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`Icodextrin Hypersensitivity in a
`CAPD Patient
`
`Icodextrin, a maltodextrin glucose polymer, is
`increasingly being used as an alternative to
`glucose as the active osmotic agent for peritoneal
`dialysis. It has improved ultrafiltration properties
`(1, 2) due to the reduced absorption of icodextrin
`compared to glucose. It may also lead to improved
`diabetic control, although this has not been
`clinically proven (1). Previous studies into its use
`have shown that it is generally well tolerated with
`very few side effects (1, 2). We report here a case
`of severe cutaneous hypersensitivity reaction to
`icodextrin.
`
`CASE
`
`REPORT
`
`This 48-year-old woman with a 37 -year history
`of insulin-dependent diabetes developed end-stage
`renal failure secondary to diabetic nephropathy in
`August 1995. Her medical history
`included
`ischemic heart disease, mitral valve disease
`(requiring a mitral valve replacement in 1993) and
`diabetic
`retinopathy. She was
`started on
`continuous
`ambulatory
`peritoneal
`dialysis
`(CAPD) (3 x 2.0 L 1.36% glucose exchanges
`during the day, 1 x 2.0 L 3.86% glucose exchange
`overnight). Dialysis went well initially although
`her diabetic control was suboptimal with a HbAlc
`of 8.1% (NR 3.8-6.0). Her peritoneal equilibrium
`test (PET) at three months from the start of CAPD
`showed that at four hours her creatinine (DIP) was
`0.79 and her glucose (D/Do) was 0.27, indicating
`
`
`
`
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2084, P. 1
`
`

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`
`antibiotics. The likely source of this episode was
`felt to be from the affected skin around the exit
`site of the peritoneal catheter, which became
`weepy through most of the duration of the rash.
`During this episode, her biochemistry remained
`stable, with a potassium of 4.2-4.9 mmol/L, a urea
`of 20-23 mmol/L, a creatinine of 446-560
`μmol/L, an albumin of 25-31 g/L, and a
`bicarbonate level of 24-27 mmol/L.
`DISCUSSI
`
`ON
`
`The diagnosis in this patient is an exfoliative
`dermatitis secondary to an allergic reaction to the
`icodextrin. We can comfortably exclude her other
`medications as the cause, since she had been on
`them
`for at
`least
`five months with no
`dermatological complications noted. We also
`considered
`the
`handcleansing
`spray
`[Frekaderm®, containing ethanol, 2benzyl-4-
`chlorphenol, o-phenylphenol and alkyl-dim-
`ethylbenzylammonium chloride] as a possible
`cause of the allergic reaction. However, the rash
`was generalized and did not start at sites exposed
`to the spray, i.e. , the hands. Moreover, she
`continued to use the spray for her conventional
`CAPD until the time ofher peritonitis, by which
`time there was already a marked improvement in
`her skin condition. There was also no other
`change in the patient's diet or lifestyle during that
`time.
`This case report also highlights the potential
`danger of superimposed infection following an
`allergic
`reaction with
`significant
`skin
`involvement. Although not proven, we feel that
`the breakdown in the skin caused by the allergic
`reaction would have contributed to the CAPD
`peritonitis in this patient. She had previously not
`had any episode of CAPD peritonitis or exit-site
`infection. The
`isolated organism
`from
`the
`peritonitis,Staphylococcus epidermidis, is part of
`normal skin flora and would
`
`
`
`a high transporter status. Despite this, her drain
`volume was 2,650 mL over four hours on a 2.0 L
`exchange. Her adequacy of dialysis, as measured
`by KTN, was 1.49 (local target > 1.7). After six
`months, she started having problems with fluid
`balance. She was found not to be ultrafiltering on
`a 2.0 L 1.36% glucose dialysate over four hours
`and she required 2 x 2.0 L exchanges of3.86%
`glucose dialysate per day. On these exchanges she
`was only filtering about 400600 mL per day.
`Nine months into her dialysis, it was decided to
`change herto a night-time exchange of7 .5%
`icodextrin to improve ultrafiltration. Ten days
`later, she developed a widespread maculopapular
`rash over her abdomen, arms, hands, legs, and
`lower back. Her face and upper trunk were
`spared. She complained of marked pruritus over
`the rash, severe enough to interfere with her sleep
`at night. Over the course of the following days the
`rash spread, and at day 13, it became exfoliative
`and erythrodermic (see Figures 1 and 2). When
`she was seen in our outpatient department on day
`15, a diagnosis of exfoliative dermatitis secondary
`to an allergic reaction was made. An anti-
`histamine and aqueous cream were prescribed.
`She had not had any change in medication during
`the past three months and her medication included
`porcine insulin, sodium valproate (for a diagnosis
`of epilepsy), warfarin,
`fludrocortisone
`(for
`autonomic postural hypotension), ferrous sulphate
`and human recombinant erythropoeitin.
`Her icodextrin dialysate was stopped and she
`reverted back to conventional glucose peritoneal
`dialysate. Over the course of the next five days
`her rash rapidly improved and there were no
`further evidence of new desquamation. However,
`she developed Staphylacaccus epidermidis CAPD
`peritonitis, which
`responded
`to
`the usual
`treatment of intraperitoneal
`
`
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2084, P. 2
`
`

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`
`by the rash and exfoliation.
`Hypersensitivity to the icodextrin is the most
`likely explanation for her severe cutaneous
`reaction. Three cases of dermatological reactions
`to icodextrin have been reported (3), with patients
`presenting with vesicular rash on their palms. In
`those cases the patients were able to continue on
`the
`icodextrin
`and
`the
`vesicular
`rash
`spontaneously resolved. Icodextrin is a polymer
`of glucose with a mean molecular weight
`of20,000 D, but is broken down as maltose (4). It
`is also similar in structure to another naturally
`occurring glucose polymer, dextran. The
`difference between dextrin and dextran is the
`polymer
`link
`(α-1,4
`and α-
`l,6Iinkages, respectively). The latter, used as
`plasma expander or as an anticoagulant, is well
`known to cause allergic type reactions including
`anaphylactoid
`reactions
`(5,6). Although
`the
`epitope(s) for the allergic reaction have not been
`identified, there have been studies that have
`confirmed the immunogenicity of dextrans (7, 8).
`It is plausible that either the same or a similar
`epitope may also be
`responsible
`for
`the
`hypersensitivity reaction seen with icodextrin.
`
`
`
`
`
`
`
`
`
`
`
`Michael K.-L. Lam-Po-Tang
`Michael R. Bending
`Jonathan T.C. Kwan
`
`South West Thames Renal
`Unit
`St. Helier Hospital
`Carshalton, Surrey, England
`REFERENCES
`
`1. MistryCD, Gokal R, Peers E. A randomized
`multicenter clinical trial comparing isosmolar
`icodextrin with
`hyperosmolar
`glucose
`solutions in CAPD. MIDAS study group.
`Multicenter Investigation of Icodextrin in Am-
`bulatory Peritoneal Dialysis. Kidney Int 1994;
`46(2):496-503.
`2. Mistry CD, Gokal R. The use of glucose
`polymer (icodextrin) in peritoneal dialysis: an
`overview. Perit Dial Int 1994; 14(Suppl
`3):S158-61.
`3. Wilkie ME, Plant M, Edwards, Brown CB.
`Indications and outcomes for the use of
`icodextrin -experience of 60 patient years
`(abstract). In XXXIIIrd Congress of
`the
`European Renal Association
`-European
`Dialysis and Transplant Association, June
`1996. Amsterdam, Netherlands; 355.
`and
`4. Alsop RM. History,
`chemical,
`pharmaceutical development oficodextrin.
`Perit Dial Int 1994; 14(Suppl 2):S5-12.
`5. Berg EM, Fasting S, Sellevold OF. Serious
`complications with dextran 70 despite hapten
`prophylaxis. Is
`it best avoided prior
`to
`delivery? Anaesthesia 1991; 46(12):1033-5.
`6. RingJ. Anaphylactoid reactions to plasma
`substitutes.
`Int Anesthesiol Clin 1985;
`23(3):67-95.
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2084, P. 3