The etiology of AKI in patients undergoing CPI treatment may be multifactorial (Fig. 3). In one of the largest series published to date, less than 40% of AKI in patients under CPI treatment were directly associated with these drugs.8 If the AKI is attributed to oncospecific treatment it would require the withdrawal of the medication and initiation of corticosteroid treatment if NTIA is suspected; this strategy may lead to possible detriment to the evolution of the neoplasm. Therefore, assessment and exclusion of other etiologies is strongly recommended.

Figure 3.

ARF in patients treated with check-point inhibitors (CPI).

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The incidence attributed to CPIs in the presence of AKI is estimated at 2−3%, with a mean onset of 15 weeks after initiating treatment.9–11 In general, the association of CTLA-4 and PD-1 inhibitors seems to result in a somewhat higher rate (5%).12

Risk factors for the development of CPI-AKI are: baseline renal function, the use of proton pump inhibitors (PPIs), the previous presence of other IRAES Is and the use of two or more CIPs, and patient's age.9–13

The PPIs along with other medications that cause ATIN, such as non-steroidal anti-inflammatory drugs (NSAIDs) or certain types of antibiotics, should be used with caution in patients receiving CPI and should be discontinued in those who develop CPI-associated acute renal failure (CPI-AKI).5 It has been shown that in those patients that develop CPI-AKI who were receiving medication that has been associated with ATIN, discontinuation of these treatments facilitates complete recovery of renal function.9 Given that the use of PPIs is a risk factor for the development of AKI in these patients, the authors of this article recommend avoiding their indiscriminate use, mainly in those patients with other additional risk factors.

Although the existence of a previous adverse immune effect (myocarditis, thyroiditis, colitis…) supports the possibility of CPI-AKI, only a 43% of patients with CPI-AKI have had this complication previously, so its absence does not rule it out.9

There have been described a number glomerular diseases associated with CPI treatment. Kitchlu et al.18 performed a systematic review and meta-analysis including 27 articles with 45 cases showing of glomerular disease with findings that clarify this pathology: paucimmune glomerulonephritis and renal vasculitis (27%); podocytopathies (minimal glomerular lesions in 9 and focal segmental hyalinosis in 2) (24%); and C3 glomerulopathy (11%). The results are summarized in Table 3. It is important to highlight that 41% of the cases had ATIN and that only 2 of the patients with vasculitis were ANCA positive. Mortality was high in this group despite treatment with corticosteroids. More than 60% of patients with podocytopathies had total or partial remission after drug withdrawal and corticosteroids and most C3 patients remitted with steroids alone. Therefore in some patients with glomerular damage the use of CPI could be resumed, particularly in those with podocytopathies although still we need more solid data to support such recommendation. Nevertheless, the evolution of the cases with glomerular disease induced "de novo" by CPI is not good. Most of the patients had their CPI interrupted (88%) and almost all of them received corticosteroid treatment (98%). Dialysis was required in 25%. Most patients had total (31%) or partially (42%) recovery from AKI; however, 19% remained dialysis-dependent, and approximately one-third died. Complete or partial remission of proteinuria was achieved in 45% and 38%, respectively.

The mechanisms by which CPIs induce glomerular disease are still poorly understood. Different hypotheses have been proposed, all of them had been already discussed previously in adverse events related to CPIs. An increase in inflammatory processes by T-cell hyperactivity, autoantibody production, or by inflammation related to C5a production that has been found to be increased when PDL-1 is blocked.19

The group has specified its position regarding the obtention of renal biopsy in patients with AKI-CPI. The recommendations are based on its experience and on different publications5,6,9,10,13,17,18,20–22 and considers that renal biopsy is a fundamental tool for the management of these patients, since it allows confirmation of the diagnosis (avoiding treatment with corticosteroids or the withdrawal of CPI in cases in which the biopsy does not confirm the presence of AIN) and helps to establish the prognosis according to the degree of fibrosis.

It is important to remember that oncology patients often have other risk factors for renal damage (hypoperfusion episodes, iodinated contrast agents, tubular toxic agents such as platinum) and that AKI recovery in non-biopsied, corticosteroid-treated patients may reflect the natural course of ATN recovery and have nothing to do with corticosteroid treatment, which makes the argument that renal recovery in patients receiving corticosteroids is confusing. Many oncologists consider that an empiric course of corticosteroids is a strategy that carries low risk in these patients, and currently recommend this approach in their guidelines.20 One could argue that this approach is reasonable in patients who have other immune-mediated organ injury, avoiding the potential complications of renal biopsy. We agree with Gupta et al.5 that empirical steroid therapy should only be considered for patients with the absence of a plausible alternative etiology for AKI and in those with an absolute contraindication to renal biopsy due to safety concerns (e.g., uncontrolled hypertension or anticoagulation). The presence of a single kidney (e.g., due to nephrectomy in renal cancer) is not an absolute contraindication for biopsy, although of course, the risk-benefit should be assessed carefully. Knowing the type of renal lesion is important because corticosteroids and/or drug withdrawal may be necessary for patients with ATIN, but are not required for ATN and other non-immune-mediated lesions.

Thus, we consider that unless absolutely contraindication, renal biopsy should be performed in all patients to obtain the diagnosis of the renal damage associated with CPI, and preferably before 48−72h. In certain circumstances with mild AKI in which the response to steroids is excellent and the clinical suspicion of immune-mediated nephritis is very high, biopsy we can avoided and consider it if there is deterioration of renal function after rapid tapering/withdrawal of steroids.

Circumstances that might justify a short empirical test with corticosteroids prior to biopsy and those in which we consider a renal biopsy to be necessary from the outset are shown in Fig. 5.

Figure 5.

Circumstances for indicating a renal biopsy in patients with Acute Kidney Injury (AKI) receiving check-point inhibitors (CPI).

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If the renal biopsy is delayed due to patient characteristics or to the management of the hospital service and the suspicion of immune-mediated nephritis is high, the initiation of corticosteroids should not be delayed until the biopsy is performed.

The treatment recommendations by the SEN Onconephrology group are as follows (Fig. 6).

Figure 6.

Management of the patient with renal failure under treatment with check-point inhibitors (CPI).

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There are only retrospective observational studies analyzing the incidence of overall adverse immune effects upon resumption of treatment; results were different depending on the drugs and their substitution; recurrent or new adverse effects may be observed. A large pharmacovigilance cohort study in individual cases from the WHO database evaluates the recurrence rate of immune adverse effects in patients after re-starting CPI treatment and found a 29% of adverse effect recurrences, most frequently colitis, hepatitis and pneumonitis27–32 (Table 4).

When a patient has had an episode of AKI-CPI, especially grade 2−3, and such treatment is necessary for cancer remission, the decision to resume CPI is complex because it could lead to new episodes of AKI which worsens the prognosis severely. According to the ASCO guidelines (Fig. 4), CPI treatment should be permanently discontinued in all patients who develop grade 2 AKI if it does not improve within days with steroids and in grade 3.20 The problem with this view is that this approach may deprive patients of potentially life-saving therapy.

The recurrence of AKI-CPI after retreatment has been evaluated in several studies and the results have been variable, but in general it is estimated to be around 20% and most of them were still receiving steroids at the time of re-exposure10,32–37 (Table 5). Given the low incidence of recurrent AKI-CPI, it seems reasonable to consider re-exposure in patients for whom CPI is the optimal treatment,27 probably with concomitant low-dose steroid therapy.

The decision to restart CPI treatment depends on the severity of the previous event and the degree of recovery from such event, the availability of alternative therapeutic options, and the overall status of the cancer. There are three important aspects to consider. First, the severity of the adverse event, because if there is life-threatening toxicity, particularly cardiac or neurological toxicity, or a massive release of cytokine, CPI should not be restarted. Also need to consider the presence of drugs that can produce ATIN-AKI and that can be withdrawn (PPIs, NSAIDs…) and the combination of CPI treatments. With these considerations and after immunosuppressive treatment (preferably corticosteroids) had produced complete or partial remission, Hermann35 proposes several possibilities:

• 1

  Change CPI class if deemed appropriate and plausible by Oncology. For example, the incidence of ICP-AKI is less than 1% with PDL1 blockade compared to an incidence of 2–5 % with other classes.38

• 2

  Continue with the same CPI or in case of double therapy suppress CTLA-4 and continue with anti-PD-1 monotherapy.

• 3

  Secondary prevention in which CPI is resumed concomitantly with immunosuppressive therapy: after the initial episode of CPI-AKI, immunotherapy is resumed upon resolution of the AKI, concomitantly with low doses of steroids (usually 10mg daily) depending on other factors such as severity of AKI and other concomitant adverse effects. However, if at resumption of CPI treatment the patient is no longer on steroids there is no evidence to recommend restarting steroids. This secondary prevention can be maintained for several cycles or continuously, but there is no published experience.

Therefore, oncologists, nephrologists and multidisciplinary teams have to balance the clinical benefit and the danger of treatment-related toxicities for each patient.39

Retreatment with CPI may be considered in patients with AKI-CPI.

• 1

  If the cancer has not yet responded due to the short time of treatment or inadequate response to treatment

• 2

  If the time period of resolution with corticosteroids of AKI-CPI is short, with creatinine decrease at 1 week (>25%).

• 3

  If the patient is on treatments that may induce ATIN (NSAIDs, PPIs, antibiotics) that have been withdrawn at the diagnosis of nephritis.

• 4

  In those receiving a combination of treatments that can be reduced to one.

• 5

  Once renal response is achieved, it is advisable to reintroduce CPI when the patient is on a dose of prednisone <20−10mg/day and is continued with the tapering of steroid regimen.

The renal risk of reinitiating CPI should always be explained to the patient and balanced against the risk of progression of the neoplasm. Before making therapeutic decisions, it is advisable to consider whether the patient can undergo renal replacement therapy (RRT) by dialysis in case of poor evolution, taking into account the overall prognosis.

Retreatment with CPI should not be considered in patients with AKI-CPI.

• 1

  History of serious life-threatening adverse immunological effects: neurological, pulmonary, myocarditis, cytokine release syndrome.

• 2

  Availability of alternative treatments in patient on a critcal situation.

• 3

  If the time to resolution of AKI-CPI with corticosteroids is slow with a decrease in creatinine at one week (<25%) (depending on the type of tumor) or poor renal recovery, leaving the patient with reduced "residual" renal function. If treatment with CPI is unavoidable due to the patient's oncologic situation, RRT should be prioritized if indicated but in agreement with the patient and then immunotherapy should be restarted.

• 4

  In case of suspected glomerular nephropathy: Do not retreat without biopsy in those patients with new-onset proteinuria (>1g/day) and a urine sediment that is not compatible with ATIN.

• 5

  Previous favorable response of the tumor treatment. If the target was achieved, it is reasonable to assume that the response is durable and retreatment should not be considered.

New treatments such as CPIs result in cellular and humoral graft rejection in 30−40% of which up to 60% result in kidney loss.41 There are several factors to be considered when using CPIs in kidney transplant recipients. Observational studies have shown that the use different CPIs produce diverse effects on acute rejection however further additional studies are needed.42–44

In a review of published cases and case series Gupta et al.5 found that the rejection rate with anti-cTLA-4 (ipilimumab) monotherapy was 33% as compared with 52% in patients receiving anti-PD-1 monotherapy. It is difficult to draw a definitive conclusion because patients had undergone different reductions or changes in immunosuppression at the time of diagnosis of metastatic cancer, which could strongly influence rejection rates. Therefore, further studies are needed.

It has been shown that increased immunosuppression at the initiation of CPI or the use of mTOR inhibitors was associated with a lower risk of rejection.41 Factors such as duration of transplantation, history of donor-specific antibodies or a previous history of rejection are also important risks to be considered.

A recent multicenter observational study by Murakami et al.41 examined the safety and efficacy of CPI in 69 kidney transplant patients from 23 institutions. The study showed that 42% of patients experienced acute allograft rejection with a median occurrence of 24 days since the initiation of CPI to rejection. Once rejection occurred, 65% of patients experienced allograft failure and required dialysis. A recent multicenter single-arm study analyzed 17 patients with kidney transplant aged >18 years treated with nivolumab for incurable, locally advanced cancer or metastatic solid tumors with a creatinine level <180mmol/L, and either without or low concentrations of donor-specific HLA antibodies. Baseline immunosuppression was not modified which did not affect the efficacy of CPI (similar to that described in this population), and it also resulted in lower rejection rates (12%) than previously published. There were no treatment-related deaths or serious adverse events.45

Table 6 shows the differential characteristics of AKI between non-transplanted patients (generally ATIN) and transplanted patients (cellular and humoral rejection). In transplants patients the AKI is much more frequent, appears earlier, is resistant to steroids and there is a high percentage of graft loss.46

Blockade of CTLA-4 and PD-1 increases T-cell activation, not only against malignant cells, but also against other cells expressing foreign antigens, such as renal allograft donor antigens. PD-1 and PD-L1 can be found in the allograft and its reactive T cells43. The activation of T-cells may lead to acute cellular rejection and activated CD4 T cells could lead to B-cell proliferation and activation through co-stimulatory ligands (e.g., CD40L) and cytokines (e.g., IL-4, IL-21 and interferon-γ) leading to antibody-mediated rejection, especially if immunosuppression is reduced.47 B cells may also be activated as a direct effect on PD1-expressing memory B cells if there was prior sensitization of the transplanted organ or a decrease in immunosuppressive drugs.44

So far there are very few published cases, but it appears that PD-1 inhibitors may be more likely to cause rejection in the transplanted kidney than CTLA-4 antagonists. This is especially true when patients receive anti-CTLA-4 agents prior to treatment with PD-1 inhibitors.48

There is contradiction in the effect that corticosteroids may have on the antitumor response of CPIs in these cases. In some trials, it may have decreased the antitumor response of CPIs,49 while in others overall survival and time to treatment failure were not affected by the use of systemic glucocorticoids.50

Barnett et al.48 published the case of a kidney transplant patient with previous bilateral nephrectomy for renal cancer and a diagnosis of metastatic adenocarcinoma in treatment with nivolumab. He received a tapering steroid regimen that was initiated one week before the introduction of CPI, and tacrolimus was replaced by sirolimus with favorable cancer progression and stable renal function. The use of mTOR inhibitors (everolimus, temsirolimus and sirolimus) have been studied in many types of cancer and in these patient, sirolimus may have played a synergistic antitumor role in addition to being an immunosuppressive agent. Jhaveri F. refers a dozen patients with this therapeutic approach with good evolution.46

However, mTOR inhibitors are associated with a higher risk of rejection than anticalcineurin inhibitors. Depending on the immunologic risk between the donor organ and the recipient, the decision to reduce or discontinue immunosuppression must be balanced against the increased risk of rejection with CPI. More studies are needed, and actually there are ongoing several clinical trials, some of them to evaluate the potential effect of prophylactic steroid minipulses with CPI cycles and conversion of CNI to mTOR inhibitors to determine both rejection rate and cancer response.

• 1

  The decision to initiate CPI treatment in kidney transplant patients is complex and it should be multidisciplinary, and always provide a correct information to the patient about the risks and benefits.

• 2

  The following should be considered in the decision: the duration of the transplant, history of specific donor antibodies, previous history of rejection or the type of immunotherapy to be used (higher risk of rejection in anti-PD1 and anti-PDL1).

• 3

  Decide against treatment with immunotherapy if an alternative treatment is available.

• 4

  Consider increasing or restarting corticosteroids prior to treatment and assess the suitability of mTOR inhibitors.