Uremia

Pathologic Diagnosis: Metastatic Calcification in Uremia With Extensive Cardiac Involvement

Pathologic calcification has been classically divided into 2 categories, dystrophic and metastatic. In simple terms, dystrophic calcification occurs in nonviable tissue surrounded by a normal chemical environment, whereas metastatic calcification affects normal tissue in an abnormal chemical environment. Rudolf Virchow is credited for first describing metastatic calcification in 1855, when he concluded that "calcium salts dissolved from bone were carried in the blood and deposited at some distant site to form `calcium metastases,' a process analogous to the dissemination of cells from a primary neoplasm."1 In 1947, R. M. Mulligan divided the underlying causes of metastatic calcification into 4 categories: destruction of the bone (from metastatic cancer, multiple myeloma, etc), chronic renal disease, primary parathyroid neoplasm, and hypervitaminosis D.2

Several types of soft tissue calcification occur in patients with chronic renal disease including, but not limited to, the arterial and visceral types seen in this case. Arterial calcification most commonly involves the tunica media. It can be diagnosed radiographically and can be found in virtually any organ system. Visceral (nonvascular) calcification has 4 classic sites of manifestation: the kidneys, stomach, lungs, and heart. Uncommonly, the liver and other organs are involved as well. Visceral calcifications are not clinically diagnosable without microscopic examination of tissue. Because of their small size, they fail to show up on radiographic imaging, and they are rarely associated with clinical manifestations. One exception to this is myocardial calcification, which can be clinically significant, especially if it involves the cardiac conducting system.1

Whereas the pathophysiology of chronic renal failure is complex, the main underlying mechanism for the development of metastatic calcification relates to the product of calcium levels and phosphorus levels (serum calcium level x serum phosphorus level). When either calcium or phosphorus is elevated enough to increase this product above a given threshold, precipitation of calcium phosphate occurs spontaneously. This effect is enhanced in the presence of an alkaline environment. Since blood calcium levels are generally low in patients with uremia, it is thought that hyperphosphatemia plays the most important role in this process. When dialysis is use for treatment, calcium is added to the dialysate to correct for hypocalcemia and to prevent renal osteodystrophy. This also increases the calcium-phosphorus product and enhances the development of metastatic calcification.3

The significance of dialysis in the development of metastatic calcification has been well documented. In a small retrospective study of renal transplant recipients with metastatic calcification, the duration of dialysis was found to correlate directly with the appearance of metastatic calcification, and successful renal transplantation was found to dramatically improve associated symptoms.4 In an autopsy study comparing patients with chronic uremia who did and did not receive dialysis, metastatic calcifications were found to be significantly more prevalent in the dialysis group. The authors also found that 80% of the patients receiving dialysis had foci of soft tissue calcification and concluded that cardiac disease, associated with calcification of the conducting system, was the most frequent cause of death.5

Cardiac-related death is very common in patients with uremia. It is often associated with electrolyte imbalances, ischemic heart disease, hypertension, and congestive heart failure, but metastatic calcification can play a prominent role. In one study, investigators found that 50% of patients dying from uremia-related causes had metastatic calcification of the myocardium, and 25% had clinical and electrocardiographic findings to support myocardial calcification as the cause of death.6 In a recent review of the subject by Isotalo et al,7 the authors describe cardiac calcification as having a multifactorial pathophysiology, ranging from arterial stenosis and small vessel disease, to myocyte degeneration with ventricular dysfunction, to disease of the conduction system. Regardless of the mechanism, studies clearly indicate the need to consider metastatic cardiac calcification when determining cause of death in the face of chronic renal failure.

References

1. Parfitt MA. Soft-tissue calcification in uremia. Arch Intern Med. 1969;124: 544-556.

2. Mulligan RM. Metastatic calcification. Arch Pathol. 1947;43:177-230.

3. Ibels LS. The pathogenesis of metastatic calcification in uraemia. Prog Biochem Pharmacol. 1980;17:242-250.

4. Takeuchi I, Chikaraishi T, Shindo J, et al. Renal transplantation for recipients with metastatic calcifications. Transplant Proc. 1998;30:3045-3046.

5. Kuzela DC, Huffer WE, Conger JD, Winter SD, Hammond WS. Soft tissue calcification in chronic dialysis patients. Am J Pathol. 1977;86:403-417.

6. Terman DS, Alfrey AC, Hammond WS, Donndelinger T, Ogden DA, Holmes JH. Cardiac calcification in uremia: a clinical, biochemical and pathological study. Am J Med. 1971;50:744-755.

7. Isotalo PA, Halil A, Green M, Tang A, Lach B, Veinot JP. Metastatic calcification of the cardiac conduction system with heart block: an under-reported entity in chronic renal failure patients. J Forensic Sci. 2000;45:1335-1338.

Adam M. Quinn, DO; Kenneth D. McClatchey, DDS, MD

Accepted for publication July 2, 2002.

From the Loyola University Medical Center, Maywood, Ill. Corresponding author: Adam M. Quinn, DO, Department of Pathology, Loyola University Medical Center, 2160 S First Ave, Building 110, Maywood, IL 60153 (e-mail: aquinn1@lumc.edu).

Reprints not available from the authors.

Copyright College of American Pathologists Apr 2003
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