1. Acute interstitial nephritis
Department of nephrology
R3 김슬기/prof 이태원

2. INTRODUCTION 
‘Cellular and fluid exudation in the interstitial tissue...’
Councilman in 1898
kidneys of patients dying of scarlet fever and diptheria
organs were sterile  allergic-type phenomenon
Incidence
Asymptomatic Finnish army recruits
: hematuria or proteinuria (+)  0.7 per
Pettersson E et al. Clin Nephrol 1984; 22:217–222
109 patients from a large centre
: unexplained renal impairment with normal sized kidneys
 29 of 109 (27%) cases
Farrington K et al. Q JMed 1989; 70: 221–233
was described by Councilman in 1898 when he examined the kidneys of patients dying of scarlet
fever and diptheria
Acute interstitial nephritis (AIN) is characterized by the
presence of inflammatory infiltrates and edema within the interstitium,
usually associated with an acute deterioration in renal function.
AIN represented 1–3% of all renal biopsies in some studies

3. ETIOLOGY Review of three series with a total of 128 patients Etiology
Review of three series with a total of 128 patients
Etiology
Distribution
Drugs
71 %
Infection-related
15 %
Idiopathic
8 %
Tubulointerstitial
nephritis and uveitis
(TINU) syndrome
5 %
Sarcoidosis
1 %
Kidney International (2010) 77, 956–961
Baker RJ et al.Nephrol Dial Transplant. 2004;19(1):8
A review of three series with a total of 128 patients reported the following distribution of
causes of acute interstitial nephritis
Drugs, with antibiotics responsible for one-third of these cases (특히 beta lactam)
SLE, sjogren 도 가능.
Drug-induced AIN
not dose-dependent phenomenon
recurrence or exacerbation can occur with a second exposure to
the same drug
Schubert C et al. Clin Nephrol. 2010;73(6):413

4. anti-tubular basement membrane (TBM) antibodies
Kidney International, Vol. 60 (2001), pp. 804–817
Possible mechanism
stimulation of chemokine release by the pathogen→ infiltration of leukocytes
anti-tubular basement membrane (TBM) antibodies
→ linear staining on immunofluorescence microscopy
Giuseppe andres et al.Kidney International. Vol. IJ (1978), pp,
Fig. 1. Mechanisms whereby a drug (or one of its metabolites) can induce acute interstitial
nephritis (AIN).
The drug can bind to a normal component of the tubular basement membrane (TBM) and act as a hapten.
(B) drug can mimic an antigen normally present within the TBM or the interstitium and induce
an immune response that will also be directed against this antigen.
(C) The drug can bind to the TBM or deposit within the interstitium and act as a planted (“trapped”)
antigen.
(D) The drug can elicit the production of antibodies and become deposited in the interstitium
as circulating immune complexes.
T-cells may have an important pathogenetic role
timeframe of illness presentation, 10 to 14 days after exposure to the drug
interstitial infiltrate is primarily of lymphocytes
most patients demonstrate activation of lymphocytes against drug haptens
Spanou Z et al. J Am Soc Nephrol 17: 2919–2927, 2006

5. A 대문자: m/c involved (B granulomatous AIN 유발 약제)
there are two criteria that must be met to have any confidence of an association for drugs not known to cause AIN
:the patient must not be taking other drugs that might cause the disease
; and a renal biopsy must be performed to confirm that AIN is the cause of the renal failure.
common with methicillin, occurring in up to 17 percent of patients who have been treated for more than 10 days. Galpin JE et al.Am J Med. 1978;65(5):756. Methicillin is no longer available in the United States.
only rare cases have been described with other H-2 blockers such as ranitidineㄻ
famotidine
Kidney International, Vol. 60 (2001), pp. 804–817

6. Drugs
Too large to list , however, only a few have been reported with any frequency
Two criteria . Drugs cause AIN:
- must not be taking other drugs
renal biopsy must be performed to confirm that AIN
AIN was particularly common with methicillin, occurring in up to 17 %of patients who have been treated for more than 10 days.
Currently, the most common drug causes of AIN include
NSAIDs, including selective COX-2 inhibitors
Penicillins and cephalosporins
Rifampin
Sulfonamides, (TMP-SMP), furosemide, bumetanide, thiazide-type diuretics
Ciprofloxacin, perhaps to a lesser degree, other quinolones
Cimetidine(only rare cases have been described with other H-2 blockers such as ranitidine)
Allopurinol
Proton pump inhibitors(omeprazole, lansoprazole)
Indinavir
5-aminosalicylates (eg, mesalamine)
Drugs — The number of drugs associated with AIN is too large to list in this topic review; however, only a few have been reported with any frequency. There are many case reports and letters to the editor describing an association between a particular drug and AIN. Since rechallenge to prove a cause-and-effect relationship is not an ethical approach, there are two criteria that must be met to have any confidence of an association for drugs not known to cause AIN: the patient must not be taking other drugs that might cause the disease; and a renal biopsy must be performed to confirm that AIN is the cause of the renal failure. Many case reports lack one or both of these features.
AIN was particularly common with methicillin, occurring in up to 17 percent of patients who have been treated for more than 10 days [4,10,11]. Methicillin is no longer available in the United States.
Currently, the most common drug causes of AIN include [1-3,11-19]:
NSAIDs, including selective COX-2 inhibitors (see "NSAIDs: Acute kidney injury (acute renal failure) and nephrotic syndrome").
Penicillins and cephalosporins
Rifampin
Sulfonamides, including trimethoprim-sulfamethoxazole and, much less often, furosemide, bumetanide, thiazide-type diuretics
Ciprofloxacin and, perhaps to a lesser degree, other quinolones
Cimetidine (only rare cases have been described with other H-2 blockers such as ranitidine) [20,21]
Allopurinol
Proton pump inhibitors, omeprazole and lansoprazole
Indinavir
5-aminosalicylates (eg, mesalamine) (see "Sulfasalazine and 5-aminosalicylates in the treatment of ulcerative colitis")

7. CLINICAL PRESENTATION
onset
: from 3-5 days with a second exposure to the offending agent
to as long as several weeks to many months with a first exposure
latent period : rifampin -one day, NSAID -18 months
N Engl J Med. 1984;310(9):563.
symptoms, and signs and features of acute renal dysfunction
: nausea, vomiting, malaise
symptoms and/or signs of an allergic-type reaction
: review of three series with a total of 128 patients
symptoms or signs
distribution
Rash
15%
Fever
27%
Eosinophilia
23%
Triad of rash, fever,
and eosinophilia
10%
However, the latent period may be as short as one day with rifampin or as long as 18 months with a
NSAID. N Engl J Med. 1984;310(9):563.
review of three series that totaled 128 patients with AIN (of whom 70 percent had drug-induced disease)
,these findings of a typical allergic response were relatively less common at presentation.
A similar incidence of findings was reported in a second retrospective study of 60 cases [31].
In this single center study, rash, fever, eosinophilia, and the triad were observed in 21, 30, 36, and less
than 10 percent of cases, respectively.
Thus, the classic triad is currently less commonly observed.
This is probably due to the absence of cases of methicillin-induced AIN,
and (perhaps) the increased inclusion of cases not directly resulting from an allergic response [9].
Baker RJ et al.Nephrol Dial Transplant. 2004;19(1):8

8. CLINICAL PRESENTATION
Charles M et al.Am Fam Physician2003;67:252734,2539
granular and epithelial cell casts and free epithelial cells in acute tubular necrosis
; red cell casts as well as red and white cells in acute glomerulonephritis
; and few if any abnormalities in prerenal disease
cf. RBC cast 는 GN 보다 rare
FeNa 는 대개 1이상 (tubule damage 때문에) but nonoliguric ARF 나 심하지 않은 ARF 에선 1미만일수도.
21. Ranitidine-associated interstitial nephritis and Fanconi syndrome.
(그림) A. white blood cell cast, three-quarters of which is filled with leukocytes
B. White cell cast in which blue stained white cells (arrow) are contained within a granular cast.
C. Eosinophiluria by Hansel's Stain (Panel A) and Wright's Stain (Panel B) (x1000) A B C
N Engl J Med Dec 11;315(24):1516-9

9. CLINICAL PRESENTATION
Total of 121 patients
mean protein excretions -0.9±1.1 g/day (range 0-6 g/day)
median protein excretions g/day (interquartile range g/day)
Concurrent nephrotic syndrome d/t MCD and MN
with NSAIDs, ampicillin, rifampin, ranitidine, interferon
However, occasional patients have a bland sediment with few cells or casts .
Arch Intern Med. 1993;153(10):1258
Thus, a relatively normal urinalysis should not exclude the diagnosis
* Eosinophiluria is considered to be present when eosinophils account for more than 1 % of urinary white
cells by Hansel's stain
In general, however, urinary eosinophils lack the specificity and sensitivity to either exclude or diagnose
acute interstitial nephritis 4. Kidney Int. 2001;60(2):804.
RPGN, renal atheroemboli 에서도 Eosinophiluria 가능!
degree of variability of protein excretion is demonstrated in two retrospective series
- a total of 121 patients and demonstrated mean and median protein excretions of 0.9±1.1 g/day
(range 0-6 g/day)
g/day (interquartile range g/day) [31,34
Concurrent nephrotic syndrome due to minimal change disease or membranous nephropathy can rarely be seen with NSAIDs, and in selected cases induced by ampicillin, rifampin, interferon, or ranitidine
estimated sensitivity of
eosinophiluria was 67%
and specificity was 83%
Je´roˆme Rossert et al. Kidney International, Vol. 60 (2001), pp. 804–817

10. DIAGNOSIS Suspected from the history and laboratory findings
Confirmed by renal biopsy
- interstitial edema
- marked interstitial infiltrate
: T lymphocytes ,monocytes, eosinophils, plasma cells, neutrophils
- tubulitis : inflammatory cells invade the tubular basement membrane
- granuloma formation A B
(LM Low power view) diffuse interstitial inflammatory infiltrate. One normal glomerulus
(High power LM ) diffuse interstitial infiltrate of inflammatory cells (Rt) uninvolved glomerulus (Lt)
Gallium scan 
- role of gallium scanning in drug-induced AIN is incompletely defined.
- Affected patients typically show diffuse, intense, bilateral uptake,
consistent with the interstitial inflammatory infiltrate clin Nephrol 1985 Aug;24(2):84-7.
- gallium scan is almost always negative in acute tubular necrosis, which is the condition that most
often must be differentiated from drug-induced AIN.
 Thus, a positive gallium scan is suggestive of AIN in the presence of the characteristic findings.
However, a negative scan does not preclude the diagnosis, since false negative results can be seen
[43].

11. Histology C D E
c.(LM,H&E stain)diffuse interstitial infiltrate with red-staining eosinophils. uninvolved glomerulus is on Lt
c.(High power,LM)diffuse interstitial infiltrate of mononuclear cells, many of which are
actively invading the tubules leading to disruption of the tubular basement membranes (arrows).
A white cell cast is present in the tubule in the upper right corner
E.(LM) granulomatous change in acute interstitial nephritis.
interstitial infiltrate is seen on the left, while the granuloma is on the right.
The granuloma consists of both giant cells (arrows) and epithelioid cells with abundant cytoplasm
which has an amorphous red appearance.
Although these findings are characteristic of sarcoid involvement in the kidney, they can be seen with
any cause (drug or infection) of acute interstitial nephritis.
Immunohistochemical staining
increased cellular infiltrates, which consistedmostly of CD4 (A) and CD8 (C) T cells, were detected in the
interstitium together with neutrophils (E)

12. PROGNOSIS Review of three series with a total of 128 patients
Prognostic indicators (controversial)
long-term outcome is worse if renal failure lasts for >3 weeks
Laberke HG et al. Clin Nephrol 1980; 14: 263–273
worse prognosis with increasing age
Kida H et al.Clin Nephrol 1984; 22: 55–60
degree of tubular atrophy
cellular infiltration (patchy VS diffuse)
degree of interstitial fibrosis
final serum creatinine concentration did not correlate with the
maximum value during AIN
64.1%
full recovery (creatinine <132 mmol/l)
23.4%
partial recovery (creatinine>132 mmol/l)
12.5%
remained on renal replacement therapy
Richard et al. Nephrol Dial Transplant (2004) 19
proportion recovering kidney function appears to be lower in AIN due to drugs other than methicillin.
prognosis of AIN due to other inciting factors (eg, sarcoidosis, infection) is not well described.
Prognostic factor 를 정립하려는 많은 연구가 있지만….
renal failure lasts for >3 weeks not useful prospectively
worse prognosis with increasing age no correlation with peak creatinine concentration
information from the renal biopsy  controversial
These conflicting observations may be due to the patchy nature of the disease and the
random sampling on renal biopsy.
The infiltrate is generally most prominent at the corticomedullary boundary,
and the medulla is relatively spared
Laberke HG et al.Clin Nephrol 1980;14: 263–273
Kidney International, Vol. 60 (2001), pp. 804–817

13. The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis
Biomarkers for acute kidney injury
such as kidney injury molecule-1 (KIM-1) and urinary neutrophil gelatinase-associated lipocalin (NGAL)
may provide additional prognostic information but are not used clinically for this purpose at this time
16. Biomarkers. 2009;14(6):423
17. Kidney Int. 2009;75(3):285.
Schwarz A et al.Clin Nephrol. 2000;54(3):179

14. MANAGEMENT Most physicians in the absence of severe disease,
begin by observing the response to discontinuation of the suspected
offending drug.
- one study in which 17 of 27 patients with biopsy-proven AIN
spontaneously improved with drug withdrawal and conservative measures
Buysen JG Nephrol Dial Transplant. 1990;5(2):94
No further evaluation or therapy may be required if renal function
begins to rapidly improve within several days to a week after drug
withdrawal.
Indications for biopsy
uncertainty as to the diagnosis
advanced renal failure
lack of spontaneous recovery following cessation of drug therapy
when early corticosteroid therapy is contemplated

15. Immunosuppressive therapy
To treat AIN that persists despite discontinuation of the offending agent
Benefits of therapy are inconclusive (no randomized controlled trials)
Retrospective multicenter study effects of steroids on the recovery
- lower percentage of dialysis by 18 months (4 vs 44 %)
- lower serum creatinine level (2.1 vs 3.7 mg/dL)
complete recovery
incomplete recovery
Several uncontrolled reports improvement in kidney function following glucocorticoid therapy for AIN
A retrospective multicenter study examined the effects of steroids on the recovery of renal function in
52 patients with biopsy-proven drug-induced AIN compared to nine untreated patients with AIN
Despite the low number of control patients, significant benefits with steroids included a
lower percentage of dialysis by 18 months (4 vs 44 %)
lower serum creatinine level (2.1 vs 3.7 mg/dL)
Among treated patients, those who started steroids within seven days of withdrawal of the offending drug were significantly more likely to recover renal function than those who received steroids after this period
(odds ratio 6.6, 95% CI ).
표)Patients with DI-AIN due to NSAIDs treated with steroids
1a, complete recovery of baseline renalfunction. NSAIDs-Group
1b, incomplete recovery.
González E et al.Kidney Int. 2008;73(8):940

16. Immunosuppressive therapy
Consider corticosteroids if they do not have significant improvement in
the serum creatinine within 3~7 days after discontinuation of the
offending agent.
prednisone  1mg/kg per day (to a maximum of 40~60 mg) for a
minimum of 1~2 weeks
 beginning a gradual taper after the serum creatinine has returned
to or near baseline (most patients will improve in the first 1~2 weeks)
 for a total therapy duration of 2~3 months
More severe acute renal failure
 therapy may be initiated with intravenous methylprednisolone
(0.5~1 g/day for 3days)
corticosteroids therapy is reasonable for potential for benefit and the relative
safety of short-term therapy, if they do not have significant improvement in the
serum creatinine within 3~7 days after discontinuation of the offending agent.
An empiric trial of glucocorticoid therapy is a reasonable alternative in patients with a strongly suggestive history of acute drug-induced AIN when kidney biopsy is not feasible
The optimal dose and duration of therapy are unclear.

17. Immunosuppressive therapy
glucocorticoid-dependent (ie, relapse during the prednisone taper)
glucocorticoid-resistant (as with NSAID-induced disease)
cannot tolerate glucocorticoids
Largest reported experience included 8 patients with biopsy-proven AIN
Glucocorticoids for at least 6 months and could not discontinue therapy
MMF was given for 13 to 34 months
Cr 2.31.6 (only 2 patients had no improvement in serum creatinine)
All were able to discontinue corticosteroids
only 2 patients had no improvement in serum creatinine
(one who was ANCA-positive and one with AIN of unknown etiology).
The applicability of these results to drug-induced AIN is limited, since only two patients had AIN known to be due to drugs.
MMF may be considered only in patients who are glucocorticoid-dependent, glucocorticoid-resistant,
or unable to tolerate glucocorticoid therapy and have biopsy-proven AIN.
Preddie DC et al.Clin J Am Soc Nephrol. 2006;1(4):718

18. The merits of immunosuppressive agents, specifically
cyclophosphamide or cyclosporine, are even less certain.
They can be used as steroid-sparing agents and should be considered
for patients who fail to respond to a 2-week course of steroid therapy.
4-week course of cyclophosphamide (2 mg/kg of body weight per day)
while renal function and white blood cell count are monitored
should suffice to determine response.
Therapy for longer than 4 to 6 weeks is not indicated.
Brenner and Rector's The Kidney, 9th ed Saunders pp1343
anecdotal use of cyclophosphamide
(Drug rash with eosinophilia and systemic symptomes)
Case of vancomycin induced DRESS syndrome with acute in terstitial nephritis.
No improvement after withdrawal of the offending agent and empiric
corticosteroid use.
After tapering the steroids, a five-day course of cyclosporine (100 mg bid)
was followed by resolution of the skin rash and recovery of renal function.
Zuliani E et al.Clin Nephrol. 2005;64(2):155

20. Results : Acute TIN was identified in 24 (8. 1%) biopsies
Results : Acute TIN was identified in 24 (8.1%) biopsies. Eight out of 14 cases with presumed drugrelated TIN could be attributed to the proton pump nhibitors omeprazole and lansoprazole. Conclusion. :Drugs are the most common cause of interstitial nephritis in the population studied. Those drugs most commonly associated with interstitial nephritis were the proton pump inhibitors omeprazoleand lansoprazole

21. 25 published reports of AIN associated with H2 antagonists:
20 cases with cimetidine, 4 with ranitidine, and 1 with famotidine (table I).
They developed AIN between 2 days and 11 months
The diagnosis of AIN was confirmed by renal biopsy in 18 cases.

22. 25 published reports of AIN associated
with H2 antagonists: 20 cases with cimetidine,
4 with ranitidine, and 1 with famotidine (table I).
They developed AIN between
2 days and 11 months after commencing H2 antagonist therapy.
The diagnosis of AIN was confirmed by renal
biopsy in 18 cases.