Pembrolizumab induced-C3 glomerulonephritis and RBC cast nephropathy: a case report

ICI-related adverse effects could involve any organ or system, such as the skin, intestine, liver, thyroid, pancreas, pituitary, and kidney [3]. Renal toxicity is generally considered a less common event caused by ICIs, which most commonly manifested as AKI. In an analysis of 3695 patients treated with ICIs (including ipilimumab, nivolumab, and pembrolizumab), the overall incidence of AKI was 2.2% in all patients and 1.4% in the pembrolizumab-treated group [4]. Some patients may also present with proteinuria, hematuria, or pyuria, which indicates glomerular lesions. Acute tubulointerstitial nephritis with infiltration of lymphocytes and plasma cells was the primary pathologic lesions manifesting as acute kidney injury [5]. In recent years, the association between ICIs and glomerular nephritis (GN) has received more attention. Several studies have indicated that ICIs could cause a wide spectrum of GN. A systematic review reported that the top three most frequent types were pauci-immune GN/vasculitis (27%), minimal-change disease (MCD) (20%), and C3GN (11%) [6]. In addition, IgA nephropathy, anti-glomerular basement membrane disease, lupus-like nephritis, membranous nephropathy, amyloid amyloidosis, focal segmental glomerulosclerosis (FSGS), and thrombotic microangiopathy (TMA) have also been reported [6]. The mechanism by which ICIs may cause GN was much less clear. Since different ICI treatments may induce varying renal manifestations and pathological patterns, multiple complex mechanisms may be involved and should be further elucidated.

To the best of our knowledge, this is the sixth case of ICI-associated C3GN [2, 7,8,9,10]. The clinical features of the other five cases and the present patient are summarized in Table 2. Among them, 4/6 were associated with pembrolizumab and manifested as AKI; 3/6 presented with concomitant tubular-interstitial injury; 2/6 presented with macroscopic hematuria, and our case is unique for its remarkable red cell casts; 2/6 presented with lower C3 serum level; 3/6 presented with skin rashes; 4/6 responded to ICIs discontinuation and initiation of glucocorticoids.

Table 2 Summary of reported cases of C3GN associated to the use of immune checkpoint inhibitors

Excessive activation of the complement alternative pathway (AP) is considered the major pathogenic factor leading to C3GN, which typically presents with low C3 serum levels, normal C4 levels and high C5b9 levels [11]. It was assumed that anti-PD-1 therapy may induce the emergence of autoantibodies against C3b promoting C3 deposition via the dysregulation of the complement AP, such as the C3b antibody detected in the case reported by Ville et al. [9]. In this study, the patient presented with low C3 serum level, MPGN-like pattern, C3 deposit in glomeruli, which supported the diagnosis of C3GN. The patient presented skin rashes and AIN which were also ICIs-associated immune injury.

For our case, the abundant infiltration of CD8-positive lymphocytes in interstitium shows an overactivation of T cells, as well as the mechanism by which pembrolizumab works, further strengthening the association between pembrolizumab and AIN. Although anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI) [12], was also a potentially nephrotoxic agent, TMA and podocytopathies, such as MCD and FSGS, were the main presentations of TKI-associated renal toxicity [13]. While, the characterization of the predominant CD8-positive T lymphocyte infiltration, may be caused by the combination of anlotinib and pembrolizumab. Anlotinib is a TKI that targets vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptors, and c-kit. Recent study showed that CD8-positive T-cell responses are boosted by dual PD-1/VEGFR2 blockade [14]. Thus, Anlotinib might act as a promoter, creating an immune-supportive microenvironment for ICIs [15] and driving the adverse effects of ICIs. However, the mechanism by which ICIs could cause C3GN was still unclear and need to be further explored.

In addition, our case presented with remarkable tubular RBC casts, which had not been reported before. RBC cast nephropathy was usually observed in anticoagulant-related nephropathy, IgA nephropathy and AIN and may cause AKI [16]. Hemoglobin, heme, iron or other molecules released from RBCs could cause direct tubular toxicity. In this patient, remarkable RBC casts were results of ICI-associated C3GN and AIN and aggravated AKI.

The National Comprehensive Cancer Network guidelines for the management of ICI nephrotoxicity are based on the severity of kidney injury [17]. As reported, for patients with ICI-associated GN, most could have either complete (31%) or partial (42%) recovery with ICI discontinuation and corticosteroid treatment, whereas nearly 20% of the cases might progress to end-stage kidney disease (ESKD) [6]. For this patient, although there was an improvement in renal function after a two-week intervention of prednisone and hemodialysis, the renal function worsened again, and we administered cyclophosphamide subsequently. According to the literature [8], patients who experienced grade 3 to 4 ICI-related nephrotoxicity can be treated with immunosuppressants, such as cyclophosphamide, azathioprine, infliximab, and mycophenolate. As the results showed, the patient's serum creatinine levels decreased after the administration of cyclophosphamide. Nevertheless, he still needed hemodialysis when he discharged, maybe due to his concomitant involvement of other organ system. As Cortazar reported, patients who had concomitant extrarenal ICI-related side effects had a lower likelihood of kidney recovery [10]. Thus, when a patient had ICI-associated side effects in more than one organ or system, an immediate diagnosis should be made and positive treatment should be provided.

In conclusion, with the increasing application of ICIs for various malignancies, ICI-associated side effects, especially renal toxicity, should be given more attention. This study presents with a rare case of ICIs-associated C3GN, AIN and RBC cast nephropathy caused by chronic use of pembrolizumab, which further expanded the spectrum of nephrotoxicity of ICIs. As a nephrologist, the recognition of ICI-associated renal side effects is critical, and a kidney biopsy may help in evaluating the underlying cause.

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