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Should corticosteroids be employed to treat biopsy-proven drug-induced acute interstitial nephritis? PRO

How to Cite this article: Andrew Donati and Namrata Krishnan, Should corticosteroids be employed to treat biopsy-proven drug-induced acute interstitial nephritis? PRO, Kidney360, Publish Ahead of Print, 10.34067/KID.0006642021 Article Type: Debates in Nephrology Should corticosteroids be employed to treat biopsy-proven drug-induced acute interstitial nephritis? PRO DOI: 10.34067/KID.0006642021 Andrew Donati and Namrata Krishnan Key Points: Abstract: This is an Early Access article. Please select the PDF button, above, to view it. Be sure to also read the CON: 10.34067/KID.0007042021 and COMMENTARY: 10.34067/KID.0008342021 Disclosures: N. Krishnan reports the following: Scientific Advisor or Membership: Kidney Medicine, Editorial board member; KSAP author; ASN core curriculum author, NKF education committee member. A. Donati has nothing to disclose. Funding: Author Contributions: Andrew Donati: Writing original draft Namrata Krishnan: Supervision; Writing review and editing Data Sharing Statement: Clinical Trials Registration: Registration Number: Registration Date:

Acute Interstitial Nephritis (AIN) is an under-recognized cause of acute kidney injury (AKI) and occurs in 13-20% of biopsies performed for AKI (1,2). Drug-induced AIN (DI-AIN) accounts for 70% of these (2). Although numerous drugs are implicated, proton-pump inhibitors (PPIs), antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) are common culprits, especially in the elderly. Immune check point inhibitors (ICIs) have recently emerged as an important cause. AIN frequently presents insidiously, as a subacute rise in serum creatinine with minimal symptoms or urinary abnormalities (3,4).
Histopathological confirmation is often necessary and may result in diagnostic delays (5). DI-AIN has a variable prognosis with 30% developing dialysis-requiring AKI and 40-60% progressing to chronic kidney disease (CKD) (2). Notably, 2% of all CKD is attributed to AIN (6,7). DI-AIN is characterized by a type-B idiosyncratic, cell-mediated immunological response triggered by the culprit drug, resulting in renal tubulointerstitial injury (8). Histology shows interstitial edema and a cellular infiltrate with predominance of CD4+ T lymphocytes, plasma cells and eosinophils (9). The drug acts as an allergen or lowers immune tolerance (e.g., ICIs). With ongoing drug exposure, acute cytokine mediated renal injury can rapidly progress to irreversible tubulointerstitial fibrosis (TIF), noted as early as 7-10 days after initial insult, and ultimately results in CKD (10,11).
Immediate discontinuation of the offending drug is the first step in management of DI-AIN.
Glucocorticoid therapy is frequently utilized If there is lack of renal improvement despite drug withdrawal, however its use is controversial. Data from randomized controlled trials (RCTs) is unavailable, and treatment guidelines are not standardized. Several case series and small, retrospective studies have demonstrated benefit of steroid therapy in DI-AIN (6, 10, 12-15), while others have not (16,17). In this article, we aim to provide rationale for why glucocorticoid therapy should be strongly considered for treatment of DI-AIN.
Glucocorticoids block cytokine production via several mechanisms, including inhibition of a key proinflammatory transcription factor NF-κB ( Figure 1) which has a pivotal role in promoting renal inflammation in various diseases including AIN (18,19). Within days after the onset of tubulointerstitial inflammation, there is activation of profibrotic processes via cytokine mediated fibroblast stimulation and epithelial-mesenchymal transformation. This results in interstitial collagen deposition, irreversible tubular atrophy and interstitial fibrosis (8). Glucocorticoids suppress cytokine mediated tubulointerstitial inflammation in AIN, and if initiated early in the disease course, may prevent TIF by attenuating the initial pro-inflammatory pathways ( Figure 1 progressed to CKD (eGFR<60ml/min). Longer interval to treatment with corticosteroids was an independent risk factor for progression to CKD (OR= 1.183, 95% CI 1.035, 1.352, p=0.014) and a delay > 22.5 days had the best predictive value for progression to CKD. This study again demonstrates that severe DI-AIN can have improved renal outcomes with timely initiation of steroids. Given the irreversibility of established TIF, several of these studies have noted poor renal recovery despite steroids, in patients with higher degrees of fibrosis (6,10).
In contrast to above, other retrospective studies have found lack of benefit of glucocorticoids in DI-AIN (16,17). There are several potential explanations for these results. a. Selection bias in these retrospective studies would generally favor outcomes in those not treated with steroids, as steroids would be trialed in patients that fail to improve with drug discontinuation. b. Delay in initiating steroid treatment and c. Presence of higher degree of TIF on renal biopsy would predict lower steroid responsiveness.
Clarkson et al showed no difference in 1 year outcome with early steroid use in biopsy proven AIN (26 controls vs 16 steroid-treated) (16). In addition to being a small study, 33% of the patients had severe TIF, which could explain the absence of observed benefit from steroids. A larger, multicenter study (N=171) by Valluri et al found a trend towards complete renal recovery in the glucocorticoid group vs. controls (48% vs 41%) although this was not statistically significant (17). A high percentage of patients in this study had an unclear duration of AKI and only 14% had a time course of less than 3 weeks which suggests that the majority may have developed significant TIF. Additionally, 35% of patients had DI-AIN attributed to PPIs. PPI induced AIN is particularly notable for poorer prognosis due to its insidious onset, delay in diagnosis, as well as baseline CKD in the elderly who are more likely to be on chronic PPI therapy (20). Finally, glucocorticoid-treated patients had a higher severity of AKI at baseline (4.0 mg/dL Cr vs. 3.2 mg/dL), therefore, similar creatinine levels in the two groups on follow up could suggest a higher magnitude of improvement in renal function in those that received glucocorticoids.
In summary, despite lack of data from RCTs, there is compelling evidence favoring early use of glucocorticoid therapy in patients with DI-AIN (ideally within 7-10 days of diagnosis). This includes patients with severe AKI, but without severe TIF on histopathology. Timely therapy may allow faster and more complete renal recovery and lower risk of residual CKD. Situations in which withdrawal of the drug may be detrimental (such as life-saving antibiotics or ICIs), treatment with glucocorticoids and drug rechallenge, may be the only option (21). A short course of high dose steroids (2-3 weeks), followed by a taper over the next 6-8 weeks is a reasonable approach. Those patients with DI-AIN that respond favorably to steroids are likely to do so by 4 weeks, and treatment beyond 6-8 weeks may increase the adverse effects with minimal additional benefit (5,10). ICIs may require longer treatment (3-6 months) and a slower taper (21). Although intravenous pulse steroids can be used for severe AKI, there does not appear to be an advantage of intravenous protocols over high dose oral steroids (22).