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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.

Soft-Tissue Calcification in Chronic Kidney Disease: The Role of Hyperphosphatemia

To provide nephrologists with up-to-date information on the treatment and management of patients with hyperphosphatemia.

This activity is designed for nephrologists. No prerequisites required.

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, the participant should be able to:
  • Recognize the underlying causes of hyperphosphatemia.
  • Analyze the impact of hyperphosphatemia on cardiovascular morbidity and mortality.
  • List the consequences of untreated hyperphosphatemia.
  • Evaluate current management strategies for hyperphosphatemia, including the pros and cons of each.
  • Discuss appropriate treatment options for hyperphosphatemia in select patient cases.
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 2 hours.

Release date: May 15, 2007. Expiration date: May 15, 2009.

The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Shire Pharmaceuticals.Full Disclosure Policy Affecting CME Activities
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:

Mohamed G. Atta, MBBCh, MPH
Assistant Professor of Medicine
Division of Nephrology
Johns Hopkins School of Medicine
Medical Director
DaVita Dialysis Unit
Baltimore, Maryland
Dr Atta reports having no financial or advisory relationships with corporate organizations related to this activity.

William F. Finn, MD
Professor of Medicine
Division of Nephrology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Dr Finn reports serving as a consultant and receiving honoraria from Shire Pharmaceuticals; and serving on the speakers' bureau for GE Healthcare and Shire Pharmaceuticals.

Hartmut H. Malluche, MD, FACP
Robert G. Luke Chair in Nephrology
Professor of Medicine
Chief, Division of Nephrology
Bone and Mineral Metabolism
Director, General Clinical Research Center
University of Kentucky
Lexington, Kentucky
Dr Malluche reports serving as a consultant for Shire Pharmaceuticals.

John P. Middleton, MD
Director of Clinical Nephrology
Medical Director, Dialysis Program
Duke University Medical Center
Durham, North Carolina
Dr Middleton reports receiving grants/research support from Amgen, Exelexis, Fibrogen, and Keryx; serving as a consultant for Genentech; and receiving honoraria from and serving on the speakers' bureau for Merck and Company and Shire Pharmaceuticals.

George A. Porter, MD, FACP
Secretary General
International Society of Nephrology's Commission on Acute Renal Failure
Emeritus Professor of Medicine
Chief, Division of Nephrology
Oregon Health and Science University School of Medicine
Portland, Oregon
Dr Porter reports serving as a consultant for GlaxoSmithKline, Pfizer Inc, and Shire Pharmaceuticals; and serving on the speakers' bureau for Pfizer Inc and Shire Pharmaceuticals.

Notice: No faculty member has indicated that his/her article will reference unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.Soft-Tissue Calcification in Chronic Kidney Disease: The Role of Hyperphosphatemia
Mohamed G. Atta, MBBCh, MPH*

In its 2006 US Renal Data Systems annual report, the National Institutes of Health estimated that, in 2004, end-stage renal disease (ESRD) affected more than 473 000 people in the United States.1 Of these individuals, approximately 71% were treated with dialysis and, despite our efforts, yearly mortality in this population remains significant at 18% (>84 000) as of 2004. The high mortality is explained, to large extent, by the consistent observation of a 10- to 20-fold higher cardiovascular event rate in this population compared to the general population.2

The majority of patients with chronic kidney disease (CKD) who undergo maintenance hemodialysis have hyperphosphatemia. An analysis of laboratory findings in 6400 patients undergoing hemodialysis conducted by Block et al showed a mean serum phosphorus level of 6.2 mg/dL.3 Of these patients, 60% had phosphorus levels greater than the common upper limit of 5.5 mg/dL for patients at stage 5 CKD, 39% had phosphorus levels above 6.5 mg/dL, 30% had levels above 7 mg/dL, and 10% had levels above 9 mg/dL.

Hyperphosphatemia predisposes patients to secondary hyperparathyroidism, with its consequent risk of high-turnover bone disease. The potential role of hyperphosphatemia and increased mortality in dialysis patients was also demonstrated by Block et al.3 Several observational and experimental studies have linked the increased risk of mortality in dialysis patients to the elevated calcium-phosphorus product.3-5 Mortality in this setting was primarily driven by hyperphosphatemia rather than changes in serum calcium concentration. The mechanism by which hyperphosphatemia increases mortality is not fully understood, although great interest has evolved around the potential role of the elevated calcium-phosphorus product in the development of cardiovascular calcification. In theory, the increased coronary calcification noted in dialysis patients may explain the increased cardiovascular event rate in this population. Furthermore, calcific uremic arteriolopathy, commonly known as calciphylaxis, may develop, causing necrosis of areas dependent on microvascular circulation resulting in high mortality due to local and systemic infections. A study by Mazhar et al found that development of calciphylaxis was observed with each 1-mg/dL increase in serum phosphorus levels.6

Therefore, early control of phosphate levels is extremely important in order to manage hyperphosphatemia and its pathological impact and prevent secondary hyperparathyroidism, metabolic bone disease, and soft-tissue and vascular calcification.7 A thorough understanding of hyperphosphatemia, its consequences, and current treatment strategies is required by nephrologists and other healthcare practitioners caring for patients with CKD.

This issue of Johns Hopkins Advanced Studies in Medicine is based on content developed for a CME lecture series comprising presentations held in various US cities to educate these healthcare practitioners about hyperphosphatemia. In their article, William F. Finn, MD, and Hartmut H. Malluche, MD, FACP, elegantly describe the complex regulation of phosphate homeostasis that include dietary, endocrine, and paracrine factors in individuals with normal renal function and the progressive changes in the highly regulated process of phosphate metabolism that occur in patients with CKD. In these patients, as glomerular filtration rate decreases, parathyroid hormone levels begins to rise, which seems to be an adaptive response to the need for increased phosphorus excretion to maintain phosphorus balance. Hyperparathyroidism and other adaptive mechanisms eventually cannot compensate for the decline in kidney function, and serum phosphate levels rise beyond the normal range.8

Drs Finn and Malluche explain the epidemiological observations, linking this disordered mineral metabolism and cardiovascular risk. The impact of early changes in mineral metabolism that accompany loss of renal function in patients with CKD may be more important to cardiovascular complications than previously thought. An understanding of these metabolic processes is critical to treating hyperphosphatemia and preventing the serious consequences of this common complication of CKD.

The specific reasons for the association between hyperphosphatemia and risk of morbidity and mortality remain speculative. However, serum phosphate levels and cardiovascular disease have been correlated across a range of renal dysfunction. Recent studies indicate that, in addition to well-established effects on osseous tissue, elevated serum phosphorus levels increase risk of soft-tissue calcification and arterial stiffness. These changes are, in turn, associated with increased cardiovascular risk. Interestingly, exposure to high extracellular phosphate concentrations has been shown to induce osteogenic gene expression in vascular smooth muscle cells.9 John P. Middleton, MD, and Hartmut H. Malluche, MD, FACP, explore the relationships among specific forms of renal osteodystrophy, calcium load, and phenotypic expression in vascular smooth muscle cells. They address how these relationships may contribute to phosphate metabolism and cardiovascular risk, and the resulting therapeutic implications.

For patients in whom serum phosphate levels are not controlled adequately with diet, agents that limit gastrointestinal phosphate uptake are indicated. Recent evidence suggests that calcium-based oral phosphate-binding agents, which are traditionally used to limit phosphate absorption in patients with CKD, may contribute excess calcium load.10 This excess calcium load may exacerbate vascular calcification in these patients, thus increasing cardiovascular risk. Therefore, alternatives to calcium-containing preparations may be important to reducing cardiovascular risk in this vulnerable population.

George A. Porter, MD, FACP, and Hartmut H. Malluche, MD, FACP, describe the evolution of treatment to reduce phosphate concentrations and compare the safety, efficacy, and tolerability profiles of calcium binders with those of sevelamer hydrochloride and lanthanum carbonate, calcium- and aluminum-free agents, with efficacy in the reduction of serum phosphate levels. Data regarding rates of arterial calcification in patients using these agents are discussed in the context of current and future options for the management of hyperphosphatemia.

With the increasing prevalence of CKD and its progression to ESRD, understanding the causes, consequences, and treatment of hyperphosphatemia in these patients is becoming increasingly important. This issue of Johns Hopkins Advanced Studies in Medicine will help clinicians who treat patients with CKD to better evaluate these patients and make decisions regarding appropriate treatment to reduce the associated morbidity and mortality.


1.    US Renal Data System. Atlas of End-Stage Renal Disease in the United States. USRDS 2006 Annual Data Report. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006.
2.    Block GA. Control of serum phosphorus: implications for coronary artery calcification and calcific uremic arteriolopathy (calciphylaxis). Curr Opin Nephrol Hypertens. 2001;10:741-747.
3.    Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31:607-617.
4.    Ganesh SK, Stack AG, Levin NW, et al. Association of elevated serum PO(4), CA x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol. 2001;12:2131-2138.
5.    Slinin Y, Foley R, Collins A. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS Waves 1, 3, and 4 Study. J Am Soc Nephrol. 2005;16:1788-1793
6.    Mazhar AR, Johnson RJ, Gillen D, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int. 2001;60:324-332.
7.    Albaaj F, Hutchinson AJ. Hyperphosphatemia in renal failure: causes, consequences, and current management. Drugs. 2003;63:577-596.
8.    Malluche HH, Mawad H, Monier-Faugere MC. The importance of bone health in end-stage renal disease: out of the frying pan into the fire? Nephrol Dial Transplant. 2004;199(suppl 10):i9-i12.
9.    Giachelli CM, Speer MY, Li X, et al. Regulation of vascular calcification: roles of phosphate and osteopontin. Circ Res. 2005;96:717-722.
10.    London GM, Marty C, Marchais SJ, et al. Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol. 2004:15:1943-1951.

*Assistant Professor of Medicine, Division of Nephrology, Johns Hopkins School of Medicine, Medical Director, DaVita Dialysis Unit, Baltimore, Maryland.
Address correspondence to: Mohamed Atta, MD, Assistant Professor of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, 1830 E Monument Street, Suite 416, Baltimore, MD 21205.

The content in this monograph was developed with the assistance of a medical writer. Each author had final approval of his article and all its contents.

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