Bullous Disease of Dialysis

Background

Bullous disease of dialysis, or bullous dermatosis of dialysis, is a syndrome of cutaneous fragility and blistering.^{[1, 2]} The skin lesions clinically and histologically resemble those of porphyria cutanea tarda. Lesions occur predominantly in sun-exposed skin—most often on the dorsal hands—of individuals treated for chronic renal failure with maintenance dialysis regimens. (See Presentation.) See the image below.

View Image

Hands of a transfusion-dependent patient on long-term hemodialysis. Several uremia-related cutaneous disorders are visible. The pigmentary alteration ....

This mechanobullous disorder has been observed in patients with end-stage renal disease who were treated with chronic ambulatory peritoneal dialysis or with hemodialysis. Typically, however, however, the condition develops only after several months or years of dialysis therapy. (See Presentation.)

Porphyrin levels in urine and stool are normal in patients with bullous disease of dialysis; plasma porphyrin levels are also normal or are most often only minimally elevated. Such findings in a patient would exclude the presence of a true porphyria, which, in anephric individuals, would result in grossly abnormal porphyrin values. (See Workup.)^[3]

The cutaneous lesions of bullous disease of dialysis are cosmetically distressing and interfere with the use of the hands. They may be painful, become secondarily infected, and eventuate in scarring, but they are not life threatening. (See Treatment and Medication.)

• References

Etiology

Because plasma porphyrin levels in individuals with chronic renal failure may be mildly elevated,^[4] or occasionally high enough to overlap levels seen in porphyria patients with normal renal function,^[5] porphyrin photosensitization may play a contributory role in some cases. It is not likely to be the primary cause, however, because many dialysis patients with similarly mild elevations of plasma porphyrin levels do not develop photocutaneous lesions.

Speculation that photosensitizers encountered during dialysis (eg, compounds emanating from plastic tubing) are responsible for the disorder remains unproven. The concomitant use of therapeutic agents with phototoxic potential (eg, furosemide) cannot be identified in most cases.

A possible, but unproven, cause of bullous disease of dialysis may be overproduction of porphyrins resulting from effects of high aluminum concentrations (from therapeutic or environmental sources) on enzymes of heme biosynthesis.^[5] In 6 dialyzed patients with bullous dermatoses and high serum aluminum levels, Gafter et al found elevated plasma porphyrins approaching or surpassing those seen in true porphyria cutanea tarda.^[5] Potential benefit from aluminum chelation with desferrioxamine in such cases was considered.

• References

Epidemiology

The frequency of bullous disease of dialysis among dialysis populations in the United States has not been accurately determined but may be similar to that reported from several European surveys.

In a large French survey, 6 of 500 individuals who underwent hemodialysis were affected by the disease after between 2 and 54 months of dialysis.^[6] Among 66 individuals who underwent hemodialysis for more than 10 years, 27% reported cutaneous fragility, and pseudoporphyria (presumably bullae) was noted in 13%.^[7] In 2 additional French surveys, 16 of 100^[8] and 6 of 136 dialysis patients were affected.^[9] Three patients with blistering were found among 70 patients at an Irish dialysis center.^[10]

Race-, sex-, and age-related demographics

Although no race predilections have been reported for bullous disease of dialysis, individuals with less melanin pigmentation of the skin have less natural photoprotection and may be more likely to develop dialysis-related cutaneous fragility and blistering.

Although some surveys have reported a male predominance for the disease, a higher female-to-male ratio has also been noted. In none of these surveys, however, was the male/female composition of the underlying population stated. Thus, the male-to-female data reported may reflect differences in the frequency with which men and women occurred in the source populations.

Most reported cases of bullous disease of dialysis have involved adults. However, this may reflect the predominance of older individuals with end-stage renal failure among populations treated with chronic dialysis regimens.

• References

Patient Education

Advise patients of the role of sunlight in aggravating their propensity for blistering. Review measures for reduction of sunlight exposure and of mechanical stress to light-exposed skin. Instruct patients to use topical sunscreen formulations designed to reduce the transmission of long ultraviolet and visible light. In addition, inform patients that they should use gloves during activities likely to traumatize the hands

• References

History and Physical Examination

History

Individuals with chronic renal failure who are afflicted with bullous disease of dialysis typically develop these lesions only after months to years of maintenance dialysis regimens. The lesions are more florid after sunlight exposure. However, patients often are unaware of the role of sunlight in evoking the lesions, since they do not note discomfort in the skin during the exposure.

Physical examination

Vesicles and bullae filled with clear or hemorrhagic fluid and exudative erosions occur chiefly on the dorsal hands, although the scalp, face, and neck also may be affected. Blistering limited to volar fingertips was observed in one case.^[11] Healing of crusted erosions leaves atrophic scars. Milia, dyspigmentation, and hypertrichosis occur infrequently.

• References

Approach Considerations

Porphyrias with photocutaneous manifestations should be considered in the differential diagnosis of bullous disease of dialysis. To exclude a true porphyria, a plasma or serum porphyrin assay is recommended. The test result will be grossly abnormal due to true porphyria in an individual with compromised renal function. Fecal porphyrin analyses may also reveal increased porphyrin excretion in such cases.^[12]

However, in patients on hemodialysis or peritoneal dialysis, plasma porphyrin levels may be increased because of reduced excretion, in the absence of enzyme deficiency.^[13]

The possibility of aluminum toxicity should be excluded.

• References

Laboratory Studies

Plasma or serum porphyrin concentrations typically far exceed normal upper limits in true porphyrias in individuals with end-stage renal disease. Quantitative fecal porphyrin analyses may reveal abnormally high porphyrin excretion in such cases. Aluminum toxicity can be excluded by obtaining a serum aluminum level.

• References

Histology

Light microscopic examination of a biopsy of a blister reveals a cell-poor subepidermal bulla indistinguishable from that of a true porphyria, with edematous dermal papillae and a scant perivascular lymphocytic infiltrate.^[1] Festooning of dermal papillae and caterpillar bodies in the epidermis can be observed. Staining with periodic acid-Schiff and collagen IV stains could show thickening of vessel walls.^[14]

Ultrastructural studies show thickening of the dermal venular walls and dermoepidermal junction due to replicated basal laminae, hypogranulated mast cells, and granulofilamentous hyaline masses in the dermal connective tissue that appear to be secreted by adjacent fibroblasts.^[15]

Direct immunofluorescence examinations have revealed the presence of IgG and, inconsistently, IgA, IgM, fibrin, and complement around the dermal venules, with IgG and complement sporadically noted at the dermoepidermal junction or bulla floor.^{[1, 8, 16]}

Deposition of IgG at the dermoepidermal junction has been found in pseudoporphyria, mostly homogenous, not intense, and finely delineated.^[14]

• References

Approach Considerations

Any photosensitizing drug that the patient may be using should be identified and, if possible, discontinued.

Sunlight avoidance, application of topical sunscreen formulations blocking long ultraviolet and visible light, and protection of exposed skin from mechanical trauma may help to reduce severity of lesions. Intermittent treatment of secondarily infected bullae or erosions with topical or systemic antibiotics may be required.

Dialyzed patients are at risk for oxidative stress due to deficiency of several antioxidant enzymes, including glutathione peroxidase and glutathione reductase.^[17]  Oral administration of N-acetylcysteine or glutamine to several patients, as an approach to glutathione repletion, was considered beneficial in all but one case (see Medication).

• References

Medication Summary

Oral administration of the glutathione precursor N-acetylcysteine (600-1200 mg/day) was followed by resolution of blistering and fragility within 3 weeks to 2 months in several cases of bullous disease of dialysis.^{[18, 19, 20, 21, 22, 23]} Another glutathione precursor, oral glutamine (at a dose of 10 g/day), plus sunlight avoidance, was similarly effective in one case.^[24] Two vitamin D‒deficient patients had resolution of bullae within 30 days with ultraviolet exposure avoidance and vitamin D supplementation.^[25] One hemodialyzed patient with photodistributed bullae said to represent "pseudoporphyria", but who also had excess urinary uroporphyrin, hypertrichosis, dyspigmentation, and sclerodermoid changes consistent with a true porphyria, had incomplete resolution of bullae after 3 months of cessation of oral contraceptive pills, sunlight avoidance, and N-acetylcysteine at 800 mg/day, but complete resolution after changing treatment to chloroquine 200 mg/wk for a month.^[26]

• References

N-acetylcysteine (Acetadote)

• Dosing, Interactions, etc.

Clinical Context:  N -acetylcysteine is a glutathione precursor. It may provide effective photoprotection by increasing the availability of glutathione, a potent antioxidant.

• References

Class Summary

Agents that scavenge oxygen-derived free radicals and improve endothelium-dependent vasodilation may be of benefit.

• References