Calciphylaxis

Dr Lobo asked this on the rounds to day so I read it up.
Source emedicine.com


Calciphylaxis is a poorly understood and highly morbid syndrome of vascular calcification and skin necrosis. Bryant and White first reported it in association with uremia.

Pathogenesis of calciphylaxis remains obscure and is likely the result of a multiplicity of comorbid factors or events. Disorders that are most often implicated in the pathogenesis of calciphylaxis include chronic renal failure, hypercalcemia,
hyperphosphatemia, an elevated calcium-phosphate product, and secondary hyperparathyroidism. Yet, although these abnormalities are extremely common in patients with end-stage renal disease (ESRD), calciphylaxis is relatively rare.

Selye defined calciphylaxis as a condition of hypersensitivity induced by a set of "sensitizing" agents, in which calcinosis occurred only in those subsequently subjected to a group of "challengers" and only after a critical lag time.

1-4% of the population with ESRD. A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran.

Mortality rate of calciphylaxis is reported to be as high as 60-80%. The leading cause of death is sepsis from infected, necrotic skin lesions. Mortality rate is higher in patients with proximal disease than in those with only distal or acral disease. A 2-fold increase in mortality is seen in those with ulcerative disease.

female-to-male ratio of approximately 3:1.

History :
long-standing history of chronic renal failure and renal replacement therapy.
renal allograft transplantation.
Lesions of calciphylaxis typically develop suddenly and progress rapidly. Lesions may be singular or numerous, and they generally occur on the lower extremities,however, lesions also may develop on the hands and torso.
Intense pain is a constant finding.

Triggers include the following:
o Long-term obesity
o Recent and sudden weight loss
o Infusion of medications such as iron dextran
o Remote and/or recent use of immunosuppressive agents, especially corticosteroids
o Concurrent use of warfarin anticoagulation: Current data suggest that warfarin therapy may lower protein C concentrations, leading to a procoagulant condition in the calcified vessel.

Clincial
* Early lesions of calciphylaxis manifest as nonspecific violaceous mottling; as livedo reticularis; or as erythematous papules, plaques, or nodules.
* More developed lesions have a stellate purpuric configuration with central cutaneous necrosis.
* Lesions are excruciatingly tender and extremely firm.
* The distribution of the lesions may be characterized as proximal or distal.
o Ninety percent of lesions of calciphylaxis occur on the lower extremities.
o Distal lesions are those that occur below the knee; proximal lesions occur on the thighs or the trunk.
* An intact peripheral pulse helps to distinguish acral calciphylaxis from atherosclerotic peripheral vascular disease.

Causes:
* The cause of calciphylaxis remains obscure. Most cases occur in the setting of chronic renal failure, abnormal calcium-phosphate homeostasis, and hyperparathyroidism.
o Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.
o Disorders associated with the development of calciphylaxis include the following:
+ Common – Chronic renal failure, hypercalcemia, hyperphosphatemia, elevated calcium-phosphate product, hyperparathyroidism, vascular calcification
+ Speculative – Aluminum toxicity, coagulation abnormalities, iron dextran infusion
+ Suggested from clinical observation – Renal transplantation, immunosuppressive agents, corticosteroid use, obesity

o Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, 2 pathologic roles may be attributed to this vascular calcification: (1) Calcification of the vascular endothelium may alter the local interaction of procoagulant and anticoagulant factors, predisposing to a microenvironment of hypercoagulability.
(2) Alternatively, extensive endothelial calcification and intimal hyperplasia, which are known to compromise the luminal size of vessels in calciphylaxis, may result in vascular occlusion. These mechanisms remain hypothetical and have not yet been proven in cases of calciphylaxis.

Imaging Studies:

* Plain films uniformly demonstrate an arborization of vascular calcification within the dermis and the subcutaneous tissue. However, this is common in ESRD and not specific for calciphylaxis.
* Bone scintigraphy may be used as a noninvasive diagnostic tool because the bone matrix protein osteopontin has recently been demonstrated in calciphylaxis lesions. Serial bone scans can also possibly be used to monitor progression or regression of disease.

Procedures:
* An incisional cutaneous biopsy is usually diagnostic.

Histologic Findings:
* Biopsy specimens typically demonstrate calcification within the media of small- and medium-sized arterioles with extensive intimal hyperplasia and fibrosis. A mixed inflammatory infiltrate frequently occurs. Subcutaneous calcium deposits with panniculitis and fat necrosis may sometimes be found. Vascular microthrombi are frequently evident.

Medical Care:
Medical care is mainly supportive. Aggravating conditions should be addressed, and trigger factors should be eliminated. This may mean the discontinuation of parenteral iron therapy, calcium, supplementation, and vitamin D supplementation. Although implicated as a trigger in the past, recent studies suggest that some patients may benefit early on from systemic glucocorticoids, unless ulcerated lesions are present.
* Serum calcium and phosphate concentrations must be brought to low-normal levels as quickly and safely as possible.
o Conservative therapy should be tried first, with dietary alteration; use of noncalcium, nonaluminum phosphate binders; and low-calcium bath dialysis. Some benefit may be achieved with increasing the frequency of dialysis sessions.
o If calcium and phosphate levels remain high, especially in the setting of hyperparathyroidism, intravenous use of a vitamin D analog may be beneficial.
o Although only speculative, calcimimetics such as cinacalcet hydrochloride may be beneficial in cases of hyperparathyroidism.
o Parathyroidectomy should be considered if conservative management fails and hyperparathyroidism is present.
* Marked improvement of calciphylaxis has now been reported with the use of intravenous sodium thiosulfate. Sodium thiosulfate increases the solubility of calcium deposits.
* Judicious use of antibiotics may be advantageous.
* In some cases, hyperbaric oxygen may be beneficial.
* Conditions of hypercoagulability should be sought and addressed.

Complications:
* Complications of calciphylaxis range from moderate interference with activity to death.
* Lesions of calciphylaxis frequently result in nonhealing ulcers and cutaneous gangrene. Acral lesions may fail to heal with conservative therapy and require amputation.
* Sepsis may result from the nonhealing wounds.
* Patients with internal involvement may develop gastrointestinal hemorrhage, infarction, or organ failure.
* Patients treated with calcimimetics, sodium thiosulfate, and parathyroidectomy must be monitored for hypocalcemia.

Prognosis:

* The prognosis is generally not good, with a mortality rate as high as 60-80% in patients with ulcerative disease. Patients who do not die of sepsis or organ failure frequently undergo amputation of an involved limb. Vascular calcification is theoretically reversible with aggressive management, but many patients have numerous comorbid diseases.

Currently, the 1- and 5-year survival rates are estimated to be 45% and 35%, respectively.

Lanthanum does not make a terrific difference?

Kidney International (2007) 71, 252–259. doi:10.1038/sj.ki.5001932; published online 11 October 2006

Cognitive function in Stage 5 chronic kidney disease patients on hemodialysis: No adverse effects of lanthanum carbonate compared with standard phosphate-binder therapy

P Altmann¹, M E Barnett^2,3 and W F Finn⁴ on Behalf of the SPD405-307 Lanthanum Carbonate Study Group

Abstract

Patients with Stage 5 chronic kidney disease who have hyperphosphatemia require treatment with phosphate binders to lower serum phosphorus levels. Existing binders are effective but may be associated with important safety disadvantages. Lanthanum carbonate is a phosphate binder with demonstrated efficacy, safety, and tolerability in clinical trials.

Changes in cognitive function were evaluated over time using the Cognitive Drug Research computerized cognitive assessment system (Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, and Delayed Picture Recognition) in 360 hemodialysis patients who were enrolled in a 2-year, multicenter, comparative study of lanthanum carbonate versus standard therapy.

A decline in cognitive function from baseline was observed in both groups. The deterioration in cognitive function was similar in both the lanthanum carbonate and standard therapy groups. One parameter – Numeric Working Memory – showed a statistically significant between-group difference in favor of lanthanum carbonate (P=0.02).

Given the magnitude of the changes, however, and the differences that were observed at baseline between treatment groups, the clinical significance of this difference is doubtful.

This study demonstrates that cognitive function deteriorates in hemodialysis patients over a 2-year time period. Use of lanthanum carbonate as a phosphate binder does not adversely affect cognitive function compared with standard therapy.

Chronic acidosis and poor osteoblast function

Kidney International (2007) 71, 201–209. doi:10.1038/sj.ki.5002035; published online 20 December 2006

Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells

S Disthabanchong¹, P Radinahamed¹, W Stitchantrakul², S Hongeng³ and R Rajatanavin⁴

Abstract

Bone histology of distal renal tubular acidosis patients showed decreased bone formation with impaired bone matrix mineralization that is not entirely explained by an alteration in the mineral balance. Data from in vitro studies suggests a direct inhibitory effect of metabolic acidosis on osteoblast function. We investigated the effects of chronic metabolic acidosis on osteoblast differentiation from mesenchymal stem cells (MSCs). Human MSCs were allowed to differentiate into osteoblasts in culture. Concentrated hydrochloric acid was added to the medium to lower the bicarbonate concentration and pH. The expression of various osteoblastic genes and proteins and bone matrix mineralization were examined. Chronic metabolic acidosis enhanced the messenger RNA (mRNA) and protein expression of early osteoblast transcription factor, runx-2, whereas inhibiting osterix and having no effect on ATF-4. The expression of type I collagen, the most abundant bone matrix protein, was increased following the same pattern of runx-2. Likewise, metabolic acidosis slightly enhanced the expression of mature osteoblastic gene, osteocalcin. Study on mineralization revealed suppressed alkaline phosphatase mRNA and enzyme activity. Despite the augmented collagen deposit in acidic culture, bone matrix mineralization was impaired. In conclusion, chronic metabolic acidosis alters osteoblast differentiation from MSCs through its diverse effect on osteoblastic genes and proteins resulting in an impairment of bone formation.

CKD patients have increased peripheral arterial disease risk

Individuals With Chronic Kidney Disease Have Increased PAD Risk CME

News Author: Marlene Busko
CME Author: Charles Vega, MD, FAAFP

January 17, 2007 — An analysis from the Atherosclerosis Risk in Communities (ARIC) study confirms that patients with chronic kidney disease (CKD) have an increased risk of developing peripheral arterial disease (PAD). Because early PAD detection is critical to prevent leg revascularization and amputation, further studies are needed to see whether PAD screening strategies in CKD patients are effective, researchers conclude.

"The findings of our study call for an increased awareness and early detection of PAD in the CKD population," the group, with lead author Keattiyoat Wattanakit, MD, from the University of Minnesota in Minneapolis, writes. They add that "Recognition of an increased risk for PAD in this population, particularly in individuals with no typical ischemic symptoms, potentially could avert adverse limb as well as cardiovascular disease (CVD) events if modification of risk factors were intensified."

The article is published in the January 10 JASN Express issue of the Journal of the American Society of Nephrology.

The ARIC study cohort comprised 15,792 participants, aged 45 to 64 years at baseline in 1987 to 1989, who were recruited in 4 communities in the United States. The current study included 14,280 participants who had no PAD, defined as an ankle-brachial index of 0.9 or higher, or intermittent claudication at baseline.

Study Highlights

• Participants were between the ages of 45 and 64 years and were of white or black race. No subject had PAD, defined by an ankle-brachial index of 0.9 or higher, at baseline.
• GFR was estimated by applying serum creatinine levels to the Modification of Diet in Renal Disease formula. Subjects were divided into 3 groups, according to GFR: more than 90 mL/minute per 1.73 m² (normal kidney function), 60 to 89 mL/minute per 1.73 m² (mildly decreased kidney function), and 15 to 59 mL/minute per 1.73 m² (chronic kidney disease).
• The main study outcome was the relationship between kidney function and the risk for PAD, which was diagnosed by a finding of ankle-brachial index less than 0.9; new intermittent claudication symptoms; or a hospital discharge diagnosis of PAD, leg amputation, or leg revascularization procedure. Only a random subgroup of participants had ankle-brachial measurements performed during the course of the study. The main study result was adjusted for the presence of existing cardiovascular risk factors, as well as glucose and lipid levels.
• 14,280 individuals comprised the study cohort. Mean age of the subjects was 54 years, and 55% of the cohort was women.
• The mean follow-up time was 13.1 years. During this period, 1016 subjects developed PAD. Nearly half of cases were found because of a low ankle-brachial index. Patients with PAD were more likely to be older and have diabetes and other cardiovascular risk factors.
• After adjustment for age, sex, race, and study center, the rates of incident PAD were 4.7, 4.9, and 8.6 per 1000 person-years among subjects with normal kidney function, mildly decreased kidney function, and CKD, respectively. The adjusted risk for PAD began to increase in linear fashion after eGFR fell below 75 mL/minute per 1.73 m².
• Compared with normal kidney function, mildly decreased kidney function did not significantly and independently increase the risk for PAD.
• Conversely, compared with normal kidney function, CKD was associated with a multivariate-adjusted relative risk of 1.56 for PAD.
• Examining subgroups of patients based on age and chronic disease failed to significantly alter the study's main findings. Reduced GFR was a particularly strong risk factor for PAD among men vs women.
• In a separate analysis, kidney disease was not related to the risk for asymptomatic PAD diagnosed by reduced ankle-brachial index scores alone. CKD remained a significant risk factor for symptomatic PAD.

Pearls for Practice

• Previous research has demonstrated that reduced renal function is an independent risk factor for cardiovascular disease, although the precise mechanisms of this association are unclear. Reduced renal function might also increase the risk for PAD among postmenopausal women.
• The current study found that an eGFR between 15 and 59 mL/minute per 1.73 m² (chronic kidney disease) is an independent risk factor for incident PAD, but that an eGFR between 60 and 89 mL/minute per 1.73 m² (mildly decreased kidney function) was not a risk factor for PAD.