Nephrotic syndrome with acute kidney injury due to combination therapy of immune checkpoint inhibitors: A case report and review of the literature

doi:10.21203/rs.3.rs-3341887/v1

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Case Report

Nephrotic syndrome with acute kidney injury due to combination therapy of immune checkpoint inhibitors: A case report and review of the literature

https://doi.org/10.21203/rs.3.rs-3341887/v1

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Journal Publication

published 09 Feb, 2024

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Background

Recent studies have focused on immune checkpoint inhibitors. Renal complications associated with the use of immune checkpoint inhibitors are uncommon compared with other immune-related adverse events. Acute interstitial nephritis accounts for most of these renal complications, with nephrotic syndrome quite rare. We herein report a case of nephrotic syndrome associated with immune checkpoint inhibitors that was more severe than that in previous cases. By comparing this case with previous reports, the possible reasons for the particular severity of this case are discussed.

Case presentation

A 75-year-old man developed nephrotic syndrome with acute kidney injury after the first combination therapy of nivolumab and ipilimumab for malignant pleural mesothelioma. The results of a kidney biopsy indicated minimal change disease with mild atherosclerosis and fusion of nearly all podocyte foot processes. Nivolumab and ipilimumab therapy were stopped, and treatment with corticosteroids was initiated. We investigated previously reported cases of nephrotic syndrome using immune checkpoint inhibitors. Seventeen cases of immune checkpoint inhibitor-related nephrotic syndrome, including ours, have been reported. Two of the 17 patients with immune checkpoint inhibitor-related nephrotic syndrome required hemodialysis treatment for acute kidney injury. Unlike many previously reported cases, the present patient was administered two different immune checkpoint inhibitors, which may be one of the reasons for the development of severe nephrotic syndrome.

Conclusions

In addition to previously reported risk factors, immune checkpoint inhibitor combination therapy can exacerbate nephrotic syndrome compared to immune checkpoint inhibitor monotherapy.

nivolumab

ipilimumab

immune checkpoint inhibitors

nephrotic syndrome

acute kidney injury

minimal change disease

Recent studies have focused on immune checkpoint inhibitors (ICIs) [1]. In patients with unresectable tumors, ICIs are used as the first-line therapy in a variety of fields [2, 3], which has contributed to substantially improved survival [2]. For example, malignant pleural mesothelioma is a highly aggressive malignancy that is often unresectable at time of the diagnosis, with less than 10% of patients surviving five years or longer [4]. Nivolumab plus ipilimumab have provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, which supported its approval in the USA as the first-in-class regimen for previously untreated unresectable malignant pleural mesothelioma [5].

Patients treated with ICIs often develop immune-related adverse events (irAEs), which are immune-mediated secondary effects of ICIs [1]. Although the exact pathophysiology of irAEs remains unclear, previous studies have suggested that irAEs are associated with improved survival [1]. Therefore, we must promptly recognize irAEs and deal with them effectively to ensure the best outcome.

Renal complications associated with the use of ICIs are uncommon compared with other irAEs [6]. Acute interstitial nephritis accounts for most of these renal complications, with nephrotic syndrome quite rare [6].

We herein report a case of nephrotic syndrome associated with ICIs that was more severe than that in previous cases. By comparing this case with previous reports, the possible reasons for the particular severity of this case are discussed.

A 75-year-old man received first-line nivolumab (1 mg/kg intravenously every 6 weeks) plus ipilimumab (treatment dose, 360 mg/body every 3 weeks), combination therapy with anti-programmed cell death 1 (anti-PD-1) antibody, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody for malignant pleural mesothelioma. His comorbidities included an artificial anus due to perforation of the sigmoid colon and slight proteinuria (urine dipstick test: +- to 1+). After the first dose of ICIs (13 days after the initial treatment), he suddenly presented with leg edema, massive proteinuria (19.85 g/day), urinary glucose (0.344 g/day), and hypoalbuminemia (2.0 g/dl). His blood pressure at presentation was 97/48 mmHg. Based on these results, the patient was diagnosed with nephrotic syndrome.

A kidney biopsy was performed, and light microscopy revealed 11 glomeruli without focal sclerosis, an increase in the mesangial matrix, or cellularity (Fig. 1a). Mild fibrosis was observed in the renal interstitium, with medial hypertrophy and fibroblastic intimal thickening of the interlobular and arch arteries (Fig. 1b). An immunofluorescence analysis yielded negative results. Electron microscopy revealed fusion of nearly all podocyte foot processes without any electron-dense deposits (Fig. 1c). Overall, the biopsy specimens indicated minimal change disease (MCD) with mild atherosclerosis.

Nivolumab and ipilimumab therapy were stopped, and treatment with corticosteroids (prednisone, 1 mg/kg) was initiated. However, his nephrotic syndrome was intractable, as might be expected from the fusion of all podocyte foot processes, which led to oliguria, pleural effusion, and deterioration of his creatinine level. Therefore, hemodialysis was initiated, and excess fluid was removed. His urinary protein and glucose levels gradually decreased with continued treatment and prednisone was tapered. Hemodialysis was discontinued because his urine output gradually increased 35 days after initiating hemodialysis.

Since discharge, the patient has continued to attend outpatient visits in good spirits, and prednisone tapering is ongoing (Fig. 2).

We encountered a case of nephrotic syndrome with MCD caused by an ICIs. Although MCD secondary to cancer is well-recognized, there is evidence that the present case was related to therapy rather than to the malignancy itself. First, nephrotic syndrome developed soon after administration of the first ICIs in this case. Second, in cases of MCD secondary to cancer, the course of proteinuria typically parallels that of the underlying malignancy, with MCD remitting after successful cancer treatment [7]. Computed tomography, performed when the patient had severe renal failure requiring dialysis, showed that his tumor had shrunk dramatically. These findings indicated that MCD is caused by ICIs.

We investigated previously reported cases of nephrotic syndrome using ICIs. PubMed was searched using the following two formulas: (1) ("Antibodies, Monoclonal, Humanized"[MeSH Terms] OR "immune checkpoint inhibitors"[MeSH Terms]) AND ("Nephritis"[MeSH Terms] OR "Nephrosis"[MeSH Terms]), and (2) (PD-1 OR CTLA-4 OR "immune checkpoint inhibitors") AND ("minimal change disease" OR nephritis); 444 and 424 articles, respectively, were identified using the search strategies. We checked all titles and abstracts of the articles to identify pertinent articles, and then examined the contents of the remaining papers to determine their applicability to this investigation.

Our survey identified 17 cases of ICI-related nephrotic syndrome, including our own (Table 1) [8–20]. The ratio of males (14) to females (3) was 4.7:1. The patients’ age ranged from 40 to 75 years, with an average age of 62.1 years old. Lung adenocarcinoma was the underlying condition in five cases, malignant melanoma in five, malignant pleural mesothelioma in two, renal cell carcinoma in two, Hodgkin lymphoma in two, and chondroma in one. Pembrolizumab was the most commonly used ICI, with multiple ICIs used in two cases. The pathological types of nephrotic syndrome were as follows: MCD in 7 (41.1%), membranous nephropathy in 3 (17.6%), focal segmental glomerulosclerosis in 2 (11.8%), IgA nephropathy in 1 (5.9%), AA-type amyloidosis in 1 (5.9%), pauci-immune glomerulonephritis with crescents in 1 (5.9%), and not performed in 1 (5.9%). As the first treatment, most patients were administered high-dose prednisone (approximately 1 mg/day), and in 1 case [8], only the ICI was discontinued. The patient was observed; however, there was no improvement, and prednisone was eventually initiated.

Table 1

Summary of reported cases of ICI-related nephrotic syndrome.
Authors	Age (years), sex	Underlying malignancies	ICI	Renal pathological diagnosis	Cre (mg/dl)	Alb (g/dl)	Proteinuria (g/day)	Proteinuria (g/gCr)	Initial steroid dose	Dialysis
Fadel, et al. 2009	60, M	Malignant melanoma	Ipilimumab	Lupus nephritis	1.01	2.5	7.5	NA	1 mg/kg/day	None
Bickel et al. 2016	62, M	Malignant pleural mesothelioma	Pembrolizumab	MCD	NA	1.5	19	NA	1 mg/kg/day	None
Daanen et al. 2017	62, M	RCC	Nivolumab	FSGS	2.95	1.9	17	NA	pulse 3 days ◊60 mg/day	None
Kitchlu, et al. 2017 -1	43, M	Hodgkin lymphoma	Pembrolizumab	MCD with acute tubular injury	3.93	1.8	10.3	NA	2 mg/kg/day	None
Kitchlu, et al. 2017 -2	45, M	Malignant melanoma	Ipilimumab	MCD	0.8	2.6	9.5	NA	1 mg/kg/day	None
Gao, et al. 2018	40, M	Hodgkin lymphoma	Camrelizumab	MCD	0.9	2.1	30	NA	1 mg/kg/day	None
Mamlouk, et al. 2019-1	69, M	Malignant melanoma	Ipilimumab + Nivolumab	IgA nephropathy	2.4	NA	NA	7.7	0.5 mg/kg/day	None
Mamlouk, et al. 2019-2	60, F	RCC	Nivolumab	MN without PLA2R	NA	NA	NA	9.7	1 mg/kg/day	None
Mamlouk, et al. 2019-3	63, M	Chondroma	Pembrolizumab	AA amyloidosis	2.25	NA	NA	31	1 mg/kg/day	None
Glutsch, et al. 2019	68, M	Malignant melanoma	Pembrolizumab	MCD with acute tubular injury	2.86	1.6	NA	NA	100 mg/day	None
Gallan, et al. 2019	71, F	Lung adenocarcinoma	Pembrolizumab	Pauci-immune glomerulonephritis with crescents	0.8	NA	5.5	NA	NA	None
Saito, et al. 2020	79, M	Lung adenocarcinoma	Pembrolizumab	MCD	NA	1.1	NA	13.8	40 mg/day	None
Ishibuchi, et al. 2020	70, M	Lung adenocarcinoma	Pembrolizumab	NA	1.63	1.0	NA	15.1	1.6 mg/kg/day	Needed
Chen, et al. 2021	74, M	Lung adenocarcinoma	Tislelizumab	MN (THSD7A-positive)	0.93	1.9	20.2	NA	60 mg/day	None
Kim, et al. 2021	46, F	Malignant melanoma	Pembrolizumab	FSGS	0.66	2.8	NA	3.3	None	None
Wakabayashi, et al. 2021	69, M	Lung adenocarcinoma	Nivolumab	MN	1.02	2.2	NA	13.3	0.8 mg/kg/day	None
The present case	75, M	Malignant pleural mesothelioma	Ipilimumab + Nivolumab	MCD	1.87	2.0	19.9	NA	1 mg/kg/day	Needed
Alb, albumin; Cre, creatinine; F, female; FSGS, focal segmental glomerulosclerosis; ICI, immune checkpoint inhibitor; IgA, immunoglobulin A; M, male; MCD, minimal change disease; MN, membranous nephropathy; NA, not available; PLA2R, phospholipase A2 receptor; RRC, renal cell carcinoma; THSD7A, thrombospondin type-1 domain-containing.

The present patient had fusion of nearly all podocyte foot processes and a more severe condition than previous cases, and required dialysis. The main factors leading to nephrotic syndrome with acute kidney injury in the general population include but are not limited to old age, hypertension, arterial/arteriolar lesions, and a serum albumin level < 2.0 g/dl [21]. Old age and arterial/arteriolar lesions were present in the present case. Furthermore, unlike many previously reported cases, our case was administered two different ICIs, which can cause nephrotic syndrome to become severe; the fact that combination therapy induces multiple concurrent irAEs more often than monotherapy [22] supports this hypothesis.

In summary, we encountered a case in which combination ICI therapy (anti-PD-1 and CTLA-4 antibodies) led to severe nephrotic syndrome with acute kidney injury. In addition to previously reported risk factors, such as advanced age and atherosclerosis, ICI combination therapy can exacerbate nephrotic syndrome compared to ICI monotherapy.

anti-PD-1, anti-programmed cell death 1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; ICIs, immune checkpoint inhibitor; irAE, immune-related adverse event; MCD, minimal change disease.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report. A copy of the written consent form is available for review by the editor of this journal.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors' contributions

RS, KK, HS, AF, KT, MY, FT, DT, KO, YS, and TM acquired the clinical data. RS, KK, and KD analyzed the patients’ clinical course and interpreted the data. RS and KK wrote a draft of the manuscript, and KO, TM, and KD critically revised the manuscript. All authors have read and approved the final manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

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Journal Publication

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You are reading this latest preprint version

Nephrotic syndrome with acute kidney injury due to combination therapy of immune checkpoint inhibitors: A case report and review of the literature

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Case presentation

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