Pseudo Acute Kidney Injury: Navigating through False Alarms

Under normal circumstances, serum creatinine values are determined by its metabolic generation from the muscle, renal excretion, and, to a minimal extent, by the extrarenal excretion through the gastrointestinal tract. In a steady state, the daily creatinine production equals the daily excretion. Primary renal excretion of creatinine occurs by passive filtration in the glomerulus where as the tubular secretion of creatinine in the proximal tubule involves the active transfer of creatinine from the peritubular capillaries into the tubular cell via specialized transport proteins called organic anion and cation transporters (OATs and OCTs), respectively. Specifically, OCT2 transporters are highly expressed on the peritubular basolateral membrane and are involved in the uptake of creatinine in the proximal tubule (1).  Subsequent creatinine secretion from the proximal tubular cell into the tubular lumen occurs via multidrug and toxin excretion proteins (MATE or SLC47A1) located on the luminal side of the proximal tubular membrane, particularly MATE1 and MATE2-K (Figure 1).

The tubular secretion of creatinine accounts for 10-20% of creatinine excretion and is more pronounced (up to 50%) in patients with renal impairment. Drugs that interfere with the tubular secretion cause decrease in creatinine clearance and corresponding spurious elevation of serum creatinine values without actual change in the GFR, hence termed "pseudo AKI". The rise in creatinine may be  > 0.2-0.4 mg/dl and may go unnoticed in patients with normal renal function but is more pronounced in patients with impaired renal function due to enhanced tubular secretion of creatinine in these patients. 

Several drugs have been implicated in causing pseudo AKI (table 1). Corticosteroids, vitamin D derivatives and fenofibrates may increase serum creatinine values due to increased creatinine production (2).The common H2-blocker, cimetidine (at doses >800-1200 mg/day), is known to have higher affinity than creatinine towards OCT2 transporter, thereby inhibiting tubular secretion of creatinine and is, for this reason, used in calculating measured CrCl that closely mimics the actual GFR. Routinely used drugs such as trimethoprim, dronedarone, ticagrelor and metformin (figure 1 and table 1) inhibit OCTs, OATs, or MATEs transporters and cause a false elevation in creatinine without any change in GFR (3,4,5). Targeted anticancer therapies such as tyrosine kinase inhibitors, MET inhibitors, PARP inhibitors etc. have shown to increase creatinine values by 10-30% (6). Antiretroviral drugs that boost HAART activity such as ritonavir and cobicistat have also been implicated in in vitro studies but recent study suggests no significant clinical effect (7).

Figure 1. Schematic representation of tubular secretion of creatinine and drugs that inhibit creatinine secretion.

Besides increased creatinine production and effects on creatinine secretion, interference with the creatinine assay is also associated with pseudo-AKI. The most commonly used methods for measuring creatinine values in the laboratory include the Jaffe’s chemical assay and the enzymatic essays (8). The Jaffe method involves adding picric acid to creatinine in an alkaline medium to produce an orange color that is measured photometrically to quantify creatinine values. Although extremely cost-effective, interference from non creatinine chromogens ( glucose, bilirubin, proteins) such as in conditions like diabetic ketoacidosis, lipemia, and hemolysis can cause spurious creatinine elevations. Cephalosporins, particularly cefoxitin and cefazolin, can be mistaken as creatinine chromogens by this assay, leading to false elevation in creatinine on measurement (9). Nitromethane, used as an industrial solvent and propellant for sports or hobby cars may cause false Cr elevation in cases of nitromethane toxicity (10).

The newer enzymatic assays involve enzymatic reactions with creatinine, producing red dye that is photometrically measured and may be better suited for people with diabetes due to lack of interference from glucose or acetoacetate. However, certain drugs like flucytosine can falsely elevate creatinine values by  >60% using enzymatic assays (11). A recent case report also suggested elevated IgM levels to interfere with the enzymatic assays. Although newer liquid chromatography-mass spectrometry techniques have been developed and are considered the gold standard in creatinine estimation, the complex methodology and costs limit their routine use. 

Causes of Pseudo AKI	Medications
Increased Metabolic Generation	Anabolic steroids Fenofibrates? Vitamin D derivatives
Decreased Tubular Secretion	H2 blockers (Cimetidine Famotidine) Trimethoprim Ticagrelor (Brilinta) Metformin Ritonavir, Dolutegravir Cobicistat PARP Inhibitors MET inhibitors Tyrosine kinase inhibitors Dronedarone
Interference with Creatinine Estimation	Cefoxitin, Cefazolin Flucytosine Non creatinine chromogens (glucose, bilirubin, acetoacetate)

Table 1. Medications associated with false elevations of serum creatinine

Therefore, in cases where drug-induced false elevation in creatinine value is suspected, other biomarkers of AKI, like Cystatin C, can be used to corroborate elevated creatinine values. Alternatively, discontinuation of offending medications for a brief period would allow creatinine values to return to baseline. When creatinine values are elevated due to interference with the calorimetric or enzymatic assays, an alternate assay can be used to estimate creatinine. Persistent elevation in serum creatinine despite these measures should warrant additional work up as several of these medications may cause true AKI.

Pseudo-AKI should be considered when evaluating patients with unexplained increases in creatinine values. Increased awareness of these false alarms can help avoid unnecessary diagnostic tests and treatments and prevent potential interruptions in the treatments that may be life-saving.

References

1. E.-I. Lepist et al., “Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat,” Kidney Int., vol. 86, no. 2, pp. 350–357, Aug. 2014.M. A. Perazella and M. H. Rosner, “Drug-Induced Acute Kidney Injury,” Clin. J. Am. Soc. Nephrol., vol. 17, no. 8, pp. 1220–1233, Aug. 2022.

2. C. Hottelart, N. El Esper, F. Rose, J.-M. Achard, and A. Fournier, “Fenofibrate increases creatininemia by increasing metabolic production of creatinine,” Nephron, vol. 92, no. 3, pp. 536–541, 2002.

3. C. Patel, G.-X. Yan, and P. R. Kowey, “Dronedarone,” Circulation, vol. 120, no. 7, pp. 636–644, Aug. 2009.

4. P. Wei, X. Wang, Q. Fu, and B. Cao, “Progress in the clinical effects and adverse reactions of ticagrelor,” Thromb. J., vol. 22, no. 1, p. 8, Jan. 2024.

5. E. Andreev, M. Koopman, and L. Arisz, “A rise in plasma creatinine that is not a sign of renal failure: which drugs can be responsible?,” J. Intern. Med., vol. 246, no. 3, pp. 247–252, Sep. 1999.

6. T. Mach, A. Qi, N. Bouganim, and E. Trinh, “Targeted Cancer Therapies Causing Elevations in Serum Creatinine Through Tubular Secretion Inhibition: A Case Report and Review of the Literature,” Can J Kidney Health Dis, vol. 9, p. 20543581221106246, Jun. 2022.

7. C. M. Wyatt et al., “Ritonavir-Boosted Protease Inhibitors Do Not Significantly Affect the Performance of Creatinine-Based Estimates of GFR,” Kidney Int Rep, vol. 5, no. 5, pp. 734–737, May 2020.

8. A. Sharma, V. Sahasrabudhe, L. Musib, S. Zhang, I. Younis, and J. Kanodia, “Time to Rethink the Current Paradigm for Assessing Kidney Function in Drug Development and Beyond,” Clin. Pharmacol. Ther., vol. 112, no. 5, pp. 946–958, Nov. 2022.

9. A. A. Nanji, R. Poon, and I. Hinberg, “Interference by cephalosporins with creatinine measurement by desk-top analyzers,” Eur. J. Clin. Pharmacol., vol. 33, no. 4, pp. 427–429, 1987.

10. M. D. Cook and R. F. Clark, “Creatinine elevation associated with nitromethane exposure: a marker of potential methanol toxicity,” J. Emerg. Med., vol. 33, no. 3, pp. 249–253, Oct. 2007.

11. E. K. Mitchell, “Flucytosine and false elevation of serum creatinine level,” Ann. Intern. Med., vol. 101, no. 2, p. 278, Aug. 1984.