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: Diagnosis of Pheochromocytoma in a Dialysis patient

Dialysis patients have ups and downs of blood pressure and a diagnosis of pheochromocytoma(PH) is always challenging. Screening for PH is always a tough challenge in non CKD/ESRD patients. It is even more challenging in ESRD patients. Many medications can interfere with measurements of catecholamine levels. Tricyclic antidepressants interfere most frequently with the interpretation of plasma fractionated metanephrines and 24-hour urinary catecholamines and metabolites.  Most of these should be tapered and discontinued at least two weeks before any hormonal assessments. 

In general, the approach to diagnosis is initial biochemical testing based upon the index of suspicion that the patient has a PH. If there is a low index of suspicion, a 24-hour urinary fractionated catecholamines and metanephrines; if there is a high index of suspicion, a plasma metanephrine level should be done. The endocrine society clinical practice guideline suggests initial biochemical testing using 24-hour urinary fractionated metanephrines or plasma fractionated metanephrines (drawn supine with an indwelling cannula for 30 minutes). However, many times the measurement of plasma fractionated metanephrines is not done under these conditions, and the test is associated with a high false-positive rate.

Biochemical tests in renal disease might not be valid. In patients without PH who are receiving dialysis, plasma norepinephrine and dopamine concentrations are increased threefold and twofold above the upper limit of normal, respectively. When patients with CKD have plasma norepinephrine concentrations more than threefold above the upper normal limit or epinephrine concentrations greater than the upper normal limit, PH should be suspected. It is hard to distinguish PH just with plasma metanephrines in ESRD and CKD patients. Studies done have shown mixed results. Most ESRD patients are anuric and hence urinary studies are not available. A new biomarker has been recently discovered in the world of PH- Plasma methoxytyramine. This is still not used in routine practice and data on ESRD-CKD is not available to my knowledge. 

What about the imaging studies?

CT dedicated to the adrenals or MRI of the abdomen and pelvis is usually performed first. Either test is a reasonable first test as both detect almost all sporadic symptomatic tumors because most are 3 cm or larger in diameter. If abdominal and pelvic CT or MRI is negative in the presence of clinical and biochemical evidence of PH, think of a perhaps a different diagnosis. If it is still considered likely, then iodine-123 (123-I) iobenguane (also known as metaiodobenzylguanidine [MIBG]) scintigraphy may be done. MIBG is a compound resembling norepinephrine that is taken up by adrenergic tissue. Normal adrenal glands take up MIBG, and the uptake may be asymmetric. One prior paper showed perhaps a false positive scan in ESRD. No newer studies have shown this. No specific studies have looked at MIBG scans in ESRD patients except one case series from Japan.

Finally, FDG-PET scan is more sensitive than 123-I MIBG and CT/MRI for detection of metastatic disease. A scan called 68-Ga DOTATATE PET — Gallium 68 (68-Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE)-positron emission tomography (68-Ga DOTATATE PET) is proving to be more sensitive in some patients than 123-I MIBG, CT/MRI, or FDG-PET for detection of metastatic disease. 

So what does one do finally for a CKD-ESRD patient?

If the plasma metanephrines are threefold the upper limit of normal and there is an abnormal CT scan or MRI localizing a lesion in one of the adrenals( depending on contrast load), a MIBG scan is reasonable. If that is positive, there is a good chance that it is a PH. Surgery decision should not be based solely on MIBG scan alone. A PET scan or a TATE scan might be required to confirm the diagnosis in the grey zone of CKD-ESRD and diagnosis of a PH.

Concept Map: Kidney Diseases with Waldenstrom's Macroglobulinemia

This is a figure that was created for one of our manuscript's in NDT using a concept map model
** Refers to those diseases that might not be truly caused by WM but might have been a coincidence.
*Others include proliferative GN and immunotactoid GN
LHCDD stands for light/heavy chain deposition diseases
TMA is thrombotic microangiopathy