Estimating Kidney Function in the Aging Adult
Pages 33 - 36
It is expected that 1 in 5 persons will be elderly by the year 2030.1 Chronic kidney disease (CKD) is an important problem in the elderly and is associated with a high risk of kidney failure, cardiovascular disease, and death.2 Among persons age 60-69 years, approximately 18% have albuminuria and 7% have an estimated glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2. In persons age 70 years or older, those percentages increase to 30% and 26%, respectively.3 The severity of CKD can be classified according to the level of the GFR, regardless of the cause, as follows3:
Stage 1: Kidney damage with a normal or increased GFR
Stage 2: Kidney damage with a mild decrease in GFR
Stage 3: A moderate decrease in GFR
Stage 4: A severe decrease in GFR
Stage 5: Kidney failure (ie, a GFR of Case Vignette
A 101-year-old African-American female with past medical history of hypertension, congestive heart failure, and a single kidney presented to the hospital with shortness of breath due to exacerbation of the heart failure. She had undergone a unilateral nephrectomy due to a renal mass approximately 18 years prior to the current presentation. Her serum creatinine (SCr) was stable at 1.0 mg/dL. After the placement of a Foley catheter, she had 24-hour urine studies for creatinine clearance (CCr). Her 24-hour urine volume was 450 mL, 24-hour creatinine was 284 mg, and CCr was 19.7 mL/min. Using the four-variable Modification of Diet in Renal Disease (MDRD) Study Group equation, her estimated GFR was 65.4 mL/min, and using the Cockcroft-Gault equation, her estimated GFR was 27 mL/min.
Physiology of the Elderly Kidney
Changes in the aging kidney can be classified into functional and structural.4
Changes in the kidney function of elderly individuals are known to occur in glomerular, tubular, and synthetic and endocrine function.4
Glomerular changes. It has been widely believed that after the age of 30 years GFR begins to decline at the rate of 1 mL per year, resulting in an inulin clearance of 65 mL/min at the age of 90 years.5 This notion has been challenged by subsequent studies.6 It is unclear whether the decline in kidney function is a consequence of the normal aging process or the result of comorbidities. In older patients, the estimation of kidney function presents unique challenges.
SCr is influenced by the nutritional status, protein intake, and muscle mass, and is therefore not an accurate measurement of GFR in the elderly.7 A decline in muscle mass with aging may keep SCr in the normal range, even with a significant fall in kidney function.8 Indirect estimates of kidney function using the Cockcroft-Gault equation or the MDRD equation have limitations.9 The Cockcroft-Gault equation allows the CCr to be estimated from the SCr in a patient with a stable SCr10:
CCr (mL/min) = ______________________________________
SCr (mg/dL) x 72
This formula takes into account the increase in creatinine production with increasing weight and the decline in creatinine production with age. For women, the formula requires multiplication of the obtained value of CCr by 0.85 to account for smaller muscle mass.
Several equations were derived from data on patients enrolled in the MDRD study who had GFR measured at baseline using urinary clearance of iothalamate. The six-variable equation was described in the original publication11:
(Age)-0.176 x (BUN [mg/dL])-0.170 x
(Alb [g/dL])+0.318 x (0.762 if female) x (1.18 if black)
To facilitate the calculation of the GFR using a simpler formula, the following abbreviated MDRD equation was also developed3:
(Age)-0.203 x (0.742 if female) x (1.21 if black)
The use of the Cockcroft-Gault and MDRD equations provided discordant estimations in over 60% of the elderly patients.12 The Cockcroft-Gault equation showed lower estimates at older ages (eg, > age 70 yr) than that obtained with the simplified MDRD study equation.12 One study showed that of all patients whose Cockcroft-Gault–estimated GFR was under 30 mL/min/1.73 m2, 14.7% were found to have a GFR greater than 60 mL/min/1.73 m2 according to the MDRD equation.13 Some authors have suggested that in advanced CKD, the Cockroft-Gault equation may be more accurate in estimating GFR than the abbreviated MDRD equation, although in late stages the difference is not much.14 One study suggested that in small elderly and female patients, drug dosing was more accurate when the Cockroft-Gault equation was used.15
In light of the above limitations, Cystatin C has been proposed to be a more accurate marker of renal function. Cystatin C is produced by all nucleated cells; its rate of production has been thought to be relatively constant and not affected by changes in diet, although this has not been proven. Cystatin C is unaffected by gender, age, or muscle mass. Cystatin C is a low-molecular-weight protein that is a member of the Cystatin superfamily of cysteine protease inhibitors. It is filtered at the glomerulus and not reabsorbed. However, it is metabolized in the tubules, which prevents use of Cystatin C to directly measure clearance. The serum Cystatin C concentration may correlate more closely with the GFR than the SCr concentration.16 Using the clearance of radioactive iothalamate as the gold standard, serum Cystatin C levels began increasing at GFR levels of approximately 90 mL/min/1.73 m2, while the SCr only increased when the GFR was approximately 70 mL/min/1.73 m2. Testing for Cystatin C is only available in a limited number of laboratories.The ability of Cystatin C to detect early renal failure in elderly subjects with greater sensitivity than creatinine has been demonstrated.17
The more direct methods of GFR estimation, such as inulin clearance, is not widely available, is more cumbersome to use, and is more expensive.18 As a result, GFR estimations using SCr continue to be used clinically.
Tubular function. Tubular function also changes with the aging process. Reduction in urinary sodium excretion in response to dietary sodium chloride deprivation is significantly impaired in the elderly.19 Elderly patients are more prone to hyperkalemia due to impaired potassium excretion,20 dehydration due to impaired urinary concentrating ability, and hyponatremia due to impaired urinary diluting capacity.21
Drug toxicities are more common in older persons, especially in the setting of polypharmacy and drug-to-drug interaction. This is especially true in decreased renal function in the setting of medication inducing tubular dysfunction.22
Synthetic and endocrine function. There are aging-related changes in the synthetic and endocrine functions of the human kidney.4 Studies have shown that elderly women have lower levels of 1,25-dihydroxyvitamin D, especially in the setting of decreased GFR.23 This is in part attributable to decreased ability of the aging kidney to convert 25-hydroxyvitamin D (25-OHD) to 1,25-dihydroxyvitamin D (1,25-[OH]2D). Erythropoietin levels have been shown to be lower in non-anemic elderly inpatients than in healthy younger persons.24 This in part reflects the compromised ability of the kidneys in older patients to synthesize erythropoietin.
Old age in humans is accompanied by a progressive loss of kidney mass. The weight of both kidneys declines from 250-270 grams in early adulthood to 180-200 grams in the eighth decade of life. The loss of kidney mass occurs primarily in the cortex, while the medulla is relatively spared.25 The glomeruli suffer from a progressive increase in the mesangial matrix, thickening of the glomerular basement membrane, and hyalinization of the arterioles.26 All of the above age-related changes could be accelerated in the presence of comorbidities such as hypertension and diabetes.27 The number of hyalinized or sclerotic glomeruli increases from 1% to 2% in the period from the third to the fifth decade to even 30% in some apparently healthy 80-year-old individuals.25 It has been suggested that “pathological” glomerulosclerosis should be seriously considered when the percentage of globally sclerosed glomeruli exceeds the number calculated by the following formula: (patient’s age/2) – 10.28 Tubular atrophy and interstitial fibrosis may be aging-related or may occur due to chronic inflammation or vascular disease.29 The distal renal tubules develop that increase in advancing age and may go on to enlarge to become simple renal cysts that may be seen even in nondiseased kidneys.30
Pathology of the Elderly Kidney
Renal aging is probably multifactorial in origin, and changes consistent with aging can be accelerated in the presence of such concomitant comorbidities as hypertension and diabetes mellitus.27 Loss of arterial elasticity may result in transmission of higher pulse pressures to arterioles, which can suffer damage and result in ischemic injury to end organs such as the kidneys.31-33 The biochemical substrate of artery aging has been researched in the last few years, which has resulted in the discovery of an increased creation of matter such as endothelin-1 and nitric oxide synthase,34 reactive oxygen species,35 and accumulation of calcium in the vessel walls of elderly persons.36 Other possible players in renal aging includes renal accumulation of advanced glycosylated end products,37 renin-angiotensin system through its effects on the angiotensin receptor (AT1), and transforming growth factor beta 1.38
The kidney undergoes functional and structural changes with aging. Functional changes can be subdivided into glomerular, tubular, and synthetic and endocrine. Pathological changes with aging are multifactorial in origin. While the elderly population is a growing demographic class, there is not yet a clear consensus about the best way to estimate kidney function in the older population. Significant discrepancy exists in the GFRs estimated by the MDRD and Cockroft-Gault equations.
The authors report no relevant financial relationships.
Drs. Subramanian, Kandarpa, Samindla, and Bloom are from the Kraftsow Division of Nephrology; Dr. Rojas-Delgado is from the Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA; and Dr. Dhar is from the Department of Medicine, Abington Memorial Hospital, Abington, PA, and is Assistant Professor of Medicine, Drexel University School of Medicine, Philadelphia, PA.