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Cardiovascular Complications in Patients with Chronic Kidney Disease: The Essential Role of Vitamin D

The Biological Importance of the Vitamin D Axis in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is an illness that, along with diabetes and hypertension, is growing in prevalence. Because the final step of vitamin D activation occurs in the kidney, vitamin D action is impaired in persons with CKD, often resulting in secondary hyperparathyroidism and associated complications, said Alex J. Brown, PhD, Research Associate Professor of Medicine, Washington University School of Medicine, St. Louis, Missouri. According to Dr. Brown, “An understanding of the function of vitamin D and its deficiency in CKD is critical to the optimal assessment and management of this disease.”

Vitamin D Metabolism and Function
Vitamin D plays a central role in calcium and phosphate homeostasis, and is essential for the proper functioning not only of the bone, but also the intestine, kidney, parathyroid, and immune system (Brown et al. Am J Physiol 1999;277: F157). Vitamin D is found in some foods, but is derived mainly from exposure to sunlight. An ultraviolet (UV) light-induced conversion begins the process of metabolism into Vitamin D3. Vitamin D3 is converted to 25(OH)D3, and is ultimately metabolized to its active form—1,25(OH)2D3 or calcitriol—in the kidney. “This is a potent hormone that acts via its receptor to regulate gene transcription,” Dr. Brown noted. While vitamin D has many functions in the body, its most critical is that of intestinal calcium transport and absorption. Other functions of active vitamin D include induction of mineralization and resorption of the bone, and inhibition of parathyroid hormone (PTH) synthesis in the parathyroid gland. In the kidney, active vitamin D inhibits its own synthesis and enhances calcium reabsorption. “In patients with CKD, vitamin D system is abnormal—with reduced calcitriol synthesis and resistance to calcitriol action. Ultimately, this impairment of vitamin D action may necessitate the use of vitamin D therapy in persons with CKD,” Dr. Brown explained.

Vitamin D and Chronic Kidney Disease
According to recently released National Kidney Foundation guidelines, CKD is defined as either kidney damage or glomerular filtration rate (GFR) < 60 mL/min/1.73m2 for Ž 3 months. Kidney damage is demonstrated by pathologic abnormalities, markers of kidney damage (eg, blood or urine composition) or imaging tests. These guidelines also define the five stages of CKD based on GFR (Table 1) (National Kidney Foundation. Kidney disease outcomes quality initiative guidelines, 2003).

In persons with CKD, changes in vitamin D metabolism and action occur early in the course of disease, with decreased active vitamin D paralleling loss of kidney function (Martinez et al. Nephrol Dial Transplant 1996;11:22). “Importantly, vitamin D deficiency in patients with CKD can result in secondary hyperparathyroidism, decreased intestinal calcium and phosphate absorption, bone disease, altered renal vitamin D metabolism, abnormal calcium reabsorption, decreased suppression of renin, impaired glucose-mediated insulin release, and reduced immune function. Ultimately, secondary hyperparathyroidism also results in increased risk for renal osteodystrophy,” Dr. Brown explained (Dusso. Kidney Int Suppl 2003;85:S6. Holick. Am J Clin Nutr 2004;79:362).

Vitamin D Therapy
“The treatment of secondary hyperparathyroidism involves the use of phosphate-binding agents, such as calcium salts, and vitamin D therapy,” said Dr. Brown. The use of vitamin D analogs can be beneficial in helping to delay or prevent the complications associated with secondary hyperparathyroidism. “New third-generation vitamin D analogs may be useful in the prevention and treatment of secondary hyperparathyroidism and safer than first-generation analog agents, exerting more selective suppression of PTH and minimal effect on serum calcium and phosphate levels,” he concluded (Brown et al.  Nephrol Dial Transpl 2002; 17(suppl 10):10).


Vitamin D Therapy and Cardiovascular Morbidity and Mortality in Patients with Chronic Kidney Disease

“In patients with chronic kidney disease [CKD], cardiovascular disease [CVD] is the leading cause of morbidity and mortality. Indeed, the prognosis for patients with CKD is poor. In those with early-stage CKD, progression of disease to renal failure is common, but not as common as death,” said Myles Wolf, MD, MMSc, Instructor in Medicine, Harvard Medical School, and Assistant Program Director, Department of Internal Medicine Residency Program, Massachusetts General Hospital, Boston (Table 1). According to Dr. Wolf, “Vitamin D deficiency plays a key role in the pathogenesis of CKD-associated hyperparathyroidism—and perhaps also CVD-related mortality in these patients.” Active vitamin D therapy is the standard of care for those with secondary hyperparathyroidism, and may prevent or delay associated CVD morbidity and mortality in patients with CKD.

CKD and Secondary Hyperparathyroidism
Because the active metabolite of vitamin D—1,25 (OH)2 D3 or calcitriol—is synthesized in the kidney, patients with CKD have decreased calcitriol production, hyperphosphatemia, and hypocalcemia. These changes can ultimately result in secondary hyperparathyroidism, which is characterized by parathyroid hyperplasia and elevated parathyroid hormone (PTH) levels (Martinez et al. Nephrol Dial Transplant 1996;11:22). “In addition, patients with secondary hyperparathyroidism commonly develop CVD complications, such as hypertension, congestive heart failure, and left ventricular hypertrophy. Emerging evidence suggests a potential association between vitamin D deficiency and CVD complications in persons with CKD,” Dr. Wolf explained.

Vitamin D and Cardiovascular Disease
Recent studies of vitamin D deficiency and therapy show potential effects on multiple cardiovascular pathways. In terms of hypertension, several studies suggest a relationship to vitamin D levels. In one analysis, normotensive men with the lowest calcitriol levels were found to have the highest blood pressure (Kristal-Boneh et al. Hypertension 1997;30:1289). In a study of older women receiving vitamin D treatment, both systolic and diastolic blood pressures were significantly reduced in those receiving therapy (Pfeifer et al. J Clin Endocrinol Metab 2001;86:1633). Another analysis showed the highest renin levels in patients with the lowest serum calcitriol levels, suggesting an inverse relationship between the vitamin D and renin-angiotensin systems (Resnick et al. Ann Intern Med 1986; 105:649). “In another study, patients on dialysis who received intravenous calcitriol therapy showed a significant reduction in left ventricular mass as well as decreased renin, angiotensin II, and ANP levels with active vitamin D therapy, suggesting a link between the vitamin D and cardiovascular systems,” Dr. Wolf explained (Park et al. Am J Kid Dis 1999;33:73).

In a recent animal study, Li and colleagues created vitamin D receptor knockout mice. The results showed that knockout mice developed significantly more hypertension than wild-type mice. The knockout mice also had marked expansion of the juxtaglomerular apparatus, increased cardiac myocyte hypertrophy, and increased renin and angio- tensin levels, suggesting that vitamin D exerts a tonic inhibitory effect on the renin-angiotensin system (Li et al. J Clin Invest 2002;110:229). In addition, Zitterman and colleagues showed that low levels of vitamin D in humans may contribute to congestive heart failure and activation of the renin-angiotensin system (Zitterman et al. J Am Coll Cardiol 2003;41:105). “These findings may be of particular interest for application to persons with early-stage CKD, as this is when proteinuria is worsening and vitamin D deficiency, hypertension, and left ventricular hypertrophy are beginning to develop,” said Dr. Wolf.

Vitamin D Therapy
New National Kidney Foundation guidelines indicate the need to consider active vitamin D therapy not only for patients on dialysis, but also for some persons with earlier stage CKD (National Kidney Foundation. Kidney disease outcomes quality initiative clinical practice guidelines for bone metabolism and disease in CKD, 2003). First-generation vitamin D analogs, such as calcitriol, show a potent ability to inhibit PTH levels. However, their use is also associated with an increased risk for hypercalcemia and hyperphosphatemia. “This observation led to the development of newer vitamin D analogs with increased selectivity for PTH suppression, and a reduced effect on calcium and phosphate absorption in the gut,” Dr. Wolf explained.

Indeed, one long-term study of patients on dialysis receiving third-generation paricalcitol demonstrated a sustained reduction in PTH, with an initial modest increase in calcium and phosphate levels that stabilized over time (Lindberg et al. Clin Nephrol 2001;56: 315). In another study, researchers compared calcitriol and paricalcitol in patients on dialysis. They found a comparable reduction in PTH levels, but with significantly less risk of sustained hypercalcemia or calcium-phosphate product > 75 in the paricalcitol group (Sprague et al. Kidney Int 2003;63:1483). “Importantly, compared with calcitriol, current data indicate that paricalcitol has a three-fold increased selectivity for PTH suppression, relative to its effects on calcium and phosphate,” Dr. Wolf noted.

Differences in survival have also been shown with the newer vitamin D analogs. In an observational study of more than 67,000 patients on dialysis at Fresenius Medical Center, patients receiving paricalcitol for secondary hyperparathyroidism showed a significant survival advantage over those receiving calcitriol. “After adjusting for other variables, such as age, gender, race, and known survival factors, the survival advantage for those receiving paricalcitol was 16%, and this benefit continued to increase over time,” Dr. Wolf stated (Teng et al. N Engl J Med 2003;349: 446). According to Dr. Wolf, these promising data warrant further study in randomized, controlled trials.

In closing, Dr. Wolf emphasized that vitamin D is critical for the normal maintenance of mineral metabolism in patients with CKD. “Emerging evidence suggests that vitamin D deficiency may contribute to the excess CVD-related morbidity and mortality in this population. While the exact mechanisms are not completely understood, active vitamin D therapy appears to confer a survival advantage in CKD patients on dialysis, and may be of benefit in those with earlier stage disease. The next research frontier is to investigate the direct impact of vitamin D therapy on CVD morbidity and mortality in those with earlier stage CKD,” he concluded.

Pathogenesis of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease: Prevention and Therapeutic Alternatives

As many as 20 million people in the United States are affected by chronic kidney disease (CKD), and the prevalence of this disease is increasing. While approximately 300,000 individuals have stage 5 kidney disease, millions are afflicted with earlier stage disease. “The recently released National Kidney Foundation guidelines define the five stages of CKD by estimated glomerular filtration rate [GFR], in order to help facilitate early detection and treatment of CKD,” said Francisco Llach, MD, Program Chairperson, Professor of Medicine and Director of Clinical Nephrology, Georgetown University Hospital, Washington, DC. According to Dr. Llach, secondary hyperparathyroidism begins to develop in the early stages of CKD, and requires aggressive monitoring and treatment to control parathyroid hormone (PTH) levels and delay or prevent progression of disease and associated bone and cardiovascular (CV) complications.

CKD and Secondary Hyperparathyroidism
In people with CKD, the kidney’s ability to convert vitamin D to its active metabolite, 1,25(OH)2D3 or calcitriol, is im-paired. Thus, active vitamin D synthesis begins to decline significantly at GFR60 mL/min/1.73 m2 (stage 2), resulting in decreased calcium and phosphorus absorption, and ultimately elevated parathyroid hormone (PTH) levels. The severity of secondary hyperparathyroidism increases as CKD progresses. Secondary hyperparathyroidism is associated with numerous complications, including renal osteodystrophy and potentially CV disease. Indeed, the most common comorbidity in patients with CKD is CV disease, with CV-related mortality being increased 10 to 100 times in patients having kidney failure. Limited calcium and phosphorus absorption can result in vascular calcification and increased CV-related morbidity and mortality. In addition, an observational study compared mortality rates by GFR in persons with CKD. The results showed a survival advantage in patients with the highest GFR over those with the lowest GFR. For each age decade, there was a 25% increased incidence of CV-related mortality. “The research shows not only increased CKD-related mortality among persons with end-stage renal disease, but also for those with earlier stage disease,” Dr. Llach said.

“To allow for optimal intervention and prevention of bone and CV complications, persons with CKD should be monitored for hematocrit, calcium, phosphorus, 1,25(OH)2D3, and PTH levels early in their disease,” said Dr. Llach. One retrospective study indicates that, even in patients with stage 4 disease, only 15% had PTH levels and only 18% had hematocrit measured on their first nephrology visit. Another study of patients on dialysis who were receiving vitamin D therapy showed that only 6% had PTH levels assessed in the preceding 3 months. “These data indicate the need for increased education regarding the monitoring, assessment, and management of CKD among general practitioners, internists, and nephrologists,” Dr. Llach explained.

Monitoring and Treatment
The treatment of secondary hyperparathyroidism requires maintenance of PTH levels, prevention of parathyroid gland hyperplasia, and maintenance of normal serum calcium and phosphorus levels. Aggressive and early treatment for CKD-associated secondary hyperparathyroidism is needed to reduce the risk of renal osteodystrophy and CV-related mortality. “As part of the management of those with CKD, regular monitoring of active vitamin D and PTH status is essential,” Dr. Llach said.

Available interventions for the management of secondary hyperparathyroidism include phosphorus-binding agents and vitamin D analogs. While first-generation vitamin D analogs are beneficial in suppressing PTH levels, they have also been associated with significant hypercalcemia and hyperphosphotemia. Thus, highly selective vitamin D analog agents have been developed to exert the same beneficial effect on PTH status, but minimize the impact on calcium and phosphorus levels. For example, one group of patients on dialysis received either paricalcitol or placebo. Paricalcitol was associated with suppression of PTH levels, but with no effect on serum calcium and phosphorus status. Similar findings were found in studies of patients with stage 3 and 4 CKD receiving paricalcitol. According to Dr. Llach, new National Kidney Foundation guidelines provide treatment recommendations by CKD stage and indicate the need for closer monitoring and control of PTH, calcium, and phosphorus levels in persons with CKD (National Kidney Foundation. Kidney disease outcomes quality initiative guidelines, 2003).

In closing, Dr. Llach stressed that the majority of patients with CKD-associated secondary hyperparathyroidism currently are not adequately monitored or managed. “This is often the result of late or suboptimal intervention,” he noted. “Early monitoring and treatment of patients with CKD is vital to prevent and treat secondary hyperparathyroidism, and perhaps also delay or prevent associated complications, such as renal osteodystrophy and CV disease,” the speaker concluded.

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