Immunotherapy in oncology and the kidneys: a clinical review of the evaluation and management of kidney immune-related adverse events

ABSTRACT

Immune checkpoint inhibitors (ICI) are now widely used in the treatment of many cancers, and currently represent the standard of care for multiple malignancies. These agents enhance the T cell immune response to target cancer tissues, and have demonstrated considerable benefits for cancer outcomes. However, despite these improved outcomes, there are important kidney immune-related adverse events (iRAEs) associated with ICI. Acute tubulo-interstitial nephritis remains the most frequent kidney iRAE, however glomerular lesions and electrolytes disturbances are increasingly being recognized and reported. In this review, we summarize clinical features and identify risk factors for kidney iRAEs, and discuss the current understanding of pathophysiologic mechanisms. We highlight the evidence basis for guideline-recommended management of ICI-related kidney injury as well as gaps in current knowledge. We advocate for judicious use of kidney biopsy to identify ICI-associated kidney injury, and early use of corticosteroid treatment where appropriate. Selected patients may also be candidates for re-challenge with ICI therapy after a kidney iRAE, in view of current data on recurrent rates of kidney injury. Risk of benefits of re-challenge must be considered on an individual considering patient preferences and prognosis. Lastly, we review current knowledge of ICI use in the setting of patients with end-stage kidney disease, including kidney transplant recipients and those receiving dialysis, which suggest that these patients should not be summarily excluded from the potential benefits of these cancer therapies.

INTRODUCTION

Immune checkpoint inhibitors (ICI) are now widely used in the treatment of many cancers, and currently represent the standard of care for multiple malignancies. These agents enhance the T cell immune response to target cancer tissues, and have demonstrated considerable benefits for cancer outcomes [1]. However, despite these improved outcomes, there are important adverse effects associated with ICI, termed immune-related adverse events (iRAEs), which may involve any organ system, including the kidneys. Kidney iRAEs were initially recognized via case reports and series describing predominantly acute tubulo-interstitial nephritis [2–4]. Increasingly, reports of glomerular disease have been recognized as occurring in association with ICI therapy. These smaller reports have since been followed by single-center cohorts [5–7] and larger multicenter studies [8–10], which have sought to better characterize clinical presentations, describe treatment approaches and report outcomes. In this review, we will summarize clinical features and identified risk factors for kidney iRAEs, including tubulo-interstitial, glomerular lesions and electrolyte disturbance, and discuss current understanding of pathophysiologic mechanisms. We will highlight the evidence basis for guideline-recommended management of ICI-related kidney injury as well as gaps in current knowledge. Lastly, we will review knowledge of ICI use in the setting of patients with end-stage kidney disease (ESKD), including kidney transplant recipients and those receiving dialysis.

PATHOPHYSIOLOGY OF KIDNEY IMMUNE-RELATED ADVERSE EVENTS

“Immune checkpoints” are the molecules/inhibitory immunoreceptors on T cells which guard against unfavorable immune responses and maintain self-tolerance [11]. These include anti-programmed cell death 1 or anti-programmed death-ligand 1 (anti-PD-1/anti-PD-L1), anti-cytotoxic T lymphocyte-associated antigen 4 antibody (anti-CTLA4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), and B and T lymphocyte attenuator (BTLA). In the tumor microenvironment, due to lack of internalization in addition to decreased ubiquitination-mediated protein degradation, there is a surge in the number of surface levels of these receptors (e.g. PD-1, CTLA4) on the T-cells [12]. When these receptors engage with the specific ligands expressed on the tumor cells (e.g. PD-L1, PD-L2) or on the antigen-presenting cells (CD80/86) [13], it leads to altered T cell signaling and anergy [14]. This decreases cancer cell susceptibility to the destructive actions of the T cells (Fig. 1). Hence, targeting the receptor–ligand interaction with the ICI has revolutionized the treatment of several malignancies in the field of immune oncology [1].

Figure 1:

In the normal physiology, quiescent CD8+ T lymphocytes become activated when antigen presenting cells (APCs) present major histocompatibility complex–bound antigen fragments to T cell receptors. The secondary activation/co-stimulatory signals (involving CD80/86 and CD28) generate effective immune response. CTLA4 receptors on the inactive T cells inhibit the activation process binding to the CD80/86 complex on the APCs resulting in T cell anergy. Monoclonal antibodies (Mabs) against CTLA4 (ipilimumab/tremelimumab) remove the inhibitory signal facilitating the activation of CD8+ T cells. In the tumor micro-environment, the cancer cells evade the T cell response by increased expression of ligands (eg.PD-L1) which bind to immune checkpoints (eg. PD-1) on the T cells preventing the immune response. This immune tolerance by the cancer cells is inhibited by the Mabs against PD-1 (pembrolizumab/nivolumab) and PD-L1 (atezolizumab/avelumab). In the presence of ICI, T cells can lose their tolerance against normal renal tubular epithelium leading on to kidney injury.

There have been ongoing efforts by various researchers on the mechanism of causation of kidney adverse events by ICI. To-date, “multi-hit” and “break release” postulates have partially explained the pathogenesis [15, 16]. These hypotheses are derived from animal models and non-kidney related IRAEs [17, 18]. In the presence of ICI, T cells could potentially lose their tolerance to native kidney antigens causing acute interstitial nephritis or glomerulonephritis (GN). The “second hit” [5] is mainly due to drug-induced hypersensitivity to ICI in the presence of proton pump inhibitors (PPI), non-steroidal anti-inflammatory drugs (NSAIDs) or vitamin K antagonists [19] which are known potentiators of ICI-related immune adverse events. These potentiator medications may act as exogenous antigens or haptens triggering an immune response (Fig. 2). Despite similarities between autoimmune diseases and iRAEs, there is unclear genetic predisposition predicting the occurrence of ICI related iRAEs [20].

Figure 2:

Potential mechanisms of kidney injury in patients treated with ICI.

Retrospective analysis of iRAEs related to anti-PD-1 agents in patients with non-small-cell lung cancer has shown that “single site” iRAEs are much more common than the “multiple-site” iRAEs [21]. The tissue specific autoreactivity of the T cell clone [22] has provided a partial explanation in animal model, which is substantiated by the evidence of T cell trafficking in the organ of origin when infiltrating T cells were transferred from one mouse to another [23]. It is possible that an “autoantigen” located in the tubular cells and the interstitium of the kidneys is targeted by the ICI, as the dominant presentation of the kidney-related adverse events is acute tubulointerstitial nephritis (ATIN). There could also be an antigenic overlap between normal renal tubular cells and tumor cells potentiating ICI to drive the self-reactive T cells against the normal cells [24]. The frequent occurrence of ICI-related kidney adverse events in conjunction with other organ system involvement has been described [6, 9]. At present, our understanding of the underlying pathophysiology of both multi-organ and kidney-specific iRAEs remains limited.

INCIDENCE AND KNOWN RISK FACTORS FOR KIDNEY IMMUNE-RELATED ADVERSE EVENTS

Immune-related toxicities affect a broad range of organs. Dermatitis, enterocolitis and thyroiditis are the most common toxicities associated with ICI [25–27]. Renal toxicities are less common but have been increasingly recognized as a potential serious complication of ICI. In a large retrospective study of 1016 patients started on ICI, the overall incidence of acute kidney injury (AKI) was 17% [5]. However, the estimated incidence of AKI directly related to ICI was 3%. In large phase 2 and 3 clinical trials, incidence of ICI-associated AKI was 2.2%–5% [3, 28]. Combination therapy with an anti-CTLA4 and anti-PD-1/anti-PD-L1 is associated with higher risk of ICI-AKI [8]. The dual blockade enhances the stimulation of autoreactive T cells and increases the risk of iRAEs for renal and extra-renal organs. Reported rate of ICI-AKI with combination therapy is 4.9% (ipilimumab–nivolumab) compared with 2% for ipilimumab, 1.9% for nivolumab and 1.4% for pembrolizumab alone [3]. There has been no significant reported association between ICI agent and risk of ICI-associated AKI [2, 6]. Many retrospective studies also found an association between PPI use and risk of ICI-AKI [2, 5, 6, 8, 9]. PPI may predispose to ICI-AKI through loss of immune tolerance and activation of memory T cells that have previously been primed. Case series and retrospective studies found that approximately 70% of patients with ICI-AKI had exposure to other medications associated with acute interstitial nephritis, mostly PPI [2, 3, 8]. However, NSAIDs or antibiotics (which may be less commonly used as compared with PPI), have not been shown to be significant risk factors for ICI-AKI in most retrospective studies, although smaller numbers of users may have resulted in limited power to detection associations [5, 6, 8, 9]. Lower baseline estimated glomerular filtration rate (eGFR) was also associated with increased risk of ICI; however, this association is may be a consequence of reduced renal reserve rather than a true increased risk of immunological injury. Indeed, Gupta et al. found that reduced baseline eGFR was not associated with risk of stage 2 or 3 ICI-AKI [5, 6, 8, 9].

DIAGNOSIS OF KIDNEY IMMUNE-RELATED ADVERSE EVENTS

Types of kidney lesions

The most common kidney injury presentation in patients receiving ICI is ATIN [9]. In the earlier case series by Cortazar et al., 12 of the 13 patients had biopsy proven ATIN, with 3 having granulomatous features and one thrombotic microangiopathy [3]. Acute tubular necrosis/acute tubular injury (ATN) could present as a separate histopathological finding. In the study by Izzedine et al., 5 of the 12 patients with pembrolizumab-associated AKI had ATN alone [29]. In a study by Cassol et al., 6 of the 15 patients treated with anti-PD-1 agents had ATN and 9 had AIN [30]. Focal segmental glomerulosclerosis (FSGS), anti-glomerular basement membrane disease, immunoglobulin A (IgA) nephropathy have been reported with use of nivolumab [31–33]. Pathological data on 16 patients treated with ICI from MD Anderson Cancer Centre revealed various glomerular pathologies including pauci-immune GN, membranous GN, C3 GN, IgA nephropathy or amyloid A (AA) amyloidosis [34]. In a systematic review of 27 articles consisting of 45 cases of biopsy-confirmed ICI-related glomerular diseases, Kitchlu et al. observed pauci-immune GN and renal vasculitis (27%), podocytopathies (24%) and C3GN as the most frequent glomerular diseases [35]. Concomitant AIN was present in 41% of these cases. In another study by Izzedine et al. in patients receiving pembrolizumab, of 12 patients who were biopsied, one had minimal change disease (MCD) and ATIN, one had MCD alone [29]. There is also a case report of anti-CTLA4 antibody-induced lupus-like nephritis [36].

Clinical features and time course of AIN

In a study of patients with solid organ malignancies treated with immunotherapy who developed biopsy-proven AIN, the most common urinary finding was subnephrotic-range proteinuria and eosinophiluria [37]. In a recent multicenter study which included 138 patients with ICI-associated AKI, half of the patients had pyuria [8]. Extra-renal iRAEs occurred in 43% of the patients and this was associated with worse kidney outcomes.

The time of onset of kidney injury depends upon the ICI used for treating the malignancies. In a large observational study by Gupta et al., the median time of onset of AKI after ICI initiation was 16 weeks [9]. The delayed onset of adverse events is because of their binding to the protective neonatal Fc receptors [38] which prevents them from undergoing lysosomal degradation and extends their half-lives [39]. Among different ICI classes, anti-CTLA4, when used as monotherapy, may be associated with higher grades of kidney injury. Anti-CTLA4 when used along with anti-PD-1 causes more kidney-related adverse events as compared with anti-PD-1 alone [40]. For CTLA4 antagonists, the time period may be as shorter (6-12 weeks), whereas for PD-1 antagonists it may be 6–8 months. The anti-CTLA4-mediated side effects are more severe as compared with anti PD-1/PD-L1 ICI [41], which is probably due to a more precise spectrum of T cell activation mediated by PD-1 blockade versus that of CTLA4 [42].

Non-invasive diagnosis (potential biomarkers and imaging studies)

As per the 2021 American Society of Clinical Oncology (ASCO) guidelines for Management of Immune-related Adverse Events in Patients Treated with ICI [43], the criteria of diagnosis of ICI-related kidney toxicity has been categorized into definite, possible and probable based on different presentations (Table 1). Serum creatinine needs to be monitored prior to every dose of ICI. Although ASCO guidelines say routine urinalysis is not necessary other than to rule out urinary tract infections, experts suggest performing baseline urinalysis prior to initiating therapy with ICI as a comparator to the changes during therapy [42]. This may also help in capturing early subclinical kidney toxicities related to ICI. ICI-related kidney injury needs to be considered after ruling out other potential causes of kidney injury including and not limited to dehydration, infections, urinary tract obstruction, concomitant nephrotoxic medications and systemic causes.

Table 1:

Diagnostic criteria of ICI-related AKI (adapted from American Society of Clinical Oncology management guideline definition of ICI-related nephritis and kidney dysfunction [43].

Diagnosis	Criteria
Definite ICI-related nephritis or AKI	Kidney biopsy-confirmed diagnosis compatible with ICI nephritis or AKI, and after clinical review of risk factorsa
Probable ICI-related nephritis or AKI	BOTH of the following: - Sustained increase in serum creatinine ≥50% on at least two consecutive values or need for RRT, after clinical review of risk factorsa - Absence of an alternative plausible etiology
	AND at least one of the following: - Sterile pyuria (≥5 WBCs/hpf)- Concomitant or recent extrarenal iRAE eosinophilia (≥500 cells per µL)
Possible ICI-related nephritis or AKI	BOTH of the following: Increase in serum creatinine ≥50% Need for RRT nephritis or AKI is not readily attributable to alternative causes

^aRisk factors include prior or concomitant nephrotoxic agent(s) use and prior or concomitant extrarenal iRAEs.

RRT: renal replacement therapy; WBCs/hpf: white blood cells per high-power field.

Biomarkers might play a significant role in diagnostic and therapeutic management. Lower neutrophil-to-lymphocyte ratio and lower platelet to lymphocyte ratio have been hypothesized to predict lower risk of iRAEs in patients with non-small-cell lung carcinoma treated with anti-PD-1 inhibitors [44]. Higher prognostic nutrition index calculated from serum and albumin and total lymphocyte count has been predictive of worse iRAEs in patients with melanoma treated with anti-PD-1 inhibitors [45]. Eosinophils have been proposed to play a role in ICI-related iRAEs although there has not been definitive evidence [46–48]. There has been some research interest in predictive value of T cell subsets, including regulatory T cells (Tregs), CD4+ T cells and T cell repertoires in determining the iRAEs related to ICI, but this remains exploratory at present [49, 50].

Cytokines and chemokines have been determined in various studies to predict the onset of iRAEs in patients with melanoma treated with ICI. Variation in the levels of proinflammatory cytokines such as low baseline interleukin (IL)-6 and higher baseline IL-17 have been associated with increased risk of high-grade iRAEs [51, 52]. C-reactive protein (CRP), which is a surrogate marker of IL-6, was elevated just before the onset of iRAEs in patients with melanoma treated with ICI [53]. Similarly, increase in the levels of chemo-attractants like CXCL9, CXCL10, CXCL11 and CXCL13 after initiation on ICI correlates with the incidence of iRAEs [54]. Urinary soluble CD163 could be possibly used to differentiate the glomerulopathy from AKI due to interstitial or tubular injuries [55]. A retrospective study comparing 33 ICI-AKI patients with 17 non-ICI-AKI patients suggested CRP and urine retinol binding protein/urine creatinine (uRBP/Cr) may help differentiate between AKI related to ICI and related to other causes [56]. Use of immunogenetics and determining the gut microbiome composition are the other areas being explored for prediction of iRAEs [57].

18F-fluorodeoxyglucose positron-emission tomography might be a valuable non-invasive modality to provide supplementary evidence of immune-mediated nephritis in selected cases where kidney biopsy may not be possible [58, 59]; however, thus far, this imaging modality's use in checkpoint inhibitor–associated AIN diagnosis has been limited to case reports [60, 61]. As such, there are insufficient data to establish the accuracy and other performance characteristics of this modality for ICI-associated AIN diagnosis.

We suggest doing routine urinalysis and microscopy for leukocyturia, and consider CRP for early detection of ICI-AKI as these are widely available and correlate well with the presence of AIN. In addition, fractional excretion of sodium may help distinguish from pre-renal causes of AKI.

Kidney biopsy indications

Although ATIN appears to be the most common pathological diagnosis for ICI-related AKI, given the diversity of lesions among different studies, kidney biopsy is indicated in selected patients to confirm the diagnosis (Fig. 3). ASCO guidelines [43] recommend treating patients empirically with steroids when suspicion of ICI-related AKI is high and no other obvious causes of AKI have been found. Kidney biopsy should be considered only if the AKI is refractory to steroids or other immunosuppressive medications. Although we agree with the notion of expedited management of iRAEs with steroid therapy, this should be gauged against the other potential etiologies of ICI-related AKI where treatment might differ. We suggest the decision for kidney biopsy needs to be individualized based on the expertise of the treating nephrologist and oncologist (Table 2).

Figure 3:

Spectrum of kidney diseases associated with ICI.

Table 2:

Indications for kidney biopsy in patients with kidney dysfunction receiving ICI.

Proposed indications for kidney biopsy in patients treated with ICI

(i) Unexplained kidney failure with urinalysis showing presence of microscopic hematuria + RBC casts and proteinuria

(ii) Nephrotic syndrome

(iii) Urologically unexplained macroscopic hematuria

(iv) Suspected systemic illnesses other than malignancy causing kidney dysfunction, e.g. low complement levels, positive ANA, positive ANCA, high LDH, hemolytic anemia

(v) Suspected ATIN due to ICI not responding to initial therapy with steroids/immunosuppressiona

(vi) Patient received concomitant nephrotoxic medications (e.g. platinum-based agents, pemetrexed) where earlier decision for biopsy may avoid exposure to or unnecessary continuation of steroids/immunosuppression

RBC: red blood cell; ANA: anti-nuclear antibody; ANCA: anti-neutrophil cytoplasmic antibody; LDH: lactate dehydrogenase.

MANAGEMENT OF KIDNEY IMMUNE-RELATED ADVERSE EVENTS

ATIN treatment

Management of ICI-AKI includes temporary cessation of immunotherapy, treating with corticosteroid and stopping medications associated with ATIN such as PPI and NSAIDs. Treatment should be started as soon as we are confident about the diagnosis of ICI-AKI and other causes of AKI have been excluded. In a multicenter cohort study of 429 patients diagnosed with ICI-AKI, early initiation of corticosteroid within 3 days following diagnosis of ICI-AKI was associated with higher odds of renal recovery compared with later initiation [9]. Different corticosteroid regimens have been recommended by oncology societies (Table 3). The usual recommendation is to initially treat stage 1 or 2 AKI with prednisone 0.8–1.0 mg/kg up to 60 mg daily for 1–2 weeks followed by taper off over 4–6 weeks. For stage 3 AKI, intravenous pulse-dose corticosteroid is preferred followed by oral prednisone treatment. Duration of corticosteroid treatment and speed of taper is not well studied. A group from Massachusetts General Hospital Cancer Center developed a clinical protocol for rapid corticosteroid taper. They compared 13 patients treated with a rapid taper protocol, beginning with prednisone 60 mg daily and tapered to 10 mg daily within 3 weeks, to 14 patients treated with a standard protocol that began at 60 mg daily and tapered to 10 mg daily within 6 weeks. This small retrospective study showed equivalent renal recovery between the two groups [62]. However, Manohar et al. found that patients treated with a rapid taper over 4 weeks had higher risk of AKI recurrence [63]. Duration of corticosteroid needs to be individualized based on clinical response and recurrence of AKI during taper. ICI agents have a long half-life from 6 to 27 days and response to treatment needs to be monitored closely [13, 42].

Table 3:

Current oncology society recommendations for management of ICI-AKI.

Severity of AKI	ASCO [43]	NCCN [67]	SITC [68]
Grade 1 (G1)SCr 1.5–2.0× baseline	Consider temporarily holding ICI and other potential contributing agents	Consider holding ICIFollow SCr every 3–7 days	Consider holding ICI
Grade 2 (G2)	Hold ICI temporarily	Hold ICI	Hold ICI temporarily
SCr 2–3× baseline	Prednisone 0.5–1 mg/kg/day	Prednisone 0.5–1 mg/kg/day	Prednisone
	If no improvement after 1 week: prednisone 1–2 mg/kg/day	If no improvement after 1 week: prednisone 1–2 mg/kg/day	If no response to steroid, consider infliximab or mycophenolate
	If improved to ≤G1: taper steroid over at least 4 weeks
Grade 3 (G3)	Permanently discontinue ICI	Permanently discontinue ICI
SCr >3× baseline or >4.0 mg/dL	Prednisone 1–2 mg/kg/day	Prednisone 1–2 mg/kg/day
Grade 4 (G4)SCr >6× baseline or dialysis indicated	If elevation persist >3–5 days or worsen, consider additional IS (e.g. infliximab, azathioprine, mycophenolate, cyclophosphamide or cyclosporine)	If SCr >2–3× baseline after 1 week of steroid, consider adding IS (e.g. infliximab, azathioprine, mycophenolate, cyclophosphamide or cyclosporine)

NCCN: National Comprehensive Cancer Network; SITC: Society for Immunotherapy and Cancer; SCr: serum creatinine; IS: immunosuppression.

ICI-AKI is usually highly sensitive to corticosteroids with approximately 90% of cases have partial or complete remission [3, 8, 9, 63]. Concomitant AIN-causing medications at the time of ICI-AKI and corticosteroid treatment were both associated with higher odds of renal recovery. Stage 3 AKI was associated with lower odds of renal recovery with only 46% of patients who required renal replacement therapy having kidney recovery [8, 9]. For patients with corticosteroid-refractory disease or significant side effects from treatment, switching or adding other immunosuppression should be considered. There are few data regarding treatment of ICI-AKI with non-corticosteroid immunosuppression. In a cohort study of 429 patients with ICI-AKI, only 5.1% of patients were treated with additional or alternative immunosuppressive agents, most commonly mycophenolate, infliximab and rituximab. Renal recovery in this sub-group was 41% [9].

Treatment of glomerular lesions associated with ICI

Recognized treatment guidelines do not distinguish between types of kidney injury associated with ICI. Therefore, there are no specific guidelines orienting the treatment of ICI-related glomerular diseases. In their systematic review of 45 cases of biopsy-proven de novo glomerular disease following ICI therapy, Kitchlu et al. [35] reported that nearly all patients (98%) received first-line corticosteroid treatment. Of note, 41% of these patients showed concomitant AIN on kidney biopsy. The reported cases of MCD, FSGS and C3GN were all treated with corticosteroid alone. However, half of the patients (6/12) who presented with pauci-immune GN/renal vasculitis were treated with another immunosuppressive agent in addition to corticosteroid, namely rituximab or cyclophosphamide, which is the standard of care [64] for pauci-immune GN. Complete and partial remission rate was similar to AIN, but the proportion of patients with ESKD was substantial at 19%. In another series, two cases of ICI-associated membranous nephropathy were treated with corticosteroid alone [6]. Recently, cases of ICI-associated AA amyloidosis have also been described [65]. Lapman et al. [66] reported a series of three cases, of which two presented with severe kidney injury necessitating dialysis. Two of these patients were treated with corticosteroid and colchicine with limited or no improvement. One received tocilizumab (anti-IL-6 agent) again without improvement.

ICI rechallenge considerations

In their most recent update, ASCO guidelines [43] indicate that ICI therapy should be permanently discontinued in all patients who develop grade 3 or higher immune-mediated AKI. However, permanently discontinuing ICI in patients who have exhausted other options for chemotherapy can significantly impact survival. National Comprehensive Cancer Network guidelines [67] suggest instead that rechallenge may be considered in patients with resolved grade 2 or 3 ICI-related AKI, after at least 2 months of holding ICI therapy.

Some retrospective studies provide us with interesting data to help with the rechallenge decision in case of renal toxicity. Gupta et al. [9] published the largest cohort study of ICI-related AKI to date. In this cohort, a total of 121 of the 429 patients (28%) with ICI-related AKI, including 42 patients with stage 3 AKI, were rechallenged with ICI therapy. Rechallenge occurred at a median interval of 1.9 months after AKI episode, and the majority (77%) had achieved renal recovery before rechallenge. Of the 121 patients rechallenged, only 20 (16.5%) developed recurrent AKI. In the Cortazar et al. cohort [8], 138 patients with ICI-associated AKI were examined. Rechallenge was attempted in 31 patients at a median of 1.8 months after the AKI episode. Most patients were rechallenged with the same ICI agent and 39% were still receiving steroid therapy at the time of rechallenge (median prednisone dose 10 mg daily). In this cohort, recurrent ICI-related AKI occurred in 23% of rechallenge patients. Of them, only one patient did not recover renal function. Patients who developed recurrent AKI were rechallenged sooner after the initial AKI episode (1.4 vs 2.1 months), suggesting that resuming ICI should be delayed if possible.

Rechallenge with ICI indeed carries a risk of subsequent toxicity, and deciding which patients should be rechallenged after experiencing serious AKI is complex. This decision should take into account the risks and benefits of retreatment, as well as the patient's preference to resume therapy. Ideally, every decision should also be discussed in a multidisciplinary team that include oncologists and nephrologists. In general, a de-escalation approach (using only one ICI agent) is preferred when dual checkpoint blockade was the original treatment modality [69]. There are limited data regarding efficacy of a class switch approach versus resuming treatment with the same ICI. However, switching from anti-PD-(L)1 to anti-CTLA4 has a higher systemic toxicity rate, and is thus not recommended [69]. At the present time, there is insufficient data to recommend concurrent use of small doses of steroids with ICI rechallenge. Of course, close monitoring is recommended when the decision is made to rechallenge. If a subsequent immune-mediated renal injury occurs, permanent discontinuation is advised in most instances.

Impact of immune-related renal adverse events on cancer outcomes and CKD

AKI is common in patients with cancer [70], and is associated with increased mortality and morbidity, including a subsequent risk of chronic kidney disease (CKD) [71–73]. For patients with cancer receiving systemic therapy, AKI is also associated with reduced treatment dose intensity and reduced progression-free survival [74]. Although treatment with immunosuppressive medication such as corticosteroids could theoretically interfere with the antitumor effect of ICI, most available data indicate that such treatment does not negatively affect tumor response [75–77].

In the setting of ICI-related AKI, failure to recover from AKI was an independent predictor of increased mortality in the Cortazar et al. study [8]. Moreover, patients who developed recurrent AKI after resuming ICI therapy had higher mortality compared with those who did not in the large cohort by Gupta et al. [9]. However, in a previous study published by Meraz-Munoz et al., AKI was not associated with increased risk of mortality [6]. Recently, in a retrospective study of 759 patients with solid organ malignancies treated with ICI, AKI was again identified as an independent risk factor for mortality [hazard ratio (HR) 1.6; 95% confidence interval 1.3–2.1] [78]. The authors pointed out that only 32% (38/118) of patients who developed ICI-related AKI were still alive at 6 months follow-up and had recovered kidney function, indicating that only 32% of patients could be eligible for new treatment after AKI. Thus, AKI while on ICI therapy significantly impacts oncologic disease course. We may hypothesize that the increased mortality associated with failure to recover with ICI-related AKI may reflect the limited cancer treatment options for these patients, and this highlights the importance of early recognition and management of ICI-related kidney injury before irreversible kidney damage occurs. Renal recovery ranged from 40% to 88% in published cohorts [6, 8, 9], indicating that a significant proportion of patients remained with CKD after the AKI episode. In a retrospective study of 637 patients with genitourinary cancers receiving ICI therapy, 18% had sustained eGFR loss (defined as >20% decline in eGFR) at 1-year follow-up [79]. In a recent systematic review and meta-analysis of 761 patients receiving ICI, overall risk of death was higher in patients who developed AKI (HR 1.42). Moreover, the presence of persistent kidney dysfunction was also associated with an increase mortality (HR 2.93) [80].

ELECTROLYTE AND METABOLIC DISTURBANCES ASSOCIATED WITH ICI

ICI have been associated with electrolytes and metabolic disturbances, the most frequent being hyponatremia [81]. A meta-analysis of 48 clinical trials of PD-1 inhibitor therapy for various malignancies showed an overall hyponatremia incidence of 1.2%, and hyponatremia accounted for more than 53% of grade 3–5 reported electrolytes abnormalities [28]. Another meta-analysis of six randomized clinical trials this time in patients with advanced non-small-cell lung cancer treated with ICI reported an higher incidence of hyponatremia of 8.7%. In this review, treatment with ICI increased the overall risk of hyponatremia compared with standard chemotherapy [82]. Recently, Seethapathy et al. published “real-world” data for incidence and risk factors of hyponatremia in a large retrospective study of 2458 patients receiving ICI therapy [83]. The overall incidence of hyponatremia in this cohort was 62%, with 6% of patients developing severe hyponatremia (Na <124 mEq/L), which is much higher than reported in previous clinical trial settings. In their adjusted multivariate model, anti-CTLA4 therapy was associated with a higher risk of severe hyponatremia.

Case reports have described ICI-induced hyponatremia due to hypophysitis and secondary adrenal insufficiency [84–87]. The incidence of immune-related hypophysitis in patients treated with ICI varies between 0.5% and 9% in clinical trials [88] and was 0.3% in a recent large cohort study [83]. A meta-analysis of 38 clinical trials with ICI therapy in patients with advanced solid cancers showed that hypophysitis occurred largely in patients with melanoma (89% of reported cases), was more frequent with combination therapy and CTLA4 inhibitors than with PD-1 inhibitors and PD-L1 inhibitors [89]. This meta-analysis also revealed an overall primary adrenal insufficiency incidence of 0.7% and again, incidence was higher in patients on combination therapy. However, not all cases of ICI-induced hyponatremia are related to immune endocrinopathies. In the study by Seethapathy et al. [83], syndrome of inappropriate antidiuretic hormone secretion (SIADH) was the most common etiology of ICI-related hyponatremia, accounting for 35% of severe hyponatremia cases. In contrast, endocrinopathies were responsible for only 0.3% of hyponatremia in this cohort.

In their review of the Food and Drug Administration Adverse Event Reporting System (FAERS) database, Wanchoo et al. [90] found that hypokalemia (19%) and hypercalcemia (10%) were the most common reported electrolyte abnormalities after hyponatremia. Hypokalemia can result from gastrointestinal losses secondary to immune-mediated colitis [91, 92] or kidney losses due to renal tubular dysfunction [93, 94]. Both distal and proximal renal tubular acidosis (RTA) have been described in various case reports, and most cases had concomitant AKI [94–97]. However, kidney biopsy described in some patients even without AKI showed mild to moderate forms of interstitial nephritis, suggesting that RTA may be an early sign of ICI kidney toxicity [98]. The underlying mechanism for developing RTA and AKI is not clear. It has been shown that PD-L1 is expressed on renal tubular epithelial cells and may play a role in immunopathology of ICI-induced kidney injury [99].

Hypercalcemia, while rarely mentioned in initial trials with ICI therapy [100], has been associated with ICI in recent case reports [101–103]. In a recent literature review, Izzedine et al. [104] identified four distinct causes for ICI-related hypercalcemia: immune endocrinopathies–related (mainly hypophysitis and adrenal insufficiency), sarcoidosis-like granulomas, ICI-induced parathyroid hormone–related protein production and hyperprogression of cancer following ICI initiation.

USE OF ICI IN DIALYSIS RECIPIENTS

ICI are not dependent on renal clearance, nor are they removed via dialysis [105]. Intracellular catabolism via lysosomal degradation following pinocytosis or receptor-mediated endocytosis is the main mechanism of elimination [39]. As such, there are no recommended dose modifications for ICI in the setting of peritoneal or hemodialysis.

As patients on dialysis have been largely excluded from clinical trials involving ICI [106], the initial data on their use in this population and associated efficacy and safety outcomes has mostly been from case reports and series [107, 108], which have largely suggested similar rates of iRAEs in patients receiving dialysis versus the general population. A systematic review of reports of dialysis patients who received ICI identified 98 patients (89 receiving hemodialysis and 9 receiving peritoneal dialysis), predominantly for renal cell carcinoma (33%) and other genitourinary cancers (24%) [105]. Of these 49% experienced iRAEs, with the majority being grade 1 and 2 events (34%). Dermatologic, hematologic and gastrointestinal iRAEs were the most common. There were four reported grade 4 events, including one death related to encephalitis, one episode of myocarditis and two pneumonitis events. These events were managed in keeping with oncology society guidelines, however the predisposition of dialysis recipients for potentially steroid-adverse comorbidities, including diabetes mellitus, heart failure, etc., must be considered when managing these events. At present there are insufficient data to compare site-specific cancer efficacy outcomes in the dialysis population versus the general population, and moreover, given the high competing risk of non-cancer causes of death in dialysis recipient such comparisons may not be appropriate. In the aforementioned systematic review, 30% of patients had complete or partial remission, while 28% had stable disease. Disease progression was observed in 36% of patients, and 31% died during reported follow-up. Additional data are needed to comment more definitively on both safety and efficacy of ICI in the dialysis population, however at present, dialysis patients should still be considered for these therapies, if appropriate in their overall clinical context and goals of care.

USE OF ICI IN KIDNEY TRANSPLANT RECIPIENTS

Presently there is no consensus on usage of ICI in kidney transplant recipients as almost all ICI trials have excluded this population. Available data show that patients with transplanted kidneys are at a higher risk of allograft rejection requiring dialysis [109]. This could be related to the immune system potentiating effects of ICI as it is determined that PD-L1:PD-1 pathway is an important regulator of renal tubular epithelial cell–mediated immune activation along with loss of self-tolerance due to ICI [99, 110]. There is also a speculated possibility of antibody mediated rejection due to B cell activation and proliferation due to active CD4 T cells through co-stimulatory signals and cytokines, especially in the setting of reduced immunosuppression [111]. A recent multicenter retrospective study that included 69 kidney transplant recipients who received ICI for melanoma and squamous cell carcinoma showed 42% rejection rates with 27% graft loss compared with 5.4% rejection rate in non-ICI cohort [109]. Median time of ICI initiation and rejection was 24 days. mTOR inhibitor use was associated with lower risk of rejection in this study. In another study from the MD Anderson Cancer Center, where 23 of 39 solid organ transplant patients had kidney allografts [112], 11 of the 23 patients (48%) had allograft rejection in a median period of 21 days, and graft loss occurred in 10 patients. The median time of ICI initiation after solid organ transplant was 9 years. Four of the patients died due to allograft rejection or rejection-related complications. Half of the patients had acute T cell–mediated rejection and the remaining had mixed cellular/antibody-mediated rejection. However, absence of C4d staining and donor-specific antibodies suggested a secondary phenomenon attributed to T cell activation related to ICI therapy. In a multicenter retrospective study of six kidney transplant recipients diagnosed with metastatic melanoma treated with ipilimumab, with a mean time of initiation of therapy 5 years post-transplant, the prognosis was poor with 100% mortality at the end of 3 years [113]. There is an ongoing debate on whether CTLA4 plays a lesser role than PD-1 pathway in transplant tolerance [114]. To prevent the rejection episodes, suggestions have been made for the modification of immunosuppression (according to patients’ age, HLA mismatch, time after transplantation and history of rejection), increasing the dose of steroids and switching calcineurin inhibitors to mTOR inhibitors prior to initiation of ICI [111, 115]. A recent multicenter, single arm, phase 1 study from Australia that evaluated 22 kidney transplant recipients with various solid tumors exposed to nivolumab assessed the risk of allograft rejection when baseline immunosuppression was left unchanged [116]. Patients were treated with median of three infusions and the median follow-up was 28 months. None of the patients had irretrievable allograft rejection without evidence of tumor response. There were no treatment-related deaths or treatment-related serious adverse events. Although the outcomes of this study are promising, physicians need to be vigilant on the possibility of rejection post-initiation of ICI and carefully weigh the balance between tumor treatment and graft loss.

KNOWLEDGE GAPS AND FUTURE DIRECTIONS

With the expanded use of ICI, oncologists and nephrologists will increasingly manage patients with AKI during ICI treatment. One important challenge is to differentiate AKI related to ICI from other causes of AKI. Non-invasive tools would be beneficial for rapid diagnosis and improved outcomes. Isik et al. found two protein biomarkers, serum CRP and urine retinol binding protein/urine creatinine, as potential identifiers of ICI-AKI [56], but more studies are needed to assess their sensitivity and specificity.

Duration of corticosteroid treatment for ICI-AKI also needs clarification. Some authors suggest a rapid corticosteroid taper, but the risks and benefits of this intervention needs to be studied in larger studies [62]. Finally, there is a need to assess potential roles of non-steroid immunosuppressive agents for treatment of ICI-AKI. The optimal treatment for patients at high-risk of side effects from corticosteroids or patients with corticosteroid-refractory disease is still unclear in the literature.

CONCLUSIONS

Kidney complications associated with ICI will become more frequent as the use of ICI for various malignancies increases. Both nephrology and oncology clinicians will need to recognize and manage ICI-associated nephrotoxicity. These remain most commonly manifested by AKI in the form of ATIN, but glomerular disease and electrolyte disturbance are important considerations as well. Judicious use of kidney biopsy may be key to diagnosis, but future work is needed to elucidate the role of non-invasive diagnostic approaches. Similarly, additional evidence is needed to guide the optimal duration of corticosteroid treatment and the potential role of subsequent-line immunosuppressives. Finally, the overall approach to kidney iRAE must prioritize the receipt of optimal cancer therapy, particular in view of relatively low recurrence rates of kidney iRAE upon ICI re-challenge and the implications of immunotherapy interruption or cessation on cancer outcomes.

DATA AVAILABILITY STATEMENT

Not applicable.

CONFLICT OF INTEREST STATEMENT

None declared.