Pathology of Resin-Induced Gastrointestinal Damage: Report of 15 Cases and Review of Literature
Smiley Annie GEORGE, Issam FRANCIS
Department of Histopathology, Mubarak Al Kabir Hospital, JABRIYA, KUWAIT
Keywords: Resins, Kayexalate, Sevelamer, Gastrointestinal tract injury
Objective: Medication resins such as Kayexalate and Sevelamer used in the setting of chronic kidney disease for the correction of hyperkalemia and hyperphosphatemia are associated with gastrointestinal mucosal injury. In this study we describe the clinico-pathological features of Resin-induced gastrointestinal mucosal injury highlighting the histo-morphological appearances and differential diagnoses. The aim of this study is to increase the awareness of pathologists and clinicians alike to an under-reported etiology and pattern of intestinal mucosal injury related to medical resin therapy which may at times pose a clinical emergency.
Material and Method: The archives of the Department of Histopathology, Mubarak Al Kabir hospital were analyzed for cases of resin-induced gastrointestinal mucosal injury between 2013 and 2018.
Results: Of the 15 cases, Kayexalate crystals were identified in 7 cases, Sevelamer in 5 cases and both together were seen in 3 cases. Resin crystals were identified in the gastric antrum&duodenum (3 cases), colon (9 cases in the left colon, 2 cases in the right colon) and anal canal (1 case). The histological tissue reactions included mucosal necrosis (1 case), inflammatory polyps (2 cases), mucosal ulcerations with granulation tissue formation (10 cases), perforation (1 case) , and luminal crystals (1 case).
Conclusion: Accurate and timely recognition of the resin crystals in biopsy samples with clinical correlation is mandatory to avoid serious complications.
The gastrointestinal tract (GIT) is a target of several types
of medical drugs including nonsteroidal anti-inflammatory
drugs, iron pills, Taxol, Cellcept, bisphosphonates,
colchicines and oral resins used in renal failure patients 1
Resins which include Kayexalate, Sevelamer and bile acid
sequestrant agents are non-absorbable medications that
facilitate ion exchange. Their main therapeutic effect is
exerted within the lumen of the GIT. Reported clinical
adverse effects related to the GIT include constipation,
nausea, diarrhea and vomiting. In addition, mucosal
ulceration including wall perforation and post-inflammatory
stricture formation are among the serious complications
which may present as a clinical emergency 2-12.
Pathologists are increasingly required to identify such
resin-induced damage in small biopsies. This however, can
be very challenging since changes reported overlap with
those seen in inflammatory bowel disease, ischemic colitis,
infectious colitis as well as microscopic colitis. One of the main distinctive features of resin mucosal damage is the
identification of resin crystals. This is reported in roughly
in 75% of cases according to a study by Gonzalez et al.
13. It is logical to think that familiarity of the reporting
pathologist with the different morphological appearances
of such resins coupled with a high index of suspicion with
clinical correlation is crucial.
In the current study, we present a series of 15 cases
encountered in our teaching hospital in which resins were
identified in various types of surgical and biopsy material of
the GIT with discussion of their pathological features and
correlation with other inflammatory disorders of the GIT.
A retrospective review of our archives between 2013 and
2018 uncovered 15 cases where resins were identified in
biopsy materials. The Hematoxylin and Eosin (H&E)
stained sections were evaluated for general morphology.
This was complemented by examination of two additional
ancillary stains: Periodic Acid-Schiff with diastase (PAS/D) and Zeihl-Neelsen Acid-Fast Bacillus (AFB) stain. The
following patient details were extracted from the electronic
file: age, sex, type of specimen, clinical history provided
on the request forms; patient clinical data from the case
files were retrieved in addition to other laboratory results
at the time of admission. These were correlated with the
type of crystal seen and the associated tissue reactions in
Kayexalate crystals were identified by their mosaic pattern
of rectangular shaped “fish scales” showing perpendicular
points of intersection; they appeared purple on H&E
(Figure 1A, B), turned magenta on PAS/D (Figure 1C) and
stained black with acid-fast stains (Figure 1D) 8,13,14.
These crystals were refractile but did not polarize.
Click Here to Zoom
|Figure 1: A) Gastric antral biopsy with ulceration and purplish Kayexalate crystals (H&E; x50). B) Purplish Kayexalate crystals with
rectangular shaped fish-scales (H&E; x400). C) Magenta colored Kayexalate crystals (PAS/D; x200). D) Black colored Kayexalate crystals
(Acid Fast stain; x200).
Sevelamer crystals were non-polarizable with broad,
curved, and irregularly spaced “fish scales” and displayed a 2-toned color imparted by bright pink linear accentuations
and a rusty yellow background (Figure 2A, B). They
acquired a violet color on PAS/D and maintained their
internal structure (Figure 2C) and magenta color on AFB
stain (Figure 2D)8.
Click Here to Zoom
|Figure 2: A) Colonic ulceration with acute inflammatory exudate and Sevelamer crystals (H&E; x50). B) Sevelamer crystals with a
2-toned color imparted by bright pink linear accentuations and a rusty yellow background and irregularly spaced fish-scales (H&E;
x400). C) Sevelamer crystals with violet hue (PAS/D; x200). D) Magenta colored Sevelamer crystals (AFB; x200).
A total of 15 cases were analyzed for this study. The
clinicopathological features are summarized in Table I
the 15 cases, 3 were surgical resections and 12 were biopsy
samples. The patients were 10 males and 5 females and
the age range was 41- 82 years. Kayexalate crystals were
identified in 7 cases, Sevelamer in 5 cases and both together
were seen in 3 cases. Resin crystals were identified in the
upper GIT (duodenum & gastric antrum, 3 cases) (Figure
) and colon (11 cases of which 9 were in the left side of
the colon and 2 cases in the right side) (Figure 2A
). Two cases showed crystals in the perianal soft tissue associated
with fistula and the other in the anal canal associated
with extensive tissue necrosis (Figure 3B
). Among the
gastrointestinal cases, three cases had concomitant
pathology such as ulcerative colitis, diverticular disease
and colonic adenocarcinoma. The remainder of the cases
presented as ulcerations endoscopically.
Click Here to Zoom
|Table I: Summary of clinical details, site of biopsy and histological features.
Click Here to Zoom
|Figure 3: A) Colonic biopsy with Kayexalate induced ulceration and granulation tissue formation (H&E; x50). B) Anal canal mucosal
necrosis with Sevelamer crystals (H&E; x200). C) Gross pathology of colonic resection with mucosal ulcerations smeared with exudates.
D) Ulcerated colonic mucosa with Sevelamer crystals and acute inflammatory exudate (H&E; x50).
None of the pathology request forms had any relevant
clinical history such as background of chronic kidney
disease (CKD) or any history of intake of these resins.
Retrieval of data from case files showed up background of
CKD and relevant drug history in 13 cases. No supporting
clinical histories were obtained in two cases.
Kayexalate is a non-absorbable ion-exchange resin
consisting of sodium polystyrene sulfonate (SPS). It is
mainly used for treating hyperkalemia in chronic renal
failure and can be administered orally or locally as an enema.
An osmotic laxative (Sorbitol) is usually added to reduce
the risk of constipation and impaction. The gastrointestinal
complications are seen more frequently in uremic patients
and in post-transplant patients 2,4,5
. Both Kayexalate
crystals and the hyperosmotic sorbitol diluent used are
considered to cause marked mucosal injury 3
Overall, the clinicopathological features associated with
Kayexalate crystals in the current report are similar to those in the literature. Ulcerations were identified in 7 of
the gastrointestinal biopsy cases and were associated with
inflamed granulation tissue (Figure 1A, 3A). In one of
the cases with concomitant adenocarcinoma, Kayexalate
crystals were noted in the lumen but without any
inflammatory tissue reaction.
Sevelamer, the newest in the family of resin medications,
is a phosphate binding anion-exchange resin which is used
to treat and prevent hyperphosphatemia caused by chronic
renal failure. It is a cross-linked polymeric amine that also
binds bile acids and is not systemically absorbed.
The histopathology of Sevelamer crystals in the GIT
was described by Swanson et al. They noted that their
presence was associated with mucosal abnormalities
such as inflammation, ulceration, ischemia and necrosis 8. Though limited, a literature search has revealed
16 case reports of Sevelamer-induced gastrointestinal
complications such as recto-sigmoid ulcerations, mass
forming lesions, and diverticular rupture 9-12. Our
cases also showed mucosal necrosis (Figure 3B), mucosal
ulcerations with granulation tissue formation (Figures 2A;
3C,D) and perforation. The mode of injury is theorized to
be linked to CKD associated gastrointestinal dysmotility,
abnormal secretion and absorption which potentially
increase the risk of Sevelamer crystallization and deposition
in tissue 8,12. However larger studies are warranted for
elucidating the exact mechanism of injury.
Of note, the histological tissue reactions seen in resininduced
gastrointestinal injury significantly overlap with
other gastrointestinal pathologies such as acute infective
colitis, ischemic colitis, inflammatory bowel disease, etc. Most of our cases had a clinical and/or endoscopic
diagnosis of either ischemic colitis or inflammatory bowel
disease. In this scenario, morphological recognition of the
crystals supported by the clinical history helps in clinching
Resins have been described in unusual locations and we
also found them in the peri-renal soft tissue of a graft
nephrectomy case and the peri-anal soft tissue in a case
of peri-anal fistula. Morphological features compatible
with Kayexalate crystals were identified in the peri-anal
soft tissue which clinically presented as a fistula but no
supporting clinical data was available in this case. The
graft nephrectomy showed both Kayexalate and Sevelamer
crystals admixed with suppurative inflammation in the
peri-renal soft tissue. The presence of vegetable matter
signaled an underlying intestinal perforation which was
masked in this case 14.
Non-classical resin morphology poses problems in the
accurate recognition of these crystals on H&E. These
crystals can show overlapping tinctorial qualities which
are affected by the background pH 13. In one of our
cases, Sevelamer crystals were purplish on routine stain
and overlapping in appearance with Kayexalate but were
magenta colored on AFB stain.
It should be noted that fish scale patterns can also be
produced by dystrophic calcifications, gall bladder calculi,
some food particles, large bile acid sequestrant fragments
and even specimen ink used in grossing. Examining the
entire histologic section as well as requesting multiple
levels and special stains such as PAS/D and AFB stain can
help in the accurate recognition of these crystals. Among
the special stains, PAS/D stain is reported to provide
inconsistent results 13. From a practical stand point,
though non-classical in location and morphology, it is
prudent to document the presence of the resins in biopsy
reports. Histological mimics of these crystals include
Cholestyramine, vegetable matter and Crospovidone.
Cholestyramine is a bile acid sequestrant that is used to
treat hyperlipidemia. Its crystals are rhomboid in shape
and are smooth and glassy without a mosaic pattern. They
stain bright orange-red on H&E, variably gray or hot pink
on PAS/D, lack internal “fish scales,” and are unassociated
with mucosal injury 8.
Lanthanum carbonate, a noncalcemic phosphate binder
also causes gastrointestinal mucosal injury and is
characterized histologically by prominent lamina propria
histiocytes containing calcium like eosinophilic mineral
Plant or vegetable matter, which is commonly encountered
in gastrointestinal biopsies, can also mimic fish-scales.
However, they are usually more rectangular and often
resemble “window panes”. In addition, vegetable material
typically will not show the characteristic colors of the
Crospovidone and Microcrystalline cellulose can also show
up in gastrointestinal biopsies but are innocent bystanders
with no specific clinic-pathologic associations. They are
water-insoluble, nonabsorbable pharmaceutical fillers
or binders incorporated into medications (i.e. tablets) to
facilitate drug delivery. Crospovidone is non-birefringent
and has coral/sponge shape segments composed of a pink
core and purple coat (Figure 4A). Microcrystalline cellulose
is brightly birefringent, resembling cotton fibers, but with a
more prominent matchstick shape and clear color (Figure
Click Here to Zoom
|Figure 4: A) Coral shaped purplish Crospovidone crystals (H&E; x 400). B) Matchstick shaped clear colored microcrystalline cellulose
(H&E; x 400).
Careful review of the medication history is mandatory in the
definite diagnosis of these crystals. Unfortunately, usually
no clinical data will be provided in the request forms. None
of our cases had any clinical data and particularly drug
history mentioned in the requests. Retrieval of the patient
case file is helpful in these instances.
In conclusion, the aim of this study is to increase the
awareness of pathologists and clinicians alike to an
under-reported etiology and pattern of intestinal mucosal
injury related to medical resin therapy. Resin-induced
intestinal injury may at times pose a clinical emergency.
Their presence in biopsy material should therefore be
reported soon to the treating clinician to watch for any
serious untoward consequences. The clinicians should
be increasingly aware of this pattern of intestinal damage
and add it to their differential diagnosis in the proper
clinical setting. Pathologist must be aware of this pattern of
intestinal injury and report it promptly. Availability of the
complete clinical history and other laboratory tests at the
time of pathological evaluation will aid in establishing the
CONFLICT of INTEREST
The authors declare no conflict of interest.
1) Panarelli NC. Drug-induced injury in the gastrointestinal tract.
Semin Diagn Pathol. 2014; 31:165-75.
2) Akagun T, Yazici H, Gulluoglu MG, Yegen G, Turkmen A.
Colonic necrosis and perforation due to calcium polystyrene
sulfonate in a uremic patient: A case report. NDT Plus. 2011;4:
3) Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick
JF, Williams GM. Intestinal necrosis due to sodium polystyrene
(Kayexalate) in sorbitol enemas: Clinical and experimental
support for the hypothesis. Surgery. 1987;101:267-72.
4) Joo M, Bae WK, Kim NH, Han SR. Colonic mucosal necrosis
following administration of calcium polystyrene sulfonate
(Kalimate) in a uremic patient. J Korean Med Sci. 2009;24: 1207-11.
5) Scott TR, Graham SM, Schweitzer EJ, Barlett ST. Colonic necrosis
following sodium polystyrene sulfonate(Kayexalate)-sorbitol
enema in a renal transplant patient; Report of a case and review
of literature. Dis Colon Rectum. 1993:36:607-9.
6) Trottier V, Drolet S, Morcos MW. Ileocolic perforation secondary
to sodium polystyrene sulfonate in sorbitol use: A case report.
Can J Gastroenterol. 2009; 239109:689-90.
7) Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract
in uremic patients as a result of sodium polystyrene sulfonate
(Kayexalate) in sorbitol: An under-recognized condition. Am J
Surg Pathol. 1997;219:60-9.
8) Swanson BJ, Limketkai BN, Liu TC, Montgomery E, Nazari K,
Park JY, Santangelo WC, Torbenson MS, Voltaggio L, Yearsley
MM, Arnold CA. Sevelamer crystals in the gastrointestinal tract
(GIT): A new entity associated with mucosal injury. Am J Surg
Pathol. 2013; 37:1686-93.
9) Yamaguchi T, Ohyama S,Furukawa H, Sato N, Ohnishi I,
Kasashima S, Kawashima A, Kayahara M. Sigmoid colon
diverticula perforation associated with sevelamer hydrochloride
administration: A case report. Ann Med Surg (LOND).
10) Okwara C, Choi C, Park JY. Sevelamer-induced colitis
presenting as a pseudotumour. Clin Gastroenterol Hepatol.
11) Tieu C, Moreira RK, Song LM, Majumder S, Ppadakis KA, Hogan
MC. A case report of sevelamer-associated recto-sigmoid ulcers.
BMC Gastroenterol. 2016;16:20.
12) Yuste C, Merida E, Hernandez E, Garcia-Santiago A, Rodriguez
Y, Munoz T, Gomez GJ, Sevillano A, Praga M. Gastrointestinal
complications induced by sevelamer crystals. Clin Kidney J.
13) Gonzalez RS, Lagana SM, Szeto O, Arnold CA. Challenges in
diagnosing medication resins in surgical pathology specimens: A
crystal-clear review guide. Arch Pathol Lab Med. 2017;141:1276-82.
14) George SA, Francis I. “Fish-scales” and graft nephrectomy: Unexpected
findings at an unusual site. J Nephropathol. 2017;6:349-51.
15) Khurram M, Montogomery E. Lanthanum carbonate-associated
injury to the small intestine. Diagnostic Histopathology.
16) Shaddy SM, Arnold MA, Shilo K, Frankel WL, Harzman AE,
Stanich PP, Singhi AD, Yearsley MM, Arnold CA. Crospovidone
and microcrystalline cellulose: A novel description of
pharmaceutical fillers in the gastrointestinal tract. Am J Surg