Treatment of acute interstitial nephritis

Authors
Abhijit V Kshirsagar, MD, MPH
Ronald J Falk, MD
Section Editor
Paul M Palevsky, MD
Deputy Editor
Alice M Sheridan, MD
Disclosures: Abhijit V Kshirsagar, MD, MPH Consultant/Advisory Boards: Fresenius (phosphate
binders). Ronald J Falk, MD Nothing to disclose. Paul M Palevsky, MD Grant/Research/Clinical
Trial Support: Spectral Diagnostics (sepsis). Consultant/Advisory Boards: Sanofi (acute kidney
injury); Complexa (acute kidney injury). Alice M Sheridan, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
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All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Sep 2014. | This topic last updated: Jan 15,
2014.
INTRODUCTION Acute interstitial nephritis (AIN) classically presents as acute
renal failure (ARF) after the use of known offending drugs and is associated with
the typical urinary findings of pyuria, hematuria, and white cell casts [1-4]. Less
frequently, AIN is secondary to infection or sarcoidosis. Signs of systemic allergy,
such as a maculopapular rash, peripheral eosinophilia, and eosinophiluria, are
present in some patients [5,6].
Proteinuria is common, but excretion is usually <1 g/day. However, nephrotic range
proteinuria may occur and presumably reflects cytokine-induced injury to the
glomerulus. It is most often seen with AIN caused by nonsteroidal antiinflammatory
drugs (NSAIDs) [7,8]. Histologically, AIN is characterized by the infiltration of Tcells, macrophages, and plasma cells in the interstitial compartment.
The treatment of AIN due to drugs will be reviewed here. The manifestations and
diagnosis of AIN and the approach to the management of patients diagnosed with
infection-induced AIN, tubulointerstitial nephritis and uveitis, and renal sarcoidosis
are presented separately. (See "Clinical manifestations and diagnosis of acute
interstitial nephritis" and "Tubulointerstitial nephritis and uveitis (TINU
syndrome)" and "Renal disease in sarcoidosis".)
PROGNOSIS For drug-induced acute interstitial nephritis (AIN), prognostic data
are most available for methicillin, which is no longer available because it was

estimated to cause AIN in up to 17 percent of patients who were treated for more
than 10 days [2,9].
Recovery of renal function was observed in the great majority of cases of AIN due
to methicillin, either with discontinuation of the offending drug or with glucocorticoid
therapy [2,9,10]. The proportion recovering kidney function appears to be lower in
AIN due to drugs other than methicillin [2,10-12]. The prognosis of AIN due to other
inciting factors (eg, sarcoidosis, infection) is not well described. Acute dialysis is
often required [13-15], but only approximately 10 percent of patients remain
dialysis dependent [3,4,11].
Recovery of kidney function is often incomplete, with persistent elevation of the
serum creatinine concentration in up to 40 percent of patients [2,3]. As an example,
in a review of published series of AIN, in which many patients had a peak serum
creatinine >5.5 mg/dL (500 micromol/L), the serum creatinine at the end of followup was less than 1.2 and 1.7 mg/dL (110 and 150 micromol/L) in 49 and 68
percent, respectively [2]. 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 nonsteroidal
antiinflammatory drug (NSAID) use, and certain histologic findings (including
interstitial granulomas, interstitial fibrosis, and tubular atrophy) on kidney biopsy.
Biomarkers for acute kidney injury (AKI), such as kidney injury molecule-1 (KIM-1)
and urinary neutrophil gelatinase-associated lipocalin (NGAL), may provide
additional prognostic information, but are not used clinically for this purpose at this
time [16,17].
TREATMENT Discontinuation of the potential causative agent is a mainstay of
therapy, and immunosuppressive therapy has been employed if there is no
subsequent improvement in kidney function. The optimal therapy of acute
interstitial nephritis (AIN) is unknown since there are no randomized controlled
trials or large observational studies. Conclusions cannot be readily drawn from
available reports as patient populations differ and results are discordant.
General issues The following theoretical considerations provide a context for
the approach to the management of AIN:
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 closelyrelated 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 lymphocytes [9,18]; and most patients demonstrate activation of
lymphocytes against drug haptens [19-21].
Given these considerations, the most important aspect of therapy of AIN is
cessation of the potentially offending agent (or treatment of the underlying
infection).
Glucocorticoid therapy Immunosuppressive therapy has been employed to
treat AIN that persists despite discontinuation of the offending agent. However, the
benefits of therapy are inconclusive since the available data are conflicting and
there are no randomized controlled trials.
Improvement in kidney function following glucocorticoid therapy for AIN has been
suggested by several uncontrolled reports [2,9,13,22]. The following illustrate these
findings:
One series evaluated 14 patients with methicillin-induced AIN who had an
average peak serum creatinine of 8 mg/dL (704 micromol/L) [9]. The eight
patients treated with glucocorticoids recovered more quickly (9 versus 54
days) and had a lower final plasma creatinine concentration (1.4 versus
1.9 mg/dL [123 versus 167 micromol/L]) than the six who received no therapy.
One series evaluated 27 patients with biopsy-proven AIN; 15 were druginduced (1 methicillin, 2 ampicillin, 3 nonsteroidal antiinflammatory drug
[NSAID], 3cimetidine, rest other), 9 were associated with infection, and 3 were
idiopathic [22]. The 10 patients who did not improve following discontinuation
of the drug or treatment of the infection (cause of AIN not specified) were
given glucocorticoids within 5 to 20 days of biopsy (intravenous
[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.
A retrospective multicenter study examined the effects of steroids on the
recovery of renal function in 52 patients with biopsy-proven drug-induced AIN
compared with 9 untreated patients with AIN [23,24]. Despite the low number
of control patients, significant benefits with steroids included a lower
percentage of dialysis by 18 months (4 versus 44 percent) and lower serum
creatinine level (2.1 versus 3.7 mg/dL [186 and 327 micromol/L]). Among
treated patients, those who started steroids within seven days of withdrawal of
the offending drug were significantly more likely to recover renal function than
those who received steroids after this period (odds ratio [OR] 6.6, 95% CI 1.333.6).
Other retrospective series demonstrated no benefit from glucocorticoid therapy
[2,4,10,14,15]. One report, for example, included 42 cases of biopsy-proven AIN
(44, 33, and 7 percent due to NSAIDs, antibiotics, and proton pump inhibitors,
respectively) [4]. Twenty-six patients were treated with IV methylprednisolone for
three days, followed by oral prednisone (initial dose 0.75 mg/kg per day, tapered

over three to six weeks), and the remaining 16 were not treated. Baseline serum
creatinine was somewhat higher in the glucocorticoid group (7.9 versus
6.2 mg/dL [700 versus 545 micromol/L]). There was no difference in serum
creatinine between the two groups at 1, 6, and 12 months (at one year, the mean
serum creatinine was 1.60 mg/dL (144 micromol/L) in both groups).
There are several possible explanations for a lack of effect from glucocorticoids in
the negative studies: the patients treated with steroids had more severe disease,
as manifested by higher maximum serum creatinine concentrations; a significant
proportion of the patients had NSAID-associated AIN, which is less likely to
respond to glucocorticoid therapy; and steroids are not effective in the treatment of
AIN [2,4,8].
Given the potential for benefit and the relative safety of short-term therapy, it
seems reasonable to treat patients with corticosteroids if they do not have
significant improvement in the serum creatinine within three to seven days after
discontinuation of the offending agent.
In such cases, a renal biopsy is preferred to confirm AIN, as well as to exclude
other possible diseases or interstitial nephritis with significant chronic damage (eg,
marked interstitial fibrosis, tubular atrophy, and minimal or no acute inflammation),
in which case immunosuppressive therapy might not be indicated. An empiric trial
of glucocorticoid therapy is a reasonable alternative in patients with a strongly
suggestive history of acute drug-induced AIN when kidney biopsy is not feasible.
The optimal dose and duration of therapy are unclear. One approach is to
administer prednisone at a dose of 1 mg/kg per day (to a maximum of 40 to 60 mg)
for a minimum of one to two weeks, beginning a gradual taper after the serum
creatinine has returned to or near baseline, for a total therapy duration of two to
three months. Most patients will improve in the first one to two weeks.
In patients with more severe acute renal failure (ARF), therapy may be initiated
with IV methylprednisolone (0.5 to 1 g/day for three days).
The duration of glucocorticoid therapy varies widely among the many (cohort)
studies in the literature, from days to 12 weeks [2,9,13,22]. There are no controlled
intervention trials on the subject. Assuming that the agent inciting allergic interstitial
nephritis has been discontinued, it is reasonable to shorten the duration of therapy
if the kidney function returns to normal before the 12 week endpoint, especially if
the patient is experiencing side effects from the therapy, such as elevated blood
glucose levels.
Other agents There is limited experience with treating AIN in patients who are
glucocorticoid dependent (ie, relapse during the prednisone taper), glucocorticoid
resistant (as with NSAID-induced disease), or cannot tolerate glucocorticoids.
There are case reports and small series using mycophenolate mofetil (MMF)
andcyclosporine [25,26], and anecdotal use of cyclophosphamide.

The largest reported experience included eight patients with biopsy-proven AIN
who had received glucocorticoids for at least six months and could not discontinue
therapy without worsening of the serum creatinine; MMF was given for 13 to 34
months [25]. All were able to discontinue corticosteroids, and only two patients had
no improvement in serum creatinine (one who was antineutrophil cytoplasmic
antibody (ANCA)-positive and one with AIN of unknown etiology). The applicability
of these results to drug-induced AIN is limited since only two patients had AIN
known to be due to drugs.
MMF may be considered only in patients who are glucocorticoid dependent,
glucocorticoid resistant, or unable to tolerate glucocorticoid therapy and have
biopsy-proven AIN.
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Basics topic (see "Patient information: Acute interstitial nephritis (The
Basics)")
SUMMARY AND RECOMMENDATIONS
Most cases of acute interstitial nephritis (AIN) due to drugs improve
spontaneously, although kidney function may not return to baseline. The rate
of recovery of AIN due to other inciting factors is less clear.
(See 'Prognosis' above.)
It is essential that the potentially offending agent be immediately
discontinued. No additional intervention is required in patients who have
minimal elevations in the serum creatinine or those who begin to recover
within three to seven days. For patients who do not fulfill these criteria, we
recommend obtaining a kidney biopsy (unless already done) to confirm the
diagnosis and to help guide subsequent therapeutic decisions.
(See 'Glucocorticoid therapy' above.)
For patients with biopsy-confirmed AIN who do not have significant chronic
damage, we recommend therapy with glucocorticoids (Grade 1C). Therapy
may also be instituted in patients with a strongly suggestive history of druginduced AIN in whom a biopsy cannot be performed. An exception to this
general recommendation is AIN due to nonsteroidal antiinflammatory drug

(NSAID) therapy, which appears to be much less likely to respond to

glucocorticoid therapy. (See 'Glucocorticoid therapy' above.)
One possible regimen is prednisone at a dose of 1 mg/kg per day (to a
maximum of 40 to 60 mg) for a minimum of one to two weeks, beginning a
gradual taper after the serum creatinine has returned to or near baseline, for a
total therapy duration of two to three months. (See 'Glucocorticoid
therapy' above.)
The optimal approach to the therapy of biopsy-proven AIN is not known in
patients who are glucocorticoid dependent (ie, relapse during
the prednisone taper), glucocorticoid resistant, or cannot tolerate
glucocorticoids. The largest experience has been with mycophenolate mofetil
(MMF). (See 'Other agents' above.)
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