Ibrutinib induced acute tubular injury: A case series and review of the literature
Authors: Sandhya Manohar, Anip Bansal, Rimda Wanchoo, Vipulbhai Sakhiya, Scott Lucia, Kenar D. Jhaveri
Journal: American Journal of Hematology (2019)

Over the last few years, treatment of chronic lymphocytic leukemia (CLL) has slowly started to evolve from regimens with significant impact on long-term outcomes and associated concomitant toxicities to the use of novel agents that specifically target dysregulated pathways.1 As noted in a recent review, most of these novel agents used for the treatment of CLL are not nephrotoxic.2 Ibrutinib is a tyrosine kinase inhibitor that irreversibly binds to and inhibits the Bruton tyrosine kinase.3 Hypertension, and tumor lysis syndrome (TLS) has been reported with this agent.4-6 At the time of this writing, no biopsy-proven cases of kidney related injury have been reported in the literature. Herein, we report two cases of biopsy proven acute tubular injury with ibrutinib. Case 1: A 63-year-old gentleman was referred to nephrology for evaluation of persistently elevated serum creatinine level. He has a history of CLL diagnosed 4 years prior with unfavorable markers del11q and unmutated IGVH. He had been on a clinical trial randomized to ibrutinib and rituximab therapy for 6 months and subsequently transitioned to single agent ibrutinib at 420 mg daily dosing with excellent disease control (3.5 years prior to this visit). His medical history was otherwise significant for Hashimoto's thyroiditis on levothyroxine, obstructive sleep apnea on positive pressure therapy, and gastroesophageal reflux disease on a proton pump inhibitor. His baseline creatinine was 1.4 mg/dL with estimated glomerular filtration rate (eGFR) of 53 mL/min/BSA at the time of diagnosis of his leukemia. As starting therapy his creatinine had been between 1.4 and 1.7 mg/dL with eGFR of 42 to 53 mL/min/BSA. Three years prior to this visit, creatinine had slowly started to rise to 1.7 to 1.8 mg/dL with no obvious precipitating factors. Urinalysis showed microscopic hematuria and 3-10 RBCs/HPF with no proteinuria. Serological workup with double-stranded DNA, antineutrophil cytoplasmic antibody, complements, monoclonal protein was negative except for a mildly elevated ANA that was considered to be nonspecific. Imaging and urological workup was negative. He had no other risk factors for chronic kidney disease other than a history of chronic proton pump inhibitor use which had been held for many months with no improvement in creatinine. Decision was made to monitor kidney function at that time as patient had refused a kidney biopsy. Few months prior to this visit, his creatinine slowly started to uptrend now more consistently in the 1.8 to 2.0 mg/dL range. Repeat urinalysis continued to show microscopic hematuria with no significant proteinuria. Repeat serological workup was similarly unremarkable. A kidney biopsy (Figure S1) was performed after holding ibrutinib for 5 days. The overall impression was that of mild acute tubular injury on a background of mild chronic changes with focal global glomerulosclerosis, mild tubular atrophy and interstitial fibrosis, and mild arteriosclerosis. These chronic changes were deemed to be associated with ibrutinib. Clinically he had no hypertension nor did he have any evidence of microangiopathic hemolytic anemia on laboratories but his histopathology brought up a question of chronic low grade vascular injury. Unfortunately, considering the unfavorable cytogenetics of his CLL, good disease control with single agent ibrutinib and unclear impact of modification of treatment regimen to the kidneys, mutual decision was made with the patient and the hematologist to continue to treat with ibrutinib and monitor renal function. At a 6-month follow up his serum creatinine continues to be stable in the 1.7 to 1.8 mg/dL range. Case 2: A 59-year-old gentleman with past medical history significant for hypothyroidism, obesity (BMI 43 kg/m2), hyperlipidemia, and diabetes mellitus type 2 for 40 years with history of retinopathy in past (with most recent hemoglobin A1c = 5.8 g/dL) was diagnosed with CLL after a routine blood test showed marked leukocytosis (white blood cell count of 196 000/μL with absolute lymphocyte count of 186 000/μL) in the absence of anemia or thrombocytopenia. His blood pressure was 115/53 mm Hg and his physical examination was unremarkable. His medications at this time included insulin with a continuous pump, aspirin, atorvastatin, levothyroxine, furosemide, and vitamin D3. His other laboratory results were significant for a serum creatinine of 1.1 mg/dL with eGFR of 73 mL/min/BSA (which was stable over the past 10 years) and absence of microalbuminuria. Given a high risk international prognostic index score, worsening leukocytosis (peak WBC count 350 000/μL), hyperuricemia and fatigue, he was started on single agent ibrutinib. He was noted to have a slow progressive worsening of his kidney function over the next 6 months with a serum creatinine of 2.71 mg/dL at the time of nephrology consultation. His blood pressure remained well controlled during this period and no new medications were started. He reported no use of herbal supplements or nonsteroidal inflammatory agents for pain. An ultrasound of the kidneys was normal. Urinalysis was negative for protein or blood and microscopy was normal. Serological workup with complements, serum protein electrophoresis and serum free light chain was normal. In view of unexplained acute kidney injury (AKI), a kidney biopsy was performed. The biopsy showed tubular degenerative changes consistent with acute tubular injury (Figure S2) with no evidence of glomerulonephritis or interstitial nephritis. Based on absence of any other etiology of his kidney injury a presumptive diagnosis of ibrutinib associated acute tubular injury was made and ibrutinib was discontinued. One month after this change his serum creatinine had improved to 2.37 mg/dL. In addition to reviewing the published literature, we also reviewed the US Federal Drug Adminstration adverse event reporting system (FAERS) quarterly legacy data file (third quarter of 2014 to fourth quarter of 2018) for ibrutinib. The adverse event terms queried were hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, hypercalcemia, hyperkalemia, hypernatremia, hyperphosphatemia, proteinuria, renal failure acute, AKI, renal failure, renal injury, renal impairment, TLS, renal insufficiency, kidney damage, acute tubular necrosis, renal necrosis, and nephritis. Table 1 summarizes the number of cases of renal toxicities with this agent reported in the last 4 years. Overall >600 adverse events were reported of which >25% presenting as AKI. Other electrolyte disorders such as hypomagnesemia, hypophosphatemia, and hyponatremia were also reported. In addition, interestingly, males were more likely to develop nephrotoxicity compared to females (P < .0001) based on available gender specific reported data. Hypertension and TLS has been rarely reported in patients treated with ibrutinib.4-6 Hypertension develops in 5% to 18% of patients.4, 6 While TLS was mentioned in the initial trials, only few published case of TLS exists5 with this agent. We describe here two cases that showed mild-moderate tubular injury associated with ibrutinib. The temporality of the culprit drug initiation and creatinine elevation without any other obvious etiologies is concerning. This is an important toxicity to keep in mind when seeing patients who receive this agent. In fact in our case 2, there was an improvement in creatinine after drug discontinuation. Ibrutinib is a highly protein bound drug with a large volume of distribution. Its metabolism is predominantly hepatic via CYP3A4 and about 20% of the metabolites are cleared through the kidney.3 The mechanism of the kidney injury is unclear. Given ibrutinib is a tyrosine kinase inhibitor, there is potential for this agent to cause endothelial injury. It is possible that the hypertension that is seen with this agent might be a harbinger of underlying endothelial injury. The FAERS database supports that that AKI is the most common renal manifestation of this agent over other electrolyte disorders. While we cannot get a true incidence of adverse renal effects, it is important to consider this toxicity. Patients receiving ibrutinib should undergo periodic blood pressure measurements, creatinine level monitoring, and maintain hydration. In summary, while ibrutinib is very well tolerated, acute tubular injury is associated with this agent. To our knowledge, this is the first report of biopsy proven tubular toxicities with ibrutinib. Based on the above mentioned cases, review of the literature and FAERS reporting, it appears that hypertension, tubular injury, and TLS are the most important renal effects to be noted with ibrutinib. Hematologists and nephrologists should be vigilant of the rare toxicities of this agent. We acknowledge Dr Sanjeev Sethi, Renal pathologist from Mayo Clinic for Figure S1 pathology images. K.D.J. serves as a consultant for Astex Pharmaceuticals. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.