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“GENERAL OVERVIEW” of KIDNEY DISEASE and-

KIDNEY FAILURE
-why we are developing the
Implantable Human Kidney Replacement Unit (IHKRU)
Referred to also as the
Implantable Artificial Kidney (IAK)
by C. Edward Jennings
© COPYRIGHT 2004

Section
(1) Scope and Purpose of this Project

(2) How Human Kidneys Function:

(3) Diseases That Cause Kidney Failure:

(4) Kidney Failure, End Stage Renal Disease (ESRD)


and Dialysis:

(5) The Composition of Blood/Plasma and Blood


Clotting:

(6) The Human Kidney Replacement Unit (HKRU) also


referred to as the Implantable Artificial Kidney
(IAK)

Actual Size in-Hand of Implantable Artificial Kidney


(IAK)

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SECTION 1

Scope and Purpose of this project is to design and develop an


implantable self contained, fully functional, compact (2-1/4” high X ½”
thick X 3” long) Human Kidney Replacement Unit (HKRU). This non-
clotting, (non-coagulating) unit initially can be worn extracorporeal
(outside the body), unnoticed, beneath the clothing of patients having
end stage renal disease ESRD ( a point at which not more than 10
percent of
the kidney functions remain). Then, after a performance trial-period of
not more than one year, a full evaluation will be performed to see how
well the patient has responded to the HKRU. If the patient is having
satisfactory chemical balance, and full excretion/urinary functions,
then at the request of the patient, the HKRU can be implanted as if t it
were an actual human donor kidney allograft.

There are currently more than 67,000 deaths in America each year
as a result of end stage renal disease. Approximately 110 out of every
100,000 people are diagnosed with ESRD; also, as far back as 1997 the
United States Renal Data System (USRDS) had estimated that more than
300,000 Americans had ESRD. Those who have survived until the
present time, and the new ones are being treated at dialysis centers right
now at an annual cost of more than $20 billion, a sharp increase from
$11.8 billion in 1997. There is an increase of more than 60,000 new
dialysis patients, each year, and steadily climbing as it has been for the
past five years. The ages of patients range from 19 years old on up.
Medical records indicate that 33.6% of these cases are caused by
diabetes; however, type 1 insulin-dependent diabetes mellitus accounts
for only 5 to 10 percent of all diagnosed cases of diabetes, but type 1
accounts for 30 percent of all the kidney failure cases caused by
diabetes. 22.9% are caused by high blood pressure. Every year,
hypertension causes more than 15,000 new cases of kidney failure in the
United States. 15.9% are caused by glomerulonephristis, 4.4% by cystic
kidney, and 1.9% other urologic. 21% are due to unknown causes,
possibly drugs and other chemicals.

There are at the present time an excess of 52,000 people on the national
waiting list for a kidney transplant in the U.S. according to the United
Network for Organ Sharing, but the actual number of kidney transplants
is around 12,000 annually , of these 70 percent are from cadavers
(deceased persons). After receiving a transplant, in order to combat
rejection, immunosuppressive agents are used, but are usually
accompanied by side effects such as infection, cardiovascular disease,
and even death.

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The Human Kidney Replacement Unit (HKRU), or the implantable
artificial kidney (IAK) is an artificial hemocatharsis type hemophoresis
device designed in compliance with the sciences of hemorheologyis,
assisted with internal artificial intelligence and sensors, for precise
homeostasis, hemoperfusion and osmoregulation. This device is more
patient friendly in every respect than the best dialyzing units and
processes in use anywhere in the world today. The HKRU will be
described in detail later in this report but to better understand the
HKRU the following should be reviewed.

SECTION2: How Human Kidneys Function

The Human Urinary System; is made up of the kidneys, the bladder,


two ureters, and a single urethra. The kidneys are a pair or organs
resembling large kidney beans. In the average adult, measuring
around 4” to 5” long and 2” to 3” wide, and situated against the rear
wall of the abdomen, in the middle of the back, located on either side
of the spine, beneath the liver on the right, and the spleen on the left.

Healthy kidneys in the average adult process about 125 ml/min or 45


gallons (180 liters) each day to filter out about 2 quarts of waste
product and extra water in the urine. They removing excess minerals
and wastes such as creatinine and urea. They regulate the
composition of the blood by keeping the relative concentrations of such
inorganic ions as sodium, phosphorus, and chloride in the blood
plasma at a nearly constant level. The kidneys help regulate the body’s
calcium/vitamin D activation as well as performing all the other
essential regulations described in detail in the following text.
Potassium for instance, is controlled very carefully by the kidneys, for
proper functioning of the nerves and muscles, particularly those of the
heart.
Blood Urea Nitrogen (BUN) is a waste product produced in the liver as
the end product of protein metabolism (or degradation). During
digestion, protein is broken down to amino acids. Amino acids contain
nitrogen, which is removed as NH4+ (ammonium ion), while the rest of
the molecule is used to produce energy etc.. The ammonia is combined
with other small molecules to produce urea, which makes its way into
the blood and is removed in the filtrate. Filtrate, extracted from the
blood in the Bowman’s capsule in the renal corpuscle of the kidney, is
composed of water, ions e.g. sodium, potassium, chloride), glucose and
small proteins measuring less than 30,000 daltons, which is a unit of
molecular weight).

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Creatinine Is a Waste Product of creatinine phosphate, an energy
storing molecule, produced largely from muscle breakdown and is
proportional to the muscle mass. High values, especially with high
BUN levels, may indicate problems with the kidneys. Uric Acid is
excreted in the urine. High values are also associated with kidney
problems. Phosphorus is largely stored in bone, and is regulated by
the kidneys. High levels may be due to kidney disease. The pH of
plasma (the plasma’s acidity) is carefully controlled by the kidneys
within the neutral range of 6.8 to 7.7

Three hormones are produced in the kidneys. Eerythropoietin


(EPO), which stimulates the bone marrow to produce the proper
number of red blood cells needed to carry oxygen to vital organs.
Renin, which regulates blood pressure, and the active form of vitamin
D, which maintains calcium for bones and for normal chemical
balance in the body.

When the kidneys are functioning properly and the concentration of an


ion in the blood, and hence in the glomerular filtrate exceeds its
kidney threshold value, the excess in the filtrate is not reabsorbed but
is released in the urine thus maintaining near constant levels, the
same is so with excess protein. This is done by sophisticated
mechanisms of osmosis, reverse osmosis and ion exchange filtration.

Most kidney diseases attack the nephrons, causing them to loose their
filtering capacity: therefore, medical professionals gauge the presence
and extent of kidney disease by measuring the level of blood
(hematuria), albumin and other proteins in the urine (proteinuria), the
amount of fluid (edema) in the tissues, and the levels of creatinine
and urea nitrogen in the blood. ESRD has occurred when the
glomerular filtration rate has decreased to less than 10 milliliters per
minute, most always accompanied by hypertension.

SECTION 3: Diseases That Cause Kidney Failure

All racial groups are at risk of developing kidney failure caused by one
or a combination of the following diseases, but records indicate that
African Americans, American Indians, and Hispanic Americans are
more likely than whites to develop kidney problems from high blood

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pressure, even when their blood pressure is only mildly elevated. In
fact , African Americans ages 25 to 44 are 20 times more likely than
whites in the same group to develop kidney failure as the result of
hypertension.

Kidney Disease: Kidney abnormalities can be anatomic in origin.


Many are hereditary and present at birth (congenital); however, most
kidney diseases attack the nephrons, causing them to loose their
filtering capacity. Chronic renal failure is characterized by progressive
destruction of the nephrons. As stated above, the most common
causes of kidney disease are diabetes and high blood pressure. Other
causes are glomerulonephristis, inherited and congenital kidney
diseases such as polycystic kidney disease (PKD), and some are
caused by poisons and trauma. Diabetes is a disease that keeps the
body from using glucose (sugar) as it should. If glucose stays in the
blood instead of breaking down, it can act like poison and damage the
nephrons in the kidneys. High blood pressure can also damage the
small blood vessels in your kidneys nephrons. The damaged vessels
cannot filter poisons from your blood as they should.
If the problems worsen and renal function drops below 10 to 15
percent “end stage renal disease”, the person cannot live long without
dialysis or transplantation.

Glomerulonephristis and glomerulosclerosis are broad terms that


include different forms of damage to the kidneys glomeruli.
Glomerulonephritis is the inflammation of the membrane tissue in the
kidney that serves as a filter, separating wastes and extra fluid from
the blood. Several different types of kidney diseases are grouped
together under this category. glomerulosclerosis is the scarring
(sclerosis) or hardening of the tiny blood vessels within the glomeruli.
In several sclerotic conditions, a systemic disease like lupus or
diabetes is responsible.

Diabetic Nephropathy is a glomerular disease that can actually be


placed in two categories: a systemic disease and a sclerotic disease,
because specific damage done to the kidneys is associated with
scarring, or sclerosis of the glomeruli. In addition to scarring the
kidney, elevated glucose levels appear to increase the speed of blood
flow through the kidney, putting a strain on the filtering glomeruli
which raises the blood pressure, causing even greater damage.
Although glomerulonephritis and glomerulosclerosis have different
causes, both can lead to end stage renal disease.

Diabetes Mellitus both diabetes mellitus and the un related diabetes


insipidus result in the excretion of large volumes of urine, and can
lead to ESRD. There are two types of diabetes mellitus. In patients

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with either type, the body does not properly process and use certain
foods. The human body normally converts carbohydrates to glucose,
the simple sugar that is the main source of energy for the body’s cells.
To enter cells, glucose needs the help of insulin, a hormone produced
by the pancreas. When a person does not make enough insulin, or the
body does not respond to the insulin that is present, the body cannot
process glucose, and it builds up in the bloodstream. High levels of
glucose in the blood or urine lead to a diagnose of diabetes. Both
types of diabetes can lead to kidney disease.

Type 1 Diabetes: Only about 1 in 20 people with diabetes has type 1


diabetes, known as insulin-dependent diabetes mellitis. (IDDM) People
with type I diabetes must receive daily insulin injections. Type 1
diabetes is more likely to lead to kidney failure. About 40 percent of
people with type 1 develop severe nephropathy and kidney failure by
the age of 50. Some develop kidney failure before the age of 30.

Type 2 Diabetes: About 95 percent of people with diabetes have type


2 diabetes, once known as noninsulin-dependent diabetes mellitus
(NIDDM) Many people with type 2 diabetes do not respond normally to
their own or to injected insulin, a condition called insulin resistance.
Type 2 diabetes occurs more often in people over the age of 40. The
deterioration that characterizes kidney disease of diabetes takes place
in and around the glomeruli. Early in the disease, the filtering
efficiency diminishes, and important proteins in the blood are lost in
the urine. Later in the disease, the kidneys lose their ability to remove
the waste products creatinine and urea from the blood. The final stage
is kidney failure in which the glomerular filtration rate drops to less
than 10 milliliters per minute.

Nephrogenic Diabetes Insipidus: The kidneys produce a large volume


of dilute urine because they fail to respond to antidiuretic hormone
and are unable to concentrate urine. There are also two types of
diabetes insipidus in existance. In nephrogenic diabetes insipidus, the
kidneys do not respond to antidiuretic hormones, so they continue to
excrete a large amount of dilute urine. In the other type, the pituitary
gland fails to secrete antidiuretic hormone. Nephrogenic diabetes
insipidus may be hereditary. The gene that causes the disorder is
recessive and carried on the X chromosome, so usually only males
develop symptoms. However, females who carry the gene can transmit
the disease to their sons.

Glomerular Disease can sometimes develop rapidly after an infection


in other parts of the body. Acute post streptococcal glomerulonephritas
(PSGN) can occur after an episode of strep throat, or in rare cases,

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impetigo (a skin infection) The streptococcus bacteria do not attack the
kidneys, but an infection may stimulate the immune system and bring
on sudden symptoms of swelling (edema), reduced urine output
(oliguria), and blood in the urine (hematuria). High blood pressure
frequently accompanies reduced kidney function in this disease which
can escalate into kidney failure.

Glomerulosclerosis: The following categories can overlap; that is a


disease might belong to two or more categories In several sclerotic
conditions, another systemic disease like Lupus Erythematosus (SLE),
or Lupus Nephritis, which is the name given to the kidney disease is
also responsible for scarring. This condition occurs when
autoantibodies form, or are deposited in the glomeruli, causing
inflammation. Ultimately, the inflammation may create scars,
stimulated by molecules called growth factors which may be made by
glomerular cells themselves or may be brought to the glomerulus by
circulating blood that enters the glomerular filter.

When kidney disorders develop, the signs that point to glomerular


disease are: proteinuria, large amounts of protein in the urine;
hematuria, blood in the urine, reduced glomerular filtration rate,
inefficient filtering of wastes from blood; hypoproteinemis, low blood
protein; and edema, swelling in parts of the body. With further
deterioration, glomerular filtration will be insufficient to remove waste
products such as creatinine, which is a waste product created by the
normal breakdown of muscle during activity. With ESRD the creatinine
level (referred to as serum creatinine) will be somewhat above the
normal range of from 0.6 to 1.2 milligrams per deciliter (mg/dL) of
blood.

Creatinine levels are verified by a creatinine clearance test, to see


how fast the kidneys remove creatinine from the blood and is
measured as milliliters per minute (mL/min), done from a 24-hour
collection of urine. The patient is said to have advanced clinical
nephropathy when the glomerular filtration rate has decreased to less
than 75 milliliters per minute, and total kidney failure when the
glomerular filtration rate drops to less than 10 milliliters per minute.
For men with healthy kidneys the normal creatinine clearance rate is
97 to 137 mL/min. For women, the normal rate is 88 to 128 mL/min.

Another formula is to use the serum creatinine measurement, plus


your age, weight, BUN, and race to calculate your creatinine clearance
accurately. BUN is blood urea nitrogen. ( a deciliter of normal blood
contains 7 to 20 milligrams of urea. More than 20 mg/dL is s sign of
disease kidneys ).

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Another indication of approaching ESRD is when albumin and other
proteins in the urine exceeds 200 micrograms per minute. Albumin
acts like a sponge drawing extra fluid from the body into the blood
stream, where the fluid would normally be removed by the kidneys, but
seeping into the urine at this rate causes the blood to loses its capacity
to absorb extra fluid from the body, thus causing excessive swelling in
the body. This condition is called uremia. Without dialysis, uremia will
lead to seizures, or coma and will ultimately result in death.

Diseased kidneys do not produce enough of the hormone


erythropoietin (EPO) which stimulates the bone marrow to produce
the proper number of red blood cells to carry oxygen to vital organs in
the body. When EPO is below ??? the patient is diagnosed with
anemia.

Patients with ESDR generally, are unable to maintain the


concentration of electrolytes such as the positive (+) cations sodium,
calcium, potassium and magnesium, and the negative (-) anions
chloride, bicarbonate, phosphate and sulfate, thus preventing the
normal system equilibrium, known as homeostasis. The rate of fluid
intake in the body is governed by thirst, and the rate of excretion is
governed by an antidiuretic hormone (ADH) also called vasopressin,
made in the hypothalamus, a gland in the base of the brain and stored
in the pituitary gland. With ESDR, the kidneys ability to respond to
ADH is impaired and cannot concentrate the urine by returning the
excess water to the bloodstream.

Systemic Lupus Erythematosus (SLE): Systemic Lupus


Erythematosus has the ability to occur in almost any system of the
body. People with SLE develop antibodies against their own tissue
which attacks self-tissue like a foreign invader. The disease has no
cure and more women develop SLE than men. Current theories link
the development of lupus with hereditary and environmental factors,
some of which include stress, infections and certain medications and
chemicals. Kidneys are frequently affected by SLE and this can be
critical because there are no outward symptoms of kidney failure until
it is too late. In SLE, DNA may appear outside the cells, floating in the
blood serum. In these cases the immune system produces large
numbers of antibodies to the DNA, called anti-DNA-one of the
indications of SLE. When these antibodies combine with their target,
the result is an immune complex Sometimes these complexes cannot
be removed from the blood by normal body processes, and they are
trapped in tissues of the kidneys, blood vessels and the brain.

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Renal Tubular Acidosis: A disorder that may be hereditary or may be
caused by drugs, heavy metal poisoning, or an autoimmune disease,
such as Systemic Lupus Erythematosus or Sjogrens syndrome. Three
types exist, each producing slightly different symptoms. When blood
potassium levels are low, neurologic problems may develop, including
muscle weakness, diminishing reflexes, and even paralysis. Kidney
stones may develop, causing damage to kidney cells and leading to
chronic kidney failure.

Renal Glycosuria: or Glucosuria, is a condition in which glucose


(sugar) is excreted into the urine, despite normal or low glucose levels
in the blood. When blood is filtered through the kidneys, glucose is
removed along with many other substances. The filtered fluid passers
through the network of tubules in the kidney, where it is reabsorbed
and returned to the bloodstream, and unwanted substances excreted
in the urine, but with renal glucosuria, glucose will be excreted into
the urine despite normal glucose levels in the blood.

Cystinuria: an inherited defect of the kidney tubules, causing


excretion of amino acid-cystine into the urine, causing cystine stones
in the urinary tract. People with this disorder must have inherited two
abnormal genes, one from each parent.

Fanconi’s Syndrome: a rare disorder of the tubule function that


results in excess amounts of glucose, bicarbonate, phosphates, and
certain amino acids in the urine.

Vitamin D-Resistant Rickets: a rare disorder is nearly always


hereditary, passed as a dominant gene that is carried on the X
chromosome. This defect causes a kidney abnormality that allows
phosphate to be excreted into the urine, resulting in low blood
phosphate levels.

Hartnup diaease: a rare hereditary disorder that occurs when a


person inherits two recessive genes for the disorder, one from each
parent. The disease affects how the body processes amino acids, which
are building blocks of proteins.

Bartter’s Syndrom: is a disorder in which the kidneys over-excrete


electrolytes (potassium, sodium, and chloride), resulting in low blood
levels of potassium (hypokalemia) and high blood levels of the
hormones aldosterone and renin. The levels of sodium chloride and
water in the blood become low. The body tries to compensate by
producing more aldosterone and rennin. These hormones reduce the
levels of potassium in the blood.

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Liddle’s Syndrom: a rare hereditary disorder in which the kidneys
excrete potassium but retain too much sodium and water, leading to
high blood pressure.

Polycystic Kidney Disease: a hereditary disorder in which many


cysts form in both kidneys; the kidneys grow larger but have less
functioning kidney tissue. Chronic infection, a frequent problem, can
worsen the kidney failure. About half of those with this disease have
high blood pressure at time of diagnosis.

Medullary Cystic Disease: a disorder in which kidney failure develops


along with cysts deep within the kidneys. A person starts to produce
excessive amounts of urine because the kidneys don’t respond to
antidiuretic hormone which normally signals the kidneys to
concentrate urine. This disease progresses slowly but relentlessly until
kidney failure occurs.

Medullary Sponge Kidney: a congenital disorder in which the urine-


containing tubules of the kidneys are dilated, causing the kidney
tissue to appear spongy. A person with this disorder is prone to
develop painful kidney stones, blood in the urine and kidney
infections.

Alport’s Syndrome: (hereditary nephritis), a hereditary disorder in


which kidney function is poor, blood is present in the urine, and
deafness and eye abnormalities sometimes occur. This disorder is
caused by a defective gene on the X chromosome, but other factors
influence how severe the disorder is in a person who has the gene.
Unlike women with two X chromosomes, men with the defective gene
(men do not have a second X chromosome to compensate for the
defect) and usually develop kidney failure. Symptoms are blood in the
urine, and the urine may also contain varying amounts of protein,
white blood cells, and casts (small clumps of material ) of various
types, which are visible under a microscope.

Nail-Patella Syndrome: a rare hereditary disorder of the connective


tissue that results in abnormalities of the kidneys, bones, joints and
fingernails. Kidney failure eventually develops in about 30 percent of
the people with affected kidneys. The diagnosis is confirmed by bone
X-rays and a biopsy of the kidney tissue.

Without the critical technological breakthrough of a Human Kidney


Replacement Unit like the one being developed here, persons with end
stage renal disease will have to undergo either dialysis or a kidney
transplant (allograft), if not, their time to live will be not more than

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from a few weeks to several months. Death will be mostly due to
complications caused by toxic wastes and fluid build-up in the body.
The amount of time left to live depends on the condition of the patient
and the amount of kidney function left.

The design intent of the Human Kidney Replacement Unit is to


make it as compact as possible, and incorporate into the logic as
many natural kidney functions as scientifically feasible, unlike
hemodialysis which is basically pumping the blood through a one-
pore-size detoxifying membrane (filter) arrangement..

The driving force, or main reason for this endeavor is because dialysis
is not only grossly inconvenient but basically it just removes toxins
from the blood, and does not regulate the chemical composition of the
blood, leaving the patient with nausea and incomplete muscle
function.

SECTION 4: Kidney Failure and Dialysis

When a patient is diagnosed with ESRD, and transplantation is not


available, dialysis is necessary to help rid your body of harmful wastes
such as urea , extra salt and extra water, all of which are removed
from the blood. Doctors suggest dialysis when kidney failure is
causing abnormal brain function (uremic encephalopathy),
inflammation of the sac around the heart (pericarditis), high acidity
(acidosis) that doesn’t respond to other treatments, heart failure, or a
very high blood potassium concentration (hyperkalemia).

Hemodialysis is a treatment method that uses a machine, having a


special blood filter or semipermeable membrane called a dialyzer. 85%
of all dialysis is performed with this technique. The other 15% of the
cases use a method known as peritoneal dialysis, which uses the
person’s own peritoneum as the semipermeable membrane. Dialysis is
performed three times a week with the treatments lasting from 3 to 5
hours. Before regular dialysis is begun, a site on the body must be
chosen for vascular access, where the blood will be removed and
returned during dialysis. There are several kinds of accesses, one of
which is arteriovenous (AV) fistula, which is said to be the best
approach, but if the patient has small veins that won’t develop
properly into a fistula, vascular access can be achieved using a
synthetic tube implanted under the skin in the arm. The tube becomes
an artificial vein that can be used repeatedly for needle placement. A
Subclavian Catheter is a plastic catheter inserted in the subclavian

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vein, beside the collar bone. A catheter placed in a vein in either the
neck, chest, or leg near the groin can be used as a temporary access.

With every hemodialysis session, two needle insertions is required—


one to carry blood to the dialyzer and one to return the cleaned blood
to the body. Extracorporeal, means outside the body. Extracorporeal
Circuit, carries the patients blood from the access to the dialyzer, and
back to the access. The circuit includes the arterial line, blood pump,
heparin infusion pump, dialyzer, venous line, and monitors for blood
flow, pressure, and air/foam detectors.

Most dialyzers (filtering cartridges) are constructed of a styrene


butadine cylinder filled with up to 11,000 cellulose hollow fibers each
having an internal diameter of approx 200-300 microns.
Blood flows through the center of the fibers, dialysate which is water
containing blood ionic substances such as sodium, potassium, and
calcium in required concentrations, flows in a countercurrent direction
outside the fibers, sometimes in cross flow direction across fibers. The
dialysate is continually replaced as waste products build up to prevent
reduction in concentration gradient and diffusion rate. It is also
important for the pH of dialysate to be within an acceptable range.
Bicarbonate-buffered dialysate should have a pH of 7.3. Normal body
pH ranges from 7.35 to 7.45, slightly alkaline.

Dialyzer First-Use Syndrome is a group of symptoms that may occur


shortly after beginning dialysis with a new cellulose dialyzer that is
insufficiently rinsed. Symptoms may include nervousness, chest pain,
back pain, palpitations (skipped or missed heartbeats) or itching.
First-use syndrome (FUS) may be caused by exposure to ethylene
oxide gas or bits of cellulose remaining in the dialyzer after
manufacturing. Re-processing a cellulose dialyzer can also reduce the
incidence of FUS by removing ethelyne oxide and cellulose bits; a
coating of blood protein remaining in the dialyzer after dialysis also
makes the reprocessed dialyzer more biocompatible—unless the
coating is removed by bleach during reprocessing.

Vitamins are substances that the body needs for normal growth and
health. Dialysis removes vitamins B12, folic acid, and pyridoxin,
which promote good blood cell growth and maturity.
Haemofiltration requires membranes with large pores to remove middle
sized molecules by convection. Pressure gradient forces water out of
blood, water drags middle sized molecules with it (solvent drag).

Filtration volumes for time spent can look impressive, for example, in
medium sized dialyzers the ultrafiltration coeffient is 60
mL/hr/mmHg. With the blood pump running at 300 Ml/min the Urea

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clearance is around 227.8 mLl/min, the Vitamin B12 clearance is
about 192.6 mL/min, and the Creatinine clearance is 248.6 mL/min.
These values sound favorable, but the immediate side effects, or
adverse reactions patients with ESRD have are; hypertension,
hypotension, headaches and nausea. Other complications include
blood loss, blood overheating, hemolysis, excessive filtration with
electrolyte imbalance. Shortness of breath with wheezing, respiratory
arrest, itching, hives, edema, hypertension above baseline, elevated
pulse rates and arrhythmia can also result.

Long term side effects of dialysis: Patients, after being on dialysis


for long periods, such as several years, develop medical problems from
bone, blood, nervous system, metabolic, gastrointestinal,
cardiovascular, and endocrine abnormalities.

Biocompatability of Dialysis Membrane (see Pages – through --)

SECTION 5: The Composition of Blood/Plasma/Clotting

Blood Is classified as a connective tissue with an intercellular liquid


matrix of from 40 to 50 percent formed elements and 50 to 60 percent
plasma. Plasma is 90% water and 10% solutes; the solutes fall in six
catagories which are: (1) inorganic ions and salts; (2) plasma proteins:
(3) organic nutrients; (4) nitrogenous waste products; (5) special
transported products; (6) dissolved gasses. The cations (positively
charged ions ) are sodium (Na+ at about 140 mM), calcium (Ca2+),
potassium (K+) and magnesium (Mg++). The inorganic anions
(negatively charged ions) are chloride (Cl-), bicarbonate (CHO3-),
phosphate( HPO4—and H2PO4--) and sulfate (SO4--); of these , chloride
and bicarbonate are the most abundant. There are also carbohydrates
(HCO3), glucose and traces of other sugars-- amino acids-- other
organic acids-- cholesterol and other lipids-- hormones-- urea and
creatinine

Whole blood, treated to prevent clotting if left standing in a test tube,


the formed elements will settle to the bottom, leaving the fluid plasma
above. The formed elements suspended in the whole blood are of
three major types. Red blood corpuscles “cells” (erythrocytes), white
blood cells (leukocytes), and the platelets, which are small disc shaped
bodies that arise as cell fragments. Red blood cells , white blood cells

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and platelets grow from a single precursor cell, known as a
hematopoietic stem cell.

Red blood cells (RBC’s) or (+red corpuscles) make up 40-45


percent of one’s blood. They are biconcave disc-shaped bodies that
resemble cells without nucli, mitochondria and golgi apparatus and
other subcellular organelles, especially in the mature cells which are
lacking many of the characteristics of living cells. In adults RBC’s are
formed in the red bone marrow, which fills the interior of the upper
ends of the long bones and the shafts of flat bones like those in the
skull, ribs and pelvis. RBC’s arise from normally necleated, rapidly
dividing connective-tissue cells of the bone marrow. The normal
survival time for RBC’s is 120 days, then the old worn out cells are
engulfed by phagocytic cells of the liver, spleen and lymph nodes.
RBC’s contain a molecule called hemoglobin (Hb, 3.8% heme and
96.2% globin with a molecular weight of 64.450, a globulin protein
composed of four independent polypeptide chains. Each of the four
chains enfolds a complex prosthetic group called heme, which has an
iron atom at its center. Each molecule of hemoglobin contains four
iron atoms, and each iron atom can bind with one molecule of oxygen
(Hb+402). This is called oxyhemoglobin, and is how blood gets its
bright red color. Oxygen is carried in the red blood cells by being
picked up in the capillaries of the lungs and released in the capillaries
of the systemic circulation system and absorbed by the body’s cells
along with food in the blood which was processed by the digestive
system into smaller components such as proteins, fats, and
carbohydrates. Hemoglobin has an affinity for oxygen due to the
influence of pH, because H+ ions act as negative allosteric modulators
for hemoglobin. CO2 produced as metabolic waste by cells , is
abundant in the tissue fluid of most parts of the body and combines
with water to form carbonic acid (H2CO3).

Hemoglobin (now giving the blood a bluish purple color) carries 95


percent of the carbon dioxide (C02) generated in tissues back to the
lungs where it is released into the air. Hemoglobin also regulates local
variation in blood pressure, by carrying a nitric oxide, a gas that
relaxes the blood vessel walls.

White blood cells (leukocytes) fight infection, but are less numerous
than red ( the ratio between the two is around 1 to 700). There are
three types: granulocytes, lymphocytes and monocytes. There are, in
turn, three kinds of granulocyte: neutrophis, eosinophils and
basophils. Granulocytes hold digestive enzymes. There are two types of
lymphhocytes, which are key parts of the body’s immune system:
T cells and B lymphocytes. T cells direct the activity of the immune
system, B lymphocytes produce antibodies, which destroy foreign

14
bodies. There are inflammatory T cells that recruit macrophages and
neutrophils to the site of infection. Cytotoxin T lymphocytes (CTLs)
that kill virus-infected and, perhaps, tumor cells. Helper T cells that
enable the production of antibodies by B cells. Although bone marrow
is where lymphocytes originate, T cells and lymphocytes that will
become T cells migrate to the thymos and mature. Both B cells and T
cells also take up residence in lymph nodes, the spleen and other
tissues where they encounter antigens, continue to divide by mitosis
and mature into fully functional cells.

Monocytes leave the blood and become macrophages, large phagocytic


cells that engulf foreign material (antigens) that enter the body, and
dead and dying cells in the body.

Neutrophils squeeze through the capillary walls and into infected


tissue where they kill the invaders (e.g. bacteria)d then engulf the
remnants by phagocytosis.

Platelets are small fragments produced from megakaryocytes and


blood normally contains 150,000 to 450,000 platelets per microliter. If
this value should drop much below 50,000 microliters, there is a
danger of uncontrolled bleeding. This shows the essential role that
platelets have in blood clotting.

Influencing Blood Pressure: The Blood pressure in the body depends


on the following conditions; (1) the force of contraction of the heart –
related to how much the heart muscle gets stretched by the incoming
blood, (2) the degree to which the arteries and arterioles constrict –
increasing the resistance to blood flow, thus requiring a high blood
pressure, (3) the circulating blood volume- the higher the circulating
blood volume, the more the heart muscle gets stretched by the
incoming blood. The kidney influences blood pressure by; (1) Causing
the arteries and veins to constrict, (2) increasing the circulating
blood volume.

15
Specialized cells are located in a portion of the distal tubule located
near and in the wall of the afferent arteriole. The distal tubule cells
(macula densa) sense the Na in the filtrate, and the arterial cells
(juxtaglomerular cells) sense the blood pressure. When the blood
pressure drops, the juxtaglomerular cells sense the drop in blood
pressure and the increase in Na is relayed to them by the macula
densa cells. The jaxtaglomerular cells then release an enzyme called
renin. Renin converts another protein from the blood called
angiotensin into antiotensin ll. Angiotensin ll causes blood vessels to
contract. The increased blood vessel constrictions elevate the blood
pressure.

How the Kidneys Increase the Circulating Blood Flow; Angiotensin


ll stimulates the adrenal gland to secrete a hormone called
aldosterone. Aldosterne stimulates more Na reabsorption in the distal
tubule, and water gets reabsorbed along with the Na. The increased
Na and water reabsorption from the distal tubule reduces urine output
and increases the circulating blood volume. The increased blood
volume helps stretch the heart muscle and causes it to generate more
pressure with each beat, thereby increasing blood pressure. The
actions taken by the kidney to regulate blood pressure are especially
important during traumatic injury, when they are necessary to
maintain blood pressure and conserve the loss of fluids.

When blood vessels are damaged fibrils of collagen are exposed.


With the aid of von Willebrand factor and thrombin, platelets become
sticky and adhere to collagen, they bind fibrinogen and release ADP
and thromboxan A2 which recruit and activate still more platelets in
the blood. Although blood clotting is desirable when we get into an
accident, cardiovascular problems arise when blood clots
inappropriately in blood vessels or the chambers of the heart. Doctors
use mild blood thinning agents, or platelet inhibition to prevent these
blood clots. Clotting is inhibited by Aspirin (acetylsalicylic acid), Ticlid
(ticlodipine), Plavix (clopidogrel). Platal (cilostazol), Persantin
(dipyridamol), Anyurane (sulfinpyrazone) and three Intravenous agents
called Rheopro (abciximab), Integrilin (eptifibatide) and Aggrastat
(tirofiban). Nitrates. Vitamin E and Ginko Biloba also have mild
antiplatelet effects.

Blood clotting (coagulation): The science that causes blood to clot


both inside and outside the human body is thoroughly researched in
this project, in order to design in the safeguards necessary to prevent
this type of phenomenon from occurring inside the Human Kidney
Replacement Unit, thyis will avoid the use of Heparin which is a

16
polysaccharide that binds to antithrombin lll, inducing an allosteric
change that greatly enhances its inhibition of thrombin systhesis,
(aka antagonist), which is an effective vitamin K antagonist, also a
blood thinner.

Blood clotting is the body’s normal response to a bleeding injury


Most blood clots dissolve back into the blood when the body has
healed the vessel, but if the clot does not dissolve it can be potentially
dangerous. Some types of blood clots are: Thrombus, which is a
blood clot that forms along the wall of the heart or a blood vessel and
slows the blood flow, unless it continues to enlarge enough to block
the blood flow altogether. An Embolus is a clot that forms in one area
of the body, and travels through the blood stream to lodge in another
vessel. Emboli, are more dangerous because they can cause a sudden
blockage in the blood flow to an organ (Embolism) and be fatal.

A blood clot consists of a plug of platelets enmeshed in a network of


insoluble fibrin, which requires the proteolytic enzyme thrombin and
calcium ions (Ca2+) (blood banks use a chelating agent to bind the
calcium so blood will not clot in the bag) and about a dozen other
protein clotting factors which circulate in the blood as inactive
precursors. They are activated by proteolytic cleavage, which becomes
active proteases, for other factors in the system.

Examining the processes of blood clotting: Damaged cells display a


surface protein called tissue factor (TF). Tissue factor binds to
activated Factor 7. The TF-7 heterodimer is a protease with two
substrates—Factor 10 and Factor 9. Factor 10 binds and activates
Factor 5. This heterodimer is called prothrombinase because it is a
protease that converts prothrombin (also known as factor ll) to
thrombin. Thrombin has several different activities. Two of them are:
proteolytic cleavage of fibrinogen (aka “Factor I”) to form: soluble
molecules of fibrin and a collection of small fibrinopeptides, activation
of Factor 13 which forms covalent bonds between the soluble fibrin
molecules converting them into an insoluble meshwork, the clot.

Amplifying the clotting process: The TF-7 complex (which started


the process) also activates Factor 9. Factor 9 binds to Factor 8, a
protein that circulates in the blood stabilized by another protein, Von
Willebrand Factor (vWF). This complex activates more Factor 10. As
thrombin is generated, it activates more Factor 5, Factor 8, and Factor
11, and Factor 11 amplifies the production of activated Factor 9.

Function of the Human Kidney Replacement Unit (HKRU)

17
Before we get into the function of the HKRU, we need to review
how the human kidneys clean and regulate the composition of the
blood.

The first stage of blood purification is ultra-filtration, which is


basically reverse osmosis (R.O.). In real kidneys this would occur
immediately after the blood enters the glomerular capillaries of the
Bowmans capsule (or renal corpuscle) through the efferent arteriole
located in the kidney cortex. Here, whole blood containing 40 to 50 %
formed elements and 50 to 60% percent plasma, enters the glomerular
capillaries..

From the plasma, the heart forces the filtrate of water, containing
ions, and waste products of urea and creatinine along with dissolved
substances and other small molecules like sodium, phosphorus and
potassium, through the membrane pores into the lumen of the
capsule. The filtrate removed here will have the same composition of
dissolved substances as blood (glucose, urea, salts, amino acids, etc.)
lacking only the formed elements, which are the erythrocytes,
leukocytes and the platelets, and the plasma proteins, all of which are
too large to filter through the membrane to any degree, and will move
on in the blood-stream.

The filtrate leaves the lumen of the bowmans capsule (approximately


170 liters per day) and moves into the lumen of the nephron where
small molecules such as ions, glucose and amino acids get reabsorbed
into the bloodstream from the filtrate.

Specialized proteins called transporters are located on the


membranes of the various cells of the nephron. These transporters
grab the small molecules from the filtrate as it flows by. Each
transporter grabs only one or two types of molecules. For example,
glucose is reabsorbed by a transporter that also grabs sodium.

Transporters are concentrated in different parts of the nephron.


Most of the Na transporters are located in the proximal tubule, while
fewer ones are spread out through other segments.

Some transporters require energy, usually in the form of adenosine


triphosphate (active transport), while others do not (passive transport).
Water gets reabsorbed passively by osmosis in response to the buildup
of reabsorbed Na in spaces between the cells that form the walls of the
nephron.

Other molecules get reabsorbed passively when they are caught up in


the flow of water (solvent drag). Reabsorption of most substances is

18
related to the reabsorption of Na, either directly by sharing a
transporter, or indirectly via solvent drag, which is set up by the
reabsorption of Na.

Two major factors affect the reabsorption process: (1)


Concentration of small molecules in the filtrate- The higher the
concentration, the more molecules are reabsorbed. There is only a
fixed number of transporters for a given molecule present in the
nephron, so there is a limit to how many molecules the transporters
can grab in a given period of time. (2) Flow rate affects the time
available for the transporters to reabsorb molecules.

The proximal tubule reabsorbs 65 percent of filtered Na, and 2/3 of


water and most other substances. The loop of Henle reabsorbs 25
percent of filtered Na. The Distal tubule reabsorbs 8 percent of filtered
Na, and the Collecting duct reabsorbs the remaining 2 percent but
only if the Hormone Aldosterone is present.

The filtrate moves through one of the two arterioles leaving the
capsule, into the proximal convoluted tubule system of the nephron.
The proximal convoluted tubule, the loop of Henle, and the distal
convoluted tubule are encapsulated in a dense network of capillaries
branching from the other arteriole leaving the Bowmans capsule,
carrying the blood in which the filtrate was removed. The capillaries
unite once more to form a small vein. The veins from the many
nephrons then fuse to form the renal vein.

As the glomular filtrate passes through, first the proximal convoluted


tubule, then through the long loop of Henle, then through the distal
convoluted tubule, and finally into the collecting tuble, which runs
from the cortex through the medulla to the renal pelvis. On the way,
water leaving the tubles by osmosis, as well as ions and small
molecules actively transported out of the tubules, can be reabsorbed
by the capillaries closely associated with the tubules. Most of the re-
absorption takes place in the proximal convoluted tubule.

Selective reabsorption occurs where as much as 99 percent of the


water is absorbed by the cells of the tubule walls and returned to the
blood. When water must be removed, all that is not absorbed by
osmosis is pumped by active ions, with water following. In this case
the pumps are in the convoluted tubules and ascending limb of the
loop of Henle. Two kinds of ion –Na+ and Cl- ions are the crucial
solutes for controlling water in living tissue. By the action of ionic
pumps, some 75 percent of the solutes and the water that follows them

19
are removed from the filtrate in the proximal convoluted tubule and
reabsorbed by the capillary network. The remaining filtrate passes into
the loop of Henle, where fine tuning of the filtrate concentration and
volume is effected. In the loop of Henle, water is reabsorbed, but ions
(Na,Cl) are not.

The removal of water serves to concentrate the Na and Cl in the


lumen. Now, as the filtrate moves up the other side (ascending limb),
Na and Cl are reabsorbed, but water is not, setting up a concentration
difference in NaCl along the length of the loop with the highest
concentration at the bottom and the lowest at the top. Salt ions Na+
and Cl- are moved out of the ascending limb, some of them, but not all
diffuse passively back into the descending limb, to produce a cycling of
some of the ions from ascending limb to tissue fluid to descending
limb to ascending limb to tissue fluid, and so on). The result is that a
salt-ion concentration gradient is maintained in the tissue fluid along
the loop, with the concentration lowest in the outer part of the kidney
cortex where the convoluted tubules are located, and highest in the
medulla, where the tip of the loop of Henle is located. The wall of the
ascending limb of the loop is impermeable to water, since water does
not diffuse out of the tubule as the salt ions are moved out. When the
urine dilute enters the collecting tubule, water is allowed to moves by
passive osmossis from the dilute urine in the tubule to the
surrounding hypertonic tissue fluid, until the final urine may become
essentially isotonic with highly concentrated tissue fluid in the inner
region of the medulla. Whether the collecting tuble finally releases
dilute or concentratrd urine depends on whether there is a deficiency
or excess of water in the body at the moment.

Anti-Diuretic Hormone (ADH) which is secreted by the pituitary


gland, controls the ability of water to pass through the cells in the
walls of the collecting ducts. If no ADH is present, then no water can
pass through the walls of the ducts. The more ADH present, the more
water passes through.

Specilized nerve cells called osmoreceptors, in the hypothalamus of


the brain sense the Na concentration of the blood. The nerve endings
of these osmoreceptors are located in the posterior pituitary gland and
secrete ADH. The human body requires at least 500 mg of sodium
per day but the average American ingests between 2,300 to 6,900
mg per day. The safe daily intake is 1,100 to 3,300 mg per day.
If the Na concentration of the blood is high, osmoreceptors secrete
ADH. If the Na concentration of the blood is low, they do not secrete
ADH. In reality, there is always some very low level of Adh secreted
from the osmoreceptors.

20
The more water absorbed in the blood reduces the Na
concentration. The reduced Na concentration in blood reduces the
amount of Filtered Na in the kidney’s glomerulus where all the Na is
reabsorbed with some of the water. The reduced Na is sensed by the
osmoreceptors, therefore not much ADH is secreted and not much
water is reabsorbed in response to the Na concentration gradient set
up by the loop of Henle. The excess water is excreted in the urine and
the Na concentration of the blood returns to normal.

Altering the Blood’s Acid/Base Balance:


The blood maintains a constant concentration of hydrogen ion (pH) by
a chemical mixture of hydrogen ions and sodium bicarbonate, which is
produced by the carbon dioxide (CO2) formed in the cells as a
byproduct of many chemical reactions. The CO2 enters the blood in
the capillaries, where red blood cells contain an enzyme called
carbonic anhydrase that helps combine CO2 and water (H2O) to form
carbonic acid (H2CO3) quickly. The carbonic acid formed then rapidly
separates into hydrogen ions (H+) and bicarbonate ions (HCO3). This
reaction can also proceed in the reverse direction, whereby sodium
bicarbonate plus hydrogen ions yields carbon dioxide and water.
CO2+H2OÅ---Æ H2CO3Å-ÆH++HCO3. The correct pH is maintained
by keeping the ratio of hydrogen ion to bicarbonate in the blood
constant. If acid (hydrogen ion) is added to the blood, the bicarbonate
concentration will be reduced, altering the pH concentration of the
blood

Diets rich in meats provide acids to the blood when digested. Diets
rich in fruits and vegetables make our blood alkaline because they are
rich in bicarbonates. Exercising muscles produce lactic acid that
must be eliminated from the body or metabolized. High altitudes and
rapid breathing makes our blood alkaline. In contrast, certain lung
diseases that block the diffusion of oxygen can cause the blood to be
acidic.

The kidneys can correct any imbalance by removing excess acid


(hydrogen ions) or bases (bicarbonate) in the urine and restore the
bicarbonate concentration in the blood to normal. The kidney cells
produce a constant amount of hydrogen ions and bicarbonate because
of their own cellular metabolism (production of carbon dioxide).
Through a carbonic anhydrase reaction similar to the red blood cells,
hydrogen ions get produced and secreted into the lumen of the
nephron. Also, bicarbonate ions get produced and secreted into the
blood. In the lumen of the nephron, filtered bicarbonate combines
with secreted hydrogen ions to form carbon dioxide and water (carbon
anhydrase is also present on the luminal surface of the kidney cells).

21
Whether the kidney removes hydrogen ions or bicarbonate ions in
the urine depends upon the amount of bicarbonates filtered in the
glomerulus from the blood relative to the amount of hydrogen ions
secreted by the kidney cells. If the amount of filtered bicarbonate is
greater than the amount of secreted hydrogen ions, then the
bicarbonate will be lost in the urine. Likewise, if the amount of
secreted hydrogen ion is greater than the amount of filtered
bicarbonate, then hydrogen ions will be lost in the urine.

If the Kidneys Are Working Properly, with an acid diet hydrogen


ions are added to the blood by breaking down a meat-rich diet
combined with bicarbonate in the blood to form carbon dioxide and
water. This reaction reduces the bicarbonate concentration and the
pH in the blood and this decreased bicarbonate concentration in the
blood reduces the amount of bicarbonate filtered in the glomerulus.
All of the filtered bicarbonate combines with the hydrogen ion secreted
by the kidney cells in the lumun to form carbon dioxide and water.
Because the filtered load of bicarbonate was less than the amount of
Hydrogen ions secreted by the kidney cells, there is an excess of
hydrogen ions in the urine so the amount of bicarbonate secreted from
the kidney cells into the blood was equal to the hydrogen ion secreted
into the lumen and greater than the filtered load of bicarbonate from
the blood- therefore, the blood has a net gain of bicarbonate. This
process continues to loose hydrogen ions in the urine and gain
bicarbonate in the blood until the concentrations of hydrogen (pH) and
bicarbonate ions in the blood are restored to normal.

An Alkaline Diet: Bicarbonate added to the blood from fruit or


vegetable-rich diet combines with hydrogen ions to form carbon
dioxide and water. This reaction reduces the hydrogen ion
concentration and increases the pH. The increased bicarbonate
concentration increases the amount of bicarbonate filtered in the
glomerulus. The filtered bicarbonate exceeds the amount of hydrogen
ion secreted by the kidney cells, and excess bicarbonate is lost in the
urine. The amount of bicarbonate secreted from the kidney cells into
the blood was equal to the hydrogen ions secreted into the lumen and
less than the filtered load of bicarbonate from the blood, therefore, the
blood has a net loss of bicarbonate. This process continues to lose
bicarbonate in the urine and reduce the bicarbinate in the blood until
the concentrations of hydrogen (pH) and bicarbonate ions in the blood
are restored to normal. A solution with a pH above 7 is alkaline, or
base; a solution with a pH below 7 is acid. A solution with a pH of 7.0
is neutral. Normal body pH ranges between 7.35-7.45, slightly
alkaline.

22
In the nephrons; water is not the only substance reabsorbed into the
adjacent capillaries. In a normal healthy person all the glucose,
almost all the amino acids, and most all the salt ions are also
reabsorbed and returned to the blood. Much of this reabsorption
involves active transport, and thus energy expenditure by the tubule
cells. To recap “the kidney functions by forcing out of the blood in the
glomerulus most molecules small enough to pass through the pores,
and then reabsorbing into the capillaries surrounding the convoluted
tubules and loop of Henle only what is to be saved”. Most substances
have a kidney threshold level. If the concentration of a substance in
the blood exceeds its kidney threshold level, the excess is not
reabsorbed from the filtrate by the capillaries but is instead excreted in
the urine. Glucose has a high threshold level, but if the blood-sugar
level is abnormally high, as it is in diabetics, sugar appears in the
urine. The kidneys help regulate the composition of the blood by
keeping the relative concentration of such inorganic ions as sodium,
potassium, and chloride in the blood plasma at a nearly constant level.
Whenever the concentration of an ion in the blood, and in the
glomerular filtrate, exceeds its kidney threshold value, the excess is
excreted in the urine.

Potassium is the primary positive ion within the cells, where 98


percent of the 120 grams is found. Potassium along with sodium,
regulates the water balance and acid-base balance in the blood and
tissue. It is one of the main body mineral electrolytes the sodium-
potassium flux generates the electrical potential that aids the
conduction of nerve impulses. The others are sodium and chloride.
Blood serum contains about 4-5 mg. (per 100 ml.) of the total
potassium. The red blood cells contain 420 mg., which is why a red
blood cell level is a better indication of an individuals potassium status
than the commonly used serum level.

Potassium Requirements: There is no specific RDA for potassium,


though it is thought that at least 2-2.5 grams per day are needed, or
about 0.8-1.5 grams per 1,000 calories consumed. The average
American diet includes from 2-6 grams per day.

Some common problems that have been associated with low potassium
levels include hypertension, congestive heart failure, cardiac
arrythmias, fatigue, depression and mood swings. People who
consume excess sodium can lose extra urinary potassium, and people
who eat lots of sugar also may become low in potassium.

Magnesium helps maintain the potassium in the cells, but the sodium
and potassium balance is as finely tuned as those of calcium and

23
phosphorus, or calcium and magnesium. Potassium is absorbed from
the small intestines, at about 90 percent absorption. Most excess
potassium is eleminated in the urine and some in sweat. The adrenal
hormone aldosterone stimulates elimination of potassium by the
kidneys

Kidneys and Calcium; As stated, the body stores calcium in the


bones, yet maintains a constant level in the blood. If the blood
calcium level falls, the parathyroid glands in your neck release a
harmone called parathyroid hormone. This increases calcium
reabsorption from the distal tuble of the nephron to restore the blood
calcium level. Parathyroid hormone also stimulates calcium release
from bone and calcium absorption from the intestine. In addition to
parathyroid hormone, the body also requires vitamin D to stimulate
calcium absorption from the kidney and intestine. Vitamin D is
found in milkproducts. A precursor to vitamin D (cholecalciferol) is
made in the skin and processed in the liver. However, the final step
that converts an inactive form of cholecalciferol into active vitamin D
occurs in the proximal tubule of the nephron. Once activated, vitamin
D stimulates calcium absorption from the proximal tubule and from
the intestine, threby increasing blood calcium levels.

Kidney stones are often caused by problems in the kidney’s


ability to handle calcium. In addition, the kidney’s role in
maintaining blood calcium is important in the bone disease
osteoporosis that afflicts many elderly people, especially women.

All Implantable Artificial Kidney (IAK) Functions will be similar to


those of healthy kidneys, processing around 170 liters of blood filtrate
per day from the patients whole blood, taken from Iliac artery. Here,
the blood will undergo the same processes, or stages in the order
occuring in the nephrons of real kidneys. These are Ultra-filtration,
Selective Reabsorption and Tubular Excretion. The IAK has many
advantages over dialysis, a few which are, patients with kidney failure
will not have to remain at home, in town, spending three days a week
in dialysis centers, but instead, will be able to commute to work, work
harder, stay longer if needed and travel for long duration’s, just like
people with healthy kidneys. Another important feature is that the
HKRU patient will feel much better by not suffering the side effects
associated with dialysis.

In the HKRU/IAK; there are a total of 20 membranes, 12 reverse


osmossis membranes for ultra-filtration, and 8 osmossis membranes
for re-absorption. Before attempting to understand how the
membranes in the HKRU function, the reader should review the next
few pages on membrane technology.

24
Membranes, or Filters; for medical use, this requires materials that
can withstand high pressures, maintaining integrity and high levels of
performance. Filters are either porous, fibrous or granular substances
used to separate some selected particles or molecules from others in
fluid.

Membranes Thickness and Pore Sizes: Membranes are normally


about 150 um thick. Membrane pore size is the average diameter of
individual pores in a membrane. Although some manufacturers report
pore diameters in precise terms, the pores are rarely perfectly
spherical. In some applications the largest pore size is more critical
than the average size. Most laboratory and medical applications call for
membrane filters that are generally less than 0.1 mm thick with a
precise pore size.

Particles Separated by Membrane filtration are normally smaller


than 100 micron in diameter- a particle range between 0.1 and 1
micron is not uncommon. Actually, the proper name for what we are
doing here is “sieving”, where large particles are separated from
smaller ones. Filtration on the other hand, by definition is the removal
of practically all particles from a solution.

Although membrane manufacturing processes have strict tolerances,


pore size is usually determined statistically by the average dimension
of the smallest particle that will pass through it.

Pore-Size Ratings reflect performance rather than actual pore size


and are expressed as nominal or absolute. A nominal rating means
that some predetermined proportion of particles, usually 98% are
retained. A membrane/filter with an absolute rating should retain
100% of the particles larger than its reported pore size. There is no
absolute method to determine pore size or even the exact properties of
a membrane. Only through testing can manufacturers be certain that
a specific filter membrane is proper for certain applications.

Membrane pore sizes can range from atomic dimensions (<10


angstroms to 100+ microns. Several standardized tests are available
to determine pore size. The bubble point test evaluates performance
under aqueous conditions. However, the bubble test cannot be used
for hydrophobic membranes, as they do not wet evenly. The water
intrusion pressure method calculates pore size based on pressure
needed to force water through the filter. Pore size is calculated from
measurements of capillary force, pressure, and water height. The
method is described in ASTM F316. Only through testing can

25
manufacturers be certain that a specific filter membrane is proper for
their application.

The majority of membranes are made of cellulose esters formed by


substituting hydroxyl groups with the appropriate reactive groups. For
example, in the two most ubiquitous forms, cellulose nitrate and
cellulose acetate, the hydroxyl group is interchanged with the nitro
group and acid anhydride or acid chloride, respectively. Other common
membrane filter materials include vinyl, nitrile, nylon, polypropylene,
and polytetra-fluoroethylene (PTFE or Teflon). Cellulose esters,
plastics and Teflon are generally hydrophobic which hinders filtration
of aqueous solutions. Most membranes are treated with wetting
agents, such as glycerol, Tween, and Triton X-100, which allow water
to flow freely.

Membranes created for reverse osmossis (RO) and ultrafiltration


and nanofiltration (NF) are generally coatings of thin verry porus
polymer, or plastic applied to a backing material. Since membrane
filtration deals with very small partacles, electric charge can greately
affect filter effeciency and performance. When wet, most filters have a
negative charge. At neutral pH, most cells, viruses and
macromolecules also exhibit a negative charge. The repulsion of like
charges can overcome electrostatic attraction and van der Waals forces
needed to absorb small particles into the membrane, leading to less
than optimal performance. For sterilization purposes, asbestos is
often chosen because of its high positive charge when wet. Raising the
ionic strength of the solution can also reduce negative charge.

Isotrophy refers to the uniformity of pore size throughout the


membrane. In an isotrophic membrane, pores are of the same size
from top to bottom. Anisotrophic membranes have a gradation of pore
sizes from top to bottom. Inks or dyes can be blotted on a membrane
to test for isotrophy consistency An isotrophic membrane will wick in
a uniform manner and form circular-shaped stains.

Chemical compatibility; of the cellulose esters, cellulose nitrile is the


least tolerant of organic solvents. Cellulose acetate behaves similarily
to cellulose nitrate but is resistant to alcahals.

Some Companies specializing in membrane filters are British


founded Whatman, Inc. (Fairfield Nj). DBCD, Inc. (webster Texas). Pall
and Gelman Companies have merged. Millipore has teamed with
Amicon and Tylan.
Gradipore is an Australian Company specializing in blood purifying
filters.

26
Membranes, or Filters/ Biocompatability of Dialysis Membranes.

Biocompatibility is defined as all potentially harmful consequences of


contact of blood with the surface of dialysis membranes. The rapid
adsorption of plasma proteins onto the surface of dialyzer membranes
is one of the initial events that occur at the start of hemodialysis. The
type of protein adsorbed varies between different membranes and may
influence biocompatability, which has been linked to activation of
several metabolic pathways including alternate pathway of
complement, interleukins, coagulation, kallikrein and eicosanoid
pathways.

Blood Clotting Caused By Artificial Surfaces (Membrane):

The Chemistry that initiates normal Blood Clotting Is Described


in Section (Four Page 17). The relevance of the activation of
coagulation is really and issue of practical performance of therapy. In
addition to biocompatibility, clotting is affected by several factors
including flow stagnation, rough surfaces, charge on surface and
shear force. Implantation of anticoagulants on membranes could
eliminate this problem but is not available for practical use.

The interaction of blood with materials is central in the


thrombogenic response obtained in extracorporeal circulation.
Thrombin generation is determined through activation of blood
coagulation, platelet activation, trauma to thr blood, blood flow, and
use of anticoagulants. It is important to note that artificial surfaces
interact with the hemostatic system wiyhout the benrfit of the
protective roles provided by the endothelium, and even without any
additional trigger factors, artifical surfaces will alter the normal
haemostatic balance in favor of thrombogenesis.

Following the initial and rapid adsorption of plasma proteins onto


the material, activation of coagulation and platelet
adhesion/aggregation occur, leading to thrombin generation and
formation of fibrin. Activation of coagulation is thought to be
triggered at the level of the contact system. This is a complex process
comprising negatively charged surfaces, factor Xll, factor Xi, plasma
killikrein and high molecular weight kininogen.

There is abundant experimental data describibg the alteration of


platelet function in response to the stimuli arising from processes
occurring in extracorporeal circulation, especially the effects of
variable flow conditions and shear stresses and air/blood interfaces
on platelet adhesion, aggregation and release of platelet contents.

27
It has been demonstrated that activation of coagulation was more
pronounced with polyacrylonitrile membrane than cellulose acetate
even though the reverse was true for complement activation. Thus,
when criteria of biocompatability are defined in order to choose a
dialysis membrane, it is important to take into account several
parameters.

First Use Syndrome: Anaphylaxis (type 1 hypersensitivity is a


syndrome including one or more of the following life threatening
responses: hypotension, bronchospasm, upper airway angio-edema.
Other manisfestations such as uricaria or rhinitis may also occur.
Anaphylaxis is due to release of mediators such as histamine or
leukotrienes: this mediator release may be due to immunological or
non-immunological mechanisms.

Ethylene oxide (ETO) is used to sterilize hemodialysers and other


medical equipment that cannot withstand heat sterilization. There is
significant scientific evidence that ETO can haptenize human proteins
such as human serum albumin (HAS), thus rendering the allergen
ETO-HAS. Approximately two-thirds of patients who experienced
dialysis anaphylaxis have IgE against ETO-HAS, whereas only about
5% of those without anaphylaxis have IgE against ETO-HAS.

Generally, not just in the kidneys but throughout the body, there
are four processes by which molecules move across biological
membranes. The first mode of transport affects ions, which are small
electrically charged atoms or molecules (e.g. Na+or K+ or Cl-or Ca++).
Because of their charges they cannot freely diffuse across the
phospholipid portion of cell membranes and their movement is
catalyzed or facilitated by transport proteins, called ion channels.
These proteins do not use energy to change their conformation but are
either ‘gated’ by ligands (hormones, neurotransmitters, neuclotides],
voltage ( transmembrane potential), or osmotic pressure difference
across the membrane (a sensitivity for pressure also called mechano-
sensitivity). Once channels provide an open pore conformation, ions
diffuse in one direction determined by the electrochemical potential
across the membrane. Ion channels or transporters do not control
the direction of ion flux, but simply provide a pathway exhibiting an
ion selective property (e.g. discriminating positive from negative
charges). The electrochemical potential is called driving force and
consists of two components: the membrane potential (positive ions
flow towards the negatively charged side of the cell membrane, mostly
the cytoplasmic side), and the chemical potential (ion or concentration
gradient, where one side has more ions than the opposite side). More
ions will flow from the higher toward the lower concentration than in
the opposite direction.

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Second, aquaporins, a specialized class of proteins promote the
diffusion of water across membranes. Although water has a high
permeability across lipid membranes, and can pass through ion
channels while they are open (along with ions, called flux coupling),
aquaporins are membrane proteins selective for water (and sometimes
glycerol). Aquaporins are found in most membranes that are involved
in physiological homeostasis, salt (electrolyte) metabolism, and water
retention and secretion. Water and salt permeability are a major
regulatory mechanism for metabolic processes. Diarrhea and asthma
are two examples where mutations, toxins and/or auto-immune
processes disturb homeostasis.

Third, glucose is a major source of metabolic energy. It is


processed by liver cells and redistributed throughout the body.
Glucose is selectively taken up by facilitators that have a high degree
of affinity for glucose. As for ion channels, it is the glucose
concentration (chemical potential) that controls directionality of flux,
not the facilitator. Carbohydrates do not carry electrical charges. In
some cases however, glucose transport is coupled to ion flux
(symporters and antiporters) and it is the ion gradient and thus the
membrane potential which pushes glucose to flow against its own
concentration gradient (called pumping). These human glucose
transporters are compared to bacterial glucose uptake systems that
use feedback signaling pathway where the level of chemical energy is
coupled to the uptake of carbohydrates. Together, ion channels,
aquaporins, and active transporters are responsible for cell volume
regulation and electrolyte homeostasis. This is an essential part of
nutrient uptake and waste disposal and exchange of metabolites
among the various organs and cell types of the body.

Fourth, a last example of membrane transport is simple,


“diffusion of hydrophobic signaling molecules across the phospholipid
(hydrophobic) portion of cell membranes”. The signaling molecules
subsequently bind to receptors in the cytoplasm or nucleus of the cell.
Examples are glucocorticoids, cholesterol derived hormones that
regulate carbohydrate metabolism through the control of gene
expression activity.

The pores in the membranes are sized to filter out, re-absorb and/or
excrete certain selected molecules in the micrometer range. The sizes
of the molecules of elements, referred to as the atomic mass units
(AMU), are a function of their molecular weights: However, in
substances, the molecular weight is the sum of all the different atoms
present in the molecule.

29
Molecules usually contain two atoms. Those containing the same
kind of atoms are molecules of elements, and molecules formed by the
union of different kinds of atoms are molecules of compounds. If the
formula of a compound is known, the atomic weights can be used to
calculate the formula weight of that compound. The molecular weight
may be calculated from the molecular formula of the substance: it is
the sum of the atomic weights of the atoms making up the molecule.
For example, water has the molecular formula H2O, indicating that
there are two atoms of hydrogen and one atom of oxygen in a
molecule of water. Rounded to three decimal places, the atomic
weight of hydrogen is 1.008 amu and that of oxygen is 15.999 amu.
The molecular weight of one molecule of ordinary water is therefore
(2X1.008)+(1X15.999)=2.016+15.999=18.015 amu. Since atomic
weights are average values, molecular weights are also average values.

The size of a molecule is not unique, that is, the bond lengths and
bond angles of the same bond type vary somewhat for different
molecules. For H2O, the H-O-H bond angle is about 104.5 degrees
and the H---O bond distance is 1.0 angstrom (100 picometers = 100
pm). The molecular weight of a substance is the sum of the atomic
weights of all the atoms present in the molecule. If the substance is
represented by an empirical formula, the sum of the atomic weight of
all the atoms in the formula is called the formula weight.

SECTION 6:

In The Human Kidney Replacement Unit (HKRU); there are a total


of 20 membranes, 12 reverse osmossis membranes for ultra-
filtration, and 8 osmossis/diffusion membranes for re-absorption.
The membranes are arranged in two-to-a-cartridge for a total of 10
individual cartridges. The cartridges are arranged in pairs in the
IHKRU; one cartridge on each side of each of the five blood chambers.
or cavities cut through the skeletal frame. The first three center
chambers in are pressurized to the normal blood pressure. The last
two center chambers are osmosis cavities. The five chambers are
lined up in series, with communication between them via narrow tall
slots through the dividing wall separating the five chambers.

As the whole blood flowing at the rate of approximately 125


ml/min or 45 gallons (180 liters) each day, containing all the
substances, leaves the tube extending from the iliac artery to the
entrance of the first of five center chambers in the IHKRU, positive
blood pressure in the center (renal) chambers forces-out only a
percentage of the bloods total water content, per time spent in the
renal chamber; however, the entire blood volume gets filtered
approximately 20 to 25 times each day by the process of reverse

30
osmosis (RO). Water, which has an Atomic Mass Unit (AMU) of
18.015, is one of the smaller molecules in the blood, but lager than
Hydrogen with an amu of 2.016. These, along with Sodium with an
amu of 22.997, Magnesium 24.32 amu, Potassium 39.10 amu,
Calcium 40.08 amu. (molecular weights are average values) will be
forced through two semi-permeable reverse osmosis membranes
located in cartridges on either side of the first blood chamber. Water
and molecules smaller than 60 amu will continue on through the
second membrane in the two cartridges, out into collecting areas.
Molecules larger than Urea at 60.06 amu will not pass through the
second (outer-most) membranes in the first cartridges and will be
channeled out special drain ports to a waste collecting area. During
filtration some molecules are caught in solvent drag with the water as
they pass through the membrane pores and enter the chambers; also,
some of the molecules are drawn through the membranes by
specialized protein transporters. The higher the concentration of the
substance, the greater the amount of filtrate, or the greater the
filtration rate, the more substance gets filtered.

Water and other substances filtered from the blood in the first
reverse osmosis chamber, are plumbed directly from the outer
collecting areas (while being isolated from the collection areas of the
second and third R.O. chambers) to the two osmosis, injection, or
diffusion feed chambers located outboard the fourth and fifth center
osmosis chambers where the substance will selectively re-enter the
blood stream by the processes of absorption, diffusion, osmosis,
solvent drag and ion exchange.

The reabsorption of most substances is related to the reabsorption


of Na, either directly, via sharing a transporter, or indirectly via
solvent drag, which is set up by the reabsorption of Na. Glucose is
reabsorbed by a transporter that also transports sodium (Na).
(Diffusion is the movement of molecules from an area of high
concentration to an area of lesser concentration across a permeable
membrane and is always down a concentration gradient. Diffusion of
different substances do not interfere with each other. The net flux
(amount of movement) is proportional to the concentration differences
and the permeability of the membranes

By the time the blood reaches the osmosis/diffusion chamber, the


blood is transporting mostly larger molecules. Since the blood
pressure inside and the filtrate on the outside of the injection
membranes are now near equal pressures, dynamic diffusion occurs
and some of the water, sodium, calcium flows from the region where
they are highly concentrated to a the region where they are less
concentrated, until a state of equilibrium is reached. Diffusion occurs

31
when a system is not at equilibrium. Osmosis is the diffusion of liquid
molecules across a semipermeable membrane.

Rate of Diffusion (Ficks’ Law)

The rate of a substance across a membrane is related to the


concentration gradient by Fick’s Law of Diffusion

Rate of penetration = DAK([C]o-[C]i ⁄ L

[C]o = Concentration of substance outside the membrane


[C]I = Concentration of substance inside the membrane
D = Diffusion coefficient (D decreases with the size of the substance
K = Partition coefficient (K increases with increasing solubility
A = Area of membrane (the greater the area, the more substance that can
pass
L = Membrane thickness (the greater the thickness, slower the rate
P = DAK/L = Permeability constant

The membranes of the first chamber will reject molecules larger


than calcium, which is 40.08 amu. glucose, urea, creatinine, salt
ions, amino acids etc. The formed elements, red blood cells, white
blood cells and platelets, along with the plasma protein molecules are
too large to be filtered out here and will travel on in the blood stream.

The minutely thicker blood leaves the first central chamber and
enters the second central chamber through a narrow elongated slot.
Here some of the Urea (60.06 amu), Creatinine (113.12 amu), Chloride
(92.57amu), Bicarbonate (84.01 amu) will be filtered out of the blood,
depending on the concentrations of each of these substances. Also
from center the chamber, additional water, sodium, hydrogen,
magnesium potassium and calcium will be removed, depending on
whether the concentrations in the blood are still excessive after
leaving the first central chamber.

All the filtrate collected in the urinary spaces of certain waste


removal membranes of the second chamber, will be recycled from the
bottom of the collection chambers, or urinary space, to the top
through concentration ports, where some of the water, sodium,
potassium and magnesium will be extracted from the urine by re-
absorption and ion exchange, after which time the concentrated
urine will flow to the ureter.

The filtrate in the lumen substances are glucose, urea, creatinine,


salts, amino acids etc. At this point the blood and filtrate are
separated. As the blood with the formed elements and plasma protein
leaves the pressurized chamber.

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Changes of the concentration at two different planes of a vessel due
to the time-dependence of diffusion (C1: concentration I, x0: covered
distance at time 0; C 2: concentration 2, Xi: covered distance at time i,
t. time) The net flow can now be described as a function of time. f(t) =
DF (C l – C 2 / X l – X 0) C l and C 1 are the concentrations of the chosen
planes, X1 - Xo is the distance between them. Since the concentration
decreases with growing distance has the concentration gradient a
negative value. If the formula is applied to any small distance then the
values have to be given as differentials.

dm / dt = DF (dc / dx) [cm 2 sec- 1]

The precept expressed in this formula is also called FICK's first law
of diffusion. It states that a substance diffuses in the direction that
eliminates its concentration gradient dc I dx at a rate proportional to
the magnitude of its gradient.

The dimensions of the quantities are m: [Mol], F: [square centimeters],


c: [ Moll cubic/ centimeters], x: [cm].

The number of moles that passes a certain plane per second is called
the net flow (Phi). Phi= -D (dc / dx) [Mol cm-2 sec-1]

Or

Phi = -D (c1 –c2/ X1 – X0)

or, when eliminating D:

D = -Phi / ( C
1 – C
2 /X1 Xo)

(C1 – c2 /21 x 1 - Xo) is called the concentration gradient. D is the


diffusion constant that is defined as
the amount of a substance (in Mol) that diffuses through a certain area
(in square centimeter) at a concentration gradient of I (Mol/ cm).

Diffusion is very quick over short distances but extremely slow at long
ones. It is the square of the distance that has an influence on the
formula and it is proportional to the available area. Diffusion is
important when regulating the molecular movements within cells or
between neighboring cells.

33
IMPLANTED
ARTIFICIAL KIDNEY