Kidney and urinary tract disease

Chapter 12 Kidney and urinary tract disease




Functional anatomy


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.







Renal arteries and arterioles

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.



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.






Renal function



Physiology


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



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).



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 concentration and the countercurrent system

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.



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















































Production Elimination

Increased by


Increased by


High-protein diet


Elevated GFR, e.g. pregnancy


Increased catabolism


Surgery


Decreased by


Infection


Glomerular disease


Trauma


Reduced renal blood flow


Corticosteroid therapy


Hypotension


Tetracyclines


Dehydration


Gastrointestinal bleeding


Urinary obstruction


Cancer


Tubulointerstitial nephritis


Decreased by


 


Low-protein diet


 


Reduced catabolism, e.g. old age


 


Liver failure


 


GFR, glomerular filtration rate.


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).



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.



image



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.



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.




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).




Investigation of tubular function in clinical practice


Various tubular mechanisms could theoretically be investigated, but, in clinical practice, tests of tubular function are required less often than glomerular function.


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.


Retinol-binding protein and β2-microglobulin are normally reabsorbed by the proximal tubule, and their urinary excretion is nonspecifically increased by diseases of the proximal tubule.


Two tests of distal tubular function are commonly applied in clinical practice:



These tests are dealt with on page 993 and page 665.




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:



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



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.



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.



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).





Autocrine function





Prostaglandins

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).





Nitric oxide and the kidney

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:





Investigations



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.









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.





Imaging techniques






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:



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



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.



Mar 31, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Kidney and urinary tract disease
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