People in developed countries live for many years after their retirement age. It is expected that by the year 2030 the number of persons aged ≥ 65 years will account for approximately 1/3 of the global population in Europe (1). It has been known for decades that kidney function declines after 40 years of age at a rate of approximately 1% per year (2). Glomerular filtration rate (GFR) reaches maximum values in the third and fourth decades of life, then drops by about 8 mL/min for every decade of life (3). In several cross-sectional and cohort studies the average GFR reduction ranged from 0.4 to 2.6 mL/min/year. In the Baltimore Longitudinal Study of Aging based on creatinine clearance measurements in men, and in the Nijmegen Biomedical Study including healthy persons aged > 65 years, the average rate of GFR reduction was 0.7 mL/min/year and 0.4 mL/min/year, respectively. In a population of people aged ≥ 65 years, including individuals with significant co-morbidities, GFR assessed by the Cockroft--Goult formula declined by 2.6 mL/min/year (1).

The age-related decrease in renal function was found to be accelerated in subjects with risk factors and pre-existing diseases. The Italian Longitudinal Study on Aging, including people aged 65-84 years, revealed that the loss of renal function, as defined by an increase in serum creatinine concentration > 2.9 mg/dL, was influenced by current smoking status (OR = 2.3), diabetes (OR = 1.8), and systolic hypertension (OR = 1.6) (4).

The results of Baltimore Longitudinal Study showed that only 2/3 of the adult population developed a decline in GFR with age, whereas 1/3 of the subjects demonstrated a stable GFR over time. It was concluded that age by itself is not necessarily a risk factor for deterioration of kidney function (5). It was suggested that the elderly population was heterogenous: some have GFR reduction connected with co-morbidities such as arteriosclerosis and hypertension, whereas in otherwise healthy people the decline in GFR is not inevitable (6).

Renal senescence is a complex, multifactorial process characterized by anatomical and functional changes accumulating during life span. Renal mass increases from birth to the fourth decade of life, and gradually decreases thereafter at an approximate rate of 10% per decade (1). Till the age of 80 years kidney mass diminishes by 25 to 30%, with the steepest decline after the age of 50 years (7). The reduction process is more pronounced in the renal cortex than in the medulla (8). Physiological aging is associated with diffuse sclerosis of glomeruli reaching 30% of glomeruli that are destroyed by 75 years of age, with the remaining ones exhibiting impaired filtering ability (9, 10). Other features of the aging glomeruli include thickening of the basement membrane, a decrease in the number of podocytes and mesangial expansion (1, 11). The number of renal tubules as well as their length and volume also decrease with age. Functional parenchyma is gradually replaced by fat and fibrous tissue. This process occurs primarily in the renal cortex and preferentially affects nephrons most important for maximal urine concentration (12).

Vascular changes within the kidneys include narrowing of the larger arteries, hypertrophy of intima and media as well as arteriosclerosis and interstitial fibrosis (1). Angiograms and histology studies show narrowing of afferent arterioles and direct shunts between afferent and efferent arterioles, allowing blood to bypass the glomeruli (13). Renal plasma flow (RPF) steadily declines with age and in healthy older men it is 40% lower than in young men. Reduction in RPF occurs mainly in the renal cortex and is disproportionate relative to GFR reduction resulting in increase in filtration fraction in individuals aged ≥ 60 years (14).

The kidneys of elderly people are able to maintain homeostasis of body fluids and electrolytes under steady-state conditions. However, their response on alterations in fluid volume or acid-base status are much slower. Enhanced proximal sodium reabsorption together with reduced distal fractional reabsorption, being the result of inadequate activation of the renin--angiotensin-aldosterone system (RAAS), reduce the ability to conserve sodium in response to low salt intake and makes elderly people exposed to volume depletion and acute kidney injury (15). On the other hand, aged individuals reveal a relative inability to excrete excessed sodium that predispose to salt retention, hypertension and cardiac insufficiency (1). Decreased capacity of concentrating urine results in nocturia and frequency, while impaired urine diluting capacity expose elderly people to an increased risk of hyponatremia after water load (16). Reduced proton pump activity in the collecting tubules and impaired capacity of generating ammonia make older people susceptible to develop acidosis in response to acid load (1). Diminished Na-K ATPase activity together with reduced GFR, dehydration, hyporeninemic-hypoaldosteronism, and metabolic acidosis enhance the tendency to hyperkalemia and may precipitate serious clinical events (14). Elderly people may develop signs and symptoms of vitamin D deficiency due to the impaired capacity of the aging kidneys to convert 25-hydoxy vitamin D (25OHD) to its active metabolite 1,25-dihydroxy vitamin D as well as due to insufficient availability of native vitamin D. It was shown that reduced serum 25OHD concentration increased the risk of bone fractures and was an independent predictor of kidney failure and death (14). It should be also remembered that older kidneys are more prone to nephrotoxicity related to medications or intravenous contrast, as well as more vulnerable to ischemic insult (17).

The current definition of chronic kidney disease (CKD) was proposed in 2002 by the National Kidney Foundation, Kidney Disease Outcomes Quality Initiative (KDOQI). CKD was defined as the reduction of GFR to less than 60 mL/min/1.73 m² and/or presence of markers of kidney damage such as albuminuria > 30 mg/day, glomerular- or tubular-based hematuria, abnormal renal imaging and pathologic abnormalities, present for ≥ 3 months, irrespective of cause (3). Kidney failure was defined as GFR < 15 mL/min/1.73 m², with or without signs and symptoms of uremia, while end stage renal disease (ESRD) was determined as kidney failure treated with renal replacement therapy (18).

The incidence of CKD with GFR < 60 mL/min/1.73 m², was shown to be markedly higher in elderly than in young population. According to three large databases: the Kidney Early Evaluation Program, Medicare, and the National Health, Nutrition Examination Survey the prevalence of CKD among people aged > 65 years was approximately 44%, with the highest representation observed in persons aged ≥ 80 years (19). Recent data reveal that around 45% of that subjects should be attributed to diabetes mellitus (20).

The current definition of CKD does not adequately separate the disease from normal renal aging. The formulas used to recognize CKD have not been validated in the elderly population and may misclassify many older individuals as having CKD. Serum creatinine concentration, as a marker of kidney function, is markedly influenced by muscle mass. Sarcopenia that is often found in elderly people diminishes the daily generation of creatinine and significantly decreases serum creatinine concentration (21). As the result the reference range for creatinine considered as normal in the young individuals can be found inappropriately high in the elderly persons and serum creatinine concentration in the high normal range may actually reflect a reduction in kidney function in older patients (1, 6). It was determined that a concentration of 1 mg/dL in 20 years-old people could correspond to a GFR of 120 mL/min/1.73 m² while the same value in 80 years-old persons could reflect a GFR of 60 mL/min/1.73 m² (22).

GFR may be determined with 24-hour urine creatinine clearance, that is cumbersome and often inaccurate, or can be estimated by a formula. Traditional formulas based on serum creatinine concentration (Scr) are unreliable in elderly people, particularly those with multiple co-morbidities (15). In old individuals GFR determined by the Cockroft-Gault formula: GFR = [(140 – age) x weight] / (72 x Scr) x 0.85 (if patient is female) is systematically underestimated. Currently GFR is most often calculated using the Modification of Diet in Renal Disease (MDRD) formula: GFR = 186 x (Scr)^-1.154 x (age)^-0,203 x 0.742 (if patient is female). This equation was developed from a population of 1628 patients enrolled in the MDRD study, with a GFR < 60 mL/min/1.73 m². It is considered more accurate in older persons but neither Cockroft-Gault nor MDRD formulas have been validated in the elderly (23). A newer formula for assessment of GFR, known as the CKD-EPI equation, uses the same variables as the MDRD equation but was developed using a more diverse cohort of patients: white women GFR = 144 x (Scr/0.7)^-1.209 x (0.993)^age; for patients with Scr > 0.7 mg/dL, white men GFR = 141 x (Scr/0.9)^-1.209 x (0.993)^age; for patients with Scr > 0.9 mg/dL (24). It was found that CKD-EPI formula, as the MDRD formula, tends to classify more individuals > 70 years of age as having CKD. In people with GFR in the range of 45-59 mL/min/1.73 m², the MDRD equation underestimates GFR by 25% and the CKD-EPI formula by 16% (25).

A more accurate marker to reliably assess renal function in the elderly seems to be serum cystatin C concentration (26). Cystatin C is an endogenous protein produced by all nucleated cells, filtered in kidney glomeruli, and both reabsorbed and catabolized in the proximal tubules (27). Serum cystatin C concentration is not dependent on muscle mass, less affected than serum creatinine concentration by age and gender, but may be influenced thyroid disease, steroid use, and inflammation (18).

There are several formulas developed to estimate GFR based on serum cystatin C concentration: GFR = 76.7 x (cystatin C)^-1.18; GFR = 127.7 x (cystatin C)^-1.17 x (age)^-0.13 x 0.91 (if patient is female).