Calciphylaxis: Risk Factors, Diagnosis, and Treatment
Calciphylaxis: Risk Factors, Diagnosis, and Treatment
In our experience, a multidisciplinary and multi-interventional approach involving input from the following disciplines is important: nephrology, dermatology, dermatopathology, wound or burn center, nutrition, and pain management. Input should be obtained as soon as the diagnosis of calciphylaxis is suspected to formulate a comprehensive and consistent management plan.
Multiple interventions have been described in the management of calciphylaxis; however, the overall quality of evidence is poor and data mostly come from retrospective cohort studies, case series, and case reports. At present, there are no published data from a randomized controlled trial that address any of the proposed interventions. Treatment recommendations are largely an expert opinion based on clinical experience and available observational published data. A summary of our approach to calciphylaxis treatment is provided in Box 1 and is described next.
Wound or burn center and dermatology teams should be consulted for recommendations regarding dressings and need for surgical debridement. The goals of wound care are to control exudate, prevent infection, facilitate wound healing, and keep the wound bed free of necrosed devitalized tissue.
Surgical wound debridement is a controversial procedure for calciphylaxis. In our experience, surgical debridement should be considered on a case-by-case basis because evidence suggests that wounds with noninfected, stable, and dry eschar with limited tissue involvement are better managed with chemical debridement than surgical debridement. The aim of surgical debridement involves removal of necrosed tissue (without interfering with the adjacent healthy tissue) to facilitate wound healing. This is best achieved by surgeons who are highly experienced in managing complex wounds. A retrospective analysis of 63 calciphylaxis cases from Mayo Clinic showed a 1-year survival rate of 61.6% for patients who underwent surgical debridement compared to 27.4% for those who did not, though the patients were not matched for disease severity or systemic illness. Deep ulcer shaving combined with split-thickness skin transplantation has been described in the management of distal calciphylaxis.
Considering that the primary cause of mortality is sepsis, infected calciphylaxis lesions may require surgical debridement. Typically, serial wound debridement combined with negative pressure wound therapy to facilitate healthy granulation bed formation that can then be closed with a split-thickness skin graft is what we consider at our center. Back grafting of the donor site with widely meshed skin (4:1) as described for burn management may facilitate donor site healing and prevent Koebner response at donor sites. The surgical debridement of necrotic eschar caused by calciphylaxis, when not infected, often depends on the involved tissue burden. Large necrotic areas may not heal with conservative treatment and may present a higher infectious risk.
Hyperbaric oxygen therapy has been proposed in calciphylaxis wound management. In our experience, claustrophobia, access to treatment, and cost can be significant limiting factors for hyperbaric oxygen therapy, and we recommend this as a second-line therapy to facilitate healing of recalcitrant calciphylaxis wounds. Sterile maggot therapy with larvae of the greenbottle fly, Lucilia sericata, has also been described as a second-line therapy for calciphylaxis, but experience is limited to case reports.
Although antibiotics are not routinely indicated in calciphylaxis, we recommend a low threshold for antibiotic initiation, as guided by the clinical appearance of lesions and accompanying systemic features.
Pain management is one of the most challenging aspects of calciphylaxis and many patients report severe pain despite administration of potent analgesics. The exact cause of pain is unclear and is thought to be ischemic in origin, but there may be a neuropathic component associated with nerve inflammation. Opioid analgesics are typically required to control severe pain, but morphine, codeine, and hydrocodone should be avoided in dialysis patients due to accumulation of neurotoxic metabolites. Oxycodone and hydromorphone can be used in patients with decreased kidney function but require close monitoring for side effects. Limited experience suggests multimodal analgesia combining opioids with nonopioid adjuvants such as neuropathic agents, and ketamine may improve symptomatic management of calciphylaxis. Use of nonsteroidal anti-inflammatory drugs may be limited in patients with decreased kidney function. Because of the severity and complexity of pain in this population, pain medicine and palliative care teams play a critical role in calciphylaxis management.
CKD–Mineral Bone Disease Axis Abnormalities. In our opinion, serum calcium and phosphorus levels should be maintained in the normal range and serum PTH level should be maintained between 150 and 300 ng/mL. Calcium supplements and high dialysate calcium bath should be avoided and limited evidence supports administration of non–calcium-based binders over calcium-based binders for management of hyperphosphatemia in patients with calciphylaxis. Cinacalcet is preferred to treat secondary hyperparathyroidism over vitamin D analogues in patients with calciphylaxis who have hypercalcemia and/or hyperphosphatemia. In the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial that randomly assigned 3,883 dialysis patients to either cinacalcet or placebo, a reduced risk of calciphylaxis was observed in the cinacalcet arm (6 vs 18 events, P = 0.009). However, the low event rate limits the ability to draw conclusions regarding cinacalcet's benefit. Furthermore, whether cinacalcet treatment after calciphylaxis diagnosis alters the disease course remains unclear. We prefer cinacalcet over surgical parathyroidectomy considering potential risks of surgical wound infection, hungry bone syndrome, and adynamic bone disease associated with surgical parathyroidectomy. Furthermore, data for survival after surgical parathyroidectomy in patients with calciphylaxis are retrospective and inconclusive. In all cases of calciphylaxis, excessive suppression of PTH, especially to < 100 ng/mL, should be avoided.
Management of Other Risk Factors. At present, there are limited to no data to support whether discontinuation or minimization of potential triggers such as warfarin, trauma related to subcutaneous injections (eg, insulin), and iron compounds leads to improvement in calciphylaxis outcomes. However, considering the morbidity and mortality associated with calciphylaxis and available epidemiologic data that link these factors to calciphylaxis development, we recommend careful risk-benefit analyses for continuing therapies such as warfarin and iron. Because alternate anticoagulation options are highly limited in dialysis patients, the decision regarding warfarin is not an easy one when a hypercoagulable condition is identified as a calciphylaxis risk factor or when the patient has other indications for anticoagulation. For insulin or subcutaneous heparin injections, rotating injection sites and avoiding trauma at lesion sites is recommended. For patients who are on immunosuppressive therapies that delay wound healing, appropriate alternate immunosuppressive agents that do not affect wound healing should be used.
Dialysis prescription should be optimized to achieve the recommended NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) goals of dialysis adequacy. Intensifying dialysis by increasing duration or frequency has been described. In the absence of confirmatory data to support this, we do not routinely recommend intensification of dialysis beyond the goals of dialysis adequacy.
In the literature, peritoneal dialysis has been described to confer higher calciphylaxis risk when compared to hemodialysis. However, experience at our center is not consistent with this observation and we do not routinely transition patients from peritoneal dialysis to hemodialysis therapy for calciphylaxis management.
We recommend a nutrition consult to address malnutrition that is frequently present in calciphylaxis patients. If patients are not able to improve dietary intake, consideration should be given to nutrition by gastric tube and parenteral nutrition. However, evidence to support these interventions is lacking.
Intravenous sodium thiosulfate is probably the most common intervention used to treat calciphylaxis (off-label indication). It is a reducing agent that forms water-soluble complexes with many metals and minerals. Its use in calciphylaxis was first reported more than 10 years ago in a case report. However, there are no prospective trial data for this agent.
We conducted a multicenter retrospective cohort study on this topic in collaboration with the investigators from Fresenius Medical Care, North America. We systematically evaluated the safety of intravenous sodium thiosulfate in 172 hemodialysis patients with calciphylaxis. Data regarding effects on calciphylaxis lesions were obtained by surveying clinicians managing these patients and were available for 53 patients. Sodium thiosulfate was most frequently administered as 25 g intravenously in 100 mL of normal saline solution given over the last half-hour of each hemodialysis session, and this is the currently recommended dose for an average 70-kg person who is on thrice-weekly hemodialysis therapy. Overall, intravenous sodium thiosulfate was well tolerated in this study. Notable side effects include nausea, vomiting, metabolic acidosis, hypotension, and volume overload. These side effects sometimes warrant dose modification or discontinuation. In our study, among surveyed patients, calciphylaxis improved in >70% of patients (resolution or improvement); however, survey bias and other limitations of any retrospective study of this nature need to be acknowledged, and at present, the best conclusion regarding sodium thiosulfate efficacy is that it remains unclear. This is further complicated by an elusive mechanism of action of sodium thiosulfate because recent investigations question the previously believed calcium-chelating properties of sodium thiosulfate and instead point toward direct vascular calcification inhibitory effects and antioxidant and vasodilatory properties. It is also unclear what the optimal duration of sodium thiosulfate treatment is. In our experience, improvement in pain within 1 to 2 weeks after initiation of sodium thiosulfate is an important predictor of long-term response.
A few additional issues regarding sodium thiosulfate deserve mention. First, its dose needs adjustment if the patient is on more frequent dialysis or on continuous renal replacement therapies (Table 3). For patients who weigh <60 kg, we suggest reducing the dose to 12.5 g to reduce the incidence of adverse events. Intraperitoneal administration of sodium thiosulfate should be avoided due to risks of chemical peritonitis. Intralesional sodium thiosulfate has also been described to aid in the resolution of calciphylaxis lesions.
A number of other treatments have been described in case reports and small case series that may have a potential role in the treatment of calciphylaxis. These include bisphosphonates, low-dose tissue plasminogen activator infusion, low-density lipoprotein apheresis, vitamin K, and kidney transplantation. In our opinion, these modalities may be considered on a case-by-case basis taking into account the cost, availability, and patient-related factors with clear understanding of the limitations of the available data.
Treatment
In our experience, a multidisciplinary and multi-interventional approach involving input from the following disciplines is important: nephrology, dermatology, dermatopathology, wound or burn center, nutrition, and pain management. Input should be obtained as soon as the diagnosis of calciphylaxis is suspected to formulate a comprehensive and consistent management plan.
Multiple interventions have been described in the management of calciphylaxis; however, the overall quality of evidence is poor and data mostly come from retrospective cohort studies, case series, and case reports. At present, there are no published data from a randomized controlled trial that address any of the proposed interventions. Treatment recommendations are largely an expert opinion based on clinical experience and available observational published data. A summary of our approach to calciphylaxis treatment is provided in Box 1 and is described next.
Wound Management
Wound or burn center and dermatology teams should be consulted for recommendations regarding dressings and need for surgical debridement. The goals of wound care are to control exudate, prevent infection, facilitate wound healing, and keep the wound bed free of necrosed devitalized tissue.
Surgical wound debridement is a controversial procedure for calciphylaxis. In our experience, surgical debridement should be considered on a case-by-case basis because evidence suggests that wounds with noninfected, stable, and dry eschar with limited tissue involvement are better managed with chemical debridement than surgical debridement. The aim of surgical debridement involves removal of necrosed tissue (without interfering with the adjacent healthy tissue) to facilitate wound healing. This is best achieved by surgeons who are highly experienced in managing complex wounds. A retrospective analysis of 63 calciphylaxis cases from Mayo Clinic showed a 1-year survival rate of 61.6% for patients who underwent surgical debridement compared to 27.4% for those who did not, though the patients were not matched for disease severity or systemic illness. Deep ulcer shaving combined with split-thickness skin transplantation has been described in the management of distal calciphylaxis.
Considering that the primary cause of mortality is sepsis, infected calciphylaxis lesions may require surgical debridement. Typically, serial wound debridement combined with negative pressure wound therapy to facilitate healthy granulation bed formation that can then be closed with a split-thickness skin graft is what we consider at our center. Back grafting of the donor site with widely meshed skin (4:1) as described for burn management may facilitate donor site healing and prevent Koebner response at donor sites. The surgical debridement of necrotic eschar caused by calciphylaxis, when not infected, often depends on the involved tissue burden. Large necrotic areas may not heal with conservative treatment and may present a higher infectious risk.
Hyperbaric oxygen therapy has been proposed in calciphylaxis wound management. In our experience, claustrophobia, access to treatment, and cost can be significant limiting factors for hyperbaric oxygen therapy, and we recommend this as a second-line therapy to facilitate healing of recalcitrant calciphylaxis wounds. Sterile maggot therapy with larvae of the greenbottle fly, Lucilia sericata, has also been described as a second-line therapy for calciphylaxis, but experience is limited to case reports.
Although antibiotics are not routinely indicated in calciphylaxis, we recommend a low threshold for antibiotic initiation, as guided by the clinical appearance of lesions and accompanying systemic features.
Pain Management
Pain management is one of the most challenging aspects of calciphylaxis and many patients report severe pain despite administration of potent analgesics. The exact cause of pain is unclear and is thought to be ischemic in origin, but there may be a neuropathic component associated with nerve inflammation. Opioid analgesics are typically required to control severe pain, but morphine, codeine, and hydrocodone should be avoided in dialysis patients due to accumulation of neurotoxic metabolites. Oxycodone and hydromorphone can be used in patients with decreased kidney function but require close monitoring for side effects. Limited experience suggests multimodal analgesia combining opioids with nonopioid adjuvants such as neuropathic agents, and ketamine may improve symptomatic management of calciphylaxis. Use of nonsteroidal anti-inflammatory drugs may be limited in patients with decreased kidney function. Because of the severity and complexity of pain in this population, pain medicine and palliative care teams play a critical role in calciphylaxis management.
Modification of Risk Factors
CKD–Mineral Bone Disease Axis Abnormalities. In our opinion, serum calcium and phosphorus levels should be maintained in the normal range and serum PTH level should be maintained between 150 and 300 ng/mL. Calcium supplements and high dialysate calcium bath should be avoided and limited evidence supports administration of non–calcium-based binders over calcium-based binders for management of hyperphosphatemia in patients with calciphylaxis. Cinacalcet is preferred to treat secondary hyperparathyroidism over vitamin D analogues in patients with calciphylaxis who have hypercalcemia and/or hyperphosphatemia. In the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial that randomly assigned 3,883 dialysis patients to either cinacalcet or placebo, a reduced risk of calciphylaxis was observed in the cinacalcet arm (6 vs 18 events, P = 0.009). However, the low event rate limits the ability to draw conclusions regarding cinacalcet's benefit. Furthermore, whether cinacalcet treatment after calciphylaxis diagnosis alters the disease course remains unclear. We prefer cinacalcet over surgical parathyroidectomy considering potential risks of surgical wound infection, hungry bone syndrome, and adynamic bone disease associated with surgical parathyroidectomy. Furthermore, data for survival after surgical parathyroidectomy in patients with calciphylaxis are retrospective and inconclusive. In all cases of calciphylaxis, excessive suppression of PTH, especially to < 100 ng/mL, should be avoided.
Management of Other Risk Factors. At present, there are limited to no data to support whether discontinuation or minimization of potential triggers such as warfarin, trauma related to subcutaneous injections (eg, insulin), and iron compounds leads to improvement in calciphylaxis outcomes. However, considering the morbidity and mortality associated with calciphylaxis and available epidemiologic data that link these factors to calciphylaxis development, we recommend careful risk-benefit analyses for continuing therapies such as warfarin and iron. Because alternate anticoagulation options are highly limited in dialysis patients, the decision regarding warfarin is not an easy one when a hypercoagulable condition is identified as a calciphylaxis risk factor or when the patient has other indications for anticoagulation. For insulin or subcutaneous heparin injections, rotating injection sites and avoiding trauma at lesion sites is recommended. For patients who are on immunosuppressive therapies that delay wound healing, appropriate alternate immunosuppressive agents that do not affect wound healing should be used.
Dialysis Modality and Dialysis Prescription
Dialysis prescription should be optimized to achieve the recommended NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) goals of dialysis adequacy. Intensifying dialysis by increasing duration or frequency has been described. In the absence of confirmatory data to support this, we do not routinely recommend intensification of dialysis beyond the goals of dialysis adequacy.
In the literature, peritoneal dialysis has been described to confer higher calciphylaxis risk when compared to hemodialysis. However, experience at our center is not consistent with this observation and we do not routinely transition patients from peritoneal dialysis to hemodialysis therapy for calciphylaxis management.
Nutrition Management
We recommend a nutrition consult to address malnutrition that is frequently present in calciphylaxis patients. If patients are not able to improve dietary intake, consideration should be given to nutrition by gastric tube and parenteral nutrition. However, evidence to support these interventions is lacking.
Sodium Thiosulfate
Intravenous sodium thiosulfate is probably the most common intervention used to treat calciphylaxis (off-label indication). It is a reducing agent that forms water-soluble complexes with many metals and minerals. Its use in calciphylaxis was first reported more than 10 years ago in a case report. However, there are no prospective trial data for this agent.
We conducted a multicenter retrospective cohort study on this topic in collaboration with the investigators from Fresenius Medical Care, North America. We systematically evaluated the safety of intravenous sodium thiosulfate in 172 hemodialysis patients with calciphylaxis. Data regarding effects on calciphylaxis lesions were obtained by surveying clinicians managing these patients and were available for 53 patients. Sodium thiosulfate was most frequently administered as 25 g intravenously in 100 mL of normal saline solution given over the last half-hour of each hemodialysis session, and this is the currently recommended dose for an average 70-kg person who is on thrice-weekly hemodialysis therapy. Overall, intravenous sodium thiosulfate was well tolerated in this study. Notable side effects include nausea, vomiting, metabolic acidosis, hypotension, and volume overload. These side effects sometimes warrant dose modification or discontinuation. In our study, among surveyed patients, calciphylaxis improved in >70% of patients (resolution or improvement); however, survey bias and other limitations of any retrospective study of this nature need to be acknowledged, and at present, the best conclusion regarding sodium thiosulfate efficacy is that it remains unclear. This is further complicated by an elusive mechanism of action of sodium thiosulfate because recent investigations question the previously believed calcium-chelating properties of sodium thiosulfate and instead point toward direct vascular calcification inhibitory effects and antioxidant and vasodilatory properties. It is also unclear what the optimal duration of sodium thiosulfate treatment is. In our experience, improvement in pain within 1 to 2 weeks after initiation of sodium thiosulfate is an important predictor of long-term response.
A few additional issues regarding sodium thiosulfate deserve mention. First, its dose needs adjustment if the patient is on more frequent dialysis or on continuous renal replacement therapies (Table 3). For patients who weigh <60 kg, we suggest reducing the dose to 12.5 g to reduce the incidence of adverse events. Intraperitoneal administration of sodium thiosulfate should be avoided due to risks of chemical peritonitis. Intralesional sodium thiosulfate has also been described to aid in the resolution of calciphylaxis lesions.
Other Treatments
A number of other treatments have been described in case reports and small case series that may have a potential role in the treatment of calciphylaxis. These include bisphosphonates, low-dose tissue plasminogen activator infusion, low-density lipoprotein apheresis, vitamin K, and kidney transplantation. In our opinion, these modalities may be considered on a case-by-case basis taking into account the cost, availability, and patient-related factors with clear understanding of the limitations of the available data.
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