This study investigates how sex hormones affect kidney function in people undergoing gender-affirming hormone therapy (GAHT). We know men have a faster progression of kidney disease. Earlier studies suggest that the female sex hormone estradiol may have a protective effect on kidney function while the male sex hormone testosterone may have the opposite effect. But the reasons why this happens remain unclear. By studying participants undergoing (GAHT) we gain insight into the mechanisms by which testosterone and estradiol influence the kidneys. People undergoing GAHT provide a unique chance to study how sex hormones interact with the kidneys. The results may help us to understand why men and women exhibit differences in kidney disease development. This study will include 30 men and 30 women, aged 18 to 40, who start GAHT. Participants will have three study visits, two of which will happen during their scheduled healthcare appointments. During the first visit, a screening will take place to check if patients can take part in the study. At study visits before and after one year of therapy, kidney function is measured, kidney MRI is performed, urine is collected and a small sample of fat tissue. Taking part in the study does not delay the start of GAHT.

Sex differences in kidney physiology are a vastly understudied area, despite known differences in sex-specific rates of chronic kidney disease. Kidney function decline is accelerated in men compared to women, suggesting a potential harmful role for testosterone. Transgender individuals undergoing hormone therapy provide a unique model to study the effects of gender affirming hormone therapy on kidney function and renal physiology. The central objectives of this study are to comprehensively assess the effects of gender affirming hormone therapy (GAHT; testosterone in transgender men or estradiol and an anti-androgen in transgender women) therapy on kidney function and physiology. This study is a prospective observational study. In total we will include 60 transgender individuals (30 transgender men and 30 transgender women) between 18-40 years old, scheduled to start GAHT. The primary endpoint is measured glomerular filtration rate (GFR) by iohexol clearance. Secondary endpoints include effects of GAHT on measures of intrarenal hemodynamic function including effective renal plasma flow (ERPF), proximal tubular function, insulin sensitivity and multiparametric kidney MRI (phase-contrast MRI [perfusion], arterial spin labeling [perfusion], BOLD imaging with a multi-echo spin-echo mapping R2* [oxygenation] and diffusion-weighted MRI [diffusion]). We will also isolate urinary tubuloids to further study the effect of sex hormones on kidney physiology and in these tubuloids we will assess whether the kidney protective effects are affected by sex hormones in vitro. Furthermore, endothelial cells will be harvested by J-wire, and single-cell RNA sequencing will be performed to investigate the transcriptional effects of GAHT in endothelial cells. And finally, we will look at adipose tissue gene expression.The burden for participants consists of three study visits, two of which will replace scheduled meetings that are a part of standard healthcare practice. In total, participants will receive one venipuncture and four intravenous cannulas, from which blood will be sampled (study total of 275 mL) and iohexol and p-aminohippurate will be administered to measure GFR and ERPF respectively. After measurement of kidney function, insulin sensitivity will be measured using a variable infusion of glucose and insulin (hyperinsulinemic euglycemic clamp). Patients will undergo kidney MRI which will take about 45 minutes; participants with claustrophobia are excluded. In addition, participants will be asked to collect a 24-hour urine sample on the days prior to the second and third study visit. Subcutaneous adipose tissue is collected by needle aspiration after local anesthesia. Finally, endothelial cells will be harvested. The total risk of negative effects for participants in the current study is considered low. The transgender population is a unique population in which the effects of exogenous cross-sex hormone administration can be studied. This study may provide additional data on the safety of hormone therapy in this population and may also lead to meaningful insights regarding the physiological effects of sex hormones on kidney function in humans that may help to understand observations from cohort studies which indicate differences in progression to kidney failure dependent on gender.

Inclusion Criteria:

• Diagnosed with gender dysphoria according to DSM-V
• Expected to start gender-affirming hormone treatment in the upcoming month

Exclusion Criteria:

• Current or prior use of gender-affirming hormone therapy
• Participation in other studies
• Concomitant use of medication (specifically: antihypertensive agents, products, antidepressants, antipsychotic agents)
• Known kidney disease (eGFR < 60 ml/min; UACR > 2.5 mg/mmol)
• Diabetes mellitus
• A history of cardiovascular disease (myocardial infarction; cardiac surgery or revascularization, unstable angina, heart failure, transient ischemic attack, cerebrovascular disease, or a previously undiagnosed arrhythmia)
• Known iodine-related allergies
• Metal in the body (such as pacemaker, ICD, neurostimulator, cochlear implant, or other metal)
• Pregnancy
• Claustrophobia

The source population consists of adult patients with gender dysphoria, who are scheduled to start with GAHT in the Amsterdam University Medical Centre (AUMC) in Amsterdam. A total of 60 transgender individuals (30 transgender women, 30 transgender men) will be selected from this outpatient clinic.