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From Nephrology Hypertension Associates of the Lehigh Valley in Easton, Pa.

Address correspondence to Nelson P. Kopyt, DO, Nephrology Hypertension Associates of the Lehigh Valley, 50 S 18th St, Easton, PA 18042-3912. E-mail: DrNPK{at}aol.com

For several decades, the healthcare needs of the American public have been shifting from predominantly acute, episodic therapy to long-term treatment of chronic conditions. Considered together, chronic conditions now make up the leading cause of illness, disability, and death in the United States.¹ Chronic conditions affect nearly half the population in the United States, accounting for the majority of resources applied to healthcare.¹ Chronic kidney disease (CKD) is an example of a chronic condition that is more common than is generally realized.

Many physicians and their patients remain unaware of the diversity of clinical characteristics of renal disease. To date, the primary focus of research and treatment regarding this illness has been on end-stage renal disease (ESRD), which is the most visible clinical consequence of CKD. By comparison, CKD in its earlier stages often shows no symptoms and has received scant attention.

Data from the United States Renal Data System (USRDS)² indicate that, in 2005, the US population with prevalent ESRD (N=452,957) consisted of 324,862 (72%) patients receiving dialysis treatment and 128,131 (28%) with a functioning renal transplant. Yet, individuals with ESRD represent only a small portion of total diagnosed CKD cases. Most CKD cases involve illnesses in earlier, milder stages. A recent analysis using data from the Third National Health and Nutrition Examination Survey³ indicates that the number of people in the United States with moderate-stage CKD (7.6 million) is approximately 20 times greater than the number of individuals with severe-stage CKD (400,000).

	Chronic Kidney Disease and Cardiovascular Events

Top Chronic Kidney Disease and... Uniform Definition Aids... Therapeutic Interventions for... Conclusion References

 
As chronic kidney disease progresses, it often leads to serious cardiovascular events. In fact, patients with CKD are more likely to die of cardiovascular disease (CVD) than to progress to kidney failure.⁴ The risk of subsequent cardiovascular events is much higher among patients with ESRD than among individuals with normal renal function. After stratification for age, race, and gender, mortality from CVD is 10 to 20 times higher in patients undergoing dialysis for renal disease than it is among the general US population (Figure 1).⁵ Chronic kidney disease is thus a great multiplier of patients' CVD risk.

View larger version (14K): [in this window] [in a new window]   Figure 1. Annual cardiovascular mortality (death as a result of arrhythmias, atherosclerotic heart disease, cardiac arrest, cardiomyopathy, myocardial infarction, or pulmonary edema) in the US general population compared with patients with end-stage renal disease who were treated with dialysis, by age, sex, and racial group. (Adapted from Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease [review]. Am J Kidney Dis. 1998;32(5 suppl 3):S112–S119. Copyright © 1998, with permission from the National Kidney Foundation.)

Another study, supported by the National Institute of Diabetes and Digestive and Kidney Diseases,⁷ highlighted how important CKD is to public health. This study, which observed more than 1.1 million ambulatory adults from the Kaiser Permanente Renal Registry, revealed a graded association between estimated GFR and cardiovascular events (Figure 2), hospitalization, and risk of death.

View larger version (19K): [in this window] [in a new window]   Figure 2. Age-standardized rates of cardiovascular events (coronary heart disease, heart failure, ischemic stroke, or peripheral arterial disease), according to estimated glomerular filtration rates (GFR) among 1,120,295 ambulatory adults. (Reproduced with permission from Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–1305. Copyright © 2004 Massachusetts Medical Society. All rights reserved.)

	Uniform Definition Aids Diagnosis of Chronic Kidney Disease

Top Chronic Kidney Disease and... Uniform Definition Aids... Therapeutic Interventions for... Conclusion References

 
We need to move from a healthcare system of reacting to acute events to a system of anticipating the needs of our patients, especially in regard to CKD. Early detection of CKD is important not only to halt the progression of early-stage renal disease to ESRD, but also to prevent morbidity and mortality from CVD. In the past, it was not uncommon to see patients with serum creatinine levels of 1.5 to 2.5 mg per deciliter and erroneously assume that they had relatively preserved renal function. Frequently overlooked in these diagnoses, however, were such important variables as age, sex, race, and body mass index. Estimated GFR provides an alternative to serum creatinine, and it is a much more reliable indicator of the level of kidney function.

The equation developed in the Modification of Diet in Renal Disease (MDRD) Study⁸ provides a useful approximation of GFR. Calculators for quickly running the complex MDRD equation are available on a number of Web sites (eg, http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm), aiding in the diagnosis of CKD.

The publication in 2002 of the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI)⁹ clinical practice guidelines for CKD has also facilitated the identification and classification of CKD. The K/DOQI guidelines define CKD as persistent kidney damage and/or a GFR of less than 60 mL per minute per 1.73 m² of body surface area for at least 3 months.⁹ Kidney damage may be confirmed by renal biopsy or by markers of damage, including abnormal blood tests, urine tests, or imaging studies. Based on the degree of decrease in GFR, the K/DOQI guidelines classify CKD into five stages of development,⁹ with higher numbers (and lower GFR values) representing increasingly severe clinical conditions (Figure 3).

View larger version (34K): [in this window] [in a new window]   Figure 3. Classification of stages of development of chronic kidney disease (CKD), according to the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines. These guidelines define CKD as persistent kidney damage and/or a glomerular filtration rate (GFR) of less than 60 mL per minute per 1.73 m2 of body surface area for at least 3 months. (Adapted from National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39[2 suppl 1]:S1–S266. Copyright © 2002, with permission from the National Kidney Foundation.)

Factors that suggest increased risk of progression of CKD to ESRD include anemia, chronic use of nephrotoxins (eg, analgesics), congenitally low nephron numbers (as in low-birth-weight infants), diabetes mellitus, hyperlipidemia, hypertension, low GFR, obesity, proteinuria, and smoking.⁹ These factors need to be identified and managed aggressively in all patients with CKD in order to slow the spread of CKD/ESRD and CVD.

With a uniform and widely accepted definition and classification of CKD, physicians can easily screen patients for CKD by measuring serum creatinine, using the MDRD equation to calculate an estimated GFR, and obtaining a ratio of urinary total protein to creatinine. Many laboratories and hospitals are now offering tests for estimating GFR values, along with tests for serum creatinine concentrations, as part of their screening programs. The National Kidney Disease Education Program has developed a format for setting up such a screening program in hospitals that currently do not have one. This information is available on the following Web pages:

• http://www.nkdep.nih.gov/resources/laboratory_reporting.htm
  
• http://www.nkdep.nih.gov/professionals/estimated_gfr.htm
  

	Therapeutic Interventions for Chronic Kidney Disease

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The therapeutic intervention that has demonstrated the greatest benefit in slowing the progression of CKD, both in patients with and without diabetes mellitus, is the use of medications targeting the renin-angiotensin-aldosterone system: angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).^10–13 Unfortunately, these medications are not widely used. According to Nissenson et al,¹⁴ only about one third of patients with CKD are prescribed ACE inhibitors.

The therapeutic goal of ACE inhibitor/ARB therapy is to slow the rate of GFR decline to less than 2 mL per minute per year and to reduce proteinuria measurements to less than 0.5 gram per day. This goal mandates that physicians closely track estimated GFR and proteinuria in all patients with CKD, titrating the ACE inhibitor/ARB therapy to achieve the desired outcomes. A review by Weir¹⁵ of clinical trials with ARBs—used for either cardiovascular or renal end points—suggests that the maximum positive effect of this therapy is achieved with the highest recommended doses. This conclusion should be considered when trying to preserve renal function and prevent cardiovascular events in patients.

In addition to specific renal therapy, adjunctive therapy for cardiovascular protection needs to be aggressively pursued in all patients with CKD. Chronic kidney disease should not be regarded as simply a risk factor for CVD, but also as an indication to develop a global risk-management strategy for patients. Such a strategy would begin with strict blood pressure control (<130/80 mm Hg), lipid control (low-density lipoprotein <100 mg/dL), diabetic control (hemoglobin A_1c <7%), and management of the stress and depression common in these patients.⁹

Furthermore, evidence increasingly supports the need for earlier intervention to reduce acidosis, anemia, and hyperparathyroidism with calcium/phosphorus abnormalities. These abnormalities are now recognized when GFR falls to less than 60 mL per minute per 1.73 m² of body-surface area.⁹ To reduce morbidity and mortality, nutrition must be addressed as patients progress through the stages of CKD.

Patients in stages 2 to 3 of CKD development (Figure 3) may be referred to nephrologists, who could make adjustments in therapeutic interventions to take into account such nontraditional risk factors as acidosis, anemia, hyperparathyroidism, and vitamin D deficiency. Nephrologists could also assist patients in optimizing control of blood pressure. Given the large number of patients with either stage 2 or stage 3 CKD—as well as the limited number of nephrologists in the United States—referrals of patients to nephrologists will require close working relationships between primary care providers and the nephrology community.

A nephrologist might recommend a clinical action plan for the optimal care of a patient. Alternatively, the patient's primary care provider might use Internet-based resources to develop his or her own therapeutic plan. An example of such a resource is the Kidney Learning System Web site, established by the National Kidney Foundation: http://www.kidney.org/professionals/kdoqi/cap/index.htm. For a patient with relatively uncomplicated stage 2 or stage 3 CKD, most of the clinical monitoring and therapeutic adjustments will be the responsibility of that patient's primary care physician. However, for a patient with late stage 3 or stage 4 CKD, a nephrologist will need to assume a more prominent role in that individual's care.

A patient with stage 2 CKD should be educated to take special care of his or her nondominant arm—such as by avoiding phlebotomy incisions or intravenous access placement—in order to preserve the veins for the possible need of surgically created arteriovenous fistulae. This type of intervention could significantly reduce the need for arteriovenous gortex grafts and tunneled catheters, both of which are associated with increased morbidity and mortality.^16,17 The K/DOQI^16,17 has established clinical practice guidelines regarding vascular access for hemodialysis.

Finally, nephrologists should begin to educate their patients who have stage 3 or stage 4 CKD about modalities for treating ESRD. Such modalities include hemodialysis, peritoneal dialysis, and kidney transplantation.¹⁸

	Conclusion

Top Chronic Kidney Disease and... Uniform Definition Aids... Therapeutic Interventions for... Conclusion References

 
Chronic kidney disease should be considered a cardiovascular risk equivalent. It is imperative not only to aggressively employ therapeutic interventions to slow the progression of CKD, but also to identify those patients with the greatest need for aggressive CVD risk-factor reduction.

	Footnotes

 
Dr Kopyt is to present ideas from this article at the American College of Osteopathic Family Physicians' (ACOFP) 43rd Annual Convention and Exhibition in Grapevine, Tex, on March 24, 2006, during the Joint Symposium of the American Society of Nephrology and the ACOFP on Chronic Kidney Disease: An Update for the Primary Care Physician.

Editor's note: The Initiative on Chronic Kidney Disease Committee of the American Society of Nephrology has developed a CKD symposium for the nonnephrologist. This symposium is scheduled to be held in 2006 at the American College of Osteopathic Family Physicians' 43rd Annual Convention and Exhibition in Grapevine, Tex (March 22–26), and at the American College of Osteopathic Internists' 2006 Annual Convention and Scientific Sessions in Phoenix, Ariz (October 18–22).

	References

Top Chronic Kidney Disease and... Uniform Definition Aids... Therapeutic Interventions for... Conclusion References

 
1. Institute of Medicine Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press; 2001. Available at: http://www.nap.edu/books/0309072808/html. Accessed January 23, 2006.

2. US Renal Data System. USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2004. Available at: http://www.usrds.org/atlas.htm. Accessed January 23, 2006.

3. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis.2003; 41:1 –12.[Medline]

4. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention [review]. Circulation. 2003;108:2154–2169. Available at: http://circ.ahajournals.org/cgi/reprint/108/17/2154. Accessed January 23, 2006.

5. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease [review]. Am J Kidney Dis. 1998;32(5 suppl 3): S112–S119.[Medline]

6. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med.2004; 351:1285 –1295.[Abstract/Free Full Text]

7. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med.2004; 351:1296 –1305.[Abstract/Free Full Text]

8. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. 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. Available at: http://www.annals.org/cgi/reprint/130/6/461.pdf. Accessed January 23, 2006.

9. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis.2002; 39(2 suppl 1):S1 –S266.[Medline]

10. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med.1993; 329:1456 –1462.[Abstract/Free Full Text]

11. Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med. 2001;135:73–87. Available at: http://www.annals.org/cgi/reprint/135/2/73. Accessed January 23, 2006.

12. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med.2001; 345:861 –869.[Abstract/Free Full Text]

13. Viberti G, Wheeldon NM, MicroAlbuminuria Reduction with VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation.2002; 106:672 –678.[Abstract/Free Full Text]

14. Nissenson AR, Collins AJ, Hurley J, Petersen H, Pereira BJ, Steinberg EP. Opportunities for improving the care of patients with chronic renal insufficiency: current practice patterns. J Am Soc Nephrol. 2001;12:1713–1720. Available at: http://jasn.asnjournals.org/cgi/content/full/12/8/1713. Accessed January 23, 2006.

15. Weir MR. Angiotensin II receptor blockers: the importance of dose in cardiovascular and renal risk reduction [review]. J Clin Hypertens. 2004;6:315 –323.

16. National Kidney Foundation–Dialysis Outcomes Quality Initiative. NKF-DOQI clinical practice guidelines for vascular access. Am J Kidney Dis.1997; 30(4 suppl 3):S150 –S191.[Medline]

17. National Kidney Foundation–Dialysis Outcomes Quality Initiative. III. NKF-K/DOQI clinical practice guidelines for vascular access: update 2000. Am J Kidney Dis.2001; 37(1 suppl 1):S137 –S181.[Medline]

18. Owen WF Jr. Patterns of care for patients with chronic kidney disease in the United States: dying for improvement [review]. J Am Soc Nephrol. 2003;14(7 suppl 2):S76–S80. Available at: http://jasn.asnjournals.org/cgi/content/full/14/suppl_2/S76. Accessed January 23, 2006.

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