Occam's Razor or Hickam's Dictum: Delayed Onset of Pembrolizumab-Induced Podocytopathy and Acute Interstitial Nephritis After Cessation of the Drug

Introduction: Pembrolizumab is a IgG4-kappa immune checkpoint inhibitor (ICI) that targets PD-1 (Programmed Cell Death Protein-1) affecting integral component of checkpoint regulation. Renal complications of pembrolizumab include acute interstitial nephritis (AIN), acute tubular injury (ATI), and minimal change disease (MCD). Most immune related adverse events present within first weeks of treatment but can present weeks to months after. We present a case of podocytopathy and AIN from pembrolizumab which occurred 6 weeks after drug cessation, for which the patient was treated with empiric steroid therapy with excellent response. Case Description: 79-year-old female with metastatic squamous cell cancer of unknown primary presented with abdominal distension and leg swelling. The patient had completed 4 cycles of pembrolizumab 6 weeks ago. Medications included levothyroxine, duloxetine, and rifaximin. She denied use of NSAIDs or Proton Pump Inhibitors. Labs revealed elevated creatinine (Cr) of 2.5 mg/dL (baseline 1.3) and albumin of 2.4 g/dL (baseline 3.5) UA showed WBCs 28/HPF, white blood cell casts, and urine protein-to-creatinine-ratio (UPCR) of 3.6 grams/gram of creatinine. Detailed serologic workup for nephrotic syndrome was negative. CT abdomen/pelvis showed no evidence of obstruction. Although kidney biopsy was deferred given patient’s choice, metastatic disease, and guarded prognosis, the clinical presentation raised concern for pembrolizumab-induced AIN and podocytopathy. Empiric treatment with prednisone 1 mg/kg/day was initiated. After 3 weeks, patient showed an improvement of Cr to 1.55 mg/dL, albumin of 2.9, and UPCR of 1.0 gram/gram of creatinine. Discussion: Pembrolizumab is an immune checkpoint inhibitor that inhibits PD-1 signaling pathway and is used to treat malignancies. It can be associated with immune-related adverse events, that can occur weeks to months after therapy cessation due to prolonged immune activation. While AIN is a relatively more common ICI-associated kidney complication, the occurrence of podocytopathy alongside AIN highlights the potential for diverse renal manifestations. Our patient showed favorable response to prednisone, with marked improvement in both proteinuria and acute kidney injury (AKI). Continued vigilance for AKI and proteinuria is required even after the ICI is stopped.