10

Chronic Kidney Disease

Chronic kidney disease (CKD) occurs when the kidneys can no longer properly manage the multiple complex and critical tasks necessary for maintaining balance, or homeostasis, in the body, including management and removal of waste products and toxins; management of excess fluid; blood filtering to manage key balances in vital electrolytes (e.g., including potassium, sodium, and calcium); and regulation of hormones that have a role in maintaining optimal blood pressure and red blood cell production. Early-stage kidney disease is not always symptomatic and may be managed with medications that slow its progression. As it progresses, kidney disease may cause painful and debilitating complications, and a person with CKD may require various forms of kidney replacement therapy—either dialysis treatments (home, in-center, or peritoneal), kidney transplant (using a kidney from either a deceased or a living donor), and sometimes conservative care. Patients experiencing kidney failure may find it difficult to continue working because of time-consuming dialysis treatments and the toll these treatments take on the body (Murtagh et al., 2007). For people who receive a kidney transplant, the recovery time required may also impact the ability to engage in substantial gainful activity and employment, as recovery from surgical complications may be substantial. In addition, advanced CKD may cause other complications—including severe bone pain, damaged nerves, muscle weakness, and vascular congestion and fluid overload syndromes—that cause significant impairment and disability. For these many reasons, some people with CKD seek disability benefits from the Social Security Administration (SSA).

While a person can meet SSA’s disability criteria for kidney disease in multiple ways (as described in brief in this chapter), SSA asked the committee to examine criteria related to “chronic kidney disease with impairment of kidney function” under disability Listings 6.05 (adult) and 106.05 (childhood), as outlined in Box 10-1. Within these Listings, questions around sex and gender are important, specifically with regard to the estimated glomerular filtration rate (eGFR) measurement used in the disability criteria under Listings 6.05A3 and 106.05C. As described in this chapter, eGFR is commonly used in clinical practice to determine or estimate kidney function. It is calculated based on a set of factors that include a patient’s sex. For this reason, it is important to understand how eGFR is calculated for transgender and gender diverse (TGD) populations and populations with variations in sex traits (VSTs), and whether there may be other appropriate

evaluation criteria for these populations, particularly for people who receive gender-affirming hormone therapy (GAHT). This chapter examines these questions.

CHRONIC KIDNEY DISEASE: PREVALENCE AMONG TRANSGENDER AND GENDER DIVERSE PEOPLE AND PEOPLE WITH VARIATIONS IN SEX TRAITS

In the United States, an estimated 35.5 million adults have CKD; prevalence is higher in older adults, cisgender women, and racial and ethnic minorities, and in adults with diabetes and hypertension (CDC, 2023; Kovesdy, 2022). Nearly 808,000 people in the United States are living with end-stage kidney disease (ESKD) (also known as end-stage renal disease or

kidney failure), 69 percent of whom are on dialysis and 31 percent of whom have had a kidney transplant (NIDDK, 2022). The most common causes of CKD among adults in the United States include diabetes and hypertension. However, many individuals are unaware of the risk these conditions pose for kidney health and become aware of the presence of CKD only at its later stages (Plantinga et al., 2010; Schoolwerth et al., 2005).

Research has not described the causes of the greater prevalence of CKD among cisgender women and of kidney failure or ESKD among cisgender men (García et al., 2022). However, several factors have been proposed as potential contributors to these disparities, including longer life expectancy among cisgender women versus men and inaccurate and/or biased kidney function estimation using existing binary (male vs. female) estimation equations (Carrero et al., 2018). Further studies have also posited that gender-related differences in exposures, including less access to nephrology care and evidence-based therapy receipt among cisgender women versus men, contribute to these disparities (Jankowska et al., 2023).

CKD and TGD Populations

An estimated 0.5 percent of the U.S. population (Herman et al., 2022), or nearly 1.3 million adults, identifies as TGD, including growing proportions of the younger population (Collister et al., 2021; Mohottige and Lunn, 2020). Based on these estimates, and assuming that people with TGD experience have CKD at the same rate as the general population, nearly 176,000 TGD people in the United States may have CKD, and an estimated 4,000 TGD people may have ESKD. However, given the lack of robust and accurate collection of sexual orientation and gender identity (SOGI) data (described in detail in Chapter 3 of this report), these figures may reflect gross underestimation of the TGD population overall. Prior studies have suggested that nearly 30–50 percent of TGD people may not disclose their identity in their medical records as a result of bias and direct or vicarious experiences of discrimination (Sequeira et al., 2021). Therefore, figures estimating the prevalence of kidney disease among TGD people may be underestimates as well. The lack of systematic and accurate SOGI data collection in health surveys and medical records complicates adequate detection, surveillance, and management of kidney disease among TGD people (Ahmed et al., 2021; Sutha and Streed, 2023).

CKD is largely unexamined in TGD populations, but polled data from the Behavioral Risk Factor Surveillance System (which included 22,114

older adults) suggest that CKD prevalence is higher among older LGBTQ+ men, who were more likely than their non-LGBTQ+ counterparts to self-report having kidney disease (Chandra et., 2023). Notably, this study did not specifically examine the prevalence of CKD or acute kidney injury among TGD people alone, and it poorly captured considerations of sex and gender.

Findings of studies examining CKD among TGD are mixed. One single-center study found a CKD prevalence of 36 percent among transgender patients—a substantially higher prevalence than would be expected relative to cisgender data (Eckenrode et al., 2022b). On the other hand, a cross-sectional study of 30,763 sexual and gender minority (SGM) adults and 316,106 non-SGM adults enrolled in the National Institutes of Health–sponsored All of Us Research Program did not identify greater odds of kidney disease among TGD people, after adjustment for age, income, employment, and other factors (Tran et al., 2023). However, this study was limited by several factors, including that researchers did not have available data to link self-reported gender identity and sex recorded at birth to electronic health record data; therefore, records for TGD study participants were potentially incomplete (Tran et al., 2023). In addition, there is known underreporting and inadequate diagnosis of CKD in electronic health records (Owosela et al., 2024; Quartarolo et al., 2007).

CKD and People with VSTs

Up to 1.7 percent of the population may have VSTs (Blackless et al., 2000). Based on this estimate, and assuming people with VSTs experience CKD at the same rate as the general population, nearly 603,500 people with VSTs in the United States may have CKD, and an estimated 13,700 people with VSTs may have ESKD. Certain people with VSTs may be at elevated risk for CKD. Testosterone deficiency (hypogonadism) is associated with CKD (Romejko et al., 2022) and is common in patients receiving dialysis (Carrero and Stenvinkel, 2012; Edey, 2017). Research shows that testosterone levels decrease in parallel with reduction of kidney function and, in patients with progressive CKD, low testosterone levels have been linked with increased risk of mortality from cardiovascular events (Carrero et al., 2010; Yilmaz et al., 2011) and risk of other chronic illnesses (Iglesias et al., 2012). Development of chronic kidney insufficiency in puberty has been associated with several gonadal disorders, such as gonadal dysgenesis, Leydig cell hypoplasia, Turner syndrome, and Klinefelter syndrome (Benz et al., 2006).

Disparities in Care and Outcomes

CKD care and outcomes in the United States are emblematic of numerous long-standing disparities that cause specific populations to experience sociostructural barriers to care, including TGD people and people with VSTs. Although racial and ethnic disparities in kidney outcomes in the United States are well described (Crews et al., 2013; Mohottige et al., 2021; Nicholas et al., 2015; Norris and Nissenson, 2008; Norton et al., 2016), other factors that may impact kidney care for TGD people are poorly understood because of the lack of uniform SOGI data collection within medical records and across the health care system, along with limited clinician and health system capture of barriers to care and other care considerations for TGD people (Streed et al., 2023; Sutha and Streed, 2023). These data collection limitations notwithstanding, people who are both TGD and racially/ethnically minoritized may experience unique, multilevel, cascading barriers to kidney care. Common risk factors for CKD—including diabetes and hypertension—are also characterized by disparities in race, ethnicity, and socioeconomic status. To date, no studies have described differences in kidney disease risk factors among TGD individuals versus their cisgender counterparts.

The literature has also described the long-standing racial and ethnic disparities in kidney transplantation. For instance, Black Americans have a four-fold higher risk of developing ESKD compared with their White counterparts, yet they remain less likely than their White counterparts to be evaluated for kidney transplant, achieve waitlist status, and receive a preemptive or living donor transplant (Mohottige et al., 2021). Gender disparities have also been described, primarily between cisgender women and cisgender men.¹ While no known studies have examined disparities in access to and receipt of kidney transplants among TGD people, the literature has described numerous inequities faced by TGD people seeking transplantation in general. More research is needed to characterize disparities in transplant access and outcomes encountered by these populations (Leeies et al., 2023; Ramadan et al., 2020).

Several risk factors for kidney disease need to be considered carefully when evaluating kidney disease risk and associated sequelae among TGD people. These include increased cardiovascular events (e.g., myocardial infarction) associated with stress from marginalization and discrimination (Streed et al., 2021), and well-documented disparities between TGD

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¹ For instance, cisgender women are less likely to be waitlisted for a kidney transplant and receive deceased and living donor kidneys compared with cisgender male counterparts, despite the fact that cisgender women are more likely than cisgender men to become living kidney donors (Katz-Greenberg and Shah, 2022).

and cisgender people in access to bias-free preventive and chronic disease care, which may impact care for predisposing risk factors for CKD, including hypertension, metabolic syndrome, and diabetes (Caceres et al., 2020).

PEDIATRIC CONSIDERATIONS FOR CHRONIC KIDNEY DISEASE

CKD is characterized by structural or functional abnormalities of the kidneys that often impact individuals from the time of birth through early adulthood. Estimating the incidence of CKD in children has been difficult, but based on registry data for U.S. children aged 0–17 the estimated incidence is 13.0 per million (Harada et al., 2022; Harambat et al., 2012).

Importantly, the etiologies of CKD and kidney failure differ between children and adults. Whereas the most common causes of CKD and ESKD among adults in the United States include diabetes and hypertension (followed by glomerular disease and cystic diseases of the kidney), the most common causes of kidney disease among pediatric populations include hereditary congenital diseases (accounting for 50 percent of cases of CKD diagnosed during the first three decades of life), glomerulonephritis, vasculitis, interstitial nephritis, and miscellaneous conditions (Harambat et al., 2012). In younger children, congenital anomalies of the kidneys and urinary tract (CAKUT) (including obstructive uropathy and renal hypodysplasia) are most common, and posterior urethral valves and prune belly syndrome more often occur among individuals with sex recorded as male at birth than as female (Lombel et al., 2022). Pediatric kidney disorders are often associated with deleterious genetic variants (Becherucci et al., 2016; Kolvenbach et al., 2023).² Renal dysplasia, which may include cystic disease as well as hypoplasia or small kidneys with reduced nephron volume, may result in functional kidney impairments as well (Lombel et al., 2022).

In children, kidney anomalies may be isolated or associated with other clinical manifestations (syndromic). Some disorders progress to kidney failure, necessitating kidney replacement therapy (dialysis or transplantation) within the first few years of life, during adolescence, or in young adulthood. Furthermore, some conditions, including forms of glomerular disease, may recur in adulthood or even after transplantation (Uffing et al., 2021; Vivarelli et al., 2017). Acute kidney injury in children can also lead to CKD as the result of a range of factors, including volume depletion or

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² Some genetic variants associated with CAKUT are also associated with ocular phenotypes, including coloboma, microphthalmia, optic disc anomalies, refraction errors (astigmatism, myopia, and hypermetropia), and cataracts (Virth et al., 2024).

acute infection, chemotherapy for childhood cancer, and nephrotoxic drugs. Studies have shown variable decline in kidney function between individuals with CAKUT and those with hereditary diseases, such as polycystic kidney disease and Alport syndrome (Mong Hiep et al., 2010), that may progress particularly rapidly, requiring earlier initiation of kidney replacement therapy. Vigilance and early detection and diagnosis are essential for each of these conditions throughout an individual’s life course.

Impact on Growth and Development

For youth with CKD, progressive kidney failure can lead to anemia, deceleration of linear growth velocity, delayed pubertal development, and impaired bone mineralization (Capossela et al., 2023; Haffner, 2020; Haffner and Zivicnjak, 2017; Silverstein, 2018). In addition to these physical manifestations, CKD extracts a psychological toll on growing youth: they are shorter than peers, have delayed pubertal development, and experience frequent school absences (Assadi, 2013). The quality-of-life and physiological changes related to CKD may require that a pediatric nephrologist and multidisciplinary care team pay careful attention to malnutrition, protein-calorie wasting, acidosis, growth hormone resistance, and metabolic derangements.

Impact on Education and Employment (Children and Caregivers)

Disease progression and intercurrent illnesses, as well as the need for dialysis and kidney transplants, which require significant time and effort to maintain a functional health status, can rapidly tip the health and quality-of-life balance for youth with CKD, impacting their ability to attend school or employment, and leading to other forms of disability. A systematic review including 34 studies concluded that children with CKD scored lower in cognition, executive function, and memory when compared with children without CKD (Chen et al., 2018). As is true for most chronic pediatric disorders, moreover, a child’s illness significantly impacts daily life for caregivers (parents or guardians), who may have to limit participation in gainful employment to provide full-time care. Furthermore, clinical transitions between pediatric and adult care may be particularly challenging for these patients and may require concerted efforts to ensure appropriate trust building and understanding of complex care needs (Harada et al., 2022). Lapses in appropriate transition due to inadequate communication among pediatric and adult teams with respect to multidisciplinary care needs may result in anxiety, distress, and challenges with medication nonadherence, leading to poor outcomes (including exacerbation of disease states or even

loss of transplant function if, e.g., immunosuppressive medications are missed) (Gold et al., 2015; Laederach-Hofmann and Bunzel, 2000; Raina et al., 2018).

CHRONIC KIDNEY DISEASE AND SSA DISABILITY DETERMINATIONS

As of December 2022, 1.8 percent of all Social Security Disability Income recipients (158,233 people) and 0.9 percent of Supplemental Security Income recipients (46,330 people) qualified for those benefits as a result of CKD, SSA’s definition of disability under Listing 6.00 Genitourinary Disorders—Adult, or 106.00 Genitourinary Disorders—Childhood (SSA, 2022, 2023). In general, a person (child or adult) with CKD can meet SSA’s definition of disability for CKD if they meet any of the following criteria:

• They require dialysis (ongoing dialysis must have lasted or be expected to last for a continuous period of at least 12 months).
• They received a kidney transplant (SSA considers a person disabled for 1 year from the date of transplant. After that, disability benefits can continue, but the recipient will need to medically qualify each year to have benefits renewed).³
• They have chronic kidney disease with impairment of kidney function. This Listing requires specific medical tests to demonstrate level of glomerular filtration, or how well (or poorly) the kidneys are removing waste products from the blood. Adult SSA applicants must also provide medical evidence of certain other conditions caused by a CKD, as outlined earlier in Box 10-1. SSA does not require child applicants to demonstrate these conditions.

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³ Transplant and related care are not within the purview of the present study. However, the committee notes that transplant care teams may consider altering the dose of or discontinuing feminizing GAHT (specifically estrogen therapies) in the context of transplantation because of possible perioperative risk of venous thromboembolism and other thromboembolic events (Getahun et al., 2018). However, there are no systematic reviews of risk associated with kidney transplantation, and there is no definitive evidence regarding risk for venous thromboembolism to suggest that low-risk individuals should stop estrogen before or after surgery (Arnold et al., 2016). Alternatives to complete discontinuation should be considered (e.g., dose reductions or transition to transdermal formulations), given the potential harm and psychological distress of GAHT discontinuation. TGD people receiving kidney transplant require comprehensive care to ensure that some side effects related to transplant medications are mitigated. All discussions regarding GAHT are essential for transplant teams to consider in consultation with a multidisciplinary team and, most notably, with an approach based on patient-centered shared and informed decision making (Collister et al., 2021; Eckenrode et al., 2022a; Jue et al., 2020; Katz-Greenberg and Shah, 2022).

• They have nephrotic syndrome.⁴
• They have complications of chronic kidney disease requiring hospitalization (at least three hospitalizations within a consecutive 12-month period and occurring at least 30 days apart).⁵

It is in the third category above, chronic kidney disease with impairment of kidney function, that questions around sex and gender identity become important. Under this category, applicants must demonstrate reduced glomerular filtration via one of three laboratory findings (following criteria outlined in Table 10-1):

• serum creatinine,
• creatinine clearance, or
• eGFR (SSA, n.d.-a,b).⁶

Among the different measures of kidney function, the eGFR is most commonly used in clinical practice. Clinicians and health care systems use eGFR because obtaining an accurate GFR through the measured GFR (mGFR)

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⁴ Nephrotic syndrome is a condition whereby specific quantities of protein and albumin are lost in the urine as a result of various forms of kidney disease. This condition is not within the purview of the present study. However, the committee notes that common measures of nephrotic syndrome may be influenced by the receipt of GAHT and the sex hormone configuration, but this connection has not been explicitly studied among TGD people. Although there are no consistently used sex-based equations for assessing urine proteinuria/albuminuria (and SSA criteria do not include sex-based measurement under Listing 6.06 and 106.06), several authors have suggested that sex-specific ranges be used to interpret spot urine creatinine measures (Marco Mayayo et al., 2016). Given the critical importance of albuminuria and proteinuria assessments among individuals with CKD risk and known kidney disease, it is essential that urine measures of proteinuria/albuminuria be carefully collected among TGD people. Guidance suggests that both male and female values be input into albumin- or protein-to-creatinine ratio conversions to assess 24-hour albuminuria/proteinuria based on spot measures. Ideally, when precision is needed, 24-hour measures of urinary protein or albumin excretion are used, as these represent common occurrences of intraindividual variability (Pierre et al., 2023). Furthermore, just as is done among cisgender populations with CKD and CKD risk factors, urine albumin and protein excretion need to be monitored carefully among TGD people to guide therapeutic and diagnostic decision making. Finally, adjudicators need to consider the potential bias introduced in 24-hour urine creatinine collections due to a range of factors, including inadequate collection techniques, as well as the potential influence of sex and gender and GAHT on these measures.

⁵ Under SSA’s childhood disability listings, in addition to the above, children can meet disability criteria based on eligibility under two additional categories: (1) “Congenital genitourinary disorder” and (2) “Growth failure due to any chronic renal disease” (Listing 106.00, Genitourinary Disorders—Childhood).

⁶ There is no standard for the use of measures of serum creatinine or creatinine clearance on its own for clinical care purposes. For instance, two adult individuals with serum creatine measurements of 4 mg/dL could have widely variable clinical symptoms that might be disabling, and/or electrolyte imbalances or other condition requiring kidney replacement therapy. Serum creatinine is often used in equations to estimate GFR, as described in this chapter.

TABLE 10-1 Historical and Current Estimated Glomerular Filtration Rate (eGFR) Equations for Adults

^a The Cockcroft–Gault (1973) equation is no longer in clinical use but may be used for drug research.

^b Some clinical laboratories are still reporting GFR estimates using the MDRD Study equation.

^c The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) maintains use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation during the transition to the updated 2021 equation.

^d The CKD-EPI 2021 equation is the new equation recommended by the National Kidney Foundation (NKF), NIDDK, American Society of Nephrology, and others.

SOURCES: Cockcroft and Gault, 1976; Delgado et al., 2022; Levey et al., 1999, 2009.

test may be challenging (Delgado et al., 2022; Hsu et al., 2011; van Eeghen, 2023). mGFR measures directly how well the kidneys remove waste products from the blood, but the test requires complicated, lengthy, and expensive evaluation methods performed in specialized centers, along with multiple blood samples taken over several hours (Gounden et al., 2023; Hsu et al., 2011). For these reasons, eGFR, and its ability to provide an estimate of GFR, is the more practical and widely used test for assessing kidney function

(NKF, 2022a; Pierre et al., 2023). eGFR assessment may, directly or indirectly, influence clinical determination of patient care needs, including (1) initiation of dialysis, (2) referral to evaluation and waitlisting for kidney transplant, (3) management or detection of conditions such as uremia (buildup of toxic waste) due to impaired kidney function or CKD, (4) detection and further evaluation for causes of nephrotic syndrome, and (5) careful consideration for medication dosing and determination of contraindicated medications.

eGFR is calculated based on a blood test that measures either serum creatinine⁷ levels or cystatin C⁸ levels in the blood, together with the patient’s age, sex, and body type. Given that normal GFR varies according to age, sex, and body size, the eGFR equation takes these factors into account (Delgado et al., 2022). The eGFR equation is different for adult versus pediatric and young adult populations.

Adult eGFR Equations

SSA criteria do not specify how eGFR submitted under Listing 6.05A3 should be calculated (see Box 10-1), and a number of different GFR estimating equations are in clinical use (see Table 10-1). However, the National Kidney Foundation (NKF), American Society of Nephrology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and American Association for Clinical Chemistry (AACC) all recommend the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) eGFR equation for adults, which estimates GFR from creatinine and/or cystatin C, age, and sex; however, in a departure from earlier estimating equations, this eGFR estimating equation does not include race as a coefficient (Delgado et al., 2022; Inker et al., 2021; NIDDK, 2022; Pierre et al., 2023). Additional studies have demonstrated promise in additional equations, such as the European Kidney Function Consortium (EKFC)–developed eGFRcr and the EKFC eGFRcys, the latter of which uses age-based rescaling factors without sex or race coefficients (yet requires cystatin C for measurement); these equations have not been widely adopted in U.S. settings (Pottel et al., 2023).

Pediatric eGFR Equations

SSA criteria do not specify how eGFRs submitted for pediatric populations under Listing 106.05C should be calculated (see Box 10-1). While the 2009 Chronic Kidney Disease in Children (CKiD) “bedside” calculator

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⁷ Creatinine is a chemical waste product of creatine (a chemical made by the body to supply energy to muscles). Creatinine is removed from the body by the kidneys, and creatinine measurements provide some idea of how the kidneys are working.

⁸ Cystatin C is a protein produced by body cells. If the level of cystatin C in the blood is too high, this may mean the kidneys are not working well.

is still used in routine clinical practice for measuring kidney function in children (NKF, n.d.-b; Schwartz et al., 2009), NIDDK prefers the 2021 CKiD U25 estimating equations, as they exhibit less bias across a broader age range (up to age 25) (NIDDK, 2022). The 2021 CKiD U25 estimating equations offer two formulas: one based on height and creatinine, the other based on cystatin C; both formulas require that age and sex be specified (Ng and Pierce, 2021; Pierce et al., 2021). If all necessary information is available—height, serum creatinine, and cystatin C—estimates are created using each formula, and an average of the two eGFR values is taken. For patients aged 18–25, NIDDK recommends comparing the estimates from both the pediatric 2021 CKiD U25 calculator and the adult CKD-EPI 2021 calculator, as doing so will provide a more informed assessment of kidney function as patients transition to adulthood (NIDDK, 2022). Just as in adults, eGFR equations in children are only estimates of kidney function and are subject to inaccuracy—even with optimal equations—notably overestimating eGFR in the setting of rapidly declining kidney function because of the time required for equilibration (den Bakker et al., 2022).

Variables Included in eGFR Equations for Adult and Pediatric Populations.

Both adult and pediatric eGFR equations use a binary definition of sex, and for this reason, SSA asked this committee to examine whether this measurement of kidney function is appropriate for TGD people and people with VSTs; whether modifications to these measures might be required for these populations; or whether alternative tests, evaluations, or laboratory values might be more appropriate for understanding kidney function—and level of disability—among TGD people and people with VSTs. Box 10-2 displays the variables included in eGFR equations for adult and pediatric populations.

The sections below examine evidence related to the impact of GAHT on measures of kidney function, the implications for measuring eGFR, and current guidelines from AACC/NKF on appropriate eGFR measurement for TGD people and people with VSTs.

Impact of GAHT on Measurements of Kidney Function

Creatinine—a key biomarker used to estimate GFR—is the most common marker for kidney function used in routine clinical practice. Creatinine may be influenced by non-GFR determinants, including skeletal muscle metabolism, muscle mass, body weight, diet, medications, and a range of other factors (Bartholomae et al., 2022; Baxmann et al., 2008; Inker et al., 2021)

that can cause eGFR over- or underestimation.⁹ Use of cystatin C (another kidney function biomarker) is less common in clinical practice, but national guidelines call for expanding its use as a confirmatory test, given its relative accuracy in eGFR equations when race is no longer a coefficient (Adingwupu et al., 2023; Baxmann et al., 2008; Inker et al., 2021; Lees et al., 2022; Pierre et al., 2023). Like creatinine, cystatin C is impacted by non-GFR determinants, including smoking, obesity, diabetes, inflammation, and thyroid disease

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⁹ eGFR may be overestimated because of decreased serum creatinine due to such factors as frailty syndromes, anorexia, sarcopenia, cirrhosis, thyroid disease, or a vegan diet (Pierre et al., 2023). Conversely, eGFR may be underestimated because of increased creatinine due to having greater muscle mass, obesity, rhabdomyolysis (muscle breakdown), higher meat consumption, or use of creatine/muscle-building formulations, as well as when a person takes medications that inhibit kidney tubule secretion of creatinine (including trimethoprim and multiple medications used to treat HIV and hepatitis) (Patel et al., 2012; Pierre et al., 2023).

(Anderson et al., 2012; Goede et al., 2009; Panaich et al., 2013; Rule et al., 2013).¹⁰

As GAHT may impact body composition (including muscle mass, body fat distribution, bone mass, and other measures of body composition, as described in Chapter 9 and Appendix C), it stands to reason that it may also impact serum creatinine (SCr), cystatin C, and other kidney function biomarkers that are influenced by body composition. However, evidence on the influence of GAHT on eGFR and SCr has been mixed (Collister et al., 2021), and data describing the impact of GAHT on cystatin C are lacking (Krupka et al., 2022).

A 2022 systematic review and meta-analysis by Krupka and colleagues (2022) aimed to characterize how GAHT changes SCr, other kidney function biomarkers, and GFR in adult TGD patients (Krupka et al., 2022). The review found that, at 12 months after initiating GAHT, SCr levels had increased in transgender men (SCr increased by 0.15 mg/dL; 95% confidence interval [CI] 0.00–0.29 mg/dL), but had not significantly changed in transgender women (SCr decreased by 0.05 mg/dL; 95% CI 0.16–0.05 mg/dL). The findings of this review are consistent with those of other studies that suggest that (1) masculinizing hormone therapies increase muscle mass, which results in increased SCr levels (Collister et al., 2021; Maheshwari et al., 2021, 2022; SoRelle et al., 2019), and (2) feminizing hormone therapies decrease muscle mass and increase fat mass, which results in variable changes in SCr over time (Allen et al., 2021; Maheshwari et al., 2022).

Although the seminal review of Krupka and colleagues (2022) provides important insights into the impact of GAHT on SCr, several noteworthy limitations reduce the generalizability and applicability of its findings. Further studies are needed to examine the long-term associations between GAHT and long-term kidney function and associated biochemical parameters. First, subjects across these studies may have used different GAHT doses, formulations (e.g., intramuscular, transdermal), durations, and combinations (e.g., spironolactone and estrogen). Chapter 5 describes the wide variability in gender-affirming care, and this factor may make it difficult to generalize about the impact of GAHT across TGD populations with CKD. Longer-term implications of

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¹⁰ Understanding discordance between eGFR creatinine- and cystatin C–based assessments often requires additional guidance, and recent findings from an observational study demonstrate that when eGFR based on cystatin C is lower than that based on creatinine, this may identify individuals at risk of poor outcomes, including acute kidney injury and the need for dialysis (Carrero et al., 2023). However, lack of published data across contexts and limited evolving familiarity with the use of cystatin C in U.S. settings has made its implementation and broad utilization challenging (Gottlieb et al., 2023).

GAHT exposure on measures of kidney function, including eGFR and albuminuria, are largely unknown, as are clear descriptions of the mechanisms through which GAHT influences kidney function. In addition, the review by Krupka and colleagues (2023) did not uncover any studies that reported the effect of GAHT on albuminuria, proteinuria, cystatin C, or measured GFR, precluding any conclusions on these important kidney function biomarkers. It is also unclear whether the changes observed only reflect changes in muscle mass or body distribution caused by GAHT or indicate actual changes in kidney function. Finally, available studies included only adult transgender populations, and these populations included were predominantly younger, healthier individuals without CKD. Therefore, it is unknown how GAHT affects kidney function biomarkers in pediatric, adolescent, or nonbinary populations or in populations with advanced kidney disease; it is also unknown how GAHT relates to the various causes of kidney disease (e.g., diabetic kidney disease, polycystic kidney disease, glomerulonephritis).

Additional reviews have demonstrated that, on average, creatinine increases by 5–10 μmol/L among transgender men receiving GAHT while decreasing 5–10 μmol/L among transgender women receiving GAHT. However, the clinical relevance of this finding and the true difference in actual GFR remain poorly understood, especially considering the lack of data on GAHT dose and formulation; achieved hormone levels; and non-GFR determinants of SCr, including medications and dietary intake (Collister et al., 2021). In addition, these studies may not take into account other factors related to TGD experience beyond GAHT. One single-center study of transgender individuals who had received GAHT had a lower prevalence of CKD and acute kidney injury versus counterparts who had not received GAHT, suggesting that the risk of CKD was not conferred by the use of GAHT, but unmeasured factors (Eckenrode et al., 2022a).

As for the impact of GAHT on cystatin C, because it is less influenced by muscle mass, relative to creatinine (Stevens et al., 2009), and is thought to be less influenced by sex hormones (Weinert et., 2010), cystatin C–based GFR estimates could, in theory, improve CKD monitoring in TGD people (Pierre et al., 2023). One recent study used data from the European Network for the Investigation of Gender Incongruence to examine changes in SCr and serum cystatin C during the first year of individual receipt of GAHT (van Eeghen et al., 2023). In this cohort, transgender women receiving estradiol and cyproterone acetate (n = 260) saw a decrease in cystatin C of 0.069 mg/L (CI 0.049–0.089 mg/L), corresponding to a 7 mL/min per 1.73 m² increase in eGFR; transgender men receiving testosterone (n = 285) saw an increase in cystatin C

of 0.062 mg/dL (CI 0.310–0.072 mg/dL), corresponding to a 6 mL/min per 1.73 m² decrease in eGFR (van Eeghen et al., 2023). Notably, creatinine-based eGFR varied depending on the sex coefficient used in the equations.

eGFR Determination, GAHT, and Pediatric Populations

Data are limited on the influence of GAHT in pediatric populations. However, the authors of one notable study calculated SCr changes among TGD youth in a cohort of patients recruited from the Trans Youth Care Study in the United States (Millington et al., 2022). The authors estimated GFR for study participants using both the CKiD U25 equation (Pierce et al., 2021) and the CKD-EPI 2021 equation (Inker et al., 2021). They found that among the total of 286 individuals, all had significant changes in SCr by 6 months of GAHT. Individuals with sex recorded male at birth who had been treated with estradiol (n = 92) had a decrease in SCr of 0.07 +/− 0.14 mg/dL over 6 months, and no changes beyond that point. Individuals with sex recorded female at birth who had been treated with testosterone (n = 194) had an increase in SCr of 0.11 +/− 0.1 mg/dL over the first 6 months of treatment and an additional increase between 6 and 12 months, for a total increase of 0.14 +/− 0.11 mg/dL over the first year. Although median doses of testosterone and estradiol were assessed in this study, the exact dose–response association between GAHT and creatinine-based eGFR is unclear. However, these results are consistent with those of studies in adult TGD populations that have found that feminizing GAHT tends to decrease SCr levels, while masculinizing GAHT tends to increase SCr levels. Additional research is needed to confirm these results and understand their impact on true kidney function and outcomes for pediatric patients.

Sex Coefficients in eGFR Determination: Evolving Guidelines

While the impact of exogenous hormones used for GAHT on SCr (and other kidney function biomarkers) remains unclear, sex differences in SCr levels form the basis of the eGFR equations. Existing eGFR equations include binary sex (male versus female) as a covariate because of findings that, on average, cisgender females generate less creatinine compared with cisgender males as the result of lower muscle mass and/or possible differences in creatinine production (Baxmann et al., 2008; Krupka et al., 2022; Malmgren and Grubb, 2023). For instance, several studies have demonstrated that serum and urine creatinine correlate significantly with lean mass and body weight (Baxmann et al., 2008).

While the CKD-EPI 2021 equation represents a substantial step forward in reassessing the inclusion of race in diagnosing CKD, it does not address potential problems with using sex as a coefficient in eGFR equations. Importantly, equations used to estimate eGFR in adults have varied over time, reflecting evolving views on the factors (including sex) hypothesized to influence muscle mass and thus SCr or other kidney function biomarkers. Since 1973, several creatinine-based GFR estimating equations have been used in clinical practice, and the evolution of their use is relevant to current practice (see Table 10-1). The female sex multiplier has changed multiple times over the years as understanding of sex differences in kidney function has evolved. Historically, efforts to develop the eGFR equations have not included TGD populations.

Given modern conceptions of sex and gender in medicine and the potential impact of GAHT on important kidney function biomarkers, some members of the nephrology community have called for recognition and reconsideration of what “sex” represents in the eGFR equations (Fadich et al., 2022; Inker et al., 2021; Levey et al., 2009, 2020; Mohottige and Tuot, 2022). To achieve greater precision in estimating kidney function for TGD people, experts have called for future estimating equations to include data from populations with a range of sexual and gender identities, including individuals receiving GAHT (Mohottige and Tuot, 2022).

Chronic Kidney Disease Guidelines and Gender-Affirming Hormone Therapy

Despite the limited research on GAHT and kidney function biomarkers presented above, no studies have described specific eGFR equations for TGD individuals based on GAHT or sex hormone configuration. However, prominent organizations have recently offered guidance on eGFR measurements for people with TGD or VST experience. According to 2023 guidance from AACC/NKF on the appropriate use of the 2021 CKD-EPI equation (Pierre et al., 2023):

Further, the AACC/NKF guidance states that the urine albumin–creatinine ratio (uACR)¹¹ and 24-hour urine creatinine clearance¹² may be a better measure than the 2021 CDK-EP1 equation for determining kidney function in TGD people. However, as urine creatinine itself may be influenced by sex hormone configurations (Forni Ogna et al., 2015), researchers have suggested that gender-specific ranges be used to improve interpretation of these measurements (Marco Mayayo et al., 2016; Yang et al., 2022). Further studies are needed to examine long-term changes in urine albuminuria/proteinuria related to GAHT.

The Kidney Disease Improving Global Outcomes also updated clinical practice guidelines for CKD evaluation and management; proposed guidelines ensure scientifically rigorous and equity-focused care for TGD patients (Stevens et al., 2024). The 2024 guidelines offer further insight into appropriate eGFR measurement for people with TGD experience, including considerations of CKD staging, as well as considerations of the circumstances in which using cystatin C may be beneficial (Stevens et al., 2024).

SUMMARY OF KEY POINTS

Inaccurate estimations of kidney function have numerous implications for health, including the potential to worsen disparities in care for TGD people, resulting, for example, in inappropriate GAHT dosing, delays in nephrology care and disease-modifying therapies, and delayed referrals for kidney transplant evaluation. To avoid exacerbating disparities in care delivery and outcomes among TGD people with imprecise eGFR measurements, clinical teams may need to consider the most precise methods for assessing kidney function among individuals with TGD or VST lived experience, including the use of 24-hour urine creatinine clearance or mGFR, where feasible. These measurements of kidney function are not currently

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¹¹ The urine albumin-to-creatinine ratio (uACR) calculates the amount of albumin and creatinine in urine and is an important test for identifying kidney damage, in addition to the eGFR test. Healthy kidneys allow very little albumin (which is a type of protein normally found in the blood) to enter the urine, but damaged kidneys may allow albumin to leak out. When a patient has albumin in their urine, it is called albuminuria or proteinuria. Where a patient has a high amount of albumin in their urine, they may be at an increased risk of having CKD progress to kidney failure. uACR may be determined from a one-time “spot” urine sample or a 24-hour collection, and the spot specimen correlates well with 24-hour urine collections (NKF, n.d.-c).

¹² Creatinine clearance measurements examine creatinine in the urine (whereas serum creatine—used in most eGFR equations—is creatine in the blood). Creatinine clearance requires a timed urine sample (usually 24 hours), the result of which shows how much creatinine has passed through the kidneys into the urine. This indicates how well kidneys are removing waste from the blood (https://www.kidney.org/es/node/27522; accessed March 15, 2024).

included in SSA criteria under Listing 6.05 or 106.05. It is true that fewer patients are likely to have access to these measures relative to those more commonly used in clinical practice, given that they are not part of routine care and may not be covered by insurance. When used to clarify kidney function in patients (including those with TGD or VST lived experience), however, these more precise measures may help inform disability determination. Furthermore, when SSA sees evidence in the medical record that eGFR was estimated using an inappropriate sex reference (e.g., when providers are mistaken about patient sex and gender identity or lack training and guidance on which sex coefficient to use for TGD patients or patients with VSTs), it may be beneficial, where clinically appropriate, to order as part of a consultive exam a test that offers more precise measurement of kidney function (e.g., mGFR). However, individual applicants should always have the choice whether to submit to a consultive examination.

In addition, until further research is available to clarify the appropriate clinical approach for people who receive GAHT, current AACC/NKF guidelines recommend estimating eGFR using both the male and female constants with the 2021 CKD-EPI eGFR equation (“dual calculations”). The committee for the present study does not know how often providers use dual calculations for estimating eGFR, but believes that this is not yet part of common practice, especially considering that the AACC/NKF guidance on this subject was so recently issued (Pierre et al., 2023). Still, in contrast to dual calculations sometimes used for evaluation of pulmonary function (described in Chapter 8) and body mass index measurements (described in Chapter 9), areas in which there are no guidelines in place for providers, the issuance of this recent guidance may make dual calculations of eGFR more commonplace in kidney care.

For this reason, SSA may see dual eGFR calculations in medical records submitted for disability determination, especially as the AACC/NKF guidance works its way into clinical practice. When disability adjudicators receive medical records containing dual eGFR calculations, they may have to determine which eGFR measure to choose, male or female, to determine eligibility for disability benefits. It is the consensus of the committee, based on its clinical expertise and professional judgment, that SSA will best serve applicants who have used GAHT at some point in their care¹³ by using the lowest eGFR value recorded to determine the presence of CKD and related conditions under Listings 6.05 and 106.05.

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¹³ The committee has evaluated the evidence base regarding factors—specifically receipt of GAHT—that may influence eGFR or other kidney function estimation among TGD individuals. There are no data to the committee’s knowledge describing shifts in eGFR among individuals who are not utilizing GAHT; hence the committee’s conclusion focuses on estimation among applicants who have used GAHT at some point in their care.

REFERENCES

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