Authors: Abimereki Muzaale ((1)Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland), Adnan Khan ((2)Department of Medicine, University of California San Diego, La Jolla, California), Richard J. Glassock ((3)Department of Medicine, University of California Los Angeles, Los Angeles, California), Ekamol Tantisattamoa ((4)Department of Medicine, University of California Irvine, Orange, California), Rebecca S. Ahdoot ((4)Department of Medicine, University of California Irvine, Orange, California), Fawaz Al Ammary ((4)Department of Medicine, University of California Irvine, Orange, California)
Categories: Article, GFR, Elderly, Aging, AKI, CKD
Source: Current opinion in nephrology and hypertension
Authors: Abimereki Muzaale, Adnan Khan, Richard J. Glassock, Ekamol Tantisattamoa, Rebecca S. Ahdoot, Fawaz Al Ammary
Kidney function declines with normal aging. But it also declines with the progression of some diseases. This review calls for a more nuanced interpretation of kidney function in the geriatric population, who may have frailty and comorbidities.
GFR declines with healthy aging kidneys. Aging kidney changes include decreased cortical volume, senescent global glomerulosclerosis, and reduced nephron numbers. Yet normal aging is not associated with increased glomerular volume or single-nephron GFR. The prevalence of GFR <60 mL/min/1.73 m2 in the geriatric population is high. However, the decline in GFR with normal aging may not reflect true CKD without albuminuria. While the risk of ESKD and mortality increases in all age groups when eGFR <45 mL/min/m2, there is no significant increased relative risk of ESKD and mortality in the geriatric population when eGFR 45 to 59 mL/min/m2 in the absence of albuminuria. Innovative approaches are needed to better estimate GFR and define CKD in the geriatric population.
The expected GFR decline in the geriatric population is consistent with normal aging kidney changes. To avoid CKD overdiagnosis and unnecessary referrals to nephrology for possible CKD, age-adapted definitions of CKD in the absence of albuminuria are needed.
The geriatric population (≥65 years old) increased to more than 55.8 million in the United States, representing 16.8% of the total population in 2020.(1) Kidney function declines with healthy, normal aging. But it also declines with the progression of some diseases. The aging process is poorly understood and involves genetic, environmental, and lifestyle factors. This process alters the structure and function of various organ systems. Since the effects of age on kidney function are subtle, cumulative, and often irreversible, they are much more apparent in the geriatric population. This article argues that the mix of three issues calls for a more nuanced interpretation of kidney function in a geriatric population. First, the interpretation of what constitutes a “normal” glomerular filtration rate (GFR) is age specific. Second, the elderly may be frail, pre-frail, or robust, leading to variations in creatinine generation on these grounds. Third, the elderly are a heterogeneous group with ages ranging from 65 to 100 years and comorbidities ranging from 0 to 20 conditions, which makes the assessment of kidney function in the geriatric population more challenging than in the general population.
Kidney cortex volume decreases with normal aging, while medullary volume increases until approximately age 50 when total parenchymal volume decreases thereafter.(2, 3) The number and size of simple renal cysts increase as we age, and as such, age-specific criteria must be met to diagnose autosomal dominant polycystic kidney disease if indicated.(4, 5)
Arteriosclerosis/arteriolosclerosis, senescent global glomerulosclerosis, interstitial fibrosis, and tubular atrophy increase with normal aging.(6, 7, 8) In healthy persons, nephrosclerosis increases from 2.7% for ages 18–29 to 73% for ages 70–75.(9) Unlike age-related global glomerulosclerosis, which is more prominent in the superficial cortical region, diabetic glomerulosclerosis is in the deep region.(10) Further, focal segmental glomerulosclerosis, when present, implies a pathological process rather than normal aging.
Nephron number declines by nearly 50% with normal aging, from 990,000 per kidney for ages 18–29 to 520,000 per kidney for ages 70–75, with about 8,200 nephron loss per year.(11) The decline in nephron number is associated with decreased kidney function over decades. Yet, normal aging is not associated with increased glomerular volume or single-nephron GFR (snGFR) that can be seen with obesity, diabetes, and low nephron endowment at birth.(12, 13, 14, 15)
The Linda Fried Physical Frailty phenotype includes six unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity.(16) The presence of three or more of these components is considered frailty. The presence of one or two components is considered pre-frailty. And the absence of all components is considered robustness. Frailty affects 4–16% of the geriatric population.(16, 17) Remarkably, robust elderly tend to remain robust.(17) Frailty is associated with an increased risk of mortality and reduced resilience to all kinds of physiological stressors. This reduced resilience is due to the overall loss of functional reserve in the frail elderly. The loss of functional reserve is also seen in the kidney, which puts the frail elderly at increased risk of acute kidney injury (AKI). While AKI is usually reversible in the younger, robust individual, it is more often resulting in CKD in the frail elderly. Sarcopenia is the age-related loss of muscle mass and strength. As muscle mass declines with age, so does the creatinine generation, which can affect the accuracy of estimated GFR (eGFR) and random urine albumin creatine ratio (ACR).
The risk of disease increases with age. And so does the risk of comorbidities. The median number of comorbidities among the elderly is 3, but this may range from 0 to 20.(18) Most prevalent comorbidities are hypertension, diabetes, and cardiovascular disease, which are common causes of CKD.(19, 20) Besides, the elderly are also at risk of AKI, another risk factor for CKD. When overlaid with the age-specific interpretation of eGFR, this clinical picture makes the assessment of kidney function in the geriatric population even more challenging.
GFR is a comprehensive indicator of kidney function, and albuminuria is a significant marker of kidney damage. GFR is a product of the number of nephrons and the average snGFR. Various studies have estimated the magnitude of the decline in GFR with normal aging, approximately 6 ml/min/1.73m2 per decade in healthy persons.(21, 22) The decline in GFR in healthy elderly is driven by the decline in nephron number, given that snGFR remains stable with normal aging. On the other hand, albuminuria, defined as ≥30 mg in a 24-hour urine collection or a urine ACR ≥30 mg/g, is not typically observed in healthy elderly. Unlike the 24-hour urine albumin excretion rate, a random ACR can be falsely elevated due to sarcopenia and reduced creatinine generation.(23, 24) Identifying albuminuria correctly in the elderly is critical to differentiate normal aging decline in GFR from CKD. Albuminuria in the elderly is also independently associated with cardiovascular and noncardiovascular mortality,(25) and linked to cognitive decline and dementia.(26) When combined with eGFR, albuminuria can better define CKD and predict mortality in the geriatric population.
GFR can be measured by the clearance of exogenous filtration markers, e.g., inulin, iohexol, and iothalamate.(27) GFR can be estimated by the clearance of endogenous filtration markers, such as 24-hour urine creatinine or serum creatinine and cystatin C.(28, 29, 30) The use of mGFR is expensive and complex, and therefore is difficult to implement in routine clinical practice. On the other hand, the 24-hour urine creatinine clearance is challenging due to timed urine collection. Hence, eGFR is the practical way to assess kidney function.
Serum creatinine-based eGFRcr is the most available, cheapest, and least invasive way to assess eGFR in the general and geriatric populations. Creatinine production decreases as we age while tubular secretion of creatinine increases, and as such, serum creatinine may stay stable despite a decline in GFR. Although creatinine-based eGFR equations account for age to model the decline in GFR that is not captured by serum creatinine, they can lead to overestimating GFR in the frail elderly or underestimating GFR in the high muscle mass elderly. Cystatin C is less influenced by muscle mass. However, obesity, diabetes, thyroid dysfunction, steroids, and inflammation can affect the cystatin C level. Unlike increased serum creatinine, increased cystatin C occurs with chronic diseases other than CKD that are associated with a higher risk for kidney failure, cardiovascular disease, and mortality independent of a person’s GFR.(31, 32) Contrary to the Kidney Disease Improving Global Outcomes (KDIGO) guideline, we do not recommend cystatin C-based eGFR equations to confirm CKD in the geriatric population with eGFRcr of 45–59 mL/min/m2. When the diagnosis of CKD is uncertain in the absence of albuminuria, i.e., CKD G3aA1, a 24-hour urine creatinine clearance or GFR measurement can help assess kidney function in the geriatric population.
Several equations are used across the world for estimating GFR.(29, 30, 33, 34, 35, 36) Both the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations were not developed in the elderly with very few participants over age 70.(29, 30, 34, 37) Thus, the accuracy of these equations in predicting eGFR is debatable in the geriatric population. The Berlin Initiative Study (BIS) equations were developed using 570 participants over the age of 70 (mean age of 78.5 years old) who had iohexol plasma clearance (mean mGFR of 60.3 ml/min /1.73m^2^).(35) Two equations were derived (BIS1: creatinine-based; BIS2: creatinine- and cystatin C-based). These two equations seem to provide a more accurate eGFR in the geriatric population. However, the BIS equations were developed in only white participants and have not been validated externally. Additionally, the BIS-derived equations do not represent healthy elderly given the sample included participants with diabetes (24%), hypertension (76%), myocardial infarction (15%), and cancer (23%) as well as the mean albumin-creatinine ratio was 86 mg/g.
While there is a need for innovative approaches to calculate eGFR in the geriatric population, an age-adjusted definition of CKD is also needed for this population. Using the age-adapted thresholds will help minimize the inclusion of elderly with age-related GFR decline, thereby impacting health services and resource utilization.
The KDIGO guideline defines and classifies CKD based on GFR (G1-G5) and albuminuria (A1-A3). CKD is defined by GFR <60 ml/min/1.73m2 that persists for over three months. Therefore, the geriatric population would have a higher CKD G3a/A1 rate, recognizing the expected decline in GFR with normal aging.(38) The prevalence of GFR <60 mL/min/1.73 m2 in the geriatric population varies from 38% to 62%, depending on the eGFR equation used.(39, 40, 41) However, the decline in GFR with normal aging may not reflect true CKD without albuminuria. Mislabeling an elderly person with CKD can have negative psychological consequences and health care costs.
Importantly, the relative mortality risk for reduced eGFR decreased with increasing age.(42) While the risk of end-stage kidney disease (ESKD) and mortality increases in all age groups when eGFR <45 mL/min/m2, there is no significant increased relative risk of ESKD and mortality in the geriatric population when eGFR 45 to 59 mL/min/m2 in the absence of albuminuria.(43, 44, 45, 46, 47, 48)
Many studies illustrate an age-related decline in mGFR among healthy persons.(21, 22, 49) The expected eGFR at age 20, 30, and 40 years is 125, 115, and 105 mL/min/1.73 m2 respectively. Even in these younger age groups, we can witness a decline in kidney function with age. But the decline is so subtle that it is not clinically significant. Anyone in these age groups with an eGFR <60 would be so far from their peers that it would be clinically significant. However, if the young person is a prior living kidney donor, then a more nuanced approach is needed because we should acknowledge the process that led to this decline in kidney function was not disease related.
If we then consider the expected eGFR at ages 50, 60, and 70 years, it is 95, 85, and 75 mL/min/1.73 m2 respectively. If any of these groups donate a kidney, it becomes apparent that some will have eGFR <60 without a progressive disease process. An even more nuanced approach would be warranted in this somewhat older population than the younger one considered before. But for those who are 80, 90, and 100 years of age, the expected eGFR is 65, 55, and 45 mL/min/1.73 m2 respectively. While an eGFR cutoff below which, regardless of age, we can say that eGFR is abnormal, this would not be 60 when including the geriatric population. And it is even more nuanced when we go beyond age and consider comorbidities and frailty.
Overall, using an age-adapted definition of CKD would reduce the CKD prevalence by approximately 50% and thus lower unnecessary referrals to nephrologists for possible CKD in the geriatric population.(50) An eGFR of 45 to 59 mL/min/1 .73 m2 is not clinically meaningful for risk stratification of ESKD and mortality in the absence of albuminuria in the geriatric population.
A healthy 90-year-old person with an eGFR of 49 ml/min/m2 may have a normal kidney function for that age. Relying solely on eGFR cutoff <60 mL/min/m2 for CKD diagnosis is not clinically meaningful in the geriatric population. The clinical assessment of kidney disease should combine blood and urine tests to support CKD diagnosis. Clinically relevant findings for identifying CKD in the geriatric population, besides medical history, include (1) eGFR below the expected age-specific level, in a steady state, rather than a universal cutoff of 60 mL/min/m2. (2) albuminuria (≥30 mg in 24-hour urine collection), (3) urinary sediment abnormalities, (4) hyperparathyroidism and hyperphosphatemia as markers of abnormal mineral metabolism, and (5) acidosis as a marker for metabolic acid-base imbalance. Additionally, imaging findings with anatomical abnormalities for kidney damage.
The expected GFR decline in the geriatric population is consistent with normal aging kidney changes, including decreased cortical volume, senescent global glomerulosclerosis, and reduced nephron numbers. Thus, a non-age-adapted GFR cutoff that does not reflect a solid outcome leads to overdiagnosis of CKD in the geriatric population, which can be avoided. Age-adapted definitions of CKD in the absence of albuminuria are needed.