Kidney Biomarkers Shift After Gender-Affirming Hormone Therapy, but Filtration Remains Hard to Pin Down
Gender-affirming hormone therapy is increasingly relevant to routine kidney care, yet the core nephrology question is still unsettled: when serum creatinine changes after treatment begins, is the kidney actually changing, or is the biomarker simply moving because body composition is changing? In a real-world Veterans Health Administration cohort, investigators followed transgender men receiving masculinizing therapy and transgender women receiving feminizing therapy for 2 years and compared their trajectories with those of cisgender veterans. The study adds something nephrologists have needed for years: longitudinal data from adults beyond the narrow age band that dominates much of the existing literature.
Among transgender men, serum creatinine rose within 3 months of starting gender-affirming hormone therapy, stabilized by 12 months, and remained 0.16 mg/dl above baseline at 24 months. eGFR also declined modestly after treatment initiation, by an additional 0.6–0.8 ml/min per 1.73 m2 per year depending on whether assigned sex or affirmed gender was used in the estimating equation. Even so, post-treatment eGFR slopes did not differ significantly from those seen in cisgender men or cisgender women across the study period.
A small creatinine rise can look alarming on paper while reflecting nothing more sinister than added muscle.
Testosterone, Muscle Mass, and the Problem of Creatinine-Based Estimates
The physiology here is not mysterious, even if the clinical interpretation is. Testosterone increases lean muscle mass, and more muscle means more creatinine generation. Diet and activity patterns also influence creatinine production, and the article points to gender-patterned differences in meat intake and exercise that can move serum creatinine independently of filtration. In transgender and gender-diverse people, those shifts may occur alongside changes in social role, physical activity, and body composition after GAHT begins, making a single creatinine value a blunt instrument.
That is why the choice of sex variable in eGFR equations carries real weight. When an equation includes sex or gender, using sex assigned at birth versus affirmed gender can yield different eGFR results, and the study showed how much that decision can alter interpretation. The authors’ decision to report both approaches is clinically useful because it exposes the uncertainty rather than hiding it behind a single number. For nephrologists, that uncertainty matters most when decisions hinge on thresholds for chronic kidney disease staging, drug dosing, or referral.
Among transgender women, serum creatinine did not change significantly after GAHT initiation. Their eGFR declined both before and after treatment, but when affirmed gender was used in the equation, the post-treatment decline was significantly slower than the pre-treatment decline and slower than the decline seen in both cisgender comparison groups. The pattern does not read like a simple linear drug effect. It looks more like a biomarker system being tugged by several forces at once, including hormone exposure, body composition, and whatever non-GFR pathways govern creatinine handling.
Cystatin C and Measured GFR Add a Second, Complicating View
Creatinine is only one lens. Cystatin C is less affected by muscle mass and meat intake, and prior studies have linked testosterone-based therapy with higher cystatin C and estrogen-based therapy with lower levels. Those changes raise the possibility that GAHT may influence kidney physiology, but cystatin C is not immune to non-GFR effects of sex hormones, so it cannot be treated as a perfect adjudicator.
Measured GFR is the reference standard, and the article places it at the center of the discussion. A recent study found no significant change in measured GFR after 3 months of testosterone-based therapy, while feminizing therapy was associated with a 3.6% increase in measured GFR. Urinary biomarker patterns added another layer: masculinizing therapy was linked to increased urinary markers of inflammation, whereas feminizing therapy was linked to decreased markers of tubular injury and inflammation. Yet urinary EGF, a marker of tubular integrity and repair, also fell with feminizing therapy, which prevents any tidy interpretation. Kidney biomarkers are moving, but not always in the same direction, and not always for the same biological reason.
What the Veteran Cohort Adds to a Thin Evidence Base
The veteran cohort is valuable because it reaches into a population that has often been absent from nephrology studies. A bibliometric review of studies cited in the World Professional Association for Transgender Health Standards of Care Version 8 found that nearly half were cross-sectional and that adults aged 18–29 years accounted for almost two thirds of the evidence base. That leaves a major gap for middle-aged and older adults, the very group in which CKD risk becomes more clinically consequential. In this context, the current cohort’s mean age at GAHT initiation — 34 years among transgender men and 48 years among transgender women — broadens the frame in a meaningful way.
The follow-up window also matters. A 2-year trajectory is long enough to see whether an early biomarker shift settles, persists, or continues to drift. In transgender men, the creatinine rise stabilized. In transgender women, creatinine remained essentially unchanged. Neither pattern yet proves a harmful kidney effect, and neither rules one out. What the data do show is that standard laboratory interpretation becomes less secure once GAHT enters the picture.
Kidney Care for TGD Patients Needs Better Reference Standards
The practical issue in nephrology is not whether GAHT should be prescribed; it is how kidney function should be assessed once therapy is underway. Creatinine-based eGFR equations were never built for the range of physiologic states seen in transgender and gender-diverse patients receiving hormones, and the article makes clear that assigning a single sex variable may misclassify kidney function in either direction. A clinician who assumes that every creatinine change is renal injury risks overreacting. A clinician who assumes every change is hormonal and harmless risks missing true kidney disease.
Measured GFR studies, broader biomarker panels, and better validation of estimating equations in transgender populations remain the path forward. So do longer studies that include older adults and more diverse patients, because current evidence is still skewed toward younger participants and short observation periods. The article closes on an unresolved but concrete problem: current markers can shift after GAHT, yet the field still cannot say with confidence how much of that shift reflects altered filtration, altered biomarker generation, or actual long-term CKD risk.