Transcript Acute Interstitial Nephritis (AIN)

Acute Interstitial Nephritis
?
Etiology
• A review of three series
with a total of 128 patients
reported the following
distribution of causes of
acute interstitial nephritis :
– Drugs, with antibiotics
responsible for one-third of
these cases — 71 %
– Infection-related — 15 %
– Idiopathic — 8 %
– Tubulointerstitial nephritis
and uveitis (TINU)
syndrome (5 %)
– Sarcoidosis — 1 %
Pathophysiology
Drug Induced AIN
•
The most common drug causes of
AIN include:
–
–
–
–
–
–
–
–
–
–
–
•
NSAIDs, including selective
COX-2 inhibitors
Penicillins and cephalosporins
Rifampin
Sulfonamides, including TMPSMX.
Furosemide, bumetanide, thiazidetype diuretics
Ciprofloxacin >>other quinolones
Cimetidine >> other H2 blockers
Allopurinol
PPIs- omeprazole and
lansoprazole
Indinavir
5-ASA (eg, mesalamine)
Unifying factor-?
Infection Induced AIN
• Infections —
–
–
–
–
–
Legionella
Leptospirosis
Cytomegalovirus
Streptococci
Many other bacterial, viral, and
other infections have been
associated with acute
interstitial nephritis, including
infection with:
•
•
•
•
Corynebacterium diphtheriae,
Epstein-Barr virus,
Yersinia,
Polyomavirus
Autoimmune Disorders
• Numerous autoimmune disorders have been
associated with AIN. These include:
– Sarcoidosis,
– Sjogren's syndrome, and others.
• In addition, patients with:
• SLE
• Wegener's granulomatosis
– often have an AIN accompanying the characteristic
glomerular disease and, rarely, present with AIN in the
absence of glomerular disease
Clinical Presentation
• Acute or subacute onset of nausea,
vomiting, malaise, and/or no
symptoms.
• The urine sediment -WBC, RBC, and
WBC casts;
– Eosinophiluria- >1%-• also found with atheroemboli, GNs,
prostatitis
• Usually normal or only mildly
increased protein excretion (less than
1 g/day).
• Onset of the disorder ranges from 3-5
days with a 2nd exposure to the
offending agent, to as long as several
weeks with a first exposure.
– However, the latent period may be as
short as one day with rifampin or as
long as 18 months with a NSAID
Clinical Presentation
• Allergic-type symptoms
–
–
–
–
Rash — 15 %
Fever — 27 %
Eosinophilia — 23 %
Triad of rash, fever, and
eosinophilia — 10 %
Clinical Presentation
Laboratory
• Laboratory — some combo of the following, with some
variation based upon the underlying cause:
– An acute rise in SCr, which (if drug-induced) is temporally related
to administration of the offending drug.
– Eosinophilia and eosinophiluria.
• Except NSAID AIN-- fever, rash, and eosinophilia are typically
absent
– A urine sediment that usually reveals WBCs, RBCs, and WBC
casts
– Normal or only mildly increased protein excretion (< 1 g/day)
• Concurrent nephrotic syndrome due to minimal change disease can be
seen with NSAIDs and in selected cases induced by ampicillin,
rifampin, interferon, or ranitidine
– Signs of tubulointerstitial damage, such as the Fanconi syndrome
and RTAs
Clinical Presentation
Laboratory- 2008 KI
• Typically think pyuria
with urine eos, no
heme, and allergic
symptoms, but
– 18% of patients do
NOT have pyuria
– Incidence of hematuria
essentially equivalent
to pyuria, and
• Double the rate of
eosinophilia, rash, or
fever (approximately)
Diagnosis
Non-Invasive
• Gallium scanning
– Diffuse, intense, bilateral uptake,
consistent with the interstitial
inflammatory infiltrate.
– Although similar findings can
occasionally be found in other
disorders, the gallium scan is
almost always negative in acute
tubular necrosis,
– A positive gallium scan is
suggestive of AIN in the presence
of the above characteristic
findings.
– A negative scan does not preclude
the diagnosis, since false negative
results can be seen
Diagnosis
Invasive
• Renal Biopsy
– ? Use 20 gauge to limit
complication risk
Prognosis
Do we need to treat?
– Acute dialysis is often required, but only about 10 percent of
patients remain dialysis-dependent
– Recovery of kidney function is often incomplete with persistent
elevation of the Scr concentration in up to 40 percent of patients.
In a review of published series of AIN:
• In pts with a peak serum creatinine >5, the serum creatinine at the end
of follow-up was less than 1.2 (50%) and 1.7 mg/dL (69%)
• The final serum creatinine concentration did not correlate with the
maximum value during AIN.
• Clinical indicators of a decreased likelihood of recovery include :
– Prolonged renal failure (greater than three weeks),
– AIN associated with NSAID use, and
– Certain histologic findings--including interstitial granulomas, interstitial
fibrosis, and tubular atrophy (but data variable)
Prognosis
Prognosis
Can you use peak Scr to determine the high risk group?
Treatment
Steroids
• Theoretical Construct
– Most cases of AIN are allergic reactions as suggested by the following:
• The majority of the immune reactions are directly to drugs or drug-induced
antigens;
• Systemic manifestations of hypersensitivity are often present;
• AIN is not a dose-dependent phenomenon and only a small percentage of
patients develop the condition;
• AIN typically improves following cessation of the drug; and
• AIN may rapidly recur with accidental re-exposure to the drug or a closely
related antigen.
– T-cells may have an important pathogenetic role in the development of
AIN as suggested from the following observations:
•
•
•
•
•
The timeframe of illness presentation,
10 to 14 days after exposure to the drug,
is typical of a T-cell mediated syndrome;
the interstitial infiltrate in the kidney is composed primarily of lymphocyte
most patients demonstrate activation of lymphocytes against drug haptens
Treatment
Only two controlled trials
• American Journal of Medicine,1978--14
patients with methicillin-induced AIN, avg
Scr of >8 mg/dL. 8 treated/6 observed
2
60
50
1.5
40
Steroids
No Treatment
30
20
Steroids
No Treatment
1
0.5
10
0
Final Scr
0
Day of Recovery
Treatment
Only two controlled trials
• Pusey, et al; Q J Med
– Treated 7 of 9 patients with steroids- treatment
group had a better outcome
Treatment
Retrospective
1990--27 patients with biopsy-proven AIN; 15 were druginduced (1 methicillin, 2 ampicillin, 3 NSAIDS, 3
cimetidine,and the rest other), 9 infection, and 3
idiopathic
– The 10 patients who did not improve following
discontinuation of the drug or treatment of the infection
(cause of AIN not specified) were given steroids within
5 to 20 days of biopsy (IV methylprednisolone 3 g/day
for three days, or oral prednisone 40 to 60 mg/day for
three to four weeks).
• In six patients, serum creatinine normalized within
approximately one month, and the remaining four had partial
improvement in kidney function
Treatment
Retrospective
Early Steroid Treatment, KI 2008
• Strongly suggests that steroid treatment is indicated in DIAIN and that it should be started immediately or soon after
the diagnosis to avoid the risk of incomplete renal function
recovery.
– No significant side effects attributable to steroids were observed,
probably due to the short duration of the treatment (8–12 weeks).
– If offending agent simply d/cd, initial improvement is frequently
exhausted and many patients will exhibit chronic renal insufficiency
as a consequence of a DI-AIN episode.
• Focus on the importance of an even mildly reduced renal function, both
in terms of a future progression into end-stage renal failure and of an
increased risk of cardiovascular events.
Treatment
Retrospective
Early Steroid Treatment, KI 2008
• 52 patients were treated with steroids 23±17 (range 2–68)
days after the withdrawal of the offending drug (Group 1).
• Although steroid doses and duration of the treatment were
not uniform due to the multi-center character of the study,
the most common scheme of treatment consisted of:
– IV pulses of prednisone (250–500 mg daily for 3–4 consecutive
days) followed by oral prednisone (1 mg/kg/day) tapering off over
8–12 weeks.
• The remaining 9 patients did not receive steroids (Group
2).
Treatment versus No Treatment
60
4
45
3.5
40
50
40
Treated
30
Non-Treated
35
3
30
2.5
25
T reated
20
N o n-T reated
15
20
0.5
5
0
0
0
Complete Recovery
1.5
1
10
10
2
F inal Scr
C hro nic D ialysis
Further Baseline Characteristics
• Notice
– Average pre-treatment creatinines approximately 5
– Required < two weeks of therapy on average
Non-responders versus responders
to steroid therapy
Argue for early treatment
Non-responders versus responders
How quickly do you need to treat?
Non-responders versus responders
When will you see a response?
4-6 weeks and both curves flatten
Non-responders versus responders
What are the risks?
No significant side effects
attributable to steroids were
observed, probably due to the
short duration of the treatment (8–
12 weeks).
Clarkson, NDT 2004
A similarly sized negative study
Clarkson, NDT 2004
A similarly sized negative study
Clarkson, NDT 2004
A similarly sized negative study
Clarkson, NDT 2004
A similarly sized negative study
• Explanation by steroid
“defenders”
– Very advanced disease
– 58% either on dialysis or
started within one week of
biopsy
– 44% were NSAID related
• Believed to be less steroid
responsive
• But subgroup analysis in
this study showed no
difference
Which drug is associated with which
profile?
Methacillin, NSAIDs, Other Medications
Which drug is associated with which
profile?
Methacillin, NSAIDs, Other Medications
Methacillin
Other
NSAIDS
Subgroup Analysis of Clark Study
Final Creatinine in the Steroid treatment group
700
600
500
400
300
200
100
0
ALL
NSAID
Baseline
1 month
6 months 12 months
?
•
•
•
•
•
•
•
•
4 major categories of etiologies
11 major drug categories
Typical urinary findings. Hematuria?
Percent of patients with classic allergic manifestations
How is NSAID associated AIN different?
What is the usual outcome of AIN?
Does the peak Scr tell you anything about the prognosis?
How quickly must you treat if you are going to see
benefit?
• When do you see a response from steroids?
• When should you throw in the towel on steroids?