Skin manifestations of kidney disease
Conditions range from benign to life-threatening
by Carrie Lynde and John Kraft, MD
Vol.15, No.02, February 2007

What's the connection between kidneys and the skin?
End-stage renal disease (ESRD) is a progressive and irreversible kidney dysfunction lasting 3 months or more. Nearly all patients with ESRD have at least one dermatological disorder, and these skin and nail changes can occur before or even after initiation of dialysis or transplantation. Some propose that the skin manifestations are due to the underlying pathologic process that induced the renal disease, while others believe that skin changes are related to the severity and duration of renal failure.

ESRD is relatively common and skin problems can affect the patient's quality of life. Physicians must be aware of cutaneous manifestations of kidney disease to properly diagnose, reassure and educate patients and to offer appropriate therapies. As well, they should know about some classical cutaneous symptoms associated with a variety of diseases that affect the kidney. With the number of renal transplant patients steadily increasing, it's also important to consider the impact of immunosuppressive medications that can cause skin problems such as malignancies and infections.

What are the most common skin manifestations of ESRD?
Xerosis
Referring simply to dry or roughened skin, xerosis occurs in 50-75% of dialysis patients. It manifests as poor skin turgor with scaling, dryness and fissuring of the skin, particularly affecting extensor surfaces of extremities. This condition can be very uncomfortable as it may promote the development of fissures, ulcers, lichen simplex chronicus and irritant or allergic contact dermatitis. It also predisposes patients to infections (e.g. cellulitis) because it compromises the normal skin barrier. Delayed wound healing in ESRD patients further increases the risk of such infections.

Pigmentary disorders
Pigmentary changes to the skin are very common in ESRD -- it's estimated that 25-70% of dialysis patients are affected to some degree. Incidence increases with the duration of renal disease. The spectrum of pigmentary changes ranges from hyperpigmentation to yellowish discolouration and pallor. Hyperpigmentation is often photodistributed and is the result of an increase in melanin in the basal layer of the epidermis. The yellow skin colour in ESRD patients is caused by lipochrome and carotenoid deposition in the dermis and subcutaneous tissues. Pallor is a result of anemia associated with chronic disease and is widespread.

Pruritus
Pruritus or itching is the most common symptom of ESRD. Of those with chronic renal failure, 15-49% experience pruritus, and of those undergoing dialysis it's up to 50-90%. But in acute renal failure, pruritus is very uncommon. Its prevalence is slightly greater amongst hemodialysis (HD) patients (42%) vs peritoneal dialysis patients (32%). As dialysis has improved, it's become less common.

The pruritus of ESRD is most often generalized and light (66%), but can be severe (8%) and unremitting. While it's not associated with any primary skin lesions, a chronic itch can result in secondary skin changes such as prurigo nodularis, excoriations and lesions of lichen simplex chronicus. Pruritus may also contribute to the koebnerization of acquired perforating dermatosis.

What are the treatment options for pruritus and xerosis?
Renal transplantation is virtually always curative. To manage pruritus prior to a transplant, we recommend a stepwise approach. Start with general measures such as emollients to help reduce xerosis that contributes to pruritus. Moisturizers, keratolytics, antihistamines and hydration are all of modest benefit.

Phototherapy is generally the most successful -- both narrowband and broadband UVB have been shown to be effective. The mechanism is speculative, but it's thought that UVB radiation induces the formation of photoproducts with antipruritic effects, and that it inactivates pruritogenic substances.

Topical tacrolimus may be another option, but ESRD patients may already have impaired immunosurveillance and special caution is advised in patients prone to skin cancer. Opioid m-receptor antagonists such as naltrexone may be effective if the above measures are unsuccessful. Such treatment is based on the hypothesis that endogenous opioids cause pruritus.

Other options are available for recalcitrant cases -- for example, charcoal can be given at 6 g per day, but side effects such as nausea and diarrhea limit its use. Cholestyramine (5 g given twice daily) may also be helpful, as well as gabapentin 3 times weekly following each HD session. Thalidomide, topical capsaicin and intravenous (IV) lidocaine are less practical options.

What else should I look out for?
Uremic frost, superficial white deposits of crystallized urea excreted from sweat, can be a late feature of severe ESRD, but it's rare these days, as advances in treatment have improved the life expectancy and quality of life of ESRD patients. (For a nice image of this rare condition, see Walsh SR, Parada NA. Images in Clinical Medicine: Uremic Frost. NEJM 2005;352:e13.) As a result, the types and frequency of skin disorders have changed. Ecchymoses are a skin condition that's more common in conjunction with ESRD; they result from platelet dysfunction.

In sun-exposed areas, elastosis is often seen as elastin is broken down. The relationship to ESRD is unclear, but it's possible that this acceleration of cutaneous aging is a function of the time a patient has been on dialysis. Elastosis refers to yellow, atrophic plaques with wrinkling of the skin.

Half-and-half nails, also referred to as Lindsay's nails, are found in roughly 33% of patients with azotemia and in up to 40% of those on dialysis. In this condition, the proximal half of the nail is white due to edema of the nail bed and capillary network. The distal portion appears normal or even brown due to increased melanocyte stimulating hormone in patients with ESRD. The nail plate is unaffected. The likeliness of these changes may increase with the time a patient's been on dialysis, but there most likely isn't a correlation with the severity of uremia. Half-and-half nails tend to disappear after successful transplantation.

What about the calcium metabolism?
When the calcium or phosphate metabolism of a patient is compromised, calcium salts may precipitate in normal tissue -- a process called metastatic calcification. It can affect kidneys, lungs, blood vessels, gastric mucosa and subcutaneous and cutaneous tissues.

Calcinosis cutis
This form is relatively rare. Calcifications are found in the skin and laboratory investigations reveal elevated serum calcium (Ca) and sometimes hyperphosphatemia. It's the most common metabolic condition associated with renal failure.

ESRD reduces the clearance of phosphate and impairs vitamin D production, decreasing intestinal Ca absorption and, consequently, serum Ca levels. Hypocalcemia causes secondary hyperparathyroidism, which mobilizes Ca and phosphate from bone into serum. When the solubility product of Ca and phosphate is exceeded in the serum, metastatic calcification occurs.

Skin examination reveals firm papules, plaques and nodules, and there may be a chalky discharge. The most common sites are periarticular areas and fingertips. Periarticular involvement is usually asymptomatic unless joint mobility is compromised, but fingertip lesions can be quite painful. The degree of involvement correlates with Ca and phosphate levels, so lesions are likely to disappear when levels return to normal.

The main principle of treatment is the normalization of calcium and phosphate levels. Decreasing dietary phosporus is key (e.g. milk and milk products, broccoli, Brussels sprouts, artichokes, oysters, liver, salmon, beer, colas, cocoa, ale). Phosphorus-binding antacids and parathyroidectomy are other options.

Calciphylaxis
A progressive cutaneous necrosis caused by small and medium vessel calcification, this condition can be life-threatening as it's usually complicated by infection and sepsis (e.g. staphylococcal sepsis after infection of chronic ulcerations). Mortality rates range from 60-80%, and incidence ranges from 1% in patients with chronic renal failure to 4% in those receiving HD. Although it's most common in ESRD, 30% of cases occur in transplant recipients, including patients with functioning grafts. Calciphylaxis affects women more often than men, and the mean age of onset is 48 years. It's a complication of secondary hyperparathyroidism in chronic renal failure.

Risk factors for the development of calciphylaxis include elevated Ca and phosphate product, raised vitamin D, elevated parathyroid hormone (PTH) levels and further compromising agents such as calcitriol, local trauma, immunosuppressants, HIV, albumin, corticosteroids and lymphoma.

Clinically, lesions are bilateral, symmetric, firm, painful and non-ulcerating purpuric plaques or nodules. There may be a mottling or violaceous discolouration on the limbs, often with a reticulated pattern. Calciphylaxis progresses to ecchymosis with cordlike nodules and livedo reticularis (net-like pattern). Flaccid or hemorrhagic bullae may form over ischemic tissue. Local necrosis results in superficial or deep angulate or stellate ulcers with gangrene. Peripheral pulses tend to be preserved distal to areas of necrosis.

The distribution of lesions has prognostic value -- patients with acral lesions (fingers, toes) and distal lesions (calves, forearms) tend to have a better prognosis than patients with proximal lesions (thighs, buttocks and trunk). Cutaneous calciphylaxis can be associated with systemic calciphylaxis, manifesting as myopathy, hypotension, fever, dementia and infarction of the central nervous system (CNS), bowel or myocardium.

Diagnosis and treatment
The most useful technique for diagnosis is incisional biopsy. As these and radiographic findings are usually non-specific, the diagnosis tends to be clinical. Laboratory investigations can help rule out vasculitides, cryoglobulinemias, connective tissue diseases and pancreatic paniculitis.

Treatment is challenging as the course tends to be progressive despite therapy. Try to minimize known triggers such as blood products, immunosuppressants, obesity and injections into proximal adipose tissue. Therapy should be aimed at normalizing calcium and phosphate products and controlling secondary hyperparathyroidism with a low phosphate diet, low calcium dialysate and the use of dietary phosphate binders without calcium carbonate. IV pamidronate therapy is used in severe cases. If there's hyperparathyroidism, a subtotal parathyroidectomy or total with autotransplantation of one gland into the forearm can be helpful.

Thorough wound care should be provided to avoid sepsis. Remove necrotic tissue, prescribe systemic antibiotics at signs of infection and provide adequate dressings to ensure proper moisture balance and barrier to infection. Hyperbaric oxygen therapy has been beneficial where patients failed to respond to the above. It promotes wound healing by increasing the partial pressure of oxygen within diseased tissue and supports phagocytosis and angiogenesis while decreasing tissue edema.

Is renal disease associated with bullous dermatosis?
Porphyria cutanea tarda (PCT) is a vesiculobullous skin disease with a prevalence of 1-18% in patients receiving HD. It's a disorder of the hepatic heme biosynthesis pathway associated with uroporphyrinogen decarboxylase deficiency. The symptoms of the disorder associated with ESRD are similar to those of sporadic PCT induced by other agents. The blistering photosensitive rash is composed of tense vesicles and bullae distributed on the dorsa of the hands, face and sometimes feet. The skin is fragile. Secondary features include erosions and crusts. Blisters heal with scarring and milia formation. Other cutaneous findings of PCT include hyperpigmentation of sun-exposed skin with hypertrichosis and sclerodermoid plaques.

Diagnosis relies on measuring porphyrins in the urine, stool and blood. Uroporphyrin levels in ESRD patients with PCT are similar to or greater than levels in those with PCT without renal failure. Patients should avoid triggers like alcohol and estrogens and also protect their skin from the sun with broad-spectrum physical blockers such as zinc oxide.

Standard HD does not effectively remove uroporphyrins, but small volume phlebotomies can be done weekly. Erythropoietin in conjunction with phlebotomies has been shown to mobilize hepatic iron stores.

Patients may also present with pseudoporphyria, which has clinical and histologic features similar to PCT, but without abnormal porphyrin levels. Most do not show hypertrichosis or sclerodermoid plaques.

Is acquired perforating dermatosis common?
Between 4 and 10% of people receiving HD should expect to develop acquired perforating dermatosis (APD). It's predominant among blacks, and the majority of cases occur in those with ESRD caused by diabetic nephropathy receiving HD. But APD has also been reported in patients who have never had dialysis, and even in renal transplant recipients.

When presenting with APD, people often complain of severe pruritus. The disease shows features of primary perforating dermatosis and is the result of altered connective tissue within the dermis being eliminated through the epidermis, with little damage to surrounding structures.

Clinically, APD manifests as keratotic, dome-shaped, grouped papules and nodules, 1-10 mm in diameter. Papules may be umbilicated with a central keratotic plug. They appear pink in lighter skin, while in darker-skinned patients, they are brown or hyperpigmented. In some cases they emerge as verrucous plaques, typically distributed on hair-bearing friction areas. The trunk and extremities are most commonly affected, followed by the face and scalp. The course is often chronic with new lesions appearing as old ones fade.

Hydrating the skin (e.g. use of emollients) and treating the pruritus of ESRD (e.g. phototherapy) can improve the perforating disorder. Topical retinoic acid, doxycycline, allopurinol and systemic isotretinoin have also been effective. APD may resolve after renal transplantation.

Does a renal transplant cure skin disease?
Most skin manifestations of ESRD resolve after transplantation. Xerosis improves markedly. Sebaceous and sweat gland function normalizes and may even lead to seborrhea. Pruritus resolves in the majority of people, and prevalence drops from more than 75% in dialysis patients to less than 2% post transplant. But premature aging is not affected by transplantation.

What are the risks after transplant?
Following renal transplantation, patients are given immunosuppressive medications to prevent rejection, predisposing them to malignancy and infections, but also to cutaneous side effects from the drugs themselves.

Renal transplant recipients (RTRs) are prone to developing squamous (SSC) and basal (BCC) cell carcinomas, with SCCs being 3 times as common as BCCs. Other cutaneous malignancies including malignant melanoma, Merkel cell tumours, cutaneous lymphomas and Kaposi's sarcoma are also common. More than 90% of these tumours occur on sun-exposed areas of the skin.

Risk factors for developing non-melanoma skin cancers after a transplant include male gender, older age, fair skin colour, childhood sun exposure and the duration of immunosuppression. Recently, the human papillomavirus (HPV) has been associated with SCCs. RTRs should see a dermatologist regularly (i.e. every 3-6 months), preferably at a specialized dermatology clinic for transplant recipients.

What about skin infections?
After cardiovascular complications, infections are the most common cause of death in the RTR. The most frequent viral infections of the skin are HPV infections (causing common warts and condyloma acuminata) and herpes simplex. Common warts (HPV 1, 2, 4, 7) are often found on the hand, fingers and face. Plantar warts (HPV 1, 2, 4) are also seen in RTRs. Destructive treatment options include cryotherapy, operative curettage or laser surgery. Genital warts are most often caused by HPV types 6 and 11, and less commonly, oncogenic types are implicated (i.e. types 16 and 18) that can cause cervical carcinoma. Herpes simplex labialis (cold sores) is the most common presentation of the herpes virus in RTRs. But beware, as these patients may be more likely to experience systemic involvement (i.e. CNS infection).

Bacterial skin infections are also common after a renal transplant. While impetigo is almost never seen in healthy adults, it can occur in RTRs, especially around the mouth and nose. Systemic antibiotic therapy is often necessary. Fungal infections such as tinea pedis, tinea corporis, tinea barbae and onychomychosis also occur more frequently during immunosuppressive therapy.

Carrie Lynde is a second-year medical student at the University of Toronto.

John Kraft, MD, is in his first year of the Dermatology Residency Program at the University of Toronto, ON.

feature image
Table 1: Cutaneous manifestations of ESRD
Table 2: Cutaneous clues associated with diseases causing renal failure
Table 3: Potential adverse skin effects of medications given after renal transplant

References

Abdelbaqi-Salhab M et al. J Cutan Pathol 2003;30:527-38.
Avermaete A et al. Nephrol Dial Transplant 2002;17:1380-3.
Fine A, Zacharias J. Kidney Int 2002;61:2210-7.
Greaves MW. Dermatol Ther 2005;18:323-7.
Hong SB et al. J Kor Med Sci 2004;19:283-8.
Moloney FJ et al. Photodermatol Photoimmunol Photomed 2005;21:1-8.
Robinson-Bostom L, DiGiovanna JJ. J Am Acad Dermatol 2000;43:975-86.

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