Physiology

A conventional diagrammatic representation of the nephron is shown in Figure 12.2a and a physiological version in Figure 12.2b.

Figure 12.2 (a) Principal parts of the nephron. The point where the distal tubule is in close proximity to its own glomerulus is called the juxtaglomerular apparatus. This contains the macula densa. (b) The countercurrent system. (i) Vasa recta: these vessels descend from the cortex into the medulla and then turn back towards the cortex. (ii) Cortical nephron: these have short descending limbs extending into the outer medulla. (iii) Juxtamedullary nephron: the descending limb dips deeply into the hypertonic inner medulla. Numbers indicate approximate osmolalities.

An essential feature of renal function is that a large volume of blood – 25% of cardiac output or approximately 1300 mL/min – passes through the two million glomeruli.

A hydrostatic pressure gradient of approximately 10 mmHg (a capillary pressure of 45 mmHg minus 10 mmHg of pressure within Bowman’s space and 25 mmHg of plasma oncotic pressure) provides the driving force for ultrafiltration of virtually protein-free and fat-free fluid across the glomerular capillary wall into Bowman’s space and so into the renal tubule (Fig. 12.3).

Figure 12.3 Pressures controlling glomerular filtration. (1) Capillary hydrostatic pressure (45 mmHg); (2) hydrostatic pressure in Bowman’s space (10 mmHg); (3) plasma protein oncotic pressure (25 mmHg). Arrows (1, 2, 3) indicate the direction of a pressure gradient.

The ultrafiltration rate (glomerular filtration rate; GFR) varies with age and sex but is approximately 120–130 mL/min per 1.73 m² surface area in adults. This means that, each day, ultrafiltration of 170–180 L of water and unbound small-molecular-weight constituents of blood occurs. If these large volumes of ultrafiltrate were excreted unchanged as urine, it would be necessary to ingest huge amounts of water and electrolytes to stay in balance. This is avoided by the selective reabsorption of water, essential electrolytes and other blood constituents, such as glucose and amino acids, from the filtrate in transit along the nephron. Thus, 60–80% of filtered water and sodium are reabsorbed in the proximal tubule along with virtually all the potassium, bicarbonate, glucose and amino acids (Fig. 12.2b). Additional water and sodium chloride are reabsorbed more distally, and fine tuning of salt and water balance is achieved in the distal tubules and collecting ducts under the influence of aldosterone and antidiuretic hormone (ADH). The final urine volume is thus 1–2 L daily. Calcium, phosphate and magnesium are also selectively reabsorbed in proportion to the need to maintain a normal electrolyte composition of body fluids.

The urinary excretion of some compounds is more complicated. For example, potassium is freely filtered at the glomerulus, almost completely reabsorbed in the proximal tubule, and secreted in the distal tubule and collecting ducts. A clinical consequence of this is that the ability to eliminate unwanted potassium is less dependent on GFR than is the elimination of urea or creatinine. Other compounds filtered and reabsorbed or secreted to a variable extent include urate, many organic acids and many drugs or their metabolic breakdown products. The more tubular secretion of a compound that occurs, the less dependent elimination is on the GFR; penicillin and cefradine are examples of drugs secreted by the tubules.

Glomerular filtration rate (GFR)

In health, the GFR remains remarkably constant owing to intrarenal regulatory mechanisms. In disease (e.g. a reduction in intrarenal blood flow, damage to or loss of glomeruli or obstruction to the free flow of ultrafiltrate along the tubule), the GFR will fall. The ability to eliminate waste material and to regulate the volume and composition of body fluid will decline. This will be manifest as a rise in the plasma urea or creatinine and as a reduction in measured GFR.

The concentration of urea or creatinine in plasma represents the dynamic equilibrium between production and elimination. In healthy subjects there is an enormous reserve of renal excretory function, and serum urea and creatinine do not rise above the normal range until there is a reduction of 50–60% in the GFR. Thereafter, the level of urea depends both on the GFR and its production rate (Table 12.1). The latter is heavily influenced by protein intake and tissue catabolism. The level of creatinine is much less dependent on diet but is more related to age, sex and muscle mass. Once it is elevated, serum creatinine is a better guide to GFR than urea and, in general, measurement of serum creatinine is a good way to monitor further deterioration in the GFR.

Table 12.1 Factors influencing serum urea levels

It must be re-emphasized that a normal serum urea or creatinine is not synonymous with a normal GFR.

Measurement of the glomerular filtration rate

Measurement of the GFR is necessary to define the exact level of renal function. It is essential when the serum (plasma) urea or creatinine is within the normal range. The most widely used measurement is the creatinine clearance (Fig. 12.4).

Figure 12.4 Creatinine clearance vs serum creatinine. Note that the serum creatinine does not rise above the normal range until there is a reduction of 50–60% in the glomerular filtration rate (creatinine clearance).

Creatinine clearance is dependent on the fact that daily production of creatinine (principally from muscle cells) is remarkably constant and little affected by protein intake. Serum creatinine and urinary output thus vary very little throughout the day.

Creatinine excretion is, however, by both glomerular filtration and tubular secretion, although at normal serum levels the latter is relatively small.

With progressive renal failure, creatinine clearance may overestimate GFR but, in clinical practice, this is seldom significant.

Given these observations, creatinine clearance, is nevertheless a reasonably accurate measure of GFR – normal or near normal renal function. Urine is collected over 24 h for measurement of urinary creatinine. A single plasma level of creatinine is measured some time during the 24-hour period.

where U = urine concentration of creatinine; V = rate of urine flow in mL/min; P = plasma concentration of creatinine. Normal ranges are 90–140 mL/min in men, 80–125 mL/min in women.

Calculated GFR. Measurement of true GFR is cumbersome, time-consuming and may be inaccurate if 24-hour urine collections are incomplete. Therefore, several formulae have been developed that allow a prediction of creatinine clearance or GFR from serum creatinine and demographics. The Cockcroft–Gault equation for creatinine clearance is shown in Box 12.1.

 Box 12.1

Estimation of glomerular filtration rate (GFR)

Cockroft–gault equation

Constant = 1.23 for males and 1.04 for women.

Modification of diet in renal disease (MDRD) equation

Calculation of estimated GFR by four variables:

To convert creatinine values in µmol/L to mg/dL multiply by 0.0113.

GFR (mL/min/1.73 m²) = 141 × min (serum creatinine/κ, 1)² × max (serum creatinine/κ, 1)^−1.209 × 0.993^Age × 1.018 [if female] × 1.159 [if black], where κ is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum or serum creatinine/κ or 1, and max indicates the maximum of serum creatinine/κ or 1.

Ckd epidemiology (CKD-EPI) collaboration equation

Adapted from: MacGregor MS, Boag DE, Innes A. Chronic kidney disease. Quarterly Journal of Medicine 2006; 99:365–375.

A prediction equation has been developed based on the data derived from the Modification of Diet in Renal Disease (MDRD) study in people with chronic kidney disease (CKD) (Box 12.1). This equation is based on age, sex, creatinine and ethnicity. A modification of MDRD equation is used by most chemical pathology laboratories to calculate eGFR but it is less reliable if actual GFR is >60 mL/min and can result in inappropriate referral to renal physicians.

A new equation, the CKD Epidemiology Collaboration (CKD-EPI) equation, uses the same four variables as the MDRD Study equation and is more accurate for estimating GFR, especially at higher GFRs. The improved accuracy is mainly due to a substantial decrease in systematic differences between mGFR and eGFR (bias). The CKD-EPI equation is more accurate than the MDRD study equation overall and across most subgroups. In contrast to the MDRD study equation, eGFR >60 mL/min/1.73 m² can be reported using the CKD-EPI equation.

All these equations have not, however, been fully validated across all ranges of renal impairment, weights or body mass index (BMI), or ethnic groups; this makes them unreliable in the monitoring of patients with acute or chronic kidney disease while being treated and some clinicians still rely on measured creatinine clearance. In clinical practice, eGFR is reliable enough.

FURTHER READING

Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150(9):604–612.

Stevens LA, Schmid CH, Zhang Y et al. Development and validation of GFR-estimating equations. Nephrol Dial Transplant 2010; 25(2):449–457.

Tubular function

The major function of the tubule is the selective reabsorption or excretion of water and various cations and anions to keep the volume and electrolyte composition of body fluid normal (see Ch. 13).

The active reabsorption from the glomerular filtrate of compounds such as glucose and amino acids also takes place. Within the normal range of blood concentrations these substances are completely reabsorbed by the proximal tubule. However, if blood levels are elevated above the normal range, the amount filtered (filtered load = GFR × plasma concentration) may exceed the maximal absorptive capacity of the tubule and the compound ‘spills over’ into the urine. Examples of this occur with hyperglycaemia in diabetes mellitus or elevated plasma phenylalanine in phenylketonuria.

Conversely, inherited or acquired defects in tubular function may lead to incomplete absorption of a normal filtered load, with loss of the compound in the urine (a lowered ‘renal threshold’). This is seen in renal glycosuria, in which there is a genetically determined defect in tubular reabsorption of glucose. It is diagnosed by demonstrating glycosuria in the presence of normal blood glucose levels. Inherited or acquired defects in the tubular reabsorption of amino acids, phosphate, sodium, potassium and calcium also occur, either singly or in combination. Examples include cystinuria and Fanconi’s syndrome (see p. 1040 and Ch. 13). Tubular defects in the reabsorption of water result in nephrogenic diabetes insipidus (p. 992). Under normal circumstances, antidiuretic hormone induces an increase in the permeability of water in the collecting ducts by attachment to receptors with subsequent activation of adenyl cyclase. This then activates a protein kinase, which induces preformed cytoplasmic vesicles containing water channels (termed ‘aquaporins’) to move to and insert into the tubular luminal membrane. This allows water entry into tubular cells down a favourable osmotic gradient. Water then crosses the basolateral membrane and enters the bloodstream. When the effect of ADH wears off, water channels return to the cell cytoplasm (see Fig. 13.5).

Endocrine function

Renin-angiotensin system

Juxtaglomerular apparatus

The juxtaglomerular apparatus is made up of specialized arteriolar smooth muscle cells that are sited on the afferent glomerular arteriole as it enters the glomerulus. These cells synthesize prorenin, which is cleaved into the active proteolytic enzyme renin. Active renin is then stored in and released from secretory granules. Prorenin is also released in the circulation and comprises 50–90% of circulating renin, but its physiological role remains unclear as it cannot be converted into active renin in the systemic circulation. In the blood, renin converts angiotensinogen, an α2 globulin of hepatic origin, to angiotensin I. Renin release is controlled by:

Pressure changes in the afferent arteriole

Sympathetic tone

Chloride and osmotic concentration in the distal tubule via the macula densa (Fig. 12.2a)

Local prostaglandin and nitric oxide release.

The renin-angiotensin-aldosterone system is illustrated in Figure 12.5.

Figure 12.5 The renin-angiotensin-aldosterone system. ACE inhibitors and angiotensin II antagonists can inhibit this system. ACE, angiotensin-converting enzyme.

Angiotensin I is inactive but is further cleaved by angiotensin-converting enzyme (ACE; present in lung and vascular endothelium) into the active peptide, angiotensin II, which has two major actions (mediated by two types of receptor, AT₁ and AT₂). The AT₁ subtype which is found in the heart, blood vessels, kidney, adrenal cortex, lung and brain mediates the vasoconstrictor effect. AT₂ is probably involved in vascular growth. Angiotensin II:

causes rapid, powerful vasoconstriction

stimulates the adrenal zona glomerulosa to increase aldosterone production (over hours or days), leading to sodium and water retention.

Both of these actions will tend to reverse the hypovolaemia or hypotension that is usually responsible for the stimulation of renin release. Angiotensin II promotes renal NaCl and water absorption by direct stimulation of Na⁺ reabsorption in the early proximal tubule and by increased adrenal aldosterone secretion which enhances Na⁺ transport in the collecting duct.

In addition to influencing systemic haemodynamics, angiotensin II also regulates GFR. Although it constricts both afferent and efferent arterioles, vasoconstriction of efferent arterioles is three times greater than that of afferent, resulting in increase of glomerular capillary pressure and maintenance of GFR. In addition, angiotensin II constricts mesangial cells, reducing the filtration surface area, and sensitizes the afferent arteriole to the constricting signal of tubuloglomerular feedback (see p. 562). The net result is that angiotensin II has opposing effects on the regulation of GFR: (a) an increase in glomerular pressure and consequent rise in GFR; (b) reduction in renal blood flow and mesangial cell contraction, reducing filtration (see Fig. 12.48). In renal artery stenosis with resultant low perfusion pressure, angiotensin II maintains GFR. However, in cardiac failure and hypertension, GFR may be reduced by angiotensin II.

The renin-angiotensin system can be blocked at several points with renin inhibitors, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (A-IIRA). These are useful agents in treatment of hypertension and heart failure (see p. 782 and p. 719) but have differences in action: ACEIs also block kinin production while A-IIRAs are specific for the AT-II receptors.

Erythropoietin

Erythropoietin (see also p. 374) is the major stimulus for erythropoiesis. It is a glycoprotein produced principally by fibroblast-like cells in the renal interstitium.

Under hypoxic conditions both the α and β subunits of hypoxia inducible factor 2 (HIF-2) are expressed forming a heterodimer, causing erythropoietin gene transcription via the combined effects of hepatic nuclear factor 4 (HNF-4) and coactivator p300. Erythropoietin, once formed, binds to its receptors on erythroid precursor cells.

Under normal oxygen conditions, only the HIF-2-β subunit is constitutively expressed. The α subunit undergoes proline hydroxylation in the presence of iron and oxygen by prolyl hydroxylase.

The hydroxylated HIF-2-α subunit binds to von Hippel-Lindau protein and a ubiquitin ligase E3 complex is activated. This leads to ubiquitination (p. 31) and subsequent degradation of HIF-2-α via proteosomes so that no erythropoietin is transcribed. In normoxic conditions HIF-2-α also undergoes asparaginyl hydroxylation which prevents HIF complex from recruiting coactivators. These hydroxylation steps have absolute requirement for molecular oxygen which forms the basis of oxygen sensing.

Loss of renal substance, with decreased erythropoietin production, results in a normochromic, normocytic anaemia. Conversely, erythropoietin secretion may be increased, with resultant polycythaemia, in people with polycystic renal disease, benign renal cysts or renal cell carcinoma. Recombinant human erythropoietin has been biosynthesized and is available for clinical use, particularly in people with chronic kidney disease (CKD) (see p. 623).

FURTHER READING

Kapitsinou PP, Liu Q, Unger TL et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 2010; 116(16):3039–3048.

Vitamin D metabolism

Naturally occurring vitamin D (see also p. 622) (cholecalciferol) requires hydroxylation in the liver at position 25 and again by a 1α-hydroxylase enzyme (mitochondrial cytochrome P450) mainly in the distal convoluted tubule, the cortical and inner medullary part of the collecting ducts and the papillary epithelia of the kidney to produce the metabolically active 1,25-dihydroxycholecalciferol (1,25-(OH)₂D₃). The 1α-hydroxylase activity is increased by high plasma levels of parathyroid hormone (PTH), low phosphate and low 1,25-(OH)₂D₃. 1,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol are degraded in part by being hydroxylated at position 24 by 24-hydroxylase. The activity of this enzyme is reduced by PTH and increased by 1,25-(OH)₂D₃ (which therefore promotes its own inactivation).

Reduced 1α-hydroxylase activity in diseased kidneys results in relative deficiency of 1,25-(OH)₂D₃. As a result, gastrointestinal calcium and to a lesser extent phosphate absorption is reduced and bone mineralization impaired. Receptors for 1,25-(OH)₂D₃ exist in the parathyroid glands, and reduced occupancy of the receptors by the vitamin alters the set-point for release of PTH in response to a given decrement in plasma calcium concentration. Gut calcium malabsorption, which induces hypocalcaemia, and relative lack of 1,25-(OH)₂D₃, contribute therefore to the hyperparathyroidism seen regularly in patients with CKD, even of modest degree.

Examination of the urine

Chemical (Stix) testing

Routine Stix testing of urine for blood, protein and sugar is obligatory in all patients suspected of having renal disease.

Blood

Haematuria may be overt, with bloody urine, or microscopic and found only on chemical testing. A positive Stix test must always be followed by microscopy of fresh urine (with the exception of menstruating women) to confirm the presence of red cells or red-cell casts and so exclude the relatively rare conditions of haemoglobinuria or myoglobinuria. Bleeding may come from any site within the urinary tract (Fig. 12.6):

Overt bleeding from the urethra is suggested when blood is seen at the start of voiding and then the urine becomes clear.

Blood diffusely present throughout the urine comes from the bladder or above.

Blood only at the end of micturition suggests bleeding from the prostate or bladder base.

Figure 12.6 Sites and causes of bleeding from the urinary tract.

Protein

Proteinuria is one of the most common signs of renal disease. Detection is primarily by Stix testing. Most reagent strips can detect protein if albuminuria exceeds 300 mg/day. They react primarily with albumin and are relatively insensitive to globulin and Bence Jones proteins.

If proteinuria is confirmed on repeated Stix testing, protein excretion in 24-hour urine collections should be measured. Healthy adults excrete up to 30 mg daily of albumin. Pyrexia, exercise and adoption of the upright posture (postural proteinuria) all increase urinary protein output but are benign.

Microalbuminuria

Normal individuals excrete less than 20 µg of albumin per minute (30 mg in 24 hours). Dipsticks, however, detect albumin only in a concentration above 200 µg (300 mg per 24 hours if urine volume is normal). An albumin excretion between these two levels – called microalbuminuria – is an early indicator of diabetic glomerular disease and systemic endothelial dysfunction and is a useful prognostic marker for future cardiovascular events.

Timed 24-hour urinary excretion rates provide the most precise measure of microalbuminuria. However, in clinical practice it is more convenient, practical and relatively accurate to test for microalbuminuria using either random or early morning urine samples in which albumin concentration is related to urinary creatinine concentration. Generally an albumin:creatinine ratio (ACR) of 2.5:20 corresponds to albuminuria of 30–300 mg daily respectively. Kits are available to test for microalbuminuria. The urinary total protein:creatinine ratio (PCR) is also used for monitoring patients with CKD of various etiologies in their clinical practice. It is relatively cheap and identifies patients whose proteinuria is of tubular rather than glomerular origin. ACR or PCR levels independently predict all-cause and cardiovascular mortality in the general population in addition to better risk stratifications of patients with CKD for future renal outcomes.

Glucose

Renal glycosuria is uncommon, so that a positive test for glucose always requires exclusion of diabetes mellitus.

Bacteriuria

Dipstick tests for bacteriuria are based on the detection of nitrite produced from the reduction of urinary nitrate by bacteria and also for the detection of leucocyte esterase, an enzyme specific for neutrophils. Although each test on its own has limitations, a positive reaction with both tests has a high predictive value for urinary tract infection (p. 593).

Microscopy

Urine microscopy should be carried out in all patients suspected of having renal disease, on a ‘clean’ sample of mid-stream urine. The presence of numerous skin squames suggests a contaminated, poorly collected sample that cannot be properly interpreted.

If a clean sample of urine cannot be obtained, suprapubic aspiration is required in suspected urinary tract infections, particularly in children.

White blood cells. The presence of ≥10 WBCs/mm³ in fresh unspun mid-stream urine samples is abnormal and indicates an inflammatory reaction within the urinary tract such as urinary tract infection (UTI), stones, tubulointerstitial nephritis, papillary necrosis, tuberculosis and interstitial cystitis.

Red cells. The presence of one or more red cells per cubic millimetre in unspun urine samples results in a positive Stix test for blood and is abnormal.

Casts are cylindrical bodies, moulded in the shape of the distal tubular lumen, and may be hyaline, granular or cellular. Coarse granular casts occur with pathological proteinuria in glomerular and tubular disease. Red-cell casts – even if only single – always indicate renal disease. White cell casts may be seen in acute pyelonephritis. They may be confused with the tubular cell casts that occur in patients with acute tubular necrosis.

Red-cell cast. Note aggregation of red cells as a ‘cast’ of the tubule.

Bacteria, see page 593. Always culture urine prior to starting antibiotic therapy for sensitivities. Stix testing for blood or protein is of no value in the diagnosis of a UTI as both can be absent in the urine of many people with bacteriuria.

Blood and quantitative tests

The use of serum urea, creatinine and GFR as measures of renal function is discussed on page 564. Other quantitative tests of disturbed renal function are described under the relevant disorders, as are diagnostic tests, e.g. ANCA, immunofluorescence and complement.

Imaging techniques

Plain X-ray

A plain radiograph of the abdomen is valuable to identify renal calcification or radiodense calculi in the kidney, renal pelvis, line of the ureters or bladder (Fig. 12.7).

Figure 12.7 Calcification in the renal tract. Calculi can occur at any site.

Ultrasonography

Ultrasonography of the kidneys and bladder has the advantage over X-ray techniques of avoiding ionizing radiation and intravascular contrast medium. In renal diagnosis it is the imaging method of choice for:

Renal measurement and for renal biopsy or other interventional procedures

Checking for pelvicalyceal dilatation as an indication of renal obstruction when chronic renal obstruction is suspected. (In suspected acute ureteric obstruction, unenhanced spiral CT is the method of choice.)

Characterizing renal masses as cystic or solid

Diagnosing polycystic kidney disease

Detecting intrarenal and/or perinephric fluid (e.g. pus, blood)

Demonstrating renal arterial perfusion or detecting renal vein thrombosis using Doppler. Doppler ultrasonography (duplex) has the advantage of being non-invasive and is based on the principle that, when incident sound waves are reflected from a moving structure, their frequency is shifted by an amount proportional to the velocity of the reflector (e.g. an RBC); this shift can be quantified and displayed as a spectral Doppler scan or colour overlay (colour Doppler). However, duplex imaging is limited by central obesity, bowel gas and certain body habitus characteristics. Moreover, it is technically demanding, highly operator dependent, and is not universally available. It is at best a screening initial investigation and always requires confirmation by more reliable imaging techniques (CTA/MRA see below) if renal stenosis is suspected

Measurement of bladder wall thickness in a distended bladder and to check for bladder tumours and stones. A scan obtained after voiding allows bladder emptying to be assessed.

The disadvantages of using ultrasonography to assess the urinary tract are:

It does not show detailed pelvicalyceal anatomy

It does not fully visualize the normal adult ureter

It may miss small renal calculi and does not detect the majority of ureteric calculi

It is operator-dependent.

In people with suspected benign prostatic hypertrophy, examination of the bladder before and after voiding, with measurement of the prostate, and examination of the kidneys to check for pelvicalyceal dilatation suffice. If prostate cancer is suspected, more detailed ultrasound examination of the prostate with a transrectal transducer, usually with transrectal prostate biopsy, is necessary.

Computed tomography (CT)

Computed tomography is used as a first-line investigation in cases of suspected ureteric colic. Multislice detector CT has both improved image resolution and allows reconstruction of the imaging data in a variety of planes. CT is also used to:

Characterize renal masses which are indeterminate at ultrasonography

Stage renal tumours

Detect ‘lucent’ calculi (low-density calculi which are lucent on plain films, e.g. uric acid stones, are well seen on CT)

Evaluate the retroperitoneum for tumours, retroperitoneal fibrosis (periaortitis) and other causes of ureteric obstruction

Assess severe renal trauma

Visualize the renal arteries and veins by CT angiography

Stage bladder and prostate tumours (MRI is increasingly used instead to stage prostate cancer).

Disadvantages include radiation and contrast nephrotoxicity (p. 614).

The use of unenhanced CT in suspected ureteric colic permits diagnosis of causes of pain other than calculi more readily than does urography.

Magnetic resonance imaging (MRI)

MRI is used:

To characterize renal masses as an alternative to CT

To stage renal, prostate and bladder cancer

To demonstrate the renal arteries by magnetic resonance angiography with gadolinium as contrast medium. In experienced hands its sensitivity and specificity approaches renal angiography.

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