Long-Term Outcomes and Role of Corticosteroids in Biopsy-Proven Acute Interstitial Nephritis

Introduction

Acute Kidney Injury (AKI) caused by acute interstitial nephritis (AIN) is often missed, and clinical diagnosis depends on a biopsy.¹ Drugs have been the most common culprit of AIN.^2-5 Non-steroidal anti-inflammatory drugs (NSAIDS), antibiotics, and proton pump inhibitors are common causes of AIN.⁶ Metabolic AIN is seen with deposition of specific crystals in kidney tissue.⁷

There are limited data on the long-term outcomes of biopsy-confirmed AIN and on the specific substances causing it in this region. Most studies are in the form of case series,⁸ and short follow-up.^9,10 Traditional drugs are also frequently associated with AIN.^11-13 Moreover, there is a lack of data on the long-term outcomes of AIN associated with these agents. A recent systematic review concluded that more data are needed to support the use of corticosteroids in the treatment of AIN.¹⁴ We studied the clinical presentation, laboratory features, possible causal association, histopathological patterns, long-term outcomes, and response to immunosuppressive therapy in biopsy-proven AIN.

Materials and Methods

We retrospectively collected medical records of patients with AIN biopsied between June 2013 and June 2023 from the hospital information system (HIS) [Figure 1]. We retrieved demographic and clinical information, including age at presentation, sex, relevant medical history, drug intake, alternative medications, hospitalizations, laboratory parameters, urinalysis, kidney replacement therapy (KRT), biopsy findings, immunosuppressive therapy, treatment response, follow-up KRT, kidney recovery, and patient survival. Patients <18 years old and those with systemic diseases such as IgG4-related disease, SLE, Sjogren’s, sarcoidosis, and paraproteinemia-associated AIN were excluded due to differences in course and treatment. The study was approved by the institute’s ethics committee and conducted in accordance with the Declaration of Helsinki.

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Figure 1:

STROBE flow chart of the study. AIN: Acute interstitial nephritis, ESKD: End stage kidney disease

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Results

A total of 4267 biopsies were screened, and AIN accounted for 5.6% of the biopsies (n=235) during the study period. The clinical characteristics and laboratory parameters are presented in Table 1. A total of 65 cases with systemic and autoimmune diseases were excluded. Thus, 170 AIN patients (age 53.5 ± 15.5 years) and 129 (75.9%) males were included in the study for analysis. The median time from symptom onset to kidney biopsy was 22 (IQR 6-32) days. At presentation, 44 patients (25.9%) had diabetes mellitus, and 67 (39.4%) had hypertension. The common symptoms included nausea or vomiting (78.2%), oliguria (58.8%), fever (50%), pedal edema (20%), joint pain (15.3%), and skin rashes (9.4%). AKI was the most common presentation observed in 151 patients (88.8%), while 15 patients (8.8%) had a subacute onset, rapidly progressive renal failure (RPRF) like presentation. Four patients (2.4%) had either proteinuria or persistent pyuria with normal serum creatinine at the time of biopsy. Upon admission, dialysis was required in 72 patients (42.4%).

Discussion

In this study, AIN accounted for 5.6% of total biopsies performed during the study period, with drugs dominating as the most common etiological factor. Medications associated with AIN remain prevalent worldwide in different studies as well,²⁰ with antibiotics being the most common culprit, followed by NSAIDs. A distinctive finding in our study was that alternative medicines emerged as the leading cause of drug-associated AIN, reflecting the increasing use of alternative medicines driven by sociocultural beliefs that they are natural and free of adverse effects, in contrast to allopathic drugs^10,12,13,20. However, the association of alternative and herbal therapies with CKD is known,²¹ and it constitutes one-fourth of the drugs causing AIN in our cohort. This trend became more evident after the COVID-19 pandemic, with increased consumption of alternative and herbal medications to boost immunity, driven by their easy availability, cultural acceptance, and low cost.^22,23 These agents also precipitated metabolic AIN, as evidenced by kidney biopsy findings of oxalate and uric acid crystals in the patients, similar to observations in other studies.^24-26

Polypharmacy is another risk factor associated with AIN, affecting mainly the elderly and males.²⁷ In our cohort, 75.9% patients were males, and 40% were elderly. Male predominance may be related to hormonal influences, increased environmental, and occupational risk factors and healthcare-seeking behaviour. Additionally, hormones can also influence kidney function recovery.²⁸ The relatively lower incidence of AIN in our cohort compared with some published series may be attributed to the inclusion of only biopsy-proven cases. Kidney biopsies were performed primarily in patients with delayed presentation or delayed recovery of kidney function, where a definitive diagnosis was required. Consequently, the clinical and laboratory presentations were heterogeneous, reflecting diverse underlying causes and immune mechanisms.²⁹ The classical triad of fever, rash, and eosinophilia, traditionally associated with allergic drug-induced AINwas observed in only 2.9% of patients with antibiotic-related AIN, consistent with contemporary literature reporting its infrequent occurrence.^20,28 The majority had sub-nephrotic proteinuria , with only 10% showing nephrotic-range proteinuria.^30,31 and dialysis requirement was observed in 42.8% of patients, a finding consistent with a previous study.³²

Beyond withdrawal of the offending agent, corticosteroids play an important role in promoting kidney recovery and improving survival.³³ Inflammatory injury in AIN typically begins within 7–10 days of exposure to the causative agent, and early initiation of corticosteroid may limit irreversible tubulointerstitial damage.^11,12,33 . In our cohort, patients treated with corticosteroids demonstrated better early recovery of kidney function, higher eGFR at 3 months, and a reduced need for dialysis during follow-up. However, there was no statistically significant difference in eGFR between steroid-treated and non-treated groups at the end of follow-up, a finding consistent with previous reports.^6,33–37 This lack of sustained benefit may be explained by delayed presentation and delayed initiation of corticosteroid therapy in our cohort.

Despite known adverse effects, including an increased risk of infections,³⁰ patients receiving corticosteroids showed better kidney patient survival. Early recovery of kidney function likely contributed to these favorable outcomes. Previous studies have shown that early corticosteroid therapy may halt progression to chronic injury,³¹ as interstitial fibrosis can develop within as little as three weeks of persistent inflammation. In our study, corticosteroids were initiated based on biopsy findings despite delayed presentation, with a median treatment duration of 2 to 6 weeks.^10,32,34 Delays were largely due to late referral to a tertiary centre and the time required for definitive diagnosis. Nevertheless, 57.6% of patients showed partial or complete recovery with corticosteroid therapy, and 66.7% of treated patients avoided long-term dialysis dependency. This favorable response may reflect patient selection based on histopathological features, including lower degrees of interstitial fibrosis and tubular atrophy, fewer globally sclerosed glomeruli, and the presence of eosinophilic and lymphocytic infiltrates, features commonly associated with drug-induced AIN and better prognosis.³⁸ Importantly, our study also highlights the role of corticosteroids in metabolic AIN, where crystal-induced inflammation may be reversible. Among patients with metabolic AIN, 70% recovered kidney function, and 20% became dialysis-independent following corticosteroid therapy. Despite a substantial proportion of patients having diabetes and delayed presentation, corticosteroid use was associated with improved kidney and patient survival without increasing mortality.

The major strengths of this study are a large cohort of biopsy-proven AIN cases and long-term follow-up, with insight into outcomes following corticosteroid therapy. Limitations include its retrospective design, lack of standardized criteria for steroid initiation, incomplete documentation of alternative medicine constituents, and delayed presentation, limiting assessment of early treatment effects. Immune checkpoint inhibitor–associated AIN is common^39,40, and was an unusual finding in the present study due to the limited development of medical oncology services at the institute.

In conclusion, drugs remain the leading cause of AIN, with alternative medicines emerging as a major contributor. Kidney biopsy is essential for accurate diagnosis and therapeutic decision-making, particularly when clinical features are nonspecific. Corticosteroid therapy facilitates kidney recovery, dialysis-free survival, and improved patient outcomes, even when initiated late. Consideration of geographical, cultural, and social factors is crucial for identifying causative agents, and early histopathological evaluation may guide timely initiation of therapy.