Clinical Features Associated with Immune Checkpoint Inhibitor Nephritis: A Single-Center Clinical Case Series

Clinical Features Associated with Immune Checkpoint Inhibitor Nephritis: A Single-Center Clinical Case Series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Clinical Features Associated with Immune Checkpoint Inhibitor Nephritis: A Single-Center Clinical Case Series Ramya Muddasani, Neel Talwar, Isa Mambetsariev, Jeremy Fricke, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3874048/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Aug, 2024 Read the published version in Cancer Immunology, Immunotherapy → Version 1 posted 9 You are reading this latest preprint version Abstract Background Acute kidney injury (AKI) has been well described as a complication of immune checkpoint inhibitor therapy. We present a series of patients, the majority with lung adenocarcinoma, who developed AKI while actively receiving immune checkpoint inhibitors. Methods This is a retrospectively analyzed clinical case series of six patients treated at City of Hope Comprehensive Cancer Center. Data was collected on gender, age, ethnicity, comorbidities, concomitant medications, type of malignancy, treatments, and renal function. All patients underwent renal biopsy for classification of the mechanism of AKI. Comprehensive genomic profiling (CGP) was performed on tumor tissue for all patients. Results Patterns of AKI included acute interstitial nephritis and acute tubular necrosis. Contributing factors included the use of concomitant medications known to contribute to AKI. All but two patients had full resolution of the AKI with the use of steroids. There were several mutations found on CGP that were notable including an Exon 20 insertion as well as multiple NF1 and TP53 mutations. There was high PD-L1 expression on tumor tissue noted in two out of six patients. In addition to AKI, a subset of patients had proteinuria with biopsies revealing corresponding glomerular lesions of minimal change disease and focal and segmental glomerulosclerosis. Conclusions Our case series demonstrates that AKI from immune checkpoint inhibitors has a variable presentation that may require an individualized treatment approach. Further studies are needed to identify biomarkers that may help identify those at risk and guide the management of this condition. Checkpoint Immunotherapy Nephritis Pembrolizumab Nivolumab Steroids AKI Renal biopsy Figures Figure 1 Figure 2 Figure 3 Introduction Immune checkpoint inhibitors (ICI) have emerged as a practice-changing treatment approach for patients with advanced solid tumor malignancies, but serious immune-related side effects (IRAEs) can occur which may hinder the ability to continue treatment in a subset of patients. An increasingly recognized IRAE is ICI-induced renal failure [ 1 – 3 ]. ICIs function by inhibiting the immune system's breakpoints leading to immune activation against cancer cells. However, this immune activation can also lead to unwanted side effects due to inflammation of healthy tissues. In this scenario, the immune system attacks the renals which can lead to renal failure which can manifest in various histopathologic fashions some of which include acute interstitial nephritis, acute tubular necrosis (ATN), glomerulonephritis, and renal vascular toxicity [ 4 ]. These conditions can impair the renal's ability to filter, maintain electrolyte balance, and regulate fluid levels in the body. Consequently, patients may experience symptoms of renal failure including decreased urine output, swelling, fatigue, electrolyte imbalances, and elevated creatinine levels. Understanding the mechanisms underlying ICI-induced renal failure is essential for early recognition and appropriate management of this adverse event. Although ICI-induced renal failure is a concerning side effect, it is important to note that only a small percentage of those who receive immunotherapy will experience renal toxicity ([ 5 , 6 ]. Risk factors for developing renal complications are still being investigated, including pre-existing renal conditions, concomitant use of other medications, and individual patient characteristics. Ongoing research aims to identify predictive biomarkers and refine treatment protocols to minimize the occurrence of renal toxicity and improve patient safety. Recognizing and managing ICI-induced renal failure is crucial for providing comprehensive care to cancer patients receiving immunotherapy. Our case series aims to advance our understanding of the risk factors associated with ICI-induced renal failure such that we can enhance patient safety and optimize treatment outcomes. In this study, we discuss a series of cases including patients with various solid malignancies treated with immunotherapy who subsequently developed IO-induced acute kidney injury (AKI). Materials and Methods This is a retrospective study of patients with solid organ malignancies treated with ICIs at City of Hope Comprehensive Cancer Center. Data was collected on fourteen patients with AKI who had received ICIs from August 2017 to December 2022. Six of the fourteen underwent renal biopsies due to suspected ICI-induced renal failure. Subsequent data collection included gender, age, ethnicity, comorbidities, concomitant medications [with an emphasis on medications known to contribute to AKI i.e. non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), antibiotics, and angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers], type of malignancy, series of oncologic treatments, baseline renal function, stage of AKI upon presentation and time to resolution. All data collected was approved by the City of Hope Comprehensive Cancer Center Institutional Review Board (IRB #20289). All patients included underwent renal biopsies which were analyzed by the Renal Pathology division at Cedars-Sinai Medical Center, department of Pathology and Laboratory Medicine. Biopsy cores were obtained under ultrasound guidance using a 16-gauge needle. Renal biopsies were evaluated by subspeciality fellowship-trained and board-certified renal pathologists and studies included light microscopy (hematoxylin and eosin, Jones' silver, periodic acid-Schiff and Masson’s trichrome stained sections), immunofluorescence microscopy (stained with fluoresceinated antisera to human IgG, IgA, IgM, C1q, C3, albumin, fibrin and kappa and lambda immunoglobulin light chains), and ultrastructural examination by electron microscopy. The degree of tubulointerstitial scarring in the renal cortex were graded as minimal (less than 10%), mild (10 to 25%), moderate (26 to 50%), and severe (more than 50%). Results Demographics/Clinical Characteristics The male to female ratio was 1:6 and the median age was 65 years. Five out of six patients (83%) had concomitant PPI use, five out of six (83%) patients were receiving antibiotics, and two out of six (33%) were on NSAIDs. Five of the six (83%) patients in our series were diagnosed with metastatic lung cancer, with the remaining patient (17%) diagnosed with endometrial adenocarcinoma. Two patients (33%) had previously received other types of oncological treatment without remission. For four patients (67%), ICIs represented the first line of oncologic treatment. The ICI therapies used were: pembrolizumab monotherapy (33%), pembrolizumab in combination with chemotherapy or TKI (50%), and dual-checkpoint inhibitor therapy with ipilimumab and nivolumab (17%). Acute kidney injury Five out of six patients (83%) had a normal baseline renal function. The time between the ICI administration and the presentation of renal disease ranged from two weeks to eleven months with a median onset of two months. We assessed renal injury using the Acute Kidney Injury Network Criteria (AKIN). Three patients (50%) met AKIN Stage 3 criteria and the others presented with Stage 1 (17%) and Stage 2 (33%). There were various patterns of renal injury noted. Four out of six patients (67%) had tubulointerstitial nephritis with concomitant acute tubular necrosis (ATN), one out of six patients (17%) had acute tubular injury (ATI)/ATN and minimal change disease (MCD), and one out of six patients (17%) had acute tubular injury and focal and segmental glomerulosclerosis ( Table 1 ). Treatment of Renal Injury For five of the six patients (83%) initial line of treatment for ICI induced-AKI included steroids of some form. However, one patient (17%; case 6) diagnosed with renal injury in the form of ATN and MCD was unable to tolerate steroids due to a prior history of steroid-induced psychosis as such she was started directly on tacrolimus. For the patient (case 3) with FSGS and ATI/ATN, it is important to note that steroid therapy was initiated approximately 1 week prior to the biopy. Of these patients, four (66%) had a full recovery, while one patient (17%) had a partial recovery, and one patient (17%) required ongoing hemodialysis. All patients required cessation of ICI treatment after the diagnosis of AKI and none were re-challenged. Comprehensive Genomic Profiling All six patients had comprehensive genomic profiling (CGP) performed on pathologic tumor specimens. Of these six patients, one (17%) presented with an actionable alteration specifically an EGFR exon 20 insertion. Three out of six patients (50%) harbored TP53 mutations in their tumor and two out of six patients (33%) exhibited NF1 mutations. Two out of six (33%) of patients had High PD-L1 expression (> 50%). Tumor mutational burden (TMB) was evaluable in three out of six patients. 2 out of 3 patients (67%) had low TMB while 1 out of 3 had intermediate TMB (33%). Microsatellite stability status (MSS) was available in all patients and all patients were noted to have tumors that were MSI-low. There were several other co-mutations present on CGP, which have been summarized in Table 2 . Case Summaries: Case #1 A 71-year-old female with Stage IV adenocarcinoma of the lung started on carboplatin/ pemetrexed/pembrolizumab developed stage 3 AKIN eleven months after treatment at which time the patient was on pemetrexed/pembrolizumab maintenance. Baseline creatinine was 0.75 mg/dL which increased to 4.35 mg/dL. Notable concurrent medications included lisinopril and antibiotics. A renal biopsy showed active tubulointerstitial nephritis, acute tubular necrosis, and arterial nephrosclerosis. Glomerular disease and thrombotic microangiopathy were not identified. There was mild tubulointerstitial scarring (Fig. 1). Notable concurrent medications included lisinopril and antibiotics. The AKI was treated with 500 mg IV methylprednisolone daily over 3 days followed by 60 mg IV daily. The patient also required a short course of hemodialysis followed by a two-week course of high-dose steroids with improvement in renal function. She was subsequently placed on a prednisone taper with full resolution of renal injury within three months. ICI therapy was permanently discontinued due to degree of renal injury. Case #2 A 60-year-old female with Stage IV adenocarcinoma of the lung started on carboplatin/pemetrexed/pembrolizumab developed stage 2 AKIN four months after treatment at which time she was on maintenance pemetrexed/pembrolizumab. Other notable factors include concomitant pantoprazole usage. Her baseline creatinine was 0.61 mg/dL which increased to a peak of 2.92 mg/dL. Renal biopsy revealed acute tubulointerstitial nephritis and acute tubular necrosis. There was also an incidental detection of segmentally thinned glomerular capillary basement membranes. Thrombotic microangiopathy was not identified. There was minimal tubulointerstitial scarring (Fig. 1). AKI was treated with prednisone 40 mg and started upon diagnosis with a subsequent slow taper with full resolution after two months. ICI therapy was permanently discontinued given renal injury. Case #3 A 55-year-old female with Stage IV endometrioid uterine carcinoma was started on second-line systemic therapy with pembrolizumab and lenvatinib developed Stage 1 AKIN one month after treatment. Concurrent medications included omeprazole and antibiotic usage. Her baseline creatinine 0.77 mg/dL which subsequently increased to 1.37 mg/dL. She was noted to have 3 + proteinuria. A renal biopsy performed one week after initiaition of prednisone revealed histologically mild acute tubular injury/acute tubular necrosis and focal and segmental glomerulosclerosis. Acute tubulointerstitial nephritis and thrombotic microangiopathy were not identified. There was minimal tubulointerstital scarring (Fig. 2 ) . AKI was treated with prednisone 1 mg/kg daily with subsequent taper and full resolution within two weeks of treatment. Furthermore, her proteinuria resolved approximately 3 months after initiation of prednisone therapy. Although the FSGS was accompanied by a partial degree of podocyte foot process effacement, this likely reflects partial restoration of podocyte foot process morphology attributed to initiation of steroid therapy prior to the biopsy. Pembrolizumab was discontinued due to renal failure. Case #4 A 69-year-old male with stage IV lung adenocarcinoma with high PD-L1 expression (90%) treated with pembrolizumab monotherapy developed stage 3 AKIN one month after treatment. Concomitant notable medications include pantoprazole, NSAID usage, and antibiotics. Her baseline creatinine was 0.88 mg/dL, and rose to 7.75 mg/dL. Renal biopsy was suboptimal due to scant sampling of renal cortex. Nonetheless, acute tubular necrosis and focal acute interstitial nephritis were detected and moreover electron microscopy study revealed subendothelial immune complex-type deposits in glomeruli which could not be further characterized due to inadequate immunofluorescence microscopy specimen. Due to scant renal cortical sampling, the degree of tubulointerstitial scarring cannot be assessed (Fig. 2). AKI was treated with 1 mg/kg IV methylprednisolone followed by an oral prednisone taper with no significant recovery. The patient remained on hemodialysis. ICI re-challenege was not attempted due to toxicity. Case #5 A 61-year-old female with stage IV lung adenocarcinoma with a high PD-L1 expression (80%) treated with pembrolizumab monotherapy developed stage 3 AKIN three months after treatment. Notable concurrent medications including pantoprazole and antibiotic usage. Baseline creatinine was 0.83 mg/dL which subsequently increased to 4.48 mg/dL. Her renal biopsy showed acute tubulointerstitial nephritis, acute tubular necrosis, mild arteriosclerosis, and mild arteriolosclerosis. Glomerular disease and thrombotic microangiopathy were not identified. There was minimal renal tubulointerstitial scarring (Fig. 3). AKI was treated with high-dose prednisone at 1 mg/kg with a subsequent taper with full resolution after five months. ICI re-challenge was not attempted due to degree of renal injury. Case #6 A 75-year-old female with stage IV adenocarcinoma of the lung with low PD-L1 expression (1%) and an EGFR Exon 20 insertion and pre-existing stage III chronic renal disease secondary to diabetes mellitus was started on third-line systemic therapy with nivolumab/ipilimumab and developed Stage 2 AKIN after 1 cycle of treatment. Concomitant medication use included antibiotics. Baseline creatinine was 1.40 mg/dL, which increased to 3.7 mg/dL. She also developed nephrotic syndrome with urine protein-to-creatinine ratio of more than 28. Her renal biopsy reveals the presence of minimal change disease, mild diabetic glomerulosclerosis, acute tubular injury, mild arteriosclerosis, and mild arteriolosclerosis. There was moderate tubulointerstitial scarring. Acute tubulointerstitial nephritis and thrombotic microangiopathy were not identified. Due to prior steroid-induced psychosis, she was started on tactolimus therapy and subsequently developed partial response. Her proteinuria improved on spot urine testing from 2,000 mg/dL to 600 mg/dL after 4 weeks on therapy. She did not require hemodialysis, but creatinine remained elevated. She was eventually transferred to hospice care due to declining health. Discussion AKI is increasingly being recognized as a potential complication for patients on ICI therapy [ 3 , 7 ]. Our case series shows that the clinical manifestations and underlying mechanisms of renal failure in these patients can vary considerably. Some patients may develop a mild rise in creatinine after starting ICIs that may not require any therapeutic intervention or cessation of treatment. Alternatively, others may present with rapidly evolving renal failure requiring the start of renal replacement therapy. Mechanisms of renal injury can include acute interstitial nephritis, acute tubular necrosis, and nephrotic syndrome (such as FSGS or MCD) [ 8 – 10 ]. Risk factors can include pre-existing renal failure due to co-morbidities (diabetes mellitus and hypertension) and chemotherapy-induced nephrotoxicity from agents such as cisplatin and pemetrexed. We also show that a significant percentage of patients that develop renal injury while on ICIs are on concomitant medications, specifically PPIs, NSAIDs, and antibiotics. There does not seem to be a predictable time to onset of renal injury after starting ICI therapy as some of our patients developed nephritis after just one cycle of therapy, while others were on therapy for nearly a year before manifesting with AKI. Furthermore, the single patient (case #6) whose serum creatinine remained elevated also had the most abundant pre-existing tubulointerstitial scarring in this case series. Although her negative outcome is confounded by her receiving tacrolimus instead of steroids (due to clinical contraindication), the patient's underlying chronic kidney disease (i.e. tubulointerstitial scarring) likely plays a significant role. Given the variable presentation of ICI-induced nephritis, treatment to prevent complications may need to be individualized. Moreover, patients with known history chronic kidney disease should be closely monitored for ICI therapy-related AKI given the potential for worse outcome. Management of ICI-induced renal failure requires a multidisciplinary approach. In addition to discontinuation or interruption of ICI therapy, first-line therapy with steroids (I.e., prednisone 0.5 to 1 mg/kg/day) remains the mainstay of treatment for most patients with ICI-related renal failure [ 8 , 11 , 12 ]. Exceptions include those who may be unable to tolerate long-term steroid taper due to side effects or underlying co-morbidities. Although steroid therapy results in significant clinical recovery in most patients with ICI-induced nephritis, there is still a significant rate of persistent renal failure, and patients may remain on renal replacement therapy long term. In those with nephritis refractory to steroids, renal biopsy may be indicated to confirm there is no alternative etiology that may be contributing to renal injury. Histopathologic findings may help guide management, which may include cessation of another offending agent, increase in steroid dosing, or additional immunosuppressant therapy (such as tacrolimus, mycophenolate, or infliximab). The use of immunosuppressant agents may help reverse renal injury and help avoid hemodialysis as seen in our patient with ICI-related minimal change disease described above. The prompt recognition and treatment of ICI-related renal injury is essential to achieving optimal recovery of renal function. Many patients may have an ongoing response to immunotherapy at the time that ICI-related AKI develops. This can cause a conundrum, as several patients will not have alternative effective treatment options available for the treatment of their advanced malignancy. ICI re-challenge may play a role in those who have developed renal failure and subsequently recovered. Given the risk of perpetuating renal damage as well as other IRAEs, a multidisciplinary discussion between oncology and nephrology would be recommended before proceeding with rechallenge in patients with grade 2 or greater nephrotoxicity. The role of continuing low-dose steroids (prednisone 10 mg or less) with re-challenge has been shown to be successful in patients' other immune adverse events such as ICI-related liver injury and may also be a potential strategy for reducing re-aggravation of renal injury in patients undergoing rechallenge [ 13 ]. Despite the break in treatment, significant overall survival and real-world progression-free survival benefits were shown in lung cancer patients who developed an IRAE [ 14 , 15 ] Of the two patients (cases #3 and #6) who had concomitant proteinuria, the patient (case #3) with FSGS had subsequent resolution of proteinuria after receiving steroid therapy. For the second patient (case #6), her severe proteinuria was due to MCD. She was started on tacrolimus with partial response (> 50% improvement in proteinuria from > 2,000 mg/dL to 600 mg/dl on spot urine protein testing), but no significant improvement in creatinine. It was unfortunate that the patient in case #6 with proteinuria, who fell within the small subset (approximately 10%) of patients with MCD, did not have a robust response to tacrolimus therapy. In this case series, these two proteinuric patients and microanatomic glomerular lesions of FSGS and MCD are best classified as paraneoplastic glomerular diseases [ 16 ]. Our aim in gathering CGP-based alterations was to check for possible associations with the occurrence of IRAEs. Evaluation of tumor tissue on Case #6 revealed an exon 20 insertion which can be treated with FDA approved target therapies. However, this patient had severe complications from ICI related renal injury that prevented the patient from starting targeted therapy. This highlights the important of utilizing CGP results for optimal therapy selection. Remaining mutational analysis did show multiple patients with TP53 and NF1 mutations, but these mutations are extremely common across the spectrum of malignancies and are unlikely to be predictive of ICI related toxicities. There was no other co-mutations noted on CGP that appeared to correlate to the development of ICI related AKI. PD-L1 expression on tumor samples was high in two out of six patients, but low in the remaining four patients. TMB was only evaluable in three patients, none of which were TMB high. All six patients were noted to be microsatellite stable. Given the limited number of patients analyzed in our study, we were not able to significantly associate any CGP mutations, level of PD-L1 expression, TMB status, or MSS status with ICI-related renal injury. Germline analysis may be of benefit in determining patients predisposed to AKI from ICIs [ 17 ]. In addition, PD-L1 testing on renal biopsy specimens may be of clinical utility [ 18 , 19 ]. In conclusion, ICI-related AKI should be recognized as a potential side effect of both single-agent and dual checkpoint inhibitor therapy. A high degree of clinical suspicion is required to ensure early diagnosis and treatment to help improve outcomes. In addition to renal tubulointerstitial diseases, there may also be concomitant glomerular and extraglomerular vascular diseases. However, thrombotic microangiopathies are not detected in our small case series. Close monitoring of blood work including BUN/Cr and urine studies to detect evolving proteinuria can help determine which patients may be developing this rare complication. A renal biopsy can be a useful tool in determining the mechanism of renal failure and can help guide treatment [ 20 ]. Escalation of treatment to higher doses of steroids or immunosuppressants should be initiated within one week in those patients who may be refractory to initial therapy [ 11 ]. More research into potential predictive biomarkers and clinical experience is needed to determine which patients may be at higher risk for ICI-related renal injury. Declarations Author Contribution R.S., R.M. and N.T. wrote the main manuscriptI.M, J.F. assisted with data collection and preparing figures and tablesM.L., A.Y. and A.R. assisted with the pathology review of each case and providing a nephrology perspective for the paper.All authors reviewed the manuscript. References Perazella MA, Sprangers B (2019) AKI in Patients Receiving Immune Checkpoint Inhibitors. CJASN 14:1077–1079. https://doi.org/10.2215/CJN.02340219 Herrmann SM, Perazella MA (2020) Immune Checkpoint Inhibitors and Immune-Related Adverse Renal Events. 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Cancers (Basel) 14:302. https://doi.org/10.3390/cancers14020302 Les I, Martínez M, Pérez-Francisco I, Cabero M, Teijeira L, Arrazubi V et al (2023) Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events. Cancers (Basel) 15:1629. https://doi.org/10.3390/cancers15051629 Isik B, Alexander MP, Manohar S, Vaughan L, Kottschade L, Markovic S et al (2021) Biomarkers, Clinical Features, and Rechallenge for Immune Checkpoint Inhibitor Renal Immune-Related Adverse Events. Ren Int Rep 6:1022–1031. https://doi.org/10.1016/j.ekir.2021.01.013 Perazella MA (2020) Renal Biopsy Should Be Performed to Document the Cause of Immune Checkpoint Inhibitor–Associated Acute kidney injury: Commentary. Renal360 1:166–168. https://doi.org/10.34067/KID.0001072019 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1AKI.jpg Table2AKI.jpg Cite Share Download PDF Status: Published Journal Publication published 06 Aug, 2024 Read the published version in Cancer Immunology, Immunotherapy → Version 1 posted Editorial decision: Revision requested 02 May, 2024 Reviews received at journal 29 Apr, 2024 Reviewers agreed at journal 18 Apr, 2024 Reviews received at journal 21 Mar, 2024 Reviewers agreed at journal 20 Mar, 2024 Reviewers invited by journal 23 Jan, 2024 Editor assigned by journal 23 Jan, 2024 Submission checks completed at journal 17 Jan, 2024 First submitted to journal 17 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Center","correspondingAuthor":false,"prefix":"","firstName":"Amna","middleName":"","lastName":"Rizvi","suffix":""},{"id":267749135,"identity":"56f85ac2-4011-40a9-b0ae-1dff4e7c7940","order_by":8,"name":"Ravi Salgia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYHACxgMMBgxyDAw8JOgBaTEmVQsDQ2ID0VrM+w8/OPilwC69v733AMPHPbWEtcjcSDM4LGOQnDvjzLkExhnPjhPWIiHBYHBYwoA5d4NEjgEzz4FjRGjhP/4BqKU+3YB4LQw5Bgc/GBxOgGqpIcZhOQWHGQyOG844c8bg4IwDB4hy2MaHP/5Uy/O39xg++HCgjrAWEGCGxQjQisPEaWH8gWATacsoGAWjYBSMKAAAFS07pDQDJe0AAAAASUVORK5CYII=","orcid":"","institution":"City Of Hope National Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Ravi","middleName":"","lastName":"Salgia","suffix":""}],"badges":[],"createdAt":"2024-01-17 23:29:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3874048/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3874048/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00262-024-03775-6","type":"published","date":"2024-08-06T15:57:49+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49975589,"identity":"341fbe50-7c1d-4846-b062-588e6a10415e","added_by":"auto","created_at":"2024-01-22 14:47:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":221834,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Figure1AKI.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3874048/v1/704fa73e9b9e8f2fd5ca6c79.jpg"},{"id":49975588,"identity":"39714f66-0b6c-4676-9f74-30213d53b503","added_by":"auto","created_at":"2024-01-22 14:47:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":76376,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Figure2AKI.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3874048/v1/f86af7ed38480cea07a476fb.jpg"},{"id":49975586,"identity":"aaa68ded-7d52-4227-a66a-7517f83f348c","added_by":"auto","created_at":"2024-01-22 14:47:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":152647,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Figure3AKI.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3874048/v1/8abf5445673565c4c1368de1.jpg"},{"id":62298796,"identity":"975797b1-938e-4336-9261-f8f52cabfd02","added_by":"auto","created_at":"2024-08-12 16:16:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":772896,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3874048/v1/d0eb0ca8-8640-46a7-8ef2-0e79f2aeb4d3.pdf"},{"id":49977532,"identity":"b56e37d3-0a74-4f94-b21a-b72220d84923","added_by":"auto","created_at":"2024-01-22 14:55:35","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":113466,"visible":true,"origin":"","legend":"","description":"","filename":"Table1AKI.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3874048/v1/bdbdc81e180f3903ca25564c.jpg"},{"id":49975585,"identity":"e32d1f0c-fe17-489c-91d9-90d014f3eecd","added_by":"auto","created_at":"2024-01-22 14:47:35","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":119084,"visible":true,"origin":"","legend":"","description":"","filename":"Table2AKI.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3874048/v1/25d0ae4681ccbbc6bec1c02e.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Features Associated with Immune Checkpoint Inhibitor Nephritis: A Single-Center Clinical Case Series","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors (ICI) have emerged as a practice-changing treatment approach for patients with advanced solid tumor malignancies, but serious immune-related side effects (IRAEs) can occur which may hinder the ability to continue treatment in a subset of patients. An increasingly recognized IRAE is ICI-induced renal failure [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. ICIs function by inhibiting the immune system's breakpoints leading to immune activation against cancer cells. However, this immune activation can also lead to unwanted side effects due to inflammation of healthy tissues. In this scenario, the immune system attacks the renals which can lead to renal failure which can manifest in various histopathologic fashions some of which include acute interstitial nephritis, acute tubular necrosis (ATN), glomerulonephritis, and renal vascular toxicity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These conditions can impair the renal's ability to filter, maintain electrolyte balance, and regulate fluid levels in the body. Consequently, patients may experience symptoms of renal failure including decreased urine output, swelling, fatigue, electrolyte imbalances, and elevated creatinine levels. Understanding the mechanisms underlying ICI-induced renal failure is essential for early recognition and appropriate management of this adverse event.\u003c/p\u003e \u003cp\u003eAlthough ICI-induced renal failure is a concerning side effect, it is important to note that only a small percentage of those who receive immunotherapy will experience renal toxicity ([\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Risk factors for developing renal complications are still being investigated, including pre-existing renal conditions, concomitant use of other medications, and individual patient characteristics. Ongoing research aims to identify predictive biomarkers and refine treatment protocols to minimize the occurrence of renal toxicity and improve patient safety.\u003c/p\u003e \u003cp\u003eRecognizing and managing ICI-induced renal failure is crucial for providing comprehensive care to cancer patients receiving immunotherapy. Our case series aims to advance our understanding of the risk factors associated with ICI-induced renal failure such that we can enhance patient safety and optimize treatment outcomes. In this study, we discuss a series of cases including patients with various solid malignancies treated with immunotherapy who subsequently developed IO-induced acute kidney injury (AKI).\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis is a retrospective study of patients with solid organ malignancies treated with ICIs at City of Hope Comprehensive Cancer Center. Data was collected on fourteen patients with AKI who had received ICIs from August 2017 to December 2022. Six of the fourteen underwent renal biopsies due to suspected ICI-induced renal failure. Subsequent data collection included gender, age, ethnicity, comorbidities, concomitant medications [with an emphasis on medications known to contribute to AKI i.e. non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), antibiotics, and angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers], type of malignancy, series of oncologic treatments, baseline renal function, stage of AKI upon presentation and time to resolution. All data collected was approved by the City of Hope Comprehensive Cancer Center Institutional Review Board (IRB #20289).\u003c/p\u003e \u003cp\u003eAll patients included underwent renal biopsies which were analyzed by the Renal Pathology division at Cedars-Sinai Medical Center, department of Pathology and Laboratory Medicine. Biopsy cores were obtained under ultrasound guidance using a 16-gauge needle. Renal biopsies were evaluated by subspeciality fellowship-trained and board-certified renal pathologists and studies included light microscopy (hematoxylin and eosin, Jones' silver, periodic acid-Schiff and Masson\u0026rsquo;s trichrome stained sections), immunofluorescence microscopy (stained with fluoresceinated antisera to human IgG, IgA, IgM, C1q, C3, albumin, fibrin and kappa and lambda immunoglobulin light chains), and ultrastructural examination by electron microscopy. The degree of tubulointerstitial scarring in the renal cortex were graded as minimal (less than 10%), mild (10 to 25%), moderate (26 to 50%), and severe (more than 50%).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDemographics/Clinical Characteristics\u003c/h2\u003e \u003cp\u003eThe male to female ratio was 1:6 and the median age was 65 years. Five out of six patients (83%) had concomitant PPI use, five out of six (83%) patients were receiving antibiotics, and two out of six (33%) were on NSAIDs. Five of the six (83%) patients in our series were diagnosed with metastatic lung cancer, with the remaining patient (17%) diagnosed with endometrial adenocarcinoma. Two patients (33%) had previously received other types of oncological treatment without remission. For four patients (67%), ICIs represented the first line of oncologic treatment. The ICI therapies used were: pembrolizumab monotherapy (33%), pembrolizumab in combination with chemotherapy or TKI (50%), and dual-checkpoint inhibitor therapy with ipilimumab and nivolumab (17%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAcute kidney injury\u003c/h2\u003e \u003cp\u003eFive out of six patients (83%) had a normal baseline renal function. The time between the ICI administration and the presentation of renal disease ranged from two weeks to eleven months with a median onset of two months. We assessed renal injury using the Acute Kidney Injury Network Criteria (AKIN). Three patients (50%) met AKIN Stage 3 criteria and the others presented with Stage 1 (17%) and Stage 2 (33%). There were various patterns of renal injury noted. Four out of six patients (67%) had tubulointerstitial nephritis with concomitant acute tubular necrosis (ATN), one out of six patients (17%) had acute tubular injury (ATI)/ATN and minimal change disease (MCD), and one out of six patients (17%) had acute tubular injury and focal and segmental glomerulosclerosis (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eTreatment of Renal Injury\u003c/h2\u003e \u003cp\u003eFor five of the six patients (83%) initial line of treatment for ICI induced-AKI included steroids of some form. However, one patient (17%; case 6) diagnosed with renal injury in the form of ATN and MCD was unable to tolerate steroids due to a prior history of steroid-induced psychosis as such she was started directly on tacrolimus. For the patient (case 3) with FSGS and ATI/ATN, it is important to note that steroid therapy was initiated approximately 1 week prior to the biopy. Of these patients, four (66%) had a full recovery, while one patient (17%) had a partial recovery, and one patient (17%) required ongoing hemodialysis. All patients required cessation of ICI treatment after the diagnosis of AKI and none were re-challenged.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eComprehensive Genomic Profiling\u003c/h2\u003e \u003cp\u003eAll six patients had comprehensive genomic profiling (CGP) performed on pathologic tumor specimens. Of these six patients, one (17%) presented with an actionable alteration specifically an EGFR exon 20 insertion. Three out of six patients (50%) harbored TP53 mutations in their tumor and two out of six patients (33%) exhibited NF1 mutations. Two out of six (33%) of patients had High PD-L1 expression (\u0026gt;\u0026thinsp;50%). Tumor mutational burden (TMB) was evaluable in three out of six patients. 2 out of 3 patients (67%) had low TMB while 1 out of 3 had intermediate TMB (33%). Microsatellite stability status (MSS) was available in all patients and all patients were noted to have tumors that were MSI-low. There were several other co-mutations present on CGP, which have been summarized in \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCase Summaries:\u003c/h2\u003e \u003cp\u003eCase #1\u003c/p\u003e \u003cp\u003eA 71-year-old female with Stage IV adenocarcinoma of the lung started on carboplatin/ pemetrexed/pembrolizumab developed stage 3 AKIN eleven months after treatment at which time the patient was on pemetrexed/pembrolizumab maintenance. Baseline creatinine was 0.75 mg/dL which increased to 4.35 mg/dL. Notable concurrent medications included lisinopril and antibiotics. A renal biopsy showed active tubulointerstitial nephritis, acute tubular necrosis, and arterial nephrosclerosis. Glomerular disease and thrombotic microangiopathy were not identified. There was mild tubulointerstitial scarring (Fig.\u0026nbsp;1). Notable concurrent medications included lisinopril and antibiotics. The AKI was treated with 500 mg IV methylprednisolone daily over 3 days followed by 60 mg IV daily. The patient also required a short course of hemodialysis followed by a two-week course of high-dose steroids with improvement in renal function. She was subsequently placed on a prednisone taper with full resolution of renal injury within three months. ICI therapy was permanently discontinued due to degree of renal injury.\u003c/p\u003e \u003cp\u003eCase #2\u003c/p\u003e \u003cp\u003eA 60-year-old female with Stage IV adenocarcinoma of the lung started on carboplatin/pemetrexed/pembrolizumab developed stage 2 AKIN four months after treatment at which time she was on maintenance pemetrexed/pembrolizumab. Other notable factors include concomitant pantoprazole usage. Her baseline creatinine was 0.61 mg/dL which increased to a peak of 2.92 mg/dL. Renal biopsy revealed acute tubulointerstitial nephritis and acute tubular necrosis. There was also an incidental detection of segmentally thinned glomerular capillary basement membranes. Thrombotic microangiopathy was not identified. There was minimal tubulointerstitial scarring (Fig.\u0026nbsp;1). AKI was treated with prednisone 40 mg and started upon diagnosis with a subsequent slow taper with full resolution after two months. ICI therapy was permanently discontinued given renal injury.\u003c/p\u003e \u003cp\u003eCase #3\u003c/p\u003e \u003cp\u003eA 55-year-old female with Stage IV endometrioid uterine carcinoma was started on second-line systemic therapy with pembrolizumab and lenvatinib developed Stage 1 AKIN one month after treatment. Concurrent medications included omeprazole and antibiotic usage. Her baseline creatinine 0.77 mg/dL which subsequently increased to 1.37 mg/dL. She was noted to have 3\u0026thinsp;+\u0026thinsp;proteinuria. A renal biopsy performed one week after initiaition of prednisone revealed histologically mild acute tubular injury/acute tubular necrosis and focal and segmental glomerulosclerosis. Acute tubulointerstitial nephritis and thrombotic microangiopathy were not identified. There was minimal tubulointerstital scarring (Fig.\u0026nbsp;2\u003cb\u003e)\u003c/b\u003e. AKI was treated with prednisone 1 mg/kg daily with subsequent taper and full resolution within two weeks of treatment. Furthermore, her proteinuria resolved approximately 3 months after initiation of prednisone therapy. Although the FSGS was accompanied by a partial degree of podocyte foot process effacement, this likely reflects partial restoration of podocyte foot process morphology attributed to initiation of steroid therapy prior to the biopsy. Pembrolizumab was discontinued due to renal failure.\u003c/p\u003e \u003cp\u003eCase #4\u003c/p\u003e \u003cp\u003eA 69-year-old male with stage IV lung adenocarcinoma with high PD-L1 expression (90%) treated with pembrolizumab monotherapy developed stage 3 AKIN one month after treatment. Concomitant notable medications include pantoprazole, NSAID usage, and antibiotics. Her baseline creatinine was 0.88 mg/dL, and rose to 7.75 mg/dL. Renal biopsy was suboptimal due to scant sampling of renal cortex. Nonetheless, acute tubular necrosis and focal acute interstitial nephritis were detected and moreover electron microscopy study revealed subendothelial immune complex-type deposits in glomeruli which could not be further characterized due to inadequate immunofluorescence microscopy specimen. Due to scant renal cortical sampling, the degree of tubulointerstitial scarring cannot be assessed (Fig.\u0026nbsp;2). AKI was treated with 1 mg/kg IV methylprednisolone followed by an oral prednisone taper with no significant recovery. The patient remained on hemodialysis. ICI re-challenege was not attempted due to toxicity.\u003c/p\u003e \u003cp\u003eCase #5\u003c/p\u003e \u003cp\u003eA 61-year-old female with stage IV lung adenocarcinoma with a high PD-L1 expression (80%) treated with pembrolizumab monotherapy developed stage 3 AKIN three months after treatment. Notable concurrent medications including pantoprazole and antibiotic usage. Baseline creatinine was 0.83 mg/dL which subsequently increased to 4.48 mg/dL. Her renal biopsy showed acute tubulointerstitial nephritis, acute tubular necrosis, mild arteriosclerosis, and mild arteriolosclerosis. Glomerular disease and thrombotic microangiopathy were not identified. There was minimal renal tubulointerstitial scarring (Fig.\u0026nbsp;3). AKI was treated with high-dose prednisone at 1 mg/kg with a subsequent taper with full resolution after five months. ICI re-challenge was not attempted due to degree of renal injury.\u003c/p\u003e \u003cp\u003eCase #6\u003c/p\u003e \u003cp\u003eA 75-year-old female with stage IV adenocarcinoma of the lung with low PD-L1 expression (1%) and an EGFR Exon 20 insertion and pre-existing stage III chronic renal disease secondary to diabetes mellitus was started on third-line systemic therapy with nivolumab/ipilimumab and developed Stage 2 AKIN after 1 cycle of treatment. Concomitant medication use included antibiotics. Baseline creatinine was 1.40 mg/dL, which increased to 3.7 mg/dL. She also developed nephrotic syndrome with urine protein-to-creatinine ratio of more than 28. Her renal biopsy reveals the presence of minimal change disease, mild diabetic glomerulosclerosis, acute tubular injury, mild arteriosclerosis, and mild arteriolosclerosis. There was moderate tubulointerstitial scarring. Acute tubulointerstitial nephritis and thrombotic microangiopathy were not identified. Due to prior steroid-induced psychosis, she was started on tactolimus therapy and subsequently developed partial response. Her proteinuria improved on spot urine testing from 2,000 mg/dL to 600 mg/dL after 4 weeks on therapy. She did not require hemodialysis, but creatinine remained elevated. She was eventually transferred to hospice care due to declining health.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAKI is increasingly being recognized as a potential complication for patients on ICI therapy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our case series shows that the clinical manifestations and underlying mechanisms of renal failure in these patients can vary considerably. Some patients may develop a mild rise in creatinine after starting ICIs that may not require any therapeutic intervention or cessation of treatment. Alternatively, others may present with rapidly evolving renal failure requiring the start of renal replacement therapy. Mechanisms of renal injury can include acute interstitial nephritis, acute tubular necrosis, and nephrotic syndrome (such as FSGS or MCD) [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Risk factors can include pre-existing renal failure due to co-morbidities (diabetes mellitus and hypertension) and chemotherapy-induced nephrotoxicity from agents such as cisplatin and pemetrexed. We also show that a significant percentage of patients that develop renal injury while on ICIs are on concomitant medications, specifically PPIs, NSAIDs, and antibiotics. There does not seem to be a predictable time to onset of renal injury after starting ICI therapy as some of our patients developed nephritis after just one cycle of therapy, while others were on therapy for nearly a year before manifesting with AKI. Furthermore, the single patient (case #6) whose serum creatinine remained elevated also had the most abundant pre-existing tubulointerstitial scarring in this case series. Although her negative outcome is confounded by her receiving tacrolimus instead of steroids (due to clinical contraindication), the patient's underlying chronic kidney disease (i.e. tubulointerstitial scarring) likely plays a significant role. Given the variable presentation of ICI-induced nephritis, treatment to prevent complications may need to be individualized. Moreover, patients with known history chronic kidney disease should be closely monitored for ICI therapy-related AKI given the potential for worse outcome.\u003c/p\u003e \u003cp\u003eManagement of ICI-induced renal failure requires a multidisciplinary approach. In addition to discontinuation or interruption of ICI therapy, first-line therapy with steroids (I.e., prednisone 0.5 to 1 mg/kg/day) remains the mainstay of treatment for most patients with ICI-related renal failure [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Exceptions include those who may be unable to tolerate long-term steroid taper due to side effects or underlying co-morbidities. Although steroid therapy results in significant clinical recovery in most patients with ICI-induced nephritis, there is still a significant rate of persistent renal failure, and patients may remain on renal replacement therapy long term. In those with nephritis refractory to steroids, renal biopsy may be indicated to confirm there is no alternative etiology that may be contributing to renal injury. Histopathologic findings may help guide management, which may include cessation of another offending agent, increase in steroid dosing, or additional immunosuppressant therapy (such as tacrolimus, mycophenolate, or infliximab). The use of immunosuppressant agents may help reverse renal injury and help avoid hemodialysis as seen in our patient with ICI-related minimal change disease described above. The prompt recognition and treatment of ICI-related renal injury is essential to achieving optimal recovery of renal function.\u003c/p\u003e \u003cp\u003eMany patients may have an ongoing response to immunotherapy at the time that ICI-related AKI develops. This can cause a conundrum, as several patients will not have alternative effective treatment options available for the treatment of their advanced malignancy. ICI re-challenge may play a role in those who have developed renal failure and subsequently recovered. Given the risk of perpetuating renal damage as well as other IRAEs, a multidisciplinary discussion between oncology and nephrology would be recommended before proceeding with rechallenge in patients with grade 2 or greater nephrotoxicity. The role of continuing low-dose steroids (prednisone 10 mg or less) with re-challenge has been shown to be successful in patients' other immune adverse events such as ICI-related liver injury and may also be a potential strategy for reducing re-aggravation of renal injury in patients undergoing rechallenge [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Despite the break in treatment, significant overall survival and real-world progression-free survival benefits were shown in lung cancer patients who developed an IRAE [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOf the two patients (cases #3 and #6) who had concomitant proteinuria, the patient (case #3) with FSGS had subsequent resolution of proteinuria after receiving steroid therapy.\u003c/p\u003e \u003cp\u003eFor the second patient (case #6), her severe proteinuria was due to MCD. She was started on tacrolimus with partial response (\u0026gt;\u0026thinsp;50% improvement in proteinuria from \u0026gt;\u0026thinsp;2,000 mg/dL to 600 mg/dl on spot urine protein testing), but no significant improvement in creatinine.\u003c/p\u003e \u003cp\u003eIt was unfortunate that the patient in case #6 with proteinuria, who fell within the small subset (approximately 10%) of patients with MCD, did not have a robust response to tacrolimus therapy. In this case series, these two proteinuric patients and microanatomic glomerular lesions of FSGS and MCD are best classified as paraneoplastic glomerular diseases [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur aim in gathering CGP-based alterations was to check for possible associations with the occurrence of IRAEs. Evaluation of tumor tissue on Case #6 revealed an exon 20 insertion which can be treated with FDA approved target therapies. However, this patient had severe complications from ICI related renal injury that prevented the patient from starting targeted therapy. This highlights the important of utilizing CGP results for optimal therapy selection. Remaining mutational analysis did show multiple patients with TP53 and NF1 mutations, but these mutations are extremely common across the spectrum of malignancies and are unlikely to be predictive of ICI related toxicities. There was no other co-mutations noted on CGP that appeared to correlate to the development of ICI related AKI. PD-L1 expression on tumor samples was high in two out of six patients, but low in the remaining four patients. TMB was only evaluable in three patients, none of which were TMB high. All six patients were noted to be microsatellite stable. Given the limited number of patients analyzed in our study, we were not able to significantly associate any CGP mutations, level of PD-L1 expression, TMB status, or MSS status with ICI-related renal injury. Germline analysis may be of benefit in determining patients predisposed to AKI from ICIs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In addition, PD-L1 testing on renal biopsy specimens may be of clinical utility [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, ICI-related AKI should be recognized as a potential side effect of both single-agent and dual checkpoint inhibitor therapy. A high degree of clinical suspicion is required to ensure early diagnosis and treatment to help improve outcomes. In addition to renal tubulointerstitial diseases, there may also be concomitant glomerular and extraglomerular vascular diseases. However, thrombotic microangiopathies are not detected in our small case series. Close monitoring of blood work including BUN/Cr and urine studies to detect evolving proteinuria can help determine which patients may be developing this rare complication. A renal biopsy can be a useful tool in determining the mechanism of renal failure and can help guide treatment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Escalation of treatment to higher doses of steroids or immunosuppressants should be initiated within one week in those patients who may be refractory to initial therapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. More research into potential predictive biomarkers and clinical experience is needed to determine which patients may be at higher risk for ICI-related renal injury.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eR.S., R.M. and N.T. wrote the main manuscriptI.M, J.F. assisted with data collection and preparing figures and tablesM.L., A.Y. and A.R. assisted with the pathology review of each case and providing a nephrology perspective for the paper.All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePerazella MA, Sprangers B (2019) AKI in Patients Receiving Immune Checkpoint Inhibitors. 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Renal360 1:166\u0026ndash;168. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.34067/KID.0001072019\u003c/span\u003e\u003cspan address=\"10.34067/KID.0001072019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Checkpoint, Immunotherapy, Nephritis, Pembrolizumab, Nivolumab, Steroids, AKI, Renal biopsy","lastPublishedDoi":"10.21203/rs.3.rs-3874048/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3874048/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAcute kidney injury (AKI) has been well described as a complication of immune checkpoint inhibitor therapy. We present a series of patients, the majority with lung adenocarcinoma, who developed AKI while actively receiving immune checkpoint inhibitors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a retrospectively analyzed clinical case series of six patients treated at City of Hope Comprehensive Cancer Center. Data was collected on gender, age, ethnicity, comorbidities, concomitant medications, type of malignancy, treatments, and renal function. All patients underwent renal biopsy for classification of the mechanism of AKI. Comprehensive genomic profiling (CGP) was performed on tumor tissue for all patients.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePatterns of AKI included acute interstitial nephritis and acute tubular necrosis. Contributing factors included the use of concomitant medications known to contribute to AKI. All but two patients had full resolution of the AKI with the use of steroids. There were several mutations found on CGP that were notable including an Exon 20 insertion as well as multiple NF1 and TP53 mutations. There was high PD-L1 expression on tumor tissue noted in two out of six patients. In addition to AKI, a subset of patients had proteinuria with biopsies revealing corresponding glomerular lesions of minimal change disease and focal and segmental glomerulosclerosis.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur case series demonstrates that AKI from immune checkpoint inhibitors has a variable presentation that may require an individualized treatment approach. Further studies are needed to identify biomarkers that may help identify those at risk and guide the management of this condition.\u003c/p\u003e","manuscriptTitle":"Clinical Features Associated with Immune Checkpoint Inhibitor Nephritis: A Single-Center Clinical Case Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-22 14:47:31","doi":"10.21203/rs.3.rs-3874048/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-02T13:56:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-29T12:13:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"fc0a1905-5929-4a56-8977-00c7fd5e73ec","date":"2024-04-18T08:15:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-21T05:28:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6adc8310-a5ed-4b5d-b52f-e829c2434a28","date":"2024-03-21T02:24:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-23T23:12:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-23T20:53:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-18T03:26:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2024-01-17T23:20:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dbdc55c9-bbc7-4b35-b801-5974bd4b8127","owner":[],"postedDate":"January 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T16:09:50+00:00","versionOfRecord":{"articleIdentity":"rs-3874048","link":"https://doi.org/10.1007/s00262-024-03775-6","journal":{"identity":"cancer-immunology-immunotherapy","isVorOnly":false,"title":"Cancer Immunology, Immunotherapy"},"publishedOn":"2024-08-06 15:57:49","publishedOnDateReadable":"August 6th, 2024"},"versionCreatedAt":"2024-01-22 14:47:31","video":"","vorDoi":"10.1007/s00262-024-03775-6","vorDoiUrl":"https://doi.org/10.1007/s00262-024-03775-6","workflowStages":[]},"version":"v1","identity":"rs-3874048","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3874048","identity":"rs-3874048","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}