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

At a symposium conducted in conjunction with the 13th Annual Meeting and Clinical Congress of
the American Association of Clinical Endocrinologists, two leaders in organ transplantation, bone health, and biophysics presented the latest data on the identification and management of chronic kidney disease. Topics included the identification of disease stage, steps to early detection, and treatment of chronic kidney disease and associated vitamin D deficiency.

This program was supported by an unrestricted educational grant from Abbott Laboratories.

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

An estimated 11 million Americans are afflicted with chronic kidney disease (CKD). “While end-stage renal disease [ESRD] is a frequent outcome of CKD, even more common is cardiovascular [CV] morbidity and mortality,” said Lawrence G. Hunsicker, MD, Professor of Internal Medicine, University of Iowa College of Medicine; Medical Director, Organ Transplantation, University of Iowa Hospitals and Clinics, Iowa City. According to Dr. Hunsicker, CKD is often diagnosed too late—after the signs and symptoms of disease have already developed. “To prevent or delay CKD-associated ESRD and CV morbidity, clinicians must monitor high-risk individuals to ensure early detection—and thus early treatment—of CKD,” he noted.

CKD Definition and Stages
The recently published National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines define CKD as either 1) glomerular filtration rate (GFR) of < 60 mL/min with or without kidney damage for 3 or more months; or 2) the presence of kidney damage for 3 or more months 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), information that is critical to the effective treatment and monitoring of CKD and its potential complications. “Importantly, measurement of proteinuria is a valuable tool in identifying early CKD. The recommended assessment for proteinuria is now albumin:creatinine ratio [non-diluted spot urine test] rather than 24-hour albumin excretion rate,” Dr. Hunsicker explained (National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification, 2002).

Renal and Cardiac Outcomes
The outcome of patients with ESRD is poor; however, even those with CKD without ESRD have a significantly reduced life expectancy. In preventing or delaying ESRD in patients with CKD, three steps are key: aggressive management of hypertension, blockade of the renin-angiotensin system, and reduction of proteinuria. For example, in the IDNT study, patients with diabetic nephropathy showed a linear inverse relationship: the lower the blood pressure, the better the renal outcomes. “Importantly, if the renin-angiotensin system is blocked and blood pressure is lowered [by 20mm], there is an additive effect, with risk of adverse renal outcomes being reduced by 63%,” Dr. Hunsicker explained (Pohl et al. J Am Soc Nephrol 2002;13:650a (abstract)).

Finally, baseline proteinuria is a predictor of renal outcome, with a doubling of adverse renal outcome for each doubling of proteinuria levels. “For every halving of proteinuria levels, there is a 50% reduction in risk of adverse renal endpoints,” he noted (Atkins et al. J Am Soc Nephrol 2002;13:7a (abstract)).

Progression of CKD can lead not only to ESRD, but also to CV disease. “Indeed, persons with CKD are 10 times more likely to die of heart disease than renal failure,” Dr. Hunsicker noted (Collins et al. Kidney Int 2003; (87 suppl):S24). According to Dr. Hunsicker, the JNC-7 notes the presence of CKD in the highest risk category for coronary artery disease and indicates the need for the same monitoring as in those who have had previous myocardial infarction. As with renal disease, the aggressive management of hypertension and blockade of renin-angiotensin can provide significant reduction in the risk of CV disease in patients with CKD.

Steps to Early Diagnosis and Treatment
The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines address the diagnosis, staging, treatment, and progression of CKD. Key to reducing the morbidity and mortality associated with CKD are identification of people at high risk and detection of the disease early. “The treatment goal is early detection of asymptomatic CKD when the potential positive impact of intervention is optimal,” Dr. Hunsicker explained. For people who have or are at increased risk for CKD (Table 2), clinicians need to provide routine assessment of blood pressure; serum creatinine for estimation of GFR; determination of albumin:creatinine ratio and microscopic urine analysis for detection of erythrocytes and leukocytes (Levey et al. Ann Intern Med 2003;139:137). “Ultimately, close monitoring of these factors is essential to the early diagnosis and optimal treatment of CKD,” he concluded.

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

“Recent data suggest a key role for vitamin D in the maintenance not only of bone health, but also of cardiovascular 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). “In patients with chronic kidney disease [CKD], vitamin D deficiency and associated hyperparathyroidism contribute to an increased risk of both end-stage renal disease [ESRD] and cardiovascular [CV] morbidity and mortality,” Dr. Holick noted. According to Dr. Holick, the early detection of CKD and monitoring of glomular filtration rate (GFR), vitamin D status, and parathyroid hormone (PTH) levels allow for effective intervention to reduce the risk for ESRD and CV disease.

Vitamin D Metabolism
According to Dr. Holick, a few foods (cod liver oil, oily fishes, fortified milk and orange juice) contain vitamin D, but 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(OH) vitamin D. This metabolite is further metabolized to 1,25(OH)₂ vitamin D—or calcitriol—in the kidney. This metabolite is the active form of vitamin D that is used by the body. Because activation occurs largely in the kidney, patients with CKD are at increased risk for 1,25(OH)₂ vitamin D deficiency and associated secondary hyperparathyroidism. As mild to moderate renal failure develops, clearance of phosphorus decreases, and serum phosphorus levels increase. Production of 1,25(OH)₂ vitamin D then significantly decreases in the kidney, intestinal calcium absorption decreases, and serum calcium levels decrease. This causes a compensatory increase in PTH, resulting in increased risk of CV disease and potentially CV calcifications (Figure 1) (Holick. Am J Clin Nutr 2004;79:362).

Vitamin D Deficiency
Vitamin D deficiency is common, especially in the wintertime, and in persons who are elderly, have darker skin, and live at higher geographic latitudes. Importantly, data indicate that 30% to 50% of African Americans are seasonally or chronically deficient in vitamin D (Nesby-ODell. Am J Clin Nutr 2002; 76:187). So too, many persons with obesity are vitamin D deficient. In one study, obese and normal-weight persons underwent UV radiation via tanning bed. Obese persons showed a 50% reduction in vitamin D production compared with the normal-weight group (Wortsman et al. Am J Clin Nutr 2000;72:650). In addition, use of sunscreen significantly reduces the production of vitamin D. In one trial, medical students with and without sunscreen (SPF 8) underwent tanning via tanning bed. In those using sunscreen, vitamin D production was reduced by nearly 98% (Matsuoka et al. J Clin Endocrinol Metab 1987;84:1165). According to Dr. Holick, “Individuals should avoid excessive sun exposure because of the increased risk of skin cancer. However, 5 to 15 minutes of casual exposure on the arms and legs, twice per week, should be enough to meet the vitamin D requirements for most people.”

Vitamin D deficiency can contribute to a number of illnesses, including secondary hyperparathyroidism, osteomalacia, osteoporosis, rickets, CV disease, and some cancers (Holick. Am J Clin Nutr 2004;79:362). Indeed, recent studies have shown vitamin D deficiency in 40% to 60% of patients with fibromyalgia, 88% of women with muscle weakness (Denmark), and 93% of persons (Minnesota) with persistent musculoskeletal pain (Plotnikoff & Quigley. Mayo Clin Proc 2003;78: 1463. Glerup et al. J Intern Med 2000; 247:260. Zitterman et al. J Am Coll Cardiol 2003;41:105. Timms et al. QJ Med 2002;95:787 ). 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 Cardioprotective and Antiproliferative Effects
According to Dr. Holick, recent data suggest that vitamin D may play a role in the reduction of both hyperproliferative cell growth and CV morbidity. In vitro studies show that introduction of 1,25(OH)2 vitamin D3 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 1,25(OH)2 vitamin D3 therapy compared with placebo petroleum jelly (Holick. Retinoids 1998;14:12). An antiproliferative effect has also been shown in patients with cancer. In certain cancer cells, vitamin D may aid in regulating cell growth and inhibiting proliferation in these cells. “1,25(OH)2 Vitamin D has been used in the adjunct treatment of both 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. Krause and colleagues treated hypertensive patients with either a UVB (vitamin D production) or a UVA (no vitamin D production) tanning bed. After 3 months of therapy, 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 decrease in systolic and diastolic 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, yielding improved CV outcomes. “The cardioprotective effect of vitamin D may be due to a number of factors, including reduction of atherosclerosis, regression of myocardial hypertrophy, downregulation of renin and angiotensin, inhibition of inflammatory factors, and reduction of coronary calcification,” Dr. Holick said.

Vitamin D Deficiency: Issues for Diagnosis
According to Dr. Holick, vitamin D deficiency is often misdiagnosed. 25(OH) vitamin D levels, he noted, should be at least 20 ng/mL, and preferably 30 ng/mL or greater. “Even persons who have 25(OH) vitamin D levels in the low range of normal can be vitamin D deficient in reality,” Dr. Holick noted. In one study, persons 49 to 83 years old with 25(OH) vitamin D levels in the low normal range (11-20 ng/mL) received 50,000 units of vitamin D once/week for 8 weeks. In these patients, 100% demonstrated increased 25(OH) D levels, and an average decrease of 22% in PTH levels (Malabanan et al. Lancet 1998;351:805).

“When diagnosing a vitamin D deficiency, clinicians need to test and monitor serum 25(OH) vitamin D status, including all patients with CKD. Patients with CKD who have a normal vitamin D status may have PTH levels that are increasing. Thus, in these individuals it is also helpful to monitor PTH,” Dr. Holick advised.

Vitamin D Deficiency: Treatment Considerations
The National Kidney Foundation recently published the Kidney Disease Outcomes Quality Initiatives Clinical Practice guidelines for the assessment and management of CKD, including the treatment of vitamin D deficiency. According to Dr. Holick, 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. “In patients with mild to moderate renal failure, use of a calcium- binding agent and consideration of vitamin D therapy are warranted in maintaining appropriate 25(OH) D and PTH levels,” Dr. Holick noted. “In persons with severe renal failure, secondary hyperparathyroidism develops and use of a vitamin D analog is helpful in decreasing PTH levels,” he said. Calcitriol was the agent first approved for this purpose, but newer agents are also available. Paricalcitol, for example, is effective in the treatment of secondary hyperparathyroidism, but is less likely than calcitriol to induce hypercalcemia. “This is because paricalcitol is selective for inhibition of PTH,” Dr. Holick explained. Indeed, in one study, patients with CKD received either calcitriol or paricalcitol. Those receiving paricalcitol had a 12% reduced risk of death after 500 days and an 18% reduced risk of death after 1000 days compared to those receiving calcitriol (Teng et al. N Engl J Med 2003;349:446). “Vitamin D analog therapy can act not only to correct calcium metabolism, but also to prolong life,” Dr. Holick explained.

In closing, Dr. Holick recommended that clinicians consult the National Kidney Foundation guidelines for the assessment and management of CKD, not only for persons with ESRD but also for those with early CKD. “Early diagnosis and intervention in patients with CKD is essential to providing optimal management of disease and reduction of risk for associated CV morbidity and mortality,” Dr. Holick concluded.