Limitations of Relying on Creatinine After Kidney Transplant

For years, serum creatinine testing has served as the primary means for monitoring the health of transplanted kidneys because of its availability and familiarity. Unfortunately, nearly 1 in 5 kidney transplant patients still suffers allograft loss within five years of surgery — demonstrating the need for better monitoring tools and interventions.

Multiple clinical studies demonstrate that serum creatinine is a lagging indicator of allograft dysfunction. Early identification of kidney injury is essential to preserving graft health, and physicians know that serum creatinine levels can prove difficult to interpret at the onset of declining renal function and can be influenced by nonrenal factors.

To ensure the best patient outcomes, there is an opportunity to find better ways of monitoring renal allograft health.

Why Creatinine Fails to Provide a Dynamic Marker

Estimated glomerular filtration rate (eGFR) calculations rely on patient demographic factors and serum creatinine levels to measure allograft health. Too frequently, though, providers find that creatinine levels do not accurately indicate current renal function.

While subclinical allograft injury typically causes a quick decline in glomerular filtration, the proximal tubules initially compensate with increased secretion. This prolongs serum creatinine level stability, giving the appearance that the allograft retains normal function — even as graft injury progresses.

By the time creatinine levels rise, substantial and irreversible loss of nephron mass and renal functional reserve may have already occurred.

Creatinine and GFR

The curvilinear relationship between serum creatinine and GFR makes it problematic to use as an exact measure of renal function, particularly at the extremes of GFR1.

During initial stages of allograft injury, a significant decline in GFR changes serum creatinine by only 0.1 to 0.2 mg/dL (or less). Even a 50% decrease in GFR may only be accompanied by a relatively small change in creatinine on the “flat” part of the curve.

On the other hand, during advanced stages of graft failure (GFR < 30 mL/min) on the “steep” part of the curve, small changes in GFR are associated with a significant increase in serum creatinine. By this point, however, significant injury may have already occurred.

BK Virus and CMV in Renal Allografts Post-Transplant

Delayed recognition of allograft tissue damage can also occur in the presence of cytomegalovirus (CMV) and BK viral infections. It is well known that the immunosuppressive medications that patients are required to take after transplantation increase their risk of developing these viral infections

Both viruses can lie dormant in patients and reactivate after transplant. CMV may also be transmitted through the donor kidney. Viruses may initially circulate in the blood, but can eventually involve the renal allograft causing nephropathy and renal dysfunction.

Since CMV and BK infections often occur asymptomatically, they can start causing allograft damage with little to no warning. Renal injury ultimately triggers a rise in creatinine, but not immediately. By the time creatinine levels increase, significant fibrosis and tissue loss may have occurred, putting patients at increased risk for allograft loss.

External Factors Also Influence Creatinine

To further complicate matters, factors unrelated to kidney physiology may also influence creatinine. These factors impact creatinine production and both renal and extrarenal secretion and can make it difficult to identify the true cause of creatinine change.

While an ideal marker would only change with renal function, physicians have identified the following non-renal factors as affecting creatinine:

  • Hydration
  • Nutritional status
  • Muscle mass
  • Race
  • Sex

Estimated GFR equations do attempt to adjust for how the variables of muscle mass, race and sex influence creatinine, but they often miscalculate due to individual differences from predicted metrics. For example, when applied to the unique cases of patients with lower extremity amputation, morbid obesity, or malnutrition, eGFR may be inaccurate. In elderly patients especially, reduced muscle mass can lead to an overestimation of GFR.

Frequent creatinine testing and establishment of baseline levels during the first year following transplant can account for some of these confounders. However, beyond the first year, transplant patients typically see their general nephrologists less frequently, and may only have labs drawn every few months. To extend graft life, physicians would agree that it is critical to detect graft injury as soon as possible.

Drugs that increase creatinine levels

Several medications can increase serum creatinine levels by inhibiting secretion of creatinine by the proximal tubules. This causes an increase in serum creatinine without decreasing GFR. Some medications that can be responsible for this include:

  • Active vitamin D metabolites
  • Corticosteroids
  • Cimetidine
  • Phenacemide
  • Pyrimethamine
  • Salicylates
  • Trimethoprim

Being Intentional with Allograft Biopsy

Without another indicator to reliably monitor kidney function, physicians may not be able to detect worsening graft injury or rejection until serum creatinine levels start to rise, which often prompts a biopsy to determine the cause of renal dysfunction. By that time, significant amounts of irreversible injury may have already occurred to the allograft and this may limit the potential for successful treatment.

Conversely, physicians may perform unnecessary biopsies if creatinine falsely indicates a change in GFR. In either case, the decision to perform a biopsy would ideally be supported by a more reliable and accurate kidney marker, as biopsy comes with its own challenges and risks.

Biopsies must be performed at a transplant center, meaning patients often must travel for the outpatient procedure, a frequently challenging task. Patients may live hours from the transplant center, be unable to drive themselves, or be encumbered by the financial costs involved.

Once at the center, an allograft biopsy can be burdensome and uncomfortable for patients, given its invasive nature. Biopsy can also be associated with significant risks, including:

  • Bruising and discomfort at the biopsy site
  • Bleeding around the kidney or blood in the urine
  • Injury to surrounding organs or structures
  • Exposure to hospital-acquired infection

The procedure places a significant burden on health care resources as well, requiring time from physicians and staff, in addition to costs associated with both the biopsy and post-procedure monitoring.

Discovering a Better Kidney Marker

Given the time-sensitivity of treating allograft injury and rejection, reliance on serum creatinine faces serious pitfalls. An optimal indicator of kidney transplant health would be more accurate than creatinine at detecting allograft injury but just as easy to acquire. It would not be influenced by nonrenal factors and would allow physicians to detect subclinical injury for earlier intervention.

Early detection and intervention could mean the difference between reversible injury and graft failure. By relying on a better marker, physicians may be able to more effectively preserve long-term kidney graft function and survival.

To learn more about alternative markers of kidney function, click here.


1. UpToDate – Assessment of Kidney Function –
2. Scholars Academic Journal of Pharmacy – Limitations of serum creatinine as a marker of renal function –
3. Swedko PJ, Clark HD, Paramsothy K, Akbari A. Serum Creatinine Is an Inadequate Screening Test for Renal Failure in Elderly Patients. Arch Intern Med. 2003;163(3):356–360. doi:10.1001/archinte.163.3.356
4. Medscape – Creatinine Clearance –
5. Kidney Foundation – “Frequently Asked Questions About GFR Estimates”
6. Kidney International – “Limitations of creatinine as a filtration marker in glomerulopathic patients”
7. Urologia Internationalis – Pseudorejection and True Rejection after Kidney Transplantation: Classification and Clinical Significance –