KIDNEY FUNCTION

TEST ESSENTIALS
HANDBOOK

Amer Wahed, MD
Table of contents
Abbreviation list 3

Renal physiology
Reviewing the excretory function of the kidneys 5
Mastering the endocrine function of the kidneys 9

Assessing kidney function

Measuring serum creatinine 13
Estimating glomerular filtration rate 15
Recognizing the superiority of cystatin C 18
Analyzing an abnormal glomerular filtration rate 19
Reviewing the importance of blood urea nitrogen 21

Urinalysis
Assessing the appearance of urine 24
Performing a urine dipstick exam 28
Examining the microscopic appearance of urine sediment 34
Exploring urine casts and crystals 39
Evaluating proteinuria 43
Reviewing specific urinalysis findings 49

Acute and chronic kidney diseases

Identifying acute renal failure 53
Diagnosing chronic kidney diseases 57
Staging chronic kidney disease 61

Appendix
Reference list 65

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Abbreviation list
ACE angiotensin-converting enzyme
ACR albumin-creatinine ratio
ADH antidiuretic hormone
AIP acute intermittent porphyria
BUN blood urea nitrogen
Cl- chlorine
CKD chronic kidney disease
eGFR estimated glomerular filtration rate
EPO erythropoietin
GFR glomerular filtration rate
H+ hydrogen
HCO3 -
bicarbonate
H2O water
K+ potassium
kDa kilodalton
MDRD Modification of Diet in Renal Disease
Na+ sodium
NH3 ammonia
NH4Cl ammonium chloride

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 Chapter 1

RENAL PHYSIOLOGY

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Reviewing the excretory function of the
kidneys
Let’s get familiar with the kidneys, a paired organ system located in the
retroperitoneal space. To perform their important roles, the kidneys receive
approximately 25% of the body’s cardiac output, and each kidney weighs
approximately 150 g.

What are the physiological roles of the kidney?

The kidneys have three very important physiological roles:
1. Excretory function
2. Regulatory function
3. Endocrine function

Excretory function
Through urine formation, the kidneys remove undesirable end products of
metabolism, such as excess dietary inorganic ions, drugs, and toxins from the
body. Two of the main end products of metabolism are dealt with or excreted via
the kidney:
1. Urea (from protein catabolism)
2. Uric acid (from nucleic acid metabolism)

Regulatory function
The kidneys’ second role is their regulatory function. The kidneys maintain the
proper acid-base balance in the body.

Endocrine function
The third role of the kidneys is their endocrine function. The kidneys produce
certain hormones such as erythropoietin and renin. They are also responsible for
the activation of several hormones.

Five components of a nephron and their functions

The functional unit of the kidney is the nephron, which contains five main
components:
1. Glomerulus
2. Proximal tubule

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3. Loop of Henle
4. Distal tubule
5. Collecting duct

Glomerulus
The glomerulus is where filtration occurs. The basement membrane of the
capillaries in the glomerulus serves as a barrier to the passage of large proteins
into the glomerular filtrate.

Molecules with a molecular weight of more than 15 kilodalton (kDa) cannot pass
through the basement membrane and are therefore not found in the glomerular
filtrate. Typically, the volume of the glomerular filtrate ranges from 150–200 L
per day.

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Proximal tubule
Approximately two-thirds of the filtrate volume is reabsorbed in the proximal
tubule, so the volume of urine produced is only 1–2 L per day. Approximately
90% of the hydrogen ions are secreted by the kidney for acid-base balance, and
this takes place in the proximal tubule.

Loop of Henle
The loop of Henle is the site where urine is concentrated.

Distal tubule
At the distal tubule, sodium and chloride are reabsorbed while potassium and
hydrogen ions are excreted. The proper function of the distal tubule is essential
in maintaining plasma acid-base and electrolyte homeostasis.

Collecting duct
The collecting duct is the site of further water reabsorption which occurs under
the influence of antidiuretic hormone (ADH).

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How do we assess the excretory function of the kidney?
The glomerular filtration rate (GFR) is a laboratory measure that tells us how
many nephrons are functioning inside the kidney to assess whether there is a
problem with kidney function.

To assess how well the kidney is removing waste products from the blood, we
can look at the blood levels of metabolites that should be cleared by the kidney
and compare these to the levels we would expect to see in a person with normal
kidney function.

Here are three common metabolites that are used to assess renal function:
1. Plasma creatinine
2. Urea
3. Cystatin C

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Mastering the endocrine function of the
kidneys
The kidneys produce two hormones and the active form of one vitamin:
1. Erythropoietin (EPO)
2. Renin
3. Active vitamin D

What does erythropoietin do?

The hormone erythropoietin plays a key role in the production of red blood
cells, which carry oxygen from the lungs to the rest of the body. Erythropoietin
is produced in response to renal hypoxia, and it acts on the bone marrow to
stimulate erythropoiesis.

What does renin do?

The hormone renin mediates the volume of extracellular fluid in the body, and
it mediates arterial vasoconstriction. There is a series of events that take
place in order for renin to have these effects, which are referred to as the renin-
angiotensin-aldosterone system:
1. Renin is produced by the juxtaglomerular cells, which are modified smooth
muscle cells located in the arterioles of the kidney.
2. Angiotensinogen is released by the liver and converted by renin into
angiotensin I.
3. In the lungs, angiotensin I is converted into angiotensin II by angiotensin-
converting enzyme (ACE).
4. Angiotensin II is a vasoconstrictor and stimulates the release of aldosterone
from the adrenal cortex.
5. Aldosterone (a mineralocorticoid) acts on the distal tubule and collecting
duct of the nephron causing the retention of water and sodium as well as the
excretion of potassium and hydrogen ions.

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What does vitamin D do?
The kidneys are also responsible for producing the active form of vitamin D.
Vitamin D is a fat-soluble vitamin essential for the absorption of calcium in the
intestines.

Calcium is needed by the body to build bones and teeth. It is also important for
blood clotting and muscle contraction.

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Vitamin D deficiency results in inadequate calcium levels which can cause two
major conditions:
1. Osteomalacia in adults
2. Rickets in children

In the presence of sunlight, human skin can synthesize an inactive form of

vitamin D, called vitamin D3. Very few foods naturally contain vitamin D, so many
foods are fortified with vitamin D3.

Inactive vitamin D3, obtained either from skin exposure to the sun or food, is
converted first in the liver and then by the kidneys into the active form of vitamin
D that is used by the body.

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 Chapter 2

ASSESSING KIDNEY
FUNCTION

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Measuring serum creatinine
Creatine is synthesized in the kidneys, liver, and pancreas. It is transported
in the blood to other organs, especially the brain and muscle, where it is
phosphorylated to phosphocreatine. Phosphocreatine is a high-energy
compound and interconversion of phosphocreatine to creatine is important for
muscle function.

Creatinine is the waste product derived from creatine and phosphocreatine.

Creatinine production is related to the muscle mass of an individual. The higher
the muscle mass, the greater the creatinine production. Women usually excrete
1.2 g of creatinine per day, while men excrete 1.5 g per day.

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What affects serum creatinine?
Serum creatinine levels are affected by five factors:
1. Gender
2. Age
3. Weight
4. Lean body mass
5. Dietary protein intake

Creatinine is filtered and excreted by the kidney, so plasma creatinine is inversely

related to the glomerular filtration rate (GFR). However, GFR can decrease by up
to 50% before plasma creatinine concentration rises above the normal range.

As GFR decreases, plasma creatinine

increases, but creatinine may still be
normal even when GFR has dropped
up to 50%.

Three main takeaways regarding the interpretation of plasma

creatinine
There are three things to consider when interpreting plasma creatinine levels:
1. A normal plasma creatinine does not necessarily mean renal function is
normal.
2. Changes in creatinine levels can occur without a change in renal function
(for example, due to a change in muscle mass).
3. In pregnancy, the level of creatinine typically falls due to an increase in GFR.

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Estimating glomerular filtration rate
Glomerular filtration is one of the major functions of the kidney. The glomerular
filtration rate (GFR) is the sum of the filtration rates in all the functioning
nephrons. Therefore, the GFR gives an estimate of the number of functioning
nephrons and it is important in assessing overall kidney function.

What factors affect GFR?

The normal value for GFR depends upon three factors:
1. Age
2. Sex
3. Body size

The GFR is approximately 130 mL / min / 1.73 m2 for men and 120 mL / min /
1.73 m2 for women. However, there is considerable variation even among normal
individuals.

How is GFR calculated?

GFR can be estimated by using the formula:

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The glomerular filtration rate formula is more accurate when using a formula that
also takes into account body surface area:

What solute is used?

An ideal solute to be used for the calculation of GFR is one that is freely filtered
by the glomerulus and is neither secreted nor reabsorbed by the tubules. Inulin is
an inert chemical that meets these criteria, and it is the gold standard. However,
clinical labs do not usually have the ability to measure inulin.

Creatinine is the next best alternative for estimating the GFR. Creatinine is
produced in the body at a constant rate and is freely filtered and not reabsorbed,
although a small amount of creatinine is secreted by the tubules.

In order to calculate GFR based on creatinine clearance, a 24-hour urine collection

is recommended which should be from one morning void to the next morning void.
However, accurately collecting all urine produced in a 24-hour period is difficult.

So, how do we estimate GFR?

Estimation of GFR can be done using the plasma creatinine concentration and
relevant formulas. However, it is also important to consider the age, sex, and
race of the patient when performing such a calculation.

This calculated value is known as the estimated glomerular filtration rate or

eGFR and the objective is to make the eGFR as accurate as possible. Many
calculations can be used to estimate GFR, and each has its own advantages and
disadvantages.

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The Cockcroft-Gault formula
In the United States, one of the most common formulas used for calculating
eGFR is the Cockcroft-Gault formula:

The Modification of Diet in Renal Disease (MDRD) formula

Another formula called the Modification of Diet in Renal Disease, or MDRD
formula, is a modified version of the Cockcroft-Gault formula. This equation is
reasonably accurate in non-hospitalized patients known to have chronic kidney
disease (CKD), regardless of diagnosis.

Which formula should I use?

The MDRD equation cannot be used for acute renal failure. It is only useful in
estimating glomerular filtration rate in stable, chronic kidney disease.

The MDRD study equation and Cockcroft-Gault equation appear to be somewhat

less accurate in obese individuals and individuals with normal or near-normal
GFR. There are also several other equations that can be used to calculate eGFR,
including one specifically for children.

We need to be aware of these formulas, but don’t worry about memorizing

them. Most of the time, software will perform the calculations for you, but it is
important that you are aware that different formulas exist, each with distinct
advantages and disadvantages.

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Recognizing the superiority of cystatin C
Cystatin C is a low molecular weight protein (13.3 kilodaltons) that can be used
for calculating the glomerular filtration rate or GFR. The normal value of plasma
cystatin C is 0.5–1.0 mg / L.

Normal range of plasma cystatin C

0.5–1.0 mg / L

There are several reasons why cystatin C is a superior marker for the estimation
of GFR:
1. Plasma concentrations of cystatin C are unaffected by sex, diet, or muscle
mass (in contrast to creatinine).
2. In the pediatric population, it has been documented that plasma cystatin C is
a better marker of kidney function than creatinine.
3. It is reasonable to use cystatin C to calculate estimated GFR in patients with
clear reductions in muscle mass.
4. In renal compromised patients with an estimated GFR around 60 mL / min /
1.73m2, estimated GFR based on serum cystatin C concentration is superior
to GFR based on serum creatinine concentration.

Are there cases where we shouldn’t use cystatin C to calculate

the GFR?
It is unclear whether cystatin C is a superior marker in diabetic patients. In
addition, its use is limited in transplant recipients because steroid use may affect
cystatin C levels.

Although cystatin C appears to be more accurate for the assessment of GFR

than serum creatinine in certain populations, whether measurement of cystatin C
levels will improve patient care is unknown.

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Analyzing an abnormal glomerular filtration
rate
In patients with kidney disease, a reduction in glomerular filtration rate (GFR)
implies one of two sets of circumstances:
1. Progression of the underlying disease
2. Development of a superimposed and often reversible problem such as
decreased renal perfusion due to volume depletion

The level of glomerular filtration rate also has prognostic implications in patients
with chronic kidney disease as GFR is used for staging these patients. However,
there is not an exact correlation between the loss of kidney mass (or nephron
loss) and the loss of GFR.

The kidney adapts to the loss of some nephrons by compensatory hyperfiltration

and / or increasing solute and water reabsorption in the remaining, normal
nephrons. Thus, an individual who has lost one-half of their total kidney mass
will not necessarily have one-half the normal amount of GFR.

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So, what does GFR tell us?
The concepts mentioned above have important clinical implications:
1. A stable GFR does not necessarily imply stable disease.
2. An increase in GFR may indicate improvement in the kidney disease or may
imply a counterproductive increase in filtration, known as hyperfiltration,
due to hemodynamic factors.
3. Some patients who have true underlying renal disease may go undiagnosed
because they have a normal GFR.

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Reviewing the importance of blood urea
nitrogen
Although serum creatinine and cystatin C are more commonly used to evaluate
renal function, urea (often measured as blood urea nitrogen or BUN) and uric
acid measurements also have some clinical value.

Urea is produced from the breakdown of proteins and amino acids. This takes
place in the liver where ammonia is converted into urea.

The kidneys are the primary route of excretion of urea accounting for over 90%
of urea excretion. Minor loss of urea takes place through the gastrointestinal
tract and skin. Urea is freely filtered at the glomerulus and is subsequently not
reabsorbed or secreted at the tubules.

Limitations to using BUN

The urea level in the blood is usually measured as BUN (blood urea nitrogen)
with a normal level between 6–20 mg / dL. However, compared to creatinine,
measurement of urea levels is inferior in assessing renal function, because the
serum concentration of urea may be increased in certain situations:
1. Dehydration
2. Hypoperfusion of the kidneys
3. Protein catabolism
4. Steroid administration
5. High protein diet

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 Normal range of blood urea nitrogen (BUN)
6–20 mg / dL

Using BUN-creatinine ratio to assess kidney function

Under similar situations, serum creatinine is not elevated but remains in the
normal range of 0.5–1.2 mg / dL. So, we can use the BUN-creatinine ratio to
help us further assess kidney function. The BUN-creatinine ratio for normal
individuals usually ranges from 12:1 to 20:1.

Normal range of serum creatinine

0.5–1.2 mg / dL

For example, if BUN is 15 mg / dL and creatinine is 1.1 mg / dL, then the BUN-
creatinine ratio is 13.6.

A BUN-creatinine ratio below 10:1 may indicate intrinsic renal disease. A BUN-
creatinine ratio above 20:1 may indicate hypoperfusion of the kidneys, including
pre-renal failure.

BUN-creatinine ratio Interpretation

12:1–20:1 Normal

< 10:1 Intrinsic renal disease

> 20:1 Hypoperfusion of the kidneys (including

pre-renal failure)

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 Chapter 3

URINALYSIS

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Assessing the appearance of urine
Urinalysis is an informative and non-invasive diagnostic tool. In conjunction
with the history, physical examination, and serum chemistries, urinalysis plays a
central role in evaluating acute and chronic kidney disease.

Abnormal findings on a routine urinalysis, even in an otherwise asymptomatic

patient, may be the first evidence of underlying kidney disease. Urinalysis can
also be used in some patients to monitor the course of established kidney
disease.

The three components of a complete urinalysis

A complete urinalysis consists of three components:
1. Gross evaluation
2. Dipstick analysis
3. Microscopic examination of the urine sediment

Upon gross evaluation, normal urine is clear and light yellow in color, but urine
turbidity and color may be altered in several settings. Turbid urine can occur
under two circumstances:
1. In the setting of infection
2. As a result of precipitated crystals or chyluria

The yellow color of urine is lighter when urine is diluted and darker when
concentrated, such as after an overnight water restriction.

What about urine that is not yellow?

Urine may be a variety of other colors. Let’s cover each possibility in detail.

Red to brown urine

The excretion of red to brown urine is observed in a variety of clinical settings:
1. Hematuria
2. Hemoglobinuria or myoglobinuria
3. With certain medications and foods
4. Acute intermittent porphyria (AIP)

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The initial step in the evaluation of this abnormality is centrifugation of the urine
to see whether the red color is in the urine sediment or the supernatant.

Hematuria
If the red color is seen only in the sediment, and the supernatant is not red, the
patient has hematuria—blood in their urine.

Hemoglobinuria or myoglobinuria
If the supernatant is red, then the supernatant should be tested for heme with
a urine dipstick. If a urine dipstick of the red supernatant is positive for heme,
the patient has either hemoglobinuria or myoglobinuria—the presence of free
hemoglobin or myoglobin in the urine.

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Certain medications and foods
If a urine dipstick of the red supernatant is negative for heme, the patient may be
taking medications like rifampin or phenytoin or may have consumed food dyes,
beets, or rhubarb, which may have colored the urine.

Acute intermittent porphyria

The rare metabolic disorder known as acute intermittent porphyria will also
cause the urine dipstick of the red supernatant to be negative for heme since AIP
affects hemoglobin production.

White urine
White urine may result from polyuria, the presence of phosphate crystals,
chyluria, or from taking propofol.

Pink urine
Pink urine, due to uric acid crystals, may occur following propofol administration.

Green urine
Green urine may be due to the administration of methylene blue, propofol, or
amitriptyline.

Black urine
Lastly, black urine may be due to hemoglobinuria, myoglobulinuria, melanuria, or
ochronosis, which is seen in alkaptonuria, a rare metabolic disorder.

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 Urine color Potential causes

Red • Hematuria
• Hemoglobinuria
• Myoglobinuria
• Certain medications and foods
• Acute intermittent porphyria
(AIP)

White • Polyuria
• Phosphate crystals
• Chyluria
• Propofol

Pink • Uric acid crystals (may

occur following propofol
administration)

Green • Methylene blue

• Propofol
• Amitriptyline

Black • Hemoglobinuria
• Myoglobulinuria
• Melanuria
• Ochronosis (seen in
alkaptonuria)

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Performing a urine dipstick exam
The urine dipstick provides a rapid semi-quantitative assessment of urinary
characteristics on a series of test pads embedded on a reagent strip. Most
dipsticks permit the analysis of several urine parameters:
• Heme
• Leukocyte esterase
• Nitrite
• Protein
• pH
• Specific gravity
• Bilirubin
• Glucose

Some dipsticks include test pads for additional parameters including

urobilinogen and ketones.

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Heme
A positive dipstick for heme may result from the presence of one of three
components in the urine:
1. Red blood cells
2. Free hemoglobin
3. Free myoglobin

The detection of heme by urine dipstick is a highly sensitive test for the presence
of red blood cells as it detects one to two red blood cells per high-powered field.
False positive results may arise if semen is present in the sample. False negative
results may arise from the presence of vitamin C.

Leukocyte esterase
Leukocyte esterase released by lysed neutrophils and macrophages is a
marker for the presence of white blood cells. However, concentrated urine may
impede cell lysis and therefore produce a false negative result. Proteinuria and
glucosuria may also lead to a false-negative test for leukocyte esterase.

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Nitrite
Nitrite-positive urine may indicate underlying bacteriuria. Many
Enterobacteriaceae species, the most common microorganisms causing urinary
tract infections, produce the enzyme nitrate reductase, which converts urinary
nitrate to nitrite.

Protein
The urine dipstick test for protein is most sensitive to albumin and provides a
semi-quantitative means of assessing albuminuria. However, there are three
important limitations of dipstick testing for the urine concentration of albumin:
1. False negatives with moderately increased albuminuria
2. False negatives with very dilute urine
3. False negatives with non-albumin proteins

False negatives with moderately increased albuminuria

In most cases, the dipstick cannot detect moderately increased albuminuria
in the range of 30–300 mg / day (formerly called microalbuminuria). This is
important in some patients at high risk for kidney disease, such as those with
diabetes, since therapy with an angiotensin-converting enzyme inhibitor or
angiotensin receptor blocker would be considered in these patients, but these
medications can artificially reduce urine protein levels.

False negatives with very dilute urine

The dipstick for protein will also be negative in a patient with very dilute urine,
even if they have severely increased albuminuria that is normally detectable by
the dipstick (more than 300 mg / day, formerly called macroalbuminuria).

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False negatives with non-albumin proteins
The dipstick is insensitive to non-albumin proteins, most notably potentially
nephrotoxic immunoglobulin light chains.

pH
The dipstick also measures the pH of the urine. In a normal kidney, the distal
convoluted tubules absorb sodium and secrete potassium and hydrogen ions.

Hydrogen ions make the urine quite acidic. Normal urine pH ranges from 4.5–
8.0, depending upon the systemic acid-base balance. The urine pH is most often
used clinically in patients with metabolic acidosis.

The appropriate renal response to acidemia is to increase urinary acid excretion,

with the urine pH falling below 5. A pH value higher than 5 in the presence of
systemic acidosis suggests renal tubular acidosis.

In renal tubular acidosis, the kidney fails to excrete hydrogen ions into the urine.
Therefore, the body has excess hydrogen ions, and the urine is less acidic.

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Specific gravity
The osmolality of the urine can be inferred by measuring the urine specific
gravity. The urine specific gravity generally varies with the osmolality.

The specific gravity will increase by approximately 0.001 for every 35–40
mOsmol / kg increase in osmolality. Thus, a urine specific gravity of 1.008 or
1.009 corresponds to a urine osmolality of 280 mOsmol / kg which is isosmotic
to (has the same osmotic pressure as) normal plasma.

Concentrated urine has high specific gravity. Dilute urine, such as that produced
in diabetes, has low specific gravity.

Glucose
Glucose is also measured with the urine dipstick. Glycosuria may be due to the
inability of the kidney to reabsorb filtered glucose in the proximal tubule despite
normal plasma glucose concentration. On the other hand, glycosuria may be due
to the overflow of high plasma glucose concentrations which overwhelm the
capacity of the renal tubules to reabsorb glucose.

In patients with normal kidney function, the plasma glucose concentration must
exceed 10 mmol / L before significant glycosuria occurs.

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Examining the microscopic appearance of
urine sediment
Microscopic examination of the urine sediment is an essential part of the
urinalysis as it enables confirmation and clarification of urine dipstick findings.

Examining the microscopic appearance of urine sediment also allows for the
identification of components that are not evaluated by the urine dipstick:
• Red blood cells
• White blood cells
• Epithelial cells
• Crystals
• Casts

Red blood cells

Hematuria may be grossly visible or microscopic. Microscopic hematuria is
commonly defined as the presence of two or more red blood cells per high-
powered field in a spun urine sediment.

Isomorphic red blood cells have an appearance similar to erythrocytes in the

circulation (small, anucleated, biconcave discs) and can be seen with any
cause of hematuria. By contrast, dysmorphic red blood cells have an altered
morphology, and their presence is suggestive of glomerular disease.

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The first step in evaluating unexplained hematuria is to distinguish between two
possibilities:
1. Glomerular causes
2. Non-glomerular causes (which may involve the kidney or bladder)

Glomerular causes
Glomerular causes of hematuria are mostly due to glomerulonephritis, which
is inflammation and damage of the glomeruli. Glomerulonephritis is further
subdivided into two types:
1. Proliferative glomerulonephritis
2. Non-proliferative glomerulonephritis

Proliferative glomerulonephritis
Proliferative glomerulonephritis may present as acute renal failure. Alternatively,
proliferative glomerulonephritis can present with nephritic syndrome.

Here are a few signs of nephritic syndrome:

• Hematuria
• Hypertension
• Oliguria
• Red cell casts
• Mild to moderate proteinuria

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Non-proliferative glomerulonephritis
Non-proliferative glomerulonephritis may present with proteinuria or hematuria,
or with nephrotic syndrome.

Here are a few signs of nephrotic syndrome:

• Severe proteinuria
• Edema
• Hypoalbuminemia
• Hyperlipidemia
• Hypertension

Non-glomerular causes
Non-glomerular causes of hematuria may come from the upper urinary tract or
the lower urinary tract. Here are a few examples of hematuria coming from the
upper urinary tract:
• Renal stones
• Pyelonephritis
• Tumors of the kidney

Here are some causes of hematuria stemming from the lower urinary tract:
• Urinary tract infection
• Enlargement of the prostate
• Tumors
• Surgical instrumentation

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White blood cells
White blood cells in the urine include neutrophils and eosinophils. Let’s go into
each of these findings in detail.

Neutrophils
Urinary neutrophils are commonly associated with bacteriuria. However, if the
corresponding urine culture is negative, known as sterile pyuria, then three
alternative diagnoses should be considered:
1. Interstitial nephritis (inflammation of the interstitium of the kidney)
2. Renal tuberculosis
3. Nephrolithiasis

Eosinophils
The presence of eosinophiluria has classically been considered a marker of
acute interstitial nephritis.

Type of white blood cells

in the urine Urine culture findings Potential diagnoses

Neutrophils Positive • Bacteriuria

Negative • Interstitial nephritis

• Renal tuberculosis
• Nephrolithiasis

Eosinophils • Acute interstitial

nephritis

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Epithelial cells
Epithelial cells may appear in the urine after being shed from anywhere within
the genitourinary tract. Thus, epithelial cells are often a normal finding in the
urine.

In some conditions, such as those associated with tubular damage, you

may see increased numbers of epithelial cells in the urine. In proliferative
glomerulonephritis, there is an increase in the number of cells in the glomerulus,
including an increase in the number of endothelial cells in the capillaries,
epithelial cells from Bowman’s capsule, and mesangial cells in the interstitium
of the glomerulus.

However, proliferative glomerulonephritis patients often have the same number

of epithelial cells in their urine as normal patients, so the number of epithelial
cells in the urine can’t be used for diagnosis in this case.

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Exploring urine casts and crystals
So far, we have discussed three types of cells that can be identified through
microscopic examination of the urine sediment: red blood cells, white blood cells,
and epithelial cells. Next, let’s focus on other structures—casts and crystals—
that can be identified under the microscope.

Casts
Casts are cylindrical structures that are formed in the tubular lumen. Casts will
assume the shape and size of the renal tubule in which they are formed. All casts
have an organic matrix composed primarily of Tamm-Horsfall protein.

The observation of cells within a cast is highly significant since their presence is
diagnostic of an intrarenal problem. There are five types of casts:
1. Red blood cell casts
2. White blood cell casts
3. Renal tubular epithelial cell casts
4. Hyaline casts
5. Granular casts

Red blood cell casts

Red blood cell casts are suggestive of proliferative glomerulonephritis.

White blood cell casts

White blood cell casts are indicative of interstitial inflammation or, less
classically, glomerular inflammation.

Renal tubular epithelial cell casts

Renal tubular epithelial cell casts may be observed in any setting where there is
desquamation of the tubular epithelium, including acute tubular necrosis, acute
interstitial nephritis, and proliferative glomerulonephritis.

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Hyaline casts
Hyaline casts are only slightly more refractile than water and have a transparent,
empty appearance. Hyaline casts may be observed with small volumes of
concentrated urine or with diuretic therapy and are generally nonspecific.

Granular casts
Granular casts represent degenerated cellular casts or the aggregation of
proteins within a cast matrix. Granular casts may be fine or coarse in nature.

Coarse, muddy brown, granular casts are characteristic of acute tubular necrosis.
In acute tubular necrosis there is necrosis of the tubular epithelial cells. There
are two types of acute tubular necrosis:
1. Ischemic-induced acute tubular necrosis
2. Toxic acute tubular necrosis

In ischemic-induced acute tubular necrosis, there is reduced blood supply to the

kidneys and the tubular cells die due to ischemia. In toxic acute tubular necrosis,
toxins such as free hemoglobin, myoglobin, or drugs cause damage to the
tubular epithelial cells.

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 Type of cast in the urine Associated conditions

Red blood cell • Proliferative glomerulonephritis

White blood cell • Interstitial inflammation

• Glomerular inflammation

Renal tubular • Desquamation of the tubular

epithelial cell epithelium including:
– acute tubular necrosis
– acute interstitial nephritis
– proliferative glomerulonephritis

Hyaline casts • Small volumes of concentrated

urine
• Diuretic therapy

Granular casts • Acute tubular necrosis

– ischemic-induced
– toxic

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Crystals
Many different crystals may be observed in the urine of normal patients and in
those with defined disorders. The presence of crystals in the urine indicates that
the patient has a specific type of kidney stones or that they are susceptible to
the development of such stones.

Here’s a table that summarizes the types of crystals that can be found in the
urine and the kidney stones that are associated with them:

Type of crystals
in the urine Associated kidney stones

• Uric acid crystals Uric acid stones

• Calcium oxalate crystals Calcium stones

• Calcium phosphate
crystals

• Cystine crystals Cystinuria and cystine stones

(hexagonal shape)

• Magnesium ammonium Struvite stones

phosphate crystals
• Calcium carbonate-
apatite crystals

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Evaluating proteinuria
Total urinary protein excretion in normal adults is less than 150 mg / day and
consists of mostly albumin, the major protein found in serum, and Tamm-
Horsfall protein, which is a glycoprotein produced by epithelial cells in the kidney.

In normal individuals, low-molecular-weight proteins and small amounts of

albumin are filtered by the glomerulus. Molecules less than 15 kDa pass freely
into the urine. A select few proteins with a molecular weight between 16 and 69
kDa also can be filtered by the kidney. The molecular weight of albumin is 67
kDa.

Most of the filtered albumin enters the proximal tubule where it is almost
completely reabsorbed. Approximately 4–7 mg of albumin is excreted daily. The
normal rate of albumin excretion is anything less than 20 mg / day.

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Causes and types of proteinuria
Elevated levels of protein in the urine, or proteinuria, can have several causes:
• Vigorous physical exercise
• Congestive heart failure
• Pregnancy
• Some medications
• High fever
• Alcohol abuse

Moderately increased albuminuria

Early renal disease may be reflected by lesser degrees of proteinuria, particularly
increased amounts of albuminuria. Persistent albumin excretion between 30 and
300 mg / day (20–200 mcg / min) is called moderately increased albuminuria
(formerly called microalbuminuria). As a reminder, this level of protein excretion
is not detected by a urine dipstick test.

In patients with diabetes, moderately increased albuminuria is usually indicative

of incipient diabetic nephropathy. In non-diabetics, the presence of moderately
increased albuminuria is associated with an increased risk for cardiovascular
disease.

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Overt proteinuria or severely increased albuminuria
Albumin excretion above 300 mg / day (200 mcg / min) is considered overt
proteinuria or severely increased albuminuria (formerly called macroalbuminuria)
and the standard dipstick becomes positive at this level. This finding denotes
glomerular disease or damage which can be due to any cause.

Albumin excretion rate Interpretation

< 30 mg / day (20 mcg / min) Normal

30–300 mg / day (20–200 mcg / min) Moderately increased albuminuria

> 300 mg / day (200 mcg / min) Severely increased albuminuria

(overt proteinuria)

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Conditions associated with proteinuria

Glomerular disease
Remember that the nephron has two major parts: the glomerulus and tubule.
Either part can be involved in disease states.

The presence of significant albumin in urine is a marker for glomerular disease. If

the glomerulus is damaged, we see albuminuria, with or without the presence of
other proteins in the urine.

There are two types of glomerular disease:

1. Selective glomerular proteinuria (only albumin in the urine)
2. Nonselective glomerular proteinuria (other proteins in the urine in addition
to albumin)

Tubular disease
If there is only tubular damage, then we do not see albumin in the urine (or we see
very little of it) and instead, we see other proteins predominate in the urine. We
call this tubular proteinuria.

Tubular proteinuria is often not diagnosed clinically, since the dipstick for protein
is not highly sensitive for the detection of proteins other than albumin, and
because the quantity of non-albumin proteins excreted is relatively low. However,
tubular proteinuria can be diagnosed using urine protein electrophoresis.

Mixed glomerular and tubular proteinuria

In mixed glomerular and tubular proteinuria, both albumin and small molecular
weight proteins such as alpha1-microglobulin and beta2-microglobulin are present
in the urine.

Post-renal proteinuria
Post-renal proteinuria develops in the urinary system after the urine has left
the kidney. Inflammation in the urinary tract, which can occur with urinary tract
infection, can give rise to increased urinary protein excretion, although the
mechanism is unclear.

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The excreted proteins are often IgA or IgG antibodies, and only small amounts are
excreted. Leukocyturia is frequently present in such patients.

Type of proteinuria Detected in the urine

Selective glomerular • Only albumin

Nonselective glomerular • Albumin

• Other proteins

Tubular • Other proteins including

small molecular weight
proteins

Mixed glomerular and • Albumin

tubular • Small molecular weight
proteins

Post-renal proteinuria • Antibodies

• Leukocytes

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Isolated proteinuria
Isolated proteinuria is defined as proteinuria without any other abnormalities such
as hematuria, reduction in glomerular filtration rate, hypertension, or diabetes. In
most cases of isolated proteinuria, the patient is asymptomatic, and the presence
of proteinuria is discovered incidentally by a dipstick during routine urinalysis.
Most patients with benign causes of isolated proteinuria excrete less than 1–2
g / day.

The extent of proteinuria can be assessed by quantifying the amount of proteinuria

as well as expressing the protein-creatinine ratio. A ratio below 0.20 is considered
normal, while anything between 0.2 and 1.0 is classified as low-grade proteinuria.
A ratio between 1 and 5 indicates moderate proteinuria whereas a ratio over 5
signals nephrotic range proteinuria.

Grades of proteinuria Protein-creatinine ratio

Normal < 0.20

Low-grade 0.2–1.0

Moderate 1.0–5.0

Nephrotic range > 5.0

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Reviewing specific urinalysis findings
Various patterns of urinary findings suggest specific categories of kidney
disease. As with all diagnostic tests, these urinary findings must be interpreted
in the context of the patient’s history, physical exam, and available laboratory
data.

Let’s go through a few different categories of kidney

disease and the findings you would expect to
encounter with each one.

Proliferative glomerular disease

The finding of hematuria with dysmorphic red blood cells, red blood cell casts,
and proteinuria is suggestive of a proliferative glomerular disease.

Non-proliferative glomerular disease

Heavy proteinuria with oval fat bodies, lipid-laden casts, and absent or minimal
hematuria is indicative of non-proliferative glomerular diseases including severe
diabetic nephropathy.

Acute tubular necrosis

In a patient with acute kidney injury, the presence of granular and / or epithelial
cell casts with or without free renal tubular epithelial cells is strongly suggestive
of acute tubular necrosis, which occurs when there is necrosis of the tubular
epithelial cells due to ischemia or toxins.

Isolated pyuria
Isolated pyuria is usually indicative of a bacterial urinary tract infection. The
differential diagnosis is broad if a concurrent urine culture is negative:
• Partially or recently treated urinary tract infection
• Non-bacterial infections (including tuberculosis)
• Prostatitis
• Interstitial nephritis (inflammation of the interstitium of the kidney)
• Nephrolithiasis (kidney stones)

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Renal tubular dysfunction
Glucose in the urine with normal blood glucose, as well as amino acids and
beta2 or alpha2-microglobulin in the urine indicate renal tubular dysfunction and
damage.

Distal tubular dysfunction

A specific test to check for evidence of distal tubular dysfunction is the fluid
deprivation test to assess renal concentrating ability. If a normal person is
deprived of fluids, then the urine osmolality increases so the urine becomes more
concentrated. If this does not happen, then there may be a problem in the renal
tubules.

A diagnosis of distal renal tubular acidosis is confirmed with an ammonium

chloride loading test. In patients with distal renal tubular acidosis, there is
impaired urinary secretion of hydrogen and ammonia ions and the urinary pH will
not decrease as expected.

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Proximal tubular dysfunction
A diagnosis of proximal renal tubular acidosis is confirmed with a bicarbonate
loading test. The urinary concentration of bicarbonate will rise following a
bicarbonate infusion because of impaired reabsorption in the proximal tubule.

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 Chapter 4

ACUTE AND CHRONIC

KIDNEY DISEASES

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Identifying acute renal failure
Acute renal failure signifies the abrupt deterioration of renal function. The
kidneys are suddenly unable to filter waste products from the blood. It is usually
reversible and is considered a medical emergency because of life-threatening
biochemical disturbances. Acute renal failure may also arise on a background of
chronic kidney disease.

Three types of acute renal failure

There are three broad categories of acute renal failure:
1. Prerenal
2. Renal
3. Postrenal

In prerenal acute renal failure, there is impaired renal perfusion. This subtype,
if untreated, may convert to acute tubular necrosis (a renal type of acute renal
failure).

There are many examples of renal acute renal failure. Here are three examples:
1. Acute tubular necrosis
2. Acute interstitial nephritis (most often results from certain medications)
3. Rapidly progressive glomerulonephritis (a type of proliferative
glomerulonephritis)

Postrenal acute renal failure is typically due to obstruction such as kidney stones.

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How do we diagnose the three types of acute renal failure?
All three types of acute renal failure are characterized by increased creatinine and
blood urea nitrogen (BUN). Postrenal acute renal failure, such as a urinary tract
obstruction, can’t be diagnosed by lab tests alone and usually requires ultrasound
imaging.

In any patient with acute renal failure and hypovolemia (possibly due to persistent
vomiting, diarrhea, or blood loss), it is important to determine whether they have
prerenal acute renal failure or have developed acute tubular necrosis (a renal type
of acute renal failure).

There are three lab tests used to differentiate prerenal from renal acute renal failure:
1. Urine osmolality
2. BUN-creatinine ratio
3. Fractional excretion of sodium in the urine

Urine osmolality
Prerenal acute renal failure is characterized by increased osmolality in the urine
while renal acute renal failure is characterized by decreased osmolality in the urine.

Prerenal Renal

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BUN-creatinine ratio
In critically ill patients with renal hypoperfusion but intact tubular function (i.e.,
prerenal acute renal failure), BUN concentration may increase out of proportion
to serum creatinine concentration and the ratio of BUN to creatinine may exceed
20:1. This will cause prerenal azotemia—a high level of nitrogen waste products
in the blood—and requires fluid replacement for treatment.

However, any critically ill intensive care unit patient may have an increased BUN-
creatinine ratio, and not all of them will have prerenal azotemia. An increased
BUN-creatinine ratio without prerenal azotemia is not treated with fluid
replacement.

Fractional excretion of sodium in the urine

Fractional excretion of sodium, a measure of the percentage of filtered sodium
that is excreted in urine, is also useful in evaluating renal function.

Here is the formula for calculating the fractional excretion of sodium:

A value less than 1% is indicative of prerenal disease (prerenal azotemia),

where reabsorption of almost all filtered sodium is an appropriate response to
renal hypoperfusion. However, a value over 2–3% is indicative of acute tubular

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necrosis or urinary tract obstruction. Fractional excretion of sodium between 1
and 2% may be observed in any type of renal failure.

Here is a table summarizing how to diagnose the three types of acute renal failure.

Type of acute Osmolality Fractional excretion Additional

renal failure Creatinine BUN in the urine of sodium testing

Prerenal • < 1% (prerenal

azotemia)
• 1–2%

Renal • 1–2%

Postrenal • 1–2% Ultrasound

• > 2–3% (acute imaging
tubular necrosis required for
or urinary tract diagnosis
obstruction)

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Diagnosing chronic kidney diseases
Kidney function depends on age. The glomerular filtration rate (GFR) is low at
birth and reaches adult levels at approximately two years of age. After the age
of 40, renal function declines, and after 65, renal function declines even further.

Early diagnosis of chronic kidney disease may delay or even prevent end-stage
renal disease. Chronic kidney disease is defined as the presence of decreased
kidney function or kidney damage for three or more months.

Decreased kidney function refers to a decreased GFR, which is usually

estimated (eGFR) using serum creatinine and any one of the available equations.
Glomerular filtration rate (GFR) is the best index of overall kidney function, and
declining GFR is the hallmark of progressive kidney disease.

Assessing kidney damage

Kidney damage refers to pathologic abnormalities, which can be established in
three ways:
1. Renal biopsy
2. Imaging studies
3. Laboratory testing

Renal biopsy
A kidney biopsy may uncover evidence of three types of disease:
1. Glomerular disease
2. Vascular disease
3. Tubulointerstitial disease

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Imaging studies
Several kidney abnormalities may be detected on imaging. Here are three
examples:
1. Polycystic kidneys
2. Hydronephrosis
3. Small, echogenic kidneys

Laboratory testing
Kidney damage can also be diagnosed using laboratory testing:
• Urinary sediment
• Albumin

Urinary sediment
Urinary sediment abnormalities such as red or white blood cell casts may
indicate the presence of glomerular injury or tubular inflammation.

Albumin
Albuminuria is the most frequently assessed marker of kidney damage.
Albuminuria reflects increased glomerular permeability to macromolecules.
Albuminuria also reflects primary kidney disease or kidney involvement in
systemic disease.

Albuminuria may represent widespread endothelial dysfunction which can be

related to several factors. Here are a few examples of risk factors for widespread
endothelial dysfunction causing increased rates of urinary albumin excretion:
• Hypertension
• Diabetes
• Hypercholesterolemia
• Smoking
• Obesity

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Although several different measurement methods have been used to assess and
define albuminuria, a random ’spot’ urine test to measure the albumin-creatinine
ratio (ACR) has many advantages. The generally accepted threshold for an
abnormally elevated ACR is 30 mg / g (3.4 mg / mmol) or greater.

Additional precautions
Watch out for certain types of patients with kidney disease:
• Patients with a history of kidney transplantation
• Patients with an eGFR below 60 mL / min per 1.73 m2

Patients with a history of kidney transplantation are assumed to have kidney

damage whether or not they have documented abnormalities on kidney biopsy or
markers of kidney damage.

In routine practice, individuals who have an estimated GFR below 60 mL / min per
1.73 m2 are defined as having chronic kidney disease. These individuals have a
significantly increased risk for all-cause mortality, cardiovascular mortality, end-
stage renal disease, acute kidney injury, and chronic kidney disease progression,
even if the albumin-creatinine ratio is normal. These patients require referral to
nephrology for treatment.

However, with patients who have an isolated decreased estimated GFR, for
example, those with an estimated GFR of 45–59 mL / min per 1.73 m2 without an
elevation in albuminuria, it is generally not recommended that they are referred to
a nephrologist for care.

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Staging chronic kidney disease
The National Kidney Foundation has developed guidelines for the detection and
evaluation of chronic kidney disease using the Kidney Disease Outcomes Quality
Initiative.

Normal kidney function can be assumed if both of the following criteria are met:
• Creatinine clearance is above 90 mL / min / 1.73 m2 (preferably above 100 mL
/ min / 1.73 m2).
• There’s an absence of any other abnormal finding (including imaging studies
and laboratory-based tests).

Chronic kidney disease is considered to be present if either one or the other of

the following criteria are met:
• Kidney damage (defined as structural damage of the kidney based on
imaging studies or functional damage based on laboratory tests) has been
present for three months or more.
• The glomerular filtration rate (GFR) is below 60 mL / min for three or more
months.

End-stage renal disease or end-stage renal failure is present if one or the other
of these two criteria are met:
• The GFR is below 15 mL / min.
• The patient requires dialysis.

Chronic kidney disease staging

The purpose of chronic kidney disease staging is to guide management,
including stratification of risk of disease progression and risk of complications.
Risk stratification is used to decide on appropriate treatments and determine the
intensity of monitoring.

Glomerular filtration rate G-stages

The glomerular filtration rate G-stages follow the chronic kidney disease
classification scheme:
• G1: GFR is greater than or equal to 90 mL / min per 1.73 m2.
• G2: GFR is 60 to 89 mL / min per 1.73 m2.

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• G3: GFR is 30 to 59 mL / min per 1.73 m2.
• G4: GFR is 15 to 29 mL / min per 1.73 m2.
• G5: GFR is less than 15 mL / min per 1.73 m2 or treatment is occurring by
dialysis.

Stage 3 chronic kidney disease (where the GFR is between 30 and 59 mL / min
per 1.73 m2) has been subdivided into GFR stages 3a and 3b to more accurately
reflect the association between the lower GFR of stage G3b and the risk of death
and adverse kidney outcomes.

Patients receiving treatment with dialysis are subclassified as GFR stage 5D to

highlight the specialized care that they require.

GFR
Stage Description (mL / min / 1.73 m2)

G1 Kidney damage with normal GFR ≥ 90

G2 Kidney damage with mildly decreased 60–89

GFR

G3a Mildly to moderately decreased GFR 45–59

G3b Moderately to severely decreased GFR 30–44

G4 Severely decreased GFR 15–29

G5 Kidney failure < 15

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Albuminuria stages
Chronic kidney disease can also be staged using the level of albuminuria. The
three albuminuria stages use definitions of normal, moderately increased, and
severely increased albuminuria.

• A1 or normal: the albumin-creatinine ratio is less than 30 mg / g (or 3.4 mg /

mmol)
• A2 or microalbuminuria: the albumin-creatinine ratio is between 30 and 299
mg / g (or 3.4 and 34.0 mg / mmol)
• A3 or macroalbuminuria: the albumin-creatinine ratio is greater than or equal
to 300 mg / g (or 34.0 mg / mmol)

Stage Definitions Albumin-creatinine ratio (mg / g)

A1 Normal < 30

A2 Moderately increased 30–299

(microalbuminuria)

A3 Severely increased ≥ 300

(macroalbuminuria)

Get familiar with these guidelines for accurately staging your chronic kidney
disease patients as they will ultimately help guide your decisions regarding
treatment.

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APPENDIX

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Brigden, ML, Edgell, D, McPherson, M, et al. 1992. High incidence of significant urinary
ascorbic acid concentrations in a west coast population--implications for routine
urinalysis. Clin Chem. 38: 426–431. PMID: 1547565

Fujita, H, Shinjoh, M, Ishii, T, et al. 2016. Utility of fractional excretion of urea in the
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Hostetter, TH, Olson, JL, Rennke, HG, et al. 1981. Hyperfiltration in remnant nephrons:
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Mazouz, B and Almagor, M. 2003. False-positive microhematuria in dipsticks urinalysis

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Miller, TR, Anderson, RJ, Linas, SL, et al. 1978. Urinary diagnostic indices in acute renal
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Nates, J, Avidan, A, Gozal, Y, et al. 1995. Appearance of white urine during propofol
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Pimstone, NR. 1972. Renal degradation of hemoglobin. Semin Hematol. 9: 31–42.

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