CLS 382 - Lecture 9

Renal Function Tests

 Glomerular function
There are three basic renal processes:
1) Glomerular filtration
2) Tubular reabsorption
3) Tubular secretion

➢ The glomerulus is the 1st part of the

nephron and functions to filter
incoming blood.

➢ Water, electrolytes, and small dissolved solutes (e.g. glucose, amino acids, low-
molecular-weight proteins, urea, and creatinine) can pass freely through the
basement membrane and enter the proximal convoluted tubule.
➢ Other blood constituents are too large to be filtered;
i. many plasma proteins (e.g. albumin)
ii. cellular elements
iii. protein-bound substances (e.g. lipids and bilirubin)
➢ In addition, because the basement membrane is negatively charged, negatively
charged molecules, such as proteins, are repelled.
 Tubular function
I) Proximal Tubule
• The proximal tubule is the next part of the nephron to receive the now cell-free
and essentially protein-free blood.
• This filtrate contains waste products, which are toxic to the body above a certain
concentration, and substances that are valuable to the body.
• The 1st function of the proximal tubule is reabsorption; to return the bulk of each
valuable substance back to the blood circulation;
➢ 75% of the water, Na+, and Cl-
➢ 100% of the glucose (up to the renal threshold)
➢ almost all of the amino acids, vitamins, and proteins
➢ varying amounts of urea, uric acid, and ions (e.g. Mg2+, Ca2+, K+, and HCO3-).
• When the concentration of the filtered substance exceeds the capacity of the
transport system, the substance is then excreted in the urine.
• The plasma concentration above which the substance appears in urine is known as
the renal threshold, and its determination is useful in assessing both tubular
function and non-renal disease states.
• A renal threshold does not exist for water because it is always transported
passively through diffusion down a concentration gradient.
• The 2nd function of the proximal tubule is secretion; the movement of substances
from peritubular capillary plasma into the filtrate in the tubular lumen.
• These include products of kidney tubular cell metabolism, such as hydrogen ions,
and drugs, such as penicillin.
II) Loop of Henle
• The loop of Henle is a hairpin-like loop between the proximal tubule and the distal
convoluted tubule.
• This facilitates the reabsorption of water, Na+, and Cl-
• The opposing flows in the loop, the downward flow in the descending limb, and
the upward flow in the ascending limb, is termed a countercurrent flow.
• The ascending limb is relatively impermeable to water
• The descending limb, in contrast, is highly permeable to water and does not
reabsorb sodium and chloride.
• This interaction of water leaving the descending loop and sodium and chloride
leaving the ascending loop to maintain a high osmolality within the kidney medulla
produces hypo-osmolal urine as it leaves the loop.
Distal Tubule
• The distal convoluted tubule is much shorter than the proximal tubule, with two or
three coils that connect to a collecting duct.
• The filtrate entering this section of the nephron is close to its final composition.
• About 95% of the sodium and chloride ions and 90% of water have already been
reabsorbed from the original glomerular filtrate.
• The function of the distal tubule is to effect small adjustments to achieve
electrolyte and acid-base homeostasis.
• These adjustments occur under the hormonal control of both antidiuretic
hormone (ADH) and aldosterone.

Collecting Duct
• The collecting ducts are the final site for either concentrating or diluting urine.
• The hormones ADH and aldosterone act on this segment of the nephron to control
reabsorption of water and sodium. Chloride and urea are also reabsorbed here.
• Urea plays an important role in maintaining the hyper-osmolality of the renal
medulla.
 Elimination of Non-protein Nitrogen Compounds
• Nonprotein nitrogen compounds (NPNs) are waste products formed in the body as
a result of the degradative metabolism of nucleic acids, amino acids, and proteins.
• Excretion of these compounds is an important function of the kidneys.
• The three principal NPNs are urea, creatinine, and uric acid
I) Urea
• Urea makes up the majority (more than 75%) of the NPN waste excreted daily as a
result of the oxidative catabolism of protein.
• Urea synthesis occurs in the liver. Proteins are broken down to amino acids, which
are then deaminated to form ammonia.
• Ammonia is readily converted to urea to prevent toxicity.
• The kidney is the only significant route of excretion for urea.
• Urea has a molecular weight of 60 Da and, therefore, is readily filtered by the
glomerulus.
• In the collecting ducts, 40%–60% of urea is reabsorbed. The reabsorbed urea
contributes to the high osmolality in the medulla, which is one of the processes of
urinary concentration (Loop of Henle).
 II) Creatinine
• Muscle contains creatine phosphate, a high-energy compound for the rapid
formation of adenosine triphosphate (ATP).
• This reaction is catalyzed by creatine kinase (CK) and is the first source of metabolic
fuel used in muscle contraction;
Creatine phosphate + ADP + H+ ⎯CK → creatine + ATP ←nonenzymatic → creatinine
• Every day, up to 20% of total muscle creatine (and its phosphate) spontaneously
dehydrates and cycles to form the waste product creatinine.
• Therefore, creatinine levels are a function of muscle mass and remain approximately
the same in an individual from day-to-day unless muscle mass or renal function
changes.
• Creatinine has a molecular weight of 113 Da and is, therefore, readily filtered by the
glomerulus.
• Unlike urea, creatinine is not reabsorbed by the tubules. However, a small amount
of creatinine is secreted by the kidney tubules at high serum concentrations.
 III) Uric Acid
• Uric acid is the primary waste product of purine metabolism.
• The purines, adenine and guanine, are precursors of nucleic acids ATP and
guanosine triphosphate (GTP), respectively.
• Uric acid has a molecular weight of 168 Da.
• Like creatinine, it is readily filtered by the glomerulus, but it then undergoes a
complex cycle of reabsorption and secretion as it courses through the nephron.
• Only 6%–12% of the original filtered uric acid is finally excreted. Uric acid exists in
its ionized and more soluble form, usually sodium urate, at urinary pH 5.75 (the
first pKa of uric acid).
• At pH < 5.75, it is undissociated. This fact has clinical significance in the
development of urolithiasis (formation of calculi) and gout.
 Glomerular disease
I) Acute Glomerulonephritis
• Is often related to recent infection by group A β-hemolytic streptococci.
• Circulating immune complexes trigger a strong inflammatory response in the
glomerular basement membrane, resulting in a direct injury to the glomerulus itself.
• Other possible causes include:
➢ drug-related exposures
➢ acute kidney infections due to other bacterial (and, possibly, viral) agents
➢ other systemic immune complex diseases (e.g. systemic lupus erythematosus (SLE)
and bacterial endocarditis).

• Histologic examination shows large, inflamed glomeruli with a decreased capillary

lumen.
• Abnormal laboratory findings usually include:
➢ rapid onset of hematuria and proteinuria
➢ rapid development of a decreased GFR, anemia
➢ elevated blood urea nitrogen (BUN) and serum creatinine
➢ oliguria
➢ sodium and water retention (with consequent hypertension and some localized
edema)
➢ congestive heart failure (sometimes)
➢ Numerous hyaline and granular casts are generally seen on urinalysis. The actual RBC
casts are regarded as highly suggestive of this syndrome.
II) Chronic Glomerulonephritis
• Lengthy glomerular inflammation may lead to glomerular scarring and the eventual loss
of functioning nephrons.
• This process often goes undetected for lengthy periods because only minor decreases in
renal function occur at first with only slight proteinuria (<3 g/day) and hematuria.
• Gradual development of uremia (or azotemia, excess nitrogen compounds in the blood)
may be the first sign of this process.

III) Nephrotic Syndrome

• Nephrotic syndrome can be caused by several different diseases that result in injury and
increased permeability of the glomerular basement membrane.
• This defect almost always yields several abnormal findings, such massive proteinuria
(>3.5 g/day) and resultant hypoalbuminemia.
• The subsequent decreased plasma oncotic pressure causes a generalized edema as a
result of the movement of body fluids out of vascular and into interstitial spaces.
• Other hallmarks of this syndrome are hyperlipidemia and lipiduria.
• Lipiduria takes the form of oval fat bodies in the urine.
• These bodies are degenerated renal tubular cells containing reabsorbed lipoproteins.
• Primary causes are associated directly with glomerular disease states.
 Tubular disease
• As the GFR falls, tubular defects may present in the progression of all renal diseases.
• Acute inflammation of the tubules and surrounding interstitium may occur as a result of
analgesic drug or radiation toxicity, methicillin hypersensitivity reactions, renal
transplant rejection, and viral-fungal-bacterial infections.
• The result would be:
➢ decreased excretion/reabsorption of certain substances or
➢ reduced urinary concentrating capability.
• Clinically, the most important defect is renal tubular acidosis (RTA), the primary tubular
disorder affecting acid-base balance.
• This is classified into two types, depending on the nature of the tubular defect:
➢ Distal RTA, in which the renal tubules are unable to keep up the vital pH
gradient between the blood and tubular fluid
➢ Proximal RTA, in which there is decreased bicarbonate reabsorption, resulting
in hyperchloremic acidosis
In general, reduced reabsorption in the proximal tubule is manifested by:
- abnormally low serum values for phosphorus and uric acid
- glucosuria and aminoaciduria
- proteinuria (usually <2 g/day)
 Renal failure
Acute renal failure Chronic kidney disease
• a sudden, sharp decline in renal • a clinical syndrome that occurs
function as a result of an acute when there is a gradual decline in
toxic or hypoxic insult to the renal function over time
kidneys
• Early detection and treatment are
• defined as occurring when the needed to prevent progression to
GFR is reduced to <10mL/minute. the uremic syndrome or end-stage
renal disease (ESRD) and
• This syndrome is subdivided into complications such as CVD.
three types, depending on the
location of the precipitating • increases in diabetes, obesity,
defect; metabolic syndrome and the aging
population all contribute to
i. Pre-renal failure increasing incidence of CKD.
ii. Primary renal failure • Diabetes mellitus has profound
iii. Post-renal failure effects on the renal system.
 Acute renal failure
I) Prerenal failure (in the blood supply before it reaches the kidney);
Causes can include cardiovascular system failure and consequent hypovolemia.
II) Primary renal failure (involves the kidney itself);
The most common cause is acute tubular necrosis; other causes include vascular
obstructions/inflammations and glomerulonephritis.
III) Post renal failure (in the urinary tract after it exits the kidney);
Occurs as a consequence of lower urinary tract obstruction or rupture of the
urinary bladder.
• Toxic insults to the kidney that are severe enough to initiate acute renal failure
include;
➢ hemolytic transfusion reactions
➢ myoglobinuria due to rhabdomyolysis
➢ heavy metal/solvent poisonings
➢ antifreeze ingestion
➢ analgesic and aminoglycoside toxicities
• These conditions directly damage the renal tubules.
• The most commonly observed symptoms of acute renal failure are oliguria and
anuria (<400 mL/day).
• The diminished ability to excrete electrolytes and water results in a significant
increase in extracellular fluid volume, leading to peripheral edema,
hypertension, and congestive heart failure.
• Most prominent, however, is the onset of the uremic syndrome or ESRD, in
which increased BUN and serum creatinine values are observed along with the
preceding symptoms.

• The outcome of this disease is either;

➢ recovery
or
➢ in case of irreversible renal damage,
progression to chronic renal failure.
 Renal function tests
Blood tests Urine tests
1) Blood Urea Nitrogen (BUN) 1) Urinalysis
- Urea nitrogen comes from the breakdown of 2) Creatinine Clearance
protein - Creatinine clearance test compares the creatinine in
- Normal BUN levels are between 7 and 20 mg/dL a 24-hr sample of urine to the creatinine level in your
(2.5-6.4 mmol/L urea) blood to show how much waste products the kidneys
are filtering out each minute.
- As kidney function decreases, BUN levels rise;
elevated level of urea in the blood is called - Reported as milliliters of creatinine per minute per
body surface area (mL/min/BSA).
azotemia
- Very high levels of plasma urea accompanied by - The typical range for men, 19 to 75 years old, is 77 to
160 mL/min/BSA.
renal failure is called uremia or the uremic
syndrome; eventually fatal if not treated by dialysis - The typical range, for creatinine clearance in women
declines by age:
2) Serum Creatinine 18 to 29 years: 78 to 161 mL/min/BSA
- Creatinine usually enters your bloodstream and is 30 to 39 years: 72 to 154 mL/min/BSA
filtered from the bloodstream at a generally 40 to 49 years: 67 to 146 mL/min/BSA
constant rate. 50 to 59 years: 62 to 139 mL/min/BSA
60 to 72 years: 56 to 131 mL/min/BSA
- The amount of creatinine in blood should be
relatively stable. An increased level of creatinine 3) Urine Protein
may be a sign of poor kidney function. - This may be done as part of a urinalysis or by a
- The typical range for serum creatinine are: separate dipstick test. Excess amount of protein in
the urine is called proteinuria.
Men 0.74 to 1.35 mg/dL (65.4 to 119.3 μmoles/L)
- A positive dipstick test (1+ or greater) should be
Women, 0.59 to 1.04 mg/dL (52.2 to 91.9 μmoles/L) confirmed using a more specific dipstick test such as
an albumin specific dipstick or a quantitative
3) Glomerular Filtration Rate (GFR) measurement such as an albumin-to-creatinine ratio.
 Renal function tests
Glomerular function Tubular function
• The first step in urine formation is the filtration • Compared with the GFR as an assessment of
of plasma at the glomeruli. glomerular function, there is no easily performed
test that measure tubular function quantitatively.
• Glomerular filtration rate (GFR) is defined as
the volume of plasma from which a given • Urine osmolality serves as a general marker of
substance is completely cleared by glomerular tubular function.
filtration per unit time. • This is because of all the tubular functions, the
• This is approximately 140 mL/min in a healthy one most frequently affected by disease is the
adult, but varies enormously with body size ability to concentrate urine.
• Conventionally, it is corrected to a body surface • Water is reabsorbed if:
area (BSA) of 1.73 m2; so the units are 1) Renal tubules and collecting ducts are
(mL/min/1.73 m2). working efficiently
• Creatinine clearance estimates the 2) AVP is sufficient
measurement of urinary excretion of creatinine
by means of a timed urine collection • Measuring urine concentration helps to assess
how well it can do that.
• It calculates the volume of plasma that would
have to be completely ‘cleared’ of creatinine • This is conveniently done by determining urine
during the time of collection in order to give the osmolality, and then comparing it to the plasma.
amount seen in the urine. • If the urine osmolality is 600 mmol/kg or more,
• Urinalysis is important in screening for disease tubular function is usually regarded as intact.
(not renal disease only); examination of a • When the urine osmolality does not differ greatly
patient’s urine is important and should not be from plasma (urine : plasma osmolality ratio ≈ 1),
restricted to biochemical tests. the renal tubules are not reabsorbing water.
 Urinalysis
• A complete urinalysis consists of three
distinct testing phases:
1) Visual examination
evaluates urine color and clarity
2) Chemical examination
tests chemically about 9 substances
that provide valuable information about
health and disease and determines the
concentration of the urine
3) Microscopic examination
- identifies and counts types of cells,
casts, crystals, and other components
like bacteria and mucus in urine.
- typically performed when there is an
abnormal finding on the visual or
chemical examination, or if it is
specifically ordered by a practitioner.
Urine can be collected at any time. In some cases, a first morning sample may be requested
because it is more concentrated and more likely to detect abnormalities.
 eGFR
• Serum creatinine is also utilized in GFR estimating equations such as:
1) The MDRD equation (Modified Diet in Renal Disease)
2) The CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration)
• These eGFR equations are superior to serum creatinine alone since they include
confounding factors like: age, sex, ethnic origin and body mass in its
calculations.
• Kidney Disease Improving Global Outcomes (KDIGO) stages of chronic kidney
disease (CKD):
➢ Stage 1 GFR greater than 90 ml/min/1.73 m²
➢ Stage 2 GFR-between 60 to 89 ml/min/1.73 m²
➢ Stage 3a GFR 45 to 59 ml/min/1.73 m²
➢ Stage 3b GFR 30 to 44 ml/min/1.73 m²
➢ Stage 4 GFR of 15 to 29 ml/min/1.73 m²
➢ Stage 5 GFR less than 15 ml/min/1.73 m² (end-stage renal disease)