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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2019  |  Volume : 30  |  Issue : 1  |  Page : 157-165
Steroid therapy in drug induced acute interstitial nephritis- Retrospective analysis of 83 cases


1 Department of Nephrology, Nizams Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Pathology, Nizams Institute of Medical Sciences, Hyderabad, Telangana, India

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Date of Submission02-Apr-2018
Date of Decision19-Jul-2018
Date of Acceptance23-Jul-2018
Date of Web Publication26-Feb-2019
 

   Abstract 


Drug-induced acute interstitial nephritis (DIAIN) is a common cause of acute deterioration of renal function. Early diagnosis and discontinuation of the offending drug usually lead to recovery of renal function. Steroid administration further hastens the recovery. However, the outcome of steroid-treated DIAIN is not well studied in the Indian scenario. We aimed to study the clinical profile and one-year renal outcome of DIAIN patients treated with steroids. We performed a retrospective study in biopsy-proven acute interstitial nephritis (AIN) and presumptive DIAIN patients who did not respond to discontinuation of the offending drug after five days of the diagnosis of AIN. Eighty-three DIAIN patients were included who were treated with 500 mg of methylprednisolone for three consecutive days followed by prednisolone of 0.5–1 mg/kg tapered over four to six weeks. We evaluated clinical profile, serum creatinine (SCr), and need of renal replacement therapy at the end of one year. We divided the patients into two groups: 1st as complete responders group (CR) when SCr is <1.5 mg/dL at the end of one year and 2nd as incomplete responders (IR) when it is ≥1.5 mg/dL and evaluated the outcome between two groups. In total, there were 39 (47%) CR and 44 (53%) were IR. Diabetes mellitus, present in a significant number of cases 27 (33%) was associated with poor response to steroids. Most common offending agents recognized were antibiotics (34%), nonsteroidal anti-inflammatory drugs (25%), herbal medications (13%), proton pump inhibitors (10%), and miscellaneous drugs (18%). There was no correlation between drug category and response to steroids. Interstitial fibrosis in renal biopsy was associated with poor response to steroids (4 cases in CR and 35 cases in IR, P ≤0.0001). Neutrophilic predominance in biopsy was associated with favorable response to steroids. Initial SCr and initial the requirement of dialysis support was not helpful in predicting the response to steroids and final recovery.

How to cite this article:
Surendra M, Raju S, Chandragiri S, Uppin MS, Raju N. Steroid therapy in drug induced acute interstitial nephritis- Retrospective analysis of 83 cases. Saudi J Kidney Dis Transpl 2019;30:157-65

How to cite this URL:
Surendra M, Raju S, Chandragiri S, Uppin MS, Raju N. Steroid therapy in drug induced acute interstitial nephritis- Retrospective analysis of 83 cases. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 19];30:157-65. Available from: http://www.sjkdt.org/text.asp?2019/30/1/157/252906



   Introduction Top


Acute interstitial nephritis (AIN) is an immunemediated cause of acute renal failure characterized by the presence of an inflammatory cell infiltrate in the interstitium of the kidney. Various etiologies have been identified including allergic or drug-induced, infectious, autoimmune or systemic, and idiopathic forms of the disease.

Drug-induced acute interstitial nephritis (DIAIN) was first described by Councilman in 1898 and now it is the most common cause of AIN.[1] In a 2004 report of pooled data from three large studies, a drug-induced etiology emerged as the most common cause of AIN, underlying 91 of the 128 cases (71.1%). Antibiotics accounted for one-third of these DIAIN cases.[2] The pathogenesis of DIAIN is postulated to involve cell-mediated immunity, and the syndrome is often associated with systemic manifestations of hypersensitivity such as rash, fever, and eosinophilia.[3],[4],[5] As immune-mediated damage is hypothesized, therapy aimed at suppressing the immune response has been the mainstay of treatment for AIN for over four decades. Management of DIAIN primarily involves discontinuation of the offending agent and administration of oral or intravenous corticosteroid therapy.[6],[7] However, results from various studies are conflicting. Whereas some studies have reported a more rapid and complete recovery of baseline renal function in those patients treated with steroids,[8],[9] others have failed to confirm these results.[10],[11],[12] In the studies that showed no benefit, patients presented with more severe kidney injury at the time of biopsy and steroids appeared to be administered later in the course of the disease as compared with the favorable studies. However, majority of reviews continued to advocate the use of corticosteroid therapy.[13],[14]

Recently, Ramachandran et al from India conducted a randomized controlled trial in DIAIN patients and in this study they compared intravenous pulse methyl prednisolone versus oral steroid therapy in 29 patients, but follow-up was very short period of three months.[15] We performed a retrospective analysis of DIAIN in a total of 83 patients who were treated with steroids and we assessed the clinical profile and outcome of renal function and need of renal replacement therapy (RRT) at the end of one year.


   Subjects and Methods Top


We performed a retrospective analysis of patients with biopsy-proven AIN and presumptive DIAIN who received steroid therapy. Patients who were admitted with acute deterioration of kidney function presumed to be secondary to drug intake and underwent renal biopsy between August 1, 2013 and July 31, 2015, and whose biopsy showed features of AIN were enrolled. Only those patients with documented normal base line serum creatinine (SCr) (<1.2 mg%) in the preceding 12 months were enrolled. The offending drug was withdrawn and waited for five to seven days for any spontaneous improvement. If SCr did not improve from baseline, steroids were administered at the dose of 500 mg intravenous methyl prednisolone for three consecutive days followed by oral prednisolone of 0.5–1 mg/kg/day tapered over four to six weeks. Those patients who received steroids according to the above-mentioned protocol were included in the study after satisfying inclusion and exclusion criteria.

Detailed clinical history with special reference to drug exposure, symptoms such as fever, rash, arthralgia, the presence of oliguria, hematuria, and proteinuria were recorded. Appropriate laboratory investigations data were noted. Light microscopy and immunofluorescence were carried on all kidney biopsy tissue. Same pathologist examined all the renal biopsies. Their follow-up data were collected through outpatient records.

We studied clinical profile, dialysis requirement, SCr at the end of one year.

Inclusion criteria were as follows: age 18–80 years and administration of steroids according to the protocol mentioned. Only those diabetes mellitus patients with pure AIN histology without any associated diabetic nephropathy changes were included in the study and in our institute in all diabetes patients with renal dysfunction we perform protocol biopsies.

Exclusion criteria were patients <18 years of age, previously diagnosed with CKD and now presenting as acute on CKD, pregnant women, patients already on steroids, any contraindication to steroid administration, any other etiology for AIN other than DIAIN and if the biopsy showed associated diabetic nephropathy changes in addition to AIN.

Complete responders (CRs) were defined as improvement of SCr to <1.5 mg/dL at the end of one year.

Incomplete responders (IR) if it is ≥1.5 mg/dL at the end of one year. Oliguria was defined as 24-h urine output <400 mL. Eosino-philuria was defined as >1% eosinophils in the urine among all leukocytes and eosinophilia was defined as eosinophils >500/mm.[3]


   Statistical Analysis Top


Online program available at vassarstats.net for analysis of results. All the results were expressed as the mean ± standard deviation for continuous variables. Responders (complete and incomplete) in both the groups were compared using the Chi-square test.

Student's t-test was used to compare the SCr, proteinuria. P <0.05 was considered statisticcally significant. Per-protocol analysis was used for statistical analysis.


   Results Top


Out of 108 biopsies of AIN who received steroids, 92 patients satisfied inclusion criteria for DIAIN. A total of 83 patients' data were available for the final analysis [Table 1].
Table 1: Baseline parameters of the study population.

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Numbers of patients in CR group were 39 (47%) patients and in IR were 44 (53%) patients [Table 2]. At the time of admission, there was history of fever in 31 (38%) patients, skin rash in nine (10%) patients, arthralgia in 11 (13%) patients, triad of these clinical features in only four patients and oliguria in 11 (13%) patients. Eosinophilia was seen in eight (9%) patients, eosinophiluria was seen in three (4%) patients and microhematuria was seen in 20 (24%) patients.
Table 2: Comparison of the parameters among complete responders and Incomplete responders.

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Overall, antibiotics were the most common offending agents. In 28 patients, antibiotics were the culprit (penicillin - 10, cephalosporin - 4, sulfonamides - 3, quinolones - 8, and -rifampicin - 3) followed by nonsteroidal anti-inflammatory drugs (NSAID) in 21 patients, proton pump inhibitors (PPI) in eight patients, herbal medicinal intake in 11 patients and other drugs (phenytoin - 4, diuretics - 3, allo- purinol - 3, unknown drugs but with definite history of recent drug intake - 5). There was no correlation between the category of drug and clinical or laboratory parameters and also no correlation with outcome.

Mean baseline SCR of the patients before AKI was 0.92 ± 0.18 mg/dL. Mean baseline SCr of the patients before AKI in CR group was 0.94 ± 0.17 mg/dL and in IR group was 0.9 ± 0.19 mg/dL (P = 0.32). Mean baseline SCr of the patients at admission was 5.4 ± 3.6 mg/dL Mean baseline SCr of the patients in CR group was 5 ± 3.7 mg/dL and in IR group was 5.8 ± 3.4 mg/dL (P value 0.33). Of all 27 diabetic patients, seven patients showed CR and 20 patients showed IR (P = 0.01) and thus diabetes is a bad prognostic factor for predicting the final outcome. Mean HbA1C levels between two groups were 7.5 ± 1.2 and 7.7 ± 1.3 (P = 0.47). Thus, glycemic control did not differ significantly between the two groups.

Mean proteinuria in CR group was 0.41 ± 0.55 g/day and in IR group, it was 0.46 ± 0.63 g/day (P = of 0.7). Twenty-two (26%) patients required RRT at the time of admission. Ten patients in CR group and 12 patients in IR group were supported with dialysis at admission (P = 0.82) signifying that initial dialytic requirement is not a prognostic factor for determining the final outcome.

Four patients in CR group and 35 patients in IR group showed interstitial fibrosis in the renal biopsy (P <0.0001) indicating fibrosis in renal biopsy at admission is a significant bad prognostic marker for final outcome. In CR group, two of four patients had mild fibrosis and two patients had moderate fibrosis. In IR group, 31 patients had moderate (n = 17)/severe fibrosis (n = 14).

All of 83 biopsy samples showed lymphocytic infiltrate. Neutrophilic infiltration was predominant in 30 biopsies in CR group and 21 biopsies in IR group (P = 0.01) and thus, neutrophilic infiltration in biopsy is a good prognostic factor for final outcome. Eosinophils were seen in 25 biopsies in CR group and 22 biopsies in IR group (P = 0.28).

At the end of one year, SCr in CR group was 1.1 ± 0.2 mg/dL and in IR group was 4.7 ± 2.9 mg/dL. A total of five (11.3%) patients in IR group progressed to end-stage renal disease (ESRD) at the end of one year indicating that in those patients who are not responding to steroids, chances of progression to ESRD is seen in a significant number of cases. Only one patient is dialysis dependent since admission and remaining four patients were declared as ESRD in due course and none of these four patients received RRT at the initial admission and three of these five patients were diabetic patients.


   Discussion Top


To the best of our knowledge, this is one of the largest studies related to DIAIN treated with steroids. There are at least six large retrospective studies that analyzed the efficacy of steroids in DIAIN. The first study was by Clarkson et al (n = 60).[12] In 2004, the second study was by González et al in 2008 (n = 61) and the third was by Muriithi et al (n = 133).[16],[17] Three other studies were recently published by Raza et al (n = 49), Valluri et al (n = 171),; and Prendecki et al (n = 187).[18],[19],[20] Ramachandran et al from PGIMER, India published a data of 29 patients of DIAIN in 2015.[15] However, response to steroids in these studies is variable and this could be due to delay in the administration of steroids and these patients had severe impairment of renal function [Table 3].[12] We believe that steroid treatment is definitely helpful if administered early in the course of disease evolution as our study showed almost half of the patients are CRs. This is especially important when discontinuation of insulting drug is not yielding favorable outcome.
Table 3: Studies examining the utility of steroids in drug-induced acute interstitial nephritis.

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Incidence of diabetes was not addressed in any of the previous studies and in the present study it is a significant bad prognostic factor; hence, all diabetic patients with DIAIN should be followed closely. Glycemic control did not differ significantly between the two groups. In this study, fibrosis was more common in diabetic patients but in the absence of data about duration of drug intake prior to presentation, the relation between diabetes and prognosis is inconclusive and this finding should be confirmed in further studies. The immunological phenomenon could be different between diabetic and nondiabetic patients and it needs further investigation.

With regard to the etiology, overall antibiotics were the most common offending agent. In 28 (34%) patients, antibiotic was the culprit (Penicillin - 10, Cephalosporin - 4, Sulfonamides - 3, Quinolones - 8, and Rifampicin - 3). In a retrospective study conducted by Muriithi et al in 2014, antibiotics accounted for 49% of DIAIN.[17] In the Ramachandran et al study, antibiotics were accounted for 17.2% of DIAIN. NSAID exposure was documented 21 (25%) patients.[15] In a retrospective study conducted by Muriithi et al in 2014, NSAID accounted for 11% of DIAIN.[17] In the Ramachandran et al study, NSAID were accounted for 31% of DIAIN. PPI exposure is seen in eight (10%) patients. In the retrospective study of Muriithi et al in 2014, PPI accounted for 14% of DIAIN. In the Ramachandran et al study, PPI were accounted for 3.4% of DIAIN. Valluri et al study showed PPIs were responsible for DAIN in 35% of cases and were more frequently implicated than NSAIDS (20%). Herbal medicinal intake was documented in 11 (13%) patients. In the Ramachandran et al study, herbal medicines were accounted for 27.5% of DIAIN. The differences in etiological agents as a cause of DIAIN could be due to the availability of the drugs as over the counter drugs and prescriptions by quacks.

At the time of admission, there was history of fever in 31 (38%) patients, skin rash in nine (10%) patients, arthralgia in 11 (13%) patients, and oliguria in 11 (13%) patients. González et al. reported oliguria in 23%, skin rash in 23%, and fever in 42% of cases. Ramachandran et al reported oliguria in 55.1%, skin rash in 20% and fever in 48% of cases.[15]

Out of 83 patients, 22 (26%) patients required RRT at the time of admission and initial RRT was not correlated with outcome. In the study conducted by Ramachandran et al initial dialytic support was given for 65% of cases and similar to our study, final outcome was not correlated with initial RRT.[15]

In the present study, interstitial fibrosis in renal biopsy is a significant bad prognostic marker for the final outcome and similar findings were observed by González et al and mild fibrosis was associated with favorable outcome.[16] Thus, the severity of fibrosis is associated with poor prognosis as it indicates irreversible damage of renal tissue.

Neutrophilic predominant infiltration was seen in 51 (61%) cases and neutrophilic infiltration in biopsy is a good prognostic factor for final outcome. Ramachandran et al reported neutrophilic infiltrate in 68% of cases and reported favorable outcome. Predominant neutrophilic infiltrate indicates recent onset and ongoing active inflammation. As it is active and ongoing inflammation, could be the reason for better response. Similar observation was found in Ramachandran et al study.[15]

In this study, in IR group five (11.3%) of 44 patients progressed to ESRD at the end of one year (P = 0.02) indicating that in those patients who are not responding to steroids, chances of progression to ESRD is seen in significant number of cases. González et al reported ESRD in two out of 24 cases in IR group and thus, long-term follow-up is important for IR.[16]

Limitations of the present study are that it was a retrospective analysis, had short duration of follow-up and data regarding duration of offending drug intake before presentation was not available which is an important limitation of the present study. The analysis was performed with SCr which is influenced by various parameters and hence calculation based on estimated glomerular filtration rate would give better analysis. Performing a randomized controlled trial with larger sample size, longer duration of follow-up with collection of complete data about duration and dosage of offending drug intake and subjecting the data to multivariate analysis would give practical recommendations.


   Conclusion Top


This study showed that diabetes was associated with poor response to steroids and significant progression of CKD. Initial SCR and initial requirement of RRT were not helpful in predicting the response to steroids and final recovery. Lack of fibrosis and neutrophils predominance in biopsy was associated with favorable response to steroid therapy.

Conflict of interest:

None declared.



 
   References Top

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D'Agati VD, Theise ND, Pirani CL, Knowles DM, Appel GB. Interstitial nephritis related to nonsteroidal anti-inflammatory agents and beta-lactam antibiotics: A comparative study of the interstitial infiltrates using monoclonal antibodies. Mod Pathol 1989;2:390-6.  Back to cited text no. 5
    
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Buysen JG, Houthoff HJ, Krediet RT, Arisz L. Acute interstitial nephritis: A clinical and morphological study in 27 patients. Nephrol Dial Transplant 1990;5:94-9.  Back to cited text no. 9
    
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Bhaumik SK, Kher V, Arora P, et al. Evaluation of clinical and histological prognostic markers in drug-induced acute interstitial nephritis. Ren Fail 1996;18:97-104.  Back to cited text no. 10
    
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Koselj M, Kveder R, Bren AF, Rott T. Acute renal failure in patients with drug-induced acute interstitial nephritis. Ren Fail 1993; 15 : 69-72.  Back to cited text no. 11
    
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Clarkson MR, Giblin L, O'Connell FP, et al. Acute interstitial nephritis: Clinical features and response to corticosteroid therapy. Nephrol Dial Transplant 2004;19:2778-83.  Back to cited text no. 12
    
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Reddy S, Salant DJ. Treatment of acute interstitial nephritis. Ren Fail 1998;20:829-38.  Back to cited text no. 13
    
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Porile JL, Bakris GL, Garella S. Acute interstitial nephritis with glomerulopathy due to nonsteroidal anti-inflammatory agents: A review of its clinical spectrum and effects of steroid therapy. J Clin Pharmacol 1990; 30: 468-75.  Back to cited text no. 14
    
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Ramachandran R, Kumar K, Nada R, Jha V, Gupta KL, Kohli HS. Drug-induced acute interstitial nephritis: A clinicopathological study and comparative trial of steroid regimens. Indian J Nephrol 2015;25:281-6.  Back to cited text no. 15
[PUBMED]  [Full text]  
16.
González E, Gutiérrez E, Galeano C, et al. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int 2008;73:940-6.  Back to cited text no. 16
    
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Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: A case series. Am J Kidney Dis 2014;64:558-66.  Back to cited text no. 17
    
18.
Raza MN, Hadid M, Keen CE, Bingham C, Salmon AH. Acute tubulointerstitial nephritis, treatment with steroid and impact on renal outcomes. Nephrology (Carlton) 2012; 17:748-53.  Back to cited text no. 18
    
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Valluri A, Hetherington L, Mcquarrie E, et al. Acute tubulointerstitial nephritis in Scotland. QJM 2015;108:527-32.  Back to cited text no. 19
    
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Prendecki M, Tanna A, Salama AD, et al. Long-term outcome in biopsy-proven acute interstitial nephritis treated with steroids. Clin Kidney J 2017;10:233-9.  Back to cited text no. 20
    

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Correspondence Address:
Sreebhushan Raju
Department of Nephrology, Nizams Institute of Medical Sciences, Hyderabad - 500 082, Telangana
India
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DOI: 10.4103/1319-2442.252906

PMID: 30804277

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    Abstract
   Introduction
   Subjects and Methods
   Statistical Analysis
   Results
   Discussion
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