Baylor University Medical Center Proceedings July 2017 - 370

Invited Commentary
Calcinosis cutis and renal disease: an evolving story
Calcinosis cutis is a term used to describe a group of disorders where there is deposition of insoluble calcium salts in
the cutaneous and subcutaneous tissues. These calcium salts
consist primarily of hydroxyapatite crystals or amorphous calcium phosphate. Even though this clinical entity was initially
described by Virchow in 1855 (1), the exact pathogenesis is not
completely understood, and likely multiple factors play a role
in diﬀerent patients.
Until recently, four main types of calcinosis cutis have been
recognized according to etiology: dystrophic, metastatic, iatrogenic, and idiopathic. However, a ﬁfth subtype is now usually
included: calciphylaxis, which some authorities prefer to call
calciﬁc uremic arteriolopathy (CUA) (2). Over the last 10 years,
there has been a marked increase in the incidence of CUA in
the end-stage renal disease population. The 1-year mortality of
these patients ranges from 40% in those with nonulcerated skin
lesions to as high as 80% in those with ulcerated and necrotic
lesions at presentation (3). The severe morbidity and mortality
of this clinical entity has fueled active investigation into the
pathogenesis of this devastating condition.
In the current issue of BUMC Proceedings, Jaeger and her
colleagues describe a young man with stage 5 chronic kidney
disease who presents with severe metastatic calcinosis cutis (4).
This case illustrates a number of important issues that merit
further discussion.
It is safe to assume that this patient has suﬀered progressive
chronic kidney disease (CKD) for many years. This is based on
his history of focal segmental glomerulosclerosis, a pathologic
diagnosis made only by a renal biopsy (which he presumably
had in the past) and a disease process that usually progresses
relatively slowly over many years, associated with hypertension
and a slow decline of renal function. In addition, he had a
congenitally solitary kidney and hence may have had reduced
total nephron mass from birth, further predisposing him to the
development of CKD. It is then fair to ask the question: What
is the presumed pathophysiology of his calcinosis cutis?
Phosphorus is ubiquitous in our diet, but unlike calcium,
its intestinal absorption is poorly regulated. As renal excretory
capacity diminishes, a complex series of events involving a
reduction in renal mass and an increase in serum phosphorus
and ﬁbroblast growth factor 23 results in less 1,25-dihydroxyvitamin D3 and a consequent reduction in intestinal phosphorus and calcium absorption (5). The fall in serum calcium
triggers an increase in parathyroid hormone (PTH), leading to
the release of phosphorus and calcium from bone. Both PTH
and ﬁbroblast growth factor 23 are phosphaturic hormones
and enhance the fractional excretion of phosphorus. Initially, as
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renal function declines, the increase in these hormones results
in the maintenance of normal phosphorus levels, but further
falls in glomerular ﬁltration rate result in quantitatively less
phosphorus excretion than absorption (5). After any osseous
needs are met, the retained phosphorus must be deposited in
nonbone sites, often complexed with calcium. Accordingly,
calciﬁcation in soft tissues is the inevitable consequence of more
phosphorus being absorbed than excreted (5). The presentation
of this young man with profound soft tissue calciﬁcations is,
however, signiﬁcantly more severe than we usually see clinically.
This may be due to multiple factors, including not taking a
phosphate binder, poor metabolic control, and the profound
elevation of his PTH.
At this point, it is important to distinguish primary
hyperparathyroidism from other forms of increased parathyroid
activity. Primary hyperparathyroidism is a disorder of the parathyroid gland(s), in which there is incompletely regulated, excessive secretion of PTH usually due to a single adenoma, or
rarely to an adenocarcinoma in one or more glands. By contrast,
in secondary or tertiary hyperparathyroidism, the glands in
question respond normally to a physiologic stimulus, such as
hypocalcemia and/or hyperphosphatemia, like in CKD. In most
cases of secondary hyperparathyroidism, the excessive secretion
of PTH can be blocked or signiﬁcantly blunted by controlling
phosphorus levels, say with the dietary binding of phosphorus,
hence leading to a more neutral balance. Tertiary hyperparathyroidism is characterized by the semiautonomous hypersecretion of PTH, often leading to hypercalcemia. Accordingly,
this pathologic entity is much harder to treat medically and
often requires surgical removal of most of the severely enlarged
glands that do not respond to usual physiologic feedback. The
increase in gland size in this condition is primarily due to diffuse cellular hyperplasia, but there is also monoclonal chief cell
growth, resulting in the formation of nodules (6). Indeed, in
the patient described in the case report, the serum calcium on
presentation was "abnormally" normal at 9.7 mg/dL, with a
markedly elevated phosphorus level of 10.6 mg/dL. It is notable
that the calcium phosphorus product was over 102, markedly
elevated, and at a level where metastatic calciﬁcations are more
likely to occur. The patient required a surgical subtotal parathyroidectomy even after the initiation of appropriate medical
therapy and the starting of hemodialysis, all of which surely
helped lower his serum phosphorus level. This attests to the
autonomous nature of PTH secretion in these patients and the
expected poor response to maximal medical therapy (6).
It is also worth noting that the patient was evaluated in an
emergency department setting prior to his hospitalization, and
Proc (Bayl Univ Med Cent) 2017;30(3):370-371

Table of Contents for the Digital Edition of Baylor University Medical Center Proceedings July 2017