Chronic Kidney Disease: It's Time to Recognize Its Presence in Our Patients With Hypertension

Chronic kidney disease (CKD) is one of the world's major public health problems, and the prevalence of kidney failure is rising steadily. CKD is defined in the Seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ¹ as either (1) an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m ² or (2) the presence of clinical proteinuria (>300 mg/d or 200 mg/g creatinine). In the United States alone, 20 million Americans, or one in nine adults, have CKD and another 20 million more are at increased risk for its development. ² Hypertension is a significant risk factor for CKD. The early stages of CKD are primarily a silent disease. While blood pressure (BP) monitoring occurs at nearly every visit to the doctor, screening for CKD occurs infrequently. The failure to screen for CKD is a missed opportunity for improving patient outcome.

How do we recognize CKD? There are two ways to detect this disease.

• 1Measure for proteinuria (macroalbuminuria), which can be detected on initial urinalysis. Patients with hypertension should have a routine urinalysis. ¹ Increased urinary protein excretion is usually a marker of kidney damage and a predictor of disease progression. ³ Testing for microalbuminuria is optional if no protein is detected on the initial dipstick, except for patients with diabetes where this should be a routine procedure. ³ Microalbuminuria (>30 mg/d and <300 mg/d) is a risk factor for progressive kidney disease and a strong risk factor for cardiovascular (CV) disease, ⁴ even in nondiabetic and nonhypertensive individuals. ⁵
• 2Determine the glomerular filtration rate (GFR). This step remains the most sensitive and specific means of assessing renal function in health and disease. While the GFR is most accurately determined by measurement of inulin clearance, this test is rarely done today because of its inherent complexity and cost. Instead, the serum creatinine is used to approximate the GFR. This measurement may overestimate GFR by 10%–40% in healthy persons and by a greater degree in people with CKD. ³ Small changes in creatinine often represent large changes in the GFR. In using serum creatinine as a measure of the GFR, we sometimes fail to identify patients who have CKD (Table I).

Table I.

Approximate Ranges of Serum Creatinine That Equate With Various Levels of GFR

GFRs (mL/min)	Creatinine Levels (mg/mL)
120	0.8–1.0
90	1.0–1.5
60	1.2–1.5 (elderly), 1.5–2.0 (young)
30	1.5–2.5 (elderly), >2.5 (young)
15	>4–5
Creatinine levels vary with muscle mass, gender, and age. They tend to be higher in men and younger individuals and lower in the elderly with similar glomerular filtration rates (GFRs).

THE PROGRESSION OF CKD

The National Kidney Foundation (NKF) ³ has recently defined five stages of CKD. In addition to the 11.2 million people diagnosed with stage 1 or 2 CKD, approximately 8.3 million people in the United States have stage 3 or higher CKD, including more than 400,000 patients with stage 5 CKD or end‐stage renal disease (ESRD). ² Once detected, CKD can be treated with clinical interventions tailored to the stage of disease, defined by the NKF in Table II. ³

Table II.

Stages of Chronic Kidney Disease: A Clinical Action Plan

Stage	Description	GFR (mL/min/1.73 m 2)	Action*
1	Kidney damage with normal or ↑ GFR	≥90	Diagnosis and treatment, treatment of comorbid conditions, slowing progression, CVD risk reduction
2	Kidney damage with mild ↓ GFR	60–89	Estimating progression
3	Moderate ↓ GFR	30–59	Evaluating and treating complications
4	Severe ↓ GFR	15–29	Preparation for kidney replacement therapy
5	Kidney failure	<15 (or dialysis)	Replacement (if uremia present)
Chronic kidney disease is defined as either kidney damage or GFR <60 mL/min/1.73 m2 for ≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. *Includes actions from preceding stages. CVD=cardiovascular disease; GFR=glomerular filtration rate Reproduced with permission from Am J Kidney Dis. 2002;39(2 suppl 1):S1–S266. 3

Worsening of kidney function is identified by a progressive lowering of the GFR or an increase in serum creatinine. A more rapid GFR decline is typically seen in patients whose kidney disease is a result of diabetes, glomerular or polycystic disease, or after renal transplantation, as compared with patients who have hypertensive or tubulointerstitial kidney disease. ³ Other factors that contribute and are associated with a rapid decline of the GFR include: African‐American race, lower baseline level of kidney function, male gender, and older age (i.e., ≥60 years old). ³ While these risk factors are non‐modifiable, other risk factors remain modifiable through lifestyle changes or drug therapy. Modifiable risk factors include an elevated level of proteinuria, high BP, hyperlipidemia, poor glycemic control, and smoking. ³

FAILURE TO RECOGNIZE CKD IS A MISSED OPPORTUNITY FOR ADDITIONAL BP REDUCTION

Hypertension occurs frequently at all stages of CKD, increasing nearly linearly as renal function deteriorates. The majority of patients who present with advanced kidney disease have elevated BP. ⁶ Recent NKF guidelines suggest that BP control is extremely important in preventing CV disease and in slowing the progression of CKD toward ESRD. ⁷ , ⁸ Renal function can be stabilized in patients with CKD by lowering BP to target levels of <130/80 mm Hg. ¹ Uncontrolled hypertension often progresses to CKD, and CKD itself causes hypertension, ³ hence the ideal goal is strict control of BP before CKD develops.

If an impact is to be made on the rising epidemic of CKD and its lethal CV consequences, physicians need to assume a more active role in diagnosing and managing CKD in its earliest stages. Unless the patient is diabetic, the BP goal should be <140/90 mm Hg. In patients with CKD, the current recommended BP goal is <130/80 mm Hg. Yet many hypertensive patients are not being evaluated for the presence of CKD with its implications for lower BP goal. Are we missing an opportunity to identify and intervene in this at‐risk population?

ESTIMATED GFR: A MEANS TO MORE EASILY RECOGNIZED CKD

For many of us facing the harried realities of a daily medical practice, assessment for CKD is perceived as being too time‐consuming and too complex. As mentioned earlier, serum creatinine concentration is often used as a means of estimating GFR and the presence of CKD (defined as a serum creatinine of >1.5 mg/dL in men or >1.3 mg/dL in women). ¹ Creatinine is, however, affected by many factors such as muscle mass, diet, and the use of certain medications that can lead to errors in the assessment of renal function. ⁹ Kidney disease is often present in people with normal serum creatinine levels. ¹ Numerous attempts to incorporate serum creatinine into mathematical equations estimating GFR have been developed. These models, based on serum creatinine as well as age, gender, ethnicity, and body size, are more accurate and precise than estimates of GFR based on the measurement of serum creatinine alone. ³ Until recently, the Cockcroft‐Gault equation, ³ using weight, age, and serum creatinine concentration, was most commonly used. While this equation more accurately reflects creatinine clearance, another mathematical model was needed to better estimate GFR. The Modification of Diet in Renal Disease (MDRD) ⁹ equation is an accurate estimate of GFR. While the MDRD equation tends to underestimate GFR in people with near normal renal function, it is now considered to be the gold standard in early as well as late manifestations of impaired kidney function. Using serum creatinine and demographic variables, including age, gender, and ethnicity, it is defined by the following complicated formula: GFR=186.3×(Pcr)−1.154×(age)−0.203×(0.742 if female)×(1.210 if black). ¹⁰ Physicians obviously have little time to search for formulas and make complicated calculations.

The good news is that the MDRD equation for eGFR can now be performed with the use of medical decision support software that is available free of charge at: www.kidney.orgklsprofessionalsgfr_calculator.cfm. The software can also be downloaded onto personal digital assistants, making it available almost anywhere and anytime. A recent initiative at the Ralph H. Johnson Veterans Administration Medical Center in Charleston, SC and veterans administration hospitals across the country has the eGFR being calculated and reported by the laboratory service along with the serum creatinine. As the patient's electronic medical record already has the age, gender, and ethnicity of the patient in the computer record, this simple calculation can be reported on all patients. This effort needs to be duplicated across the country so that GFR assessment will be taken out of the physician's domain and factored into the routine assessment of patients with hypertension, which will allow the early detection of CKD and the appropriate reduction of BP to <130/80 mm Hg in people with stage 3 or greater CKD in an effort to prevent continuing injury, declining renal function, and the progression of CV disease.

CKD AS A CORONARY RISK EQUIVALENT

The burden of CV disease among patients with CKD is substantial. As noted, CV disease remains the most common cause of death in individuals with CKD, and CKD remains an independent risk factor for CV disease. Individuals with stage 3 CKD (eGFR <60 cc/min) have a 16% increase in CV disease mortality while those with stage 4 or 5 CKD (eGFR <30 cc/min) have a 30% increase. ¹¹ An analysis of >40,000 high‐risk hypertensive patients enrolled in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ¹² using the MDRD study equation to estimate GFR found 57% of patients had stage 2 CKD (60–89 mL/min per 1.73 m²), while almost one of every five subjects had stage 3 or greater CKD (≤59 mL/min per 1.73 m²). Compared to subjects with stage 2 CKD, patients with stage ≥3 CKD were more likely to have had a prior myocardial infarction or stroke, have ischemic changes on electrocardiography, and have left ventricular hypertrophy on ECG (ECG‐LVH). For every 10 mL/min/1.73 ² reduction in GFR, individuals experienced a 6% higher risk for CV disease and 14% higher risk for ECG‐LVH. ¹²

The increased risk of CV disease with CKD is partly the result of some of the same risk factors for CV disease seen in the general population. Although risk factors such as age, hypertension, hyperlipidemia, diabetes, and physical inactivity are found in patients with CKD, these risk factors are compounded by additional factors, such as proteinuria. ¹³ For example, a risk for CV disease exhibits a continuous relationship with albuminuria: the presence of microalbuminuria confers a 50% increase in risk and the presence of macroalbuminuria (clinical proteinuria) a 350% increase. ¹⁴ In addition, a recent meta‐analysis of clinical trials indicates that lipid lowering preserves GFR and decreases proteinuria in patients with CKD. ¹⁵ Although evidence suggests that patients with CKD have an expected 10‐year coronary heart disease risk of >20%, CKD has not been included as a coronary risk equivalent in the Adult Treatment Panel III guidelines. ¹⁶ The Kidney Disease Outcomes Quality Initiative (K/DOQI) ¹⁷ guidelines do, however, recognize CKD as a coronary risk equivalent and recommend a low‐density lipoprotein cholesterol (LDL‐C) goal of <100 mg/dL in these patients. Physicians need to assume a more active role in diagnosing and managing CKD in its early stages if we hope to impact the rising epidemic of CKD and its lethal cardiovascular consequences.

RECOGNITION OF SECONDARY HYPERPARATHYROIDISM IN CKD: THE ROLE OF VITAMIN D THERAPY

Bone disease and disorders of calcium, phosphorus, and vitamin D metabolism are common comorbidities in CKD. As renal function declines, the kidneys lose their ability to excrete phosphorus. Phosphate retention inhibits the renal enzyme responsible for the kidneys' ability to convert vitamin D to its active metabolite, 1,25 (OH)2D3. This reduction in active vitamin D synthesis begins to decline early (i.e., even before GFR of <60 mL/min/1.73 m ² [stage 3 CKD]). ¹⁸ In CKD, hyperphosphatemia, hypocalcemia, deficiency of the active form of vitamin D (i.e., calcitriol), and diminished expression of receptors for calcium and vitamin D lead to partial resistance to the metabolic actions of the parathyroid hormone (PTH), contributing to its excessive production. ¹⁹ Deleterious effects of excess PTH (greater than the target range of 150–300 pg/mL—secondary hyperparathyroidism) have been demonstrated in both classical (e.g., bone, kidney) and nonclassical (e.g., brain, heart, smooth muscle) target organs. ²⁰ A significant association between levels of PTH and CV disease (myocardial infarction and heart failure) has been observed in a cohort of 218 ethnically‐diverse renal patients with a variety of comorbidities; the higher the PTH, the more likely they were to have CV disease. ²¹

A recent clinical investigation suggests that low vitamin D status may be a contributing factor in the pathogenesis of heart failure, ²² which is characterized by the reduced left ventricular ejection fraction and occurs in more than 70% of patients commencing dialysis. ²³ Other studies have shown that normalization of calcium and active vitamin D levels produce restoration of parathyroid function ²⁴ and BP reduction. ²⁴ , ²⁵ An observational study in a cohort of ESRD patients looked beyond the palliative effects of vitamin D therapy in CKD and found that treatment with vitamin D led to a reduction in the risk of CV death. ²⁶

The recently published Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney disease (NKF K/DOQI) ²⁷ recommend that PTH, calcium, and phosphorus levels be monitored no less than every 12 months in people with stage 3 CKD and every 3 months in patients with stage 4 and 5 CKD. In addition, these recommendations provide target levels for serum calcium, phosphorus, and PTH in an effort to improve clinical outcome. Randomized controlled trials need to be conducted to evaluate the role of vitamin D and its analogs in improving the survival of patients with CKD. ²⁸

A FINAL WORD

The early detection of CKD in patients with hypertension is the sine qua non for an early multipronged intervention. Patients with CKD are more likely to die of CV disease than to develop ESRD. Physicians continue to miss opportunities to recognize the early stages of CKD and to intervene to reduce other CV risk factors. By reporting eGFR, especially in people with hypertension, these individuals will be identified. Early, aggressive, and effective control of BP to a level <130/80 mm Hg substantially slows the progression of kidney failure. Treating dyslipidemia to an LDL‐C of <100 mg/dL, as well as stabilization of bone and mineral metabolism, remain integral parts of effective therapy in patients with CKD. These interventions represent a practical step toward improving global CV risk status in patients with hypertension and often unrecognized CKD. ²⁹