Calciphylaxis in chronic, non-dialysis-dependent renal disease
© Pliquett et al; licensee BioMed Central Ltd. 2003
Received: 26 May 2003
Accepted: 29 September 2003
Published: 29 September 2003
Calciphylaxis cutis is characterized by media calcification of arteries and, most prominently, of cutaneous and subcutaneous arterioles occurring in renal insufficiency patients.
A 53-year-old woman with chronic cardiac and renal failure complained of painful crural, non-varicosis ulcers. She was hospitalized in an immobilized condition due to both the crural ulcerations and the existing heart-failure state (NYHA III-IV) having pleural and pericardial effusions, atrial fibrillation and weight loss of 30 kg over the past year. Despite normalization of calcium-phosphorus balance and improvement of renal function, the clinical course of crural ulcerations deteriorated during the following 3 months. After failure of surgical debridements, multiple courses of sterile-maggot therapy were introduced at a late stage to stabilize the wounds. The patient died of recurrent wound infections and sepsis paralleled by exacerbations of renal malfunction.
The role of renal disease in vascular complications is discussed. Sterile-maggot debridement may constitute a therapy for the ulcerated calciphylaxis at an earlier stage, i.e. when first ulcerations appear.
Calciphylaxis cutis is characterized by media calcification of arteries and, most prominently, of cutaneous and subcutaneous arterioles , as well as by intimal proliferation and fibrosis . The pathogenesis of Calciphylaxis remains unclear as it differs from intima-based common atherosclerosis and extravascular calcium-phosphate deposits in organs such as the skin in Calcinosis cutis are not involved. However, it appears to be associated with an elevated serum calcium or phosphate concentration elicited either by hyperparathyroidism or by vitamin-D intake. Female gender appears to be a risk factor. Although singular cases associated with non-renal diseases including inflammatory bowel disease, cancer, and primary hyperparathyroidism were reported , Calciphylaxis cutis mainly occurs in end-stage renal insufficiency, almost exclusively in patients undergoing kidney-replacement therapy [2–4]. The prognosis in Calciphylaxis patients is dramatically poor, with up to 6 months life expectancy after appearance of ulcerations . Emphasizing its difference from intima-based atherosclerosis, it is also called calcific uremic arteriolopathy .
Laboratory tests revealed a normal plasma concentration of parathyroid hormone (5.02 pmol/l, normal: 1.1–6.9), Vitamin (1,25-OH)-D3 deficiency (7.1 pg/ml, normal: 20.2–46.2), however, slightly elevated calcium (2.66 mmol/l, normal: 2.02–2.6) concentration. Potassium (4.3 mmol/l) and phosphate (1.26 mmol/l) concentrations were normal. Glomerular filtration rate estimated by MDRD equation  was 25.4 ml/min (creatinine: 207 μmol/l; urea: 30.2 mmol/l; albumin: 35.1 g/l) at admission indicative for renal failure. Further, low HDL cholesterol (0.86 mmol/l, normal: >0.9), high triglycerides (3.06 mmol/l, normal: <2.3), yet a normal LDL cholesterol (3.49 mmol/l, normal: <4.2) in absence of statins to which the patient claimed to be allergic, were found. Leukocyte count and C-reactive protein were found to be elevated at least during the 12 months prior to admission, ranging from 10–15 Gpt/l (normal:4–9) and 60–200 mg/l (normal: <5), respectively. Ferritin was in the normal range between 200 and 300 ng/ml (normal: 13–300), neither supporting an infection as an acute-phase reactant nor being the reason for the prevalent normocytic, normochromic anemia (hemoglobin 6 mmol/l, hematocrit 31%). However, an iron deficiency could have limited further rises of ferritin due to infection. The anemia was not due to erythropoietin deficiency as reticulocytes were 15 Gpt/l. Urine tests showed a microproteinuria (0.25 g/l) and leukocyturia (25/μl). After cessation of coumadin therapy for atrial fibrillation, the International Normalized Ratio leveled off at 1.42 (normal: 1) in presence of low-dose heparine. Liver enzymes including serum alcaline phosphatasis were between 16 and 19 μmol/l*s (normal: <4.2) and gamma-glutamyl transferase between 9 and 14 μmol/l*s (normal: <0.6), while transaminases were within normal range. Ultrasound examination revealed small kidneys (9 cm longitudinally) with loss of clarity of architecture and multiple cysts. The renal cortex was narrowed to 7 mm, ureters were not dilated. A whole-body bone scintigraphy was negative for bone metastases or osteomyelitis. Ultrasonographic examinations of the thyroid gland were unrevealing; parathyroid bodies were not identified. The radiologic search for nonvascular soft-tissue calcifications was negative. Systemic lupus erythematosus or other types of autoimmune diseases were ruled out by negative antibody screening tests. The diagnosis Calciphylaxis cutis was established by cutaneous biopsy.
Hypercalcaemia was readily normalized by diuretic therapy with torasemide in combination with standard heart-failure therapy including aldosterone antagonist, ACE inhibitor, beta-adrenergic blockade and digitalis over a one-month period. Possible reasons for the hypercalcaemia like hyperparathyroidism or high vitamin D serum levels were ruled out, parathyroid hormon-related peptide was not determined. Glomerular filtration rate improved to 33.1 ml/min under balanced fluid-substitution. Thus, renal function in this patient was mid-stage impaired with potential to recover under therapy. However, fluid overload had to be avoided because of the heart-failure condition. Once electrolytes, including plasma potassium fell, an incessant ventricular tachycardia triggered the ICD. Therefore, potassium was given to obtain a high-normal plasma concentration, and an amiodarone therapy was started.
Here we report a case of ulcerated Calciphylaxis cutis in the presence of a moderate renal insufficiency in contrast to most previous observations that suggest Calciphylaxis cutis to be associated with terminal renal insufficiency [3, 4]. Moreover, the actual plasma levels of calcium and phosphorus seemed to play a minor role than assumed from previous evidence . However, in spite of measures to preserve renal function, the clinical course of Calciphylaxis cutis was rapidly progressive and virtually undeterred by treatment in our patient. The skin ulcerations due to Calciphylaxis cutis constantly deteriorated over less than 6 months from first admission. Alternative therapeutic options including glucocorticoids were not deemed salutary in the presence of ulcerations . Sterile maggot debridement therapy was more successful than surgical debridement in this patient. However, it was introduced late. In line with previous evidence , we strongly encourage its use in ulcerated Calciphylaxis cutis in combination with a broad-spectrum, Pseudomonas – effective antibiotic earlier on to avoid superinfections and to facilitate the granulation process. Overall, screening of renal-disease patients for Calciphylaxis cutis in the non-ulcerated stage seems to be crucial to timely address risk factors associated with the disease. Classic and putative risk factors for Calciphylaxis cutis derived from this case are summarized below.
Cardiovascular risk factors were low HDL cholesterol and high triglycerides, history of cigarette smoking during the previous 10 years (20-pack years) and arterial hypertension. The prevalent renal disease appears to be both a cardiovascular risk factor  and risk factor for Calciphylaxis . Further, the patient may have had a genetic disposition to cardiovascular disease, as her mother died of myocardial infarction prematurely. Lipoprotein (a) and homocysteine levels were not determined. C-reactive protein elevation is likely due to the skin ulcers. However, it was high during the 12 months prior to death and was probably high even before that as her history of urinary-tract infections revealed, thus, making it eligible as a contributing factor for atherosclerosis . A slight disturbance of calcium-phosphorus metabolism as well as a history of obesity, former coumadin use, and a possible underlying vitamin-K deficiency based on a steadily elevated international normalized ratio after coumadin discontinuation are prevalent, putative risk factors for Calciphylaxis . Yet, the mechanism of these disseminated calcifications in small cutaneous arteries, and capillaries as well as in conductive arteries, pulmonary arteries and the left atrium is by far not explained. Future research will clarify whether matrix-protein dysfunction elicited by Vitamin-K deficient state is in play [9, 10] which may affect both pyrophosphate and calcium metabolism [1, 11] as well as wound healing .
Taken together, Calciphylaxis cutis is thought to arise from the arterial media layer rendering it different from intimal calcifications seen in common atherosclerosis and from extravascular organ calcifications such as Calcinosis cutis. The in-stent restenosis problem in our patient may reflect a propensity of intimal proliferation and fibrosis usually seen in Calciphylaxis . Here, we speculate that the patient actually had both Calciphylaxis cutis represented by calcifications of small arteries, arterioles and capillaries of the skin as well as systemic atherosclerosis as primarily seen in conductive arteries.
List of abbreviations used
angiotensin converting enzyme
implantable cardioverter defibrillator
Modification of Diet in Renal Disease (Study)
New York Heart Association class
Written consent for autopsy to further medical science and teaching was given by the patient before she died.
- Qunibi WY, Nolan CA, Ayus JC: Cardiovascular calcification in patients with end-stage renal disease: A century-old phenomenon. Kidney Int Suppl. 2002, 73-80. 10.1046/j.1523-1755.62.s82.15.x.Google Scholar
- Wilmer WA, Magro CM: Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002, 15: 172-186. 10.1046/j.1525-139X.2002.00052.x.View ArticlePubMedGoogle Scholar
- Fine A, Zacharias J: Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002, 61: 2210-2217. 10.1046/j.1523-1755.2002.00375.x.View ArticlePubMedGoogle Scholar
- Davis CA, Valentine RJ: Wet gangrene in hemodialysis patients with calciphylaxis is associated with a poor prognosis. Cardiovascular Surgery. 2001, 9 (6): 565-570. 10.1016/S0967-2109(01)00084-9.View ArticlePubMedGoogle Scholar
- Levey AS, Bosch JP, Levis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999, 130 (6): 461-470.View ArticlePubMedGoogle Scholar
- Tittelbach J, Graefe T, Wollina U: Painful ulcers in calciphylaxis – combined treatment with maggot therapy and oral pentoxyfillin. J Dermatolog Treat. 2001, 12: 211-214. 10.1080/09546630152696035.View ArticlePubMedGoogle Scholar
- Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001, 134: 629-636.View ArticlePubMedGoogle Scholar
- Ridker PM, Hennekens CH, Buring JE, Rifai N: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000, 342: 836-843. 10.1056/NEJM200003233421202.View ArticlePubMedGoogle Scholar
- Speer MY, McKee MD, Guldberg RE, Liaw L, Yang HY, Tung E: Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med. 2002, 196: 1047-1055. 10.1084/jem.20020911.View ArticlePubMedPubMed CentralGoogle Scholar
- Ketteler M, Vermeer C, Wanner C, Westenfeld R, Jahnen D, Floege J: Novel insights into uremic vascular calcification: role of matrix gla protein and alpha-2-Heremans Schmid glycoprotein/fetuin. Blood Purif. 2002, 20: 473-476. 10.1159/000063554.View ArticlePubMedGoogle Scholar
- Schäfer C, Heiss A, Schwarz A, Westenfeld R, Kettler M, Floege J: The serum protein alpha2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest. 2003, 112 (3): 357-366. 10.1172/JCI200317202.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/4/8/prepub
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