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      Gender differences in the susceptibility of hospital-acquired acute kidney injury: more questions than answers

      review-article
      International Urology and Nephrology
      Springer Netherlands
      Hospital-acquired acute kidney injury, Sex dimorphism, Testosterone

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          Abstract

          Hospital-acquired acute kidney injury (HA-AKI) is a heterogeneous renal syndrome which occurs in different clinical settings. It is characterized by multiple aetiologies, various pathogeneses and unpredictable outcomes. HA-AKI, once predominantly viewed as a self-limited and reversible short-term condition, is now recognized as a harbinger for chronic kidney disease and a cause of long-term morbidity with an increased risk of cardiovascular, renal and cancer mortality. Recent clinical studies contradict the generally held belief that female sex is a risk factor for HA-AKI. They show, consistent with basic research performed with experimental models of AKI, that only male sex is associated with HA-AKI. The presence of testosterone, more likely than the absence of estrogen, plays a critical role in sex differences in the susceptibility of ischemia/reperfusion kidney injury. The conflicting data in epidemiological studies related to sex as susceptibility variable for human AKI, underscore the need for more rigorous, well designed observational studies taking into account the menopausal status and hormone therapy.

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          Most cited references18

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          KDIGO Clinical Practice Guidelines for Acute Kidney Injury

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            Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001.

            This study's objective was to determine the incidence and mortality of acute renal failure (ARF) in Medicare beneficiaries. Data were from hospitalized Medicare beneficiaries (5,403,015 discharges) between 1992 and 2001 from the 5% sample of Medicare claims. For 1992 to 2001, the overall incidence rate of ARF was 23.8 cases per 1000 discharges, with rates increasing by approximately 11% per year. Older age, male gender, and black race were strongly associated (P < 0.0001) with ARF. The overall in-hospital death rate was 4.6% in discharges without ARF, 15.2% in discharges with ARF coded as the principal diagnosis, and 32.6% in discharges with ARF as a secondary diagnosis. In-hospital death rates were 32.9% in discharges with ARF that required renal dialysis and 27.5% in those with ARF that did not require dialysis. Death within 90 d after hospital admission was 13.1% in discharges without ARF, 34.5% in discharges with ARF coded as the principal diagnosis, and 48.6% in discharges with ARF as a secondary diagnosis. Discharges with ARF were more (P < 0.0001) likely to have intensive care and other acute organ dysfunction than those without ARF. For discharges both with and without ARF, rates for death within 90 d after hospital admission showed a declining trend. In conclusion, the incidence rate of ARF in Medicare beneficiaries has been increasing. Those of older age, male gender, and black race are more likely to have ARF. These data show ARF to be a major contributor to morbidity and mortality in hospitalized patients.
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              Effect of gender differences on the regulation of renal ischemia-reperfusion-induced inflammation in mice

              Inflammation is a key mediator of renal ischemia-reperfusion (IR) injury. Gender disparities have been reported in acute and chronic kidney disease. In particular, males are considered to be more susceptible to renal ischemic injury compared with females according to animal studies. The purpose of the present study was to investigate the effect of gender on the renal inflammatory response following acute renal IR injury in mice. Experiments were performed in male and female C57BL/6 mice. Two weeks prior to the study, castration or ovariectomy were performed and testosterone propionate (100 μg/kg) or 17β-estradiol (100 μg/kg) was injected. Acute kidney injury (AKI) was induced by bilateral clamping of the renal pedicle for 23 min. Histological examination, western blot analysis and quantitative polymerase chain reaction were performed. In the acute renal IR injury model, the female mice were more resistant to kidney injury compared with the male mice. However, castration of the male mice reduced the levels of IR-induced tubular injury and macrophage infiltration compared with those in the injured male mice. Supplementation of testosterone reversed this protective effect in the male AKI model. Depletion of estrogen in the female mice increased the levels of IR-induced tubular injury and macrophage infiltration compared with those in the injured female mice. However, supplementation of estrogen in the ovariectomized female mice attenuated the IR-induced tubular injury and reduced the levels of macrophage infiltration. The expression levels of inflammatory cytokines, including tumor necrosis factor-α, monocyte chemotactic protein-1, interferon-γ and chemokine (C-C motif) ligand 17, were elevated in the male AKI mice compared with those in the control male mice, and were attenuated by castration. Estrogen depletion in the female mice significantly increased the expression levels of the renal inflammatory cytokines compared with those in the injured female mice, and were attenuated by estrogen supplementation in the ovariectomized female mice. These results suggested that the male gender confers greater susceptibility to IR renal injury due to an enhanced inflammatory response.
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                Author and article information

                Contributors
                h-schiffl@t-online.de
                Journal
                Int Urol Nephrol
                Int Urol Nephrol
                International Urology and Nephrology
                Springer Netherlands (Dordrecht )
                0301-1623
                1573-2584
                13 July 2020
                13 July 2020
                2020
                : 52
                : 10
                : 1911-1914
                Affiliations
                GRID grid.411095.8, ISNI 0000 0004 0477 2585, Department of Internal Medicine IV, , University Hospital LMU Munich, ; Ziemssenstr. 1, 80336 Munich, Germany
                Author information
                http://orcid.org/0000-0003-0604-6109
                Article
                2526
                10.1007/s11255-020-02526-7
                7515943
                32661623
                35ae0a26-fe4b-4ae5-a0cf-ce95911a6f0f
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 April 2020
                : 25 May 2020
                Categories
                Nephrology - Review
                Custom metadata
                © Springer Nature B.V. 2020

                Nephrology
                hospital-acquired acute kidney injury,sex dimorphism,testosterone
                Nephrology
                hospital-acquired acute kidney injury, sex dimorphism, testosterone

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