2006年11月14－19日

美国加利福尼亚州圣地亚哥

November 14 - 19, 2006, San Diego, California

Craig B Langman, MD   

Introduction

There is an epidemic in our maintenance dialysis population and it is called death! The 1-year mortality is 20%, and the overall yearly mortality from most cancers in adults over 65 years of age is 600-1800 per 100,000, which pales in comparison.^[1] Kamyar Kalantar-Zadeh, MD, PhD, MPH, FASN,^[2] started with a discussion of how we can understand this crisis and began to unravel some data that may lead to improved outcomes for our patients in the near future.

Epidemiologic data have revealed an increasing death rate as estimated glomerular filtration rate declines in patients with chronic kidney disease (CKD), with mortality rates exponentially higher at the end of the continuum of the staging paradigm.^[3,4] Death appears to result from cardiovascular events (ie, arrhythmia, myocardial infarction, congestive heart failure), and in several studies of patients with advanced CKD, death was more common than progression to dialysis.^[5-7] In the past, we have looked to traditional risk factors that are associated with increased cardiovascular risk, such as obesity, hypertension, hyper-homocysteinemia, and hyperlipidemia as explanations for the higher mortality. However, specific trials designed to intervene in many of these risk factors have been unrewarding, finding no differences at all in mortality,^[8,9] or paradoxically, finding that such factors as increasing obesity or higher blood pressures may be associated with better outcomes in maintenance dialysis patients!^[10,11] Thus, we need to turn to emerging risk factors that confer excess mortality from cardiovascular disease in patients with CKD and end-stage kidney disease (ESKD [patients on maintenance dialysis]). Three general areas that may be important are:

• Systemic alterations of mineral metabolism, recently named chronic kidney disease-mineral bone disorder (CKD-MBD)^[12]
  
  
• Malnutrition and inflammation^[13,14]
  
  
• Anemia with associated iron deficiency^[15]

The remainder of this article will focus only on CKD-MBD as a major risk factor.

CKD-MBD

As we examine the individual components of CKD-MBD, we will first look at serum levels of the minerals phosphorus and calcium as independent risk factors for dialysis-associated mortality. We now have data (obtained from the patient registries of the 2 largest independent dialysis companies in the United States) at initiation of dialysis, showing that increasing serum phosphorus levels, increasing serum calcium levels (adjusted for albumin concentration), and increasing calcium X phosphate product (C X P) each prospectively confers great excess mortality risk, and hyperphosphatemia confers the greatest independent risk of all.^[16,17] So, too, does the rising baseline level of the major hormonal marker of renal osteodystrophy, parathyroid hormone (PTH), a condition termed secondary hyperparathyroidism (SHPT). Notably, the data for these studies were analyzed using the National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) recommendations for desired mineral and hormonal level ranges,^[18] thereby lending further credibility for use of these data for improving outcomes.

While the pathophysiologic mechanisms for such findings remain elusive at the present time, it is interesting to speculate that it is the presence, and perhaps the progression of, vascular calcification that is intimately tied to poor outcome (mortality) in dialysis patients. Further evidence for this hypothesis was presented by Spiegel and colleagues,^[19] who reported that a noncalcium-based dietary phosphate binder, sevelamer hydrochloride, when compared with a calcium-based dietary phosphate binder in incident dialysis patients, led to both lower incidence of cardiovascular calcification (demonstrated by electron-beam computed tomography) and improved 5-year survival, despite similar efficacy of phosphate control by either agent.

Vitamin D

Additional data support the presence of other CKD-MBD factors that influence patient mortality as well. Progressive CKD is associated with a progressive decline in levels of the kidney-produced active vitamin D metabolite 1,25-dihydroxyvitamin D. Thus, vitamin D and its metabolites have gained considerable attention in the past few years as being important in this regard. Originally, we thought that provision of this metabolite in pharmacologic quantities would solve the apparent deficiency of the activated hormone. Analyzing data from an historical cohort, Teng and colleagues^[20] indeed demonstrated a survival advantage in dialysis patients receiving any intravenous (IV) vitamin D vs none, and across all ranges of calcium, phosphorus, C X P, or PTH levels. Notably, and as yet unexplained, however, is the finding that the choice of vitamin D metabolite confers a distinct survival advantage. A vitamin D₂-based agent (eg, paricalcitol or doxercalciferol, both available in the United States) confers a greater survival advantage to new or existing dialysis patients than a vitamin D₃-based agent, such as calcitriol.^[17,21,22]

Not only have we learned the importance of the active metabolite for patient survival, but it seems that nutritional vitamin D deficiency influences the dialysis patient's overall and cardiovascular mortalities as well. Using a nested case-control study design, Wolf and colleagues^[23] studied more than 10,000 incident hemodialysis patients who lived or died within the first 90 days of the onset of dialysis. Severe vitamin D deficiency, defined as a serum 25-hydroxyvitamin D level < 10 ng/mL (4 nM), in patients not treated with any IV form of vitamin D was associated with a 5.6-fold risk of increased mortality!^[23] Thus, KDOQI guidelines for determination of vitamin D nutritional status in patients with modest CKD^[17] may need to be extended to patients on hemodialysis as well, as none of the traditional mineral levels or PTH level factored out those who were so deficient.

Retrospective design is the limiting factor of all studies of vitamin D and survival advantage (or advantage based on choice of a D₂ vs a D₃ analogue) and, thus, we await prospective trials for demonstration of similar benefit. Of interest in this regard is experimental work pointing to the interactive effects of hyperphosphatemia and active hormone-vitamin D deficiency in downregulating or dampening effects that are mediated by the vitamin D receptor (VDR) in human coronary artery smooth muscle cells.^[24] These data suggest that appropriate control of hyperphosphatemia, avoidance of or limiting progression of vascular calcification, and use of a selective vitamin D agonist may indeed lead to enhanced patient survival.

How Can We Use These Population-Based Morbidity and Mortality Data When Making Individual Decisions in the Treatment of Hemodialysis Patients?

Isidro B. Salusky, MD, FASN,^[25] discussed renal osteodystrophy, the complex metabolic disease of bone, in an effort to illustrate how to translate population-based data to everyday practice. After all, we choose therapies for CKD-MBD on the basis of K/DOQI guidelines in order to control hyperphosphatemia and SHPT.

Dr. Salusky's data showing that bone disease in patients with ESKD is first determined by PTH levels from high-turnover bone disease with high bone formation rates (BFR) through normal to reduced or absent BFR (adynamic disease) is well accepted. Factors that modulate the bone's response to PTH include both vitamin D and calcium, factors that in excess drive the equation toward lower to absent BFR.^[26]

Consider what have we done for the majority of the past 2 decades. Until the K/DOQI guidelines were published in 2003,^[18] we took advantage of the original observations made in 6 hemodialysis patients that IV calcitriol lowered PTH levels^[27] by administering higher and higher doses of this pharmacologic metabolite, while we conveniently forgot that blood calcium levels were driven upward above normal limits! Worse still was our use of relatively high dialysate calcium (≥ 3 mM) and the substitution of oral calcium-based dietary phosphate binders when we realized we could no longer use aluminum-containing agents for this purpose. So, in effect, we were driving bone towards the adynamic state, and, coupled with an excess of patients with adynamic disease associated with diabetes mellitus, we were left with increasing numbers of patients with this terrible bone disease.^[28,29] The adynamic state is associated with increasing vascular calcification, which negatively influences patient mortality.^[30]

Unfortunately for our specialty, PTH levels must be interpreted according to the patient's stage of CKD in order to understand what is happening at the level of bone. This is why the K/DOQI target ranges for PTH level vary from stage 3 at 35-70 pg/mL to stage 5 at 150-300 pg/mL. Dr. Salusky presented data demonstrating that the same PTH level predicts a high BFR in stage 3 CKD and mildly abnormal or normal BFR in stage 5 CKD!

Of importance, while we wish to ameliorate SHPT and the associated high BFR that defines it at the bone level, the agents we choose to reduce BFR toward normal greatly influence patient morbidity along the way. In Dr. Salusky's study based on adolescents and young adults with severe SHPT bone disease in a 2x2 matrix study, we saw that the choice of either a calcium-based, or noncalcium, nonmetal-based dietary phosphate binder (sevelamer hydrochloride) and the choice of either calcitriol or doxercalciferol reduced high-turnover bone disease and SHPT equivalently. However, there was a 4-fold greater likelihood of hypercalcemia or elevated C X P in the groups treated with either a calcium-based dietary phosphate binder or calcitriol when compared with the other groups treated with sevelamer hydrochloride or doxercalciferol.

Thus, we have come to realize that our approach to patients with CKD and ESRD must take into account the systemic nature of the disorder we have historically called renal osteodystrophy, which is now more aptly named CKD-MBD.^[12] While there is still a role for the percutaneous bone biopsy in individual patients (not limited to those with unexplained hypercalcemia, markedly elevated PTH with low alkaline phosphatase levels, or unexplained fractures),^[18] we must realize that for the large population of patients on maintenance hemodialysis, our approach to care must change radically to improve mortality and reduce morbidity. Avoidance of excessive calcium from all sources and perhaps judicious use of a vitamin D₂-based metabolite will do the best job for 1 patient at a time and, therefore, the overall population.

Stay tuned during the next few years, as we start seeing results from the many additional trials of agents designed to reduce hyperphosphatemia or repair vitamin D deficiency and active-metabolite deficient states that are in progress.^[31] Let's hope that we can figure out the root causes of this epidemic of death that permeates our dialysis populations, and promote vascular health as well in early CKD.

References

1. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality - All COD, Public-Use With State, Total U.S. for Expanded Races/Hispanics (1990-2003), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006. Underlying mortality data provided by NCHS. Available at: www.cdc.gov/nchs. Accessed November 26, 2006.
2. Kalantar-Zadeh K. Vitamin D and survival in ESRD. Morbidity and mortality in CKD: evidence-based choices in the therapy of SHPT. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California.
3. Kovesdy CP, Trivedi BK, Anderson JE. Association of kidney function with mortality in patients with chronic kidney disease not yet on dialysis: a historical prospective cohort study. Adv Chronic Kidney Dis. 2006;13:183-188. Abstract
4. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305. Abstract
5. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164:659-663. Abstract
6. Rahman M, Pressel S, Davis BR, et al. Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med. 2006;144:172-180. Abstract
7. Mafham MM, Emberson J, Landray M. Meta-analysis of observational studies relating estimated glomerular filtration rate to risk of death or major cardiovascular events. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California.
8. Abstract TH-PO405.
9. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-248. Abstract
10. Stam F, van Guldener C, Ter Wee PM, et al. Effect of folic acid on methionine and homocysteine metabolism in end-stage renal disease. Kidney Int. 2005;67:259-264. Abstract
11. Kalantar-Zadeh K, Ikizler TA, Block G, Avram MM, Kopple JD. Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis. 2003;42:864-881. Abstract
12. Zager PG, Nikolic J, Brown RH, et al."U" curve association of blood pressure and mortality in hemodialysis patients. Kidney Int. 1998;54:561-569. Abstract
13. Moe S, Drueke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69:1945-1953. Abstract
14. Kovesdy CP, Anderson J, Kalantar-Zadeh K. Low body mass is associated with higher mortality in patients with chronic kidney disease not yet on dialysis. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California. Abstract TH-PO425.
15. Kovesdy CP, Anderson J, Kalantar-Zadeh K. Inverse association between blood cholesterol and mortality in patients with chronic kidney disease not yet on dialysis: The effect of malnutrition-inflammation complex syndrome. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California. Abstract TH-PO426.
16. Gorriz JL, Castelao AM, De-Alvaro F, et al. One year mortality and risk factors management in diabetic vs. non-diabetic patients with chronic kidney disease stages 3 and 4. MERENA Study. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California. Abstract PUB344.
17. 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. Abstract
18. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006;70:771-780. Abstract
19. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42:S3:1-201.
20. Spiegel DM, Raggi P, Bellasi A, Block GA. Risk factors for mortality in patients new to dialysis. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California. Abstract F-FC080.
21. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16:1115-1125. Abstract
22. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446-456. Abstract
23. Tentori F, Hunt WC, Stidley CA, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 2006;70:1858-1865. Abstract
24. Wolf M, Gutierrez E, Ankers M, et al. Vitamin D levels and mortality among US hemodialysis patients. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California.
25. Abstract TH-FC093.
26. Kroeger PE, Nakane M, Ma J, Ruan X, Wu-Wong J. High phosphorus dampens VDR-mediated responses in human coronary artery smooth muscle cells. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California. Abstract TH-FC089.
27. Salusky IB. The role of bone biopsy in managing CKD. Morbidity and Mortality in CKD: Evidence-based Choices in the Therapy of SHPT. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California.
28. Hernandez JD, Wesseling K, Salusky IB. Role of parathyroid hormone and therapy with active vitamin D sterols in renal osteodystrophy. Semin Dial. 2005;18:290-295. Abstract
29. Slatopolsky E, Weerts C, Thielan J, et al. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest. 1984;2136-2143.
30. Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone disease in end-stage renal failure--an evolving disorder. Kidney Int. 1993;43:436-442. Abstract
31. Torres A, Lorenzo V, Hernandez D, et al. Bone disease in predialysis, hemodialysis, and CAPD patients: evidence of a better bone response to PTH. Kidney Int. 1995;47:1434-1442. Abstract
32. 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. Abstract
33. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed December 6, 2006.

Sangeetha Satyan, MD   Pooneh Alborzi, MD   Rajiv Agarwal, MD   

　

　

Introduction

Substantial interest has been generated within the nephrology community by recent epidemiologic observations that point to the role of vitamin D as a survival factor in patients with end-stage renal disease (ESRD). The pleiotrophic (see footnote*) nature of vitamin D beyond bone disease is stirring a therapeutic interest in vitamin D and its analogs as a means to cardiovascular protection in patients with ESRD.

It is well known that cardiovascular mortality rates are higher in chronic kidney disease (CKD) populations than in the general population and that atherosclerosis is not the only pathologic mechanism involved. Instead, cardiovascular disease in CKD is the result of an interplay among multiple factors. In this regard, there has been increasing attention on the disorders of calcium and phosphorus metabolism and abnormal bone turnover and its treatment, which result in medial calcification and contribute to the excess cardiovascular morbidity and mortality in CKD.

Vitamin D Therapy and Increased Survival: An Emerging Body of Data

Myles Wolf, MD,^[1] of Boston, Massachusetts, presented prospective data on vitamin D replacement and survival in hemodialysis patients. The National Kidney Foundation Kidney Dialysis Outcomes Quality Initiative (K/DOQI) clinical practice guideline recommendations for vitamin D therapy in CKD patients^[2] are "bone-centric" and parathyroid hormone (PTH)-driven, and this thought process needs to change on the basis of current and evolving data regarding the benefits of vitamin D, noted Dr. Wolf.

A historical cohort study of incident hemodialysis patients in which 37,173 patients received intravenous (IV) vitamin D compounds and 13,864 patients received no vitamin D showed a reduction in overall (13.8 vs 28.6/100-person years) and cardiovascular (7.6 vs 14.6/100-person years) mortality rates at 2 years in patients who received vitamin D.^[3] The hazard ratios were significantly lower for the vitamin D-treated group regardless of serum calcium, phosphorus, and PTH levels. In an earlier 2-year cohort study of 58,058 hemodialysis patients, those who received paricalcitol (n= 37,395) had better overall and cardiovascular survival.^[4] Several smaller studies have also demonstrated a survival advantage of vitamin D therapy. In addition, no studies to date have shown an association between vitamin D therapy and increased mortality. However, critics have warned against overinterpretation of the findings of these studies on the basis of their retrospective designs, use of historical cohorts, and the potential for unmeasured factors that may account for mortality. In another session, Ravi Thadhani, MD,^[5] of Boston, pointed out that the consistent findings of these studies do not imply causality, and emphasized the need for randomized controlled trials to directly study the impact of vitamin D replacement on outcomes in hemodialysis patients.

Wolf and colleagues^[6] conducted a prospective, nested case-control study of 10,000 incident hemodialysis patients to assess the risk for 90-day all-cause and CVD mortality associated with baseline levels of 25 hydroxy vitamin D (25D) and 1,25 dihydroxy vitamin D (1,25D); 25D and 1,25D levels were measured within 14 days of initiation of hemodialysis, and patients were excluded if they received IV vitamin D therapy prior to collection of the first blood sample. The potential for effect modification between vitamin D levels and survival by vitamin D therapy was analyzed. Vitamin D (25D and 1,25D) deficiencies were common; approximately 80% had 25D levels < 30 ng/mL and 76% had 1,25D levels < 15 pg/mL. Blacks were more likely than whites to be severely 25D deficient (< 10 ng/mL, 30% vs 14%; P < .01). The 90-day all-cause and cardiovascular mortality rates were significantly higher in patients who were not treated with vitamin D. Among untreated patients, those with 25D levels < 10 ng/mL and 1,25D levels < 15 pg/mL had significantly higher mortality rates. Moreover, the serum PTH level was a poor correlate of vitamin D deficiency manifested by low 25D and 1,25D levels. Historically, PTH levels have defined the need for vitamin D therapy. The emerging perspective is that 1,25D deficiency is the real problem and the PTH level is often but not always a marker of 1,25D deficiency. However, the K/DOQI guidelines do not recommend treatment with vitamin D in patients with low PTH levels, even though these patients are likely to be deficient in 1,25D and at increased risk of death, and vitamin D therapy seems to ameliorate the risk. This is not likely to change until prospective, randomized trials are done that show causality between vitamin D and survival benefit and answer questions related to the dose of vitamin D necessary for the survival benefit, timing of initiation of vitamin D therapy, and parameters to use for titration of treatment.

Should Vitamin D Therapy Be Used in Patients With Adynamic Bone Disorder?

One of the fears related to vitamin D therapy in CKD patients is the development of adynamic bone disorder. Clinically, adynamic bone disorder is thought to occur when vitamin D analog therapy suppresses the PTH level in CKD patients (which is normally 3 times the upper limit of normal [ULN] in a healthy population) to levels less than 2x ULN. Suppression to less than 3x ULN (150 pg/mL using the Nichols intact hormone assay as the reference), which is the lower limit of the recommended K/DOQI guideline range for stage V CKD, will generally be associated with adynamic bone disease.

The idea that vitamin D should not be used in patients with adynamic bone disorder may be incorrect since vitamin D doesn't cause adynamic bone disease; in fact, kidney injury directly suppresses bone remodeling in animals, according to Keith Hruska MD,^[6] of St Louis, Missouri. Hruska and colleagues^[7] developed 2 animal models to study the effect of vitamin D analogs on the production of adynamic bone disorder. In the first model, 10-week-old C57Bl6 mice were divided into 5 groups and fed a low-phosphorus (0.2%) diet for 12 weeks. Calcitriol at doses of 10 ng/kg and 20 ng/kg and paricalcitol at doses of 100 ng/kg and 400 ng/kg were injected thrice weekly for 12 weeks in CKD mice, and bone formation was compared with that of control sham mice. Bone formation did not decrease in calcitriol-treated (20 ng/kg) or paricalcitol-treated (100 ng/kg) mice compared with control mice. Somewhat unexpectedly, the bone volume increased in paricalcitol-treated mice, possibly as a result of a greater decrease in stimulation of osteoclast formation compared with calcitriol.

In the second model, induction of CKD in high-fat fed, low-density lipoprotein receptor-deficient mice resulted in adynamic bone disorder, despite the presence of secondary hyperparathyroidism. Treatment with paricalcitol or calcitriol did not reduce bone formation rates. In addition, there was a tendency toward increased bone formation in low-dose calcitriol-treated mice. As in the first model, paricalcitol increased bone volume mass, probably as a result of inhibition of osteoclast activity. Thus, vitamin D analogs did not decrease bone formation in animals with adynamic bone disorder. Pharmacologic doses of calcitriol and paricalcitol administered for 22-28 weeks in a similar mouse study diminished vascular calcification, demonstrating that clinical doses of the vitamin D analogs were protective against the development of vascular calcification in an animal model.^[8]

Implications for Practice

What should clinicians do in the absence of randomized controlled data? First, we have to be cautious in interpreting the findings of the studies presented here. Although treatment with vitamin D use has consistently been shown to be associated with better survival, without randomized controlled trials we cannot conclude that vitamin D is causally related to survival. A case in point is the consistent association of anemia with poor mortality outcomes from cohort studies in CKD. Yet, when hemoglobin was raised to a more normal level, increased rates of hospitalization for heart failure and death were observed.^[9,10]

Since 25D deficiency is so common in patients with CKD, it would seem prudent to correct vitamin D deficiency via adequate dietary intake, which may well be more than the recommended dietary allowance in healthy patients. Exogenous supplementation with vitamin D₂ (ergocalciferol) or D₃ (cholecalciferol) is also an option. A case for this type of therapy can be made even in patients with lower serum PTH levels, since impaired 1 alpha hydroxylase activity may not further suppress intact PTH in these patients. Thus, at the very least, wide screening for vitamin D deficiency and appropriate supplementation to correct deficiency may be warranted in patients with CKD.

References

1. Wolf M. Vitamin D replacement and survival: new prospective data. Cardiovascular disease and the morbidity and mortality in ESRD: Role of vitamin D and bone. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California.
2. National Kidney Foundation. KDOQI. Available at: www.kidney.org/professionals/KDOQI/guidelines_bone/index. Accessed December 1, 2006.
3. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446-456. Abstract
4. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16:1115-1125. Abstract
5. Thadhani RI. New clinical evidence for a survival effect of vitamin D in CKD. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California.
6. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and mortality among U.S. hemodialysis patients. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California. Abstract TH-FC093.
7. Hruska K. Interplay of bone and CVD. Cardiovascular disease and the morbidity and mortality in ESRD: role of vitamin D and bone. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California.
8. Mathew S, Lund R, Hruska KA. Evidence for selective modulation of tissue vitamin D receptors (VDR) by vitamin D analogs. Program and abstracts of the American Society of Nephrology Renal Week 2006; November 13-19, 2006; San Diego, California. Abstract SA-PO559.
9. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098. Abstract
10. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084. Abstract

Hariprasad S Trivedi, MD, DM, DNB   

　

　

Introduction

Patients with end-stage renal disease (ESRD) have much higher cardiovascular morbidity and mortality rates compared with patients without renal failure.^[1] The death rate due to coronary disease is 5-90 times greater in dialysis patients than in the general population, the differences being greatest in younger age groups. Therefore, defining the cardiovascular risk profile of ESRD patients is of great importance in order to improve outcomes in this population. Several recent observations point to phenomena of reverse epidemiology and altered relations between cardiovascular risk factors and morbidity and mortality in ESRD patients.^[2] Observational data have shown a variation in the cardiovascular risk imparted by known risk factors, such as hypertension, or in some instances a reversal of the risk, such as in the case of body mass index and mortality. Therefore, unconventional cardiovascular risks may be of greater consequence in patients with ESRD, a topic of increasing interest in recent times.

Potential Role of Altered Mineral Metabolism

ESRD patients have excessive vascular calcification that begins at a much earlier age compared with individuals who do not have renal failure, according to Myles Wolf, MD,^[3] of Boston, Massachusetts. Significant coronary calcification has been observed in ESRD patients as early as the third decade, and progressively increases over time.^[4] There appear to be differences in the morphology of vascular calcification in ESRD patients. In chronic kidney disease (CKD), vascular calcification is predominantly medial, as opposed to the intimal calcification that occurs in atherosclerosis.

Vascular calcification leads to increased stiffness of the arterial wall as assessed by aortic pulse wave velocity measurements. Increased stiffness leads to decreased vascular compliance, elevated systolic pressure, and widening of pulse pressure. The net effect is increased cardiac afterload, leading to cardiac stress and, ultimately, cardiovascular morbidity and mortality. Both vascular calcification and aortic pulse wave velocity have been shown to be associated with increased risk of death in ESRD patients.^[5,6]

There is a significant amount of data that relates abnormalities in calcium and phosphorus metabolism to vascular calcification and mortality. Serum phosphate and calcium-phosphorus product (C X P) correlate with coronary calcification in young ESRD patients. Further, increased calcium intake, both dietary and that due to use of calcium-based phosphorus binders, is associated with increased vascular calcification.^[4,7]

Serum phosphate has been shown to be an independent predictor of death in ESRD and predialysis CKD patients. Further, observational data in a select group of subjects who were at high risk of coronary events (post myocardial infarction) showed serum phosphate to be an independent predictor of death, even in patients without CKD.^[8] At the cellular level, increased extracellular phosphate leads to morphologic changes in vascular smooth muscle cells, resulting in mineralization in the microenvironment.^[9]

As further evidence of the role of altered mineral metabolism on outcome, intriguing data are available related to the treatment of ESRD patients with vitamin D sterols and decreased mortality. Abnormalities in vitamin D metabolism occur early in CKD. Relative or absolute vitamin D deficiency evolves by stage 2 and 3 CKD. In the absence of supplementation, dialysis patients typically have no measurable active vitamin D [1, 25(OH)₂D₃] levels. Using a sophisticated statistical model, investigators have demonstrated in a large dataset of dialysis patients that any use of active vitamin D is associated with improvement in cardiovascular and all-cause mortality.^[10] This benefit was observed irrespective of serum parathyroid hormone, calcium, and phosphate levels. The mechanism whereby vitamin D is beneficial merits investigation, but is possibly related to pleiotrophic effects (see footnote*) of the hormone.

In summary, observational evidence suggests that abnormalities in mineral metabolism, including high serum phosphate levels, accelerated vascular calcification, and vitamin D deficiency, represent risk factors for mortality in patients with ESRD.

Inflammation in CKD and Cardiovascular Risk

Another potential unconventional cardiovascular risk factor includes the inflammatory milieu related to the uremic state. Peter Stenvinkel, MD, PhD,^[11] of Stockholm, Sweden, discussed altered cytokine balance in CKD. While inflammation is part of the body's normal response to infection and the healing process, it has become clear over the past several years that excessive or unnecessary inflammation is harmful. Further, it has become evident that atherosclerosis represents an inflammatory state.^[12] Subclinical inflammation, assessed by markers such as C-reactive protein (CRP), has been linked to increased cardiac and all-cause mortality in several populations.^[13] Elevated CRP has been detected in a significant number of CKD patients, in several populations. Besides CRP, there are a number of candidate molecules that might play a role in the genesis of the inflammatory state in CKD, such as interleukin (IL)-6, IL-8, and IL-18, tumor necrosis factor-alpha, and a newly discovered molecule called high-mobility group box protein 1. IL-6 and IL-8 have been shown to be associated with an increased risk of cardiovascular and all-cause death in ESRD.^[14,15]

Inflammation leads to worsening anemia, resistance to hormones such as erythropoietin and insulin, catabolism, and oxidative stress. The inflammatory and reactive oxygen species systems, besides enhancing each other, could lead to endothelial dysfunction, an important predictor of long-term prognosis. The interaction between reactive oxygen species, inflammation, and endothelial dysfunction, and the prognostic significance of the latter, are well known.

The mechanism of inflammation in CKD is not known, but several potential pathways might be involved. An inflammatory response could be stimulated by infection or low-grade exposure to microbiologic agents or toxins during the dialysis procedure. On the other hand, there could be diminished breakdown of inflammatory molecules either due to kidney dysfunction or via release of inhibitors. Kidney damage by itself might lead to an inflammatory milieu due to related stresses such as reactive oxygen species, volume overload, or sympathetic hyperactivity. Interesting observations relate decreased vagal activity to inflammation, and reduced vagal tone has been detected in CKD. Genetic factors are also likely involved in the genesis of the inflammatory state.

To summarize, abundant data link inflammation with cardiovascular disease (CVD) and mortality. Inflammation is present in a great majority of patients with CKD, through a variety of potential pathways, and constitutes a potentially important unconventional cardiovascular risk of the uremic state.

Nonerythroid Effects of Erythropoietin (EPO)

Recent experimental evidence suggests that EPO has biologic effects distant from its traditional site of action, via the erythroid tissue. Iain C. Macdougall, MD,^[16] of London, UK, presented information regarding nonerythroid effects of erythropoietin. EPO receptors have been detected in many tissues, such as the brain and heart. EPO has been shown to possess antiapoptotic effects in many (nonerythroid) cell lines. Further, animal experiments demonstrate a beneficial effect of EPO after induced ischemia of various organs (heart, brain, spinal cord, kidney, and retina), and EPO was found to be protective in ischemic and toxic acute renal failure models.^[17,18] In a rat study in which animals subjected to subtotal nephrectomy were administered darbepoietin alfa or saline, the former group had a reduced death rate and a lesser degree of kidney damage.

A recent area of interest relates to certain circulating cells of bone marrow origin called endothelial progenitor cells (EPC), which migrate to sites of vascular injury and lead to repair. CKD is associated with a decrease in the number and a decline in the function of EPCs, and EPO boosts EPC number.

Finally, in a preliminary study of patients randomized to EPO vs saline at the time of ischemic cerebrovascular accident, evidence of a lesser degree of tissue damage was observed in the former group. These data regarding the nonerythroid beneficial effects of EPO raise the provocative question of whether EPO deficiency due to CKD confers risks of morbidity and mortality in addition to that related to anemia.

Conclusion

Several lines of evidence indicate that many nontraditional cardiovascular risks exist in the CKD state and likely contribute to the high cardiovascular morbidity and mortality seen in this disease process. Of note, intensive treatment of conventional cardiovascular risk factors has not resulted in improved outcomes in CKD subjects.^[19] It is the author's opinion that unconventional risks may be even more important in CKD than is currently recognized. Our own preliminary analysis suggests that incident dialysis patients with preexisting CVD have a higher risk of noncardiovascular death than subjects without CVD, raising a possibility that in CKD, CVD might be representative of a higher overall morbidity state.^[20] Future efforts need to be directed toward defining interventions aimed at targeting unconventional risks and confirming their benefit in large, prospective, randomized clinical trials.

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