Renal toxicities have been increasingly recognized as complications of the immune checkpoint inhibitors (ICIs). Recent studies have outlined the incidence and potential risk factors for nephrotoxicity. For clinicians, the key question is how to manage patients who develop these adverse renal effects. This is of paramount importance to providers as ICI use for cancer therapy becomes more widespread and nephrotoxicity increasingly develops. As clinicians encounter ICI-associated nephrotoxicity, an appropriate approach to management is required to facilitate the best outcomes in patients with cancer. Importantly, ICI rechallenge in patients who developed ICI-related acute kidney injury (AKI) is unclear and represents a conundrum for providers. Clinicians struggle with the "if, when, and how to" questions related to ICI rechallenge in this subset of patients. In addition, ICI use in the transplant population raises concerns for promoting acute rejection when treating cancer in these patients. We herein review current information on these various topics.© 2020 International Society of Nephrology. Published by Elsevier Inc.

Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers.In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important.© 2017 S. Karger AG, Basel.

The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.

The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects.We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center.We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6-56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery.Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Background: Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management.Case presentation: We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive.Conclusions: The rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.

Due to recent advantages in cancer therapy, immune checkpoint inhibitors (ICIs) are new classes of drugs targeting programmed cell death protein 1 (PD-1) or its ligand programmed cell death protein 1-ligand 1 (PD-L1) used in many cancer therapies. Acute interstitial nephritis (AIN) is a potential and deleterious immune-related adverse events (irAE) in the kidney observed in patients receiving ICIs and the most common biopsy-proven diagnosis in patients who develop acute kidney injury (AKI). Based on previous reports, AIN in patients receiving ICIs is associated with tubular positivity for PD-L1, implicating that PD-L1 positivity reflects susceptibility to develop renal complications with these agents. It remains unclear if PD-L1 positivity is acquired specifically during ICI therapy or expressed independently in the kidney.

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. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Expanded clinical experience with patients treated by pembrolizumab has accumulated. However, renal toxicities associated with this anti-programmed cell death 1 agent are poorly described because kidney histology is rarely sought. As a nephrology referral centre, we aimed to describe the clinic-biological and histopathological characteristics of pembrolizumab-related nephropathy and its response to treatment.We conducted a monocentric large case series study, including all pembrolizumab-treated cancer patients presenting a renal toxicity addressed to our centre from 2015 to 2017.A total of 12 patients (7 men) out of 676 pembrolizumab-treated patients (incidence 1.77%) were included (median age 69.75 years). Patients were referred for acute kidney injury ( = 10) and/or proteinuria ( = 2). A kidney biopsy was performed in all patients, with a median duration of use of 9 months (range 1-24 months) after the beginning of treatment. Biopsy showed that four patients had acute interstitial nephritis (AIN), whereas five had acute tubular injury (ATI) alone, one had minimal change disease (MCD) and ATI, and one had MCD alone. Pembrolizumab withdrawal coupled with corticosteroid therapy was the most effective treatment for kidney function recovery. Drug reintroduction resulted in a more severe recurrence of AIN in one patient who required maintenance of pembrolizumab. Two patients died of cancer progression with one of them developing severe renal failure requiring dialysis.In our series, ATI, AIN and MCD are the most frequent forms of kidney involvement under pembrolizumab therapy. Kidney dysfunction is usually isolated but can be severe. Use of corticosteroids in case of AIN improves the glomerular filtration rate.

The objective of this case cohort study was to describe our experience in the care of patients with immune checkpoint inhibitor–related acute interstitial nephritis (ICI-AIN) including rechallenge.

The main manifestation of acute interstitial nephritis (AIN) due to immune checkpoint inhibitors is acute kidney injury. We report here a biopsy-proven AIN revealed by tubular acidosis. This case highlights that immune checkpoint inhibitor prescribers must be aware of electrolytic disorders since tubular dysfunction can precede serum creatinine increase and reveal renal toxicity.© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.

Programmed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors.This was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records.The final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (<1%) experienced suspected PD-L1-related AKI. The PD-L1-related AKI occurred a median of 99 days after starting therapy. All patients concurrently received another medication known to cause acute interstitial nephritis (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or antibiotics) at the time of the suspected PDL1-related AKI.Although AKI is common in patients receiving PD-L1 therapy, the incidence of suspected PD-L1-related AKI is low (<1%) and may be less common when compared to other classes of ICIs. This cohort provides further validation that other drugs associated with acute interstitial nephritis may be involved in the pathogenesis of ICI-related AKI.© 2020 International Society of Nephrology. Published by Elsevier Inc.

Immune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint inhibitors.

Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse.We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI.Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI.This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.Copyright © 2020 by the American Society of Nephrology.

Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms.Copyright © 2017 Elsevier Inc. All rights reserved.

Immune checkpoint inhibitors (ICIs) have brought a paradigm shift to cancer treatment. However, little is known about the risk of renal adverse events (RAEs) of ICI-based regimens, especially ICI combination therapy.

Immune checkpoint inhibitors (ICIs) are effective in treating several cancers; however, acute kidney injury (AKI) can occur as part as an immune-related adverse event (iRAE). Biomarkers at the time of AKI diagnosis may help determine whether they are ICI- related and guide therapeutic strategies.In this retrospective study, we reviewed patients with cancer treated with ICI therapy between 2014 and 2020 who developed AKI (defined as a ≥1.5-fold increase in serum creatinine [SCr]) that was attributed to ICI (ICI-AKI) and compared them with an adjudicated non-ICI-AKI group. Clinical and laboratory features, including SCr, serum C-reactive protein (CRP), and urine retinol binding protein/urine creatinine (uRBP/Cr) levels at AKI event were evaluated.There were 37 patients with ICI-AKI and 13 non-ICI-AKI referents in the cohort for analysis. At time of AKI, SCr, CRP, and uRBP/Cr were significantly higher in the ICI-AKI compared with the non-ICI-AKI patients (median [interquartile range (IQR)] SCr 2.0 [1.7, 2.9] vs. 1.5 [1.3, 1.6] mg/dl, serum CRP 54.0 [33.7, 90.0] vs. 3.5 [3.0, 7.9] mg/l, and uRBP/Cr 1927 [1174, 46,522] vs. 233 [127, 989] μg/g Cr, respectively,  < 0.05 for all). Compared with the referent group, time from ICI initiation to AKI was shorter in the ICI-AKI patients. Among the ICI-AKI group, complete renal recovery occurred in 39% of patients by 3 months; rechallenge occurred in 16 (43%) of patients, of whom 3 (19%) had recurrence of AKI.Our findings suggest that serum CRP and uRBP/Cr may help to differentiate AKI due to ICI from other causes.© 2021 International Society of Nephrology. Published by Elsevier Inc.

Obese and overweight body mass index (BMI) categories have been associated with increased immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metabolic syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs.We conducted a retrospective observational study of patients receiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabolic disease risk category: (1) normal weight (BMI 18.5-24.9 kg/m)/low metabolic risk (<2 metabolic diseases [diabetes, dyslipidemia, hypertension]), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥25 kg/m)/low metabolic risk, and (4) overweight/high metabolic risk.Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was significantly associated with ≥grade 2 irAEs (hazard ratio [HR]: 2.0, 95% confidence interval [95% CI]: 1.2-3.4) when compared to normal weight/low metabolic risk, while overweight/high metabolic risk (HR: 1.3, 95% CI: 0.7-2.2) and normal weight/high metabolic risk (HR: 1.5, 95% CI: 0.7-3.0) were not.Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in the context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment since their introduction ∼15 years ago. However, these monoclonal antibodies are associated with immune-related adverse events that can also affect the kidney, resulting in acute kidney injury (AKI), which is most commonly due to acute tubulointerstitial nephritis (ATIN). Limited data are available on the true occurrence of ICI-associated AKI. Furthermore, evidence to guide the optimal management of ICI-associated AKI in clinical practice is lacking. In this issue, Oleas report a single-center study of patients with nonhematologic malignancies who received ICI treatment during a 14-month period, experienced AKI and underwent a kidney biopsy at the Vall d'Hebron University Hospital. Importantly, they demonstrate that only a minority of ICI-associated AKI patients was referred to the nephrology service and kidney biopsy was only performed in 6.4% of patients. Although the authors add to our knowledge about ICI-associated AKI, their article also highlights the need for the development of noninvasive diagnostic markers for ICI-associated ATIN, the establishment of treatment protocols for ICI-associated ATIN and recommendations for optimal ICI rechallenge in patients with previous ICI-associated AKI.© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.

Acute interstitial nephritis is an immune-related adverse event that can occur in patients receiving immune checkpoint inhibitor therapy. Differentiating checkpoint inhibitor-associated acute interstitial nephritis from other causes of acute kidney injury in patients with cancer is challenging and can lead to diagnostic delays and/or unwarranted immunosuppression. In this case report, we assess the use of F-flourodeoxyglucose positron-emission tomography imaging as an alternative diagnostic modality in the evaluation of potential acute interstitial nephritis.A 55-year-old woman with metastatic vulvar melanoma underwent treatment with two cycles of ipilimumab plus nivolumab, followed by seven cycles of nivolumab combined with radiation therapy. During her treatment, she developed non-oliguric acute kidney injury to a creatinine of 4.5 mg/dL from a baseline of 0.5 mg/dL. A clinical diagnosis of acute interstitial nephritis was made, and steroids were initiated, with rapid improvement of her acute kidney injury. Retrospectively, four positron-emission tomography scans obtained for cancer staging purposes were reviewed. We found a markedly increased F-flourodeoxyglucose uptake in the renal cortex at the time acute interstitial nephritis was diagnosed compared to baseline. In three cases of acute kidney injury due to alternative causes there was no increase in F-flourodeoxyglucose uptake from baseline.To our knowledge, this is the first report describing increased F-flourodeoxyglucose uptake in the renal cortex in a patient with checkpoint inhibitor-associated acute interstitial nephritis. Our findings suggest that F-flourodeoxyglucose positron-emission tomography may be a valuable test for diagnosing immune-mediated nephritis, particularly in patients where timely kidney biopsy is not feasible.

Immune checkpoint inhibitors (ICIs) are nowadays widely used in clinical oncology treatment, and significantly improve the prognosis of cancer patients. However, overactivation of T cells and related signaling pathways caused by ICIs can also induce immune-related adverse effects (irAEs). Renal immune side-effects are relatively rare, but some are serious and fatal. Acute kidney injury (AKI), diagnosed mainly by percentage increases in serum creatinine (sCr), is the most common clinical manifestation, while acute tubulointerstitial nephritis (ATIN) is the main cause of ICI-related AKI. Urinalysis analysis and sediment evaluation, 24 hour urine protein and sCr are helpful in screening and monitoring renal irAEs. Multiple potential causes for AKI are involved during cancer therapy, and should be differentiated from the immune mechanisms of ICIs. Under these circumstances, a renal biopsy should be considered which is essential for clinical decision-making. Steroids are an effective treatment option for renal irAEs. Most patients who experience ICI-related ATIN achieve a partial or complete renal recovery with prompt diagnosis and treatment. Multidisciplinary collaborations of different specialists will improve the effectiveness and outcome in the management of ICI irAEs.© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF).We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival.Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids.IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.© 2015 by American Society of Clinical Oncology.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies directed at negative regulatory components on T cells, such as cytotoxic T lymphocyte-associated antigen 4, programmed cell death-1 (PD-1), and its ligand, programmed cell death ligand-1. ICIs initate antitumor immunity; however, these agents are associated with immune-related adverse events (irAEs) that may affect a variety of organs. Renal irAEs most commonly present with asymptomatic acute kidney injury (AKI), which is often detected by routine laboratory testing. The severity of AKI associated with irAEs ranges from mild (grade 1-2) to severe (grade 3-4). It is often challenging to diagnose because this group of patients often have multiple reasons to have AKI (dehydration, sepsis, or nephrotoxic medication exposure). We present an illustrative case of a 60-year-old man with metastatic melanoma who presented with AKI during treatment with nivolumab and review the literature to address frequently asked questions concerning the diagnosis and management of renal irAEs in patients with advanced cancer. Importantly, most patients will recover completely, and some may tolerate a rechallenge of ICI therapy, with prompt and effective treatment. KEY POINTS: Renal immune-related adverse events (irAEs) are less frequently reported than other irAEs; however, it is possible that available data underestimate their true incidence because of missed diagnoses and under-reporting. Although severe renal irAEs are more easily detected, smaller rises in creatinine may not be appreciated or may be attributed to other causes, because the differential diagnosis of acute kidney injury (AKI) in patients with cancer is broad.Baseline creatinine should be established prior to beginning immune checkpoint inhibitorss (ICIs), and it should be monitored with every cycle. If a patient develops AKI, the ICI should be held while the evaluation is pursued. A thorough workup of suspected renal irAEs must exclude other potential causes of AKI such as infection, dehydration, urinary tract obstruction, and nephrotoxin exposure.Acute kidney injury after ICI therapy does not appear to be more common in patients with baseline estimated glomerular filtration rate <60 mL per min per 1.73 m. One particular concern, however, is that those with baseline renal disease have less "renal reserve," and repeated AKI events may push a patient closer to end-stage renal disease. Thus, clinicians must exert caution when rechallenging patients with pre-existing renal disease with ICI therapy in the event of a prior AKI from ICI-related allergic interstitial nephritis.© AlphaMed Press 2019.

Immune checkpoint inhibitors have dramatically improved cancer therapy for many patients. These humanized monoclonal antibodies against various immune checkpoints (receptors and ligands) effectively treat a number of malignancies by unleashing the immune system to destroy cancer cells. These drugs are not excreted by the kidneys or liver, have a long half-life, and undergo receptor-mediated clearance. Although these agents have greatly improved the prognosis of many cancers, immune-related end organ injury is a complication that has come to light in clinical practice. Although less common than other organ involvement, kidney lesions resulting in acute kidney injury and/or proteinuria are being described. Acute tubulointerstitial nephritis is the most common lesion seen on kidney biopsy, while acute tubular injury and glomerular lesions occur less commonly. Clinical findings and laboratory tests are suboptimal in predicting the underlying renal lesion, making kidney biopsy necessary in the majority of cases to definitely diagnose the lesion and potentially guide therapy. Immune checkpoint inhibitor discontinuation and corticosteroid therapy are recommended for acute tubulointerstitial nephritis. Based on a handful of cases, re-exposure to these drugs in patients who previously developed acute tubulointerstitial nephritis has been mixed. Although it is unclear whether re-exposure is appropriate, it should perhaps be considered in patients with limited options. When this approach is taken, patients should be closely monitored for recurrence of acute kidney injury. Treatment of cancer in patients with a kidney transplant with immune checkpoint inhibitors risks the development of acute rejection in some patients and requires close surveillance.Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.