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• W4313325146 abstract "Immune checkpoint inhibitors (ICI) have significantly improved outcomes for patients with neoplasms in advanced stages [1Postow M.A. Callahan M.K. Wolchok J.D. Immune checkpoint blockade in cancer therapy.J Clin Oncol. 2015; 33 (–1982): 1974Google Scholar]. On the other hand, ICI have immune related adverse events (irAE). These adverse events affect mostly other organs than the kidney, such as skin or gastrointestinal tract [2Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168Google Scholar]. The incidence of nephrotoxicity with monotherapy with any ICI is about 2%, which increases to 5% in combination therapy [S1]. Acute tubulointerstitial nephritis (AIN) is the most common pattern of kidney damage related to ICI [3Perazella M.A. Shirali A.C. Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do?.Kidney Int. 2020; 97: 62-74Google Scholar]. Globally, without considering ICI nephrotoxicity, AIN is estimated to account for 15-20% of cases of AKI. [4Raghavan R. Eknoyan G. Acute interstitial nephritis - a reappraisal and update.Clin Nephrol. 2014; 82: 149-162Google Scholar]. This is crucial because patients who are treated with ICI, may also be taking other drugs that potentially cause AIN, and therefore, knowing the particularities about ICI-related AIN could be helpful in clinical practice to better understand the phenotypic differences between the two types of AIN. In addition, several studies have shown now that being on proton pump inhibitors (PPI) is a risk factor for AIN from ICI therapy. [S1-S4]. We aimed to answer if the kidney histopathological findings with special staining help differentiate ICI related AIN from non-ICI related AIN. We also review the management and results of AKI in this context, focusing on the characteristics of corticosteroid therapy used. Table 1 summarizes the main clinical data at presentation of patients with ICI-related and non-ICI-related AIN. The clinical presentation consisted of AKI in all 23 patients. AKI occurred on previous chronic renal disease in two patients of the ICI group and presented with severe proteinuria (8.8 g per 24 hours) in one non-ICI related case.Table 1Main clinical and biological characteristics according to the etiology of the AIN.ICI-related (N=11)Non-ICI related (N=12)pAge70 (60-74)56 (53-60)0.25Drugs involved (nº of cases)*More than one drug per patient is possibleSex, female/maleNIV (4), PEM (2), DOS (1), CEM (1), NIR (2), IPI (2), DUR (1), ATE (2), TRE (1)6 (55%)/5 (45%)NSAIDs (2), PPI (3), ALL (1), CIP (2), LEV (1), CEF (4), AMP-B (1)6(50%)/6(50%)ComorbiditiesDiabetes mellitus9 (81%)9 (81%)1.0Hypertension6 (55%)2 (18%)0.07Serum creatinine3.2 (2.3-4.2)3.6 (3.2-4.2)0.22Hyperkalemia3 (27%)None0.06Hypokalemia1 (9%)None0.3Acidosis6 (54%)2 (18%)0.07Proteinuria, mg/24 h333 (240-498)267 (203-797)0.87Normal range25Proteinuria range (200 – 1000 mg/24 h)615Proteinuria range (> 1000 mg/24 h)23Microhematuria3 (27%)5 (45%)0.37Pyuria9 (82%)6 (55%)0.17Abbreviations: NIV: Nivolumab (anti-PD1); PEM: Pembrolizumab (anti-PD1); DOS: Dostarlimab (anti-PD1); CEM: Cemiplimab (anti-PD1); NIR: Niraparib (PARP inhibitor); IPI: Ipilimumab (anti-CTLA4); DUR: Durvalumab (anti-PD-L1); ATE: Atezolizumab (anti-PD-L1); TRE: Tremelimumab (anti-CTLA-4). NSAIDs: Non-steroidal anti-inflammatory drugs; PPI: Proton pump inhibitor; ALL: Allopurinol; CIP: Ciprofloxacin; LEV: Levofloxacin; CEF: Ceftriaxone; AMP-B: Amphotericin-B Open table in a new tab Abbreviations: NIV: Nivolumab (anti-PD1); PEM: Pembrolizumab (anti-PD1); DOS: Dostarlimab (anti-PD1); CEM: Cemiplimab (anti-PD1); NIR: Niraparib (PARP inhibitor); IPI: Ipilimumab (anti-CTLA4); DUR: Durvalumab (anti-PD-L1); ATE: Atezolizumab (anti-PD-L1); TRE: Tremelimumab (anti-CTLA-4). NSAIDs: Non-steroidal anti-inflammatory drugs; PPI: Proton pump inhibitor; ALL: Allopurinol; CIP: Ciprofloxacin; LEV: Levofloxacin; CEF: Ceftriaxone; AMP-B: Amphotericin-B The median time between the start of ICI treatment and the presentation with AKI was 14.6 months (IQR: 3.1 – 54.2). The Interval between non-ICI related AIN diagnosis by kidney biopsy and the start of the culprit drug was 87 days (IQR days (23-694:). Among the 12 patients with non-ICI related AIN, three had previously been exposed to penicillins, four to sulfonamides, three to allopurinol, one to NSAIDs, and one to omeprazole. No patient in the ICI group referred prior exposure to proton-pump inhibitors. The histological diagnosis was AIN in 8 and 10 of the ICI-related and non-ICI related AKI cases, respectively, with chronic-active tubulointerstitial nephritis in the remaining cases. Table 2 summarizes the main histopathological findings in both groups. The percentage of cortical tissue affected was significatively larger in the ICI-related cases. Positive staining for the PD1 molecule and its ligand, PD-L1, was observed in 10 of the 11 ICI-related cases but only in one of the non-ICI related (p<0.001). PD1 was expressed on interstitial inflammatory cells, whereas PD-L1 was presented manly in isolated tubular cells. Supplementary figure 1 shows the characteristic findings described in tubulointerstitial nephritis associated with ICI.Table 2Histological findings in ICI-related and non-ICI related AIN.FindingICI-relatedN=11Non-ICI relatedN=12pCortical tissue affected (%)50 (50-60)25 (20-25)< 0.001Interstitial inflammatory cells other than lymphocytes EosinophilsPlasma cellsHistiocytes7 (64%)5 (45%)5 (45%)6(50%)3(25%)3 (25)0.410.400.40Tubulitis moderate and severe7 (64%)*3 (25)0.09IFTA <25%8 (72%)10 (83%)0.64IHCPD110 (91%)1 (9%)< 0.001PDL1PD-L110 (91%)1 (9%)< 0.001Abbreviation IFTA: interstitial fibrosis and tubular atrophy. IHC: immunohistochemistry Open table in a new tab Abbreviation IFTA: interstitial fibrosis and tubular atrophy. IHC: immunohistochemistry All 23 patients discontinued the drug associated with AIN and started on corticosteroids at diagnosis, with an initial intravenous bolus in the 11 ICI-related cases and 10 of the non-ICI related. Only one patient in the ICI group received additional immunosuppressive therapy with MMF. Dialysis was necessary for one patient in each group. Corticosteroids were started within the first week after the histological diagnosis in 10 of the 11 patients with ICI-related AIN, and 9 of the 12 patients with non-ICI related AIN who were started on this therapy. Treatment duration was 74 (55-102) days in the whole cohort, there were no differences among ICI-related and not related groups. Supplementary Figure 2 shows the serum creatinine levels at fixed landmarks during follow-up. Despite variability, there was a decreased trend to normal levels after the first month of follow-up. There was no statistically significant difference between both groups at any follow-up landmark. Nine patients with non-ICI related AKI and all 11 with ICI-related recovered renal function after a median time of 3 months (Supplementary Figure 3), without any significant difference between both groups. There are various major findings in this study. First, ICI-related AIN has some differential morphological and phenotypical aspects compared to non-ICI related AIN. The percentage of cortical tissue affected was larger in the ICI-related cases. Positive staining for the PD1 molecule and its ligand, PD-L1, was also observed in 10 of the 11 ICI-related cases but only in one of the non-ICI related. These findings agree with the previous publication by Cassol C et al [5Cassol C, Satoskar A, Lozanski G, et al. Anti-PD-1 Immunotherapy May Induce Interstitial Nephritis With Increased Tubular Epithelial Expression of PD-L1. Kidney Int Rep. 2019;20; 4(8):1152-1160Google Scholar] that described that immunohistochemistry with anti PD-L1 antibodies might help in the differential diagnosis in this clinical setting. On the other hand, they contrast with the experience published by Hakroush S et al [6Hakroush S. Kopp S.B. Tampe D. et al.Variable Expression of Programmed Cell Death Protein 1-Ligand 1 in Kidneys Independent of Immune Checkpoint Inhibition.Front Immunol. 2021; 21624547Google Scholar], who described a distinct PD-L1 expression in renal compartments in multiple murine models of kidney injury and in some human cases with various underlying kidney diseases. PD-L1 was frequently expressed in various renal pathologies independent of ICI therapy and the authors argued that it could potentially be a prerequisite for susceptibility to develop AKI and deleterious immune-related AIN. Unfortunately, the study lacks the clinical and histological description of the patients included. Being able to confirm histologically that an AIN is or is not related to ICI treatment is relevant for several reasons. First, because the use of multiple drugs in cancer patients is very common and these two types of AIN have a different mechanism of injury and therefore the therapeutic approach should not be necessarily the same. In classic drug-induced AIN, there is an antigen that activates the immune response through a delayed hypersensitivity immune reaction [3Perazella M.A. Shirali A.C. Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do?.Kidney Int. 2020; 97: 62-74Google Scholar]. Thus, given the relevance of the antigen in the process, the importance of permanently withdrawing medication when AIN occurs is understandable. Secondly, in ICI-related AIN (irAE), it is not clear why some patients have serious immune-related adverse events and others do not; but considering the multifactorial mechanism of injury, it could be feasible and safe to treat a patient with ICI again after presenting this type of adverse event, if the oncological disease requires it, and the complication has been detected and treated on time [2Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168Google Scholar]. The short time interval between clinical suspicion and biopsy and the low rate of chronicity found in the specimens confirm that the diagnosis of AIN related and not related to ICI was made early in this cohort. This fact allowed early initiation of steroid treatment and as we will explain later, it had a positive impact on renal prognosis. It has been suggested that delayed onset of corticosteroid treatment might be a reason to explain the lack of efficacy of corticosteroids in some patients with drug-induced AIN. A previous study [7Fernandez-Juarez G. Perez J.V. Caravaca-Fontán F. et al.Duration of Treatment with Corticosteroids and Recovery of Kidney Function in Acute Interstitial Nephritis.Clin J Am Soc Nephrol. 2018; 13: 1851-1858Google Scholar] suggested that early administration of corticosteroids was associated with a greater recovery of baseline kidney function, whereas a delay in treatment longer than 3 weeks significantly decreased the likelihood of complete kidney function recovery. Our study corroborates these findings. Furthermore, since most cases of ICI-related AIN in this cohort are resolved within weeks or months of starting steroid therapy, in our experience it would be feasible and safe to resume immune checkpoint blockade after the adverse event has been resolved. However, data on long-term kidney prognosis, including patients with more severe form are lacking. In conclusion, our results suggests that there is a specific histological profile that segregates AIN related and not related to ICI in real world practice. Immunohistochemistry with anti PD-L1 antibodies is necessary to make this differential diagnosis. We also suggest the key value of early kidney biopsy to establish the time of evolution and the potential response to steroid treatment in this clinical setting. These results contribute to the stratification of patients into more consistent disease groups for therapeutic, epidemiological, and basic research. Prospective studies are warranted to confirm these findings. LFQ reports fees form GSK, Akcea, Otsuka and Alexion outside the submitted work; MB reports fees from Otsuka, Novartis and Alexion outside the submitted work; KDJ serves as a consultant for PMV pharmaceuticals, Secretome, George Clinicals and Calliditas and is the current co-president of the American Society of Onconephrology (ASON) and is a paid contributor to uptodate.com. KDJ reports serving on the editorial boards of American Journal of Kidney Diseases, CJASN, Clinical Kidney Journal, Journal of Onconephrology, Kidney International, and Nephrology Dialysis Transplantation; reports serving as Editor-in-Chief of ASN Kidney News and section editor for onconephrology for Nephrology Dialysis Transplantation; and reports other interests/relationships as the President of American Nephrologist of Indian Origin The rest of authors declare no conflicts of interest. CERCA Programme / Generalitat de Catalunya Download .pdf (.65 MB) Help with pdf files" @default.
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• W4313325146 date "2023-03-01" @default.
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• W4313325146 title "Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes" @default.
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