Kidney Function Restoration Program

Kidney function commonly declines with age, although not universally (6-9). Approximately one-third of elderly adults do not exhibit an age-related decline in kidney function (6). This has led to the suggestion that a decline in GFR is not a normal accompaniment of aging, but rather due at least in part to concomitant hypertension, cardiovascular disease, and diabetes mellitus. By the age of 80 years, mean GFR, depending on how it is measured or estimated, is approximately 50-80 mL/min, compared to

120 mL/min or greater in subjects in their 20s-40s. The prevalence of CKD in 65-74 year olds and individuals 75 years and greater is increasingly steadily, and there are more patients 70 years or older starting dialysis each year than any other age group (10). Despite this reduced level of GFR with advanced age, serum creatinine levels tend to remain relatively unchanged or increase only modestly over time in the absence of other conditions, a reflection of the reduced muscle mass that often accompanies aging (6, 11, 12).

Until recently, in routine clinical practice kidney function has been most commonly assessed by simple measurement of serum creatinine, collection of a 24-h urine for creatinine clearance, or use of simple equations, such as the Cockcroft-Gault equation (Table 5.1), to estimate GFR. In the elderly, reduction in muscle mass compared to younger subjects distorts the relationship between serum creatinine and estimated GFR (eGFR) using the Cockcroft-Gault formula so that serum creatinine typically underestimates the severity of CKD. Further complicating discussion of impaired kidney function has been the use of undefined terms such as "chronic renal failure" and "chronic renal insufficiency."

Recent developments have greatly improved the clinical evaluation of kidney function. First, as the result of the analysis of a wealth of data from the Modification of Diet in Renal Disease (MDRD) Study, prediction equations were derived that can more precisely provide an eGFR than previously available methods, including 24-h urine collections (13). While still imperfect due to lack of a standardized serum creatinine assay (a national standard is expected in the US in 2008) and uncertain validity in certain populations (such as the elderly; see below), use of the so-called abbreviated or modified MDRD prediction equation (Table 5.1) has increasingly gained acceptance as an important clinical tool for assessing

Table 5.1. Cockcroft-Gault and abbreviated MDRD prediction equations Cockcroft-Gault formula:

Creatinine clearance (ml/min) = (140-age) x (w^ghrt) (xQ 85 if female)

72 x Scr

Abbreviated (4-variable) MDRD equation:

Estimated GFR (mL/min/1.73 m2) = 186 x (Scr)-1154 x (age)-0203 x (0.742 if female) x (1.210 if black)

S = serum creatinine; age in years; weight in kg

Table 5.2. Stages of chronic kidney disease

Stage Description GFR (mL/min/1.73 m2)

1 Kidney damage with normal or increased GFR >90

2 Kidney damage with mild decrease in GFR 60-89

3 Moderate decrease in GFR 30-59

4 Severe decrease in GFR 15-29

5 Kidney failure <15 (or dialysis)

Chronic kidney disease is defined as a GFR < 60 mL/min/1.73 m2 for 3 or more months, or the presence of structural or functional abnormalities of the kidneys (pathologic abnormalities or abnormal findings on blood or urine tests or in imaging studies), with or without decreased GFR, for at least 3 months. Adapted from (14).

GFR. More recently, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) Chronic Kidney Disease Workgroup published a CKD classification scheme that has quickly been adopted by the renal community (Table 5.2) (14). Thus, in 2007 we find ourselves with improved prediction equations for determination of eGFR and a useful schema for categorizing levels of CKD.

The Cockcroft-Gault formula was derived over 30 years ago from 236 hospitalized men between the ages of 18 and 92 years (15). Several MDRD equations, with the 4-variable version in most common use, were derived and validated in 1,628 subjects (mean age of 50.6 years) with precise GFR measurements and laboratory data (13), thus their generalizability to older subjects was initially unclear. A few studies have recently evaluated the Cockcroft-Gault and MDRD equations in the elderly.

Fehrman-Ekholm and Skeppholm (8) measured kidney function with the iohexol clearance method as the gold standard against which other formulae were compared in 52 Swedish subjects between the ages of 71 and 110 years (mean 82.3 years). The mean iohexol GFR was 67.7 mL/min/1.73 m2. One of the MDRD equations (using serum creatinine, age, gender, age, BUN, and serum albumin) and the Cockcroft-Gault formula both correlated reasonably well (R2 = 0.53 and 0.50, respectively), although the Cockcroft-Gault formula tended to systematically underestimate GFR. Verhave and colleagues (16) compared the Cockcroft-Gault formula and modified MDRD equation (using serum creatinine, gender, and age) with 99mTc-DTPA renal clearance measurements in 850 subjects as old as 93 years. Among subjects 65 years or older, both the Cockcroft-Gault formula

MDRD Equation | ||||||

European-American |
African-American |
Cockcroft- |
-Gault formula | |||

Age (Yrs) |
Men |
Women |
Men |
Women |
Men |
Women |

50 |
1.34 |
1.03 |
1.58 |
1.22 |
1.50 |
1.28 |

60 |
1.30 |
1.00 |
1.53 |
1.18 |
1.33 |
1.13 |

70 |
1.26 |
0.97 |
1.49 |
1.15 |
1.17 |
0.99 |

80 |
1.23 |
0.95 |
1.46 |
1.12 |
1.00 |
0.85 |

Calculations assume weight of 72 kg and body surface area of 1.73 m2. Creatinine in mg/dL. Adapted from (14).

Calculations assume weight of 72 kg and body surface area of 1.73 m2. Creatinine in mg/dL. Adapted from (14).

and MDRD formula both underestimated GFR, with the magnitude of the underestimate influenced by the creatinine assay methodology. The Cockcroft-Gault formula underestimated mean GFR by 11.3-20.2 mL/min/1.73 m2 and the MDRD formula underestimated mean GFR by 3.7-17.8 mL/min/1.73 m2. Other investigators have also reported a greater degree of underestimation of GFR in elderly patients using the Cockcroft-Gault formula compared to the MDRD equations (17, 18). This tendency for greater underestimation of GFR with the Cockcroft-Gault formula leads to the inevitable conclusion that the prevalence of CKD is substantially lower if one uses the MDRD equations rather than Cockcroft-Gault formula, regardless of which is more accurate (19).

The need to avoid dependence on serum creatinine levels, particularly in the elderly, is made apparent in Table 5.3, showing the level of serum creatinine above which eGFR is below 60 mL/min/1.73 m2 or estimated creatinine clearance is below 60 mL/min, i.e., stage 3 CKD or less. Other methods for assessing kidney function, such as use of plasma cystatin C concentration, remain to be validated in the elderly, and are not yet in generally widespread use (20-22).

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