Chapter 12 Kidney and urinary tract disease
The kidneys are paired organs, 11–14 cm in length in adults, 5–6 cm in width and 3–4 cm in depth. They lie retroperitoneally on either side of the vertebral column at the level of T12 to L3. The renal parenchyma comprises an outer cortex and an inner medulla. The functional unit of the kidney is the nephron, of which each contains approximately one million. Each nephron is made up of a glomerulus, proximal tubule, loop of Henle, distal tubule and collecting duct. The renal capsule and ureters are innervated via T10–12 and L1 nerve roots, and renal pain is felt over the corresponding dermatomes.
Arterial blood is supplied to the kidneys via the renal arteries, which branch off the abdominal aorta, and venous blood is conveyed to the inferior vena cava via the renal veins. Approximately 25% of humans possess dual or multiple renal arteries on one or both sides. The left renal vein is longer than the right and for this reason the left kidney, where possible, is usually chosen for live donor transplant nephrectomy.
The renal artery undergoes a series of divisions within the kidney (Fig. 12.1) forming successively, the interlobar arteries, which run radially to the corticomedullary junction, arcuate arteries, which run circumferentially along the corticomedullary junction, and interlobular arteries, which run radially through the renal cortex towards the surface of the kidney. Afferent glomerular arterioles arise from the interlobular arteries to supply the glomerular capillary bed, which drains into efferent glomerular arterioles. Efferent arterioles from the outer cortical glomeruli drain into a peritubular capillary network within the renal cortex and then into increasingly large and more proximal branches of the renal vein. By contrast, blood from the juxtamedullary glomeruli passes via the vasa recta in the medulla and then turns back towards the area of the cortex from which the vasa recta originated.
(After Standring S (ed) 2008 Gray’s Anatomy, 40th edn. Edinburgh: Churchill Livingstone).
Vasa recta possess fenestrated walls, which facilitates movement of diffusible substances. The collecting ducts merge in the inner medulla to form the ducts of Bellini, which empty at the apices of the papillae into the calyces. The calyces, in common with the renal pelvis, ureter and bladder, are lined with transitional cell epithelium.
Mesangial cells are believed to be related to macrophages of the reticuloendothelial system and have a phagocytic function and contractile capabilities that can control blood flow and filtration surface area along the glomerular capillaries in response to a host of mediators. They also secrete the mesangial matrix, which provides a skeletal framework for the glomerular capillaries. The glomerular capillary basement membrane lies between the endothelial and the visceral epithelial cells. The latter put out multiple long foot processes which interdigitate with those of adjacent epithelial cells. Together the endothelial cells, basement membrane and epithelial cells form the filtration barrier or sieve (see Fig. 12.12a).
The renal tubules are lined by epithelial cells, which are cuboidal except in the thin limb of the loop of Henle where they are flat. Proximal tubular cells differ from other cells of the system as they have a luminal brush border. The cortical portion of the collecting ducts contains two cell types with different functions, namely principal cells and intercalated cells (see p. 561). Fibroblast-like cells in the renal cortical interstitium have been shown to produce erythropoietin in response to hypoxia (p. 567).
The juxtaglomerular apparatus comprises the macula densa, the extraglomerular mesangium and the terminal portion of the afferent glomerular arteriole (which contains renin-producing granular cells) together with the proximal portion of the efferent arteriole. The macula densa is a plaque of cells containing large, tightly packed cell nuclei (hence the name macula densa; see Fig. 12.2) within the thick ascending limb of the loop of Henle. This anatomical arrangement is such as to allow changes in the renal tubule to influence behaviour of the adjacent glomerulus (tubuloglomerular feedback).
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.
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.
Urine is concentrated by a complex interaction between the loops of Henle, the medullary interstitium, medullary blood vessels (vasa recta) and the collecting ducts (see p. 640). The proposed mechanism of urine concentration is termed ‘the countercurrent mechanism’. The countercurrent hypothesis states that: ‘a small difference in osmotic concentration at any point between fluid flowing in opposite directions in two parallel tubes connected in a hairpin manner is multiplied many times along the length of the tubes’. Tubular fluid moves from the renal cortex towards the papillary tip of the medulla via the proximal straight tubule and the thin descending limb of the loop of Henle, which is permeable to water and impermeable to sodium. The tubule then loops back towards the cortex so that the direction of the fluid movement is reversed in the ascending limb, which is impermeable to water but permeable to sodium. This results in a large osmolar concentration difference between the corticomedullary junction and the hairpin loop at the tip of the papilla, and hence countercurrent multiplication. There is an analogy with heat exchangers.
Since the urine that emerges from the proximal tubule is iso-osmotic, the first nephron segment actually involved in urinary concentration is the descending limb of Henle’s loop. There are two types of descending limbs (Fig. 12.2b).
Both the ascending limb in the outer and inner medulla and the first part of the distal tubule are impermeable to water and urea. Through the Na+/K+/2Cl− cotransporter, the thick ascending limb actively transports sodium chloride, increasing the interstitial tonicity, resulting in tubular dilution with no net movement of water and urea on account of low permeability. The hypotonic fluid under ADH action undergoes osmotic equilibration with the interstitium in the late distal and the cortical and outer medullary collecting duct, resulting in water removal. Urea concentration in the tubular fluid rises on account of low urea permeability. At the inner medullary collecting duct, which is highly permeable to urea and water, especially in response to ADH, the urea enters the interstitium down its concentration gradient, preserving interstitial hypertonicity and generating high urea concentration in the interstitium.
The hypertonic interstitium pulls water from the descending limb of the loop of Henle, which is relatively impermeable to NaCl and urea. This makes the tubular fluid hypertonic with high NaCl concentration as it arrives at the bend of the loop of Henle. Urea plays a key role in the generation of medullary interstitial hypertonicity. The urea that is reabsorbed into the inner medullary stripe from the terminal inner medullary collecting duct is carried out of this region by ascending vasa recta, which deposit urea into the adjacent descending limb of both short and long loops of Henle, thus recycling the urea to the inner medullary collecting tubule. This process is facilitated by the close anatomical relationship that the hairpin loop of Henle and the vasa recta share.
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.
Elevated GFR, e.g. pregnancy
Reduced renal blood flow
Reduced catabolism, e.g. old age
GFR, 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.
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.
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.
Estimation of glomerular filtration rate (GFR)
GFR (mL/min/1.73 m2) = 141 × min (serum creatinine/κ, 1)2 × max (serum creatinine/κ, 1)−1.209 × 0.993Age × 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.
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.
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).
Twenty-four-hour sodium output may be helpful in determining whether a patient is complying with a low-salt diet and in the management of salt-losing nephropathy. Tests of proximal tubular function may be required in the diagnosis of Fanconi’s syndrome or isolated proximal tubular defects (e.g. urate clearance). Bicarbonate, glucose, phosphate and amino acid are all reabsorbed in the proximal tubule. Their presence in the urine is abnormal, and though formal methods of measuring maximal reabsorption are available, they are seldom necessary.
The kidney is a major site for the catabolism of many small-molecular-weight proteins and polypeptides, including many hormones such as insulin, parathyroid hormone (PTH) and calcitonin, by endocytosis carried out by the megalin-cubilin complex in the brush border of proximal tubular cells. In chronic kidney disease the metabolic clearance of these substances is reduced and their half-life is prolonged. This accounts, for example, for the reduced insulin requirements of patients with diabetes as their renal function declines.
A substantial fraction of prescription drugs are handled and eliminated by the kidney. Many of these medications (e.g. penicillins, cephalosporins, diuretics, NSAIDs, antivirals and methotrexate) circulate in the plasma as small organic anions. These organic anions, which are often bound to albumin, are actively eliminated by the proximal tubule of the nephron by an organic anion transporter (OAT) system. The OAT system translocates drugs as well as endogenous substances and toxins.
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:
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:
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.
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.
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).
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.
The endothelins ET-1, ET-2 and ET-3 are a family of similar potent vasoactive peptides that also influence cell proliferation and epithelial solute transport. They do not circulate but act locally. ETs are produced by most types of cells in the kidney. The vascular actions are mediated by two receptors, with ETA (specific for ET-1) mediating vasoconstriction and ETB (responsive to all ETs) causing vasodilatation. Endothelins inhibit sodium and water absorption by suppressing Na+/K+-ATPase and Na+/H+ antiporter activity in the proximal tubule and antagonizing the action of ADH and aldosterone in the collecting duct. Tubular transport actions are mediated by ETB. Endothelins, through vasoconstriction by ETA and salt and water retention via ETB receptors, cause hypertension. Endothelins, mainly through ETA receptors, can also alter cell proliferation and matrix accumulation by increasing tissue inhibitor of metalloproteinase (TIMP), cytokines, fibronectin and collagen. These peptides also stimulate the proliferation of a variety of renal cell types.
Prostaglandins are unsaturated, oxygenated fatty acids, derived from the enzymatic metabolism of arachidonic acid, mainly by constitutively expressed cyclo-oxygenase-1 (COX-1) or inducible COX-2 (see Fig. 15.30). COX-1 is highly expressed in the collecting duct, while COX-2 expression is restricted to the macula densa. Both COX isoforms convert arachidonic acid to the same product, the bioactive but unstable prostanoid precursor, prostaglandin H2 (PGH2). PGH2 is converted to:
They all act through G-coupled transmembrane receptors, maintaining renal blood flow and glomerular filtration rate in the face of reductions induced by vasoconstrictor stimuli such as angiotensin II, catecholamines and α-adrenergic stimulation. In the presence of renal underperfusion, inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs results in a further reduction in GFR, which is sometimes sufficiently severe as to cause acute kidney injury. Renal prostaglandins also have a natriuretic renal tubular effect and antagonize the action of antidiuretic hormone. Renal prostaglandins do not regulate salt and water excretion in normal subjects, but in some circumstances, such as CKD, prostaglandin-induced vasodilatation is involved in maintaining renal blood flow. Patients with CKD are thus vulnerable to further deterioration in renal function on exposure to non-steroidal anti-inflammatory drugs, as are elderly people, in many of whom renal function is compromised by renal vascular disease and/or the effects of ageing upon the kidney. Moreover, in conditions such as volume depletion, which are associated with high renin release (facilitated by prostaglandins), inhibition of prostaglandin synthesis may lead to hyperkalaemia due to hyporeninaemic hypoaldosteronism (since angiotensin II is the main stimulus for aldosterone).
Atrial natriuretic peptides (ANP), a family of varying length forms, are secreted from atrial granules in response to atrial stretch. They produce marked effects on the kidney, increasing sodium and water excretion and glomerular filtration rate. ANP is also a direct vasodilator, lowering BP; it reduces renin release and aldosterone secretion and consequently inhibits angiotensin II synthesis.
Nitric oxide (see Fig. 16.18), a molecular gas, is formed by the action of three isoforms of nitric oxide synthase (NOS; p. 879). The most recognized cellular target of nitric oxide is soluble guanylate cyclase. The stimulation of this enzyme enhances the synthesis of cyclic GMP from GTP. All three isoforms are expressed in the kidney with eNOS in the vascular compartment, nNOS mainly in the macula densa and inner medullary collecting duct, and iNOS in several tubule segments. Nitric oxide mediates the following physiological actions in the kidney:
This is of little value in the differential diagnosis of renal disease except in the diagnosis of haematuria. Overt ‘bloody’ urine is usually unmistakable but should be checked using dipsticks (Stix testing).
In health, the volume of urine passed is primarily determined by diet and fluid intake. In temperate climates it lies within the range 800–2500 mL per 24 h. The minimum amount passed to stay in fluid balance is determined by the amount of solute – mainly urea and electrolytes – being excreted and the maximum concentrating power of the kidneys would be approximately 650 mL.
In diseases such as CKD or diabetes insipidus, impairment of concentrating ability requires increased volumes of urine to be passed, given the same daily solute output. An increased solute output, such as in glycosuria or increased protein catabolism following surgery, also requires increased urine volumes.
Urine specific gravity is a measure of the weight of dissolved particles in urine, whereas urine osmolality reflects the number of such particles. Usually the relationship between the two is close. Measurement of urine specific gravity or osmolality is required only in the differential diagnosis of oliguric renal failure or the investigation of polyuria or inappropriate ADH secretion. Specific gravity is usually fixed at 1.010 in CKD or acute tubular necrosis as compared to pre-renal acute kidney injury and inappropriate ADH secretion where specific gravity is very high – close to 1.025.
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):
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.
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.
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).
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.
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.
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.
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.
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.
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:
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.)
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
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 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: