AZOTEMIA

DEPT BIOCHEMISTRY
Azotemia is an elevation of blood urea nitrogen (BUN) and serum
creatinine levels.

The reference range :

BUN is 8-20 mg/dL,
serum creatinine is 0.7-1.4 mg/dL.
Each human kidney contains approximately 1 million
functional units known as nephrons, which are primarily
involved in urine formation.

Urine formation ensures that the body eliminates the final

products of metabolic activities and excess water in an
attempt to maintain a constant internal environment
(homeostasis).
Urine formation by each nephron involves 3 main processes :
◦ Filtration at the glomerular level
◦ Selective reabsorption from the filtrate passing along the renal
tubules
◦ Secretion by the cells of the tubules into this filtrate

Perturbation of any of these processes impairs the kidney’s

excretory function, resulting in azotemia.
The quantity of glomerular filtrate produced each minute by all
nephrons in both kidneys is referred to as the glomerular filtration
rate (GFR).
On average, the GFR is about 125 mL/min (10% less for women), or
180 L/day.
◦ About 99% of the filtrate (178 L/day) is reabsorbed,
◦ the rest (2 L/day) is excreted.
Measurement of renal function
 Radionuclide
• is the best available test
◦ expensive
◦ not widely available
 serum creatinine concentration and creatinine clearance (CrCl)
 more commonly are used to estimate GFR.
• not sensitive measures of kidney damage :
• substantial renal damage can take place before any decrease in the GFR
occurs
• a substantial decline in the GFR may lead to only a slight elevation in serum
creatinine.
Because of compensatory hypertrophy and hyperfiltration of the remaining healthy
nephrons, an elevation in serum creatinine is apparent only when the GFR falls to
about 60-70 mL/min.

Graph shows relation of glomerular

filtration rate (GFR) to steady-state
serum creatinine and blood urea
nitrogen (BUN) levels. In early renal
disease, substantial decline in GFR
may lead to only slight elevation in
serum creatinine. Elevation in serum
creatinine is apparent only when
GFR falls to about 70 mL/min.
More accurate determinations of GFR require the use of inulin
clearance or a radiolabeled compound (eg, iothalamate).
In practice, the disease process usually can be adequately monitored
by using the estimated GFR (eGFR), which may be obtained with a
number of different methods.
CrCl is best calculated by obtaining a 24-hour collection for creatinine and
volume and then using the following formula:
CrCl (mL/min) = U/P × V

U is the urine creatinine in mg/dL,

P is the serum creatinine in mg/dL
V is the 24-hour volume divided by 1440 (the number of minutes in 24 hours).
An adequate 24-hour collection usually reflects a creatinine generation of 15-
20 mg/kg in women and 20-25 mg/kg in men.
When 24-hour creatinine is measured, the adequacy of the collection must be
established prior to calculation of the creatinine clearance.
Cockcroft and Gault formula,
 a bedside formula that uses the patient’s serum creatinine (mg/dL), age (y), and
lean weight (kg), as follows:
CrCl (mL/min) = [(140 – age) × weight]/(72 × serum creatinine)
For women, the result of the equation is multiplied by 0.85.
Modification of Diet in Renal Disease (MDRD) study.
• also called the Levey formula,
• is now widely accepted
• more accurate than the Cockcroft and Gault formula
• considered an alternative to radioisotope clearance.
pathophysiology
There are three pathophysiologic states in azotemia :
Prerenal azotemia
Intrarenal azotemia
Postrenal azotemia
Prerenal azotemia
Prerenal azotemia refers to elevations in BUN and creatinine levels
resulting from problems in the systemic circulation that decrease
flow to the kidneys.
decreased renal flow stimulates salt and water retention to
restore volume and pressure.
When volume or pressure is decreased, the baroreceptor reflexes
located in the aortic arch and carotid sinuses are activated.
This leads to sympathetic nerve activation, resulting in renal
afferent arteriolar vasoconstriction and renin secretion through
β1 -receptors.
Constriction of the afferent arterioles causes a decrease in intraglomerular
pressure, which reduces the GFR proportionally.
Renin converts angiotensin I to angiotensin II, which, in turn, stimulates
aldosterone release.
Increased aldosterone levels results in salt and water absorption in the
distal collecting tubule.
A decrease in volume or pressure is a nonosmotic stimulus for hypothalamic
production of antidiuretic hormone, which exerts its effect in the medullary
collecting duct for water reabsorption.
Through unknown mechanisms, activation of the sympathetic nervous system
leads to enhanced proximal tubular reabsorption of salt and water, as well as
BUN, creatinine, calcium, uric acid, and bicarbonate.
The net result of these mechanisms of salt and water retention is decreased
output and decreased urinary excretion of sodium (< 20 mEq/L).
Intrarenal azotemia
Intrarenal azotemia, also known as acute renal failure (ARF), renal-renal
azotemia, and acute kidney injury (AKI),
refers to elevations in BUN and creatinine resulting from problems in the
kidney itself.
There are several definitions, including a rise in serum creatinine levels of
about 30% from baseline or a sudden decline in output below 500 mL/day.
If output is preserved, AKI is nonoliguric;
if output falls below 500 mL/day, ARF is oliguric.
Any form of AKI may be so severe that it virtually stops formation; this
condition is called anuria (< 100 mL/day).
The most common causes of nonoliguric AKI :
acute tubular necrosis (ATN),
aminoglycoside nephrotoxicity,
lithium toxicity, and
cisplatin nephrotoxicity.
Normal output in nonoliguric AKI does not reflect a normal
GFR.
Patients may still make 1440 mL/day of urine even when the GFR
falls to about 1 mL/min because of decreased tubular reabsorption.
The pathophysiology of acute oliguric or nonoliguric AKI
depends on the anatomic location of the injury.

In ATN :
epithelial damage leads to functional decline in the ability of the
tubules to reabsorb salt, water, and other electrolytes.
Excretion of acid and potassium is also impaired.
In more severe ATN, the tubular lumen is filled with epithelial
casts, causing intraluminal obstruction and resulting in a declining
GFR.
Acute interstitial nephritis :
 is characterized by inflammation and edema,
 which result in azotemia, hematuria, sterile pyuria, white blood
cell (WBC) casts with variable eosinophiluria, proteinuria, and
hyaline casts.
The net effect is a loss of urinary concentrating ability, with low
osmolality (< 500 mOsm/L), low specific gravity (< 1.015), high
urinary sodium (>40 mEq/L), and, occasionally, hyperkalemia and
renal tubular acidosis.
Glomerulonephritis or vasculitis :
 the presence of hematuria, red blood cells (RBCs), WBCs, granular and cellular casts,
and a variable degree of proteinuria.
Nephrotic syndrome usually is not associated with active inflammation and often presents
as proteinuria greater than 3.5 g/24 h.
Glomerular diseases :
reduce GFR by changing basement membrane permeability and stimulating the renin-
aldosterone axis.
nephrotic syndrome : the urinary sediment is inactive, and there is gross proteinuria (>3.5
g/day), hypoalbuminemia, hyperlipidemia, and edema. Azotemia and hypertension are
uncommon initially, but their presence may indicate advanced disease.
In nephritic syndrome :
the urinary sediment is active with WBC or RBC casts, granular
casts, and azotemia.
Proteinuria is less obvious, but increased salt and water retention in
glomerulonephritis can lead to hypertension, edema formation,
decreased output, low urinary excretion of sodium, and increased
specific gravity.
In addition to accumulation of urea creatinine and other waste products,
a substantial reduction in GFR in CKD results in the following:

Decreased production of erythropoietin (causing anemia) and vitamin D-3

(causing hypocalcemia, secondary hyperparathyroidism, hyperphosphatemia, and
renal osteodystrophy)
Reduction in acid, potassium, salt, and water excretion (causing acidosis,
hyperkalemia, hypertension, and edema)
Platelet dysfunction (leading to increased bleeding tendencies)
The syndrome associated with the signs and symptoms of accumulation of
toxic waste products (uremic toxins) is termed uremia and often occurs at a
GFR of about 10 mL/min. Some of the uremic toxins (eg, urea, creatinine,
phenols, and guanidines) have been identified, but none have been found
responsible for all the manifestations of uremia.
 Postrenal azotemia
Postrenal azotemia refers to elevations in BUN and creatinine levels
resulting from obstruction in the collecting system.
Obstruction to flow leads to reversal of the Starling forces
responsible for glomerular filtration.
Progressive bilateral obstruction causes hydronephrosis with an
increase in the Bowman capsular hydrostatic pressure and
tubular blockage that leads to progressive decline in and ultimate
cessation of glomerular filtration, azotemia, acidosis, fluid overload,
and hyperkalemia.
Unilateral obstruction rarely causes azotemia.
 There is evidence that if complete ureteral obstruction is relieved within 48
hours of onset, relatively complete recovery of GFR can be achieved within a
week; little or no further recovery occurs after 12 weeks.
 Complete or prolonged partial obstruction can lead to tubular atrophy and
irreversible renal fibrosis.
Hydronephrosis may be absent if obstruction is mild or acute or if the collecting
system is encased by retroperitoneal tumor or fibrosis.
etiologi

Prerenal azotemia occurs as a consequence of impaired renal blood

flow or decreased perfusion resulting from decreased blood volume,
decreased cardiac output (congestive heart failure), decreased
systemic vascular resistance, decreased effective arterial volume from
sepsis or hepatorenal syndrome, or renal artery abnormalities.
It may be superimposed on a background of chronic renal failure.
Iatrogenic factors, such as excessive diuresis and treatment with ACE
inhibitors, should be ruled out.
Intrarenal azotemia :
occurs as a result of injury to the glomeruli, tubules, interstitium, or
small vessels.
It may be acute oliguric, acute nonoliguric, or chronic.
Systemic disease, nocturia, proteinuria, loss of urinary
concentrating ability (low urine specific gravity), anemia, and
hypocalcemia are suggestive of chronic intrarenal azotemia.
Postrenal azotemia :
occurs when an obstruction to urine flow is present.
It is observed in bilateral ureteral obstruction from tumors or stones,
retroperitoneal fibrosis, neurogenic bladder, and bladder neck
obstruction from prostatic hypertrophy or carcinoma and posterior
urethral valves.
It may be superimposed on a background of chronic renal failure.