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Transgender Man Being Evaluated for a Kidney Transplant.

Case Description

A 33-year-old female-to-male transgender individual (height, 5'1"; weight, 135 lb) presented to emergency care with acute otitis media and hypertension (170/110). Currently prescribed medications include daily atorvastatin and intramuscular testosterone cypionate injections (100 mg/week). The patient refused admission because of discrimination concerns as a transgender man, but presented to his primary care physician the following morning. Laboratory results revealed a urine total protein concentration of 199.5 mg/dL (random collection, 0.0-10.0 mg/dL) and an estimated glomerular filtration rate [(eGFR).sup.3] of 31 mL/min/1.73 [m.sup.2] if assessed using the male equation or 23 mL/min/1.73 [m.sup.2] if assessed using the female equation. On the basis of male categorization, the patient was diagnosed with stage 3 chronic kidney disease (CKD3), prescribed carvedilol, and strongly encouraged to discontinue testosterone, to which he agreed. The patient transferred to an alternate institution; here testosterone administration was restarted, lisinopril was prescribed, and reduction in protein and sodium intake was encouraged. Incidentally, the patient had maintained a vegan diet for >10 years.

Renal transplant evaluation was initiated several months later. Corresponding male eGFR was 24 mL/ min/1.73 [m.sup.2], but the corresponding female eGFR was 18 mL/min/1.73 [m.sup.2]. Urine protein excretion was 3 g/day. Because transplant candidates require a GFR <20 mL/ min/1.73 [m.sup.2] (1) and because the patient's male-calculated eGFR was above the cutoff, he was not listed. An evaluation 4 months later documented an eGFR of 21 and 15 mL/min/1.73 [m.sup.2] for corresponding male and female levels, respectively. In the patient's medical chart, only the corresponding male eGFR was documented, and the medical care team did not consider that the sex-based equations will lead to a different interpretation. All eGFR values were calculated using the Modification of Diet in Renal Disease study equation.

Case Discussion

Sex-specific cutoffs are often used to diagnose, monitor, and define treatment strategies. However, virtually no studies have determined reference intervals appropriate for transgender patients (2). There are few areas where sex-specific recommendations are more concrete than kidney function, but a literature search for "transgender and kidney disease" resulted in no applicable publications.

Kidney assessment evaluates renal function (GFR) and damage (proteinuria) (3). In general, creatinine-based eGFR calculations are adequate for CKD staging. However, creatinine concentration may be confounded by other variables, which can be generalized to either increasing or decreasing mean creatinine excretion. For instance, individuals with low muscle mass have less creatinine and hence their eGFR may be apparently high, giving the perception that filtration is occurring at an improved rate. In contrast, diets rich in animal protein can artificially increase serum creatinine, decreasing the effective eGFR. Analytical interferences can cause deviations in creatinine concentration; drugs that inhibit renal secretion or antibiotics that decrease bacterial metabolic enzymes will increase serum creatinine, thereby decreasing the effective eGFR. Finally, because creatinine-based eGFR equations are dependent on sex/gender congruence and racial demographics, gender nonconformity and mixed ancestry challenge their applicability. Combined, eGFR will only accurately reflect true GFR (within 30%) 75%-90% of the time.

When eGFR calculations are confounded by such variables, cystatin C-based eGFR calculations or a clearance-based GFR should be determined. Inulin clearance, measured under continuous inulin infusion and urine collection, is the gold standard clearance test for approximating GFR because it evaluates the kidneys' ability to filter an exogenous molecule that is neither secreted nor reabsorbed. However, this test is not performed in any routine clinical setting, and laboratory tests to quantify inulin are rare (Table 1) (4). Evidence suggests that renal clearance can also be assessed using chromium 51-labeled EDTA ([sup.51]Cr-EDTA) or iothalamate infusion and plasma clearance of [sup.51]Cr-EDTA or iohexol. In this case, the physicians neither assessed renal function using a sex-independent method nor consulted the laboratory for assistance with eGFR interpretation.

For a patient to undergo kidney transplantation, a GFR <20 mL/min/1.73 [m.sup.2] (1) is required. Candidates must pass an extensive physical and mental evaluation and show that they can adhere to the recommended medical regimen posttransplant. Their financial responsibility and insurance coverage is evaluated. This patient met all criteria for transplant candidacy except for the GFR, but his transgender status complicated the validity of the calculated eGFR used as a GFR surrogate. Of note, he is a relatively small person, short stature and thin frame; therefore, his muscle mass is similar to that of an average female. He is also vegan, which would further decrease his endogenous creatinine concentration relative to a person that includes animal protein in their diet. The largest deviations in eGFR to GFR comparisons are a function of muscle mass and diet (3). In combination, the patient's eGFR level likely overestimated his renal function.

Transgender refers to a person whose gender identity or expression differs from their assigned sex (5). In contrast, nontransgender people are cisgender. Transgender men (female-to-male) are individuals who were born female, but identify/live as men; transgender women (male-to-female) are individuals who were born male, but identify/live as women. Transgender individuals may seek hormones and/or various surgeries, but these gender-affirming strategies are not universal, resulting in a diverse transgender population. The medical community assumes that most sex-specific physiological variability is because of the differential reproductive organs and hormone profiles between sexes. Gender and social influences that can lead to variability are less tangible. The amalgam of diverse treatment strategies, hormone profiles, and socialization makes interpreting sex-specific reference intervals in the transgender population complex. Here, the transgender man had been on testosterone hormone therapy for 15 years, but retained female reproductive organs.

Sex-specific ranges for renal function biomarkers stem primarily from the differences in muscle mass between men and women because creatinine, the most commonly used indicator of kidney function, is a product of normal muscle metabolism (3). There is no literature indicating that maintaining a testosterone concentration within male-specific normal ranges affects kidney function. Moreover, studies on cisgender men show that decreasing testosterone concentration portends worse CKD outcomes (6, 7).

Evidence- or consensus-based publications indicating which eGFR equation or creatinine reference interval should be applied to transgender individuals do not exist. Roberts et al. performed a retrospective analysis of transgender women on estrogen therapy, comparing their laboratory values to those of matched cisgender women and men (8). These authors found that the creatinine concentrations of transgender women resembled those of cisgender men. This statement can be interpreted as follows: for these women, the so-called "male" reference interval may be more appropriate and classification as female would place a transgender woman on the transplant list before her effective eGFR reached 20 mL/min/ 1.73 [m.sup.2]. Alternatively, transgender men may be overlooked if their effective eGFR more appropriately resembles a female number, but they are categorized using the male eGFR levels.

Several other laboratory results are influenced by sex. For example, hemoglobin and hematocrit levels are difficult to interpret in the transgender population (9). Sex-specific cutoffs are also used to detect cytopenia and/or cythemia. Data indicate that hematologic parameters are influenced by exogenous hormone administration, but there is relatively less information identifying clinically relevant changes or "normal" ranges for transgender men or women. Similarly, estrogen administration in transgender women leads to pituitary stimulation and subsequent prolactin production (9). Physicians with experience caring for transgender patients recognize this increase but have no evidence to support what defines an abnormal concentration.

Increased eGFR was the primary barrier to the patient not being considered for transplantation. The patient's kidney disease etiology was unrelated to his transgender identity, it was attributed to him having Kawasaki's disease as a toddler. The early suggestions to immediately stop testosterone treatment and comments documented in the medical chart such as "but this man has a uterus," underline the lack of awareness around the transgender state and the care team's inaccurate assumptions about gender dysphoria therapy (10).

This highlights a broader need for transgender education within medical communities. There are at least 1.4 million transgender people in the US (5). Kidney disease impacts >10% of adults, meaning that there are approximately 140000 transgender people who may not be receiving adequate care on the basis of current medical recommendations that adhere to sex-specific parameters. Here, strictly enforcing the requirement of GFR <20 mL/min/1.73 [m.sup.2] delayed transplant initiation in an individual whose kidney filtration capacity was likely well below the minimum.

Case Follow-Up

At the patient's and his wife's insistence, the physician team approved the transplant request. At their first transplant meeting, a year after the patient's initial presentation, they faced more resistance because the corresponding male eGFR values were still >20 mL/min/1.73 [m.sup.2]. The patient was officially placed on the transplant recipient list 2 months after the first transplant meeting when his corresponding "male" and female eGFR were 18 and 13 mL/min/1.73 [m.sup.2], respectively.

The patient is presently on the transplant list but determining when to initiate dialysis was also complicated by differences in the sex-specific eGFR values, and therefore clinical criteria became the primary focus. The patient was placed on peritoneal dialysis when the eGFR was 8 (corresponding male level) or 6 mL/min/1.73 [m.sup.2] (corresponding female level). He weighed 100 lbs. Following port placement, the clinic was concerned about determining the most effective dialysis regime because the dialysis adequacy equation (Kt/V urea) requires a sex-specific constant to estimate total body water. After 2 weeks of the initially prescribed dialysis regime, the adequacy calculations indicated insufficient solute removal, and therefore, the number of times dialysis needed to be conducted was increased. Dialysis improved his wellbeing, but crucial time was lost because of sex-specific eGFR criteria that is imposed on transgender men.

QUESTIONS TO CONSIDER

1. What genetic, biological, and environmental factors can influence creatinine concentration and lead to subsequent uncertainty in the eGFR interpretation?

2. Does exogenous testosterone administration influence kidney function?

3. What other laboratory results may be difficult to interpret in transgender patients?

POINTS TO REMEMBER

* A transgender individual is a person whose biological sex does not match their gender identity.

* Kidney health is evaluated using laboratory measurements to estimate function (GFR) and damage (proteinuria).

* Interpreting sex-specific reference limits in transgender individuals is complicated, particularly for eGFR where muscle mass is an integral component.

* When assessing renal function in transgender patients, consideration should be given to sex-independent methods such as iothalamate clearance.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) University of Pennsylvania. https://www.pennmedicine.0rg/~/media/ documents%20and%20audio/patient%20guides%20and%20instructions/transplant/ kidney_transplant_selection_criteria.ashx?la=en (Accessed October 2016).

(2.) Roberts TK, Fantz CR. Barriers to quality health care for the transgender population. Clin Biochem 2014;47:983-7.

(3.) Levey AS, Becker C, Inker LA. Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review. JAMA 2015;313:837-46.

(4.) Soveri I, Berg UB, Bjork J, Elinder CG, Grubb A, Mejare I, et al. Measuring GFR: a systematic review. Am J Kidney Dis 2014;64:411-24.

(5.) Winter S, Diamond M, Green J, Karasic D, Reed T, Whittle S, Wylie K. Transgender people: health at the margins of society. Lancet 2016;388:390-400.

(6.) Haring R, Nauck M, Volzke H, Endlich K, Lendeckel U, Friedrich N, et al. Low serum testosterone is associated with increased mortality in men with stage 3 or greater nephropathy. Am J Nephrol 2011;33:209-17.

(7.) Neugarten J, Golestaneh L. Gender and the prevalence and progression of renal disease. Adv Chronic Kidney Dis 2013;20:390-5.

(8.) Roberts TK, Kraft CS, French D, Ji W, Wu AH, Tangpricha V, Fantz CR. Interpreting laboratory results in transgender patients on hormone therapy. Am J Med 2014;127: 159-62.

(9.) Wierckx K, Van Caenegem E, Schreiner T, Haraldsen I, Fisher AD, Toye K, et al. Cross-sex hormone therapy in trans persons is safe and effective at short-time follow-up: results from the European network for the investigation of gender incongruence. J Sex Med 2014;11:1999-2011.

(10.) Bradford J, Reisner SL, Honnold JA, Xavier J. Experiences of transgender-related discrimination and implications for health: results from the Virginia transgender health initiative study. Am J Public Health 2013;103:1820-9.

Commentary

W. Greg Miller [1] *

In the present case, a transgender man (female to male) received inappropriate medical care because the clinical guidelines were based on an incorrect interpretation of estimated glomerular filtration rate (GFR) [2] calculated from serum creatinine and the patient's declared rather than biological gender. The National Kidney Disease Education Program (NKDEP) website states, "The terms for age, sex, and race in both equations only capture some of the non-GFR determinants of creatinine concentration in blood plasma, and the coefficients represent average effects observed in the population used to develop the equations." Muscle mass, and not gender, is the primary influence on the creatinine concentration. Thus, basing the clinical criteria on GFR is appropriate. Using an estimated GFR when the patient does not represent an "average" individual is not appropriate. It should have been obvious that a person who is 5 feet 1 inch in height, 100 pounds in weight, and is of slight build is not an "average" individual for whom an estimate of GFR from creatinine would be suitable for use. This limitation would be correct irrespective of the actual gender, but the estimate for a biological female is more likely to be correct in this case. In addition, the NKDEP website specifically states that estimated GFR based on creatinine is not suitable for people eating either a vegetarian or a low-meat diet, as was the patient in this case.

Looking at the bigger picture, laboratorians need to reach out to the clinical organizations that set practice guidelines, explain the limitations of laboratory tests, and work with them to include limitations, as well as alternate laboratory tests, in the guidelines. In addition, laboratorians should join patient advocacy groups to encourage and promote development of guidelines that best meet the needs of the affected people.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: W.G. Miller, Clinical Chemistry, AACC.

Consultant or Advisory Role: None declared.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: None declared.

Expert Testimony: None declared.

Patents: None declared.

W. Greg Miller [1] *

[1] Virginia Commonwealth University Health System, Richmond, VA.

* Address correspondence to the author at: Virginia Commonwealth University Health System, Richmond, VA 980286. Fax 804-828-0353; e-mail gmiller@vcu.edu.

Received February 13,2017; accepted February 16,2017.

DOI: 10.1373/clinchem.2017.272708

[2] Nonstandard abbreviation: GFR, glomerular filtration rate.

Commentary

Christopher B. Lewis [1] *

Although guidelines and standards of care (1) have been established, transgender healthcare needs continued research on best practices, monitoring, and outcomes. A review of the current literature shows very few publications focusing on the interpretation of common blood work in transgender patients on hormone therapy. Laboratories with male- or female-specific reference ranges frequently leave clinicians questioning which set of normative values to use. Subsequently, many have adopted the practice of interpreting results dependent on the patient's hormonal status.

Uniformly comparing laboratory results for transgender patients with their cisgender counterparts can result in unwarranted changes in management decisions. For example, calculating glomerular filtration rate (GFR) [2] for a transgender male receiving testosterone on the basis of male categorization may lead to overestimation of GFR and delay necessary intervention. Obtaining a precise measurement of GFR, which depends on age, sex, diet, ethnicity, and body size/ muscle mass, is usually unnecessary. However, in some situations, such as renal transplant evaluation, it may be reasonable to measure GFR to make important medical decisions. Formulas for estimating GFR, such as the Modification of Diet in Renal Disease study equation, use age, sex, ethnicity, and creatinine concentration.

Creatinine status is proportional to muscle mass, but solid clinical data showing that testosterone therapy in transgender males induces a male-standard creatinine status are lacking. Although hormone therapy can affect the body composition, results vary between patients and are influenced by factors other than hormone exposure. Moreover, 1 study found that the creatinine values for male-to-female individuals on estrogen therapy resembled male values (2). Some measurands such as hemoglobin and hematocrit may have foreseeable responses to hormone therapy, whereas others are more difficult to predict. This result highlights only 1 aspect of transgender-related care that needs more investigation.

Author Contributions: AH authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, DeCuypere G, Feldman J, et al. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, Version 7. Int J Transgenderism 2012;13:165-232.

(2.) Roberts T, Kraft C, French D, Wuyang J, Wu A, Tangpricha V, et al. Interpreting laboratory results in transgender patients on HRT. Am J Med 2014;127:159-62.

Christopher B. Lewis [1] *

[1] Washington University School of Medicine, One Children's Place, St. Louis Children's Hospital, St. Louis, MO.

* Address correspondence to the author at: Washington University School of Medicine, One Children's Place, St. Louis Children's Hospital, St. Louis, MO 63110. Fax 314-4546225; e-mail lewis_c@wustl.edu.

Received March 15, 2017; accepted March 20, 2017.

DOI: 10.1373/clinchem.2017.272716

[2] Nonstandard abbreviation: GFR, glomerular filtration rate.

Cameron T. Whitley [1] and Dina N. Greene [2] *

[1] Department of Sociology, Michigan State University, East Lansing, MI;2 Departmentof Laboratory Medicine, University of Washington, Seattle, Washington.

* Address correspondence to this author at: Department of Laboratory Medicine, University of Washington, Campus Box 357110, Seattle, Washington 98195-7110. Fax 5105595306; e-mail dngreene@uw.edu.

Received November 1, 2016; accepted January 10, 2017.

DOI: 10.1373/clinchem.2016.268839

[3] Nonstandard abbreviations: eGFR, estimated glomerular filtration rate; CKD3, stage 3 chronic kidney disease.
Table 1. Methods to estimate GFR. (a)

GFR estimate            Sex-        Factors influencing
                        dependent   measurement or interpretation

Inulin clearance        No          Technically difficult;
(gold standard)                     expensive; not performed in
                                    routine clinical settings;
                                    laboratory tests for
                                    quantification are rare

Creatinine based        Yes         Readily available; influenced
                                    by muscle mass, diet, or
                                    certain drugs; analytical
                                    interferences are common; MDRD
                                    (b) study equation is not
                                    useful for eGFR >60 mL/min/
                                    1.73 [m.sup.2]

Cystatin C based        No          Influenced by corticosteroids,
                                    hyperthyroidism, systemic
                                    infection, smoking and
                                    obesity; assays are not
                                    currently standardized

Creatinine clearance    No          Overestimates GFR,
                                    particularly in cases of lower
                                    renal function; not
                                    recommended

[sup.51]Cr-EDTA         No          Radioactive label allows
clearance                           quantification (generally
                                    preformed within nuclear
                                    medicine clinics); shows good
                                    correlation to inulin
                                    clearance

Iohexol clearance       No          Contrast agent quantified
                                    using LC-MS/MS or HPLC
                                    spectrophotometry

Iothalamate clearance   No          Available as either
                                    radiolabeled or unlabeled
                                    small molecule; radioactive
                                    label allows quantification
                                    (generally preformed within
                                    nuclear medicine clinics);
                                    unlabeled molecule quantified
                                    using either LC-MS-MS or HPLC-
                                    UV; shows good correlation to
                                    inulin clearance

(a) Glomerular filtration rate.

(b) Modification of Diet in Renal Disease.
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Title Annotation:Clinical Case Study
Author:Whitley, Cameron T.; Greene, Dina N.
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Nov 1, 2017
Words:3358
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