- Email: [email protected]
Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients
Case Report Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients Anushree C. Shirali, MD,1 Mark A. Perazella, MD,1 and Scott Gettinger, MD 2 Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling pathway have recently been approved for use in advanced pretreated non–small cell lung cancer and melanoma. Clinical trial data suggest that these drugs may have adverse effects on the kidney, but these effects have not been well described. We present 6 cases of acute kidney injury in patients with lung cancer who received anti–PD-1 antibodies, with each case displaying evidence of acute interstitial nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN, but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The association of AIN with these drugs in our patients raises the possibility that PD-1 inhibitor therapy may release suppression of T-cell immunity that normally permits renal tolerance of drugs known to be associated with AIN. Am J Kidney Dis. -(-):---. ª 2016 by the National Kidney Foundation, Inc. INDEX WORDS: Programmed cell death 1; PD-1; PDCD1; anti–PD-1 antibody; PD-1 inhibitor; nivolumab; pembrolizumab; acute interstitial nephritis (AIN); acute kidney injury (AKI); non-small cell lung cancer (NSCLC); advanced melanoma; ipilimumab; immune checkpoint inhibitor; nephrotoxicity; renal biopsy.
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mmune checkpoint inhibitors are expanding the armamentarium of anticancer agents by recruiting the body’s defenses to treat various malignancies. This approach is complicated because the immune system is normally balanced by checkpoints that guard against autoimmunity. Tumors evade immune surveillance by co-opting such checkpoints, including the programmed death 1 (PD-1) membrane protein expressed on activated effector T cells. PD ligand 1 (PD-L1), the primary PD-1 ligand, is upregulated on various tumors and its binding to PD-1 on activated T cells results in T-cell exhaustion and anergy.1,2 Immune checkpoint inhibitors relieve suppression of antitumor T-cell activation and function. Current US Food and Drug Administration–approved agents include the cytotoxic lymphocyte-associated antigen 4 (CTLA-4) antagonist antibody ipilimumab for advanced melanoma and the PD-1 antagonist antibodies nivolumab and pembrolizumab for advanced melanoma and non–small cell lung cancer (NSCLC). They are currently being evaluated in later stage clinical trials across several tumor types. Although most patients tolerate these drugs, serious immune-related adverse events including pneumonitis, hepatitis, and endocrinopathies have been described.3,4 Additionally, clinical trials report an incidence of grade 3/4 nephrotoxicity ranging from 0.4% to 3% without identifying a clear cause.5,6 We present 6 cases of acute kidney injury (AKI) secondary to biopsy-proven acute interstitial nephritis (AIN) associated with nivolumab or pembrolizumab use in patients with advanced NSCLC. Details for medical history, medications, and serum and urine laboratory data are provided in Table 1. Pathology findings are summarized in Table S1, and a representative biopsy is provided as Fig S1. Am J Kidney Dis. 2016;-(-):---
CASE REPORTS Case 1 The index case, a 73-year-old man with NSCLC, presented with a serum creatinine (Scr) level (1.9 mg/dL) increased from baseline (1.2-1.3 mg/dL). Eleven months earlier, he had started intravenous (IV) nivolumab therapy (10 mg/kg biweekly [ie, every other week]) as part of a clinical trial. On presentation, blood pressure (BP) was 132/72 mm Hg, pulse rate was 75 beats/min, and examination revealed edema (11) of the right lower extremity. Reduced furosemide dosing did not improve kidney function. Kidney biopsy was performed and revealed focal AIN. Omeprazole and furosemide treatment were discontinued, but he continued receiving nivolumab. The patient’s Scr levels fluctuated from 1.4 to 1.7 mg/dL for the next 8 months before nivolumab treatment was withdrawn due to progressive disease. Over the next 6 months, Scr levels declined to the pre–nivolumab therapy baseline.
Case 2 A 78-year-old man with NSCLC was evaluated for an acute increase in Scr level (from 0.9 to 1.8 mg/dL) over a 6-week period. For 16 months prior to AKI, he received IV nivolumab (10 mg/kg biweekly) as part of a clinical trial. BP was 124/60 mm Hg, pulse rate was 97 beats/min, and physical examination showed bilateral lower-extremity edema (11). Omeprazole and celecoxib therapy were discontinued and kidney biopsy revealed diffuse AIN. Nivolumab therapy was withdrawn, and prednisone therapy (60 mg/d) was initiated and tapered over 1 month, with recovery to baseline kidney function. From the Sections of 1Nephrology and 2Oncology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. Received August 28, 2015. Accepted in revised form February 17, 2016. Address correspondence to Anushree C. Shirali, MD, Section of Nephrology, Department of Internal Medicine, PO Box 208029, New Haven, CT 06520-8029. E-mail: [email protected] 2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.02.057 1
Shirali, Perazella, and Gettinger
Case 3 A 60-year-old woman with NSCLC was hospitalized for an increase in Scr level to 5.5 mg/dL from 0.9 mg/dL 3 weeks prior. Ten months earlier, she enrolled in a clinical trial evaluating administration of bevacizumab (15 mg/kg) combined with nivolumab (3 mg/kg) every 3 weeks. This regimen was continued with stable disease until AKI hospitalization. At that time, the patient reported diffuse rash and fever followed by nausea, headache, fatigue, and decreased urine output. BP was 102/62 mm Hg and pulse rate was 81 beats/min. Physical examination findings were unremarkable. Kidney biopsy revealed AIN (Fig S1). IV methylprednisolone, 125 mg, was administered for 3 days, followed by oral prednisone, 60 mg/d, which was tapered over the next month. Kidney function rapidly returned to baseline.
Case 4 A 69-year-old woman with NSCLC developed AKI, with an increase in Scr level from 1.0 to 1.9 mg/dL. As part of a clinical trial, the patient received IV pembrolizumab 10 mg/kg biweekly for 3 months prior to AKI. Physical examination findings were unremarkable, with BP of 114/65 mm Hg and pulse rate of 75 beats/min. Omeprazole, lisinopril, and pembrolizumab therapy were discontinued and kidney biopsy revealed diffuse AIN. Prednisone, 60 mg/d, was administered with a 4-week taper; Scr level improved to 1.3 mg/dL. However, 2 weeks after completing the steroid taper, Scr level increased to 2.5 mg/dL. The patient reported having restarted omeprazole therapy. Treatment with prednisone, 60 mg/d, was restarted and tapered over a 3-month period, with normalization of kidney function.
Case 5 A 59-year-old man with NSCLC developed an increase in Scr level from 0.9 to 2.5 mg/dL. The patient was receiving clinical trial dosing of IV nivolumab (3 mg/kg biweekly) combined with ipilimumab (1 mg/kg every 12 weeks). The patient’s course was complicated by hypophysitis with secondary adrenal insufficiency, for which replacement steroid therapy was started. The patient continued nivolumab therapy with sustained tumor response until AKI developed 6 months after trial initiation. BP was 154/98 mm Hg and pulse rate was 96 beats/min. Physical examination findings were unremarkable. Kidney biopsy revealed focal AIN. Omeprazole and nivolumab/ipilimumab therapy were discontinued and Scr level declined to 1.3 mg/dL 2 weeks later. Trial therapy was reinitiated; 2 months later, Scr level increased to 10.6 mg/dL. Upon questioning, the patient reported intermittent use of omeprazole. Pulse IV methylprednisolone 125 mg was administered for 3 days, followed by oral prednisone taper over 1 month. Scr level improved to 1.4 mg/dL without further trial therapy.
Case 6 A 69-year-old woman with NSCLC was evaluated for an increase in Scr level from 0.8 to 2.3 mg/dL. One year prior, IV pembrolizumab (10 mg/kg every 3 weeks) was initiated as part of a clinical trial. The patient’s course was complicated by hypophysitis and secondary adrenal insufficiency, for which replacement steroid therapy was initiated. Pembrolizumab therapy was continued with sustained tumor response until AKI developed. The patient’s BP was 174/119 mm Hg and pulse rate was 94 beats/min. Physical examination findings were unremarkable. The kidney biopsy specimen displayed diffuse AIN. Pantoprazole and pembrolizumab therapy were discontinued, and prednisone was administered at 60 mg/d with a 1-month taper. Steroid therapy was complicated by myopathy, but kidney function normalized.
2
DISCUSSION We report 6 cases of AKI of variable severity from biopsy-proven AIN in patients exposed to either nivolumab or pembrolizumab. None of the patients required dialysis, and all except patient 1 received corticosteroid therapy and recovered kidney function to or near baseline. One patient was rechallenged with PD-1 inhibitor treatment after initial recovery of kidney function without steroid use, resulting in recurrent severe AKI from steroid-responsive AIN. Mild serum eosinophilia occurred in some cases, but no uniform laboratory findings were noted. With increasing use of PD-1 inhibitors, we may gain more insight into adverse renal events, allowing institution of assessment and treatment algorithms. Until then, kidney biopsy should be considered in cases of AKI to confirm AIN. An incorrect diagnosis may lead to therapy discontinuation and high-dose steroid dosing, which could abrogate antitumor effects. We acknowledge that our patients were also receiving medications with known associations with the development of AIN. All except patient 3 took proton pump inhibitors (PPIs), which are well associated with the idiosyncratic development of AIN.7 However, except for case 5, PPI therapy began long before the initiation of PD-1 inhibitor therapy. Patients 2 and 3 were also taking nonsteroidal antiinflammatory drugs (NSAIDs). In patient 2, NSAID use preceded PD-1 inhibitor therapy by years, whereas in patient 3, it followed 11 months after starting PD-1 inhibitor therapy and 5 months before AKI development. Moreover, in our clinical experience, the incidence of AIN from PPIs and NSAIDs appears to greater than what we had previously observed prior to the advent of PD-1 inhibitor therapy. We speculate that PD-1 inhibitor therapy in our patients may have disrupted long-standing tolerance of NSAIDs and/or PPIs, resulting in clinically significant AIN. There was a delay between PD-1 inhibition and the development of AIN, similar to reports of pneumonitis with PD-1 inhibitors occurring weeks to months after the start of therapy.8 Although unclear, this suggests that the time from drug initiation to a break in tolerance is variable across patients. With respect to the concurrent glomerular podocyte injury in case 3, vascular endothelial growth factor inhibition from bevacizumab was likely responsible,9 but the absence of proteinuria and hypertension suggests that this injury was clinically insignificant. Of note, in addition to PD-1 blockade, patient 5 was receiving CTLA-4 inhibition with ipilimumab, which has been associated with lupus-like nephritis and 2 cases of granulomatous AIN10-13; thus, ipilimumab use may have further contributed to AIN development in this case. Am J Kidney Dis. 2016;-(-):---
Case
Pt Age, y j Sex j Comorbid Conditions
D in Kidney Function
Laboratory Findings
Timing of AKI
NSCLC Type j Prior Systemic Therapy
Other Potential Nephrotoxins
Clinical Course
1
73 j M j HTN, CKD3, prior tobacco use, Afib, treated laryngeal carcinoma
Scr: 1.3➔1.9; eGFR: 57➔35
Eos: 7%; UPCR: 0.1 mg/mg; bland urine sediment
11 mo after nivolumab started
Advanced squamous j 1: cisplatin/vinorelbine, cetuximab; 2: docetaxel; 3: erlotinib
Omeprazole, furosemide (both preceding nivolumab by .1 y)
Omeprazole held; nivolumab continued, w/ Scr varying from 1.4 to 1.7 for 8 mo; Scr Y to prenivolumab baseline 6 mo after nivolumab held
2
78 j M j HTN, T2DM, prior tobacco use
Scr: 0.9➔1.8; eGFR: .60➔37
Eos: 6%; no protein on UA; sediment: 2 WBC casts/HPF
16 mo after nivolumab started (5 mo after starting celecoxib)
Advanced adenocarcinoma j 1: cisplatin, etoposide; 2: docetaxel; 3: pemetrexed/ bevacizumab
Omeprazole (preceding nivolumab by .1 y), celecoxib (begun 11 mo after starting nivolumab)
Nivolumab and celecoxib held; treated w/ 1-mo steroid taper, w/ normalization of Scr
3
60 j F j HTN, prior tobacco use, hypothyroid
Scr: 0.9➔5.5; eGFR: .60➔8
Eos: 3%; UPCR: 0.6 mg/mg; sediment: 2-5 WBCs/HPF
10 mo after nivolumab 1 bevacizumab started
Advanced adenocarcinoma j 1: carboplatin/ pemetrexed/bevacizumab
Ibuprofen (intermittent use preceding nivolumab by .1 y, w/ [ in use prior to AKI)
Ibuprofen held; treated w/ 1-mo steroid taper, w/ normalization of Scr
4
69 j F j HTN, COPD, prior tobacco use
Scr: 1.0➔1.9 & 1.3➔2.5; eGFR: 55➔26 & 41➔19
No eosinophilia; no protein on UA; sediment: numerous WBCs/ HPF
3 mo after pembrolizumab started
Advanced adenocarcinoma j 1: carboplatin/paclitaxel/ bevacizumab; 2: docetaxel; 3: pemetrexed
Omeprazole (preceding pembrolizumab by 3 mo)
Pembrolizumab and omeprazole held; treated w/ 1-mo steroid taper, w/ Y of Scr to 1.3; 2 wk after steroid course, Scr [ to 2.5; retreated w/ 3-mo steroid taper, w/ normalization of Scr
5
59 j M j tobacco user
Scr: 0.8➔2.5 & 1.3➔10.6; eGFR: .60➔27 & 57➔5
Eos: 2%; no protein on UA; sediment: 1 WBC cast/slide
8 mo after nivolumab 1 ipilimumab starteda
Advanced adenocarcinoma j none
Omeprazole (begun 3 mo after starting nivolumab/ipilimumab)
Nivolumab, ipilimumab, and omeprazole held; Scr Y to 1.3 w/o steroids; nivolumab/ ipilimumab re-started, w/ severe AKI (pt reported interim omeprazole use); Scr Y to 1.4 w/ 1-mo steroid taper
6
69 j F j HTN, hypothyroid, prior tobacco use, HPL
Scr: 0.8➔2.3; eGFR: .60➔37
Eos: 1%; no protein on UA; sediment: 15-30 WBCs/HPF
1 y after pembrolizumab starteda
Advanced adenocarcinoma j carboplatin/pemetrexed
Pantoprazole (preceding pembrolizumab by 6 mo)
Pembrolizumab held; treated w/ 1-mo steroid taper, w/ normalization of Scr
3
Note: Normal Scr level range is 0.5 to 1.2 mg/dL at our laboratory and the creatinine assay is IDMS traceable. eGFRs were calculated with the 4-variable IDMS-traceable MDRD Study equation. Abbreviations and definitions: Afib, atrial fibrillation; AKI, acute kidney injury; CKD3, chronic kidney disease stage 3; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); Eos, eosinophils; HPF, high-power field; HPL, hyperlipidemia; HTN, hypertension; IDMS, isotope-dilution mass spectrometry; MDRD, Modification of Diet in Renal Disease; NSCLC, non–small cell lung cancer; PD-1, programmed death 1; pt, patient; Scr, serum creatinine (in mg/dL); T2DM, type 2 diabetes mellitus; UA, urinalysis; UPCR, urine protein-creatinine ratio; WBC, white blood cell. a Treatment also complicated by hypophysitis.
Acute Interstitial Nephritis and PD-1 Inhibitor Therapy
Am J Kidney Dis. 2016;-(-):---
Table 1. Demographics and Clinical Features of NSCLC Patients With AKI Associated With PD-1 Inhibitor Use
Shirali, Perazella, and Gettinger
autoimmune diabetes, possibly mediated by loss of peripheral tolerance to self-reactive T cells.17 Another explanation is that disruption of PD-1 signaling breaks tolerance to drug-specific effector T cells that are critical to the pathogenesis of AIN.18 In this scenario, PD-1 inhibitor therapy reactivates exhausted drug-specific T cells primed by exposure to nephritogenic drugs, including NSAIDs and PPIs, but subsequently inhibited by PD-1 signaling. Either scenario results in increased effector T-cell migration and function (Fig 1), leading to clinically significant kidney injury. In support of the latter scenario is our index case, in which mild AIN was successfully treated with discontinuation of PPI therapy alone despite continuation of PD-1 inhibitor therapy. Based on available clinical trial data, AKI is a rare complication of PD-1 inhibitor therapy. Our experience suggests that if AKI is confirmed as AIN, it is also manageable. Our therapeutic approach to AIN included drug discontinuation and a variable course of corticosteroids. We cannot recommend a definitive dose and duration of steroid therapy based on 6
As shown in Fig 1, PD-1 interacts with 2 known ligands: PD-L1, residing on the surface of immune and nonimmune cells, and PD-L2 (programmed cell death ligand 2), expressed primarily on dendritic cells and macrophages. PD-L1 is overexpressed across several cancer cell types, and by binding to PD-1 on T cells in the tumor microenvironment, inactivates them. Nivolumab and pembrolizumab bind to PD-1, prevent downstream signaling, and restore antitumor immunity. Because the PD-1 pathway operates in nonpathogenic states to limit autoimmunity, interference with this pathway can lead to detrimental autoimmunity. Murine models have shown that PD-1 signaling is essential to peripheral tolerance of selfantigens by limiting the activation and expansion of self-reactive T cells and stimulating tolerogenic dendritic cells.14 Specific to the kidney, PD-1 signaling limits CD8-positive T-cell–mediated inflammatory injury and PD-1 knockout mice spontaneously develop glomerulonephritis.15,16 Thus, PD-1 inhibitor therapy may drive an autoimmune variant of interstitial nephritis, similar to the induction of
Normal PD-L1/L2
PD-1
Drug-specific or Self-specific T cell
PD-1 InhibiƟon
MHC
CD3
PD-L1/L2 PD-L1
PD-1
Drug-specific or Self-specific T cell
T Cell
+
Co-sƟmulatory molecules
MHC
CD3
AnƟ-PD-1 mAbs
+
Co-sƟmulatory molecules
+
T Cell
AcƟvated cƟvate T cell T PD-1
T Cell C
Cell
Exhausted T cell
T Cell
Re-acƟvated T cell T Cell
SƟmulaƟon of: T cell proliferaƟon 2. Cytotoxicity 3. Cytokine producƟon 4. InfiltraƟon of circulaƟng immune cells
1.
T Cell
InhibiƟon of: T cell proliferaƟon 2. Cytotoxicity 3. Cytokine producƟon
1.
PD-L1 ?PD-L2
=
T Cell
T Cell
T Cell
T Cell Cell
T Cell
T Cell
T Cell C
Figure 1. Hypothetical model of programmed death 1 (PD-1) signaling inhibition in acute interstitial nephritis (AIN). (Left panel) In the normal state, antigen- (including drug) and self-reactive T-cell activation require T-cell receptor recognition of the major histocompatibility complex (MHC), as well as costimulation. This interaction is negatively regulated by PD-1 axis signaling. In addition, PD-1 signaling also limits downstream T-cell effector function, limiting unchecked inflammation in the kidney. (Right panel) Inhibition of PD-1 signaling may cause AIN by unchecked reactivation, as well as function of effector self-specific T cells or drug-specific T cells. Abbreviation: mAbs, monoclonal antibodies. 4
Am J Kidney Dis. 2016;-(-):---
Acute Interstitial Nephritis and PD-1 Inhibitor Therapy
patients, but our experience suggests that prednisone, 1 mg/kg, with a 1-month taper may be sufficient. We additionally recommend weekly Scr monitoring for 1 month after completing steroid therapy. Rechallenge with PD-1 inhibitor therapy may be reasonable if other potentially offending agents are withdrawn and AIN has resolved. With this approach, Scr should be checked regularly, with reinstitution of steroid therapy at the first sign of AKI without another cause.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Shirali once participated in a meeting of the Bristol-Myers-Squibb safety advisory board. Dr Gettinger is a consultant for Bristol-Myers-Squibb. Peer Review: Evaluated by 2 external peer reviewers, a pathologist, a Co-Editor, and the Editor-in-Chief.
SUPPLEMENTARY MATERIAL Table S1: Summary of biopsy findings. Figure S1: Kidney biopsy from patient 3. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2016.02.057) is available at www.ajkd.org
REFERENCES 1. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin10 secretion. Nat Med. 1999;5(12):1365-1369. 2. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 3. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454. 4. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134-144. 5. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028.
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6. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. 7. Geevasinga N, Coleman PL, Webster AC, Roger SD. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol. 2006;4(5):597-604. 8. Nishino M, Sholl LM, Hodi FS, Hatabu H, Ramaiya NH. Anti-PD-1-related pneumonitis during cancer immunotherapy. N Engl J Med. 2015;373(3):288-290. 9. Eremina V, Cui S, Gerber H, et al. Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol. 2006;17(3):724-735. 10. Voskens CJ, Goldinger SM, Loquai C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PloS One. 2013;8(1):e53745. 11. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med. 2009;361(2): 211-212. 12. Izzedine H, Gueutin V, Gharbi C, et al. Kidney injuries related to ipilimumab. Invest New Drugs. 2014;32(4): 769-773. 13. Porta C, Cosmai L, Gallieni M, Pedrazzoli P, Malberti F. Renal effects of targeted anticancer therapies. Nat Rev Nephrol. 2015;11(6):354-370. 14. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236: 219-242. 15. Waeckerle-Men Y, Starke A, Wuthrich RP. PD-L1 partially protects renal tubular epithelial cells from the attack of CD81 cytotoxic T cells. Nephrol Dial Transplant. 2007;22(6): 1527-1536. 16. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141-151. 17. Hughes J, Vudattu N, Sznol M, et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015;38(4):e55-e57. 18. Spanou Z, Keller M, Britschgi M, et al. Involvement of drug-specific T cells in acute drug-induced interstitial nephritis. J Am Soc Nephrol. 2006;17(10):2919-2927.
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I
mmune checkpoint inhibitors are expanding the armamentarium of anticancer agents by recruiting the body’s defenses to treat various malignancies. This approach is complicated because the immune system is normally balanced by checkpoints that guard against autoimmunity. Tumors evade immune surveillance by co-opting such checkpoints, including the programmed death 1 (PD-1) membrane protein expressed on activated effector T cells. PD ligand 1 (PD-L1), the primary PD-1 ligand, is upregulated on various tumors and its binding to PD-1 on activated T cells results in T-cell exhaustion and anergy.1,2 Immune checkpoint inhibitors relieve suppression of antitumor T-cell activation and function. Current US Food and Drug Administration–approved agents include the cytotoxic lymphocyte-associated antigen 4 (CTLA-4) antagonist antibody ipilimumab for advanced melanoma and the PD-1 antagonist antibodies nivolumab and pembrolizumab for advanced melanoma and non–small cell lung cancer (NSCLC). They are currently being evaluated in later stage clinical trials across several tumor types. Although most patients tolerate these drugs, serious immune-related adverse events including pneumonitis, hepatitis, and endocrinopathies have been described.3,4 Additionally, clinical trials report an incidence of grade 3/4 nephrotoxicity ranging from 0.4% to 3% without identifying a clear cause.5,6 We present 6 cases of acute kidney injury (AKI) secondary to biopsy-proven acute interstitial nephritis (AIN) associated with nivolumab or pembrolizumab use in patients with advanced NSCLC. Details for medical history, medications, and serum and urine laboratory data are provided in Table 1. Pathology findings are summarized in Table S1, and a representative biopsy is provided as Fig S1. Am J Kidney Dis. 2016;-(-):---
CASE REPORTS Case 1 The index case, a 73-year-old man with NSCLC, presented with a serum creatinine (Scr) level (1.9 mg/dL) increased from baseline (1.2-1.3 mg/dL). Eleven months earlier, he had started intravenous (IV) nivolumab therapy (10 mg/kg biweekly [ie, every other week]) as part of a clinical trial. On presentation, blood pressure (BP) was 132/72 mm Hg, pulse rate was 75 beats/min, and examination revealed edema (11) of the right lower extremity. Reduced furosemide dosing did not improve kidney function. Kidney biopsy was performed and revealed focal AIN. Omeprazole and furosemide treatment were discontinued, but he continued receiving nivolumab. The patient’s Scr levels fluctuated from 1.4 to 1.7 mg/dL for the next 8 months before nivolumab treatment was withdrawn due to progressive disease. Over the next 6 months, Scr levels declined to the pre–nivolumab therapy baseline.
Case 2 A 78-year-old man with NSCLC was evaluated for an acute increase in Scr level (from 0.9 to 1.8 mg/dL) over a 6-week period. For 16 months prior to AKI, he received IV nivolumab (10 mg/kg biweekly) as part of a clinical trial. BP was 124/60 mm Hg, pulse rate was 97 beats/min, and physical examination showed bilateral lower-extremity edema (11). Omeprazole and celecoxib therapy were discontinued and kidney biopsy revealed diffuse AIN. Nivolumab therapy was withdrawn, and prednisone therapy (60 mg/d) was initiated and tapered over 1 month, with recovery to baseline kidney function. From the Sections of 1Nephrology and 2Oncology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. Received August 28, 2015. Accepted in revised form February 17, 2016. Address correspondence to Anushree C. Shirali, MD, Section of Nephrology, Department of Internal Medicine, PO Box 208029, New Haven, CT 06520-8029. E-mail: [email protected] 2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.02.057 1
Shirali, Perazella, and Gettinger
Case 3 A 60-year-old woman with NSCLC was hospitalized for an increase in Scr level to 5.5 mg/dL from 0.9 mg/dL 3 weeks prior. Ten months earlier, she enrolled in a clinical trial evaluating administration of bevacizumab (15 mg/kg) combined with nivolumab (3 mg/kg) every 3 weeks. This regimen was continued with stable disease until AKI hospitalization. At that time, the patient reported diffuse rash and fever followed by nausea, headache, fatigue, and decreased urine output. BP was 102/62 mm Hg and pulse rate was 81 beats/min. Physical examination findings were unremarkable. Kidney biopsy revealed AIN (Fig S1). IV methylprednisolone, 125 mg, was administered for 3 days, followed by oral prednisone, 60 mg/d, which was tapered over the next month. Kidney function rapidly returned to baseline.
Case 4 A 69-year-old woman with NSCLC developed AKI, with an increase in Scr level from 1.0 to 1.9 mg/dL. As part of a clinical trial, the patient received IV pembrolizumab 10 mg/kg biweekly for 3 months prior to AKI. Physical examination findings were unremarkable, with BP of 114/65 mm Hg and pulse rate of 75 beats/min. Omeprazole, lisinopril, and pembrolizumab therapy were discontinued and kidney biopsy revealed diffuse AIN. Prednisone, 60 mg/d, was administered with a 4-week taper; Scr level improved to 1.3 mg/dL. However, 2 weeks after completing the steroid taper, Scr level increased to 2.5 mg/dL. The patient reported having restarted omeprazole therapy. Treatment with prednisone, 60 mg/d, was restarted and tapered over a 3-month period, with normalization of kidney function.
Case 5 A 59-year-old man with NSCLC developed an increase in Scr level from 0.9 to 2.5 mg/dL. The patient was receiving clinical trial dosing of IV nivolumab (3 mg/kg biweekly) combined with ipilimumab (1 mg/kg every 12 weeks). The patient’s course was complicated by hypophysitis with secondary adrenal insufficiency, for which replacement steroid therapy was started. The patient continued nivolumab therapy with sustained tumor response until AKI developed 6 months after trial initiation. BP was 154/98 mm Hg and pulse rate was 96 beats/min. Physical examination findings were unremarkable. Kidney biopsy revealed focal AIN. Omeprazole and nivolumab/ipilimumab therapy were discontinued and Scr level declined to 1.3 mg/dL 2 weeks later. Trial therapy was reinitiated; 2 months later, Scr level increased to 10.6 mg/dL. Upon questioning, the patient reported intermittent use of omeprazole. Pulse IV methylprednisolone 125 mg was administered for 3 days, followed by oral prednisone taper over 1 month. Scr level improved to 1.4 mg/dL without further trial therapy.
Case 6 A 69-year-old woman with NSCLC was evaluated for an increase in Scr level from 0.8 to 2.3 mg/dL. One year prior, IV pembrolizumab (10 mg/kg every 3 weeks) was initiated as part of a clinical trial. The patient’s course was complicated by hypophysitis and secondary adrenal insufficiency, for which replacement steroid therapy was initiated. Pembrolizumab therapy was continued with sustained tumor response until AKI developed. The patient’s BP was 174/119 mm Hg and pulse rate was 94 beats/min. Physical examination findings were unremarkable. The kidney biopsy specimen displayed diffuse AIN. Pantoprazole and pembrolizumab therapy were discontinued, and prednisone was administered at 60 mg/d with a 1-month taper. Steroid therapy was complicated by myopathy, but kidney function normalized.
2
DISCUSSION We report 6 cases of AKI of variable severity from biopsy-proven AIN in patients exposed to either nivolumab or pembrolizumab. None of the patients required dialysis, and all except patient 1 received corticosteroid therapy and recovered kidney function to or near baseline. One patient was rechallenged with PD-1 inhibitor treatment after initial recovery of kidney function without steroid use, resulting in recurrent severe AKI from steroid-responsive AIN. Mild serum eosinophilia occurred in some cases, but no uniform laboratory findings were noted. With increasing use of PD-1 inhibitors, we may gain more insight into adverse renal events, allowing institution of assessment and treatment algorithms. Until then, kidney biopsy should be considered in cases of AKI to confirm AIN. An incorrect diagnosis may lead to therapy discontinuation and high-dose steroid dosing, which could abrogate antitumor effects. We acknowledge that our patients were also receiving medications with known associations with the development of AIN. All except patient 3 took proton pump inhibitors (PPIs), which are well associated with the idiosyncratic development of AIN.7 However, except for case 5, PPI therapy began long before the initiation of PD-1 inhibitor therapy. Patients 2 and 3 were also taking nonsteroidal antiinflammatory drugs (NSAIDs). In patient 2, NSAID use preceded PD-1 inhibitor therapy by years, whereas in patient 3, it followed 11 months after starting PD-1 inhibitor therapy and 5 months before AKI development. Moreover, in our clinical experience, the incidence of AIN from PPIs and NSAIDs appears to greater than what we had previously observed prior to the advent of PD-1 inhibitor therapy. We speculate that PD-1 inhibitor therapy in our patients may have disrupted long-standing tolerance of NSAIDs and/or PPIs, resulting in clinically significant AIN. There was a delay between PD-1 inhibition and the development of AIN, similar to reports of pneumonitis with PD-1 inhibitors occurring weeks to months after the start of therapy.8 Although unclear, this suggests that the time from drug initiation to a break in tolerance is variable across patients. With respect to the concurrent glomerular podocyte injury in case 3, vascular endothelial growth factor inhibition from bevacizumab was likely responsible,9 but the absence of proteinuria and hypertension suggests that this injury was clinically insignificant. Of note, in addition to PD-1 blockade, patient 5 was receiving CTLA-4 inhibition with ipilimumab, which has been associated with lupus-like nephritis and 2 cases of granulomatous AIN10-13; thus, ipilimumab use may have further contributed to AIN development in this case. Am J Kidney Dis. 2016;-(-):---
Case
Pt Age, y j Sex j Comorbid Conditions
D in Kidney Function
Laboratory Findings
Timing of AKI
NSCLC Type j Prior Systemic Therapy
Other Potential Nephrotoxins
Clinical Course
1
73 j M j HTN, CKD3, prior tobacco use, Afib, treated laryngeal carcinoma
Scr: 1.3➔1.9; eGFR: 57➔35
Eos: 7%; UPCR: 0.1 mg/mg; bland urine sediment
11 mo after nivolumab started
Advanced squamous j 1: cisplatin/vinorelbine, cetuximab; 2: docetaxel; 3: erlotinib
Omeprazole, furosemide (both preceding nivolumab by .1 y)
Omeprazole held; nivolumab continued, w/ Scr varying from 1.4 to 1.7 for 8 mo; Scr Y to prenivolumab baseline 6 mo after nivolumab held
2
78 j M j HTN, T2DM, prior tobacco use
Scr: 0.9➔1.8; eGFR: .60➔37
Eos: 6%; no protein on UA; sediment: 2 WBC casts/HPF
16 mo after nivolumab started (5 mo after starting celecoxib)
Advanced adenocarcinoma j 1: cisplatin, etoposide; 2: docetaxel; 3: pemetrexed/ bevacizumab
Omeprazole (preceding nivolumab by .1 y), celecoxib (begun 11 mo after starting nivolumab)
Nivolumab and celecoxib held; treated w/ 1-mo steroid taper, w/ normalization of Scr
3
60 j F j HTN, prior tobacco use, hypothyroid
Scr: 0.9➔5.5; eGFR: .60➔8
Eos: 3%; UPCR: 0.6 mg/mg; sediment: 2-5 WBCs/HPF
10 mo after nivolumab 1 bevacizumab started
Advanced adenocarcinoma j 1: carboplatin/ pemetrexed/bevacizumab
Ibuprofen (intermittent use preceding nivolumab by .1 y, w/ [ in use prior to AKI)
Ibuprofen held; treated w/ 1-mo steroid taper, w/ normalization of Scr
4
69 j F j HTN, COPD, prior tobacco use
Scr: 1.0➔1.9 & 1.3➔2.5; eGFR: 55➔26 & 41➔19
No eosinophilia; no protein on UA; sediment: numerous WBCs/ HPF
3 mo after pembrolizumab started
Advanced adenocarcinoma j 1: carboplatin/paclitaxel/ bevacizumab; 2: docetaxel; 3: pemetrexed
Omeprazole (preceding pembrolizumab by 3 mo)
Pembrolizumab and omeprazole held; treated w/ 1-mo steroid taper, w/ Y of Scr to 1.3; 2 wk after steroid course, Scr [ to 2.5; retreated w/ 3-mo steroid taper, w/ normalization of Scr
5
59 j M j tobacco user
Scr: 0.8➔2.5 & 1.3➔10.6; eGFR: .60➔27 & 57➔5
Eos: 2%; no protein on UA; sediment: 1 WBC cast/slide
8 mo after nivolumab 1 ipilimumab starteda
Advanced adenocarcinoma j none
Omeprazole (begun 3 mo after starting nivolumab/ipilimumab)
Nivolumab, ipilimumab, and omeprazole held; Scr Y to 1.3 w/o steroids; nivolumab/ ipilimumab re-started, w/ severe AKI (pt reported interim omeprazole use); Scr Y to 1.4 w/ 1-mo steroid taper
6
69 j F j HTN, hypothyroid, prior tobacco use, HPL
Scr: 0.8➔2.3; eGFR: .60➔37
Eos: 1%; no protein on UA; sediment: 15-30 WBCs/HPF
1 y after pembrolizumab starteda
Advanced adenocarcinoma j carboplatin/pemetrexed
Pantoprazole (preceding pembrolizumab by 6 mo)
Pembrolizumab held; treated w/ 1-mo steroid taper, w/ normalization of Scr
3
Note: Normal Scr level range is 0.5 to 1.2 mg/dL at our laboratory and the creatinine assay is IDMS traceable. eGFRs were calculated with the 4-variable IDMS-traceable MDRD Study equation. Abbreviations and definitions: Afib, atrial fibrillation; AKI, acute kidney injury; CKD3, chronic kidney disease stage 3; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); Eos, eosinophils; HPF, high-power field; HPL, hyperlipidemia; HTN, hypertension; IDMS, isotope-dilution mass spectrometry; MDRD, Modification of Diet in Renal Disease; NSCLC, non–small cell lung cancer; PD-1, programmed death 1; pt, patient; Scr, serum creatinine (in mg/dL); T2DM, type 2 diabetes mellitus; UA, urinalysis; UPCR, urine protein-creatinine ratio; WBC, white blood cell. a Treatment also complicated by hypophysitis.
Acute Interstitial Nephritis and PD-1 Inhibitor Therapy
Am J Kidney Dis. 2016;-(-):---
Table 1. Demographics and Clinical Features of NSCLC Patients With AKI Associated With PD-1 Inhibitor Use
Shirali, Perazella, and Gettinger
autoimmune diabetes, possibly mediated by loss of peripheral tolerance to self-reactive T cells.17 Another explanation is that disruption of PD-1 signaling breaks tolerance to drug-specific effector T cells that are critical to the pathogenesis of AIN.18 In this scenario, PD-1 inhibitor therapy reactivates exhausted drug-specific T cells primed by exposure to nephritogenic drugs, including NSAIDs and PPIs, but subsequently inhibited by PD-1 signaling. Either scenario results in increased effector T-cell migration and function (Fig 1), leading to clinically significant kidney injury. In support of the latter scenario is our index case, in which mild AIN was successfully treated with discontinuation of PPI therapy alone despite continuation of PD-1 inhibitor therapy. Based on available clinical trial data, AKI is a rare complication of PD-1 inhibitor therapy. Our experience suggests that if AKI is confirmed as AIN, it is also manageable. Our therapeutic approach to AIN included drug discontinuation and a variable course of corticosteroids. We cannot recommend a definitive dose and duration of steroid therapy based on 6
As shown in Fig 1, PD-1 interacts with 2 known ligands: PD-L1, residing on the surface of immune and nonimmune cells, and PD-L2 (programmed cell death ligand 2), expressed primarily on dendritic cells and macrophages. PD-L1 is overexpressed across several cancer cell types, and by binding to PD-1 on T cells in the tumor microenvironment, inactivates them. Nivolumab and pembrolizumab bind to PD-1, prevent downstream signaling, and restore antitumor immunity. Because the PD-1 pathway operates in nonpathogenic states to limit autoimmunity, interference with this pathway can lead to detrimental autoimmunity. Murine models have shown that PD-1 signaling is essential to peripheral tolerance of selfantigens by limiting the activation and expansion of self-reactive T cells and stimulating tolerogenic dendritic cells.14 Specific to the kidney, PD-1 signaling limits CD8-positive T-cell–mediated inflammatory injury and PD-1 knockout mice spontaneously develop glomerulonephritis.15,16 Thus, PD-1 inhibitor therapy may drive an autoimmune variant of interstitial nephritis, similar to the induction of
Normal PD-L1/L2
PD-1
Drug-specific or Self-specific T cell
PD-1 InhibiƟon
MHC
CD3
PD-L1/L2 PD-L1
PD-1
Drug-specific or Self-specific T cell
T Cell
+
Co-sƟmulatory molecules
MHC
CD3
AnƟ-PD-1 mAbs
+
Co-sƟmulatory molecules
+
T Cell
AcƟvated cƟvate T cell T PD-1
T Cell C
Cell
Exhausted T cell
T Cell
Re-acƟvated T cell T Cell
SƟmulaƟon of: T cell proliferaƟon 2. Cytotoxicity 3. Cytokine producƟon 4. InfiltraƟon of circulaƟng immune cells
1.
T Cell
InhibiƟon of: T cell proliferaƟon 2. Cytotoxicity 3. Cytokine producƟon
1.
PD-L1 ?PD-L2
=
T Cell
T Cell
T Cell
T Cell Cell
T Cell
T Cell
T Cell C
Figure 1. Hypothetical model of programmed death 1 (PD-1) signaling inhibition in acute interstitial nephritis (AIN). (Left panel) In the normal state, antigen- (including drug) and self-reactive T-cell activation require T-cell receptor recognition of the major histocompatibility complex (MHC), as well as costimulation. This interaction is negatively regulated by PD-1 axis signaling. In addition, PD-1 signaling also limits downstream T-cell effector function, limiting unchecked inflammation in the kidney. (Right panel) Inhibition of PD-1 signaling may cause AIN by unchecked reactivation, as well as function of effector self-specific T cells or drug-specific T cells. Abbreviation: mAbs, monoclonal antibodies. 4
Am J Kidney Dis. 2016;-(-):---
Acute Interstitial Nephritis and PD-1 Inhibitor Therapy
patients, but our experience suggests that prednisone, 1 mg/kg, with a 1-month taper may be sufficient. We additionally recommend weekly Scr monitoring for 1 month after completing steroid therapy. Rechallenge with PD-1 inhibitor therapy may be reasonable if other potentially offending agents are withdrawn and AIN has resolved. With this approach, Scr should be checked regularly, with reinstitution of steroid therapy at the first sign of AKI without another cause.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Shirali once participated in a meeting of the Bristol-Myers-Squibb safety advisory board. Dr Gettinger is a consultant for Bristol-Myers-Squibb. Peer Review: Evaluated by 2 external peer reviewers, a pathologist, a Co-Editor, and the Editor-in-Chief.
SUPPLEMENTARY MATERIAL Table S1: Summary of biopsy findings. Figure S1: Kidney biopsy from patient 3. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2016.02.057) is available at www.ajkd.org
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