Calciphylaxis or calcific uremic arteriolopathy (CUA) is a fatal disease in patients due to calcification of cutaneous blood vessels. It is commonly associated with renal failure and dialysis patients. It is a devastating disease with a high rate of mortality and morbidity.
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DISEASE ASSOCIATIONS CHARACTERIZATION AIDS
Widespread cutaneous and systemic calcification (calciphylaxis) in patients with the acquired immunodeficiency syndrome and renal disease.
Cockerell CJ, Dolan ET.
University of Texas Southwestern Medical Center, Dallas.
J Am Acad Dermatol 1992 Apr;26(4):559-62 Abstract quote
ACKGROUND: Calciphylaxis is a form of widespread calcification that may occur in patients with renal disease and hyperparathyroidism. The skin is often affected secondary to vascular compromise and ischemia. Patients infected with the human immunodeficiency virus (HIV) are predisposed to renal failure and thus may develop this serious complication.
OBJECTIVE: The purpose of this article is to describe two cases of fatal calciphylaxis in patients with the acquired immunodeficiency syndrome and renal disease.
METHODS: Two patients were examined clinically and through the performance of serologic studies and skin biopsies.
RESULTS: Both patients had a widespread livedo reticularis-like eruption, which rapidly progressed to cutaneous gangrene. Patient 1 had elevated serum calcium and phosphorus levels whereas patient 2 had normal values but had markedly elevated serum parathyroid hormone levels. Biopsy specimens in both cases showed vascular thrombosis and soft tissue calcification.
CONCLUSION: Widespread calcification may develop in patients with HIV infection and renal failure and, in some cases, calcium and phosphorus levels may be normal.
CHRONIC RENAL FAILURE
Wet gangrene in hemodialysis patients with calciphylaxisis is associated with a poor prognosis.
Davis CA, James Valentine R.
Division of Vascular Surgery, Department of Surgery, The University of Texas Southwestern Medical Center, 75235-9031, Dallas, TX, USA
Cardiovasc Surg 2001 Dec;9(6):565-70 Abstract quote
Calciphylaxis is a rare syndrome characterized by progressive vascular calcification and ischemic tissue loss in patients with chronic renal failure. We report our five-year experience with five patients who developed foot gangrene due to calciphylaxis. All five patients had characteristic clinical, laboratory, and radiologic findings of the disorder, but no diagnostic variable was uniformly present. All five had progressed to advanced gangrene at the time of surgical consultation. Despite aggressive local attempts to control infection, all five patients died of septic complications. Parathyroidectomy was performed in three patients but did not alter the course in any case. This small experience suggests that the outcome of foot gangrene associated with calciphylaxis is predicated on the degree of tissue loss. Aggressive local wound care does not appear to be adequate to control infection in patients who have already developed gangrene.
Although parathyroidectomy may have important long-term advantages in patients with calciphylaxis, it does not appear to affect outcome in these advanced cases.
Calciphylaxis associated with cholangiocarcinoma treated with low-molecular-weight heparin and vitamin K.
Riegert-Johnson DL, Kaur JS, Pfeifer EA.
Department of Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA.
Mayo Clin Proc 2001 Jul;76(7):749-52 Abstract quote
Calciphylaxis is a rare disorder of small-vessel calcification and cutaneous infarction associated with chronic renal failure. Rare cases of calciphylaxis not associated with chronic renal failure have been reported with breast cancer, hyperparathyroidism, and alcoholic cirrhosis.
To our knowledge, we report the first case of calciphylaxis without chronic renal failure associated with cholangiocarcinoma and the first attempt to treat calciphylaxis with vitamin K.
A 56-year-old woman presented with necrotic leg ulceration. She was treated initially with low-molecular-weight heparin, with no effect. A coagulation work-up showed vitamin K deficiency. During vitamin K therapy, the patient had fulminant progression of the calciphylaxis. She died, and an autopsy showed metastatic cholangiocarcinoma. Thrombosis and protein C deficiency have been implicated in the pathophysiology of calciphylaxis.
Functional protein C deficiency may be one of several factors contributing to the development of calciphylaxis. Vitamin K therapy was ineffective in our patient and may have been detrimental.
Fulminant and relentless cutaneous necrosis with excruciating pain caused by calciphylaxis developing in a patient undergoing peritoneal dialysis.
Sato N, Teramura T, Ishiyama T, Tagami H.
Department of Dermatology, Akita Kumiai General Hospital, Japan.
J Dermatol 2001 Jan;28(1):27-31 Abstract quote
A 50-year-old Japanese female with chronic renal failure who had been on continuous ambulatory peritoneal dialysis developed fulminant systemic cutaneous necrosis that began as painful livedo reticularis-like skin lesions on her thighs. Because of disseminated vascular calcification within the muscular layer of her lower limbs, we eventually diagnosed her with calciphylaxis. The skin necrosis progressed rapidly, and she died of sepsis and pneumonia on the 53rd hospital day. In addition to her long-lasting severe hyperparathyroidism and extremely elevated serum phosphorus and calcium levels, mechanical, frictional stimulation inflicted on the local skin and administration of corticosteroids were suspected to have precipitated the calciphylaxis.
Our lack of awareness of this disease in its early stages resulted in our missing the chance to do a parathyroidectomy that might have changed the course. It is important to know the clinical features of this rare disease in order to make a diagnosis as early as possible.
An unusual presentation of calciphylaxis due to primary hyperparathyroidism.
Mirza I, Chaubay D, Gunderia H, Shih W, El-Fanek H.
Departments of Pathology (Drs Mirza, Gunderia, and El-Fanek) and Internal Medicine (Drs Chaubay and Shih), Danbury Hospital, Danbury, Conn.
Arch Pathol Lab Med 2001 Oct;125(10):1351-3 Abstract quote
We present the case of a 69-year-old woman with calciphylaxis due to primary hyperparathyroidism. A 0.5-g parathyroid adenoma was surgically removed, which resulted in complete recovery of the patient.
Review of the literature revealed 7 other cases of calciphylaxis due to primary hyperparathyroidism and showed that prompt surgical removal of the autonomous parathyroid gland lesion results in clinical recovery of calciphylactic skin lesions.
NEPHROGENIC FIBROSING DERMOPATHY
Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy
Lisa C. Edsall, Joseph C. English III and James W. Patterson
Journal of Cutaneous Pathology
Volume 31 Issue 3 Page 247 - March 2004 Abstract quote
Background: Calciphylaxis and metastatic calcification are known complications of chronic renal failure. Recently, a sclerosing condition of the skin termed nephrogenic fibrosing dermopathy (NFD) has been described in patients with renal disease, many of whom have undergone hemodialysis and/or renal transplantation. To our knowledge, the simultaneous occurrence of both conditions in the same patient, in the same lesion, has not been previously reported.
Case report: We report the clinical, microscopic, and immunohistochemical features of two patients with chronic renal failure whose lesional skin biopsies showed both subcutaneous calcification and NFD. We consider the possible mechanisms that might explain the coexistence of these two disorders.
Results: Both patients presented with erythematous, indurated skin over the lower extremities. Purpuric, reticulated patches, necrosis, or ulceration were not observed. Microscopic examination showed the characteristic changes of NFD involving dermis and subcutaneous septa. In addition, biopsies of both individuals showed subcutaneous calcification, one in a diffuse distribution and the other involving the walls of subcutaneous vessels, as seen in calciphylaxis. Calcification was not suspected clinically in either case.
Conclusions: Metastatic calcification or calciphylaxis and NFD can occur simultaneously in patients with chronic renal failure and may be found together in the same lesion. Because subcutaneous calcification may not be suspected clinically in these cases, and in view of the adverse outcomes frequently associated with calciphylaxis, we recommend deep incisional biopsy of patients presenting with the clinical features of NFD. Both the fibrosis and the calcification of chronic renal failure may be related to the activity of transforming growth factor-/Smad signaling cascades
PATHOGENESIS CHARACTERIZATION GENERAL
Three-dimensional analysis of a calciphylaxis plaque: clues to pathogenesis.
Au S, Crawford RI.
Division of Dermatology, Department of Pathology, University of British Columbia, Vancouver, BC, Canada V6Z 1Y6
J Am Acad Dermatol 2002 Jul;47(1):53-7 Abstract quote
BACKGROUND: Calciphylaxis is a rare, life-threatening disorder associated with chronic renal failure, presenting with ulcerating plaques leading to death by sepsis in 60% of patients. Calcification of subcutaneous arterioles, thromboses, and extravascular calcification have been demonstrated in incisional biopsy specimens. However, the sequence of these pathologic events is unknown.
OBJECTIVE: We examined a calciphylaxis plaque to document the wave of pathologic change from its center to its periphery.
METHODS: A calciphylaxis plaque was excised postmortem from a female patient. It was examined histologically along 12 radii from the center of the lesion to its periphery.
RESULTS: Calcification of small subcutaneous vessels was present in all histologically abnormal sections and extended further peripherally than extravascular calcification by up to 3.0 cm and further than subcutaneous thrombosis by up to 1.5 cm.
CONCLUSION: Vascular mural calcification is an early and essential process in the development of a calciphylaxis plaque.
Consequences of hyperphosphatemia and elevated levels of the calcium-phosphorus product in dialysis patients.
Levin NW, Hoenich NA.
Renal Research Institute, New York, New York, USA.
Curr Opin Nephrol Hypertens 2001 Sep;10(5):563-8 Abstract quote
Control of serum phosphorus levels is a central goal in the management of patients with chronic renal failure. Inadequate control of serum phosphorus leads to elevated levels of the calcium-phosphorus product. This plays a pivotal role in vascular calcification, cardiovascular disease, calciphylaxis, and death.
Elevated phosphorus and elevated levels of the calcium-phosphorus product are both significant predictors of cardiovascular mortality, at phosphorus and calcium-phosphorus product levels that were considered safe until recently.
A lowering of levels such that phosphorus is maintained between 2.2 and 5.5 mg/dl, calcium-phosphorus product is below 55 mg2/dl2, and serum calcium is at 9.2-9.6 mg/dl, respectively, might well be the goal of therapeutic management strategies.
Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells.
Ahmed S, O'Neill KD, Hood AF, Evan AP, Moe SM.
Departments of Medicine, Pathology, and Anatomy, Indiana University School of Medicine, Indianapolis 46202, USA.
Am J Kidney Dis 2001 Jun;37(6):1267-76 Abstract quote
Calciphylaxis or calcific uremic arteriolopathy (CUA) is a fatal disease in dialysis patients due to calcification of cutaneous blood vessels. The pathogenesis has been attributed to elevated parathyroid hormone (PTH). However, recent studies evaluating vascular calcification in nondialysis patients have found that the smooth muscle cells play an active role, including production of the bone matrix protein osteopontin.
To examine the involvement of various clinical parameters and smooth muscle cells of CUA, we performed a case-control analysis comparing 10 CUA patients with our current dialysis patients.
Available histologic sections were immunostained for osteopontin, markers of smooth muscle cells, endothelial cells, and macrophages. Compared with our current dialysis population, patients with CUA were more likely to be obese, white, and female (P < 0.02). Comparison of laboratory values found CUA patients with lower serum albumin, greater serum phosphorus, and greater calcium X phosphorus product (P < 0.01). In contrast, there was no difference in the concentration of PTH or calcium between the 2 groups. Immunostaining of calcified blood vessels showed that all calcified vessels stained positive for osteopontin, whereas all the noncalcifed vessels showed no osteopontin localization. Staining for smooth muscle alpha-actin decreased in the medial layer with calcification, with cells appearing to be sloughed off, leading to near occlusion of the vessel lumen.
Our case-control study demonstrates that hyperphosphatemia and an elevated calcium X phosphorus product is associated with CUA. Histologic examination suggests that the calcification is associated with increased expression of osteopontin by smooth muscle cells.
The development of the pathophysiological concept of calciphylaxis in experiment and clinic.
Vasků V V, Vasků J.
VACORD Bioengineering Research Company, 614 00 BRNO-Husovice, 53, Cacovicka, Czech Republic
Pathophysiology 2001 Mar;7(4):231-244 Abstract quote
An attempt to clarify some pathophysiological aspects of calciphylaxis from both experimental and clinical points of view is presented. Until now, we cannot explain precisely various forms of calcification, affecting either soft tissues or biomaterial as well, only on the basis of metastatic or dystrophic calcification including the pure topical, local aspects. Therefore, the biological phenomenon of calciphylaxis can be useful in searching the ways for the inhibition of soft tissues and biomaterial calcification.
The experiments with experimental progeria have also made it possible to study the so-called reversed calciphylaxis. The systemic reversed calciphylaxis, or 'anacalciphylaxis' was shown in the authors experiments with the total artificial heart as a very effective factor in the inhibition of mineralization of the TAH driving diaphragms. The discovery of the ubiquitous organ regulator of calcification, osteopontin, can greatly contribute to further elucidation of the calciphylactic mechanisms in general, and also to the prevention of calcifying lesions. It is pointed to some clinical states, predominantly the end-stage renal disease with hemodialysation where many authors pay attention to calciphylaxis as a clinical entity in a series of such cases.
Calciphylaxis has been described in dermatology, nephrology and other clinical disciplines. In the area of attempts to prevent the ectopic organ calcification and also mineralization of biomaterials, a vast field of stimulation of endogenic inhibitors of calcification remains open.
CHARACTERIZATION RADIOLOGIC LABORATORY MARKERS
Transcutaneous oxygen tension in patients with calciphylaxis.
Wilmer WA, Voroshilova O, Singh I, Middendorf DF, Cosio FG.
Department of Internal Medicine, Division of Nephrology, Ohio State University, Columbus, OH, USA. w
Am J Kidney Dis 2001 Apr;37(4):797-806 Abstract quote
Calciphylaxis is a severe complication of chronic renal failure, confined almost exclusively to patients on dialysis therapy. Histological characteristics of calciphylaxis include small-vessel calcifications of skin, subcutaneous tissue, and visceral organs. These vascular changes promote tissue ischemia that often results in tissue necrosis.
In this study, we investigated the extent of skin ischemia in patients with calciphylaxis by means of transcutaneous oxygen tension (TCPO(2)) measurement, a noninvasive test that accurately assesses skin oxygenation.
TCPO(2) levels were measured in 21 patients with calciphylaxis and 21 age- and sex-matched patients without evidence of calciphylaxis (controls). TCPO(2) levels were measured bilaterally at the chest, anterior abdomen, and upper thigh while patients breathed room air and after a 30-minute exposure to 100% fraction of inspired oxygen (FIO(2)). Compared with controls, patients with calciphylaxis showed significantly lower TCPO(2) levels at each body region. In both controls and patients with calciphylaxis, lower TCPO(2) levels correlated with increased weight and use of hemodialysis. No correlation with serum parathyroid hormone (PTH), serum calcium, or serum phosphorus values was present, although 39% of the patients with calciphylaxis had markedly elevated PTH values (sixfold greater than normal; >300 pg/dL). Low TCPO(2) levels in patients with calciphylaxis were documented in body regions with and without skin lesions. In patients with calciphylaxis, extremely low TCPO(2) values (=30 mm Hg while patients breathed room air) were present in 62% of the body regions with skin lesions and 26% of the body regions without lesions. Room-air TCPO(2) levels =30 mm Hg were present in only 0.8% of the body regions of control patients. TCPO(2) levels obtained while patients breathed 100% FIO(2) remained lower in patients with calciphylaxis than in controls.
In conclusion, TCPO(2) levels are abnormally low in patients with calciphylaxis, indicating that severe and diffuse skin ischemia exists, even at areas free of skin lesions. Low TCPO(2) values did not substantially increase with 100% FIO(2) in many patients with calciphylaxis, suggesting a fixed insufficiency of the skin vessels. This study shows that TCPO(2) measurements may allow rapid and noninvasive screening for skin ischemia before the development of skin lesions in patients with calciphylaxis.
CHARACTERIZATION GENERAL VARIANTS PROXIMAL
A case control study of proximal calciphylaxis.
Bleyer AJ, Choi M, Igwemezie B, de la Torre E, White WL.
Department of Pathology, Bowman Gray School of Medicine, Winston-Salem, NC 27157, USA.
Am J Kidney Dis 1998 Sep;32(3):376-83 Abstract quote
The purpose of this investigation was to describe the clinical presentation of nine patients with calciphylaxis involving the proximal lower extremities or trunk and to compare the clinical characteristics of these patients with those of 347 hemodialysis patients from the same geographic area.
Patients were identified primarily through a computer search of pathology records, identifying patients with the term "calciphylaxis" in the biopsy report. All patients had pathologic specimens consistent with calciphylaxis. All the calciphylaxis patients were white and were markedly obese. While two patients had markedly elevated parathyroid hormone levels, most patients did not show severe derangements of calcium phosphate metabolism compared with other dialysis patients. A logistic regression model identified body mass index and low serum albumin 3 months before diagnosis as being highly associated with a diagnosis of calciphylaxis.
Diabetes mellitus and parameters of calcium-phosphate metabolism were not significantly associated with proximal calciphylaxis. These findings suggest that white race, morbid obesity, and poor nutritional status are associated with proximal calciphylaxis in dialysis patients.
Penile calciphylaxis: rare necrotic lesions in chronic renal failure patients.
Jhaveri FM, Woosley JT, Fried FA.
Department of Pathology, University of North Carolina School of Medicine, Chapel Hill 27599-7235, USA.
J Urol 1998 Sep;160(3 Pt 1):764-7 Abstract quote
PURPOSE: Calciphylaxis is a rare devastating condition of cutaneous necrosis resulting from calcification of small blood vessels in patients with end stage renal failure and secondary hyperparathyroidism. We describe 5 patients with penile calciphylaxis at a single institution.
MATERIALS AND METHODS: From 1992 to 1996, 5 patients had penile calciphylaxis. The charts of these patients were reviewed to determine the nature of the lesions, association with hyperparathyroidism and treatment outcomes.
RESULTS: All 5 patients had chronic renal failure, secondary hyperparathyroidism and painful necrotic lesions at multiple sites. Radiographs showed stippled calcification of small vessels, which was confirmed histologically. Three patients had undergone parathyroidectomy with a significant decrease in mean calcium x phosphorus ion products from 86.01 to 45.37 mg.2/dl.2 (p < 0.001), and in 1 calciphylaxis resolved postoperatively. The penile lesions were treated with debridement and aggressive wound care.
CONCLUSIONS: The increase in the number of patients with chronic renal failure on dialysis may make penile calciphylaxis more prevalent in the future. Lowering of serum calcium and phosphorus levels, and debridement of these necrotic lesions help to diminish this aggressively destructive process.
Calciphylaxis, a poorly understood clinical syndrome: three case reports and a review of the literature.
Howe SC, Murray JD, Reeves RT, Hemp JR, Carlisle JH.
Division of Vascular Surgery, Naval Medical Center San Diego, 92134-5000, USA.
Ann Vasc Surg 2001 Jul;15(4):470-3 Abstract quote
Systemic calcification syndromes are a recognized complication occurring in some patients with end-stage renal disease (ESRD) and secondary hyperparathyroidism. These patients develop severe livedo reticularis and subcutaneous tissue lesions progressing to frank necrosis and ultimately large areas of eschar. Clinically this syndrome is known as calciphylaxis; these lesions are usually resistant to aggressive debridement, systemic antibiotics, and revascularization procedures.
We report three patients with somewhat different clinical presentations but all sharing a common link of exquisitely painful leg ulcers initially being treated as ischemic lesions or venous stasis-type ulcerations. These three patients were diagnosed with calciphylaxis on the basis of clinical, biochemical, and histopathological criteria. Two patients underwent parathyroidectomy late in the progression of their disease, with some resolution of their ulcerative lesions.
Acute respiratory failure due to "pulmonary calciphylaxis" in a maintenance haemodialysis patient.
Matsuo T, Tsukamoto Y, Tamura M, Hanaoka M, Nagaoka T, Kobayashi Y, Higashihara M, Yokoyama H, Saegusa N.
Fourth Department of Internal Medicine, Kitasato University, Kanagawa, Japan.
Nephron 2001 Jan;87(1):75-9 Abstract quote
Calciphylaxis is a rapidly developing, fatal process of vascular calcium deposition with prominent cutaneous manifestation. We treated a long-term haemodialysis patient who developed an analogous disorder limited to the lungs.
A 57-year-old man was admitted for initiation of peritoneal dialysis because limited cardiac reserve precluded further haemodialysis. He was treated successfully for pneumonia until hypoxia and progressive hypercalcaemia developed. (99m)Tc-methylene disphosphonate scintigraphy showed diffusely increased pulmonary uptake. Death supervened despite aggressive and successful treatment of hypercalcaemia.
Autopsy studies included immunohistochemistry and morphometric studies of bone. Alveolar capillary walls showed diffuse calcium deposition. Both gross and microscopical findings differed from those of typical metastatic calcification in dialysis patients. Immunoreactivity for parathyroid hormone-related protein was present in the lesions. Bone histomorphometry indicated mild osteitis fibrosa. Pneumonia is believed to have caused local synthesis of parathyroid hormone-related protein that, along with high calcium x phosphorus product, contributed to calcium deposition.
By analogy with the cutaneous process we termed the deposition "pulmonary calciphylaxis".
RENAL FAILURE ABSENCE
Calciphylaxis in a patient with Crohn's disease in the absence of end-stage renal disease.
Barri YM, Graves GS, Knochel JP.
Department of Medicine, Presbyterian Hospital of Dallas, TX 75231, USA.
Am J Kidney Dis 1997 May;29(5):773-6 Abstract quote
Calciphylaxis is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small and medium-sized vessel calcification previously described in patients with end-stage renal disease and hyperparathyroidism. Early diagnosis may be important in improving the poor outcome in these patients since early intervention may forestall the development of life-threatening complications.
We describe a patient with Crohn's disease complicated by short-bowel syndrome and modest renal insufficiency (not requiring renal replacement therapy) who developed calciphylaxis. It appears that longstanding Crohn's disease and the short-bowel syndrome accelerated the development of calciphylaxis as the chronic renal disease was not end stage. Considering the possibility of calciphylaxis in this setting may avoid delaying the diagnosis and its consequences.
Calciphylaxis in the absence of renal failure.
Pollock B, Cunliffe WJ, Merchant WJ.
Departments of Dermatology and Histopathology, Leeds General Infirmary, UK.
Clin Exp Dermatol 2000 Jul;25(5):389-92 Abstract quote
We report a patient with severe bilateral leg ulceration that was resistant to treatment. A biopsy confirmed the cause as calciphylaxis. Calciphylaxis refers to a syndrome of calcium deposition in the small and intermediate dermal vasculature which can lead to epidermal ischaemia, ulceration and necrosis. Most cases occur in those with chronic renal failure and secondary hyperparathyroidism. We describe the rare presentation of calciphylaxis in a patient with normal renal function and primary hyperparathyroidism who had many classical features. Unfortunately she developed gangrene, sepsis and died.
HISTOLOGICAL TYPES CHARACTERIZATION
Pathogenesis of calciphylaxis: study of three cases with literature review.
Fischer AH, Morris DJ.
Department of Pathology, Carney Hospital, Boston, MA, USA.
Hum Pathol 1995 Oct;26(10):1055-64 Abstract quote
Calciphylaxis is characterized by ischemic necrosis, primarily of skin. The early phase of the ischemia has not been studied, and the pathogenesis is uncertain.
In this study of early calciphylaxis, the vessels responsible for the ischemia seem to be within the material available for microscopic review, and the various stenosing vascular lesions are quantified.
A distinctive and previously described small vessel calcification with superimposed endovascular fibrosis is most common, and is much more frequent than two other lesions proposed to cause the ischemia (thrombosis and global calcific obliteration). The calcified stenotic vessels average 100 microns in diameter. Calcification precedes the endovascular fibrosis. Vessels with early endovascular fibroblastic activation are found statistically to be strongly associated with the presence of a giant cell reaction. This endovascular giant cell reaction has not been previously described in calciphylaxis. Two additional cases show similar findings.
The histology resembles the reaction to calcium in a variety of other extraosseous calcification syndromes, for example, pseudogout, as if calciphylaxis were an endovascular form of calcium crystal-induced inflammatory disease. The literature is reviewed, and the clinicopathologic, radiographic, and therapeutic implications are discussed.
Calciphylaxis with histologic changes of pseudoxanthoma elasticum.
Nikko AP, Dunningan M, Cockerell CJ
Division of Dermatopathology, University of Texas Southwestern Medical Center, Dallas, USA.
Am J Dermatopathol 1996 Aug;18(4):396-9 Abstract quote
Calciphylaxis is a rare condition of widespread calcification of tissues and blood vessels with accompanying vascular thrombosis and ischemic necrosis. Most cases develop in association with hyperparathyroidism in patients with chronic renal failure.
Pseudoxanthoma elasticum (PXE) is a hereditary condition of abnormal elastic tissue structure that leads to widespread abnormalities of the skin, retina, and visceral organs. Histologic changes of PXE have been observed as coincidental findings in several conditions such as following trauma to the skin manifest as isolated plaques often in scars.
We observed histologic findings of PXE in a patient with chronic renal failure who developed fatal calciphylaxis. Complete evaluation failed to reveal evidence of systemic findings of PXE. Histologic changes of PXE may be seen in patients with calciphylaxis as a coincidental finding. Rapidly developing soft tissue calcification may lead to the expression of the characteristic histopathologic findings of PXE without evidence of classic clinical manifestations of PXE.
Calciphylaxis should be added to the list of disorders that may lead to microscopic PXE-like changes.
Cutaneous calciphylaxis. An underrecognized clinicopathologic entity.
Essary LR, Wick MR.
Department of Pathology, University of Alabama at Birmingham Medical Center, USA.
Am J Clin Pathol 2000 Feb;113(2):280-7 Abstract quote
Calciphylaxis (CPX), an uncommon syndrome characterized, in part, by progressive cutaneous vascular calcification, is seen principally in the setting of renal failure-associated hyperparathyroidism and is difficult to distinguish histologically from other microvasculopathies.
We assessed histologic specimens from 13 cases of clinicopathologically classic CPX of the skin and reviewed documented histologic findings in the literature.
Our series included 7 "early" and 6 "late" lesions (absence or presence of tissue necrosis, respectively). Histologically, early lesions were subtle and almost inapparent microscopically. Late lesions were easier to recognize because of obvious epidermal ulceration, dermal necrosis, and easily seen mural vascular calcification.
The most common finding in both groups was acute and chronic calcifying septal panniculitis. Endovascular fibroblastic proliferation was more common in advanced lesions. Necrosis of dermal collagen was identified in only a few early lesions. Frank luminal vascular thrombosis was infrequent in both groups. The cited histologic findings largely were mirrored by those in the literature.
Although they are relatively nonspecific when considered in isolation, the cited histopathologic features of cutaneous CPX allow for the diagnosis of this potentially lethal disorder when they are seen in combination with one another, particularly if detailed clinical data also are available.
CHARACTERIZATION SPECIAL STAINS von Kossa stain will highlight the calcium deposits
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES DERMATOMYOSITIS
Calciphylaxis mimicking dermatomyositis: ischemic myopathy complicating renal failure.
Flanigan KM, Bromberg MB, Gregory M, Baringer JR, Jones CR, Nester TA, Klatt EC, Townsend JJ.
Department of Neurology, University of Utah School of Medicine, Salt Lake City 84132, USA.
Neurology 1998 Dec;51(6):1634-40 Abstract quote
BACKGROUND: Among the complications of chronic renal failure is a syndrome of medial calcification of small- to medium-sized arteries associated with ischemic necrosis of the skin and other organ systems, leading to gangrene and a poor prognosis. The syndrome has been reviewed in the renal, dermatologic, and surgical literature under the term calciphylaxis, which describes a postulated pathogenetic mechanism whereby sensitization to an endogenous or exogenous substance (such as parathyroid hormone) predisposes to calcium deposition after exposure to a challenging agent. Myopathy has rarely been reported as the presenting feature, and the syndrome has not been discussed in the neurologic literature.
METHODS: We report two patients with renal failure and systemic calciphylaxis who presented to our hospital with myopathic complaints and signs suggesting dermatomyositis. We also discuss possible disease mechanisms and treatment.
CONCLUSIONS: Because early treatment (including aggressively lowering the calcium and phosphate levels and parathyroidectomy) may improve the outcome, early recognition of the syndrome of calciphylaxis is essential.
Fatal cutaneous necrosis mimicking calciphylaxis in a patient with type 1 primary hyperoxaluria.
Somach SC, Davis BR, Paras FA, Petrelli M, Behmer ME.
Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
Arch Dermatol 1995 Jul;131(7):821-3 Abstract quote
BACKGROUND: Cutaneous necrosis of the proximal lower extremities in a patient with end-stage renal disease is the classic presentation of calciphylaxis, an untreatable, rare, generally fatal necrotizing cutaneous syndrome. Type 1 primary hyperoxaluria (PH-1) usually presents in childhood with recurrent urolithiasis. Since enzymatic studies to confirm the metabolic defect are now available, some cases of idiopathic renal failure in adulthood have been shown to be caused by PH-1. These patients may develop vascular oxalate deposits resulting in livedo reticularis and distal acral vascular insufficiency.
OBSERVATIONS: We describe a patient who presented in end-stage renal failure with proximal lower extremity cutaneous necrosis suggestive of calciphylaxis. A cutaneous biopsy specimen revealed oxalate crystals within blood vessels, and a diagnosis of PH-1 was confirmed enzymatically.
CONCLUSIONS: This patient illustrates that PH-1 may present in adulthood, and, in the setting of cutaneous necrosis associated with end-stage renal disease, it may be confused with calciphylaxis. The importance of making a diagnosis of PH-1 is the potential ability to achieve long-term survival by reversing the underlying metabolic defect with hepatic transplantation.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS GENERAL
Risk factors and mortality associated with calciphylaxis in end-stage renal disease.
Mazhar AR, Johnson RJ, Gillen D, Stivelman JC, Ryan MJ, Davis CL, Stehman-Breen CO.
University of Washington, Division of Nephrology, Seattle, Washington, USA.
Kidney Int 2001 Jul;60(1):324-32 Abstract quote
BACKGROUND: We conducted a case control study to determine risk factors and mortality associated with calciphylaxis in end-stage renal disease.
METHODS: Cases of calciphylaxis diagnosed between December 1989 and January 2000 were identified. Three controls were identified for each hemodialysis patient, with calciphylaxis matched to the date of initiation of hemodialysis. Laboratory data and medication doses were recorded during the 12 months prior to the date of diagnosis and at the time of diagnosis of calciphylaxis. Conditional logistic regression was used to identify risk factors for calciphylaxis. Cox proportional hazards models were used to estimate the risk of death associated with calciphylaxis.
RESULTS: Nineteen cases and 54 controls were identified. Eighteen patients were hemodialysis patients, and one had a functioning renal allograft. Diagnosis was confirmed by skin biopsy in 16 cases. Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007). There was a 21% lower risk of calciphylaxis associated with each 0.1 g/dL increase in the mean serum albumin during the year prior to diagnosis and at the time of diagnosis of calciphylaxis (OR = 0.79, 95% CI, 0.64 to 0.99, P = 0.037, and OR = 0.80, 95% CI, 0.67 to 0.96, P = 0.019, respectively). There was a 3.51-fold increase in the risk of calciphylaxis associated with each mg/dL increase in the mean serum phosphate during the year prior to diagnosis (95% CI, 0.99 to 12.5, P = 0.052). At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P < 0.001).
CONCLUSIONS: Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are risk factors for calciphylaxis. Calciphylaxis is associated with a very high mortality.
Wet gangrene in hemodialysis patients with calciphylaxisis is associated with a poor prognosis.
Davis CA, Valentine RJ.
Division of Vascular Surgery, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75235-9031, USA.
Cardiovasc Surg 2001 Dec;9(6):565-70 Abstract quote
Calciphylaxis is a rare syndrome characterized by progressive vascular calcification and ischemic tissue loss in patients with chronic renal failure.
We report our five-year experience with five patients who developed foot gangrene due to calciphylaxis. All five patients had characteristic clinical, laboratory, and radiologic findings of the disorder, but no diagnostic variable was uniformly present. All five had progressed to advanced gangrene at the time of surgical consultation. Despite aggressive local attempts to control infection, all five patients died of septic complications. Parathyroidectomy was performed in three patients but did not alter the course in any case. This small experience suggests that the outcome of foot gangrene associated with calciphylaxis is predicated on the degree of tissue loss. Aggressive local wound care does not appear to be adequate to control infection in patients who have already developed gangrene.
Although parathyroidectomy may have important long-term advantages in patients with calciphylaxis, it does not appear to affect outcome in these advanced cases.
Calciphylaxis: a poor prognostic indicator for limb salvage.
Mureebe L, Moy M, Balfour E, Blume P, Gahtan V.
Section of Vascular Surgery, the Department of Orthopedics, Yale University School of Medicine, New Haven, Conn, USA.
J Vasc Surg 2001 Jun;33(6):1275-9 Abstract quote
INTRODUCTION: Calciphylaxis (calcific uremic arteriolopathy) is a rare complication of end-stage renal disease in patients with secondary hyperparathyroidism. Subcutaneous skin nodules and extensive tissue necrosis with vascular calcification characterize this process.Design and Setting: The design of the study included case series and literature review. The study was set in a tertiary care hospital.
PATIENTS: Four patients presented over an 8-month period with extensive tissue loss and the subsequent diagnosis of calciphylaxis. Two of these patients were revascularized. One underwent primary amputation, and the final patient died before revascularization. The mortality rate for this group was 75%. All patients had significant vascular complications outside the area of initial presentation.
CONCLUSIONS: These individuals represent a subset of patients who may not benefit from revascularization or may require extensive regulation of divalent metabolism before consideration for revascularization.
Intensive tandem cryofiltration apheresis and hemodialysis to treat a patient with severe calciphylaxis, cryoglobulinemia, and end-stage renal disease.
Siami GA, Siami FS.
Vanderbilt University Medical Center, Department of Medicine, Nashville, Tennessee, USA.
ASAIO J 1999 May-Jun;45(3):229-33 Abstract quote
This is the first report on tandem cryofiltration apheresis (CFA) and hemodialysis (HD).
A 44 year old white man with Type II mixed cryoglobulinemia, hepatitis C virus (HCV), severe skin lesions, and end-stage renal disease (ESRD) on maintenance hemodialysis was air-transferred for CFA, which is only available at our medical center. The patient failed to respond to high dose steroids, immunosuppression, intravenous immunoglobulin (IVIG), and plasma exchange for the treatment of his cryoglobulinemia, and he failed alpha-interferon therapy for his HCV. On arrival, he was also found to have severe calciphylaxis secondary to ESRD with generalized, painful skin ulceration, necrosis, and penile gangrene. To treat both conditions, intensive, tandem CFA/HD was initiated. He received extensive wound care and surgical debridement. To prevent pressure ulcers and worsening of skin lesions, he was placed on the FluidAir (Kinetic Concepts Inc., San Antonio, TX) controlled air bed. The patient received 18 tandem CFA/HD treatments, and four extra HD treatments in one month. Sodium citrate was used as an anticoagulant for the CFA procedure. His plasma cryoglobulin (CG) level dropped from 6,157 to 420 microg/ml, and his calciphylaxis also improved. The CFA effectively removed 93% of CG, without significant removal of IgG, IgM, IgA, albumin, and fibrinogen. No albumin or fresh frozen plasma (FFP) was required as replacement fluid for CFA. No citrate toxicity or evidence of complement activation with the cryofilter was observed.
The entire CFA procedure time (3(1/2) hours) was considered. Intensive, tandem CFA/HD was performed in a critically ill patient with no apparent adverse consequences.
Calciphylaxis treated with neurolytic lumbar sympathetic block: case report and review of the literature.
Green JA, Green CR, Minott SD.
Multidisciplinary Pain Center, the Department of Anesthesiology, University of Michigan Health Systems, Ann Arbor 48109, USA.
Reg Anesth Pain Med 2000 May-Jun;25(3):310-2 Abstract quote
BACKGROUND AND OBJECTIVE: Calciphylaxis is a painful complication of end-stage renal disease and secondary hyperparathyroidism. Calcification most commonly affects skin and soft tissue of the lower extremities resulting in excruciatingly painful skin ulcers. Treatment involves correction of hypercalcemia and hyperphosphatemia, parathyroidectomy, and supportive measures.
METHODS: The literature and the merits of neurolytic lumbar sympathetic blockade (LSB) for the treatment of pain associated with calciphylaxis are reviewed.
CONCLUSIONS: The neurolytic LSB provided pain relief and is a treatment modality to be considered in managing the pain associated with calciphylaxis.
Is calciphylaxis best treated surgically or medically?
Kang AS, McCarthy JT, Rowland C, Farley DR, van Heerden JA.
Division of Gastroenterologic and General Surgery, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Surgery 2000 Dec;128(6):967-71;discussion 971-2 Abstract quote
BACKGROUND: Calciphylaxis is a rare, painful, life-threatening problem of cutaneous necrosis and refractory healing in patients with uremia and secondary hyperparathyroidism. The pathogenesis involves abnormalities in calcium and phosphorus metabolism and acute deposition of calcium in tissues.
METHOD: The clinical course of 16 patients who were diagnosed with calciphylaxis at our institution from 1994 through 1998 was reviewed.
RESULTS: Fourteen female patients and 2 male patients had chronic renal disease, secondary hyperparathyroidism, and characteristic skin necrosis (mean age, 56 years; range, 39-70 years). All patients underwent intensive medical therapy, including ongoing hemodialysis (n = 16 patients), parathyroidectomy (n = 7 patients), and debridement of cutaneous lesions (n = 8 patients). Mean serum values in surgical and nonsurgical patients were significantly different for phosphorus, calcium-phosphorus product, and parathormone levels. Median survival was 9.4 months; 15 patients (93%) have died. The median survival time for parathyroidectomy versus nonparathyroidectomy was 14.8 and 6.3 months (P =.22), for skin debridement versus nondebridement was 14.1 and 6.1 months (P =.08), and for diabetic versus nondiabetic patients was 6.5 and 13.9 months (P =.11).
CONCLUSIONS: Calciphylaxis has a female preponderance, with a dismal prognosis. A multidisciplinary approach that uses frequent hemodialysis to normalize calcium and phosphorus levels and local debridement of skin lesions seems prudent. Parathyroidectomy cannot be recommended routinely in all patients, unless severe hyperparathyroidism mandates intervention.
Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism.
Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H.
Departments of Surgery and Pathology, The Johns Hopkins Medical Institutions, Baltimore, Md.
Surgery 2001 Oct;130(4):645-51 Abstract quote
Background. Calciphylaxis is a rare but life-threatening condition occasionally affecting patients with secondary hyperparathyroidism. Parathyroidectomy has been advocated as the only potentially curative intervention.
Methods. Between January 1989 and May 2000, 13 patients with pathologic/clinical criteria of calciphylaxis were treated at our institution. Of these 13 patients, 7 were managed with medical therapy alone, and 6 were referred for parathyroidectomy. The medical records were reviewed, and patients/relatives were interviewed.
Results. All patients had cutaneous wounds requiring local debridement predominantly located on the lower extremities or abdominal wall. Six patients underwent subtotal (3.5 gland) parathyroidectomy without morbidity. All 6 had significant reductions in parathyroid hormone levels after surgery (mean decrease, 94% +/- 0%), and all reported resolution of pain and healing of cutaneous wounds. Of the remaining 7 patients who had medical management alone, 5 eventually died of complications related to calciphylaxis. In comparing the 2 groups, patients who underwent parathyroidectomy had a significantly longer median survival than those who did not have surgery (36 vs 3 months, P =.021).
Conclusions. Calciphylaxis frequently causes gangrene, sepsis, and eventual death. Parathyroidectomy can be performed with minimal morbidity and is associated with resolution of pain, wound healing, and a significantly longer median survival. Therefore, patients with secondary hyperparathyroidism and signs/symptoms of calciphylaxis should be referred promptly for consideration of parathyroidectomy.
- Dermatology. 2006;212(4):373-6. Abstract quote
A 35-year-old haemodialysis-dependent woman with chronic renal failure developed large, very painful necrotic ulcers and necrosis on the thighs, buttocks and the abdomen with signs of fast progression. The skin biopsy specimens showed a broad necrosis of the epidermis and thrombosed dermal vessels with focal calcium deposits within the wall. In addition, laboratory findings presented an increased product of serum calcium and phosphate concentrations. Thus, we diagnosed calciphylaxis on the basis of clinical, biochemical and histopathological criteria.
We initiated a therapy in which our patient was treated with intravenous sodium thiosulphate 3 times weekly. Already after 2 weeks of treatment, no new lesions were detectable and there was a dramatic pain relief. In the following 4 weeks, a successive decline of the ulcers and the healing of individual tissue defects could be seen. Four months after the start of the therapy, the patient underwent successful renal transplantation.
Thus, the intravenous therapy of calciphylaxis with sodium thiosulphate might be a new effective alternative in the treatment of this life-threatening disease.
- Ren Fail. 2006;28(4):361-3. Abstract quote
Calcific uremic arteriolopathy (or calciphylaxis) is a severe complication of renal failure characterized by subcutaneous calcification of the small arteries and tissue necrosis.
We describe the case of a woman receiving continuous cycling peritoneal dialysis with calciphylaxis involving upper and lower extremities. After intolerance of intravenous sodium thiosulfate and limited intravenous access options, we administered sodium thiosulfate intraperitoneally and quantitated the amount of extra calcium removed.
Intraperitoneal administration of sodium thiosulfate was well tolerated and led to removal of extra calcium with peritoneal dialysis.
- Semin Dial. 2005 Sep-Oct;18(5):431-4. Abstract quote
Calciphylaxis is a disabling and life-threatening complication that primarily affects patients who are dialysis dependent. This disease entity is characterized by calcification, intimal hypertrophy, and thrombosis of small vessels, which results in necrotizing, nonhealing ulcers. The development of these lesions portends a grim prognosis, as they are often accompanied by severe and sometimes fatal infectious complications. Although several strategies aimed at treating and preventing this affliction have been reported in the literature, the outcome for most patients with calciphylaxis remains quite poor.
We describe an anuric hemodialysis patient who developed severe calciphylaxis that proved refractory to conventional treatment. Following extensive debridement of several wounds, intravenous sodium thiosulfate was utilized as an adjunctive therapy four times a week. Within 6 months, excellent wound healing ensued as well as a dramatic improvement in the lesions that were not previously resected. Aside from occasional nausea, these treatments were well tolerated, despite the development of an anion gap metabolic acidosis. After 34 months of continued treatment the patient remains free from disease recurrence and has demonstrated no untoward effect of prolonged therapy. In an effort to delineate the pharmacokinetics of this drug in a hemodialysis patient, serum thiosulfate levels were obtained 15 minutes after infusion as well as before and after subsequent dialysis treatments.
Consistent with prior studies in anuric canines, we found measurable quantities of the drug more than 50 hours after treatment, in addition to a markedly elevated half life of 478 minutes. However, given the lack of significant toxicity, as well as a dramatic clinical improvement, we feel that sodium thiosulfate may have an important adjunctive role in the treatment of calciphylaxis in dialysis patients.
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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