scholarly journals P0306ACUTE KIDNEY INJURY AFTER CHECKPOINT INHIBITOR TREATMENT: FACING THE FUTURE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Clara Garcã­a Carro ◽  
Mónica Bolufer ◽  
Diana Oleas ◽  
María A Azancot ◽  
Irene Agraz ◽  
...  
Keyword(s):  
Kidney Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Complete Recovery ◽  
Acute Interstitial Nephritis ◽  
University Hospital ◽  
Induction Treatment ◽  
Renal Lesion ◽  
Solid Organ

Abstract Background and Aims Checkpoint inhibitors (CPI) are used to treat solid organ metastatic malignancies. They act on by triggering a vigorous immune response against tumoral cells, preventing their proliferation. CPIs reinvigorate antitumor immune responses by interrupting co-inhibitory signaling pathways and promote immune-mediated elimination of tumor cells.This is not a selective response, deriving in immune related adverse events (irAEs). The kidney can potentially be damaged with an incidence of 13-29%. The most frequent type of toxicity is acute interstitial nephritis (AIN). Method We evaluated all the patients with solid organ metastatic malignancies treated with immunotherapy that developed acute renal injury (AKI) and underwent to kidney biopsy from March 2018 to November 2019 at Vall d’Hebron University Hospital. Results 11 patients with solid organ metastatic malignancies treated with immunotherapy developed AKI and underwent to kidney biopsy during the study period. The most frequent malignancy was lung cancer - in 6 patients-, followed by 3 patients with melanoma. 8 patients (72%) had already received previous oncological therapy, and for the remaining 3 patients (27%), CPI was the first line therapy. 8 patients (72%) were treated with anti-PD1 (programmed cell death protein 1), 4 patients (36 %) received anti PDL-1 (programmed death-ligand 1) 1 of these patients in combination with an anti CTLA-4 (cytotoxic T-lymphocyte antigen 4) and another patient received both anti PD1 and anti PDL-1. The time between the start of CPI and the onset of the AKI ranged between 2-11 months. The most frequent urine findings were subnephrotic range proteinuria with a mean protein/creatinine (mg/g creatinine) 503.6 ± 190.5 and leukocyturia in 9 of 11 patients. Mean creatinine (mg/dl) at diagnosis was 3.4 ± 1.3. 10 out of the 11 patients were diagnosed of AIN after performing a kidney biopsy. The remaining patient presented chronic changes (IFTA and glomerulosclerosis) in the biopsy, performed after receiving steroids for a month. 3 patients who presented AIN received pulses of methylprednisolone 250-500mg as induction treatment and 7 patients received prednisone 1mg/kg/day. Mean prednisone accumulated dose (mg) during the first month of treatment was 1387.5 ± 540. 9 patients experienced complete recovery of kidney function and two patients progressed to CKD. Conclusion We reported 11 patients who presented AKI associated to CPI treatment and underwent to kidney biopsy in the last 20 months at our center. 10 out of 11 presented biopsy confirmed CPI related AIN. In our experience, CPI related AIN is the most frequent renal lesion associated to the novel immunotherapy treatments. This entity seems to have good renal prognosis as long as steroid treatment is early started.

scholarly journals Acute interstitial nephritis associated with immune checkpoint inhibitors: a single-centre experience

2020 ◽  
Author(s):  
Diana Oleas ◽  
Mónica Bolufer ◽  
Irene Agraz ◽  
Enriqueta Felip ◽  
Eva Muñoz ◽  
...  
Keyword(s):  
Interstitial Nephritis ◽  
Kidney Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
University Hospital ◽  
Solid Organ ◽  
First Line Therapy ◽  
Proliferation And Metastasis

Abstract Background Checkpoint inhibitors (CPIs) are used to treat solid organ metastatic malignancies. They act by triggering a vigorous immune response against tumoural cells, preventing their proliferation and metastasis. However, this is not a selective response and can cause immune-related adverse events (irAEs). The kidney can potentially be damaged, with an incidence of irAEs of 1–4%. The most frequent type of toxicity described is acute interstitial nephritis (AIN). Methods We conducted a study of patients with solid organ metastatic malignancies treated with immunotherapy who developed acute renal injury and underwent kidney biopsy in the last 14 months at the Vall d’Hebron University Hospital. Results In all, 826 solid organ malignancies were treated with immunotherapy in our centre, 125 of them (15.1%) developed acute kidney injury (AKI), 23 (18.4% of AKI) visited the nephrology department and 8 underwent kidney biopsy. The most frequent malignancy was lung cancer, in five patients (62%), followed by two patients (25%) with melanoma and one patient (12%) with pancreatic cancer. Four patients (50%) had already received previous oncological therapy, and for the remaining four patients (50%), CPI was the first-line therapy. Five patients (62%) were treated with anti-programmed cell death protein 1, three patients (37%) received anti-programmed death ligand 1 and two (25%) patients were treated in combination with anti-cytotoxic T-lymphocyte antigen 4. The time between the start of CPI and the onset of the AKI ranged from 2 to 11 months. The most frequent urine findings were subnephrotic-range proteinuria, with a mean protein:creatinine ratio of 544 mg/g (standard deviation 147) and eosinophiluria. All patients were biopsied after being diagnosed with AIN. Three patients (37%) received treatment with pulses of methylprednisolone 250–500 mg/day and five patients (62%) received prednisone 1 mg/kg/day. Seven patients (87%) experienced recovery of kidney function and one patient (12%) progressed to chronic kidney disease. Conclusions We report on eight patients with CPI-related AIN diagnosed in the last 14 months at our centre. The novel immunotherapy treatment of metastatic solid organ malignancies carries a higher risk of irAEs. The kidney is one of the most commonly affected organs, frequently presenting as an AIN and exhibiting a favourable response to steroid treatment.

scholarly journals Acute kidney injury from immune checkpoint inhibitor use

2019 ◽  
Vol 12 (10) ◽  
pp. e231211 ◽  
Author(s):  
Lexis Gordon ◽  
Pouneh Dokouhaki ◽  
Kimberly Hagel ◽  
Bhanu Prasad
Keyword(s):  
Acute Kidney Injury ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Programmed Death ◽  
Programmed Death 1

Immune checkpoint inhibitors are novel oncological medications, current classes of which include monoclonal antibodies that target inhibitory receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 protein (PD-1) and programmed death-ligand 1. While they are novel in their ability to treat cancer, they also have a unique spectrum of immune-related adverse events. Renal-related immune adverse events, though rare, are an increasingly recognised clinical entity. We present the case of a 67-year-old man with acute kidney injury (AKI) after the second cycle of combination anti-CTLA-4 and anti-PD-1 antibodies for metastatic cutaneous melanoma. He presented with vomiting and diarrhoea, and AKI secondary to dehydration was treated with aggressive rehydration. After failing to recover biochemically, a renal biopsy was performed, which demonstrated severe acute interstitial nephritis. The culprit medications were held and he was treated with steroids. With immunosuppression, creatinine improved to pretreatment values.

scholarly journals Development of Nivolumab/Ipilimumab-Associated Autoimmune Nephritis during Steroid Therapy

2021 ◽  
pp. 270-274
Author(s):  
Ellen Gebauer ◽  
Wibke Bechtel-Walz ◽  
Christoph Schell ◽  
Michelle Erbel ◽  
Gerd Walz ◽  
...  
Keyword(s):  
Steroid Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Oral Steroid ◽  
High Dose ◽  
Immune Mediated

Immunotherapy using immune checkpoint inhibitors revolutionized therapies for a variety of malignancies. Nivolumab, an antibody blocking programmed cell death 1 protein, and ipilimumab that blocks cytotoxic T-lymphocyte-associated protein 4 effectively target tumor cells by disinhibiting the endogenous immune response. At the same time, unrestrained T-cell activation may trigger a range of immune-mediated side effects including kidney injury. Steroid therapy constitutes the mainstay of treatment of these adverse events, but dosage, route of administration, and approach to nivolumab re-exposure remain unclear. Here, we report the case of a 72-year-old male patient who developed severe nivolumab/ipilimumab-associated acute kidney injury while on oral steroid therapy for immune-mediated colitis. Acute interstitial nephritis was confirmed by renal biopsy. Administration of high-dose intravenous steroid doses was required to revert declining renal function.

scholarly journals Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review

2017 ◽  
Vol 45 (2) ◽  
pp. 160-169 ◽  
Author(s):  
Rimda Wanchoo ◽  
Sabine Karam ◽  
Nupur N. Uppal ◽  
Valerie S. Barta ◽  
Gilbert Deray ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Incidence Rates ◽  
Primary Data ◽  
Medline Search ◽  
Main Adverse Effect

Background: 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. Summary: 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.

scholarly journals TO017CLINICAL CHARACTERISTICS AND INDEPENDENT PREDICTORS OF CHECK POINT INHIBITORS-ASSOCIATED AKI: WHAT DO WE KNOW?

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Mónica Bolufer ◽  
Clara Garcia Carro ◽  
Roxana Bury ◽  
Eva Muñoz ◽  
Enriqueta Felip ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Biopsy ◽  
Checkpoint Inhibitors ◽  
Obstructive Uropathy ◽  
Demographic Data ◽  
Complete Recovery ◽  
Older Age ◽  
Solid Organ ◽  
Common Diagnosis ◽  
Baseline Creatinine

Abstract Background and Aims Checkpoint inhibitors (CPI) are used to treat solid organ malignancies. CPI–associated acute renal injury (AKI) is an adverse effect of these therapies and its incidence is 13-29%. Clinical data on this complication is scarce. The aim of our study is to define clinical characteristics and risk factors of CPI-associated AKI. Method Clinical and demographic data of all patients receiving immunotherapy between March 2018 and May 2019 at our center were evaluated. Patients were divided into two groups depending on the development of AKI during the study period. AKI was defined according to AKIN classification. We compared clinical and demographic characteristics between these two groups and patients who developed mild AKI and severe AKI. Results During the study period, 821 patients received CPIs. Mean age 62.03±12.06 years and 486(59.2%) men. Malignancies were lung in 249 (30.3%), urogenital tract in 168 (20.5%), melanoma in 89 (10.8%) and others in 315 patients (38.4%). 446(54.3%) patients received anti-PD1, 230(28%) anti-PDL1, 13 (1.6%) anti-CTLA4, 36 (4.4%) received other drug and 96(11.7%) were treated with both anti-CTLA4 and anti-PD1 or anti.PDL1. Baseline creatinine was 0.85±0.30 mg/dL and 188 (22.9%) patients presented creatinine>1 mg/dL before starting CPI. 125 patients (15.2%) developed AKI during the study period, 85(68%) men and mean age 65.1±10.7 years. Baseline creatinine of these patients 0.97±0.45 mg/dL and 44 (35.2%) presented basal creatinine>1mg/dL. Mean creatinine at the diagnosis of AKI 2.27±1.34 mg/dL and two patients required haemodialysis. Leukocyturia was present in 21 patients(16.8%) and haematuria in 12 (9.6%). 5 patients presented AKI secondary to obstructive uropathy. Mean time from CPI initiation to AKI was 5.6±5.8 months. Of those 125 patients, 23 (18.4%) were referred to Nephrology and 9 (7.2%) underwent kidney biopsy. 1 patient presented endocapillar proliferative non-CPI related glomerulonephritis and 8 (6.4%) acute tubule-interstitial nephritis (ATIN). 23 (18.4%) patients were treated with corticosteroids. Mean creatinine at 6 months after AKI was 1.04±0.34 mg/dL (data from 45 patients) and 40 patients (data from 45 patients) showed complete recovery of kidney function at 6 months. Patients who developed a severe AKI stage 2 or 3 were more frequently women (41.8% vs 24.3%, p=0.03), had lower basal creatinine (0.86±0.25 vs 1.06±0.54 mg/dL, p=0.0130), showed and increased latency from CPI initiation to AKI (6.9±6 vs 4.5±5.5 months, p=0.0267) and presented worse recovery of kidney function at 6 months than patients with AKI stage 1(creatinine 6 months 1.18±0.40 mg/dL, p=0.0398 and complete recovery of kidney function at 6 months 70.5% vs 93.3%, p=0.0353). There was no association between the severity of AKI and type of CPI and type of malignance. When comparing patients who developed AKI with patients whit patient who did not, patients with AKI were older (65.1±10.7 vs 62.03±12.06 years old, p=0.0017), more frequently men (68% vs 57.9%), p=0.0296) and presented higher baseline creatinine (0.97±0.45 vs 0.85±0.30 mg/dL, p<0.0001), as well as more frequently a baseline creatinine > 1 mg/dL (35.2% vs 20.7%, p=0.0004). Type of CPI and type of malignance were not associated with the presence of AKI. Older age (OR 1.020, CI 95% 1.002-1.038) and baseline creatinine (OR 3.293, CI 95% 1.678-6.461) were identified as independent predictors of AKI development in our CPI treated patients Conclusion CPI-associated AKI incidence in our centre is 15.2%. Of them, 44% developed severe AKI. Only 18.4% were referred to a nephrologist and kidney biopsy performed in 7.2%. ATIN was the most common diagnosis. 18.4% received corticosteroids. Older age and higher baseline creatinine were identified as independent predictors for AKI development in patients with cancer CPI-treated. Patients developing a severe AKI showed worse kidney function at 6 months.

scholarly journals Ipilimumab-induced renal granulomatous arteritis: a case report

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Mathilde Lemoine ◽  
Baptiste Dilly ◽  
Alexandre Curie ◽  
Vivien Hébert ◽  
Charlotte Laurent ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Adverse Events ◽  
Kidney Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Oral Prednisone ◽  
Kidney Injury ◽  
New Drugs ◽  
Case Presentation ◽  
Cell Death Protein

Abstract Background Immune Checkpoint Inhibitors (ICPIs) are promising new drugs in treatment of advanced tumours targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD1) or its ligand (PDL-1). Ipilimumab is a monoclonal antibody targeting the CTLA-4 receptor used in treatment of metastatic melanoma. By increasing activity of the immune system, ICPIs lead to immune-related adverse events, such as dermatitis, colitis or hepatitis. ICPIs-related kidney adverse events are rare and acute tubulointerstitial nephritis with or without granuloma have mainly been reported. Case presentation We report a case of acute kidney injury in a patient with melanoma treated by ipilimumab. Kidney biopsy revealed acute interlobular and juxtaglomerular granulomatous arteritis, which has not yet been reported in patients treated by ICPIs. Kidney function partially recovered after ipilimumab discontinuation and oral prednisone. Unfortunately, the patient died a few months later from progression of his melanoma. Conclusion This case highlights a new mechanism of acute kidney injury related to ICPIs and supports the interest of kidney biopsy in case of ICPIs related acute renal failure.

scholarly journals Efficacy of Plasmapheresis in Nivolumab-Associated ANCA Glomerulonephritis: A Case Report and Pathophysiology Discussion

2021 ◽  
pp. 376-383
Author(s):  
Reda Laamech ◽  
Florian Terrec ◽  
Camille Emprou ◽  
Anne Claire Toffart ◽  
Thomas Pierret ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Exceptional Case ◽  
Solid Organ ◽  
Glomerular Injury ◽  
Cancer Treatments ◽  
Drug Induced ◽  
Hematologic Cancer ◽  
Lung Hemorrhage

Immune checkpoint inhibitors (ICIs) have revolutionized solid organ and hematologic cancer treatments by improving overall prognoses. However, they can lead to overactivation of the immune system and several immune-related adverse events and sometimes affecting the renal system. Although acute interstitial nephritis is well described, we know little about ICI-associated glomerular injury. Herein, we report an exceptional case of renal ANCA positive-associated vasculitis (AAV) after nivolumab therapy. Three weeks after the last nivolumab injection, the patient presented with proteinuria at 1.73 g/g of creatininuria, hematuria, and acute kidney injury needing dialysis associated with lung hemorrhage; anti-neutrophil cytoplasmic antibody (ANCA titer ≥1,280 with myeloperoxidase specificity of 780 U/mL) was positive, and kidney biopsy confirmed glomerular injury with crescents. The patient underwent treatment with steroid pulses, rituximab, and plasmapheresis, resulting in an improvement of the renal function and lung hemorrhage and produced a negative ANCA titer. Despite the results of the PEXIVAS study and the absence of clear benefit of plasmapheresis demonstrated in idiopathic AAV, we suggest that drug-induced AAV may be effectively treated by plasmapheresis, steroids, and rituximab.

scholarly journals Checkpoint inhibitor therapy-associated acute kidney injury: time to move on to evidence-based recommendations

2021 ◽  
Author(s):  
Mark A Perazella ◽  
Ben Sprangers
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Biopsy ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Hematologic Malignancies ◽  
University Hospital ◽  
Treatment Protocols ◽  
Non Invasive ◽  
Single Center Study ◽  
Checkpoint Inhibitor Therapy

Abstract 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 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 are lacking. In this issue, Oleas et al. report a single center study of patients with non-hematologic 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 were referred to the nephrology service and kidney biopsy was only performed in 6.4% of patients. While the authors add to our knowledge about ICI-AKI, their paper also highlights the need for the development of non-invasive 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.

scholarly journals Acute interstitial nephritis and drug-induced systemic lupus erythematosus due to chlorthalidone and amiodarone: A case report

2020 ◽  
Vol 8 ◽  
pp. 2050313X2091002 ◽  
Author(s):  
Umut Selamet ◽  
Ramy M Hanna ◽  
Anthony Sisk ◽  
Lama Abdelnour ◽  
Lena Ghobry ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Interstitial Nephritis ◽  
Lupus Erythematosus ◽  
Kidney Biopsy ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Systemic Lupus ◽  
Drug Induced ◽  
Systemic Manifestations

Drug-induced lupus erythematosus has features distinct from primary systemic lupus erythematosus. It can occur with a wide variety of agents that result in the generation of anti-histone or other types of antibodies. Systemic manifestations of drug-induced systemic lupus erythematosus may include renal dysfunction due to circulating immune complexes or due to other immune reactions to the culprit medication(s). Acute interstitial nephritis occurs due to DNA–drug or protein–drug complexes that trigger an allergic immune response. We report a patient who developed acute kidney injury, rash, and drug-induced systemic lupus diagnosed by serologies after starting chlorthalidone and amiodarone. A renal biopsy showed acute interstitial nephritis and not lupus-induced glomerulonephritis. It is important to note that systemic lupus erythematosus and acute interstitial nephritis can occur together, and this report highlights the role of the kidney biopsy in ascertaining the pathological diagnosis and outlining therapy in drug-induced lupus erythematosus.

Tubulitis in a patient treated with nivolumab: Case report and literature review

2018 ◽  
Vol 2 (2-3) ◽  
pp. 107-112
Author(s):  
Viral Vakil ◽  
Mark Birkenbach ◽  
Katti Woerner ◽  
Lihong Bu
Keyword(s):  
Acute Kidney Injury ◽  
Immune Checkpoint Inhibitors ◽  
Kidney Biopsy ◽  
Tubulointerstitial Nephritis ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Metastatic Urothelial Carcinoma ◽  
Programmed Death 1

Kidney injury associated with use of immune checkpoint inhibitors that target the programmed death-1 molecule commonly manifests as acute tubulointerstitial nephritis on kidney biopsy. We present a case of a 66-year-old man who developed acute kidney injury at 6 months after initiation of treatment with anti-programmed death-1 antibody, nivolumab, for treatment of metastatic urothelial carcinoma. A renal biopsy showed focal moderate-to-severe lymphocytic tubulitis with minimal interstitial inflammation. Programmed death ligand-1 immunopositivity was detected only in tubules exhibiting lymphocytic tubulitis. The patient’s renal function improved to baseline with conservative management consisting of discontinuation of nivolumab followed by prednisone treatment.

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