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Calciphylaxis or vascular oxalosis?

Abstract We report the case of a 31-year-old female with primary hyperoxaluria type 1 with end-stage kidney disease who developed severe peripheral vascular disease leading to limb amputation initially thought to be secondary to calciphylaxis. However, polarized review of the pathologic specimen revealed calcium oxalate deposition in the lumen of blood vessels. This unusual presentation of systemic oxalosis demonstrates the adverse consequences of elevations of serum oxalate in patients with hyperoxaluria and that levels can acutely worsen with abrupt onset of kidney failure.


BACKGROUND
Primary hyperoxaluria (PH) is a rare autosomal recessive disorder of oxalate overproduction due to genetic defects in enzymes critical in the metabolism of oxalate in the liver. PH type 1 (PH-1), the most severe type, is caused by the deficiency of the liverspecific peroxisomal enzyme alanine-glyoxylate aminotransferase (AGXT) [1]. Clinical presentation ranges from infantile nephrocalcinosis and failure to thrive secondary to renal dysfunction to recurrent nephrolithiasis in adulthood. Oxalosis is the term describing the deposition of calcium oxalate crystals in multiple tissues with resulting damage.

CASE REPORT
A 31-year-old white female presented in infancy with nephrocalcinosis, hyperoxaluria and kidney failure. She carried a presumed diagnosis of PH but genetic testing was not done. She underwent two kidney transplants, the first from her father at 15 months of age, with subsequent failure due to severe cytomegalovirus infection. She restarted dialysis and had a second transplant from her mother at 23 months of age. She did well until she became pregnant at the age of 31 years and self-discontinued her immunosuppression, leading to the rapid onset of end-stage kidney disease (ESKD) requiring hemodialysis (HD) thrice weekly. Shortly after dialysis initiation, she presented with acute lower extremity deep vein thrombosis (DVT) and a negative workup for clotting disorders and was treated with warfarin. A few months later she developed nonhealing wounds on both lower extremities that were felt to be calciphylaxis exacerbated by warfarin, a known risk factor for calciphylaxis [2]. Due to the severe peripheral vascular disease and the worsening ulcerated lesions, the patient underwent a right below the knee amputation and left transmetatarsal amputation.
She was then evaluated for a kidney transplant and genetic testing was done, revealing type I PH with two AGXT gene mutations: c.33dupC and Gly170Arg type I (courtesy of the Rare Kidney Stone Consortium). The histology collected from tissue at the time of amputation was retrieved and revealed heavy deposition of calcium oxalate crystals in the medial layer of arteries ( Figure 1), demonstrating the etiologies of the vascular occlusions and amputations were likely due to widespread oxalate deposition from acute rejection/kidney failure in a setting of PH-1. The patient was listed for a combined kidney-liver transplant and underwent HD six times per week to optimize oxalate removal. Pyridoxine was added to her treatment regimen since it has been found that patients with PH-1 with the Received: 4.11.2019; Editorial decision: 9.12.2019 V C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Gly170Arg and Phe152Ile gene mutations are highly responsive to pyridoxine supplementation, which is a cofactor to the AGXT enzyme, leading to a significant reduction of urinary oxalate levels [1,3]. The liver-kidney transplant was done and she is doing well 5 years posttransplant.

DISCUSSION
Our patient had an unusual presentation of vascular oxalosis mimicking calciphylaxis, thought to be precipitated from warfarin administered for a DVT. Vascular oxalosis is extremely rare in PH, with only a few case reports (Table 1). Table 2 compares the histologic characteristics of vascular oxalosis with those of calciphylaxis. It is important to note that routine staining for calcium deposition with alizarin red or silver stain on biopsy would demonstrate medial calcification in both disease states; visualization under polarized light is needed to differentiate the crystal type and the etiology. Systemic deposition of calcium oxalate occurs in every organ and begins once the saturation point of plasma oxalate is reached. Urine is the primary route of oxalate clearance and thus the saturation is accelerated in patients with chronic kidney disease. In patients with PH-1 and ESKD, oxalate levels remain supersaturated despite aggressive HD, leaving patients at high risk of progressive systemic oxalosis [4]. Unfortunately, thrice-weekly HD and even peritoneal dialysis are unable to alleviate the burden of excess oxalate production; weekly oxalate elimination with either modality equals only 2-3 days of oxalate production [5]. Therefore the ultimate treatment in PH-1 to limit the progression of systemic oxalosis is combined liver-kidney transplantation coupled with daily HD to maximize the dialytic clearance of oxalate postoperatively.
In summary, vascular presentations in patients with hyperoxaluria, especially those with impaired renal function limiting excretion, should be biopsied to determine the diagnosis.