Many laboratories are moving forward with implementing the updated 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations for estimated glomerular filtration rate (eGFR), which remove factors that adjust the resulting estimates for race (1). This update stands to benefit Black and mixed-race populations, while also eliminating the logistic challenges of either extracting information on race and ethnicity from electronic medical records (EMRs) or reporting two eGFR values (Black and non–Black). Institutions are realizing the value and improved equity such an update brings.
Although use of the updated equations is generally agreed to be a step in the right direction in the domain of laboratory medicine, a new consideration needs to be addressed: how eGFR differs for transgender patients, and how to address this difference in equations that still clearly depend on factoring for male or female gender. A broader challenge is how to interpret laboratory test results in transgender and nonbinary populations.
STANDARDS OF CARE FOR TRANSGENDER PATIENTS
Transgender people experience incongruence between sex assigned at birth and gender identity (personal sense of gender). Cisgender individuals are congruent between sex assigned at birth and gender identity. Transgender women were assigned sex as male at birth but identify as women; in contrast, transgender men were assigned sex as female at birth but identify as men.
There are also those who identify as something other than male or female, such as identifying with neither gender or with both genders. This group is often described with the umbrella term nonbinary, but other subterms such as gender fluid, genderqueer, and third gender are also used.
Transgender and nonbinary people may seek medical interventions that affirm their gender identity, known as gender-affirming therapy. Current standard of care for gender-affirming therapy includes hormone therapy (testosterone or estrogens and sometimes additional medications) and/or surgical procedures such as orchidectomy (removal of testes) or ovariectomy (removal of ovaries). Note that for a variety of reasons some transgender and nonbinary individuals do not use gender-affirming therapy.
EFFECTS OF GENDER-AFFIRMING THERAPY ON LABORATORY TESTS
A growing body of literature has documented the effects of gender-affirming therapy on the results of clinical chemistry and hematology tests (2). Early studies were predominantly either observational studies of transgender cohorts or retrospective analyses of laboratory data in individuals who received gender-affirming therapy.
More recently, a prospective research study determined reference ranges for chemistry analytes (including creatinine) in individuals who had been stably taking gender-affirming hormones for at least 12 months (3). In that study, the reference interval for transgender men and nonbinary individuals stably taking testosterone aligned with that for cisgender men (higher creatinine values) and not cisgender women. The observed shift to higher creatinine values with masculinizing therapy is consistent with previous retrospective studies.
One hypothesis is that use of testosterone increases muscle mass and thus production of creatinine. The results for feminizing hormones were more complicated. In the prospective study, transgender women and nonbinary individuals stably taking estrogen showed little difference in the creatinine reference interval from cisgender women (3), although the results of some retrospective and observational studies have varied.
With regard to eGFR, and a call for further review of the assessment of kidney function in the transgender population (9), a recent study by Fadich, et al., demonstrates the need for and value of addressing eGFR reporting in the transgender adult population (10). The authors retrospectively reviewed creatinine results obtained in transgender adults taking gender-affirming hormonal therapies—namely, testosterone or estrogens—before, during, and in maintenance phases of therapy. They also calculated estimated creatinine clearance (eCrCL, by using the Cockcroft–Gault equation) and eGFR (with the Modification of Diet in Renal Disease Study and CKD-EPI equations) and reported significant differences in these estimations over time.
These authors’ findings in a relatively small transgender cohort are compelling preliminary data that issue a strong call for more prospective study, while reinforcing the ideas that creatinine significantly changes over time as a patient progresses through transitioning with gender-affirming therapy and then enters a steady-state phase of therapy, and current eCrCL and eGFR calculations are not adequate for expressing estimated renal function in the adult transgender population.
THE ELECTRONIC MEDICAL RECORD PROBLEM
In calculating eGFR, the challenge thus arises as to which sex or gender is appropriate for the calculations. First is the issue of the “legal sex” used by the EMR for the main designation of a patient as male or female. By default, legal sex is usually sex assigned at birth unless intentionally changed later.
Recently, some EMR vendors have incorporated fields for sexual orientation and gender identity (SOGI) in patient records (4,5). These fields can capture information such as legal sex, sex assigned at birth, gender identity, and sexual orientation. Additional variables may include gender-affirming therapy and organ inventory. In current practice, the fields are typically voluntary for the patient to include.
One recent case example published by Fernandez-Prado and Ortiz illustrates the diagnostic challenges that may arise with creatinine and eGFR in the transgender population (6). In the case study, a transgender woman was classified in the EMR as male for legal sex until administrative change of her legal sex to female. With the use of female as the legal sex, the eGFR result was substantially lower than previous measurements when the individual was classified as male in the EMR. The fact that she was a transgender patient came to light only when clinicians investigated the abrupt shift in laboratory results.
HOW CLINICAL LABORATORIES CAN CLOSE CARE GAPS
Even if all the potential financial and basic-access barriers to healthcare experienced by transgender persons are equalized or ignored, the situation described by Fernando-Prado and Ortiz exposes cultural and resource-related barriers to care for many transgender patients. Laboratorians can and should consider addressing these barriers sooner rather than later. The constant narrative between a transgender patient and a new or unfamiliar care team can result in emotional triggers, recounting of past trauma, and the potential for discrimination on the part of the care team (7,8).
Clinical laboratories are an integral part of this care team and are poised to close care gaps by providing clinicians with better tools for laboratory-based testing and results reporting and interpretation. In this way, healthcare systems can streamline diagnosis and treatment for transgender and nonbinary individuals receiving gender-affirming therapies.
While laboratorians wait for evidence that can be incorporated into standardized renal function estimators, they must consider what to do in the meantime, particularly regarding reporting in EMRs. Whereas many institutions have sought to offer comparisons of legal and preferred gender in their EMRs, there is much variability in how these tools work and which reference intervals are posted to the EMR when testing is performed. In some cases, a patient’s legal gender does not equal their preferred gender (5).
One major EMR vendor offers a calculation to determine whether all gender fields in a record are equal. If the fields are not equal, gender is categorized as “unspecified.” The easy answer appears to be to place both the cis-male and cis-female reference intervals in a result comment when gender is categorized as unspecified and to caution the provider that gender-specific differences need to be considered for key tests.
However, most EMRs do not place calculated, specific results in comments as part of standard functionality. Thus, the challenge becomes how to make comments and reference intervals more data-rich and flexible to give more guidance to providers handling results for patients taking gender-affirming hormonal therapy. Solutions will likely be most straightforward for tests with discrete measurements (e.g., hepatic enzyme or thyroid function tests).
The problem with eGFR in this scenario is that any calculated output still requires the selection of one or another gender. If the eGFR built into the EMR is designed to give only one output (most currently equate gender with male or female), the institution needs to carefully consider how to most accurately express eGFR for the transgender or nonbinary patient. Accurate reporting may require a discrete build that houses two outputs—a cisgender male equivalent and a cisgender female equivalent—for the provider to review and consider while treating the patient. Such information can prove critical to eGFR results interpretation in transgender and nonbinary individuals, because the calculations applied likely assume that the patient will be taking gender-affirming hormonal therapy.
Currently, scientific reports on implementing such calculations for transgender and nonbinary individuals are lacking. Until studies reflect the best way to calculate eGFR for these individuals, we are left with room for creativity and information-sharing between institutions. Many institutions are choosing not to calculate eGFR in the interim for these individuals and to instead provide a creatinine or cystatin C result. The provider can then choose a result and calculate the eGFR using a preferred online tool. However, this approach lacks standardization and laboratory oversight, both of which could prove valuable as more research is published regarding eGFR estimations in these populations.
FUTURE RESEARCH NEEDS
The dialogue on gender and eGFR has only begun. First, increased adoption of EMR-based tools for documenting gender identity, gender-affirming therapy, and sex assigned at birth in addition to legal sex are clearly needed. Along with this, how these reporting fields are used by patients and providers should be studied, and any barriers or concerns relating to their use (e.g., discrimination, confusion with terms) should be addressed. A more detailed study of how gender-affirming therapy affects creatinine and eGFR, including the time course during hormone therapy, is also needed.
Research must also tackle cystatin C and other markers of renal function in transgender and nonbinary populations to clarify marker utility, reference intervals, and clinical decision points relating to renal function assessment in these individuals. Finally, clinical laboratories must standardize how to report laboratory values for tests such as creatinine to deal with discordance between legal sex, gender identity, and sex assigned at birth.
Danyel H. Tacker, PhD, DABCC, FADLM, is a clinical professor in the department of pathology, anatomy, & laboratory medicine at West Virginia University (WVU), medical director of chemistry & clinical mass spectrometry laboratories at WVU Hospital, and CLIA medical director of blood-gas testing at WVU Hospital (Morgantown) and WVU Hospitals Fairmont Medical Center Laboratory in Fairmont, West Virginia. +Email: [email protected]
Matthew D. Krasowski, MD, PhD, is clinical professor of pathology, Walter I. Bierring Professor of Clinical Education, medical director of clinical chemistry and point of service laboratories, and vice chair for clinical pathology and laboratory services at University of Iowa Healthcare in Iowa City, Iowa. +Email: [email protected]
References
- Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin c-based equations to estimate GFR without race. N Engl J Med 2021; doi:10.1056/NEJMoa2102953.
- Goldstein Z, Corneil TA, Greene DN. When gender identity doesn't equal sex recorded at birth: The role of the laboratory in providing effective healthcare to the transgender community. Clin Chem 2017; doi:10.1373/clinchem.2016.258780.
- Humble RM, Greene DN, Schmidt RL, et al. Reference intervals for clinical chemistry analytes for transgender men and women on stable hormone therapy. J Appl Lab Med 2022; doi:10.1093/jalm/jfac025.
- Cahill SR, Baker K, Deutsch MB, et al. Inclusion of sexual orientation and gender identity in stage 3 Meaningful Use guidelines: A huge step forward for LGBT health. LGBT Health 2016;3:100-2. doi:10.1089/lgbt.2015.0136
- Thompson HM, Kronk CA, Feasley K, et al. Implementation of gender identity and assigned sex at birth data collection in electronic health records: Where are we now? Int J Environ Res Public Health 2021; doi:10.3390/ijerph18126599.
- Fernandez-Prado R, Ortiz A. A sudden decrease in serum creatinine and estimated glomerular filtration rate: Clinical implications of administrative gender assignment in transgender persons. Clin Kidney J 2020; doi:10.1093/ckj/sfz152.
- Safer JD, Coleman E, Feldman J, et al. Barriers to healthcare for transgender individuals. Curr Opin Endocrinol Diabetes Obes 2016; doi:10.1097/MED.0000000000000227.
- Hostetter CR, Call J, Gerke DR, et al. "We are doing the absolute most that we can, and no one is listening": Barriers and facilitators to health literacy within transgender and nonbinary communities. Int J Environ Res Public Health 2022; doi:10.3390/ijerph19031229.
- Collister D, Saad N, Christie E, et al. Providing care for transgender persons with kidney disease: A narrative review. Can J Kidney Health Dis 2021; doi:10.1177/2054358120985379.
- Fadich SK, Kalayjian A, Greene DN, et al. A retrospective analysis of creatinine-based kidney function with and without sex assigned at birth among transgender adults. Ann Pharmacother 2021; doi:10.1177/10600280211050120.