Does Gender-Affirming Hormone Therapy Affect the Kidney?

It is estimated that approximately 0.5% of the adult population identifies as transgender, which means that there are approximately 1 million transgender adults in the United States and over 25 million globally.¹ Gender-affirming hormone therapy (GAHT) modifies a person's sex hormones to align with that of their affirmed gender identity to change their secondary sexual characteristics. Masculinizing GAHT typically includes injectable or transdermal testosterone, and femininizing GAHT typically includes exogenous oral, sublingual, transdermal, or injectable estradiol with antiandrogen therapy (cyproterone acetate [CPA], mineralocorticoid receptor antagonists [MRAs], gonadotropin-releasing hormone agonists), but many different GAHT strategies exist.² GAHT improves quality of life but requires monitoring to avoid supratherapeutic sex hormone levels and adverse events such as thromboembolism and cardiovascular disease.³

Serum creatinine and cystatin C are biomarkers of kidney function that are used to estimate GFR using equations that adjust for their non-GFR determinants, such as age and sex/gender.^4,5 However, whether sex assigned at birth or gender identity is the appropriate input for these eGFR equations is unknown. This is relevant to transgender and gender-diverse patients whose sex assigned at birth and gender identity are not congruent, and discrepant eGFR values may lead the incorrect diagnosis, staging, and management of CKD.⁶ This uncertainty is further compounded by GAHT's different effects on body composition, lean muscle mass, and serum creatinine. We recently summarized the impact of masculinizing and femininizing GAHT on kidney function biomarkers in a systematic review and meta-analysis of nine studies with heterogeneity in study design, populations, GAHT routes, and dosing.⁷ At 12 months after initiating GAHT, serum creatinine increased by 0.15 mg/dl (95% CI [confidence interval], 0.00 to 0.29) in 370 transgender men and decreased by −0.05 mg/dl (95% CI, −0.16 to 0.05) in 361 transgender women. However, no study reported the impact of GAHT on albuminuria, proteinuria, cystatin C, or measured GFR. High-quality prospective data on how sex hormones such as oral contraception, sex hormone replacement therapy (estrogen, progesterone, testosterone), sex hormone deprivation therapy, and menopause/andropause affect kidney function in cisgender populations are also lacking.

In this issue of CJASN, van Eeghen et al. present the results of a kidney substudy of the European Network for the Investigation of Gender Incongruence (ENIGI), a large European multicenter prospective cohort study of GAHT in adults from centers in The Netherlands, Belgium, Germany, Norway, and Italy.⁸ They report the impact of GAHT on cystatin C, creatinine, and eGFR and contextualize changes in kidney function biomarkers relative to changes in lean body mass and sex hormones.⁸ They included ENIGI participants from Amsterdam with serum cystatin C and serum creatinine measurements in addition to lean body mass by dual x-ray absorptiometry measured before and after 12 months of GAHT.⁸ The population included 260 adult transgender women treated with oral (52%) or transdermal (45%) estradiol or delayed estrogen (2%) plus CPA (99%) (participants using other antiandrogens including spironolactone were excluded) targeting an estradiol level of >27 pg/ml and testosterone level of <58 ng/dl as well as 285 adult transgender men treated with injection (50%) or gel (50%) testosterone targeting a testosterone level of >288 ng/dl. GAHT dosage was ultimately guided by individual preferences, quality of life, symptoms, and comorbidities. eGFR was calculated using both the full-age spectrum cystatin C and creatinine equations (FAS_Cys and FAS_Cr) which do not include sex/gender and the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations for creatinine and combined creatinine and cystatin C (CKD-EPI_Cr, CKD-EPI_CrCys) using both sex and gender inputs. The study showed that cystatin C decreased by 0.069 mg/L (95% CI, 0.049 to 0.089) in transgender women corresponding to a 7 ml/min per 1.73 m² increase in eGFR FAS_Cys and increased by 0.052 mg/L (95% CI, 0.031 to 0.072) in transgender men corresponding to a 6 ml/min per 1.73 m² decrease in eGFR FAS_Cys. Creatinine decreased (−0.065 mg/dl; 95% CI, −0.076 to −0.054) in transgender women and increased (+0.131 mg/dl; 95% CI, 0.119 to 0.142) in transgender men, which is consistent with our previous work, which included 278 transgender men and 248 transgender women from the ENIGI study.⁷ However, the results of this study are more precise despite a smaller sample size, presumably related to a more homogeneous patient population, GAHT prescribing, and creatinine assay standardization. A sensitivity analysis that excluded participants with other GAHT regimens or medications that may affect kidney function/biomarkers did not alter their results, which were also consistent across subgroups defined by age and achieved recommended sex hormone targets. Interestingly, the change in serum cystatin C weakly correlated with both changes in estradiol and testosterone concentrations at 12 months, but this was only based on single hormone‐level measurements without any multivariable adjustment. The change in cystatin C was also less in transgender women after adjustment for changes in lean body mass and was no longer statistically significant in transgender men, suggesting that changes in cystatin C were driven by changes in body composition and not kidney function, but this cannot be confirmed without actually measuring GFR.

This study is novel because it is the first study to date reporting differences in serum cystatin C pre-GAHT or post-GAHT in transgender men and women in comparison with changes in sex hormones and body composition. Strengths include its size, power, use of standardized and calibrated creatinine/cystatin C assays, and the consistency of its sensitivity and subgroup analyses. As highlighted by the authors, limitations include the lack of any participants with CKD with an eGFR <60 ml/min per 1.73 m², noncontemporary estradiol targets, a follow-up duration of only 1 year without any repeated measures during this time, the potential influence of the glucocorticoid properties of CPA which may increase GFR, and a lack of any concurrent direct GFR measurements, which means that all changes in kidney function biomarkers cannot be fully adjusted for both their GFR and non-GFR determinants. In addition, the ENIGI study only recruited transgender adults and not gender-diverse persons at large, including adolescents and children where pubertal blockade typically precedes GAHT.⁹ Finally, generalizability to other settings may be a concern, especially to older patients with CKD risk factors given that the mean ages of transgender men and women in the study were 22 and 29 years, respectively. Furthermore, <5% of participants were non-White, and patients treated with spironolactone as an antiandrogen were excluded, which is particularly relevant given this MRA is the most commonly used androgen blocker in North America.

This is an important study, but there are many remaining questions regarding the intersection of gender-affirming care with kidney disease. First, studies in which measured GFR has been assessed pre-GAHT or post-GAHT in transgender or gender-diverse populations relative to serum creatinine and cystatin C and other kidney biomarkers are nonexistent. This is needed to properly determine whether changes in kidney function biomarkers are simply due to changes in body composition and lean muscle mass or due to actual changes in GFR or a combination of both mechanisms. Second, the performance of eGFR equations (accuracy, precision, and bias), including the CKD-EPI,⁴ European Kidney Function Consortium,⁵ and Chronic Kidney Disease in Children Under 25 equations, in adult, adolescent, and child transgender/gender-diverse populations need to be rigorously evaluated and potentially modified if they do not perform adequately pre-GAHT or post-GAHT because systematic errors in eGFR may exacerbate health inequities in transgender/gender-diverse populations and potentially result in harm on an individual patient basis. In the interim, clinicians are forced to rely on imputing both sex assigned at birth and gender to provide a range of possible eGFR values to be interpreted relative to lean muscle mass and timing relative to GAHT. Third, there are currently no studies in which quantified urine albuminuria, urine proteinuria, or urine creatinine (by either spot collections or 24‐hour urines) have been quantified pre-GAHT or post-GAHT, which is relevant because GAHT may influence urine creatinine excretion, which is known to vary by sex/gender, and postmenopausal hormone therapy is associated with decreased albuminuria/proteinuria in the cisgender population. The nephrology and gender-affirming care communities must pursue answers to these questions to provide equitable care to their transgender/gender-diverse patients, which can only be addressed in high-quality, adequately powered, prospective observational studies, such as the ENIGI study. Ideally, future studies will have more diverse and representative populations relative to geography, age, race, comorbidities, GAHT regimens, and socioeconomic and psychological factors and include patients across the spectrum of CKD. Ideally, these will also be powered for subgroups not only by sex/gender, age, and eGFR but also different GAHT regimens with multivariable adjustment by achieved estrogen and testosterone levels and lean body mass with consideration of other sex hormone cointerventions and gender-affirming surgery (oophorectomy, orchiectomy) if applicable over follow-up. Finally, the acute and chronic effects of MRAs and CPA in the context of GAHT on BP, renal blood flow, GFR, and proteinuria will need to be considered.¹⁰ This work will require international collaboration by nephrologists, endocrinologists, family physicians, gender-affirming care providers, clinical biochemists, researchers, transgender/gender-diverse organizations, and persons with lived experience, with support by funding bodies and institutions.

Disclosures

S.B. Ahmed reports advisory or leadership roles as Chair of Canadian Institutes of Health Research Institute of Gender and Health Advisory Board (volunteer position) (http://www.cihr-irsc.gc.ca/e/50746.html), President-Elect of Organization for the Study of Sex Differences (https://www.ossdweb.org/) (volunteer position), and Canadian Medical Association Journal Governance Council Member (volunteer position). D. Collister reports research funding from Boehringer Ingelheim/Research Manitoba, Canadian Institutes of Health Research, and Kidney Foundation of Canada; honoraria from CSL Behring (donation of National Leader fees for POSIBIL-6 trial to research program); and advisory or leadership role for Canadian Nephrology Trials Network (Executive Committee, Scientific Operations Committee) (unpaid).

Funding

None.

Author Contributions

Writing – original draft: Sofia B. Ahmed, David Collister.

Writing – review & editing: Sofia B. Ahmed, David Collister.