Clinical Kidney Journal, 2021, vol. 14, no. 3, 884–890 doi: 10.1093/ckj/sfaa027 Advance Access Publication Date: 4 May 2020 Original Article ORIGINAL ARTICLE Acute tubulointerstitial nephritis induced by checkpoint inhibitors versus classical acute tubulointerstitial nephritis: are they the same disease? Juliana B. Draibe1,*, Clara Garcı́a-Carro2,*, Laura Martinez-Valenzuela1, Irene Agraz2, Xavier Fulladosa1, Monica Bolufer2, Ariel Tango1, Joan Torras1,3,4,# and Marı́a José Soler 2,3,# 1 Nephrology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain, 2Nephrology Research Group, Vall d’Hebron Research Institute, Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, 3Red de Investigación Renal (REDINREN), Instituto Carlos III, FEDER, Madrid, Spain and 4Clinical Sciences Department, Barcelona University, Barcelona, Spain Correspondence to: Marı́a José Soler; E-mail: mjsoler01@gmail.com; Joan Torras; E-mail: 15268jta@comb.cat; Twitter handle: @PepaSolerR, Juliana B. Draibe; E-mail: jbordignon@bellvitgehospital.cat *These authors contributed equally to this work. # These authors share credit for senior authorship. ABSTRACT Background. The incidence of acute tubulointerstitial nephritis (ATIN) related to drugs has dramatically increased over recent years. A new subtype of ATIN, apparently different from classical drug-related ATIN, has emerged that has been related to the administration of immune checkpoint inhibitors (ICIs). We investigated these differences between ICI-related ATIN (ICI ATIN) and non-ICI-related ATIN in terms of clinical features, response to treatment with steroids and the evolution of kidney function. Methods. A total of 47 patients diagnosed with ATIN from two centres were recruited. Of these, 13 patients presented with ATIN during ICI treatment and 34 were diagnosed with ATIN attributed to other drugs. The main demographic, clinical and analytical variables such as gender, age and current medication were recorded. The type of malignancy, oncological treatment, ICI dose and presence of extrarenal immune-related adverse events were also reviewed. Renal biopsy diagnosis, time to drug withdrawal and ATIN-specific treatment, as well as laboratory data during follow-up, were also studied. Results. Patients diagnosed with ICI ATIN presented with lower creatinine (ICI ATIN 3.8 6 1.03 versus classical ATIN 5.98 6 4.15 mg/dL, P ¼ 0.007) at diagnosis and higher urinary leucocyte counts (ICI ATIN 263.2 6 418.04 versus classical ATIN 133.55 6 284.62, P ¼ 0.048) compared with patients with non-ICI-related ATIN. Time from initiation of the culprit drug to ATIN diagnosis was longer in patients with ICI ATIN than in those with classical ATIN (197.07 6 184.99 versus 114.4 6 352.16 days, P ¼ 0.006). In addition, during follow-up, the slope of decreasing creatinine over time was lower for ICI ATIN compared with non-ICI-related ATIN. Received: 7.11.2019; Editorial decision: 28.1.2020 C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 884 ATIN induced by ICIs versus classical ATIN | 885 Conclusions. In this study, we analysed differences between ICI ATIN and classical ATIN. We found that patients with ICI ATIN presented with a larger latency period after culprit drug initiation, milder acute kidney injury and slower creatinine amelioration compared with those with classical ATIN. These results may, in part, be ascribed to potential differences in the pathological mechanisms involved in ATIN development, suggesting that ICI and classical ATIN may be different diseases with similar renal histologies. Keywords: acute kidney injury, acute tubular nephritis, immune checkpoint inhibitors, kidney biopsy, steroid therapy INTRODUCTION response to treatment with steroids and follow-up. Moreover, in both cases, available data are almost limited to case series. The incidence of acute tubulointerstitial nephritis (ATIN) re- Thus, the aim of this study is to evaluate differences between lated to drugs has dramatically increased over recent decades. ICI ATIN and non-ICI-related ATIN, to examine clinical features, Data from the Spanish Registry of Glomerulonephritis have response to treatment with steroids and the evolution of kidney demonstrated that the diagnosis of biopsy-proven ATIN has in- function. creased from 3% to 20% over the last 20 years [1]. ATIN has be- come the third most common cause of acute kidney injury (AKI) in hospitalized patients [2]. The main trigger associated with MATERIALS AND METHODS ATIN development is the use of certain nephritogenic drugs Patients that are able to induce antigen-initiated cell-mediated injury in kidney tubule cells. The remaining cases are attributable to au- All cases of biopsy-proven ATIN between January 2015 and May toimmune conditions and infections, and a few cases are classi- 2019 at Bellvitge University Hospital and Vall d’Hebron fied as idiopathic. Diagnosis is based on histological findings, University Hospital were eligible for the study. Exclusion criteria mainly tubulointerstitial lymphocytic infiltrates without im- were as follows: age <18 years old, ATIN related to autoimmune mune deposits [3]. Early withdrawal of the offending drug and conditions and presence of urinary tract infections at the time early treatment with corticosteroids constitute the basis of of inclusion. All patients were prospectively followed by expert treatment of the disease [4]. clinicians in the outpatient clinics of both hospitals. The Ethical Over the last decade, a new subtype of ATIN has emerged Committee of Bellvitge University Hospital approved the study that is different from classical drug-related ATIN, which has protocol (PR143/19). been related to the administration of immune checkpoint inhib- itors (ICIs). This group of drugs has shown promising results in Biopsies the treatment of tumours with limited responses to conven- Two kidney cores were obtained with ultrasound guidance us- tional chemotherapeutic treatment such as melanoma, non- ing a 16-gauge spring-loaded biopsy gun: one for optical micros- small-cell lung carcinoma, renal cell carcinoma and Hodgkin copy (haematoxylin and eosin and saffron, periodic acid–Schiff lymphoma. ICIs are antibodies directed against programmed and Masson trichrome) and one for immunofluorescence (IF). cell death-1 (PD-1), PD-1 ligand 1 (PD-L1) and cytotoxic T lym- Biopsies contained at least one glomerular and one arterial pro- phocyte antigen 4 (CTLA4). The PD-1/PD-L1 and CTLA4 path- file, and sufficient tubulointerstitial tissue to grade interstitial ways control the differentiation of autoreactive T lymphocytes inflammation, tubulitis, interstitial fibrosis and tubular atrophy. in order to maintain tolerance to self-antigens [5]. The blockade All ATIN diagnoses were confirmed by kidney biopsy reviewed of these pathways stimulates the immune response toward by the local pathologist. ATIN histopathological diagnosis was cancer cells that express negative T cell surface ligands, but the defined by the presence of diffuse interstitial oedema and in- immune response triggered by ICIs may result in immune- flammatory cell infiltrate mainly composed of lymphocytes and mediated adverse events [6]. The incidence of ICI-induced AKI eosinophils, tubulitis and fibrosis, with negative IF. The defini- varies between 2.2% and 29% [7, 8]. ATIN is the dominant pat- tion of severity of the tubulointerstitial lesions was made tern of ICI-induced AKI [7] and is histologically indistinguish- according to the percentage of tissue affected. Cell infiltration able from ATIN secondary to other drugs. The exact and atrophy were considered severe when >75% of the tubular mechanisms of ICI-related ATIN (ICI ATIN) are not completely surface was affected. Severe fibrosis was defined when it af- understood, but there are some clues in the literature. ICI may fected >75% of the renal parenchyma. promote T cell migration to the kidney, reducing tolerance to endogenous antigens and initiating an inflammatory response that could lead to ATIN. ICI could also reactivate exhausted Clinical variables drug-specific T cells and induce loss of tolerance to other medi- We recorded key demographic, clinical and analytical variables cations [9]. Interestingly, many cases of ICI ATIN occur in such as gender, age, ethnicity, comorbidities and current medica- patients receiving drugs independently associated with ATIN, tion with special emphasis on ICIs, NSAIDs, PPIs, angiotensin- such as non-steroidal anti-inflammatory drugs (NSAIDs) or pro- converting enzyme inhibitors, angiotensin II receptor blockers ton pump inhibitors (PPIs), preceding ICI treatment [10]. and antibiotics. Medical records regarding the type of malig- Although the clinical characteristics seem to be similar, the nancy, oncological treatment, first and last dose of ICI, and pres- pathogenic mechanisms of ICI ATIN and classical ATIN do not ence of extrarenal immune-related adverse events were also appear to be the same, which suggests that they may require reviewed. At the time of ATIN onset, serum creatinine level, sedi- different clinical management and confer different prognoses. ment findings, proteinuria, urine cytology, serological informa- To the best of our knowledge, there is no study comparing ICI tion, renal biopsy diagnosis, time to withdrawal of the offending ATIN and classical ATIN in terms of clinical presentation, and drug and specific treatment of ATIN were registered, as well as 886 | J. B. Draibe et al. Table 1. Baseline characteristics of the population Clinical data ICI ATIN Non-ICI-related ATIN P-value n ¼ 13 n ¼ 34 Age (years) 71 6 8.48 63.09 6 16.12 0.101 Sex: male/female (% patients) 69.24/30.76 50/50 0.453 Hypertension (% patients) 53.84 64.7 0.52 Diabetes (% patients) 23.08 23.53 1 Creatinine prior to ATIN (mg/dL) 1.01 6 0.32 0.96 6 0.37 0.69 Creatinine at diagnosis (mg/dL) 3.8 6 1.033 5.98 6 4.15 0.007 C-reactive protein at diagnosis (mg/mL) 59.95 6 95.74 37.1 6 67.22 0.408 Blood eosinophil count at diagnosis ( 10e9/L) 0.2531 0.3424 0.394 Proteinuria at diagnosis (mg/g creatinine) 467.12 6 183.73 1086 6 1558.95 0.808 Haematuria at diagnosis (% patients) 66.7 37.5 0.084 Urinary leucocyte count at diagnosis (count/mL) 263.20 6 418.04 133.55 6 284.62 0.048 Systemic symptoms at presentation (% patients) Rash 0 11.8 0.564 Fever 30.8 22.1 0.7 Arthralgia 15.4 5.9 0.304 Histologic features in diagnostic kidney biopsy (% patients) Severe inflammatory infiltrate 46.2 35.3 0.516 Severe tubular atrophy 15.4 11.8 0.086 Severe interstitial fibrosis 0 8.8 0.544 Presence of granuloma 8.3 8.8 1 Presence of eosinophilic infiltrate 69.2 88.2 0.35 Presence of plasma cells infiltrate 33.3 41.2 0.739 Data are presented as mean 6 standard deviation unless otherwise indicated. laboratory data during the follow-up period. Baseline kidney Table 1 shows the main baseline characteristics of both function was defined as the value of serum creatinine 6 months cohorts. Patients diagnosed with ICI ATIN presented with lower before ATIN. The evolution of clinical and analytical parameters creatinine levels and higher urinary leucocyte counts compared was registered during the prospective follow-up of the patients. with patients with non-ICI-related ATIN at diagnosis. We did Relapse was defined as worsening of kidney function not attribut- not find differences in the prevalence of systemic symptoms at able to other causes together with the presence of compatible uri- presentation such as fever, arthralgias or rash. We found a ten- nalysis and inflammation parameters. Normalization of kidney dency towards a more severe tubulointerstitial infiltrate and tu- function was defined as glomerular filtration rate (GFR) >60 mL/ bular atrophy, together with lesser fibrosis, in the diagnostic min/1.73 m2 or GFR prior to the ATIN episode. kidney biopsies of ICI ATIN patients compared with non-ICI-re- lated ATIN cases, but differences did not reach statistical signif- icance (see Table 1). The length of treatment with ICIs for Statistical analysis patients who presented with ICI ATIN was 197.07 6 184.99 days. Data were analysed using GraphPad Prism version 6.00 Regarding neoplasia, malignancies found were: lung (nine (GraphPad Software, La Jolla, CA, USA) and IBM SPSS Statistics patients), melanoma (three patients) and pancreas (one pa- Version 20.0 (IBM Corp., Armonk, NY, USA). Results were tient). Five patients did not receive any oncospecific treatment expressed as frequencies for categorical variables or as the mean before ICI treatment. Three patients received cisplatin before ICI 6 standard deviation for continuous variables. The Kolmogorov– treatment: one of these three received cisplatin only, one in Smirnov test was applied to determine whether quantitative vari- combination with docetaxel, and one in combination with eto- ables were normally distributed. For comparison of means of two poside, chimeric human/mouse immunoglobulin G1 monoclo- groups, a Student’s t-test or Mann–Whitney U test was used nal antibody and paclitaxel. Five patients received carboplatin depending on the distribution of the variable. The Chi-square test before ICI treatment: four of these five received carboplatin only was used for qualitative variables. Actuarial survival analysis was and the other in combination with folate antagonist/antineo- performed by Kaplan–Meier curves. P < 0.05 was considered plastic agent. Finally, one patient received five lines of treat- significant. ment before initiating ICI treatment, one of which was with anti-PD-L1 plus an anti-CTLA4. Among patients treated with ICIs, the most frequently in- RESULTS volved drugs were antibodies against PD-1 (61.5%). Nine out of Baseline characteristics 13 patients in the ICI ATIN group were chronically treated with PPIs (omeprazole). Three of those nine patients were also Forty-seven patients diagnosed with ATIN were recruited treated with NSAIDs (ibuprofen), while the remaining four according to the inclusion and exclusion criteria of the study. Of patients did not receive any other drugs that have been classi- these, 13 patients presented with ATIN during treatment with cally associated with ATIN. Regarding patients presenting with an ICI and 34 patients were diagnosed with ATIN attributed to ATIN attributed to other drugs, NSAIDs (29.4%) and fluoroquino- other drugs. Mean time since diagnosis to end of follow-up was lones (20.6%) were the most frequent aetiologies. Table 2 sum- 27.04 6 20.75 months (range 0.5–69). marizes the more probable aetiologies of ATIN in both cohorts. ATIN induced by ICIs versus classical ATIN | 887 Table 2. Aetiology of ATIN in the cohorts of ICI ATIN and non-ICI-related patients ICI related ATIN (n ¼ 13) Non-ICI related ATIN (n ¼ 34) Drug % cases Drug % cases Anti-PD-1 61.5 NSAIDs 29.4 Anti-PD-L1 23.1 Fluoroquinolones 20.6 Anti-PD-1 þ anti-CTLA4 7.7 b-Lactams 8.8 Anti-PD-L1 þ anti-CTLA4 7.7 PPIs 2.9 Others 38.2 The non-ICI-related ATIN cases were attributed to: sitagliptin, rifampicin, repaglinide, fosfomycin, lenalidomide, cocaine, vandetanib and cobimetinib. FIGURE 1: Evolution of creatinine (A), proteinuria (B), leucocyturia (C), eosinophil count (D) and C-reactive protein (E) after 5 months to 1 year of follow-up. Follow-up and evolution of ATIN function (defined as GFR >60 mL/min/1.73 m2 or GFR prior to the ATIN episode). We noticed that there tended to be slower renal Creatinine. AKI was less severe in ICI ATIN patients compared function recovery in ICI ATIN compared with non-ICI-related with non-ICI-related ATIN patients. At the time of diagnosis, ATIN patients, but differences did not reach statistical signifi- creatinine levels were significantly lower in ICI ATIN patients cance. A similar percentage of patients achieved normal renal (3.8 6 1.03 versus 5.98 6 4.15 mg/dL, P ¼ 0.007). Peak creatinine function at the end of follow-up (44.1% versus 30.8% of patients levels reached during AKI were also lower in ICI ATIN compared in the ICI ATIN versus the non-ICI-related ATIN cohort of with non-ICI-related ATIN patients (4.19 6 1.43 versus patients, P ¼ 0.4). Of note, a year after prednisone initiation, the 6.22 6 4.63 mg/dL, P ¼ 0.034). Time from initiation of the culprit percentage of patients who showed kidney function recovery drug to the ATIN diagnostic biopsy was longer in ICI ATIN com- remained stable during the rest of the follow-up period (see pared with non-ICI-related ATIN patients (197.07 6 184.99 ver- Figure 2). sus 114.4 6 352.16 days, P ¼ 0.006). During follow-up, the slope of decreasing creatinine over time was lower in ICI ATIN compared with non-ICI-related Proteinuria. We did not find differences in proteinuria at patients. Creatinine decrease (D creatinine) was lower from diagnosis between ICI ATIN and non-ICI-related ATIN baseline to Month 1, from baseline to Month 3, and from base- patients (P ¼ 0.808). Despite this, the amelioration of protein- line to Month 6 in ICI ATIN patients compared with non-ICI-re- uria (D proteinuria) was lower in ICI ATIN compared with lated ATIN patients. (P ¼ 0.023, 0.014 and 0.004, respectively). non-ICI-related ATIN patients. Decrease in proteinuria was Figure 1A shows mean serum creatinine evolution during the lower in ICI ATIN patients between baseline and Month 1, first year after diagnosis of ATIN in both cohorts. and between baseline and Month 3, compared with non-ICI We registered the time elapsed since the initiation of ATIN related patients (P ¼ 0.015 and 0.033, respectively) (see treatment with prednisone to the normalization of kidney Figure 1B). 888 | J. B. Draibe et al. Urinary leucocyte count. Urinary leucocyte count was higher in prednisone initiation was similar in both cohorts (P ¼ 0.387). ICI ATIN compared with non-ICI-related ATIN patients at diag- Table 3 compares the dosing of prednisone in the two cohorts. nosis (P ¼ 0.048). Both cohorts presented similar outcomes of this parameter (see Figure 1C). Relapses Blood eosinophil count. Mean blood eosinophil count remained Relapse rate did not differ between the two cohorts of ATIN patients (P ¼ 0.334). Three cases of relapse were identified dur- lower in ICI ATIN patients compared with non-ICI-related ATIN ing follow-up in each cohort. The main characteristics of patients during the follow-up period, but differences did not patients who relapsed are displayed in Table 4. reach statistical significance (see Figure 1D). Serum C-reactive protein levels. Mean serum C-reactive protein DISCUSSION levels were higher in ICI ATIN patients compared with non-ICI- Herein, we present 13 biopsy-proven cases of ATIN in the set- related ATIN patients from Month 3, although differences did ting of treatment with ICIs, and we compare their baseline char- not reach statistical significance at the time points evaluated acteristics and evolution with 34 cases of ATIN related to other (see Figure 1E). drugs. To the best of our knowledge, this is the largest case se- ries of ICI-related ATIN reported to date and the only published Treatment of the ATIN episode clinical comparison that has attempted to find differences in The offending drug was withdrawn in all cases. All patients features compared with other forms of nephritis. were treated with prednisone. Three out of 13 patients in the ICI ICI ATIN patients in our cohort presented with milder forms ATIN cohort and 3/34 patients in the non-ICI-related ATIN co- of AKI compared with non-ICI-related cases. In agreement with hort received intravenous methylprednisolone pulses at diag- this finding, other case series in the literature have also nosis. Three out of 34 patients in the non-ICI-related cohort reported slight increases in creatinine in patients with ICI AKI. received mycophenolate mofetil compared with 0/13 patients in In the case series published by Cortazar et al. [7], 12 patients the ICI ATIN cohort. treated with ICIs presenting with ATIN showed a mean peak Time to initiation of treatment with steroids was inferior in creatinine level of 4.5 mg/dL, similar to the peak creatinine no- ICI ATIN compared with non-ICI-related ATIN cases (P ¼ 0.027). ticed in our cohort (4.15 mg/dL). Cassol et al. [11] published a re- The dosing and schedule of prednisone was similar for ICI ATIN port of nine cases of ICI ATIN with peak creatinine levels and non-ICI-related ATIN patients. The prednisone cumulative between 1.4 and 4.3 mg/dL. In concordance, Shirali et al. dose was similar between patients in the two cohorts reported six cases of ICI ATIN with a peak creatinine ranging be- (P ¼ 0.883), as was the duration of the treatment (P ¼ 0.932). tween 1.8 and 2.3 mg/dL in five cases, and a peak creatinine of There were no differences in the prednisone cumulative dose 5.5 mg/dL in the remaining one [10]. Only in one case series of during the first 3 months of treatment. Time since diagnosis to five patients with ATIN related to ICI treatment [12] did the authors observe higher peak creatinine levels between 4.8 and 7.8 mg/dL. Urinary leucocyte counts at diagnosis were signifi- cantly higher in ICI ATIN compared with non-ICI-related ATIN patients. Although a similar proportion of patients recovered baseline kidney function at the end of follow-up, renal function recovery was slower in ICI ATIN compared with non-ICI-related ATIN patients. This is reflected by the differences in D creatinine be- tween diagnosis and Months 1, 3 and 6, which were statistically lower in ICI ATIN compared with non-ICI-related ATIN patients. The same pattern was followed by D proteinuria followed dur- ing the first 3 months. Although differences did not reach statis- tical significance, slower recovery of the kidney function of ICI-treated patients was observed via Kaplan–Meier survival analysis curves. One could hypothesize that slower renal recov- ery after ICI discontinuation may be ascribed to the longer half- FIGURE 2: Time from ATIN diagnosis to renal function recovery in both studied life of ICIs, ranging between 20 and 25 days [13], and the fact ATIN groups. that this class of drugs can remain bound to lymphocytes for up Table 3. Treatment comparison between patients with ICI ATIN and non-ICI-related ATIN patients Steroid treatment ICI ATIN Non-ICI-related ATIN P-value Time since ATIN diagnosis to steroid initiation (days) 9.92 6 17.57 2.52 6 6.15 0.027 Initial methylprednisolone bolus administration (% patients) 25 8.82 0.178 Prednisone cumulative dose (g) 9.39 6 21.92 3.59 6 2.78 0.883 Months of prednisone treatment 5 6 3.32 9 6 9.87 0.932 Prednisone cumulative dose per month of treatment (g/month) 1.31 6 1.96 0.62 6 0.407 0.132 Prednisone cumulative dose at Month 1 (mg) 1564.38 6 511.28 1456 6 637 0.597 Prednisone cumulative dose at Month 2 (mg) 2270.92 6 693.67 2115.5 6 741.56 0.537 Prednisone cumulative dose at Month 3 (mg) 2735.73 6 1026.31 2454.30 6 1070.19 0.959 ATIN induced by ICIs versus classical ATIN | 889 Table 4. Cases of patients with ATIN relapse, treatment and evolution Prednisone cu- Time to relapse mulative dose at Serum creati- Sex/age (years)/ since diagnosis the moment of nine at re- ATIN cause (months) relapse (mg) Relapse cause lapse (mg/dL) Relapse treatment Evolution M/71/anti-PD-1 8 4075 Offending drug re- 2.07 Prednisone 30 mg/day Normalization of initiation serum creatinine M/81/anti-PD-1 4 2425 Ciprofloxacin initiation 3.02 Prednisone 30 mg/day Normalization of plus decrease in pred- serum nisone dose creatinine F/83/anti-PD-1 3 2572.5 Prednisone withdrawal 10.59 Methylprednisolone Stabilization— 750 mg (bolus) þ pred- creatinine nisone 40 mg/day 1.4 mg/dL M/77/NSAIDs 15 3750 Prednisone withdrawal 2.51 Prednisone 40 mg/day Stabilization— creatinine 1.5 mg/dL M/74/amoxicillin 5 4125 Unknown 2.49 Prednisone 30 mg/day Stabilization— creatinine 2.5 mg/dL M/66/ 5 2060 Unknown 2.03 Prednisone 15 mg/day Stabilization— ciprofloxacin creatinine 1.5 mg/dL to 57 days [14]. Other case series have described variable kidney diagnosis of such patients compared with those with non-ICI- function normalization rates ranging from as few as 2/12 related ATIN. Another difference between ICI and non-ICI-re- patients [7] to almost all patients in a case series (5/6 patients) lated ATIN reported in the literature is the occurrence of a flare [10]. These differences were not related to ATIN treatment. All after drug re-exposure. Recurrence of classical drug-induced patients were treated with steroids and there were no differen- ATIN upon re-exposure to the offending drug has been widely ces in prednisone cumulative doses and the duration of treat- described [3]. In contrast, Cortazar et al. [17] recently reported a ment. Time to steroid initiation has been proposed to be one of low prevalence of recurrence of ATIN upon ICI re-challenge af- the main factors that determines the outcome of classical ATIN ter successful treatment of the first episode. [15]. In our study, the initiation of steroid treatment after ATIN The observational, retrospective nature of the study consti- was delayed in non-ICI-related cases. However, this differential tutes its main limitation. Although differences in treatment of delay did not influence the outcome: we did not find differences ATIN episodes were not noticed between the two cohorts, stan- in renal function at the end of the follow-up period. dardization of the prednisone schedule would allow stronger The period of time between offending drug initiation and conclusions about differences in ATIN evolution between ICI ATIN diagnosis was longer in ICI ATIN compared with non-ICI- and non-ICI-related ATIN. related cases. Long latency periods until ATIN development in patients treated with ICIs have been previously reported [7, 14]. This may, in part, be explained by differential pathological CONCLUSION mechanisms of ATIN development. It has been demonstrated In this study, we present the largest case series of ICI ATIN to previously that classical drug-induced ATIN is an allergic drug date and, to our knowledge, the first published comparison with hypersensitivity reaction mediated by T lymphocytes. However non-ICI-related ATIN cases. We observe that ICI ATIN patients the pathological mechanisms of ICI ATIN are unknown. It has manifest a longer latency period after offending drug initiation, been hypothesized that the use of an ICI breaks down immune milder AKI and slower creatinine amelioration compared with tolerance to antigens that would not otherwise be nephritogenic ATIN in the setting of another drug treatments. This differential [10]. In agreement, Koda et al. [16] performed a lymphocyte stim- evolution may be ascribed to potential differences in the patho- ulation test in a nivolumab-associated ATIN patient and con- logical mechanisms behind ATIN development. Further investi- firmed drug-induced (lansoprazole) lymphocyte stimulation, although it had been used safely for a long time before the initi- gation and cumulative experience are required to determine ation of anti-PD-1 therapy. Further research focusing on the im- whether the differences between classical ATIN and ICI ATIN plicated molecular mechanisms is necessary to confirm this are enough for them to be considered as two different diseases. hypothesis. Longer latency periods together with strict monitor- ing of patients who undergo ICI therapy may explain the lower ACKNOWLEDGEMENTS creatinine levels of these patients at the moment of diagnosis compared with the faster development of ATIN in the setting of We gratefully acknowledge the support of FIS/Fondos FEDER other drugs in individuals who are not monitored. (REDinREN RD016/0009). Although differences did not reach statistical significance, ICI ATIN patients showed more inflammatory infiltrates and less fibrosis. 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