Chronic kidney disease in geriatric patients: Estimating glomerular filtration rate in older patients with comorbidities

Abstract

Aging is an inevitable process that is usually measured by chronological age, with people aged 65 and over being defined as "older individuals". There is disagreement in the current scientific literature regarding the best methods to estimate glomerular filtration rate (eGFR) in older adults. Several studies suggest the use of an age-adjusted definition to improve accuracy and avoid overdiagnosis. In contrast, some researchers argue that such changes could complicate the classification of chronic kidney disease (CKD). Several formulas, including the Modification of Diet in Renal Disease, CKD-Epidemiology Collaboration, and Cockcroft-Gault equations, are used to estimate eGFR. However, each of these formulas has significant limitations when applied to older adults, primarily due to sarcopenia and malnutrition, which greatly affect both muscle mass and creatinine levels. Alternative formulas, such as the Berlin Initiative Study and the Full Age Spectrum equations, provide more accurate estimates of values for older adults by accounting for age-related physiological changes. In frail older adults, the use of cystatin C leads to better eGFR calculations to assess renal function. Accurate eGFR measurements improve the health of older patients by enabling better medication dosing. A thorough approach that includes multiple calibrated diagnostic methods and a detailed geriatric assessment is necessary for the effective management of kidney disease and other age-related conditions in older adults.

Key Words: Chronic kidney disease; Estimated glomerular filtration rate; Renal alterations; Geriatric patients; Chronic Kidney Disease-Epidemiology Collaboration; Modification of Diet in Renal Disease; Cockcroft-Gault formula; Berlin initiative study; Full age spectrum equation

Core Tip: Older people often battle with multiple health issues, such as diabetes, high blood pressure and heart disease, making treatment considerably more challenging, particularly if they have kidney problems. This specific cohort presents a meaningful diagnostic challenge in identifying kidney problems because of the large difficulty in differentiating normal aging from early chronic kidney disease. Accurate glomerular filtration rate estimation is important to prevent misdiagnosis, improper treatment and medication errors resulting from inaccurate calculations.

TO THE EDITOR

We read with great interest the article by Hamarat[1] “Glomerular filtration rate and comorbidity factors in elderly hospitalizations”, recently published in the World Journal of Nephrology.

Aging can be defined as an inevitable phenomenon that is usually assessed by chronological age, with people aged 65 or older being defined as “older individuals”[2]. A significant proportion of older adults receiving medical care have multiple co-occurring health problems, making treatment much more difficult. Diabetes, hypertension and heart disease often co-occur and affect overall health; this combination also affects kidney function. The author of the study emphasized the link between kidney function and comorbidities in this frail population. Differentiating between normal aging and the early stages of chronic kidney disease (CKD) can sometimes be challenging, leading to delays in interventions[3]. Therefore, an accurate estimation of glomerular filtration rate (GFR) is critical, as misclassification of CKD can lead to inappropriate treatment decisions, inaccurate medication dosing, and erroneous assessments of disease severity. The Kidney Disease Improving Global Outcomes guideline classifies CKD into six categories based on GFR (G1 to G5, with G3 divided into 3a and 3b). Furthermore, it also includes staging based on three levels of albuminuria (A1, A2, and A3), with each stage of CKD further subcategorized according to the urinary albumin-creatinine ratio[4].

Experts are currently debating[5-8] the most appropriate methods for estimating GFR in older adults and adapting CKD definitions to age[9,10]. One proposed approach involves using an age-adapted definition of estimation of GFR (eGFR) and CKD stage; in this context, the use of an eGFR threshold of < 45 mL/min/1.73 m² to define CKD stage 3a could decrease overdiagnosis and help to create better diagnostic tools for this group[11]. Conversely, Levey et al[12] argued that use of an age-calibrated definition of CKD is overly complex and probably not able to solve the issue of correct CKD staging; indeed, a comprehensive assessment of CKD severity and complications is considered important for the accurate diagnosis and treatment of CKD among older people[10,13].

Impaired physical and cognitive performance, along with physical and cognitive frailty, have a negative impact on renal function and prognosis in older people. A thorough meta-analysis of data from 114 cohorts including more than 27 million people showed an increased risk of hospitalization associated with a creatinine-based eGFR of 45-59 mL/min, which was substantially higher than that observed at greater eGFR levels[14]. For this reason, choosing the appropriate equation for GFR estimation is essential, because it considerably impacts outcomes and treatment options for many older patients. In fact, several equations are used for GFR estimation, each with their own strengths and weaknesses; however, their accuracy in older patients remains debated[15,16].

In his study, Hamarat[1] used the modification of diet in renal disease (MDRD) study equation to calculate eGFR values, but relying on this single method can be controversial[1]. Comparative research indicated that the CKD-epidemiology collaboration (CKD–EPI) equation generally provides a more accurate eGFR estimate, thus prompting its use in clinical practice[17]. However, choosing the most appropriate equation requires a more detailed consideration.

The CKD-EPI 2021[18] is one of the most commonly used equations for estimating GFR worldwide, yet it can systematically overestimate renal function in older patients, leading to potential underdiagnosis of CKD[7]. Its accuracy in this population is still controversial, given evidence of a persistent U-shaped correlation between creatinine-based eGFR and mortality, indicating a possible increased risk of mortality among older patients with apparently acceptable eGFR values.

If the CKD-EPI and the MDRD equations have multiple limitations, the Cockcroft-Gault equation may underestimate the eGFR. Roberts at al[19] examined the differences between the MDRD equation and the Cockcroft-Gault equation in older people. While the MDRD equation appears to overestimate renal function with increasing age, the Cockcroft-Gault equation tends to underestimate it. Moreover, the results of a study on the use of the MDRD or CKD-EPI equation instead of the Cockcroft–Gault equation to assess renal function and adjust medication dosing in older patients underlined the detrimental effects of inaccurate eGFR assessment in this population. Using the MDRD and CKD-EPI equation instead of the Cockcroft–Gault equation resulted in dosing discrepancies in 20%-25% of patients and 15% of medication prescriptions, leading to potential overdose in 95% of cases. The use of the MDRD or CKD-EPI equations led to an increased assessment of renal function, which may influence dosing decisions and drug safety in older patients[20].

As older adults often experience sarcopenia and malnutrition, creatinine-based equations alone may not be reliable, as they do not consider the age-related decline in muscle mass. In these circumstances, decreased muscle mass may lead to decreased serum creatinine, which may falsely elevate eGFR. Emerging research suggests that two alternative equations, such as the Berlin initiative study (BIS) and the full age spectrum (FAS) equation, have significantly improved the accuracy of CKD diagnosis in geriatric patients. Numerous studies have shown that the BIS/FAS equations improve eGFR estimation and predictive risk classification in older individuals[21-23]. In contrast to the CKD-EPI equation, which calculates eGFR in adults and was developed and validated in studies with an insufficient number of older patients, the BIS equation considers age-related changes in muscle mass to more accurately estimate GFR in older individuals. In contrast, the FAS equation is applicable to all age groups and is therefore beneficial for the diagnosis and management of CKD across the lifespan[22,24]. A recent meta-analysis of eGFR equations in the geriatric population found that BIS and FAS are more accurate than CKD-EPI in calculating GFR in this population[22]. The recently introduced EKFC equations represent an improvement to FAS[25] but should be tested more thoroughly in older patients.

To further improve the calculation of eGFR in older patients with decreased muscle mass, the biomarker cystatin C, which is less influenced by muscle mass variations compared to serum creatinine, has been included in the eGFR equation to improve the assessment of renal function in older adults with sarcopenia and frailty.

Confirmatory testing using eGFR based on cystatin C (eGFRcys) or on both creatinine and cystatin (eGFRcr-cys) performed around the threshold of 60 mL/min/1.73 m² may provide greater accuracy in assessing renal function[26]. Equations that incorporate cystatin C improved the specificity of CKD diagnosis and the accuracy of GFR calculations in older adults, which has implications for medication dosing and for prevention of nephrotoxic burden. Further confirmatory studies in different older populations would be desirable. Cystatin C-based eGFR (eGFRcys or eGFRcr-cys), unlike eGFRcr alone, may improve the identification of high-risk CKD patients near the diagnostic threshold[27] and help identify older adults who are more likely to benefit from early intervention against cardiovascular disease, kidney failure, and premature mortality.

In conclusion, a combined eGFR equation that includes both creatinine and cystatin C can significantly improve the accuracy of renal function assessment in older adults. This thoroughly removes the limitations associated with creatinine and cystatin-C alone and utilizes the complementary benefits of both biomarkers to improve the accuracy of GFR prediction.