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Early Identification and Treatment of Chronic Kidney Disease: Reaching Patients with Hypertension and Diabetes

Steps to Early Diagnosis of Chronic Kidney Disease in Patients with Hypertension and Diabetes 

Chronic kidney disease (CKD) is a serious condition that affects 11% of the US population and is rapidly increasing in incidence and prevalence around the world. This increase is due largely to the prevalence of diabetes and hypertension, which together, are responsible for every two of three cases of CKD. “Importantly, early detection and treatment of CKD has been associated with longer dialysis-free survival and reduced cardiovascular morbidity and mortality in persons with this disease,” said JudyAnn Bigby, MD, Medical Director, Community Health Programs; Attending Physician, Brigham and Women’s Hospital; Associate Professor of Medicine; Director, Center of Excellence in Women’s Health; Harvard Medical School, Boston (Coresh et al. Am J Kidney Dis 2003;41:1. Hostetter. J Am Soc Nephrol 2003;14:S144). According to Dr. Bigby, primary care physicians play a critical role in ensuring the early assessment and treatment of individuals with CKD.

CKD Morbidity and Mortality
Chronic kidney disease is defined as either 1) a glomerular filtration rate (GFR) of < 60 mL/min/1.73 m2 of 3 or more months, with or without kidney damage or 2) kidney damage of 3 or more months, characterized as a structural or functional abnormality of the kidney with or without decreased GFR and demonstrated by abnormalities by pathology, blood, urine, or imaging tests. Routine monitoring and identification of CKD stage is key to early and appropriate intervention (Table 1).

CKD is associated with significant morbidity and mortality: not only end-stage renal disease requiring dialysis or transplantation, but also cardiovascular disease (CVD). “In fact, more patients with CKD will develop CVD than will develop kidney failure,” Dr. Bigby explained (Sarnak et al. Hypertension 2003;42:1050).

Diabetes and hypertension are the leading causes of reported kidney failure in the United States, and the cause of CKD clearly has an impact on morbidity and mortality associated with this disease (United States Renal Data System. 2000 Annual Data Report). “The people with kidney failure who have the poorest outcomes are those with diabetes. In addition, in patients who are having dialysis or hemodialysis, cardiac arrest is the most common cause of death,” Dr. Bigby noted (United States Renal Data System. 2000 Annual Data Report). Fortunately, some adverse outcomes can be prevented or delayed through the early detection and treatment of CKD.

Steps to Early Detection and Treatment
Clinical practice guidelines developed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative address the diagnosis, staging, treatment, progression, and complications of CKD. To reduce CKD-associated morbidity and mortality, identifying people at high risk and detecting the disease early are key (Table 2). Recognizing the stage of disease is imperative to effective treatment. Importantly, early-stage CKD often shows no symptoms. “For all those who have or are at increased risk for CKD, clinicians need to provide routine assessment of blood pressure; serum creatinine for GFR; and urine analysis of albumin:creatinine ratio, erythrocytes, and leukocytes,” Dr. Bigby noted (Levey et al. Ann Intern Med 2003;139:137). According to Dr. Bigby, screening for microalbuminuria, proteinuria, and GFR is easy and effective in the diagnosis and monitoring of CKD. Other recommended laboratory tests include ultrasound, serum electrolytes, urinary concentration or dilution, and urinary pH.

Disease Progression and Complications
The progression of CKD can result in serious complications, including secondary hyperparathyroidism, CVD, anemia, malnutrition, neuropathy, reduced functioning, and bone disease (Levey et al. Ann Intern Med 2003;139: 137). Treatment to slow the progression of CKD includes measures such as: aggressive treatment of the primary disease, hypertension, and proteinuria; aggressive management of glycemic levels; and early referral to a nephrologist (Levey et al. Ann Intern Med 2003; 139:137. Yu. Arch Intern Med 2003; 163:1417).

In closing, Dr. Bigby stressed the importance of primary care physicians in the identification and treatment of patients with CKD. “As the first to see patients with CKD, primary care physicians play a critical role in identifying and treating these individuals, co-managing with a nephrologist, and hopefully preventing or delaying the serious complications of CKD,” Dr. Bigby said.

The Progressive Stages of Chronic Kidney Disease and Cardiovascular Disease Morbidity

“The reduction of morbidity and mortality from end-stage renal disease [ESRD] and cardiovascular disease [CVD] is a primary goal in persons with chronic kidney disease [CKD],” said George L. Bakris, MD, Program Chairperson, Professor of Preventive Medicine and Internal Medicine, Rush Medical College; Director, Rush University Hypertension Center; Vice Chairman, Department of Preventive Medicine; Rush University Medical Center, Chicago. “Importantly, CKD is associated with a progressive deterioration of kidney function, with an early decrease in vitamin D. This results in
secondary hyperparathyroidism and an elevated calcium-phosphate product, which is clearly linked to increased CKD-related morbidity and mortality,” he noted. According to Dr. Bakris, the use of vitamin D therapy can be an important intervention in reducing the risk of ESRD, CVD, and bone complications in patients with CKD. “Important are identification of CKD stage and early treatment in accordance with the recently published National Kidney Foundation guidelines,” Dr. Bakris explained.

Progression of Disease
Persons at highest risk for both CKD and CVD are those who are older, have diabetes mellitus, and/or have hypertension. In addition, CVD mortality is increased 10 to 100 times in persons with CKD (Levey et al. Ann Intern Med 2003;139: 137). Early stages of CKD show albuminuria as well as proteinuria, along with increased coronary heart disease and left ventricular hypertrophy. As CKD progresses, glomerular filtration rate (GFR) is decreased and arteriosclerotic CVD is increased. End-stage CKD may result in kidney or heart failure (Eknoyan. Am J Kidney Dis 2002;39:S1-S266). “The presence of abnormal kidney function is itself a CVD risk factor; the higher the proteinuria, the greater the risk of CVD,” Dr. Bakris explained.

The Role of Vitamin D
According to Dr. Bakris, patients with CKD experience a decrease in calcitriol—an activated vitamin D metabolite—early in the disease process. “Vitamin D synthesis occurs in the kidney, and begins to decline significantly at GFR 60 mL/ min/1.73 m2,” he explained. This decline results in elevations in parathyroid hormone (PTH) levels, and potential bone and CVD complications (Martinez et al. Nephrol Dial Transplant 1996;11:22).

In one study, patients with heart failure were evaluated for atrial natriuretic peptide (ANP), vitamin D metabolites, and mineral homeostasis markers. The results showed ANP and phosphorus levels to be increased, both 25(OH) vitamin D3 and calcitriol decreased, and PTH levels elevated in patients with heart failure compared with controls (Zitterman et al. J Am Coll Cardiol 2003;41:105). In addition, Ganesh and colleagues found increased all-cause mortality and coronary artery disease with elevated phosphorus; increased CAD mortality and sudden death with elevated calcium phosphate product; and increased sudden death with elevated PTH in persons with advanced kidney disease (Ganesh et al. JASN 2001; 12:2131).

“In addition to increased CVD risk, a decline in vitamin D can result in serious bone complications,” Dr. Bakris explained. As vitamin D synthesis drops, calcium levels fall, parathyroid hormone synthesis and secretion increase, and bone disease develops. “Importantly, active vitamin D can shut down this hyperparathyroid activity,” Dr. Bakris said (Figure 1). Active vitamin D has been shown to inhibit inflammatory markers and downregulate renin, potentially resulting in reductions in atherosclerosis, myocardial hypertrophy, heart failure, and ultimately morbidity and mortality (Li et al. J Clin Invest 2002; 110:229. Mathieu & Adorini. Trends Mol Med 2002;8:174. Park et al. Am J Kidney Dis 1999;33:73. Timms et al. QJM 2002;95:787. Yu et al. Proc Natl Acad Sci 1995;92:10990). Watson and colleagues also demonstrated an inverse correlation with vitamin D serum levels and coronary calcification (Watson et al. Circulation 1997;9:1755).

Treatment Goals and Directions
The stages of CKD offer multiple targets for therapeutic intervention (Figure 2). Immediate treatment goals in persons with CKD include maintaining normal PTH, serum phosphorus, serum calcium levels; preventing parathyroid gland hyperplasia; and maintaining normal skeletal function. Long-term treatment strategies are directed at reducing the
risk of renal osteodystrophy and CVD morbidity and mortality.

According to Dr. Bakris, monitoring of calcium, phosphorus, and PTH levels is essential to evaluate CKD status. In addition, vitamin D analogs provide an effective treatment option for controlling secondary hyperparathyroidism and thus preventing or delaying associated skeletal and CVD morbidity and mortality. Calcitriol exerts a number of direct and indirect therapeutic effects (Figure 1), and has been associated with left ventricular mass regression in patients with stage 5 CKD (Park et al. Am J Kidney Dis 1999;33:73). Paricalcitol, a newer agent, provides selective lowering of PTH with no significant difference in hyperphosphatemia or hypercalcemia incidence compared to placebo (Lindberg et al. Clin Nephrol 2001;56:315). Recent study data indicate that patients with kidney failure receiving paricalcitol for the management of hyperparathyroidism had a 16% increased survival over those receiving calcitriol (Teng et al. N Engl J Med 2003;349:496). Other studies in patients with stage 5 CKD have shown benefits in the control of calcium, phosphate, and PTH levels (Sprague et al. Kidney Int 2003;63:1483. Martin et al. J Am Soc Nephrol 1998;9:1427). For example, in one phase III placebo-controlled study of patients with ESRD on hemodialysis, 68% of those receiving paricalcitol had at least a 30% decrease in serum PTH. In addition, mean serum calcium levels remained within normal range, and mean serum phosphorus levels did not change significantly compared with baseline values. Efficacy and safety studies of paricalcitol use in patients with stage 3 and 4 CKD are currently underway.

In closing, Dr. Bakris stressed that new National Kidney Foundation guidelines urge closer monitoring and control of PTH, calcium, and phosphate levels in patients with CKD. “In the future, it is hoped that highly selective vitamin D analogs used in the early stages of CKD may be effective in achieving improved control of secondary hyperparathyroidism—and ultimately reduced CVD morbidity and mortality,” the speaker concluded.

New Horizons in Vitamin D Management and Patient Care:
Cardioprotective and Antiproliferative Effects


“The health benefits of vitamin D in calcium regulation and bone metabolism are well known. However, recent data also suggest a key role in the maintenance of cardiovascular (CV) health, immune function, and cell proliferation,” said Michael F. Holick, PhD, MD, Professor of Medicine, Physiology, and Biophysics; Director, General Clinical Research Center; Director, Bone Health Care Clinic; Director, Heliotherapy, Light, and Skin Research Center; Boston University Medical School, Boston, Massachusetts (Holick. Am J Clin Nutr 2004;79:362). “This emerging evidence indicates that maintenance of adequate vitamin D status is critically important throughout one’s life—not only for bone health, but also for the prevention of numerous chronic diseases,” Dr. Holick noted. In patients with chronic kidney disease (CKD), vitamin D status and control of secondary hyperparathyroidism are critical in the prevention or delay of CV and bone morbidity.

Vitamin D Deficiency
According to Dr. Holick, most of the body’s vitamin D requirement is met through casual exposure to sunlight. The skin responds to the ultraviolet (UV) rays, and the liver metabolizes vitamin D to 25(hydroxy) vitamin D. This metabolite is further metabolized to 1, 25 dihydroxy vitamin D—or calcitriol—in the kidney. This metabolite is the active form of vitamin D that is used by the body.

“Vitamin D deficiency is common, especially in the wintertime, and in persons who are elderly, have darker skin, and live at higher geographic latitudes,” said Dr. Holick.

Vitamin D deficiency can contribute to a number of illnesses, including secondary hyperparathyroidism; CV disease; osteomalacia; osteoporosis; rickets; autoimmune diseases, including type 1 diabetes, multiple sclerosis, and rheumatoid arthritis; and some cancers (Holick. Am J Clin Nutr 2004;79:362). In addition, persons who live at higher latitudes and are more likely to be vitamin D deficient have been shown to be at increased risk for hypertension and for some cancers. There also appears to be an increased risk for cancer-related mortality in persons having minimal exposure to sunlight (Grant. Cancer 2002;94:1867).

Vitamin D Antiproliferative and Cardioprotective Effects
Emerging evidence suggests that vitamin D may play a role in the reduction of both hyperproliferative cell growth and CV morbidity. Indeed, in vitro studies show that introduction of calcitriol to skin cells results in inhibition of cell proliferation and induction of terminal cell differentiation (Holick. Am J Clin Nutr 2004;79:362). A double-blind study of persons with psoriasis showed a marked improvement with topical calcitriol therapy compared with placebo petroleum jelly. (Holick. Am J Clin Nutr 2004;79:362). In certain cancer cells, vitamin D may aid in regulating cell growth and inhibiting proliferation in these cells. “Active vitamin D analogs have been used in the adjunct treatment of prostate and colon cancers,” Dr. Holick pointed out (Chen et al. Trends Endocrinol Metab 2003;14:423).

In terms of CV disease, data suggest that vitamin D therapy may be beneficial in the management of hypertension as well as reduction of heart failure risk. Holick and colleagues treated hypertensive patients with either a UVB (vitamin D production) or a UVA (no vitamin D production) tanning bed. After 3 months, the group receiving UVA rays showed no change in vitamin D levels and no reduction in hypertension. However, those receiving UVB rays experienced an average increase in vitamin D levels of 180%, along with an average 6 mmHg in blood pressures (Krause et al. Lancet 1998;352:709). Vitamin D deficiency is also a risk factor for congestive heart failure (Zitterman et al. J Am Coll Cardiol 2003;41:105), and a contributor to the pathogenesis of CV morbidity in persons with CKD. According to Dr. Holick, vitamin D analog therapy may act on multiple pathogenic pathways. “The cardioprotective effect of vitamin D may be due to a number of factors, including reduction of atherosclerosis, regression of myocardial hypertrophy, downregulation of the renin and angiotensin, inhibition of inflammatory factors, and reduction of coronary calcification,” Dr. Holick said.

Deficiency Diagnosis and Treatment
According to Dr. Holick, vitamin D deficiency is often misdiagnosed. “When diagnosing a vitamin D deficiency, clinicians need to test and monitor serum 25 (hydroxy) vitamin D status,” he advised. For persons who have CKD, vitamin D metabolism is compromised and an active vitamin D analog is often needed to prevent or delay secondary hyperparathyroidism and associated bone and CV disease morbidity. Dr. Holick recommended that clinicians consult the recently published National Kidney Foundation’s Kidney Disease Outcomes Quality Initiatives Clinical Practice Guidelines for the assessment and management of CKD, including treatment of vitamin D deficiency. “Vitamin D analogs offer a valuable intervention option not only for patients with end-stage CKD, but also for select individuals with stage 3 or 4 disease,” he concluded.

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