Kidney Complications of Immune Checkpoint Inhibitors: A Review

In Practice

Kidney Complications of Immune Checkpoint Inhibitors: A Review Roman Shingarev and Ilya G. Glezerman Immunologic control of malignancy has long been recognized as an important determinant of disease progression. Recent advances in immunology have led to the focus on several mechanisms that can be targeted to achieve tumor suppression. In particular, checkpoint inhibition has evolved in less than a decade to become one of the most important strategies in cancer therapy, with a meaningful improvement in patient survival. Six agents have been approved for clinical use to date and many more are in the industry pipeline. The spectrum of malignancies responsive to immunotherapy ranges from advanced melanoma, for which the first immune checkpoint inhibitor ipilimumab was approved, to Hodgkin lymphoma, non–small cell lung cancer, renal cell carcinoma, and others. Notwithstanding its clinical benefits, checkpoint inhibition carries a risk for significant off-target toxicity stemming from the immune system activation. In this review, we discuss general principles of checkpoint inhibition, mechanisms of toxicity, and kidney complications of the treatment and propose diagnostic and treatment strategies when kidney injury occurs.

Clinical Vignette A 68-year-old man with stage IV non–small cell lung cancer presented to the hospital with dysphagia to liquids and acute kidney injury (AKI). Before presentation, the patient received 2 doses of cisplatin (75 mg/m2), 3 doses of pemetrexed (500 mg/m2), and 3 doses of nivolumab (10 mg/kg). Baseline serum creatinine (Scr) level 2 weeks after the last dose of cisplatin was 0.8 mg/dL. The last doses of nivolumab and pemetrexed were given 15 days before admission. On presentation, Scr level was 4.1 mg/dL. Vital signs revealed blood pressure of 118/ 84 mm Hg, pulse rate of 103 beats/min, and oral temperature of 36.7 C. Physical examination findings were otherwise unremarkable. Urinalysis was significant for pyuria, mild hematuria (red blood cells, 2-5/highpower field), but no casts or crystals. Urine culture was negative. Urinary proteincreatinine ratio was 0.7 mg/mg. Fractional excretion of sodium was 1.9%. An ultrasound revealed kidneys of normal size with no hydronephrosis. The patient received aggressive hydration, but Scr level continued to increase and peaked at 6.5 mg/dL, so kidney biopsy was performed. Histopathology showed extensive, diffuse, and active interstitial inflammation and tubulitis that was accompanied by severe tubular injury (Fig 1). Acute interstitial nephritis (AIN) was diagnosed and the patient was treated with prednisone (tapered after an initial dose of 60 mg daily) and sulfamethoxazole/ trimethoprim prophylaxis. AJKD Vol XX | Iss XX | Month 2019

Background Onconephrology is a rapidly growing subspecialty focusing on kidney complications of cancer and cancer treatment. Its growth is spurred by several factors, including the evolution of understanding of complex interaction between cancer cells and the kidney; the development of novel cancer therapies that can be nephrotoxic and lead to AKI, proteinuria, or electrolyte derangement1-3; and greater efficacy of cancer treatment, resulting in considerably longer survival of patients with cancer, who are often burdened by the newly acquired chronic kidney disease.4,5 Because an adequate glomerular filtration rate (GFR) is essential for the clearance of many drugs and is frequently used as a criterion for clinical trial enrollment, preservation of GFR is an important priority for onconephrologists that has a potential of improving cancer treatment and patient outcomes. Similarly, accurate assessment of a patient with cancer and reduced GFR is important to differentiate a drug toxicity from many other competing causes and has a significant impact on the subsequent cancer treatment in addition to the appropriate management of kidney disease itself. Complications arising from the use of novel checkpoint inhibitors exemplify the many dilemmas faced by onconephrologists.

Am J Kidney Dis. XX(XX): 1-9. Published online Month X, XXXX. doi: 10.1053/ j.ajkd.2019.03.433

© 2019 by the National Kidney Foundation, Inc.

FEATURE EDITOR: Holly Kramer ADVISORY BOARD: Linda Fried Ana Ricardo Roger Rodby Robert Toto In Practice is a focused review providing in-depth guidance on a clinical topic that nephrologists commonly encounter. Using clinical vignettes, these articles illustrate a complex problem for which optimal diagnostic and/or therapeutic approaches are uncertain.

Antitumor Activity of Immune Checkpoint Inhibitors Cancer immunotherapy is based on the principle of modulating the immune system to 1

In Practice

Figure 1. Kidney biopsy specimens from the patient with acute kidney injury while undergoing treatment with programmed cell death 1 checkpoint inhibitor. Light microscopy: (A) low power, (B) higher power. Hematoxylin and eosin stain shows severe acute interstitial nephritis with tubulitis accompanied by acute tubular injury (images courtesy of Dr Surya V. Seshan).

enhance the recognition and elimination of tumor cells. This process is dependent on the complex interplay between multiple immune system components, including cytotoxic, helper, and regulatory T cells; macrophages; natural killer cells; and myeloid-derived suppressor cells. The balance between a hyperactive immune response resulting in immune-mediated damage to healthy tissues and a hypoactive immune response resulting in infections and malignancies is achieved through a redundant and multilevel regulation of lymphocyte cytotoxic activity through immune checkpoint inhibition. An important aspect of immune regulation focuses on the “immune synapse,” a concept describing T lymphocytes interacting with the major histocompatibility complex on antigen-presenting cells (APCs) or with the target cell itself, as is the case with natural killer cells.6 In the immune synapse between the killer CD8+ T cell and APC, lymphocyte activation is dependent on the variable CD8 receptor engaging the antigen carried by an APC. This interaction between the killer CD8+ T cell and APC is followed by the intracellular signaling cascade, which occurs 2

through the nonvariable CD3 coreceptor and culminates in cytotoxins released by killer T cells (Fig 2).7 The CD28 molecule is a transmembrane protein expressed by T cells. After binding to CD80/86 on the APC, the CD28 molecule provides costimulation for lymphocyte proliferation and cytokine production.8 In the absence of such costimulation, T cells fail to activate and may undergo apoptosis. Immune checkpoint molecules downregulate CD28-mediated costimulation, which then favors immune tolerance. Subsequent to the discovery of immune checkpoint molecules, a range of targets for pharmacological interventions have been designed to inactivate some of the inhibitory regulators of lymphocytes. The first immune checkpoint drug of this type, ipilimumab, was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of advanced melanoma. Ipilimumab, a human immunoglobulin G1 (IgG1) monoclonal antibody against cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), exerts its immune inhibition by competitively binding CD80/86 on APCs.9 Programmed cell death 1 (PD-1) protein is found on lymphocytes, and its ligand (PD-L1) is found on native tissue, as well as some tumor cells. PD-1 and PD-L1 were the next pharmacological targets based on the evidence of an inhibitory effect of the PD-1:PD-L1 complex on T cells.10 Pembrolizumab and nivolumab (both PD-1 inhibitors) were approved in 2014 by the FDA. A similar drug, atezolizumab, a PD-L1 inhibitor, was approved in 2016. Although the early success of ipilimumab was somewhat overshadowed by the greater efficacy and safety of PD-1/PD-L1 inhibitors,11 considerable effort is directed at the investigation of the clinical synergism of the combined use of CTLA-4 and PD-1 blockade.12 In addition to metastatic melanoma, immune checkpoint inhibitors have been shown to be effective for Hodgkin lymphoma, renal cell and urothelial carcinoma, non–small cell lung cancer, and head and neck cancer.13-16 The mechanism of action and clinical application of the available drugs are listed in Table 1. Immune-Related Adverse Effects Off-target inflammatory responses to checkpoint inhibitors are commonly referred to as immune-related adverse effects (irAEs). These adverse effects can affect almost every organ system and their manifestations closely resemble autoimmune diseases. More than 50 checkpoint inhibitors have been discovered and their respective adverse effects have been demonstrated in animal models. For example, inhibition of PD-1 and the FCγRIIB inhibitory receptor on B cells leads to the development of inflammatory rheumatic diseases.17,18 Abnormal CTLA-4 expression and function in humans has been demonstrated in systemic lupus erythematosus,19 and elevated soluble PD-1 level has been linked with rheumatoid arthritis.20 Prevention of costimulatory signaling by CD28 receptor (the exact AJKD Vol XX | Iss XX | Month 2019

In Practice

An gen-presen ng cell

CTLA-4

PD-L1

Tumor cell

CD8 PD-1

Nivolumab

Ipilimumab

TCR

CD8+ T cell

T cell exhaus on

T cell prolifera on, survival, differen a on

T cell anergy

CPI

Immunogenic drug/metabolite INFLAMMATION Na ve an gen

Figure 2. Schematic representation of T-cell activation regulated by checkpoint inhibition with 3 hypothetical mechanisms of acute tubulointerstitial nephritis. Antigen carried by the antigen-presenting cell (APC) activates a T-cell receptor (TCR) with intracellular signal transduction by CD3 resulting in T-cell proliferation, survival, and differentiation. This signal also stimulates the expression of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), which competes for binding CD80/86 with CD28, the costimulatory protein required for T-cell activation, thereby leading to T-cell anergy. Programmed cell death 1 ligand (PD-L1) is variably expressed by many native and tumor cells. By binding to PD-1 on a T cell, it suppresses its activation and promotes immunotolerance leading to Tcell exhaustion. A T cell can be activated peripherally by an immunogenic checkpoint inhibitor, an immunogenic metabolite presented by the tubuloepithelial cells, or exhibit lesser immunotolerance for native kidney antigen. Abbreviations: Ag, antigen; CPI, checkpoint inhibitor; MHC, major histocompatibility compex.

opposite of the ipilimumab effect) has been demonstrated with abatacept, a CTLA-4–like CD80/86 ligand approved for the treatment of several autoimmune diseases.21,22 Despite the similarities between autoimmune diseases and irAEs, it is unclear whether genetic risk factors for autoimmune disease in the general population predict the development of irAEs in patients with cancer treated with checkpoint inhibitors.23-25 The relatively infrequent reports of serious exacerbations of pre-existing autoimmune AJKD Vol XX | Iss XX | Month 2019

diseases occurring while on checkpoint inhibition therapy suggest that the checkpoint inhibitors are not the main drivers of autoimmune diseases.26,27 Likewise, the highly variable pattern of organ involvement with irAEs remains unexplained. These observations underscore the redundant nature of the immune activation regulation that requires concurrent derangement of several mechanisms. This is further supported by the higher reported incidence of irAEs with the 3

In Practice Table 1. Mechanism of Action and Clinical Applications of Currently Available Immune Checkpoint Inhibitors Drug Ipilimumab Nivolumab

Mechanism of Action Anti–CTLA-1 antibody Anti–PD-1 antibody

Pembrolizumab

Anti–PD-1 antibody

Atezolizumab Avelumab Durvalumab

Anti–PD-L1 antibody Anti–PD-L1 antibody Anti–PD-L1 antibody

FDA-Approved Indications CRC,a melanoma, RCCa CRC, HCC, HL, melanoma, NSCLC, RCC, SCHNC, SCLC, urothelial carcinoma B-Cell lymphoma, cervical cancer, gastric cancer, SCHNC, HCC, HL, melanoma, MCC, MSI-H, NSCLC, urothelial carcinoma NSCLC, urothelial carcinoma MCC, urothelial carcinoma NSCLC, urothelial carcinoma

Abbreviations: CRC, colorectal cancer; CTLA, cytotoxic T-lymphocyte–associated protein; FDA, US Food and Drug Administration; HCC, hepatocellular carcinoma; HL, Hodgkin lymphoma; MCC, Merckel cell carcinoma; MSI-H, microsatellite instability-high cancer; NSCLC, non–small cell lung cancer; PD-1, programmed cell death 1; PDL1, programmed cell death 1 ligand; RCC, renal cell carcinoma; SCHNC, squamous cell head and neck cancer; SCLC, small cell lung cancer. a In combination with nivolumab.

combination of ipilimumab and nivolumab compared to a single-agent therapy.28 In addition, higher toxicity with ipilimumab versus PD-1/PD-L1 inhibitors can be explained by the “upstream” and less specific effect of CTLA-1 inhibition on T-cell activation and development.29 This difference in toxicity profiles with different checkpoint inhibitors appears to hold true for all organ systems involved. The largest organ, skin, is often affected with irAEs first, and this usually occurs within the first month of treatment. Almost half the patients treated will develop a maculopapular erythematous rash, which is occasionally pruritic and has no predilection for any specific body part.30 Diarrhea is the next most common toxicity associated with immune checkpoint inhibition.31 Although one-third of patients report increased bowel movement frequency in the first 2 months of treatment, diarrhea appears to be partly due to disruption of the normal intestinal flora by checkpoint inhibitors, while severe colitis is endoscopically confirmed in only 5% of all treated patients in studies with protocol-driven endoscopies.32,33 Hepatitis, characterized by elevation of alanine aminotransferase and aspartate aminotransferase levels in the absence of discrete radiographic findings, affects up to 10% of patients after 2 to 3 months of treatment.34 Other organ toxicities are considerably less frequent (<5%) but may be life-threatening. Such severe adverse effects include pneumonitis and primary adrenal insufficiency and require prompt recognition and treatment.35,36

Reduced Kidney Function Associated With Checkpoint Inhibitor Use Epidemiology and Clinical Features The reporting and communication of irAEs involving kidneys are limited by the use of Common Terminology Criteria for Adverse Effects (CTCAE) to classify and grade the severity of adverse effects of cancer therapy, including AKI (Table 2).37 Notwithstanding the many limitations of the KDIGO AKI classification system,38 applying CTCAE criteria fails to capture lower grade kidney complications as defined by KDIGO that have been validated in highquality studies.39-41 For example, a 1.5-fold increase in Scr level from 0.6 to 0.9 mg/dL in a hospitalized patient would be classified as stage 2 AKI by KDIGO definitions, but would be dismissed completely using CTCAE owing to the use of an “upper limit of normal” cutoff parameter. Although other signs of kidney injury such as hematuria or proteinuria are graded in CTCAE, urine testing is frequently not required in new cancer drug studies. The true incidence of GFR declines among patients treated with checkpoint inhibitors is thus difficult to estimate. Based on a recent review of 251 cases of irAEs, CTCAEdefined “renal failure” accounted for 2% of these cases42 and was seen only with ipilimumab. However, there are several case reports of AKI occurring with the use of PD-1/ PD-L1 inhibitors.43,44 A recent review of 48 clinical trials with 11,482 patients receiving these agents reported a pooled relative risk for AKI of 4.19 (95% confidence

Table 2. Comparison of NCI CTCAE and KDIGO Definitions of AKI AKI Stage 1 2 3 4

CTCAE Version 5.0 Scr > ULN to 1.5 × ULN Scr >1.5-3.0 × baseline or >1.5-3.0 × ULN Scr > 3.0 × baseline or >3.0-6.0 × ULN Scr > 6.0 × ULN

KDIGO38,a Scr = 1.5-1.9 × baseline or ≥0.3 mg/dL increase Scr = 2.0-2.9 × baseline Scr = 3.0 × baseline or increase to ≥4.0 mg/dL or initiation of RRT

Note: Conversion factor for Scr in mg/dL to μmol/L, ×88.4. Abbreviations: AKI, acute kidney injury; KDIGO, Kidney Disease: Improving Global Outcomes; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Effects; RRT, renal replacement therapy; Scr, serum creatinine; ULN, upper limit of normal. a KDIGO grades simplified by omitting the duration of AKI and urine output criteria.

4

AJKD Vol XX | Iss XX | Month 2019

In Practice interval, 1.57-11.18).45 The pooled incidence of AKI was 2.1%, compared to 2.0% seen with ipilimumab. The combination of CTLA-1 and PD1 inhibitors appears to increase the AKI incidence to 5%.46 In most patients, suspicion for checkpoint-induced AIN is based on the elevated Scr level accompanied by sterile pyuria, mild proteinuria, and rarely microhematuria. Only a minority of patients exhibit classic fever, eosinophilia, or rash; however, many of them experience at least 1 extrarenal irAE preceding AIN. In stark contrast to a typical drug-induced AIN, the temporal association with the offending agent is less distinct with checkpoint inhibitor–induced AIN. All checkpoint inhibitors have a long half-life of 2 to 3 weeks (with the exception of the 1-week half-life of avelumab). However, the frequently delayed onset of AKI (from 1-8 months following treatment initiation, with some cases presenting up to 2 months after the last dose) argues against the direct toxicity of these agents. This delayed presentation parallels the durability of the intended drug effect, which is more likely to be a function of longevity of T-cell activation rather than the elimination half-life of an individual drug.30 Although the use of medications known to cause AIN (such as nonsteroidal anti-inflammatory drugs and proton pump inhibitors) is common in this patient population, their treatment initiation usually predates the AIN diagnosis by at least several weeks. It must be noted that owing to the earlier approval of checkpoint inhibitors for the treatment of melanoma, there is a greater wealth of information on irAEs in this patient population. Accordingly, the accumulated irAE data are based on events mainly in white men. Thus, the impact of sex and race on patterns of exhibited autoimmune-like toxicities remains poorly explored.42,45 Kidney Histopathology In a series of 13 patients with checkpoint inhibitor–induced AKI who underwent kidney biopsy, the primary pathologic lesion in 12 patients was acute tubulointerstitial nephritis (AIN), characterized by diffuse interstitial infiltrates of CD3+ and CD4+ T lymphocytes accompanied by granulomas in 3 cases.46 Plasma cells and eosinophils were rarely present. Thrombotic microangiopathy was a defining feature of one patient’s pathology in this series, whose comorbid conditions included pre-existing hypertension. In another smaller series, AIN was found in all 6 patients treated with checkpoint inhibitors who underwent kidney biopsy for AKI.44 Other authors also reported several biopsy-confirmed cases of AIN with and without granulomatosis.47,48 Glomerular lesions are less common, but minimal change disease has been reported with both PD-1 and CTLA-4 checkpoint blockade.49,50 Focal segmental glomerulosclerosis, Goodpasture disease, and IgA glomerulonephritis were all reported with nivolumab.51-53 Recently, Mamlouk et al54 reported only 5 cases of AIN from 16 performed biopsies; the rest demonstrated a wide

AJKD Vol XX | Iss XX | Month 2019

spectrum of glomerular diseases, including pauci-immune glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, membranous nephropathy, acute tubular necrosis, and AA amyloidosis. There is also an isolated case of lupus nephritis.55 It is unknown whether any of the patients with these glomerular diseases had clinical or laboratory evidence of kidney diseases predating their cancer treatment or whether these glomerular lesions are at all related to the treatments. Mechanism of Kidney Injury In a typical drug-induced AIN, the hypothesized mechanism of kidney injury involves activation of circulating T cells directly by a drug56 or its metabolites, which may acquire immunogenicity locally by tubular cell processing or systemically by binding to carrier proteins and forming a drug-carrier complex (Fig 2).57 Activated T cells are then homed to the kidney as the site of local antigen presentation, where they infiltrate the parenchyma and orchestrate the local hypersensitivity reaction through cytokine release. Similar immunogenicity of checkpoint inhibitors or their metabolites can possibly result in irAEs; however, no study to date reported detection of ipilimumab-, pembrolizumab-, or nivolumab-specific T cells in peripheral blood. Furthermore, the delayed onset of AKI after checkpoint inhibitor initiation argues against the direct causation of AIN by the formation of an immunogenic drug metabolite. The stated mechanism of action of checkpoint inhibitors itself lends credence to the “multi-hit” or “brake release” theories supported by most researchers, in which T cells are more likely to lose tolerance to native antigens in the presence of PD1/PD-L1/CTLA1 inhibitors.46,48,58 Alternatively, uninhibited T cells may activate the typical druginduced hypersensitivity reaction pathway more vigorously when a known immunogenic compound is involved, implying a “2-hit” mechanism, although this is not supported by animal PD-1 and CTLA-1 knockout models that exhibit AIN in the absence of foreign immunogenic stimuli.18,59 Pre-existing genetic determinants of autoimmunity may play an important role in the likelihood and localization of irAEs. However, the lack of studies demonstrating an association between a pattern and frequency of irAEs and patients’ sex or ethnicity is discouraging in this respect.

Treatment Strategy In general, the American Society of Clinical Oncology (ASCO) recommends withholding checkpoint inhibitor therapy for patients developing grade 2 CTCAE complications until at least partial symptom improvement.60 Oral corticosteroids are given for patients whose symptoms persist more than 1 week. For those developing grades 3 and 4 complications, checkpoint inhibitor therapy is discontinued and a more intensive corticosteroid regimen is

5

In Practice administered. Objective response rate, overall survival, and time to treatment failure do not seem to be affected by irAE development or corticosteroid administration.61,62 Based on the experience with Crohn disease,63 anti–tumor necrosis factor agents (eg, infliximab), mycophenolic acid, and rarely, cyclophosphamide have been applied for refractory cases of irAEs with variable degree of success, but data are too scarce to judge on the efficacy of these agents.64,65 For AKI, ASCO guidelines suggest a nephrology consult for greater than stage 2 AKI and recommend against a kidney biopsy if other causes of AKI can be excluded on clinical grounds. Given the nonspecific signs and symptoms of AIN, as well as multiple competing causes of AKI in patients with metastatic cancer, biopsy can be of greater importance than suggested by the guidelines. Nevertheless, in practice, pausing the checkpoint inhibitor treatment and administering corticosteroids are often pursued empirically. Corticosteroids have been deployed in most of the reported cases, including glomerular lesions, with at least partial improvement of kidney function.44,46,55 One case of biopsy-confirmed thrombotic microangiopathy did not improve with corticosteroids.46 Mycophenolic acid in addition to corticosteroids has been used in 1 case of AIN; however, the patient developed pancytopenia and died of sepsis.48 The duration of corticosteroid therapy for irAEs may need to be longer than 4 to 6 weeks, which is the duration typically recommended in most cases of drug-induced AIN.66 PD-1 checkpoint inhibitors have high affinity for its ligand and can remain bound to the circulating lymphocytes for up to 57 days, with mean plateau occupancy of 72%. However, the duration of receptor occupancy on lymphocytes is unknown.67 In patients who demonstrate objective response to immunotherapy and develop irAEs of up to grade 3 severity, immunotherapy is generally restarted if irAE severity reverts to grade 1 or less.60 Because of the lower incidence of AKI relative to other irAEs, broad recommendations regarding immunotherapy resumption are more problematic because most patients have other antecedent or concurrent irAEs. In published reports, there are only 3 patients with biopsy-confirmed AIN who were reported to have continued or resumed immunotherapy after recovering from AKI without subsequent deterioration in kidney function.44,46 However, our experience suggests that oncologists are more aggressive in their treatment approach. After AKI reverts to CTCAE grade 1 or lower, some oncologists will restart either the same immunotherapy drug or switch to a different one, sometimes concurrently with low-dose prednisone. In the absence of published outcomes of these strategies, it is difficult to assess their efficacy and safety. Based on the available literature documenting a substantial proportion of AKI ascribed to the lesions other than AIN that are less likely to respond to empirical

6

corticosteroid therapy,54 we suggest that nephrology consultation be obtained at the time of initiation of corticosteroid therapy, and certainly if GFR continues to decline despite this intervention. Assessment of kidney histology in these situations may provide invaluable information necessary for decisions regarding cancer treatment continuation and management of AKI. Empirical corticosteroid treatment may mask the progression of glomerular disease only to be diagnosed much later in the course of the disease. However, biopsy-confirmed acute tubular necrosis does not require discontinuation of checkpoint inhibitor therapy, and while corticosteroid treatment appears to be harmless as far as oncologic outcomes are concerned, even a short-term course is associated with multiple systemic adverse effects that may be detrimental to the survival of these vulnerable patients.68 Special Considerations for Patients With Kidney Allografts Data are limited on the outcomes of solid-organ transplant recipients because of the presumed high risk for organ rejection. De Bruyn et al69 reported rejection rates of 45% in patients with kidney allografts undergoing cancer treatment with checkpoint inhibition coupled with reduction of immunosuppression. It must be noted that tumor control was achieved in 30% of these patients. Provided that the patients are well informed, use of checkpoint inhibitors for cancer treatment may represent a viable option for some patients even with high risks for allograft dysfunction or failure. Sequelae of AKI Publications have reported the long-term sequelae of immunotherapy-associated AKI. Among a series of 24 patients and 6 individual case reports with biopsyconfirmed AIN with follow-up of up to 12 months, 8 patients recovered kidney function completely, and all but 1 patient received corticosteroid therapy of various intensity and duration for the treatment of AIN.44,46,47,54 Eleven other patients exhibited partial improvement of AIN and 3 patients required long-term renal replacement therapy. One patient died of disease progression and 1 died of sepsis. Four patients with AIN experienced another episode of AKI 2 to 8 weeks after completing the initial corticosteroid course. Only 1 of those patients with recurrent AIN was rechallenged with immunotherapy. Not surprisingly, a lower degree of interstitial fibrosis in the kidney parenchyma appeared to correlate with better kidney outcomes in the reported series, emphasizing the need for earlier diagnosis and glucocorticoid treatment initiation.46 In pooled analysis of all irAEs, close to 100% of patients with CTCAE grades 3 to 4 kidney dysfunction reverted to at least grade 1, although the overall number of patients with kidney irAEs is fairly small.70,71

AJKD Vol XX | Iss XX | Month 2019

In Practice Case Review Treatment with the PD-1 checkpoint inhibitor was permanently discontinued in our patient. His Scr level declined to 1.3 mg/dL with initiation of corticosteroid treatment. However, 8 weeks after the biopsy was performed, Scr level increased to 2.7 mg/dL when the prednisone dose was reduced to 20 mg daily. To address this increase in Scr level, the sulfamethoxazole/trimethoprim therapy was discontinued and the prednisone dose was increased to 60 mg daily. Scr level declined again, but the patient remained on variable doses of corticosteroids for nonrenal indications until his death 18 months after the initial diagnosis of AIN. The patient’s Scr level remained mildly elevated, with a new baseline of 1.2 to 1.5 mg/dL, for the rest of the follow-up period until his death. Conclusion The present case demonstrates the challenges of AKI diagnosis and treatment in patients treated with checkpoint inhibitors and highlights the importance of kidney biopsy in diagnosing AIN, as opposed to cisplatin- or ifosfamideinduced acute tubular necrosis. With the growth of immunotherapy treatment choices and applications, nephrologists should be aware of the kidney effects of these agents and the potential treatment strategies and kidney prognosis in cancer survivors. Article Information Authors’ Full Names and Academic Degrees: Roman Shingarev, MD, and Ilya G. Glezerman, MD. Authors’ Affiliations: Memorial Sloan Kettering Cancer Center (RS, IGG); and Weill Medical College of Cornell University, New York, NY (RS, IGG). Address for Correspondence: Ilya G. Glezerman, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065. E-mail: [email protected] Support: This article was supported in part through the National Institutes of Health/National Cancer Institute Cancer Center support grant P30 CA008748. Financial Disclosure: Dr Glezerman owns Pfizer Inc stock. Dr Shingarev declares that he has no relevant financial interests. Acknowledgements: We thank Mr Ricardo Cano for help with formatting Figures 1 and 2. Peer Review: Received October 11, 2018, in response to an invitation from the journal. Evaluated by 2 external peer reviewers and a member of the Feature Advisory Board, with direct editorial input from the Feature Editor and a Deputy Editor. Accepted in revised form March 29, 2019.

References 1. Abelson HT, Fosburg MT, Beardsley GP, et al. Methotrexateinduced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. J Clin Oncol. 1983;1(3):208-216. 2. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Druginduced Fanconi’s syndrome. Am J Kidney Dis. 2003;41(2): 292-309.

AJKD Vol XX | Iss XX | Month 2019

3. Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC. VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer. 2010;46(2):439-448. 4. Hansen SW, Groth S, Daugaard G, Rossing N, Rorth M. Longterm effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol. 1988;6(11):1728-1731. 5. Hingorani S, Guthrie KA, Schoch G, Weiss NS, McDonald GB. Chronic kidney disease in long-term survivors of hematopoietic cell transplant. Bone Marrow Transplant. 2007;39(4):223-229. 6. Grakoui A, Bromley SK, Sumen C, et al. The immunological synapse: a molecular machine controlling T cell activation. Science. 1999;285(5425):221-227. 7. Kane LP, Lin J, Weiss A. Signal transduction by the TCR for antigen. Curr Opin Immunol. 2000;12(3):242-249. 8. Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family. Immunol Rev. 2011;241(1):180-205. 9. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889-1894. 10. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239-245. 11. Petrella TM, Robert C, Richtig E, et al. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017;86:115-124. 12. Wolchok JD, Rollin L, Larkin J. Nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(25): 2503-2504. 13. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319. 14. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. 15. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-smallcell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030): 1837-1846. 16. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856-1867. 17. Bolland S, Ravetch JV. Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity. 2000;13(2):277-285. 18. 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. 19. Jury EC, Flores-Borja F, Kalsi HS, et al. Abnormal CTLA-4 function in T cells from patients with systemic lupus erythematosus. Eur J Immunol. 2010;40(2):569-578. 20. Liu C, Jiang J, Gao L, et al. Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways. Arthritis Res Ther. 2015;17:340-353. 21. van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med. 1997;185(3):393-403.

7

In Practice 22. Mease P, Genovese MC, Gladstein G, et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a sixmonth, multicenter, randomized, double-blind, placebocontrolled, phase II trial. Arthritis Rheum. 2011;63(4):939-948. 23. Graham RR, Hom G, Ortmann W, Behrens TW. Review of recent genome-wide association scans in lupus. J Intern Med. 2009;265(6):680-688. 24. Prokunina L, Castillejo-Lopez C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002;32(4):666-669. 25. Fanciulli M, Norsworthy PJ, Petretto E, et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet. 2007;39(6): 721-723. 26. Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2(2):234-240. 27. Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28(2):368-376. 28. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356. 29. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148. 30. Weber JS, Kahler KC, Hauschild A. Management of immunerelated adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697. 31. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS; MXD 01020 Investigators. Patterns of onset and resolution of immunerelated adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675-1682. 32. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic Tlymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283-2289. 33. Berman D, Parker SM, Siegel J, et al. Blockade of cytotoxic Tlymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 2010;10:11-21. 34. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 Study. J Clin Oncol. 2017;35(34):3851-3858. 35. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017. 36. Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitorrelated pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol. 2016;2(12): 1607-1616. 37. National Cancer Institute. Division of Cancer Treatment and Diagnosis. Common Terminology Criteria for Adverse Events, Version 5.0. https://ctep.cancer.gov/protocolDevelopment/ electronic_applications/ctc.htm#ctc_50. Accessed August 30, 2018. 38. Kellum JA, Lameire N; Kidney Disease Improved Global Outcomes Acute Kidney Injury Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (part 1). Crit Care. 2013;17(1):204-219.

8

39. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16(11):3365-3370. 40. Coca SG, King JT Jr, Rosenthal RA, Perkal MF, Parikh CR. The duration of postoperative acute kidney injury is an additional parameter predicting long-term survival in diabetic veterans. Kidney Int. 2010;78(9):926-933. 41. Newsome BB, Warnock DG, McClellan WM, et al. Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction. Arch Intern Med. 2008;168(6):609-616. 42. Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PloS One. 2016;11(7):e0160221. 43. Vandiver JW, Singer Z, Harshberger C. Severe hyponatremia and immune nephritis following an initial infusion of nivolumab. Targeted Oncol. 2016;11(4):553-556. 44. Shirali AC, Perazella MA, Gettinger S. Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients. Am J Kidney Dis. 2016;68(2): 287-291. 45. Manohar S, Kompotiatis P, Thongprayoon C, Cheungpasitporn W, Herrmann J, Herrmann SM. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis. Nephrol Dial Transplant. 2019 Jan 1;34(1):108-117. 46. Cortazar FB, Marrone KA, Troxell ML, et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016;90(3):638-647. 47. Izzedine H, Gueutin V, Gharbi C, et al. Kidney injuries related to ipilimumab. Investig New Drugs. 2014;32(4):769-773. 48. Murakami N, Borges TJ, Yamashita M, Riella LV. Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma. Clin Kidney J. 2016;9(3):411-417. 49. Kitchlu A, Fingrut W, Avila-Casado C, et al. Nephrotic syndrome with cancer immunotherapies: a report of 2 cases. Am J Kidney Dis. 2017;70(4):581-585. 50. Kidd JM, Gizaw AB. Ipilimumab-associated minimal-change disease. Kidney Int. 2016;89(3):720. 51. Daanen RA, Maas RJH, Koornstra RHT, Steenbergen EJ, van Herpen CML, Willemsen A. Nivolumab-associated nephrotic syndrome in a patient with renal cell carcinoma: a case report. J Immunother. 2017;40(9):345-348. 52. Takahashi N, Tsuji K, Tamiya H, Shinohara T, Kuroda N, Takeuchi E. Goodpasture’s disease in a patient with advanced lung cancer treated with nivolumab: an autopsy case report. Lung Cancer. 2018;122:22-24. 53. Jung K, Zeng X, Bilusic M. Nivolumab-associated acute glomerulonephritis: a case report and literature review. BMC Nephrol. 2016;17(1):188. 54. Mamlouk O, Selamet U, Machado S, et al. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer. 2019;7(1):2-15. 55. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibodyinduced lupus nephritis. N Engl J Med. 2009;361(2):211-212. 56. Pichler WJ. Pharmacological interaction of drugs with antigenspecific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol. 2002;2(4):301-305. 57. Spanou Z, Keller M, Britschgi M, et al. Involvement of drugspecific T cells in acute drug-induced interstitial nephritis. J Am Soc Nephrol. 2006;17(10):2919-2927.

AJKD Vol XX | Iss XX | Month 2019

In Practice 58. Izzedine H, Mateus C, Boutros C, et al. Renal effects of immune checkpoint inhibitors. Nephrol Dial Transplant. 2017;32(6): 936-942. 59. Zha Y, Blank C, Gajewski TF. Negative regulation of T-cell function by PD-1. Crit Rev Immunol. 2004;24(4): 229-237. 60. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768. 61. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33(28):3193-3198. 62. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785-792. 63. Stidham RW, Lee TC, Higgins PD, et al. Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn’s disease. Aliment Pharmacol Ther. 2014;39(12):1349-1362. 64. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):709-717.

AJKD Vol XX | Iss XX | Month 2019

65. Pages C, Gornet JM, Monsel G, et al. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res. 2013;23(3):227-230. 66. Krishnan N, Perazella MA. Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment. Iran J Kidney Dis. 2015;9(1):3-13. 67. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of singleagent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167-3175. 68. Waljee AK, Rogers MA, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357:1-8. j1415. 69. De Bruyn P, Van Gestel D, Ost P, et al. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go? Curr Opin Oncol. 2019;31(2):54-64. 70. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807-3814. 71. Eigentler TK, Hassel JC, Berking C, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev. 2016;45: 7-18.

9