Acute Interstitial Nephritis

Acute interstitial nephritis
The right clinical information, right where it's needed
Last updated: May 18, 2015
Table of Contents
Summary
Basics
Definition
Epidemiology
Aetiology
Pathophysiology
Prevention
Secondary prevention
Diagnosis
6
6
7
Case history
Step-by-step diagnostic approach
Risk factors
History & examination factors
Diagnostic tests
10
Differential diagnosis
12
Treatment
14
Step-by-step treatment approach
14
Treatment details overview
14
Treatment options
16
Emerging
20
Follow up
21
Recommendations
21
Complications
21
Prognosis
22
Guidelines
23
Diagnostic guidelines
23
Treatment guidelines
23
References
24
Disclaimer
28
Summary
Caused by acute inflammation of the renal interstitium, most probably mediated by a hypersensitivity reaction.
Usually triggered by an offending medication, of which >100 are known. Also occurs in chronic inflammatory
disease.
Presents with acute renal failure and the 'hypersensitivity triad' of rash, fever, and eosinophilia. Nephrotic
syndrome may also be present in cases triggered by non-steroidal anti-inflammatory drugs.
Usually resolves once the offending medication is discontinued.
Treatment is largely supportive, with management of fluid electrolyte balance and fluid retention. Corticosteroid
therapy may be given to increase the rate and extent of renal functional recovery.
Prognosis is good, although most patients have some residual renal impairment.
Basics
BASICS
Definition
Acute interstitial nephritis is a pattern of acute renal inflammation, usually triggered by medications, which is localised
to the renal interstitium (the area between the tubules, glomeruli, and blood vessels).[1] [2] [3]
Epidemiology
The incidence in the US remains unknown. Best available estimates come from measuring the incidence of unexpected
acute interstitial nephritis (AIN) at autopsy (<1%), in unselected renal biopsies (1% to 6%),[12] and in renal biopsies
selected for patients with acute renal failure (11% to 15%).[13]
Definitive diagnosis requires a biopsy, which may not be clinically indicated, and hence the incidence is underestimated.
The estimated incidence may be higher if clinical diagnosis alone is used to identify cases.
Non-steroidal anti-inflammatory drug (NSAID)-induced AIN is more common in older patients, which most probably
reflects increased NSAID use by these patients.
Aetiology
Most cases are triggered by an offending medication, of which >100 are known,[1] [2] [3] [6] [14] and resolve when the
triggering medication is stopped. Some patients are taking multiple offending medications, making it unclear which drug
is responsible. Common offenders include:
Antibiotics: virtually all penicillins and cephalosporins, as well as many sulfonamides, rifampicin, and some quinolones;
beta-lactam antibiotics are the most common cause of acute interstitial nephritis (AIN).[15] [16] [17] [18] [19] [20]
Diuretics (several classes).[21] [22]
Non-steroidal anti-inflammatory drugs (virtually all): trigger a unique reaction consisting of AIN with a concurrent
nephrotic syndrome.[8] [10]
Proton-pump inhibitors.[23]
Antihistamines: cimetidine and ranitidine.[24]
Other medications: allopurinol, phenindione, phenytoin, sulfadiazine, mesalazine, and warfarin.[25] [26]
Uncommonly, AIN can occur in the context of chronic inflammatory diseases such as sarcoidosis, Sjogren's syndrome,
IgG4-related syndrome, or SLE. In some patients, there is no discernible cause.
A known variant of AIN is tubulo-interstitial nephritis, which has features of both AIN and acute tubular necrosis.
Erythromycin, polymyxin, aciclovir, foscarnet, and vancomycin are known triggers of this variant.[27] [28] [29] [30] [31]
It is also known to occur as part of the extremely rare tubulo-interstitial nephritis with uveitis (TINU) syndrome.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 18, 2015.
BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use
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Basics
Pathophysiology
A number of features point to involvement of an allergic-hypersensitivity mechanism:

Only a small proportion of patients receiving the triggering medications develop the reaction, a classic pattern for
drug allergies.
The presence of rash, eosinophilia, eosinophiluria, and eosinophils on the renal biopsy specimen suggests an allergic
mechanism.
Some patients have elevated circulating IgE levels and IgE-containing cells that react to the offending drug.[37]
Some patients have a recurrence of the disease when re-challenged by the same or a similar offending medication.
The triggering drug molecules bind to proteins in the interstitial or tubular basement membrane. This explains the
localisation of the allergic reaction. However, binding alone is not always associated with AIN, so it is unclear how the
allergic reaction is actually triggered. It is also unclear which components of the immune system contribute to the
hypersensitivity; both cell-mediated and humoral mechanisms have been implicated.[38] [39] [40]
BASICS
The exact pathogenesis is unknown.[7] [32] [33] [34] Renal biopsy reveals an inflammatory infiltrate with variable numbers
of eosinophils, lymphocytes, and plasma cells.[14] [35] [36] If nephrotic syndrome is present, the pattern is usually
minimal change disease, although membranous nephropathy has also been reported.
Prevention
Secondary prevention
PREVENTION
The most important preventative action is to avoid exposure to the trigger of the acute episode. If the offending medication
has clearly been identified, then avoiding future use of the medication is recommended, because acute interstitial
nephritis may recur on re-exposure to the original antigen. Where known cross-reactivity exists, for example between
penicillins and cephalosporins, the risk of using a related agent should be carefully weighed up against the benefit of
using it. If such an agent is used, the patient should be appropriately monitored for any adverse effects. For the few
patients who have chronic inflammatory diseases such as Sjogren's syndrome, sarcoidosis, or SLE, adequate control of
the underlying condition is important.
Diagnosis
Case history
Case history #1
A 67-year-old man has been receiving amoxicillin treatment for bronchitis for 2 weeks. He develops a macular rash
on his neck, torso, and back. The amoxicillin is therefore changed to cefalexin for an additional 7 days. The rash
resolves, but he returns complaining of fatigue and a low-grade temperature that has persisted despite the resolution
of bronchitis. He has a history of hypertension, hyperlipidaemia, a previous myocardial infarction (6 years ago), and
symptoms suggestive of gastric reflux. There is no history of renal disease. He has been on a stable regimen of lisinopril,
metoprolol, simvastatin, and omeprazole. Physical examination reveals a BP of 140/85 mmHg, pulse 68 bpm regular,
temperature 37.8C (100F), and respirations of 16/minute. Head, eye, ENT, heart and lung, and abdominal examination
are negative. He has no oedema and no rash.
Other presentations
The classic presentation is of non-oliguric acute renal failure with rash and fever triggered by a medication.[4] [5]
Arthralgia and costovertebral angle tenderness may also be present. However, many patients present with acute renal
failure alone. Beta-lactam antibiotics are the most common offenders, but >100 triggering medications are known.[6]
[7] Patients with non-steroidal anti-inflammatory drug-induced acute interstitial nephritis (AIN) typically present with
acute renal failure and oedema secondary to concurrent nephrotic syndrome.[8] [9] [10] [11] Patients with bacterial
pyelonephritis, sarcoidosis, Sjogren's syndrome, SLE, or tubulo-interstitial nephritis with uveitis (TINU) syndrome can
also develop AIN.
Step-by-step diagnostic approach
Clinical assessment
Patients present with non-oliguric acute renal failure. Many patients will also have rash, fever, or eosinophilia of the
peripheral blood, but few will have all 3 at the time of presentation.[1] [2] [3] [14] Arthralgia is sometimes seen as an
associated symptom.
Over 100 medications are known to trigger AIN; the use of any of these should raise suspicion of AIN. Antibiotics,
particularly beta-lactams, are the most common offenders. Almost all penicillins and cephalosporins, many
sulfonamides, rifampicin, and a variety of quinolones are known triggers. Other triggers include diuretics, non-steroidal
anti-inflammatory drugs (NSAIDs), proton pump inhibitors, antihistamines (cimetidine and ranitidine), allopurinol,
phenindione, phenytoin, sulfadiazine, mesalazine, and warfarin. Erythromycin, polymyxin, aciclovir, foscarnet, and
vancomycin trigger tubulo-interstitial nephritis, a variant of AIN.
Uncommonly, patients with Sjogren's syndrome, sarcoidosis, IgG4-related syndrome, and SLE can also develop AIN.
Patients with AIN occurring as part of the tubulo-interstitial nephritis with uveitis (TINU) syndrome will also have
uveitis; this is extremely rare.
DIAGNOSIS
The classic presentation is of non-oliguric acute renal failure with rash, fever, and eosinophilia (the 'hypersensitivity triad')
triggered by a medication.[4] [5] Acute interstitial nephritis (AIN) should be suspected in all patients who develop
non-oliguric acute renal failure, and particularly those taking multiple medications. Other causes of acute renal failure,
including acute tubular necrosis, acute glomerulonephritis, and acute vascular changes, should be excluded. Referral to
a nephrology specialist is advisable with significant acute renal failure.
Diagnosis
Clinical examination is usually unremarkable. Pyrexia is a common sign. The associated rash is usually macular or
maculopapular. Costovertebral angle tenderness may be present in some patients. NSAIDs trigger a unique reaction
consisting of AIN with a concurrent nephrotic syndrome; these patients develop oedema secondary to
hypoalbuminaemia. The site of oedema is influenced by posture and is typically periorbital in the morning and pedal
in the evening.
Initial investigations
Blood tests
Serum urea and serum creatinine are required to detect and assess the severity of acute renal failure.
FBC with WBC differential reveals significant eosinophilia in some cases.
Anti-neutrophil cytoplasmic antibody (ANCA), anti-nuclear antibody (ANA), extractable nuclear antigens (ENAs),
and complement profile if associated systemic disease suspected. ANCA is associated with systemic vasculitis,
and ANA and ENA are associated with systemic lupus erythematosus.
Urinalysis[1] [2] [3] [14] [41]
Usually shows microhaematuria with sterile pyuria (leukocytes with a negative urine culture for bacteria).
Absence of RBC casts excludes acute glomerulonephritis.
Once infection is excluded, Hansel's or Wright's staining is required to detect eosinophilia: the staining shows
clusters of binucleated eosinophils.
Heavy proteinuria suggests the presence of nephrotic syndrome. If the patient has nephrotic syndrome but is
not taking NSAIDs, other causes should be investigated.
DIAGNOSIS
Trial of discontinuation of offending medication

Symptoms usually resolve following discontinuation of the offending medication; a retrospective diagnosis of
AIN can be made if this occurs.
If symptoms do not resolve, other diagnoses should be excluded.
Subsequent investigations
Renal biopsy
Provides a definitive diagnosis, but is reserved for patients who have not responded to discontinuation of the
triggering medication or who have a relative contraindication to corticosteroid use.[1] [2] [3] [14]
Requires a careful risk-benefit assessment in consultation with a nephrologist.
Typical findings are of an interstitial or tubulo-interstitial inflammatory infiltrate with variable numbers of
eosinophils, lymphocytes, and plasma cells,[14] [35] [36] with no bacteria, fungi, or other organisms found on
special stains of the biopsy.
Diagnosis
If nephrotic syndrome is present, the pattern is usually minimal change disease, although membranous
nephropathy has also been reported.
Renal ultrasound[1] [2] [3] [14]
Shows large swollen kidneys that are often echogenic due to the inflammatory interstitial infiltrates.
Main use is to exclude hydronephrosis, renal calculi, or shrunken kidneys (a sign of chronic renal failure).
Gallium scan[42] [43] [44]
Can be used to detect AIN, but findings are non-specific.
Probably more useful when negative to exclude the diagnosis.
Renal blood flow scans or magnetic resonance angiography
Can be used to exclude large-vessel vascular lesions such as emboli or renal vein thrombosis.
Risk factors
Strong
use of a triggering medication
Weak
chronic inflammatory disease
Acute interstitial nephritis can occur in the context of sarcoidosis, Sjogren's syndrome, IgG4-related syndrome,
SLE, or tubulo-interstitial nephritis with uveitis (TINU) syndrome.
History & examination factors

Key diagnostic factors
presence of risk factors (common)
Use of any potential offending medication is a strong risk factor. Common offending medications include antibiotics
(particularly beta-lactams), non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, proton pump inhibitors, and
antihistamines. Over 100 triggering medications are known.[8] [10] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
fever (common)
DIAGNOSIS
Over 100 medications are known to trigger acute interstitial nephritis (AIN). Antibiotics are the most common
offenders (almost all penicillins and cephalosporins, many sulfonamides, rifampicin, and a variety of quinolones).
Others include diuretics, almost all non-steroidal anti-inflammatory drugs, proton pump inhibitors, antihistamines
(cimetidine and ranitidine), allopurinol, phenindione, phenytoin, sulfadiazine, mesalazine, and warfarin. Erythromycin,
polymyxin, aciclovir, foscarnet, and vancomycin trigger tubulo-interstitial nephritis, a variant of AIN.
Diagnosis

Mild pyrexia is seen in most patients.
Forms part of the 'hypersensitivity triad' of rash, fever, and eosinophilia.
rash (common)
A macular or maculopapular rash is often seen.
Forms part of the 'hypersensitivity triad' of rash, fever, and eosinophilia.
oedema (common)
Occurs with non-steroidal anti-inflammatory drug (NSAID) use due to a concurrent nephrotic syndrome that causes
protein loss and hypoalbuminaemia.
The site is influenced by posture, being periorbital in the morning and pedal in the evening.
decreased urinary volume (uncommon)

May be present in more severe cases.
Most patients have non-oliguric acute renal failure.
Other diagnostic factors

arthralgia (uncommon)
May be present in some patients.
uveitis (uncommon)
Occurs as part of tubulo-interstitial nephritis with uveitis (TINU) syndrome. Extremely rare.
costovertebral angle tenderness (uncommon)

May be present in some patients.
DIAGNOSIS
Diagnostic tests
1st test to order
Test
Result
serum urea and creatinine
elevated
All patients have an elevated serum urea and creatinine.

FBC with WBC differential
may show eosinophilia
Eosinophilia is a common finding and forms part of the 'hypersensitivity triad'

of rash, fever, and eosinophilia.
urinalysis
Microhaematuria with sterile pyuria (leukocyturia with a negative bacterial
urine culture) is usually present.
The absence of RBC casts excludes acute glomerulonephritis.
Heavy proteinuria is seen with concurrent nephrotic syndrome.
urine Hansel's or Wright's eosinophil stain
microhaematuria; sterile
pyuria; proteinuria
eosinophiluria
Considered once infection is excluded as a cause of haematuria and pyuria.

Hansel's staining is preferred.
Shows clusters of binucleated eosinophils. A finding of >1% eosinophils is taken
as positive.[41]
10
Diagnosis
Test
Result
trial of discontinuing offending medication
resolution of renal failure
Symptoms usually resolve following discontinuation of the offending

medication; a retrospective diagnosis of acute interstitial nephritis (AIN) can
be made if this occurs.
anti-neutrophil cytoplasmic antibody (ANCA)
Performed if associated systemic disease suspected.
anti-nuclear antibody (ANA)
extractable nuclear antigens (ENAs)
complement profile
positive result with positive

ELISA suggestive of systemic
vasculitis
positive result consistent with
systemic lupus erythematosus.
positive result consistent with
systemic lupus erythematosus
low C4 levels consistent with
systemic lupus erythematosus.
Other tests to consider

Test
Result
renal ultrasound
large, swollen, echogenic

Shows large, swollen kidneys that are often echogenic due to the inflammatory kidneys
interstitial infiltrates.[1] [2] [3] [14]
Main use is to exclude hydronephrosis, renal calculi, or shrunken kidneys (a
sign of chronic renal failure).
renal biopsy
renal gallium scan
interstitial lesions
Findings are non-specific.

More useful when negative to exclude a diagnosis of acute interstitial nephritis
(AIN).[42] [43] [44]
renal blood flow scan
normal
Can be used to exclude large vessel vascular lesions such as emboli or renal
vein thrombosis.
renal magnetic resonance angiography
normal
Can be used to exclude large vessel vascular lesions such as emboli or renal
vein thrombosis.
11
DIAGNOSIS
interstitial inflammatory
infiltrate with variable numbers
Provides a definitive diagnosis.
of eosinophils, lymphocytes,
Reserved for patients who have not responded to discontinuation of the
triggering medication or who have a relative contraindication to corticosteroid and plasma cells
use.[1] [2] [3] [14]
If nephrotic syndrome is present, the pattern is usually minimal change disease,
although membranous nephropathy has also been reported.
Requires a careful risk-benefit assessment in consultation with a nephrologist.
Diagnosis
Differential diagnosis
Condition
DIAGNOSIS
Acute glomerulonephritis
Differentiating signs /
symptoms
Differentiating tests
May be asymptomatic, presenting

symptoms are indistinguishable
from acute interstitial nephritis
(AIN).
Will not respond to withdrawal of
offending medication.
Acute tubular necrosis
May be asymptomatic, presenting

symptoms are indistinguishable
from AIN.
A history of hypotension, fluid
depletion, or exposure to a
nephrotoxin known to cause
acute tubular necrosis is usually
present.
Urine shows sloughed tubular

epithelial cells or bland urinary
sediment.
Acute vascular injury
Flank pain with gross haematuria

is usually present. There may be
evidence of vasculitis elsewhere
in body.
Renal blood flow scans or

magnetic resonance angiography
shows large vessel vascular
lesions such as emboli or renal
vein thrombosis.
Acute pyelonephritis
Symptoms of fever, chill, flank

pain, nausea, and vomiting are
present.
Patients have pyuria with positive

urine culture.
Diabetic nephropathy
Nephrotic syndrome is usually

present.
Patient usually has a history of
diabetes.
offending medication (usually a
non-steroidal anti-inflammatory
drug [NSAID]).
HbA1c is elevated.
Renal biopsy is diagnostic and
shows mesangiolysis,
glomerulosclerosis, and
Kimmelstiel-Wilson nodules.
Focal segmental
glomerulosclerosis

present.
offending medication (usually an
NSAID).
Rash is absent.
Renal biopsy shows focal and

segmental sclerosis of the
glomeruli.
HIV is a known cause, and may be
positive.
12
Urine shows RBC casts and/or

large amounts of proteinuria.
Renal biopsy can distinguish from
AIN.
Diagnosis
Condition
Membranous nephropathy
Differentiating signs /
symptoms
present.
Malignancy, viral hepatitis, and
syphilis are known causes.
NSAID).
Differentiating tests
IgA nephropathy

present.
NSAID).
Renal biopsy shows thickening of

basement with sub-epithelial
electron-dense deposits.
Chest x-ray or CT scan may show
a mass consistent with a lung
tumour or other malignancy.
Stools may be haem-positive in
cases of gastrointestinal
malignancy.
Hepatitis B and C serologies or
rapid plasma reagin (RPR) syphilis
test may be positive.
Renal biopsy shows IgA deposits
on immunofluorescent
examination.
DIAGNOSIS
13
Treatment
Step-by-step treatment approach

Treatment depends on the underlying cause. Most cases are caused by medication, but acute interstitial nephritis (AIN)
can also occur in the context of chronic inflammatory disease. In general, advice should be sought from a nephrologist,
and patients who do not rapidly respond (in <1 week) to the withdrawal of the underlying cause should be referred to a
nephrologist for prompt treatment and to exclude other diagnoses, especially where a renal biopsy is indicated.
Medication related
The initial treatment of suspected or confirmed AIN is discontinuation of the offending medication. Most patients
will have resolution of their acute renal failure and a progressive return of renal function.[1] [2] [3] [4] [5] [6] [14] [35]
[36] If the patient is taking several known offending medications, it will not be clear which medication is the cause.
In this situation, all medications should be switched to drugs from a different class. For example, a penicillin would be
changed for a quinolone rather than a cephalosporin, and omeprazole would be changed for sucralfate rather than
lansoprazole.
Supportive care includes attention to fluid and electrolyte balance. All patients should have serum electrolytes, urea,
and creatinine monitored daily during the acute episode. Sodium and volume restriction may be required, along with
limitation of potassium and phosphorus intake. Diuretics may be required for treatment of fluid retention. If a diuretic
is suspected as the trigger, a diuretic from a different class should be used. Dialysis may be needed in severe cases,
but this is usually a temporary supportive measure; most patients will recover sufficient renal function to come off
dialysis.
Corticosteroid therapy has been suggested to improve the rate and extent of renal recovery, although there is limited
evidence that corticosteroids affect the final outcome. Randomised controlled trials have not yet confirmed the use
of corticosteroids, although delay in using them (up to 1 month after diagnosis) in patients who are not rapidly
improving does appear to result in worse long-term renal impairment.[36] [45] [46] [47] A short course of prednisolone
should be considered in most patients, unless corticosteroid therapy is contraindicated, if there has not been a
significant reduction in their creatinine following withdrawal of the offending agent. This should ideally be undertaken
with the results of a renal biopsy confirming the diagnosis of AIN and excluding other possible diagnoses, unless
contraindicated for other reasons. If patients relapse on withdrawal of corticosteroid treatment, a repeat course
should be given. A few patients have recurrence of renal failure every time corticosteroid therapy is discontinued;
these patients are corticosteroid dependent and will require long-term treatment.
Chronic inflammatory disease related
TREATMENT
Corticosteroids are the preferred therapy for interstitial nephritis associated with Sjogren's syndrome, sarcoidosis,
IgG4-related syndrome, SLE, and tubulo-interstitial nephritis with uveitis (TINU) syndrome. Patients with chronic
inflammatory disease may also be taking known triggering medications, and these should be discontinued. Supportive
care is the same as for medication-related episodes (monitoring of electrolytes and renal function, sodium and volume
restriction, diuretics, dialysis if needed). If patients relapse on withdrawal of corticosteroid treatment, a repeat course
should be given. A few patients have recurrence of renal failure every time corticosteroid therapy is discontinued;
these patients are corticosteroid dependent and will require long-term treatment.
Treatment details overview

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interactions, and alternative dosing. ( see Disclaimer )
14
Treatment
Acute
Patient group
medication related
chronic inflammatory disease related
( summary )
Tx line
Treatment
1st
discontinue triggering medication
plus
supportive care
adjunct
diuretic
adjunct
oral corticosteroid
adjunct
dialysis
1st
oral corticosteroid
plus
discontinue potential triggering medication
plus
supportive care
adjunct
diuretic
adjunct
dialysis
TREATMENT
15
Treatment
Treatment options
Acute
Patient group
medication related
Tx line
1st
Treatment
discontinue triggering medication
Over 100 triggering medications are known. Common
offenders include antibiotics (particularly beta-lactams),
diuretics, non-steroidal anti-inflammatory drugs
(NSAIDs), proton-pump inhibitors, antihistamines (e.g.,
cimetidine, ranitidine), allopurinol, phenytoin,
sulfadiazine, mesalazine, and warfarin. Erythromycin,
polymyxin, aciclovir, foscarnet, and vancomycin trigger
tubulo-interstitial nephritis, a variant of acute interstitial
nephritis (AIN).
Most patients will have resolution of their acute renal
failure and a progressive return of renal function when
the offending medication is discontinued.[1] [2] [3] [4]
[5] [6] [14] [35] [36]
If the patient is taking several known offending
medications, all medications should be switched to
drugs from a different class.
plus
supportive care
All patients should have serum electrolytes, urea, and
creatinine monitored daily during the acute episode.
Careful attention should be paid to fluid and
electrolyte balance. Sodium and volume restriction
may be required, along with limitation of potassium
and phosphorus intake.
adjunct
diuretic
Diuretics are used primarily for the treatment of fluid
retention. Loop diuretics are generally effective.
If a diuretic is suspected as the trigger, a diuretic from
a different class should be used.
Primary options
furosemide: 40-100 mg intravenously every 8-12
hours, maximum 600 mg/day
Secondary options
TREATMENT
torasemide: 20-200 mg intravenously once daily

OR
bumetanide: 0.5 to 1 mg intravenously every 2-3
OR
16
Treatment
Acute
Patient group
Tx line
Treatment
metolazone: 5-20 mg orally once daily
adjunct
oral corticosteroid
Corticosteroid therapy has been suggested to
improve the rate and extent of renal recovery, although
long-term outcome is generally unchanged. Routine
use has not been confirmed in randomised trials.[36]
[45] [46] [47]
A short course of prednisolone should be attempted
in most patients unless corticosteroid therapy is
contraindicated.
Most patients respond in the first 2 weeks of
treatment. The dose can be tapered as the creatinine
returns towards baseline for a total of 2-3 months
treatment.
If a patient relapses on withdrawal of corticosteroid
treatment, a repeat course should be given.
Primary options
prednisolone: 40-60 mg orally once daily for 2
weeks, then taper gradually over 2-3 months
adjunct
dialysis
Supportive dialysis is indicated in acute kidney injury
if the patient has severe symptoms, or severe fluid
balance or metabolic derangement that is not
responding to medical therapy.
chronic inflammatory disease related
1st
oral corticosteroid
Corticosteroids are the preferred therapy for
interstitial nephritis associated with Sjogren syndrome,
sarcoidosis, IgG4-related syndrome, SLE, and
tubulo-interstitial nephritis with uveitis (TINU)
syndrome.
Corticosteroid therapy has been suggested to
improve the rate and extent of renal recovery, although
long-term outcome is generally unchanged. Routine
use has not been confirmed in randomised trials.[36]
[45] [46] [47]
Most patients respond in the first 2 weeks of

treatment. The dose can be tapered as the creatinine
17
TREATMENT
A short course of prednisone should be attempted

in most patients unless corticosteroid therapy is
contraindicated.
Treatment
Acute
Patient group
Tx line
Treatment
returns towards baseline for a total of 2-3 months
treatment.
Primary options
prednisolone: 40-60 mg orally once daily for 2
weeks, then taper gradually over 2-3 months
plus
discontinue potential triggering medication

Over 100 triggering medications are known. Common
offenders include antibiotics (particularly beta-lactams),
diuretics, non-steroidal anti-inflammatory drugs
(NSAIDs), proton-pump inhibitors, antihistamines (e.g.,
cimetidine, ranitidine), allopurinol, phenytoin,
sulfadiazine, mesalazine, and warfarin. Erythromycin,
polymyxin, aciclovir, foscarnet, and vancomycin trigger
tubulo-interstitial nephritis, a variant of acute interstitial
nephritis.
If the patient is taking several known offending
medications, all medications should be switched to
drugs from a different class.
plus
supportive care
All patients should have serum electrolytes, urea, and
creatinine monitored daily during the acute episode.
Careful attention should be paid to fluid and
electrolyte balance. Sodium and volume restriction
may be required, along with limitation of potassium
and phosphorus intake.
adjunct
diuretic
Diuretics are used primarily for the treatment of fluid
retention. Loop diuretics are generally effective.
If a diuretic is suspected as the trigger, a diuretic from
a different class should be used.
Primary options
furosemide: 40-100 mg intravenously every 8-12
TREATMENT
Secondary options
torasemide: 20-200 mg intravenously once daily
OR
bumetanide: 0.5 to 1 mg intravenously every 2-3
18
Treatment
Acute
Patient group
Tx line
Treatment
OR
metolazone: 5-20 mg orally once daily
adjunct
dialysis
Supportive dialysis is indicated in acute kidney injury
if the patient has severe symptoms, or severe fluid
balance or metabolic derangement that is not
responding to medical therapy.
TREATMENT
19
Treatment
Emerging
Mycophenolate
TREATMENT
Mycophenolate has been shown, in small uncontrolled studies, to be effective in patients with frequent relapses or who
become prednisolone dependent.[46] Larger controlled studies are required to establish a role for mycophenolate in
acute interstitial nephritis (AIN) management.
20
Follow up
Recommendations
Serum urea and creatinine, and urinalysis with sediment check, should be repeated 1 month after resolution of the
acute episode, and subsequently at 3 months to ensure that no relapse has occurred.
Annual BP measurement, serum urea and creatinine, and urinalysis are necessary to detect progression of renal
disease as a residual of the prior renal insult.
Patient instructions
Patients should be encouraged to keep follow-up appointments and instructed about which medications ought to
be avoided.
Complications
Complications
corticosteroid-dependent interstitial nephritis
Timeframe
variable
Likelihood
medium
Some patients have recurrence of renal dysfunction every time corticosteroids are withdrawn. These patients are
corticosteroid dependent and require long-term corticosteroid therapy.
Corticosteroid adverse effects can be a significant source of morbidity in these patients.
chronic renal failure
variable
medium
Most patients with acute interstitial nephritis are left with a small degree of renal impairment as a residual of the prior
renal insult; the impairment is usually clinically insignificant and does not progress.
Some patients may progress to chronic kidney disease.
All patients require annual monitoring. If disease progression is detected, treatment with angiotensin-converting
enzyme (ACE) inhibitors may be required.
hypertension
variable
medium
Some patients may develop hypertension as a consequence of chronic kidney disease.

All patients require annual BP monitoring.
Patients with chronic kidney disease require ACE inhibitor therapy, but additional antihypertensive medication may
be required if hypertension is not adequately controlled by ACE inhibitors alone.
21
FOLLOW UP
Monitoring
Follow up
FOLLOW UP
Prognosis
The prognosis for acute interstitial nephritis (AIN) is good. Most patients with medication-related AIN will have significant
improvement of renal function after discontinuing the offending medication(s).[1] [3] [4] [5] [6] Only a few progress to
require dialysis, and most of these patients will regain enough renal function to come off renal replacement therapy.
However, renal function remains abnormal in a few patients with some residual renal dysfunction.[6] Tubulo-interstitial
fibrosis, on biopsy, remains a long-term consequence of AIN.[48] Some patients have multiple relapses, requiring repeated
courses of corticosteroids. A few patients become dependent on long-term corticosteroid therapy to maintain renal
function.
22
Guidelines
Diagnostic guidelines
Europe
Clinical practice guidelines: acute kidney injury
Published by: UK Renal Association
Last published: 2011
Summary: Clinical examination must include assessment of volume status, which is guided by signs (e.g. core
temperature, peripheral perfusion, heart rate, blood pressure, and jugular venous pressure). In patients presenting
with acute kidney injury, interstitial nephritis may be suspected if there is an accompanying rash. A baseline set of
laboratory investigations should be ordered, including urinalysis, biochemistry, haematology, and microbiology (urine
culture blood culture). More specific renal investigations and imaging should be considered based on the history
and clinical presentation.
Treatment guidelines
GUIDELINES
Europe
Clinical practice guidelines: acute kidney injury
Published by: UK Renal Association
Last published: 2011
Summary: Most patients can be effectively treated by adequate volume replacement, treatment of the underlying
medical condition, and avoidance of nephrotoxic medications. Bladder catheterisation is not essential but allows
measurement of hourly urine output and total urine volume.
23
References
REFERENCES
Key articles
Bhat P, Appel GB. Tubulointerstitial diseases. In: ACP medicine. New York, NY: WebMD Inc.; 2006:2027-2043.
Rossert J. Drug-induced acute interstitial nephritis. Kidney Int. 2001;60:804-817. Full text Abstract
Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. 2004;19:8-11.
Full text Abstract
Kodner CM, Kudrimoti A. Diagnosis and management of acute interstitial nephritis. Am Fam Physician.
2003;67:2527-2534. Full text Abstract
Markowitz GS, Perazella MA. Drug-induced renal failure: a focus on tubulointerstitial disease. Clin Chim Acta.
2005;351:31-47. Abstract
References
1.
Bhat P, Appel GB. Tubulointerstitial diseases. In: ACP medicine. New York, NY: WebMD Inc.; 2006:2027-2043.
2.
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3.
Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. 2004;19:8-11.
Full text Abstract
4.
Kodner CM, Kudrimoti A. Diagnosis and management of acute interstitial nephritis. Am Fam Physician.
5.
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6.
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7.
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8.
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10.
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11.
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24
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2005;351:31-47. Abstract
15.
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N Engl J Med. 1968;279:1245-1252. Abstract
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Galpin JE, Shinaberger JH, Stanley TM, et al. Acute interstitial nephritis due to methicillin. Am J Med. 1978;65:756-765.
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Pract Nephrol. 2007;3:456-461. Abstract
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Nephrol. 1983;3:38-42. Abstract
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Am J Kidney Dis. 1993;22:598-602. Abstract
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hydrochlorothiazide/amiloride. Am J Nephrol. 1995;15:270-273. Abstract
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Lyons H, Pinn VW, Cortell S, et al. Allergic interstitial nephritis causing reversible renal failure in four patients with
idiopathic nephrotic syndrome. N Engl J Med. 1973;288:124-128. Abstract
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from a single UK renal unit. Nephrol Dial Transplant. 2004;19:1441-1446. Full text Abstract
24.
Gaughan WJ, Sheth VR, Francos GC, et al. Ranitidine-induced acute interstitial nephritis with epithelial cell foot
process fusion. Am J Kidney Dis. 1993;22:337-340. Abstract
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World MJ, Stevens PE, Ashton MA, et al. Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant.
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following cyclosporine treatment. Clin Nephrol. 2005;64:155-158. Abstract
31.
Rashed A, Azadeh B, Romeh SH. Acyclovir-induced acute tubulo-interstitial nephritis. Nephron. 1990;56:436-438.
Abstract
32.
Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int. 1989;35:1257-1270. Abstract
33.
Border WA, Lehman DH, Egan JD, et al. Antitubular basement-membrane antibodies in methicillin-associated
interstitial nephritis. N Engl J Med. 1974;291:381-384. Abstract
34.
Clayman MD, Michaud L, Brentjens J, et al. Isolation of the target antigen of human anti-tubular basement membrane
antibody- associated interstitial nephritis. J Clin Invest. 1986;77:1143-1147. Full text Abstract
35.
Michel DM, Kelly CJ. Acute interstitial nephritis. J Am Soc Nephrol. 1998;9:506-515. Full text Abstract
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37.
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Wood BC, Sharma JN, Germann DR, et al. Gallium citrate Ga 67 imaging in noninfectious interstitial nephritis. Arch
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43.
Linton AL, Richmond JM, Clark WF, et al. Gallium67 scintigraphy in the diagnosis of acute renal failure. Clin Nephrol.
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44.
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26
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45.
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28
Contributors:
// Authors:
James Marsh, MD
Consultant Nephrologist and Joint Medical Director
Renal Services, Epsom & St Helier Hospitals, Carshalton, UK
DISCLOSURES: JM declares that he has no competing interests.
Kate Shiell, MD
Consultant
Renal Services, Epsom & St Helier Hospitals, Carshalton, UK
DISCLOSURES: KS declares that she has no competing interests.
// Acknowledgements:
Dr James Marsh and Dr Kate Shiell would like to gratefully acknowledge Dr Alice Appel and Dr Gerald Appel, previous contributors
to this monograph.
DISCLOSURES: AA and GA declare that they have no competing interests.
// Peer Reviewers:
Irfan Moinuddin, MD
Assistant Professor
Chicago Medical School, Rosalind Franklin University, Lombard, IL
DISCLOSURES: IM declares that he has no competing interests.
Catherine Clase, BA, MB, MSC, FRCPC
Associate Professor
Nephrologist, McMaster University, Hamilton, Ontario, Canada
DISCLOSURES: CC declares that she has no competing interests.
Robert Mactier, MD, FRCP
Consultant Nephrologist/Lead Clinician
Renal Unit, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, UK
DISCLOSURES: RM declares that he has no competing interests.

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Acute interstitial nephritis

The right clinical information, right where it's needed

Last updated: May 18, 2015

Step-by-step diagnostic approach

History & examination factors

Step-by-step treatment approach

Treatment details overview

Usually resolves once the offending medication is discontinued.