Immune checkpoint inhibitor interstitial nephritis

Question

A 57-year-old woman with urothelial cancer is evaluated for a subacute rise in her serum creatinine. Six months ago, her creatinine was 1.1 mg/dL, and it has steadily risen to 1.8 mg/dL today. The patient does not have orthostatic or new urinary symptoms. Her urothelial cancer was diagnosed 2.5 years ago, and she was treated with cisplatin and gemcitabine before undergoing radical cystectomy with ileal conduit. Eleven months ago, she was prescribed nivolumab and ipilimumab (immune checkpoint inhibitors) for progressive disease. Her other medications include omeprazole, ondansetron, and folic acid. She does not use NSAIDs or other over-the-counter or herbal medications. On examination, BP is 123/67 mm Hg, and heart rate is 76/min without postural changes. She is afebrile. She has a well-healed and pink ileal stoma in the right lower quadrant of her abdomen. The remainder of her examination is unremarkable. Laboratory data: WBC count 13,500/μL (reference 4000–11,000); hemoglobin 10.2 g/dL (12–16); platelets 302,000/μL (150,000–450,000); serum sodium 138 mEq/L (136–145); potassium 3.7 mEq/L (3.5–5.0); chloride 101 mEq/L (98–106); total CO₂ 24 mEq/L (23–28); BUN 23 mg/dL (8–20); creatinine 1.8 mg/dL (0.5–1.1). Urine: sodium 72 mEq/L (varies); creatinine 45 mg/dL (varies); protein trace (negative); blood trace (negative); ketones negative (negative); leukocyte esterase 3+ (negative); nitrite negative (negative). Urine microscopy shows 0–2 RBCs/HPF, 16–30 WBCs/HPF, and few bacteria. CT scan of the abdomen and pelvis with contrast shows mild bilateral hydroureter to the level of the urinary diversion, unchanged from 1 year ago. Which of the following is the MOST likely cause of decreased kidney function?

Accepted Answer

D. Nivolumab — This patient with slowly progressive kidney disease most likely has acute interstitial nephritis (AIN) because of exposure to immune checkpoint inhibitors (ICPIs).

ICPIs include anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies and programmed death-1 (PD-1) inhibitors, which reverse T-cell tolerance against tumors and prevents cancer from evading the immune response. These agents cause several immune-related adverse effects (IRAEs), including skin rash (41%), gastrointestinal disease (45%), various endocrinopathies (16%), and AIN (2%–5%).

ICPI-AIN has been found to develop within a prolonged time frame of 6–37 weeks after initiation of therapy rather than the 7–14 days seen after exposure to many other drugs.

Combination therapy with anti-CTLA-4 agents (ipilimumab) and PD-1 inhibitors (nivolumab) is associated with higher incidence of AIN and other IRAE. Patients with CKD and those taking proton-pump inhibitors, antibiotics, and NSAIDs are at relatively higher risk of developing CPI-AKI. Proteinuria occurs sporadically and is frequently sub-nephrotic.

Although this patient's CT scan shows evidence of chronic, mild hydronephrosis, related to either the urothelial cancer itself or sequelae of surgery, there has been no change in this finding to explain the intercurrent increase in creatinine.

Gemcitabine and cisplatin are both associated with decreased kidney function. Gemcitabine has been implicated in thrombotic microangiopathy, which manifests as microangiopathic hemolytic anemia with thrombocytopenia. Cisplatin has been associated with tubular injury and Fanconi syndrome. There is no evidence for either gemcitabine or cisplatin toxicity in this patient.

Although WBCs and bacteria are present in the urine, these are frequently noted in the urinalysis of patients with ileal conduits, as the urine is in direct contact with the nonsterile bowel wall. There are no signs, symptoms, or other evidence of urinary tract infection in this patient.

Immune checkpoint inhibitor interstitial nephritis

Explanation

Why each option

More AKI questions

Browse other topics