Category Archives: Renal disease

Tests for renal disease or malfunction

Renal disease is suspected if there are:
• Symptoms referable to the urinary tract
• Hypertension
• An elevated blood urea or creatinine concentration
• Abnormalities on urinalysis

Relationship between diet. kidney function and urine volume.

Relationship between diet. kidney function and urine volume.

THE URINE

Appearance

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). Very concentrated urine may also appear dark or smoky. Other causes of discoloration of urine include cholestatic jaundice, haemoglobinuria, drugs such as rifampicin, use of fluorescein or methylene blue, and ingestion of beetroot. Discoloration of urine after standing for some time occurs in porphyria, alkaptonuria and in patients ingesting the drug L-dopa. In patients with frequency or dysuria the passage of crystal clear urine usually indicates that significant bacteriuria is absent.

Volume

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 hours. 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. On a normal diet, some 800 mosmol of solute are passed daily. Since the maximum urine concentration is approximately 1200 mosmollitre-1, the minimum volume of urine obligated by excretion of 800 mosmol of solute would thus be approximately 650 ml. Fluid intake is generally greater than this, so that larger volumes of more dilute urine are passed. A diet rich in carbohydrate and fat and low in protein and salt results in a lower solute excretion and as little as 300 ml of urine per day may be required. Conversely, a high-salt, high-protein intake obligates a larger urine flow and, via the thirst mechanism, a higher fluid intake. The appropriateness of a given daily urine output must therefore be related to factors such as diet, body size and fluid intake. In disease, impairment of concentrating ability requires increased volumes of urine to be passed, given the same daily solute output (Table 9.3). An increased solute output, e.g. in glycosuria or increased protein catabolism following surgery or associated with sepsis, also demands increased urine volumes.
The maximum urine output depends on the ability to produce a dilute urine. Intakes of 10 or even 20 litres daily can be tolerated by normal humans but, given a daily solute output of 800 mosmol, require the ability to dilute to 80 and 40 mosmol litre “, respectively. Where diluting ability is impaired, the ability to excrete large volumes of ingested water is also impaired.

Oliguria

Oliguria, usually defined as the excretion of less than 300 ml of urine per day, may be ‘physiological’, e.g. in patients with hypotension and hypovolaemia, where urine is maximally concentrated in an attempt to conserve water. More often, it is due to intrinsic renal disease or obstructive nephropathy. Anuria (no urine) suggests urinary tract obstruction until proved otherwise; bladder outflow obstruction must always be considered first.

Polyuria

Polyuria is a persistent, large increase in urine output, usually associated with nocturia. It must be distinguished from frequency of micturition with the passage of small volumes of urine. Documentation of fluid intake and output may be necessary. Polyuria is the result of an excessive (hysterical) intake of water, an increased excretion of solute (as in hyperglycaemia and glycosuria), or a defective renal concentrating ability or failure of production of ADH.

Specific gravity and osmolality

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. An exception exists when a relatively small number of relatively large particles are present in urine, as occurs in multiple myeloma. Measurement of urine specific gravity or osmolality is only required under limited circumstances, such as the differential diagnosis of oliguric renal failure or the investigation of polyuria or inappropriate ADH secretion.

pH

Measurement of urinary pH is unnecessary except in the investigation and treatment of renal tubular acidosis.

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 to confirm the presence of red cells and so exclude the relatively rare conditions of haemoglobinuria or myoglobinuria. Bleeding may come from any site within the urinary tract:
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. Careful urine microscopy is mandatory as the presence of red-cell casts is diagnostic of bleeding from the kidney, most often due to glomerulonephritis. In the absence of red-cell casts, further investigations, such as urine cytology, intravenous urography and cystoscopy, are required to define the site of bleeding. Renal biopsy may be required.

Protein

Proteinuria is one of the most common signs of renal disease. Detection is now primarily by Stix testing. Most reagent strips can detect a concentration of 150 mg litre-1 or more in urine. They react primarily with albumin and are relatively insensitive to globulin and Bence-lones proteins.
If proteinuria is confirmed on repeated Stix testing, protein excretion in 24-hour urine collections should be measured. Normal values for urinary protein excretion are dependent on the laboratory methods used and in particular whether or not the method measures Tamm-Horsfall glycoprotein, which is a normal constituent of urine. Results must therefore take account of the laboratory’s normal reference range. Given this caveat, healthy adults excrete approximately 60-100 mg of protein daily but up to 150-200 mg daily is within the acceptable range. Slightly higher values-up to 300 mg daily-may be excreted by adolescents. Pyrexia, exercise and adoption of the upright posture all increase urinary protein output. Proteinuria, while occasionally benign, always requires further investigation.

Sites and causes of bleeding from the urinary tract.

Sites and causes of bleeding from the urinary tract.

particular whether or not the method measures Tamm- Horsfall glycoprotein, which is a normal constituent of urine. Results must therefore take account of the laboratory’s normal reference range. Given this caveat, healthy adults excrete approximately 60-100 mg of protein daily but up to 150-200 mg daily is within the acceptable range. Slightly higher values-up to 300 mg daily-may be excreted by adolescents. Pyrexia, exercise and adoption of the upright posture all increase urinary protein output. Proteinuria, while occasionally benign, always requires further investigation.
POSTURAL PROTEINURIA. This term is used to refer to proteinuria present on dipstick testing which becomes undetectable after a period of hours lying flat. Typically, a negative dipstick result is obtained on the first urine passed on rising in the morning, whereas subsequent specimens give a positive result. This is regarded by many-including some insurance companies-as a benign condition. Renal biopsy sometimes discloses glomerular abnormalities but progressive renal failure is rare.

Glucose

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

Bacteriuria

Dipsticks are available for testing for bacteriuria based on detection of nitrite produced from the reduction of urinarynitrate by bacteria. Unfortunately, there is an unacceptable  false-negative detection rate and urine culture is still required.

Microalbuminuria

The term microalbuminuria is an unfortunate one since the albumin referred to is of normal molecular size and weight. Normal urine contains albumin in a concentration of less than 20 mg litre-I. Dipsticks, however, only detect albumin in a concentration around 150 mg litre – I. An increase in albumin between these two levels-socalled microalbuminuria-is now known to be an early indicator of diabetic glomerular disease. It is now widely used as a predictor of the development of nephropathy in diabetics and may be extended to other conditions. Measurement is done by radioimmunoassay. Timed 24-hour urinary excretion may be measured. Microalbuminuria is then defined as an excretion rate between 30 and 150 p.g min-I. Equally reliable results may be more conveniently obtained using random samples in which albumin concentration is related to urinary creatinine concentration (normal range <0.2-2.8 mg of albumin per mmollitre-I creatinine).

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. 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 x 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 the Fanconi syndrome . Tubular defects in the reabsorption of water (nephrogenic diabetes insipidus) or. bicarbonate (proximal renal tubular acidosis) and defective acidification of the urine (distal renal tubular acidosis) are dealt. Investigation of tubular function in clinical practice.

Proximal tubular function

Five tests of proximal tubular function are employed in clinical practice: measurement of serum potassium and serum phosphorus concentrations, and detection of glycosuria, generalized aminoaciduria and ‘tubular’ proteinuria.
Hypokalaemia in the face of a normal or increased urinary potassium excretion (>40 mmol in 24 hours) is indicative of proximal tubular failure of potassium reabsorption. Unless other explanations exist such as treatment with thiazide diuretics or hyperaldosteronism, the defect can be assumed to lie in the proximal tubule. Similarly, hypophosphataemia may be attributed to a proximal tubular abnormality, provided alternative explanations, such as the use of gut phosphorus binders and primary hyperparathyroidism, can be ruled out. Glycosuria in the absence of hyperglycaemia and generalized aminoaciduria are also indicative of failure of proximal tubular reabsorption of glucose and amino acids, respectively. Proteins derived from tubular cells, such as f32- microglobulin, are reabsorbed in the proximal nephron.
If proteinuria is present, and urine electrophoresis shows the characteristic ‘tubular’ as distinct from ‘glomerular’ pattern (i.e. albumin) a proximal tubular defect is demonstrated.

Distal tubular function

Two tests of distal tubular function are commonly applied in clinical practice: measurement of urinary concentrating capacity in response to water deprivation, and measurement of urinary acidification.

ENDOCRINE FUNCTION

Renin-angiotensin system

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 secrete renin, which converts angietensinogen in blood 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
• Local prostaglandin release
Angiotensin II is generated from angiotensin I by angiotensin- converting enzyme (ACE). Angiotensin II is both a vasoconstrictor and the most important stimulus for the release of aldosterone by the adrenal cortex. It also modifies intrarenal blood flow.

Erythropoietin

Erythropoietin is a glycoprotein produced principally by the kidney and is the major stimulus for erythropoiesis. Loss of renal substance, with decreased erythropoietin production, results in a normochromic, normocytic anaemia. Conversely, erythropoietin secretion may be increased, with resultant polycythaemia, in patients with polycystic renal disease, benign renal cysts or renal cell carcinoma.
Recombinant human erythropoietin has now been biosynthesized and is available for clinical use, particularly in patients with renal failure.

Prostaglandins

Prostaglandin E2 is the primary prostaglandin produced by the kidney and is known to be a powerful vasodilator agent. Its precise role in regulating intrarenal blood flow and its interaction with renin release remains unclear. It may also have some direct or indirect role in the renal handling of sodium and water.

Kallikrein-kinin system

The role of this system is not fully understood but it probably also plays a part in the control of the distribution of renal blood flow and in salt and water excretion.

Natriuretic hormones

There is considerable evidence that atrial tissue contains a group of pep tides that contribute to the regulation of sodium balance-atrial natriuretic peptides (ANP). Intravenous infusion of one of these is followed by a marked natriuresis with a rise in GFR and a fall in blood pressure. These pep tides appear to oppose the reninangiotensin system in four ways: reduced renin secretion, reduced aldosterone secretion, opposition to the action of angiotensin II and to the sodium-retaining action of aldosterone on the renal tubule. Their role in the long-term regulation of sodium balance and blood pressure in humans remains to be clarified.
Endopeptidase inhibitors are becoming available and show therapeutic promise as potent new diuretic agents. Vitamin D metabolism.
Naturally occurring vitamin D requires hydroxylation in the liver and again by a Ie-hydroxylase enzyme in the kidney to produce the powerfully metabolically active 1,25-dihydroxycholecalciferol (1,25-(OH)2D3)’ Reduced l o-hydroxylase activity in diseased kidneys results in relative deficiency of 1,25-(OH)2D3′ As a result, gastrointestinal calcium 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 parathyroid hormone (PTH) in response to a given decrement in plasma calcium concentration. Gut calcium malabsorption, which induces a tendency to hypocalcaemia, and relative lack of 1,25-(OH)2D3 contribute therefore to the hyperparathyroidism seen regularly in patients with renal impairment, even of modest degree.

Protein and polypeptide metabolism

It is clear that the kidney is a major site for the catabolism of many small molecular-weight proteins and polypeptides, including many hormones such as insulin, PTH and calcitonin. In renal failure the metabolic clearance of these substances is reduced and their half-life is prolonged. This accounts, for example, for the reduced insulin
requirements of diabetic patients as their renal function declines.

Renal disease

Renal function and structure

The kidneys’ principal role is the elimination of waste material and the regulation of the volume and composition of body fluid . The kidneys have a unique system involving the free ultrafiltration of water and non-protein-bound low-molecular-weight compounds from the plasma and the selective reabsorption and/or excretion of these as the ultra filtrate passes along the tubule.
The functioning unit is the nephron, of which there are approximately one million in each kidney. A conventional diagrammatic representation is shown  and a physiological version. An essential feature of renal function is that a large volume of blood-25% of cardiac output or approximately 1300 ml min-I-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.
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 between 170 and 180 litres of water and unbound small-molecular-weight constituents of blood occurs. The ‘need’ for this high filtration rate relates to the elimination of compounds present in relatively low concentration in plasma (e.g. urea). If these large volumes of ultra filtrate 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 . Further water and sodium chloride are reabsorbed more distally, and fine tuning of salt and water balance is achieved in the distal and collecting tubules under the influence of aldosterone and antidiuretic hormone (ADH). The final urine volume is thus 1-2 litres daily. Calcium, phosphate, and magnesium are also selectively reabsorbed in proportion to need to maintain a normal electrolyte composition of body fluids.

Functions of the kidney.

Functions of the kidney.

The urinary excretion of some compounds is more complicated. For example, potassium is freely filtered at the glomerulus, almost completely absorbed in the proximal tubule, and excreted in the distal tubule and collecting ducts. An important clinical consequence of this is that the ability to eliminate unwanted potassium is less dependent on GFR than is the elimination of urea Dr creatinine. Other compounds filtered and reabsorbed or excreted to a variable extent include urate and many organic acids, including many drugs or their metabolic breakdown products. The more tubular secretion of a compound occurs, the less dependent is elimination on the GFR; penicillin and cephradine are examples of compounds secreted by the tubules.
Tubular function is also critical to the control of acidbase balance. Thus, filtered bicarbonate is largely reabsorbed and hydrogen ion is excreted mainly buffered by phosphate.

The principal parts of the nephron.

The principal parts of the nephron.

Pressures controlling glomerular filtration.

Pressures controlling glomerular filtration.

Glomerular filtration rate

In health the GFR remains remarkably constant owing to intrarenal regulatory mechanisms. In disease, with 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 and 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 blood level of urea or the plasma level of creatinine and in a reduction in measured GFR.

Uraemia

The concentration of urea or creatmme in blood or plasma, respectively, 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 the production rate. 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.
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 blood urea or serum creatinine are within the normal range.
Inulin clearance-the gold standard of physiologists is not practical or necessary in clinical practice. The most widely used measurement is the creatinine clearance.

Factors influencing serum urea levels.

Factors influencing serum urea levels.

The use of 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. This permits the use of 24-hour urine collections, which reduce collection errors, and the measurement of a single serum creatinine value during the 24 hour.

Creatinine clearance versus serum creatinine.

 

 

Creatinine excretion is, however, by both glomerular filtration and tubular secretion, although at normal serum levels the latter is relatively small. As most laboratory methods for measurement of serum creatinine give slight overestimates, the calculation of clearance fortuitously gives a value close to that of inulin.
With progressive renal failure, creatinine clearance may overestimate GFR but, in clinical practice, this is seldom important. Certain drugs-for example cimetidine, trimethoprim, spironolactone and amiloride-reduce tubular secretion of creatinine, leading to a rise in serum creatinine and a fall in measured clearance. Given these observations, creatinine clearance, nevertheless, is a reasonably accurate measure of GFR in those situations in which it is most required-normal or near normal renal function.
Where urine collections are difficult (e.g. with ileal conduits) or deemed inaccurate, the GFR may be measured by the single injection of compounds such as [SICrlEDTA (ethylenediamine tetra-acetic acid), [99ffiTclDTPA (diethylenetriaminepenta-acetic acid) or [‘2SIliothalamate, their excretion being primarily by glomerular filtration. Following intravenous injection of the compound, three blood samples are obtained at 2, 3 and 4 hours (or rather longer intervals if the patient is oedematous or if renal failure is suspected). The GFR may then be calculated from the slope of the exponential fall in blood level of the compound. Urea clearance is not an accurate measure of GFR, particularly when urine flow rate is low, and should not be used as a measure of GFR.

To obtain a timed 24-hour urine collection and to measure creatinine clearance.

To obtain a timed 24-hour urine collection
and to measure creatinine clearance.