Acute interstitial nephritis Manuel Praga and Ester Gonza´lez

mini review
http://www.kidney-international.org
& 2010 International Society of Nephrology
Acute interstitial nephritis
Manuel Praga1 and Ester Gonza´lez1
1
Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
Acute interstitial nephritis (AIN) represents a frequent
cause of acute kidney injury, accounting for 15–27% of renal
biopsies performed because of this condition. By and large,
drug-induced AIN is currently the commonest etiology of
AIN, with antimicrobials and nonsteroidal anti-inflammatory
drugs being the most frequent offending agents.
Pathogenesis is based on an immunologic reaction against
endogenous nephritogenic antigens or exogenous antigens
processed by tubular cells, with cell-mediated immunity
having a major pathogenic role. The characteristic interstitial
infiltrates, mostly composed of lymphocytes, macrophages,
eosinophils, and plasma cells, experience a rapid
transformation into areas of interstitial fibrosis. A significant
proportion of AIN has nowadays an oligosymptomatic
presentation, although the presence of specific extrarenal
symptoms such as fever, skin rash, arthralgias, and peripheral
eosinophilia has an important role to orientate clinical
diagnosis. Identification and removal of the offending drug
are the mainstay of the treatment, but recent studies strongly
suggest that early steroid administration (within 7 days after
diagnosis) improves the recovery of renal function,
decreasing the risk of chronic renal impairment. Delayed
steroid treatment, when interstitial fibrosis has taken place,
would have a less pronounced or nule therapeutic benefit.
Kidney International (2010) 77, 956–961; doi:10.1038/ki.2010.89;
published online 24 March 2010
KEYWORDS: acute interstitial nephritis; drug-induced; interstitial fibrosis;
NSAIDs-induced; steroid treatment
Correspondence: Manuel Praga, Department of Nephrology, Hospital
Universitario 12 de Octubre, Hospital 12 de Octubre, Avda de Co´rdoba s/n,
28041 Madrid, Spain. E-mail: [email protected]
Received 8 January 2010; revised 25 February 2010; accepted 2 March
2010; published online 24 March 2010
956
DEFINITION AND ETIOLOGY
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.1,2 However, when the analysis was restricted to
patients with acute kidney failure, AIN accounted for 15–27%
of lesions.3,4 These studies suggest that AIN is a common
cause of acute renal dysfunction, but its true incidence might
even be underestimated by several reasons. First, a significant
number of patients in whom AIN is suspected on clinical
grounds is not submitted to a confirmatory renal biopsy
because empirical treatment is preferred, particularly in
elderly and frail patients. Second, milder forms of AIN can be
underdetected, either because of the absence or vagueness of
clinical symptoms or because acute renal failure is attributed
to other causes of renal injury.
As shown in Table 1, the main causes of AIN can be
grouped as drug induced, infection related, idiopathic forms
(which would include tubulointerstitial nephritis and uveitis
syndrome (TINU) and anti-tubular basement membrane
(anti-TBM) disease), and AIN associated with sarcoidosis
and other systemic diseases (systemic lupus erythematosus,
Sjo¨gren, malignancies). Tubulointerstitial lesions that frequently accompany primary glomerulonephritis are usually
not included within AIN. Regarding the frequency of these
different etiologies, drug-induced AIN currently accounts for
more than two-thirds of the cases, infection-related AIN for
15%, idiopathic forms for 10%, and TINU for 4%, the
remaining ones being associated with systemic disorders.5–7
However, the prevalence of drug-induced AIN could have
even increased in the last years: according to our own
experience (data not published), drugs were responsible for
more than 90% of biopsy-proven AIN occurring during the
period 2000–2008.
A large and expanding number of drugs has been
implicated in causing AIN and it can be stated that any drug
can theoretically induce an episode of AIN. However, the
majority of cases have been caused by antimicrobial agents
and nonsteroidal anti-inflammatory drugs (NSAIDs). Table 1
lists those drugs most commonly involved in AIN.
PATHOGENESIS
It is generally accepted that the initial event unleashing an
AIN episode is the expression of endogenous nephritogenic
antigens or exogenous antigens processed by tubular cells.
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M Praga and E Gonza´lez: Acute interstitial nephritis
Table 1 | Etiology of biopsy-proven AIN
Drugs (475% of AIN)
Infections (5–10%)
Idiopathic (5–10%)
Associated with systemic
diseases (10–15%)
Antibiotics: ampicillin, cephalosporins,
ciprofloxacin, cloxacillin, methicillin, penicillin,
rifampicin, sulfonamides, vancomycin.
NSAIDs
Other: allopurinol, acyclovir, famotidine,
furosemide, omeprazole, phenytoin
Bacteria: Brucella, Campylobacter, Escherichia
coli, Legionella, Salmonella, Streptococcus,
Staphylococcus, Yersinia
Viruses: cytomegalovirus, Epstein–Barr,
hantavirus, human immunodeficiency virus,
polyomavirus
Other: Leptospira, Mycobacterium tuberculosis,
Mycoplasma, Rickettsia, Schistosoma,
Toxoplasma
Anti-TBM
TINU
Sarcoidosis, Sjo¨gren, systemic lupus
erythematosus
Abbreviations: AIN, acute interstitial nephritis; NSAID, nonsteroidal anti-inflammatory drug; TBM, tubular basement membrane; TINU, tubulointerstitial nephritis and
uveitis syndrome.
Most commonly involved causative agents.
Immunization of rabbits or rats with Tamm–Horsfall protein
or megalin (a protein localized in the brush border of
proximal tubular cells) induced an AIN,8 thus suggesting a
possible pathogenic role of these proteins as endogenous
antigens in the development of some human AIN. Other
endogenous antigens implicated in AIN have been identified
as components of TBM, such as the tubulointerstitial
nephritis antigen, a glycoprotein important for TBM
integrity and whose molecular composition has been cloned
and sequenced.9 Tubulointerstitial nephritis antigen is likely
to be the target for some human cases of anti-TBM AIN, an
uncommon entity in which circulating anti-TBM antibodies
that react specifically with proximal TBM are found. The
mechanisms involved in the appearance of such antibodies, as
well as the proportion of human idiopathic AIN that are
caused by this pathogenic mechanism, remain unknown.
Anti-TBM AIN is occasionally manifested in association with
membranous nephropathy.10
The above-referred antigens are likely to be responsible for
most idiopathic types of AIN. The pathogenesis of the more
common drug-induced AIN is also believed to have an
immunologic basis, as indicated by the relatively common
appearance of extrarenal manifestations of hypersensitivity,
its dose-independent character, and the recurrence of AIN
after re-exposure to the offending drug.11 Medications and
specific microbial antigens could elicit an immune reaction
after their interstitial deposition (planted antigens). Conversely, tubular cells have the capacity to hydrolyze and
process exogenous proteins. In this regard, medications can
bind to a normal component of TBM, behaving as a hapten,
or can mimic an antigen normally present within the TBM,
inducing an immune response directed against this antigen
(reviewed by Rossert11). Although evidence is not so strong,
some microbial antigens could also induce AIN through
these mechanisms.
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The fact that only a minority of patients treated with a
particular drug or suffering an infectious process develop AIN
indicates that the expression of nephritogenic antigens at renal
tubulointerstitium is likely counterbalanced by complex
protective mechanisms, mainly involving suppressor T cells.12
When these protective mechanisms are surpassed (likely on the
basis of a genetically determined susceptibility) and AIN
ensues, both experimental studies and cumulative evidence in
humans indicate that cell-mediated immunity has the major
pathogenic role.12,13 Target antigen, or one cross-reactive with
it, is presented to T cells. Activated T-helper cells induce the
differentiation of other effector T cells, such as those mediating
delayed-type hypersensitivity and cytotoxicity. With the exception of anti-TBM disease and some cases of drug-induced AIN
(mainly those related to methicillin), immunofluorescence
studies in renal biopsies of patients with AIN are generally
negative, indicating the absence of antibody-mediated immunity that has a marginal, if any, pathogenic role.
The inflammatory cellular infiltrates that characterize
AIN, mainly composed of T lymphocytes and macrophages,
are a powerful source of cytokines that increase the
production of extracellular matrix and the number of
interstitial fibroblasts, and induce an amplification process
recruiting more inflammatory cells and eosinophils into the
interstitium.12,13 Particularly decisive for the final outcome of
renal function is the rapid transformation of these inflammatory lesions into destructive fibrogenesis, a process that
can be detected after only 7 days of interstitial inflammation.14 Interstitial fibrosis is marked by the loss of renal
tubules and the accumulation of fibroblasts and extracellular
matrix proteins (collagens, fibronectin, laminin). There is a
number of profibrotic cytokines and growth factors actively
synthetized by inflammatory cells that have a crucial role
in the progression of interstitial fibrosis, such as transforming growth factor-b, platelet-derived growth factor-BB,
endothelin-1, epidermal growth factor, and fibroblast growth
factor-2. These mediators are also an important stimulus for
local epithelial-to-mesenchymal transition that affects tubular epithelium after injury.14 Fibroblasts derived from
epithelial-to-mesenchymal transition have a crucial role in
tubulointerstitial fibrosis.15 However, some recent studies
have cast doubts about the implication of epithelial-tomesenchymal transition in renal fibrosis.16
PATHOLOGY
The characteristic inflammatory cell infiltrates of AIN
(Figure 1) can be diffuse or patchy. Interstitial edema is a
typical finding, whereas glomeruli and vessels are distinctly
normal. Interstitial infiltrates are mostly composed of
lymphocytes (CD4 þ T cells being the most abundant type),
macrophages, eosinophils, and plasma cells. Interstitial
granulomas can be observed in some cases of drug-induced
AIN, but the possibility of sarcoidosis, tuberculosis, and some
other infections must be kept in mind when they are found.
Results of immunofluorescence studies are negative in
most of patients, although granular or linear deposits of IgG
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M Praga and E Gonza´lez: Acute interstitial nephritis
Figure 1 | Interstitial inflammatory infiltrates in a case of druginduced acute interstitial nephritis (AIN; hematoxylin and
eosin original magnification 10).
Figure 2 | Extensive interstitial fibrosis (green areas) in a renal
biopsy obtained 4 weeks after the onset of acute interstitial
nephritis (AIN; Masson original magnification 10).
or complement along the TBM can occasionally be observed.
The rare finding of homogeneous linear deposits of IgG along
the TBM is indicative of antibodies directed against TBM
antigens, as in anti-TBM disease, but it has also been
described in some cases of drug-induced AIN. Electron
microscopy reveals nonspecific lesions. In those patients with
NSAIDs-induced AIN accompanied by nephrotic syndrome,
diffuse effacement of podocyte’s foot processes is observed.17
Fibrotic changes can already be seen within 7–10 days of
initiation of the inflammatory process and they progress to
advanced interstitial fibrosis accompanied by tubular atrophy
(Figure 2) unless rapid withdrawal of offending drug or onset
of steroid treatment take place.18
Table 2 | Clinical and laboratory features at presentation in
patients with AIN (pooled data from Gonza´lez et al.18 and
Clarkson et al.19)
Features
Acute renal failure
Acute renal failure requiring dialysis
Arthralgiasa
Fever
Skin rash
Eosinophilia (4500 eosinophils per mm3)
Microhematuriab
Gross hematuriab
Leukocyturiab
Non-nephrotic proteinuria
Nephrotic-range proteinuria
Complete nephrotic syndrome
CLINICAL FEATURES
a
In patients with drug-induced AIN, mean delay between the
starting of the offending drug and the appearance of renal
manifestations is 10 days,11 although the latent period may be
as short as 1 day after some antibiotics or as long as several
months with NSAIDs. Table 2 shows the clinical and
laboratory features at presentation in two large and recently
published series of patients with AIN that included a total of
121 cases.18,19 Drug-induced AIN accounted for the majority
(91%) of the cases (of whom, 44% corresponded to NSAIDsinduced AIN). All the patients presented with an acute
worsening of renal function, whose severity led to dialysis
requirement in a significant proportion of cases. AIN-related
renal failure can be asymptomatic or accompanied by some
clinical or laboratory findings that, when present, are very
valuable to orientate the diagnosis. The specific clinical
findings in drug-induced AIN are related to an allergic-type
reaction and their incidence is shown in Table 2: low-grade
fever in 36% and maculopapular skin rash in 22% (Figure 3),
whereas arthralgias were more frequently reported (45%) in
some series.19 The presence of eosinophilia (35% of patients)
is considered as an another expression of this allergic-type
b
958
100%
40%
45%
36%
22%
35%
67%
5%
82%
93%
2.5%
0.8%
Data from Clarkson et al.19
Data from Gonza´lez et al.18
reaction. Eosinophilia is significantly less common in
NSAIDs-related AIN than in other types of drug-induced
AIN.18 Another clinical condition characterized by acute or
subacute renal impairment, eosinophilia, and skin lesions is
atheroembolic renal disease, which should be considered in
the differential diagnosis of AIN, particularly in the elderly.20
Earlier series emphasized the diagnostic importance of the
classic triad of fever, rash, and eosinophilia. However, only a
minority of patients (o10–15%) showed these three
characteristics together in the last series.5,18,19
Other diagnostic features have also changed after the
earliest clinical reports, in which methicillin was the
predominant causative agent.21 Thus, gross hematuria was
reported as a common type of presentation, whereas it is
currently a very uncommon initial symptom. Microscopic
hematuria, however, is found in almost two-thirds of the
patients, although the presence of red blood cell casts is rare.
A very common finding (more than 80% of cases) is
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M Praga and E Gonza´lez: Acute interstitial nephritis
renal dysfunction.25 Several patients with AIN coincidental with
autoimmune pancreatitis have been reported.26,27 A distinctive
feature of this entity is a dense infiltration of IgG4-positive
mononuclear cells in renal interstitium.
TREATMENT OF DRUG-INDUCED AIN
Conservative treatment
Figure 3 | Medicamentous skin rash in a patient with druginduced acute interstitial nephritis (AIN).
leukocyturia, frequently accompanied by leukocyte casts.
Conversely, in spite of stimulating earlier reports, the search
for urinary eosinophils have not conclusively confirmed its
diagnostic usefulness.22 Monitoring of sensitive urinary
markers of tubulointerstitial damage, such as neutrophil
gelatinase-associated lipocalin, liver-type fatty acid-binding
protein, and kidney injury molecule-1, has been suggested as
a noninvasive test to evaluate early damage and evolution of
interstitial nephritis.23,24 However, more investigations are
required before translation to clinical practice.
A great majority of patients presents moderate, nonnephrotic proteinuria, but the finding of nephrotic-range
proteinuria or complete nephrotic syndrome with hypoalbuminemia appears to be rather uncommon, even in those
patients with NSAIDs-induced AIN (Table 2). Thus, in two
relatively large series recently published,18,19 only 3 patients
out of a total of 121 showed nephrotic-range proteinuria at
presentation, although NSAIDs were the causative drug in
40% of the patients.
In patients with AIN secondary to infectious diseases
(Table 1), extrarenal manifestations are dominated by the
underlying infection. Clinical findings that typically orientate the
diagnosis of a patient with acute renal dysfunction toward AIN
(maculopapular rash, arthralgias, eosinophilia) are uncommon
or absent and the same is true in patients with idiopathic AIN.
TINU syndrome is characterized by AIN accompanied by a
bilateral anterior uveitis that can precede, concur with, or follow
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Initial reports, most of them based on series of methicillininduced cases, depicted drug-induced AIN as a benign
condition, with a rapid improvement of renal function after
the removal of the inducing agent. However, later studies
with a larger number of patients and a longer follow-up
revealed that a significant proportion of patients, ranging
from 30 to 70%, did not fully recovered their baseline renal
function.6,11,21,28–31 Duration of treatment with the offending
drug or duration and severity of renal failure have not shown
a clear correlation with the levels of serum creatinine at the
end of follow-up. Whereas some studies found a predictive
role of diffuse interstitial infiltrates in opposition to patchy
ones,30 other ones have not corroborated these findings.6
Conversely, the extent of interstitial fibrosis has shown a clear
impact on the risk of chronic renal impairment after a druginduced AIN in some studies.18,31
Regarding the withdrawal of the causative agent, it is
important to remark that in some patients with biopsyproven AIN and in whom clinical and pathological findings
strongly point out to a drug-induced form, the offending
drug cannot be identified even after meticulous investigations. Reasons for such failure include self-treatment with
antibiotic mixtures, polymedication, and the huge and largely
uncontrolled consumption of NSAIDs among the general
population, the two latter issues being particularly relevant
among elderly people.
Steroid treatment
The role of steroids in the treatment of drug-induced AIN
remains controversial. Several studies reported a significantly
better outcome in patients who were treated with steroids.6,21,28 In some cases, the response to steroids was
dramatic, with a rapid recovery of diuresis and serum
creatinine decrease. However, the number of patients
included in such positive studies was short and other studies
failed to found a beneficial influence of steroids in
comparison with conservative measures.11,32
Clarkson et al.19 performed a retrospective study in a
relatively large series of 60 patients with biopsy-proven AIN
to define the influence of steroids on this disease. AIN was
drug related in 92% of cases and NSAIDs were the most
common offending drug, accounting for 44% of cases.
Follow-up data were available in 42 patients. Of them, 25
patients (60%) received steroid treatment, whereas the
remaining 17 (40%) received only supportive care. No
difference in serum creatinine levels was observed between
the two groups after 1, 6, and 12 months following AIN. Of
note, a significant proportion of patients in both groups
showed chronic renal impairments at the end of follow-up.
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An important aspect of Clarkson’s study that should be
kept in mind when interpreting its results is the considerable
delay between the onset of AIN symptoms and the
performance of renal biopsy (median time 3 weeks); steroids
were always started after renal biopsy.19 Whether the timing
of treatment initiation might affect the response to steroids
was investigated by Gonza´lez et al.,18 for the Grupo
Madrilen˜o de Nefritis Intersticiales. This retrospective multicenter study collected 61 patients with biopsy-proven, druginduced AIN. Antibiotics (56%) and NSAIDs (37%) were the
most common inciting drugs. Strengths of the study were the
knowledge of the baseline renal function and a follow-up
long enough (at least 6 months) to evaluate recovery of renal
function in all the patients. A majority of patients (85%)
received steroids and their outcome was significantly better
than that of the remaining 15% of patients treated
conservatively (need of chronic dialysis 3.8 vs 44%). When
analyzing the course of those patients treated with steroids
more carefully, it was found that 53% of the patients had
completely recovered their baseline renal function, whereas in
the remaining 47% renal function did not reach the baseline
values (final serum creatinine 1.1±0.2 vs 3.2±2.7 mg/dl).
There were no significant differences at baseline between both
groups of steroid-treated patients regarding clinical characteristics, type of the causative agent, or highest serum
creatinine values. Duration and doses of steroids were
similar, but those patients who experienced incomplete renal
function recovery had a significantly longer interval between
withdrawal of the offending drug and start of steroid
treatment (34±17 vs 13±10 days). Multivariate regression
analysis showed that an interval of 47 days was associated
with a more than six times increased risk of experiencing
incomplete recovery of renal function. The separate analysis
of those patients in whom NSAIDs had been the causative
drug yielded similar results: a significant beneficial effect of
steroids but only when they had been started shortly after the
withdrawal of NSAIDs.
The study of Gonza´lez et al.,18 therefore, suggests that
steroid treatment is indicated in drug-induced AIN and that
it should be started soon or immediately after the diagnosis
to diminish the risk of chronic renal impairment. However, it
is important to remark that this study consisted of a
multicenter and retrospective collection of patients with
biopsy-proven drug-induced AIN and that treatment regimens, regarding steroid doses and duration, showed
considerable variations between participating centers. Prospective, randomized studies about steroid treatment in AIN
are needed to resolve these questions. A prospective
randomized study designed to compare early steroid treatment (administered immediately after AIN diagnosis and
offending-drug withdrawal) vs late treatment (steroids
administered only to those patients who had not started to
improve renal function some weeks after offending-drug
withdrawal) would give very valuable information about the
indication of steroid treatment in AIN and when they should
be given.
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M Praga and E Gonza´lez: Acute interstitial nephritis
The physiopathological rationale to explain the benefits
of early steroid treatment in drug-induced AIN could
be related to the rapid transformation of interstitial cellular
infiltrates (responsive to high-dose steroids) into areas
of irreversible interstitial fibrosis, a process that starts
after only 7 days of interstitial inflammation as stated
above.14 Early steroid administration would likely reduce the
number and extent of inflammatory infiltrates, thus decreasing the risk of subsequent fibrosis. In the study of Gonza´lez
et al.,18 a second renal biopsy was performed 4–6 weeks after
the first one in three patients who had received a delayed
course of steroids; interstitial fibrotic areas that have
largely replaced inflammatory infiltrates were observed in
all these cases.
If the efficacy of steroids relies on the rapid disappearance
of interstitial infiltrates, a logical recommendation is to
initiate treatment with high doses of steroids followed by a
rapid tapering off. Our current therapeutic scheme consists
of intravenous pulses of methylprednisolone (250 mg daily
for 3 consecutive days) followed by oral prednisone
(0.5–1 mg/kg/day) tapering off over 4–6 weeks. The number
of side effects when using this protocol is relatively low in our
experience.
TREATMENT OF OTHER TYPES OF AIN
Steroids are the mainstay of treatment in idiopathic AIN,
TINU, and AIN associated with systemic diseases, including
the recently reported association of AIN with autoimmune
pancreatitis.11,12,26,27 Plasmapheresis and cytotoxics have
been used in anti-TBM disease. In patients with idiopathic
AIN resistant to steroids, anecdotal reports suggest benefit
from cyclophosphamide and cyclosporine.33 A recent report
of eight patients with steroid-dependent, recurrent AIN
documented an interesting beneficial effect of mycophenolate
mofetil.34 In patients with NSAID-induced AIN and
nephrotic syndrome, withdrawal of the offending drug has
proved to be the most effective treatment, whereas the
addition of steroids does not alter the clinical course.17
CONCLUSIONS
AIN represents a frequent cause of acute kidney injury. Druginduced AIN is currently the commonest etiology of AIN,
antimicrobials and NSAIDs being the most frequent offending agents. Pathogenesis is based on a cell-mediated immune
response in most patients and removal of the offending drug
is the mainstay of the treatment. However, a significant
proportion of patients, ranging from 30 to 70%, did not fully
recovered their baseline renal function, likely because of the
rapid transformation of interstitial cellular infiltrates into
large areas of fibrosis. Although prospective randomized
trials in AIN are lacking, recent retrospective studies suggest
that early steroid treatment (within 7 days after diagnosis)
improves the recovery of renal function.
DISCLOSURE
All the authors declared no competing interests.
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M Praga and E Gonza´lez: Acute interstitial nephritis
ACKNOWLEDGMENTS
We are grateful to Inmaculada Garcı´a Cano (Department of
Dermatology, Hospital 12 de Octubre) and Oscar Toldos (Department
of Pathology, Hospital 12 de Octubre) for their kind and valuable
contribution in preparing this paper.
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