Renal Disease and the Skin

Key Points

Skin manifestations of chronic kidney disease (CKD) are commonly encountered and can be due to (1) the cause of the underlying renal disease, either acquired or heritable; (2) conditions unique to uremia; or (3) immunosuppressive therapies and/or immunosuppression itself in renal transplant recipients.
Diabetes and hypertension account for most cases of end-stage renal disease (ESRD) in the United States; however, many diseases, such as amyloidosis, connective tissue diseases, hepatitis C and B viral infections, and numerous genetic diseases may also cause ESRD. These conditions often possess characteristic cutaneous findings, which may be the first clue to an underlying kidney disease.
Skin findings such as alopecia, nail changes, pigmentary alteration, pruritus, and xerosis are not specific to uremia per se, but are frequently observed in patients with impaired renal function and impact quality of life.
Calciphylaxis is a rare but severe syndrome with high morbidity and mortality that involves calcium deposition in small vessels within the dermis and subcutaneous tissue, leading to exquisitely tender, retiform purpuric plaques that frequently ulcerate.
Acquired perforating dermatoses represent a spectrum of disorders with transepidermal elimination of material from the dermis with little damage to surrounding tissue, clinically presenting as keratotic lesions most commonly on the trunk and extremities.
Nephrogenic systemic fibrosis is characterized by thickened collagen in the skin and other organs, hyperpigmented, brawny plaques and papules most frequently starting on the extremities, and an association with exposure to gadolinium-based contrast agents in patients with renal compromise.
Bullous diseases in CKD include porphyria cutanea tarda (PCT), pseudoporphyria, and bullous disease of dialysis.
Renal transplant recipients are at risk for medication-related cutaneous changes, infections, and cutaneous malignancies secondary to immunosuppression.

Introduction

Chronic kidney disease (CKD) has numerous deleterious systemic effects including impaired function of the heart, brain, and nervous system, altered hormonal balance and bone metabolism, and increased susceptibility to infections. Cutaneous disorders are common in patients with CKD and can be due to various genetic or acquired conditions or metabolic abnormalities. These dermatologic manifestations can be summarized in three categories: (1) dermatologic signs of diseases causing renal failure ( Table 38-1 ); (2) dermatologic conditions relatively unique to uremia ( Table 38-2 ); and (3) cutaneous disorders in renal transplant recipients (RTR) related to immunosuppression and/or drugs used to immunosuppress ( Table 38-3 ). This chapter will focus on dermatologic conditions unique to uremia, while disorders in categories 1 and 3 are summarized in table format only. Given that mortality from CKD is decreasing, the prevalence of this disease is increasing. Therefore, dermatologists will continue to encounter cutaneous manifestations of CKD and may be the first to identify and treat many of these conditions.

TABLE 38-1

Dermatologic Conditions in Diseases Causing Chronic Kidney Disease

Disease	Dermatologic Manifestations	Renal Features
Metabolic Disorders
Diabetes mellitus	Acanthosis nigricans	Diabetic nephropathy
	Eruptive xanthomas	Nephrotic syndrome
	Necrobiosis lipoidica
	Diabetic dermopathy
	Bullous diabeticorum
Amyloidosis	Macroglossia	Nephrotic syndrome
Amyloidosis	Purpura (most classically in the periorbital region)	Nephrotic syndrome
Atherosclerosis/cholesterol emboli	Blue toes	Renal emboli with hematuria and eosinophiluria
	Cutaneous necrosis
	Retiform purpura
	Splinter hemorrhage
Connective Tissue Diseases
Systemic sclerosis	Calcinosis cutis	Malignant hypertension
	Cutaneous sclerosis	Renal crisis
	Distal digital infarcts
	Nailfold capillary changes
	Sclerodactyly
	Mat telangiectases
	Salt-and-pepper depigmentation
Polyarteritis nodosa	Palpable purpura	Glomerulonephritis
	Nodules	Vasculitis
	Ulcers
Systemic lupus erythematosus	Acute cutaneous lupus erythematosus (butterfly rash)	Glomerulonephritis
	Chronic cutaneous lupus (discoid lupus)	Nephrotic syndrome
	Livedo reticularis
	Subacute cutaneous lupus erythematosus
Granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis)	Palpable purpura	Glomerulonephritis
	Petechiae	Vasculitis
	Saddle nose deformity
	Strawberry gums
Hepatitis Viruses
Hepatitis C	Lichen planus	Glomerulonephritis
	Porphyria cutanea tarda:
	Photodistributed
	Milia
	Sclerodermatous changes
	Vesicles/bullae
	Hypertrichosis (on temples)
	Necrolytic acral erythema
	Mixed cryoglobulinemia:
	Digital infarcts
	Livedo reticularis
	Palpable purpura
Hepatitis B	Polyarteritis nodosa	Glomerulonephritis
Genetic Disorders
Fabry’s disease	Angiokeratomas of lower abdomen, hip, and inguinal region	Varying degrees of proteinuria
Fabry’s disease		Urinary globotriaosylceramide
Inheritance: X-linked recessive		Cortical and parapelvic cysts
Defect: α-galactosidase-A deficiency		Renal failure is more common in men
Birt–Hogg–Dubé	Trichodiscomas	Renal cancers of variable histology
Inheritance: autosomal dominant	Fibrofolliculomas
Defect: folliculin gene (FLCN) mutation	Acrochordons (see Chapter 17 )
Tuberous sclerosis	Facial angiofibromas	Angiomyolipomas
Inheritance: genetically heterogeneous; autosomal dominant transmission with high spontaneous mutation rate	Connective tissue nevi	Renal cysts
	Hypopigmented macules (“ash-leaf macules”)	Polycystic kidneys
	Shagreen patch	Renal cell carcinoma
Defect: genes TSC1/TSC2 with protein products hamartin and tuberin	Periungual fibromas (see Chapter 17 )
Nail–patella syndrome	Nail dysplasia:	Varying degrees of proteinuria
Inheritance: autosomal dominant	Triangular lunulae	Renal tubular defects
Defect: LIM-homeodomain protein LMX1B	Hypoplastic nails Lack of creases over distal interphalangeal joints
Hereditary multiple leiomyomas of skin	Multiple cutaneous leiomyomas, typically regionally grouped (see Chapter 17 )	Renal cell carcinoma
Inheritance: autosomal dominant
Defect: mutation in gene encoding fumarate hydratase

TABLE 38-2

Dermatologic Diseases Associated with Uremia

Alopecia
Calcinosis cutis
Calciphylaxis
Kyrle disease (acquired perforating dermatosis)
Nail changes:

Beau’s lines
Half-and-half nails (Lindsay’s nails)
Nailfold capillary abnormalities

Nephrogenic systemic fibrosis
Pruritus-related skin changes
Pigmentary alteration
Porphyria cutanea tarda
Pseudoporphyria
Xerosis
Uremic frost

TABLE 38-3

Diseases Associated with Renal Transplantation

Disease	Notable Features
Medication-Related Disorders
Cushingoid Changes
Moon facies Cervical fat pad (buffalo hump) Striae distensae Cutaneous atrophy Telangiectases Senile purpura	Develop in 50–90% of patients Associated with systemic corticosteroid use; may improve with corticosteroid dose reduction
Gingivial hyperplasia	Occurs in one-third of patients on cyclosporine Occurs early and improves with time
Disorders of the Pilosebaceous Unit
Acne vulgaris/steroid acne Folliculitis Hypertrichosis Keratosis pilaris Sebaceous gland hyperplasia	Steroid acne is seen in 15% of patients, mainly on chest and back, improves with corticosteroid dose reduction Acne vulgaris may occasionally be seen secondary to cyclosporine use Hypertrichosis is seen in 60% of patients; known to be associated with cyclosporine; may be associated with keratosis pilaris
Immunosuppression-Related Disorders
Infections
Bacterial Fungal Mycobacterial Parasitic Viral	Often related to degree of immunosuppression Heightened risk during first 6 months following transplantation Fungal infections are more common overall, seen in 7–75% of patients; pityrosporum is the most common fungal infection Viral infections, mainly from herpes viruses, are typically most severe in the first year following transplantation; diseases related to human papilloma viruses develop later
Malignancies
Actinic keratosis (precancerous) Basal cell carcinoma (BCC) Kaposi sarcoma (KS) Melanoma Merkel cell carcinoma Squamous cell carcinoma (SCC)	Risk varies according to the degree of immunosuppression, time after transplantation, geographic location, amount of ultraviolet light exposure, and predominant skin type Nonmelanoma skin cancer incidence is 20–40 times that of the general population Nonmelanoma skin cancers are more aggressive, have a higher recurrence rate, and a greater metastatic potential than in the general population Of the immunosuppressive medications used in the transplant population, sirolimus is the least likely to cause an increase in the risk for skin cancer SCC is the most common cutaneous malignancy following transplantation, with a risk of 50–250 times that of the general population BCC occurs 6–10 times more frequently than in the general population KS incidence is 400–500 times higher than in the general population; the greatest risk is in the first year following transplantation Melanoma is seen 2–9 times more frequently than in the general population

Dermatologic Manifestations of Systemic and Genetic Disorders Causing Chronic Renal Disease

A number of systemic and heritable disorders have both cutaneous and renal manifestations, summarized in Table 38-1 .

Dermatologic Manifestations of Uremia

Many patients with end-stage renal disease (ESRD) are maintained by hemodialysis or peritoneal dialysis; however, these modalities cannot fully compensate. As such, most patients develop significant metabolic abnormalities including: anemia, metabolic acidosis, altered calcium-phosphate homeostasis, hyperparathyroidism, and glucose intolerance. These derangements are responsible for the uremic condition and significantly impact many organ systems. Whereas some dermatologic manifestations are relatively unique to patients undergoing dialysis, such as calciphylaxis; others, such as xerosis and pruritus, are not specific to uremia, but have a high prevalence in patients with ESRD ( Table 38-2 ).

Alopecia

While common in patients with ESRD, alopecia has not been studied specifically in this patient population. Conditions associated with alopecia include systemic lupus erythematosus (SLE), malnutrition, or a chronic telogen effluvium, possibly due to other comorbidities or medications commonly used in this population including antihypertensives, lipid-lowering agents, or anticoagulants.

Calcinosis Cutis

Initially described by Virchow in 1855, calcinosis cutis results from calcification of the skin due to local or systemic factors. Four major types of calcinosis cutis exist: dystrophic, metastatic, iatrogenic, and idiopathic. The metastatic type, which occurs in association with an elevated calcium/phosphate ratio, is most common in ESRD. Reported in 1% of ESRD patients on hemodialysis, metastatic calcinosis cutis is generally a late complication. Clinically, patients develop rock-hard papules, nodules, or plaques, which may exude a chalky discharge through the epidermis ( Fig. 38-1 ); periarticular sites or fingertips are most commonly affected. While generally asymptomatic, mobility can be compromised and lesions are occasionally tender. Histology reveals homogeneous blue material in the dermis, occasionally with foreign body giant cells; calcium deposition can be confirmed by special staining. There is no gold-standard treatment; however, normalization of calcium and phosphate levels may result in lesion regression. For refractory cases in the setting of hyperparathyroidism, parathyroidectomy may be beneficial.

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