Acute Interstitial Nephritis and Checkpoint Inhibitor Therapy

Abstract

Background The objective of this case cohort study was to describe our experience in the care of patients with immune checkpoint inhibitor-related acute interstitial nephritis (ICI-AIN) including rechallenge. Methods A descriptive case series of patients that received an ICI and had an AKI (defined as a $1.5-fold increase in serum creatinine) as an immune-related adverse event (irAE), with biopsy-proven or clinically suspected ICI-AIN from January 1, 2014 to December 1, 2018 at Mayo Clinic, Rochester. We studied details regarding diagnosis, clinical course, management, and outcomes of rechallenge of immunotherapy. Complete response (CR) was defined as return of kidney function back to baseline or ,0.3 mg/dl above baseline creatinine; partial response (PR) was defined as creatinine .0.3 mg/dl from baseline, but less than twofold above the baseline by the end of steroid course. Results A total of 14 cases of biopsy-proven (35%) or clinically suspected (65%) ICI-AIN was identified. All patients had their ICI withheld and 12 patients received steroids. Steroid regimens were highly variable. The starting equivalent dose of prednisone was higher in those that had a CR versus a PR (median 0.77 mg/kg versus 0.66 mg/kg). Proton pump inhibitors (PPIs) were used in 11 patients and were stopped in eight (73%) patients at the time of the AKI event. A CR was seen in five (63%) of the eight patients who discontinued PPIs. Rechallenge was attempted in four of the 14 patients: three were successful with no recurrence of AKI, but one patient had recurrent AKI and fatal pneumonitis. Conclusions Careful review, withholding ICI and concomitant known AIN-inducing medications, along with prompt initial steroid management were the key in complete renal kidney recovery. A kidney biopsy should be strongly considered. Rechallenge of immunotherapy after a kidney irAE, although challenging, is possible and would need careful evaluation on an individual basis.

Biomarkers, Clinical Features, and Rechallenge for Immune Checkpoint Inhibitor Renal Immune-Related Adverse Events

“…As previously reported by our group and others, AIN is the most common histopathological dominant lesion seen in patients with ICI-AKI, found in 100% of biopsied patients in our institution at the time of AKI. 10 , 12 , 13 , 14 …”

“… 5 Kidney toxicity while on ICI therapy occurs in up to 17% in reported series, but only a fraction is related to ICI, varying from 1% to 5% (depending on the type of ICI or use of combined ICI agents). 10 , 11 , 12 , 13 , 14 , 15 Acute interstitial nephritis (AIN) is the most common histopathological lesion, and depending on the severity of the renal or extra-renal iRAE, further treatment with immunotherapy may be limited. 16 In general, the use of systemic cancer agents is associated with AKI of diverse etiologies, and it is important to understand the likely cause so as to not unnecessarily limit future chemotherapeutic treatment options.…”

A Systematic Review of Immune Checkpoint Inhibitor–Associated Glomerular Disease

“…Median age of patients with glomerular disease following ICI use was 63 (IQR, [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] years and 75% were male ( Table 1) The vast majority of patients had ICI discontinued (88%) and nearly all received corticosteroid treatment (98%). Most patients had either complete (31%) or partial (42%) recovery from AKI.…”

“…Similarly, Manohar et al described 4 patients who underwent re-challenge after removing AIN-associated drugs in 3 out of the 4 patients. 62 Re-challenge was done along with a low dose of corticosteroid therapy (prednisone 10-20 mg daily) in 3 out of 4 patients.…”

Renal Complications Related to Checkpoint Inhibitors: Diagnostic and Therapeutic Strategies

“…ICIs could lead to very early graft rejection, graft intolerance syndrome, as well as cytokine storm, requiring graft nephrectomy [ 52 ] A kidney biopsy is also essential for diagnosis. A recent systematic review of twenty-seven articles with a total of 44 kidney transplant patients treated with ICI, reported a rejection rate of 40.9% [ 53 ]. The median time from ICI to a diagnosis of acute rejection was 24 (interquartile range, 10–60) days, which is shorter than the median time reported from ICI to AKI in non-transplant patients.…”