LAUSR

To the Editor: Immune checkpoint inhibitors (ICIs) have revolutionized cancer chemotherapy. Pembrolizumab has improved survival in patients with non–small-cell lung cancer (NSCLC) and advanced melanoma.1–3 We present a case of pembrolizumab-induced acute tubulointerstitial nephritis leading to cessation of therapy. A 73-year-old woman with stage-IV NSCLC presented with her creatinine elevated to 5 mg/dL in outpatient investigation. The patient had recently initiated treatment with pembrolizumab and had received a course 3 weeks before. She was taking no other medications. Her vital signs were normal on presentation. Detailed examination was normal except conjunctival pallor. Initial investigations revealed anemia with a hemoglobin level of 8.1 gm/dL, and elevated blood urea nitrogen (BUN) and creatinine at 83 and 6.53 mg/dL, respectively. We also noted metabolic acidosis (bicarbonate 19 mmol/L) with an elevated anion gap of 16. Urinalysis showed 1+ proteinuria (30 mg/dL) without hematuria, casturia, or eosinophiluria. A renal ultrasound noted bilaterally normal echogenic kidneys of normal size (12.6 cm) without any pathologies. Two weeks before initiation of pembrolizumab, her baseline BUN and creatinine were 14 and 0.8 mg/dL, respectively, and she had normal urine output (UO) till now. She was given a bolus of intravenous normal saline and started on maintenance intravenous fluids as well as strict input/output monitoring. Her investigations and UO were monitored as depicted in Table 1. The Naranjo score was 8; hence, prednisone 60 mg daily (1 mg/kg body weight) was initiated on suspicion of drug-induced acute interstitial nephritis (AIN). Phosphorus was elevated at 6 mg/dL; hence, calcium acetate 1334 mg thrice daily was initiated. On hospital day #3, the hemoglobin level was down to 7.4 g/dL, and we decided to transfuse a unit of packed red blood cells. She also had mild hyperkalemia (5.1 mmol/L) which was treated. Further investigations noted normal complement 3 and 4 levels, normal immunoglobulin G, negative anti–neutrophil-cytoplasmic antibody, and elevated ferritin (1295.8 ng/mL). The creatinine continued to climb upward, and on day #4, she underwent a computed tomogram guided renal biopsy without any complications. The biopsy revealed acute tubulointerstitial nephritis with tubular atrophy and interstitial fibrosis, which was attributed to pembrolizumab (Figures 1–C). She continued to maintain normal UO during hospitalization. She was discharged on day #6 with a plan to continue oral prednisone for 4 weeks and then taper based on response. Pembrolizumab therapy was discontinued. At her 4 week followup, she was noted to be well with a hemoglobin level of 9 gm/dL and normal UO. Her BUN and creatinine had trended down to 46 and 2.56 mg/dL, respectively. The ICIs target key immunomodulatory pathways, thereby unleashing a T-cell mediated antitumor response. Proteins such as cytotoxic T-lymphocyte– associated antigen-4 (CTLA-4) and programmed death ligand-1 (PD-1) serve as negative costimulatory receptors to down-regulate activated T-cells.1,4–7 The cancer cells express these molecules to evade immunological destruction. The ICI target these, thereby enhancing tumor recognition and destruction by harnessing the body’s own immunity.1,4–7 Pembrolizumab is a highly selective, humanized monoclonal immunoglobulin-G4 kappa-isotype antibody against PD-1. It is approved for the treatment of melanoma, NSCLC, classic Hodgkin’s lymphoma, squamous cell carcinoma, and others.1–3,8 However, the flip-side of this enhanced immune response is inflammatory adverse side effects, termed immune-related adverse events (iRAEs), which often limits the scope of therapy. These are reported according to the common terminology criteria for adverse effects.9–11 Often, the Naranjo score is useful to identify adverse drug reactions. Here, it was 8, suggesting probable adverse drug reaction.12 iRAEs can affect almost every organ, but the skin, gastrointestinal tract, liver, and endocrine system involvement is common.4,8 The kidneys are less commonly affected, with incidence ranging from 2% with single drug to 5% with combination therapy.4,5,13,14 The onset of renal dysfunction as acute kidney injury (AKI) after ICI therapy varies widely. It is common in the first few weeks (up to 12–14 weeks).4,6,8,10 It can even develop after several months to more than a year after ICI discontinuation.4,6,8,10,15 Interestingly, AKI may develop earlier with combination ICI therapy.4 The pathophysiology American Journal of Therapeutics 0, 1–3 (2020)