Clinical Biochemistry - Lecture 6 Investigation of renal ...

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Investigation of renal function (1) Functions of the kidney - regulation of water, electrolyte and acid-base balance - excretion of the products of protein and nucleic acid metabolism: e.g. urea, creatinine and uric acid. - The kidney are also endocrine organs, producing a number of hormones, and are subject to control by others. Dr.F.AL-Quobaili Clinical Biochemistry - Lecture 6

Transcript of Clinical Biochemistry - Lecture 6 Investigation of renal ...

Investigation of renal function (1)

• Functions of the kidney

- regulation of water, electrolyte and acid-base

balance

- excretion of the products of protein and nucleic

acid metabolism: e.g. urea, creatinine and uric

acid.

- The kidney are also endocrine organs,

producing a number of hormones, and are subject

to control by others.

Dr.F.AL-Quobaili

Clinical Biochemistry - Lecture 6

Dr.F.AL-Quobaili

Dr.F.AL-Quobaili

Glomerular function

Serum creatinine

-The glomerular filtration rate (GFR) is the

volume of plasma from which a given substance

is completely cleared by glomerular filtration per

unit time.

-GFR is 140 ml/min in healthy adult, it is

corrected to a body surface area (BSA) of 1.73

m2, so the units are ml/min/1.73m2.

Dr. F. AL-Quobaili

- Serum creatinine is used as a convenient but insensitive

measure of glomerular function. The reference range of serum

creatinine in adults is 55- 120 μmol/L. Consider an asymptomatic

person who shows a serum creatinine of 130 µmol/L.

- In young woman this might well be abnormal and requires follow up.

- In a muscular young man this is the expected result.

- In an elderly person this may simply reflect the physiological decline of

GFR with age.

Dr. F. AL-Quobaili

- Creatinine clearance

It is the volume of plasma that would have to be completely

`cleared` of creatinine during the time of collection in order to

give the amount seen in the urine.

Volume of plasma = UXV

P

U: urine creatinine concentration; V: volume of urine collected;

P: the plasma concentration of creatinine.

-Estimated GFR (eGFR)

The relatively poor inverse correlation between serum

creatinine and GFR can be improved by taking into account

some of the confounding variable, such as age, sex, ethnic origin

and body weight. The four-variable equation derived from the

Modification of Diet in Renal Disease (MDRD).

Dr.F.AL-Quobaili

Dr.F.AL-Quobaili

Cockcroft and Gault equation

Ccr (mls/min) = 140-Age x Weight (kg)

0.814 x Scr (mmol/l)

Note correction for Women x 0.85

Ccr (mls/min) = 140-Age x Weight X 0.85 (for female)

0.814 x Scr (mmol/l)

Example: Mr U., Age 20, weight 90kg, Scr 140

Estimated Ccr (mls/min) = 140-20 x 90

140 x 0.814

= 95

• Limitations of eGFR

Many hospital laboratories do not report a specific result

when the GFR is greater than 60 ml/min/1.73 m2.

eGFR is less accurate in patients with abnormal body

shape or mass, e.g. muscle wasting, amputees.

The GFR estimated by modification of diet in renal

disease (MDRD) formula is affected by consumption of

meat.

• eGFR- additional observations

To calculate GFR, it is easy to apply the MDRD equation.

Reduced glomerular function, is known to be associated

with cardiovascular risk and subsequent progression to

more sever renal failure.

Dr. F. AL-Quobaili

Dr. F. AL-Quobaili

- Other measures

• Cystatin C is a cysteine protease inhibitor produced by

all nucleated cells. It is a low- molecular- weight protein

(13 kDa) which is freely filtered by the glomerulus and

almost completely reabsorbed and catabolised by the

proximal tubules.

Serum levels of cystatin C are independent of weight,

height, muscle mass, age (over 1 year) or sex, and it has

a stable production rate.

Serum levels correlate well with GFR, performing at

least as well as creatinine, and being less subject to

confounding influences.

• Isotope tests

A number of isotope markers (e.g. 51 Cr-EDTA, 99Tc-DTPA)

are almost entirely cleared from the circulation by

glomerular filtration. They are injected or infused, and the

measurement of their disappearance from the circulation or

appearance in urine can be used to calculate the GFR.

Inulin clearance is widely regarded as the most accurate.

• Proteinuria

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.

Albumin excretion in the range 25 - 300 mg/24 hours is

termed microalbuminuria.

Dr.F.AL-Quobaili

-To ensure that important constituents, such as water,

sodium, glucose and amino acids, are not lost from the

body, tubular reabsorption must be equally efficient.

- Compared with the GFR as an assessment of glomerular

function, there are no easily performed tests that measure

tubular function in a quantitative manner.

Dr.F.AL-Quobaili

Renal tubular function

Tubular dysfunction

- Some disorders of tubular function are inherited.

However, renal tubular damage is much more frequently

secondary to other conditions or insults.

Dr.F.AL-Quobaili

Investigation of tubular function

• Osmolality measurements in plasma and urine.

The function of tubules and collecting ducts to reabsorb

water, can be assessed by measuring urine concentration.

This is conveniently done by determining the osmolality,

and then comparing this to the plasma.

-If the urine osmolality is 600 mmol/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.

Dr. F. AL-Quobaili

• The water deprivation test.

The causes of polyuria are summarized in this table.

- The normal physiological response to water deprivation is

water retention, which minimizes the rise in plasma

osmolality that otherwise be observed.

- The body achieves this water retention by means of AVP,

the action of which on the renal tubules may inferred

from a rising urine osmoality.

- If the urine osmolality rises to 600 mmol/kg or more in

response to water deprivation, diabetes insipidus is

effectively excluded.

- A flat urine osmolality response is characteristically seen

in diabetes insipidus.

- It should be noted that the water deprivation test is

potentially dangerous if there is severe inability to retain

water.

Dr. F. AL-Quobaili

Dr. F. AL-Quobaili

- The test must be terminated if more than 3 L of urine ispassed. An alternative approach, is to fluid restrictovernight and measure the osmolality of urine voided in themorning.

- If the urine osmolality fails to rise in response to waterdeprivation, desmopressin (DDAVP), a synthetic analogue ofAVP, is administered.

- In central diabetes insipidus, the renal tubules respondnormally to the DDAVP and the urine osmolality rises.

- Nephrognic diabetes insipidus is characterized by failure ofthe tubules to respond; the urine osmolality responsereamins flat.

• Urine pH and the acid load test

Renal tubular acidosis (RTA) may be characterized asfollows:

- Type I. There is a defective hydrogen ion secretion in the

distal tubule that may be inherited or acquired.

- Type II. The capacity to reabsorb bicarbonte in the

proximal tubule is reduced.

- Type III. Is a paediatric variant of type I renal tubular

acidosis.

- Type IV. Bicarbonate reabsorption by the renal tubule is

impaired as a consequence of aldosterone deficiency,

aldosternoe receptor defects, or drugs which block

aldosterone action .

If RTA is suspected, a fresh urine specimen should be

collected for measurement of urine pH. The normal response

to a metabolic acidosis is to increase acid excretion, and a

urine pH of less than 5.3 makes diagnosis of RTA unlikely as

the cause of the acidosis.

Dr.F.AL-Quobaili

- An acid load test involves administering ammonium

chloride (NH4Cl) (which makes the blood more acidic) and

measuring the urine pH in serial samples collected hourly

for about 8 hours. In response to the NH4Cl load, urine pH

normally falls to below 5.3 in at least one specimen.

- This test should not be performed in patients who are

already severely acidotic or who have liver disease.

• Specific proteinuria

Glomerular filtrate normally contains about 30 mg protein

/L. Less than 200 mg protein is normally excreted each

day (half of which is Tamm- horsfall mucoprotein, secreted

by tubular cells).

- Glomerular proteinuria occurs when the glomerulus

becomes abnormally leaky.

Dr.F.AL-Quobaili

-Tubular proteinuria occurs when the tubular reabsortption

of protein becomes defective.

Dr.F.AL-Quobaili

Glomerular and tubular proteinuria

Dr.F.AL-Quobaili

Dr.F.AL-Quobaili

• Glycosuria

Glycosuria in the presence of a normal plasma glucose

occurs in proximal tubular malfunction causing a reduced

renal threshold. This can be benign (occur during

pregnancy), or a part of a more generalised disorder (the

Fanconi’s syndrome).

• Aminoaciduria

- Normally, the renal tubules reabsorb all the filtered

amino acids except for small amounts of glycine, serine,

alanine and glutamine.

- Amino aciduria may be due to disease of the renal tubule.Renal aminoaciduria may be due to impairment of one ofthe specific transport mechanisms (e.g. cystinuria).

Dr.F.AL-Quobaili

- Renal amino aciduria may also occur as a nonspecific

abnormality due to generalised tubular damage, together

with reabsorption defects affecting glucose or phosphate,

or both.

Specific tubular defects

- The Fanconi syndromeIt is term used to describe the occurrence of generalized

tubular defects such as renal tubular acidosis,

aminoaciduria and tubular poteinuria.

It may be inherited (e.g. in cystinosis) or secondary of

other disorders (e.g. Heavy metal poisoning, multiple

myeloma).

Dr.F.A-Quobaili

- Renal stones

Acute renal failure

- In acute renal failure (ARF), the kidneys fail over a

period of hours or days. Chronic renal failure (CRF)

develops over months or years and leads eventually to

end-stage renal failure (ESRF).

Clinical Biochemistry - Lecture 4

Dr. F. AL-Quobaili

Aetiology

- ARF arises from a variety of problems affecting the

kidneys and/or their circulation.

Usually, urine output falls to less than 400 ml/24 hours,

and the patients is said to be oliguric or he may be anuric.

Kidney failure or uraemia can be classified as: Pre-renal,

post-renal and renal.

Dr. F. AL-Quobaili

The first step in assessing the patient with ARF is to

identify any pre- or post-renal factors that could be readily

corrected and allow recovery of renal function.

The history and examination of the patient, drug history

and time course of the onset of the ARF, may well provide

important clues.

Biochemical findings in pre-renal uraemia include the

following:

• Serum urea and creatinine are increased. Urea is increased

proportionally more than creatinine because of its

reabsorption by the tubular cells.

• Metabolic acidosis: because of the inability of the kidney to

excrete hydrogen ions.

Dr.F.AL-Quobaili

Diagnosis

• Hyperkalaemia: because of the decreased glomerular

filtration rate and acidosis.

• A high urine osmolality.

Causes of post-renal uraemia include:

• renal stones

• carcinoma of cervix, prostate, or occasionally bladder.

Acute tubular necrosis

It may develop in the absence of pre-existing pre-renal or

post-renal failure. The causes include:

acute blood loss in severe trauma

septic shock

specific renal disease, such as glomerulonephritis

nephrotoxins, such as the aminoglycosides, analgesics or

herbal toxins.Dr. F. AL-Quobaili

Dr. F. AL-Quobaili

• Patients in the early stages of acute tubular necrosis may

have only modestly increased serum urea and creatinine

that then rise rapidly over a period of days.

It may be difficult to decide the reason for a patient`s

oliguria. The biochemical features are shown in this table.

Biochemical features in the differential diagnosis

of the oliguric patient

Intrinsic renal damagePre-renal failureBiochemical feature

> 40 mmol/L< 20 mmol/LUrine sodium

< 3:1> 10:1Urine/serum urea

< 11:1>15:1Urine/plasma osmolality

Important issues in the management of the patient with ARF

include:

Correction of pre-renal factors, if present, by replacement of

any ECF volume deficit.

Treatment of the underlying disease (e.g. to control

infection).

Biochemical monitoring. Assessment of body fluid volume,

serum creatinine and serum potassium.

Dialysis

There may be three distinct phases in the resolving clinical

course of a patient with acute renal failure (These are

illustrated in the following figure).

Dr.F.AL-Quobaili

Management

Recovery

Dr.F.AL-Quobaili

Dr.F.AL-Quobaili

Chronic renal failure

Chronic renal failure (CRF) is the progressive irreversible

destruction of kidney tissue by disease which, if not treated

by dialysis or transplant, will result in the death of the

patient.

Patients may have few if any symptoms until the

glomerular filtration rate falls below 15 ml/minute (i.e. to

10% of normal function).

Consequences of CRF

Sodium and water metabolism

Most CRF patients retain the ability to reabsorb sodium

ions, but the renal tubules may lose their ability to reabsorb

water and so concentrate urine.

Dr. F. AL-Quobaili

Potassium metabolism

Hyperkalaemia is a feature of advanced CRF and poses a

threat to life.

Acid-base balance

As CRF develops, the ability of the kidneys to regenerate

bicarbonate and excrete hydrogen ions in the urine

becomes impaired.

Calcium and phosphate metabolism

The ability of the renal cells to make 1,25-dihydoxy-

cholecalciferol falls as the renal tubular damage

progresses.

- Calcium absorption is reduced and there is a tendency

towards hypocalcaemia.

- PTH is stimulated in an attempt to restore plasma

calcium to normal, and high circulating PTH may have

adverse effects on bone if this is allowed to continue (renal

osteodystrophy).

Dr. F. AL-Quobaili

Dr. F. AL-Quobaili

Erythropoietin synthesis

- Anaemia is often associated with chronic renal disease.

- The normochromic normocytic anaemia is due primarily to

failure of erythropoietin production.

Dr.F.Al-Quobaili

Clinical features

Conservative measures involve:

• Dietary sodium restriction and diuretics may be required

to prevent sodium overload.

• Hyperkalaemia may be controlled by oral ion-exchange

resins (Resonium).

• Hyperphosphataemia may be controlled by oral aluminium

or magnesium salts.

• The administration of hydroxylated vitamin D metabolites

may prevent the development of secondary hyperpara-

thyroidism.

• Dietary restriction of protein, to reduce the formation of

nitrogenous waste products, may give symptomatic impro-

vement.

Dr.F.AL-Quobaili

Management

Most patients with CRF will eventually require dialysis, in

which case these conservative measures must be continued.

In contrast, after a successful kidney transplant, normal

renal function is re-established.

Haemodialysis and peritoneal dialysis will sustain life when

other measures can no longer maintain fluid, electrolyte and

acid-base balance.

Although transplant of a kidney restores almost all of the

renal functions, patients require long-term immunosuppr-

ession.

Dr.F.AL-Quobaili

Dialysis

Renal transplant