Abstract:The main manifestation of acute interstitial nephritis (AIN) due to immune checkpoint inhibitors is acute kidney injury. We report here a biopsy-proven AIN revealed by tubular acidosis. This case highlights that immune checkpoint inhibitor prescribers must be aware of electrolytic disorders since tubular dysfunction can precede serum creatinine increase and reveal renal toxicity.
“…Interestingly, only five of their patients had AIN alone, whereas the remaining nine patients had simultaneous presentation of AIN with a glomerulopathy (pauci-immune vasculitis, membranous nephropathy, IgA nephropathy, C3 glomerulopathy, FSGS, and AA amyloidosis) (7). Furthermore, tubular damage by ICIs may also cause electrolyte abnormalities and some ICIs have been reported in association with renal tubular acidosis in the setting of AIN (18,19). Mechanistically, this is believed to be an autoimmune process causing an alteration of H1-ATPase or Cl-/HCO3-in in the type A intercalated cells (19).…”
Section: Discussionmentioning
confidence: 99%
“…Furthermore, tubular damage by ICIs may also cause electrolyte abnormalities and some ICIs have been reported in association with renal tubular acidosis in the setting of AIN (18,19). Mechanistically, this is believed to be an autoimmune process causing an alteration of H1-ATPase or Cl-/HCO3-in in the type A intercalated cells (19).…”
Background The objective of this case cohort study was to describe our experience in the care of patients with immune checkpoint inhibitor-related acute interstitial nephritis (ICI-AIN) including rechallenge. Methods A descriptive case series of patients that received an ICI and had an AKI (defined as a $1.5-fold increase in serum creatinine) as an immune-related adverse event (irAE), with biopsy-proven or clinically suspected ICI-AIN from January 1, 2014 to December 1, 2018 at Mayo Clinic, Rochester. We studied details regarding diagnosis, clinical course, management, and outcomes of rechallenge of immunotherapy. Complete response (CR) was defined as return of kidney function back to baseline or ,0.3 mg/dl above baseline creatinine; partial response (PR) was defined as creatinine .0.3 mg/dl from baseline, but less than twofold above the baseline by the end of steroid course. Results A total of 14 cases of biopsy-proven (35%) or clinically suspected (65%) ICI-AIN was identified. All patients had their ICI withheld and 12 patients received steroids. Steroid regimens were highly variable. The starting equivalent dose of prednisone was higher in those that had a CR versus a PR (median 0.77 mg/kg versus 0.66 mg/kg). Proton pump inhibitors (PPIs) were used in 11 patients and were stopped in eight (73%) patients at the time of the AKI event. A CR was seen in five (63%) of the eight patients who discontinued PPIs. Rechallenge was attempted in four of the 14 patients: three were successful with no recurrence of AKI, but one patient had recurrent AKI and fatal pneumonitis. Conclusions Careful review, withholding ICI and concomitant known AIN-inducing medications, along with prompt initial steroid management were the key in complete renal kidney recovery. A kidney biopsy should be strongly considered. Rechallenge of immunotherapy after a kidney irAE, although challenging, is possible and would need careful evaluation on an individual basis.
“…Interestingly, only five of their patients had AIN alone, whereas the remaining nine patients had simultaneous presentation of AIN with a glomerulopathy (pauci-immune vasculitis, membranous nephropathy, IgA nephropathy, C3 glomerulopathy, FSGS, and AA amyloidosis) (7). Furthermore, tubular damage by ICIs may also cause electrolyte abnormalities and some ICIs have been reported in association with renal tubular acidosis in the setting of AIN (18,19). Mechanistically, this is believed to be an autoimmune process causing an alteration of H1-ATPase or Cl-/HCO3-in in the type A intercalated cells (19).…”
Section: Discussionmentioning
confidence: 99%
“…Furthermore, tubular damage by ICIs may also cause electrolyte abnormalities and some ICIs have been reported in association with renal tubular acidosis in the setting of AIN (18,19). Mechanistically, this is believed to be an autoimmune process causing an alteration of H1-ATPase or Cl-/HCO3-in in the type A intercalated cells (19).…”
Background The objective of this case cohort study was to describe our experience in the care of patients with immune checkpoint inhibitor-related acute interstitial nephritis (ICI-AIN) including rechallenge. Methods A descriptive case series of patients that received an ICI and had an AKI (defined as a $1.5-fold increase in serum creatinine) as an immune-related adverse event (irAE), with biopsy-proven or clinically suspected ICI-AIN from January 1, 2014 to December 1, 2018 at Mayo Clinic, Rochester. We studied details regarding diagnosis, clinical course, management, and outcomes of rechallenge of immunotherapy. Complete response (CR) was defined as return of kidney function back to baseline or ,0.3 mg/dl above baseline creatinine; partial response (PR) was defined as creatinine .0.3 mg/dl from baseline, but less than twofold above the baseline by the end of steroid course. Results A total of 14 cases of biopsy-proven (35%) or clinically suspected (65%) ICI-AIN was identified. All patients had their ICI withheld and 12 patients received steroids. Steroid regimens were highly variable. The starting equivalent dose of prednisone was higher in those that had a CR versus a PR (median 0.77 mg/kg versus 0.66 mg/kg). Proton pump inhibitors (PPIs) were used in 11 patients and were stopped in eight (73%) patients at the time of the AKI event. A CR was seen in five (63%) of the eight patients who discontinued PPIs. Rechallenge was attempted in four of the 14 patients: three were successful with no recurrence of AKI, but one patient had recurrent AKI and fatal pneumonitis. Conclusions Careful review, withholding ICI and concomitant known AIN-inducing medications, along with prompt initial steroid management were the key in complete renal kidney recovery. A kidney biopsy should be strongly considered. Rechallenge of immunotherapy after a kidney irAE, although challenging, is possible and would need careful evaluation on an individual basis.
“…As an example, a few reports of distal renal tubular acidosis have emerged in the setting of AIN. 39 , 40 Mechanistically, this is believed to be an autoimmune process causing an alteration of H+-ATPase or Cl−/HCO3− in type A intercalated cells. 40 Therefore, vigilance for disturbances in kidney function, development of proteinuria, and acid-base and electrolyte abnormalities is warranted.…”
Section: Mechanisms Of Immune Checkpoint Inhibition and Associated Admentioning
confidence: 99%
“… 39 , 40 Mechanistically, this is believed to be an autoimmune process causing an alteration of H+-ATPase or Cl−/HCO3− in type A intercalated cells. 40 Therefore, vigilance for disturbances in kidney function, development of proteinuria, and acid-base and electrolyte abnormalities is warranted. Figure 2 Immune checkpoint inhibitor (ICI)–related hyponatremia.…”
Section: Mechanisms Of Immune Checkpoint Inhibition and Associated Admentioning
Renal toxicities have been increasingly recognized as complications of the immune checkpoint inhibitors (ICIs). Recent studies have outlined the incidence and potential risk factors for nephrotoxicity. For clinicians, the key question is how to manage patients who develop these adverse renal effects. This is of paramount importance to providers as ICI use for cancer therapy becomes more widespread and nephrotoxicity increasingly develops. As clinicians encounter ICI-associated nephrotoxicity, an appropriate approach to management is required to facilitate the best outcomes in patients with cancer. Importantly, ICI rechallenge in patients who developed ICI-related acute kidney injury (AKI) is unclear and represents a conundrum for providers. Clinicians struggle with the “if, when, and how to” questions related to ICI rechallenge in this subset of patients. In addition, ICI use in the transplant population raises concerns for promoting acute rejection when treating cancer in these patients. We herein review current information on these various topics.
SouhrnVýchodiska: Akutní poškození renálních funkcí je relativně vzácnou komplikací protinádorové imunoterapie. Incidence renální toxicity následkem imunoonkologické léčby je relativně nízká -přibližně 2 % u nemocných léčených inhibitory PD-1/ PD-L1 a 4,5 % u kombinace anti--PD-1/ PD-L1 léků s inhibitorem CTLA-4. Nejčastější základní patologií je akutní tubulointersticiální nefritida. Dalším typem renálního postižení je autoimunitní nefropatie projevující se iontovou dysbalancí. U pa cientů se středně závažným a závažným poškozením ledvin je indikováno přerušení imunoterapie a léčba kortikosteroidy. Případ: Pa cient ve věku 61 let s metastatickým renálním karcinomem byl po 7 měsících léčby nivolumabem hospitalizován pro celkové zhoršení stavu, výraznou slabost, nevolnosti a nechutenství. Laboratorní vyšetření prokázalo zhoršení glomerulární filtrace, těžkou hyperkalemii a metabolickou acidózu. Hladiny hormonů štítné žlázy a kortizolu byly v normálním rozmezí. Stanovili jsme dia gnózu renální tubulární acidózy následkem imunoonkologické léčby a zahájili léčbu metylprednisolonem. Při této léčbě došlo k rychlé úpravě iontogramu i potíží. Ambulantně jsme dávku prednisonu postupně snižovali, ale po snížení na 5 mg denně došlo k rekurenci hyperkalemie a u pa cienta byla ponechána trvale dávka 10 mg prednisonu denně orálně. Imunoterapie nebyla znovu nasazena. Závěr: Renální toxicita imunoonkologické léčby se zpočátku obvykle projevuje zvýšeným sérovým kreatininem bez jakýchkoli klinických příznaků. Postupně se mohou rozvinout poruchy elektrolytů, oligurie, anurie a otoky. V rámci diferenciální dia gnostiky iontového rozvratu je nutné vyloučit endokrinní a metabolické poruchy, jako nově vzniklý diabetes mellitus 1. typu, hypofyzitida, adrenální insuficience a hypotyreóza. Léčbou volby jsou kortikoidy v běžné imunosupresivní dávce. Prognóza je příznivá, protože renální toxicita bez ohledu na patofyziologický podklad dobře reaguje na léčbu kortikoidy.
Klíčová slovanefritida -hyperkalemie -kortikosteroidy -imunoterapie Autor obdržel honoráře, cestovní granty a podporu výzkumu od následujících firem s produkty v oblasti nádorové imunoterapie: Bristol Myers Squibb, MSD, Roche, Astra Zeneca, Merck.
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