Download Acute renal failure

An Introduction to the Urinary System
1. Excretion &
Elimination:
–
removal of organic
wastes and waste
products from body
fluids
2. Homeostatic
regulation:
–
of blood plasma
volume and solute
concentration
3. Enocrine function:
-
Hormones
Homeostatic Functions of Urinary System
1. Regulate blood volume and blood pressure:
– by adjusting volume of water lost in urine
– releasing erythropoietin and renin
2. Regulate plasma ion concentrations:
– sodium, potassium, and chloride ions (by controlling
quantities lost in urine)
– calcium ion levels
3. Help stabilize blood pH:
– by controlling loss of hydrogen ions and bicarbonate
ions in urine
4.
Conserve valuable nutrients:
– by preventing excretion while excreting organic waste
products
5. Assist liver to detoxify poisons
The excretory function
 Mechanism for excretion of excess electrolytes,
nitrogenous wastes and organic acids are similar.
 The maximal excretory rate is limited or established by
their plasma concentrations and the rate of their filtration
through the glomeruli
 The maximal amount of substance excreted in urine does
not exceed the amount transferred through the glomeruli
by ultrafiltration except in the case of those substances
capable of being secreted by the tubular cells.
 The primary objective in evaluation of renal excretory
function is to detect quantitatively the normal capacities
or the improvement of impaired ones.
The regulatory function
 Kidneys has a major role in homeostasis. The
glomerular filtrate passes into the proximal
convoluted tubule where much of it is reabsorbed.
 Under normal circumstances, all the glucose, amino
acids, potassium and bicarbonate, and about 75%
of sodium, is reabsorbed isotonically here by
energy dependent mechanisms.
The endocrine function
 Kidneys have primary endocrine function since they produce hormones
 In addition, the kidneys are site of degradation for hormones such as insulin
and aldosterone.
 In their primary endocrine function, the kidneys produce erythropoietin, renin
and prostaglandin.
 Erythropoietin is secreted in response to a lowered oxygen content in the
blood. It acts on bone marrow, stimulating the production of red blood cells.
 Renin the primary stimuli for renin release include reduction of renal
perfusion pressure and hyponatremia. Renin release is also influenced by
angiotension II and ADH.
 It is a key stimulus of aldosterone release. The effect of aldosterone is
predominantly on the distal tubular network, effecting an increase in sodium
reabsorption in exchange for potassium.
 The kidneys are primarily responsible for producing vitamin D3 from
dihydroxycholecalciferol.
Each kidney consists of one million functional
units: Nephrone
Tubular reabsorption
 As the filtrate passes through the renal tubules, about 99 percent of
it is reabsorbed into the blood.
 Only about 1 percent of the filtrate actually leaves the body (about 1.5
liters a day).
 Materials that are reabsorbed include water, glucose, amino acids,
urea, and ions such as Na+, K+, Ca2+ , Cl-, HC03 -, and HPO3- .
 Tubular reabsorption allows the body to retain most of its nutrients.
 Wastes such as urea are only partially reabsorbed.
 Reabsorption is carried out through both passive and active transport
mechanisms.
 Glucose and amino acids are reabsorbed by an active process cotranspotred with (Na+) ions.
 Normally, all the glucose filtered by the glomeruli (125 mg/l00 ml of
filtrate/min) is reabsorbed by the tubules.
Water reabsorption is driven by sodium transport.
As Na + ions are transported from the proximal convoluted tubules into the blood,
the osmotic pressure of the blood becomes higher than that of the filtrate. Water
follows the Na + ions into the blood in order to reestablish the osmotic equilibrium
 80 percent of the water is reabsorbed by this method from the proximal
convoluted tubule and it sis called obligatory water reabsorption.
The descending limb of the loop of the nephron is passively permeable to the
passage of water while ascending part chloride and more sodium without water are
reabsorbed, generating a dilute urine. In the distal tubule secretion is the
prominent activity.
Passage of most of the remaining water in the filtrate can be regulated.
The permeability of the cells of the distal and collecting tubules is controlled by
the antidiuretic hormone (ADH), produced by the hypothalamus and released into
the blood by the pituitary gland
When osmotic pressure is increased  osmoreceptors in the hypothalamus detect
the stimulus and secrete more ADH  increases the permeability of the plasma
membranes of the distal tubule and collecting tubule cells  more water
molecules pass into the cells and then into blood.
Tests for renal function
 The kidneys’ excretory, regulatory and endocrine roles show complex
interactions.
 The composition of blood and urine reflects not only functional
disorders of the nephron but also various systemic disorders.
To evaluate kidney status in renal disease the following are tested:
1. The nephron functions of glomerular filtration.
2. The secretary capacity for particular endogenous and exogenous
compounds.
3. The kidney’s re-absorptive capacity for water and electrolytes as
manifested by the urine-concentrating ability of the kidneys.
•
Biochemical Tests of Renal
Function
Measurement of GFR
– Clearance tests
– Plasma creatinine
– Urea, uric acid and β2-microglobulin
• Renal tubular function tests
–
–
–
–
Osmolality measurements
Specific proteinurea
Glycouria
Aminoaciduria
• Urinalysis
– Appearance
– Specific gravity and osmolality
– pH
– Glucose
– Protein
– Urinary sediments
Biochemical Tests of renal function
 Diseases affecting the kidneys can selectively damage
glomerular or tubular function
 In acute and chronic renal failure, there is effectively a
loss of function of whole nephrons
 Filtration is essential to the formation of urine  tests of
glomerular function are almost always required in the
investigation and management of any patient with renal
disease.
The most frequently used tests are those that assess
either the GFR or the integrity of the glomerular filtration
barrier.
Measurement of glomerular filtration rate
 GFR can be estimated by measuring the urinary excretion of a substance that is
completely filtered from the blood by the glomeruli and it is not secreted,
reabsorbed or metabolized by the renal tubules.
 Clearance is defined as the (hypothetical) quantity of blood or plasma completely
cleared of a substance per unit of time.
 Clearance of substances that are filtered exclusively or predominantly by the
glomeruli but neither reabsorbed nor secreted by other regions of the nephron can
be used to measure GFR.
 Inulin (a plant polysaccharide) can be used.
The Volume of blood from which inulin is cleared or completely removed in one minute
is known as the inulin clearance and is equal to the GFR.
Measurement of inulin clearance requires the infusion of inulin into the blood and is
not suitable for routine clinical use
The most frequently used clearance test is based on the measurement of creatinine.
V is not urine volume, it is urine flow rate
(Uinulin  V)
GFR =
Pinulin
Creatinine clearance and clinical utility
 Creatinine released into body fluids at a constant rate and its plasma
levels maintained within narrow limits  Creatinine clearance may be
measured as an indicator of GFR.
 The most frequently used clearance test is based on the measurement
of creatinine.
 Small quantity of creatinine is reabsorbed by the tubules and other
quantities are actively secreted by the renal tubules  So creatinine
clearance is approximately 7% greater than inulin clearance.
The difference is not significant when GFR is normal but when the GFR is
low (less 10 ml/min), tubular secretion makes the major contribution to
creatinine excretion and the creatinine clearance significantly
overestimates the GFR.
Creatinine clearance clinical utility
An estimate of the GFR can be calculated from the creatinine content
of a 24-hour urine collection, and the plasma concentration within this
period.
The volume of urine is measured, urine flow rate is calculated (ml/min)
and the assay for creatinine is performed on plasma and urine to obtain
the concentration in mg per dl or per ml.
Creatinine clearance in adults is normally about of 120 ml/min,
The accurate measurement of creatinine clearance is difficult, especially
in outpatients, since it is necessary to obtain a complete and accurately
timed sample of urine
Plasma creatinine
Plasma creatinine concentration is inversely related to the GFR
 The reference range for plasma creatinine in the adult
population is 60-120 μmol/L,
But GFR can decrease by 50% before plasma creatinine
concentration rises beyond the normal range this means that a
normal plasma creatinine does not necessarily imply normal renal
function,
A Raised creatinine usually indicates impaired renal function
Changes in plasma creatinine concentration can occur,
independently of renal function, due to changes in muscle mass.
 Decrease can occur as a result of starvation and in wasting
diseases, immediately after surgery.
Use of Formulae to Predict Clearance
• Formulae have been derived to predict Creatinine
Clearance (CC) from Plasma creatinine.
• Plasma creatinine derived from muscle mass
which is related to body mass, age, sex.
• Cockcroft & Gault Formula
CC = k[(140-Age) x weight(Kg))] / Creatinine (µmol/L)
k = 1.224 for males & 1.04 for females
• Modifications required for children & obese subjects
• Can be modified to use Surface area
Plasma Urea (BUN): Blood Urea Nitrogen
 Urea is the major nitrogen-containing metabolic product of protein
catabolism in humans
 Its elimination in the urine represents the major route for nitrogen
excretion.
 More than 90% of urea is excreted through the kidneys, with losses
through the GIT and skin
 Urea is filtered freely by the glomeruli
 But it is moves passively out of the renal tubule and into the
interstitium, ultimately to re-enter plasma
 Plasma urea concentration is often used as an index of renal
glomerular function
 Urea production is increased by a high protein intake and it is
decreased in patients with a low protein intake or in patients with
liver disease.
Plasma Urea
 Many renal diseases with various glomerular, tubular, interstitial or vascular
damage can cause an increase in plasma urea concentration.
Measurement of plasma creatinine provides a more accurate assessment
than urea because there are many factors that affect urea level.
Non-renal factors can affect the urea level (normal adults is level 5-39
mg/dl) like:
Mild dehydration,
high protein diet,
increased protein catabolism, muscle wasting as in starvation,
reabsorption of blood proteins after a GIT haemorrhage,
treatment with cortisol or its synthetic analogous
decreased perfusion of the kidneys may cause azotemia (increased blood
urea) that is called prerenal azotemia. Impaired perfusion may be due to
decreased cardiac output or shock secondary to blood loss or other causes.
The key to identifying the azotemia as prerenal is the increase of
plasma urea without parallel increase of plasma creatinine.
Postrenal azotemia is caused by conditions that obstruct urinary outflow
through the ureters, bladder or urethra.
 With obstruction, both plasma urea and creatinine increase, but there
is greater rise of urea than of creatinine because the obstruction of
urine flow  backpressure on the tubule and back diffusion of urea into
blood from the tubule.
Clinicians frequently calculate a convenient relationship, the urea
nitrogen/creatinine ratio:
Serum urea nitrogen (mg / dl)
Serum creatinine (mg / dl)
For a normal person on a normal diet, the reference interval for
the ratio ranges between 12 and 20.
Factors affecting the ratio of plasma urea to creatinine are:
Causes of abnormal plasma urea to creatinine ratio
Urea tubular reabsorption increases at low rates of urine flow (e.g. in fluid depletion)
and this can cause increased plasma urea concentration even when renal function is
normal.
Reference intervals
The reference interval for serum urea of healthy adults is 5-39 mg/dl. Plasma
concentrations also tend to be slightly higher in males than females. High protein diet
causes significant increases in plasma urea concentrations and urinary excretion.
Urea (in mmol/L) = BUN (in mg/dL of nitrogen) / 2.8
Uric acid
Renal handling of uric acid is complex and involves four sequential steps:
Glomerular filtration of virtually all the uric acid in capillary plasma
entering the glomerulus.
Reabsorption in the proximal convoluted tubule of about 98 to
100% of filtered uric acid.
Subsequent secretion of uric acid into the lumen of the distal
portion of the proximal tubule.
Further reabsorption in the distal tubule.
 The net urinary excretion of uric acid is 6 to 12% of the amount
filtered.
 The pka of uric acid is 5.57; above this pH, uric acid exists mainly as
urate ion, which is more soluble than uric acid. At a urine pH below 5.75,
uric acid is the predominant form.
Clinical Significance of Uric acid
 Hyperuricemia is defined by serum or plasma uric acid concentrations higher
than 7.0 mg/dl (0.42mmol/L) in men or greater than 6.0 mg/dl (0.36mmol/L)
in women.
 Gout occurs when monosodium urate precipitates from supersaturated body
fluids;
 Gouty arthritis may be associated with urate crystals in joint fluid as well as
with deposits of crystals (tophi) in tissues surrounding the joint.
 The deposits may occur in other soft tissues as well, and wherever they occur
they elicit an intense inflammatory response.
Renal disease associated with hyperuricemia may take one or more of several
forms:
 Gouty nephropathy with urate deposition in renal parenchyma.
 Acute intratubular deposition of urate crystals.
 The formation of crystal aggregates in the urinary tract results in kidney
stones: about 20 % patients with gout also has urinary tract urate stones.
Plasma β2-microglobulin
β2-microglobulin is a small peptide (molecular weight 11.8 kDa),
It is present on the surface of most cells and in low
concentrations in the plasma.
It is completely filtered by the glomeruli and is reabsorbed and
catabolized by proximal tubular cells.
The plasma concentration of β2-microglobulin is a good index of
GFR in normal people, being unaffected by diet or muscle mass.
It is increased in certain malignancies and inflammatory diseases.
Since it is normally reabsorbed and catabolized in the tubules,
measurement of β2-microglobulin excretion provides a sensitive
method of assessing tubular integrity.
•
Biochemical Tests of Renal
Function
Measurement of GFR
– Clearance tests
– Plasma creatinine
– Urea, uric acid and β2-microglobulin
• Renal tubular function tests
– Osmolality measurements
– Specific proteinuria
– Glycouria
– Aminoaciduria
• Urinalysis
– Appearance
– Specific gravity and osmolality
– pH
– Glucose
– Protein
– Urinary sediments
Renal tubular function tests
•
The glomeruli provide an efficient filtration mechanism for ridding
the body of waste products and toxic substances
•
To ensure that important constituents such as water, sodium, glucose
and a.a. are not lost from the body, tubular reabsorption must be
equally efficient
180 liters of fluid pass into the glomerular filtrate each day, and
more than 99% of this is recovered
•
Compared with the GFR as an assessment of glomerualr function,
there are no easily performed tests which measure tubular function
in quantitative manner
•
Investigation of tubular function:
1. Osmolality measurements in plasma and urine; normal urine: plasma
osmolality ratio is usually between 1.0-3.0
2. Specific proteinuria
3. Glycosuria
4. Aminoaciduria
Assessment of glomerular integrity
 Injury of glomerular integrity results in the filtration of large molecules which
are normally retained and is marked as proteinuria: the appearance of abnormal
quantity of protein in the urine.
Proteinuria may be due to:
1. An abnormality of the glomerular basement membrane.
2. Decreased tubular reabsorption of normal amounts of filtered proteins.
3. Increased plasma concentrations of free filtered proteins.
4. Decreased reabsorption and entry of protein into the tubules consequent
to tubular epithelial cell damage.
Measurement of individual proteins such as β2-microglobulin have been used
in the early diagnosis of tubular integrity.
With severe glomerular damage, red blood cells are detectable in the urine
(haematuria), the red cells often have an abnormal morphology in glomerular
disease.
 Haematuria can occur as a result of lesions anywhere in the urinary tract,
Proteinuria
The glomerular basement membrane does not usually allow
passage of albumin and large proteins. A small amount of albumin,
usually less than 25 mg/24 hours, is found in urine.
When larger amounts, in excess of 250 mg/24 hours, are
detected, significant damage to the glomerular membrane has
occurred.
Quantitative urine protein measurements should always be made
on complete 24-hour urine collections.
Albumin excretion in the range 25-300 mg/24 hours is termed
microalbuminuria
Proteinuria
– Normal < 200 mg/24h.
– Causes: • overflow (raised plasma Low MW Proteins, Bence Jones, myoglobin)
• glomerular leak
• decreased tubular reabsorption of protein (RBP, Albumin)
• protein renal origin
•
Biochemical Tests of Renal
Function
Measurement of GFR
– Clearance tests
– Plasma creatinine
– Urea, uric acid and β2-microglobulin
• Renal tubular function tests
– Osmolality measurements
– Specific proteinuria
– Glycouria
– Aminoaciduria
• Urinalysis
– Appearance
– Specific gravity and osmolality
– pH
– Glucose
– Protein
– Urinary sediments
Urinalysis
Urinalysis is important in screening for disease is routine test for every
patient, and not just for the investigation of renal diseases
Urinalysis comprises a range of analyses that are usually performed at the point
of care rather than in a central laboratory.
Urinalysis is one of the commonest biochemical tests performed outside the
laboratory.
 Examination of a
patient's urine should
not be restricted to
biochemical tests.
Urinalysis using disposable strips
Biochemical testing of urine involves the use of commercially available disposable
strips When the strip is manually immersed in the urine specimen, the reagents
react with a specific component of urine in such a way that to form color
 Colour change produced is proportional to the concentration of the component
being tested for.
To test a urine sample:
fresh urine is collected into a clean dry container
the sample is not centrifuged
 the disposable strip is briefly immersed in the urine specimen;
The colour of the test areas are compared with those provided on a colour
chart
Urinalysis
•
•
Fresh sample = Valid sample.
 fresh urine is collected into a clean dry container
 the sample is not centrifuged
Appearance: – Blood
– Colour (haemoglobin, myoglobin,)
– Turbidity (infection, nephrotic syndrome)
Causes of colouration
in urine
Blue Green
Pink-OrangeRed
Red-brown-black
Methylene Blue Haemoglobin
Haemoglobin
Pseudomonas Myoglobin
Myoglobin
Riboflavin
Phenolpthalein
Red blood cells
Porphyrins
Homogentisic Acid
Rifampicin
L -DOPA
Melanin
Methyldopa
•
Urinalysis: Specific gravity : – This is a semi-quantitative measure of concentration.
–
A higher specific gravity indicates a more concentrated urine.
– Assessment of urinary specific gravity usually just confirms the
impression gained by visually inspecting the colour of the urine. When
urine concentration needs to be quantitated,
– Urinalysis: Osmolality measurements in plasma and urine
– Osmolality serves as general marker of tubular function. Because the
ability to concentrate the urine is highly affected by renal diseases.
– This is conveniently done by determining the osmolality, and then
comparing this to the plasma.
– If the urine osmolality is 600mmol/kg or more, tubular function is
usually regarded as intact
– When the urine osmolality does not differ greatly from plasma (urine:
plasma osmolality ratio=1), the renal tubules are not reabsorbing water
Urinalysis
• pH: – Urine is usually acidic
– Measurement of urine pH is useful in:
• suspected drug toxicity, abuse..,
• or where there is an unexplained metabolic acidosis (low serum
bicarbonate or other causes…).
– Many tightly regulated mechanisms affect the blood hydrogen ion
concentration normal H+ excretion via renal tubules by
– disruption of one of these mechanisms  an acidosis (so-called renal
tubular acidosis or RTA).
– Measurement of urine pH is used to screen for RTA in unexplained
metabolic acidosis.
Urine sediments
Microscopic examination of sediment from freshly passed urine involves
Looking for cells, casts, fat droplets
 Blood: haematuria is consistent with various possibilities ranging from
malignancy through urinary tract infection to contamination from
menstruation.
 Red Cell casts could indicate glomerular disease
Crystals
Leucocytes in the urine suggests acute inflammation and the presence of a
urinary tract infection.
Proteinuria
The glomerular basement membrane does not usually allow passage of
albumin and large proteins. A small amount of albumin, usually less than 25
mg/24 hours, is found in urine.
When larger amounts, in excess of 250 mg/24 hours, are detected,
significant damage to the glomerular membrane has occurred.
Red blood cell cast in urine
White blood cell cast in urine
Urinary casts. (A)
Hyaline cast (200 X);
(B) erythrocyte cast (100
X); (C) leukocyte cast
(100 X); (D) granular
cast (100 X)
Urinary crystals. (A) Calcium oxalate crystals (arrows; 100
X); (B) uric acid crystals (100 X); (C) triple phosphate
crystals with amorphous phosphates (400 X); (D) cystine
crystals (100 X)
Urine volume
-
Water homeostasis is determined by several interrelated
processes:
1. Water intake and water formed through oxidation of food stuffs.
2. Extra-renal water loss: insensible water loss the via faeces, and
sweating.
3. A solute load to be excreted that is derived from ingested minerals
and nitrogenous substances.
4. The ability of the kidneys to produce concentrated or dilute urine.
5. Other factors such as vomiting and diarrhoea become important in
various disease states;
loss of ability to produce concentrated urine is a feature of
virtually all types of chronic renal diseases.
Urine volume
To maintain water homeostasis, the kidneys must produce urine in a
volume precisely balances water intake and production to equal water
loss through extra renal routes.
 Minimum urine volume is determined by the solute load to be excreted
whereas maximum urine volume is determined by the amount of excess
water that must be excreted
Causes of polyurea
Increased osmotic load, e.g due to glucose
Increased water ingestion
Diabetes insipidus: - Failure of ADH production results in marked polyuria
(diabetes insipidus), which stimulates thirst and greatly increases water
intake
Nephrogenic diabetes insipidus: The kidneys’ lack of response to ADH has
similar effect ( failure of the tubules to respond to Vassopressin (ADH))
Bilirubin
•
Bilirubin exists in the blood in two forms, conjugated water soluble and
unconjugated.
•
Bilirubinuria indictaes the presence of conjugated bilirubin in urine.
•
This is always pathological.
•
Conjugated bilirubin is normally excreted through the biliary tree into the gut
mechanical obstruction  results in high levels of conjugated bilirubin in the
systemic circulation excreted into the urine.
Urobilinogen
•
In the gut, conjugated bilirubin is broken down by bacteria to urobilinogen, or
stercobilinogen.
•
Urobilinogen is found in the systemic circulation and is often detectable in the
urine of normal subjects. Thus the finding of urobilinogen in urine is of less
diagnostic significance than bilirubin.
•
High levels are found in any condition where bilirubin turnover is increased, e.g.
haemolysis, or where its enterohepatic circulation is interrupted by, e.g. liver
damage.
Ketones
• Ketones are the products of fatty acid breakdown.
• Their presence usually indicates that the body is using fat to
provide energy rather than storing it for later use.
• This can occur in uncontrolled diabetes, where glucose is unable to
enter cells (diabetic ketoacidosis), in alcoholism (alcoholic
ketoacidosis), or in association with prolonged fasting or vomiting.
Nitrite
• This test depends on the conversion of nitrate (from the diet) to
nitrite by the action in the urine of bacteria that contain the
necessary reductase
• A positive result points towards a urinary tract infection.
Renal disorders:
• Many renal diseases are defined in terms of their clinical presentation
and structural change. Aetiology and pathophysiology of many disorders
are not well defined
• Renal failure is the impairment of kidney function:
• In acute renal failure (ARF): the kidneys fail rapidly over a period of
hours or days, producing the syndrome of acute renal failure. This is
potentially reversible and normal renal function can be recovered.
• Chronic renal failure (CRF) develops gradually over months or years and
is irreversible  leading eventually to end-stage renal failure (ESRF)
• Patient with end-stage renal failure require long-term renal replacement
treatment (i.e., dialysis) or a successful renal transplant in order to
survive.
Signs and Symptoms of Renal
Failure
• Symptoms of Uraemia (nausea, vomiting, lethargy)
• Disorders of Micturation (frequency, retention, nocturia (is the
need to get up during the night in order to urinate, thus
interrupting sleep), dysuria (difficult or painful discharge of
urine))
• Disorders of Urine volume (polyuria: excessive urination,
oliguria: decreased production of urine, anuria: absent urine
production)
• Alterations in urine composition (haematuria, proteinuria,
bacteriua, leukocyturia, calculi)
• Pain
• Oedema (hypoalbuminaemia, salt and water retention)
Acute renal failure
• Acute renal failure is characterized by a rapid loss of renal function,
with retention of urea, creatinine, hydrogen ions and other
metabolic products and usually oliguria (less than 400 ml
urine/24hrs).
• The term ‘uraemia’ (meaning ‘urine in blood’) is often used as a
synonym for renal failure (both acute and chronic).
• Azotemia refers to an increase in the blood concentration of
nitrogenous compounds mainly urea.
• ARF could be reversible. But its consequences to homeostatic
mechanisms are so dangerous  associated with high mortality.
• Acute renal failure often develops in patients who are already
severely ill.
• ARF arises from a variety of problems affecting the
kidneys and/or their circulation.
• It usually presents as a sudden deterioration of renal
function indicated by rapidly rising serum urea and
creatinine concentrations. As acute renal failure is common
in the severely ill, sequential monitoring of kidney function
is important for early detection in this group of patients.
• Usually, urine output falls to less than 400 ml/24 hours, and
the patient is said to be oliguric.
• The patient may pass no urine at all, and be anuric.
•
Occasionally urine flow remains high when tubular
dysfunction predominates.
Types of Acute renal failure
•
Acute kidney failure or uraemia is conventionally divided into three
categories :
•
Pre-renal: the kidney fails to receive a proper blood supply (a decrease in
renal blood flow).
• Post-renal: the urinary drainage of
the kidneys is impaired because of an
obstruction (urinary tract
obstruction).
•Renal: intrinsic damage to the
kidney tissue. This may be due to a
variety of diseases, or the renal
damage may be a consequence of
prolonged pre-renal or post-renal
problems, it is called acute tubular
necrosis.
Prerenal acute renal failure
• This is caused by circulatory insufficiency and decreased plasma
volume, as sever haemorrhage, burns, fluid loss as in prolonged
vomiting, or diarrhoea, cardiac failure or hypotension  decrease
renal perfusion  induces intense renal vasoconstriction  decrease
in GFR but tubular function is normal.
• Prerenal uraemia is a result of normal physiological response to
hypovolaemia or a fall in blood pressure. Stimulation of the reninangiotensin-aldosterone system and vassopressin secretion results in
production of a small volume of highly concentrated urine with a low
sodium concentration.
• Prerenal uraemia may progress into intrinsic failure (acute tubular
necrosis)  it should be treated before structural damage.
Biochemical findings in pre-renal uraemia include the following:
 Decreased GFR and normal renal tubular function result in retention
of substances normally excreted by filtration, such as urea and
creatinine. Serum urea and creatinine are increased.
 Urea is increased proportionally more than creatinine because of its
reabsorption by the tubular cells, particularly at low urine flow rates.
This leads to a relatively higher serum urea concentration than
creatinine that is not so reabsorbed.
 The decreased delivery of sodium to the distal tubule impairs hydrogen
ion and potassium excretion; acidosis and hyperkalaemia are
characteristic features of acute renal failure.
 Metabolic acidosis: because of the inability of the kidney to excrete
hydrogen ions.
 Hyperkalaemia: because of the decreased glomerular filtration rate and
acidosis.
 A high urine osmolality.
Postrenal renal failure
• Obstruction to the flow of urine leads to an increase in hydrostatic
pressure  acts in opposition to glomerular filtration  prolonged
obstruction leads to secondary renal tubular damage.
• Causes of obstruction include renal caliculi (renal stones), prostatic
enlargement and other neoplasms of the urinary tract.
• Complete anuria is strongly indicative of the presence of an
obstruction.
• Obstruction may be discontinuous or incomplete and urine production
may even be normal in obstruction with overflow.
• The degree of reversibility of renal damage depends on time of
standing
If these pre- or post-renal factors are not corrected, patients will
develop intrinsic renal damage (acute tubular necrosis).
Intrinsic acute renal failure (Acute tubular necrosis)
• Acute tubular necrosis may develop in the absence of
preexisting pre-renal or post-renal failure. Most causes are
due:
 Nephrotoxins, including several drugs such as
aminoglycosides, some cephalosporins, analgesics or herbal
toxins,
 Renal ischaemia: acute blood loss in severe trauma, septic
shock
 Specific renal disease, such as glomerulonephritis
• All these causes can lead to renal tubular necrosis.
• The pathogenesis is not completely understood.
Biochemical changes in plasma in acute renal failure
• Increased: potassium, urea, creatinine, phosphate, magnesium, hydrogen
ion, urate
• Decreased: sodium, bicarbonate, calcium
•
Hyponatraemia is common; in many patients, water is retained in
excess of sodium..
• Hyperkalaemia occurs as a result of decreased excretion of potassium
together with both a loss of intracellular potassium to ECF (due to
tissue breakdown) and intracellular buffering of retained hydrogen ions.
• Decreased hydrogen ion excretion causes a metabolic acidosis.
Retention of phosphate and leakage of intracellular phosphate into the
interstitial fluid leads to hyperphosphataemia.
• Hypermagnesaemia is also often present as a result of decreased
magnesium excretion.
• Patients in the early stages of acute tubular necrosis may have
only a moderately increased serum urea and creatinine, then they
rise rapidly over a period of days, in contrast to the slow increase
over months and years seen in chronic renal failure.
• The biochemical features that distinguish pre-renal uraemia from
intrinsic renal damage
Management of ARF
•
Important issues in the management of the patient with ARF include:
 Correction of pre-renal factors e.g giving fluid in the case of decreased ECF, in
cardiac failure, inotropic agents may be indicated.
 Relieving the obstruction if present.
 Treatment of the underlying disease (e.g. to control infection).
 If oliguria persists and acute tubular necrosis is diagnosed  minimize the sever
adverse consequences of renal failure.
 The general principles of treatment include: strict control of sodium and water
intake, to prevent overload; nutritional support (low protein) minimize
nitrogenous compounds; prevention of metabolic complication, such as
hyperkalaemia and acidosis, and prevention of infection. Avoid the use of
potentially nephrotoxic drugs.
 Monitor the patient’s plasma creatinine, sodium, potassium, bicarbonate, calcium
and phosphate concentrations, urinary volume and sodium and potassium
excretion.
 Dialysis: in case of rapidly rising serum potassium concentration, severe acidosis,
and fluid overload.
Chronic renal failure
• Many diseases lead to progressive, irreversible,
impairment of renal function  decrease in the
number of functional nephrons  progression to endstage renal failure, where dialysis or transplantation
becomes necessary to save the patient’s life.
• The time between presentation and end-stage renal
failure is very variable; it may be a matter of weeks or
as long as several years.
• The major pathological and clinical features are similar
in all patients with chronic renal failure, whatever the
cause.
The important metabolic features of end-stage renal
failure are:
 Impairment of urinary concentration and dilution: the
urine specific gravity tends to be fixed.
 Impairment of electrolyte and hydrogen ion homeostasis
 Retention of waste products of metabolism
 Impaired vitamin D metabolism
 Decreased erythropoietin synthesis
 Disturbances of sodium balance
 Hyperkalaemia is a late feature of chronic renal failure;
it may be precipitated by a sudden deterioration in renal
function or by use of potassium-sparing diuretics.
• Patients with chronic renal failure tend to be acidotic because of
decreased phosphate excretion, and decreased ammonia synthesis,
impaired bicarbonate reabsorbtion,
• Most patients with chronic renal failure become hypocalcaemic and
many develop renal osteodystrophy (is a bone disease that occurs
when kidneys fail to maintain the proper levels of calcium and
phosphorus ).
• Retention of phosphate causes a tendency to hyperphosphataemia
• Decreased testosterone and oestrogen synthesis; abnormalities of
thyroid function tests, and abnormal glucose tolerance with
hyperinsulinaemia due to insulin resistance.
• Anaemia (a normochromic normocytic anaemia) is usual in end-stage
renal failure, due to depression of bone marrow function by retained
toxins and a decrease in the renal production of erythropoietin.
Management of chronic renal failure
• Identification and subsequent treatment of the cause of chronic renal
failure may prevent, or at least delay, further deterioration, before
dialysis or transplantation becomes necessary,
• Diuretics are often used to promote sodium excretion since adequate
dietary salt restriction may be unacceptable to the patient.
• Bicarbonate can be given orally to control acidosis.
• Hyperkalaemia is usually of less significance in chronic than in acute
renal failure, because it develops more slowly.
• Hyperphosphataemia can be controlled by giving aluminium or
magnesium salts by mouth. These will bind phosphate in the gut and
prevents its absorption.
• Some limitation in dietary protein is beneficial to reduce the formation
of nitrogenous waste products,
Proteinuria and the nephrotic syndrome
•
The glomeruli normally filter 7-10 g of protein
/ 24 hours, but almost all is reabsorbed by
endocytosis and subsequently catabolized in
the proximal tubules.
•
Normal urinary protein excretion is less than
about 150 mg/24 h.
•
Approximately half of this is Tamm-Horsfall
protein, a glycoprotein secreted by tubular
cells; less than 30 mg is albumin.
The nephrotic syndrome
•
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged,
causing them to leak large amounts of protein
•
Glomerulonephritis:is a primary or secondary immune-mediated renal disease
characterized by inflammation of the glomeruli, or small blood vessels in the kidneys.
Some types of glomerulonephritis responds to corticosteroids or immunosuppressive
drugs.
•
If large amounts (exceed 5 g/24 h) of protein are excreted in the urine,
Hypoproteinaemia with oedema may develop
•
Much of the filtered protein is catabolized by renal tubular cells and lost from the
circulation, although it is not excreted in the urine.
•
There are two aspects to management: treatment of the underlying disorder, where
the disorder can be identified and treatment is possible, and treatment of the
consequences of protein loss.
•
High protein, low salt diet, high protein intake must be introduced with caution when
there is parallel renal failure.
•
Management of edema using diuretics
•
Prevention of infection is vital and antibiotics are often administered prophylactically.
Specific tubular defects
Renal tubular disorders can be congenital or acquired; they can involve single or
multiple aspects of tubular function
Glycosuria
• The presence of glucose in urine may due to:
– Increased blood glucose( hyperglycemia, exceeding the glucose
reabsorption threshold, as in the case of diabetes mellitus)
– Low renal threshold or other tubular disorders
• Glycosuria when blood glucose is normal usually reflects the inability of
the tubules to reabsorb glucose because of a specific tubular lesion.
• This is called renal glycosuria and is a benign condition.
• Glycosuria can also present in association with other disorders of tubular
function
Renal excretion of amino acids (Aminoaciduria)
•
Amino acids in plasma are filtered by the glomeruli and appear in the
glomerular filtrate in the same proportions as they do in plasma.
•
A great portion of amino acids are reabsorbed by the renal tubular cells
(the proximal tubules) through a process of active transport
•
Thus normal urinary excretion of amino acids is only a small fraction of the
filtered load and is about 50 to 200 mg/day.
•
Amino acids may present in urine in excessive amount because of the
plasma concentration exceeds the renal threshold, or because there is
specific failure of normal tubular reabsorptive mechanisms,
•
Some congenital disorders are characterised by a defect in the
reabsorption of amino acids that results in aminoaciduria.
•
An example of such condition is cystinuria, marked by a failure to
reabsorb dibasic amino acids (cystine, lysine, arginine and ornithine).
The Fanconi syndrome
• The Fanconi syndrome is a term used to describe
the occurrence of generalized tubular defects such
as renal tubular acidosis, aminoaciduria
and tubular proteinuria.
• It can occur as a result
of heavy metal poisoning,
or from the effects of
toxins and inherited
metabolic diseases such as
cystinosis.
Renal function and acid-base disorders
Renal tubular acidosis (RTA):
• In renal disease, a decreased GFR may result in retention of metabolic
acids with resulting acidosis and accumulation of anions such as
phosphates, sulphates, keto acids, amino acids and so on.
• The decreased filtration of phosphates reduces the ability of the body
to remove H+ by formation of dihydrogen phosphate ion (H2PO4-).
• The decreased ability of ammonia (NH3) formation results in the
decreased formation of ammonium ion (NH4+) and the associated
decrease in removal of H+.
• There may also be an impairment of the Na+-H+ exchange, especially in
renal tubular acidosis (RTA).
Renal tubular acidosis (RTA):
Impaired of bicarbonate reabsorption and hydrogen ion excretion in the
renal tubules
• It could be a component of the Fanconi syndrome or isolated
phenomenon.
• RTA is characterized by hyperchloremia, and urinary HCO3- or H+
excretion inappropriate for the plasma pH.
• Hyperchloremia is caused by enhanced Cl- reabsorption stimulated by
contraction of the extracellular volume and retention of H+.
• RTA is the result of loss of bicarbonate: decreased reabsorption by
the proximal tubules
• The aetiology is not always well established.
• Treatment consists of administering large amounts of bicarbonate
Renal stones (Urinary calculi)
•
Renal stones (calculi) are usually composed of products of metabolism
present in normal filtrate at concentrations near their maximum solubility
Minor changes in urinary composition causes precipitation
•
Renal stones produce severe pain and discomfort, and are common causes
of obstruction in the urinary tract
•
Factors predisposing to this are (conditions favouring calculus formation):
1. High urinary concentration of one or more the stone constituents of the
glomerular filtrate, due to:
A. low urinary volume, with normal renal function, because of restricted
fluid intake or excessive fluid loss over a long period of time
(dehydration).
B. high rate of excretion of the metabolic product forming the stone, due
either to a high plasma therefore filtrate levels, or to impairment of
normal tubular reabsorption from the filtrate.
Renal stones (Urinary calculi)
2. Change in pH of the urine, often due to bacterial infection,
which favors precipitation of different salts at different
hydrogen ion concentrations.
3. Urinary stagnation due to obstruction of urinary outflow.
4. Lack of normal inhibitors, such as pyrophosphate, citrate
and glycoproteins, which inhibit the growth of calcium
phosphate and calcium oxalate crystals. The absence of
these compounds in the urine of some patients increases the
risk of calcium stones
Types of stone include:
• Constituents of urinary calculi
1. Calcium-containing salts:
calcium oxalate
calcium phosphate
with or without magnesium ammonium phosphate (‘triple
phosphate’)
2. Uric acid
3. Cystine
4. Xanthine
Uric acid stones
•
About 10% of renal caliculi contain uric acid; these are sometimes associated
with hyperuricaemia, with or without clinical gout. Precipitation is favoured in an
acid urine.
Cystine and xanthine stones
•
Both are rare and may be a result of rare in born error cystinuria and
xanthinuria,
The history and examination may suggest an underlying cause for renal caliculi
Biochemical investigations that should be performed are:
– Analysis of calculus (if available), the most useful test
– Plasma: calcium, urate and phosphate
– Urine: pH, qualitative test for cystine, 24hr excretion of calcium, oxalate
and urate and urinary acidification test.
– The urine must be examined for evidence of infection in all patients
presenting with urinary caliculi.
Management
•
Small calculi are often passed spontaneously.
•
Larger calculi may require surgical removal or disintegration by ultrasound.
•
Any urinary tract infection should be treated.
•
The identification of the cause of urinary calculus formation should make
it possible to design an effective regimen to prevent further stone
formation.
•
In calcium-containing calculi urinary calcium concentration should be
reduced:
– By treating the primary condition, such as urinary infection or
hypercalcaemia.
– If this is not possible, by reducing dietary calcium and oxalate intake.
– By reducing the concentration by maintaining a high fluid intake day and
night, unless there is glomerular failure.
Management
• Hyperurecaemia should be treated with allopurinol. A low purine diet
may help. If the plasma urate concentration is normal, fluid intake
should be kept high and the urine alkalinised.
• The management of cystinuria: cystine may be kept in solution if the
urine is kept sufficiently dilute and alkaline. If calculi continue to form,
penicillamine may be used; the drug complexes with cysteine (from
which cystine is derived) and reduces the urinary excretion of cystine.
• Alkalinisation of the urine increases the solubility of both cystine
and uric acid but may be difficult to achieve. A high fluid intake is
appropriate in all patients with a tendency to form urinary calculi.
• The End
Investigation of low urinary output
Simple hypovolemia
Acute renal failure
Urine osmolality
Usually> 500mmol/kg
Usually < 400mmol/kg
Urine [urea]: plasma [urea]
Usually > 10
Usually < 5
Urine [sodium]
Usually < 20mmol/L
Usually > 40mmol/L
Investigation