and the Estimated Glomerular

Hypertension Kidney Specialists

The ability to assess kidney function properly has important health implications; chronic kidney disease (CKD) is progressive, most often irreversible, and associated with multiple comorbidities and adverse outcomes. This is particularly true in regard to the risk of cardiovascular disease and cardiovascular events, which increases with worsening renal function. More than 50% of deaths in patients with end-stage renal disease (ESRD) are due to cardiovascular complications.¹ Any degree of kidney dysfunction—not just the most severe—can hasten the onset and progression of cardiovascular disease, and dramatically worsen prognosis.^2,3 Accurate and early detection of CKD, along with appropriately aggressive interventions, may help retard the progression of both of these interrelated diseases.

An estimated 20 million Americans are living with some degree of kidney disease ranging from mild damage to ESRD requiring transplantation, hemodialysis, or peritoneal dialysis. This latter group constitutes the smallest proportion of CKD patients, but consumes a staggering proportion of healthcare resources. (This small subset is easier to track than the generalized CKD population, and most economic data are therefore based on ESRD care.) In 2001, an estimated $22.8 billion were spent on ESRD care—more than 6% of the entire Medicare budget.⁴ During the same year, the annual mortality rate in this relatively small group of patients exceeded 20%.⁴ Over the course of 1, 2, 5, and 10 years, the survival rates of dialysis patients are 80%, 67%, 40%, and 18%, respectively.⁵ Because of these poor survival rates, the

National Kidney Foundation (NKF) initiated the Kidney Disease Outcome Quality Initiative (KDOQI) to help all clinicians identify, stage, and treat kidney disease. To date, NKF has published 10 sets of guidelines. The centerpiece of the program is the 2002 CKD guidelines,⁶ which provide definitions of CKD, and recommend an estimated glomerular filtration rate (GFR) as the best overall measure of kidney function.

The KDOQI guidelines define CKD as kidney damage of 3 or more months’ duration caused by structural or functional abnormalities with or without a decreased GFR. Pathological markers, abnormalities in the blood or urine, or imaging tests, may reveal kidney dysfunction. CKD may also be defined as a persistently low GFR of <60 mL/min/1.73m² for 3 or more months, with or without identifiable kidney damage.

The best available method to estimate GFR is the equation from the Modification of Diet in Renal Disease

(MDRD) study (Figure 1). The equation was developed in 1999 based on data from 1,628 men and women with CKD (average GFR 40 cc/min). The MDRD equation adjusts for 4 variables: body-surface area, race, gender, and age. GFR is expressed as mL/min/1.73m²; race is categorized as either black or not black. Based on estimated GFR, the NKF guidelines categorize CKD into 5 stages, which are reflective of kidney function regardless of the underlying pathological cause of dysfunction. (Table 1)

 

Stage	Description	GFR (mL/min/1.73 m2)	Prevalence* N(1000s)                                 %
1	Kidney damage with normal or ↑ GFR	≥90	5,900                                      3.3
2	Kidney damage with mid ↓ GFR	60-89	5,300                                      3.0
3	Moderate ↓ GFR	30-59	7,600                                      4.3
4	Severe ↓ GFR	15-29	400                                         0.2
5	Kidney failure	<15 (or dialysis)	300                                         0.1

* Data for Stages 1–4 from NHANES 111 (1988–1994)1. Population of 177 million adults age  20 years. Data for Stage 5 from USRDS (1998)2 include approximately 230,000 patients treated by dialysis, and assume 70,000 additional patients not on dialysis. GFR estimated from serum creatinine using MDRD Study equation based on age, gender, race and calibration for serum creatinine. For Stages 1 and 2, kidney damage estimated by spot albumin-to-creatinine ratio 17 mg/g in men or 25 mg/g in women on two measurements.

 

Sources: National Kidney Foundation. Available at: http://www.kidney.org/professionals/KDOQI/guidelines.cfm. Accessed June 11, 2006. Printed with permission from the National Kidney Foundation, Inc.

 

Medication use also requires consideration. Many drugs such as cimetidine and trimethoprim interfere with

creatinine tubular secretion and thus elevate serum creatinine levels. The result is a decrease in estimated GFR even though there has been no real effect on renal function. Likewise, fluctuating kidney function will produce unreliable estimated GFRs, since a steady state must be achieved before the GFR can be estimated.⁹ Finally, it is important that laboratories use the same calibration used to develop the equation, since different calibrations will produce different results. The error introduced by noncalibrated creatinine is mainly seen at near normal GFRs, which are already reported as a generalized >60 cc/min. A national initiative is underway to make uniform laboratory calibration a reality.

Figure 2: Outcomes for Medicare patients during 2-year follow-up: risk of death or endstage renal disease. CKD = chronic kidney disease; DM = diabetes mellitus; ESRD = endstage renal disease

 

 

 

Source: Collins AJ, Li S, Gilbertson DT, et al. Chronic kidney disease and cardiovascular disease in the Medicare population. Kidney Inter 2003;64(suppl 87):S24-31. Adapted by permission from Macmillan Publishers Ltd: copyright 2003.

Cardiovascular disease worsens with worsening CKD. In the Atherosclerotic Risk in Communities study,

Figure 3: Kaplan–Meier Estimates of the Rates of Death at Three Years from Cardiovascular (CV) Causes, Reinfarction, Congestive Heart Failure (CHF), Stroke, Resuscitation after Cardiac Arrest, and the Composite End Point, According to the Estimated GFR at Baseline. Data on patients with noncardiovascular events were censored. The P value is from the Cox model.

 

 

 

Source: Anavekar NS, McMurray JJV, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285-1295. Copyright © 2004, with permission from Massachusetts Medical Society. All rights reserved.

Similar findings were observed in the Kaiser Permanente of Northern California Renal Registry,¹¹ which enrolled 1,120,295 adults (≥20 years) between 1996 and 2000. In the unadjusted analysis, a GFR of ≥60 mL/min/1.73m² was associated with an annual mortality rate of 1.1% and cardiovascular event rate of 2.8%. These rates increased to 24.8% and 51.8%, respectively, among those with a GFR <15mL/min/1.73m². The risk of both adverse outcomes increased in a linear fashion across the five stages

Figure 4: Multivariable association between levels of estimated GFR and the risks of death and

CV events. All categories of GFR are compared with GFR 60 mL/min/1.73 m².

 

 

Source: Go AS, HSU CY. Chronic Kidney Disease and Risk of Adverse Outcomes. Nephrology Rounds Aug/Sept 2005;3(7):1-6. Available at: http://www.nephrologyrounds.org/cgibin/templates/framesets/nephrologyRoundsUSA/fs_snell.cfm. Accessed June 13, 2006. Permission granted by Snell Medical Publications.

The causal relationship between cardiovascular disease and CKD has not been fully elucidated. Investigators hypothesize that impaired renal function increases arterial calcification, endothelial dysfunction, arterial stiffness, inflammation, and thrombogenesis, and that CKD patients with cardiovascular disease are less aggressively treated than those with normal function.¹¹ Nevertheless, that there is a relationship is clear: progressive declines in kidney function of any degree generate or accelerate

cardiovascular disease. This progression may be slowed by accurately staged CKD, and early intervention.

Several clinical markers may be used to identify kidney dysfunction and for individualized risk stratification.

Interventions that address these risks should be implemented early, and before patients are referred to a nephrologist.

Hypertension—Hypertension worsens CKD, and blood

pressure should be maintained at less than130/80 mm

 

Hg in CKD patients. Among those with a gram or more of proteinuria per day (or >1 gram of urine protein per gram of creatinine on a spot urine specimen), blood pressure should be even lower (120/80 mmHg or less).¹² Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the first-line therapeutic choices. Diuretics and salt restriction potentiate the effects of these agents. Three to four drugs are usually required to achieve these blood pressure goals. ACE inhibitors and ARBs (and even aldosterone antagonists) may be combined for optimal lowering of proteinuria, but such combinations may increase the risk of hyperkalemia.

Proteinuria—Trace amounts of protein in the urine are normal. However, persistently elevated levels (proteinuria), are associated with progressive CKD. Even small amounts—microalbuminuria—are widely appreciated as a marker of “endothelial mischief” in patients with type 2 diabetes and/or hypertension. All patients with even trace amounts of proteinuria should be considered candidatesfor cardiac stress testing, and further workup

Dyslipidemia—Dyslipidemia is associated with progressive CKD. Statin therapy can help decrease proteinuria, and is cardioprotective. LDL cholesterol should be less than 100 mg/dL in CKD patients.

Diabetes—Diabetes is a common complication of CKD that requires aggressive management. HgbA1C should be reduced to less than 7%. Higher levels are associated with CKD progression.

 

Concomitant medications—Avoid or curtail nephrotoxic drugs (e.g., use non-steroidal antiinflammatory drugs intermittently and for short durations).

Urinalysis—Urinalysis for active sediment (red blood cell casts and dysmorphic red cells) is important, even in early disease stages. Positive tests may indicate kidney and/or systemic inflammation. Renal biopsy and specific therapy may be required in such patients.

Anemia—As patients progress to Stage 3 and beyond, regularly screen for anemia. Initiate iron replacement therapy and erythropoietic stimulating agents when appropriate.

Bone mineral abnormalities—Bone mineral abnormalities become more common in Stage 3. Hyperparathyroidism is usually the first indication of a problem. Treatment involves restoring vitamin D deficits (measure 25 OH vitamin D), and/or prescribing activated vitamin D to maintain a parathyroid hormone level of 35-70 pg/mL in Stage 3 disease, and 70-110 pg/mL in Stage 4.

Referral to a nephrologist is needed as patients approach Stage 4. At this point, pre-ESRD education regarding treatment modality is provided (hemodialysis or peritoneal dialysis), an arteriovenous fistula is placed (they require months to mature), and patients are evaluated for transplantation. Nationwide, only approximately 60% of patients see a nephrologist prior to starting dialysis. Late referrals (i.e., fewer than 6 months before dialysis) results in higher costs and worse outcomes.¹³ Patients with active sediment, high-grade proteinuria, and refractory blood pressure need referral sooner.

CKD is a major public health problem, and places an enormous burden on the healthcare system. Patients

with CKD are at risk for multiple comorbidities, most notably cardiovascular disease. A proper understanding of the methodologies used to estimate GFR can help alert physicians to needed interventions, and help slow disease progression.

 

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myocardial infarction among patients on long-term dialysis. N Engl J Med

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risks of death, cardiovascular events, and hospitalization. N Engl J Med

3. Anavekar NS, McMurray JJV, Velazquez EJ, et al. Relation between

renal dysfunction and cardiovascular outcomes after myocardial infarction.

4. Bailie GR, Uhlig K, Levey AD. Clinical practice guidelines in

nephrology: evaluation, classification, and stratification of chronic kidney

disease. Available at: www.medscape.com/viewarticle/503813. Accessed

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kidney disease: evaluation, classification, and stratification. Available at:

www.kidney.org/professionals/kdoqi/guidelines_ckd/p1-exec.htm. Accessed

7. Stevens LA, Levey AS. Clinical implications of glomerular filtration

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org/cgi-bin/templates/framesets/nephrologyRoundsUSA/fs_snell.

8. Collins AJ, Li S, Gilbertson DT, et al. Chronic kidney disease and cardiovascular

disease in the Medicare population. Kidney Inter 2003;64(suppl

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function-measured and estimated glomerular filtration rate. N Engl J Med

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as a risk factor for atherosclerotic cardiovascular outcomes in the

11. Go AS, Hsu C. Chronic kidney disease and risk of adverse outcomes.

Available at: http://www.nephrologyrounds.org/cgi-bin/templates/framesets/

12. Jafar TH, Starck PC, Schmid CH, et al. Progression of chronic kidney

disease: the role of blood pressure control, proteinuria, and angiotensinconverting

enzyme inhibition. A patient-level meta-analysis. Ann Intern

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2002;137:479-486.

 

Laurence E. Carroll, M.D., F.A.S.N.

Hypertension Kidney Specialists

2112 Harrisburg Pike - Suite 2112

Lancaster, PA 17604

lecjtc@comcast.net