Interpretation of laboratory tests in transgender individuals can be challenging in routine care, especially when the analytes have sex-specific reference intervals (1, 2). Health care professionals may be asked whether to use reference ranges based on assigned sex, self-identified gender, or a combined approach (3). Factors such as the type of hormone therapy initiated or its duration may influence this decision (4). Accurate interpretation is crucial for appropriate clinical decision-making.

This issue becomes particularly relevant when assessing the effects of gender-affirming hormone therapy (GAHT) on kidney function, a parameter influenced by several clinical and lifestyle-related factors (e.g., hydration, nutrition, comorbidities, and medications) and monitored through various biochemical markers. Available evidence does not clearly establish whether, and to what extent, testosterone preparations affect renal function in cisgender individuals (5), nor whether GAHT may exacerbate pre-existing renal impairment in transgender people assigned female at birth (AFAB) (6, 7).

Indeed, the assessment of kidney function in this population undergoing testosterone-based GAHT (T-GAHT) presents several challenges. First, testosterone treatment, by increasing muscle mass—and consequently serum creatinine (SCr) levels—could lead to an overestimation of renal dysfunction or may lead to a misclassification of kidney function (8). Second, there is still no specific formula validated for estimating glomerular filtration rate (eGFR) in transgender individuals. Currently, the most widely used formula is the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (9), which incorporates sex as a covariate because creatinine production is lower in cisgender females than in cisgender males due to differences in muscle mass; in addition, substantial sex- and gender-related differences in diet may exist. Consequently, if these factors are not properly accounted for, eGFR may be systematically overestimated in cisgender females (10).

In an attempt to overcome this limitation, some researchers suggest calculating an “intermediate” GFR value by averaging male and female estimates (11), while others recommend using the sex corresponding to the individual’s gender identity if GAHT has been ongoing for more than six months, although this approach is better validated for transgender men (12).

While these methodological challenges are important and deserve careful consideration, the central clinical question remains whether testosterone-based GAHT itself induces measurable changes in renal function in AFAB individuals. To address this question, we conducted a comprehensive systematic review and meta-analysis aimed at evaluating whether T-GAHT leads to clinically meaningful alterations in renal parameters—including eGFR, SCr, uric acid, and blood urea nitrogen (BUN)—over a follow-up period of up to 24 months. By doing so, we aimed to contribute to the expanding field of transgender medicine by offering a clearer understanding of the renal effects of masculinizing hormone therapy, beyond the technical difficulties inherent to laboratory test interpretation.

The study was conducted according to the statement Preferred Reporting Items for Systematic reviews and Meta-analyses protocols (PRISMA-P) (13); it also complies with the guidelines for Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE) (14). The study protocol was registered in the international prospective registry for systematic reviews (PROSPERO) with registration number CRD42024596106.

To our knowledge, this is the first systematic review and meta-analysis assessing the impact of testosterone-based gender affirming hormone therapy (T-GAHT) on kidney function in transgender individuals assigned female at birth (AFAB).

The direct effect of testosterone administration on kidney physiology has been explored in several preclinical studies using murine models, yielding inconclusive findings. Sex hormones appear to exert opposing actions on renal tissue: testosterone induces podocyte injury, while estrogens are protective (41–43). Conversely, in male rats, testosterone has been shown to mitigate renal ischemia–reperfusion injury, independently of estradiol (44). Lichtenecker et al. reported that testosterone treatment in female rats increased glomerular area and kidney size after four months, although this was associated with reduced GFR and histological changes (45). Other studies in male rodents have shown that early orchiectomy may prevent proteinuria and delay glomerulosclerosis (46), suggesting a detrimental role of androgens. In humans, androgens have been implicated in increased blood pressure and impaired renal function (47, 48), potentially through enhanced tubular sodium and water reabsorption (49) and activation of vasoconstrictive pathways such as the renin–angiotensin system and endothelin (48, 50–52). In line with these findings, our analysis showed a transient increase in systolic blood pressure after six months of T-GAHT, followed by stabilization.

In recent years, several studies have examined how best to estimate GFR in transgender individuals receiving hormone therapy (12, 31, 35), including whether to use the sex assigned at birth or the individual’s self-identified gender. In our analysis, we assessed changes in eGFR using both approaches across all follow-up timepoints. As highlighted by Krasowski, this choice impacts CKD stage classification according to KDIGO 2013 guidelines (53). Most of the included studies relied on the 2009 version of the CKD-EPI equation, which incorporates a race-based correction. Although the updated 2021 race-neutral equation (54) is now recommended, particularly in the United States (55), we used the published eGFR values without recalculating them due to the lack of access to individual-level data. This is acknowledged as a methodological limitation.

Using the female coefficient in CKD-EPI, despite ongoing masculinization and male gender identification, may overestimate renal function during follow-up. This explains the artifactual increase in eGFR observed when switching from sex-assigned-at-birth to affirmed-gender coefficients ( Figure 3 ). However, when a consistent coefficient is applied over time, eGFR values decrease at 6 and 12 months and then stabilize at 18 and 24 months.

Whether this pattern reflects true renal impairment remains uncertain. The observed rise in SCr during the first year of T-GAHT, as reported in several studies (56, 57), likely reflects testosterone-induced increases in muscle mass and altered body composition (58, 59). This interpretation is supported by the concomitant rise in uric acid levels, which plateau after 12 months ( Supplementary Figure 2 ), consistent with increased purine metabolism.

Transient hemodynamic changes, such as the rise in systolic blood pressure at six months ( Supplementary Figure 4B ), may also contribute to these changes. However, the absence of significant alterations in BUN ( Supplementary Figure 3 ) and the lack of reported cases of new-onset hypertension or antihypertensive treatment suggest that these variations are more likely to represent a physiological adaptation to masculinization rather than early signs of pathological renal involvement (60, 61), consistent with recent insights into testosterone’s cardiovascular effects during gender-affirming therapy (62). Future research should clarify whether T-GAHT poses any clinically significant risk of hypertension.

This meta-analysis has several limitations. The observational nature of all included studies, combined with the absence of control groups, limits the ability to control for confounding variables. Attrition bias is also notable, as several studies reported substantial loss to follow-up. Moreover, most participants were young and had normal kidney function at baseline, which restricts the generalizability of our findings to older individuals or those with pre-existing renal disease. Additionally, none of the included studies assessed alternative biomarkers of renal function, such as cystatin C, which is less influenced by muscle mass and may better reflect glomerular filtration in individuals undergoing masculinizing hormone therapy. Although van Eeghen et al. (35) acknowledged the potential value of cystatin C, no longitudinal data were reported. Finally, while a few studies mentioned the concurrent use of GnRH agonists (30, 33), none stratified renal outcomes by treatment regimen or explored the specific impact of GnRH suppression. This remains an important area for future investigation.

In conclusion, testosterone-based GAHT appears to have a statistically significant impact on eGFR in healthy, young AFAB individuals during the first two years of therapy. However, these changes are unlikely to reflect clinically meaningful renal impairment. eGFR values—regardless of whether calculated using male or female CKD-EPI coefficients—tend to stabilize after 12 months and remain well above thresholds for renal dysfunction. These findings underscore the importance of cautious interpretation of renal function markers during early T-GAHT. Further studies are needed to evaluate these effects in more diverse populations, particularly in older individuals and those with existing kidney disease, and to validate sex-independent tools for accurately monitoring renal function in transgender people receiving gender-affirming hormone therapy.