Proteinuria following administration of immune check point inhibitor: a case-control observational study

Abstract

Purpose

Proteinuria during treatment of immune checkpoint inhibitors (ICIs) was another renal adverse event besides from acute kidney injury. We aim to investigate the incidence and associated factors of proteinuria associated with ICIs.

Method

A case-control observational study about ICIs-treated cancer patients was conducted. Clinical and laboratory data at the baseline and during the follow-up was collected. Patients developed proteinuria during ICIs-treatment were classified to the proteinuria group.

Results

Between March 2019 and August 2022, 440 patients were included in the study. Forty-eight patients (10.9%) developed proteinuria after ICIs-treatment. The occurrence of acute kidney injury between the proteinuria group and the control showed no difference[1(2.1%) vs. 9(2.3%), p = 1.000]. By multivariable logistic analysis, accumulative cycle of ICIs-administration (OR 1.079, 95% CI 1.033 to 1.127, p = 0.001) and comorbidity of liver cirrhosis (OR 2.198, 95% CI 1.082 to 4.468, p = 0.030) were associated with occurrence of proteinuria after ICIs-treatment independently.

Conclusions

Proteinuria could develop during the course of ICIs-therapy. Urinalysis should be monitored, especially for patients received multi-cycle of ICIs-administration and comorbid with liver cirrhosis.

Introduction

With the increasing application of immune checkpoint inhibitors (ICIs) in cancer patients, more and more immune related adverse events (irAEs) have been reported. With regarding to renal irAEs, acute kidney injury (AKI) owing to acute interstitial nephritis (AIN) was the most common manifestation. Moreover, proteinuria following administration of ICIs has also been reported [1].

Proteinuria was an independent predictor of kidney prognosis [2]. Mild proteinuria might appear in AIN, while moderate to severe proteinuria usually occurred in glomerulonephritis. ICIs-associated glomerular disease may be correlated with poor kidney outcomes and mortality [1]. Pathological manifestations of ICIs-related glomerulopathy included minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), membranous nephropathy (MN), renal vasculitis with pauci-immune complex, thrombotic microangiopathy, complement 3 glomerulonephritis, renal amyloidosis, and so forth [3].

Besides the case reports, seldom clinical research about proteinuria following ICIs-therapy has been reported. The incidence and risk factors of proteinuria as an adverse event of ICIs hasn’t been investigated yet, comparing with those on AKI. Hence, a case-control observational study was conducted to investigate the incidence and predictors of proteinuria associated with ICIs.

Method

Study design and participants

An observational study about ICIs-treated cancer patients over 18 years old at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between March 2019 and August 2022 was conducted. The following patients were excluded: (a) pre-existing chronic kidney disease (CKD) [4] before initiation of ICIs; (b) lack of baseline and follow-up renal data (urine testing and serum creatine). The study had received approval from the Ethics Review Board of Sun Yat-sen Memorial Hospital (No. SYSEC-KY-KS-2021-057).

Data collection

The following data was collected: (a) baseline information: demographics; body mass index (BMI); estimated glomerular filtration rate (eGFR); ICI drug names; comorbidities including hypertension, diabetes, chronic obstructive pulmonary disease (COPD), liver cirrhosis, urolithiasis, and infection; (b) information during the course of ICIs-treatment: urinary protein, urinary red blood cell count and serum creatinine; accumulative cycles of ICIs-administration before proteinuria occurrence or until data collection in the protein-negative group; concurrent other anti-tumor therapeutic strategies including surgery and radiotherapy before proteinuria occurrence or until data collection in the protein-negative group; concurrent nephrotoxic anti-tumor drugs including anti-vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR), tyrosine kinase inhibitor (TKI), platinum, anti-metabolites, and anti-tumor hormone drugs before proteinuria occurrence or until data collection in the protein-negative group; extrarenal immune-related adverse events (irAEs). Patients developed proteinuria during ICIs-treatment were classified to the proteinuria group, whereas the others were included in the proteinuria-negative group.

Definitions

Proteinuria was defined when the amount of total protein in the urine being more than 150 mg/24 h or the qualitative test of protein in the urinalysis being positive for two consecutive measurements. According to Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0) [5], adverse event of proteinuria grade 1 refers to 1 + proteinuria, grade 2 refers to 2 + and 3 + proteinuria, while grade 3 refers to 4 + proteinuria. Nephritic hematuria was considered with the presence of more than three red blood cells per high-power field in urine sediment or urine red blood cell count exceeding the upper limit of normal value for two consecutive measurements, excluding conditions such as urinary stone, infection, tumor, and bleeding. The definition of AKI was based on the Kidney Disease: Improving Global Outcomes (KDIGO) guideline [6].

Statistical analysis

Categorical variables were demonstrated as numbers and percentages. For normally distributed continuous variables, the mean ± standard deviation (SD) was used to represent the results, while abnormally distributed continuous variables were presented as median [interquartile range (IQR)]. To compare the characteristics between proteinuria group and proteinuria-negative group, relevant statistical tests such as t-test, Mann-Whitney test, chi-squared test, or Fisher exact test were applied. To identify the risk factors associated with proteinuria after ICIs-treatment, variables with p-values < 0.05 from the comparative test above were put into multivariable logistic regression analyses subsequently. All p-values were calculated using a two-tailed test, and statistical significance was considered with a p-value < 0.05. Statistics analysis was performed by IBM SPSS Statistics Version 25.0.

Results

Patients’ characteristics

Between March 2019 and August 2022, 440 patients were included ultimately in our study. Characteristics of the included patients were demonstrated in Table 1. The median age of the total population was 56.0 (48.0, 64.0) years old. Male accounted for 75.0% in the total population. The median baseline eGFR was 99.0 (90.0, 108.0). The median accumulative cycle of ICIs-treatment was 5.0 (2.8,9.0). Among all cases, camrelizumab represented the most frequently administered ICI with 156 patients (35.5%) (Supplementary Table 1). The majority of the primary tumor belonged to the digestive system (59.8%) (Supplementary Table 2). Hypertension accounted for 24.1% in the population, representing the most common comorbidity. In addition, 46 (10.5%) patients had been treated with platinum concurrently.

Table 1 Characteristics of the included patients with cancer

Incidence, clinical feature and associated factors of proteinuria after ICIs-treatment

Forty-eight patients, accounted for 10.9% of the total population, experienced proteinuria following ICIs-treatment. Proteinuria of 39 (81.2%) patients belonged to grade 1, 8 (16.7%) patients to grade 2 while only 1 (2.1%) patient to grade 3 according to CTCAE v5.0. More nephritic hematuria [2 (4.2%) vs. 1 (0.3%), p = 0.033] was found in the proteinuria group, whereas the incidence of AKI [1 (2.1%) vs. 9 (2.3%), p = 1.000] was similar (Table 2).

Table 2 Distribution of acute kidney injury and nephritic hematuria in included patients

Patients those developed proteinuria received more cycles of ICIs-treatment [7.0 (4.0, 14.0) vs. 5.0 (2.0, 9.0), p = 0.001] and more anti-VEGF/VEGFR drugs [8 (16.7%) vs. 23 (5.9%), p = 0.014]. More patients comorbid with liver cirrhosis [15 (31.3%) vs. 68 (17.3%), p = 0.020] was found in proteinuria group. (Table 1)

By multivariable logistic analysis (Table 3), accumulative cycle of ICIs-administration (OR 1.079, 95% CI 1.033 to 1.127, p = 0.001) and comorbidity of liver cirrhosis (OR 2.198, 95% CI 1.082 to 4.468, p = 0.030) were associated with occurrence of proteinuria after ICIs-treatment independently.

Table 3 Associated factors of proteinuria following ICIs-treatment

Discussion

In order to investigate the incidence and associated factors of proteinuria following ICIs-therapy, a case-control observational study was conducted in our center. Proteinuria was found to occur in 10.9% of patients who had received ICIs-therapy. Accumulative cycle of ICIs-administration and comorbidity of liver cirrhosis were revealed to associate with proteinuria independently.

Adverse event of proteinuria has been reported in ICIs-treated patients [1], with renal pathology of MCD, FSGS, IgAN, MN, vasculitis an so forth [7,8,9,10,11,12,13]. Moreover, ICIs were found to further aggravate proteinuria in patients with metastatic renal cell carcinoma after long-term targeted therapy [14]. According to the National Comprehensive Cancer Network guideline(Management of Immunotherapy-Related Toxicities), permanent discontinuation of ICIs is suggested in the setting of severe proteinuria [15], which might influence the prognosis of patient with cancer. In our study, 10.9% of patients developed proteinuria during the treatment of ICIs. Results from our study and previous reports all indicated that urinalysis should be monitored during the course of ICIs-therapy. In case of severe proteinuria developed, prompt referral to nephrologist might be essential.

It was reported previously that more cycles of anti-PD1 and more cumulative doses of anti-PD1 had been administered in ICIs-treated patients with AKI compared with those without AKI [16]. Similar to the result of AKI, more cycles of ICIs-administration were observed in proteinuria group, perhaps sharing the similar mechanism with AKI owing to a dose-dependent mechanism or delayed immune response. Moreover, accumulative cycle of ICIs-administration was revealed to be an independent associated factor of proteinuria in patients with cancer. It was indicated that monitoring of the urinalysis could be warranted in patients with cancer treated with ICIs.

Proteinuria was not rare in the patients with liver cirrhosis, including primary diseases of hepatitis B, hepatitis C, alcoholic, and so forth [17, 18]. Owing to immune response, kidney involvement was observed in patients with liver diseases [17, 18]. Moreover, proteinuria was discovered as a predictor of prognosis in patients with liver cirrhosis [19, 20]. In patient with hepatocellular carcinoma, proteinuria was also reported as an adverse event after treating with nivolumab [21]. In our study, it was revealed that patients with liver cirrhosis were apt to occurring proteinuria, which may due to the pathophysiological basis of the primary liver disease. Hence, for patients with liver cirrhosis who received ICIs treatment, more vigilance of proteinuria should be raised.

There still be some limitations in our study. Firstly, most of proteinuric cases included in our study haven’t undergone kidney biopsy, which may limit the implication of our results. Secondly, only retrospective observational study has been performed, while prospective study may offer stronger evidence.

In conclusion, proteinuria could develop during the course of ICIs-therapy, hence urinalysis should be monitored. Accumulative cycle of ICIs-administration and comorbidity of liver cirrhosis were both independent associated with the occurrence of proteinuria.