Two acute kidney injury episodes after ICI therapy: a case report

Abstract

A 74-year-old Japanese male with lung squamous cell carcinoma received his first dose of immune checkpoint inhibitors (ICIs): ipilimumab and nivolumab. He developed acute kidney injury (AKI) and was admitted to our department. We diagnosed kidney immune-related adverse effects (irAE), and a kidney biopsy revealed acute tubulointerstitial nephritis. We started oral prednisolone (PSL) and his AKI immediately improved. The patient maintained stable findings after PSL was tapered off. However, seven months after the ICI administration, he developed rapid progressive glomerular nephritis and was admitted to our department again. The second kidney biopsy showed findings consistent with anti-glomerular basement membrane glomerulonephritis. Although the patient was treated with pulse methylprednisolone followed by oral PSL and plasma exchange, he became dependent on maintenance hemodialysis. To our knowledge, no case report has described two different types of biopsy-proven nephritis. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered.

Introduction

Immune checkpoint inhibitors (ICIs) have prevailed as the standard of care for the treatment of several cancers [1, 2]. While ICIs have been demonstrated to be highly effective, they have caused a unique spectrum of side effects termed immune-related adverse events (irAEs) [1, 2]. Kidney irAEs are not as common as other irAEs such as dermatitis, enterocolitis, and thyroiditis [3]. The estimated incidence of acute kidney injury (AKI) attributable to irAEs ranges from 1.4 to 4.9% [1]. The most common pathological diagnosis of kidney irAEs is acute tubulointerstitial nephritis (ATIN) [2, 4]. However, cases of glomerulonephritis have also been reported [5].

Here, we report a patient who developed ATIN and anti-glomerular basement membrane (GBM) glomerulonephritis after a single ICI dose.

Case report

A 74-year-old Japanese man with lung squamous cell carcinoma in the right inferior lobe underwent right pulmonary dissection. He experienced a relapse of lung cancer that was treated with cisplatin and vinorelbine. However, the regimen was terminated because of nausea. His serum creatinine (Cr) levels ranged from 0.9 to 1.1 mg/dL. He was a former smoker. His only medication was rosuvastatin.

In April 2022 (Day 1), the patient received his first dose of ICIs: ipilimumab 60 mg (approximately 1 mg/kg) and nivolumab 360 mg. He developed a rash 2 weeks after ICI administration. Fever and loss of appetite developed on Day 18 and lasted for a week. On Day 26, the patient presented to the hospital. He was febrile, and his laboratory findings included an elevated serum Cr level (2.33 mg/dL). He was diagnosed with AKI and admitted to the hospital. Although hydration and antibiotic therapy were initiated for suspected bacterial infection and prerenal AKI, his AKI did not improve. Other laboratory findings included primary hyperthyroidism (thyroid-stimulating hormone, 0.01 μIU/L; free triiodothyronine, 6.25 pg/mL; free tetraiodothyronine, 5.70 ng/dL). Thyroid tenderness and elevated thyroid stimulating hormone receptor antibody levels were absent, consistent with ICI-related thyroiditis. On Day 28, he was transferred to our department for investigation and AKI treatment. On transfer, his blood pressure and body temperature were 131/70 mmHg and 37.8 °C, respectively. Physical examination did not reveal a significant finding. Laboratory examinations revealed serum Cr elevation (4.34 mg/dL), proteinuria (2.68 g/gCr), isomorphic hematuria (20–29/high-powered field [HPF]), urine β-2 microglobulin elevation (11,652 ng/mL), and urine N-acetyl-β glucosaminidase (NAG) elevation (12.48 U/gCr). Hyperthyroidism was also present. Autoantibodies including anti-GBM antibodies were negative. We suspected ICI-related ATIN because of his medical history. On Day 29, further elevation of Cr was observed, and hemodialysis (HD) was initiated. The patient completed four HD sessions during hospitalization until Day 33. After the transfer, urinary abnormalities showed spontaneous improvements: proteinuria 0.28 g/gCr, hematuria 5–9/HPF, urine β-2 microglobulin 6539 ng/mL on Day 32. Oral prednisolone (PSL) 30 mg/day (approximately 0.5 mg/kg/day) was started on Day 33. Kidney biopsy was performed on Day 35. The pathological findings included tubular atrophy, lymphocyte infiltration, and granuloma in the interstitium (Fig. 1a, b). Severe glomerular lesions were not observed (Fig. 1c, d). The lymphocytes were predominantly CD3-positive and CD4-positive (Fig. 1e, f), partially CD8-positive and CD20-positive (Fig. 1g, h). Immunofluorescence (IF) staining did not reveal a significant deposit (data not shown). The patient was diagnosed with ATIN. On Day 35, 2 days after the initiation of PSL, proteinuria and hematuria disappeared. Thyroiditis also improved after PSL initiation. The patient was discharged on Day 41. ICIs as well as any other curative therapy have been permanently withheld since his discharge to date. The PSL dose was tapered and stopped on Day 93. After discharge, no proteinuria or hematuria was observed, although a moderate decrease in kidney function (serum Cr, 1.3–1.4 mg/dL) persisted.

Fig. 1.

Pathological findings of the first kidney biopsy. a Hematoxylin–eosin (HE) staining shows lymphocyte infiltration and granuloma (×200). b PAS staining shows lymphocyte infiltration in interstitium (×200). c, d PAS staining shows a glomerulus without significant lesions (×200, ×400, respectively). e–h CD-3 positive (e) and CD-4 positive (f) lymphocytes are dominant. CD-8 positive (g) and CD-20 positive (h) lymphocytes are also present (×200)

In November 2022 (Day 211), the patient presented to our department with complaints of fever and a loss of appetite that had lasted for more than 10 days. His body temperature was 37.7 °C. His vital signs were within the normal ranges. Laboratory examinations revealed increases in serum Cr (3.14 mg/dL) and serum C-reactive protein levels (19.18 mg/dL), dysmorphic hematuria (30–49/HPF), proteinuria (0.41 g/gCr), and mildly elevated urine β-2 microglobulin (754 ng/mL) and urine NAG levels (23.21 U/gCr). Thyroid hormone levels were normal. The patient was immediately re-admitted to our department because of suspected rapid progressive glomerulonephritis. This time, serologic testing was positive for anti-GBM antibody (65.6 U/mL). The next day (Day 212), a second kidney biopsy was performed. The sample contained 17 glomeruli, five of which displayed global sclerosis. Mesangial and endocapillary hypercellularity was found in most glomeruli. Four cellular crescents, leucocyte infiltration around a glomerulus, ruptured Bowman’s capsule, and minor interstitial neutrocyte infiltration were also present (Fig. 2a–c). IF staining revealed linear IgG deposition, consistent with the findings of anti-GBM glomerulonephritis (Fig. 2d). IgG subclass staining showed predominantly IgG1, IgG2, and IgG4-positive deposits (Fig. 2e–h). Electron microscopy disclosed infiltrating macrophages and severe glomerular sclerosis, but these findings were not helpful for diagnosis. During hospitalization, there was no sign of pulmonary hemorrhage.

Fig. 2.

Pathological findings of the second kidney biopsy. a PAS staining shows mesangial and endocapillary hypercellularity in a glomerulus (×400). b PAM staining shows a ruptured Bowman’s capsule (×400). c Hematoxylin–eosin staining shows leucocyte infiltration, mainly neutrophils, around a glomerulus (×200). d Immunofluorescence(IF) staining shows linear IgG deposit (×40). e–h IgG subclass IF staining. IgG1 (e), IgG2 (f) and IgG4 (h) are dominant (×40)

The patient received pulse intravenous methylprednisolone (mPSL; 500 mg/day for 3 consecutive days), followed by 40 mg/day oral PSL (approximately 0.6 mg/kg/day). On Day 214, HD was initiated because of oliguria, and plasma exchange (PE) was started. Cyclophosphamide was spared considering the high risk of infection and low likelihood of kidney recovery. Although his fever and appetite immediately improved after the first pulse steroid course, he remained on dialysis even after finishing 3 courses of pulse mPSL and 14 sessions of PE (Fig. 3). PE was ceased and PSL tapering was started before the patient was discharged. During the clinical course, the progression of the lung cancer has not been observed. The patient has remained stable on HD and PSL tapering to date. The lung cancer has also remained stable.

Fig. 3.

The patient’s clinical course

Discussion

Kidney irAEs are uncommon but are increasingly being reported, including multiple reports of glomerulonephritis [2, 5]. However, to our knowledge, no case report has described two different types of biopsy-proven nephritis developed at different times after ICI administration.

IrAEs can occur at any point during or after cessation of treatment [6, 7]. The median time from the initiation of ICIs to the onset of AKI attributable to irAEs is 3–4 months, and only 1–7% of patients with kidney irAEs require kidney replacement [1, 2, 4]. In our case, ATIN was observed within 1 month after the first ICI administration, and HD was required. Combination therapy with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death 1 (PD-1) antibodies, such as ipilimumab and nivolumab, is associated with a higher risk of ICI-related AKI [3, 8] and a higher risk of early-onset irAEs in general [9]. The early and severe ATIN in our case might have resulted from the combination therapy. In the first episode of AKI, it is unclear why hematuria and proteinuria were also present despite the lack of severe glomerular lesions. Studies showed that some ATIN cases had hematuria and/or proteinuria [10, 11], so this might have been the case for our patient.

Anti-GBM glomerulonephritis, the diagnosis of the second AKI, is a rare manifestation of kidney irAEs. There are eight reported cases of ICI-related anti-GBM glomerulonephritis [12–19] (Table 1). The onset of anti-GBM nephritis ranged from 2 to 16 months (median approximately 4 months) after the initiation of ICIs, slightly later than ATIN. The kidney prognosis of ICI-related anti-GBM glomerulonephritis is generally poor. Two patients remained HD-dependent and died within 2 months [12, 18]. Four patients necessitated maintenance dialysis [13, 15, 17, 19]. No patient showed complete recovery of the kidney function. The treatments were not different from that of normal anti-GBM glomerulonephritis.

Table 1.

Previous case reports of ICI-related anti-GBM glomerulonephritis

First author	Age/Gender Cancer	Cancer treatment Onset of glomerulonephritis	Clinical findings	Pathological findings	Treatments for anti-GBM glomerulonephritis	Kidney Prognosis
Takahashi [12]	74/Male Lung adeno-carcinoma	Nivo 16 weeks after the first administration	sCr 1.98 mg/dL U-RBC > 100/HPF UPCR 7.0 g/gCr	Crescents (No detailed description)	Pulse mPSL →  PSL PE	On dialysis. Died of alveolar hemorrhage
Sammartino [13]	50/Male Melanoma	Tremelimumab 6 weeks after final administration (13.5 months after first administration)	sCr 3.3 mg/dL Macroscopic hematuria	Cellular crescents with segmental necrosis. Linear IgG/C3 deposition	Pulse mPSL →  PSL + CY PE	On maintenance peritoneal dialysis
Hultin [14]	50s/Male Melanoma	Ipi + Nivo 51 weeks after the first administration	sCr 1382 μmol/L (≈15.6 mg/dL) Hematuria Proteinuria	Necrotizing cellular crescents. Tubulointerstitial injury/inflammation. Linear IgG-κ/λ deposition	PE Pulse steroid →  PSL + CY	On HD for 5 months. →  Stage G4 CKD
Kyriazis [15]	58/Male Melanoma	Ipi + Nivo →  dabrafenib +  trametinib 13 months after first ICI administration	sCr 2.4 mg/dL UPCR 2 g/gCr Dysmorphic RBC, RBC casts Negative anti-GBM antibody	Cellular crescents. Linear IgG, IgA, κ/λ deposition	Pulse mPSL →  PSL + CY	Temporally off dialysis. →  Maintenance HD after Nivo rechallenge
Hoshina [16]	65/Male Lung adeno-carcinoma	Pem 3 months after final administration (7 months after the first administration)	sCr 2.6 mg/dL UPCR 2.22 g/gCr U-NAG 52.3 IU/L Weakly positive anti-GBM antibody	Cellular & fibrocellular crescents. Interstitial lymphocyte infiltration. Linear and partially granular IgG (dominantly IgG1 and IgG3), IgA, C3 deposition	Pulse mPSL →  PSL	Incomplete kidney recovery (Cr≈1.5 mg/dL)
Javaugue [17]	74/Male squamous cell lung cancer	Pem + carboplatin + paclitaxel 2 months after first administration	sCr 4.0 mg/dL UP 11 g/day Hematuria Negative anti-GBM antibody	Fibrocellular & cellular crescents with fibrinoid necrosis. Diffuse acute tubular injury, erythrocyte casts, and moderate interstitial fibrosis. Diffuse linear IgG (IgG2 only) deposition	PSL →  Rituximab PE	Maintenance HD
Tani [18]	74/Male Non-small cell lung cancer	Nivo 3 months after the first administration	sCr 2.97 mg/dL UPCR 0.78 g/gCr U-RBC > 100/HPF Anti-GBM antibody > 350 IU/L	Necrotizing cellular crescentic glomerulonephritis. Linear IgG (IgG1 > IgG3 >> IgG2, IgG4) and C3 deposition. Tubulointerstitial nephritis with infiltration of lymphocytes	Pulse mPSL →  PSL + CY PE	On HD Died of cytomegalovirus pneumonia
El Yamani [19]	65/Female Cervical squamous cell carcinoma	Pem + carboplatin + paclitaxel 4 months after the first administration	sCr 3.07 mg/dL UP 0.875 g/day U-RBC 4–10/HPF Anti-GBM antibody 24 U/mL	Cellular & fibrocellular crescents. Erythrocyte casts, tubulointerstitial inflammation (lymphoplasmacytic with eosinophils and neutrophils). Linear IgG (IgG2 > IgG3) deposition	Oral PSL →  Pulse mPSL + PE + CY	On HD until the patient and her family wished for comfort measures

Cr creatinine, CKD chronic kidney disease, CY cyclophosphamide, HD hemodialysis, Ipi ipilimumab, mPSL methylprednisolone, Nivo nivolumab, Pem pembrolizumab, PSL prednisolone, sCr serum creatinine, U-NAG urine N-acetyl-β-d-glycosaminidase, UP urine protein, UPCR urine protein to creatinine ratio, U-RBC urine red blood cells

The mechanism of anti-GBM glomerulonephritis in these cases was unclear. However, we suggest that ICIs may have had a relationship with the development of anti-GBM glomerulonephritis in this case. Soluble forms of CTLA4, namely CTLA4-Ig and CTLA4-Fc, ameliorated glomerular and tubulointerstitial damage in anti-GBM glomerulonephritis model animals [20, 21]. Stimulation of PD-1 signaling by a Fc fusion protein of PD-1 ligand resulted in the amelioration of anti-GBM glomerulonephritis in model rats [22]. These findings underpin the hypothesis that ICI therapy induced a pro-inflammatory state conducive to glomerulonephritis.

In summary, we have reported a patient who experienced two AKI episodes after a single dose of ICIs, and he was diagnosed with ATIN and anti-GBM glomerulonephritis. Although the relationship between ICI therapy and anti-GBM glomerulonephritis remains unclear, this is the first case report in which two different types of biopsy-proven nephritis developed at different times after ICI administration. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered.

Declarations

Conflict of interest

All the authors have declared no competing interest.

Informed consent

Informed consent was obtained from the patient in the case report.