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

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.

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P0306ACUTE KIDNEY INJURY AFTER CHECKPOINT INHIBITOR TREATMENT: FACING THE FUTURE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0306 ◽

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.

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

SAGE Open Medical Case Reports ◽

10.1177/2050313x20910029 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2091002 ◽

Cited By ~ 1

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.

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Acute kidney injury from immune checkpoint inhibitor use

BMJ Case Reports ◽

10.1136/bcr-2019-231211 ◽

2019 ◽

Vol 12 (10) ◽

pp. e231211 ◽

Cited By ~ 1

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.

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

Case Reports in Nephrology and Dialysis ◽

10.1159/000517502 ◽

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.

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Acute Interstitial Nephritis With Karyomegalic Epithelial Cells After Nivolumab Treatment—Two Case Reports

Clinical Medicine Insights Case Reports ◽

10.1177/1179547619853647 ◽

2019 ◽

Vol 12 ◽

pp. 117954761985364 ◽

Cited By ~ 4

Author(s):

Masaki Ryuzaki ◽

Hirobumi Tokuyama ◽

Kiyotaka Uchiyama ◽

Hideaki Nakaya ◽

Kazuhiro Hasegawa ◽

...

Keyword(s):

Renal Function ◽

Epithelial Cells ◽

Interstitial Nephritis ◽

Checkpoint Inhibitors ◽

Case Reports ◽

Kidney Injury ◽

Corticosteroid Treatment ◽

Acute Interstitial Nephritis ◽

Tubular Epithelial Cells ◽

Ki 67

Clinical application of immune checkpoint inhibitors (CPIs) including nivolumab is expanding in the field of oncology treatment. Nivolumab is an anti-programmed death 1 protein (PD-1) antibody designed to augment an immunologic reaction against cancer cells. On the contrary, CPIs are known to cause a unique variety of side effects termed as immune-related adverse events, which can affect any organ including kidney. However, the characteristics of renal disorders by nivolumab treatment are poorly described. We describe two cases of acute kidney injury that were treated with nivolumab. Two patients, one with renal-cell carcinoma and the other with lung cancer, exhibited progressive renal dysfunction after the initiation of nivolumab treatment. By kidney biopsy, each case was diagnosed as acute interstitial nephritis (AIN). Of note, tubular epithelial cells enlarged with hyperchromatic nuclei were focally observed, and this finding was consistent with karyomegalic tubular epithelial cells. In immunostaining, most of the enlarged tubular epithelial cells were positive for Ki-67, which suggested regeneration of tubular epithelial cells. Clinically, in one case, renal function was partially recovered with the discontinuation of nivolumab, while in another case renal function was fully recovered with additional corticosteroid treatment. We presented nivolumab-induced AIN with karyomegalic changes of tubular epithelia. We propose that immunosuppressive therapy may be necessary for the full recovery from renal impairment.

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Acute interstitial nephritis and PR3-ANCA following reintroduction of pembrolizumab: a case report

Immunotherapy ◽

10.2217/imt-2020-0223 ◽

2021 ◽

Author(s):

Matthew Mulroy ◽

Sanaz Ghafouri ◽

Anthony Sisk ◽

Antoni Ribas ◽

Ray Goshtaseb ◽

...

Keyword(s):

Interstitial Nephritis ◽

Renal Toxicity ◽

Checkpoint Inhibitors ◽

Kidney Injury ◽

Antineutrophil Cytoplasmic Antibody ◽

Acute Interstitial Nephritis ◽

Patients With Cancer ◽

Previously Treated ◽

Grade 3 ◽

Timing Of Onset

Renal toxicity from immune checkpoint inhibitors (ICIs) is an increasingly recognized cause of acute kidney injury among patients with cancer. ICI-associated acute kidney injuries typically present as acute interstitial nephritis and the timing of onset is highly variable. Herein, we present a case of a patient with relapsed metastatic melanoma previously treated with pembrolizumab who developed grade 3 immune-related renal toxicity after reintroduction of the same ICI, secondary to acute interstitial nephritis with accompanying high PR3-antineutrophil cytoplasmic antibody titer. The patient improved after steroid treatment and discontinuation of pembrolizumab. This case highlights the importance of not excluding ICI-related nephrotoxicity as a possible cause of renal failure, including in those who previously tolerated ICI treatment, since it is a treatable entity.

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Diagnosing acute interstitial nephritis: considerations for clinicians

Clinical Kidney Journal ◽

10.1093/ckj/sfz080 ◽

2019 ◽

Cited By ~ 1

Author(s):

Eliezer Zachary Nussbaum ◽

Mark A Perazella

Keyword(s):

Interstitial Nephritis ◽

Kidney Biopsy ◽

Laboratory Data ◽

Kidney Injury ◽

Clinical History ◽

Acute Interstitial Nephritis ◽

Single Test ◽

Common Cause ◽

Tubular Necrosis ◽

Common Causes

Abstract Acute interstitial nephritis (AIN) is a common cause of acute kidney injury (AKI), particularly in hospitalized patients. It can be difficult for clinicians to differentiate between AIN and other common causes of AKI, most notably acute tubular necrosis (ATN) and prerenal injury. Clinicians often struggle with the clinical history and laboratory data available to definitively diagnose AIN. Sometimes they diagnose ATN or AIN based on these flawed data. Thus it is important that clinicians be familiar with the utility of commonly ordered tests used to aid in the diagnosis. Unfortunately, no single test performs particularly well on its own, and until a biomarker is rigorously shown to be diagnostic of AIN, most patients require a kidney biopsy to definitively establish the diagnosis and direct further management.

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Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review

American Journal of Nephrology ◽

10.1159/000455014 ◽

2017 ◽

Vol 45 (2) ◽

pp. 160-169 ◽

Cited By ~ 146

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.

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Drug-induced acute interstitial nephritis

Siberian medical review ◽

10.20333/25000136-2021-4-34-50 ◽

2021 ◽

pp. 34-50

Author(s):

O.D. Ostroumova ◽

◽

M.V. Klepikova ◽

S.N. Litvinova ◽

◽

...

Keyword(s):

Interstitial Nephritis ◽

Immune Checkpoint Inhibitors ◽

Kidney Biopsy ◽

Checkpoint Inhibitors ◽

Interstitial Fibrosis ◽

Acute Interstitial Nephritis ◽

Accurate Diagnosis ◽

Antitumor Drugs ◽

Drug Induced ◽

Nephrotoxic Drugs

Among the causes of acute interstitial nephritis, drug-induced acute interstitial nephritis accounts for 50 to 78 % of all cases. Th e review summarizes the literature data on drugs that cause acute interstitial nephritis. Search in eLibrary databases.RU, PubMed®, MEDLINE, EMBASE, manuals and guidelines, materials of adverse drug reactions databases, instructions for the medical use of drugs. it was held until October 2020. Th e most probable mechanisms of its development are considered. Most attention is paid to non-steroidal anti-infl ammatory drugs, anticoagulants, antibiotics, antitumor drugs (immune checkpoint inhibitors), which are widely used in clinical practice. Th e symptoms of drug-induced acute interstitial nephritis are variable and oft en non-specific; therefore, a kidney biopsy is required for an accurate diagnosis. The main direction of treatment of drug-induced acute interstitial nephritis is the cancellation of nephrotoxic drugs, if this condition is not feasible and/or the duration of acute interstitial nephritis is less than 3 weeks, the biopsy has minimal interstitial fibrosis and there are no serious contraindications, then the possibility of using it should be considered.

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Ipilimumab-induced renal granulomatous arteritis: a case report

BMC Nephrology ◽

10.1186/s12882-019-1552-2 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

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.

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