Chronic kidney disease (CKD) is defined by a reduction in the glomerular filtration rate (GFR) and/or urinary abnormalities or structural abnormalities of the renal tract. The severity of CKD is classified from 1 to 5 depending upon the level of GFR (Table 18.1). It is a common condition affecting up to 10% of the population in Western societies and is more common in some ethnic minority populations and in females. The incidence increases exponentially with age such that some degree of CKD is almost inevitable in persons over 80 years of age. Social deprivation is also associated with a higher prevalence of CKD. The scale of CKD and the consequences for the health service has been appreciated only in the last few years.

Table 18.1 Classification of chronic kidney disease

Estimates for the incidence of the various grades of CKD are shown in Table 18.1 and have been derived from large American studies, although data suggests the rates in the UK are similar (UK Renal Registry, 2008). In the past, patients with CKD were often unrecognised owing to difficulties in measuring or estimating the GFR and their health needs were largely unmet. The recent development of simple methods to estimate GFR has revealed a huge population of patients with significant kidney disease. This will pose a considerable challenge to health services in the future. National guidance on the management of CKD has been published (NICE, 2008) and includes management in primary and secondary care.

CKD differs from acute kidney injury (AKI) by virtue of chronicity and a different spectrum of causes. However, AKI and CKD are not mutually exclusive; patients with AKI may not recover renal function to their baseline and may be left with residual CKD. In addition, patients with CKD may experience episodes of AKI sometimes causing reversible step-wise declines in renal function.

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.

Serum creatinine

While serum creatinine concentration is related to renal function, it is also dependent upon the rate of production of creatinine by the patient. Creatinine is a by-product of normal muscle metabolism and is formed at a rate proportional to muscle mass (20 g muscle equates to approximately 1 mg creatinine production) and therefore is related to age, sex and ethnicity.

Creatinine is freely filtered by the glomerulus, so when muscle mass is stable any change in serum creatinine levels reflects a change in its renal clearance. Consequently, measurement of serum creatinine can be utilised to give an estimate of the kidney function. It is important to note, however, that creatinine also undergoes significant tubular secretion (~10–20%). This becomes important in advanced CKD (stages 4 and 5) and limits the value of measuring serum creatinine to determine renal function in advanced CKD.

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

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.

Table 18.2 Primary diagnosis in renal replacement therapy patients by age and gender (Renal Registry, 2008)

Ischaemic/hypertensive renal disease

Ischaemic nephropathy has traditionally been referred to under perfusion of the kidneys caused by renal artery stenosis. This explanation has fallen from favour recently and this term is now taken to mean impairment of renal function beyond occlusion of the main renal arteries. Hypertension results in atherosclerosis which can cause occlusive renovascular disease and small vessel damage. In patients with significant large vessel occlusive disease arteriolar nephrosclerosis, interstial fibrosis and glomerular collapse may be present (Lerman and Textor, 2001). These diagnoses account for around 30% of CKD and a smaller proportion of end stage renal disease. The effective management of hypertension is crucial to reduce renal damage.

Metabolic diseases

Diabetes mellitus is the most common metabolic disease that leads to CKD, whilst the predominant lesion is glomerular and referred to as diabetic nephropathy. Diabetes accounts for around 13% of CKD (see Table 18.2) and is associated with faster renal deterioration than other pathologies: these patients are at very significant cardiovascular risk by virtue of both CKD and diabetes. Both type 1 and 2 diabetes can result in diabetic nephrophy, patients with type 1 diabetes usually present with renal complications at a younger age and may benefit from combined kidney and pancreas transplantation. Patients with diabetes may present with no proteinuria, micro albuminuria or overt proteinuria, though as the level of proteinuria increases the GFR usually declines and in many patients this represents an inexorable decline towards end stage renal disease.

Chronic glomerulonephritis

All types of chronic glomerulonephritis (GN) combined cause about 15% of cases of advanced CKD. The commonest cause of glomerulonephritis is IgA nephropathy which is characterised by deposition of polymeric IgA in the glomerulus with subsequent immune activation. Other patterns of glomerulonephritis include membranous nephropathy, where there is granular deposition of immunoglobulin on the glomerular capillary basement membrane. Systemic autoimmune diseases such as systemic lupus erythematosus can cause a variety of types of glomerulonephritis. Finally, some chronic forms of glomerulonephritis are pauci-immune, that is they have no immune deposition. This is seen in focal and segmental glomerulosclerosis.

Hereditary/congenital diseases

There are many inherited renal diseases and together they represent 5% of CKD cases. It is, however, important to remember that they make up a higher proportion of cases of end stage renal disease. The commoner inherited conditions are APKD and Alport’s syndrome. Autosomal dominant polycystic kidney disease is an inherited condition which results in the formation of multiple cysts in both kidneys throughout life. The kidneys become enlarged and frequently fail in middle age. Alport’s syndrome is a disorder of glomerular basement membranes caused by a mutation affecting type IV collagen; X-linked, autosomal dominant and autosomal recessive forms of inheritance are all seen. The clinical manifestations include progressive nephritis with haematuria, proteinuria and sensorineural deafness.

Unknown cause

It is not uncommon for the cause of CKD to be unknown and this is the case in around 30% of patients who typically present with small kidneys and unremarkable immunological investigations. When the kidneys are small it is often not possible to carry out a renal biopsy or if possible the histology often shows severe scarring with no indication of the underlying cause.

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.

Urinary tract features

Both polyuria and nocturia are found in CKD though neither is universal and many patients with CKD have no urinary symptoms. Proteinuria is common in CKD and can be present to varying degrees. Proteinuria is commonly measured using single urine samples to determine the albumin creatinine ratio (ACR). This method has almost entirely replaced the 24 h urine collection which was inconvenient and often unreliable. An ACR of 3-30 mg/mmol is described as microalbuminuria while in nephrotic-range proteinuria it is >250 mg/mmol. Haematuria may also be present and can reflect either glomerular or lower urinary tract pathology. The presence of blood and/or protein in the urine is described as an active urinary sediment. Whenever blood in the urine is detected an infection should be considered and excluded by urine microscopy for white cells and culture for organisms.

Polyuria and nocturia

Polyuria, where the patient frequently voids high volumes of urine, is often seen in CKD and results from medullary damage and the osmotic effect of a high serum urea level (>40 mmol/L). The ability to concentrate urine is also lost in CKD, which together with failure of physiological nocturnal antidiuresis, invariably results in nocturia, where the patient will be wakened two or three times a night with a full bladder.

Proteinuria

A degree of proteinuria is common in CKD and the prevalence of proteinuria increases with the severity of CKD. There are a number of precipitating factors including glomerular disease, failure of protein reabsorption in the tubules and rarely overflow of excess plasma proteins as seen in myeloma. Pronounced proteinuria (>1 g of protein in a 24-h collection, equivalent to an ACR >70 mg/mmol) usually indicates a glomerular aetiology. The presence and quantity of proteinuria are major determinants of progressive CKD.

Haematuria

Haematuria can be either macroscopic or microscopic; macroscopic haematuria is likely to result from lower urinary tract pathology (such as bladder lesions) and microscopic haematuria is most often of glomerular origin. Microscopy can identify the presence of casts which are also seen in glomerular diseases and allow the discrimination of the course of haematuria.

Hypertension and fluid overload

Most patients with CKD will have hypertension and this may be a cause or a consequence (or a combination of both) of their kidney disease. Furthermore, raised blood pressure may exacerbate renal damage and lead to accelerated deterioration of CKD.

Severe renal impairment leads to sodium retention, which in turn produces circulatory volume expansion with consequent hypertension. This form of hypertension is often termed ‘salt-sensitive’, as it may be exacerbated by salt intake. Lesser degrees of renal impairment reduce kidney perfusion, which activates renin production, with subsequent angiotensin-mediated vasoconstriction. Treatment of blood pressure, irrespective of choice of therapy, generally improves the course of CKD. As the GFR falls to very low levels the kidneys are unable to excrete salt and water adequately, resulting in the retention of extravascular fluid. All patients with fluid overload will by definition also have salt retention, even if this is not manifest in the serum sodium concentration.

Clinical findings

Eye damage in the form of hypertensive retinopathy may be found in those patients whose blood pressure has not been adequately controlled. This can be prevented by appropriate and timely antihypertensive therapy. Fluid retention can manifest as peripheral and pulmonary oedema and ascites. Oedema may be seen around the eyes on waking, the sacral region in supine patients and from the feet upwards in ambulatory patients. Volume-dependent hypertension occurs in about 80% of patients with CKD and becomes more prevalent as the GFR falls.

Uraemia

Many substances including urea, creatinine and water are normally excreted by the kidney and accumulate as renal function decreases. Some of the substances responsible for the toxicity of uraemia are intermediate in size between small, readily dialysed molecules and large non-dialysable proteins. These are described as ‘middle molecules’ and include phosphate, guanidines, phenols and organic acids. Clearly, there are a wide range of uraemic toxins but it is the blood level of urea that is often used to estimate the degree of toxin accumulation in uraemia. True symptomatic uraemia only occurs in very advanced CKD.

Clinical findings

The symptoms of uraemia include anorexia, nausea, vomiting, constipation, foul taste and skin discolouration that is presumed to be due to pigment deposition compounded by the pallor of anaemia. The characteristic complexion is often described as ‘muddy’, and is frequently associated with severe pruritus without an underlying rash. In extremely severe cases, crystalline urea is deposited on the skin (uraemic frost).

In uraemia, there is also an increased tendency to bleed, which can exacerbate pre-existing anaemia because of impa-ired platelet adhesion and modified interaction between platelets and blood vessels resulting from altered blood rheology.

Anaemia

Anaemia is a common consequence of CKD and affects most people with CKD stages 4 and 5. The fall in haemoglobin level is a slow, insidious process accompanying the decline in renal function. A normochromic, normocytic pattern is usually seen with haemoglobin levels falling to around 8 g/dL by end stage renal disease.

Several factors contribute to the pathogenesis of anaemia in CKD, including shortened red cell survival, marrow suppression by uraemic toxins and iron or folate deficiency associated with poor dietary intake or increased loss, for example, from gastro-intestinal bleeding. However, the principal cause results from damage of peritubular cells leading to inadequate secretion of erythropoietin. This hormone, which is produced mainly, although not exclusively, in the kidney, is the main regulator of red cell proliferation and differentiation in bone marrow. Hyperparathyroidism also reduces erythropoiesis by damaging bone marrow and therefore exacerbates anaemia associated with CKD. The RAAS is also involved in erythropoiesis since renin increases erythropoietin production and this explains how ACE inhibitors can cause small reductions in haemoglobin.

Clinical findings

Anaemia in CKD is a major cause of fatigue, breathlessness at rest and on exertion, lethargy and angina. Patients may also complain of feeling cold, poor concentration and reduced appetite and libido. Compensatory haemodynamic changes occur with CKD, cardiac output is increased to improve oxygen delivery to tissues, although this may result in tachycardia and palpitations. The anaemia of CKD usually responds to treatment with erythropoietin-stimulating agents (ESAs).

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).

	Mechanism	Cause/effect
Hypernatraemia	Sodium overload	Drugs, for example, antibiotic sodium salts
	Hypotonic fluid loss	Osmotic diuresis
		Sweating
	↓ Water intake	Unconsciousness
Hyponatraemia	Dilution by intracellular water movement	Mannitol
Hyperglycaemia	Water overload	Acute dilution by intravenous fluids, for example, 5% dextrose infusion
		Excessive intake
		Congestive cardiac failure
		Nephrotic syndrome

Potassium

Potassium levels can be elevated in CKD. Hyperkalaemia is a potentially dangerous condition as the first indication of elevated potassium levels may be life-threatening cardiac arrest. Potassium levels of over 7.0 mmol/L are life-threatening and should be treated as an emergency. Hyperkalaemia may be exacerbated in acidosis as potassium shifts from within cells.

ECG changes accompany any rise in serum potassium and become more pronounced as levels increase. T waves peak (‘tenting’), there is a reduction in the size of P waves, an increase in the PR interval and a widening of the QRS complex. P waves eventually disappear and the QRS complex becomes even wider. Ultimately, the ECG assumes a sinusoidal appearance prior to cardiac arrest (see Fig. 18.10).

Fig. 18.10 Typical ECG changes in hyperkalaemia.

Hydrogen ions

Hydrogen ions (H⁺) are a common end-product of many metabolic processes and about 40–80 mmol are normally excreted via the kidney each day. In renal failure, H⁺ is retained, causing acidosis; the combination of H⁺ with bicarbonate (HCO^3–) results in the removal of some hydrogen as water, the elimination of carbon dioxide via the lungs, and a reduction in serum bicarbonate level.

Diagnosis, investigations and monitoring

Although the diagnosis of CKD may be suspected because of signs and symptoms of renal disease, more often it is discovered incidentally. There are patients with CKD for whom no cause can be identified, often because they have two small kidneys which are not safe to biopsy. This appearance results from damage at some unspecified time in the past.

Family, drug and social histories are all important in elucidating the causes of renal failure, since genetics or exposure to toxins, including prescription, over-the-counter and herbal drugs, might be implicated.

Physical examination may be helpful. Signs of anaemia and skin pigmentation, excoriations owing to scratching and whitening of the skin with crystalline urea (‘uraemic frost’) may point to severe disease. Palpable or audible bruits over the femoral arteries are strongly associated with extensive arteriosclerosis and are commonly found in patients with renal vascular disease. Ankle oedema and a raised jugular venous pressure suggest fluid retention and in severe CKD a fishy smell on the breath known as ‘uraemic foetor’ is characteristic. In some patients, the kidneys may be palpable. Large irregular kidneys are indicative of polycystic disease, whereas smooth, tender enlarged kidneys are likely to be infected or obstructed. However, in the large majority of CKD the kidneys are small and are impalpable. A palpable bladder suggests outflow tract obstruction which is often due to prostatic hypertrophy in men.

Functional assessment of the kidney may be performed by testing serum and urine. The serum creatinine level is a more reliable indicator of renal function than the serum urea level though both are normally measured. Hyperkalaemia, acidosis with a correspondingly low serum bicarbonate level, hypocalcaemia and hyperphosphataemia are frequently present and can help to differentiate a new presentation of CKD from AKI.

Urine should be examined visually and microscopically and urinalysis performed for assessment of urinary sediment and a spot urine assessment of the ACR. The patient may report a change in urine colour, which might result from blood staining by whole cells or haemoglobin, drugs or metabolic breakdown products. Urine may also appear milky after connection with lymphatics, cloudy following infection, contain solid material such as stones, crystals, casts, or froth excessively in proteinuria.

Dipstick tests enable simple, rapid estimation of a wide range of urinary parameters including pH, specific gravity, leucocytes, nitrites, glucose, blood and protein. Positive results should, however, be quantified by more specific methods.

Structural assessments of the kidney may be performed using a number of imaging procedures, including:

• ultrasonography

• intravenous urography (IVU)

• plain abdominal radiography

• computed tomography (CT), magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA).

Ultrasonography

This method produces two dimensional images using sound waves and is used as the first-line investigational tool in many hospitals. The technique is harmless, non-invasive, quick, inexpensive, enables measurements to be made and produces images in real time. The latter feature allows accurate and safe positioning of biopsy needles. Ultrasonography is particularly useful in the differentiation of renal tumours from cysts and in the assessment of renal tract obstruction. Doppler ultrasonography is a development that enables measurement of flow rate and direction of the intra- and extrarenal blood supply.

Intravenous urography

IVU is now used very infrequently because it uses high doses of radiation and contrast media, newer modalities such as CT scanning can provide more information. Timed serial radiographs are taken of the kidneys and the full length of the urinary tract following an intravenous injection of an iodine-based contrast medium that is filtered and excreted by the kidney. IVU will show the following:

• the presence, length and position of the kidneys; in CKD the kidneys generally shrink in proportion to nephron loss, the exception being the enlarged kidneys seen in polycystic disease

• the presence or absence of renal scarring and the shape of the calices and renal pelvis; renal cortical scarring and caliceal distortion indicate chronic pyelonephritis

• obstruction to the ureters, for example, by a stone, tumour or retroperitoneal fibrosis; these require surgical intervention

• the shape of the bladder and the presence of residual urine; enlargement and a post-micturition residue suggest urethral obstruction such as prostatic hypertrophy.

Nuclear medicine investigations

There are two commonly used nuclear medicine investigations, the first uses mercapto acetyl tri-glycerine (MAG3). This is used for assessment of renal perfusion and the identification of outflow obstruction. The other is a dimercapto succinic acid (DMSA) scan, the purpose of which is to ascertain the percentage that each kidney contributes to overall function.

Renal biopsy

If imaging techniques fail to give a cause for the reduction in renal function, a renal biopsy may be performed, although in advanced disease extensive scarring of the renal tissue may obscure the original (primary) diagnosis. Also, the small shrunken kidneys often seen in CKD are difficult to biopsy and may subsequently bleed. Most clinicians do not biopsy in this setting. In patients whose GFR is below 30 mL/min, injection of vasopressin (ADH) might minimise bleeding following renal biopsy, although evidence for this is limited and use is not widespread.

Graphical plots of glomerular filtration rate

All patients with CKD should have their serum biochemistry and haematology monitored regularly to detect any of the sequelae of the disease. In some patients with CKD, the decline in renal function progresses at a constant rate and may be monitored by plotting the estimated GFR against time (Fig. 18.11). The intercept with the x-axis indicates the time at which renal function will fall to zero and can be used to predict when the GFR will reach approximately 10 mL/min, that is, the level at which renal replacement therapy should be initiated (Fig. 18.11A). If an abrupt decline in the slope of the reciprocal plot is noted (Fig. 18.11B), this indicates a worsening of the condition or the presence of an additional renal insult. The cause should be detected and remedied if possible. It is, however, increasingly recognised that most patients with CKD do not sustain a predictable decline. Many stabilise or follow a path of episodes of accelerated decline followed by months or years of stability. These observations are of great interest and are an increasing focus of clinical research.

Fig. 18.11 Stylised reciprocal creatinine plots. (A) Linear, uniform progression in the decline in renal function. (B) Sudden decline in renal function (arrow).

Prognosis

When the GFR has declined to about 20 mL/min, a continuing deterioration in renal function to end stage renal disease is common even when the initial cause of the kidney damage has been removed and appropriate treatment instigated. The mechanisms for the decline in renal function include uncontrolled hypertension, proteinuria and damage resulting from hyperfiltration through the remaining intact nephrons. Serial GFR measurements should be monitored in conjunction with the patient’s clinical condition to ensure the detection of the most appropriate point at which to commence renal replacement therapy. When a patient reaches an eGFR of 20 mL/min, plans should be in place for choice of renal replacement modality, transplantation or conservative management and where appropriate ongoing management of anaemia and bone disease.

Treatment

The aims of the treatment of CKD can be summarised as follows:

• Reverse or arrest the process causing the renal damage (this may not be possible)

• Avoid conditions that might worsen renal failure (Box 18.1)

• Treat the secondary complications of CKD (renal anaemia and bone disease)

• Relieve symptoms

• Implement regular dialysis treatment and/or transplantation at the most appropriate time.

Box 18.1 Factors that might exacerbate established chronic renal failure

Reduced renal blood flow

Hypotension

Hypertension

Nephrotoxins including drugs

Renal artery disease

Obstruction, for example, prostatic hypertrophy

Reversal or arrest of primary disease

By definition, CKD rarely has a readily reversible component, in contrast to acute renal failure. However, it is sometimes possible to identify a disease specific factor that is contributing to declining renal function and remove it. A postrenal lesion such as a ureter obstructed by a stone or a ureteric tumour may be successfully treated surgically. Glomerulonephritis may respond to immunosuppressants and/or steroids. Clearly, when drug-induced renal disease is suspected the offending agent should be stopped. These factors predominantly cause acute renal failure but they can cause acute on chronic failure and their reversal may prevent further deterioration.

Hypertension

Optimum control of blood pressure is one of the most important therapeutic measures since there is a vicious cycle of events whereby hypertension causes damage to the intrarenal vasculature resulting in thickening and hyalinisation of the walls of arterioles and small vessels. This damage effectively reduces renal perfusion, contributing to stimulation of the RAAS. Arteriolar vasoconstriction, sodium and water retention result, which in turn exacerbates the hypertension.

Antihypertensive therapy with certain agents might produce a transient reduction in GFR over the first 3 months of treatment as the systemic and glomerular blood pressure drop; this is mainly seen with ACE inhibitors/angiotensin receptor blockers (ARBs). However, it is possible to ultimately halt or slow the decline in many cases.

The drugs used to treat hypertension in renal disease are generally the same as those used in other forms of hypertension, although allowance must be made for the effect of renal failure on drug disposition (NICE, 2008).

Management of symptoms associated with CKD

Gastro-intestinal symptoms

Nausea and vomiting may persist after starting a low-protein diet. Metoclopramide is useful to treat this, but sometimes accumulation of the drug and its metabolites may occur, leading to extrapyramidal side effects. Patients should be started on a low dose, which should then be increased slowly. Prochlorperazine or cyclizine may also be useful. The 5-HT₃ antagonists such as ondansetron have also been shown to be effective. The anaemic patient often becomes less nauseated when treated with an erythropoiesis stimulating agent.

Constipation is a common problem in patients with renal disease, partly as a result of fluid restriction and anorexia and partly as a consequence of drug therapy with agents such as phosphate binders. It is particularly important that patients managed with peritoneal dialysis do not become constipated, as this can reduce the efficacy of dialysis. Conventional laxative therapy may be used, such as bulk-forming laxatives or increased dietary fibre for less severe constipation. Alternatively, a stimulant such as senna with enemas or glycerine suppositories may be used for severe constipation. Higher doses of senna, typically 2–4 tablets at night, may be required. It should be noted that certain brands of laxatives that contain ispaghula husk may also contain significant quantities of potassium, and should be avoided in renal failure because of the risk of hyperkalaemia. Sterculia preparations are an effective alternative.

Pruritus

Itching associated with renal failure can be extremely severe, distressing and difficult to treat. It can also be disfiguring as a result of over-enthusiastic scratching. The exact mechanism responsible for the itching is not clear and several possibilities have been suggested including: xerosis (dry skin), skin micro-precipitation of divalent ions, elevated PTH levels and increased dermal mast cell activity. Generally, however, no underlying cause is found and it is likely that a multifactorial process is responsible.

Sometimes correction of serum phosphate or calcium levels improves the condition, as does parathyroidectomy. Conventionally, oral antihistamines are used to treat pruritus; however, topical versions should not be used owing to the risk of allergy. Non-sedating antihistamines such as loratidine are generally less effective than sedating antihistamines such as chlorphenamine or alimemazine which may be useful, particularly at night. Topical crotamiton lotion and creams may also be useful in some patients. Other non-drug therapies include either warming or cooling the skin using baths, three times weekly, UVB phototherapy and modified electrical acupuncture.

Dietary modifications for uraemic symptoms

Although urea is only one of the toxins encountered in uraemia, many patients experience a symptomatic improvement when dietary protein intake is reduced, presumably through a reduction in the output of nitrogenous waste. There is some evidence that, as well as reducing the symptoms of uraemia, protein restriction slows the progression of CKD, but this remains controversial. Protein-restricted diets have been used extensively in the past but they are unpalatable and the benefits marginal, so they are used infrequently in modern medical practice.

Dietary modifications in CKD

Low protein diets have already been discussed. Other dietary modifications include sodium and fluid restriction to reduce the risk of fluid overload, potassium restriction to reduce the risk of hyperkalaemia and vitamin supplementation. The dietary restrictions for patients with CKD can be arduous and difficult to follow.

Fluid retention

Oedema may occur as a result of sodium retention and the resultant associated water retention. Patients with CKD may also have hypoalbuminaemia following renal protein loss, and this can result in an osmotic extravasation of fluid and its retention in tissues. By end stage renal disease pulmonary and peripheral oedema is best controlled with dialysis but diuretics can be useful. The daily fluid intake should be restricted to between one and three litres, depending upon the volume of urine produced by the patient (if any). It is important to note that the fluid allowance must include fluids ingested in any form, including sauces, medicines and fruits, in addition to drinks. The fluid restriction is very difficult to maintain. Sucking ice cubes may relieve an unpleasantly dry mouth, but patients should be encouraged not to swallow the melted water.

Sodium restriction

Sodium intake can be reduced to a satisfactory level of 80 mmol/day by avoiding convenience foods and snacks or the addition of salt to food at the table. This is usually tolerable to patients. It is important to be aware of the contribution of sodium-containing medication, including some antibiotics, soluble or effervescent preparations, magnesium trisilicate mixture, Gaviscon, sodium bicarbonate and the plasma expanders hetastarch and gelatin.

Potassium restriction

Hyperkalaemia often occurs in CKD and may cause life-threatening cardiac arrhythmias. If untreated, asystolic cardiac arrest and death may result. Patients are often put on a potassium-restricted diet by avoiding potassium-rich foods such as fruit and fruit drinks, vegetables, chocolate, beer, instant coffee and ice cream. Many medicines have a high potassium content, for example, potassium citrate mixture, some antibiotics and ispaghula husk sachets. The use of these drugs is less of a problem in dialysed patients. Emergency treatment is necessary if the serum potassium level is above 7.0 mmol/L or if there are ECG changes. The most effective treatment is dialysis but if this is not available other measures may be tried (see Chapter 17).

The rationale and necessity for a renal diet and fluid restriction can be difficult for a patient to understand and adherence may be a problem. Consequently, the involvement of a specialist renal dietician can be valuable in optimising dietary therapies.

Anaemia

The normochromic, normocytic anaemia of CKD does not respond to iron or folic acid unless there is a coexisting deficiency. Traditionally, the only treatment available was to give red blood cell transfusions, but this is time-consuming, expensive, an infection risk, may lead to fluid and iron overload and promotes antibody formation, which may give problems if transplantation is subsequently attempted. The introduction of ESAs, initially as recombinant human erythropoietins (epoetin alfa and beta) have transformed the management of renal anaemia. Epoetin alfa and beta were thought to be indistinguishable in practical terms, as well as being immunologically and biologically indistinguishable from physiological erythropoietin. However, it has now been recognised that epoetins can be associated with the production of anti-erythropoietin antibodies leading to a severe anaemia which is unresponsive to exogenous epoetin. This is known as pure red cell aplasia (PRCA) and is more commonly associated with epoetin alfa when given by the subcutaneous route. The subcutaneous route is preferred as it provides equally effective clinical results while using similar or smaller doses (up to 30% less) when given three times a week. Most patients report a dramatically improved quality of life after starting epoetin therapy.

Darbepoetin alfa is a novel erythropoiesis-stimulating protein (NESP) that is a recombinant hyperglycosylated analogue of epoetin which stimulates red blood cell production by the same mechanism as the endogenous hormone. The terminal half-life in man is three times longer than that of epoetin and consequently requires a once weekly or alternate weekly dosing schedule. Recently, a longer acting ESA has been introduced (methoxy polyethylene glycol-epoetin beta, pegzerepoetin alfa). This is a continuous erythropoietin receptor activator (CERA), which can be used in a once monthly dosing schedule.

Iron and folate deficiencies must be corrected before therapy is initiated, while patients receiving epoetin generally require concurrent iron supplements because of increased marrow requirements. Supplemental iron is often given intravenously owing to bioavailability problems with oral forms. Maintaining iron stores ensures the effect of epoetin is optimised for minimum cost, as with insufficient iron stores a patient will not respond to treatment with epoetin.

Epoetin therapy should aim to achieve a slow rise in the haemoglobin concentration to avoid cardiovascular side effects associated with a rapidly increasing red cell mass, such as hypertension, increased blood viscosity/volume, seizures and clotting of vascular accesses. Blood pressure should be closely monitored.

An initial subcutaneous or intravenous epoetin dose of 50 units/kg body-weight three times weekly, increased as necessary in steps of 25 units/kg every 4 weeks, should be given to produce a haemoglobin increase of not more than 2 g/dL per month. The target haemoglobin concentration is commonly 10.5–12.5 g/dL with most aiming for a target around 11.5 g/dL. Once this has been reached, a maintenance dose of epoetin in the region of 33–100 units/kg three times a week or 50–150 units/kg twice weekly should maintain this level.

There have been several studies of ESAs which have shown an increased risk of cardiovascular morbidity and overall mortality in people treated to a target >12.5 g/dL (Phrommintikul et al., 2007). This has lead to more conservative dosing strategies and prompt discontinuation or reduction of dose in patients with Hb >12.5 g/dL.

Correcting anaemia usually helps control the symptoms of lethargy and myopathy, and often greatly reduces nausea. Improved appetite on epoetin therapy can, however, increase potassium intake, and may necessitate dietary control.

Acidosis

Since the kidney is the main route for excreting H⁺ ions, CKD may result in a metabolic acidosis. This will cause a reduction in serum bicarbonate that may be treated readily with oral doses of sodium bicarbonate of 1–6 g/day. As the dose of bicarbonate is not critical, it is easy to experiment with different dosage forms and strengths to suit individual patients. If acidosis is severe and persistent then dialysis may be required. Correction of acidosis may slow the decline in renal function.

Neurological problems

Neurological changes are generally caused by uraemic toxins and improve on the treatment of uraemia by dialysis or diet. Muscle cramps are common and are often treated with quinine sulphate. Restless legs may respond to low doses of clonazepam or co-careldopa.

Osteodystrophy

The osteodystrophy of renal failure is due to three factors: hyperphosphataemia, vitamin D deficiency and hyperparathyroidism.

Hyperphosphataemia

The management of hyperphosphataemia depends initially upon restricting dietary phosphate. This can be difficult to achieve effectively, even with the aid of a specialist dietician, because phosphate is found in many palatable foods such as dairy products, eggs, chocolate and nuts. Phosphate-binding agents can be used to reduce the absorption of orally ingested phosphate in the gut, by forming insoluble, non-absorbable complexes when taken a few minutes before or with meals. Traditionally, phosphate-binders were usually salts of a di- or trivalent metallic ion, such as aluminium, calcium or occasionally magnesium. Whilst calcium containing phosphate binders remain in widespread use, sevelemar and lanthanum-based binders are increasingly used.

Calcium acetate is widely used as a phosphate binder. The capacity of calcium acetate and calcium carbonate to control serum phosphate appears similar. However, phosphate control is achieved using between half and a quarter of the dose of elemental calcium when calcium acetate is used. Whether this translates to a decreased likelihood of producing unwanted hypercalcaemia with calcium acetate therapy is as yet unclear.

Calcium carbonate has been used as a phosphate binder. Unfortunately, it is less effective as a phosphate binder than aluminium, and sometimes requires doses of up to 10 g daily. Calcium carbonate has advantages, however, in that correction of concurrent hypocalcaemia can be achieved.

Sevelamer, a hydrophilic but insoluble polymeric compound is used increasingly as a phosphate binder. Sevelamer binds phosphate with an efficacy similar to calcium acetate but with no risk of hypercalcaemia. Mean levels of total and low-density cholesterol are also reduced with sevelamer use. This compound does not appear to present any risk of toxicity but may cause bowel obstruction and is relatively expensive when compared to other phosphate binders.

Lanthanum, like sevelamer, is a non-calcium containing phosphate binder; there is therefore no resultant risk of hypercalcaemia but there are gastro-intestinal side effects and the drug is significantly more expensive than the alternatives. While both of the non-calcium containing phosphate binders available have been shown to reduce phosphate levels and keep calcium within acceptable levels, no improvements in cardiovascular endpoints have been demonstrated to date.

Historically, aluminium hydroxide was widely used as a phosphate binder owing to the avid binding capacity of aluminium ions. However, a small amount of aluminium may be absorbed by patients with CKD owing to poor clearance of this ion, which can produce toxic effects including encephalopathy, osteomalacia, proximal myopathy and anaemia. Dialysis dementia was a disease observed among haemodialysis patients associated with aluminium deposition in the brain and exacerbated by aluminium in the water supply and the use of aluminium cooking pans. Desferrioxamine (4–6 g in 500 mL of saline 0.9% per week) has been used to treat this condition by removing aluminium from tissues by chelation. The tendency of aluminium to cause constipation is an added disadvantage. Therefore, aluminium as a phosphate binder in CKD should be used with caution.

Vitamin D deficiency and hyperparathyroidism

Vitamin D deficiency may be treated with the synthetic vitamin D analogues 1α-hydroxycholecalciferol (alfacalcidol) at 0.25–1 μcg/day or 1,25-dihydroxycholecalciferol (calcitriol) at 1–2 μcg/day. The serum calcium level should be monitored, and the dose of alfacalcidol or calcitriol adjusted accordingly. Hyperphosphataemia should be controlled before starting vitamin D therapy since the resulting increase in the serum calcium concentration may result in soft tissue calcification.

A new agent, paricalcitol, has recently been suggested for use in patients who either do not respond to alfacalcidol or who need doses of alfacalcidol that are impractical because of hypercalcaemia. Paricalcitol is a synthetic, biologically active vitamin D analogue that selectively upregulates the vitamin D receptor in the parathyroid glands reducing PTH synthesis and secretion. It also upregulates the calcium sensing receptor in the parathyroids and reduces PTH by inhibiting parathyroid proliferation, PTH synthesis and secretion without affecting calcium or phosphorus levels.

The rise in 1,25-dihydroxycholecalciferol and calcium levels that result from starting vitamin D therapy usually suppresses the production of PTH by the parathyroids. If vitamin D therapy does not correct PTH levels then parathyroidectomy, to remove part or most of the parathyroid glands, may be needed. This surgical procedure was once commonly performed on CKD patients, but is now less frequent owing to effective vitamin D supplementation.

Cinacalcet is a calcimimetic which increases the sensitivity of calcium sensing receptors to extracellular calcium ion, this results in reduced PTH production. The benefit of this treatment is the suppression of PTH without resultant hypercalcaemia. It is recommended (NICE, 2007) for use as an alternative to parathyroidectomy for patients who are not fit enough to undergo this procedure. Common therapeutic problems in chronic renal failure are summarised in Table 18.4.

Table 18.4 Common therapeutic problems in chronic renal failure

Problem	Comment
Drug choice	Care with choice/dose of all drugs. Care to avoid renotoxic agents pre-dialysis to preserve function. Beware herbal therapies as some contain immune system boosters (reverse immunosuppressant effects) and some are nephrotoxic
Drug excretion	CKD will lead to accumulation of drugs and their active metabolites if they are normally excreted by the kidney
Dietary restrictions	Restrictions on patient often severe. Fluid allowance includes foods with high water content, for example, gravy, custard, and fruit
Hypertension	Frequently requires complex multiple drug regimens. CCBs can cause oedema that might be confused with fluid overload
Analgesia	Side-effects are increased. Initiate with low doses and gradually increase. Avoid pethidine as metabolites accumulate. Avoid NSAIDs unless specialist advice available
Anaemia	Epoetin requires sufficient iron stores to be effective. Absorption from oral iron supplements may be poor and i.v. iron supplementation might be required. Care required to make sure that epoetin use does not produce hypertension
Immunosuppression	Use of live vaccines should be avoided (BCG, MMR, mumps, oral polio, oral typhoid, smallpox, yellow fever)
Pruritis (itching)	Can be severe. Treat with chlorphenamine; less sedating antihistamines often less effective. Some relief with topical agents, for example, crotamiton
Restless legs	Involuntary jerks can prevent sleep. Clonazepam 0.5–1 mg at night may help

Renal transplantation

Renal transplantation has transformed the outlook for many patients with end stage renal disease. The clinical outcomes of renal transplantation are now excellent. One-year patient and graft survival is 98% and 90–95%, respectively, and most patients who receive a transplant will never need to return to dialysis treatment. A renal transplant performed today in the developed world will continue to function, on average, in excess of 15 years. However, an important consideration is that renal transplantation is the treatment of choice for patients with end stage renal disease who are fit to receive a renal transplant; this recognises that many patients in end stage renal disease are frail and elderly and/or have a number of co-existing medical problems such that they are not fit to undergo a major operation (implantation of the kidney) or to tolerate the immunosuppressive drugs that are required to prevent the transplant rejecting. This means that at any given time the majority of patients are not actually on a national waiting list for a renal transplant.

For those patients who are fit enough to receive a renal transplant and are successfully transplanted, there is a profound survival benefit compared to remaining on dialysis treatment. The average transplant recipient lives two or three times as long as a matched dialysis patients who does not receive a renal transplant but remains on dialysis treatment. In addition, a transplant patient is less likely to be hospitalised and has a better quality of life than a dialysis patient. The secondary complications of CKD such as anaemia and bone disease resolve in many patients who are successfully transplanted. Furthermore, there are major health economic benefits to renal transplantation compared to dialysis. Transplantation is a far less expensive treatment than dialysis, particularly after the first year, when the large majority of the costs are limited to payment for the immunosuppressive drugs.

One of the major challenges for renal transplantation is the identification of a sufficient number of donor kidneys to fulfil demand. This is reflected in the increasing number of people who are waiting for a kidney; in the UK the average time on the waiting list before transplantation is around 3 years. Kidneys donated for the national waiting list are harvested from deceased donors. At the time of donation, donors are classified as dead as a consequence of either brain stem or cardiac death; these are also called heart beating and non-heart beating donors, respectively.

The numbers of deceased donors as a proportion of those on the waiting list for a kidney transplant have fallen. Therefore, living donor transplantation has become increasingly common. In addition to part addressing the scarcity of donor organs, patients who receive kidney transplants from living donors have better outcomes than patients who receive deceased donor kidneys. This is due to a number of factors, including the quality of the organs, because living donors undergo a detailed health screening and if there is any indication that they have significant medical problems they are excluded from donation.

One of the major factors responsible for excellent outcomes for kidney transplant recipients is the use of immunosuppressive drugs to control the response the immune system of the recipient mounts against the donor kidney. This is called an alloresponse. Alloimmunity refers to an immune response against tissue derived from an individual of the same species as the recipient of the tissue.

The major disadvantage of all immunosuppressive agents is their relative non-specificity, in that they cause a general depression of the immune system. This exposes the patient to an increased risk of malignancy and infection, which is an important cause of morbidity and mortality.

Immunosuppressants

The major pharmacological groups of immunosuppressive agents are summarised in Table 18.5.

Table 18.5 Mechanism of action of immunosuppressants commonly used following renal transplantation

Drug	Mechanism	Comment
Steroids	Bind to steroid receptors and inhibit gene transcription and function of T-cells, macrophages and neutrophils	Prophylaxis against and reversal of rejection
Ciclosporin	Forms complex with intracellular protein cyclophilin → inhibits calcineurin. Ultimately inhibits interleukin-2 synthesis and T-cell activation	Long-term maintenance therapy against rejection
Tacrolimus	Forms complex with an intracellular protein → inhibits calcineurin	Long-term maintenance therapy against rejection Rescue therapy in severe or refractory rejection
Sirolimus	Inhibits interleukin-2 cell signalling → blocks T-cell cycling and inhibits B-cells	Usually used in combination with ciclosporin ± steroids
Mycophenolate	Inhibits inosine monophosphate dehydrogenase → reduces nucleic acid synthesis → inhibits T- and B-cell function	Usually used in combination with ciclosporin/tacrolimus ± steroids
Azathioprine	Incorporated as a purine in DNA → inhibits lymphocyte and neutrophil proliferation	Usually used in combination with ciclosporin/tacrolimus ± steroids
Muromonab (OKT3, mouse monoclonal anti-CD3)	Binds to CD3 complex → blocks, inactivates or kills T-cell. Short t_1/2	Prophylaxis against rejection Reversal of severe rejection
Polyclonal horse/rabbit antithymocyte or antilymphocyte globulin (ATG, ALG)	Antibodies against lymphocycte proteins → alter T- and B-cell activity	Prophylaxis against rejection Reversal of severe rejection
Humanised or chimaeric anti-CD25 (basiliximab and daclizumab)	Monoclonal antibodies that bind CD25 in interleukin-2 complex → prevent T-cell proliferation	Prophylaxis against acute rejection in combination with ciclosporin and steroids

Transplant recipients receive a high load of immunosuppression at the time of transplantation; this is known as induction immunosuppression. Induction immunosuppression is to protect the transplant from the high immunological risk that is present in the first few weeks after surgery. In the months following the transplant, the immunosuppression load is then incrementally reduced. Most patients will reach long-term low dose maintenance immunosuppression sometime between 6 and 12 months after the transplant. However, whilst the transplant remains in the recipient it continues to represent an immunological risk; whilst overt, late rejection is uncommon, it can occur at any time if the patient stops taking their immunosuppressants. For a transplant to last many years, sustained day on day adherence with treatment is essential.

The commonest combination used at induction is the calcineurin inhibitor (CNI) tacrolimus, the anti-proliferative agent mycophenolate mofetil (MMF) and corticosteroids. Most patients also receive antibody induction. The antibody that is most commonly used is a monoclonal anti-CD25 antibody for people at low or medium immunological risk and anti-T-cell polyclonal antibodies (thymoglobulin or ATG) for people at high immunological risk. Patients at high immunological risk include: those who have lost a previous transplant because of rejection; the presence of preformed circulating anti-HLA antibodies at the time of transplantation (sensitisation); and major HLA mismatches (particularly at HLA-DR) between donor and recipient. Guidelines for the use of immunosuppressive therapy in kidney transplant patients have been issued (NICE, 2004). More recent international consensus guidelines recommend use of newer agents such as MMF and emphasise the use of tacrolimus (rather than ciclosporin) as the CNI of choice. Tacrolimus is associated with less acute rejection than ciclosporin and may be associated with better graft function at one year and less graft loss (Knoll and Bell, 1999). However, there is no overwhelming evidence as yet that patients who receive tacrolimus as a CNI from induction have a survival benefit compared to patients who receive ciclosporin. It should be noted that generic/proprietary formulations of some drugs (e.g. tacrolimus and ciclosporin) are not interchangeable.

Calcineurin inhibitors (ciclosporin and tacrolimus)

The discovery and development of ciclosporin and latterly tacrolimus has led to a step improvement in one-year renal transplant survival from 50–70% to 85–95%.

In T-cells that have been exposed to T-cell receptor (TCR) ligation (signal 1) and co-stimulation (signal 2), there is activation of intra-cytoplasmic signalling pathways that include mobilisation of a molecule called calcineurin. Calcineurin contributes to the activation of a molecule called nuclear factor of activated T-cells (NFAT). This factor then migrates to the nucleus and initiates transcription of IL-2 and other pro-inflammatory cytokines which are involved in driving an activated T-cell into a proliferative phase, so that it makes multiple copies of itself. Ciclosporin and tacrolimus affect calcineurin through blocking binding proteins (cyclophilin and tacrolimus-binding protein, respectively) that are important for calcineurin activity.

The action of CNIs is partially selective in that they predominantly target T-cells and have no direct effect on B cells; as a consequence, CNIs are associated with infections seen in people with deficiencies in the cellular limb of the immune response. These are predominantly intracellular infections such as viral, fungal, protozoal and mycobacterial infections.

Both ciclosporin and tacrolimus are critical dose drugs. That is, there is a narrow therapeutic window between under-dosing and toxicity. Both drugs, therefore, require monitoring by serum levels. Trough levels are usually taken 12 h after the previous dose and immediately before the next dose.

Ciclosporin

Ciclosporin causes a wide range of side effects, including nephrotoxicity, hypertension, fine muscle tremor, gingival hyperplasia, nausea and hirsutism. Hyperkalaemia, hyperuricaemia, hypomagnesaemia and hypercholestraemia may also occur. Nephrotoxicity is a particularly serious side effect and occasionally necessitates the withdrawal of ciclosporin. There is tremendous inter- and intra-patient variation in absorption of ciclosporin. Blood level monitoring is required to achieve maximum protection against rejection and minimise the risk of side effects. The range regarded as acceptable varies between centres, but is commonly around 100–200 ng/mL in the first 6 months after transplantation and 80–150 ng/mL from 6 months onwards.

Ciclosporin interacts with a number of drugs that either lead to a reduction in ciclosporin levels, increase the risk of rejection or cause an elevation in ciclosporin levels leading to increased toxicity. Some drugs enhance the nephrotoxicity of ciclosporin (Box 18.2).

Box 18.2 Examples of drug interactions involving ciclosporin

• Reduce ciclosporin serum levels (hepatic enzyme inducers): phenytoin, phenobarbital, rifampicin, isoniazid

• Increase ciclosporin serum levels (hepatic enzyme inhibitors): diltiazem, erythromycin, corticosteroids, ketoconazole

• Enhance ciclosporin nephrotoxicity: aminoglycosides, amphotericin, co-trimoxazole, melphalan

Ciclosporin should not be administered with grapefruit juice, which should also be avoided for at least an hour pre-dose, as this can result in marked increases in blood concentrations. This effect appears to be due to inhibition of enzyme systems in the gut wall resulting in transiently reduced ciclosporin metabolism.

Tacrolimus

Tacrolimus is not chemically related to ciclosporin, but acts by a similar mechanism. The side effect profile is similar to that of ciclosporin with some subtle differences. Disturbances of glucose metabolism leading to impaired glucose tolerance and new onset diabetes after transplantation (NODAT) occurs in around 10–15% of patients who receive tacrolimus, this is twice as common as the incidence seen in patients who receive ciclosporin. In contrast, hirsutism is less of a problem in patients who receive tacrolimus than those who receive ciclosporin. In patients who are commenced on ciclosporin and then develop an episode of acute rejection, conversion to tacrolimus lowers the risk of recurrent rejection. Tacrolimus is an easier drug to use than ciclosporin. Careful monitoring is required with a target level of 8–15 ng/mL in the first weeks following transplantation which is usually decreased in patients who follow an uncomplicated course to 5–8 ng/mL from 6 months.

Steroids

Prednisolone is the oral agent commonly used for immunosuppression after renal transplantation, while high-dose intravenous methylprednisolone is given as a single dose at induction with further use limited for cases of acute rejection. The maintenance dose of prednisolone to minimise adrenal suppression is around 0.1 mg/kg/day given as a single dose in the morning. The use of steroid therapy often leads to complications, particularly if high doses are given for long periods. In addition to a cushingoid state, the use of steroids may cause gastro-intestinal bleeding, hypertension, dyslipidaemia, diabetes, osteoporosis and mental disturbances. Patients who are temporarily unable to take oral prednisolone should be given an equivalent dose of hydrocortisone intravenously.

In the past decade, there has been an increasing use of steroid avoidance regimens. This term is misleading as patients still receive steroids, but use is restricted to the first week of transplantation. Currently, there is no long-term evidence to show this approach provides equivalence to a continuous steroid dosing regimen, but one-year outcomes are comparable. If steroids are subsequently withdrawn months after the transplant, then outcomes with steroid avoidance regimens are worse.

Azathioprine

Azathioprine is derived from 6-mercaptopurine and is, therefore, an antimetabolite which reduces DNA and RNA synthesis-producing immunosuppression.

Azathioprine is given orally in a dose of up to 2 mg/kg/day. There is no advantage in giving it in divided doses. Since azathioprine interferes with nucleic acid synthesis, it may be mutagenic, and pharmacy and nursing staff should avoid handling the tablets. Azathioprine has a significant drug interaction with allopurinol, causing fatal marrow suppression and this combination should be avoided.

Mycophenolate mofetil (MMF)

MMF is a pro-drug of mycophenolic acid. It inhibits the enzyme inosine monophosphate dehydrogenase needed for guanosine synthesis which leads to reduced B-cell and T-cell proliferation. However, other rapidly dividing cells are less affected, as guanosine is produced in other cells. Consequently, mycophenolate has a more selective mode of action than azathioprine.

The drug is given in combination with tacrolimus at a dose of 1 g twice a day which can subsequently be reduced after 6 weeks to 750 mg twice a day. A dose of 1.5 g twice a day is prescribed when used in combination with ciclosporin because the ciclosporin interferes with enterohepatic recirculation of mycophenolate metabolites with consequent lower exposure at a similar dose.

Compared to azathioprine, MMF reduces the risk of acute rejection episodes and improves long-term graft survival. However, it is a more potent immunosuppressant than azathioprine and is associated with a significant increased risk of opportunistic infections.

Sirolimus (rapamycin)

Sirolimus is a macrolide antibiotic that binds to the FKBP-25 cellular receptor. This complex initiates a sequence that produces modulation of regulatory kinases that ultimately interfere with the proliferative effects of IL-2 on lymphocytes. The progression of T-cells from the G1 to S phase is blocked, so inhibiting cell division and therefore cell proliferation.

Adverse effects include hyperkalemia, hypomagnesemia, hyperlipidemia, hypertriglyceridemia, leukopenia, anemia, imp-aired wound healing, and joint pain. Currently, the role of sirolimus in renal transplantation has not been clearly defined. In combination with CNIs, it produces additive nephrotoxicity; when used with MMF it increases the risk of marrow suppression and mucosal side effects. Most experts currently limit the use of sirolimus to patients who have declining kidney function as a consequence of CNIs, but where graft function is still maintained to a GFR of >40 mL/min without significant proteinuria.

Monoclonal antibodies

The humanised or chimeric anti-CD25 monoclonal antibodies basiliximab and daclizumab are clinically similar and bind to CD25 in the IL-2 complex of activated T-lymphocytes. This renders all T-cells resistant to IL-2 and therefore prevents T-cell proliferation. They are used as prophylaxis against acute rejection in combination with CNIs and steroids (NICE, 2004). Daclizumab is currently not available in the UK.

Polyclonal antibodies

These were the first antibodies used as immunosuppressants and contain antibodies with a number of different antigen- combining sites. Polyclonal antibodies are used peri-operatively as prophylaxis against rejection and in some cases to reverse episodes of severe rejection. The main preparations are antithymocyte globulin (ATG) or antilymphocyte globulin (ALG).

ATG is produced from rabbit or equine serum immunised with human T-cells. It contains antibodies to human T-cells, which on injection will attach to, neutralise and eliminate most T-cells, thereby weakening the immune response. ALG is similar to ATG, is of equine origin, but is not specific to T-cells as it also acts on B-cells.

It is not certain how polyclonal antibodies act to inhibit T-cell mediated immune responses but depletion of circulating T-cells, modulation of cell surface receptor molecules, induction of energy and apoptosis of activated T-cells have all been proposed.

The main drawback to the use of anti-T-cell sera is the relatively high incidence of side effects, notably anaphylactic reactions including hypotension, fever and urticaria. These reactions are more frequently observed with the first dose and may require supportive therapy with steroids and antihistamines. Severe reactions may necessitate stopping treatment. Steroids and antihistamines may be given prophylactically to prevent or minimise allergic reactions. Pyrexia often occurs on the first day of treatment but usually subsides without requiring treatment. Tolerance testing by administration of a test dose is advisable, particularly in patients such as asthmatics who commonly experience allergic reactions. In the event of adverse reactions, ALG and ATG can be substituted for each other.

Other precautions

Transplant patients are given prophylactic antibiotic therapy for varying periods postoperatively owing to the risks of infection associated with immunosuppression. Treatment with co-trimoxazole to prevent Pneumocystis carinii, isoniazid and pyridoxine in high-risk patients to prevent tuberculosis, valganciclovir to prevent cytomegalovirus, and nystatin or amphotericin to prevent oral candidiasis are commonly used. Vaccination with live organisms (e.g. BCG, MMR, oral poliomyelitis, oral typhoid) must be avoided in the immunosuppressed patient.

Implementation of regular dialysis treatment

End stage renal failure is the point at which the patient will die without the institution of renal replacement by dialysis or transplantation.

The principle of dialysis is simple. The patient’s blood and a dialysis solution are positioned on opposing sides of a semi-permeable membrane across which exchange of metabolites occurs. The two main types of dialysis used in CKD are haemodialysis and peritoneal dialysis. Neither has been shown to be superior to the other in any particular group of patients and so the personal preference of the patient is important when selecting dialysis modality. Haemodialysis and acute peritoneal dialysis are discussed in Chapter 17.

As patients with end stage renal failure may require dialysis treatment for many years, adaptations to the process of peritoneal dialysis have been made that enable the patient to follow a lifestyle as near normal as possible. Continuous ambulatory peritoneal dialysis (CAPD) involves a flexible non-irritant silicone rubber catheter (Tenckhoff catheter) that is surgically inserted into the abdominal cavity. Dacron cuffs on the body of the catheter become infiltrated with scar tissue during the healing process, causing the catheter to be firmly anchored in place. Such catheters may remain viable for many years. During the dialysis process thereafter, a bag typically containing 2.5 L of warmed dialysate and a drainage bag are connected to the catheter using aseptic techniques. Used dialysate is drained from the abdomen under gravity into the drainage bag, fresh dialysate is run into the peritoneal cavity and the giving set is disconnected. The patient continues his or her activities until the next exchange some hours later. The procedure is repeated regularly so that dialysate is kept in the abdomen 24 h a day. This is usually achieved by repeating the process four times a day with an average dwell time of 6–8 h. A number of different dialysis solutions are available of which the majority are glucose based.

Another form of peritoneal dialysis is known as automated peritoneal dialysis (APD) in which exchanges are carried out overnight while the patient sleeps. Dialysis fluid is exchanged – three to five times over a 10-h period with volumes of 1.5–3 L each time. During the day time the patient usually has a dwell of fluid within the abdominal cavity.

Since peritoneal dialysis is continuous and corrects fluid and electrolyte levels constantly, dietary and fluid restrictions are less stringent. Blood loss is also avoided, making the technique safer in anaemic patients. Unfortunately, peritoneal dialysis is not an efficient process; it only just manages to facilitate excretion of the substances required and, as albumin crosses the peritoneal membrane, up to 10 g of protein a day may be lost in the dialysate. It is also uncomfortable and tiring for the patient, and is contraindicated in patients who have recently undergone abdominal surgery.

Peritonitis is the most frequently encountered complication of peritoneal dialysis. Its diagnosis usually depends on a combination of abdominal pain, cloudy dialysate or positive microbiological culture. Empirical antibiotic therapy should, therefore, be commenced as soon as peritonitis is clinically diagnosed. Gram-positive cocci (particularly Staphylococcus aureus) and Enterobacteriaceae are the causative organisms in the majority of cases, while infection with Gram-negative species and Pseudomonas species are well recognised. Fungal infections are also seen, albeit less commonly.

Most centres have their own local protocol for antibiotic treatment of peritonitis. In one example, levofloxacin, a quinolone with good Gram-negative activity is given orally, in combination with vancomycin, which has excellent activity against Gram-positive bacteria, is administered via the intraperitoneal route. As in all situations, the antibiotic regimen should be adjusted appropriately after the results of microbiological culture and sensitivity have been obtained.

Haemodialysis is particularly suitable for patients producing large amounts of metabolites, such as those with high nutritional demands or a large muscle mass, where these substances are produced faster than peritoneal dialysis can remove them. It also provides a back-up for those patients in whom peritoneal dialysis has failed.

The various techniques of haemofiltration, a technique rela- ted to haemodialysis, are also discussed in detail in Chapter 17.

Case studies

Case 18.1

Mr D, a 19-year-old undergraduate student, visited his university health centre complaining of a 3-month history of fatigue, weakness, nausea and vomiting that he had attributed to ‘examination stress’. His previous medical history indicated an ongoing history of bed wetting from an early age. Laboratory results from a routine blood screen showed the following:

		Reference range
Sodium	137 mmol/L	(135–145)
Potassium	4.8 mmol/L	(3.5–5.0)
Phosphate	2.5 mmol/L	(0.9–1.5)
Calcium	1.6 mmol/L	(2.20–2.55)
Urea	52 mmol/L	(3.0–6.5)
Creatinine	620 μmol/L	(50–120)
Haemoglobin	7.5 g/dL	(13.5–18.0)

Subsequent referral to a specialist hospital centre established a diagnosis of chronic renal failure secondary to reflux nephropathy.

Question

Explain the signs and symptoms experienced by Mr D and the likely course of his disease?

Answer

Mr D is suffering from the signs and symptoms of uraemia resulting from chronic renal failure. Mechanical reflux damage to his kidneys has compromised renal function and resulted in an accumulation of toxins, including urea and creatinine that, in turn, have contributed to his nausea, vomiting and general malaise. His biochemical results indicate other features typical of uraemic syndrome associated with chronic renal failure. The low haemoglobin is indicative of reduced erythropoetin production following progressive kidney damage. Renal osteodystrophy is also present, as inadequate vitamin D production and the raised serum phosphate have contributed to the hypocalaemia.

This patient is likely to have remained symptom free for a period of years despite progressively worsening renal function. The kidneys operate with a substantial functional reserve under normal conditions. Patients generally remain asymptomatic as their renal reserve diminishes. Eventually there is a failure in the ability of the damaged kidney to compensate and symptoms appear late in the condition.

Case 18.2

Mr K, a 43-year-old male with established CKD, had been maintained for 3 years on continuous ambulatory peritoneal dialysis. He was admitted to hospital for cadaveric renal transplantation. On examination he was found to have slight ankle oedema. He weighed 60 kg and his blood pressure was 135/90 mmHg and pulse rate 77 min⁻¹. He was administered the following immunosuppressants preoperatively: an anti-CD25 antibody, tacrolimus, mycophenolate and prednisolone.

Question

How should the immunosuppressants be administered to Mr K and how should immunosuppression be managed postoperatively?

Answer

Anti-CD25 antibodies and high-dose methylprednisolone are given intravenously at the time of the operation. Typically, tacrolimus at 200–300 µcg/kg/day as two split doses, it is important to note that there are two preparations of tacrolimus, a once daily dose and a divided dose preparation. The once daily preparation is called Advagraf® and the twice daily preparation is Prograf®, the preparations are not interchangeable and as a result they must be prescribed by brand name, changes between preparations must only be made by a transplant specialist. MMF at 1 g twice a day and prednisolone at 10 mg twice a day are given as oral doses to continue in the days and weeks following transplantation. These are commenced within 12 h of the operation. In living kidney donation where the transplant operation is planned, patients are preloaded for several days before the transplant. Intravenous tacrolimus is available, but should only be used in exceptional circumstances, usually when the gut is not working and all drugs and nutrition need to be given by the parenteral route.

Early dose adjustments in tacrolimus following transplantation are common and directed by drug levels. These are checked daily for the first week following transplantation; by 6 months they will be checked on alternate weeks. In the long-term, the median dose of tacrolimus is around 2 mg twice a day and the dose of MMF can be reduced to 500–750 mg twice a day in the large majority of patients. The dose of prednisolone is titrated down so that by 3 months it is 5–10 mg/day. Acute rejection episodes, diagnosed on a renal biopsy performed for a decline in graft function are treated with high-dose steroids. For antibody mediated (severe) rejection, plasma exchange and intravenous immunoglobulin are used.

Case 18.3

Mr A is a patient with CKD secondary to chronic interstitial nephritis. He complains of chronic fatigue, lethargy and breathlessness on exertion, palpitations and poor concentration. His recent haematological results were found to be:

		Reference range
Haemoglobin	5.6 g/dL	(13.5–17.5)
Red cell count	2.92 × 10⁹ L⁻¹	(4.5–6.5 × 10⁹ L⁻¹)
Haematocrit	0.208	(0.40–0.54)
Serum ferritin	88.0 μcg/L	(15–300)