Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

BackgroundDiagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy.Case presentationA 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy.ConclusionThis report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment

Renal functional reserve

Serum creatinine and glomerular filtration rate (GFR) are the current standard tests to measure kidney function. The baseline GFR does not reflect full function of the kidney since human kidneys do not always work at full capacity. Similarly, serum creatinine is not a sensitive measure for kidney function or injury. In healthy individuals the GFR physiologically increases in response to certain stresses or stimuli, such as protein loading. Renal functional reserve (RFR) is defined as the difference between the maximal glomerular filtration rate (generally determined after oral or intravenous protein loading) and the baseline glomerular filtration rate. The absence of a normal RFR can help identify patients who are more susceptible to kidney injury. The RFR is also important in patients who develop acute kidney injury and chronic kidney disease. Even though the GFR might return to a baseline level, there may be some loss of RFR which can make the patient more susceptible to another episode of kidney injury. Acute kidney injury and chronic kidney disease are considered interconnected syndromes; each is a risk factor for the other. There are no current recommendations regarding the performance of routine determinations of RFR. Physicians should focus on clinical history and physical examination in patients with a history of prior episodes of acute kidney injury, monitor renal function, and avoid nephrotoxic insults