The Adrenal Gland Laboratory

The adrenal gland is really two glands in one.
The adrenal cortex,

the outer portion of the adrenal gland is responsible for the majority
of the body's steroid production. The term corticosteroids is derived
from this origin. Steroids have many functions but their main action
is in form of salt retention which in turn leads to regulation of the
blood pressure as well as sex steroid production.
The adrenal medulla is the central portion of the gland and is primarily responsible for
the production of catecholamines (epinephrine, norepinephrine, and dopamine).
Biopsies of the adrenal gland are uncommon but often performed to distinguish
between a primary malignancy of the adrenal gland versus a metastasis, which is more
common. Frequently, a CT guided fine needle aspiration is performed by the
radiologist. The pathologist will take the aspiration specimen, smear it on a slide and
stain it. Frequently, a diagnosis can be rendered sparing the patient a very invasive
surgical procedure.
What is it?
The adrenal glands which are also called the suprarenal glands, are small,
triangular glands located on top of both kidneys. An adrenal gland is made of
two parts: the outer region is called the adrenal cortex and the inner region
is called the adrenal medulla. Both parts of the adrenal glands -- the adrenal
cortex and the adrenal medulla -- perform very separate functions.
The adrenal glands work interactively with the hypothalamus and pituitary
gland in the following process:
• the hypothalamus produces corticotropin-releasing hormones, which

stimulate the pituitary gland.
• the pituitary gland, in turn, produces corticotropin hormones, which
stimulate the adrenal glands to produce corticosteroid hormones.
We'll describe each part individually:
The Adrenal Cortex
Anatomy
The outer covering (adrenal cortex) is derived from the fetal mesodermal
ridge, a structure that also gives rise to the kidneys so that the juxtaposition
of the two organs is not surprising. Within the adrenal cortex are three zones
known as the outer (zona glomerulosa), the middle (zona fasciculata), and
the inner (zona reticularis). Under the microscope the cells are rather typical
endocrine cells; the distinction between zones is made by differing staining
characteristics.
Adrenal Cortex Functions
The adrenal cortex, the outer portion of the adrenal gland, secretes
hormones that have an effect on the body's metabolism, on chemicals in the
blood, and on certain body characteristics. The adrenal cortex secretes
corticosteroids and other hormones directly into the bloodstream. The
hormones produced by the adrenal cortex include:
• corticosteroid hormones
• hydrocortisone hormone - this hormone, also known as

cortisol, controls the body's use of fats, proteins, and
carbohydrates.
• corticosterone - this hormone, together with
hydrocortisone hormones, suppresses inflammatory reactions in
the body and also affects the immune system.
• aldosterone hormone - this hormone inhibits the level of sodium

excreted into the urine, maintaining blood volume and blood pressure.
• androgenic steroids (androgen hormones) - these hormones have
minimal effect on the development of male characteristics
Hormones
Adrenocortical cells synthesize and secrete chemical derivatives (steroids)

from cholesterol, the major animal sterol. While cholesterol can be
synthesized in many body tissues, further differentiation into steroid
hormones takes place only in the adrenal cortex and in its embryological
cousins, the ovaries and the testes.
The adrenal cortex is capable of synthesizing all of the steroid hormones

produced by the body, including the progestogens and estrogens (see
{ovaries} the ovary), androgens (see {testes} the testis), mineralocorticoids
(which are secreted from the zona glomerulosa), and glucocorticoids (which
are synthesized and released from the zona fasciculata and zona reticularis
of the adrenal cortex). Although upwards of 60 steroids are manufactured in
the adrenal cortex, only a few members of these three major categories are
important in body functioning.
Aldosterone
The biologic effect of aldosterone, the principal mineralocorticoid, is to set in

motion a set of reactions at the cell surface of all body tissues in order to
enhance the uptake and retention of sodium in all cells and the extrusion of
potassium from them. It also has a major impact on kidney function, to
retain sodium within the circulation while increasing the excretion of
potassium into the urine. At the same time, aldosterone tends to decrease
the acidity of body fluids.
Cortisol
Cortisol (hydrocortisone) is the major human glucocorticoid. It exerts

multiple and varied effects. It also serves as a mineralocorticoid but is
considerably less effective than aldosterone. Cortisol plays a major role in
the body's response to stress. In fasting, for example, it sustains the blood
sugar concentration by blocking the egress of glucose into all tissues other
than the critically important brain and spinal cord, while it simultaneously
increases the breakdown of protein from muscle and other organs and
hastens the conversion of newly generated amino acids to glucose to
replenish the supply constantly being consumed by the brain.
Cortisol, along with more potent and longer-acting synthetic derivatives like
prednisone, methylprednisolone, and dexamethasone exerts powerful anti-
inflammatory effects. Physicians take advantage of these properties in
treating patients with serious inflammatory illnesses such as rheumatoid
arthritis, disseminated lupus erythematosus, and multiple sclerosis. If,
however, the inflammation has a bacterial or viral origin, the steroids may
do more harm than good because the spread of the infection is facilitated
while the signs of inflammation are masked (see {immune_system} immune
system). Finally, corticosteroids in large doses impair the functioning of the
immune system so that the production of harmful antibodies, such as those
produced in allergic diseases, may be suppressed. It is important to note
that these beneficial effects are offset by serious side effects of large-dose,
long-term corticosteroid therapy, effects that closely mimic many of the
symptoms of Cushing's syndrome (see below).
Adrenal androgens
Adrenal androgens are not as potent as testosterone, the major steroid

secreted by the testis, but a number of them, including androstenedione,
dehydroepiandrosterone (DHEA), and its sulfate (DHEAS) may be converted
to stronger androgens such as testosterone. Although little androgen is
secreted before puberty, the output increases dramatically at puberty so
that the adrenal cortex makes a significant contribution, known as the
adrenarche, to developmental changes in both sexes.
Regulation of hormone secretion
The three classes of corticosteroids (the mineralocorticoids, the

glucocorticoids, and the adrenal androgens) are regulated largely by
separate mechanisms. Glucocorticoids are regulated by way of the classical
hypothalamic-hypophyseal feedback system. Within the family of
glucocorticoids, the cortisol level is the one most closely guarded.
Furthermore, the ongoing feedback control is modulated by hypothalamic
biorhythmic activity illustrated in the case of cortisol in the figure to the left.
When the individual is exposed to physical or emotional stress, the self-
regulating mechanism is interrupted and plasma cortisol is increased to deal
with the stress. Adrenal androgen secretion is controlled primarily by ACTH,
although there is evidence that prolactin stimulates the secretion of adrenal
androgens as well.
Aldosterone secretion is modulated directly by serum electrolyte levels.

Lowered serum sodium concentrations enhance aldosterone secretion, but a
far more potent stimulus is a high serum potassium level.
Aldosterone increases the reabsorption of sodium (and the excretion of

potassium) by the distal tubules in the kidney. The reabsorption of sodium
results in an increased reabsorption of water which can result in
{hypertension1} hypertension. Low blood aldosterone levels are seen in
{addisons} Addison's disease and toxemia of pregnancy. Higher levels can
be seen in {cushings} Cushing's syndrome, primary hyperaldosteronism,
malignant hypertension, severe swelling in congestive heart failure, and
nephrotic syndrome.
Laboratory Tests
Cortisol. Levels normally vary in the blood, peaking in the early morning. If the adrenal gland
is either not functioning normally or not being stimulated by ACTH, then cortisol levels will
be consistently low. Cortisol levels are used, along with ACTH and ACTH stimulation tests, to
help diagnose adrenal insufficiency.
ACTH. ACTH is a pituitary hormone that signals the adrenal glands to produce cortisol. This
test is primarily ordered as a baseline test to evaluate whether or not the pituitary is
producing appropriate amounts of ACTH. In a patient with adrenal insufficiency, low ACTH
levels indicate secondary adrenal insufficiency, while high levels indicate primary adrenal
insufficiency (Addison’s disease). The ACTH test is often ordered along with the ACTH
stimulation test.
ACTH stimulation test. This test involves measuring the level of cortisol in a patient’s blood
before and after an injection of synthetic ACTH. If the adrenal glands are functional, cortisol
levels will rise in response to the ACTH stimulation. If they are damaged or non-functional,
then their response to ACTH will be minimal. This rapid screening test may be ordered along
with a baseline ACTH test and, if abnormal, may be followed with a 1 to 3 day prolonged
ACTH stimulation test to help differentiate between primary and secondary adrenal
insufficiency.
Aldosterone. Blood or urine aldosterone levels are measured to help diagnose Addison’s
disease - to determine whether the adrenal gland is producing aldosterone. If the levels are
low, it is another indication that the patient may have a primary adrenal insufficiency.
Electrolytes. Electrolytes (Sodium, Potassium, Chloride and Carbon dioxide) are measured to
help detect and evaluate the severity of an existing electrolyte imbalance and to monitor
the effectiveness of treatment. Electrolytes may be affected by many conditions; with
Addison’s disease the sodium, chloride, and carbon dioxide levels are often low, while the
potassium level may be very high.
BUN and Creatinine are tests done to monitor kidney function.
Glucose levels may be very low during an adrenal crisis. Glucose may be ordered in order to
help monitor a patient during a crisis.
Occasionally used tests

Insulin-induced hypoglycemia test. Occasionally, a doctor will order this test to assist in the
detection of adrenal insufficiency. Glucose and cortisol levels are measured at
predetermined intervals after an injection of insulin is used to stress the pituitary gland. In
healthy people, blood glucose levels fall and cortisol concentrations increase. In those with
adrenal insufficiency, cortisol levels will remain low and glucose levels will fall, then recover
slowly.
Renin. Renin activity is elevated in primary adrenal insufficiency because a lack of

aldosterone causes increased renal sodium losses. This lowers blood sodium levels and
decreases the amount of fluid in the blood (which lowers blood volume and pressure), which
in turn stimulates renin production by the kidney.
21-hydroxylase autoantibodies are sometimes ordered as part of the diagnostic process

when autoimmune Addison’s disease is suspected. They are considered a good marker of
autoimmune Addison's disease but are not widely used at this time.
Non-Laboratory Tests
X-rays may be used to look for calcification on the adrenal cortex that may be due to a
tuberculosis infection.
CT (computerized tomography) or MRI (magnetic resonance imaging) scans are sometimes

used to look at the size and shape of the adrenal glands and the pituitary. The adrenal
glands can be enlarged with infections and cancers. With autoimmune diseases and
secondary adrenal insufficiency, the adrenal glands are often normal or small in size.
cortisol
The Test
1. How is it used?
2. When is it ordered?
3. What does the test result mean?
4. Is there anything else I should know?
How is it used?
Blood and urine tests for cortisol are used to help diagnose Cushing's syndrome and Addison's disease, two serious
adrenal disorders. Some physicians are using salivary cortisol to diagnose Cushing's syndrome as well as to evaluate
possible stress-related disorders, although these uses are not widespread.
Both the urine and saliva tests are most frequently used to evaluate excess cortisol production.
Once an abnormal cortisol concentration has been detected, the doctor will do additional testing to help confirm the
excess or deficiency and to help determine its cause.
Dexamethasone Suppression
If there is excess cortisol production, the doctor may perform a dexamethasone suppression test to help determine
whether the cause of the cortisol is related to excess ACTH production by the pituitary. This test involves giving the
patient oral dexamethasone (a synthetic glucocorticoid) and then measuring their blood and urine cortisol levels.
Dexamethasone suppresses ACTH production and should decrease cortisol production if the source of the excess is
pituitary related. There are a variety of dosing schedules, but the medication is usually given every 6 hours for either
2 or 4 days prior to blood or urine collection. Separate 24-hour urine samples are collected prior to and throughout
the testing period and then the blood and urine samples are measured for cortisol and evaluated.
ACTH Stimulation
If the findings of the initial blood and/or urine tests indicate insufficient cortisol production, the doctor may order an
ACTH stimulation test. This test involves measuring the concentration of cortisol in a patient's blood before and after
an injection of synthetic ACTH. If the adrenal glands are functioning normally, then cortisol levels will rise with the
ACTH stimulation. If they are damaged, then the response will be limited. A longer version of this test (1-3 days) may
be performed to help distinguish between adrenal and pituitary insufficiency.
When is it ordered?
A cortisol test may be ordered when a patient has symptoms that suggest Cushing's syndrome(obesity, muscle
wasting, and muscle weakness) or Addison's disease (weakness, fatigue, increased pigmentation, among others).
Suppression or stimulation testing is ordered when initial findings are abnormal. Cortisol testing may be ordered at
intervals when patients are being or have been treated for Cushing's syndrome or Addison's disease to monitor the
effectiveness of treatment.
What does the test result mean?
In normal people, cortisol levels are very low at bedtime and at their highest just after waking. This pattern will change
if a person works irregular shifts (such as the night shift) and sleeps at different times of the day. With Cushing's
syndrome, this pattern is typically lost.
Increased or normal cortisol concentrations in the morning along with levels that do not drop in the afternoon and
evening suggest an overproduction of cortisol. If this excess cortisol is suppressed during a dexamethasone
suppression test, it suggests that the excess cortisol is due to increased pituitary ACTH production. If it is not
suppressed, then the increased cortisol could be due to an ACTH-producing tumor outside of the pituitary, due to a
problem with theadrenal gland, or due to a medication that the patient is taking.
If the adrenal glands are overactive, then a patient may have Cushing's syndrome, with symptoms and signs caused
by prolonged exposure to the effects of too much cortisol. This may be due to excess production of cortisol by the
adrenal glands (which is frequently due to a benign adrenal tumor) or excess ACTH stimulation (due to a pituitary or
other ACTH-producing tumor). It can also be seen in patients who must take corticosteroid medications, such as
those used to treatasthma. If insufficient cortisol is present and the patient responds to an ACTH stimulation test, then
the problem is likely due to insufficient ACTH production by the pituitary. If cortisol levels do not respond to the ACTH
stimulation test, then it is more likely that the problem is based in the adrenal glands. If the adrenal glands are
underactive, due to adrenal damage or insufficient ACTH production, then the patient is said to have adrenal
insufficiency. If decreased cortisol production is due to adrenal damage, then the patient is said to have Addison's
disease.
Once an abnormality has been identified and associated with the pituitary gland, adrenal glands, or other cause, then
the doctor may use other testing such as CT (computerized tomography) or MRI (magnetic resonance imaging)
scans to locate the source of the excess (such as a pituitary, adrenal, or other tumor) and to evaluate the extent of
any damage to the glands.
Is there anything else I should know?

Pregnancy, physical and emotional stress, and illness can increase cortisol levels. Cortisol levels may also increase
as a result of hyperthyroidism or obesity. A number of drugs can also increase levels, particularly oral contraceptives
(birth control pills), hydrocortisone (the synthetic form of cortisol), and spironolactone. Adults have slightly higher
cortisol levels than children do.
Hypothyroidism may decrease cortisol levels. Drugs that may decrease levels include some steroid hormones.
Salivary cortisol testing is being used more frequently to help diagnose Cushing's syndrome and stress-related
disorders but still requires specialized expertise to perform.
ACTH
Also known as: Corticotropin
Formal name: Adrenocorticotropic Hormone
Related tests: Cortisol, Cortrosyn (ACTH) stimulation test, Dexamethasone suppression test
The Test
1. How is it used?
How is it used?
ACTH levels in the blood are measured to help detect, diagnose, and monitor conditions associated with excessive or
deficient cortisol in the body. These conditions include:
• Cushing's disease: excess cortisol that is due to an ACTH-producing tumor in the pituitary gland (usually
a benign tumor)
• Cushing's syndrome: refers to the symptoms and signs associated with excess exposure to cortisol. In
addition to Cushing's disease, Cushing's syndrome may be due to an adrenal tumor, adrenal hyperplasia, the
use of steroid medications, or due to an ACTH-producing tumor that is ectopic, located outside the pituitary
(such as in the lungs).
• Addison's disease, primary adrenal insufficiency: decreased cortisol production due to adrenal gland
damage
• Secondary adrenal insufficiency: decreased cortisol production because of pituitary dysfunction
• Hypopituitarism: pituitary dysfunction or damage that leads to decreased (or no) hormone production by the
pituitary, including ACTH production
Measuring both ACTH and cortisol can help to differentiate among some of these conditions because the level of
ACTH normally changes in the opposite direction to the level of cortisol.
^ Back to top
When is it ordered?
This test is ordered when a patient has signs or symptoms associated with excess or deficient cortisol.
Too much cortisol can cause symptoms that include:
• obesity, with majority of the weight on the trunk of the body and not the arms and legs
• rounded face
• fragile and thin skin
• purple lines on the abdomen
• muscle weakness
• acne
• increased body hair
These are often accompanied by findings such as high blood pressure, low potassium, highbicarbonate,
high glucose levels, and sometimes diabetes.
People with insufficient cortisol production may exhibit symptoms such as:
• muscle weakness
• fatigue
• weight loss
• increased skin pigmentation, even in areas not exposed to the sun
• loss of appetite.
These are often accompanied by findings such as low blood pressure, low blood glucose, lowsodium, high
potassium, and high calcium.
Symptoms suggestive of hypopituitarism include loss of appetite, fatigue, irregular menstrual cycle, hypogonadism,
decreased sex drive, frequent nighttime urination, and weight loss. When the condition is due to a pituitary tumor
(usually benign), the affected person may also have symptoms associated with the compression of nearby cells and
nerves. The tumor can affect the nerves controlling vision, causing symptoms such as "tunnel vision" (inability to see
things off to the side), loss of vision to some localized areas, and double vision, and can cause a change in a pattern
of headaches.
Changes in ACTH and cortisol are usually evaluated together. The table below indicates the common patterns of
ACTH and cortisol seen with different diseases involving the adrenal and pituitary glands.
DISEASE CORTISOL ACTH
Cushing's disease (pituitary tumor making ACTH) High High

DISEASE CORTISOL ACTH
Adrenal tumor High Low
"Ectopic" ACTH (ACTH made by a tumor outside the pituitary, usually in the High High
lung)
Addison's disease (adrenal damage Low High
Hypopituitarism Low Low
An increased ACTH result can mean that a patient has Cushing's disease, Addison's disease, or ectopic ACTH-
producing tumors. A decreased ACTH result can be due to an adrenal tumor, steroid medication, or hypopituitarism.
In some cases, the interpretation of the results can be complex. Concentrations of both ACTH and cortisol vary
throughout the day. Normally, ACTH will be at its highest level in the morning and lowest at night. It will stimulate
cortisol production, which will follow the same daily pattern but will rise after ACTH does and fall to its lowest level
very late in the evening. Conditions that affect the production of ACTH and cortisol often disrupt this diurnal variation.

Testing the change in cortisol when certain drugs are given to stimulate or suppress hormone production often helps
the doctor make the right diagnosis. The most commonly used drugs are cortrosyn (cosyntropin, a drug form of
ACTH) for an ACTH stimulation test and dexamethasone for a dexamethasone suppression test.
• Cortrosyn, like ACTH, stimulates the adrenal glands to make cortisol. If cortisol levels don't rise after
cortrosyn is given, this indicates adrenal failure as can occur in Addison's disease orhypopituitarism.
• Dexamethasone is a potent drug that acts like cortisol. Dexamethasone should stop ACTH production. By
testing the ability of different doses of dexamethasone to stop ACTH production, a doctor can tell if the person
has Cushing's syndrome and determine its cause.
A number of other drugs are sometimes used to stimulate or suppress cortisol production, including insulin,
corticotropin releasing hormone, and metyrapone (metapyrone).
Some drugs and conditions can cause ACTH levels to rise, including amphetamines, insulin, levodopa,
metoclopramide, and RU 486.
Drugs that cause ACTH to fall include dexamethasone and other drugs that act like cortisol, including prednisone,
hydrocortisone, prednisolone, and methylprednisolone, and megestrol acetate.
Secretion of ACTH may be increased by stress.
ACTH has also been used therapeutically as a drug to treat Multiple Sclerosis.
ACTH (cosyntropin) stimulation test

ACTH (cosyntropin) stimulation test measures how well the adrenal glands respond to the
hormone ACTH. ACTH is a hormone produced in the pituitary gland that stimulates the
adrenal glands to release cortisol.
How the Test is Performed
The health care provider will measure the cortisol in your blood before and 60 minutes after
an ACTH injection.
Blood is typically drawn from a vein, usually on the inside of the elbow or the back of the
hand. The site is cleaned with germ-killing medicine (antiseptic). The health care provider
wraps an elastic band around the upper arm to apply pressure to the area and make the
vein swell with blood.
Next, the health care provider gently inserts a needle into the vein. The blood collects into
an airtight vial or tube attached to the needle. The elastic band is removed from your arm.
Once the blood has been collected, the needle is removed, and the puncture site is covered
to stop any bleeding.
In infants or young children, a sharp tool called a lancet may be used to puncture the skin
and make it bleed. The blood collects into a small glass tube called a pipette, or onto a slide
or test strip. A bandage may be placed over the area if there is any bleeding.
Once the blood has been collected, the health care provider will use a needle to inject
cosyntropin. Other timed specimens are also collected.
Along with the blood tests, sometimes you may also have a urinary free cortisol test or
urinary 17-ketosteroids test in which the urine is collected over a 24-hour period.
How to Prepare for the Test
You may need to limit activities and eat a high-carbohydrate diet 12-24 hours before the
test. You may be asked to fast for 6 hours before the test.
How the Test Will Feel
When the needle is inserted to draw blood, some people feel moderate pain, while others
feel only a prick or stinging sensation. Afterward, there may be some throbbing.
Why the Test is Performed
This test can help determine whether your adrenal and pituitary glands are normal. It is
most often used when the health care provider suspects adrenal gland disorders, such as
Addison's disease or pituitary insufficiency.
Normal Results
An increase in cortisol after stimulation by ACTH is normal. Blood cortisol after ACTH
stimulation should be greater than 18 - 20 mcg/dL, depending on the dose of cosyntropin
used.
Note: mcg/dL = micrograms per deciliter
Normal value ranges may vary slightly among different laboratories. Talk to your doctor
about the meaning of your specific test results.
What Abnormal Results Mean
This test is helpful in determining if you have:
* Acute adrenal crisis

* Addison's disease (decreased adrenal output)
* Low pituitary function
* Pituitary tumors
Risks
Veins and arteries vary in size from one patient to another and from one side of the body to
the other. Obtaining a blood sample from some people may be more difficult than from
others.
Other risks associated with having blood drawn are slight but may include:
* Excessive bleeding
* Fainting or feeling light-headed
* Hematoma (blood accumulating under the skin)
* Infection (a slight risk any time the skin is broken)
Aldosterone and Renin

Also known as: Aldosterone and plasma renin activity; PRA
Formal name: Aldosterone, serum; Aldosterone, urine; Renin
Related tests: Cortisol; Electrolytes; Potassium; Aldosterone/Renin activity calculation or ratio;

Aldosterone stimulation test; Aldosterone suppression test
The Test
1. How is it used?
How is it used?
Aldosterone and renin tests are used to evaluate whether appropriate amounts of aldosterone are being produced
and to distinguish between the potential causes of excess or deficiency. Aldosterone may be measured in the blood
or in a 24-hour urine sample; renin is always measured in blood. These tests are most useful in screening for primary
hyperaldosteronism, also known as Conn's syndrome, which causes high blood pressure. If the screening test is
positive, aldosterone production may be further evaluated through the use of stimulation and suppression testing.
Both aldosterone and renin levels are highest in the morning and vary throughout the day. They are affected by a
person's position, by stress, and by a variety of prescribed medications.
When is it ordered?
A plasma aldosterone and a plasma renin are usually ordered together when a patient has high blood pressure and a
low potassium. Even if potassium is normal, testing may be done if typical medications do not control the high blood
pressure or if hypertension develops at an early age. Primary aldosteronism is a potentially curable form of
hypertension, so it is important to detect and treat it properly. Aldosterone levels are occasionally ordered, along with
other tests, when a doctor suspects that a patient has adrenal insufficiency.
The table below indicates the changes in renin, aldosterone, and cortisol that occur with different disorders.
DISEASE ALDOSTERONE CORTISOL RENIN
Primary hyperaldosteronism (Conn’s High Normal Low

syndrome)
Secondary hyperaldosteronism High Normal High
Cushing’s syndrome Low-normal High Low
Adrenal insufficiency (Addison's disease) Low Low High
Primary hyperaldosteronism is caused by the overproduction of aldosterone by the adrenal glands, usually by
a benign tumor of one of the glands. The high aldosterone level increases reabsorption of sodium (salt) and loss of
potassium by the kidneys, resulting in an electrolyte imbalance. Primary hyperaldosteronism is sometimes called
Conn's syndrome. Symptoms are not typically present, although muscle weakness can occur if potassium levels are
very low. The presence of hypokalemia in a person with hypertension suggests the need to look for
hyperaldosteronism.
Secondary hyperaldosteronism, which is more common, can occur as a result of anything that decreases blood flow
to the kidneys, decreases blood pressure, or lowers sodium levels. The most important cause is narrowing of the
blood vessels that supply the kidney, termed renal artery stenosis. This causes high blood pressure due to high renin
and aldosterone that may be cured by surgery or angioplasty. Sometimes, to see if only one kidney is affected, a
catheter is inserted through the groin and blood is collected directly from the veins draining the kidney (renal vein
renin levels); if the value is significantly higher in one side, this indicates where the narrowing of the artery is present.
Similarly, blood may sometimes be taken from both of the adrenal veins to determine whether there is a difference in
the amount of aldosterone (and sometimes cortisol) produced by each of the adrenal glands. Secondary
hyperaldosteronism may also be seen withcongestive heart failure, cirrhosis, kidney disease, and toxemia of
pregnancy.
A low aldosterone (hypoaldosteronism) usually occurs as part of adrenal insufficiency; it causesdehydration, low
blood pressure, and low blood levels of sodium and potassium. In infants with congenital adrenal hyperplasia, the
infant lacks an enzyme needed to make cortisol; in some cases, this also decreases production of aldosterone. This
is a rare cause of low aldosterone.
^ Back to top
The amount of salt in the diet and medications, such as over-the-counter pain relievers of the non-steroid class (such
as Motrin and Advil), diuretics (water pills), beta blockers, steroids, angiotensin-converting enzyme (ACE) inhibitors,
and oral contraceptives can affect the test results. Some of these drugs are used to treat high blood pressure. Your
doctor will tell you if you should change the amount of sodium (salt) you ingest in your diet, your use of diuretics or
other medications, or your exercise routine before aldosterone testing.
Aldosterone levels become very low with severe illness, so testing should not be done at times when a person is very
ill. Stress and strenuous exercise can temporarily increase aldosterone values.
http://ndt.oxfordjournals.org april 5,2010

PHYSIOLOGICAL PROBLEMS
Pregnancy after renal transplantation: points to consider
Mahboob Lessan-Pezeshki
Department of Nephrology, Dialysis and Transplantation, Tehran University of Medical Science, Tehran, Iran
Keywords: pregnancy; renal transplantation
Introduction
Women with chronic renal failure suffer from loss of libido, anovulatory vaginal
bleeding or amenorrhea and high prolactin levels [1]. On dialysis most experience
decreased libido and reduced ability to reach orgasm [2–4]. Conception is rarefor
women on dialysis. It occurs at a rate of no more than one in every 200 patients [5].
Fertility is usually restored in women with renal transplants. Pregnancy is then

common, occurring in 12% of women at childbearing age in one series [6]. Pregnancy
success rate exceeds 90% after the first trimester. The recovery of fertility is less
common in women who undergo transplantation close to the end of their childbearing
years [3]. The first reported successful pregnancy occurred in a recipient of a kidney
transplant from an identical twin sister performed in 1958 [7]. Since then, there have
been hundreds of successful pregnancies reported in renal transplant recipients [8].
Effect of pregnancy on graft function

Pregnancy causes an increase in the glomerular filtration rate. In theory, this could
lead to hyperfiltration and glomerulosclerosis. However, the hyperfiltration of
pregnancy is related to increased plasma flow, with no concomitant increase in
intraglomerular pressure [9].
In cyclosporin-treated patients, graft dysfunction after pregnancy was seen in patients

with higher mean serum creatinine levels and lower mean cyclosporin doses prior to
conception [10]. Overall, in the majority of recipients studied, pregnancy does not
appear to cause excessive or irreversible problems with graft function if the function of
transplant organ is stable prior to pregnancy [11].
Immunosuppressive drugs in pregnancy
Currently, we have limited information regarding the toxicities and teratogenic

potentials of these agents, although our knowledge has recently increased as more
women maintained on immunosuppressive therapy for solid organ transplants have
opted to become pregnant.
Glucocorticoids
The most commonly used glucocorticoids are the short acting agents; prednisone,
prednisolone and methyl prednisolone. Radiolabelled prednisone and prednisolone can
cross the placenta, but maternal- to cord-blood ratios are approximately 10:1 [12].
Adrenal insufficiency and thymic hypoplasia have occasionally been described in
the infants of transplant recipients, but these problems are unlikely if the dose of
prednisone has been decreased to 15 mg [13]. Cases of cleft palate or mental
retardation have also been described in humans after in utero corticosteroid exposure
[14]. Steroids may be implicated in the increased frequency of premature rupture of
membranes of transplant recipients. They can also aggravate hypertension in the
mother. Doses of prednisone greater than 20 mg/day have been associated with serious
maternal infection. Treatment of rejection with steroids, if necessary, is not
contraindicated, however, during pregnancy.
Azathioprine
Azathioprine is used during pregnancy in many transplant recipients. Radioactive
labelling studies in humans have shown that 64–93% of azathioprine administered to
mothers appears in fetal blood as inactive metabolites [15]. In the adult, azathioprine
is metabolized to 6-mercaptopurine. The immature fetal liver lacks the enzyme
inosinate pyrophosphorylase needed for conversion, and the fetus is relatively
protected from the effects of the drug. In high doses (6 mg/kg), azathioprine is
teratogenic in animals. In human studies low birth weights, prematurity,
jaundice, respiratory distress syndrome and aspiration have been reported in kidney
transplant recipients. Azathioprine has been associated with a dose-related
myelosuppression in the fetus, but leukopenia is not usually a problem in the neonate
if the maternal whiteblood count is maintained at values higher than 7500/mm3 [16].
Cyclosporin
There is little or no transplacental passage of cyclosporin in rodents [17]. In
comparison, there are conflicting reports on the transfer of cyclosporin across the
human placenta. Studies in pregnant rats have generally shown no effect of
cyclosporin on organogenesis, although some renal proximal tubular cell damage can
occur [18]. Human data showed that adminstration of cyclosporin was associated with
low birth weights and a higher incidence of maternal diabetes, hypertension and renal
allograft dysfunction. Cyclosporin metabolism appears to be increased during
pregnancy and higher doses may be required to maintain plasma levels in the
therapeutic range [19]. Some of the pregnancies in cyclosporin-treated women were
complicated by pre-eclampsia. Cyclosporine increases production of thromboxane and
endothelin, which have both been implicated in the pathogenesis of pre-
eclampsia. Because of this, some physicians have suggested that the dose be limited to
2–4 mg/kg per day [20].
Tacrolimus
There is a paucity of data concerning the effect of tacrolimus on pregnancy. Among
100 pregnancies in 84 women treated with tacrolimus, of whom 27% were renal
transplant recipients, 68 progressed to a live birth, with 60% of deliveries being
premature [21]. As with cyclosporin, patients taking tacrolimus require frequent
monitoring of renal function and drug levels. During pregnancy, the hepatic
cytochrome P450 enzymes may be inhibited, which can lead to increased serum level
of tacrolimus. The dose may therefore have to be significantly reduced to prevent
toxicity (sometimes by as much as 60%).
Mycophenolate mofetil
There is concern based on animal studies that the risk of birth defect or abortion is
increased in pregnant women exposed to MMF. Nevertheless, one recent report
showed successful use of MMF during pregnancy. Because precise data are limited at
the moment we do not recommend its use [11,22].
OKT3 and polyclonal antibodies

OKT3 is an immunoglubolin G (IgG) that crosses the placenta. The National
Transplantation Pregnancy Registry (NTPR) has reported on treatment of five women
with OKT3 during pregnancy, with four surviving infants [23]. The effect of
polyclonal antibodies on the developing fetus is not known, but the IgG
component would be expected to cross the placenta.
Management guidelines
All women of childbearing age should be counselled concerning the possibility and
risks of pregnancy after kidney transplantation. Women who are not rubella immune
should receive the rubella vaccine before transplantation, because live virus
vaccines are contraindicated post-transplantation [3]. Women are usually advised to
wait at least 1 year after living related donor transplantation and 2 years after cadaver
transplantation. However, waiting 5 or more years may result in impaired renal
function post-partum that fails to recover, because of gradually deteriorating
renal function secondary to chronic rejection.
Contraceptive counselling should begin immediately after transplantation, because

ovulatory cycles may begin within 1–2 months of transplantation in women with well
functioning grafts. Low dose oestrogen–progesterone oral contraceptive
preparations are advised. The risk of infection from the use of intrauterine devices is
increased in immunocompromised patients. The efficacy of IUDs may be reduced
because of the anti-inflammatory properties of immunosuppressive agents.
Criteria that should be ideally met before conception are shown in Table 1 .
View this Table 1. Criteria for transplant recipients

table: contemplating pregnancy
[in this
window]
[in a new
window]
Management of hypertension
Women with mild to moderate hypertension should be watched closely, warned about
signs of early pre-eclampsia and delivered at 37 weeks of gestation.
Antihypertensive drugs used in pregnancy

-Methyldopa
Its safety and efficacy are supported by the results of several randomized trials and by
a 7.5 years follow-up study of children born to mothers treated with -methyldopa.
Beta Blockers
Cardiovascular beta blockers, especially atenolol and metoprolol, appear to be safe
and efficacious in late pregnancy; but fetal growth retardation has been noted when
treatment was started in early or midgestation [24]. Non-selective beta blockers
should not be used because of the risk of uterine contractions.
Hydralazine
Hydralazine is safe and used frequently as adjunctive therapy with -methyldopa and
beta blockers.
Calcium channel blockers
Nifedipine, nicardipine and verapamil have been used in severe hypertension of
pregnancy. They do not appear to be associated with any increase in congenital
anomalies when used in the first trimester [3]. Calcium channel blockers may
potentiate the hypotensive effects and neuromuscular blockade of magnesium and the
interaction should be kept in mind when the drugs are used in women with a
possibility of developing pre-eclampsia [25].
Labetalol
Labetalol appears to be as effective as methyldopa, but there is little follow up
information on children born to motherstreated with this drug.
ACE inhibitors
Exposure to ACE inhibitors during the second and third trimester may be associated
with serious adverse fetal effects. Most of these problems relate to disturbances of
fetal and neonatal renal function, such as oligohydramnios, neonatal anuria,
renal failure and death [26]. The fetal outcome is generally good in women who
present in early pregnancy while taking an ACE inhibitor if the drug is stopped.
Continued administration of an ACE inhibitor during pregnancy is contraindicated
[27].
Diuretics
The use of thiazide diuretics has been approved in women with chronic hypertension
if prescribed before gestation, however, the recommendation is against their use in
pre-eclamptic women, who often manifest decreased intravascular volumes and
poor placental perfusion.
Management of infection
Bacterial
Urinary tract infections are the most common bacterial infections and occur in up to
40% of pregnant transplant recipients. They are particularly common in patients who
develop end-stage renal disease due to pyelonephritis. These women should have
monthly screening urine cultures [28], if asymptomatic bacteriuria is present; the
patient should be treated for 2 weeks and may be treated with suppressive doses of
antibiotics for the rest of the pregnancy. If there is a need for invasive procedures
such as fetal monitoring with scalp electrodes or intrauterine pressure monitoring,
prophylactic antibiotics are recommended. The selection of antibiotics should consider
potential fetal toxocity. Penicillins which do not interact with eukaryote metabolism
are the preferred antibiotic agents.
Viral
Cytomegalovirus (CMV) remains the most frequent cause of viral infection post-
transplantation; however, if the patient waits the recommended time after
transplantation to become pregnant, she has passed the peak time of risk for CMV
infection.
Infection of the fetus can be diagnosed by culturing the amniotic fluid. Ganciclovir has
caused birth defects in animals whenadministered at twice the human dose [3].
Herpes simplex virus (HSV) infection before 20 weeks of gestation is associated with
an increased rate of abortion. A positive HSV cervical culture at term is an indication
for Caesarean section. This can minimize the risk for neonatal herpes. Acyclovir can
be safely used in pregnancy [29].
An infant born to an HBSAg-positive mother should be given hepatitis B

immunoglobulin within 12 h of birth and HBV vaccine at another site within 48 h
followed by a booster injection at 1 and 6 months.
The combination of immunoglobulin and vaccine offers protection for more than 90%
of infants.
Vertical transmission is believed to be low (<7%) with hepatitis C unless the patient is
also infected with the human immunodeficiency virus.
Labour and delivery
Vaginal delivery is recommended in most transplant recipient women. Caesarean

section should be performed only for standard obstetric reasons. Care must be taken to
avoid fluid overload and infection. At the time of delivery, instrumentation should be
minimized. Patients with renal insufficiency may be particularly at risk of water
retention secondary to oxytocin.
In the perinatal period, the steroid dose should be augmented to cover the stress of
labour and to prevent post-partum rejection. Hydrocortisone, 100 mg every 6 h, should
be given during labour and delivery. Breastfeeding is discouraged for patients
taking any immunosuppressive drugs. Cyclosporin measurement in maternal blood
and breast milk revealed a mean breast milk/maternal blood level ratio of 0.84 [30].
These levels can be toxic to a newborn. Similar recommendations exist for tacrolimus
or other immunosuppressive agents.
Conclusion
Pregnancy does not appear to have generally any adverse effect on the long-term
survival of renal allografts. Because the outcomes of pregnancy in transplanted
women are so different from those in women on intermittent dialysis, it is advisable to
treat end-stage renal disease patients with transplantation and wait until renal function
has been stable for 1–2 years before undertaking a planned pregnancy. Such planned
pregnancies offer to the mother and fetus the best chance of a favourable outcome.
Notes
Correspondence and offprint requests to: Dr M. Lessan-Pezeshki, Shafa Clinic No.

87, Italy Avenue, Tehran, Iran. Email: lessanpezeshki@bmsu.ac.ir
References
1. Zingraff J, Jungers P, Pelissier C et al. Pituitary and ovarian

dysfunction in women on hemodialysis. Nephron1982; 30: 149–
153[Web of Science][Medline]
2. Toorians AWFT, Janssen E, Laan E et al. Chronic renal failure

and sexual functioning: clinical status versusobjectively
assessed sexual response. Nephrol Dial Transplant1997; 12:
2654–2663[Abstract/Free Full Text]
3. Hou S. Pregnancy in chronic renal insufficiency and end stage

renal disease. Am J Kidney Dis1999; 33: 235–252[Web of
Science][Medline]
4. Diemont WL, Vruggink PA, Meuleman EJ et al. Sexual

dysfunction after renal replacement therapy. Am J Kidney
Dis2000; 35: 845–851[Web of Science][Medline]
5. Rizzoni G, Ehrich JHH, Broyer M et al. Successful pregnancies in

women on renal replacement therapy: report from the EDTA
registry. Nephrol Dial Transplant1992; 7: 279–
287[Abstract/Free Full Text]
6. Sturgiss SN, Davison JM. Effect of pregnancy on long term
function of renal allografta. Am J Kidney Dis1992; 19: 167–
7. Murray JE, Reid DE, Harrison JH et al. Successful pregnancies

after human renal transplantation. N Engl J Med1963; 269: 346
8. Davison JM. Pregnancy in renal allograft recipients: prognosis

and management. Ballier Clin Obstet Gynecol1987; 1: 1027–
9. Baylis C. Glomerular filtration and volume regulation in gravid

animal models. Ballier Clin Obstet Gynecol1994; 8: 235–
10. Armenti VT, Ahlswede KM, Ahlswede A et al. Variables affecting

birthweight and graft survival in 197 pregnancies in
cyclosporine treated female kidney transplant recipients.
Transplantaion1995; 59: 476–479
11. Armenti VT, Radomski JS, Moritz MJ, Philip LZ, McGrory
CH, Cosci LA. Report from the National Transplantation
Pregnancy Registry (NTPR) outcome of pregnancy after
transplantation. Clin Transplant2000; 123–134
12. Beitins IZ, Bayard F, Ances IG et al. The transplacental passage

of prednisone and prednisolone in pregnancy near term. J
Pediatr1972; 81: 936–945[Web of Science][Medline]
13. Penn I, Makowski EL, Harris P. Parenthood following renal

transplantation. Kidney Int1980; 18: 221–223[Web of Science]
[Medline]
14. Chabria S. Aicardi's syndrome: are corticosteroids teratogens?

Arch Neurol1981; 38: 70[Abstract/Free Full Text]
15. Sarikoski S, Seppala M. Immunosuppression during pregnancy:

transmission of azathioprine and its metabolites from the
mother to the fetus. Am J Obstet Gynecol1973; 115: 1100[Web
of Science][Medline]
16. Davison
JM, Dellagrammatika SH, Parkin JM. Maternal
azathioprine therapy and depressed haemopoiesis in the
babies of renal allograt patients. Br J Obstet Gynecol1985; 92:
233–239[Web of Science][Medline]
17. Backman L, Brandt I, Appelkvist EL, Dallner G. Tissue and

subcellular localization of 3-h-cyclosporine A in mice.
Pharmacol Toxicol1988; 62: 110–117[Web of Science][Medline]
18. MasonRG, Thomson AW, Whiting PH et al. Cyclosporine

induced fetotoxity in the rat. Transplantation1985; 39: 9[Web
19. MurirheadN, Sabharwal AR, Reider MJ et al. The outcome of

pregnancy following renal transplantation–the experience of a
single center. Transplantation1992; 54: 429–432[Web of
Science][Medline]
20. LindheimerMD, Katz AI. Pregnancy in the renal transplant

patients. Am J Kidney Dis1992; 19: 173–176[Web of Science]
[Medline]
21. KanizA, Harabacz I, Cowirick IS et al. Review of the course and

outcome of 100 pregnancies in 84 women treated with
tacrolimus. Transplantation2000; 70: 1718–1721[Web of
Science][Medline]
22. Pergola PE, Kancharla A, Riley DJ. Kidney transplantation during

the first trimester of pregnancy: immunosuppression with
mycophenolate mofetil, tacrolimus, and prednisone.
Transplantation2001; 71: 994–997[Web of Science][Medline]
23. Eisenberg
JA, Armenti VT, Mc Grovy CH et al. National
transplantation pregnancy registry (NTPR): Use of muromonab-
CD3 (OKT3) during pregnancy in female transplant recipients.
Am Soc Transplant Phys1997; 20: 108
24. Lindheimer
MD, Davison JM, Katz AI. The kidney and
hypertension in pregnancy: twenty exciting years. Semin
Nephrol2001; 21: 173–189[Web of Science][Medline]
25. Dynder SW, Cardwell MS. Neuromuscular blockade with
magnesium sulfate and nifedipine. Am J Obstet Gynecol1988;
161: 35–36[Web of Science]
26. Pryde PG, Sedman AB, Nugent CE, Barr M Jr. Angiotensin
converting enzyme inhibitor fetopathy. J Am Soc Nephrol1993;
3: 1575–1582[Abstract]
27. Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin

converting enzyme inhibition during pregnancy: experimental
and clinical evidence, potential mechanisms and
recommendations for use. Am J Med1994; 96: 451–456[Web of
Science][Medline]
28. Davison JM. Pregnancy in renal allograft recipients:

prognosis and management. Clin Obstet Gynecol1994; 8: 501–
525
29. Andrew EB, Yankaskas BC, Cordero JF, Schoeffler K, Hampp S.

Acylovir in pregnancy registry: six years experience. Obstet
Gynecol1992; 79: 7–13[Web of Science][Medline]
30. Munoz-Flores-Thiagaralan KD, Easterling T, Davis C, Bond EF.

Breast-feeding by a cyclosporine-treated mother. Obstet
Gynecol2001; 97: 816–818[Web of Science][Medline]
Complications
Problems after a transplant may include:
 Transplant rejection (hyperacute, acute or chronic)

 Infections and sepsis due to the immunosuppressant drugs that are required to decrease risk of
rejection
 Post-transplant lymphoproliferative disorder (a form of lymphoma due to the immune
suppressants)
 Imbalances in electrolytes including calcium and phosphate which can lead to bone problems
amongst other things
 Other side effects of medications including gastrointestinal inflammation and ulceration of the
stomach and esophagus, hirsutism (excessive hair growth in a male-pattern distribution), hair
loss, obesity, acne, diabetes mellitus type 2, hypercholesterolemia, and others.
The average lifetime for a donated kidney is ten to fifteen years. When a transplant fails a patient may opt
for a second transplant, and may have to return to dialysis for some intermediary time.
http://www.ncbi.nlm.nih.gov
Physiological problems and diseases after renal transplantations were seen such as 38.4% had infections in urinary
and respiratory tract. Some had hypertension (22.4%) hypercholesterolaemia (26.5%) and 5.6% had malignancy.
Most (67.2%) developed antirejection drugs side-effects. About 55.2% were admitted to hospital after renal
transplantation and 68.8% had not received any training after transplantation from a health professional. Only 35.2%
knew the signs and symptoms of rejection entirely or partly. It was determined that 55.2% stated that they avoid
sunlight and 56% stated that they exercise regularly. Only 26.8% of female patients do regular breast self-
examination. While 52.8% listed the forbidden foods correctly, only 27.2% could list the forbidden beverages
accurately.
PSYCHOLOGICAL PROBLEMS http://psy.psychiatryonline.org
On the 12th day after the transplant, the mother exhibited

depressive symptoms that included sleep disturbance, appetite loss,
depressed mood, loss of volition, back pain, and neck pain. She had
no prior history of depression or other psychiatric disorder.
Her depressive state met DSM-IV diagnostic criteria for major
depression. Tetramide (mianserin) at a dose of 10 mg/day was
prescribed orally, and amytriptyline (25 mg/day) was injected
intravenously. These were effective in relieving the depression 8
weeks after administration.
http://ndt.oxfordjournals.org
Bone disease after renal transplantation

MUSCULOSKELETAL PROBLEMS
Heide Sperschneider and Günter Stein
Department of Internal Medicine IV, Friedrich-Schiller-University, Jena, Germany
Keywords: ß2 microglobulin amyloidosis; bone disease; hyperparathyroidism;

osteoporosis; renal transplantation
Introduction
Kidney transplantation largely restores defective exocrine and endocrine renal
function in patients with end-stage renal disease (ESRD). This in turn is expected to
lead to a progressive correction of established renal bone disease. This widely held
assumption, however, lacks convincing evidence from experimental and clinical data
published thus far. A major obstacle to the investigation of renal osteodystrophy in
transplant recipients has been its unpredictable evolution under the multiple
biochemical and hormonal influences that regulate mineral metabolism and bone
turnover independently. The clinical and histological features of the pre-existing
uraemic bone disease at the time of kidney transplantation are highly variable.
Moreover, its course after transplantation depends on persisting abnormalities such as
hypercalcaemia, hypophosphataemia and hypomagnesaemia as well as on the
type, dose and duration of immunosuppressive medications that are needed to
minimize allograft rejection. These factors operate additively and their effects are
often difficult to dissociatefrom the already existing osteopathy.
The existence and type of post-transplant bone disease may not be recognized
correctly and appropriate therapy may not be started in time. Although glucocorticoid
therapy represents a pathogenetic key factor other immunosuppressive drugs such as
cyclosporine, tacrolimus, azathioprine and rapamycin clearly contribute to its
prevalence and expression through their pleiotropic pharmacological effects. These
drugs have been shown to increase overall bone turnover and/or to stimulate loss of
bone mass independently. Based on currently available data, only mycophenolate
mofetil appears to have a neutral effect in this regard [1].
Only a limited number of reports dealt with this problem in the past. There is an
obvious need for well-designed prospective studies with sufficient patient numbers to
determine the relative importance of the numerous factors involved in the
perturbed bone remodelling following kidney transplantation. Furthermore, a
consensus-based classification of the various types of renal allograft-associated
osteopathy, including clinical, radiological and histomorphological criteria, might lead
to a more reliable basis for experimental research into this particular disease and
facilitate the comparison between studies. When working up a patient for symptoms
and signs of renal transplant-associated bone disease, clinical data for an effective
evaluation and treatment of this condition are often lacking. A longitudinal analysis of
the disease process would undoubtedly allow a more precise diagnosis and a more
appropriate care of post-transplant bone disease. In many cases, follow-up data from
the time of transplantation or before are unavailable or inaccessible.
Radiographicexaminations of the thoracic and lumbar spine with a bone
densitometry of the femoral neck or other sites, and an iliac crest biopsy with a
histomorphometric analysis in at last some patients should be ideally obtained before a
diagnosis is made and a treatment is initiated. Several main osteological complications
of kidney transplantation will be reviewed in the following, as summarized in Table 1
.
Table 1. Post-transplant bone disease INCIDENCE
Persistent secondary hyperparathyroidism >50%

Post-transplant osteoporosis 44% (28–88%)
Symmetric bone pain syndrome 11%
Spontaneous femoral head necrosis/localized osteonecrosis ß2M amyloidosis 3%
Disturbances of mineral metabolism
Hypercalcaemia 50% 3 months
15% 2 years
Hypophosphataemia 90% 4 months
40% 1 year
Hypomagnesaemia 40%
View this Table 1. Post-transplant bone

table: disease
[in this
window]
[in a new
window]
Persistent secondary hyperparathyroidism (HPT)
The diagnosis of persistent secondary HPT is rarely based on histomorphological data,

but only on elevated serum immunoreactive parathyroid hormone (iPTH) levels.
Increased serum iPTH concentrations are regularly found until 6 months after renal
transplantation. After 1 year, iPTH values greater than twice the normal limit are still
present in more than 50% of patients, and after 2 years in 27% of patients [2,3].
Persistently high serum iPTH levels have been attributed to a relatively slow decrease
of an oversized total parathyroid gland mass [4], in particular in association with
monoclonal, autonomous parathyroid tissue growth.
Persistent HPT is a known risk factor for increased bone turnover and decreased
overall bone density. Patients with serum iPTH levels >25 pmol/l prior to renal
transplantation have the highest rate of bone loss post-transplant and are at
increased risk for a delayed recovery of renal transplant function [5]. Most studies
documented an increased bone turnover during the first 5–6 months after
transplantation based on serum biochemistry, characterized by an increase in serum
iPTH, alkaline phosphatases and osteocalcin. Since PTH tonically
stimulates osteoblast function this may result in an apparent normalcy of serum
markers of active bone formation, although there may be a decrease in total osteoblast
reserve. The repeatedly observed inverse relation between serum 25(OH)D3 and iPTH
points to a disturbed feedback regulation between these two factors although serum
1,25(OH)2D3 generally remains within normal limits. Pre-existinghistological bone
abnormalities usually fail to resolve within 2 years after renal transplantation [6].
Recent studies suggest that serum iPTH alone may not be a valid marker of bone
turnover in renal transplant recipients. Other serum markers of bone metabolism
should be determined as well [6–10]. This leads to the question whether we
possibly overestimate serum iPTH when monitoring kidney transplant recipients, and
which cut-off value should be used to define secondary HPT in this condition.
Torres et al. [3], who performed a meta-analysis of several reports with determinations
of serum iPTH levels at various time intervals after kidney transplantation [8–
11], surprisingly noticed elevated iPTH concentrations in the presence of high and also
of low bone turnover (i.e. respectively, osteitis fibrosa and adynamic bone disease). To
make things even more complicated, low turnover osteopathy may go along with
eitherpreserved or defective bone mineralization, depending on bone receptor density
and/or the presence or absence of steroid medication [9,11]. The main risk factors for
persistent HPT in renal transplant recipients are long-term pre-transplant dialysis
treatment and an increase in pre-transplant serum iPTH levels to more than three times
the upper limit of normal.
These observations suggest that in renal patients with secondary HPT, who are on a
transplantation waiting list, the medical treatment of parathyroid overfunction should
be intensified, and surgery should be considered timely for those resistant to medical
treatment. The estimated frequency of parathyroidectomy following renal
transplantation is currently 5%. However, this type of surgery has its own risks,
including a possible deterioration of graft function in up to 20% of the patients owing
to chronic hypocalcaemia. The possible value of calcimimetic agents to prevent this
problem is unclear at present [12].
Finally, hypophosphataemia is a frequent problem after kidney transplantation. It is

observed in 90% of graft recipients for the first 4 months and in 20–40% at 1 year. Its
pathogenesis is complex, and it is often associated with subnormal graftfunction.
Moreover, it may promote osteomalacia. In clinical practice, oral phosphate
supplementation is often maintainedbeyond actual needs and at unnecessarily high
doses. Such overtreatment can even induce secondary HPT [13–15].
Post-transplant osteoporosis
Rapid loss of bone mass has been reported in 28–88% of graft recipients after renal
transplantation. The loss may beextensive, at an estimated rate of 6.8% during the first
year after transplantation [16–21]. The rate at which bone mass is lost gradually
decreases with time, with a residual annual rate of 1.7% being found by the 10th year
after renaltransplantation based on bone histology with a large prevalence of
osteoporosis. This condition arises from an overall decrease in bone mineralization
together with a reduction in bone formation. Long-term glucocorticoid administration
and possibly cyclosporine treatment may chronically activate osteoclasts in spongy
and/or cortical bone while osteoblast activity is inhibited. This in general goes along
with a low bone turnover state. As a consequence, up to 40% of renal graft recipients
have spontaneous osteoporotic pain. The highest incidence of bone fractures occurs
at 2 years post-transplant. Approximately 22% of the patients will
experience fractures at least once during follow-up, with an absolute risk three times
that of age-matched controls [19,22]. From a clinical point of view, two caveats are
important to consider when osteodensitometry findings are evaluated in patients with
suspected post-transplant osteoporosis. (i) Pre-existing abnormalities such as renal
osteodystrophy, extra-osseous calcifications and mechanical bone deformation owing
to hypophosphataemic osteomalacia may significantly bias the diagnostic power and
preclude any specific conclusion in the absence of a longitudinal follow-up.
Furthermore, since osteoporosis is frequent in post-menopausal patients, it may be
indistinguishable from post-transplant osteoporosis based on radiographic criteria
[23]. (ii) When interpreting radiographicstudies, it should be borne in mind that
osteoporosis in renal transplant recipients is usually associated with high bone
turnover and an increase in serum levels of various markers of bone metabolism.
Several circulating markers such as tartrate-inhibitable alkaline phosphatase 5b

(TRAP 5b), pyridinium cross-laps or cross-linked telopeptide have been shown to
correlate with osteoclast activity. However, their clinical value for the diagnosis of
low bone remodelling is as yet unproven. These markers are acceptable clinical
parameters for the evaluation of the effectiveness of anti-resorptive therapies, although
their usefulness as predictors of fracture risk in place of radiographic scores still
remains to be determined.
Steroid medication is a well known risk factor for osteoporosis and there is no known
threshold dose. In clinical practice,some patients fail to benefit from daily doses as
low as 2.5–7.5 mg of prednisone, whereas daily doses >7.5 mg will definitively induce
osteoporosis in the majority of patients. An inverse relation between cumulative
steroid dose and decreased bone mass has been demonstrated by Monier-Faugere et al.
[9]. Furthermore, vitamin D receptor polymorphism may play a role [24].
Considering cyclosporine, solely experimental animal data suggest an independent
pathogenetic role in post-transplant osteoporosis [1].
In the absence of established clinical data, current guidelines for the prevention and
treatment of osteoporosis in renal transplant recipients mainly rely on published
evidence from other forms of osteoporosis. The following preventive measures have
been suggested to reduce the risk of fractures: (i) use of low corticosteroid doses for a
limited time period in the pre-transplant period in patients with ESRD waiting for
transplantation; (ii) 30 min of vigorous physical exercise or daily physiotherapy;
(iii) identification and treatment of risk factors for osteoporosis; (iv) no alcohol or
nicotine consumption; and (v) hormone replacement therapy in post-menopausal
women.
Specific drug treatment includes supplementation of calcium via calcium carbonate

and prescription of anti-resorptive drugs, e.g. vitamin D metabolites, bisphosphonates,
calcitonin and/or oestrogens depending on the clinical picture. Thus,
repeated intravenous administration of 0.5 mg/kg pamidronate immediately after
transplantation and 4 weeks later led to a significant reduction in bone loss at the
femoral neck and lumbar vertebrae over a period of 12 months [25]. In patients with a
bone density T-score >2.5 and in those with a history of bone fractures, diabetes
mellitus or a combined kidney/pancreas transplantation, a treatment with
bisphosphonate, vitamin D3, and/or calcium supplementation is strongly recommended
[21,26]. The administration of low doses of active vitamin D derivatives and calcium
has been shown to prevent partial bone loss at the lumbar spine and proximal femur
when given for the first 6 months after transplantation.Bisphophonates may also be
symptomatically useful, by reducing osteoporotic bone pain [27]. Finally, recombinant
PTH administration may be indicated in the future [28,29].
Pain in the distal extremities [‘symmetric bone pain syndrome’; ‘calcineurin

inhibitor-induced pain syndrome’ (CIPS)]
Primary musculoskeletal pain has been reported in 19–35% of renal transplant

recipients [30–32]. The syndrome ischaracterized by symmetrical resting pain in the
legs [30,33]. More than 10% of patients receiving cyclosporine therapy for kidney
transplantation will experience spontaneous symmetrical musculoskeletal pain of no
obvious other origin [30]. The syndrome is at present recognized as an independent
entity and may be difficult to differentiate from musculoskeletal pain secondary to
HPT, sensory polyneuropathy, gout, osteoporosis or avascular bone necrosis. The
diagnosis therefore is largely one by exclusion. Its pathogenesis remains unclear.
Microscopic epiphyseal fractures with marrow oedema, localized micro-vasculitis and
ill-defined alterations of the pain threshold have all been implicated. Magnetic
resonance imaging (MRI) and bone scintigraphy may help identify areas of localized
inflammation to establish the diagnosis. In the case of cyclosporine-associated pain,
FK-506 may be used instead [30,32,33]. Finally, calcitonin may be useful to
treatskeletal pain. Alternatively, calcium-channel antagonists, active vitamin D
derivatives, and short-term administration of non-steroidal anti-inflammatory drugs
may be worthwhile.
Spontaneous femoral head necrosis/localized osteonecrosis
The prevalence of spontaneous osteonecrosis of the femoral head has declined in the
past from 15 to 4.8% at present. The main risk factor remains chronic corticosteroid
administration [34,35]. Localized vasculitis of the bone, vascular thrombosis and
fatty embolism have been shown to cause osteonecrotic lesions. Conventional X-ray or
better MRI will allow the diagnosis in most cases. The condition is usually treated by
early surgical decompression of the femoral head to prevent venous congestion or
endoprosthetic replacement. Calcitriol treatment has been shown to normalize bone
metabolism, to decrease bone loss and to substantially reduce the risk of femoral head
necrosis in kidney transplantpatients [34].
ß2 Microglobulin (ß2M) amyloidosis
The recovery of normal renal function in renal graft recipients leads to the regression
of ß2M-associated disturbances of bone metabolism. Articular ß2M deposits are
frequently present and may remain detectable 10 years after transplantation[39]. ß2M
amyloidosis may promote local inflammation and thereby favour chronic destructive
arthropathy. Therefore,symptomatic patients with localized bone pain and no other
diagnosis should be additionally screened for ß2M amyloidosis using X-ray, MRI,
bone scintigraphy, or a biopsy. Fortunately, in the majority of patients the clinical
expression of ß2M amyloidosis decreases or even disappears after renal
transplantation [36].
Conclusion
The persistently high prevalence of post-transplantation osteopathies, particularly of

HPT and osteoporosis, should prompt us to place greater and more rigorous emphasis
on active diagnostic and therapeutic measures to minimize treatable risk factors.
Ideally, the careful monitoring of each patient's clinical course should start long ahead
of renal transplantation, with target serum iPTH levels being meticulously kept at two
to three times the upper limit of normal by adequate medical or surgical therapy. The
use of non-steroidal immunosuppressants or low-dose corticosteroid regimens to
prevent allograft rejection in combination with prophylactic anti-resorptive bone
therapy at the time of transplantationwill help to avoid an accelerated loss of bone
mass with age in renal transplant patients. Future research will need to focuson these
aspects.
Notes
Correspondence and offprint requests to: Prof. Dr Heide Sperschneider, KfH

Kuratorium für Dialyse und Nierentransplantation e. V., Zur Lämmerlaide 1, D-07751
Jena-Drackendorf, Germany. Email:heide.sperschneider@kfh-dialyse.de
References
1. Goodmann GR, Dissamayake JR, Sodam BR et al.

Immunosuppressant use without bone loss-implications for
bone loss after transplantation. J Bone Miner Res 2001; 16:72–
78[CrossRef][Medline]
2. Evenepoel P, Kuypers D, Maes B, Messiaen T, Vanrenterghem

Y. Persistent hyperparathyroidism requiring parathyroidectomy
after successful kidney transplantation. In 10. ESOT-Congress,
5–11 October, 2001, Lissabon, Abstract
3. Torres A, Lorenzo V, Salido E. Calcium metabolism and skeletal

problems after transplantation. J Am Soc Nephrol 2002;
13:551–558[Free Full Text]
4. Drüeke TB. Cell biology of parathyroid gland hyperplasia in

chronic renal failure. J Am Soc Nephrol 2000; 11:1141–
1152[Free Full Text]
5. Traindl O, Längle F, Reading S et al. Secondary

hyperparathyroidism and acute tubular necrosis following renal
transplantation. Nephrol Dial Transplant 1993; 8:173–
6. Reinhardt W, Bartelworth H, Jockenhövel F et al. Sequential

changes of biochemical bone parameters after kidney
transplantation. Nephrol Dial Transplant 1998; 13:436–
7. Carlini RG, Rojas E, Arminio A, Weisinger JR, Bellorin-Font E.

What are the bone lesions in patients with more than four
years of a functioning renal transplant? Nephrol Dial Transplant
1998; 13:103–104[Abstract/Free Full Text]
8. Briner VA, Thiel G, Monier-Faugere MC et al. Prevention of

cancellous bone loss but persistence of renal bone disease
despite normal 1,25 vitamin D levels two years after kidney
transplantation. Transplantation 1995; 59:1393–1400[Medline]
9. Monier-Faugere MC, Mawad H, Qi Q, Friedler RM, Malluche HH.

High prevalence of low bone turnover and occurrence of
osteomalacia after kidney transplantation. J Am Soc Nephrol
2000; 11:1093–1099[Abstract/Free Full Text]
10. Weisinger JR, Carlinini RG, Rojas E, Bellorin-Font G. Bone

disease after renal transplantation. Transplant Proc 1999;
31:3033–3034[CrossRef][Web of Science][Medline]
11. Velasques-Forero F, Mondragón A, Herrero B, Pena JC.

Adynamic bone lesion in renal transplant recipients with
normal renal function. Nephrol Dial Transplant 1996; 11:58–
12. Drüeke TB. The place of calcium and calcimimetics in the

treatment of secondary hyperparathyroidism. Nephrol Dial
Transplant 2001; 16 [Suppl 6]:15–17[Medline]
13. Levi M. Post-transplant hypophosphatemia. Kidney Int 2001;

59:2377–2387[Web of Science][Medline]
14. Felsenfeld AJ, Gutman RA, Drezner M, Llach F.

Hypophosphatemia in long-term renal transplant recipients:
effects on bone histology and 1,25-dihydroxycholecalciferol.
Miner Electrolyte Metab 1986; 12:333–341[Web of Science]
[Medline]
15. Caravaca F, Fernández MA, Ruiz-Calero R et al. Effects of oral

phosphorus supplementation on mineral metabolism of renal
transplant recipients. Nephrol Dial Transplant 1998; 13:2605–
16. Pichette V, Bonnardeaux A, Prudhomme L, Gagné M, Cardinal J,

Quimet D. Long-term bone loss in kidney transplant recipients:
a cross-sectional and longitudinal study. Am J Kidney Dis 1996;
28:105–114[Web of Science][Medline]
17. Grotz
W, Rump LC, Niessen A et al. Treatment of osteopenia
and osteoporosis after kidney tranplantation. Transplantation
1998; 66:1004–1008[Medline]
18. CaycoAV, Wysolmerski JJ, Simpson C et al. Posttransplant bone

disease: evidence for a high bone resorption state.
Transplantation 2000; 70:1722–1728[Web of Science][Medline]
19. GianniniS, D'Angelo A, Carraro G et al. Persistently increased

bone turnover and low bone density in long-term survivors to
kidney transplantation. Clin Nephrol 2001;353–363
20. CruzDN, Wysolmerski JJ, Brickel HM et al. Parameters of high

bone-turnover predict bone loss in renal transplant patients: a
longitudinal study. Transplantation 2001; 72:83–88[Medline]
21. Keller T, Lehmann G, Sperschneider H, Stein G.

Ibandronat steigert die Knochenmineraldichte bei Osteoporose
nach Nierentransplantation. Med Klin (Abstr) 2002; 97:143
22. Patel
S, Kwan JTC, Mc Closkey E et al. Prevalence and causes of
low bone density and fractures in kidney transplant patients. J
Bone Miner Res 2001; 16:1863–1870[CrossRef][Web of
Science][Medline]
23. Weber TJ, Quarles LD. Preventing bone loss after renal
transplantation with bisphosphonates: we can... but should we.
Kidney Int 2000; 57:735–737[CrossRef][Web of Science]
[Medline]
24. TorresA, Machado M, Concepción T et al. Influence of vitamin

D receptor genotype on bone mass changes after renal
transplantation. Kidney Int 1996; 50:1726–1733[Medline]
25. FanSLS, Almond MK, Ball E, Evans K, Cunningham J.

Pamidronate therapy as prevention of bone loss following renal
transplantation. Kidney Int 2000; 57:684–690[Web of Science]
[Medline]
26. Grotz
W, Nagel C, Poeschel D et al. Effect of ibrandronate on
bone loss and renal function after kidney transplantation. J Am
Soc Nephrol 2001; 12:1530–1537[Abstract/Free Full Text]
27. Grotz
W, Rump JA, Niessen A, Schmidt-Gayk H, Schollmeyer P.
Treatment of bone pain after kidney transplantation.
Transplant Proc 1998; 30:2114–2116[Medline]
28. Neer
RM, Arnaud CD, Zanchetta JR et al. Effect of parathyroid
hormone (1–34) on fractures and bone mineral density in
postmenopausal women with osteoporosis. N Engl J Med 2001;
344:1434–1441[Abstract/Free Full Text]
29. LaneNE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud

CD. Parathyroid hormone treatment can reverse corticosteroid-
induced osteoporosis. J Clin Invest 1998; 102:1627–1633[Web
30. GrotzWH, Breitenfeldt MK, Braune SW et al. Calcineurin-

inhibitor induced pain syndrome (CIPS): a severe disabling
complication after organ transplantation. Transplant Int 2001;
14:16–23[CrossRef][Web of Science][Medline]
31. Tuncay IC, Demirag A, Haberal M. Muscoskeletal problems

after kidney transplantation. Transplant Proc 1995; 27:2581–
2582[Medline]
32. Barbosa
LM, Gauthier VJ, Davis CL. Bone pain that responds to
calcium channel blockers. Transplantation 1995; 59:541–
544[Medline]
33. Stevens
JM, Hilson AJW, Sweny P. Post-renal transplant distal
limb bone pain. Transplantation 1995; 60:305–307[Medline]
34. NeubauerE, Neubauer N, Ritz E, Dreikorn K, Krause KH. Bone

mineral content after renal transplantation. Klin Wochenschr
1984; 62:93–96[Medline]
35. Tang
S, Chan TM, Lui SL, Li FK, Lo WK, Lai KN. Risk factors for
avascular bone necrosis after renal transplantation. Transplant
Proc 2000; 32:1873–1875[CrossRef][Web of Science][Medline]
36. BardinT, Le Bail-Darné JL, Zingraff J et al. Dialysis arthropathy
outcome after renal transplantation. Am J Med 1995; 99:243–
248[CrossRef][Medline]
http://www.fmshk.org
Medical Complications After Renal Transplantation

Dr. Ho Yiu-Wing
Department of Medicine & Geriatrics, United Christian Hospital
With better control of adverse immunological events during early post-renal transplantation
period, graft loss caused by rejection has significantly been reduced and successful
transplantation is common. There are increasingly more elderly as well as patients with multiple
co-morbidities received renal allografts. As a result, renal transplant recipients may develop a
spectrum of complications related to the transplantation, the immunosuppression, their
underlying disease or the
previous uremia state.There were 71 deaths among 999 transplant recipients followed up in Hong
Kong with transplant operation between 1st January 1995 and 31st December 2000. The major
causes of death were: Cardiac 14.1%; CVA 4.2%; Infection 35.2%; Liver failure 16.9% (14.1%
related to HBV); Malignancy 8.5%; Suicide 1.4% and Unknown 19.7%. The causes of graft
failure among 132 recipients were: Technical/Vascular 12.9%; Died with functioning graft
30.3%; Missing/Defaulted
0.8%; Non-functioning 6.1%; Non-Immune failure 3%; Original disease recurrence 4.5%; Acute
rejection 22.7%; Chronic rejection 8.3%; Hyperacute rejection 1.5% and Unknown reasons 9.9%
respectively. (Data from the Hong Kong Renal Registry).
Complications Affecting Graft Function .
The medical causes of early graft dysfunction include a broad spectrum of diagnosis
encompassing acute rejection, acute tubular necrosis, or drug toxicity.
Acute tubular necrosis can be minimized by careful management of fluid status and the
avoidance of prolonged warm and cold ischaemic time during organ procurement.
Rejection Hyperacute rejection occurs within minutes or hours of graft revascularization and is
due to the presence of pre-existing cytotoxic antibodies in the recipient's blood reacting with
antigens on the transplanted kidney leading to rapid allograft destruction with extensive
thrombosis and acute inflammatory infiltrates. Sensitive cross-matching prevents this
complication.
Accelerated acute rejection occurs sooner than expected by the first exposure to antigens and
occurs within 7-10 days after transplant. The recipient has both memory T cells and B
cells/plasma cells capable of producing anti-graft response. The recipient may have been
sensitized to HLA antigens by multiple blood transfusions, multiple pregnancies or previous
transplants. Current or prior circulating anti-HLA antibodies are detected by routine PRA
screening done by the Tissue Typing Laboratory.
Hyperacute and accelerated acute rejection are not prevented by medications. Acute cellular and
vascular rejection accounts for most of the immunological graft loss. The risk of acute rejection
is greatest during the first 2 months after transplantation, diminishing significantly afterwards.
Nowadays acute renal allografts rejection seldom presents with the "classic" triad of fever,
oliguria and a tender, swollen graft. The most common presentation of acute rejection is a
modest, asymptomatic rise in the serum creatinine level and the diagnosis can be confirmed by
renal biopsy. High dose pulse steroids can reverse 75% of first acute rejections and antibody
treatment with OKT3, ALG or ATG
may be required for recurrent or refractory rejections. Switching from cyclosporine to tacrolimus
or adding mycophenolate mofetil (MMF) in patients who have not previously received it, have
been shown to be effective treatment of refractory rejections.
Chronic rejection or chronic allograft nephropathy is an important cause of long-term graft loss.
The pathogenesis is poorly understood. Poor early graft function; acute rejection episodes
(especially multiple or occurring after 6 months); suboptimal immuno-suppression;
histocompatibility mismatch and medical noncompliance are the major risk factors for chronic
rejection. The most common time of presentation is during the second post transplant year
though it can still present after more than 10 or 20 years, and is most often characterized by
progressive graft dysfunction. Proteinuria and
hypertension occur in at least 70% of patients who have chronic rejection. Reversal or arrest in
the progressive deterioration in renal function is seldom possible.
Drug toxicity Both calcineurin-inhibitors, cyclosporine and tacrolimus, produce nephrotoxicity.

Acute elevation in serum creatinine level that reverses with dose reduction may occur, apparently
caused by renal vasoconstriction. Chronically, cyclosporine and tacrolimus can induce a
tubulointerstitial fibrosis with characteristic afferent arteriolar hyalinosis. Moreover, both agents
can also induce haemolytic-uraemic syndrome, which is usually associated with elevated drug
levels, and
cause deterioration in allograft function.
Recurrent disease in the renal transplant Recurrence of original disease accounts for 4.5% of
allograft failures. Patients usually present with deterioration in renal function, proteinuria,
hypertension, active urinary sediments or a combination of these. They may also be
asymptomatic. Renal biopsy is required to establish the diagnosis. The use of
immunofluorescence staining and/or electron microscopic examination may be required.
Mesangiocapillary glomerulonephritis type II, Henoch-Schonlein purpura, IgA nephropathy,
primary focal segmental glomerulosclerosis, Mesangiocapillary glomerulonephritis type I, and
membranous nephropathy, anti-GBM nephritis etc
tend to recur after renal transplantation, with the chance of recurrence in descending order.
Certain metabolic disorders like diabetes, amyloidosis, oxalosis and cystinosis do recur after
transplant.
De novo diseases These include de novo membranous nephropathy leading to heavy proteinuria
or nephrotic syndrome. The occurrence of anti-GBM antibody disease in transplant recipients
with Alports syndrome may represent the sensitization of the recipient to antigenic components
in the donor kidney GBM during the transplantation process and the antigens had not previously
been recognized.
Pre-renal, renovascular as well as obstructive causes of renal allograft dysfunction need to be
ruled out in cases of post-transplant deterioration in renal function.
Complications Secondary to Immuno-suppressive Therapies

Drug side effects
Corticosteroids are commonly used in the induction and maintenance phase of
immunosuppressive therapy and also in the management of acute rejections. In addition to the
side effects associated with immunosuppression, steroids commonly induce cushingoid features,
skin thinning, osteoporosis, avascular necrosis of bone as well as diabetes. Azathioprine may
cause bone marrow suppression leading to leucopenia, anaemia and thrombocytopenia and
megaloblastoid
changes. There is an increased risk of malignancy, hepatotoxicity and hair loss. Calcineurin
inhibitors, cyclosporine and tacrolimus may induce nephrotoxicity, neurotoxicity (especially
tremor), diabetes, hypertension, hyperkalaemia, hyperuricaemia and hypomagnesaemia. Skin
changes such as hirsuitism, gingival hypertrophy, hypertension and hyperlipidaemia are more
common with cyclosporine whereas tremor and glucose intolerance are more common with
tacrolimus. Mycophenolate Mofetil can induce diarrhoea. It may also cause leucopenia and
perhaps and its analogs may cause hyperlipidaemia and thrombocytopenia.
Infection Infection is the most important cause of early morbidity and mortality following
transplantation. It is closely linked to the degree of immunosuppression and thus to the frequency
and intensity of rejection and its therapy. Moreover, infection with cytomegalovirus (CMV) has
been implicated in the development of rejections in both clinical and experimental settings and
late acute rejection has been ascribed to clinically covert CMV infection. Infections after renal
transplantation are best categorized according to their usual time of occurrence following
transplantation. Infections
that occur shortly after transplantation are usually from common bacteria or nosocomial
infections involving the urinary tract, respiratory tract or surgical wound. Infections between 1
and 4 post transplant months, at the height of immuno-suppression, are typically opportunistic
infections cause by viruses like CMV, Epstein-Barr virus (EBV), Varicella-zoster virus (VZV);
parasites like pneumocystis, toxoplasma sp.; bacteria like Nocardia, listeria, mycobacterium spp.
and fungal organisms like aspergillus, mucor and cryptococcus. Infections that occur late (after 3
or 4 months) may be persistent infections, opportunistic infections or infections associated with
malignancies.
Common organisms that are involved in late infections include CMV, VZV, Cryptococcus,
HBV, HCV, and the malignancy associated viruses like EBV, herpes simplex virus HHV-8.
Liver failure secondary to hepatitis B virus (HBV) infection or reactivation is a significant cause
of death among recipients who are HbsAg positive.
Malignancies Immunosuppression increases the risk for malignancy. The overall incidence of
post renal transplant malignancies in Hong Kong was 2.4% and the risk ratio was 4.8 when
compared with the general population. (Chau et al., Hong Kong Journal of Nephrology, 2000;
2(2):84-90). The risks for transplant recipients are related to the dose, duration and type of the
nonsteroidal immunosuppressants, and in part on the ability of these agents to promote the
growth of various oncogenic viruses, such as papillomaviruses, HSV and EBV. The relative risk
for occurrence is high with Kaposi sarcoma, non-Hodgkin's lymphoma (PTLD or post transplant
lymphoproliferative
disorders), carcinoma of vulva or anus and skin cancer. Malignancy may occur at any time after
transplantation. However, some are more likely to occur earlier after transplantation and these
include PTLD and Kaposi sarcoma. The incidence of malignancy continues to increase
throughout the late post-transplantation period and the cumulative incidence of non-skin
malignancy may reach 33% 30 years after transplantation.
Complications Affecting the Patient, Increasing the Morbidity and Mortality
Cardiovascular complications Patients with end-stage renal disease are predisposed to

cardiovascular complications and the prevalence of coronary heart disease is even greater in
renal transplant recipients especially if they are diabetic and old (>60 y.o.). Hyperlipidaemia is
common after renal transplantation. Cyclosporine as well as corticosteroid therapies clearly
contribute to the hyperlipidaemia and hypertension. Management of renal transplant recipients
includes the pharmacological as well as the non-pharmacological correction of hypertension and
hyperlipidaemia. Coronary as well as cerebral vascular risk factors need to be evaluated and
modified if present. Patients at risk should have their coronary heart disease identified earlier and
managed proactively. They are advised to have their blood pressure and hyperlipidaemia under
good control, to abstain from smoking, to reduce excess body weight and to have regular
exercise.
Haematologic complications. There is an initial burst of erythropoietin at the time of

engraftment but does not result in erythropoeisis. A second burst occurs at about 1 month post-
transplant and is normally followed by effective production of erythrocytes. Anaemia after renal
transplant may be the result of diminished iron store and is unable to respond to the
erythropoietin production by the allograft. Treatment with Azathioprine or MMF may lead to
bone marrow suppression. Neutropenia may be due to the dose related marrow suppression by
drugs like Azathioprine or MMF or an idiosyncratic response to a number of drugs that are used.
Neutropenia may also be the anifestation
of systemic infection by viruses, fungi or mycobacteria. Post-transplant erythrocytosis (PTE) is
the persistently elevated haematocrit level of >51%. It affects 5-19% of post-transplant
recipients, usually presents within the first 2 years in those with excellent graft function.
Hypertension and thromboembolic events have been reported. Current therapy is based on the
use of angiotensin II receptor blockers and ACE inhibitors.
Gastrointestinal complications .Gingival hyperplasia can be a severe and aggravating problem

in renal transplant recipients and is related to the use of cyclosporine, poor dental hygiene, dental
prothestics and the use of drugs like phenytoin. Esophagitis may be caused by Candida albicans
as well as HSV type I and CMV. Both MMF and tacrolimus can cause bloating, nausea,
vomiting and diarrhoea. However, diarrhoea may also be caused by a variety of organisms
including CMV,
Strongyloides sp., Clostridium difficile (toxin), other parasites and enteric pathogens.
Liver disease Liver disease may be responsible for 8-24% of the late mortality. Acute liver
dysfunction may be caused by acute viral hepatitis (HAV, HBV, HCV, CMV, HSV, HHV-6,
EBV), medications (notably Azathioprine, cyclosporine, acetaminophen and antibiotics), and
etiologies
(e.g. alcohol) that can be associated with chronic active hepatitis, cirrhosis or carcinoma of liver.
The patient as well as graft survival for HbsAg positive recipients are inferior when compared
with those who are negative. The use of Lamivudine, a nucleoside analog that interferes with
reverse transcriptase activity of HBV, has been shown to be effective in reducing HBV DNA to
undetectable level. However, the emergence of resistant strains is a long term concern. A more
rapid progression of liver disease has been reported in renal transplant recipient who are HCV-
positive especially in those who are older with ALG therapy. The graft as well as patient
survivals are also inferior when compared with those HCV-ve subjects. However, HCV-positive
transplant recipients appear to have better survival than those HCV-positive patients on dialysis.
Musculoskeletal and metabolic complications. Mild hypercalcaemia associated with persistent

hyperparathyroidism is not uncommon post-transplant. Persistent hyperparathyroidism may
occur, often the result of continuous autonomous production of parathyroid hormone requiring
total parathyroidectomy with or without auto-implantation. Osteoporosis with progressive loss of
bone mineral density may occur after renal transplant. Two persistent contributing factors
include corticosteroid treatment and the female gender. Avascular necrosis and gout may
complicate the
post-transplant course. Episodic bone pain in the knees and/or ankles may occur in patients on
cyclosporine. The pain is usually worse at night or with recumbency and may be relieved by
upright position or walking.
Post-transplantation diabetes mellitus (PTDM) may complicate the post-transplant course in

5-10% of calcineurin based immunosuppressive therapy. The onset of PTDM may be within 3
weeks to more than 20 years after transplantation. Diabetic nephropathy has been reported in
patients who develope de novo PTDM.
Ocular complications. The most common ocular complication in renal transplant recipients is
posterior subcapsular cataract secondary to corticosteroid treatment. However, Ophthalmic
herpes zoster, retinitis by CMV or toxoplasmosis, enophthalmitis by invasive sinus infection may
progress rapidly with devastating consequences and require immediate attention. Regular
ophthalmologic examinations should be routine in renal transplant recipients, especially if they
are diabetic.
Conclusion
Renal transplantation results in excellent rehabilitation and better quality of life among patients
on renal replacement therapies. A delicate balance should be maintained between the amount of
immunosuppression to prevent allograft rejection and the side effects that are related to
medications as well as immunosuppression. Proactive management in the prevention of
cardiovascular and metabolic complications may further reduce the post-transplant morbidity and
mortality in the future
Signs of Kidney Transplant Infection

• Fever
• Tiredness or fatigue
• Diarrhea or vomiting
• Redness or drainage around your incision
• Cough and sore throat
Signs of kidney transplant rejection

- Increase temp.
- Increase bp
- Sudden increase in wt or ankle swelling
- Decrease urine output
- Pain, tenderness or swelling of the new kidney
- Elevated creatinine
•
http://www.springerlink.com imaging uretral/urinary system problem
smoking causes afferent vasoconstriction, presumably protecting

the glomerulus against the acute rise in blood pressure. In
contrast, in the patient with renal disease, preglomerular vessels
are vasodilated. Apparently smoking induced vasoconstriction is
unable to overcome vasodilation, so that the smoking‐induced
increase in blood pressure can be transmitted into the
glomerulus, causing glomerular hypertension
• With exception of infection, ureteral obstruction is the most common urinary tract problem
associated with transplantation. It may occur early or late. Early obstruction may result from clot,
edema, or technical problems associated with the ureteroneocystostomy. When Foley catheter
placement and expectant management does not resolve the problem, surgical revision of the
ureteroneocystostomy over a stent may be required. Late obstruction, when not caused by
external compression (eg, lymphocele, pregnancy), is associated most typically with fibrosis
or nephrolithiasis. Management is typically by radiologic or cystoscopic stent placement and
stricture dilatation.
• Urine can leak at any level of the urinary tract, from the renal pelvis to the urethra. Suspect urine
leak when a patient with good or improving graft function develops a fluid leak from the wound or
abdominal pain or perineal swelling, typically within a month of transplantation. Fluid leaking from
the wound can be collected and assayed for creatinine. Nuclear renal scan is probably the most
sensitive test for urine leak. Small bladder leaks often can be managed by bladder
decompression with a Foley catheter. Larger and more proximal leaks typically require
exploration and repair.

The Adrenal Gland Laboratory

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Adrenal Gland Laboratory

Uploaded by

Copyright:

Available Formats

The adrenal gland is really two glands in one.

The adrenal cortex,

• the hypothalamus produces corticotropin-releasing hormones, which

We'll describe each part individually:

The Adrenal Cortex

Adrenal Cortex Functions

• hydrocortisone hormone - this hormone, also known as

• aldosterone hormone - this hormone inhibits the level of sodium

Adrenocortical cells synthesize and secrete chemical derivatives (steroids)

The adrenal cortex is capable of synthesizing all of the steroid hormones

The biologic effect of aldosterone, the principal mineralocorticoid, is to set in

Cortisol (hydrocortisone) is the major human glucocorticoid. It exerts

Adrenal androgens are not as potent as testosterone, the major steroid

Regulation of hormone secretion

The three classes of corticosteroids (the mineralocorticoids, the

Aldosterone secretion is modulated directly by serum electrolyte levels.

Aldosterone increases the reabsorption of sodium (and the excretion of

BUN and Creatinine are tests done to monitor kidney function.

Occasionally used tests

Renin. Renin activity is elevated in primary adrenal insufficiency because a lack of

21-hydroxylase autoantibodies are sometimes ordered as part of the diagnostic process

CT (computerized tomography) or MRI (magnetic resonance imaging) scans are sometimes

What does the test result mean?

Is there anything else I should know?

Too much cortisol can cause symptoms that include:

• fragile and thin skin

• purple lines on the abdomen

• increased body hair

• increased skin pigmentation, even in areas not exposed to the sun

What does the test result mean?

DISEASE CORTISOL ACTH

Cushing's disease (pituitary tumor making ACTH) High High

Adrenal tumor High Low

Addison's disease (adrenal damage Low High

Hypopituitarism Low Low

Is there anything else I should know?

Secretion of ACTH may be increased by stress.

ACTH (cosyntropin) stimulation test

Note: mcg/dL = micrograms per deciliter

* Acute adrenal crisis

Aldosterone and Renin

Related tests: Cortisol; Electrolytes; Potassium; Aldosterone/Renin activity calculation or ratio;

What does the test result mean?

DISEASE ALDOSTERONE CORTISOL RENIN

Primary hyperaldosteronism (Conn’s High Normal Low

Secondary hyperaldosteronism High Normal High

Cushing’s syndrome Low-normal High Low

Adrenal insufficiency (Addison's disease) Low Low High

http://ndt.oxfordjournals.org april 5,2010

Keywords: pregnancy; renal transplantation

Fertility is usually restored in women with renal transplants. Pregnancy is then

Effect of pregnancy on graft function

In cyclosporin-treated patients, graft dysfunction after pregnancy was seen in patients

Immunosuppressive drugs in pregnancy

Currently, we have limited information regarding the toxicities and teratogenic

OKT3 and polyclonal antibodies

Contraceptive counselling should begin immediately after transplantation, because

View this Table 1. Criteria for transplant recipients

Antihypertensive drugs used in pregnancy

An infant born to an HBSAg-positive mother should be given hepatitis B

Labour and delivery

Vaginal delivery is recommended in most transplant recipient women. Caesarean

Correspondence and offprint requests to: Dr M. Lessan-Pezeshki, Shafa Clinic No.