ACKD

The Association of Mesalamine With Kidney

Disease
Avinash Adiga and David S. Goldfarb

The package inserts for products containing 5-aminosalicylic acid, or mesalamine, include the following language regarding the
risk of adverse kidney effects: “renal impairment, including minimal change nephropathy, acute and chronic interstitial
nephritis, and rarely renal failure, has been reported in patients given products such as mesalamine delayed-release tablets
that contain mesalamine or are converted to mesalamine.” In this article, we review the data regarding this nephrotoxicity
and the recommendations regarding appropriate monitoring. Chronic interstitial nephritis is a rare occurrence in patients
treated with these drugs for Crohn disease and ulcerative colitis. Patients often present with asymptomatic reductions in
glomerular filtration rate, without accompanying pyuria, skin lesions, or eosinophilia, unlike cases of acute interstitial nephritis.
Drug cessation is usually associated with improved kidney function. However, if left undetected, more prolonged exposure to
the drug can lead to irreversible kidney failure and end-stage kidney disease. No convincing studies demonstrate efficacy of
treatment with corticosteroids. Frequent monitoring of serum creatinine, especially in the first years after initiation of therapy,
is recommended.
Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
Key Words: 5-Aminosalicylic acid, Chronic kidney disease, Crohn disease, Nephritis, interstitial, Ulcerative colitis

T he package inserts for products containing 5-

aminosalicylic acid (5-ASA), or mesalamine, include
the following language regarding the risk of adverse kid-
ney effects: “Renal impairment, including minimal change
nephropathy, acute and chronic interstitial nephritis, and
rarely renal failure, has been reported in patients given
products such as mesalamine delayed-release tablets that
contain mesalamine or are converted to mesalamine.”1
In this article, we review the data regarding this nephro-
toxicity and the recommendations regarding appropriate
monitoring.
PHARMACOLOGY
There are several 5-ASA derived compounds: sulfasala-
zine, mesalamine, olsalazine, and balsalazide. They consti-
tute first-line drugs in the treatment of inflammatory
bowel disease (IBD), including both Crohn disease and ul-
cerative colitis. The drugs are anti-inflammatory, and are
thought to work by blocking cyclooxygenase, thereby in-
hibiting prostaglandin production in the bowel. Inhibition
of the release of leukotrienes and other cytokines are also
likely to contribute to efficacy. These effects occur locally,
due to increased mucosal production of arachidonic acid
metabolites and other mediators of inflammation.
Sulfasalazine was first used in the United States in 1950
and is sold under the trade name Azulfidine. Upon reach-
ing the colon sulfasalazine is metabolized by the intestinal
microbiome into 5-ASA and sulfapyridine, and has an oral
From Division of Nephrology, NYU Langone Health, New York, NY (A.A.);
and Division of Nephrology, NYU School of Medicine, New York Harbor VA
Healthcare System, New York, NY (D.S.G.).
Financial Disclosure: D.S.G. is an owner of Dr. Arnie’s Inc. and A.A. has no
relevant financial interests.
Address correspondence to David S. Goldfarb, MD, Division of Nephrology,
New York Harbor VA Healthcare System, 423 East 23rd St./111 G, New York,
NY 10010. E-mail: david.goldfarb@nyulangone.org
Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2019.09.002
bioavailability of only 15% of the ingested drug. 5-ASA re-
mains in the colon while sulfapyridine is absorbed and
then further metabolized. 5-ASA is thought to act locally
and then passes into feces. Sulfapyridine is nondialyzable
because of significant binding to plasma proteins, but its
metabolites are dialyzed.2 Sulfasalazine is excreted in the
urine, requires no dose adjustment in renal impairment,
but should be used with extreme caution. The sulfapyri-
dine component of sulfasalazine causes, in a dose-related
manner, cyanosis of uncertain cause, transient reticulocy-
tosis, hemolytic anemia, rash, skin discoloration, and vom-
iting.3 Because of these adverse effects, active 5-ASA
preparations were developed and largely replaced sulfasa-
lazine.
Another result of the adverse effects associated with sul-
fasalazine was the development of mesalamine, which re-
leases 5-ASA from an enteric coating or a semipermeable
membrane, in a pH-dependent manner. It has a better
overall side effect profile.4 Mesalamine is also known as
mesalazine. Mesalamine was approved for medical use
in the United States in 1987, is available in generic forms,
and is also sold under the brand names Lialda, Asacol,
and Pentasa, which are based on different release formula-
tions (see Table 1). It can be administered by mouth or via
the rectum for ulcerative colitis. Mesalamine is currently
the most widely used therapy and has replaced sulfasala-
zine as it is better tolerated. Chemically, the drug is 5-
amino-2-hydroxybenzoic acid and has a molecular weight
of 153.14 Da. Approximately 28% of ingested mesalamine
is systemically absorbed. Mesalamine is also excreted by
the kidneys so that dose adjustment is recommended
based on kidney function. Both the drug and its metabo-
lites, including its major metabolite, N-acetyl-5-ASA, are
effectively cleared by dialysis.5
5-AMINOSALICYLIC ACID PREPARATIONS AND
KIDNEY DISEASE
Animal studies have proven that kidney is the principal
target organ for adverse effects of 5-ASA. At higher doses

72 Adv Chronic Kidney Dis. 2020;27(1):72-76

 Mesalamine and Kidney Disease 73

it can also cause renal papillary necrosis in rats; however, reported that 5-ASA was the only medication patients
this lesion is not seen in humans.6,7 were taking.16
The most common, if very infrequent, kidney-related Male patients are more severely affected than female
adverse reaction due to 5-ASA preparations is interstitial patients and half of the cases occurred within the first
nephritis. There are both acute and chronic forms of this year of treatment with mesalamine. Some cases can
disorder. The classic form of acute interstitial nephritis is present up to 5 years after the initiation of treatment.
thought to be due to a hypersensitivity reaction, is not Average time for mesalamine-induced interstitial nephritis
dose-related, and usually occurs in the first is between 4 and 48 months after the initiation of drug. In 1
6 months after initiation of prescription of the drug. This study of 151 adjudicated world-wide cases, 68% were
sort of 5-ASA-related interstitial nephritis can present as males, nephrotoxicity occurred at a median age of
a separate entity or rarely, as a part of systemic DRESS 39.4 years, and the median time for development of renal
syndrome (Drug Reaction with Eosinophilia and Systemic injury after starting 5-ASA was 3.0 years.17 The median
8
Symptoms). In such cases, fever, hepatitis, skin lesions, mesalamine dose in 1 report was 1.5-2.3 g/d.18
and lymphadenopathy may also be present. The classic A genome-wide association study of those 151 cases of
presentation includes pyuria and eosinophilia. mesalamine-induced interstitial disease compared the pa-
The more insidious form of kidney disease most tients with a control cohort of 1748 Crohn disease and 2361
frequently presents as an indolent, severe, chronic, pro- ulcerative colitis cases.17 There was a signal for the devel-
9
gressive, but asymptomatic interstitial nephritis. These opment of nephrotoxicity in the human leukocyte antigen
cases do not appear to be manifestations of hypersensitiv- (HLA) region (single nucleotide polymorphism rs3135349,
ity reactions as fever, eosinophilia, and skin rashes are usu- odds ratio 2.04, P ¼ 1 3 1027). A 3-fold increased risk of
ally not seen. These cases probably therefore represent a renal injury after 5-ASA administration was noted with
cell-mediated reaction. Given their relative symptomatic carriers of the risk allele and the signal was strengthened
silence, they may not be recognized promptly and may if cases were limited to those with kidney biopsy-proven
be present for months or interstitial nephritis. A high
longer before being detected prevalence of this single
CLINICAL SUMMARY
when an abnormal serum nucleotide polymorphism
creatinine is first demon- limits its clinical utility in
strated.  The most common adverse kidney effect of 5-ASA determining risk so geno-
preparation is interstitial nephritis.
The rate of mesalamine- typing was not recommen-
associated renal disease has  Chronic interstitial nephritis is usually asymptomatic, ded as a tool to guide
often, but not consistently, leading to delayed presentation, more commonly in first treatment choices or moni-
been thought to be more com- year after initiation of drug. toring intervals.17
mon than sulfasalazine-  Higher doses of 5-ASA are associated with tubular A study of patients with
associated disease, occurring proteinuria and Fanconi syndrome. IBD treated with greater
in less than 1 in 500 pa- amounts of 5-ASA showed
tients.10-12 According to a UK  Renal tubular acidosis and minimal change disease due to an increased prevalence
5-ASA are also reported.
General Practice Research of tubular proteinuria.19
Database calculation, Accompanying enzyme
incidence of mesalamine-related kidney disease is about levels suggested that proximal tubular epithelial cells
0.17 cases per 100 patients per year.13 Over a period of were the source. There were no other manifestations of
7 years, 393 and 514 adverse reactions per million prescrip- proximal tubular dysfunction suggestive of Fanconi syn-
tions of mesalamine and sulfasalazine were identified. drome. However, the study could not distinguish between
Twenty-three percent of the adverse reactions to mesal- proteinuria deriving from 5-ASA exposure and being the
amine were renal-related, which amounts to about 100 result of active IBD. There is no convincing evidence that
in a million prescriptions and no serious renal complica- the development of tubular proteinuria is a precursor or
tions were reported for sulfasalazine.4 This raised predictor of the development of interstitial nephritis.
the possibility that this report was incomplete, with One case of interstitial nephritis attributed to mesalamine
sulfasalazine-associated renal complications under- was accompanied by renal tubular acidosis.20 There are a
14
reported or under-recognized. A systematic review of small number of case reports attributing minimal change
the topic concluded that “the nephrotoxicity potential disease with typical nephrotic syndrome to sulfasalazine
of mesalazine and sulfasalazine seems to be and mesalamine for IBD.21
similar, and, if differences exist, they are probably mi-
nor.”7 In a survey of nephrologists from Belgium, France,
and Netherlands, all cases of IBD with renal impairment, DIAGNOSIS
whether or not they were associated with mesalamine The chronic interstitial nephritis resulting from mesal-
therapy, were sought.15 Forty cases of IBD with renal fail- amine use may be irreversible and can progress to end-
ure were reported by 71 nephrologists, with interstitial state kidney disease. The poor prognosis underscores the
nephritis the leading diagnosis. Only 26 of 40 patients importance of prompt diagnosis of kidney impairment
had been treated with mesalamine. Numerous case and discontinuation of 5-ASA treatment. Diagnosis of
reports of mesalamine-induced interstitial nephritis mesalamine-induced renal dysfunction is challenging

Adv Chronic Kidney Dis. 2020;27(1):72-76

74 Adiga and Goldfarb
Table 1. 5-Aminosalicylic Acid Formulations Available in United States
Medication
Sulfasalazine
Mesalamine
Delayed and extended release tablet
Delayed release enteric-coated granules in capsule
Controlled release capsule
Olsalazine
Balsalazide
Capsule
Tablet
because patients with the greatest decline in glomerular
filtration rate often present with asymptomatic azotemia.
The low incidence of renal disease makes it further chal-
lenging, since measuring serum creatinine is not sensitive
enough to detect early changes, even when pathological
changes consistent with interstitial nephritis are demon-
strated. Studies attempting correlation of urinary markers
of renal damage and 5-ASA treatment, hoping to refine
risk, have revealed mixed results. Currently, there are no
recommendations to measure urine biomarkers in patients
who are at risk for chronic kidney disease as the result of
mesalamine. Therefore, despite the poor sensitivity, and
often late nature of serum creatinine measures, they
remain a frequent, if unsatisfactory, method of diagnosing
chronic interstitial nephritis. Urinalysis is often relatively
normal, with few if any white blood cells and minimal pro-
teinuria. A partial or complete improvement in kidney
function upon stopping the drug and worsening after
resuming the drug supports the role of mesalamine in gen-
eration, development, and maintenance of the interstitial
inflammatory response. Persistently abnormal kidney
function after drug cessation then constitutes an indication
for kidney biopsy.
DIFFERENTIAL DIAGNOSIS: INFLAMMATORY BOWEL
DISEASE AND KIDNEY DISEASE
IBD is a chronic systemic disorder mainly involving the
gastrointestinal tract, but extraintestinal manifestations,
including kidney disease, are not uncommon.22 Renal
manifestations are seen in about 4-23% of patients with
longstanding disease and may be considered secondary
to disease itself or due to side effects of therapy. The
most common kidney complications of IBD are uric acid
and calcium oxalate nephrolithiasis, nephrocalcinosis, im-
mune complex glomerulonephritis, and secondary
amyloidosis.23 These disorders may be considered in the
differential diagnosis of patients treated with 5-ASA deriv-
atives who develop reduced glomerular filtration rate.
Patients with IBD have 10-100 times higher risk to
develop renal stones, which further increases with bowel
resection due to uncontrolled disease. Stone-related pyelo-
nephritis, hydronephrosis, and ureteric obstruction can
also be seen.24 Intestinal inflammation due to IBD results
in malabsorption of bile salts and fatty acids, which bind
to intraluminal calcium, thereby decreasing the amount
of calcium binding to oxalate. The result is enteric
hyperoxaluria: increased intestinal oxalate absorption,
Dosage Trade Name (US)
500 mg Azulfidine (Pfizer), generic
1200 mg Lialda (Cosmo)
375 mg Apriso (Salix Pharmaceuticals)
250, 500, 1000 mg Pentasa (Shire US Inc)
250, 500 mg Dipentum (Alaven Pharmaceuticals)
750 mg Colazal (Salix Pharmaceuticals)
1100 mg Giazo (Salix Pharmaceuticals)
hyperoxaluria, and calcium oxalate stones.25 Intestinal
fluid and bicarbonate losses lead to metabolic acidosis
and increased ammoniagenesis. The result is a decrease
in urine pH predisposing to the formation of uric acid
stones.26 Imaging studies to rule out nephrolithiasis are
appropriate in these patients due to their higher risk. Renal
ultrasound is often used for diagnosis of asymptomatic
stones in this population, although computed tomography
has higher sensitivity.
Sulfonamides such as sulfapyridine are relatively poorly
soluble and may cause crystalluria, which in turn may be
associated with acute kidney injury.27 Rarely, kidney
stones are also seen, with typical episodes of renal colic re-
sulting. Under-recognition of sulfasalazine-induced neph-
rolithiasis might be possibly due to association between
IBD and oxalate stones. Failure to demonstrate renal
calculi on imaging in sulfasalazine-treated patients does
not exclude sulfasalazine-induced crystalluria as precipi-
tates of such metabolites have low attenuation on
computed tomography and are poorly visualized on ultra-
sonography.
Systemic manifestations of secondary amyloidosis can be
seen in about 0.3-10.9% of Crohn disease patients and from
0% to 0.7% in ulcerative colitis patients. IBD especially
Crohn disease is noted among the more common causes
of renal amyloid A, AA type, amyloidosis.28 These patients
are distinguished from those with interstitial nephritis
given their frequent nephrotic range albuminuria and
more striking hematuria. Cases of immunoglobulin A
(IgA) nephropathy, immunoglobulin M (IgM) nephropa-
thy, membranous nephropathy, mesangiocapillary
glomerulonephritis, focal segmental glomerulosclerosis,
and antiglomerular basement membrane glomerulone-
phritis have all been reported in association with IBD. Pre-
sentations include hematuria, albuminuria, oliguria, along
with edema and elevated creatinine levels. In a retrospec-
tive series of 83 patients with IBD, IgA nephropathy was
the most common kidney histology (24%).10 Tubulointer-
stitial inflammation may or may not be present with any
of the glomerular histologic lesions.
Glomerulonephritis is usually directly associated with
intestinal or biliary disease activity, and kidney function
improves with remission of bowel inflammation.
Tubular abnormalities may account for about 20-30% of
renal dysfunction in IBD patients. Urinary enzymes beta-
N-acetyl-D-glucosaminidase, dipeptidyl peptidase-4, and
alanine aminopeptidase were elevated in both active and
Adv Chronic Kidney Dis. 2020;27(1):72-76
 Mesalamine and Kidney Disease
inactive Crohn disease patients even in the presence of
normal creatinine levels and in treatment of naïve patients,
suggesting that persistent tubular dysfunction and tubular
proteinuria is due to disease per se.11 The possible mecha-
nisms for renal involvement in IBD include genetic factors,
infectious agents, circulating bacterial endotoxins, and
immune-complex deposition. It is also hypothesized that
renal involvement is independent of bowel disease and
can be related to metabolic disorders that develop in IBD.12
Interstitial nephritis that may not easily be distinguished
from the 5-ASA-induced disease has been reported in pa-
tients with Crohn disease who were not exposed to the
drug, some of whom first presented with kidney disease
and bowel disease.23
HISTOLOGY
Renal biopsy in mesalamine-related kidney disease shows
chronic interstitial nephritis. It can be differentiated from
acute interstitial nephritis, as up to 58% of cases show
only chronic inflammatory changes in the interstitium
and 20% of cases show acute-on-chronic interstitial inflam-
mation.17 In the interstitium, mild fibrosis, tubular atro-
phy, and lymphocytic cell infiltrates are present. Direct
tissue immunofluorescence for immunoglobulins is nega-
tive.29 The renal interstitial inflammation can persist
several months after stopping the drug. Granulomatous
interstitial nephritis with non-caseating granulomas can
also be seen on biopsy and is thought to be from IBD per
se but also is possibly drug induced.10,30
TREATMENT
Kidney function mostly improves to a degree after stop-
ping mesalamine but significant reductions in glomerular
filtration rate can persist despite withdrawal of the drug.
Recovery of kidney function to baseline occurs in 85% of
patients if the drug is stopped within 10 months of initia-
tion of therapy, but renal recovery is seen in only one-
third of patients if the time to diagnosis and drug with-
drawal is longer than 18 months.23,31 At least 10% of these
patients progress to end-stage kidney disease.32 No
consensus exists regarding the use of corticosteroids for
treatment of chronic interstitial nephritis. There are several
anecdotal case reports suggesting some benefit and no ran-
domized controlled trials.7 The result is that the benefit of
anti-inflammatory therapy cannot be considered
evidence-based. Given that caveat, 1 review promotes a
trial of high dose steroids (60 mg/d for up to 3 months),
with consideration of pulsed intravenous methylpredniso-
lone in severe cases.31
RENOPROTECTIVE EFFECTS OF 5-AMINOSALICYLIC
ACID
In contrast to the above discussion, animal studies have
also shown that 5-ASA inhibits nitric oxide production
and expression at therapeutically relevant concentrations
in a dose-dependent manner.33 An ischemia-reperfusion
injury model study suggested that 5-ASA, when
compared to controls, significantly reduced serum creati-
nine in rats subjected to ischemia reperfusion, possibly
due to nitric oxide scavenging effects.34 In another rat
Adv Chronic Kidney Dis. 2020;27(1):72-76
75
study, 5-ASA was effective in preventing acrylamide-
induced nephrotoxicity due to its antioxidative
properties.35
RECOMMENDATIONS
FDA recommends cautious use of mesalamine or other
compounds which contain or are converted to mesalamine
or its metabolites in patients with known renal dysfunc-
tion or history of kidney disease. All patients must have
an evaluation of kidney function prior to initiation of me-
salamine and periodically while on therapy. American
Gastroenterology Society (2010) recommends to monitor
kidney function before initiating mesalamine and every
3-6 months for the first year and then annually.36 Current
British Society of Gastroenterology guidelines (2011)
recommend annual monitoring of kidney function in pa-
tients taking 5-ASA agents, and the European Crohn’s
and Colitis Organization (2012) recommends monitoring
every 3-6 months in high-risk patients.37,38 A survey in Eu-
rope showed kidney function is monitored every 2 years
on average.17 Some authors promote a longer course of
more frequent monitoring, such as monthly for the first
3 months, every 3 months for the next 9 months, every
6 months thereafter, and annually after 5 years of treat-
ment.31 Patients with pre-existing renal impairment, with
concomitant use of other potential nephrotoxic drugs or
comorbidities, need more frequent monitoring of kidney
function while on 5-ASA therapy.
CONCLUSIONS
The chronic tubulointerstitial nephritis associated with
exposure to 5-ASA and mesalamine carries a significant
risk of irreversibility. Its therapy is simply cessation of
the drug with some authors advocating for trials of cortico-
steroids, with only anecdotal suggestions of benefit.
Avoidance of continued exposure to the drug once this
rare disorder commences is therefore the best option.
Only frequent monitoring of serum creatinine, especially
in the first years of initiation of therapy, appears to be
the means of identifying the disorder before it progresses
to an irreversible and catastrophic stage.
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Adv Chronic Kidney Dis. 2020;27(1):72-76