Sunday, December 13, 2015

Topic Discussion: Anti-PD-1 Therapy and the Kidney

Anti PD-1 Inhibitors and the Kidney

This includes two proteins called programmed death-1 (PD-1), which is expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), which is expressed on cancer cells. When PD-1 and PD-L1 join together, they form a biochemical "shield" protecting tumor cells from being destroyed by the immune system. Another protein involved in the pathway and also expressed by cells in the immune system, programmed death ligand -2 (PD-L2).
Anti-PD-1 agents are humanized monoclonal antibodies that bind the PD-1 receptor, which are present on tumor infiltrating lymphocytes and Tregs. They prevent the engagement of PD-1 to its ligand on the tumor cells (PD-L1 and PD-L2) thereby asserting its antitumor activity.

Nivolumab is the first anti-PD-1 antibody tested initially in melanoma.  In December 2014, the U.S. Food and Drug Administration (FDA) granted an accelerated approval to nivolumab for the treatment of patients with unresectable or metastatic melanoma. Since then, there have been use of this agent’s approval in lymphoma and renal cell cancer as well.  There also has been some interest of this agent to be used in myeloma.
In one trial, there was an increased incidence of elevated creatinine in the nivolumab-treated group as compared to the chemotherapy-treated group (13% vs. 9%).  Steroids help resolve the renal dysfunction in 50% of the cases. It is presumed to be AIN from an immune mediated process. The FDA label has guidelines to start steroids as the creatinine rises rapidly.  A pubmed search revealed no published cases of AIN or acute renal failure in the peer reviewed literature.
Pembrolizumab (MK-3475) is another monoclonal antibody (MAb) therapy designed to directly block the interaction between PD-1 and its ligands, without antibody dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). This drug also has been used in melanoma and other hematological malignancies since 2014. 

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4.
The time to onset of autoimmune nephritis was 11.6 months after the first dose of pembrolizumab(5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy.
Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3-4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper.

Mae et al. from Yale presented a poster in ASN Kidney Week 2015 that highlighted 2 cases of biopsy proven AIN from this agent (Abstract: [TH-PO1051).
It’s not just the kidney- apparently this immune mediated reaction that is initiated might be leading to hepatitis, uveitis, pancreatitis, myocarditis and other concerns. 
Literature search thus far has not revealed any published cases of AIN from this agent. Given this immune mediated reaction- the kidney can be a potential target. I won’t be surprised if both vasculitis and allergic nephritis can be noted on kidney biopsies with these agents. 

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