Recognizing the link between CKD and CVD in the primary care setting: accurate and early diagnosis for timely and appropriate intervention.

Abstract: Chronic kidney disease (CKD), which is becoming increasingly prevalent in the US and worldwide, eventually progresses to end-stage renal disease (ESRD), requiring renal replacement therapy. Diabetes and hypertension, the two leading causes of CKD, are themselves reaching near epidemic proportions. Hypertension can cause both the development and progression of CKD, and CKD is a significant risk factor for the development of cardiovascular disease. Indeed, CKD patients are more likely to die of cardiovascular complications than progress to ESRD. However, data indicate that early recognition and management of CKD can have a significant positive impact on disease outcome. This creates an important interventional opportunity for the primary care physician. This report describes the major risk factors and comorbidities associated with the development and progression of CKD and offers suggestions for timely diagnosis and management of CKD in the primary care setting.

Key Words: chronic kidney disease, diabetes, hypertension, cardiovascular disease, proteinuria, anemia

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Chronic kidney disease (CKD) is a significant problem in the United States (US), and its incidence is increasing at an alarming rate. Nearly 20 million Americans are affected by CKD, and some 20 million more are at risk of developing it. (1,2) CKD progresses through stages of severity until renal failure occurs, requiring renal replacement therapy (RRT) in the form of dialysis or transplantation. An increasing amount of literature suggests that timely diagnosis and treatment of CKD can delay disease progression and may decrease adverse cardiovascular outcomes. Nevertheless, data continue to report that CKD is not recognized in its early stages, and when it is diagnosed, care is often suboptimal, such that many more CKD patients die than reach dialysis. (3)

CKD and its associated risk factors are likely to be encountered in a primary care setting. The fact that CKD remains under-diagnosed and under-treated means that opportunities for intervention are being lost. The need for increased awareness presents an important opportunity for the primary care physician to recognize the risk factors associated with CKD, screen high-risk patients, and start treatment early enough to positively impact disease progression. This paper will describe the risk factors for the development and progression of CKD with emphasis on cardiovascular disease (CVD) in CKD. The importance of early diagnosis and management, and suggestions for CKD diagnosis and management in the primary care setting will be discussed.

Definition of CKD

The National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (KDOQI) describes the identification and classification of CKD, and the stratification of risk factors that increase the progression of CKD. (1) The established criteria for a diagnosis of CKD is 1) kidney damage for at least 3 months as defined by structural or functional abnormalities with or without decreased glomerular filtration rate (GFR), or 2) a GFR <60 mL/min/1.73 [m.sup.2] with or without kidney damage. Functional and structural kidney damage can be detected by aberrations in blood or urine composition, and abnormalities found in imaging studies, respectively.

CKD is divided into 5 stages based on the criteria of GFR and/or kidney damage (Table 1). Stage 5 is defined as a GFR less than 15 mL/min/1.73 [m.sup.2], and constitutes renal failure requiring RRT, while stages 1 to 4 represent the CKD population with varying degrees of renal insufficiency. Stages 1 through 3 are the most prevalent, and it is in this population that recognition and treatment of CKD can have the greatest impact on disease outcome, although slowing the rate of progression is still possible in Stage 4. (4)

Timely diagnosis and treatment of chronic kidney disease can delay disease progression and may decrease adverse cardiovascular outcomes.

CKD Risk Factors

There are a variety of risk factors that contribute to the development and progression of CKD, but diabetes and hypertension are by far the most common (Table 2). (5)

Hypertension

Hypertension and CKD form a "vicious cycle" such that untreated hypertension can lead to CKD, and CKD to hypertension. (6) Thus, hypertension is both a risk factor for, and a serious comorbidity of, CKD. Hypertension is defined as a systolic blood pressure of 140 mm Hg or higher, or a diastolic blood pressure of 90 mm Hg or higher. (7) Between 50% and 75% of patients with a GFR less than 60 mL/min/1.73 [m.sup.2] are hypertensive. (1) The strong association between hypertension and the risk of developing CKD starts at blood pressure levels considered to be prehypertensive (130-139 mm Hg systolic; 85-89 mm Hg diastolic). (8) Recent data have demonstrated that even a modest increase in blood pressure in the absence of baseline renal disease is an independent risk factor for the progression of CKD to ESRD. (9) These results suggest that high blood pressure is a strong predictor of, and may be an initiation factor for, the development of CKD.

Proteinuria

Nephropathy is characterized by the presence of protein (albumin) in the urine as a result of increased glomerular permeability secondary to glomerular damage. Normal urinary excretion of albumin is less than 30 mg/d (Table 3). Microalbuminuria refers to an albumin concentration between 30 and 300 mg/d, and is most accurately detected by determination of the albumin-to-creatinine ratio. Microalbuminuria is often the first sign of kidney disease, predicts progressive kidney damage, and increases the risk of the development of CVD. (10) Albuminuria (macroalbuminuria) is defined as an albumin concentration of greater than 300 mg/d and denotes advanced kidney disease that is typically followed by a decline in the GFR.

The strong association between hypertension and the risk of developing chronic kidney disease starts at prehypertensive blood pressure levels.

CVD in CKD

CVD is extremely prevalent in CKD, more so than in the general population. Nearly half of all patients with CKD die of cardiovascular event, particularly heart failure (HF) and acute myocardial infarction (MI). (11) The NKF task force on CVD in CKD suggested that CKD patients be considered the highest risk group for subsequent cardiovascular events. (12)

The strong predictive capacity of elevated serum creatinine or decreased GFR for CVD risk and mortality has been demonstrated in a variety of trials. Elevated serum creatinine/decreased GFR is as important a CV risk factor in predicting poor CV outcome as the more traditional risk factors of diabetes, hypertension, atherosclerosis, or previous MI. (13) CKD patients at high risk for CV events include those who have established CVD or those in whom a number of CV risk factors is present. However, patients with even mild renal insufficiency and few or no CV risk factors are also at higher risk for developing CVD. (14) A recent retrospective analysis of several large trials demonstrated that CKD was significantly associated with CVD and all-cause mortality in a relatively healthy community-based population, compared with subjects without CKD. This was true even though patients without CKD had some traditional CV risk factors, such as smoking and diabetes. (15)

While the burden of CVD morbidity and mortality has significantly improved in the general population in the past 10 years, these same factors remain virtually unchanged in the CKD population. (11) This may be due partly to the general lack of awareness of the prevalence of CKD, or the failure to recognize CVD as a common and significant comorbidity of CKD.

Elevated serum creatinine/decreased glomerular filtration rate is as important in predicting poor cardiovascular outcome as the more traditional risk factors of diabetes, hypertension, atherosclerosis, or previous myocardial infarction.

CV Risk Factors in CKD: Appropriate Management Strategies

Traditional risk factors for the progression of CVD in CKD include diabetes, proteinuria/albuminuria, hypertension, and hyperlipidemia. A nontraditional factor that increases CV risk in CKD patients, perhaps by enhancing some of the traditional risk factors, is anemia. An understanding of the various interventional strategies available may influence the course of CKD. Many CV risk factors in patients with CKD are modifiable.

Hypertension

Hypertension is common in all stages of CKD, contributes to nephropathy, gets progressively worse in parallel with declining kidney function, and increases the risk of coronary heart disease and stroke. (11) Increased systemic blood pressure directly damages the small vessels of the kidney, thereby compromising glomerular filtration rate. Hypertension can also lead to left ventricular hypertrophy (LVH), and in patients with CKD, the prevalence of LVH is inversely proportional to the level of kidney function, and affects approximately 31 to 45% of patients with Stage 3 or 4 CKD. (16)

Proteinuria

Proteinuria is a powerful risk multiplier in CKD, and accurately predicts the progression of renal damage. (17) It is generally accepted that proteinuria, as a consequence of renal damage, mediates tubular injury resulting in the progression of renal disease and end-organ failure. (11) However, evidence is accumulating which suggests that microalbuminuria is a reflection of general vascular endothelial dysfunction that is associated with a higher susceptibility to renal and CV events. (18) Proteinuria is also associated with clinical factors that directly or indirectly result in CVD, including hyperglycemia, hypertension, renal dysfunction, and dyslipidemia. The presence of small amounts of protein in the urine, even in the setting of normal GFR and blood pressure, remains a strong predictor for cardiovascular risk. (19) For this reason, the definition of proteinuria and microalbuminuria for hypertensive patients is more stringent than that for normotensive patients (Table 3). (7) Increased CV risk occurs with an elevation in the albumin/creatinine ratio, and starts well below the traditional cutoff for microalbuminuria. (10)

Hypertension Management/Proteinuria Reduction

Aggressive blood pressure control retards the progression of renal disease. (20) Maintenance of optimal blood pressure slows the reduction in GFR, reduces the degree of proteinuria, and reduces the risk of poor CV outcomes. (21,22) To underscore the importance of blood pressure control in reducing the rate of renal decline and the risk of CV events in patients with CKD, the recommended target blood pressure is less than 130/80 mm Hg. (7)

Microalbuminuria is a reflection of general vascular endothelial dysfunction that is associated with a higher susceptibility to renal and cardiovascular events.

Several lines of evidence have shown that antihypertensives that disrupt the renin-angiotensin system (RAS) can reduce proteinuria, preserve GFR and kidney function, and reduce CV morbidity and mortality. (20,23) The RAS-targeting angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may have renoprotective effects independent of blood pressure control. Several lines of evidence suggest that the degree of proteinuria reduction with ACEIs and ARBs is correlated with the degree of cardioprotection, irrespective of the effects on other CV risk factors. (18) ACEIs have been shown to have positive effects, including reducing the amount of proteinuria, the decline of GFR, and the progression to ESRD beyond that attributed to blood pressure reduction. (24) On the other hand, some evidence suggests that the degree of renoprotection with antihypertensive therapy is directly proportional to the extent of blood pressure reduction. (25) Optimal blood pressure control is often achieved by a combination of medications and indeed, dual blockade of the RAS can achieve better blood pressure control as well as additional renal and cardiovascular protection in patients with nephropathy. (26) Additional randomized controlled trials examining the various combinations of antihypertensive medications and their effect on blood pressure control and proteinuria reduction are needed to better understand the contributions of these two parameters on the ability to provide cardio- and renoprotection.

Proteinuria is a powerful risk multiplier in chronic kidney disease, and accurately predicts the progression of renal damage.

Dyslipidemia

Hyperlipidemia is a risk factor for CVD, and is relatively common in CKD, especially as renal decline progresses. (27) Lipid abnormalities in CKD patients include elevated triglycerides and an increased ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol. Micro- and macroalbuminuria are associated with elevated cholesterol, and the combination of microalbuminuria and early renal disease is associated with an increase in LDL cholesterol and a significant decrease in HDL cholesterol. (11) These conditions set the stage for the development of atherosclerosis and heart disease. (27)

Lipid Management

In addition to dietary modifications, lipid-lowering statins are effective in reducing cholesterol and albuminuria, and can be used safely in patients with mild renal insufficiency; but without clinical trial evidence, it remains unclear whether statin therapy can decrease progression of renal decline in this population. (18,28) Nonetheless, the KDOQI guidelines recommend lipid lowering therapy in CKD patients, and suggest that LDL cholesterol levels be less than 100 mg/dL (ie, CKD as a cardiovascular equivalent) and triglyceride levels be under 200 mg/dL. (28)

Anemia

Anemia is a common feature of CKD and worsens as kidney function declines. Anemia is an important CVD risk factor in those with CKD because of its association with LVH. (16,29) Indeed, anemia has been recognized as the "fifth CV risk factor," along with smoking, hypercholesterolemia, diabetes, and hypertension in those with CKD. (30) In conjunction with CKD and HF, anemia becomes a risk multiplier, increasing the risk of mortality compared either to CKD and HF alone, or in combination. Anemia is a modifiable risk factor, and correction of anemia with recombinant human erythropoietin (rHuEPO) in patients not yet on dialysis may decrease the progression of CKD, delay renal failure, improve quality of life, and improve overall cardiac function. (31) Because of the large amount of information regarding the impact of anemia in CKD and CVD, the identification and management of anemia will be discussed in detail in the next paper of this series.

Anemia has been recognized as the "fifth CV risk factor," along with smoking, hypercholesterolemia, diabetes, and hypertension in patients with chronic kidney disease.

CKD and Comorbidity Identification and Management in the Primary Care Setting

CKD is highly under-recognized and under-treated, and although many patients are at risk for CKD, only a small number are being screened for it. (32) As a result, by the time many patients are referred to a nephrologist, substantial loss of renal function has already occurred. (33) In light of these recent findings, an enormous opportunity presents itself for primary care physicians to be aware of CKD risk factors in their patients, initiate testing for renal function in their high-risk patients, and deliver timely and appropriate treatment of comorbidities. The 2002 NKF KDOQI guidelines include practical clinical information for assessing and treating CKD (Table 1). (1) Assessments to identify high risk patients and diagnose CKD can be as simple as obtaining blood pressure measurements, a urinalysis, and blood work, and are easily performed in the office. Diagnostic codes corresponding to the different stages of CKD have been developed to better differentiate patients based on the severity of their disease (Table 1). (34) The following segments describe diagnostic and interventional strategies that can be easily performed in the primary care setting to identify and properly manage patients at risk for CKD.

[FIGURE OMITTED]

Is the Patient at Risk?

Table 2 lists the risk factors that either directly cause, or are associated with, the development of CKD. All routine healthcare visits should include evaluations to determine whether an individual is at increased risk for developing CKD. (1) Simple office assessments and physical examination and history can be extremely helpful in deciding whether a patient is at risk for CKD. Blood pressure measurements are usually taken at each office visit, and lipid and glucose levels can be determined by a routine blood test. If a patient is deemed high risk, kidney damage should be evaluated by estimating the GFR and assessing the presence of proteinuria. If there is no evidence of renal damage, high risk patients should be counseled for appropriate risk reduction, and reevaluated periodically. (35)

Calculate the GFR

Although creatinine levels alone are relatively inaccurate in determining the presence of kidney disease, especially mild kidney disease, physicians can estimate GFR using standard equations such as the Cockroft-Gault or the MDRD (modification of diet in renal disease) (Table 4) that are available on the NKF web site. (36-38) Many clinical labs are now routinely reporting the estimated GFR based on these calculations when reporting the serum creatinine. Normal GFR varies according to age, sex, and body size; in young adults, it is approximately 120 to 130 mL/min/1.73 [m.sup.2] and declines with age. (35) A persistent reduction in GFR is a specific indication of CKD. KDOQI guidelines advise that patients be referred to a nephrologist when the GFR declines to less than 30 mL/min/1.73 [m.sup.2], or when the physician is unable to develop an action plan. (1) Even before reaching CKD stages 4 or 5, the progression of renal decline can be attenuated, and the guidelines suggest action steps that can be taken at different stages of CKD to achieve this goal (Table 1). (1) Individuals with an estimated GFR of under 60 mL/min/1.73 m2, who often go unrecognized in daily clinical practice, should have their blood pressure reduced to the recommended goal of less than 130/80 mm Hg. (7)

Assessment of Proteinuria

A urine dipstick can usually detect proteinuria of 1+ or greater (between 300-500 mg/d), and should be performed on any patient with risk factors, regardless of GFR (Fig.). If the dipstick test is negative for protein, an albumin-to-creatinine ratio should be determined from a fresh (1st morning void) sample. In high risk patients, an albumin-to-creatinine ratio of greater than 300 mg/g (macroalbuminuria) warrants further diagnostic evaluation. A ratio of higher than 30 mg/g on successive measurements (microalbuminuria) suggests progressive kidney disease, and is a powerful predictor of cardiac disease as well as renal disease. (33,39) Patients with CKD should have urine protein levels measured quantitatively by an albumin-to-creatinine ratio. (1) While proteinuria remains a powerful risk factor in those with hypertension and diabetes, and reflects the degree of underlying CKD, no clinical trial evidence currently exists for reducing urinary protein to a specific level for outcome improvement.

Summary

Chronic kidney disease affects millions of people in the US and worldwide. The prevalence of CKD has been increasing, and this trend is likely to continue. Not surprisingly, many of the risk factors that contribute to the development of CKD also contribute to its progression. Fortunately, many risk factors that lead to the progression of CKD are modifiable, and primary care physicians should be aware that these conditions can be routinely detected and managed in the office setting. Physicians have an opportunity to potentially modify the course of a disease that affects millions of patients through integration of diagnostic and therapeutic guidelines. As discussed, this will translate into the early detection and appropriate treatment of CKD in the primary care setting.

References

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2. Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kid Dis 2003;41:1-12.

3. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States medicare population, 1998 to 1999. J Am Soc Nephrol 2005;16:489-495.

4. St. Peter WL, Schoolwerth AC, McGowan T, et al. Chronic Kidney disease: issues and establishing programs and clinics for improved patient outcomes. Am J Kidney Dis 2003;41:903-924.

5. McClellan WM, Flanders WD. Risk factors for progressive chronic kidney disease. J Am Soc Nephrol 2003;14:S65-S70.

6. National Kidney Foundation. K/DOQI Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kid Dis. 2004;43(1 Suppl):S1-S290.

7. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-1252.

8. Haroun MK, Jaar BG, Hoffman SC, et al. Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington county, Maryland. J Am Soc Nephrol 2003;14:2934-2941.

9. Hsu C, McCulloch CE, Darbinian J, et al. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med 2005;165:923-928.

10. Gerstein HC, Mann JFE, Yi Q, et al. Albuminuria and risk of cardiovascular events, death and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286:421-426.

11. Wali RK, Henrich WL. Chronic kidney disease: a risk factor for cardiovascular disease. Cardiol Clin 2005;23:343-362.

12. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know, what do we need to learn, where do we go from here? National Kidney Task Force on Cardiovascular Disease. Am J Kidney Dis 1998;32:853-906.

13. Shulman NH, Ford CE, Hall WD, et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension 1998;13(5 Suppl):I80-I93.

14. Henry RMA, Kostense PJ, Bos Griet, et al. Mild renal insufficiency is associated with increased cardiovascular mortality: the HOORN study. Kidney Int 2002;62:1402-1407.

15. Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol 2004;15:1307-1315.

16. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis 1996;27:347-354.

17. Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK). Am J Kidney Dis 2003;42:617-622.

18. deZeeuw D, Parving HH, Henning RH. Microalbuminuria as an early marker for cardiovascular disease. J Am Soc Nephrol 2006;17:2100-2105.

19. Arnlov J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation 2005;112:969-975.

20. Parving HH, Andersen AR, Smidt UM, et al. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J 1987;294:1443-1447.

21. Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134-1146.

22. UK Prospective Diabetes Study Group. UKPDS 38: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. Br Med J 1998;317:703-713.

23. de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309-2320.

24. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.

25. Bakris GL, Weir MR, Shnifar S, et al. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med 2003;163:1555-1565.

26. Jacobsen P, Andersen S, Jensen BR, et al. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 2003;14:992-999.

27. Snively CS, Gutierrez C. Chronic kidney disease: prevention and treatment of common complications. Am Fam Physician 2004;70:1921-1928.

28. National Kidney Foundation. K/DOQI Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J Kid Dis 2003;41(13 Suppl):S1-S290.

29. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass increase in early renal disease: impact in decline in hemoglobin. Am J Kidney Dis 1999;34:125-134.

30. Silverberg D, Wexler D. Anemia, the fifth cardiovascular risk factor. Transfus Med Hemother 2004;31:175-179.

31. McCullough PA, Lepor NE. Piecing together the evidence on anemia: the link between chronic kidney disease and cardiovascular disease. Rev Cardiovasc Med 2005;6(suppl 3):S4-S12.

32. Stevens LA, Fares G, Fleming J, et al. Low rates of testing and diagnostic code usage in a commercial clinical laboratory: evidence for lack of physician awareness of chronic kidney disease. J Am Soc Nephrol 2005;16:2439-2448.

33. Hebert CJ. Preventing kidney failure: primary care physicians must intervene earlier. Cleve Clin J Med 2003;70:337-344.

34. Centers for Medicare and Medicaid Services. ICD-9 Coding Resources. www.cms.hhs.gov/medlearn/icd9code.asp. Accessed March 2, 2007.

35. Johnson CA, Levey AS, Coresh J, et al. Clinical practice guidelines for chronic kidney disease in adults: part II, glomerular filtration rate, proteinuria and other markers. Am Fam Physician 2004;70:1091-1097.

36. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.

37. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation: Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-470.

38. http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm. Accessed. March 2, 2007.

39. Bakris GL. Implications of albuminuria on kidney disease progression. J Clin Hypertens (Greenwich) 2004;6(suppl 3):18-22.

40. Basile J. Chronic kidney disease: it's time to recognize its presence in our patients with hypertension. J Clin Hypertens 2004;6:548-552.

A cynic is a man who, when he smells flowers, looks around for a coffin.
--H.L. Mencken

Jan N. Basile, MD

From Ralph H. Johnson VA Medical Center, Charleston, Medical University of South Carolina, Charleston, South Carolina.

Reprint requests to Dr. Jan N. Basile, Ralph H. Johnson VA Medical Center, Medical University of South Carolina, 109 Bee Street, Charleston, SC 29401. E-mail: [e-mail]

Accepted July 28, 2006.

RELATED ARTICLE: Key Points

* Chronic kidney disease (CKD) is becoming increasingly prevalent, due in part to the increase in its two leading causes: diabetes and hypertension. CKD eventually progresses to end-stage renal disease (ESRD), a condition requiring renal replacement therapy such as dialysis or renal transplantation.

* CKD is a significant risk factor for cardiovascular disease (CVD).

* Treatable comorbidities such as proteinuria, hyperlipidemia, and anemia can exacerbate CVD in those with CKD and significantly hasten the progression of CKD to ESRD, increasing the risk of death.

* CKD in its early stages often goes unrecognized and is underdiagnosed, such that CKD patients are often referred to a specialist in the later stages of the disease.

* More patients with CKD die from cardiovascular complications than reach renal replacement therapy.

* Evidence shows that appropriate and timely management of traditional risk factors and comorbidities can result in increased quality of life and a decrease in the rate of progression to ESRD.

* Primary care physicians have an important opportunity, through the recognition of risk factors, for early screening and diagnosis of CKD. Appropriate treatment of associated comorbidities can delay CKD progression and improve disease outcome.

Table 1. Stages of CKD defined by GFR. ICD-9 diagnostic codes, and
action steps

CKD stage            GFR* (mL/min/1.73 [m.sup.2])  Description

1 ([double dagger])  [greater than or equal to]90  Kidney damage and DM
                                                     with normal or
                                                     [up arrow] GFR
2 ([double dagger])  60-89                         Kidney damage with
                                                     mild [down arrow]
                                                     GFR
3                    30-59                         Moderate [down arrow]
                                                     GFR
4                    15-29                         Severe [down arrow]
                                                     GFR
5                    [less than or equal to]15     Kidney Failure
                       (or dialysis)

                     ICD-9 Diagnostic
CKD stage            codes ([dagger])  Action

1 ([double dagger])  585.1             Screening and CKD risk reduction
2 ([double dagger])  585.2             Diagnosis and treatment,
                                         management of comorbidities,
                                         slow progression of CKD, and
                                         CVD risk reduction
3                    585.3             Estimate CKD progression
4                    585.4             Evaluate and treat complications
5                    585.5             Prepare for RRT

*GFR estimated from serum creatinine using Modification of Diet in Renal
Disease (MDRD). Study equation based on age, gender, race and
calibration for serum creatinine.
([dagger]) www.cms.hhs.gov/medlearn/icd9code.asp, accessed October 10,
2005. (34)
([double dagger]) Kidney damage estimated by spot albumin-to-creatinine
ratio [greater than or equal to]17 mg/g in men or
[greater than or equal to]25 mg/g in women in two measurements.
CKD = chronic kidney disease; CVD = cardiovascular disease; GFR =
glomerular filtration rate; RRT = renal replacement therapy.
Adapted from NKF KDOQI Clinical Practice Guidelines for Chronic Kidney
Disease. (1)

Table 2. CKD risk factors

Disease states that directly cause renal damage
Autoimmune disease (lupus nephritis, Goodpasture syndrome)
Antibody deposition disease and IgA nephropathy
Focal segmented glomerular sclerosis

Modifiable CKD associations or risk factors
Diabetes mellitus
Hypertension
Obesity
Smoking
Hyperlipidemia
Analgesic abuse
Illicit drug use

Nonmodifiable CKD associations or risk factors
Advanced age (>60 years of age)
Family history
Non-Caucasian race
Low socioeconomic status/low education level

Summarized in McClellan. (5)

Table 3. Normal and elevated urine levels of protein/albumin

JNC Definition*  NKF Definition ([dagger])
(mg/g)           (mg/g)                     Description

<20              <30                        Normal urinary albumin
                                              excretion
20-200           30-300                     Microalbuminuria
>200             >300                       Macroalbuminuria (clinical
                                              proteinuria)
                 >3000                      DM-related nephrotic
                                              syndrome

Adapted from: *Chobanian (7), and ([dagger]) Grundy. (21)
JNC -- Joint National Committee; NKF -- National Kidney Foundation;
DM -- diabetes mellitus.

Table 4. Equations to estimate GFR

Abbreviated Modification of Diet in Renal Disease (MDRD) study Equation
GFR (mL/min/1.73 [m.sup.2]) = 186 X (sCr)[.sup.-1.154] X
  (Age)[.sup.-0.203] X 0.742 if female X 1.210 if African American

Cockroft-Gault equation
Creatinine clearance (mL/min) = (140-Age) X Weight X 0.85 if Female
  72 X sCr

sCr = serum creatinine.
From Cockroft and Levey. (36,37)