Renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system (RAAS) has a critical role in the progression of CKD and an awareness of this system is important for understanding the pathophysiology of CKD and the targets for therapeutic intervention. Most of the renal effects of this system are through regulating intraglomerular pressures and salt and water balance. Renin is an enzyme which is formed and stored in the juxtaglomerular apparatus and released in response to decreased afferent intra-arterial pressures, decreased glomerular ultrafiltrate sodium levels and sympathetic nervous system activation. In patients with CKD, intra-renal pressures are often low and sympathetic overactivity is common; these factors lead to increased renin secretion. This can occur with normal or elevated systemic blood pressure.

Renin promotes cleavage of the protein angiotensinogen, which is produced by the liver, to produce angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II has two major physiological effects. First, it acts on the zona glomerulosa of the adrenal cortex to promote production of the mineralocorticoid hormone aldosterone, with resultant increased distal tubular salt and water reabsorption. Furthermore, it promotes antidiuretic hormone (ADH) release, which increases proximal tubular sodium reabsorption and promotes thirst. In combination, these lead to salt and fluid retention, high intravascular volumes, hypertension and oedema. Second, it is a direct vasoconstrictor and promotes systemic and (preferential) renal hypertension. The renal effects are predominantly on the efferent glomerular arteriole. Vasoconstriction at this site is mediated by a high density of angiotensin II receptors. When these receptors are ligated by angiotensin II, there is increased intra-glomerular pressures. Whilst this leads to an overall increase in GFR in the short-term, over a longer period glomerular hypertension promotes accelerated glomerular scarring and worsening CKD. In addition to the vascular and endocrine effects of the RAAS, it is now recognised that there is a local immune modulatory role for this system. Both resident (e.g. tubular epithelial) cells and inflammatory (monocytes and macrophages) cells synthesise components of the RAAS and are themselves targeted by the system. For example, monocytes and macrophages express the angiotensin II receptor and activation through this receptor leads to an enhanced inflammatory and fibrotic phenotype of the cell. This raises the intriguing concept that some of the effects of blocking the RAAS are due to direct anti-inflammatory and anti-fibrotic effects. Figure 18.1 shows this pathway and identifies the points at which pharmacological interventions targeted for a biological effect translates into clinical outcomes.

Fig. 18.1 The renin–angiotensin–aldosterone system and targets for pharmaceutical intervention.

Measurement of renal function

The scale of CKD has only been recognised in recent years because detection is dependent upon an accurate estimation of the GFR. The GFR is defined as the volume of filtrate produced by the glomeruli of both kidneys each minute and is a reliable indicator of renal function.

It is laborious and expensive to measure GFR by gold standard tests such as inulin or radiolabelled isotope clearance. These tests are only used when extremely accurate assessment of kidney function is required. An example of this is measurement of kidney function in a potential living kidney donor where an individual is proposing to donate a kidney to a family member or close friend.

As a consequence, a number of equations have been validated for use in the routine clinical setting. These equations provide an estimate of glomerular filtration rate (eGFR) based on the combination of serum or plasma creatinine and a number of variables which add precision to the estimation of kidney function. The commonest eGFR equation used in clinical practice is the four-variable MDRD (Modification of Diet in Renal Disease Study) equation. The biochemical variable that provides the basis of the MDRD and most other GFR equations is serum creatinine.

MDRD glomerular filtration rate equation

Eight eGFR equations were validated for the MDRD study (Levey et al., 1999). These used demographic and serum variables (including serum creatinine level, age, gender, non-black ethnicity, higher serum urea levels, and lower serum albumin levels) in a series of equations. The four-variable equation (also known as the abbreviated (a)MDRD equation) has been adopted into clinical practice and incorporates age, creatinine, gender and ethnicity (Fig. 18.2).

Fig. 18.2 Four-variable MDRD equation used to calculate eGFR.

The MDRD equation is more accurate than serum creatinine alone as an estimator of kidney function; however, it has not been validated in the elderly, those with creatinine levels within the normal range or transplant recipients. The CKD classification system is based on the aMDRD eGFR.

Other estimates of kidney function

Creatinine clearance

This is similar to the GFR as nearly all the filtered creatinine appears in the urine. It is a measurement of the volume of blood that is cleared of creatinine with time. Measurements of creatinine clearance (Cl_Cr) require accurate collection of 24 h urine samples with a serum creatinine sample midway through this period. This is time-consuming, inconvenient and prone to inaccuracy and as such is now rarely used in clinical practice. Figure 18.3 shows the equation for measuring creatinine clearance.

Fig. 18.3 Creatinine clearance calculation.

Cockroft–Gault equation

The Cockroft–Gault equation uses weight, sex and age to estimate creatinine clearance and was derived using average population data (Cockroft and Gault, 1976). The equation is shown in Fig. 18.4.

Fig. 18.4 The Cockroft–Gault formula.

Estimates of glomerular filtration rate in paediatric patients

Estimates of GFRs in paediatric patients can be made using the Schwartz formula (Schwartz, 1985) or the Counahan–Barratt method (Counahan et al., 1976) which both rely upon inclusion of the height of the child in estimating creatinine clearance, since height correlates with muscle mass.

Urea

Urea is also used in the assessment of renal function despite a variable production rate and diurnal fluctuation in response to the protein content of the diet. Levels of urea may also be elevated by dehydration or an increase in protein catabolism such as that accompanying gastro-intestinal haemorrhage, severe infection, trauma (including surgery) and high-dose steroid therapy. Serum urea levels are, therefore, an unreliable measure of renal function, but can be used as an indicator of the patient’s general condition and state of hydration. A rapid elevation of serum urea, before any rise in corresponding creatinine levels, is often a sign of an impending deterioration in renal function or a marker for pre-renal failure associated with intravascular volume depletion.

Significance of CKD

CKD is significant as it indicates the possibility of progression to end-stage renal disease, and a strong association with accelerated cardiovascular disease, similar in magnitude to that observed in diabetics. The cardiovascular risk increases with the severity of CKD but is detectable at all levels. Thus, it is important to pay particular attention to traditional cardiovascular risk factors such as smoking, cholesterol and blood pressure in patients with CKD. However, it is known from previous studies that these risk factors only contribute around 50% of the total cardiovascular disease risk and recent interest has focused on the identification of novel risk factors to explain the remainder of the risk.

It is important to make a distinction between cardiovascular disease related to macrovascular atherosclerosis and that related to microvascular changes, often found in individuals with CKD. The cardiovascular disease found in CKD is more likely to be related to small vessel disease initiated by endothelial dysfunction rather than atherosclerotic disease. In addition, patients with CKD often have associated left ventricular hypertrophy which may be related to chronic volume overload and uraemia.

Progression to more advanced stages of CKD may occur, particularly if the blood pressure is inadequately controlled and there is significant proteinuria, but this is by no means the rule and many patients with CKD remain stable for years or even decades. These patients need to be followed up with regular blood and urine tests to detect progression, if it occurs. Low risk patients, that is, those with unchanging GFR over time, with controlled blood pressure and no proteinuria may not require long-term follow up by a kidney specialist and surveillance can be carried out satisfactorily in primary care.

Patients with CKD 1–3 (Table 18.1) are frequently asymptomatic. The reduction of GFR is insufficient to cause uraemic symptoms and any minor abnormalities in the urine such as proteinuria or haematuria are usually not noticed by patients. There is a frequent association with high blood pressure which may be the cause or a consequence of renal damage. Recognition of these patients is important as it allows early modification of traditional cardiovascular risk factors. These patients should be investigated to determine if there is a treatable cause for their CKD and followed up to identify those individuals with progressive disease.

Patients with CKD stages 4 and 5 (Table 18.1) should usually be followed up in a nephrology clinic because they will require specialist management of the complications of CKD such as anaemia and bone disease, whilst many will also be undergoing preparation for renal replacement therapy.

Causes of CKD

The reduction in renal function observed in CKD results from damage to the infrastructure of the kidney in discrete areas rather than throughout the kidney. The nephron is the functional unit of the kidney and while the mechanism of damage depends on the underlying cause of renal disease, as nephrons become damaged and fail, remaining nephrons compensate for loss of function by hyperfiltration secondary to raised intra-glomerular pressure. This causes ‘bystander’ damage with secondary nephron loss. This vicious cycle is illustrated in Fig. 18.5. The patient remains well until so many nephrons are lost that the GFR can no longer be maintained despite activation of compensatory mechanisms. As a consequence there is a progressive decline in kidney function.

Fig. 18.5 Mechanism of progressive renal damage.

CKD arises from a variety of causes (Table 18.2), although by the time a patient has established CKD it may not be possible to identify the exact cause. However, attempting to establish the cause is useful in the identification and elimination of reversible factors, to plan for likely outcomes and treatment needs, and for appropriate counselling when a genetic basis is established. The causes of CKD listed in Table 18.2 are ordered according to prevalence. It is important to note the prevalence of these factors is different in CKD and end stage renal disease. In end stage renal disease, diseases such as adult polycystic kidney disease (APKD) are overrepresented and ischaemic/hypertensive nephropathy underrepresented. The reasons for this are that individuals with APKD are likely to survive to reach end stage renal disease while those with diabetes or ischaemic renal damage may succumb to cardiovascular disease before end stage renal disease is reached.

Clinical manifestations

While uraemic symptoms are rare in CKD stage 4, they become more apparent as the patient approaches end stage renal disease. The onset of symptoms is slow and insidious so that patients may not realise that they are unwell. It is not uncommon for patients to present in end stage renal disease and require immediate dialysis at their first contact with the medical profession.

End stage renal disease is characterised by the requirement of renal replacement therapy to sustain life and it is often accompanied by uraemia, anaemia, acidosis, osteodystrophy, neuropathy and is frequently accompanied by hypertension, fluid retention and susceptibility to infection (Fig. 18.6). It results from a significant reduction in the excretory, homeostatic, metabolic and endocrine functions of the kidney that occur over a period of months or years.

Fig. 18.6 Typical signs and symptoms of chronic kidney disease.

In the following section, the clinical features of CKD are described, along with the pathogenesis.

Bone disease (renal osteodystrophy)

Renal osteodystrophy describes the four types of bone disease associated with CKD:

• secondary hyperparathyroidism

• osteomalacia (reduced mineralisation)

• mixed renal osteodystrophy (both hyperparathyroidism and osteomalacia)

• adynamic bone disease (reduced bone formation and resorption).

Cholecalciferol, the precursor of active vitamin D, is both absorbed from the gastro-intestinal tract and produced in the skin by the action of sunlight. Production of active vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), requires the hydroxylation of the colecalciferol molecule at both the 1α and the 25 position (Fig. 18.7).

Fig. 18.7 Renal and hepatic involvement in vitamin D metabolism.

Hydroxylation at the 25 position occurs in the liver, while hydroxylation of the 1α position occurs in the kidney; this latter process is impaired in renal failure. The resulting deficiency in vitamin D leads to defective mineralisation of bone and subsequent osteomalacia which is almost inevitable in those with CKD stage 3 and beyond.

The deficiency in vitamin D with the consequent reduced calcium absorption from the gut in combination with the reduced renal tubular reabsorption results in hypocalcaemia (Fig. 18.8).

Fig. 18.8 Disturbance of calcium and phosphate balance in chronic renal failure.

These disturbances are compounded by hyperphosphataemia caused by reduced phosphate excretion, which in turn reduces the concentration of ionised serum calcium by sequestering calcium phosphate in bone and in soft tissue. Hypocalcaemia, hyperphosphataemia and a reduction in the direct suppressive action of 1,25-dihydroxycholecalciferol on the parathyroid glands results in an increased secretion of parathyroid hormone (PTH).

Since the failing kidney is unable to respond to PTH by increasing renal calcium reabsorption, the serum PTH levels remain persistently elevated, and hyperplasia of the parathyroid glands occurs. The resulting secondary hyperparathyroidism produces a disturbance in the normal architecture of bone and this is termed osteosclerosis (hardening of the bone). A further possible consequence of secondary hyperparathyroidism produced in response to hypocalcaemia is that sufficient bone reabsorption may be caused to maintain adequate calcium levels. This, in combination with hyperphosphataemia, may result in calcium phosphate deposition and soft tissue calcification.

Clinical findings

Bone pain is the main symptom, and distinctive appearances on radiography may be observed, such as ‘rugger-jersey’ spine, where there are alternate bands of excessive and defective mineralisation in the vertebrae (Fig. 18.9).

Fig. 18.9 Lateral radiograph of the spine in a patient with chronic renal failure. Characteristic endplate sclerosis (arrows) are referred to as ‘rugger-jersey spine’

(reproduced by kind permission of Dr M. J. Kline, Department of Diagnostic Radiology, Cleveland Clinic Foundation).