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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
1
SECTION 1
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.
2
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.
3
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
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.
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
4
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.
5
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.
6
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.
7
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.
8
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.
9
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.
10
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 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.
11
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.
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
12
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.
13
and platelets grow from a single precursor cell, known as a
hematopoietic stem cell.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
25
manufacturers be certain that a specific filter membrane is proper for
their application.
26
Membranes, or Filters/ Biocompatability of Dialysis Membranes.
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.
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.
28
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.
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:
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.
31
when a system is not at equilibrium. Osmosis is the diffusion of liquid
molecules across a semipermeable membrane.
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.
32
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.
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 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
D = -Phi / ( C
1 – C
2 /X1 Xo)
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