Icodextrin‐induced acute generalized exanthematous pustulosis in a patient with peritoneal dialysis

Icodextrin has been widely prescribed for peritoneal dialysis (PD) patients with inadequate ultrafiltration, but icodextrin induced acute generalized exanthematous pustulosis (AGEP) has been not well recognized in clinical practice. We described a young‐aged female with IgA nephropathy and end stage kidney disease under continuous automated peritoneal dialysis. She developed skin erythema with exfoliation over the groin 7th day after initiation of icodextrin based PD dialysate. Initially, her scaling skin lesion with pinhead‐sized pustules affected the bilateral inguinal folds, and then it extended to general trunk accompanied by pruritus. She was admitted because of deterioration of skin lesion on 14th day of icodextrin exposure. She was afebrile and physical examination was notable for widespread erythematous papules with pruritus extending over her groins and trunk. Pertinent laboratory examination showed leukocytosis of 18 970 cells/μL with neutrophile count of 17 642 cells/μL (92.3%), and c‐reactive‐protein: 3.39 mg/dL. Skin biopsy revealed multifocal sub corneal abscess with papillary dermal edema, and upper‐dermal neutrophilia with perivascular accentuation, consistent with the diagnosis of AGEP. After discontinuation of PD, she underwent temporary high‐flux haemodialysis with treatment of steroid and antihistamine. Her dermatologic lesion resolved without any skin sequalae completely within 4 days, and she underwent icodextrin‐free peritoneal dialysis at 17th day. This case highlighted the fact that icodextrin‐induced AGEP should be early recognized to avoid inappropriate management.


| INTRODUCTION
Icodextrin, a high molecular glucose polymer that can be slowly absorbed through the peritoneal cavity, is able to sustain peritoneal ultrafiltration for peritoneal dialysis patients with ultrafiltration failure. 1 Although icodextrin is relative safe and has provided better ultrafiltration function, several adverse reports related to icodextrin have been shown.It has been reported that incidence of icodextrin-associated complications ranged from 32.6% to 14.3%, including non-bacterial peritonitis (32.6%), upper respiratory tract infection (23.4%), and cutaneous rash (range from 2.3% to 18.9%). 2Compared to non-bacterial peritonitis, icodextrin-associated acute generalized exanthematous pustulosis (AGEP) has been reported but not well recognized clinically. 3e features of AGEP manifests with acute onset of numerous sterile and non-follicular pustules on a background of erythema, commonly exhibiting on the trunk and intertriginous flexure, and leukocytosis accompanied by fever. 4,5AGEP typically progresses rapidly, with symptoms developing within several days.Early recognition of AGEP induced by icodextrin is essential to cease causative agent immediately for the prevention of severe adverse reaction, such as insufficiency of internal organ. 5Upon icodextrin withdrawal, skin lesions resolved within 1 weeks, characterized by gradual exfoliation without new macules. 5Our case highlights that early recognition of AGEP after icodextrin infusion in PD patient could prevent potentially dermatologic complications.

| CASE REPORT
A 31-year-old female with history of hypertension and IgAN-related ESKD under CAPD for 10 months suffered from acute eruption of generalized skin rash 7 days after starting 7.5% icodextrin PD prescription and then was admitted due to deteriorated skin lesions.Before icodextrin exposure, her prescription for automated peritoneal dialysis was 4 exchanges per night in 8 h on the cycler with a fill volume of 1700 mL of 1.5% dextrose for each exchange, followed a daytime dwell with 1500 mL of 2.5% dextrose solution.Because of ultrafiltration failure, a daytime dwell was changed to 1500 mL of a 7.5% dextrose solution.
During admission, she was afebrile with normal blood pressure, heart rate, and respiratory rate.She denied a history of allergy to food or specific medication and only took Amlodipine and Olmesartan for controlling blood pressure.Otherwise, she did not take any new medications such as antibiotics or non-steroidal anti-inflammatory drugs.
On physical examination, she had pale conjunctiva and there were no signs of lymphadenopathy.Of note, confluent papules with diffuse exfoliation, featuring with positive Nikolsky sign, exhibited on the trunk and thigh accompanied by pruritus and tingly.Pinhead-sized pustules only emerged on intertriginous flexure erythema (Figure 1A).
After eruption of skin rash, the papulopustular lesion successively spread to her extremities and face, showing flexural accentuation with intolerant purity and tingly.Pustules manifested within areas of erythema, complicated by systemic inflammation characterized by leukocytosis and elevated CRP levels, on the 14th day post-infusion of icodextrin.Skin biopsy revealed multifocal sub-corneal abscess parakeratosis and superficial perivascular neutrophilic infiltration at upper dermis (Figure 1B), consistent with the diagnosis of icodextrin-related AGEP.Based on worsened adverse reactions, high-flux haemodialysis was performed for toxins removal.The adjunctive treatment included intravenous betamethasone (4 mg twice daily for 2 days), followed by a shift to oral dexamethasone (4 mg once daily) along with antihistamine.Subsequently, a characteristic healing process marked by widespread desquamation occurred (Figure 1C).Complete resolution of skin lesions (Figure 1D) was achieved after 4th day of icodextrin withdrawal.There were no adverse skin reactions after resuming original automated peritoneal dialysis regimen with 4 exchanges per night in 8 h on the cycler with a fill volume of 1700 mL of 2.5% dextrose for each exchange, followed a daytime dwell with 1500 mL of 2.5% dextrose solution on the 17th day of icodextrin withdrawal afterwards.

| DISCUSSION
We reported this PD patient who developed AGEP at 7th day after exposure of icodextrin.Although icodextrin-induced dermatologic  complication has been reported in few cases, AGEP is one of this complication but not well early recognized in clinically.The recognition of AGEP should be highly raised in PD patients who exhibit acute eruption of skin rash after initial exposure to icodextrin.Therefore, physicians should be alert to the possibility of AGEP to ensure timely diagnosis and management.From literature and our case, the 11 cases show temporal correlations between the development of skin lesion associated with icodextrin exposure, as shown in Table 1.Females were more susceptible to icodextrin-related skin lesions, primarily on the trunk and extremities, with rare mucous membrane involvement.
The onset time were within 7-14 days.Among these reported cases in Table 1, five patients had diabetes mellitus who may be prone to volume overload and required icodextrin to reduce glucose overexposure and provide better control of fluid status.Therefore, icodextrin related AGEP developed in diabetic patients could attribute to poor skin hygiene and micro-perfusion.Extra-dermatologic symptoms were occasionally associated with onycholysis.Only two cases (including our case) without history of diabetes mellitus exhibited erythema with non-follicular pustules and laboratory findings revealed leukocytosis.
The skin biopsy performed in both two cases were compatible with the diagnosis of AGEP.Three patients were satisfactory to adjuvant treatment with steroid and antihistamine, which improved skin lesion in resolution within 3 to 5 days.Conspicuously, resolution of skin lesion in our case under adjunctive treatment appeared more rapid than other cases.
To evaluate the potential culprit drug for AGEP in our case, we had applied Naranjo adverse drug probability scale to the administrated drugs, and icodextrin was the only one indicating the 'probable' association (5 points) to the adverse reactions to skin lesion (Table 1).
The Naranjo score to other concomitant drug including sevelamer carbonate and darbepoetin all showed 'doubtful' association. 6From literatures, two cases subjected to icodextrin rechallenge exhibited recurrent skin lesion, favour definitive icodextrin withdrawal. 7,8erefore, early recognition of icodextrin-related AGEP was crucial to avoid misdiagnosis of other dermatoses and to discontinue icodextrin infusion.
To date, the mechanisms of icodextrin causing AGEP remain uncertain, which could possibly be explained by immunological recall response triggered by icodextrin itself. 3Cessation of causative icodextrin is the mainstay treatment for icodextrin-related AGEP, and the adverse skin reaction will spontaneously resolve in approximately 1 week following icodextrin withdrawal. 3,5This clinical response is likely consistent with the pharmacokinetic properties of icodextrin, which has a plasma half-life of 14.7 h, and that its metabolites are eliminated from the plasma within 3 to 7 days in PD patients. 9other proposal involves an immunological recall phenomenon, where specific memory T lymphocytes produce cytokines. 3 conclusion, clinicians should be alarmed by the dermatologic lesion after initiation of icodextrin infusion, which is easily masked by uremic symptoms.Early recognition and prompt withdrawal of icodextrin accompanied with steroid or antihistamine often ends up with uneventful outcome.
Dermatologic and pathologic presentation of AGEP.Erythema with scattered desquamations and nonfollicular pustules (A) over the trunk and inguinal areas successively.The skin biopsy reviews multifocal subcorneal abscess, mild acanthosis, nurtrophils exocytosis, and superficial perivascular neutrophilic infiltrate at upper dermis (B, Haematoxylin-eosin stain; original magnification: 200Â).Partial (C) and complete (D) resolution of skin lesion on 1st and 4th day of icodextrin withdrawal respectively.T A B L E 1 Features with icodextrin -related erythematous rash.