Skin Problems in Chronic Kidney Disease

Box 1.

Skin Disorders in Patients With Chronic Kidney Disease

Udayakumar P et al. (2006) Cutaneous manifestations in patients with chronic renal failure on hemodialysis. Indian J Dermatol Venereol Leprol 72: 119-125
Abdelbaqi-Salhab M et al. (2003) A current review of the cutaneous manifestations of renal disease. J Cutan Pathol 30: 527-538
Robinson-Bostom L et al. (2000) Cutaneous manifestations of end-stage renal disease. J Am Acad Dermatol 43: 975-986
Patel TS et al. (2007) An update on pruritus associated with CKD. Am J Kidney Dis 50: 11-20
Pisoni RL et al. (2006) Pruritus in haemodialysis patients: International results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 21: 3495-3505
Mistik S et al. (2006) An epidemiology study of patients with uremic pruritus. J Eur Acad Dermatol Venereol 20: 672-678
Dyachenko P et al. (2006) Hemodialysis-related pruritus and associated cutaneous manifestations. Int J Dermatol 45: 664-667
Keith-Reddy SR et al. (2007) Uremic pruritus. Kidney Int 72: 373-377
Lin HH et al. (2008) Uremic pruritus, cytokines, and polymethylmethacrylate artificial kidney. Artif Organs 32: 468-472
Narita I et al. (2006) Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 69: 1626-1632
Garssen J et al. (1999) UVB exposure-induced systemic modulation of TH1- and TH2-mediated immune responses. Immunology 97: 506-514
Kimmel M et al. (2006) The role of micro-inflammation in the pathogenesis of uremic pruritus in haemodialysis patients. Nephrol Dial Transplant 21: 749-755
Qureshi AR et al. (2002) Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients. J Am Soc Nephrol 13 (Suppl): S28.S36
Umueuchi H et al. (2003) Involvement of central µ-opioid system in the scratching behavior in mice, and the suppression of itch by the activation of µ-opioid system. Eur J Pharmacol 477: 29-35
Kumagai H et al. (2004) Prospects for a novel kappaopioid receptor agonist, TRK-820, in uremic pruritus. In Itch, Basic Mechanisms and Therapy, 279-286 (Eds Yosipovitch G et al.) New York, NY: Dekker
Wikstrom B et al. (2005) Kappa-opioid system in uremic pruritus: multicenter, randomized, doubleblind, placebo-controlled clinical studies. J Am Soc Nephrol 16: 3742-3747
Peer G et al. (1996) Randomised cross-over-trial of naltrexone in uraemic pruritus. Lancet 348: 1552-1554
Cho YL et al. (1997) Uremic pruritus: roles of parathyroid hormone and substance P. J Am Acad Dermatol 36: 538-543
Chou FF et al. (2000) A study on pruritus after parathyroidectomy for secondary hyperparathyroidism. J Am Coll Surg 190: 65-70
Momose A et al. (2004) Calciums ions are abnormally distributed in the skin of haemodialysis patients with uraemic pruritus. Nephrol Dial Transplant 19: 2061-2066
Szepietowski J et al. (1995) Pruritus and mast cell proliferation in the skin of haemodialysis patients. Inflamm Res 44 (Suppl 1): S84.S85
Dugas-Breit S et al. (2005) Baseline serum levels of mast cell tryptase are raised in hemodialysis patients and associated with severity of pruritus. J Dtsch Dermatol Ges 3: 343-347
Balaskas EV et al. (1998) Histamine and serotonin in uremic pruritus: effect of ondansetron in CAPDpruritic patients. Nephron 78: 395-402
Ashmore SD et al. (2000) Ondansetron therapy for uremic pruritus in hemodialysis patients. Am J Kidney Dis 35: 827-831
Fantini F et al. (1992) Cutaneous innervation in chronic renal failure patients: an immunohistochemical study. Acta Derm Venereol 72: 102-105
Johansson O et al. (1989) Intra-epidermal neuronspecific enolase (NSE)-immunoreactive nerve fibres: evidence for sprouting in uremic patients on maintenance hemodialysis. Neurosci Lett 99: 281-286
Morton CA et al. (1996) Pruritus and skin hydration during dialysis. Nephrol Dial Transplant 11: 2031-2036
Okada K et al. (2004) Effect of skin care with an emollient containing a high water content on mild uremic pruritus. Ther Apher Dial 8: 419-422
Chen YC et al. (2006) Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. Am J Kidney Dis 48: 69-76
Wasik F et al. (1996) Relief of uraemic pruritus after balneological therapy with a bath oil containing polidocanol (Balneum Hernal Plus): an open clinical study. J Dermatol Treat 7: 231-233
Szepietowski JC et al. (2005) Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerol Croat 13: 97-103
Breneman DL et al. (1992) Topical capsaicin for the treatment of hemodialysis-related pruritus. Am Acad Dermatol 26: 91-94
Tarng DC et al. (1996) Hemodialysis-related pruritus: a double-blind, placebo-controlled, cross-over study of capsaicin 0.025% cream. Nephron 72: 617-622
Kuypers DK et al. (2004) A prospective proof of concept study of the efficacy of tacrolimus ointment on uremic pruritus (UP) in patients on chronic dialysis therapy. Nephrol Dial Transplant 19: 1895-1901
Duque MI et al. (2005) Lack of efficacy of tacrolimus ointment 0.1% for treatment of hemodialysis-related pruritus: a randomized, double-blind, vehiclecontrolled study. J Am Acad Dermatol 52: 519-521
US Food and Drug Administration (online 10 March 2005) FDA Public Health Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. [www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Elidel] (accessed 2 January 2009)
Naylor M et al. (2005) Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus. J Dermatolog Treat 16: 149-153
Munzenberger PJ et al. (2007) Safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Pharmacotherapy 27: 1020-1028
Gilchrest BA et al. (1979) Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanism of action. Ann Intern Med 91: 17-21
Ada S et al. (2005) Treatment of uremic pruritus with narrowband ultraviolet B phototherapy: an open pilot study. J Am Acad Dermatol 53: 149-151
Seckin D et al. (2007) Generalized pruritus treated with narrowband UVB. Int J Dermatol 46: 367-370
Gunal AI et al. (2004) Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebocontrolled, double-blind trial. Nephrol Dial Transplant 19: 3137-3139
Manenti L et al. (2005) Gabapentin in the treatment of uremic itch: an index case and pilot evaluation. J Nephrol 18: 86-91
Pauli-Magnus C et al. (2000) Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study. J Am Soc Nephrol 11: 514-519
Imaizumi A et al. (2003) Effective treatment of pruritus on atopic dermatitis using H1 antihistamines (second-generation antihistamines): changes in blood histamine and tryptase levels. J Dermatol Sci 33: 23-29
Pederson JA et al. (1980) Relief of idiopatic generalized pruritus in dialysis patients treated with activated oral charcoal. Ann Intern Med 93: 446-448
Giovannetti S et al. (1995) Oral activated charcoal in patients with uremic pruritus. Nephron 70: 193-196
Layegh P et al. (2007) Effect of oral granisetron in uremic pruritus. Indian J Dermatol Venereol Leprol 73: 231-234
Silva SR et al. (1994) Thalidomide for the treatment of uremic pruritus: a crossover randomized doubleblind trial. Nephron 67: 270-273
De Marchi S et al. (1992) Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 326: 969-974
Janigan DT et al. (2000) Calcified subcutaneous arterioles with infarcts of the subcutis and skin ('calciphylaxis') in chronic renal failure. Am J Kidney Dis 35: 588-597
Wilmer W et al. (2002) Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial 15: 172-186
Weenig RH et al. (2007) Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 56: 569-579
Rogers NM et al. (2007) Calcific uremic arteriolopathy: advances in pathogenesis and treatment. Semin Dial 20: 150-157
Mazhar AR et al. (2001) Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int 60: 324-332
Essary LR et al. (2000) Cutaneous calciphylaxis: an underrecognized clinicopathologic entity. Am J Clin Pathol 113: 280-287
Bleibel W et al. (2006) A case report comparing various radiological tests in the diagnosis of calcific uremic arteriolopathy. Am J Kidney Dis 48: 659-661
Wilmer WA et al. (2001) Transcutaneous oxygen tension in patients with calciphylaxis. Am J Kidney Dis 37: 797-806
Soni S et al. (2008) Bone scan findings in metastatic calcification from calciphylaxis. Clin Nucl Med 33: 502-504
Shroff RX et al. (2007) The vascular biology of calcification. Semin Dial 20: 103-109
Weenig RH (2008) Pathogenesis of calciphylaxis: Hans Selye to nuclear factor κB. J Am Acad Dermatol 58: 458-471
Moe SM et al. (2003) Calciphylaxis and vascular calcification: a continuum of extra-skeletal osteogenesis. Pediatr Nephrol 18: 969-975
Griethe W et al. (2003) Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis. J Nephrol 16: 728-732
Ahmed S et al. (2001) Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 37: 1267-1276
Vattikuti R et al. (2004) Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 286: E686-E696
Schafer C et al. (2003) The serum protein α2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopy calcification. J Clin Invest 112: 357-366
Cranenburg EC et al. (2008) The circulating inactive form of Matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res 45: 427-436
Chen NX et al. (2006) Uremic vascular calcifications. J Investig Med 54: 380-384
Girotto JA et al. (2001) Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery 130: 645-651
Galimberti RL et al. (2005) Cutaneous necrosis by calcific uremic arteriolopathy. Int J Dermatol 44: 101-106
Velasco N et al. (2006) Successful treatment of calciphylaxis with cinacalcet—an alternative to parathyroidectomy? Nephrol Dial Transplant 21: 1999-2004
Guerra G et al. (2005) Rapid resolution of calciphylaxis with intravenous sodium thiosulfate and continuous venovenous haemofiltration using low calcium replacement fluid: case report. Nephrol Dial Transplant 20: 1260-1262
Meissner M et al. (2007) Sodium thiosulfate: a new way of treatment for calciphylaxis? Dermatology 214: 278-282
Mataic D et al. (2006) Intraperitoneal sodium thiosulfate for the treatment of calciphylaxis. Ren Fail 28: 361-363
Shiraishi N et al. (2006) Successful treatment of a patient with severe calcific uremic arteriolopathy (calciphylaxis) by etidronate sodium. Am J Kidney Dis 48: 151-154
da Costa JB et al. (2007) Pamidronate as a treatment option in calciphylaxis. J Eur Acad Dermatol Venereol [doi:10.1111/j.1468-3083.2007.02532.x]
Hanafusa T et al. (2007) Intractable wounds caused by calcific uremic arteriolopathy treated with bisphosphonates. J Am Acad Dermatol 57: 1021-1025
Basile C et al. (2002) Hyperbaric oxygen therapy for calcific uremic arteriolopathy: a case series. J Nephrol 15: 676-680
Mendoza FA et al. (2006) Description of twelve cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 35: 238-249
The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR) [http://www.icnfdr. org/] (accessed 2 January 2009)
DeHoratius DM et al. (2006) Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial 19: 191-194
Evenepoel P et al. (2004) Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure. Nephrol Dial Transplant 19: 469-473
Fazeli A et al. (2004) Nephrogenic fibrosing dermopathy: are ACE inhibitors the missing link? Arch Dermatol 140: 1401
Wiginton CD et al. (2008) Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR Am J Roentgenol 190: 1060-1068
Swaminathan S et al. (2006) Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 145: 234-235
Broome DR (2008) Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol 66: 230-234
Perazella MA (2007) Nephrogenic systemic fibrosis, kidney disease and gadolinium: is there a link? Clin J Am Soc Nephrol 2: 200-202
Perazella MA et al. (2007) Gadolinium use in patients with kidney disease: a cause for concern. Semin Dial 20: 179-184
Khurana A et al. (2008) Quantification of gadolinium in nephrogenic systemic fibrosis: re-examination of a reported cohort with analysis of clinical factors. J Am Acad Dermatol 59: 218-224
Kucher C et al. (2005) Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol 32: 484-490
Digby S et al. (2008) Nephrogenic systemic fibrosis: a histopathological study of eight cases of a recently described entity. Histopathology 52: 531-534
Penfield JG and Reilly RF Jr (2007) What nephrologists need to know about gadolinium. Nat Clin Pract Nephrol 3: 654-668
Abraham JL et al. (2008) Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 158: 273-280
Edward M et al. (2007) Cutaneous mucinosis associated with dermatomyositis and nephrogenic fibrosing dermopathy: fibroblast hyaluronan synthesis and the effect of patient serum. Br J Dermatol 156: 473-479
Edward M et al. (2008) Gadodiamide contrast agent 'activates' fibroblasts: a possible cause of nephrogenic systemic fibrosis. J Pathol 214: 584-593
Kelly B et al. (2008) Nephrogenic systemic fibrosis is associated with transforming growth factor β and Smad without evidence of renin-angiotensin system involvement. J Am Acad Dermatol 58: 1025-1030
Schroeder JA et al. (2008) Ultrastructural evidence of dermal gadolinium deposits in a patient with nephrogenic systemic fibrosis and endstage renal disease. Clin J Am Soc Nephrol 3: 968-975
High WA et al. (2007) Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 56: 21-26
High WA et al. (2007) Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 56: 710-712
Wiginton CD et al. (2008) Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR Am J Roentgenol 190: 1060-1068
Thakral C et al. (2007) Automated scanning electron microscopy and X-ray microanalysis for in situ quantification of gadolinium deposits in skin. J Electron Microsc (Tokyo) 56: 181-187
Yerram P et al. (2007) Nephrogenic systemic fibrosis: a mysterious disease in patients with renal failure—role of gadolinium-based contrast media in causation and the beneficial effect of intravenous sodium thiosulfate. Clin J Am Soc Nephrol 2: 258-263
Baron PW et al. (2003) Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol 25: 204-209
Richmond H et al. (2007) Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis. Arch Dermatol 143: 1025-1030
Weiss AS et al. (2007) A case of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis. Nat Clin Pract Nephrol 3: 111-115
Kay J et al. (2008) Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 58: 2543-2548
Prchal D et al. (2008) Nephrogenic systemic fibrosis: the story unfolds. Kidney Int 73: 1135-1137
Rodby RA (2008) Dialytic therapies to prevent NSF following gadolinium exposure in high-risk patients. Semin Dial 21: 145-149
Prince MR et al. (2008) Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology 248: 807-816
Abu-Alfa A (2008) The impact of NSF on the care of patients with kidney disease. J Am Coll Radiol 5: 45-52
Morton CA et al. (1996) Acquired perforating dermatosis in a British dialysis population. Br J Dermatol 135: 671-677
Saray Y et al. (2006) Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol 20: 679-688
Glynne P et al. (1999) Bullous dermatoses in endstage renal failure: porphyria or pseudoporphyria? Am J Kidney Dis 34: 155-160
Shieh S et al. (2000) Management of porphyria cutanea tarda in the setting of chronic renal failure: a case report and review. J Am Acad Dermatol 42: 645-652

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Calcific Uremic Arteriolopathy (Calciphylaxis)

Epidemiology and Clinical Characteristics

CUA, or calciphylaxis, is a potentially life-threatening vasculopathy of the skin and subcutaneous tissues that is usually associated with CKD. The incidence of CUA is estimated to be approximately 4% in patients on dialysis and less than 1% in patients with CKD.^[51,52] The reported incidence of CUA has increased over the past 10 years as a result of improved clinical awareness.^[53-55]

Risk factors for the development of CUA include obesity, diabetes mellitus, female sex, white ethnicity, time on renal replacement therapy and the use of coumarin anticoagulants.^[51,53,55] Other factors reported to be associated with CUA include the use of vitamin D analogs, calcium-containing phosphate binders, iron-substitution therapy and glucocorticosteroids.^[51,53,55]

CUA has an insidious onset that is marked by the occurrence of livedo-reticularis-like skin lesions predominantly on the abdomen, buttocks and thighs, all of which are areas with large amounts of subcutaneous fat. 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)^[53] (Figure 2). These areas of ischemic, necrotic skin and subcutaneous fat can extend into deeper tissues including muscle and can become infected. The onset of CUA is often associated with a history of recent trauma, the initiation of coumarin treatment or with hypotensive episodes. 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.^[51,53] CUA is associated with high mortality, with a 1-year survival rate of 45% and a 5-year survival rate of 35%; death is predominantly the result of infectious complications.^[51,53-55]

Figure 2. (click image to zoom) Calcific uremic arteriolopathy in a 48-year-old female patient on hemodialysis with painful abdominal subcutaneous purpuric plaques and nodules and the start of necrotic ulcerations.

An early clinical diagnosis of the nonulcerative stage of CUA is very important as it allows the early initiation of therapeutic measures, which improves prognosis. 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. A histological diagnosis is preferable but skin biopsies must be obtained with caution as they might produce nonhealing ulcerations. The histological lesions characteristically involve epidermal ulceration, dermal necrosis, and vascular medial wall calcifications with subintimal or intimal hyperplasia and fibrosis of small and medium-sized blood vessels in the dermis and subcutaneous tissues^[56] (Figure 3). Thrombotic occlusion of cutaneous vessels and extravascular calcium depositions are conspicuous. The histological lesions described, including calcifying septal panniculitis, are not pathognomonic for CUA.^[51,56]

Figure 3. (click image to zoom) Histological skin lesions of calcific uremic arteriolopathy. (A) Hematoxylin and eosin stain (original magnification × 100) showing calcification (arrow). (B) Von Kossa stain (original magnification × 100) showing calcification (arrow). (C) Hematoxylin and eosin stain (original magnification × 100) showing a thrombus. Abbreviations: sc, subcutis; t, thrombus.

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.^[57,58] 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.^[59]

CUA should be differentiated from coumarininduced skin necrosis, atherosclerotic peripheral vascular disease, systemic vasculitis, cryoglobulinemia, cholesterol embolization, pyoderma gangrenosum, oxalosis and benign nodular calcification (a common condition in patients with CKD).

Pathophysiology

CUA is thought to involve an imbalance between inducers and inhibitors of calcification of the vascular wall.^[60-62] In affected patients, 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.^[63,64] In addition, vascular smooth muscle cells in CUA transform into (osteogenic) osteoblast-like cells (via expression of core-binding factor-1) and express bone-related proteins such as osteocalcin, bone sialoprotein, type 1 collagen and osteopontin.^[61,65] Conversely, some researchers have postulated that production of inhibitors of vascular calcification (e.g. fetuin A and osteoprotegerin) are suppressed (via the nuclear factor κB cascade) by the inflammatory changes encountered in uremia.^[61,66] In addition, the actions of the matrix γ-carboxyglutamate (Gla) protein can be inhibited by coumarin-induced inhibition of vitamin-K-dependent carboxylation, which results in increased vascular calcifications.^[67] 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.^[68] This complex balance can be shifted further in favor of tissue calcification by coexisting disturbances of calcium and phosphate metabolism, the use of vitamin D analogs, hyperparathyroidism, ischemia and deficiencies of proteins C and S. Indeed, very low protein C or protein S activities have been documented in patients on hemodialysis with CUA who have only slightly diminished protein levels.^[52] 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

The primary measures used to treat CUA focus on intensive wound care (including repeated surgical resections of necrotic tissue) and provision of systemic antibiotics and adequate opioid analgesia. In some cases, the use of vacuum dressings can be considered to improve wound healing. Aggressive surgical wound cleaning with autologous split-skin grafting has also been successfully attempted.^[53,54]

Secondary treatment measures include 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), and discontinuation of vitamin D analogs. In the presence of elevated intact parathyroid hormone levels, urgent parathyroidectomy might be necessary.^[69,70] Case reports have described the calcimimetic cinacalcet to be effective for the rapid control of secondary hyperparathyroidism in patients with CUA, with complete healing of skin ulcers.^[71] 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.

Sodium thiosulfate, an inorganic salt, reduces metastatic tissue calcifications by chelating calcium from soft tissues. Sodium thiosulfate also acts as an antioxidant and induces endothelial nitric oxide synthesis, which improves blood flow and tissue oxygenation. Intravenous sodium thiosulfate at a dosage of 5-25 g during dialysis seems to be a successful treatment for CUA in combination with the above-mentioned therapies^[72,73] (Figure 4). The main doselimiting 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. A case study reported the successful use of intraperitoneal sodium thiosulfate in a patient with CUA.^[74]

Figure 4. (click image to zoom) Calcific uremic arteriolopathy of the abdomen in a 44-year old male patient on hemodialysis. (A) Before treatment and (B) following treatment with intensified hemodialysis, parathyroidectomy and intravenous sodium thiosulfate 20 g thrice weekly for 7 weeks.

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.^[75-77] The mechanism of action of bisphosphonates in CUA is unknown, but alterations in ectopic deposition of calcium phosphate, suppression of inflammatory changes and direct inhibition of calcification (via the nuclear factor κB cascade) are thought to be involved as bisphosphonates are structurally similar to pyrophosphate.^[61] 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.^[78]