Prevalence of chronic kidney disease by age group in the National Health and Nutrition Examination Survey (NHANES) for 1988–1994 and 1999–2004. (Reproduced with permission from Coresh et al. )
6.3 Diagnosis of and Controversy Concerning CKD in the Elderly
Beginning at the age of 40 years, the glomerular filtration rate (GFR) declines by approximately 8 mL/min/1.73 m2 per decade in a healthy individual although the rate of decline is highly variable. After approximately 75 years of age, the rate of GFR decline may accelerate; however, such progressive GFR decline is not fast enough to cause kidney failure throughout the human life span [13, 14]. According to contemporary diagnostic criteria for CKD, any subject, regardless of age, with a measured or estimated GFR <60 mL/min/1.73 m2 present for at least 3 months is considered to have CKD (stages 3–5) irrespective of the presence or absence of other signs of kidney injury, as recommended in the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline [15, 16]. Consequently, a great majority of the elderly can be “diagnosed” with CKD although this can and does occur in healthy aging . Therefore, considerable controversy exists as to whether the GFR decline in the elderly indicates disease status or occurs with natural aging. This has been suggested as an example of “overdiagnosis” of CKD in the elderly, which leads to unnecessary medical expenses due to the inappropriate use of CKD definition based on measured GFR or eGFR [17, 18]. It is debatable whether the diagnosis of stage 1–2 CKD in the elderly should be cut off. Although the 2012 KDIGO clinical practice guideline proposed a “special concern” for the diagnosis of CKD in the elderly, no special recommendation concerning the diagnostic criteria for CKD in the elderly has been put forward. In a meta-analysis that included 46 cohort studies and approximately two million patients, Hallan et al. discussed in 2012 the correlation between progression to end-stage renal disease (ESRD), mortality, age, proteinuria, and GFR level. Furthermore, their analysis showed that eGFR decline and urinary protein level were independent risk factors and were associated with the relative risk of all-cause mortality and ESRD in the general population, supporting the current KDIGO guideline on the analysis of GFR and proteinuria level [19, 20]. It is also based on these findings that the 2012 KDIGO clinical practice guideline does not have specific diagnostic criteria for CKD in the elderly. Findings from the study of Dousdampanis et al. also supported the diagnostic criteria for CKD without the boundary value for age [18, 21, 22]. However, the lack of evidence from studies on CKD in the elderly underlines the need for a large number of prospective studies on the diagnostic criteria for CKD in elderly patients.
6.4 Renal Function Evaluation Formula for the Elderly
GFR is the most important indicator for the diagnosis and staging of CKD. Inulin clearance is the gold standard for GFR determination, but its high price and complex operation limit its clinical use. Thus far, a total of more than 25 GFR estimation formulas based on serum creatinine (SCr) exist, with the simplified version of the Modification of Diet in Renal Disease (MDRD) Study formula and Cockcroft–Gault (CG) formula being the most widely applied [23, 24].
The MDRD formula was designed based on patients with CKD, and its applicability has been widely validated in patients with CKD. With respect to its application in healthy individuals with normal renal function and patients with CKD who have mild renal insufficiency (GFR >60 mL/min/1.73 m2), the equation appears to provide a low estimate of the true value, resulting in error in estimating the clinical renal function. Owing to the limitation of the MDRD formula, the CKD-EPI research group in 2009 proposed the CKD-EPI formula and performed a larger investigation . This study included healthy individuals and patients with CKD as subjects, and the MDRD formula was subsequently further modified. The CKD-EPI formula is better than the MDRD formula with respect to accuracy and relevance, especially in population with high GFR [26–28]. Recent studies have shown that cystatin C is an ideal endogenous marker of glomerular function that cannot be affected by inflammation, tumor, age, sex, muscle mass, stress, immunity, and endocrine diseases. Cystatin C can be used for the early detection of CKD, as its concentration sensitively reflects impaired renal function . With the widespread use of cystatin C, some GFR estimation formulas have been based on cystatin C measurement [30, 31]. In 2012, the CKD-EPI research group also advanced two improvements: CKD-EPIcys formula, which is based on cystatin C, and CKD-EPISCr–cys formula, which is based on the combination of SCr and cystatin C. However, there were considerable controversies as to which GFR estimation formula might be more suitable for the elderly. Studies using GFR estimation formulas were not specifically designed for the elderly, and there was no medical evidence supporting the evaluation of these formulas in older patient populations.
Drenth-van Maanen et al., Péquignot et al., and Helou considered the CG formula to be the most accurate in older patients, especially those with malnutrition and chronic inflammatory disease, because values corrected by the ideal body mass are used in the CG formula [32–34]. However, Flamant et al. recommended the use of MDRD and CKD-EPI formulas for the elderly, as the CG formula underestimated the renal function in older individuals . In the study of Nyman et al., which had a small European elderly sample, the deviation and accuracy of the CKD-EPI formula were better than those of the improved simplified version of the MDRD formula . Dowling et al. believed that the CG formula should be used when the drug dosage is adjusted according to the renal function of older patients . Many studies examined the bias in different GFR estimation formulas in relation to measured GFR [37–39]. SCr-based renal function evaluation often showed deviation due to reduced physical function and chronic diseases in older patients . Owing to the overestimation of the prevalence rate of stage 3a CKD (GFR, 45–59 mL/min/1.73 m2) by the SCr-based GFR equation, the 2012 KDIGO clinical practice guideline further recommended the use of GFR estimation formulas based on cystatin C to validate whether patients were diagnosed with stage 3a CKD in the absence of evidence of renal injury in order to reduce excessive diagnosis of stage 3a CKD. According to the guideline, GFR estimation formulas based on cystatin C had less bias than other formulas used to calculate GFR in the elderly [16, 41]. In 2016, the European clinical practice guideline on the management of older patients with stage 3b or higher CKD (GFR <45 mL/min/1.73 m2) advised the use of estimation formulas instead of SCr measurements to assess renal function in older patients. No equation was preferred, and the CKD-EPISCr–cys formula was considered an acceptable choice [42, 43]. In view of current controversies, epidemiologic studies on the elderly are required to develop a more suitable GFR estimation formula for this particular group.
6.5 Treatment and Intervention for Older Patients with CKD
The elderly, particularly those with comorbidities, are not enrolled in most reported studies, and clinical guidelines for them are lacking [44–46]. Some treatments proposed by clinical guidelines for older patients with CKD, including the use of renin–angiotensin system blockers, are controversial . Treatment for adults with CKD is different from that of older patients with CKD, as the clinical manifestations of the latter mainly include eGFR reduction and unapparent proteinuria or albuminuria. For the elderly without albuminuria, the benefit of renoprotection therapy is very limited . Clinicians could not mechanically apply CKD guidelines in the elderly and should pay attention to delaying the progression of CKD. It is more important to reduce renal damage under stress and preserve renal function because older individuals could have more serious injury and more difficult recovery than younger individuals under the same stress . Many risk factors could be avoided, including the use of nephrotoxic drugs, cardiac surgery, interventional therapy, ischemia, and inflammation . At the same GFR level, the risk of death, myocardial infarction, and stroke in older patients with CKD is greater than the risk of developing ESRD . A high risk of all-cause and cardiovascular disease mortality in community-dwelling elderly individuals with CKD has been reported . These patients could benefit from slowing down renal impairment and improving metabolic acidosis, anemia, and hyperphosphatemia, and the risk of cardiovascular events could be reduced. Sufficient evidence on the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) to delay the progression of CKD in most older patients with CKD remains lacking. There is an increasing risk of renal injury under the circumstances of hypovolemia, excessive diuresis, renal artery stenosis, severe left heart failure, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs).
No randomized controlled trials have compared dialysis and nondialysis treatment in older patients diagnosed with ESRD . In a retrospective analysis of patient survival among those older than 75 years with CKD stage 5, the first- and second-year survival rates of the dialysis group were superior to those of the conservative group. However, this survival advantage was lost in patients with multiple comorbidities . Decisions about whether to receive dialysis or not are difficult before dialysis, and the choice between hemodialysis and peritoneal dialysis should remain individualized in the elderly [55–57]. Age alone does not necessarily preclude candidacy for renal transplantation. In 2011, 60% of renal transplant recipients were older than 50 years, of whom 18% were older than 65 years . Improvement in the quality of life is the most important goal and should be evaluated from various aspects such as organ function, prognosis, cognitive status, social support, treatment burden, and nutritional status. Renal replacement therapy (RRT) is an appropriate option for older individuals with good baseline quality of life.
6.5.1 Changes in the Management of the Elderly with CKD
Changes in the decision-making model for the treatment of chronic kidney disease in the elderly
• Diagnosis, prevention, and treatment of the disease
• Particularity and priority of patients
• Pathophysiology of the disease
• Variable factors affecting the health of patients
• Determined by the disease
• Determined by the specific priority of patients
• The first goal of treatment and prevention
• One of the goals
• Pathological causes of the disease (mental, environmental, social, and other secondary factors) are not the main determinants of the disease
• The state of health is due to the interaction of complex factors, such as hereditary, religious, environmental, and social factors
Because GFR can be affected by the aging process, the prevalence of CKD increases with advancing age [61, 62]. However, several features of aging may limit the utility of disease-oriented models of care. In older individuals, complex comorbidities and geriatric syndromes are common, and signs and symptoms often do not reflect a single underlying pathophysiological process. Information on the safety and efficacy of recommended interventions is often lacking [63, 64]. For all these reasons, an individualized patient-centered model of care tends to be applied to the elderly over more traditional disease-oriented approaches (Table 6.1). An individualized patient-centered approach prioritizes patient preferences and embraces the notion that observed signs and symptoms often do not reflect a single unifying disease process but instead reveal the complex interplay among several different factors, including aging, social, pathological, and psychological factors . This model focuses on alterable outcomes that matter to the patient. Prognostic information related to these and other outcomes is generally used to shape rather than dictate treatment decisions. For older populations with CKD, an individualized patient-centered approach to care may offer more than a traditional disease-oriented approach [64, 66].
6.5.2 Clinical Practice Guideline on the Management of Older Patients with CKD
Considering that the proportion of older patients with severe CKD increased at the end of 2016 based on the increasing number of older patients with infirmity although evidence from existing studies remains limited, the European Renal Best Practice released the clinical practice guideline on the management of older patients with CKD stage 3b–5 . The new guideline is based on the old CKD-related research data, and its main contents include renal function evaluation in elderly patients with CKD and assessment of the benefits of diagnosing CKD during follow-up.
Renal function evaluation is recommended in the selection section of the renal function formula. The guideline recommends the four-variable Kidney Failure Risk Equation (KFRE), as it performs sufficiently well for use in older patients with advanced CKD and eGFR <45 mL/min/1.73 m2 [67, 68]. The four-variable KFRE (age, sex, eGFR, and albuminuria) predicted the risk of ESRD at 2 and 5 years and achieved excellent discrimination (pooled c-statistic 0.91 and 0.88 at 2 and 5 years, respectively) in further validation cohorts that included 721,357 individuals with CKD stage 3–5 in North America, Asia, Europe, and Australasia [19, 69]. This guideline suggests the use of the Bansal score to predict the individual 5-year risk of mortality before ESRD in non-frail older patients with CKD stage 3–5 and recommends that an assessment of frailty be performed for patients at low risk based on the Bansal score [70, 71]. The final risk prediction model includes nine readily available demographic, clinical, and biochemical predictors: age, sex, ethnicity, eGFR, urinary albumin-to-creatinine ratio, diabetes, smoking status, history of heart failure, and stroke. It is recommended that patients at low risk based on the Bansal score be evaluated for physical weakness [72–74]. High-risk management should be implemented for patients with physical weakness who require dialysis. The guideline also recommends that the Renal Epidemiology and Information Network (REIN) score be used to predict the risk of mortality in older patients with CKD stage 5 . The risk prediction model developed from 12,500 French incident dialysis patients and validated in 11,848 different dialysis patients, includes nine predictors: age, sex, history of congestive heart failure, peripheral vascular disease, dysrhythmia, cancer, severe behavioral disorder, mobility, and baseline serum albumin concentration [69, 76, 77].
The guideline recommends that a simple score be regularly used to assess functional status in older patients with CKD stage 3b–5d in order to identify those who would benefit from a more in-depth geriatric assessment and rehabilitation [78–80]. Furthermore, according to this guideline, most simple scores, including self-report scales and field tests (sit-to-stand, gait speed, and 6-min walk tests), have comparable and sufficient discriminating power to identify patients with decreased functional status [81–83]. As exercise has a positive effect on the functional status of older patients with CKD stage 3b or higher, the guideline recommends that exercise training be offered in a structured and individualized manner to avoid adverse events. The formulation of sports training programs should be systematized and individualized to avoid the occurrence of adverse events [84–86]. Exercise training under supervision at 2 hours before dialysis and regular follow-up are very important for patients on dialysis [87–89]. The guideline proposes subjective global assessment as the gold standard for assessing the nutritional status of older patients with CKD stage 3b or higher and suggests that a score including serum albumin concentration, BMI, SCr normalized to body surface area, and normalized protein nitrogen appearance may be used to assess the nutritional status of older patients on hemodialysis [90, 91]. The elderly are mostly in a high-energy consumption risk state, and nutritional assessment can predict the survival rate of patients on dialysis, which has important clinical implication [92, 93].
6.5.3 RRT vs. Conservative Treatment
Some scholars believe that the survival benefit from RRT is not obvious in elderly patients with CKD [94, 95]. Taking into account the reduced organ functional status and poor quality of life in patients with CKD, complicated treatment processes, and increased medical expenses, conservative treatment is considered appropriate [96, 97]. The European guideline recommends a comprehensive assessment of renal function and survival risk and selection of appropriate RRT method. With respect to the choice of management methods for ESRD, conservative treatment is recommended in the shared decision-making [98, 99]. The REIN score is recommended to predict short-term (6-month) prognosis in RRT patients . At the same GFR level, the risk of death, myocardial infarction, and stroke in older patients with CKD is greater than the risk of developing ESRD. Slowing down renal damage and improving metabolic acidosis, anemia, and hyperphosphatemia can reduce the risk of cardiovascular events and benefit elderly patients with CKD [95, 99].
For most elderly patients with CKD, evidence on the use of ACEIs/ARBs to delay the progression of the disease, especially in combination with insufficient blood volume or excessive diuretic use, remains lacking . Renal artery stenosis, obvious left-sided heart failure, and NSAID use also increase the risk of kidney injury. There is no unified answer as to whether elderly patients with end-stage CKD require dialysis or conservative treatment [102, 103]. In developed countries, older patients with end-stage CKD have gradually switched from conservative treatment to dialysis. Under suitable conditions, age is not a contraindication for renal transplantation [104, 105]. Improvement in the quality of life is the most important goal and should be evaluated from various aspects such as organ function, prognosis, cognitive status, social support, treatment burden, vision or hearing, and nutritional status [106, 107]. RRT is a suitable option for the elderly with good baseline quality of life.
Many problems concerning the diagnosis and treatment of CKD in the elderly still exist, such as the suitable diagnostic criteria, causes of CKD, therapeutic targets, and related complications. The treatment for these patients requires a comprehensive balance, and management using a patient-centered approach rather than a disease-oriented approach should be established.
The prevalence of CKD is higher in the elderly than in the younger population. Various renal functions are affected by the complex process of aging. The GFR in older patients with CKD declines with normal aging and disease progression.
There is currently no special recommendation with respect to the diagnostic criteria for CKD in the elderly. The criteria proposed by the 2012 KDIGO clinical practice guideline could overestimate the prevalence of CKD in the elderly.
No equation for renal function evaluation in the elderly is preferred. The MDRD and CG formulas are the most widely applied, and the CKD-EPISCr–cys formula is an acceptable choice in the elderly.
For the management of CKD in older populations, an individualized patient-centered approach may offer more benefits than a traditional disease-oriented approach.
The treatment of CKD in older patients requires overall consideration because the risk of cardiovascular disease mortality is greater than the risk of developing ESRD at the same GFR level.
In 2016, the European Renal Best Practice released the clinical practice guideline on the management of the elderly with CKD stage 3b–5. This guideline recommends the use of four-variable KFRE (age, sex, eGFR, and albuminuria) to predict the risk of ESRD and of the REIN score to predict the risk of mortality in older patients with CKD stage 5.