible mice. Am. J. Pathol. 162, 1441–1448 (2003).

  31. 31.

    Reckelhoff, J. F. & Baylis, C. Glomerular metalloprotease activity in the aging rat kidney: inverse correlation with injury. J. Am. Soc. Nephrol. 3, 1835–1838 (1993).

  32. 32.

    Melamed, M. L. et al. Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis. Kidney Int. 79, 241–249 (2011).

  33. 33.

    Sandberg, K., Pai, A. V. & Maddox, T. Sex and rigor: the TGF-beta blood pressure affair. Am. J. Physiol. Ren. Physiol. 313, F1087–F1088 (2017).

  34. 34.

    Inada, A. et al. Adjusting the 17beta-estradiol-to-androgen ratio ameliorates diabetic nephropathy. J. Am. Soc. Nephrol. 27, 3035–3050 (2016).

  35. 35.

    Dixon, A. & Maric, C. 17beta-Estradiol attenuates diabetic kidney disease by regulating extracellular matrix and transforming growth factor-beta protein expression and signaling. Am. J. Physiol. Ren. Physiol. 293, F1678–F1690 (2007).

  36. 36.

    Doublier, S. et al. Testosterone and 17beta-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice. Kidney Int. 79, 404–413 (2011).

  37. 37.

    Catanuto, P. et al. 17 beta-estradiol and tamoxifen upregulate estrogen receptor beta expression and control podocyte signaling pathways in a model of type 2 diabetes. Kidney Int. 75, 1194–1201 (2009).

  38. 38.

    Keck, M., Romero-Aleshire, M. J., Cai, Q., Hoyer, P. B. & Brooks, H. L. Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause. Am. J. Physiol. Ren. Physiol. 293, F193–F199 (2007).

  39. 39.

    Sullivan, J. C., Semprun-Prieto, L., Boesen, E. I., Pollock, D. M. & Pollock, J. S. Sex and sex hormones influence the development of albuminuria and renal macrophage infiltration in spontaneously hypertensive rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1573–R1579 (2007).

  40. 40.

    Lopez-Ruiz, A., Sartori-Valinotti, J., Yanes, L. L., Iliescu, R. & Reckelhoff, J. F. Sex differences in control of blood pressure: role of oxidative stress in hypertension in females. Am. J. Physiol. Heart. Circ. Physiol. 295, H466–H474 (2008).

  41. 41.

    Manigrasso, M. B., Sawyer, R. T., Marbury, D. C., Flynn, E. R. & Maric, C. Inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induced diabetic rats. Am. J. Physiol. Ren. Physiol. 301, F634–F640 (2011).

  42. 42.

    Manigrasso, M. B., Sawyer, R. T., Hutchens, Z. M. Jr., Flynn, E. R. & Maric-Bilkan, C. Combined inhibition of aromatase activity and dihydrotestosterone supplementation attenuates renal injury in male streptozotocin (STZ)-induced diabetic rats. Am. J. Physiol. Ren. Physiol. 302, F1203–F1209 (2012).

  43. 43.

    Fortepiani, L. A., Yanes, L., Zhang, H., Racusen, L. C. & Reckelhoff, J. F. Role of androgens in mediating renal injury in aging SHR. Hypertension 42, 952–955 (2003).

  44. 44.

    Baltatu, O. et al. Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. J. Am. Soc. Nephrol. 13, 2681–2687 (2002).

  45. 45.

    Ji, H. et al. Sex chromosome effects unmasked in angiotensin II-induced hypertension. Hypertension 55, 1275–1282 (2010).

  46. 46.

    Jean-Faucher, C. et al. Sex-related differences in renal size in mice: ontogeny and influence of neonatal androgens. J. Endocrinol. 115, 241–246 (1987).

  47. 47.

    Neugarten, J., Kasiske, B., Silbiger, S. R. & Nyengaard, J. R. Effects of sex on renal structure. Nephron 90, 139–144 (2002).

  48. 48.

    Oudar, O. et al. Differences in rat kidney morphology between males, females and testosterone-treated females. Ren. Physiol. Biochem. 14, 92–102 (1991).

  49. 49.

    Baylis, C. Sexual dimorphism of the aging kidney: role of nitric oxide deficiency. Physiology 23, 142–150 (2008).

  50. 50.

    Munger, K. & Baylis, C. Sex differences in renal hemodynamics in rats. Am. J. Physiol. 254, F223–F231 (1988).

  51. 51.

    Remuzzi, A., Puntorieri, S., Mazzoleni, A. & Remuzzi, G. Sex related differences in glomerular ultrafiltration and proteinuria in munich-wistar rats. Kidney Int. 34, 481–486 (1988).

  52. 52.

    Sabolic, I. et al. Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am. J .Physiol. Cell Physiol. 302, C1174–C1188 (2012).

  53. 53.

    Veiras, L. C. et al. Sexual dimorphic pattern of renal transporters and electrolyte homeostasis. J. Am. Soc. Nephrol. 28, 3504–3517 (2017).

  54. 54.

    Herak-Kramberger, C. M. et al. Sex-dependent expression of water channel AQP1 along the rat nephron. Am. J. Physiol. Ren. Physiol. 308, F809–F821 (2015).

  55. 55.

    Breljak, D., Brzica, H., Sweet, D. H., Anzai, N. & Sabolic, I. Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys. Am. J. Physiol. Ren. Physiol. 304, F1114–F1126 (2013).

  56. 56.

    Breljak, D. et al. Renal expression of organic anion transporter Oat5 in rats and mice exhibits the female-dominant sex differences. Histol. Histopathol. 25, 1385–1402 (2010).

  57. 57.

    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. Ren. Physiol. 315, F692–F700 (2018).

  58. 58.

    Pelletier, G. Localization of androgen and estrogen receptors in rat and primate tissues. Histol. Histopathol. 15, 1261–1270 (2000).

  59. 59.

    Boese, A. C., Kim, S. C., Yin, K. J., Lee, J. P. & Hamblin, M. H. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am. J. Physiol. Heart. Circ. Physiol. 313, H524–H545 (2017).

  60. 60.

    Marrocco, J. & McEwen, B. S. Sex in the brain: hormones and sex differences. Dialogues Clin. Neurosci. 18, 373–383 (2016).

  61. 61.

    Barton, M. Position paper: the membrane estrogen receptor GPER — clues and questions. Steroids 77, 935–942 (2012).

  62. 62.

    Stefkovich, M. L., Arao, Y., Hamilton, K. J. & Korach, K. S. Experimental models for evaluating non-genomic estrogen signaling. Steroids 133, 34–37 (2018).

  63. 63.

    Chang, C., Yeh, S., Lee, S. O. & Chang, T. M. Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells. Nucl. Recept. Signal 11, e001 (2013).

  64. 64.

    Arnold, A. P. & Chen, X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front. Neuroendocrinol. 30, 1–9 (2009).

  65. 65.

    Pessoa, B. S. et al. Angiotensin II Type 2 receptor- and acetylcholine-mediated relaxation: essential contribution of female sex hormones and chromosomes. Hypertension 66, 396–402 (2015).

  66. 66.

    Caeiro, X. E., Mir, F. R., Vivas, L. M., Carrer, H. F. & Cambiasso, M. J. Sex chromosome complement contributes to sex differences in bradycardic baroreflex response. Hypertension 58, 505–511 (2011).

  67. 67.

    Arnold, A. P., Chen, X. & Itoh, Y. What a difference an X or Y makes: sex chromosomes, gene dose, and epigenetics in sexual differentiation. Handb. Exp. Pharmacol. 67–88 (2012).

  68. 68.

    Ramsey, J. M., Cooper, J. D., Penninx, B. W. & Bahn, S. Variation in serum biomarkers with sex and female hormonal status: implications for clinical tests. Sci. Rep. 6, 26947 (2016).

  69. 69.

    Sobhani, K. et al. Sex differences in ischemic heart disease and heart failure biomarkers. Biol. Sex Differ. 9, 43 (2018).

  70. 70.

    Rogowski, O. et al. Gender difference in C-reactive protein concentrations in individuals with atherothrombotic risk factors and apparently healthy ones. Biomarkers 9, 85–92 (2004).

  71. 71.

    Seppi, T. et al. Sex differences in renal proximal tubular cell homeostasis. J. Am. Soc. Nephrol. 27, 3051–3062 (2016).

  72. 72.

    Tsuji, S., Sugiura, M., Tsutsumi, S. & Yamada, H. Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats. J. Toxicol. Sci. 42, 615–627 (2017).

  73. 73.

    Lew, J. et al. Sex-based differences in cardiometabolic biomarkers. Circulation 135, 544–555 (2017).

  74. 74.

    Soldin, O. P. & Mattison, D. R. Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet. 48, 143–157 (2009).

  75. 75.

    Liu, J. et al. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17beta-oestradiol-dependent and sex chromosome-independent. Biol. Sex Differ. 1, 6 (2010).

  76. 76.

    Sandberg, K. & Ji, H. Sex and the renin angiotensin system: implications for gender differences in the progression of kidney disease. Adv. Ren. Replace. Ther. 10, 15–23 (2003).

  77. 77.

    Roberts, M. A. Commentary on the KDIGO Clinical Practice Guideline for the management of blood pressure in chronic kidney disease. Nephrology 19, 53–55 (2014).

  78. 78.

    Ko, D. et al. Comparative effectiveness of ACE inhibitors and angiotensin receptor blockers in patients with prior myocardial infarction. Open Heart 6, 1 (2019).

  79. 79.

    Hudson, M., Rahme, E., Behlouli, H., Sheppard, R. & Pilote, L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — a population study. Eur. J. Heart Fail. 9, 602–609 (2007).

  80. 80.

    Kahan, B. D. et al. Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplant. 41, 459–464 (1986).

  81. 81.

    Zimmerman, J. J. Exposure-response relationships and drug interactions of sirolimus. AAPS J. 6, e28 (2004).

  82. 82.

    Magee, M. H., Blum, R. A., Lates, C. D. & Jusko, W. J. Prednisolone pharmacokinetics and pharmacodynamics in relation to sex and race. J. Clin. Pharmacol. 41, 1180–1194 (2001).

  83. 83.

    Tornatore, K. M. et al. Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients. Clin. Pharmacokinet. 54, 423–434 (2015).

  84. 84.

    Stolarz, A. J. & Rusch, N. J. Gender differences in cardiovascular drugs. Cardiovasc. Drugs Ther 29, 403–410 (2015).

  85. 85.

    Abdel-Rahman, A. A. Influence of sex on cardiovascular drug responses: role of estrogen. Curr. Opin. Pharmacol. 33, 1–5 (2017).

  86. 86.

    Wiik, A. et al. Metabolic and functional changes in transgender individuals following cross-sex hormone treatment: design and methods of the Gender Dysphoria Treatment in Sweden (GETS) study. Contemp. Clin. Trials Commun. 10, 148–153 (2018).

  87. 87.

    Getahun, D. et al. Cross-sex hormones and acute cardiovascular events in transgender persons: a cohort study. Ann. Intern. Med. 169, 205–213 (2018).

  88. 88.

    Kreukels, B. P. et al. A European network for the investigation of gender incongruence: the ENIGI initiative. Eur. Psychiatry 27, 445–450 (2012).

  89. 89.

    Zucker, I. & Beery, A. K. Males still dominate animal studies. Nature 465, 690 (2010).

  90. 90.

    Becker, J. B., Prendergast, B. J. & Liang, J. W. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol. Sex Differ. 7, 34 (2016).

  91. 91.

    Silbiger, S. R. Raging hormones: gender and renal disease. Kidney Int. 79, 382–384 (2011).

  92. 92.

    de Caestecker, M. et al. Bridging translation by improving preclinical study design in AKI. J. Am. Soc. Nephrol. 26, 2905–2916 (2015).

  93. 93.

    Karp, N. A. et al. Prevalence of sexual dimorphism in mammalian phenotypic traits. Nat. Commun. 8, 15475 (2017).

  94. 94.

    Sullivan, J. C. & Gillis, E. E. Sex and gender differences in hypertensive kidney injury. Am. J. Physiol. Ren. Physiol. 313, F1009–F1017 (2017).

  95. 95.

    Boddu, R. et al. Unique sex- and age-dependent effects in protective pathways in acute kidney injury. Am. J. Physiol. Ren. Physiol. 313, F740–F755 (2017).

  96. 96.

    de Alencar Franco Costa, D. et al. Sex-dependent differences in renal angiotensinogen as an early marker of diabetic nephropathy. Acta Physiol. 213, 740–746 (2015).

  97. 97.

    Kang, K. P. et al. Effect of gender differences on the regulation of renal ischemia-reperfusion-induced inflammation in mice. Mo. Med. Rep. 9, 2061–2068 (2014).

  98. 98.

    Bloor, I. D., Sebert, S. P., Mahajan, R. P. & Symonds, M. E. The influence of sex on early stage markers of kidney dysfunction in response to juvenile obesity. Hypertension 60, 991–997 (2012).

  99. 99.

    Abd-Elmoniem, K. Z. et al. X chromosome parental origin and aortic stiffness in turner syndrome. Clin. Endocrinol. 81, 467–470 (2014).

  100. 100.

    Van, P. L., Bakalov, V. K. & Bondy, C. A. Monosomy for the X-chromosome is associated with an atherogenic lipid profile. J. Clin. Endocrinol. Metab. 91, 2867–2870 (2006).

  101. 101.

    Bakalov, V. K., Cheng, C., Zhou, J. & Bondy, C. A. X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J. Clin. Endocrinol. Metab. 94, 3289–3296 (2009).

  102. 102.

    He, N. et al. At Term, XmO and XpO mouse placentas show differences in glucose metabolism in the trophectoderm-derived outer zone. Front. Cell Dev. Biol. 5, 63 (2017).

  103. 103.

    NIDDK. Kidney disease centers. NIH https://www.niddk.nih.gov/research-funding/research-programs/kidney-disease-centers (2019).

  104. 104.

    NIDDK. Effects of chronic kidney disease in adults study: CRIC. NIH https://www.niddk.nih.gov/about-niddk/research-areas/kidney-disease/effects-chronic-kidney-disease-adults-study-cric (2019).

  105. 105.

    CKID. Chronic kidney disease in children. John Hopkins University Bloomberg School of Public Health https://statepi.jhsph.edu/ckid (2019).

  106. 106.

    USRDS. United states renal data system. USRDS https://www.usrds.org (2019).

  107. 107.

    NIDDK. Kidney precision medical project. NIH https://www.niddk.nih.gov/research-funding/research-programs/kidney-precision-medicine-project-kpmp (2019).

  108. 108.

    Clayton, J. A. & Collins, F. S. Policy: NIH to balance sex in cell and animal studies. Nature 509, 282–283 (2014).

Download references

Acknowledgements

The authors thank all the invited speakers: K. Korach, S. Hammes, C. Smith, C. Disteche, F. Mauvais-Jarvis, A. Ricardo, J. Morton, J. Fuscoe, V. Garovic, J. Charlton and V. Miller, and all workshop participants for their thoughtful comments and ideas offered during the workshop. The authors thank the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) for providing funding for the workshop. The views expressed in this article are those of the authors and do not necessarily represent the views of the NIDDK, the US National Institutes of Health (NIH) or the United States Department of Health and Human Services.

Author information

All authors wrote the manuscript, made substantial contributions to discussions of the content and reviewed or edited the manuscript before submission. C. M.-B. researched data for the article.

Correspondence to Christine Maric-Bilkan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Related links

NIDDK Information Network: https://dknet.org/

Glossary

Parental imprinting

A process that results in allele-specific differences in transcription, DNA methylation and DNA replication timing.

X chromosome mosaicism

The presence of two populations of cells in the body: some cells have two X chromosomes whereas others have only one X chromosome.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark