Calcific cerebral embolism in systemic calciphylaxis

Calciphylaxis represents a rare complication of end-stage renal disease with hyperparathyroidism. We report the case of a 26-year-old woman with systemic calciphylaxis secondary to chronic renal failure who developed mitral annular calcification and a right middle cerebral artery stroke. The high-density lesion seen on CT scan of the brain probably represents a calcified cerebral embolus originating from the mitral valve.     

A case of early intrauterine parvovirus B19 infection

Cutaneous and subcutaneous gangrene are serious sequelae of secondary or tertiary hyperparathyroidism which may accompany chronic renal failure. Based on analysis of the present typical case and a retrospective survey of similar cases in the literature, we propose the term 'uraemic gangrene syndrome' for this association. These skin lesions in chronic renal failure patients represent the most serious clinical manifestation of calciphylaxis, a condition originally described by Selye. The appearance of early skin lesions should be regarded as an indication for subtotal parathyroidectomy. The association of cutaneous gangrene with vascular calcification was first described by Bryandt and White in 1989, and was termed by these authors as 'gangrenous calcification'. A total of 80 cases of this rare complication of chronic renal disease had been reported up to early 1994. A retrospective review of these reports has strongly suggested a close interrelationship between renal failure, secondary hyperparathyroidism, vascular calcification and cutaneous gangrene. The present report concerns a characteristic case to draw attention to this syndrome which is accompanied by serious, predominantly cutaneous, changes.     

Calciphylaxis mimicking dermatomyositis: ischemic myopathy complicating renal failure

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.     

Systemic calciphylaxis revisited

A syndrome characterized by rapidly progressive ischemic necrosis involving large areas of the skin and muscle, and by peripheral gangrene associated with extensive vascular calcifications was observed in a patient with end-stage renal failure on chronic hemodialysis. In an effort to control the disease, parathyroidectomy was performed which resulted in rapid improvement of tissue perfusion. However, the patient eventually died from sepsis within 2 months after admission. This case presents the typical features of the syndrome of systemic calciphylaxis. The literature is reviewed searching for similar cases of this poorly recognized, but life-threatening, clinical syndrome. The pathogenesis, clinical manifestations, and therapy of this unusual and rapidly progressive, but potentially reversible, condition are reviewed with emphasis on its prompt recognition and appropriate management.     

Calciphylaxis in patients on hemodialysis: a prevalence study

BACKGROUND: Calciphylaxis is characterized by painful, violaceous, mottled skin lesions (livedo reticularis) that may progress to tissue necrosis, nonhealing ulcers, gangrene, and potentially amputation, sepsis, or death. The prevalence and characteristics of patients who have calciphylaxis need further identification to predict which patients on dialysis may benefit from close monitoring or early surgical intervention. METHODS: All 242 patients undergoing hemodialysis in an outpatient unit were reviewed retrospectively during a 15-month cross-sectional study of the prevalence and characteristics of calciphylaxis. RESULTS: Ten patients (prevalence, 4.1%) had calciphylaxis. Patients with calciphylaxis were significantly younger (49 versus 60 years; p = 0.01), had undergone hemodialysis longer (80 versus 20 months; p < 0.0001), and had higher median serum calcium (9.7 versus 9.2 mg/dl; p = 0.03), phosphate (8.2 versus 5.7 mg/dl; p = 0.001), calcium phosphate product (81.5 versus 52.9; p = 0.0004), parathyroid hormone (1496 versus 138 pg/ml; p < 0.0001), and alkaline phosphatase levels (188 versus 89 IU/L; p = 0.0001). Bone surveys were positive in all 10 patients with calciphylaxis compared with 49 (21%) of the 232 patients without calciphylaxis (p < 0.0001). All patients who underwent parathyroidectomy for calciphylaxis had dramatic healing of the ulcers. CONCLUSIONS: The presence of calciphylaxis is higher among younger patients who had undergone longer periods of hemodialysis. Therefore this group of patients should be monitored aggressively and treated expeditiously for complications of secondary hyperparathyroidism.     

Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1

Pseudoxanthoma elasticum (PXE) is a classic inherited disorder of the elastic tissue characterized by progressive calcification of elastic fibers with a pathognomonic histological appearance. The clinical manifestations of PXE typically involve the skin, the eye and the cardiovascular system, resulting in skin lesions, decreased vision and vascular disease. Clinically, a more common autosomal recessive and a less common autosomal dominant pattern of inheritance, with high penetrance, have been described; the estimated prevalence of the disease is 1 in 70,000-100,000. Previous failure to link the disease to any of several candidate genes prompted us to conduct a genome-wide screen on a collection of 38 families with two or more affected siblings, using allele sharing algorithms. Excess allele sharing was found on the short arm of chromosome 16 and confirmed by conventional linkage analysis, localizing the disease gene under a recessive model with a maximum two point lod score of 21.27 on chromosome 16p13.1, an area so far devoid of any obvious candidate genes. Under a dominant transmission pattern linkage with a maximum two point lod score of 14.53 was observed to the same region. Linkage heterogeneity analysis predicted the presence of allelic heterogeneity with different variants of a single gene that resides in this chromosomal region accounting for recessive and dominant forms of PXE.     

Stress-induced apoptosis and the sphingomyelin pathway

Thirteen myelodysplastic children with 19 chronic physeal fractures were treated. All were treated with prolonged immobilization (average, 5.8 months; range, 3-18 months) in either braces or casts; four of the fractures required operative fixation to facilitate healing. All were healed at 4.8-years follow-up but, in four of the fractures, the growth plate closed prematurely. Three of the children underwent magnetic resonance imaging (MRI) of the injured physes, and one underwent physeal biopsy as part of her operative epiphysiodesis. Histologic analysis revealed three distinct zones of physeal pathoanatomy: a normal zone of proliferation; a thickened, disorganized zone of hypertrophy; and a vascularized zone of fibrous tissue adjacent to the metaphysis. On MRI, there was thickening of the physis and irregularity of the zone of provisional calcification. The physeal cartilage and the juxtametaphyseal fibrovascular tissue enhanced with gadolinium. These findings corroborate earlier mechanistic proposals for physeal injury in myelodysplasia: chronic stress or trauma to the poorly sensate limb produces micromotion at the zone of hypertrophy, yielding a widened, disorganized physis, and leading to fracture, displacement, and delayed union.     

Differential ulcus cruris diagnosis

Most leg ulcers are of venous or arterial origin (85%). Advanced chronic venous insufficiency is the most common underlying condition (65%), followed by advanced peripheral arterial occlusive disease (10%), and combined chronic venous insufficiency and peripheral arterial occlusive disease (10%). Chronic ulcers in diabetic feet (5%) are of great socio-economic importance, as well. They are a consequence of diabetic polyneuropathy which in part of the patients may be combined with peripheral arterial occlusive disease, usually of the calf arteries. However, a leg ulcer can also be caused by a large array of other underlying conditions, such as ulcerating skin tumours, trauma followed by disturbed wound healing, infectious ulcerations, ulcerations in angiodysplasias, vasculitic ulcerations, pyoderma gangrenosum, cholesterol-embolism, idiopathic livedo reticularis with ulceration, primary and secondary antiphospholipid-antibody-syndrome, coumarin-necrosis, calciphylaxis in chronic renal insufficiency, necrobiosis lipoidica, different forms of panniculitis, hematologic disorders, autoimmun diseases and autoimmun-bullous dermatoses. The following article discusses the differential diagnosis, examination and treatment of leg ulcers in these less common underlying conditions.     

Laser-activated solid protein bands for peripheral nerve repair: an in vivo study

As clinical dermatologists, we are all striving to achieve the highest possible accuracy in our clinical acumen and diagnostic skills. Over the past decade, one relatively simple advance, epiluminescence microscopy with the use of the dermatoscope, has significantly contributed to our diagnostic skills in the detection of benign versus pigmented lesions. In the paper by Kawabata and Tamaki, these authors delineate distinctive dermatoscopic features of acral lentiginous melanoma in situ, and contrast this with melanocytic nevi. The restructuring of healthcare delivery systems by third party payers and governmental programs is impacting on the pattern of our medical practices. In Canada, this has limited access to widespread use of techniques such as Mohs' micrographic surgery. The article by Arlette and colleagues has further supported the well-established studies indicating that Mohs' micrographic surgery for high-risk skin cancers has a dramatic benefit. Healthcare restructuring has also led to a decreased number of trainees in a number of subspecialties, including dermatology. This decrease in manpower has been an impetus to look at alternative forms of care for underserviced areas. Telemedicine, the use of telecommunications technology to provide healthcare services over a distance, has been examined as one attempt at solving this problem. In the Point-Counterpoint articles, we have two distinct views on the future of telemedicine as it applies to dermatology. Over the past decade, there have been dramatic advances in our understanding at a molecular nature of various disease processes. This rapid development has translated into a large number of therapies. Regulatory agencies such as the Food and Drug Administration in the United States, or the Health Protection Branch in Canada, are caught between demands to bring effective therapies to the market in an expedited fashion, and yet establish efficacy and maintain safety of new therapeutic entities. This occurs by a multistaged approval process. During the early phases, exposure is limited in order to accumulate preliminary data on pharmacology and toxicity. In the Critical Appraisal CME series, Muglia and DiGiovanna describe early testing processes in Phase 1 clinical trials. Calciphylaxis is a severe disease associated with calcification of the skin, subcutaneous tissue and potentially, internal organs. While the disease itself is relatively uncommon, the manifestations are quite distinctive. In this issue of the Journal, we have a review of calciphylaxis from Richard Worth, as well as a preamble by Dr. Goodall and a case report by Kalaaji et al. illustrating the consequences of this rare but distinctive entity.     

Rural Eastern Carolina Health (REACH). A model community health improvement program

Most patients with chronic renal failure who are on maintenance hemodialysis are anovulatory and have menstrual abnormalities. This study was designed to determine the prevalence of organic causes of abnormal uterine bleeding in this group of patients exposed to unopposed estrogens. Eighteen patients with chronic renal failure and abnormal uterine bleeding underwent vacuum curettage. The histopathologic findings were compared with a group of 154 premenopausal women who had abnormal uterine bleeding without detectable organic causes. Excluding patients with secretory and atrophic endometrium, only 2 of 8 patients (25%) with chronic renal failure had endometrial lesions while 44 of 131 patients (33.6%) had either endometrial polyp, simple or atypical endometrial hyperplasia or endometrial carcinoma (p > 0.05). The uremic environment caused by chronic renal failure does not alter the endometrial responsiveness to unopposed estrogens and may lead to the development of endometrial lesions.     

Uremic tumoral calcinosis: acute hand presentations mimicking infection

Tumoral calcinosis is an uncommon condition of the hand characterized by deposition of calcium salts in the soft tissues of the extremities. The condition may be hereditary or acquired. Acquired tumoral calcinosis, also called tumoral calcification, is a rare manifestation of renal osteodystrophy due to derangement in divalent ion metabolism. Two chronic dialysis patients with tumoral calcification of the hand are presented. These cases are unusual in their rapid onset of presentation, mimicking acute infection. Prompt recognition of the condition may allow early nonsurgical intervention to preserve function.     

The surgical treatment of painful traumatic neuromas

The aims of this review on the use of skeletal surveys in the radiological assessment of renal osteodystrophy were threefold: to describe the radiological pattern of renal osteodystrophy in a local cohort of patients with chronic renal failure, to assess whether serial radiographs of the hands may effectively replace full radiological skeletal surveys in the long-term follow-up assessment of renal bone disease, and to formulate a grading system for bone resorption due to hyperparathyroidism. A radiological study of 61 patients with chronic renal failure revealed 20 (32.8%) patients with unequivocal radiological signs of renal osteodystrophy. The main abnormal radiological features observed in descending order of frequency were: osteopenia with associated cortical thinning and coarsened bone trabecular pattern (75%), subperiosteal resorption (60%), osteosclerosis (50%), extraosseous calcification (30%) and periosteal new bone formation (15%). A five-grade method of assessing the severity and extent of bone resorption was formulated. The study showed that 40% of the patients with a radiological diagnosis of renal osteodystrophy did not show changes in the hand radiographs. This finding precluded a recommendation of hand radiographs being used alone in the long-term radiological follow-up of patients with renal bone disease. An alternative was proposed and this was a limited radiological skeletal survey of three projections: radiographs of both hands, chest including the clavicles and the pelvis. This limited study would result in a cost saving of 62% as compared to a full study.     

Medical education on the World Wide Web

(Report of four cases and review of the literature) Calcification of the myocardium is a rare condition. The cause may be dystrophic or metastatic. An autosomal recessive inherited idiopathic arterial calcification of infancy is more rare abnormality. A dystrophic calcification is the more common of the three and may occur in areas of necrosis, hemorrhage, or fibrosis of the myocardium. Metastatic calcification is associated with hyperparathyroidism, D hypervitaminosis or renal failure, usually accompanied by the deposit of calcium in other organs, particularly the lungs, stomach, kidneys, spleen and liver. Authors report four cases of myocardial calcification diagnosed in intrauterine life. They give a review of literature of fetal and neonatal myocardial calcification.     

Are we mismanaging calcium and phosphate metabolism in renal failure?

Secondary hyperparathyroidism and renal osteodystrophy are the consequences of abnormal calcium, phosphate, and calcitriol metabolism ensuing from renal failure. Evidence suggests that calcium balance tends to become negative as we grow older than 35 years of age; however, the current dialysis modalities provide patients regardless of age with excessive calcium during dialysis. Administration of calcitriol in the management of hyperparathyroidism further increases the calcium and phosphate absorption. Furthermore, the current thrice-weekly renal replacement therapies fail to remove the daily absorbed phosphate, and we have to use calcium carbonate as a primary phosphate-binding agent to reduce intestinal phosphate absorption. The large calcium mass transfer and phosphate retention could lead to soft tissue calcification, especially in older end-stage renal disease (ESRD) patients. Consequently, only by maintaining a negative calcium balance during renal replacement therapy can we safely use calcitriol and calcium carbonate for the management of secondary hyperparathyroidism. Recent studies have indicated that phosphate restriction alone independent of plasma calcitriol or calcium can lower plasma parathyroid hormone (PTH) in renal failure and prevent hyperplasia of parathyroid glands. Therefore, phosphate control perhaps is the most important means to prevent secondary hyperparathyroidism. Previous studies have shown that ferric compounds are potent phosphate-binding agents; hence, these compounds warrant further trial in the management of phosphate metabolism in renal failure.     

Snapping elbow caused by the synovial fold in the radiohumeral joint

We report herein the case of a patient with chronic renal failure in whom mitral valve stenosis with extensive mitral anular calcification involving the entire anulus and leaflets was successfully treated surgically. Excision of both leaflets and partial resection of the anular calcification enabled the insertion of a 23-mm St. Jude Medical prosthetic valve. The technical difficulties involved with inserting the appropriate-sized prosthetic valve in a narrowed mitral anulus with heavy calcification are discussed following this case report.     

Secondary hyperparathyroidism: pathophysiology, histopathology, and medical and surgical management

It is generally accepted that morphological changes of the parathyroid glands appear early in renal failure. When diffuse hyperplasia develops into a nodular type, the cells grow monoclonally and proliferate aggressively, with abnormal suppression of parathyroid hormone (PTH) secretion under high extracellular calcium. Based on histopathological and pathophysiological findings, patients with nodular hyperplasia in renal hyperparathyroidism might be refractory to medical treatment, including calcitriol pulse therapy. Thus, parathyroid surgery is indicated for individuals developing hypercalcemia, elevated PTH levels, and/or bone disease, who cannot be effectively treated medically. The detection of enlarged parathyroid glands by image diagnosis is another criterion for surgery. In our experience, parathyroidectomy is an effective treatment; however, the timing of the operation is important, because skeletal deformity and vessel calcification cannot be expected to diminish even after successful surgery. Technically, it is important to identify all parathyroid glands and, in autotransplantation, to use an adequate amount of suitable tissue, namely, a diffuse type of hyperplastic tissue, to guarantee satisfactory postoperative function.     

Lead and the kidney: nephropathy, hypertension, and gout

Lead intoxication in human beings has been documented since the second century B.C. Renal disease, hypertension, and gout have all been linked to lead by strong circumstantial evidence. Both acute and chronic nephropathy can occur as a result of lead poisoning. Acute renal failure develops following acute lead intoxication and is often associated with gastrointestinal, neurologic, and hematologic disorders. Both blood and urinary laboratory abnormalities are associated with acute intoxication and are often diagnostic. Chronic lead nephropathy, a chronic tubulointerstitial nephritis on biopsy, occurs in the setting of long-term lead exposure and is often associated with hypertension and gout. Diagnosis of chronic lead nephropathy is more difficult since the laboratory abnormalities seen with acute lead intoxication are not present with chronic lead exposure. The typical clinical picture and the exclusion of other causes of renal disease allow the diagnosis of chronic lead nephropathy to be made. Evaluation of lead stores by either the calcium disodium edetate (EDTA) mobilization test or K-x-ray fluorescence are helpful in clinching the diagnosis. Treatment with EDTA lead mobilization is effective for acute lead poisoning while avoidance of further lead exposure prevents recurrence of lead intoxication. Treatment of chronic lead nephropathy with EDTA lead mobilization is useful if renal failure is modest; however, EDTA mobilization is of no benefit in patients with more severe renal insufficiency.     

Cardiac valve calcification in haemodialysis patients: role of calcium-phosphate metabolism

BACKGROUND: Cardiac valve calcification (VC) has been detected with increased frequency in haemodialysis (HD) patients, making it necessary to determine the potential pathogenic factors in uraemic patients. METHODS: A total of 92 chronic HD patients (39 female, 53 male) and 92 age and gender-matched nondialysis control subjects were evaluated by echocardiography and a severity score for VC was determined. Calcium phosphate metabolism was evaluated at the beginning of haemodialysis. RESULTS: We found a greater prevalence of VC in dialysis patients than in normal patients (mitral annulus 44.5% vs 10%, P = 0.02; aortic annulus 52% vs 4.3%, P = 0.01). HD patients with mitral calcification were found to be older than patients without calcification, were on long-term renal replacement therapy, had longer duration of predialysis arterial hypertension, had greater values of the highest value of mean calcium phosphate product in 6 successive months (CaxP) and the highest absolute value of calcium-phosphate product (CaxPmax). We also found a positive correlation between calcification score, age, and CaxP. No correlation was found between actual VC and arterial hypertension or parathyroid hormone. Multiple stepwise regression analysis selected age and CaxP as the most predictive parameters for mitral calcification (r = 0.47). Mitral calcification was associated more frequently with rhythm and cardiac conduction defects, valvular insufficiency and with peripheral vascular calcification. Aortic calcification was correlated with age (r = 0.42) and longer duration of predialysis arterial hypertension. CONCLUSION: Our study confirmed an increased prevalence of VC in HD patients and selected age and calcium phosphate product as the most predictive parameters. These findings support careful monitoring of calcium metabolism beginning at the early stages of end-stage renal failure to reduce the risk of heart disease.     

The pathogenesis and consequences of AGE formation in uraemia and its treatment

Advanced glycation endproducts (AGEs) accumulate in uraemia as a consequence of diminished clearance of low molecular weight forms which retain their reactivity and may subsequently combine with circulating and tissue macromolecules. Successful renal transplantation is the only form of renal replacement therapy which effectively clears these circulating AGEs; both haemodialysis and peritoneal dialysis are comparatively ineffective although high-flux haemodialysis confers some benefits. De novo AGE formation may be accelerated in uraemia due to carbonyl and oxidative stress leading to further accumulation. The consequences for the patient with chronic renal failure may be acceleration of vascular disease, renal failure progression and dialysis-related amyloidosis. Accelerated peritoneal AGE formation as a consequence of treatment with peritoneal dialysis fluids may be detrimental to peritoneal membrane function but does not appear to contribute to systemic elevation of AGEs.     

Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure

Eleven patients with chronic renal failure and presumed secondary hyperparathyroidism developed a syndrome of medial calcinosis of the arteries and painful ischemic ulcers of the fingers, legs, or thighs, or any combination of the three. Five patients required maintenance hemodialysis; six had functioning renal homografts. Severe hyperphosphatemia had existed in each; seven showed roentgenographic evidence of subperiosteal resorption. Similarities are evident between the lesions and experimentally produced calciphylaxix. The lesions demonstrated a relentless, progressive course, with serious morbidity and mortality. Hyperplastic or adenomatours parathyroid tissue was removed from ten of 11 patients unergoing surgical procedures; healing followed in seven patients. Treatment with phosphate-binding antacids to lower serum phosphorus levels may prevent this syndrome. Total or subtotal parathyroidectomy should be considered when ischemic skin lesions appear in uremic patients or in renal transplant recipients.