In this patient, AKI, rash, thyroiditis, and pneumonia were the main clinical manifestations and programmed death receptor 1 (PD-1) inhibitor tislelizumab and second-generation organoplatinum antitumor agent nedaplatin were used in the medical history. Skin rash, thyroid dysfunction, increased TSH, increased serum creatinine, pathological examination of renal biopsy revealed acute tubulointerstitial nephritis and no thrombotic microangiopathy-like changes. Nedaplatin nephrotoxicity was weak, and no cases of severe renal impairment caused by nedaplatin alone were reported in the literature; therefore, ICI-related AKI, rash, and hypothyroidism were considered in this case. Renal function, rash, and thyroid function improved after glucocorticoid treatment, supporting the diagnosis of ICI-related AKI, rash, and hypothyroidism. Breathing difficulty once occurred during treatment, and ICI-related pneumonia was considered in combination with imaging findings. All clinical manifestations were significantly improved after increasing the hormone dose, supporting the diagnosis of ICIs-related pneumonia. During follow-up, the patient switched to anlotinib hydrochloride, renal function serum creatinine recovered to 105 µmol/L, and pulmonary imaging conditions improved.
Existing studies have demonstrated that the mechanism of ICIs-related renal injury supports the "multiple hit" or "brake release" theory, affecting the immune tolerance of T cells to renal intrinsic antigen (autoimmune-related) or concomitant drugs (drug-induced) in the presence of PD 1, PD L1, and CTLA 4 inhibitors, activated T cells infiltrate in the renal parenchyma, and release cytokines leading to renal injury [1]. Its main clinical manifestation is AKI; the most common pathological type is tubulointerstitial nephritis (TIN) [2], and other pathological changes include thrombotic microangiopathy[3], immune complex glomerulonephritis [4], anti-GBM glomerulonephritis [5], glomerular minimal change disease, membranous nephropathy, immune glomerulonephritis, and IgA nephropathy[6]. If the patient has elevated serum creatinine after receiving ICIs (the patient's serum creatinine level is 1.5 times higher than before ICI treatment[7]), the possibility of ICI-related AKI should be considered in clinical diagnosis and treatment. If there is no puncture contraindication, it is recommended to perform renal biopsy and intervention as early as possible [2, 8]. Wang et al [9] concluded that patients with AKI associated with early identified ICIs have a better prognosis than those with delayed detection. The latest American Society of Clinical Oncology (ASCO) guidelines recommend the following for the grading and treatment of AKI associated with ICIs [10]. G1: serum creatinine increased by 0.3 mg/dL or 1.5 to 2.0 times from baseline. ICIs and/or drugs that may cause renal impairment were suspended. Grade G2: serum creatinine was 2 ~ 3 times higher than the baseline value, and the measures recommended by the guidelines included: (1) suspension of ICIs use, prednisone 0.5 ~ 1.0 mg · kg-1 · d-1 or equivalent dose of other types of glucocorticoids after nephrology specialist consultation to rule out other related renal injury factors; (2) prednisone increased to 1.0 ~ 2.0 mg · kg-1 · d-1 when renal function did not improve or worsen after one week; (3) glucocorticoids gradually decreased when the renal function returned to grade G1 or below; (4) no chronic renal insufficiency occurred and glucocorticoids were used at a dose of less than 10 mg/d, and the use of ICIs could be considered with full consideration of risks and benefits. Grade G3: Serum creatinine was higher than 4.0 mg/dL or three times higher than the baseline value. After nephrology consultation to exclude other renal injury factors, nephrotoxicity was considered directly related to ICIs. ICIs should be stopped, and prednisone 1.0 ~ 2.0 mg·kg-1·d-1 should be given. Grade G4: serum creatinine six times or more above the baseline value requires dialysis; the treatment was the same as G3. After excluding contraindications to renal biopsy, hormone therapy was started as soon as this patient was found at the same time as renal biopsy. Serum creatinine decreased to 105 µmol/L during subsequent follow-up.
This patient developed immune-related pneumonia during hormone therapy, suggesting that irAEs could appear successively rather than simultaneously. Immune-related adverse reactions in other systems must be vigilant after hormone therapy. The time to onset of ICIs-related pneumonia varies, with Cho et al[11] finding that pneumonic complications occur on average 54 days after immunosuppressive therapy and Delaunay et al[12] reporting an average of 2.8 months. The mechanism of pneumonia has remained unclarified, and it is believed that the possible mechanisms include: 1) persistently activated T cells attack both tumor and other autoantigens; 2) activation of pre-existing autoantibodies; 3) excessive secretion of inflammatory factors, such as IL-7; and 40 complement-mediated inflammatory response caused by direct binding of CTLA-4 antibody to CTLA-4 antigen expressed in normal tissues. Imaging findings showed heterogeneity[11]. Naidoo et al [13] identified imaging changes and divided them into five subtypes: occult organizing pneumonia, ground-glass opacities, interstitial pneumonia, hypersensitivity pneumonitis, and nonspecific pneumonitis. We observed interstitial pneumonitis changes in our patient's chest CT. According to the American Society of Clinical Oncology (ASCO) guidelines, the classification and treatment of pneumonia associated with ICIs are as follows: G1 grade asymptomatic, imaging 25% of the lung parenchyma is involved; suspension of ICIs is recommended; G2 asymptomatic, imaging 25 ~ 50% of the lung parenchyma is involved, if the symptoms do not improve after 48 ~ 72 h of intravenous hormone therapy, treat as G3 ~ 4: severe symptoms or respiratory failure, permanently discontinue ICIs, if the symptoms do not improve after 48 h of intravenous hormone therapy, consider infliximab or mycophenolate mofetil or cyclophosphamide treatment. In this case, the patient was given methylprednisolone 40 mg bid according to ASCO after developing pneumonia symptoms, and the condition was improved, supporting the diagnosis of immune-related pneumonia, suggesting that the treatment was effective.
The patient also presented with immune-related thyroiditis and rash. The former presented with hypothyroidism, which was easily recognized in clinical practice, and the symptoms were relieved after hormone therapy.
In summary, patients with a history of taking ICIs must be closely monitored for irAEs, including AKI, and ICIs should be discontinued immediately upon diagnosis. Glucocorticoids are the main treatment, and close attention should be paid to the presence or absence of new irAEs during the process. Early detection and intervention are essential for prognosis.
