Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes.
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ABSTRACT:
SUBMITTER: Casals J
PROVIDER: S-EPMC10014382 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
Publications
Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes.
Casals J J Acosta Y Y Caballero G G Morantes L L Zamora C C Xipell M M Viladot Margarita M Guillen E E Piñeiro G G Blasco M M Marco J J Padrosa J J Pereira A A Jhaveri Kenar D KD Quintana L F LF García-Herrera A A
Kidney international reports 20221229 3
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Project description:Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014-2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells.
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Project description:BackgroundAcute interstitial nephritis (AIN) is the most common renal immune-related adverse event after immune check-point inhibitors (ICI). We hypothesized that alternatively activated macrophages (CD163-M) could be involved in ICI-AIN and wished to evaluate the use of their soluble urinary form (us)CD163 as a non-invasive diagnostic marker.MethodsCD163-M infiltrates were evaluated by both immune-histochemistry and multiplex immunofluorescence and imaging. usCD163 was detected with ELLA technology and evaluated together with urinary creatinine to be expressed as a ratio to creatinuria in ng/mmol. Clinical data were collected to perform correlations with renal function assessed by estimated glomerular filtration rate (eGFR).ResultsA retrospective cohort of 63 ICI-exposed patients with tubular acute kidney injury profile requiring a biopsy were selected. AIN patients (n = 44) were compared to acute tubular necrosis (ATN) patients (n = 19). CD163-M staining was detectable in all ICI-AIN patients, which was significantly higher than in ATN patients (18.4% vs 3.6% of area, P = .005). CD163-M staining was restricted to the interstitial compartment. CD163-M infiltrate inversely correlated with initial eGFR (r = -0.6, P = .003), and was positively correlated with delta eGFR, reflecting a renal improvement outcome (r = 0.48; P = .02). usCD163 was well detected in urines of patients, but did not allow us to distinguish ATN from AIN patients at diagnosis. No correlation was observed, neither between usCD163 and CD163-M staining nor with renal response after 3 months of glucocorticoid tapering.ConclusionCD163-M are detected in ICI-AIN and correlate both with severity at diagnosis and better prognosis at 3 months. CD163-M may help us to distinguish AIN from ATN but, it does not allow us to assess ICI imputability. Although detected in urine, usCD163 is clearly not a surrogate biomarker for AIN diagnosis.
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| S-EPMC3537780 | biostudies-literature
Project description:Acute tubular interstitial nephritis (ATIN) is the most frequently reported pathology in patients with checkpoint inhibitor (CPI) induced acute kidney injury (AKI). Glucocorticoid (GC) therapy and discontinuation of CPI are the mainstay of treatment to prevent permanent renal dysfunction and dialysis. However, less than 50% of patients have complete kidney recovery and relapse of ATIN can occur. Infliximab is effective in treating other immune-related adverse events but its use for the treatment of CPI-ATIN is not well established. We report the first retrospective study examining the steroid-sparing potential of infliximab in achieving durable and complete renal recovery for patients with CPI-ATIN. Data were collected from medical records of patients diagnosed with CPI-AKI with a kidney biopsy or clinical diagnosis of ATIN that was managed with GC and infliximab. Infliximab-containing regimens were used to treat 10 patients with CPI-ATIN. Four patients relapsing after GC therapy achieved durable and complete renal recovery, four patients experienced partial renal recovery, and two patients showed no improvement in kidney function. This is the first study evaluating clinical outcomes using an infliximab-containing regimen for treatment of relapsed CPI-ATIN in patients or patients failing to achieve complete response after primary therapy. Our data suggest that infliximab may be a treatment option for achieving durable and complete renal recovery in this patient population and represents a potential steroid-sparing strategy in challenging cases of CPI-ATIN. Rigorous clinical studies are warranted to evaluate the risk-benefit analysis for infliximab usage in CPI-ATIN patients.
| S-EPMC7872057 | biostudies-literature
Project description:IntroductionAcute kidney injury (AKI) in cancer patients receiving immune checkpoint inhibitors (ICIs) may recognize multiple causes. Here, we reviewed cases of biopsy-proven acute tubulointerstitial nephritis (ATIN) to describe the clinical characteristics and outcomes of this condition.MethodWe conducted a pooled analysis of clinical cases of ICI-related biopsy-proven ATIN up to 1 May 2022. We collected data on clinical characteristics, AKI, biopsy findings, laboratory examinations, and renal outcomes.ResultsEighty-five patients (61.4 ± 19 years, 56 male) were evaluated. Melanoma was the most prevalent diagnosis (51%), followed by non-small cell lung cancer (30%). ICI treatment consisted of PD-1, PDL-1 (nivolumab, pembrolizumab, atezolizumab), and CTLA-4 inhibitors (i) (ipilimumab) or combination PD-1i+CTLA4i. Renal toxicity developed after a median of four cycles of therapy. Fifty-one patients (65.5%) developed the most severe form of AKI- stage 3, including five patients requiring dialysis. All the 19 patients treated with dual ICI blockade developed AKI-stage 3, compared with 29 patients out of the 60 receiving a single agent (p<0.001). Most events were managed with corticosteroids associated with ICI withdrawal. In 15 patients ICI was restarted, but in six (40%) AKI recurred. Overall, 32 patients (40%) presented a complete renal recovery, which chance was inversely associated with dual ICI blockade (OR 0.15, 95CI 0.03-0.7, p=0.01).ConclusionICI-related ATIN may develop late after the therapy initiation, presenting as severe AKI, particularly in patients with dual ICI blockade. Although this complication may be partially reversible, concerns remain about the renal function sequelae and the possibility of restarting ICI treatment.
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Project description:Background and objectives: Immune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint inhibitors.Design, setting, participants, & measurements: We included all patients who received checkpoint inhibitor therapy from May 2011 to December 2016 at Massachusetts General Hospital. Baseline serum creatinine, averaged 6 months before checkpoint inhibitor start date, was compared with all subsequent creatinine values within 12 months of starting therapy. AKI was defined by Kidney Disease: Improving Global Outcomes criteria for fold changes in creatinine from baseline. Sustained AKI events lasted at least 3 days and was our primary outcome. The cause of sustained AKI was determined by chart review. Cumulative incidence and subdistribution hazard models were used to assess the relationship between baseline demographics, comorbidities, and medications, and sustained AKI and potential checkpoint inhibitor-related AKI.Results: We included 1016 patients in the analysis. Average age was 63 (SD 13) years, 61% were men, and 91% were white. Mean baseline creatinine was 0.9 mg/dl (SD 0.4 mg/dl), and 169 (17%) had CKD (eGFR<60 ml/min per 1.73 m2) at baseline. A total of 169 patients (17%) experienced AKI, defined by an increase in creatinine at least 1.5 times the baseline within 12 months; 82 patients (8%) experienced sustained AKI and 30 patients (3%) had potential checkpoint inhibitor-related AKI. The first episode of sustained AKI occurred, on average, 106 days (SD 85) after checkpoint inhibitor initiation. Sixteen (2%) patients experienced stage 3 sustained AKI and four patients required dialysis. Proton pump inhibitor use at baseline was associated with sustained AKI.Conclusions: AKI is common in patients receiving checkpoint inhibitor therapy. The causes of sustained AKI in this population are heterogenous and merit thorough evaluation. The role of PPI and other nephritis-inducing drugs in the development of sustained AKI needs to be better defined.
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