M Espi

C Teuma

E Novel-Catin

D Maillet

P J Souquet

S Dalle

L Koppe

D Fouque

Renal adverse effects of Immune Checkpoints Inhibitors in clinical practice: ImmuNoTox (INT) study

Keywords: Checkpoint inhibitors, adverse renal events, IRAEs, acute kidney injury

Background/objectives: Acute Kidney Injury induced by Checkpoint Inhibitors therapies (CPI-induced AKI) is an uncommon but severe Immune Related Adverse Event (IRAE). The aim was to describe the epidemiology, risks factors, clinical, and laboratory characteristics of these renal AE in a real-life cohort treatment.

Design/participants: Consecutive patients undergoing a CPI therapy at the Hôpital Lyon Sud from January 2015 to July 2017 were included. A systematic retrospective analysis of medical files was performed, monthly serum creatinine levels, associated treatments, and occurrence of other IRAEs data were collected. AKI episodes explained by classic AKI etiologies (pre-renal, obstructive, septic) were excluded from the analysis.

Results: CPI-induced AKI incidence was 3.7% (13/352), and appeared to be timedependent (7.7% (11/143) for patients with >3 months of CPI exposure), ranging from 1 to 16 months. All cases with available histology were acute tubulointerstitial nephritis, with poor urinary sediment. The severity of AKI was mild (stage 1 in 50% of cases), with no need for renal-replacement therapy. Although CPI-induced AKI patients had more frequently other IRAEs (77% vs 39%), this was not associated with a greater risk of AKI. Pre-existing chronic kidney disease (defined as an estimated glomerular filtration rate <60mL/min) was not associated with a greater risk of CPIinduced AKI. Treatments of CPI-induced AKI were heterogeneous, with discontinuation of CPIs, and inconstant systemic corticosteroid therapy.

Conclusion: The monitoring of renal function and early identification of AKI during

CPIs treatment is essential. The optimal management of CPI-induced AKI remains unclear and requires a close collaboration between the oncology and nephrology departments.

Clinical Relevancy Statement:

Immune checkpoint inhibitors (CPIs) have dramatically improved patient outcomes in different malignant contexts such as melanoma, non-small cell lung cancers (NSCLC), or urologic cancers. Usually well-tolerated, CPIs are however associated with immune related adverse events (IRAEs). Among them, acute kidney injury (AKI) is uncommon, and not well-described. Following the exponential increase in the prescription of CPIs, previously uncommon cases of IRAE (such as AKI) became of common occurrence in referral centers. Data regarding the epidemiology, risk factors, or management of CPI-induced AKI are currently lacking or can be discordant. Data regarding CPI-induced AKI, in a large real-life cohort were reported herein.

INTRODUCTION:

Immune checkpoint inhibitors (CPI) such as anti PD-(L)1 or anti CTLA-4 lead to the restoration of anti-tumor immunity. They are largely used for the treatment of several solid malignancies (such as advanced melanoma, advanced non-small cells and small cells lung cancer, or urologic cancers) [START_REF] Robert | A decade of immune-checkpoint inhibitors in cancer therapy[END_REF]. The toxicity profiles of CPI are very heterogeneous and depend on their type as well as on their association with other CPI, chemotherapy, or a targeted therapy. Among CPI toxicities, Immune Related Adverse Events (IRAEs) are secondary to non-specific activation of the immune system. Every organ can be involved [START_REF] Hofmann | Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy[END_REF], the most frequent are the skin, the liver, and the digestive tract. In randomized clinical trials, single agent CPI were globally well tolerated as grade ≥ 3 IRAEs occurred in less than 15% of patients treated with an anti PD-(L)1 and in less than 40% of patients treated with an anti CTLA-4 [START_REF] Arnaud-Coffin | A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors[END_REF].

Rarely, IRAEs are life threatening as they can induce severe immune-related renal adverse events that impose the treatment to be discontinued.

The exact incidence of renal adverse events is uncertain and ranges from 0.4% [START_REF] Iacovelli | Renal Toxicity in Patients Treated with Anti-Pd-1 Targeted Agents for Solid Tumors[END_REF] to 29% [START_REF] Wanchoo | Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review[END_REF] depending on studies. These estimated incidences mostly rely on large meta-analyses of controlled, randomized clinical trials [START_REF] Hofmann | Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy[END_REF][START_REF] Abdel-Rahman | A network meta-analysis of the risk of immunerelated renal toxicity in cancer patients treated with immune checkpoint inhibitors[END_REF] that included highly selected patients, which is hardly a reflection of real life conditions, and for which there was no specific renal outcome as primary or secondary endpoints. Only three 'real life' studies (retrospective studies including consecutive treated patients) [START_REF] Seethapathy | The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors[END_REF][START_REF] Meraz-Muñoz | Acute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes[END_REF][START_REF] Stein | Acute kidney injury in patients treated with anti-programmed death receptor-1 for advanced melanoma: a real-life study in a single-centre cohort[END_REF] investigating CPI-induced acute kidney injury (AKI) were performed. In these studies, the incidence of AKI was respectively 17, 16.5, and 17%, but only 3, 3.9, and 3.3% of AKI could be attributed to the CPI therapy itself.

The most common manifestation of renal adverse event associated with CPI therapy is CPI-induced AKI [START_REF] Shingarev | Kidney Complications of Immune Checkpoint Inhibitors: A Review[END_REF] with histological description of acute interstitial nephritis (AIN) [START_REF] Cortazar | Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors[END_REF]. Less frequently, glomerular lesions (such as minimal change disease [START_REF] Gao | Minimal change disease associated with anti-PD1 immunotherapy: a case report[END_REF][START_REF] Daanen | Nivolumab-associated nephrotic syndrome in a patient with renal cell carcinoma: a case report[END_REF][START_REF] Kitchlu | Nephrotic Syndrome With Cancer Immunotherapies: A Report of 2 Cases[END_REF], immune complex glomerulonephritis [START_REF] Fadel | Anti-CTLA4 antibody-induced lupus nephritis[END_REF], pauci-immune glomerulonephritis [START_REF] Mamlouk | Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience[END_REF], membranous nephropathy [START_REF] Mamlouk | Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience[END_REF], IgA nephropathy [START_REF] Kishi | IgA Nephropathy after Nivolumab Therapy for Postoperative Recurrence of Lung Squamous Cell Carcinoma[END_REF]), thrombotic microangiopathy [START_REF] Cortazar | Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors[END_REF], acute tubular necrosis have been described, or even ionic disturbance [START_REF] Charmetant | A new expression of immune checkpoint inhibitors' renal toxicity: when distal tubular acidosis precedes creatinine elevation[END_REF][START_REF] Manohar | Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis[END_REF][START_REF] El Bitar | Renal Tubular Acidosis an Adverse Effect of PD-1 Inhibitor Immunotherapy[END_REF] without AKI.

The clinical presentation of CPI-induced AKI is usually non-specific, with inconstant leucocyturia, mild or no proteinuria, and variable setting of occurrence. As of today, no specific risk factors have been identified, but concomitant treatment with medications known to induce allergic AIN (such as proton-pomp inhibitors [PPIs] or non-steroidal anti-inflammatory drugs [NSAID]) are thought to trigger CPI-induced AKI [START_REF] Shirali | Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients[END_REF]. The optimal management of AKI during CPI treatment remains unclear, the use of systemic corticosteroid therapy, as well as CPI discontinuation, are favored event though the level of proof is low for this recommendation [START_REF] Puzanov | Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group[END_REF]. The renal outcome is variable, and the risk-benefit ratio of the subsequent reintroduction of the same or another CPI is uncertain. In this context, the ImmuNoTox (INT) study was conducted, it is a retrospective monocentric study including patients treated with either an anti CTLA-4, anti PD-1, or anti PD-L1 CPI, which aimed at 1-describing their specific renal tolerance in a large, real life treatment cohort and 2-assessing the risk factors that might contribute to CPI-induced AKI.

PATIENTS AND METHODS:

Population:

Data from all patients treated with CPI therapy in the dermatology, oncology, or pneumology departments at the Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France from January 2015 to July 2017 were retrospectively analyzed.

Considered CPIs were anti CTLA-4 antibodies (Ipilimumab), anti PD-1 antibodies (Nivolumab or Pembrolizumab), and anti PD-L1 antibodies (Avelumab, Atezolizumab or Durvalumab).

This study was approved by a national ethical research committee "Ile de France II" in October 2017 (IRB registration #00001072) and registered on clinicaltrials.gov (NCT03316417). The Comission nationale de l'informatique et des libertés (CNIL, French national commission for the protection of digital information) gave a positive opinion for the study. Patients were informed of the nature of the collected data and their right to retract from the study by an individual letter of information.

Inclusion criteria:

All consecutives adult patients (≥ 18 year-old) treated with CPI were included, except those for whom no serum creatinine value (neither at baseline nor during follow-up) was available. The follow-up period corresponded to the duration of the CPI treatment, until its discontinuation for either tumoral progression, IRAEs requiring treatment modification and/or discontinuation, or death.

Data collection:

Demographic data, medical history, clinical, laboratory, and histological data at presentation were collected from medical files. CPI treatment characteristics, comedications, and the cumulated volume of iodinated contrast agent were also reported. The co-medications were grouped into medications known to alter renal hemodynamic (renal HD drug i.e. diuretics and renin-angiotensin system [RAS] blockers) and medications historically known to induce allergic AIN (i.e. proton pump inhibitors [PPIs], non-steroidal anti-inflammatory drugs [NSAIDs] and fluindione).

CKD was defined by an estimated glomerular filtration rate (eGFR) < 60mL/min using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula adjusted on body surface area (BSA), described as more suitable for cancer patients [START_REF] Janowitz | New Model for Estimating Glomerular Filtration Rate in Patients With Cancer[END_REF][START_REF] Sleilalty | Evaluation of chronic kidney disease in cancer patients: is there a preferred estimation formula?[END_REF], who are commonly sarcopenic.

Information about the occurrence of extra renal IRAEs (hepatic, cutaneous, endocrine, gastrointestinal, neurologic, pulmonary, cardiac, rheumatologic, hematologic IRAEs defined by the CTCAE v5.0) was also collected.

Outcomes:

The primary outcome was the incidence of CPI-induced AKI. AKI was defined as a serum creatinine (SCr) level 1.5-fold higher than baseline, measured by enzymatic method (Roche, France) with calibrators defined by an isotope-dilution mass spectrometry and according to the v5.0 Common Terminology Criteria for Adverse Events (CTCAE) [START_REF]Common Terminology Criteria for Adverse Events[END_REF]. The SCr level before the first injection defined the baseline SCr level. AKI were divided in three severity groups based on the magnitude of the SCr level increase, according to KDIGO clinical practice guidelines: 1.5 -1.9 fold from baseline SCr (AKI stage 1), 2 -2.9 fold from baseline SCr (AKI stage 2), and over 3 fold from baseline SCr (AKI stage 3). Based on the clinical history, laboratory analysis, ultrasound imaging, evident drug nephrotoxicity, and histological analysis when available, AKI events were classified by two independent nephrologists (ME and CT) as either CPI-induced (if no other potential cause of AKI was identified) or non CPI-induced. If there was a discrepancy in opinion between both nephrologists, a third independent nephrologist was consulted (ENC). All non CPI-induced AKI were excluded from the final analysis.

Secondary outcomes were the assessment of pre-specified baseline characteristics, risk factors, and treatments against the development of AKI during CPI therapy.

Additionally, the cases of nephrologist-confirmed CPI-related nephrotoxicity were reported and characterized (in terms of clinical, laboratory and histological presentations, severity, reversibility). AKI management was studied, including the use of a systemic corticosteroid regimen or not. SCr level 3 months after the initial episode was also recorded, and the reversibility of AKI was defined as a SCr level elevation less than 1.3-fold from the baseline after 3 months.

Statistical analysis:

Characteristics of patients were expressed as count (percentage) or median [interquartile range, IQR] because variables were not normally distributed (tested using the D'Agostino-Pearson test). The two groups were compared using the Mann and Whitney test for quantitative variables and the Fisher exact test for the qualitative ones. A univariate regression was performed to evaluate the relationship between all measured baseline characteristics and AKI episodes. Age, baseline eGFR, and others IRAE were chosen a priori as variables of interest for the multivariate regression analysis. In addition, baseline variables with a P value < 0.1 in the univariate analysis were included in the multivariate regression. Covariates were expressed as OR [95%CI] (odds ratio [95% confidence interval]). The analysis was carried out using the R software v4.0, R Foundation for Statistical Computing, Vienne, Austria and GraphPad Prism 8.0.1 for Windows, San Diego, California USA.

A p-value < 0.05 was retained for statistical significance.

RESULTS:

Patients:

Data from 352 patients (Figure 1) were collected; there were 223 males and the sex ratio M/F was 1.73, their median [IQR] age was 67 [57 -76] years (Table 1). In the whole cohort, 300 (85.2%) patients were treated with anti PD-1, 10 (2.8%) with anti PD-L1, 38 (10.8%) with anti CTLA-4 monotherapy (Ipilimumab), and 4 (1.2%) with a combination of anti PD-1 and anti CTLA-4 (Nivolumab and Ipilimumab). A total of 189 (53.7%) patients suffered from advanced melanoma, 142 (40.3%) patients were treated for advanced non-small cells lung cancer, and the remaining patients (n=21; 6%) were treated for urologic cancers (renal or urothelial carcinoma).

AKI incidence:

A total of 14 CPI-induced AKI occurred in 13 patients, corresponding to an incidence of 3.7% appearing at a median (range) time of 148 (35 -480) days. There were 4 cases of AKI excluded from the CPI-induced AKI group, as another likely cause of AKI was found: 1 case of septic shock associated with glycopeptide accumulation, 1 case of septic shock alone, 1 case of manifest pre-renal AKI associated with diarrhea, and 1 case of obstructive pyelonephritis (Figure 1). The clinical features of patients from the CPI-induced AKI group are described in Table 2. CPI-induced AKI were attributed to anti PD-1 agents in 13/300 (4.3%) patients (9/230, 3.9% treated with Nivolumab and 4/70, 5.7% treated with Pembrolizumab). No CPI-induced AKI was recorded in patients treated with anti CTLA-4 agents or anti PD-L1 agents alone, or with a combined therapy. The incidence of AKI according to therapy and underlying cancer is described in Figure 2. The median (range) SCr peak level was 2.1 (1.3 -5.0) mg/L. The severity of kidney failure was predominantly mild to moderate: 6 (43%) patients presented with AKI stage 1, 5 (36%) with AKI stage 2, and 3 (21%) with stage 3. No patient required renal-replacement therapy.

Identification of risk factors for AKI

In the CPI-induced AKI group, there was significantly more extra renal IRAE (n=10/13, 77%, pneumonia in one patient, thyroiditis in 5 patients, colitis in 2 patients, skin rash in 2 patients, and hepatitis in 5 patients) compared to the other group (p=0.0088, Table 1), however extra renal IRAE was not significantly associated with a greater risk of AKI (Table 3). The use of the vitamin K antagonist fluindione (historically well known to induce allergic AIN) was significantly associated with a greater risk of developing AKI in the multivariate analysis (OR=6.40, 95%CI [1.42; 26.08]; p=0.01; Table 3).

Interestingly, pre-existing CKD (identified in 68 (19%) patients, 21 (31%) of whom had an eGFR < 45mL/min) was not an associated risk factor of developing CPIinduced AKI (OR = 1.27, 95%CI [0.22; 5.112]; p=0.72). Likewise, the overall incidence of IRAEs in CKD patients (17.5%) was not higher than the one of non-CKD patients (45%). The etiology of CKD was "undetermined nephropathy" in 41/68 (60%) patients, the others were hypertensive nephropathy (12/68, 18%), diabetic nephropathy (8/68, 12%), drug-induced nephropathy (4/68, 6%), and consequences of sepsis-induced ATN (3/68, 4%). No patient had an identified auto-immune cause of CKD, although it was not an exclusion criterion. Some other patients had autoimmune disease, but without associated CKD.

There was no type of primary tumor that was associated with a greater risk of AKI compared to other types of tumor (Table 3).

To study the impact of CPI treatment duration on AKI occurrence, two subgroups of patients with different time exposure (i.e. ≤ 3 months, and > 3 months) were formed.

The CPI-induced AKI incidence was 0.96% (2/209) for the ≤ 3 months subgroup, and 7.7% (11/143) for the > 3 months subgroup (p<0.01), suggesting an exposure-timedependent risk to develop AKI.

Renal outcomes in the CPI-induced AKI group:

Urinary analysis was available for 8 of the 14 patients with CPI-induced AKI. The proteinuria/creatininuria ratio was < 50 mg/mmol in all cases. Significant leucocyturia (> 30/mm 3 ) was found in 7/14 cases, and eosinophiluria in none. One patient presented with microscopic hematuria. The median [IQR] baseline eGFR was 71.6

[60 -87.5] mL/min, and 3 patients had pre-existing CKD (Table 2).

Histological features:

Kidney biopsies were performed in 6/14 patients from the CPI-induced AKI group, with histological findings compatible with the diagnosis of tubulo-interstitial nephritis in all cases (Figure 3). A total of 5 patients had a typical allergic AIN. The cellular infiltrates were polymorphic, with a predominance of CD3+ cells. Infiltrates of eosinophil polymorphonuclear leukocytes were present in 2 cases. One patient had an isolated acute tubular necrosis; 2 patients had associated tubulitis. No patient had glomerular injury or acute vascular lesions.

Treatment management and reversibility (Table 2):

Patients with AKI were managed according to the practice in place in the care center (i.e. treatment decision in multidisciplinary meeting, and tight collaboration between the referent oncologist and the nephrologist).

Among the AKI+ patients, 7/14 (50%) were treated with systemic corticosteroid (CS) therapy. CS regimens in the present cohort were all oral prednisone, with heterogeneous doses (0.5 mg/kg/day for 4 of them, 1 mg/kg/day for 2 patients, and 2mg/kg/day for 1 patient). All patients discontinued CPI therapy at AKI diagnosis.

CPI treatment was reintroduced for 5 patients (patients 5, 6, 7, 8, and 12) with the same drug, with no recurrence of AKI for patients 5, 6, 8, and 12. For patient 7, the CPI treatment with Nivolumab was restarted after AKI resolution, and AKI reoccurred 4 weeks later. A repeated kidney biopsy confirmed the relapse of CPI-induced AKI. In the particular case of patient 12, AKI was treated by discontinuing PPI treatment, with no associated CS therapy. Pembrolizumab was then reintroduced without recurrence of AKI.

DISCUSSION:

A low overall incidence of 3.7% of CPI-induced AKI was reported herein. These data are consistent with those from the available literature, as it was 2.1% [START_REF] Abdel-Rahman | A network meta-analysis of the risk of immunerelated renal toxicity in cancer patients treated with immune checkpoint inhibitors[END_REF] and between 0.7% and 6% [START_REF] Manohar | Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis[END_REF] in 2 meta-analysis of randomized clinical trials (RCTs) with renal follow-up, and 3.8% in a retrospective review of IRAEs cases [START_REF] Abdel-Wahab | Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports[END_REF]. Three recent real life studies reported an incidence of 3% [START_REF] Seethapathy | The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors[END_REF] and 3.8% [START_REF] Meraz-Muñoz | Acute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes[END_REF] of CPI-induced AKI in North American patients, and of 3.3% [START_REF] Stein | Acute kidney injury in patients treated with anti-programmed death receptor-1 for advanced melanoma: a real-life study in a single-centre cohort[END_REF] in European patients. The present study corroborates these results and allows a reliable measure of incidence of CPI-induced AKI in the studied population. A comparable degree of severity (mild to moderate) was also reported herein.

Although the use of PPIs has been described in previous studies as a risk factor of CPI-induced AKI [START_REF] Seethapathy | The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors[END_REF][START_REF] Shirali | Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients[END_REF][START_REF] Koda | Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report[END_REF], it was not found as a significant risk factor for developing AKI in the present study. However, the particular case of patient 12 (for whom baseline renal function was restored after PPI discontinuation only, with no associated CS therapy) shows that these medications have to be closely monitored.

Surprisingly, in the present cohort, the co-medication with fluindione (an indanedionederived vitamin K antagonist, well-known to induce allergic AIN [START_REF] Cam | Acute and chronic nephropathy induced by fluindione must be addressed[END_REF]) was found associated with a high risk of developing CPI-induced AKI. These discordant data suggest that CPI-induced AKI is an immunological disease that could be, in some cases but not all, triggered by medications.

Despite the higher proportion of extra-renal IRAEs among patients from the CPIinduced AKI group, there were not found significantly associated with a greater risk of developing AKI. This description of CPI-induced AKI often associated with extra-renal IRAE has been previously described by Meraz-Munoz et al. [START_REF] Meraz-Muñoz | Acute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes[END_REF]. This could be surprising considering that IRAEs are commonly described as more often "singlesite" than "multiple-site" [START_REF] Cortellini | Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients[END_REF]. IRAEs are described as resulting from an aberrant immune-self response elicited by CPI. "Single-site" IRAEs could be explained by the reactivation of a resting "tissue-specific" auto-reactive T-cell clone, or by similarity between tumoral antigen and organ antigen [START_REF] Berner | Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer[END_REF]. If CPI-induced AKI are in future studies confirmed as "multiple-site" IRAEs, it will suggest a different underlying pathophysiological mechanism, such as a global/multi-organ loss of tolerance. The explanation for a global loss of tolerance induced by CPIs remains largely ununderstood. It is therefore of outmost importance to closely monitor renal function in patients who previously presented with extra renal IRAEs. In the present cohort, the clinical and laboratory findings associated with CPI-induced AKI were poor, and there was no case of acute glomerulopathy, as previously reported [START_REF] Cortazar | Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors[END_REF]. Glomerular injuries have however been reported in other studies [START_REF] Mamlouk | Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience[END_REF], but remain uncommon [START_REF] Gao | Minimal change disease associated with anti-PD1 immunotherapy: a case report[END_REF][START_REF] Daanen | Nivolumab-associated nephrotic syndrome in a patient with renal cell carcinoma: a case report[END_REF][START_REF] Fadel | Anti-CTLA4 antibody-induced lupus nephritis[END_REF], which has been confirmed in a large multicentric retrospective cohort study [START_REF] Cortazar | Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study[END_REF] describing anecdotic glomerulonephritis, and commonly acute interstitial nephritis. However, oncologic patients are indeed already at high nephrological risk because of other nephrotoxic medications, comorbidities, risk of paraneoplastic syndrome with renal involvement. In the absence of contraindication, we therefore recommend a systematic kidney biopsy in case of AKI during CPI treatment. Surprisingly, all cases of AKI in the present study occurred in patients under anti PD-1 treatment. Contrary to some data in the literature [START_REF] Abdel-Wahab | Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports[END_REF], there was herein no case of AKI in patients under anti CTLA-4 or anti PD-1 + anti CTLA-4 treatment, whereas the incidence of AKI has been reported to be higher for the combination treatment compared to each treatment alone [START_REF] Cortazar | Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors[END_REF]. This is probably due to a lack of statistical power in the present study as only a minority of patients was treated with these CPI regimens.

The results presented herein also suggest that patients with eGFR < 60mL/min were not prone to more AKI or IRAE than patients with no preexisting CKD, even though they were treated with the same posology of CPI agents. The efficacy and safety of CPI were, to our knowledge, not evaluated in case of pre-existing CKD. These data encourage the use of these molecules in the CKD population without any delay nor dose adaptation, but with a close monitoring. Moreover, the basal eGFR was significantly lower in AKI+ patients compared to AKI-patients, but still > 60mL/min without marker of kidney damage, which can be explained by the significantly higher age of patients in the AKI+ group compared to patients in the AKI-group [START_REF] Levin | Summary of KDIGO 2012 CKD Guideline: behind the scenes, need for guidance, and a framework for moving forward[END_REF].

The present study has some limitations. First, data were collected only during CPI treatment, although IRAE can occur later after CPI treatment [START_REF] Nigro | Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study[END_REF], which resulted in a lack of follow-up of patients who potentially developed AKI following CPI withdrawal, especially since CPIs have relatively long half-lives. This could result in an underestimation of the incidence of CPI-induced AKI. Second, many reports have suggested that IRAEs could be associated with an increased overall survival and progression-free survival [START_REF] Cortellini | Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients[END_REF][START_REF] Cortellini | Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes[END_REF][START_REF] Maillet | Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors[END_REF], and we do not describe here the oncological outcome of our patients. This is an important topic, but the present study was not designed to analyze it. Third, the low incidence of CPI-induced AKI in the present cohort did not allow sufficient statistical strength in the analysis. Finally, the present study was not designed to evaluate the effects of previous therapies, nor to determine the AKI incidence follow after CPI discontinuation, although it may have a longer-term impact on AKI [START_REF] El Rassy | The nephrotoxicity of immune checkpoint inhibitor-based combinations[END_REF][START_REF] Rassy | Immune checkpoint inhibitors renal side effects and management[END_REF]. CPI-related AKI is a severe, life-threatening IRAE, and usually implicates treatment discontinuation [START_REF] Shingarev | Kidney Complications of Immune Checkpoint Inhibitors: A Review[END_REF]. Renal recovery after CPI-induced AKI is inconstant, as described in the present cohort, and coherent with previous data [START_REF] Seethapathy | The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors[END_REF][START_REF] Meraz-Muñoz | Acute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes[END_REF][START_REF] Cortazar | Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors[END_REF][START_REF] Shirali | Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients[END_REF]. The present study did not allow to assess specific treatment regimens and their efficiency because of it retrospective design. Moreover, the statistical power was too low to assess the safety of CPI therapy reintroduction after a first episode of AKI, either with the same or with another molecule. This issue of CPI treatment reintroduction is quite arduous, with a subtle balance between the risk of terminal kidney disease in case of AKI recurrence and the risk of oncologic progression in case of prolonged cessation.

The possibility to resort to another immune checkpoint inhibitor is not yet evaluated.

Therefore, facing the lack of large therapeutic studies investigating the question of management of CPI-induced AKI, the decision of reintroduction of CPI molecule must be discussed in specialized centers with an expertise in the management of these rare cases of IRAEs. A very tight collaboration between nephrologists and oncologists is of the essence.

Proceeding to a systematic description of renal adverse events under CPI treatment remains mandatory in order to improve the understanding of the underlying mechanisms. Nowadays, this adverse event still seems uncommon, but the rapidly increasing use of double checkpoint blockade raises concerns about a sharp rise in their absolute number in the near future.

Disclosures:

All the authors have no conflict of interest to disclose

Table 2 : Clinical features of CPI-induced AKI patients

 2

	Patient	Sex/ Age	Malignancy	Molecule and cumulative dose	SCr/eGFR -SCr peak	AKI stage	Proteinuria RBC	WBC	Other IRAE	Days before AKI	Histologic diagnosis (Y/ N)	Treatment	Reversibility (Y/N) -SCr +M3
	1	M / 63	Epidermoid pulmonary cancer	Nivolumab 42mg/kg	1.14/88 -1.87	1	0	1	6	Thyroidis	180	N	CS 2mg/kg	N -1.71
	2	M / 66	Pulmonary adenocarcinom	Nivolumab 123mg/kg	1.20/76 -2.07	1	0	0	0	None	480	Y	CS 1mg/kg	N -2.05
	3	M / 68	Melanoma	Pembrolizumab 16mg/kg	1.02/89 -1.87	1	0	0	0	Thyroidis	147	Y	CS 0.5mg/kg	N -1.64
	4	M / 69	Pulmonary adenocarcinom	Nivolumab 24mg/kg	1.24/70 -2.09	1	NA	NA	NA	Thyroidis	120	N	None	NA (death)
	5	M / 70	Melanoma	Pembrolizumab 10mg/kg	0.97/87 -1.62	1	NA	NA	NA	Hepatic	90	N	None	Y -0.98
	6	F / 74	Melanoma	Nivolumab 153 mg/kg	0.67/71 -1.3	2	NA	NA	NA	Hepatic / skin	270	N	None	Y -0.67
	7	F / 77	Melanoma	Nivolumab 45mg/kg	0.78/77 -1.60	2	21	34	18	Hepatic / skin colitis / thyroidis /	60	Y	CS 0.5mg/kg	Y -0.96
	7bis	F / 77	Melanoma	Nivolumab 45mg/kg	0.78/77 -1.98	2	14	55	0	Hepatic / skin colitis / thyroidis /	150	Y	CS 1mg/kg	N -1.39

Abbreviations: M, Male; F, Female; NA, Non Available; SCr, serum creatinine; eGFR, estimate Glomerular function rate (BSAadjusted CKD-EPI); RBC, Red Blood cell; WBC, White Blood Cells; IRAE, immune related Adverse Events; AKI, Acute Kidney Injury; CS, corticosteroid. Doses of corticosteroids are given in prednisone-equivalent, and all patients received here oral prednisone.

Units: age in years; SCr in mg/dL; eGFR in mL/min; Proteinuria in mg/mmol; RBC in el.mm3; WBC in el./mme3; AKI in days

Acknowledgments

This study was supported by the Hospices Civils de Lyon and the Université Claude Bernard Lyon 1. We thank Hélène Boyer (DRCI, Hospices de Civils de Lyon) for help in manuscript revision. We thank the pathology department (Drs C.Picard, M.Rabeyrin, and F.Dijoud) for providing renal biopsies analysis. Research idea and study design: CT, ME; recruiting and following of patients: CT, LK, DF, ENC, DM, PJS, SD; data acquisition: ME; data analysis and interpretation: ME, CT, LK, ENC, DF; statistical analysis: ME, LK. ME is the guarantor of this work and, as such, takes full responsibility for it. We thank all the patients who have agreed to participate in this study.

BIBLIOGRAPHY:

Tables


Marie Emilie Forget
email: marie.forget@univ-smb.fr

Magali Rossi
email: magali.rossi@univ-smb.fr

Mining region value and vulnerabilities: Evolutions over the mine life cycle

Keywords: Values, vulnerabilities, mining regions, territorial trajectories, multidisciplinary approach

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Production of raw materials has increased exponentially since the early 20th century. Demand up to 2050 is forecast to follow a similar trend (+3% to +6% per year depending on the metal; Christmann, 2018) due to world population growth, increase in urban populations and rapid expansion of the middle class. Primary production (mining) and discovery of new deposits will remain a necessity considering that secondary raw-metal production (recycling) and present-day reserves will not be sufficient to face the forthcoming demand [START_REF] Christmann | Towards a more equitable use of mineral resources[END_REF].

Mining activity (metal extraction and ore processing) strongly impacts the environment. We can see the evidence in landscape modifications; removal of topsoils (in open-pit mining); hydrological side-effects; air, water and soil contamination; dust emission, increased noise, and habitat degradation, etc. [START_REF] Ripley | Environmental Effects of Mining[END_REF][START_REF] Dudka | Environmental impacts of metal ore mining and processing: a review[END_REF][START_REF] Younger | Mine water: hydrology, pollution, remediation, Environmental pollution[END_REF]. And when mining becomes the main economic activity of a region, it also has significant impact on social and cultural structures: it increases economic inequalities, results in land-use and resource conflicts, and modifies community identity in depth, etc. [START_REF] Werner | Assessing impacts of mining: Recent contributions from GIS and remote sensing[END_REF][START_REF] Horowitz | Indigenous peoples' relationships to large-scale mining in post/colonial contexts: Toward multidisciplinary comparative perspectives[END_REF][START_REF] Smart | The political economy of Latin American conflicts over mining extractivism[END_REF].

The socio-environmental impacts of mining cover a wide range of situations and depend mainly on territorial identity, local and national governance, and the type of mine and mining techniques. This article looks at industrial mining only (artisanal and small-scale mining will not be considered here). We can see three types of mining regions:

1) Regions with a long mining history and a strong mining identity, where mining has been taking place for more than a century (Ireland, Scandinavia, USA, Canada, Australia, Chile, etc.). In these regions, mining remains one of the main economic activities, and its social acceptance is rather significant [START_REF] Devenin | Characterizing a mining space: Analysis from case studies in Chile and Australia[END_REF]. 2) Former mining regions. These had mining activities in the 19th and early 20th centuries but no longer have active mines (e.g., most European countries). Mining identity in those regions has often been lost or relegated to cultural heritage [START_REF] Hendrychová | An analysis of 200-year-long changes in a landscape affected by large-scale surface coal mining: History, present and future[END_REF][START_REF] Oakley | After mining: Contrived dereliction, dualistic time and the moment of rupture in the presentation of mining heritage[END_REF]. Most raw materials are imported, and the social acceptability of new potential mining projects is very low (NIMBY and BANANA syndromes). 3) Regions which previously had no mining activity but which have been affected by a relatively recent (i.e., in the last few decades) and rapid mining boom. This latter often generates socio-environmental conflicts (e.g., Latin America, Africa; Haslam and Tanimoune, 2016; Walter and Urkidi, 2017).

Literature on mining and its territorial impacts is often segmented by discipline. Metallogeny studies, for example, focus on the characterisation and formation of ore deposits in order to propose metallogenic models (Hedenquist et al., 2005) and to provide updated exploration guides for mining companies (e.g., [START_REF] Rossi | Isotopic and geochemical constraints on lead and fluid sources of the Pb-Zn-Ag mineralization in the polymetallic Tighza-Jbel Aouam district (central Morocco), and relationships with the geodynamic context[END_REF]. In contrast, environmental studies focus on understanding the processes involved in:

1) contamination of soil, water, sediment, fauna and plants by trace metals [START_REF] Ripley | Environmental Effects of Mining[END_REF][START_REF] Dudka | Environmental impacts of metal ore mining and processing: a review[END_REF][START_REF] Younger | Mine water: hydrology, pollution, remediation, Environmental pollution[END_REF]; 2) the legacy of former mining activity on present-day ecosystems [START_REF] Baron | Dispersion of Heavy Metals (Metalloids) in Soils from 800-Year-Old Pollution (Mont-Lozère, France)[END_REF][START_REF] Casiot | Hydrological and geochemical control of metals and arsenic in a Mediterranean river contaminated by acid mine drainage (the Amous River, France); preliminary assessment of impacts on fish (Leuciscus cephalus)[END_REF][START_REF] Camizuli | Trace metals from historical mining sites and past metallurgical activity remain bioavailable to wildlife today[END_REF]; and 3) the effects of mining on health [START_REF] Carvalho | Human health risks in an old gold mining area with circum-neutral drainage, central Portugal[END_REF][START_REF] Hadzi | Contamination impact and human health risk assessment of heavy metals in surface soils from selected major mining areas in Ghana[END_REF]. Such environmental degradation caused by mining activities can lead to conflicts on a local or national scale. In fact, in human geography, anthropology and sociology, mining activity is often analysed through the conflicts that arise during mine construction and operation (Martinez-Alier, 2001; [START_REF] Bebbington | Social conflict, economic development and the extractive industry: Evidence from South America[END_REF][START_REF] Forget | Territorial Trajectories within a New Centre for the Globalised Mining Industry: the Andes of Northern Argentina[END_REF][START_REF] Forget | Co-constructions territoriales face à l'émergence de l'activité minière dans le Nord-Ouest argentin[END_REF]Karakaya and Nur, 2018). Most of the literature claims affiliation with political ecology; it analyses the relations of power within regions and often denounces the hand of transnational firms and the weakness of state policies [START_REF] Acosta | Extractivism and neoextractivism: two sides of the same curse[END_REF][START_REF] Svampa | Resource extractivism and alternatives: Latin American perspectives on development[END_REF].

Meanwhile, territorial analysis emphasises the struggle for transversal resources, such as water and energy, between mining companies and local populations [START_REF] Forget | Territorial Trajectories within a New Centre for the Globalised Mining Industry: the Andes of Northern Argentina[END_REF][START_REF] Bos | L'eau : ressource naturelle, ressource politique ?. Reconstruction de la ressource hydrique en contexte d'opposition au secteur minier dans le nord du Pérou[END_REF] and investigates the role of governance and local vs national politics [START_REF] Liping | Global mining governance evaluation methods[END_REF]Coumans, 2019;[START_REF] Haikola | Evolutionary governance in mining: Boom and bust in peripheral communities in Sweden[END_REF]. Furthermore, the social sciences have documented the notion of "social licence to operate" [START_REF] Moffat | The paths to social licence to operate: An integrative model explaining community acceptance of mining[END_REF][START_REF] Zhang | Understanding the social licence to operate of mining at the national scale: a comparative study of Australia, China and Chile[END_REF][START_REF] Vanclay | Conceptualizing Company Response to Community Protest: Principles to Achieve a Social License to Operate[END_REF], territorial identity changes and the construction of a mining identity [START_REF] Harner | Place Identity and Copper Mining in Sonora, Mexico[END_REF]Ballesteros and Ramirez, 2007;[START_REF] Parmenter | Aboriginal cultural awareness training for mine employees: Good intentions, complicated outcomes[END_REF] as well as inequalities and environmental justice (Rodríguez-Labajos and Özkaynak, 2018).

While scientific literature does cover many aspects of the impacts of mining on the local area, it most often covers particular case studies. It would benefit from the inclusion of economic, environmental, social and cultural aspects, with regard to local and national governance and to the ore deposit properties. Indeed, ore mineralogy, ore grade, rock and mineral textures, and deposit geometry determine the exploitation and ore-processing techniques, and these latter in turn determine the economic and environmental impacts. In contrast, local and national governance as well as the political context (democratic vs nondemocratic) directly determine the social impacts.

Sustainable development of extractive industries should (i) contribute to health, wealth and well-being for all, (ii) maintain the quality of the environment and other resources, and (iii) rely on inclusive governance by all stakeholders (IRP, 2020). For these reasons, environmental, social and cultural values must be identified and taken into consideration together with economic value. To facilitate this process, this paper seeks to provide a framework for representing the trajectories of mining regions via the changes of territorial values and vulnerabilities related to mining. First, we will define territorial values and vulnerabilities, and then break them down into geological, economic, environmental, social and cultural components. We will then discuss how these values and vulnerabilities change over the mine life cycle. Finally, we will present and discuss several specific territorial trajectories.

Framework and methods

The framework we propose for representing territorial trajectories is based on data visualisation of changes in territorial values and vulnerabilities over the mine life cycle. Only industrial metal mines will be considered here. In this paper, a broad definition of the concept of "value" has been adopted. Here, it is considered as a socio-cultural construction that means something important to a person or a social group [START_REF] Stephenson | The Cultural Values Model: An Integrated Approach to Values in Landscapes[END_REF]; de la Torre, 2013). This concept is therefore not restricted to monetary value, but also includes direct-use values (economic provisioning of goods, etc.) and non-use values (e.g., habitat support and related ecological diversity preservation, heritage conservation, indirect cultural services such as locally perceived value, etc.). In this paper, the territorial value has been broken down into economic value (financial gains), environmental value (environmental quality and the capacity to use or preserve it), social value (value given by the inhabitants, taking into account well-being and wealth) and cultural value (identity, revealed heritage or cultural potential). The ore-deposit mineralogy and geometry determine the extraction type (underground vs open-pit), the scale of the mining site and the ore-processing techniques, which directly impact economic and environmental values and indirectly impact social and cultural values. Therefore, the authors define geological value in relation with the ore deposit (geometry, ore grade, mineralogy, etc.). Generally speaking, vulnerability can be defined as the inability of a system to withstand the disturbances of external stressors (Becerra, 2017;[START_REF] Mathis | Vulnérabilités environnementales : perspectives historiques[END_REF]. In this paper, territorial vulnerability has been broken down into geological vulnerability (e.g., changes of the ore grades), economic vulnerability (global market volatility or destabilisation of the economic system), environmental vulnerability (contamination or ecosystem degradation), social vulnerability (potential harm to people) and cultural vulnerability (potential modification of the territorial identity). Table 1 summarises the main quantitative and qualitative indicators used to estimate the territorial values and vulnerabilities, which are extremely dynamic concepts. Evolution of these indicators over the mine life cycle helps to evaluate the changing values and vulnerabilities of mining regions over time. The framework proposed in this paper is based on visualisation of these changes using graphs, where the vertical axis represents the values and vulnerabilities and the horizontal axis represents time (Figures 2 to 11). Time thus integrates the mine life cycle, which has been broken down into the following stages (Figure 1): (1) prior to mining, (2) exploration, (3) mine and processing plant construction, (4) mine operation and mineral processing, (5) mine closure, (6) post-mining management, [START_REF] Ballesteros | Identity and community-Reflections on the development of mining heritage tourism in Southern Spain[END_REF] postmining development. The territorial trajectory over the mine life cycle is constructed by compiling the trajectories of each stage (Figures 12 and13).

Evolution of values and vulnerabilities

The discussion below focuses chiefly on regions with no strong mining identity. However, when relevant, the specific case of regions with a long or strong mining identity is also presented.

Prior to a mining project

In the case of regions that have not previously experienced mining activity, their main economic activity is usually based on agriculture, livestock farming, or other ecosystem services. In regions with past mining activities, it may be based on industries (e.g., metallurgy, power plants, etc.). Economic and social values and vulnerabilities depend on the economic activity dynamics, the global market and local policies (Figure 2). At this stage, the geological value is considered to be null or stable in case of promotion of the local geology (landscape, former mining heritage, etc.), and cultural values are considered stable. Environmental value depends on the ecosystem services, and environmental vulnerability depends on the environment quality and local contamination due to the presence of ore. Cultural value depends on the territorial identity, and its vulnerability depends on policies.

Exploration phase

Exploration is carried out to identify and target ore deposits to develop mining projects. Early exploration, which involves mainly airborne and terrestrial geochemical and geophysical surveys, has no or limited incidence on the regions. If mining potential is identified from early exploration, advanced exploration follows to fully characterise the ore deposit (ore type, grade and tonnage, mineralogy, geometry, geological context, etc.) and to estimate the mineral resources and reserves. The geological value thus increases considerably at this stage, according to the mining potential. Advanced exploration involves drilling and trenching, which often require road opening. As a result, environmental value starts to decline and environmental vulnerability increases (Figure 3).

Next, market speculation starts as the mining potential of the targeted ore occurrence is revealed by advanced exploration and the resources and reserves are estimated. As market speculation intensifies, both economic value and vulnerability increase. At this stage, mining is seen either as an opportunity, especially in fragile and peripheral regions [START_REF] Forget | Territorial Trajectories within a New Centre for the Globalised Mining Industry: the Andes of Northern Argentina[END_REF][START_REF] Forget | Territorial Trajectories within a New Centre for the Globalised Mining Industry: the Andes of Northern Argentina[END_REF]Carrizo, 2016, 2018), or as a threat when the prospect of mining makes the region susceptible to dispossession and jeopardises other economic activities such as subsistence farming [START_REF] Harvey | The New Imperialism[END_REF][START_REF] Svampa | Resource extractivism and alternatives: Latin American perspectives on development[END_REF]. Economic vulnerability depends on trends in the global metal market, available infrastructure, the political context and social acceptability [START_REF] Bebbington | Contention and ambiguity: mining and the possibilities of development[END_REF][START_REF] Bridge | Global production networks and the extractive sector: governing resource-based development[END_REF][START_REF] Forget | Le nexus mine-énergie dans les territoires du Nord de l'Argentine[END_REF]. Use of the new infrastructure (power lines, roads) for the regions is one of the main challenges in negotiating a mining project with local authorities [START_REF] Jackson | Dusty roads and disconnections: Perceptions of dust from unpaved mining roads in Mongolia's South Gobi province[END_REF][START_REF] Loutit | Emerging practices in community development agreements[END_REF][START_REF] Forget | Le nexus mine-énergie dans les territoires du Nord de l'Argentine[END_REF].

When exploration reveals significant mining potential, thereby leading to a feasibility study, the prospect of mine operation becomes public. When allowed by the country's political regime (in a democratic system), mobilisation may start in defence of the region against nonnative interests and in order to avoid future conflicts of a social, resource (water and energy) and land-use nature. In response to that mobilisation or according to obligation for public consultation, public meetings and negotiations usually take place between the region's inhabitants and the representants of the exploiting firm (which is usually national or transnational).

Feasibility and construction phase

About 1 discovery out of 200 goes beyond the exploration stage to feasibility studies. Among them, about 50% end up in mine development (IRP, 2020). Economic value drops during the feasibility studies (capital is needed for future mine development but there are no cash inputs yet), before rising again during mine construction (Figure 4). At this stage, the ore deposit is now well known, so geological value and vulnerability are unchanged.

Employment is highest during mine construction: specialised workers come from outside the region, but local subcontractors are involved in roads and masonry work, plumbing, and logistics on-site (laundry, catering, etc.). The temporary job creation and the prospect of obtaining future jobs at the mine may decrease social vulnerability. In regions without a mining history, mine construction rapidly becomes the main activity: by impacting traditional land use, it contributes to the breakdown of the local community, leading to social conflicts and increased social vulnerability. Furthermore, slowdown in the mine's activity has significant impact on the local society, which is organised around services to the mine, and on the pace of successive labour migrations. In most projects, cultural value rapidly decreases as the mining culture quickly takes precedence over local traditions, resulting in frequent loss of territorial identity. Mine construction leads to the first significant environmental impacts: the building of infrastructure, levelling works and transport of material significantly increase noise and dust emissions and damage the land. Consequently, environmental vulnerability rises significantly, and environmental value starts to decline. However, these impacts may be limited, as they depend on the environmental constraints determined by local policies.

Operation phase

As in the case of exploration, economic value during the mine operation is closely related to geological value and to trends in the metal market (Figure 5). The volatility of metal prices on global markets may weaken the region. At this stage, geological value is highest but may evolve according to unforeseen events and to ongoing exploration. For example, if the ore grade turns out to be higher than had been expected during exploration, geological and economic values will both increase. However, geological and economic values can drop if the reverse occurs, or if the mining methods become unsuitable in the event of unexpected changes in the mineralogy or structural geology. Mining involves extraction of ore minerals from deep in the earth, where metal-bearing minerals are rather stable, and their accumulation at the surface in waste deposits (tailings and slags). These waste deposits generally contain rather high amounts of trace metals (As, Cd, Sb, Pb, Cu, Zn, etc.) which can easily be leached out by weathering and infiltration of water, causing acid mine drainage. This results in the transfer of trace metals into the environment (soils, stream and lake sediments, vegetation, biota, etc.) and contamination at various scales at the mine site or in river catchments, downstream to estuaries [START_REF] Ripley | Environmental Effects of Mining[END_REF][START_REF] Dudka | Environmental impacts of metal ore mining and processing: a review[END_REF][START_REF] Younger | Mine water: hydrology, pollution, remediation, Environmental pollution[END_REF].

Dust and noise emissions due to intense transport (of ore, metal and workers) are still present at this stage. Furthermore, metal processing usually requires the use of chemicals (e.g. cyanide for gold extraction) which may be released into the environment in the event of accidents or bad management, thus putting local people at risk (Bose-O' Reilly et al., 2008;Harmanescu et al., 2011). Therefore, during the mine operation, environmental vulnerability is highest and environmental value is lowest. However, depending on local policies, the environmental impacts may be restricted: suitable management of tailings and waste deposits may reduce the development of acid mine drainage and thus limit contamination.

Mine operation requires qualified workers. In regions without previous mining, most qualified workers usually come from other regions, whereas the local people live from economically insecure services to the mine. Upgrading of work qualifications usually tends to decrease social value during the mine operation [START_REF] Russell | The subtle labour process and the great skill debate: evidence from a potash mine-mill operation[END_REF]. Indeed, as mining employees often enjoy relatively good income compared to people working in other activities, inequalities and social vulnerability increase. Public policies regarding employment of local people may help mitigate these inequalities. In regions with previous mining activity, qualified workers can be hired locally, thus increasing social value and decreasing social vulnerability. In whatever region, mining plays a significant role in structuring the local society. Informal and sometimes illegal activities such as prostitution may occur [START_REF] Laite | Historical perspectives on mining, industrial development, and prostitution[END_REF]. As mining requires transversal resources (water, energy and land), the operation stage is characterised by the rise of socio-environmental conflicts. Indeed, in regions without previous mining activities, destabilisation of traditional land use and of local arts and crafts may increase cultural vulnerability due to a loss of territorial identity and the weakening of heritage values. In regions with a strong mining identity, cultural and social values are closely related to mining.

Mine closure and post-mining management

Mine closure generally induces strong territorial destabilisation (Figure 6; Baiton and Holcombe, 2018). Drop in interest in the ore body results in a rapid decline in the geological and economic values that were very closely correlated with those results during the mine operation. Consequently, economic vulnerability rises significantly as the benefits come to an end and cash is needed for mine closure and post-mining management. Without any new territorial project, economic value is thus lower than before mining, due to the socioenvironmental impacts mining has generated. At this stage, the cultural value of the mining site may have been identified if a mining identity has been built, but development of cultural value must wait for development of a new territorial project.

Dismantlement of the mining infrastructure starts at mine closure. Transition from mining to post-mining activities then requires management of the socio-environmental impacts. Lima et al. (2016) distinguish four post-mining management strategies: (i) remediation, to decontaminate the site by removing trace metal contaminants or preventing their transfer to the ecosystem; (ii) restoration, to recover the ecosystem and its functions; (iii) reclamation, to recover the original ecosystem services and biogeochemical functions; and (iv) rehabilitation, which prioritises the ecosystem services to be reclaimed or the building of new infrastructures for new economic activities.

These strategies help enhance environmental value, which was lowest at mine closure. However, if there is no post-mining strategy, environmental value remains low and stable, and environmental vulnerability remains high. At mine closure, social value drops significantly, and vulnerability is high due to the loss of employment and income. Employment of local people for post-mining management may aid in hindering the drop in social value and in tempering its vulnerability. On the contrary, employment of outside people will generally lead to social contestation. Local or national policies can provide constraints for post-mining management. If these constraints are low or lacking, the mining sites might well be abandoned, in which case social and environmental values are kept very low. The more constraining the policies are, the higher the environmental and social values become and the lower the socio-environmental vulnerabilities become. Post-mining management helps curb economic vulnerability, by allowing the territorial stakeholders to plan future post-mining trajectories.

Post-mining trajectories

Four main territorial trajectories have been identified following completion of the mine life cycle: a new mining project, reprocessing of mine wastes, promotion of the mining heritage, or any other economic activity (Figure 1; e.g., Kivinen, 2017).

New mining project

Depending on the metal market and on geological value, an ore body that had not been mined before may become of economic interest. New exploration may also take place for the metals that were formerly mined, or for other metals with a higher mining potential. A new mining project may thus arise. In the case of new exploration (Figure 8A), the evolutions of geological, economic and environmental values and vulnerabilities are similar to those of the previous mine life cycle. If infrastructure is still present, the construction stage may be limited or unneeded. If the exploration companies hire local employees, social value will increase and vulnerability will decrease. Depending on local policies and mine management (i.e., employment of mainly local people), social value will remain stable or increases during the mine operation, and social vulnerability will either be stable or decrease (Figure 8B). Indeed, mining usually leads to low social vulnerability in former mining regions because the social pattern already matches the needs. Therefore, a new mining project reinforces the mining territorial profile. Cultural values and vulnerabilities are either unchanged or increase due to reinforcement of the mining identity.

Reprocessing of waste deposits

Mine wastes usually contain significant amounts of metals, especially in tailings. Reprocessing of waste deposits leads to the production of secondary ore that had not been recovered during previous processing, or to the production of metals that had been considered as by-products during the former mining operation (Edraki et al., 2014 and references therein; [START_REF] Longhi | Valorisation of a kaolin mining waste for the production of geopolymers[END_REF]. Reprocessing of mine wastes leads to increased geological value, but geological vulnerability remains stable. Removal of mine waste deposits for reprocessing usually involves removal of residual trace metals. As it contributes to decontamination, it induces a slight increase in environmental value and a significant drop in environmental vulnerability.

Reprocessing tailings is a way to extend the life of the mining site by maintaining an economic activity; in this case, economic and social vulnerability can be expected to decrease as economic and social value increase. However, depending on local governance, social value and vulnerability may differ considerably among mining regions. Very few studies have investigated the social effects of waste reprocessing, but high economic and social value can be expected, as it maintains employment for the local population.

Promotion of mining heritage

After mine closure, most traces of the mining activity slowly disappear: gallery entrances are sealed, waste deposits are most of the time covered with vegetation, and mine infrastructure is largely dismantled. However, some tangible and intangible remains are left behind, and these can be promoted as mining heritage in such forms as thematic trails, museums and underground tours (Conlin and Jollife, 2011;[START_REF] Bergstrom | The curious case of Cuyuna: Re-Envisioning former extractive sites to stimulate local communities[END_REF][START_REF] Oakley | After mining: Contrived dereliction, dualistic time and the moment of rupture in the presentation of mining heritage[END_REF]. Development of mining heritage leads to increased geological, economic, social and cultural values. Geological vulnerability remains stable or decreases if securing of the mine site occurs. As promotion of mining heritage implies a new economic activity (most of the time tourism), cultural, economic, and social vulnerabilities decrease in the event that the activity becomes profitable and mining becomes part of the territorial identity. In this case, environmental value and vulnerability are unchanged.

Other economic activity

Besides promotion of mining heritage, any other activity not directly related to mining can be developed. Former mining sites are often used for recreational or cultural activities: open-pits are most often transformed into lakes to practice deep-diving or nautical activities; hiking, biking or motorbiking trails are opened; golf courses are developed on tailings; and the mine buildings may be transformed into holiday villages or museums, etc. [START_REF] Kivinen | Sustainable post-mining land use: are closed metal mines abandoned or re-used Space?[END_REF]. In addition, open pits can take advantage of the opportunities provided by the characteristics of the mining site and become privileged grounds for the installation of photovoltaic solar plants, whereas underground galleries and former buildings may be well-suited for the development of mushroom plantations [START_REF] Deshaies | La transition énergétique offre-t-elle de nouvelles potentialités aux bassins d'exploitation du charbon et du lignite en Allemagne ?[END_REF][START_REF] Kivinen | Sustainable post-mining land use: are closed metal mines abandoned or re-used Space?[END_REF]. As mining is usually the first step towards industry, the infrastructure and skills that have been developed for mining may be used for other industrial activities, such as metallurgy, energy power or other industrial activity (e.g., Pessina, this volume).

Territorial trajectories of some case studies

Figures 2 to 11 highlight shifts in the territorial values at each stage of the mine life cycle. These shifts depend on governance and territorial development strategies, suggesting that the territorial trajectories are nonlinear and that bifurcations are possible at each stage. The framework discussed above was applied to Murdochville (Canada) and Chuquicamata (Chile) to display two different trajectories of mining regions facing different issues. Murdochville, a boom town developed for mining in a remote area in the mid-20th century, is a good example for discussing the full mine life cycle and post-mining strategies. In contrast, Chuquicamata is a long-standing anthropised region with several centuries of past mining activities, with new mining projects and diverse economic activities. As not all the indicators listed in Table 1 are available, the trajectories focus on a selection of quantitative and qualitative indicators (Figures 12 and13). A strong anti-correlation between value and vulnerability trajectories has been highlighted from Figures 2 to 11. Therefore, their representation evolves in opposite directions in the following examples.

4.1. The boom town of Murdochville (Quebec, Canada) Murdochville (Quebec, Canada) is a boom town that developed in the 20th century following the discovery of copper in 1909 in a river. Starting in the 1920s, prospection led to the discovery of the ore body (a skarn and porphyry-copper deposit; [START_REF] Allcock | Skarn and porphyry copper mineralization at Mines Gaspe, Murdochville, Quebec[END_REF] and estimation of copper reserves of 19.6 Mt in 1940. Mining operations and ore processing started in 1953 after settlement in that remote part of central Gaspésie (40 km to the closest village of Anse-Pleureuse, and 90 km to the closest town of Gaspé). Because of the lack of data about First Nation settlement and land use in the Murdochville area, it is assumed that geological, economic, social and cultural values and vulnerabilities were null prior to mining and that they all increased during exploration and operation because of the economic and job prospects. The mine rapidly developed and employed about 1000 workers by the end of the 1950s. Ten years later, the city of Murdochville had nearly 5000 inhabitants, and 2000 people worked for the Gaspé Copper Mines, which was renamed Mines de Cuivre Gaspé. The reserves were estimated at 67 Mt of ore containing 1.3% Cu. The rapid territorial development contributed to the development of a strong mining identity. In 1982, as the copper market dropped and its reserves declined, open-pit and then underground mine production came to an end. Half of the employees were made redundant. The following year, no more ore from Murdochville was being processed in the smelter and the mine closed; as a result, geological, economic and social values dropped. In 1989, due to market changes, the mine reopened with 500 employees, but it closed down ten years later, in 1999, as the reserves ran out: 300 people became unemployed at that time. The smelter was definitively stopped in 2002: 300 more people became unemployed. Meanwhile, environmental value had significantly decreased over time. Environmental studies clearly show that the mining operation and ore processing contributed to soil and vegetation contamination [START_REF] Aznar | Mining and Smelting Activities Produce Anomalies in Tree-growth Patterns (Murdochville, Québec)[END_REF](Aznar et al., , 2008a, b), b). Without any prospects of further re-opening, 70% of the local residents voted the closure of the town of Murdochville; their demands for compensation were refused by the Quebec Government. As the town had developed exclusively for mining, mine closure affected all economic activities: debt and unemployment both exploded, and the real estate market dropped drastically, etc. People who could afford it moved out of Murdochville, lowering social value significantly. The town, which had almost 5000 inhabitants in the 1970s, had only 1600 in 1991 after mine reopening, less than 1000 in 2002, 651 in 2016 and 635 in 2019. In 1989, the Copper Interpretative Centre opened and helped increase cultural value; it proposed an interactive exhibition and underground guided tours in the mine until 2017, when it closed following a fatal accident. In 2003, the creation of a call centre for the Quebec Automobile Insurance Society, employing 60 workers, helped maintain an economic activity. In 2005, some Murdochville inhabitants found work in a wind blade factory that was built in Gaspé, 90 km away. Today, the Murdochville economy relies essentially on the call centre, on recreational outdoor activities (off-piste skiing, hiking, fishing, etc.) and on renewable energies. Murdochville proposes business opportunities for companies for which energy costs are strategic, by allowing them to use the low-geothermal potential of the flooded mine galleries to produce energy for free [START_REF] Raymond | Low-temperature geothermal potential of the flooded Gaspé Mines, Québec, Canada[END_REF]. Therefore, after mine closure, while economic and social values dropped drastically, decline has to some extent been limited by the development of new activities. Past mining has transformed the representation and therefore the perceived value of the region by the local population, increasing its resilience.

The example of Chuquicamata (Chile), an active copper mine

The mine life cycle of Chuquicamata (Chile) has not yet come to an end: its open pit is still being mined, and a new underground project is about to start up activity for the next forty years. Figure 13 represents only the most significant mine development via open-pit exploitation. Situated in a desert environment, this region is traditionally the land of indigenous communities who used to live from livestock and oasis agriculture. In 1899, the discovery of "Copper Man", a mummy dated at about 550 A.D., provided evidence that copper has been mined there for centuries [START_REF] Fuller | The production of copper in 6th century Chile's Chuquicamata mine[END_REF]. The extraction of ore went on during the Inca invasion and after the arrival of the Spaniards. By 1910, the exploitation and extraction of the mine was in the hands of foreign capital, and the copper mining industry had become the most important economic activity in the country.

Flotation and smelting facilities were set up in the 1950s and expanded ten years later. They produced 500,000 tons of copper per year in the late 1970s. In 1957 the Exotica deposit was discovered beneath tailings, leading the Anaconda copper company to build an oxide plant, concentrator, smelter, refinery and a town next to the mine, and an additional power plant in Tocopilla. In 1971, the mine was nationalised, and operations were then taken over by the Chilean state enterprise CODELCO. Since the 1990s, Chuquicamata has been the largest open pit in the world. The Chuquicamata mine has played a key role in the territorial development of the region (Garces Feliu et al., 2010). Its geological, economic and social value started to rise quickly during exploration because of the high mining potential that was identified, speculation and the increasing number of workers needed. Indeed, the successive companies decided to build a company town equipped with modern conveniences for the well-being of the workers. It hosted an ultramodern modern hospital, a cinema and a football stadium. But when it appeared that the ore extended under the city, the company decided to move the town to Calama City, located 50 km further south. The workers were then deprived of basic services (housing and health care) that had been historically provided by the mining company, and they now lived under harsher conditions, in a city known for its delinquency, with the result that social vulnerability increased. Meanwhile, the unemployment rate, which varies mainly according to copper prices, tended to increase. There began to be conflicts, in which working conditions were denounced, giving rise to a hunger strike in 1985 and 1986. Additionally, the ore grade dropped, leading to a decrease in geological value. At the same time, environmental value has fallen, mainly because of high dust emission and freshwater capture in a desert environment. The Chuquicamata project is still continuing: the creation of a new underground mine and tailing reprocessing have postponed mine closure. This has had a positive effect on economic and social values and reduced their vulnerabilities. At the same time, the cultural heritage of the mine is being developed: CODELCO organises touristic tours of the open pit and the former city, which has been slowly buried beneath tailings. These tours attract mainly Chilean tourists.

From framework to decision-making

This paper proposes a framework to represent and understand changes in values and vulnerabilities of a mining region over the mine life cycle. It emphasises the influence of the local political, geological, cultural and economic contexts on the territorial trajectories. Application of this framework to different mining regions highlights the impact of governance and identity on these trajectories, and it allows comparison of the evolution of the different values and vulnerability. Even though the framework has been discussed for industrial metal mines, it could be adapted to other extractive activities (e.g., industrial minerals, iron, etc.), to other regions by adding adapting the mine life cycle (single mine, several mines at the same time, successive mine cycles, etc.), and at various spatial scales (local, national or global scale). In most mining regions, economic value takes precedence over the other values. However, this is not necessarily always the case, as political choices and regulation can help maintain high levels of social, cultural and environmental values for sustainable mining (IRP, 2020). Obtaining and maintaining a social licence to operate requires fair distribution of the mining benefits combined with fair procedures in the interactions between the mining industry and society, which can be achieved only with strong governance that involves the local population in decision-making [START_REF] Zhang | Understanding the social licence to operate of mining at the national scale: a comparative study of Australia, China and Chile[END_REF][START_REF] Corrigan | Deriving social benefits from mining through regulation: Lessons learned in South Africa[END_REF]. Long-term territorial sustainability must rely on economic diversification and coexistence with other economic activities that will continue long after mine closure [START_REF] Bergstrom | Community development in the face of resource extraction in northern Minnesota, USA[END_REF]. For activities such as agriculture, forestry, hunting, fishing, recreation and tourism to thrive after mine closure, a high level of environmental value must be maintained by limiting the environmental impacts of the mining activity [START_REF] Daily | Nature's Services: Societal Dependence on Natural Ecosystems[END_REF][START_REF] Costanza | The value of ecosystem services: putting the issues in perspective[END_REF]. Our simple way of visualising the changing values and vulnerabilities of mining regions over time proposed here may be useful for understanding and explaining the economic, social, cultural and environmental issues to stakeholders, and for planning future territorial trajectories. However, for decision-making, the framework should evolve towards modelling [START_REF] Lechner | Challenges of integrated modelling in mining regions to address social, environmental and economic impacts[END_REF]. Even though most indicators listed in Table 1 to determine geological, economic, environmental, social and cultural values and vulnerabilities are quantitative indicators, they do not have the same units, and some indicators are only qualitative. Some questions arise for future research work: How to quantify the qualitative indicators? How to weight the different indicators? How to merge all the indicators into a unique index for each value and vulnerability component? Which algorithm to use? And for which stakeholders? The methodology developed to determine the social risk index [START_REF] Bergeron | Mesurer l'acceptabilité sociale d'un projet minier : essai de modélisation du risque social en contexte québécois[END_REF][START_REF] Yates | Indice du risque social : un outil pour mieux saisir les enjeux, risques et opportunités des projets miniers[END_REF] could be an inspiring reference to define geological, economic, environmental, social and cultural indexes for mining projects.

Concluding remarks

In this paper we have asserted that the value of mining regions depends not only on economic value, but also on their environmental, social, cultural and geological values. For this reason, an integrative approach is necessary to understand the territorial trajectory of a given mining region. We have proposed a simple graphical framework to visualise the changes in geological, economic, environmental, social and cultural values and vulnerabilities over the mine life cycle, in relation with local governance and political choices. Application of this integrative representation to multiple regions with various mining histories would improve knowledge on the role mining activity has in territorial development, and on

Figure 1 .

 1 Figure 1. The different stages of the mine life cycle.

Figure 2 .

 2 Figure 2. Territorial values and vulnerabilities prior to a mining project.

Figure 3 .

 3 Figure 3. Territorial values and vulnerabilities during advanced exploration.

Figure 4 .

 4 Figure 4. Territorial values and vulnerabilities during mine construction.

Figure 5 .

 5 Figure 5. Territorial values and vulnerabilities during mine operation.

Figure 6 .

 6 Figure 6. Territorial values and vulnerabilities during mine closure.

Figure 7 .

 7 Figure 7. Territorial values and vulnerabilities during post-mining management.

Figure 8 .

 8 Figure 8. Territorial values and vulnerabilities for a new mining project. A) exploration stage; B) operation stage.

Figure 9 .

 9 Figure 9. Territorial values and vulnerabilities during reprocessing of waste deposits.

Figure 10 .

 10 Figure 10. Territorial values and vulnerabilities during the promotion of mining heritage.

Figure 11 .

 11 Figure 11. Values and vulnerabilities related to other economic activities.

Figure 12 .

 12 Figure 12. Territorial trajectory of Murdochville (Quebec, Canada), evidenced through the evolution of territorial values and vulnerabilities.

Figure 13 .

 13 Figure 13. Territorial trajectory of Chuquicamata (Antofagasta, Chile), evidenced through the evolution of territorial values and vulnerabilities.

Table caption Table 1 .

 caption1 Parameters and indicators that contribute to the geological, economic, environmental, social and cultural values and vulnerabilities of mining regions.

the governance required for sustainable development of mining regions. Further research work is needed to determine how to upgrade from this proposed framework to modelling of territorial trajectories.

Quantitative indicators

Qualitative