Nephrology Reviews 2013; volume 5:e4
Acute interstitial nephritis: etiology, pathogenesis, diagnosis, treatment
and prognosis
Insara Jaffer Sathick,1 Ladan Zand,1 Afrin N. Kamal,2 Suzanne M. Norby,1 Vesna D. Garovic1
1
Department of Medicine, Mayo Clinic, Rochester, MN; 2Department of Medicine, Barnes-Jewish
Hospital, Washington University, St. Louis, MO, USA
Abstract
Acute interstitial nephritis (AIN) is an
important and common cause of acute kidney
injury, particularly in hospitalized patients.
The classic presentation of AIN includes fever,
rash, arthralgias, eosinophilia, and acute kid-
ney injury. While renal biopsy is considered
the gold standard for diagnosis, the clinical
presentation of fever and rash along with lab-
oratory evidence of peripheral blood
eosinophilia, eosinophiluria, and low-grade
proteinuria strongly suggest the diagnosis.
Histologically, interstitial inflammation with
interstitial edema and tubulitis is the hall-
mark of interstitial nephritis. The most com-
mon causative factors are drugs, infections,
and certain immune-mediated disorders.
Discontinuation of the offending agent is con-
sidered the mainstay of therapy while the use
of corticosteroids to hasten renal recovery
may be beneficial. The role of interstitial
nephritis in the pathogenesis of chronic kid-
om
Correspondence: Vesna D. Garovic, Division of
Nephrology and Hypertension, Department of
-c
Medicine, Mayo Clinic, 200 First St SW, Rochester
55905, MN, USA.
on
Tel. +1.507.266.1963 - Fax: +1.507.266.7891.
E-mail: garovic.vesna@mayo.edu
N
Key words: interstitial nephritis, acute kidney
injury, drug-induced acute renal failure.
Contributions: the authors contributed equally.
Conflict of interests: the authors declare no
potential conflict of interests.
Received for publication: 28 November 2013.
Revision received: 12 July 2013.
Accepted for publication: 12 July 2013.
This work is licensed under a Creative Commons
Attribution NonCommercial 3.0 License (CC BY-
NC 3.0).
©Copyright I.J. Sathick et al., 2013
Licensee PAGEPress, Italy
Nephrology Reviews 2013; 5:e4
doi:10.4081/nr.2013.e4
ney disease and end-stage renal disease is
increasingly recognized, further emphasizing
the importance of its early diagnosis and time-
ly treatment.
Introduction
on
Originally described by Councilman in 1898
in The Journal of Experimental Medicine,1
acute interstitial nephritis (AIN) is an impor-
se
tant cause of acute kidney injury (AKI), which
remains a major cause of morbidity and mor-
lu
tality in the United States. At present, under-
lying AIN as a cause of AKI has been implicat-
ed in 5-15% of hospitalized patients admitted
a
for AKI.2 AIN was reported in approximately
ci
1% of renal biopsies performed to evaluate
hematuria or proteinuria in a Finnish study of
er
male military personnel.3 The role of AIN as an
important factor contributing to chronic kid-
m
ney disease (CKD) and subsequent end-stage
kidney disease is increasingly recognized.
The following discussion provides a detailed
review of the definition of AIN, causative
agents and pathological mechanisms, treat-
ment strategies, and long-term prognosis,
along with future research opportunities.
Definition
AIN is defined by its distinctive histological
and functional characteristics. The histologi-
cal hallmark of AIN is an inflammatory
mononuclear cell infiltrate, often with numer-
ous eosinophils, in the renal interstitium,
with associated edema. Tubulitis may also be
present.4 Councilman’s original description
from 1898 was an acute inflammation of the
kidney characterized by cellular and fluid exu-
dation in the interstitial tissue.1 Injury occurs
primarily within the renal tubules and inter-
stitium, which represent 80% of renal vol-
ume.4 At advanced stages, however, it may be
difficult to distinguish interstitial nephritis
clinically from other causes of renal failure.5
The infiltrative lesions can be patchy or dif-
fuse and are most prominent in the deep cor-
[Nephrology Reviews 2013; 5:e4]
tex and the outer medulla.2 The inflammatory
cell infiltrate primarily consists of T lympho-
cytes and monocytes/macrophages, with vary-
ing numbers of eosinophils, plasma cells, neu-
trophils, and non-caseating granulomas.2 The
ratio between CD4+ and CD8+ T cells in the
interstitial infiltrates varies among patients,
ly
likely affected by the type of offending agent
and patient genetics. T lymphocytes may
cross the tubular basement membrane (TBM)
and migrate between tubule cells, causing
tubulitis.6 Most commonly, the inflammatory
cell infiltrate is localized to the renal tubules
and interstitium, rarely disturbing the
glomeruli and/or vasculature. In addition to
cellular infiltration and interstitial edema,
tubular lesions varying from mild cellular
changes to widespread epithelial cell necrosis
with disruption of the basement membrane
can be found predominantly near areas of
intense inflammatory infiltrates.6 These
inflammatory infiltrates are powerful fibro-
genic stimuli due to interstitial fibroblast
activity and extracellular matrix production.
Evidence of fibrogenesis may be detected as
early as seven days after the development of
interstitial inflammation. As a result, substan-
tial permanent damage manifested by inter-
stitial fibrosis and diffuse tubular atrophy may
occur.7
Clinical features
AIN has a rapid onset, with laboratory evi-
dence of AKI, such as elevated blood urea
nitrogen (BUN) and creatinine along with
proteinuria, sterile pyuria, and hematuria.
Peripheral blood eosinophilia and eosinophil-
uria may also be noted. Presenting symptoms
are variable, ranging from asymptomatic to
non-specific symptoms such as nausea, vomit-
ing, malaise, arthralgias, and flank pain, to a
generalized hypersensitivity syndrome, mani-
festing as fever, maculopapular rash,
eosinophilia, and renal failure.2 Hypersen-
sitivity symptoms are common in drug-
induced AIN. In a retrospective series of 128
patients with AIN in which 70% of cases were
[page 13]
Review
determined to be drug-induced, 15% of
patients presented with rash, 27% with fever,
and 23% with eosinophilia, while the triad of
rash, fever, and eosinophilia was present in
only 10% of patients.8 Acute initiation of dialy-
sis was needed in approximately 58% of
patients in one series, with creatinine values
averaging 670 μmol/L upon presentation.9
Compared to glomerular diseases, patients
with AIN tend to have lower blood pressures,
less edema, and lower risk of progression to
CKD.4 Differentiating between interstitial
nephritis and glomerular diseases as etiolo-
gies of AKI relies on the absence of signs of
glomerular injury in the former and the pres-
ence of either nephrotic range proteinuria
(>3.5 g/day) or nephritic features such as
hematuria with red blood cell casts in the lat-
ter. Conversely, interstitial nephritis typically
presents with mild proteinuria (<1.0 g/day)
and sterile pyuria with white blood cell casts.4
Eosinophiluria may be present but is a non-
specific finding. Urinalysis demonstrates signs
of renal tubular dysfunction, with low specific
gravity, high pH, and glycosuria in conjunction
with symptoms of polyuria and nocturia.
Reduced acid excretion and proximal tubular
bicarbonate wasting in AIN lead to metabolic
acidosis.
Causes of acute interstitial
nephritis
The different causes of AIN can be catego-
rized into 3 groups: drug-induced, infection-
om
related, and immune complex-mediated. All
three groups will be discussed in the following
sections.
-c
on
Drug-induced acute interstitial
N
nephritis
Drugs, particularly antibiotics, are the most
common etiology of AIN. Over fifty medications
have been reported to cause AIN, but the over-
all drug-specific incidence still remains low.10
Drug-induced interstitial nephritis is currently
considered to be allergic in nature, resulting in
immune-mediated injury. This is further sup-
ported by the lack of correlation between drug
dose and incidence, recurrence of symptoms
after the second exposure to the same or a
related medication, and the presence of
extrarenal manifestations of hypersensitivity.
Both endogenous renal antigens and non-
renal antigens can induce damage. The offend-
ing drug may either work as a hapten or
behave as a renal antigen. After either oral or
parenteral administration, drug components
[page 14]
may get trapped in the renal interstitium,
behaving as antigens and triggering local
immune responses. Animal models offer clues
to test this hypothesis. After immunization
with different renal TBM components and
endogenous renal proteins (such as Tamm-
Horsfall protein, uromodulin), mice, rats, rab-
bits, and guinea pigs all demonstrated AIN.11
Additional supporting evidence is provided by
experiments in rabbits treated with bovine
serum albumin; their respective renal sections
demonstrated the presence of antigens and
granular deposits of immunoglobulins and
complement C3 within the interstitium, at the
basal aspect of interstitial capillaries, and
along the TBM. Similarly, pre-sensitized rats
and guinea pigs injected with aggregated
bovine gamma globulin demonstrated intersti-
tial damage through a delayed-type hypersen-
sitivity reaction. Trapping of globulins in the
interstitium, similar to human drug-induced
AIN, may explain these findings.11 The
on
immune reaction in AIN can consist of either
cell-mediated or antibody-mediated immunity.
In humans, the injury in drug-induced AIN is
mainly cell-mediated.6 By applying monoclonal
se
antibodies directed towards particular mem-
brane antigens on renal biopsy, immunofluo-
lu
rescence and biotin-avidin-peroxidase
revealed predominantly a T-lymphocyte infil-
a
tration. In a 1989 study performed by Cheng et
al., tubular cross-sections of 28 biopsies were
ci
taken from 27 patients with tubular interstitial
er
nephritis and then compared to 7 controls
taken from normal donor kidneys and patients
m
with minimal change nephropathy. In patients
affected with AIN, up to 1500 leukocytes per
100 tubules were detected, comprised of T lym-
phocytes and monocytes/macrophages. Control
biopsies, however, displayed fewer than 50
cells per 100 tubules.12 T cells may contribute
to renal injury by either delayed hypersensitiv-
ity and/or direct cytotoxicity. The former uti-
lizes a greater proportion of primed CD4+ cells
(T-helper) and monocytes to mediate injury. In
cytotoxicity, CD8+ cells release perforin and
granulysin, which instigate apoptosis within
cells. The less common cell-mediated cytotoxi-
city through natural killer cells causes cell lysis
leading to interstitial nephritis. Although all
three routes of injury have been demonstrated,
delayed hypersensitivity mediated by CD4+
cells appears to predominate in AIN.10
The recognition that T lymphocytes signifi-
cantly contribute to the pathogenesis of AIN
has led to research studying the role of the
major histocompatibility complex (MHC).
Under normal conditions, MHC Class I anti-
gens are present in all nucleated cells in the
kidney, while MHC Class II antigens are found
on the vascular endothelium and dendritic
cells in relation to the peritubular capillaries.12
During times of stress, both MHC classes may
be induced and up-regulated. Consequently,
[Nephrology Reviews 2013; 5:e4]
during inflammation, tubular epithelial cells
can be induced by lymphokines to express
MHC Class II antigens.13 This may explain the
finding of increased MHC Class II expression
in all forms of human tubulo-interstitial
nephritis. As these tubular MHC II cells begin
to present antigen to T cells, the activation of
helper/inducer T cells begins with the propaga-
tion of lymphocytes and further activation of
cytotoxic T lymphocytes. Similar events have
been observed in autoimmune thyroiditis and
acute type I insulin-requiring diabetes, leading
to organ damage.12
In addition, a correlation between the anti-
gen HLA-DR and AIN has been shown. Cheng
and colleagues also compared the presence of
the HLA-DR antigen in a group of AIN patients
to the control groups consisting of normal kid-
ney donors and patients with minimal change
nephropathy. Using kappa-IgG2a murine mon-
oclonal antibodies and 2-dimensional gel elec-
ly
trophoresis, HLA-DR was found to be
expressed in a majority of the AIN group.
Moreover, a positive relationship between
HLA-DR expression and the severity of tubular
atrophy and interstitial fibrosis was demon-
strated. Also, a positive association with the
total number of DR-positive cells in the inter-
stitium and tubules was noted (P<0.01). The
study, however, did not demonstrate an associ-
ation between tubular HLA-DR-positive cells
and the total number of leukocytes, T lympho-
cytes, t helper cells/ t suppressor cells ratio,
monocytes, or severity of renal disease based
on plasma creatinine level.12
Although cell-mediated immunity predomi-
nates in AIN, humoral-mediated immunity
may contribute to renal injury as well. A for-
eign antigen (e.g. a drug) can cause a cascade
of reactions to form IgE antibodies (type I
hypersensitivity). These antibodies then bind
to mast cells or basophils, causing them to
release mediators of inflammation, such as
eosinophil chemotactic factors. This mecha-
nism has been seen in cases of tubulo-intersti-
tial nephritis, as demonstrated by high serum
IgE concentrations, peripheral blood
eosinophilia, eosinophiluria, and eosinophils
in the renal interstitium. A type II hypersensi-
tivity reaction can involve anti-TBM antibodies
directed against tissue antigens, instigating
complement activation and chemotaxis.13
However, anti-TBM antibodies are rarely found
in patients’ sera. In these instances, immuno-
fluorescent (IF) staining demonstrates linear
IgG deposition along the TBM. Several medica-
tions that may cause positive IF staining
include methicillin, non-steroidal anti-inflam-
matory drugs (NSAIDs), phenylhydantoin, and
allopurinol.6 For example, case reports of
methicillin-induced AIN have identified anti-
bodies targeting a dimethoxyphenylpenicilli-
noyl hapten in the TBM.10
The inflammatory reaction seen in drug-
 Review

induced AIN is associated with complement
activation, inflammatory and tubular cell inter-
actions, and inflammatory molecule secretion.
Tubular damage is thought to be an important
mechanism of AKI in AIN patients. After tubu-
lar cell lesions develop, inflammatory cells
become attracted to the area. At the same time,
these damaged cells activate and generate pro-
inflammatory chemokines, cytokines, growth
factors, such as platelet-derived growth factor
(PDGF) and transforming growth factor-
(TGF-β), and adhesion molecules. These
cytokines can induce the proliferation of
fibroblasts and/or increase the production of
the extracellular matrix, resulting in renal
injury.4,6
Although the time course varies, drug-
induced AIN generally develops three weeks
after the first, and 3-5 days after the second
exposure. The latent period may range from
hours with rifampin to up to several months
cillin, the hematuria and pyuria resolve rapid-
ly and body temperature returns to normal
after 7-10 days, but renal recovery may take up
to 1.5 months.6 Given the high incidence of
AIN and progression to renal failure, methi-
cillin is no longer available in the United
States.
Non-steroidal anti-inflammatory
drugs
In the current era, NSAIDS have become the
most frequent and clinically relevant cause of
AIN.2 Most individuals who experience NSAID-
induced AIN are older than 50 years and are
chronic users, taking these drugs for weeks,
months, or even years before the reaction
occurs.6,10 Elderly patients are at a particularly
high risk for AIN, as they commonly take
NSAIDs and have underlying co-morbidities
that increase their overall risk.14
An analysis of more than 80 cases showed
that in a large percentage (70%) of individuals,
NSAID-induced AIN is associated with
nephrotic syndrome, with fenoprofen showing
the highest potential to cause the latter.6
Rifampin
Over 100 case reports document nephritis
induced by rifampin, which is frequently used
for the treatment of tuberculosis.6,10 Patients
can develop the disease after short-term use or
intermittent administration, although most
react after long-term therapy.6 Patients develop
fever, headache, chills, oliguria, and dark-col-
ored urine without hematuria, nausea, vomit-
ing, diarrhea, flank pain, rash, and myal-
gias.6,10 Occasionally, thrombocytopenia,
hemolysis, and proliferative glomerulonephri-
tis have been seen.10 The majority of these
patients require acute dialysis, but most

ly
with NSAIDs.13 The effect of medications is not Although all NSAIDS can be pathogenic, although not all, subsequently recover renal
cases have shown that some non-selective function. Unlike methicillin-induced AIN, the

dose-dependent and recurrence can develop
after using the same or a similar class of drug.2
While Table 1 displays all medications reported
to cause AIN, the following discussion will
on
NSAIDS are less toxic than others. Of these, rate of rifampin-induced AIN is equal between
low-dose aspirin (100 mg/day), low-dose males and females.10
ibuprofen (0.2-0.8 g/day), and sulindac have

se
focus on those that are most commonly men- been reported to be safer, as they have fewer
tioned.6 effects on renal prostaglandins.15-18
Infection-induced acute
lu
Nevertheless, all three have been reported to
Methicillin adversely impact renal function.2 interstitial nephritis
a
Among the many drugs that can induce AIN, NSAID-induced AIN develops after an aver-
methicillin-induced nephritis is considered age use of six months, with a presentation In 1898, when Councilman first described
ci

the prototype, and patients display features of similar to methicillin-induced AIN, except for AIN, he associated the disease with an infec-
er

an allergic reaction.2 Most patients develop a the common absence of microscopic hema- tious cause.1 After the emergence and wide-
fever, while rashes and/or arthralgias are less turia and a lower incidence of extrarenal symp- spread use of antibiotics to treat infections,
m

common.6 The majority present with macro- toms (10%). In addition, numerous studies this cause of AIN dramatically declined among
scopic hematuria, pyuria (with or without have reported a trend towards heavier protein- adults, particularly in developed countries. In
om

leukocyte casts), and peripheral eosinophilia. uria (nephrotic range), a lymphocyte-predomi- areas of the world where infectious diseases
Methicillin-induced AIN shows a 2-3:1 male to nant infiltrate, lack of systemic eosinophilia, are still prevalent, infection-induced AIN still
female ratio and is typically seen in older chil- and a less positive outcome compared to AIN occurs. In developed countries, the majority of
-c

dren and young adults.10 After stopping methi- induced by infection or other drugs.2,9 infection-related AIN occurs in children,
on
N

Table 1. Drugs associated with acute interstitial nephritis.

Antimicrobial agents Acyclovir, Amoxicillin, Ampicillin, Aztreonam, Carbenicillin, Cefaclor, Cefamandole, Cefazolin,Cefotaxime, Cefotetan,
Cefoxitin, Cephalexin, Cephaloridine, Cephalothin, Cephapirin, Cephradine, Ciprofloxacin, Cloxacillin, Colistin, Co
trimoxazole, Erythromycin, Ethambutol, Foscarnet, Gentamicin, Indinavir, Interferon, Isoniazid, Lincomycin,
Methicillin, Mezlocillin, Minocycline, Nafcillin, Nitrofurantoin, Norfloxacin, Oxacillin, Penicillin, Piperacillin,
Piromidic acid, Polymyxin acid, Quinine, Rifampin, Spiramycin, Sulfonamides, Teicoplanin, Tetracycline, Vancomycin
Non-steroidal anti-inflammatory drugs Aclofenac, Aspirin, Azapropazone, Benoxaprofen, Diclofenac, Diflunisal, Fenclofenac, Fenoprofen, Flurbiprofen,
Ibuprofen, Indomethacin, Ketoprofen, Mefenamic acid, Meloxicam, Mesalazine, Naproxen, Niflumic acid, Phenazone,
Phenylbutazone, Piroxicam, Pirprofen, Sulfasalazine, Sulindac, Suprofen, Tolmetin, Zomepirac
Analgesics Aminopyrine, Antipyrine, Antrafenin, Clometacin, Floctafenin, Glafenin, Metamizol, Noramidopyrine
Anticonvulsants Carbamazepine, Diazepam, Phenobarbital, Phenytoin, Valproate sodium
Diuretics Chlorthalidone, Ethacrynic acid, Furosemide, HCTZ, Indapamide, Tienilic acid, Triamterene
Others Allopurinol, Alpha-methyldopa, Azathioprine, Bethanidine, Bismuth salts, Captopril, Carbimazole, Chlorpropamide,
Cimetidine, Clofibrate, Clozapine, Cyamethazine, Cyclosporine, D-penicillamine, Fenofibrate, Gold salts,
Griseofulvin, Interleukin-2, Omeprazole, Phenindione, Phenothiazine, Phenylpropanolamine, Probenecid,
Propranolol, Propylthiouracil, Ranitidine, Streptokinase, Sulphinpyrazone, Warfarin

[Nephrology Reviews 2013; 5:e4] [page 15]

Review
whose rates of medication-induced or
immune-related AIN are quite low. Table 2 pro-
vides a list of organisms that have been shown
to be likely causes of AIN.2,10
Both systemic infections and direct renal
infections can lead to AIN. In systemic infec-
tions, two processes can occur: direct patholog-
ical injury to the kidney or indirect damage by
medications to treat the initial infection. For
example, a patient with HIV may develop AIN
through opportunistic infections, medications
such as sulfonamide to treat an infection, or as
a result of depressed immunity.2
Immune complex-induced
acute interstitial nephritis
Many patients with systemic lupus erythe-
matosus, Sjögren’s syndrome, or essential
mixed cryoglobulinemia present with immune
complex-induced interstitial nephritis. This
form has been understudied, but in 2 patients
with this class of disease, granular antibody
deposits to the tubular brush border antigen
gp330 were reported. As mentioned previously,
animals given endogenous renal proteins,
such as Tamm-Horsfall or bovine serum albu-
min, showed similar granular deposits in and
around the TBM and glomeruli. While these
animal models do not explain the complete
mechanism of injury, they have illustrated
granular deposition with little or no interstitial
injury and mononuclear cell infiltration.10
om
Other syndromes
-c
Although drug-induced AIN remains the
most frequent cause, other syndromes have
on
been linked to AIN. These etiologies include
sarcoidosis, tubulointerstitial nephritis-uveitis
N
syndrome (TINU), toxin-induced (primarily
lead exposure), and HIV-associated renal dis-
ease.2 Sarcoidosis and TINU will be discussed
further.
Interstitial nephritis with granulomatous
disease can be seen in sarcoidosis. The preva-
lence of renal involvement has been estimated
to be approximately 20% in postmortem analy-
sis and 35-50% in small studies of biopsy
series. Acute sarcoidosis, however, does not
commonly demonstrate renal involvement.19-23
Renal histological changes are caused by the
hyperabsorption of dietary calcium and result-
ant hypercalcemia in 2.5-20% of patients.
Although most affected subjects remain
asymptomatic, occasionally complications of
nephrolithiasis, nephrocalcinosis, renal insuf-
ficiency, and polyuria can occur.24-26
Progression of sarcoidosis-related intersti-
[page 16]
Table 2. Infectious organisms linked to acute interstitial nephritis.
Bacteria Streptococcus, Diphtheria, Brucellosis, Legionella, Staphylococci, Yersinia,
Pneumococcus, Tuberculosis
Viruses Measles virus, Cytomegalovirus, Epstein-Barr virus, Hanta virus, Hepatitis C virus, Herpes
Simplex virus, Human immunodeficiency virus, Mumps, Polyoma
Spirochetes Syphilis, Leptospirosis
Other Toxoplasma, Mycoplasma, Mycobacterium, Rickettsia
tial nephritis to renal failure is rare. Renal
biopsies in those affected show normal
glomeruli, interstitial nephritis with a predom-
inance of mononuclear cells, noncaseating
granulomas, and tubular damage. These find-
ings, however, are not diagnostic of sarcoido-
sis itself, as similar presentations can be seen
with tuberculosis, Mycobacterium avium infec-
tion, granulomatosis with polyangiitis (previ-
ously known as Wegener’s granulomatosis,
leprosy, and Crohn’s disease.27
Treatment of granulomatous interstitial
nephritis due to sarcoidosis involves the use of
on
corticosteroid therapy, with prednisone up to 1
mg/kg/day. Although plasma creatinine
decreases following treatment, recovery is fre-
se
quently incomplete due to irreversible damage
from chronic disease. Patients are more sensi-
tive to relapse when the steroid is tapered too
lu
rapidly or if they receive less than 20 mg/day of
a steroid, as seen in a series of 5 patients.28-31
a
In general, end-stage renal disease is uncom-
mon, with a higher risk of hypercalcemic
ci
nephropathy rather than nephritis in this
er
patient population.32
Tubulo-interstitial nephritis-uveitis syn-
m
drome syndrome is rare, with 133 cases identi-
fied in a review of the literature in 2001.33 The
majority of patients are female, with a median
age of 15 years. In a series of 18 patients diag-
nosed with TINU, associations with HLA-
DQA1*01, HLA-DQB1*05, and HLA-DQB1*01
were seen.34 Patients display symptoms of
interstitial nephritis with uveitis, including eye
pain and redness. Uveitis is most commonly
bilateral and associated with photophobia and
lower visual acuity. Uveitis can occur as early
as two months prior, simultaneous to, or up to
14 months after presentation of renal disease.33
While still not completely understood, the
mechanism of insult is proposed to be due to
cell-mediated immunity. A predominance of T
lymphocytes has been observed on the renal
biopsy, with IL-2 being an important modula-
tor, as evidenced by the expression of IL-2
receptors on the T-lymphocyte surface.35
Unfortunately, no particular risk factor has
been identified. Infections, such as chlamydia
and Epstein-Barr virus, as well as prior use of
antibiotics and NSAIDS, have been seen in
patients affected with TINU. TINU has also
been observed in patients with autoimmune
diseases, such as hypoparathyroidism, hyper-
thyroidism, IgG4-related diseases, and
rheumatoid arthritis.33,36-39
[Nephrology Reviews 2013; 5:e4]
Interstitial nephritis in TINU presents simi-
larly to other AIN etiologies. Patients may com-
plain of flank pain and hematuria, with signs
of proteinuria, sterile pyuria, and AKI.
Laboratory tests may show peripheral
eosinophilia, anemia, abnormal liver function
tests, and elevated an ESR.40 Beta-2 microglob-
ulin and glycoprotein Krebs Von Den Lunge-6
(KL-6) have also been found to be elevated in
TINU patients. Interestingly, KL-6 is a glyco-
protein found in healthy lung tissue, but in
TINU patients, KL-6 also begins to appear in
ly
the distal renal tubules. Although not a specif-
ic marker, KL-6 may be useful in separating
other etiologies of tubulo-interstitial nephritis
and uveitis, such as sarcoidosis, Sjögren’s, and
Behçet’s, from TINU syndrome.41 A definitive
diagnosis is commonly established based on
the presence of renal disease, uveitis, and
renal biopsy confirming AIN.29
Often TINU is self-limiting and resolves
spontaneously. For patients who develop renal
failure, prednisone 1 mg/kg per day is often
started and continued for 3-6 months, although
the length of therapy may be extended. Topical
and systemic steroids can also be used for
uveitis, although relapses are common.42 In
addition to the conditions described above,
other causes of AIN include lymphoprolifera-
tive disorders and plasma cell dyscrasias. In
some cases, the interstitial nephritis may be
idiopathic. 8
Diagnosis
While the mechanisms of renal injury in AIN
may be quite distinct and offending agent-spe-
cific, different forms of AIN share similar clin-
ical manifestations. A complete laboratory
workup for AIN includes urinalysis with
microscopy, complete blood count, serum
chemistry profile including creatinine level,
and liver function tests. Proteinuria is com-
monly less than 1 g/day, except in AIN caused
by NSAIDs or interferon, in which proteinuria
can exceed 1 g/day and may be in the nephrot-
ic range. Pyuria with leukocytes and leukocyte
casts are common, while hematuria may be
seen, and red blood cell casts are rare.
Although the presence of abnormalities on
urine microscopy is more common, at times,
patients can present with few urinary cells or
casts.
 Review

Major basic protein in the urine may be ele-
vated, but lacks the predictive value to verify
the diagnosis.2 The typical urinary findings
can help differentiate AIN from other renal
pathologies, such as acute tubular necrosis,
pyelonephritis, acute glomerulonephritis, and
pre-renal azotemia. In tubular necrosis, granu-
lar and epithelial casts are more commonly
present; white blood cell casts and red blood
cell casts are common in pyelonephritis and
glomerulonephritis, respectively, while typical-
ly no significant abnormalities in the urinary
sediment are found in pre-renal azotemia.5
Thus, urinalysis can provide important clues in
the evaluation of patients with AKI.
Another frequent finding in AIN is
eosinophiluria, i.e. eosinophils comprising
over 1% of the urinary white cells.6 The pres-
ence of eosinophiluria, noted mostly in drug-
induced AIN, is currently determined using
Hansel’s stain. Among 51 patients studied,2
and chronic cases, and its low specificity, lim- underlying infections and AIN caused by
its the value of gallium scanning. Renal ultra- antibiotics: a tissue diagnosis may justify
sounds can display normal to enlarged kidneys starting and continuing prednisone for 2-3
with enhanced cortical echogenicity, but the months, as prolonged immunosuppression in
findings are not sensitive or specific for AIN.2 these patients is otherwise viewed with cau-
The gold standard for the diagnosis of AIN is tion (Figure 1).46
a renal biopsy. A biopsy is not essential for Although a renal biopsy is the gold standard
patients with minimal elevations in the serum for diagnosis of AIN, some patients may pres-
creatinine, or for those with signs of recovery ent with contraindications for a renal biopsy
of renal function within 3-7 days of discontin- (Table 3).2,47 For patients with these condi-
uation of the offending agent. However, for all tions, empiric corticosteroid therapy may also
other patients, a biopsy is needed to confirm be considered in the presence of a history
the diagnosis and guide treatment. This may strongly suggestive of drug-induced AIN.
be particularly important for patients with
Table 3. Contraindications to renal biopsy in acute interstitial nephritis patients.
Absolute contraindications End-stage renal disease, uncorrectable bleeding diathesis, severe
uncontrolled hypertension, uncooperative patient

ly
this had a sensitivity and specificity of 63-91% Relative contraindications Renal, perirenal, cutaneous, bilateral, multiple, renal cysts or tumor,

on
and 85-93%, respectively, a positive predictive pregnancy, hydronephrosis, solitary native kidney
value of 38% (95% confidence interval (Cl) 15-
65%), and a negative predictive value of 74%
(95%CI: 57-88%). Overall, Hansel’s stain has

se
been shown to be more sensitive than Wright’s
stain (sensitivity 11-89%, specificity 52-93%), lu
which was used previously.6,43,44 The presence
of urinary eosinophils may be explained by the
a
release of eosinophil granules after activation,
with the potential for leaking into the tubules
ci

and being excreted into the urine.2 As the sen-

er

sitivity and specificity of eosinophiluria is not

ideal this finding is not considered specific for
m

AIN.6 In patients presenting with urinary

eosinophils, the differential diagnosis must
om

also include prostatitis, cystitis, pyelonephri-

tis, atheroembolic disease, and rapidly pro-
gressive glomerulonephritis.13
The leukocyte differential may demonstrate
-c

eosinophilia, particularly in cases of AIN

on

induced by drugs, such as beta-lactam antibi-

otics. A serum chemistry profile typically
reveals an elevated BUN and creatinine, hyper-
N

kalemia or hypokalemia, hyperchloremic meta-

bolic acidosis, and a fractional excretion of
sodium of over 1%. Patients with drug-induced
AIN can occasionally suffer drug-induced liver
injury as well, leading to elevated serum
transaminase levels. Elevated serum immune
globulin E (IgE) levels have also been shown.2
A number of researchers have used gallium
scanning to help in the diagnosis of AIN. As a
ferric ion analog, gallium binds to ferritin,
transferrin, lactoferrin, bacterial siderophores,
and lymphocyte plasma membranes. Patients
classically exhibit diffuse, bilateral uptake of
gallium characteristic of an interstitial infil-
trate. Although other pathologies can demon-
strate similar findings, a gallium scan is typi-
cally negative in acute tubular necrosis.45 The
prospect of false-positive results, iron over-
load, the variability of the results in subacute
Figure 1. A 20-year old female was treated at another hospital for acute kidney injury fol-
lowing treatment of osteomyelitis with ciprofloxacin, vancomycin, and ertapenem.
Creatinine rose from a baseline of 0.6 mg/dL to 2 mg/dL, with associated clinical find-
ings of rash, fever, mild proteinuria, peripheral eosinophilia, and eosinophiluria. A pre-
sumed diagnosis of AIN was made, and she received a 2-week course of corticosteroid
therapy, with a marked improvement in her symptoms and normalization of renal func-
tion (creatinine 0.8 mg/dL). Prednisone was rapidly tapered. Upon transfer to our insti-
tution, three days after discontinuation of prednisone, her symptoms and signs, as well
as proteinuria and elevation of creatinine to 1.7 mg/dL, recurred. A renal biopsy was per-
formed and this showed a predominantly mononuclear interstitial infiltrate with
eosinophils and tubulitis (H&E stain, x40), consistent with the diagnosis of acute inter-
stitial nephritis. The patient was treated with prednisone over a period of 12 weeks, with
return of creatinine to baseline in two months.

[Nephrology Reviews 2013; 5:e4] [page 17]

Review
Predisposing factors
Unfortunately, AIN does not have defined
patient risk factors. Although AIN can be seen
in children and adults, the median age at pres-
entation is approximately 65 years. The wide-
spread usage of medications in this age group
(e.g. NSAIDs), in addition to an age-related
decrease in renal drug clearance, result in an
increased rate of AIN in this population.9 AIN
does not have racial or gender related risk fac-
tors. A US study on 2598 renal biopsies during
a 12-year period demonstrated a male to
female percent ratio of 47% to 53%.6,9
Originally, serum creatinine levels were
thought to be prognostic for AIN, but no corre-
lation has been found. A less favorable progno-
sis has been reported with diffuse compared to
patchy interstitial infiltrate on renal biopsy,
while renal interstitial granulomas have been
associated with a poor prognosis. The most
notable prognostic factor is the duration of
reduced renal function and AKI.6
Treatment
In drug-induced AIN, discontinuation of the
offending agent is the most important thera-
peutic intervention. Frequently, these patients
completely recover from the renal injury.
Supportive care measures should be initiated
during periods of treatment, including suffi-
cient hydration, electrolyte management, pre-
venting volume depletion or overload, avoiding
om
nephrotoxic medications and pharmacothera-
py affecting renal blood flow.2 Instances have
occurred in which the disease worsens into
-c
chronic nephritis. Due to fibrosis resulting in
additional loss of kidney function, treatment
on
with corticosteroids is commonly initiated in
an attempt to reduce the rate of chronic inter-
stitial nephritis and fibrosis.6
N
In addition, AIN is believed to be an
immune-mediated disorder, primarily driven
by T lymphocytes; therefore, immunosuppres-
sive therapy is often indicated. Also, AIN cases
are commonly associated with allergic-like
reactions, as demonstrated by systemic hyper-
sensitivity symptoms. Thus, an immunosup-
pressive regimen, such as corticosteroids, is
indicated for treatment. However, the role of
corticosteroid therapy is not entirely clear.
Studies examining patients with AIN caused
by methicillin found that patients treated with
prednisolone experienced a shorter phase of
oliguria than those not treated. In a study pub-
lished in 2008, 61 patients from various hospi-
tals in Madrid, Spain, were analyzed. Fifty-two
patients were treated with corticosteroids
(Group 1) 23±17 days after the offending drug
withdrawal, and 9 were not treated (Group 2).
[page 18]
The study indicated that the most important
factor negatively affecting recovery was delay-
ing steroid treatment, with a period greater
than seven days between the withdrawal of the
offending drug and starting steroid treatment
resulting in a greater risk for the development
of interstitial fibrosis.48 In a 1990 study, twen-
ty-seven patients with biopsy-proven AIN were
evaluated. Seventeen patients had sponta-
neous recovery in their renal function after
withdrawal of the offending agent. The
remaining 10 patients who continued to have
worsening renal function despite discontinua-
tion of the offending agent were treated with
prednisone. All had improvement in their renal
function, with 6 returning back to their base-
line creatinine values.49 In a 1978 study, 14
patients with methicillin-induced AIN were
evaluated after corticosteroid treatment. All
patients developed renal dysfunction, with an
average peak creatinine of 8 mg/dL, an
increase of the total peripheral eosinophil
on
count, and sterile pyuria. Eight were treated
with corticosteroids while the rest were not
treated. Of the treated group, all subjects
se
demonstrated faster recovery (average of 9 vs
54 days) and lower serum creatinine concen-
trations (1.4 vs 1.9 mg/dL).50
lu
Some studies, however, have demonstrated
no significant improvement after steroid treat-
a
ment. The effects of corticosteroid therapy on
ci
renal outcomes of adult patients over a 12-year
period (1988-2001) were analyzed in a retro-
er
spective study. Of the 42 patients studied, 60%
had received methylprednisone 500 mg intra-
m
venously for 2-4 days, followed by a tapering
dose of oral prednisone for an additional 3-6
weeks. The rest obtained supportive therapy.
No significant differences were observed
between the groups in terms of median serum
creatinine levels at one, six, and 12 months
after diagnosis. Thus, corticosteroid therapy
did not significantly affect patient renal out-
comes, as assessed by serum creatinine val-
ues.9 Why some studies fail to show benefit
from corticosteroid therapy is not fully known.
Some possible explanations could be that the
patients treated had more severe AIN, or
NSAID-induced AIN, which is less likely to
respond to steroids. Steroids may confer a ben-
efit to AIN patients with relatively little risk
after a short-term course (grade 1C recom-
mendation). Treatment can start either with
oral prednisone at 1 mg/kg/day (to a max. 60
mg) or, for patients presenting with more
severe AKI, with intravenous methylpred-
nisolone (0.5-1 g/day for 3 days) and subse-
quent conversion to oral prednisone. A gradual
taper should begin after the serum creatinine
has returned to or near baseline, for total dura-
tion of therapy of 2-3 months.
[Nephrology Reviews 2013; 5:e4]
Prognosis
The majority of patients with drug-induced
AIN recover, with a higher incidence of recov-
ery seen in cases due to antibiotics.
Unfortunately, the prognoses of AIN caused by
other etiologies, such as infection or autoim-
mune disorders, have not been fully deter-
mined. In up to 40% of patients, recovery
remains incomplete, with continued elevation
of the serum creatinine. The final serum crea-
tinine concentration has not been shown to
correlate with the peak value. Factors shown to
reduce the probability of a full renal recovery
include: duration of renal failure for over three
weeks, AIN secondary to NSAID use, and biop-
sy findings of interstitial granulomas, fibrosis,
or tubular atrophy. The role of ACE inhibitors
in preventing CKD in patients with tubulo-
interstitial injury still has to be determined.
ly
Experimental data show that the deposition of
extracellular matrix is increased by
angiotensin II and, in particular, the pathway
mediated by TGF beta.6 While ACE inhibitors
do slow progression of CKD in patients with
glomerular injury and proteinuria exceeding 1
g/day, there are no data to date suggesting the
same for patients with tubulo-interstitial
injury.51
Conclusions
Acute interstitial nephritis is an important
and common cause of AKI, particularly in hos-
pitalized patients.52 With the high prevalence,
early recognition is crucial. A renal biopsy is
considered the gold standard for diagnosis,
with the clinical presentation of fever, rash,
arthralgias, flank pain, and oliguria in addition
to the laboratory findings of an elevated serum
creatinine level, peripheral eosinophilia and
eosinophiluria, strongly suggesting the diag-
nosis. Histologically, mononuclear interstitial
infiltrates with a predominance of CD4+ T-
helper cells, monocytes, and varying numbers
of eosinophils, along with interstitial edema
and tubulitis are seen.
The major causes of AIN include medica-
tions, infectious agents, and immune-mediat-
ed disorders. Over fifty medications have been
linked to drug-induced AIN. Typical symptoms
and laboratory features usually develop a few
weeks after exposure. The classic triad of fever,
skin rash, and arthralgia is rarely present.
Many medications may demonstrate slight dif-
ferences in symptoms that can help narrow the
search for the causative drug. Numerous bac-
teria, viruses, and spirochetes have been
found to cause infection-induced AIN. After the
introduction of antibiotics in developed coun-
tries, the prevalence of infectious diseases

decreased, with a similar drop in infection-
induced AIN. This category of AIN is still com-
mon in developing countries. Immune-mediat-
ed AIN can be seen in patients with systemic
lupus nephritis, Sjögren’s syndrome, and
essential mixed cryoglobulinemia, among
other disorders. The mechanisms of action are
still being studied.
Elderly patients are at a particularly high
risk for AIN. The etiology of AIN in these
patients is typically multifactorial, including
the cumulative effects of polypharmacy,
decreased drug metabolism, and decreased
renal drug clearance. Overall, treatment with
corticosteroids coupled with discontinuation of
the offending agent has been shown to
improve renal function when given shortly
after diagnosis. The vast majority of patients
experience complete renal recovery, with only
a small percentage developing progressive
CKD. Our understanding of the etiologies,
pathophysiology, and renal histological fea-
tures of AIN is rapidly evolving. Further
progress in the treatment of AIN crucially
depends upon research into the underlying
mechanisms and mediators of renal injury,
such as those related to immune mechanisms.
Future research may identify new therapeutic
targets, leading to more specific therapies
than the corticosteroid regimens that are cur-
rently used.
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