Renal failure is common in the United States with an estimated prevalence of 660,000 treated end-stage renal disease patients in 2015 . Causes of renal failure are many, and complications from renal failure, underlying disease, and treatment are not infrequent. Examples of common skin manifestations include xerosis, pigmentary change, and nail dystrophies. Frequent disease-specific skin changes may be helpful in the diagnosis of primary disorders leading to renal disease or severity of disease including bullosis diabeticorum, sclerodactyly, or leukoctoclastic vasculitis. Some cutaneous changes, such as the multiple angiokeratomas of Fabry disease or the plexiform neurofibromas of neurofibromatosis, are pathognomonic of genetic disorders, which often lead to renal failure. Careful examination of the skin can provide crucial clues to diagnosis of renal failure causation and aid in monitoring complications.
Historically, diagnosis in medicine was based primarily on obtaining an accurate history and performing a visual inspection. The accessibility of easily obtainable, sophisticated laboratory tests and diagnostic equipment has greatly enhanced the ability of the medical profession to accurately diagnose a multitude of diseases. There is a danger, however, in reliance upon these tests leading to the exclusion of careful visual inspection of the patient. Clues obtained by such an examination may be crucial in determining which tests and imaging studies to consider first. Basing laboratory evaluation on clues provided by a dermatological examination and recognizing early skin signs of disease reduce patient morbidity and medical cost. Familiarity with diagnostic clues observed by a thorough skin examination is therefore essential. Nephrology is one of the many specialties in which the skin may provide early diagnostic clues to etiology of disease. Additionally, it can provide a window into timely recognition of side effects and complications of treatment.
Nonspecific Skin Changes
Nonspecific skin manifestations are found in over half of all end-stage renal disease (ESRD) patients . Among the most common of these are pigmentary change, nail changes, and xerosis/ichthyosis. Specific changes associated with the etiology of renal failure are also common, including changes associated with diabetes, connective tissue disorders, and genetic disorders such as Fabry disease. One may see disorders associated with ESRD such as calciphylaxis, uremic frost, or nephrogenic fibrosing dermopathy.
There are several pigmentary changes that have been reported in ESRD patients, including hyperpigmentation, pallor, a slate-grey discoloration, and a yellow skin hue. Pallor is likely related to anemia, while the slate-grey discoloration is due to hemosiderin deposition . Yellowing of the skin may be seen due to the deposition of carotenoids and urochromes within the skin and subcutaneous tissue. Hyperpigmentation is most prominent in sun-exposed areas and is attributed to increase in skin melanin due to excessive beta-melanocyte stimulating hormone .
As beta-melanocyte-stimulating hormone, carotinoids and urochromes are poorly dialyzed, yellow hue and hyperpigmentation may be persistent and progressive despite adequate dialysis treatment . An increase in beta-melanocyte-stimulating hormone is also believed to account for the nail appearance in Half-and-Half nails (also known as Lindsay nails) which occurs in up to 40% of ESRD patients. This involves fingernails more frequently than toenails and is seen as a reddish to brown discoloration of the distal 20–60% of the nail and proximal white discoloration . This resolves with renal transplantation (Fig. 1).
Significant xerosis (dry skin) is noted in 50–90% of patients with ESRD and persists or worsens in many patients despite dialysis. It is often accompanied by pruritus although correlation of pruritus to severity of xerosis is poor . Ichthyosiform skin changes, characterized by dry skin, thick rhomboidal scales, and fissures are frequently observed. Theories regarding the etiology of xerosis in renal failure include observed structural skin alteration with fragmentation of elastic fibers and atrophy of eccrine sweat and sebaceous glands, loss of stratum corneum integrity, and hypervitaminosis A with resultant alteration in maturation of the stratum corneum. Diuretic treatment may also play a role . Management of xerosis with emollients containing salicylic acid or urea and a gentle skin care regimen may be beneficial. Pruritus is reported in 12–90% of patients and may have a severe impact on quality of life. Patients may present with excoriations, skin lichenification (thick, leathery skin patches due to irritation), prurigo nodularis (“scratch bumps”), and accentuation of perforating disorders (disorders resulting in transepidermal elimination of altered collagen and dermal debris) due to the Koebner phenomenon. In the Koebner phenomenon, skin lesions develop in areas of trauma. Multiple factors are believed important in pathogenesis of pruritus including xerosis, mast cell proliferation and degranulation, metabolic disequilibrium with hyperparathyroidism, hypercalciumia, hyperphosphatemia, increased aluminum level, increase of circulating pruritic cytokines, abnormalities in cutaneous innervation, and potential allergy to components of dialysis membranes [3, 8].
Kidney transplantation generally resolves pruritus, while initiation of dialysis has a variably reported effect . Management is challenging. Symptoms may improve with optimal skin hydration using emollients and a gentle skin care regimen. Use of antihistamines, topical corticosteroids, topical calcineurin inhibitors, topical and oral retinoids, serotonin antagonists, activated charcoal, cholestyramine, thalidomide, acupuncture, cryotherapy, opioid antagonists, topical substance P depletion, and topical keratolytics has been tried and all these products are of variable benefits. Ultraviolet B phototherapy is often beneficial but is not easily available in some communities, requires an additional patient time commitment beyond that required by dialysis, and may increase the risk of skin cancer [7, 9]. Pruritic patients with hyperparathyroidism may benefit from parathyroidectomy .
Etiology of Renal Failure
Etiology of renal disease, as well as clues to suggest presence of kidney compromise in as yet undiagnosed patients, may be identified by cutaneous examination. According to the U.S. Renal Data System 2015 Annual Data Report, the leading causes of ESRD in the United States are diabetes and hypertension . Other disorders potentially resulting in renal failure, such as vasculitis, infection and several genetic diseases, may result in skin changes that provide clues to diagnosis on examination.
Complications of diabetes mellitus accounted for development of new onset renal failure in 37% of patients in the United States in 2015 . Cutaneous disease may be the presenting feature of diabetes or may develop at any point during the course of the disease; skin manifestations may be specific to diabetes or present in increased frequency among diabetics while also potentially present in the non-diabetic population. Among these disorders are acanthosis nigricans, diabetic dermopathy, scleredema diabeticorum, necrobiosis lipoidica diabeticorum, rubeosis faceii, bullosis diabeticorum, and perforating disorders. Cutaneous infections, psoriasis, eruptive xanthoma and multiple acrochordons are also common in diabetics .
Skin lesions of acanthosis nigricans consist of thickened, velvety, hyperpigmented plaques seen most frequently in folds of the neck, axillae, and groin. Acanthosis nigricans is associated with hyperinsulinemia. Hyperinsuliemia also plays a role in the development of acrochordons, pedunculated benign neoplasms of skin or “skin tags,” which also favor skin folds. Both acanthosis nigricans and acrochrodons may precede the development of clinical diabetes.
Diabetic dermopathy is characterized by small scar-like atrophic depressions occurring on the shins of diabetic patients; its presence is associated with microangiopathic complications of diabetes, such as nephropathy, neuropathy, and retinopathy . Correlation with nephropathy and other microangiopathic complications is also seen with rubeosis facei diabeticorum. This disorder presents in approximately 3–5% of diabetics as facial redness and is a frequently overlooked microangiopathic condition . Necrobiosis lipopidica diabeticorum, while rare, is a clinically distinctive disorder that has been associated with diabetes mellitus. It presents as well-defined red-brown to orange-yellow plaques often with central waxy, atrophic and occasionally eroded skin. Squamous cell carcinoma may develop in eroded areas. Management is difficult, and multiple treatment modalities have been tried including topical or intralesional corticosteroids, ultraviolet light therapy, and combination dipyridamole/aspirin therapy. Leading theories suggest that microangiopathy plays a significant role in disease pathogenesis, and it may precede or follow a diagnosis of diabetes. Necrobiosis lipopidica diabeticorum may also occur in non-diabetic patients  (Fig. 2).
Scleredema diabeticorum and bullosis diabeticorum are generally seen in patients with longstanding diabetes mellitus. In scleredema diabeticorum, there is a degradation of collagen fibers in the skin. This disorder manifests as a thickening and hardening of the skin, generally occurring at the nape, back, and shoulders. Erythema may be present. Treatment is challenging, although ultraviolet A/PUVA therapy may be beneficial . Bullosis diabeticorum is a noniflammatory blistering disorder of the acral skin in diabetics that occurs spontaneously and generally heals without treatment in 2–6 weeks. Secondary skin infection may occur . Skin biopsy may be necessary to distinguish this disorder from similar appearing bullous diseases such as porphyria cutanea tarda, pseudoporphyria , and bullous drug eruption, which also occur in this patient population.
Perforating disorders present as hyperkeratotic papules or nodules, which are sites of transepidermal extrusion of altered keratin or dermal connective tissue and cellular debris. Several entities exist: Kyrle disease, perforating folliculitis, elastosis perforans serpiginosa, reactive perforating collagenosis, and acquired perforating dermatosis. Reactive perforating collagenosis, acquired perforating dermatosis, and perforating folliculitis are reported in association with diabetes and chronic renal failure. There is overlap among the perforating disorders, and differentiating diagnostic criteria are not well defined. Papules occur predominately on the extremities and buttocks at follicular units. Lesions are often highly pruritic, and they may be mistaken for excoriation or folliculitis. Tretinoin or phototherapy may be beneficial therapeutically, and secondary infection is not uncommon. The disorder may resolve post renal transplantation .
Vascular Disorders and Connective Tissue Disease
Vascular disorders commonly play a role in the development of renal failure. Vascular damage may result from infection, rheumatologic disease, tumors, emboli, medication, and multiple other causes.
Systemic lupus erythematosis was the most commonly reported rheumatologic cause of ESRD in the United States in 2015 . Renal failure most commonly occurs in patients with anti-double stranded DNA noted on antibody testing. Multiple cutaneous markers for systemic lupus erythematosis may be seen including a “butterfly” eruption consisting of facial erythema over the malar (cheekbone) region of the face, photosensitivity, hypopigmentation or purplish discoloration of digits with Reynaud’s phenomenon, alopecia (hair loss), and mucosal ulceration.
Another rheumatologic disorder that may result in renal failure is systemic sclerosis. Acute or chronic renal disease occurs in fewer than 20% of these patients but is often precipitous and associated with malignant hypertension. Renal involvement may be preceded by rapidly progressive fibrotic skin change, seen as a thickening of the skin on examination . Other skin signs of systemic sclerosis include cutaneous calcinosis, pigmentary disorders, Reynaud’s phenomenon, telangiectasia, and sclerodactyly (a thickening and tightening of the skin of the digits).
Vasculitis and vascular compromise frequently affect multiple organs including the skin. Leukocytoclastic vasculitis (LCV) refers to small vessel damage due to the infiltration of leukocytes, generally neutrophils. On the skin, LCV frequently presents as palpable purpura. Clinically this is seen as 1–3 mm erythematous, generally round papules that may coalesce to form plaques, and occasionally progress to bullae or ulcerations. As the name suggests, lesions are palpable, although this may be subtle. Palpable purpura is usually noted on dependent areas of the skin, such as the lower legs or buttocks, and the Koebner phenomenon may occur. Among the disorders in which LCV occurs are granulomatosis with polyangiitis , eosinophilic granulomatosis with polyangiitis , cryoglobulinemia , Henoch-Schonlein purpura , and infection. Large and medium vessel vasculitis, also seen in granulomatosis with polyangiitis as well as in other diseases such as polyarteritis nodosa , usually manifest in the skin as bullae from acute infarction, ulcerations, cutaneous nodules, and livedo reticularis (a mottled reticular red to purple discoloration of the skin; Fig. 3; Table 1).
Cutaneous markers may be useful in identifying several genetic disorders with both skin and kidney involvement. Among these are Fabry disease, nail-patella syndrome, neurofibromatosis, and multiple endocrine neoplasia 2B.
Fabry disease is an X-linked disorder with deficiency of alpha-galactosidase A, a lysosomal enzyme. ESRD develops in nearly all males and is frequent in females. Skin manifestations include multiple angiokeratomas. Angiokeratomas are small vascular papules found on the skin or mucosa, often red in color, which do not blanch with pressure. They may enlarge over time and become grouped.
Hyperkeratotic or verrucous (“wart-like”) appearance is common as the disease progresses (Fig. 4). Hypohydrosis or anhidrosis (decreased or absent sweating), hypotrichosis (decreased hair), lymphedema, and Reynaud’s phenomenon may also be seen in Fabry disease  (Table 2).
The nail-patella syndrome results in ESRD in approximately 15% of cases . Fingernail involvement is more frequent than toenail involvement and is most prominent at the thumb on the hand and the 5th toe on the foot. Nails are dysplastic; they are often small and narrow and may be depressed, thickened, discolored, or split.
Neurofibromatosis may cause renal failure due to renal artery stenosis, infarction, and aneurysm . Skin manifestations include axillary freckling, café au lait macules (flat, hyperpigmented macules), cutaneous neurofibromas, and plexiform neurofibromas. Most patients complain of pruritus.
Multiple endocrine neoplasia 2B is a rare genetic disorder characterized by pheochromocytoma, medullary thyroid carcinoma, and neuromas. Renal failure may occur due to renal malformation  or hypertension. Skeletal abnormalities may include kyphoscoliosis or lordosis, joint laxity and marfanoid habitus. A characteristic facial appearance develops due to mucosal neuromas.
Patients with ESRD may also develop skin lesions from therapy or kidney disease complications. Immunosuppressant medications used for disease control or anti-transplant rejection may predispose patients to cutaneous and systemic infections. Squamous cell carcinoma occurs more frequently in renal transplant patients than in the general population due to medication-induced reduction in cell-mediated immunity and may affect over 50% of patients  (Fig. 5).
Malignancies such as Kaposi sarcoma, basal cell carcinoma, and melanoma also occur more frequently in transplanted individuals. Disorders of calcification, such as calciphylaxis, may be recognized readily on skin examination. In calciphylaxis, patients may present with livedo reticularis, purpura, or indurated nodules before painful ulceration and necrosis of the skin occurs. The diagnosis of nephrogenic fibrosing dermopathy may be suspected in a patient with thickening of the skin and bronze discoloration. Regular examination of the skin may allow early intervention of these and other disorders.
Cutaneous involvement is common in many kidney disorders. Careful skin examination in renal failure patients may be a valuable aid in diagnosis and monitoring of therapy. Familiarity with skin signs of systemic diseases, which may cause renal failure and possible dermatological complications of ESRD and renal failure treatment is essential to maximize early diagnosis and proper utilization of resources.
Dr. Karen M. Van de Velde-Kossmann has no conflicts of interest to disclose.