Age-related structural (e.g., number of glomeruli) and functional changes (e.g., glomerular filtration rate, renal blood flow, and tubular secretion) are associated with renal organ aging [24]. Decreased cardiac output leads to a reduction in renal blood flow and therefore renal size, as seen with the liver [24]. Structural renal alterations are decrease in weight, decreases in renal and cortical area, and number of glomeruli. Initially, until the age of 40–50 years, an increase in kidney size can be observed [24]. After age 50, there is a constant decline of organ size [24]. In addition to a decreased number of glomeruli, there is a multitude of generally aging-associated changes such as tubule-interstitial infarction, scarring, and fibrosis [24–26]. Scarring and fibrosis of glomeruli are most notably seen in the cortical zone, with a loss of functioning glomeruli of up to 50% by the age of 80 [5, 26]. Along with these changes in the number of tubules, there is a decrease in volume and length of tubule, as well as an increase in diverticula and atrophy [24, 25].

Reduced cardiac output as well as other concomitant diseases in the elderly leads to a decrease in renal blood flow. Along with the reduction of renal blood flow, there is a decrease in glomerular filtration rate (GFR) as well as creatinine clearance with increasing age [11, 24, 25]. A decline in GFR from approximately 130 to 80 mL/min can be seen between the ages of 30 and 80, with an acceleration of the decline after the age of 65 [25]. Creatinine clearance, often used as a measure of GFR, also declines in a similar fashion, even in the face of normal creatinine concentrations [11, 18, 27]. The decrease in GFR is not as great as the decrease in renal plasma flow, due to an increase in filtration fraction and a state of hyperfiltration [25, 26]. This can be seen more prominently in the deeper glomeruli and may be an adaptive compensation to help preserve function due to the reduced number of functional glomeruli [25].

Decreased renal plasma flow and GFR can affect the pharmacokinetics of drugs by reducing their elimination. These changes in metabolism may contribute to the increased adverse drug reactions noted in the elderly population [11]. For example, morphine-6-glucuronide, the active metabolite of glucuronidation of morphine by the liver, is renally excreted and may accumulate in cases of decreased renal function, leading to prolonged duration of analgesia and potentially adverse outcomes [16, 28]. Consideration for adjustments in dosing for medications excreted by the kidneys should also be made for drugs that will have prolonged half-lives (e.g., digoxin), taking longer to reach steady state [18].

Hypertension and diabetes are comorbid conditions that are often associated with worsening glomerulosclerosis and arteriolar sclerosis of the afferent, efferent, and cortical systems, potentially accelerating the negative impact of aging on renal function [24–26]. Comorbid conditions such as diabetes and hypertension can lead to an increase in mean arterial pressure, further causing a decline in GFR. However, these effects may not be clinically relevant until there is a critical decrease in functional renal reserve [24, 26].

Typically, under nonstressed conditions, aging has little effect on the kidney’s ability to maintain fluid balance. Functional reserve of the kidney may be preserved in the healthy older adult, and electrolyte balance is maintained similar to their younger counterpart. However, in stressful states, as seen with surgery, the changes within the tubule lead to a decreased ability to retain sodium, concentrate urine, or even excrete free water [24, 25, 29–31]. Because the adaptive responses are lessened, there is often an inability to maintain sodium homeostasis resulting in dehydration in the elderly patient [24]. Dehydration is further aggravated due to the impairment of counteractive mechanisms, such as the thirst response, which is impaired in elderly and frail patients [30–32].

In the aging kidney, the remaining functional renal tubules become less responsive to autoregulation due to a reduced sensitivity to hormonal influence of aldosterone, vasopressin, and atrial natriuretic peptide (ANP) [24]. Increased ANP secretion is responsible for reduction in renin, and therefore aldosterone concentrations, contributing to dehydration and electrolyte dysfunction [30]. Suppression of renin compounded with downregulation of the renin-angiotensin system contributes to the hyponatremia and hyperkalemia often seen in the elderly [24]. Reduction in antidiuretic hormone (ADH) can also reduce the ability to concentrate urine in response to decreases in intravascular volume [30, 32].

Healthy older individuals generally maintain acid-base homeostasis under baseline conditions. However, due to an impaired ability to excrete hydrogen ion load, elderly patients are more prone to metabolic acidosis [32] in stressful conditions.

The acute stress response to surgery includes secretion of ADH and increased water retention, as well as increased renin and aldosterone secretion contributing to additional water and sodium absorption. Thus, despite the often-blunted activity of the renin-angiotensin aldosterone system (RAAS) the elderly patient is still susceptible to retention of salt and water [30, 31]. In fact, the elderly might be particularly vulnerable in times of stress involving larger volume shifts. Even small changes in plasma volume might have deleterious effects due to, for example, reduced cardiac function or fluid overload leading to heart failure. Caution should be taken with fluid management in the perioperative setting, with close monitoring of fluid balance using blood pressure, pulse rate, and urine output as guides [29, 30].

A summary of the physiologic changes in pharmacokinetics due to aging can be seen in Table 13.2.

The endocrine system undergoes a multitude of changes with aging [33]. However, few of the observed natural changes with aging have an immediate effect on anesthetic considerations. However, the increase in incidence of insulin resistance, diabetes mellitus, and thyroid abnormalities as well as decrease in sexual hormone levels should be taken into consideration when evaluating elderly patients in the perioperative setting. Physiological aging-related endocrine changes, such as loss of muscle mass, particularly in males with andropause as well as the increased incidence of pathological endocrine abnormalities are a concern for the elderly patient [34, 35].

Probably the most prominent axis affected is the gonadal axis with a fairly sudden cessation of female hormone production around menopause and a slow decline of male sexual hormones with age (andropause). These hormonal changes lead to changes in general gene expression and a consequent decrease in muscle mass, further predisposing to sarcopenia, osteoporosis, and frailty [36]. These changes may also influence drug metabolism, but this is currently only a theoretical concern. In addition to the gonadal axis, there is an age-related decline in the activity of the somatotrope axis, decreasing insulin-like growth factor type 1 (IGF1) and growth hormone (GH) levels, which further predisposes to sarcopenia [37].

Dysfunction of the thyroid axis, including frank hypo- or hyperthyroidism, is more common in elderly [35]. TSH levels tend to be on average higher, particularly in the oldest of the old, and have been associated with longevity [38]. This needs to be factored in when making decisions on thyroid hormone replacement and TSH level targets for elderly patients, which may likely be higher than in the general reference population. However, it still remains a consensus that TSH levels >10mIU/l need to be evaluated for clinical hypothyroidism and possible hormone replacement. Frank symptomatic hypothyroidism in the elderly as well as biochemical hypothyroidism with elevated TSH and low thyroxine (T4) levels should definitely lead to initiation of replacement therapy. In the elderly, replacement therapy is ideally started with sub-physiological replacement doses and a slow increase guided by normalization of TSH levels to prevent stress on the cardiovascular system. However, a slightly increased TSH value in the setting of normal thyroid hormone levels and in the absence of symptoms can be accepted as normal in the elderly without the necessity for treatment.

Diabetes mellitus is by far more prevalent in the elderly population due to many of the metabolic changes associated with aging. Impaired glucose tolerance can be observed in 50% of individuals older than 80 years of age [39]. A decline in β-cell mass and insulin production and an increase in insulin resistance are responsible for the age-related increase in patients with impaired glucose tolerance and diabetes mellitus [40]. Although the interrelationship of sarcopenia and insulin resistance is not well understood, it is clear that muscle is a main organ of glucose disposal and muscle mass is reduced in sarcopenia. In addition, exercise increases insulin-independent glucose uptake and increases insulin sensitivity of muscle tissue. β-Cell function can decline by up to 25% by the age of 85. This decline, in combination with decreased glucose uptake by non-insulin-mediated receptors, may lead to an increase in glucose load for clearance by the renal system [41–43]. Renal clearance of glucose is reduced with aging, increasing circulating levels of blood glucose [41]. Gluconeogenesis , a homeostatic process by which cells are provided glucose in times of stress or food deprivation, may be upregulated causing an additional source of abnormally high blood glucose levels [44]. Elderly patients are more prone to the development of stress-related hyperglycemia and intraoperative as well as postoperative temporary treatment with insulin might become necessary in these patients.