Targeted Cancer Therapies Causing Elevations in Serum Creatinine Through Tubular Secretion Inhibition: A Case Report and Review of the Literature

Abstract

Rationale: Targeted cancer therapies have revolutionized the field of oncology by selecting for specific molecular pathways, thus improving overall clinical prognosis. However, many of these targeted treatments have been reported to have adverse kidney effects, including acute kidney injury, interstitial nephritis, and glomerular disease. Furthermore, some of these targeted therapies have also been found to cause an asymptomatic rise in serum creatinine levels through inhibition of active tubular secretion. Presenting concerns: A 79-year-old woman was being followed for stage 4 A2 chronic kidney disease secondary to type 2 diabetes and longstanding hypertension. She was diagnosed with invasive mammary carcinoma and was initiated on letrozole, an aromatase inhibitor, and palbociclib, a selective cyclin-dependent kinase inhibitor, was subsequently added. Prior to the initiation of her treatments, her baseline estimated glomerular filtration rate (eGFR) fluctuated between 25 and 28 mL/min/1.73 m2 over the previous year. After initiating palbociclib, her serum creatinine progressively increased, despite having well-controlled blood pressure and diabetes. In addition, there was no history of pre-renal events nor any sonographic evidence of obstruction. Within 7 months, her eGFR based on serum creatinine had decreased down to 12 mL/min/1.73 m2. Interventions: Given that there were no clinical or other biochemical changes suggestive of worsening renal function, a serum cystatin C was measured using an immunoturbidimetric assay, which was 1.71 mg/L and correlated with an eGFR of 33 mL/min/1.73 m2 based on the chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C equation (2012). This value was consistent with her previous baseline. Based on these findings, the significant decrease in eGFR measured by serum creatinine was attributed to the inhibitory effects of palbociclib on tubular creatinine secretion, rather than representing true kidney damage. Thus, a kidney biopsy was not performed in this context. Outcomes: Seven months later, a repeat serum cystatin C was repeated to assess for any worsening of the patient’s kidney function and revealed an eGFR of 35 mL/min/1.73 m2 based on the CKD-EPI cystatin C equation (2012), thus revealing stable kidney function and reinforcing the inhibitory effects of palbociclib on tubular creatinine secretion through its direct effects on kidney transporters. Teaching points: This case report and literature review acknowledges the importance of using alternative methods of assessing kidney function when patients are undergoing targeted cancer therapies known to affect tubular creatinine secretion, which include cyclin-dependent kinase 4/6 inhibitors, poly(adenosine diphosphate-ribose) polymerase inhibitors, tyrosine kinase inhibitors, and mesenchymal-epithelial transition inhibitors. The use of non–creatinine-based markers of glomerular filtration rate (GFR), such as cystatin C and nuclear renal scans, will allow for more accurate estimation of kidney function in the appropriate setting, thus avoiding invasive diagnostic tests and unnecessary adjustments of treatment plans. However, certain targeted cancer therapies have also been proven to cause true kidney injury; therefore, physicians must still maintain a high degree of suspicion and consider invasive investigations and/or cessation or reduction of treatments when alternative measurements of kidney function do not suggest an underestimation of GFR via serum creatinine.

Estimating kidney function in patients with cancer: A narrative review

“…They derived the equation through stepwise variable selection and the final model included age, body surface area (BSA), and serum creatinine. Using mGFR determined by 51 Cr-EDTA as the reference, the CamGFR was more accurate than the 2009 CKD-EPI Cr for estimating GFR in patients with cancer. Additionally, only 14.7% of patients had a carboplatin dose with percentage error above 20% with use of the CamGFR equation, as compared to 18.6% with the 2009 CKD-EPI Cr equation.…”

“…Third, many commonly used medications and anti‐cancer agents are known to competitively inhibit creatinine secretion in the proximal tubule and thus cause an asymptomatic rise in serum creatinine, without additional clinical findings associated with a depressed GFR (Figure 2A). 51,52 Using a falsely elevated serum creatinine to then calculate eGFR will result in underestimation of GFR, while the true GFR remains unchanged 52 . Anti‐cancer medications that have this effect include cyclin‐dependent kinase inhibitors (palbociclib, ribociclib, abemaciclib), polyadenosine diphosphate‐ribose inhibitors (olaparib), tyrosine kinase inhibitors (crizotinib, ceritinib, alectinib), mesenchymal‐epithelial transition inhibitors (capmatinib), and cisplatin 51,52 .…”

“… 51,52 Using a falsely elevated serum creatinine to then calculate eGFR will result in underestimation of GFR, while the true GFR remains unchanged 52 . Anti‐cancer medications that have this effect include cyclin‐dependent kinase inhibitors (palbociclib, ribociclib, abemaciclib), polyadenosine diphosphate‐ribose inhibitors (olaparib), tyrosine kinase inhibitors (crizotinib, ceritinib, alectinib), mesenchymal‐epithelial transition inhibitors (capmatinib), and cisplatin 51,52 . However, some of these agents are also known to cause acute interstitial nephritis or acute tubular injury and differentiating the etiology of a rising serum creatinine requires alternative estimates of GFR 8 .…”

Pseudo-AKI associated with targeted anti-cancer agents—the truth is in the eye of the filtration marker

“…Urinary markers of tubular injury, NGAL and KIM-1, were unaffected, further corroborating the hypothesis of benign pseudo-AKI [ 24 ]. Two case reports have described similar observations consistent with a pseudo-AKI associated with palbociclib; both were female patients (66 and 79 years old) with HR-positive, HER2-negative breast cancer, both displayed striking rises in SCr level and corresponding decline of SCr-based eGFR compared with baseline (42–52 to 33 mL/min/1.73 m², 25–28 to 12 mL/min/1.73 m²) and in both CysC-based eGFR remained stable during treatment indicating that no real kidney injury had occurred [ 28 , 29 ]. Finally, there is also a case report on a ribociclib-induced pseudo-AKI [ 30 ].…”

“…On the other hand, even for the latter a clear molecular mechanistic basis exist. Nevertheless, it is of critical importance that nephrologist and oncologists are aware of the phenomenon and characteristics of pseudo-AKI caused by targeted agents to avoid premature discontinuation of therapeutically effective and prognostically important drugs and to shield patients from unnecessary and possibly harmful invasive diagnostic tests such as a kidney biopsy [ 8 , 20 , 29 , 30 ]. It should indeed be stressed that (many) targeted anti-cancer agents in eligible patients are superior to conventional (chemo)therapy with respect to tumour response, disease control and survival, and that those patients will often be taking these agents for a prolonged time (months to years) [ 20 ].…”