Nephrotoxicity Ntawm Immune Checkpoint Inhibitors: Kev Ntsuam Xyuas Tsis Zoo Los Ntawm 2013 txog 2020

Cov txiaj ntsig

Kev piav qhia

A total of 52,583,692 records from the FAERS database were involved in this study, and 7,204 reports were AEs of nephrotoxicity after treatment with ICIs. The clinical characteristics of patients with kidney toxicity using ICIs are shown in Tables 2 and 3. Among all reports of nephrotoxicity associated with ICIs, the proportion of males was larger than that of females (63.66% vs. 29.96%). With further analysis, the signal was also detected (ROR025 = 2.32, IC025 = 0.49). Among all reports of nephrotoxicity associated with each ICI, the signal of males was larger than that of females (Table 4). Significant differences existed between different age groups, too. The proportion of the elderly (>65) yog loj dua cov uas tsis yog neeg laus (< 65) (51.94% vs. 33.94%), and the difference was significant (ROR025 = 1.12, IC025 = 0.04), which might be attributed to the degenerative change of the elderly. The most frequently reported severe outcomes were other serious medical events and hospitalization. Hospitalization (ROR025 = 2.18, IC025 = 0.79), death (ROR025 = 1.50, IC025 = 0.53), and life-threatening (ROR025 = 2.08, IC025 = 1.01) events associated with renal AEs after ICI treatment were reported, indicating the potentially life-threatening nature ofICI hais txog nephrotoxicity.

Table 2 qhia cov yam ntxwv kho mob ntawm cov neeg mob nrograum toxicitysiv ICIs thiab lwm yam tshuaj. Tus naj npawb thiab feem pua ​​yog qhia. * Tus nqi ploj lawm hauv FAERS database. AEs, cov xwm txheej tsis zoo; IC025, qis kawg ntawm 95% kev ntseeg siab ntawm IC; ROR025, qis qis ntawm 95% kev ntseeg siab lub sijhawm ntawm ROR; Cov hlwb khoob; tsis muaj ntaub ntawv txaus los xam.

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Txawm li cas los xij, qhov sib txawv ntawm ntau yam tshwj xeeb nephrotoxic AEs tau pom nyob rau hauv tag nrho cov txheej txheem ICI. Ntawm tag nrho cov lus ceeb toom ntawm AEs ntawm nephrotoxicity, mob raum raug mob (2,404, 33.37%), lub raum tsis ua haujlwm (1,128, 15.66%), lub raum tsis zoo (778, 10.8%), tubulointerstitial nephritis (617, 8.56%), nephritis (617, 8.56%), 4. Cov ntawv ceeb toom no suav txog 77.47% ntawm tag nrho cov ntawv ceeb toom. Lwm cov lus ceeb toom ntawm AEs ntawm nephrotoxicity yog suav tias tsis tshua muaj.

Cov spectrum ntawm nephrotoxicity AEs sib txawv hauv cov tshuaj tiv thaiv kab mob, feem ntau, ICIs tsis tshua muaj feem cuam tshuam nrog rau lub raum AEs.

Thaum soj ntsuam ntxiv lawm, muaj qhov sib txawv tseem ceeb ntawm AEs ntsig txog nephrotoxicity thiab atezolizumab tag nrho (IC025: 0.05; ROR025: 1.04), tab sis tsis yog Lwm yam ICIs (Table 6). Kaum ib nqe lus nyiam (PTs) tau cuam tshuam nrog kev kho mob atezolizumab, xws li phonephrenitis (ROR025=1.20, IC025=0.07) mus rau glomerulonephritis ntev (ROR025=51.95, IC{ {13}}.17). Nivolumab yog nrog qhov dav tshaj plaws ntawm lub raum AEs nrog 26 PTs kuaj pom raws li cov cim, xws li los ntawm anuria (ROR025=1.02, IC025=−0.03) mus rau autoimmune nephritis (ROR025=29.03) , IC025=3.46). Nees nkaum ib PTs tau cuam tshuam nrog kev kho mob pembrolizumab, xws li los ntawm lub raum tubular necrosis (ROR025=1.06, IC025=0.04) mus rau lub raum tsis zoo (ROR025=185.22) , IC025=1.69). Cuaj PTs tau cuam tshuam nrog kev kho ipilimumab, xws li nephrotic syndrome (ROR025=1.08, IC025=−0.04) mus rau autoimmune nephritis (ROR025=72.67, IC{{42}) }.77). Rau durvalumab, 7 qhov teeb meem tsis sib haum xeeb tau kuaj pom, xws li biotic microangiopathy (ROR025= 1.97, IC025=0.77) mus rau autoimmune nephritis (ROR025=18.27, IC{{51} }.72). Ib tug me me ntawm lwm cov teeb liab tau tshaj tawm. Tab sis qee qhov teeb meem muaj zog heev tau pom. Avelumab muaj zog ntau txuam nrog pyelonephritis (ROR025=5.27, IC025=1.17). Cemiplimab muaj zog ntau dua nrog rau autoimmune nephritis (ROR025=375.35, IC025=0.83) thiab kev hloov raum raum (ROR025=13.22, IC025=0.20) . Tremelimumab muaj zog ntau cuam tshuam nrog nephritis (ROR025=27.90, IC025=2.83), thiab lwm yam (Daim duab 1 thiab 2).

Kev sib tham

Kev txheeb cais yog cov cuab yeej siv tau

Table 6 qhia cov ntaub ntawv ntawm tag nrho thiab tshwj xeeb ICI suav hauv 2 * 2 lub rooj sib tham thiab suav cov txiaj ntsig los ntawm kev txheeb xyuas qhov tsis sib xws. Cov ntawv sau yuav ua siab tawv yog ROR025 siab dua 1 lossis IC025 siab dua 0. (a) Cov ntaub ntawv muaj raum AEs qhia rau ICIs. (b) Tus naj npawb ntawm cov ntaub ntawv nrog lwm cov AEs qhia rau ICIs. (c) Tus naj npawb ntawm cov ntaub ntawv nrog rau lub raum AEs rau lwm yam tshuaj. (d) Tus naj npawb ntawm cov ntaub ntawv qhia lwm yam AEs rau lwm yam tshuaj. ROR, qhia qhov sib txawv piv txwv; ROR025, qis kawg ntawm 95% kev ntseeg siab ntawm ROR; IC, cov ntaub ntawv tivthaiv; IC025, qis kawg ntawm 95% kev ntseeg siab ntawm IC.

nyob rau hauv pab teeb liab nrhiav kom tau nyob rau hauv spontaneous ceeb toom systems. Hauv kev tshawb fawb yav dhau los, ROR tau raug xaiv los ua qhov kev txheeb xyuas haiv neeg tsis tsim nyog los ua tus yam ntxwv ntawm spectrum, zaus, thiab kev kho mob ntawm ICI ntsig txog cov xwm txheej tsis zoo (Raschi li al. 2019). Txawm li cas los xij, tsis muaj ib tus neeg txoj hauv kev los txheeb xyuas cov teeb liab txaus thiab kev siv lwm txoj hauv kev yog qhov tseem ceeb (van Puijenbroek li al. 2002). Yog li ntawd, ob txoj kev, ROR thiab BCPNN, yog siv nyob rau hauv txoj kev tshawb no. Kev xaiv ntawm lub sijhawm luv luv yuav tsum tau them sai sai rau. Hauv kev tshawb fawb yav dhau los, kev tsis sib haum xeeb thiab kev tsom xam Bayesian tau siv hauv cov ntaub ntawv mining los tshuaj xyuas qhov xav tias lub raum tsis zoo tom qab kev tswj hwm ntawm ICIs sib txawv, raws li FAERS txij Lub Ib Hlis 2004 txog Lub Cuaj Hli 2019 (Chen li al. 2020). Txawm li cas los xij, ICI qhov kev lag luam loj dua, ipilimumab, tau teev nyob rau hauv 2011. Cov ntaub ntawv rov qab ua rau qhov kev soj ntsuam ua rau muaj qhov yuam kev. Peb txoj kev tshawb fawb yog kev tshawb fawb pharmacovigilance ntawm ICI-koom nrog neph toxicities raws li ntau dua 50 lab cov ntaub ntawv nyob rau lub sijhawm tsim nyog. Qhov no ua rau peb cov lus xaus ruaj khov dua piv nrog lwm cov kev tshawb fawb.

Feem ntau cov kev sim tshuaj ntawm ICIs tau soj ntsuam cov teebmeem kev kho mob uas tsis yog AEs thiab tsuas yog muab cov lus piav qhia luv luv ntawm cov AEs hnyav lossis tuag taus. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, txoj kev tshawb no yog qhov kev sau ntau tshaj plaws thiab muaj kev sib sau kom txog thaum tsis ntev los no los sib piv cov koom haum ntawm lub raum tsis zoo tom qab ICIs sib txawv hauv kev coj ua tiag tiag raws li FAERS pharmacovigilance database. Cov kev tshawb fawb yav dhau los qhia tau tias ICIs tuaj yeem ua rau muaj kev pheej hmoo ntawm cov kab mob hauv nruab nrog cev xws li endocrine, hematological, pob ntseg, thiab labyrinth toxicity (Zhai li al. 2019; Hu et al. 2020; Ye et al. 2020). Nephrotoxicity yog tsawg. Kev suav nyiaj rau 2.47% ntawm tag nrho cov ntaub ntawv ICI nrog cov ntaub ntawv tshiab los ntawm Lub Ib Hlis 1, 2013, txog rau Lub Rau Hli 30, 2020.

Nephrotoxicity raws li kev sib deev

Qhov tseem ceeb, piv nrog cov txiv neej cov neeg mob, nephrotoxic AEs tau tshaj tawm ntau dua li cov lus qhia ntawm cov poj niam cov neeg mob (63.66% vs. 29.96%). Qhov tshwm sim qhia tau hais tias cov txiv neej yog cov neeg muaj kev pheej hmoo siab rau nephrotoxic AEs tom qab kho nrog ICI tshuaj. Kev tshawb fawb yav dhau los kuj tau lees paub qhov no (Chen li al. 2020). Yog vim li cas rau qhov sib txawv ntawm qhov tshwm sim ntawm nephrotoxicity ntawm cov txiv neej thiab poj niam tej zaum yuav muaj feem xyuam rau qib ntawm cov tshuaj hormones poj niam txiv neej. Cov txiv neej cov tshuaj hormones ua rau muaj kev cuam tshuam loj heev nyob rau hauv cov nqe lus ntawm kev ua kom oxidative kev nyuaj siab, ua rau lub cev renin-angiotensin, thiab ua rau fibrosis nyob rau hauv lub raum puas, tab sis poj niam cov tshuaj hormones ua rau cov nyhuv renoprotective (Valdivielso li al. 2019). Yog li, kev siv tshuaj kho mob ICI yuav tsum tsom mus rau qhov tshwm sim ntawm nephrotoxicity hauv cov txiv neej cov neeg mob.

Kev sib koom ua ke ntawm tag nrho nephrotoxicity hauv tag nrho ICI siv

Lub raum yog lub cev tseem ceeb rau kev tsim cov zis, tswj cov electrolytes thiab dej, thiab homeostasis ntawm cov as-ham thiab metabolites hauv lub cev (Liu li al. 2019). Cov tshuaj yog ib qho ua rau mob raum (Markowitz thiab Perazella 2005; Perazella 2005, 2009, 2012; Uchino li al. 2007; Izzedine et al. 2009; Moffett and Goldstein 2011; Hoste et al. 2011). Drug-induced nephrotoxicity muaj ntau dua hauv cov neeg mob hauv tsev kho mob, tshwj xeeb tshaj yog cov neeg mob hauv tsev kho mob hnyav (Mehta li al. 2004; Uchino li al. 2007; Moffett thiab Goldstein 2011; Hoste et al. 2015), thiab cuam tshuam los ntawm qhov muaj peev xwm ntawm nephrotoxic hauv lub cev. cov tshuaj, cov yam ntxwv hauv qab ntawm tus neeg mob uas txhim kho txoj kev pheej hmoo rau lub raum raug mob, thiab cov metabolism thiab tso tawm ntawm cov neeg ua txhaum cai los ntawm lub raum (Perazella 2003, 2005, 2009; Markowitz thiab Perazella 2005). Cov pab pawg tswj yuav qhia tau ntau dua ntawm lub raum toxicity. Tsis tas li ntawd, ICI cov ntaub ntawv tuaj yeem qhia ntau dhau ntawm lwm yam kabmob hauv nruab nrog cev, uas yuav ua rau tsis muaj kev cuam tshuam tseem ceeb ntawm lub raum AEs thiab ICIs.

Nephrotoxicity thiab atezolizumab

Lub raum yog tsim los ntawm glomeruli thiab tubules. Tsis muaj kev xav ntawm toxicity ntawm txhua feem yog pom tseeb nyob rau hauv pawg atezolizumab (Table 7), uas tej zaum yuav raug ntaus nqi rau cov txheej txheem ntawm cov tshuaj no. Atezolizumab yog ib tug engineered humanized monoclonal IgG1 antibody uas khi xaiv rau PD-L1 thiab tiv thaiv nws cov kev cuam tshuam nrog PD-1 thiab B7.1 thaum nws yog sparing kev sib cuam tshuam ntawm PD-L2 thiab PD-1. Rau qee qhov kev kawm, atezolizumab yuav muaj kev noj qab haus huv ntau dua ntawm PD-L1 receptors uas tau tawg mus rau hauv lub raum, uas yuav tsum tau lees paub los ntawm kev tshawb fawb ntau dua.

Muaj pov thawj nephrotoxicity thiab ICIs

Cov txiaj ntsig tau pom tias mob raum raug mob, IgA nephropathy, thiab nephritis qhia qhov sib txawv tseem ceeb nrog ICIs ib nrab, thiab qee qhov ntawm cov cim no muaj zog dua lwm tus (Daim duab 2). Qhov no tej zaum yuav muaj feem xyuam nrog cov txheej txheem ntawm ICIs. CTLA-4 yog ib feem ntawm B7: CD28 immunoglobulin tsev neeg pom nyob rau ntawm T-cells thiab xa cov teeb liab inhibitory mus rau T-cell. PD-1 tau nthuav tawm ntawm T-cells thiab khi rau nws cov ligands PD-L1 thiab PD-L2 uas tau nthuav tawm hauv cov qog nqaij hlav cancer thiab lwm lub cev tiv thaiv kab mob. Cov tshuaj tiv thaiv kab mob tiv thaiv PD-1, xws li nivolumab, pembrolizumab, thiab palivizumab, lossis PD-L1, xws li MEDI4736 thiab MPDL3280A ua kom cov qog nqaij hlav T-cell los tiv thaiv kev cuam tshuam ntawm PD1 thiab PD-L1 los tiv thaiv T. -cell inactivation (Curran li al. 2010). Mob raum raug mob, IgA nephropathy, thiab nephritis yog cov kab mob nyuaj nrog ntau yam subtypes, thiab muaj ntau yam ua rau tus kab mob (Cortazar li al. 2016; Mamlouk et al. 2019). Kev tshawb fawb yav dhau los tsis muaj peev xwm piav qhia txog cov txheej txheem pathological. Tab sis dab tsi yog qhov tseeb yog tias kev hloov pauv hauv lub cev tiv thaiv kab mob yuav cuam tshuam rau lwm cov ntaub so ntswg, uas yog raws li cov yam ntxwv ntawm tib neeg lub cev.

autoimmune nephritis thiab ICIs

Cov txiaj ntsig tau pom tias autoimmune nephritis thiab ntau yam tshuaj muaj feem cuam tshuam, suav nrog atezolizumab (ROR025=20.97, IC025=1.11), cemiplimab (ROR025=375.35, IC{{ 6}}.83), ipilimumab (ROR025=72.67, IC025=3.77), durvalumab (ROR025=18.27, IC025=0.72), nivolumab (ROR025=29.03, IC025=3.46) thiab pembrolizumab (ROR025=38.15, IC025=3.21). Nws tsis tau hais nyob rau hauv cov kev tshawb fawb yav dhau los. Tus kab mob autoimmune nephritis yog ib yam kab mob uas tshwm sim los ntawm kev puas tsuaj autoimmune. Cov txheej txheem tshuaj tau hais los saum toj no ntawm ICIs muaj feem cuam tshuam rau autoimmune nephritis. Yog li ntawd, cov neeg ua haujlwm kho mob yuav tsum tau saib xyuas lub cev ntawm cov neeg mob xws li kev siv tshuaj kho mob.

Xaus

Txoj kev tshawb no tau soj ntsuam tag nrho cov koom haum ntawm ICIs thiab muaj peev xwm nephrotoxicities los ntawm kev xyaum tiag tiag. Zuag qhia tag nrho, tsis muaj kev koom tes tseem ceeb ntawm ICIs thiab raum AEs, thaum muaj qhov sib txawv tseem ceeb ntawm AEs ntsig txog nephrotoxicity thiab atezolizumab tag nrho. Thiab cov chav kawm tshwj xeeb nephrotoxicities tau kuaj pom hauv ntau lub tswv yim ICI immunotherapy. Cov txiaj ntsig ib nrab tau ua raws li cov ntaub ntawv yav dhau los. Cov txiaj ntsig tau pom tias mob raum raug mob, IgA nephropathy, thiab nephritis qhia qhov sib txawv tseem ceeb nrog ICIs ib nrab. Nyob rau tib lub sij hawm, discoveries kuj tshwm sim. Autoimmune nephritis thiab ntau yam tshuaj muaj feem xyuam nrog, suav nrog atezolizumab, ceiplimab, ipilimumab, nivolumab, thiab pembrolizumab. Hauv kev kho mob ntawm ICIs, kev saib xyuas yuav tsum tau them rau cov neeg mob, tshwj xeeb tshaj yog cov neeg mob txiv neej thiab cov neeg laus, nrogmob raum raug mob, nephritis, autoimmune nephritis, thiablwm yam nephrotoxicAEs. Related AEs ntawm nephrotoxicity raug lees paub los ntawm cov kws kho mob.

Kev lees paubTxoj kev tshawb no yog nyiaj txiag los ntawm National Natural Science Foundation ntawm Tuam Tshoj (81303315) thiab Natural Science Foundation ntawm Liaoning Province (20180550342).

Tsis sib haum xeebCov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab

Cov ntaub ntawv

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Peters, S., Syrigos, K., et al. (2019) Nivolumab ntxiv rau ipilimumab hauv kev mob qog noj ntshav uas tsis yog me me.N. Engl. J. Med., 381, 2020-2031 ib. Hoste, EAJ, Bagshaw, SM, Bellomo, R., Cely, CM, Colman, R., Cruz, DN, Edipidis, K., Forni, LG, Gomersall, CD, Govil, D., Honoré,

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