A raised creatinine on testosterone replacement therapy (TRT) often reflects muscle mass rather than kidney damage. At Longevity Benchmark, we review trial evidence to separate marker artefacts from genuine organ pathology. Creatinine is a breakdown product of creatine in muscle tissue.
Adding muscle raises serum levels independently of kidney filtration. The TRAVERSE trial did detect a small excess of acute kidney injury (AKI) events. This finding keeps TRT and kidney function under active clinical discussion.
The Verdict
Physiological Origins of Serum Creatinine on TRT
Creatinine is a metabolic breakdown product of creatine located in skeletal muscle tissue. Serum creatinine levels reflect both kidney filtration and total muscle mass. When therapy adds lean tissue, daily creatinine production rises without any change in renal clearance.
Standard blood work uses creatinine to estimate kidney clearance on a comprehensive metabolic panel. The standard formula assumes average muscularity. Because of this assumption, higher muscle mass pushes the calculated clearance rate lower.
A muscular man can register a flagged creatinine level while possessing normal kidney function. Cystatin C provides an alternative filtration estimate. Nucleated cells produce cystatin C continuously regardless of changes in body composition.
Divergence Between Filtration Markers in Population Data
Free testosterone levels correlate in opposite directions with creatinine and cystatin C filtration estimates. A population study from the Rotterdam Study, published by van der Burgh and colleagues in Kidney International Reports in 2023, evaluated 4,095 men and 5,389 women. The cohort had a mean age of 65.2 years.
Investigators measured circulating testosterone, sex hormone-binding globulin (SHBG), creatinine, and cystatin C. In men, higher free testosterone was associated with a lower eGFR calculated from creatinine. That same higher testosterone was associated with a higher eGFR calculated from cystatin C.
Both kidney markers moved in opposing directions within the exact same men. The authors stated that low testosterone is associated with lower muscle mass, which lowers creatinine and raises creatinine-based clearance. They concluded that cystatin C-based eGFR might be the better parameter for evaluating how testosterone relates to kidney function.
Filtration Discrepancies in Men with Muscle Hypertrophy
Substantial muscle mass can cause serum creatinine to underestimate renal function. A retrospective study by Ashouri and colleagues, published in 2024 in the American Journal of Men's Health, evaluated 227 men. All participants had testosterone-induced muscle hypertrophy and trained as competitive or recreational athletes at a men's health tertiary care clinic.
Researchers compared creatinine against cystatin C across body mass index (BMI) and body fat percentages. The authors pointed out that in men carrying high muscle mass, creatinine may underestimate renal function, making kidney function look worse than it is.
Among patients with a normal body mass index, there was no clinically significant correlation between creatinine and cystatin C. This single-clinic retrospective analysis highlights the diagnostic limitations of creatinine in athletic cohorts.
Acute Kidney Injury Signals in the TRAVERSE Trial
Large trial data show a modest increase in acute kidney injury diagnoses among men taking testosterone. The TRAVERSE trial, published in the New England Journal of Medicine in 2023 by Lincoff and colleagues, examined 5,246 men. The study is indexed on PubMed.
Participants were aged 45 to 80 with preexisting cardiovascular disease or high cardiovascular risk, hypogonadal symptoms, and two fasting testosterone levels below 300 ng/dL. Men were randomized to daily transdermal 1.62% testosterone gel or placebo gel. Treatment lasted an average of 21.7 ± 14.1 months, with a mean follow-up of 33.0 ± 12.1 months.
Primary cardiovascular endpoints occurred in 182 patients (7.0%) on testosterone and 190 (7.3%) on placebo. Testosterone was noninferior for major adverse cardiac events, with a hazard ratio of 0.96 (95% confidence interval, or CI, 0.78 to 1.17, P<0.001). However, secondary findings showed higher rates of atrial fibrillation, pulmonary embolism, and acute kidney injury.
Acute kidney injury occurred in 60 testosterone patients against 40 placebo patients (P=0.04).
| Trial Arm | Assigned Patients | AKI Cases | Incidence (Per Arm) |
|---|---|---|---|
| Testosterone gel (1.62%) | Roughly 2,600 | 60 | 2.3% |
| Placebo gel | Roughly 2,600 | 40 | 1.5% |
Denominator Discrepancies in Published Trial Analyses
Different calculation methods have produced two conflicting sets of percentages for the acute kidney injury events in TRAVERSE. The trial recorded 60 cases in the testosterone group and 40 in the placebo group. Dividing by roughly 2,600 men per arm gives rates of 2.3% versus 1.5%.
These per-arm figures answer what risk looked like for patients assigned to each therapy. In 2025, Geoffrey Hackett published a review of TRAVERSE in the World Journal of Men's Health. Hackett used the same 60 and 40 counts but divided by the total 5,204 men who received a dose.
That pooled calculation produced rates of roughly 1.2% versus 0.8%. Both sets of figures describe the exact same trial events. The difference is purely a mathematical reading problem based on which denominator is chosen.
Potential Confounders Behind Reported Renal Events
Clinical reviews have raised questions about whether the excess events in TRAVERSE represent direct drug toxicity. In his 2025 review, Hackett argued that the excess acute kidney injury cases may be confounded rather than drug effects. He cited increased physical activity among treated men.
Hackett also highlighted baseline comorbidities as a factor that could influence acute kidney injury rates.
This argument represents an interpretation rather than an established finding. The trial recorded a mathematical difference between arms (P=0.04) that cannot be dismissed. Whether lifestyle changes or drug mechanisms drove the numerical gap remains unresolved.
Clinical Guidelines and Routine Monitoring Protocols
Major practice guidelines for testosterone therapy do not mandate routine surveillance of kidney function. The Endocrine Society outlined monitoring recommendations in their 2018 guideline published in The Journal of Clinical Endocrinology & Metabolism. Their protocol specifies measuring hematocrit at baseline, at 3 to 6 months, and then annually.
Therapy stops if hematocrit exceeds 54% until it falls, alongside an evaluation for hypoxia and sleep apnea. Guidelines also advise checking prostate-specific antigen (PSA) and testosterone levels. Our analysis of high hematocrit on TRT details how clinics manage that threshold.
The Endocrine Society guideline contains no recommendation for routine creatinine, eGFR, or cystatin C testing. Kidney markers are not part of the specified endocrine monitoring schedule. When clinicians track TRT side effects and risks, renal panels function as general medical checks rather than mandatory hormone-specific requirements.
Evidence Limits for TRT and Kidney Function
Marker discrepancies explain why creatinine shifts with muscle mass, but they do not prove that altering therapy improves clinical outcomes. Neither TRAVERSE nor the studies by Ashouri and van der Burgh tested whether switching to cystatin C changes patient outcomes. They demonstrate a measurement artefact without establishing a superior treatment pathway.
Men with existing chronic kidney disease are not represented by any of this evidence. Anyone managing preexisting renal pathology requires specialized nephrological guidance rather than general marker interpretation.
What would change our answer is a randomized trial testing whether cystatin C management reduces clinical kidney complications compared to creatinine. Until such trials are conducted, a flagged reading remains a topic for clinical discussion rather than self-directed adjustments. Could increased muscle mass account for my higher creatinine, and would a cystatin C measurement change how you read it?
Frequently Asked Questions
Does TRT raise creatinine?
Testosterone replacement therapy can raise serum creatinine by increasing skeletal muscle mass. Creatinine is a breakdown product of creatine in muscle tissue, so having more muscle generates more creatinine daily. When muscle mass increases during treatment, blood levels of creatinine often rise even though the kidneys continue to filter blood at a normal rate. This physiological rise reflects muscular development rather than renal organ damage.
Does a high creatinine on TRT mean kidney damage?
A raised creatinine does not automatically mean kidney damage has occurred. Because serum creatinine reflects both muscle mass and kidney filtration, muscular men often produce higher baseline levels. However, clinical trials have documented rare acute kidney injury events, so elevated values cannot be assumed to be harmless without clinical review. A physician can weigh whether recent training or genuine renal impairment explains the finding.
Should I get a cystatin C test instead of creatinine on TRT?
Cystatin C is a filtration marker produced by nucleated cells that does not depend on muscle mass, making it a useful secondary test when creatinine readings are ambiguous. Observational research indicates that cystatin C resolves discrepancies caused by high muscularity. However, no clinical trial has tested whether switching to cystatin C monitoring changes health outcomes or reduces complication rates. Deciding whether to order cystatin C is a clinical choice to discuss with your prescribing physician.
Why is my eGFR low on testosterone?
Estimated glomerular filtration rate (eGFR) is commonly calculated from serum creatinine using standard formulas that assume average muscle volume. If testosterone therapy increases your lean muscle mass, your body produces more creatinine, which lowers the calculated eGFR mathematically. In the Rotterdam Study, men with higher free testosterone showed lower creatinine-based eGFR but higher cystatin C-based eGFR. The low score often reflects this mathematical assumption rather than reduced kidney filtration.
Did TRAVERSE show testosterone causes kidney injury?
The TRAVERSE trial recorded 60 acute kidney injury events in the testosterone group compared to 40 events in the placebo group among 5,246 participants, reaching statistical significance (P=0.04). This represents an incidence of 2.3% versus 1.5% within each treatment arm. While the trial established noninferiority for major cardiovascular events, the kidney signal was noted as a secondary adverse event. Some medical reviews argue these cases may involve confounding factors like increased exercise, but the finding remains under active evaluation.
Can TRT be used with chronic kidney disease?
None of the trials and observational studies examining testosterone and kidney markers here evaluated men with advanced chronic kidney disease. Whether testosterone therapy is appropriate for someone with chronic renal impairment depends on individual clinical factors, cardiovascular health, and nephrological oversight. Management for individuals with preexisting kidney disease remains under the direct supervision of an endocrinologist and nephrologist.
How often is kidney function checked on TRT?
Clinical practice guidelines from the Endocrine Society do not recommend routine kidney function or cystatin C testing as part of their standard testosterone monitoring schedule. The guideline's monitoring recommendations cover hematocrit, prostate-specific antigen and testosterone level, with hematocrit measured at baseline, at 3 to 6 months, and then annually. No kidney-marker interval appears in that schedule.