Chronic kidney disease (CKD) is defined in the current “Kidney Disease | Improving Global Outcomes” (KDIGO) guidelines published in January 2013, as the presence of an estimated glomerular filtration rate (EGFR) below 60ml/min/1.73m2 (for at least three months), or the existence of kidney damage observed directly in a kidney biopsy or indirectly by the presence of albuminuria, alterations in urine sediment or in imaging techniques.1,2

CKD classification is determined by taking into account the patient's GFR, albuminuria level and aetiology.2 The GFR levels (G1 to G5) and the albuminuria levels (A1 to A3) are shown in Table 1.

There are now predictive equations for estimating kidney function, the formulas of which include patients’ creatinine, sex, age and weight. The abbreviated equation in the Modification of Diet in Renal Disease (MDRD) study called the Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI), and the Cockcroft-Gault formula are tools that are considered to be useful methods.3 Nevertheless, it should be noted that in spite of the increased use of the GFR as a screening method in clinical practice, a GFR level <60ml/min/1.73m2 does not necessarily indicate the existence of CKD, and this can lead to a false increase of this pathology, especially amongst the elderly.

In addition to having a decreased GFR, CKD also entails an inflammatory condition leading to physiological changes that affect other organs (see the section on Ageing and the mechanisms involved in chronic kidney disease). In this regard a formula has been developed that includes hematocrit, urea and gender (HUGE) and which attempts to discern whether patients with GFR <60ml/min actually have kidney disease or a GFR reduction associated with the ageing process.4 This formula has also been associated with long-term life expectancy forecasts in non-hospitalised elderly patients.5

The current prevalence of CKD in Spain is estimated to be around 9.2% of the adult population, with an overall prevalence of 6.8% in stages 3–5, but this number increases to 20.6% in patients over age 64.1,6 This increase is attributed to this population being older, due to their having greater cardiovascular risk factors, and because of earlier diagnosis.

In addition to having a higher prevalence with a forecasted increase over the coming years, CKD is also associated with adverse clinical and functional events, and with a significant cardiovascular morbidity/mortality,7–10 which justifies a considerable use of resources and a substantial increase in healthcare spending. The annual cost for treating the most advanced stages of CKD in Spain is estimated to be over €800 million.11

All this has resulted in intense attention being focused in recent years on detecting this pathology early so that its progression can be reduced. In addition to this, a decision also needs to be made whether the patient would be a candidate for replacement kidney therapy or conservative treatment, preparing the patient sufficiently in advance for therapeutic programmes such as the various types of dialysis and transplant.12–15

Descriptions have been given of how after age 30 a process occurs whereby glomerulus is replaced with fibrous tissue (glomerulosclerosis) that increases as time progresses.1,12,16,17 Meanwhile there is also an increase in mesangial tissue, with predominant obliteration of the juxtamedullary nephrons, accompanied by subendothelial deposits of hyaline tissue and collagen in the arterioles, with thickening of the intima, atrophy of the media and dysfunction of the autonomic vascular reflex. On the other hand, there are also changes in the tubules, which undergo fat tissue degeneration with enlargement of the basal membrane, with increased areas of atrophy and fibrosis.14,18,19

The anatomic changes described above lead to a decrease in the elderly patient's GFR and a decrease in effective renal plasma flow (ERPF), with a tendency towards an increase in the filtration fraction (the GFR/ERPF ratio)14,18, at the expense of a disproportionate decrease of the ERPF denominator compared to the GFR.

In approximately the third decade of life, the GFR reaches a peak of around 140ml/min/1.73m2, and from that point it begins to decrease progressively by approximately 8ml/min/1.73 m2 per decade. This is accompanied by a decrease in creatinine production, associated with a process some refer to as “senile sarcopenia”,15 which is the reason why plasma creatinine does not increase in spite of the progressive decrease in GFR.

All of these physiological changes explain the decrease in sodium reabsorption, which causes increased fractional sodium excretion in elderly patients, and a decrease in both their kidney plasma concentration and their response to stimulus, creating a state of medullary hypotonicity with a decreased urine concentration capacity.14,18

Here it is important to emphasise that even though a senile kidney will present a series of changes associated with a decrease in GFR, this is different in many aspects from the decrease in GFR that is associated with CKD (see Table 2).

In this regard, CKD per se represents a state of characteristic biochemical alterations. This is associated with a chronic inflammatory state that is predicated on the premature development of alterations in the patient's cytokine catabolism (IL-1 beta, IL-6, tumour necrosis factor-alpha [TNF-alpha]) and growth factors (insulin-like growth factor [IGF-I]).7,20 CKD patients experience a decrease in their IGF-I levels and an increase in their TNF-alpha. They are also observed to have an increase of other catabolic hormones (parathyroid hormone, glucagon, corticosteroids and angiotensin ii) in addition to deficiency or resistance to anabolic hormones such as insulin, growth hormones, testosterone and 25(OH) D3.

This occurs following a decrease in erythropoietin (EPO) production resulting from nephron loss combined with increased resistance to EPO.7 Anaemia is a state of deficient tissue oxygenation with symptoms of low energy, impaired cognitive response and decreased physical performance,7,20 and it translates into an inability to autonomously perform the basic everyday life activities. Alterations of both EPO metabolism and iron occur with CKD, and they are associated with poor clinical evolution and deteriorating quality of life.

As noted above, CKD is a proinflammatory state with increased C-reactive protein (CRP), IL-6 and elevated procoagulant markers, related to an increased likelihood of frailty.7,20 Some studies have observed that frail patients have higher blood levels of CRP, factor viii and D-dimer, in addition to finding an inverse relationship between patients’ physical functionality tests and their CRP and IL-6 levels.30,32 Meanwhile, due to their oxidative stress, these patients experience protein glycation (advanced glycation end products: AGEs) that is particularly accelerated in diabetic nephropathy,7 associated with deterioration of their illness.

The assumption is that if CKD worsens inflammation, then it will also worsen the patient's catabolic state, which would entail a loss of muscle mass and cachexia,25,31 and this may explain the cause of the patient's frailty and the deterioration of physical function in patients who have CKD.

CKD may occur simultaneously with other medical conditions, such as diabetes mellitus, chronic hypertension or malnutrition, that may play a key role in its aetiology or which may be related the physiological changes occurring in these patients.2,7,26,28 There are also other factors, such as occupational illnesses or tobacco use, that may increase the risk of developing obstructive pulmonary disease and heart failure. It is now clear that multi-morbidity is a major factor that significantly contributes to the onset of frailty in the CKD population.33

There are multiple factors that link malnutrition to CKD. The main mechanisms whereby CKD contributes to the development of malnutrition are loss of appetite, dietary restrictions, a loss of nutrients (in dialysis patients) and inflammation associated with hormonal alterations and changes in catabolism.7

The loss of appetite is created by inflammation and the metabolic disorder, and this is exacerbated in the pre-dialysis stage which usually entails extremely strict dietary restrictions that aim at slowing down the progression of the CKD. This low-protein diet has been recognised as a clear factor that leads to malnutrition in these patients.

Furthermore, as noted above, biochemical changes and kidney failure boost patients’ metabolism with a significant hormonal activation. This results in a catabolic, low-energy state with progressive loss of muscle mass and strength (sarcopenia) and cachexia.25,34

Though elderly patients are recommended to add 1.0 to 1.2g/kg to their daily protein intake to maintain their physical activity, and this should be increased further if they are acutely or chronically ill or malnourished (1.2 to 1.5g/kg), this diet should nevertheless be avoided in elderly CKD patients in the pre-dialysis stage because it would hasten the advance of their kidney damage and cause them to experience uraemia secondary to retention of nitrogenous products. According to the recommendations of the PROT-AGE study on the optimal protein intake in the elderly,35 pre-dialysis CKD patients with EGF <30ml/min/1.73m2 should not ingest over 0.8g/kg per day. Nevertheless, patients undergoing dialysis may add 1.2–1.5g/kg of protein to their daily intake.

With regard to nutritional tests, the Geriatric Nutritional Risk Index (GNRI) is considered to be a useful predictor of mortality, especially for patients on haemodialysis, while the Subjective Global Assessment (SGA) is useful for pre-dialysis patients, and the MNA-SF is another useful method that has been proven to be appropriate in various patient populations.9

Physiological ageing has been associated with structural and physiological changes in the brain. The neuron loss in the cortical regions is low, but the neurons with elevated metabolism, such as neurons in the hippocampus, can be affected disproportionately by changes in synaptic function, carrier proteins and mitochondrial function. Cerebral ageing is also characterised by structural and functional changes in the microglia,25 which are the cells that are responsible for the immunity of the central nervous system. These cells are activated by brain damage and by local or systemic inflammation, and they become hyperreactive to the slightest stimulus, causing damage or even death to neurons.

Cognitive impairment is common in the various stages of CKD,36 and even though it is caused by various factors, vascular disease and specifically cerebrovascular disease clearly play a major role in the onset of CKD, especially impacting executive cognitive functions.32,36 Various studies in the literature have associated CKD patients with GFR <60, with an increased risk of ischaemic and haemorrhagic stroke.32,37

The current evidence from various observational studies supports the association between frailty, cognitive impairment and dementia.15,16,20,25

Alterations in bone and mineral metabolism entail an abnormal bone architecture combined with the occurrence of fractures, that in part may explain why CKD patients have decreased mobility.7 Major studies have been conducted that showed a high prevalence of hip fractures in CKD patients with GF levels under 60ml/min/1.73m2.7,15,20 Several mechanisms involving hypocalcaemia, hyperphosphataemia, hyperparathyroidism, vitamin D deficiency and metabolic acidosis have been implicated.

Various studies of the CKD population have shown that treatment with vitamin D decreased the incidence of falls and improved patients’ postural stability, thus indicating an important role in physical function and frailty.15

Other recent studies have associated the Klotho gene in the pathophysiology of CKD, finding that a decrease in the gene's expression is associated with alterations in how patients metabolise calcium (e.g., ectopic calcifications), and considering it as a possible biomarker for detecting the progression of frailty or as a future target for therapy.32,38

Functional status assessments are performed by evaluating patients’ basic and instrumental activities and their mobility. Adequate physical and cognitive capacity are needed to perform instrumental activities, and this is related to elderly patients’ independence in their activities of daily living.15,21 Aside from the factors described above (anaemia, malnutrition, cerebrovascular disease, osteoporosis, among others) that are related to impaired functional status, it should be noted that a relationship has been established between higher plasma creatinine levels and limited physical activity, with the lowest GF levels associated with dependency for at least 2 of the activities of daily living.21

CKD has also been demonstrated to have predictive value with regard to mobility limits and impaired functionality15,23,39: conditions that are induced by the illness itself and which are more transcendent than the illness itself per se.

Lastly it should be noted that these multi-factor changes that present in CKD patients indicate that their treatment must be multi-disciplinary, in that all the potential frailty mechanisms must be involved. Effective strategies need to be found that will improve these patients’ quality of life and their prognosis.