A case of biopsy proven acute tubular injury from cyclin dependent kinase 4/6 inhibitor

Introduction

Cyclin-dependent kinase (CDK) 4/6 inhibitors are one of the new cornerstones in the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. This targeted therapy inhibits the transition from the G1 to the S phase of the cell cycle, a checkpoint controlled by the D-type cyclins and CDK4/6, effectively inducing cell cycle arrest.^1,2 While the common side effects of this medication are neutropenia, leukopenia, and fatigue, knowledge regarding how these medications impact the kidneys remains an ongoing area of research. ³ Data regarding renal toxicities from CDK 4/6 inhibitors is evolving. Some of the current literature suggests a link to pseudo-acute kidney injury, while others indicate a true AKI and a potential intrinsic injury.^4–6 Alternative filtration markers, such as Cystatin C, a low molecular weight protein predominantly free-filtered by the glomerulus and almost completely reabsorbed by the proximal tubule, have been employed to unmask pseudo-AKI. ⁷ Targeted therapies that selectively interfere with molecular pathways have revolutionized the field of oncology and concurrently challenged the nephrology practice. Nephrologists are constantly challenged with the diagnosis and management of the growing list of renal toxicities associated with these agents. We report a case of a 66-year-old woman with metastatic breast cancer who developed a true AKI on ribociclib, a CDK4/6 inhibitor.

Case description

A 66-year-old female with a past medical history significant for hypertension, diabetes mellitus, gout, neuropathy, and metastatic breast cancer presented to our onconephrology clinic for management of elevated creatinine. Regarding her oncologic history, she was diagnosed 5 years before presentation with infiltrative ductal carcinoma, which was estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor two negative. The patient had a mastectomy and was treated with doxorubicin and cyclophosphamide (completed 4 cycles), Paclitaxel (completed 12 cycles), and radiation. Six months before nephrology evaluation, she had a bone scan demonstrating axilla and rib metastatic disease and a CT scan of the chest, abdomen, and pelvis, which demonstrated a 3.1 cm liver lesion. She started letrozole and ribociclib 600 mg orally once a day.

Upon evaluation, she was asymptomatic. Her other home medications included amlodipine 10 mg orally daily, metformin 1000 mg orally twice daily, metoprolol 50 mg orally daily, and rosuvastatin 10 mg orally daily. She denied the use of non-steroidal anti-inflammatory drugs and herbal medications. She had no family history of kidney disease. Vital signs were significant for blood pressure that ranged from 121 to 140 mm Hg systolic and 67–94 mm Hg diastolic. Physical examination was unremarkable.

Prior to the initiation of ribociclib, her baseline serum creatinine (sCR) was 1.2 mg/dL, correlating to an eGFR of 46 mL/min/1.73 m². Four months after initiation of ribociclib, she began developing an increase in the sCr to 1.7 mg/dL with an eGFR of 32 mL/min/1.73 m². Urinalysis at that time demonstrated 1+ protein, urine protein to creatinine ratio of 0.8 g, and urine albumin to creatinine ratio of 0.4 g. A simultaneous sCr and serum Cystatin C (sCysC) were checked. Her sCr was 1.64 mg/dL, correlating with an eGFR of 34 mL/min/1.73 m², and a sCysC of 1.76 mg/dL, correlating to an eGFR of 33 mL/min/1.73 m². Urine microscopy at that time only demonstrated squamous epithelial cells; no casts or red blood cells were seen. Complement levels were within normal limits. Kappa free light chain was 5.11 mg/dL, lambda free light chain was 3.98 mg/dL with a ratio of 1.28. Kidney function assessments were serially performed in the following weeks while on ribociclib and repeated sCr was 1.76 mg/dL correlating with an eGFR of 32 mL/min/1.73 m² and a sCysC of 1.86 mg/dL correlating to an eGFR of 31 mL/min/1.73 m² (Figure 1). Based on these findings it was believed that the patient had a true acute kidney injury and ultimately underwent a kidney biopsy (Figure 2) showing acute tubular injury, diabetic glomerulopathy with diffuse and nodular mesangial sclerosis, severe arteriosclerosis, mild to moderate interstitial fibrosis, and tubular atrophy. Over the following weeks, her creatinine decreased to 1.4 mg/dL, correlating with a eGFR of 41 mL/min/1.73 m². She was continued on ribociclib, though her dose was reduced because of neutropenia due to the patient having sustained benefits from the medication for her breast cancer.

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Figure 1.

Line graph showing the trend over time of the estimated glomerular filtration based on creatinine and cystatin C.

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Figure 2.

Kidney biopsy showing acute tubular injury and diabetic nephropathy. (a) Hematoxylin and eosin stain (original magnification, 200×) Renal cortex with two patent glomeruli and features of acute tubular injury with marked attenuation of the proximal tubular epithelial cells. (b) Periodic acid-Schiff stain (original magnification, 200×) The glomeruli show an increase in mesangial matrix, and there is prominent dilation of the proximal tubular lumens. (c) Periodic acid-Schiff stain (original magnification, 400×) The proximal tubules show epithelial attenuation with cytoplasmic sloughing and variable loss of the brush borders. (d) Periodic acid-Schiff stain (original magnification, 400×) Features of diabetic glomerulopathy with diffuse and nodular mesangial sclerosis and thickening of the glomerular basement membranes.

Discussion

One of the preferred first-line treatment regimens for individuals with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer is endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitors (abemaciclib, palbociclib, and ribociclib). ³ Data regarding renal toxicities from CDK 4/6 inhibitors is conflicting and limited due to the novelty of the treatment. The federal drug enforcement adverse event reporting system states that renal injury occurs at a frequency of 44%–60% in individuals on CDK 4/6 inhibitors. ⁶ Initial reports stated that CDK 4/6 inhibitors caused a pseudo-AKI secondary to inhibiting the tubular secretion of creatinine.^4,5 Clinical studies of abemaciclib have indicated a reversible increase in creatinine levels (15%–40%), challenging the accuracy of serum creatinine as a reliable marker of kidney function in individuals receiving this treatment. This discrepancy is attributed to the inhibition of solute carrier transporters crucial for creatinine tubular secretion. ⁸ The clinical study suggests the use of alternative methods to assess kidney function, like cystatin C eGFR in patients who receive CDK 4/6 inhibitors. In contrast, in a multicenter case series by Gupta et al. ⁶ six patients with AKI associated with CDK 4/6 inhibitors underwent kidney biopsy. They were found to have an intrinsic [Acute tubular injury (N = 5) and acute tubulointerstitial nephritis (n = 1)] etiology of their kidney injury event. ⁶ The median time to AKI was 278 days. All patients had proteinuria on urine dipstick and a negative serological workup. Most recently, a retrospective cohort study by Hanna et al., ⁹ compared patients treated with CDK4/6 inhibitors plus aromatase inhibitors to patients only receiving aromatase inhibitors alone. The investigators found no significant difference between mean eGFR at month 12 in individuals who received ademaciclib, palbociclib, or endocrine therapy alone. Ribociclib was excluded due to low numbers. ⁹ We report a case of a 66-year-old woman with metastatic breast cancer who developed a true AKI on ribociclib. Upon evaluation, her urinalysis demonstrated protein, and her serologic workup (including complements and free light chains) was within normal limits. Her Cystatin C- based eGFR was also found to be decreased, ruling out pseudo-AKI. Her kidney biopsy demonstrated acute tubular injury. Other factors causing ATI were ruled out, including hemodynamic causes from poor oral intake, vomiting, diarrhea, and other medications, thus the etiology of her ATI was thought to be secondary to her CDK 4/6 inhibitor. The patient did have multiple other medical comorbidities, specifically hypertension and diabetes, that resulted in chronic changes also seen on her kidney biopsy. It is essential to acknowledge the limitations in interpreting the effects of palbociclib in this case, given the patient’s pre-existing medical conditions and chronic changes present in her kidney before medication initiation. While ribociclib was continued for our patient, a shared decision should be made between nephrology and oncology regarding the risks and benefits of continuing the medication when patients experience ATI from ribociclib.

Conclusion

This case highlights that although much attention is put on CDK 4/6 inhibitors causing pseudo-AKI, it is imperative to ensure that patients are not experiencing true AKIs by assessing kidney function with alternative methods outside of creatinine, such as Cystatin C and exogenous filtration markers such as contrast agents or radionuclides. Additionally, future studies are needed to understand the anticipated renal disease progression following ATI from ribociclib when the medication is continued given CDK4/6 essential role in breast cancer management.