Calcific Uraemic Arteriolopathy (CUA) or calciphylaxis, is a thrombotic disorder of skin and subcutaneous tissue which typically presents with painful purpuric nodules that may progress to necrotic ulcers, and is a severe, life-threatening condition. CUA is an uncommon clinical entity that affects mostly haemodialysis (HD) patients. Although the process of vascular calcification was initially thought to be the result of a passive deposition of calcium-phosphate crystals, current knowledge suggests a distinct mechanism, including cellular activity with differentiation of vascular smooth muscle cells (VSMCs) into chondrocyte as well as osteoblast-like cellular phenotypes and deficiencies in calcification inhibitors. Although multiple studies suggest a potential relationship between warfarin and CUA, larger prospective studies are needed in order to better evaluate this association, and randomised controlled trials are needed to assess the benefit of distinct interventions in this setting. In this article the topic of CUA is reviewed based on a clinical case of a 65-year-old man undergoing haemodialysis, who underwent an aortic valve replacement one year earlier, receiving a mechanical heart valve, and who has been under warfarin therapy since the

Agapii, Rodica

Fragoso, Andr?

Jerónimo, Teresa

Mendes, Filipa

Neves, Pedro L

Pimentel, Ana

Rocha, Sofia Couto

Silva, Ana

Portuguese Journal of Nephrology & Hypertension

English

Sapientia

108     ABSTRACTCalcific Uraemic Arteriolopathy (CUA) or calciphylaxis, is a thrombotic disorder of skin and subcutaneous tissue which typically presents with painful purpuric nodules that may progress to necrotic ulcers, and is a severe, life--threatening condition. CUA is an uncommon clinical entity that affects mostly haemodialysis (HD) patients. Although the process of vascular calcification was initially thought to be the result of a passive deposition of calcium -phosphate crystals, current knowledge suggests a distinct mechanism, including cellular activity with differentiation of vascular smooth muscle cells (VSMCs) into chondrocyte as well as osteoblast -like cellular phe-notypes and deficiencies in calcification inhibitors. Although multiple studies suggest a potential relationship between warfarin and CUA, larger prospective studies are needed in order to better evaluate this association, and randomised controlled trials are needed to assess the benefit of distinct interventions in this setting. In this article the topic of CUA is reviewed based on a clinical case of a 65 -year -old man undergoing haemodialysis, who underwent an aortic valve replacement one year earlier, receiving a mechanical heart valve, and who has been under warfarin therapy since then.Key ‑Words: Calciphylaxis, Fetuin -A, Gas -6, MGP, Vitamin K, Warfarin.Calcific uraemic arteriolopathy – A mini‑reviewFilipa Brito Mendes1, Sofia Couto Rocha2, Rodica Agapii2, Ana Silva1,3, André Fragoso1,  Teresa Jerónimo1, Ana Pimentel1, Pedro L Neves1,31 Department of Nephrology, Algarve Hospital Centre, Faro, Portugal2 Department of Internal Medicine, Algarve Hospital Centre, Portugal3 Department of Biomedical Sciences and Medicine, Faro, PortugalReceived for publication: Dec 13, 2015Accepted in revised form: May 16, 2016MINI-REVIEWPort J Nephrol Hypert 2016; 30(2): 108-112 • Advance Access publication 20 May 2016 INTRODUCTIONCalcific Uraemic Arteriolopathy (CUA), also known as calciphylaxis, is a severely morbid and life -threatening condition. It is characterised by medial vascular calci-fication, affecting small arterioles, and results in ischae-mic subcutaneous necrosis with vulnerable skin ulcerations.1Despite being rare, it is increasingly identified and reported worldwide.2CUA usually occurs in patients with chronic kidney disease (CKD), mostly in advanced stages of kidney disease (ESRD).We report a case of calciphylaxis occurring after starting warfarin therapy. CASE SUMMARYWe report the case of a 65 -year -old male gender patient with end -stage renal disease (ESRD) due to diabetes mellitus type 2, who had been on haemodi-alysis for the last 6 years. The patient had a body mass index of 25 Kg/m2, and had recently switched to hae-modiafiltration with a dialysate composition of 1.50 mmol/L of calcium, 0.50 mmol/L of magnesium and 32 mmol/L of bicarbonate. The patient underwent an Nefro - 30-2 - MIOLO OK.indd   108 28/06/2016   12:29:19Port J Nephrol Hypert 2016; 30(2): 108-112    109aortic valve replacement one year earlier, receiving a mechanical heart valve, and he has been under warfarin therapy since then. Secondary hyperparathyroidism was not a major problem, as the patient maintained serum parathormone levels in the range of 200 to 400 pg/mL for the last few years (Table I) taking sevelamer 1600mg/day and cinacalcet 90mg/week.On February 2014, the patient was referred to the Nephrology department due to a painful violaceous lesion of 3 cm diameter on the dorsal region of the right leg.A diagnosis of CUA was considered. The frequency of haemodialysis sessions was increased to 5 per week (4 hours x 5 /week); the dialysate’s calcium was reduced to 1.25 mmol/L, and warfarin was stopped and replaced by low molecular weight heparin (1mg/Kg/day). Sodium thiosulfate (STS) therapy was initiated the first day of hospital stay, which was one week after the onset of the clinical picture. The patient received STS treatment 3 x /week at the end of dialysis session, at a 25g dose with no side -effects.Mineral metabolism parameters (Table 1), calcium, phosphorus and parathormone levels were within acceptable limits. Hand and foot X -rays confirmed ecto-pic calcifications (Fig. 1). Blood cultures were negative and arterial and venous eco -doppler of lower limbs was normal.On the fourth day of hospital stay, a skin biopsy was performed and showed epidermis atrophy with focal necrosis as well as vascular calcifications in deep der-mis. The biopsy, performed in the smallest lesion, had a proper healing.However, despite all therapeutic measures, the skin lesion continued to increase in dimension while numer-ous other identical skin lesions appeared in the region. The confluence of these small isolated lesions, which subsequently suffered necrosis and non -healing ulcerations (Fig. 2 and 3), led, after three months, to bilateral above -knee amputation. By that time, STS was stopped.Figure 2Right leg Figure 1hands with vascular calcifications Table IPatient’s mineral metabolism valuesBefore hospitalisationDuring hospitalisation2009 2010 2011 2012 2013Calcium X Phosphorus (mg/dL)2 39.6±8.0 39.0±6.0 52.6±1.4 42.1±7.2 52.0±1.1 54.3±10.5Phosphorus (mg/dL) 4.3±0.8 3.7±1.6 4.1±1.2 4.9±0.3 5.1±0.8 6.0±1.2Calcium (mg/dl) 8.2±0.2 8.6±0.9 4.1±1.2 8.0±1.9 9.0±0.2 9.1±0.5Parathormone (ng/mL) 198.9±10.2 450.0±110.0 400.0±90.2 235.1±10.6 225.3±90.8 311.0 Calcific uraemic arteriolopathy – A mini‑reviewNefro - 30-2 - MIOLO OK.indd   109 28/06/2016   12:29:20110    Port J Nephrol Hypert 2016; 30(2): 108-112At two years of follow -up, the patient did not show any additional complications and was alive and on chronic haemodialysis. MINI ‑REVIEWCUA is estimated to occur in 1% of patients with chronic renal failure and 4% of patients undergoing haemodialysis2-5 and is associated with a high morbidity and a mortality rate of 60% -80%, most commonly caused by infectious complications, culminating in sep-sis and organ failure.2,3Several risk factors for CUA have been suggested, such as female gender, diabetes mellitus, obesity, hyperphosphataemia, ESRD with severe secondary hyperparathyroidism and the use of warfarin or of calcium -based phosphate binders.2,3The insights into the pathogenesis of vascular calcifi-cation in CKD have changed significantly. Until recently, the process of vascular calcification was thought to be merely the result of a passive deposition of calcium--phosphate crystal.2,6 However, current evidence sug-gests it is an active and coordinated process which not only involves cellular activity with differentiation of vas-cular smooth muscle cells (VSMCs) into chondrocytes, but that it also encompasses osteoblast -like cellular phenotypes and deficiencies in calcification inhibitors. This process is initiated by the uraemic milieu, which is characterised by the presence of hyperphosphataemia, uraemic toxins and reactive oxygen species, although it is also associated with a decrease in vascular calcification inhibitor proteins.3,4Fetuin­A/α2 -Heremans Schmid glycoprotein (AHSG), a 48 -kDa protein, acts as a negative regulator of soft--tissue calcification, and it is synthetised in the liver and then secreted into circulation. AHSG acts as a sys-temic inhibitor of hydroxyapatite synthesis, and is reduced in states of renal failure, inflammation and patients with CUA.2,4,7,8Some other important inhibitors of vascular calcifica-tion are Matrix Gla protein (MGP) and Growth arrest--specific gene 6 (Gas -6), assuming special importance in patients taking vitamin K antagonists, as both are vitamin K dependent proteins (VKDPs).9MGP, which was first described in 1983 and is an 84 -amino acid protein produced by bone and VSMCs, acts as a local inhibitor of calcification.4,5,10 It binds to insoluble calcium salts preventing hydroxyapatite crys-tals growth and, by blocking osteo -inductive properties of bone morphogenic protein -2, inhibits VSMCs from differentiating into osteoblast -like phenotypes.3,5,6 Although studies by Murshed et al. have demonstrated that MGP is also produced by the liver, such hepatic production does not seem to be protective against vascular calcification.5,8 In CKD patients, MGP function appears to be impaired.9Gas -6 plays a double role. On the one hand, Gas -6, produced by platelets, promotes thrombus formation as it contributes to platelet degranulation and aggrega-tion, and on the other hand, Gas -6 produced by VSMCs, by binding the receptor Axl, stimulates the anti -apoptotic protein Bcl -2 and inhibits the proapoptotic protein cas-pase 3, which allows it to play a protective role against vascular injury.5 The exact role of Gas -6 and MGP in humans still needs further confirmation studies.Both Gas -6 and MGP share a common characteristic – they are VKDPs as they need to undergo gamma--carboxylation, a vitamin K dependent process, in order to achieve full biological activity.3,4,9Warfarin shares a common ring structure with vita-min K, interfering with vitamin K epoxide reductase (VKOR), an enzyme responsible for the reduction of the naturally oxidised form of vitamin K, which interrupts the recycling of this vitamin and ultimately the neces-sary gamma -carboxylation of VKDPs.5,8 There are two subtypes of vitamin K, vitamin K1, a plant -synthesised Figure 3Right leg with non-healing ulcers Filipa Brito Mendes, Sofia Couto Rocha, Rodica Agapii, Ana Silva, André Fragoso, Teresa Jerónimo, Ana Pimentel, Pedro L NevesNefro - 30-2 - MIOLO OK.indd   110 28/06/2016   12:29:20Port J Nephrol Hypert 2016; 30(2): 108-112    111phylloquinone, needed for hepatic carboxylation of coagulation factors which activate them and vitamin K2, a family of menaquinones which are important for the peripheral gamma -carboxylation of proteins such as MGP and Gas -6 produced and locally activated at VSMCs.7 Animal and clinical studies support the concept that hepatic and peripheral carboxylation have unique vitamin K dependence. Vitamin K2 mainly affects periph-eral carboxylation so that supplementation prevents arterial calcification while vitamin K1 mostly affects hepatic carboxylation and its supplementation does not prevent vascular calcification. Phylloquinone (vitamin K1) is found in green leafy vegetables. The exact source of vitamin K2 is controversial. Some authors claim that it comes either from enterocyte conversion of vitamin K1 or from indigenous intestinal bacteria.5 Others state fermented food, such as cheese, is the main source of menaquinones.6 Despite that, both vitamins K1 and K2 are absorbed from the small ileum and jejunum and both are affected by warfarin use.10Hepatic carboxylation for coagulation factors’ activa-tion has priority when compared to peripheral carboxy-lation of VKDPs. So, the first sign of a low functional vitamin K status is the incomplete carboxylation of extrahepatic Gla proteins, resulting in desphospho--uncarboxylated matrix Gla protein (dp -ucMGP) increase. The dp -ucMGP is inversely correlated with the amount/function of vitamin K and its levels are significantly higher in patients under VKA, among other situations. Only further studies may demonstrate its value as a risk marker for cardiovascular disease and mortality.8 According to recent data, low doses of war-farin are able to inhibit peripheral carboxylation, while they have no effect on hepatic carboxylation.5Some studies with supplementation of vitamin K have been conducted. Spronk et al. found in rodents that menaquione -4 inhibited warfarin -induced arterial cal-cification, while phylloquinone did not.8 In human stud-ies it has also been shown that menaquinone supple-mentation decreased dp -ucMGP plasma levels.6,8,9Many researchers suggest that warfarin usage may be a risk factor for the development of CUA by the inhi-bition of VKDPs. Price et al. have shown that warfarin, in doses which inhibit gamma -carboxylation of MGP, induces widespread vascular calcification in rodents and that its combination with Vitamin D–induced hyper-phosphataemia exacerbates vascular calcification in young growing rats and not in mature ones. Those cal-cifications occur more often in medium -sized vessels, sparing capillaries and veins, and predominantly involve the elastic lamellae of the media, sparing the intima. It was also reported, by Hayashi et al, that warfarin increased the risk of calciphylaxis 10 -fold.3Booth et al. have shown that subclinical vitamin K deficiency (normal coagulation studies but low con-centrations of vitamin K1) is present in almost 30% of dialysis patients, combined with elevated serum phos-phate levels. Patients with end -stage renal disease show an increased risk of vascular calcification associated with warfarin use as compared with that of the general population, which might be explained by the use of vitamin D and diminished MGP levels observed in the ESRD population.5However, these data on the role of Gas -6 and MGP have not been confirmed in human studies 5.The registry of the German section of the Interna-tional Collaborative Calciphylaxis Network (ICCN) has shown that about half of all calciphylaxis patients have been treated with vitamin K antagonists before the onset of symptoms. Furthermore, a Japanese survey among dialysis centres estimated the risk of calciphy-laxis to be 11 -fold higher in patients under warfarin as compared with those patients not under VKA treat-ment.9 However, these results may be biased by con-founding by indication due to the observational nature of these studies.Some data suggest that some patients may show an increased susceptibility to warfarin, due to genetic polymorphism in carboxylation enzymes which leads to a wide range of VKDP phenotypes, something that may explain why many people under this drug do not develop CUA.5CUA typically presents as firm painful purpuric plaques and nodules, surrounded by erythema and livedo reticularis. Skin lesions may progress to soft--tissue ulceration, necrosis and non -healing ulcera-tions.2,3 The lower extremities are involved in 90% of the cases and are the most frequent site involved, but skin lesions can occur in multiple other sites.3 Skin biopsy usually shows medial calcification and intimal hyperplasia of small and medium -sized arteries, primarily in dermal and subcutaneous tissues. Inflam-mation with endovascular fibrosis and microthrombi are usually also present.2-4 Nevertheless, the benefit of performing a skin biopsy should be weighed against the risk of profuse bleeding which is sometimes associ-ated with a poor healing in CUA.Calcific uraemic arteriolopathy – A mini‑reviewNefro - 30-2 - MIOLO OK.indd   111 28/06/2016   12:29:20112    Port J Nephrol Hypert 2016; 30(2): 108-112Several case reports and small case series have sug-gested that STS, a cations chelator, may be useful in treating calciphylaxis. However, published data has shown inconsistent results.2,3,11Nigwekar et al. studied 172 patients from North America undergoing maintenance haemodialysis who developed CUA and were treated with STS. They observed a clinical improvement in the majority of patients as well as a lower 1 -year mortality compared with historical data from patients not treated with STS.12However, there is no effective treatment to treat this disorder. Suggested treatment usually includes several distinct measures such as initiation of non--calcium -based phosphate binder, discontinuation of calcium -based phosphate binder, initiation of cinacal-cet, discontinuation of vitamin D compounds, lowering of dialysate calcium, discontinuation of warfarin, increased frequency of haemodialysis sessions, surgical parathyroidectomy, and wound care 12 However, there is no proof of benefit of any of these measures.Randomised controlled trials are needed to better understand whether warfarin increases the risk for CUA, as well as whether vitamin K2 supplementation and other interventions could be therapeutic options in order to improve the management of this devastating condition. Until that data is available from human trials, no definitive answers can be provided on the role of warfarin in CUA or on the best treatment for CUA.Disclosure of potential conflicts of interest: None declaredReferences 1.  Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R. Vascular ossification -calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis--calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol 2005, 4:4. 2.  Sowers KM, Hayden MR. Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches. Oxid Med Cell Longev 2010, 3: 109–21. 3.  Saifan C, Saad M. Warfarin -induced calciphylaxis: a case report and review of literature. Int J Gen Med 2013, 6:665. 4.  Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: A sys-tematic review. Clin J Am Soc Nephrol. 2008, 3:1139–43. 5.  Danziger J. Vitamin K -dependent proteins, warfarin, and vascular calcification. Clin J Am Soc Nephrol. 2008, 3:1504–10. 6.  Caluwé R, Vandecasteele S, Van Vlem B, Vermeer C, De Vriese AS. Vitamin K2 supple-mentation in haemodialysis patients: a randomized dose -finding study. Nephrol Dial Transplant 2014, 29:1385–90. 7.  Cadavid JC, DiVietro ML, Torres EA, Fumo P, Eiger G. Warfarin -induced pulmonary metastatic calcification and calciphylaxis in a patient with end -stage renal disease. Chest. 2011, 139:1503–6. 8.  Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft -tissue calcification. Adv Nutr 2012, 3:166–73. 9.  Ketteler M, Rothe H, Brandenburg VM, Westenfeld R. The K -factor in chronic kidney disease: biomarkers of calcification inhibition and beyond. Nephrol Dial Transplant 2014, 29:1267–70. 10. Price PA, Faus SA, Williamson MK. Warfarin -induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000, 20:317–27. 11.  Malabu UH, Manickam V, Kan G, Doherty SL, Sangla KS. Calcific uremic arteriolopathy on multimodal combination therapy: Still unmet goal. Int J Nephrol 2012; 390768, 2012 12.  Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E. Sodium Thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013,8:1162–70.Correspondence to:Filipa Brito MendesNephrology DepartmentAlgarve Hospital Centre, Faro, Portugalfilipabritomendes@gmail.comAuthors’ Contributions:Filipa Brito Mendes: manuscript writingSofia Couto Rocha: grammatical correction and abstract writingRodica Agapii, André Fragoso, Teresa Jerónimo, Ana Pimentel: clini-cal and laboratory researchAna Silva and Pedro Leão: project orientation and critical analysisFilipa Brito Mendes, Sofia Couto Rocha, Rodica Agapii, Ana Silva, André Fragoso, Teresa Jerónimo, Ana Pimentel, Pedro L NevesNefro - 30-2 - MIOLO OK.indd   112 28/06/2016   12:29:20

Calcific uraemic arteriolopathy - A mini-review

Universidade do Algarve

108    
 ABSTRACT
Calcific Uraemic Arteriolopathy (CUA) or calciphylaxis, is a thrombotic disorder of skin and subcutaneous tissue 
which typically presents with painful purpuric nodules that may progress to necrotic ulcers, and is a severe, life-
-threatening condition. CUA is an uncommon clinical entity that affects mostly haemodialysis (HD) patients. 
Although the process of vascular calcification was initially thought to be the result of a passive deposition of 
calcium -phosphate crystals, current knowledge suggests a distinct mechanism, including cellular activity with 
differentiation of vascular smooth muscle cells (VSMCs) into chondrocyte as well as osteoblast -like cellular phe-
notypes and deficiencies in calcification inhibitors. Although multiple studies suggest a potential relationship 
between warfarin and CUA, larger prospective studies are needed in order to better evaluate this association, 
and randomised controlled trials are needed to assess the benefit of distinct interventions in this setting. In this 
article the topic of CUA is reviewed based on a clinical case of a 65 -year -old man undergoing haemodialysis, who 
underwent an aortic valve replacement one year earlier, receiving a mechanical heart valve, and who has been 
under warfarin therapy since then.
Key ‑Words: Calciphylaxis, Fetuin -A, Gas -6, MGP, Vitamin K, Warfarin.
Calcific uraemic arteriolopathy – A mini‑review
Filipa Brito Mendes1, Sofia Couto Rocha2, Rodica Agapii2, Ana Silva1,3, André Fragoso1,  
Teresa Jerónimo1, Ana Pimentel1, Pedro L Neves1,3
1 Department of Nephrology, Algarve Hospital Centre, Faro, Portugal
2 Department of Internal Medicine, Algarve Hospital Centre, Portugal
3 Department of Biomedical Sciences and Medicine, Faro, Portugal
Received for publication: Dec 13, 2015
Accepted in revised form: May 16, 2016
MINI-REVIEW
Port J Nephrol Hypert 2016; 30(2): 108-112 • Advance Access publication 20 May 2016
 INTRODUCTION
Calcific Uraemic Arteriolopathy (CUA), also known 
as calciphylaxis, is a severely morbid and life -threatening 
condition. It is characterised by medial vascular calci-
fication, affecting small arterioles, and results in ischae-
mic subcutaneous necrosis with vulnerable skin 
ulcerations.1
Despite being rare, it is increasingly identified and 
reported worldwide.2
CUA usually occurs in patients with chronic kidney 
disease (CKD), mostly in advanced stages of kidney 
disease (ESRD).
We report a case of calciphylaxis occurring after 
starting warfarin therapy.
 CASE SUMMARY
We report the case of a 65 -year -old male gender 
patient with end -stage renal disease (ESRD) due to 
diabetes mellitus type 2, who had been on haemodi-
alysis for the last 6 years. The patient had a body mass 
index of 25 Kg/m2, and had recently switched to hae-
modiafiltration with a dialysate composition of 1.50 
mmol/L of calcium, 0.50 mmol/L of magnesium and 32 
mmol/L of bicarbonate. The patient underwent an 
Nefro - 30-2 - MIOLO OK.indd   108 28/06/2016   12:29:19
Port J Nephrol Hypert 2016; 30(2): 108-112    109
aortic valve replacement one year earlier, receiving a 
mechanical heart valve, and he has been under warfarin 
therapy since then. Secondary hyperparathyroidism 
was not a major problem, as the patient maintained 
serum parathormone levels in the range of 200 to 400 
pg/mL for the last few years (Table I) taking sevelamer 
1600mg/day and cinacalcet 90mg/week.
On February 2014, the patient was referred to the 
Nephrology department due to a painful violaceous 
lesion of 3 cm diameter on the dorsal region of the 
right leg.
A diagnosis of CUA was considered. The frequency 
of haemodialysis sessions was increased to 5 per week 
(4 hours x 5 /week); the dialysate’s calcium was reduced 
to 1.25 mmol/L, and warfarin was stopped and replaced 
by low molecular weight heparin (1mg/Kg/day). Sodium 
thiosulfate (STS) therapy was initiated the first day of 
hospital stay, which was one week after the onset of 
the clinical picture. The patient received STS treatment 
3 x /week at the end of dialysis session, at a 25g dose 
with no side -effects.
Mineral metabolism parameters (Table 1), calcium, 
phosphorus and parathormone levels were within 
acceptable limits. Hand and foot X -rays confirmed ecto-
pic calcifications (Fig. 1). Blood cultures were negative 
and arterial and venous eco -doppler of lower limbs 
was normal.
On the fourth day of hospital stay, a skin biopsy was 
performed and showed epidermis atrophy with focal 
necrosis as well as vascular calcifications in deep der-
mis. The biopsy, performed in the smallest lesion, had 
a proper healing.
However, despite all therapeutic measures, the skin 
lesion continued to increase in dimension while numer-
ous other identical skin lesions appeared in the region. 
The confluence of these small isolated lesions, which 
subsequently suffered necrosis and non -healing 
ulcerations (Fig. 2 and 3), led, after three months, to 
bilateral above -knee amputation. By that time, STS was 
stopped.
Figure 2
Right leg
 
Figure 1
hands with vascular calcifications
 
Table I
Patient’s mineral metabolism values
Before hospitalisation
During hospitalisation
2009 2010 2011 2012 2013
Calcium X Phosphorus (mg/dL)2 39.6±8.0 39.0±6.0 52.6±1.4 42.1±7.2 52.0±1.1 54.3±10.5
Phosphorus (mg/dL) 4.3±0.8 3.7±1.6 4.1±1.2 4.9±0.3 5.1±0.8 6.0±1.2
Calcium (mg/dl) 8.2±0.2 8.6±0.9 4.1±1.2 8.0±1.9 9.0±0.2 9.1±0.5
Parathormone (ng/mL) 198.9±10.2 450.0±110.0 400.0±90.2 235.1±10.6 225.3±90.8 311.0 
Calcific uraemic arteriolopathy – A mini‑review
Nefro - 30-2 - MIOLO OK.indd   109 28/06/2016   12:29:20
110    Port J Nephrol Hypert 2016; 30(2): 108-112
At two years of follow -up, the patient did not show 
any additional complications and was alive and on 
chronic haemodialysis.
 MINI ‑REVIEW
CUA is estimated to occur in 1% of patients with 
chronic renal failure and 4% of patients undergoing 
haemodialysis2-5 and is associated with a high morbidity 
and a mortality rate of 60% -80%, most commonly 
caused by infectious complications, culminating in sep-
sis and organ failure.2,3
Several risk factors for CUA have been suggested, 
such as female gender, diabetes mellitus, obesity, 
hyperphosphataemia, ESRD with severe secondary 
hyperparathyroidism and the use of warfarin or of 
calcium -based phosphate binders.2,3
The insights into the pathogenesis of vascular calcifi-
cation in CKD have changed significantly. Until recently, 
the process of vascular calcification was thought to be 
merely the result of a passive deposition of calcium-
-phosphate crystal.2,6 However, current evidence sug-
gests it is an active and coordinated process which not 
only involves cellular activity with differentiation of vas-
cular smooth muscle cells (VSMCs) into chondrocytes, 
but that it also encompasses osteoblast -like cellular 
phenotypes and deficiencies in calcification inhibitors. 
This process is initiated by the uraemic milieu, which is 
characterised by the presence of hyperphosphataemia, 
uraemic toxins and reactive oxygen species, although it 
is also associated with a decrease in vascular calcification 
inhibitor proteins.3,4
Fetuin­A/α2 -Heremans Schmid glycoprotein (AHSG), 
a 48 -kDa protein, acts as a negative regulator of soft-
-tissue calcification, and it is synthetised in the liver 
and then secreted into circulation. AHSG acts as a sys-
temic inhibitor of hydroxyapatite synthesis, and is 
reduced in states of renal failure, inflammation and 
patients with CUA.2,4,7,8
Some other important inhibitors of vascular calcifica-
tion are Matrix Gla protein (MGP) and Growth arrest-
-specific gene 6 (Gas -6), assuming special importance 
in patients taking vitamin K antagonists, as both are 
vitamin K dependent proteins (VKDPs).9
MGP, which was first described in 1983 and is an 
84 -amino acid protein produced by bone and VSMCs, 
acts as a local inhibitor of calcification.4,5,10 It binds to 
insoluble calcium salts preventing hydroxyapatite crys-
tals growth and, by blocking osteo -inductive properties 
of bone morphogenic protein -2, inhibits VSMCs from 
differentiating into osteoblast -like phenotypes.3,5,6 
Although studies by Murshed et al. have demonstrated 
that MGP is also produced by the liver, such hepatic 
production does not seem to be protective against 
vascular calcification.5,8 In CKD patients, MGP function 
appears to be impaired.9
Gas -6 plays a double role. On the one hand, Gas -6, 
produced by platelets, promotes thrombus formation 
as it contributes to platelet degranulation and aggrega-
tion, and on the other hand, Gas -6 produced by VSMCs, 
by binding the receptor Axl, stimulates the anti -apoptotic 
protein Bcl -2 and inhibits the proapoptotic protein cas-
pase 3, which allows it to play a protective role against 
vascular injury.5 The exact role of Gas -6 and MGP in 
humans still needs further confirmation studies.
Both Gas -6 and MGP share a common characteristic 
– they are VKDPs as they need to undergo gamma-
-carboxylation, a vitamin K dependent process, in order 
to achieve full biological activity.3,4,9
Warfarin shares a common ring structure with vita-
min K, interfering with vitamin K epoxide reductase 
(VKOR), an enzyme responsible for the reduction of the 
naturally oxidised form of vitamin K, which interrupts 
the recycling of this vitamin and ultimately the neces-
sary gamma -carboxylation of VKDPs.5,8 There are two 
subtypes of vitamin K, vitamin K1, a plant -synthesised 
Figure 3
Right leg with non-healing ulcers
 
Filipa Brito Mendes, Sofia Couto Rocha, Rodica Agapii, Ana Silva, André Fragoso, Teresa Jerónimo, Ana Pimentel, Pedro L Neves
Nefro - 30-2 - MIOLO OK.indd   110 28/06/2016   12:29:20
Port J Nephrol Hypert 2016; 30(2): 108-112    111
phylloquinone, needed for hepatic carboxylation of 
coagulation factors which activate them and vitamin 
K2, a family of menaquinones which are important for 
the peripheral gamma -carboxylation of proteins such 
as MGP and Gas -6 produced and locally activated at 
VSMCs.7 Animal and clinical studies support the concept 
that hepatic and peripheral carboxylation have unique 
vitamin K dependence. Vitamin K2 mainly affects periph-
eral carboxylation so that supplementation prevents 
arterial calcification while vitamin K1 mostly affects 
hepatic carboxylation and its supplementation does not 
prevent vascular calcification. Phylloquinone (vitamin 
K1) is found in green leafy vegetables. The exact source 
of vitamin K2 is controversial. Some authors claim that 
it comes either from enterocyte conversion of vitamin 
K1 or from indigenous intestinal bacteria.5 Others state 
fermented food, such as cheese, is the main source of 
menaquinones.6 Despite that, both vitamins K1 and K2 
are absorbed from the small ileum and jejunum and 
both are affected by warfarin use.10
Hepatic carboxylation for coagulation factors’ activa-
tion has priority when compared to peripheral carboxy-
lation of VKDPs. So, the first sign of a low functional 
vitamin K status is the incomplete carboxylation of 
extrahepatic Gla proteins, resulting in desphospho-
-uncarboxylated matrix Gla protein (dp -ucMGP) 
increase. The dp -ucMGP is inversely correlated with 
the amount/function of vitamin K and its levels are 
significantly higher in patients under VKA, among other 
situations. Only further studies may demonstrate its 
value as a risk marker for cardiovascular disease and 
mortality.8 According to recent data, low doses of war-
farin are able to inhibit peripheral carboxylation, while 
they have no effect on hepatic carboxylation.5
Some studies with supplementation of vitamin K have 
been conducted. Spronk et al. found in rodents that 
menaquione -4 inhibited warfarin -induced arterial cal-
cification, while phylloquinone did not.8 In human stud-
ies it has also been shown that menaquinone supple-
mentation decreased dp -ucMGP plasma levels.6,8,9
Many researchers suggest that warfarin usage may 
be a risk factor for the development of CUA by the inhi-
bition of VKDPs. Price et al. have shown that warfarin, 
in doses which inhibit gamma -carboxylation of MGP, 
induces widespread vascular calcification in rodents and 
that its combination with Vitamin D–induced hyper-
phosphataemia exacerbates vascular calcification in 
young growing rats and not in mature ones. Those cal-
cifications occur more often in medium -sized vessels, 
sparing capillaries and veins, and predominantly involve 
the elastic lamellae of the media, sparing the intima. It 
was also reported, by Hayashi et al, that warfarin 
increased the risk of calciphylaxis 10 -fold.3
Booth et al. have shown that subclinical vitamin K 
deficiency (normal coagulation studies but low con-
centrations of vitamin K1) is present in almost 30% of 
dialysis patients, combined with elevated serum phos-
phate levels. Patients with end -stage renal disease show 
an increased risk of vascular calcification associated 
with warfarin use as compared with that of the general 
population, which might be explained by the use of 
vitamin D and diminished MGP levels observed in the 
ESRD population.5
However, these data on the role of Gas -6 and MGP 
have not been confirmed in human studies 5.
The registry of the German section of the Interna-
tional Collaborative Calciphylaxis Network (ICCN) has 
shown that about half of all calciphylaxis patients have 
been treated with vitamin K antagonists before the 
onset of symptoms. Furthermore, a Japanese survey 
among dialysis centres estimated the risk of calciphy-
laxis to be 11 -fold higher in patients under warfarin as 
compared with those patients not under VKA treat-
ment.9 However, these results may be biased by con-
founding by indication due to the observational nature 
of these studies.
Some data suggest that some patients may show an 
increased susceptibility to warfarin, due to genetic 
polymorphism in carboxylation enzymes which leads 
to a wide range of VKDP phenotypes, something that 
may explain why many people under this drug do not 
develop CUA.5
CUA typically presents as firm painful purpuric 
plaques and nodules, surrounded by erythema and 
livedo reticularis. Skin lesions may progress to soft-
-tissue ulceration, necrosis and non -healing ulcera-
tions.2,3 The lower extremities are involved in 90% of 
the cases and are the most frequent site involved, but 
skin lesions can occur in multiple other sites.3
 Skin biopsy usually shows medial calcification and 
intimal hyperplasia of small and medium -sized arteries, 
primarily in dermal and subcutaneous tissues. Inflam-
mation with endovascular fibrosis and microthrombi 
are usually also present.2-4 Nevertheless, the benefit 
of performing a skin biopsy should be weighed against 
the risk of profuse bleeding which is sometimes associ-
ated with a poor healing in CUA.
Calcific uraemic arteriolopathy – A mini‑review
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112    Port J Nephrol Hypert 2016; 30(2): 108-112
Several case reports and small case series have sug-
gested that STS, a cations chelator, may be useful in 
treating calciphylaxis. However, published data has 
shown inconsistent results.2,3,11
Nigwekar et al. studied 172 patients from North 
America undergoing maintenance haemodialysis who 
developed CUA and were treated with STS. They 
observed a clinical improvement in the majority of 
patients as well as a lower 1 -year mortality compared 
with historical data from patients not treated with 
STS.12
However, there is no effective treatment to treat 
this disorder. Suggested treatment usually includes 
several distinct measures such as initiation of non-
-calcium -based phosphate binder, discontinuation of 
calcium -based phosphate binder, initiation of cinacal-
cet, discontinuation of vitamin D compounds, lowering 
of dialysate calcium, discontinuation of warfarin, 
increased frequency of haemodialysis sessions, surgical 
parathyroidectomy, and wound care 12 However, there 
is no proof of benefit of any of these measures.
Randomised controlled trials are needed to better 
understand whether warfarin increases the risk for CUA, 
as well as whether vitamin K2 supplementation and 
other interventions could be therapeutic options in 
order to improve the management of this devastating 
condition. Until that data is available from human trials, 
no definitive answers can be provided on the role of 
warfarin in CUA or on the best treatment for CUA.
Disclosure of potential conflicts of interest: None declared
References
 1.  Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R. Vascular ossification -calcification in 
metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-
-calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc 
Diabetol 2005, 4:4.
 2.  Sowers KM, Hayden MR. Calcific uremic arteriolopathy: pathophysiology, reactive oxygen 
species and therapeutic approaches. Oxid Med Cell Longev 2010, 3: 109–21.
 3.  Saifan C, Saad M. Warfarin -induced calciphylaxis: a case report and review of literature. 
Int J Gen Med 2013, 6:665.
 4.  Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: A sys-
tematic review. Clin J Am Soc Nephrol. 2008, 3:1139–43.
 5.  Danziger J. Vitamin K -dependent proteins, warfarin, and vascular calcification. Clin J Am 
Soc Nephrol. 2008, 3:1504–10.
 6.  Caluwé R, Vandecasteele S, Van Vlem B, Vermeer C, De Vriese AS. Vitamin K2 supple-
mentation in haemodialysis patients: a randomized dose -finding study. Nephrol Dial 
Transplant 2014, 29:1385–90.
 7.  Cadavid JC, DiVietro ML, Torres EA, Fumo P, Eiger G. Warfarin -induced pulmonary 
metastatic calcification and calciphylaxis in a patient with end -stage renal disease. Chest. 
2011, 139:1503–6.
 8.  Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft -tissue calcification. Adv 
Nutr 2012, 3:166–73.
 9.  Ketteler M, Rothe H, Brandenburg VM, Westenfeld R. The K -factor in chronic kidney 
disease: biomarkers of calcification inhibition and beyond. Nephrol Dial Transplant 2014, 
29:1267–70.
 10. Price PA, Faus SA, Williamson MK. Warfarin -induced artery calcification is accelerated 
by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000, 20:317–27.
 11.  Malabu UH, Manickam V, Kan G, Doherty SL, Sangla KS. Calcific uremic arteriolopathy 
on multimodal combination therapy: Still unmet goal. Int J Nephrol 2012; 390768, 2012
 12.  Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E. Sodium Thiosulfate 
therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013,8:1162–70.
Correspondence to:
Filipa Brito Mendes
Nephrology Department
Algarve Hospital Centre, Faro, Portugal
filipabritomendes@gmail.com
Authors’ Contributions:
Filipa Brito Mendes: manuscript writing
Sofia Couto Rocha: grammatical correction and abstract writing
Rodica Agapii, André Fragoso, Teresa Jerónimo, Ana Pimentel: clini-
cal and laboratory research
Ana Silva and Pedro Leão: project orientation and critical analysis
Filipa Brito Mendes, Sofia Couto Rocha, Rodica Agapii, Ana Silva, André Fragoso, Teresa Jerónimo, Ana Pimentel, Pedro L Neves
Nefro - 30-2 - MIOLO OK.indd   112 28/06/2016   12:29:20


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Calcific uraemic arteriolopathy - A mini-review

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