Dr.

Waheed Ahmad

Registrar Nephrologist

y These diseases are sometimes related to the

underlying renal illness but are more frequently directly or indirectly associated with uremia in its broadest sense. y almost 100% prevalence in dialysis populations y A basic knowledge of the dermatological conditions that can arise in the setting of kidney disease is, therefore, very useful to practicing nephrologists.

y Skin diseases have a considerable negative effect

on a patient s quality of life. y Induces serious discomfort, anxiety, depression and sleeping disorders and have an overall negative effect on mental and physical health. y Early recognition of these severe skin disorders and prompt initiation of treatment can dramatically alter their course and even save a patient s life

UREMIC PRURITUS

Epidemiology and clinical characteristics

y The prevalence of UP has declined in the past 10

years y 22% to 48% of adults with CKD y The occurrence, duration and intensity of UP can change over time and the itching is usually worst at night causing sleep disturbances and skin damage. y Areas most commonly affected
y y y y y

Back Limbs Chest Head and face generalized pruritus(20-50%)

y Aggravating Factors
y y y

External heat sweat stress cold or hot showers

y Relieving Symptoms
y

y Contradictory reports have been published on the acute effect of dialysis on UP y The type of biocompatible dialysis membrane does not seem to affect the incidence of UP, but a recent, noncontrolled study showed the use of polymethylmethacrylate high-flux dialysis membranes to be associated with a significant reduction in pruritus score

y CAUSES

A number of factors may contribute to uremic pruritus y secondary hyperparathyroidism , dry skin (caused by sweat gland atrophy) , hyperphosphatemia with increased calcium phosphate deposition in the skin , inadequate dialysis , increased beta 2 microglobulin levels, anemia (or possibly some other manifestation of erythropoietin deficiency), peripheral neuropathy, high aluminum levels , hypervitaminosis A, and immune dysfunction

y substantial effect on quality of life, as it causes

serious discomfort, anxiety, depression and sleeping disorders. y Japanese study and the DOPPS demonstrated an association between UP and an increased risk of mortality. y UP often leads to considerable mechanical skin damage as a result of continuous scratching, with excoriations, superimposed infections and chronic lesions of prurigo nodularis or skin lichenification

Pathophysiology
y The pathophysiology of UP is complex y Two hypotheses on the underlying pathophysiological

mechanisms of UP have been postulated

y y

the immuno hypothesis the opioid hypothesis

y The immunohypothesis considers UP to be an

inflammatory systemic disease rather than a local skin disorder. y This idea is supported by studies that have demonstrated beneficial effects of ultraviolet B (UVB) radiation exposure on UP, and those that have shown amelioration of UP with thalidomide treatment or calcineurin inhibitors such as tacrolimus.

y UVB phototherapy has been shown to attenuate the development of

TH1-type lymphocytes in favor of TH2-type lymphocyte differentiation, and hence to decrease the production of interleukin (IL). The number of CXC chemokine receptor 3 (CXCR3)-expressing and interferon secreting CD4+ cells (which indicate TH1 cell differentiation) is significantly higher in patients on dialysis with UP than in those without UP. and IL-6, are increased in patients with UP

y serum levels of inflammatory biomarkers, such as C-reactive protein y UP as a potentially novel marker of malnutrition inflammation

atherosclerosis (MIA) syndrome, a known risk factor for death in dialysis populations.

y The opioid hypothesis proposes that UP is partly a result of changes in the endogenous opioidergic system, with over expression of opioid -receptors in dermal cells and lymphocytes. y Overactivity of the opioid -receptor (and concomitant down regulation of opioid -receptors) might be caused by the increased serum -endorphin to dynorphin. A ratio observed in patients with CKD and could explain the development of UP. y Activation of the -opioid system by administration of a receptor agonist such as nalfurafine reduces the severity of pruritus in patients on hemodialysis.

y Parathyroid hormone and divalent ions (e.g.

calcium, phosphate and magnesium ions) have also been implicated in the pathogenesis of UP, as itching frequently accompanies severe secondary hyperparathyroidism and an elevated calcium phosphate product. y The lack of consistent correlation between levels of parathyroid hormone, calcium and phosphorus and UP severity, however, indicates that other factors are more important in the pathogenesis of UP.

y Histamine, which is released from mast cells in response to substance P, has also been implicated in UP;
y y y

the number of dermal mast cells is increased in patients with CKD increased plasma levels of tryptase and histamine. The role of elevated plasma serotonin (5-hydroxytryptamine [5-HT]) levels in patients on dialysis with UP is still being debated

y Xerosis (dry skin) can facilitate the development of UP in patients with CKD. y Xerosis is caused by
y y y y

atrophy of sweat glands and sebaceous glands impaired sweat secretion disturbed dermal hydration abnormal arborization of free, cutaneous type C nerve fibers.

y The pathophysiological processes that underlie UP are clearly very complex and remain largely unknown.

XEROSIS AND PRURITIS IN PATIENT WITH CHRONIC RENAL FAILURE ON HEMODIALYSI S

Treatment
y General measures
y y y y

optimization of dialysis efficacy use of biocompatible dialysis membranes improvement of the nutritional status of the patient Adequate control of plasma levels of calcium and phosphorus . liver diseases (e.g. hepatitis) primary skin diseases (e.g. atopic dermatitis, contact dermatitis, psoriasis and urticaria) endocrine disorders (e.g. Graves disease, hypothyroidism and diabetes mellitus)

y Other causes of pruritus

y y

Topical treatments
y Skin emollients y capsaicin cream y tacrolimus. y The primary therapy in patients with CKD who have

UP is the application of skin emollients with a high water content to hydrate the stratum corneum

Systemic treatments
y ultraviolet light
y Gabapentin

y opioid receptor antagonists and agonists

y y y y y

anti histamines activated charcoal 5-HT3 antagonists immunomodulators erythropoietin

CALCIFIC UREMIC ARTERIOLOPATHY (CALCIPHYLAXIS)

Epidemiology and clinical characteristics

y potentially life threatening vasculopathy of the skin and subcutaneous tissues that is usually associated with CKD. y Incidence of CUA y approximately 4% in patients on dialysis y less than 1% in patients with CKD y Risk factors y Obesity y diabetes mellitus y female sex y white ethnicity y time on renal replacement therapy y use of coumarin anti coagulants y use of vitamin D analogs y calcium containing phosphate binders y iron-substitution therapy y glucocorticosteroids

y Insidious onset that is marked by the occurrence of livedoreticularis-like skin lesions predominantly on the abdomen, buttocks and thighs, all of which are areas with large amounts of subcutaneous fat. y Over a period of days or weeks, these lesions transform into painful, subcutaneous, purpuric plaques and nodules and subsequently become necrotic ulcers covered by eschars (dry scabs or sloughs formed on the skin. y These areas of ischemic, necrotic skin and subcutaneous fat can extend into deeper tissues including muscle and can become infected.

y The onset of CUA is often associated with

y y y

history of recent trauma initiation of coumarin treatment hypotensive episodes.

y Less commonly, CUA affects distal extremities such as the hands or lower legs; systemic involvement with ischemic infarction of the bowel, myocardium, brain, optic nerve or muscles, has been reported rarely. y High mortality
y y

1-year survival rate of 45% 5-year survival rate of 35%

y death is predominantly the result of infectious complications.

y An early clinical diagnosis of the nonulcerative

stage of CUA is very important y The sudden appearance of painful violaceous plaques and nodules on the trunk or proximal extremities of patients with CKD and those on dialysis who are at risk of CUA should trigger prompt further diagnostic work-up. y A histological diagnosis is preferable y skin biopsies must be obtained with caution as they might produce nonhealing ulcerations.

y The histological lesions characteristically

y y y y y y

epidermal ulceration dermal necrosis vascular medial wall calcifications with subintimal or intimal hyperplasia fibrosis of small and medium-sized blood vessels in the dermis and subcutaneous tissues Thrombotic occlusion of cutaneous vessels extravascular calcium depositions

y The histological lesions described, including calcifying septal

panniculitis, are not pathognomonic for CUA y Radiological assessment with xerography (the X-ray technique used in mammography) might reveal small-vessel calcifications and measurement of transcutaneous oxygen saturation can confirm underlying tissue ischemia. y In some patients with CUA, a technetium-99m methylene diphosphate bone scan reveals superficial tracer localization in the subcutaneous tissues as well as visceral tracer activity

Bone scintigraphic abnormalities in calcific uremic arteriolopathy. Calf calcification in a patient with gross ulcerations in both legs from the popliteal fossae to the ankles (arrows).

Histopathologic features of calcific uremic arteriolopathy. Medial calcification and intimal hyperplasia of an arteriole at the dermal-subcutaneous junction. Note calcification of interlobular capillaries in the subcutaneous tissue (arrows). Van Kossa staining. (From

Differential Diagnosis
y coumarin induced skin necrosis y atherosclerotic peripheral vascular disease y systemic vasculitis y Cryoglobulinemia y cholesterol embolization y pyoderma gangrenosum y oxalosis y benign nodular calcification (a common condition

in patients with CKD).

Pathophysiology
y

the vascular wall. y the expression of osteopontin and bone morphogenic protein 4, both inducers of vascular calcification, is increased in vascular smooth muscle cells and dermal cells, respectively
y

CUA is thought to involve an imbalance between inducers and inhibitors of calcification of

Vascular smooth muscle cells in CUA transform into (osteogenic) osteo blastlike cells (via expression of core-binding factor-1) and express bone-related proteins such as osteocalcin, bone sialoprotein, type 1 collagen and osteopontin. production of inhibitors of vascular calcification (e.g. fetuin A and osteoprotegerin) are suppressed (via the nuclear factor B cascade) by the inflammatory changes encountered in uremia. the actions of the matrix -carboxyglutamate (GLA) protein can be inhibited by coumarin-induced inhibition of vitamin-K dependent carboxylation, which results in increased vascular calcifications. Loss of pyrophosphate (which inhibits mineralization) from endothelial and vascular smooth muscle cells is associated with an increased risk of CUA in patients with CKD Why CUA develops only in a small number of patients with CKD and what triggers it is not clear at present, but the occurrence of various procalcific events in concert with ischemia, inflammation and endothelial injury seems to ultimately lead to the initiation of this devastating disease

Treatment
y Parrimy measures
y y y y y

intensive wound care (including repeated surgical resections of necrotic tissue) provision of systemic antibiotics adequate opioid analgesia vacuum dressings Aggressive surgical wound cleaning with autologous split-skin grafting

y Secondary treatment measures

y y y y y y

restoring the patient s calcium and phosphate balance by use of intensified dialysis (with low calcium dialysate) the use of non-calcium based phosphate binders (e.g. sevelamer or lanthanum carbonate) discontinuation of vitamin D analogs presence of elevated intact parathyroid hormone levels, urgent parathyroidectomy might be necessary. For patients in whom urgent surgical parathyroidectomy is contraindicated, calcimimetic therapy can be attempted. Vitamin K supplementation is advised in patients with coumarin-associated CUA.

y Sodium thiosulfate, an inorganic salt, reduces metastatic tissue calcifications, y y y

antioxidant and induces endothelial nitric oxide synthesis. dosage of 5 25 g during dialysis The main dose limiting adverse effect of sodium thiosulfate is nausea. Sodium thiosulfate treatment should be continued for a sufficiently long period (i.e. weeks to months) in order to maintain an initial positive response. Both intravenous bisphosphonates (e.g. pamidronate and ibandronate) and oral bisphosphonates (e.g. etidronate) have also been used successfully to treat CUA, with rapid reduction in pain and decreased signs of inflammation. The use of bisphosphonates in patients with CKD and those on dialysis seems to be relatively safe, but only limited data are available. Hyperbaric oxygen therapy improves oxygen delivery to damaged tissues and promotes wound healing through increased neoangiogenesis and collagen formation and improved neutrophil-mediated bacterial killing. Hyperbaric oxygen therapy has been used successfully in patients with CUA with few adverse effects

NEPHROGENIC SYSTEMIC FIBROSIS

Epidemiology and clinical characteristics

y NSF, previously known as nephrogenic fibrosing dermopathy, is a scleroderma-like fibrosing disorder that occurs in patients with CKD, renal transplant recipients and patients with acute kidney injury. y characterized by painful and debilitating, progressive fibrosis and thickening of the skin, with occasional involvement of other organs and tissues such as the lungs, heart, liver, esophagus, testes, dura mater and striated muscles. y The first cases of NSF were reported in 1997, and the international NSF registry now contains more than 215 confirmed cases. y The disorder occurs across all ethnicities and affects men and women equally

y initial complain of tightening and swelling of the skin of the lower or upper y y

y y y

extremities, with light or dark red discoloration of the skin. Lesions usually form in symmetrical patterns on the ankles, lower legs, wrists or forearms and appear as plaques, papules or nodules. Over a period of days or weeks, a progressive confluence of erythematous lesions ensues and the skin becomes markedly thickened with a woody texture and brownish peau d orange (orange peel) indurations; these changes increasingly restrict the movement of adjacent joints, which results in contractures and immobilization. The lesions expand proximally; they usually spare the head but occasionally a marked swelling of the hands and feet with secondary bullae occurs. Patients complain of painful tightness in the affected limbs and joints and occasionally mention that they have pruritus, a burning sensation or muscle weakness. Although NSF does not directly cause death, its debilitating course can induce secondary complications that ultimately lead to prolonged hospital stays and are associated with a 30% mortality

y Factors reported to be associated with NSF (without definitive proof)

include
y y y y y y y y

coagulation abnormalities (e.g. a hypercoagulable state) recent vascular surgery deep vein thrombosis thrombosed arteriovenous access failure or primary non function of a transplanted kidney hepatic disease hyperphosphatemia use of high doses of recombinant erythropoietin.

y Angiotensin-converting-enzyme inhibitors, on the other hand, might

protect against NSF. y High doses of erythropoietin increase numbers of circulating hematopoietic stem cells and can trigger an exaggerated, fibrininduced, wound-repair response; both of these events occur in NSF. y Exposure to gadolinium-based MRI contrast agents is associated with the development of NSF in patients with CKD.

y The diagnosis of NSF is made on the basis of a patient s history and

medical examination and is confirmed by skin biopsy y Histology shows a

y

thickened dermis with pathologic changes that include the marked proliferation of spindle cells with interstitial mucin deposition, the presence of thickened collagen bundles and a lack of inflammatory cells. Dendritic cells and histiocytes are present. Metastatic calcifications and even ossifications have been described in some cases.

y Whole-body PET scans of patients with NSF using 18F-

fluorodeoxyglucose have shown that metabolic activity is increased at the sites of clinical lesions. This technique can be used to confirm the diffuse inflammatory skin changes associated with active NSF and theoretically might be useful for evaluating the response to therapy.

Differential diagnosis
y systemic sclerosis (scleroderma) y Scleromyxedema y eosinophilic fasciitis y Lipodermatosclerosis y graft-versus-host disease y dermatomyositis y amyloidosis.

Pathophysiology
y The role of gadolinium in the development of NSF is now clearly y y

recognized: exposure to gadolinium before the onset of disease was confirmed in over 95% of reported cases. Free gadolinium ions are highly toxic to tissues, and, therefore, gadolinium is used in the form of inert chelates bound to large organic molecules such as diethylene triamine pentaacetic acid. Some chelating agents dissociate more easily from gadolinium than others. Such dissociation depends on characteristics of the chelate: configuration (macrocyclic or linear), charge (ionic or non ionic), thermodynamic stability and the amount of excess chelate that is present. Metabolic acidosis and high levels of endogenous ions such as Zn2+, Cu2+, Ca2+ and Fe3+ might enhance dissociation of gadolinium from its chelate through the transmetalation process

y Under normal circumstances, gadolinium based contrast agents are eliminated by the

y y

kidney through glomerular filtration. The half life of these agents increases from approximately 1.3 h in individuals with normal renal function to 60 h in those with a reduced glomerular filtration rate (<15 ml/min/1.73m2) This increased dissociation is thought to lead to increased tissue uptake of free gadolinium, particularly in proinflammatory conditions. Gadolinium in the tissues undergoes phagocytosis by macrophages, which in turn attract circulating fibrocytes positive for CD34 and procollagen I; the latter cells can transform into dermal fibro blast-like cells and produce excessive amounts of mucin constituents such as hyaluronan and sulfated glycosaminoglycans. Transforming growth factor , produced by CD68+ and factor XIIIa+- activated dendritic cells, has also been implicated in this profibrotic process. The hypothesis that increased tissue uptake of free gadolinium occurs as a result of increased dissocia tion has been strengthened by the demonstration that tissue gadolinium levels are 35-fold to 150-fold higher in patients with NSF than in healthy volunteers exposed to gadolinium contrast agents. Scanning electron microscopy and energy-dispersive X-ray spectroscopy have confirmed the presence of gadolinium in tissues of patients with NSF

Treatment
y At present, NSF has no effective treatment. y Therapies that have been tested include
y y y y y y y y y y y y y

Corticosteroids Thalidomide Cyclophosphamide Sirolimus Ciclosporin Immunoglobulins topical calcipotriene psoralen ultraviolet A (PUVA) therapy interferon sodium thiosulfate Plasmapheresis imatinib mesylate and extracorporeal photopheresis (after administration of 8methoxypsoralen).

y In cases of NSF associated with acute kidney injury, restoration of renal

function is a primary goal. y Physiotherapy, deep-tissue massage and swimming are advocated in all patients with NSF in order to maintain mobility and prevent contractures

y At present, prevention of NSF seems more important than any of the y y y y

currently available interventions and widespread clinical awareness of this condition is required. The use of gadolinium contrast should be limited to an absolute minimum in patients with CKD low osmolar or iso-osmolar iodine-based contrast agents provide a valid alternative to gadolinium-based agents in most instances Some prophylactic strategies for the prevention of radiocontrastinduced nephropathy are available, but these methods are not always effective. In cases where administration of gadolinium-based contrast is necessary, use of the lowest doses of the more stable types of gadolinium-based contrast agent, such as gadobenate dimeglumine, is advisable.

y Gadolinium contrast is readily cleared by hemodialysis, with 92% of y y y y y y

administered gadolinium eliminated after two dialysis sessions (and 99% after three sessions). Such a strategy could, therefore, be considered in patients with stages 4 and 5 CKD who require MRI with gadolinium contrast. However, no prospective study has demonstrated a clinical benefit of hemodialysis in the prevention of NSF. A retrospec tive analysis published in 2008 suggested that hemodialysis helped to prevent NSF in patients with an estimated glomerular filtration rate below 15 ml/min/1.73m2 who received high doses of gadolinium-based contrast agent. Peritoneal dialysis is not effective for the elimination of gadolinium No consensus guidelines have yet been formulated regarding gadolinium contrast use for patients with stage 3 CKD, but avoidance of large volumes of linear, nonionic, gadolinium-based contrast agent seems advisable. Whether prompt dialysis after exposure would be beneficial in this particular group of patients is even less clear than it is for those with stages 4 and 5 CKD.

ACQUIRED PERFORATING DERMATOSIS

y Acquired perforating dermatitis (APD, also known as Kyrle disease) has a prevalence of y y y y y y y

approximately 10% in dialysis populations and occurs predominantly in African Americans and patients with diabetes mellitus. APD is also associated with other entities such as hepatic disease, thyroid illnesses, malignancies, scabies and AIDS. APD is usually characterized by a linear confluence of papules with a central, oystershelllike keratotic plug on the trunk, proximal extremities, scalp and face. Lesions are red or pink in white patients, and hyperpigmented in black patients initiate intense pruritus with secondary development of scratch marks (Koebner phenomenon). The origin of APD lesions is not known; suspected causes include an inflammatory skin reaction secondary to the presence of uremic toxins, uric acid deposits or scratchinginduced trauma. Histological changes include the presence of epidermal invaginations with a central, basophilic, keratotic plug, uric acid and calcium hydroxyapatite deposits and chronic inflammatory granulomas.112 Treatment of APD is often frustrating as lesions can persist and chronic scars can develop. Lubricants, steroids, keratolytics, vitamin A, cryotherapy, UVB therapy and oral or topical isotretinoin preparations have all been tried with variable degrees of success

PORPHYRIA CUTANEA TARDA

y y y y

y y

Porphyria cutanea tarda (PCT) in patients with CKD commonly presents as bullae on the dorsal surfaces of the hands and feet; bullae sometimes occur on the face as well, usually accompanied by facial hyper pigmentation (sclerodermoid plaques) and hypertrichosis. Secondary infection of the bullous lesions often occurs and healing of these lesions is associated with scarring. The sporadic form of PCT occurs in approximately 5% of patients on dialysis; this form is caused by increased uroporphyrin concentrations triggered by y ingestion of alcohol y Estrogens y iron y chronic infections such as hepatitis B, hepatitis C or HIV. Typical linear staining of IgG, C3 and fibrin at the dermoepidermal junction is noted on skin biopsy in patients with PCT; blood vessels are surrounded by periodic acid Schiff-positive material with little inflammation. Pseudoporphyria is triggered by medications (e.g. amiodarone, tetracyclines and naproxen); this condition presents in the same way as PCT but differs from PCT in that the patient s uroporphyrin levels are normal Sun protection is a crucial element of treatment for patients with PCT. Uroporphyrin levels can be lowered by improving dialysis efficacy through use of high-flux membranes. Drastic measures to lower uroporphyrin concentrations further (e.g. phlebotomy) are not routinely advocated. Iron or estrogen supplementation should be interrupted during treatment for PCT, vitamin B1 deficiency should be excluded, and patients should abstain from alcohol

y y y y

CONCLUSIONS

y Skin disorders are a common problem in patients with CKD and can

seriously affect the patient s physical and mental health and thus their quality of life. y A basic knowledge of the most common dermatological entities encountered in CKD will enable renal physicians to optimize daily patient care and to recognize potentially life-threatening conditions. y The clinical management of UP remains a challenge, and a more detailed understanding of its underlying complex mechanisms is required. Further research into the pathological pathways of UP will ultimately provide novel therapeutic strategies with improved efficacy. y CUA is a dangerous complication of CKD that requires prompt diagnosis and treatment to alter its devastating course. Emerging new therapeutic options such as the use of bisphosphonates, sodium thiosulfate, calcimimetics and noncalcium- containing phosphate binders seem to have beneficial effects on CUA and hold promise for the future.

y NSF is now clearly known to be associated with the use of gadolinium-based contrast agents in patients with CKD. The current lack of any efficient therapy for NSF emphasizes the need for intensive campaigns to increase the clinical awareness of this debilitating condition so that it can be prevented whenever possible. y Preventive measures, particularly in patients with stages 4 and 5 CKD, include the use of alternative iodine-based contrast agents if possible, or the administration of low volumes of the more stable types of gadolinium-based contrast agent if this type of agent is necessary. In cases of gadolinium exposure, hemodialysis treatment might theoretically offer benefits, but prospective studies that investigate this option are lacking at present.

THANK YOU

Figure 84.5 Benign nodular calcification (calcinosis cutis). Firm subcutaneous nodule adjacent to the elbow.

Figu cutanea tarda. Tense bullae, erosions, and crusts of the dorsal hands re 84.4 Porphyria. (From refe

84.11 Histopathologic features of nephrogenic systemic fibrosis. Haphazardly arranged dermal collagen bundles with surrounding clefts and a strikingly increased number of similarly arranged spindled and plump fibroblast-like cells.