In the NEWS: A new paradigm in calciphylaxis

A recent small report from the MGH group found that apixaban can be used in ESRD HD patients with calciphylaxis who require anticoagulation.  It is well know that warfarin is a risk factor for calciphylaxis. Most of the patients on HD that require anticoagulation are on warfarin. Given the risk of calciphylaxis, the concept of changing over to a factor Xa inhibitor was used in this study to see if that be used for replacement of warfarin.  It was a retrospective study at a single center and they found 20 patients who were on dialysis who were on apixaban following a diagnosis of calciphylaxis.  27% of the drug is renally excreted and hence not a bad choice for an ESRD patient. 

There are although no trials of this agent on ESRD on dialysis and specifically not in calciphylaxis patients. A large retrospective trial did show that use of apixaban compared to warfarin was associated with less bleeding in ESRD patients and less stroke risk and mortality with 5mg BID dosing.

While the study really highlighted that the switch from warfarin to apixaban  was ok and there were no significant bleeding and clotting episodes, there were some additional surprise findings. What was surprising to me was that the majority of the patient got better with their calciphylaxis part. The cohort that got apixiban had a lower mortality compared to the established published rates of patients with calciphylaxis not on apixiban.

Have the investigators just stumbled upon a potential treatment for this deadly disease? Given calciphylaxis has a component of TMA and having them on an anticoagulant that doesn’t inhibit vitamin K might be beneficial.  The question remains that would you start apixiban in someone with calciphylaxis who was not on anticoagulation?

Topic Discussion: Non-nephrogenic calciphylaxis

Calciphylaxis in Patients With Normal Renal Function is usually unusual as most of the cases we encounter as nephrologists are in ESRD and or CKD patients

A recent review and literature update by the MGH researchers defined concomitant risk factors, treatment, and outcomes for patients with nonnephrogenic calciphylaxis.

116 patients today were reviewed.  Vitamin K antagonism and obesity were the most common concomitant factors. In the literature review, lower age and higher body mass index  were associated with the central location of lesions, whereas vitamin K antagonism was associated with the peripheral locations.  None of the treatments were associated with lesion improvement or survival.

As summarized by the authors: the risk factors are the 4Ws:- Warfarin, White race, Women and overWeight in patients with normal renal function. Interesting that warfarin is a risk factor in both renal and non renal calciphylaxis. It’s perhaps about time the renal community embrace apixaban over warfarin

A larger set of risk factors exists that were mentioned in the recent NEJM review in 2018 that also add: ESRD( what we see), hypercalcemia( probably in setting of CKD as pure – not really evident), DMII, hyperparathyroidism( we have seen this), Vitamin K deficiency, Autoimmune disorders, metastatic cancers, rapid weight loss, skin trauma to name a few.

Check out this interesting tweetorial from ISN education on this topic

Topic Discussion: Non uremic causes of calciphylaxis

Calciphylaxis, or calcific uremic arteriolopathy(CUA), is a well-described entity in end-stage kidney disease and renal transplant patients; however, little systematic information is available on calciphylaxis from nonuremic causes.

A review I found in CJASN from 2008 discusses non renal causes of CUA.

Besides renal disease, the non uremic( CKD and ESRD) causes are: the top 4 being the most cases of. The remaining were just 1-2 case reports.  Most of these patients listed below had normal renal function, over 50% had normal calcium and >60% had normal phosphorus levels and 50% had low or normal pth levels. One most keep these causes in mind when ESRD or CKD does not explain the cause of CUA.

Primary hyperparathyroidism
Malignancy( Classically breast, melanoma, gall bladder, myeloma)
Alcoholic liver disease
Connective tissue diseases
Chemo induced protein C and S deficiency
Crohn’s disease
Vitamin D deficiency
POEMS syndrome
Diabetes

CONSULT ROUNDS: Calciphylaxis Treatment Options

A Pathophysiology based treatment strategy has been suggested:
1. High bone turnover/ high pth levels:- Therapy that works is cinacalcet, Vitamin D analogs, non calcium based phosphate binders, bisphosphanates, and perhaps surgical parathyroidectomy
2. high calcium phos product:- tight control with daily dialysis, avoiding calcium based binders, low Ca dialysate
3. Extracellular matrix associated soft tissue or vascular calcium deposition effects:- sodium thiosulfate enhances calcium solubility, bisphosphanates via multiple ligand pathways
4. Hypercoagulability mechanism:- avoid warfarin, change to non warfarin based agent, hyperbaric oxygen for wound healing
5. Tissue ischemia mechanism:- hyperbaric oxygen, optimize anemia, sodium thiosulfate
6. Macrophage activation:- avoid biopsies if possible.


Traditionally above treatments have always been mentioned
Bisphosphanates have now started coming into the literature to be used in this disease entity.

1. Mechanism might be calcium mediated and control of high bone absorption
2. Independent effet on bone and tissue calcification via NF-B pathways and RANKL
3. Inhibition of phosphate transport and calcium phosphate crystal formation
4. Anti inflammatory effects towards macrophages and TNF and interleukins


When to use them?
1. No clinical improvement with above mentioned common therapies
2. Failed 2 weeks of sodium thiosulfate as well
3. Usually use Pamidronate 30mg IV ( 5 doses over 48 days) or Aldentronate 35mg weekly
4. Successful treatment has been described in the literature.


Check out the original references:


http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ArtikelNr=332221&Ausgabe=255569&ProduktNr=223979&filename=332221.pdf

http://www.ncbi.nlm.nih.gov/pubmed/18070019
http://www.ncbi.nlm.nih.gov/pubmed/18021849
http://www.ncbi.nlm.nih.gov/pubmed/15252173