448
Nephrol Dial Transplant (2001) 16: Editorial Comments
Nephrol Dial Transplant (2001) 16: 448±451
The evolving pattern of calciphylaxis: therapeutic considerations
Francisco Llach
Nephrology Division, Newark Beth Israel Medical Center, Newark, NJ 07112, USA
Keywords: hyperparathyroidism; calcium load; hyperphosphataemia; phosphorous; uraemia
Introduction
The syndrome of calciphylaxis has evolved over the
last three decades. In 1962, Selye ®rst described a syndrome in the experimental animal w1x and postulated
that two steps are required to produce ectopic systemic
calci®cation. First, a systemic sensitization induced by
agents such as parathyroid hormone (PTH), vitamin D
or a diet high in calcium (Ca) and phosphorus (P).
Correspondence and offprint requests to: Francisco Llach, MD,
Newark Beth Israel Medical Center, 201 Lyons Avenue, Newark,
NJ 07112, USA.
#
Secondly after a time interval (the `critical period')
exposure to appropriate challenging agents by subcutaneous injection which results in macroscopically
visible deposits of calcium salts (hydroxapatite) systemically and at the site of injection within 2 to 3 days. The
challenging agents include local trauma, iron salt, egg
albumin, polymycin and glucocorticoids. Selye named
the syndrome calciphylaxis. A few years later a syndrome characterized by peripheral ischaemic tissular
necrosis, vascular calci®cations and cutaneous ulcerations was reported in uraemic patients, and because of
its resemblance to Selye's animal model, it was also
named calciphylaxis w2±3x. However, the syndrome
described in the uraemic patients only resembles
Selye's model. Though a useful concept, the analogy
with Selye's model may not be warranted, since the
term calciphylaxis has pathogenic implications that
have not been con®rmed in humans. Thus, signi®cant differences exist between Selye's model and
2001 European Renal Association±European Dialysis and Transplant Association
Nephrol Dial Transplant (2001) 16: Editorial Comments
calciphylaxis in uraemia. The former is characterized
by metastatic systemic calci®cations developing after
signi®cant invasive manipulations of the animal model,
but vascular calci®cations are not present. The latter
occurs primarily in the presence of uraemia with
abnormalities in divalent ions, i.e. high plasma PTH,
hypercalcaemia and hyperphosphataemia and, most
importantly, small vessel calci®cations are noted at the
site of lesions.
Retrospectively, it appears now that the syndrome
that is most analogous to Selye's is that of uraemic soft
tissue calci®cations. Seyle's model did not exhibit the
histology consistently described with uraemic calciphylaxis, i.e. small vessel calci®cations and intimal
hypertrophy in association with panniculitis and small
vessel thrombosis w2x.
As more cases with uraemic calciphylaxis have been
described over the last two decades, it is becoming
inappropriate to use the term calciphylaxis. It is
misleading, since in many instances abnormalities in
plasma Ca, P or PTH are absent. A more appropriate
term, as suggested by Coates et al. w4x, is calci®c
uraemic arteriolopathy (CUA).
The ®rst description of CUA were made in the late
1960's and early 1970's, as a syndrome characterized
by cutaneous eruptions usually occurring in patients
on dialysis or after renal transplantation w5±6x. The
skin lesions often presented as areas of painful
mottling, resembling livedo reticularis with super®cial
violaceous nodules involving the tip of the toes or
®ngers, or occurring at the ankles, thighs or buttocks.
As the lesions progress, they become haemorrhagic
with ischaemic `dry' necrosis. The bilateral symmetry,
super®cial nature of these lesions and persistence of
palpable pulses distal to the necrosis are characteristic
®ndings (Figure 1). As the lesions progress cutaneous
necrosis ensues as well as the development of ischaemic
digital pain and in many cases gangrene of the digits.
At that time, biopsy of the skin nodules show calcium
deposits within small arteris (30±600 mm, average
100 mm) in the vessel walls. This is associated with
lobular fat necrosis, calci®cations and an in®ltrate
of neutrophils, lymphocytes and macrophages. In the
early reports, the lesions were located distally in the
extremities and there was clinically signi®cant hyperparathyroid bone disease w6x. A link between CUA
and hyperparathyroidism (HPT) was further supported by the early observations that parathyroidectomy (PTx) dramatically improved the syndrome
w6±7x. Thus, ulcerations that had persisted for
months healed dramatically within weeks after PTx w6x.
Later, PTx performed in other patients did not result
in improvement of the patient and aggravated the
condition further, leading to a high mobility and
mortality w8x.
Therefore, the pathogenesis of CUA remains
unclear. This has to a great extent been due to the
lack of an experimental animal model. It is worth
emphasizing that even in those early days, at a time
when secondary HPT was common, CUA was
449
Fig. 1. Bilateral cutaneous necrosis in a uraemic patient with calci®c
uraemic arteriolopathy (CUA) and high circulating PTH levels.
Note the bilateral location of the lesions.
uncommon. Paradoxically, in the last 15 years, as HPT
has been better treated, the incidence of CUA
has signi®cantly increased. It may not be a coincidence
that it occurred together with cessation of aluminiumcontaining P binders and the wide usage of large
amounts of Ca-containing phosphate binders. It may
be that Ca toxicity plays an important role. Thus, the
Ca content in the skin has been noted to be high in
dialysis patients w9x. In addition, while a high Ca
dialysate was noted to aggravate CUA w10x, a decrease
in dialysate Ca dramatically improved CUA in some
patients w9x. Furthermore, a high dose of CaCO3
was associated with CUA, which was reversible with
cessation of CaCO3 w11x.
It is apparent that this syndrome has evolved and
changed over the last few years. The presence of
obesity, especially in Caucasian females, has been
noted to be an important predisposing factor to
develop CUA w4,12x. Supposedly, the areas rich in
adipose tissue may be more prone to damage of the
small vessels, thus promoting calci®cations before the
cutaneous lesions and necrosis of the skin become
clinically apparent. Obese patients usually develop
CUA proximally in the abdomen, buttocks and
thighs, presenting as deeply seated painful nodules,
in contrast the more distal super®cial lesions noted
450
earlier in patients with high PTH levels (acral CUA).
Furthermore, a low serum albumin together with
a relatively low PTH in the obese dialysis patient
is predictive of CUA w12x. Others have noted an
association with insulin-dependent diabetes mellitus
and CUA w13x. Of special interest is the observation
that in four patients the lesions developed in areas that
had previously been the site of insulin injections w13x.
Local trauma such as subcutaneous injections of
heparin or iron dextran may also be precipitating
factors in the local development of CUA w13±14x.
Finally, protracted hyperphosphataemia still remains
an important predisposing factor. It has become more
so in the patient with adynamic bone lesion, and in
the parathyroidectomized patient. In these patients
successful strict control of the hyperphosphataemia has
been shown to reverse CUA w6,15,16x. Obese patients
with proximal CUA have a poorer prognosis than
those with acral CUA w17±19x.
Therapeutic considerations
The prognosis of patients with CUA is poor. Most of
them die of sepsis and ischaemic events. Since we do
not have a clear understanding of the pathogenesis,
treatment of this syndrome is extremely dif®cult. The
®rst step is normalization of the Ca 3 P product.
Hyperphosphataemia, as mentioned above, should be
strictly controlled. Thus dietary compliance, use of
appropriate phosphate binders and adequate dialytic
treatment are mandatory. The use of Ca-containing
phosphate binders should be avoided, since ingestion
of large amounts of Ca can trigger CUA w11x. In our
Nephrol Dial Transplant (2001) 16: Editorial Comments
experience, emphasis should be placed on using a low
dialysate Ca. We have evaluated 17 patients with CUA
over the last 5 years w20x. In eight patients we used a
zero Ca dialysate for at least 8±12 weeks; in addition,
patients were dialyzed 5±6 days a week. The rationale
behind this approach was to induce hypocalcaemia and
establish a Ca gradient favouring a shift of Ca from
soft tissue to intravascular space. Figure 2 displays
a decrease in serum Ca during a 4-h dialysis with a zero
Ca dialysate and a dramatic increase in serum Ca 3 h
post-dialysis in a patient with CUA. It can be noted
that serum Ca decreased from 9.7 mgudl (pre-dialysis)
to 6.7 mgudl (post-dialysis), and 3 h later it increased
again to 9.9 mgudl. These changes suggest a shift of Ca
from the intracellular space, most likely skin and soft
tissue, to the intravascular space. These changes were
noted with each dialysis over the ensuing 8- to 12-week
period. Symptoms related to dialysis-induced hypocalcaemia did not develop, most likely re¯ecting the
continuous shift of Ca from tissue ameliorating the
hypocalcaemia. In addition to the zero Ca dialysis,
Ca-containing phosphate binders were discontinued
and hyperphosphataemia was managed with Renagel.
Six of the eight patients had a dramatic improvement
of skin lesions, and in four there was total healing of
the lesions. A second important therapeutic step is
aggressive wound care with debridement of necrotic
tissue and systemic antibiotic therapy, since sepsis is
the major cause of mortality. Thirdly, PTx should be
performed only in those cases with signi®cantly
elevated plasma PTH levels. Early reports recommending PTx described mostly patients with severe HPT w6x.
Later, PTx was not successful in many patients w8,18x.
Thus, Chan et al. reviewed 47 cases with CUA and
noted that the survival rate of patients who underwent
Fig. 2. Serum Ca concentration in a patient with calciphylaxis during and after dialysis with zero Ca dialysate. Note the rebound in serum Ca
in the post-dialysis period.
Nephrol Dial Transplant (2001) 16: Editorial Comments
PTx was similar to those who did not w19x. Not only
did patients with low PTH levels develop CUA which
failed to respond to PTx, but CUA has also been
described with increasing frequency in patients after
PTx. Thus, the available data strongly suggest that
PTx should not be performed in patients with low
PTH. Budisavijevic et al. reviewed 47 patients with
CUA, of whom 31 patients had PTx performed after
the development of CUA w17x. Fifty percent of these
patients died within a median period of 9 weeks after
PTx w17x.
Finally, factors triggering CUA should be minimized. Thus, local injections into adipose areas where
the lesions usually develop should be avoided
whenever possible. Potential factors triggering CUA
such as blood products, corticosteroids and immunosuppressants should be avoided. Hyperbaric oxygen
therapy has improved CUA in one CAPD patient w21x.
In summary, CUA is a relatively rare, but lifethreatening complication in uraemic patients. Its
frequency seems to have increased over the last 15
years. The overall clinical picture of this syndrome has
gradually evolved as our therapeutic approach has
changed. In this regard certain points should be
made: ®rst, the term calciphylaxis does not describe
this syndrome adequately, since it resembles only
remotely Seyle's syndrome of calciphylaxis. It may be
advisable to use another term such as Calci®c Uraemic
Arteriolopathy. Secondly, at present the classic divalent ion abnormalities such as overt hypercalcaemia
or hyperphosphataemia as well as high PTH are not
common; thus, parathyroidectomy is rarely indicated
unless PTH levels are signi®cantly elevated. Thirdly,
other causes predisposing to CUA should be considered. They include obesity, mild hyperphosphataemia and an increased calcium load. Fourthly, in the
future prevention is indicated to minimize predisposing systemic and local factors, especially in the
obese patient.
References
1. Seyle H. Calciphylaxis. University of Chicago Press, Chicago,
1962
2. Anderson DC, Stewart WK, Pierce DM. Calcifying panniculitis
with fat and skin necrosis in a case of uremia with autonomous
hyperparathyroidism. Lancet 1968; 2: 323±325
451
3. Cobb J Jr, Krumlowshy PA, Delgrasso F et al. Calciphylaxis
etiology of progessive vascular claci®cation and gangrene. Ann
Surg 1973; 177: 206±210
4. Coates T, Kirkland GSm Dymock RB et al. Cutaneous
necrosis from Calci®c Uremic Arteriolopathy. Am J Kidney Dis
1998; 32: 384±391
5. Massry SG, Gordon A, Coburn JW et al. Vascular calci®cation
and peripheral necrosis in renal transplant recipient. Am J Med
1970; 49: 416±422
6. Gipstein RM, Coburn JW, Adams DA et al. Calciphylaxis in
man. Arch Intern Med 1976; 136: 1273±1280
7. Fox R, Banowsky L, Cruz AB. Post-renal transplant
calciphylaxis: Successful treatment with parathyroidectomy.
J Urol 1983; 129: 362±363
8. Androgue HJ, Frazier MR, Zeluff B, Suki WN. Systemic
calciphylaxis revisited. Am J Nephrol 1981; 1: 177±183
9. Massry SG, Coburn JW, Hartenbower DL et al. The effect of
calcemic disorders and uremia or the mineral content of the skin.
Israel J Med Sci 1971; 7: 514±517
10. Massry SG, Coburn JW, Hartenbower DL et al. Mineral content
of human skin in uraemia. Effect of secondary hyperparathyroidism and haemodialysis. Proc Eur Dial Transplant Assoc
1970; 7: 146±148
11. Campistol JM, Almirall J, Martin E, Torras A,
Revert L. Calcium-carbonate-induced calciphylaxis. Nephrol
1989; 51: 549±550
12. Bleyer AJ, Choi M, Igwemezie B et al. A case control study of
proximal calciphylaxis. Am J Kidney Dis 1998; 32: 376±383
13. Handa SP, Sohi PS. Proximal calciphylaxis in four insulin
requiring diabetic hemodialysis patients. Am J Kidney Dis
1997; 29: 812
14. Braden G, Goerdt P, Pekow P et al. Calciphylaxis in hemodialysis patients: patient pro®les and temporal association with
IV iron dextran. J Am Soc Nephrol 1997; 8: 549 (abstract)
15. McAuley K, Devereux F, Walker R. Calciphylaxis in two noncompliant patients with end stage renal failure. Nephrol Dial
Transplant 1997; 12: 1061±1063
16. Richens G, Piepkora MW, Kruege GC. Calcifying panniculitis
associated with renal failure. J Am Acad Dermatol 1982;
6: 537±539
17. Budisavijevic MN, Cheek D, Ploth DW. Calciphylaxis in
chronic renal failure. J Am Soc Neph 1996; 7: 978±982
18. Hafner J, Keusch G, Wahl C et al. Uremic small artery disease
with medical calci®cation and intimal hypertrophy (so called
calciphylaxis): a complication of chronic renal failure and bene®t
from parathyroidectomy. J Am Acad Dermatol 1984; 33: 954±962
19. Chan YL, Mahoney JF, Turner JJ, Posen S. The vascular
lesions associated with skin necrosis in renal disease. Br J
Dermatol 1983; 109: 85±95
20. Llach F, Goldblat M, Freundlich RE et al. The evolving pattern
of Calci®c Uremic Arteriolopathy (calciphylaxis). Submitted to
American Society Nephrology Annual Meeting, Toronto, 2000.
21. Vassa N, Twardowski J, Campbell J. Hyperbaric oxygen therapy
in calciphylaxis induced skin necrosis in a peritoneal dialysis
patient. Am J Kidney Dis 1995; 23: 878±888