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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 theImplantable 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 BloodClotting:

(6) The Human Kidney Replacement Unit (HKRU) alsoreferred 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 animplantable 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 havingend stage renal disease ESRD ( a point at which not more than 10percent 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 havingsatisfactory 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 yearas a result of end stage renal disease. Approximately 110 out of every100,000 people are diagnosed with ESRD; also, as far back as 1997 theUnited States Renal Data System (USRDS) had estimated that more than300,000 Americans had ESRD. Those who have survived until thepresent time, and the new ones are being treated at dialysis centers rightnow 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 newdialysis patients, each year, and steadily climbing as it has been for thepast 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 accountsfor only 5 to 10 percent of all diagnosed cases of diabetes, but type 1accounts for 30 percent of all the kidney failure cases caused bydiabetes. 22.9% are caused by high blood pressure. Every year,hypertension causes more than 15,000 new cases of kidney failure in theUnited States. 15.9% are caused by glomerulonephristis, 4.4% by cystickidney, 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 transplantsis around 12,000 annually , of these 70 percent are from cadavers(deceased persons). After receiving a transplant, in order to combatrejection, immunosuppressive agents are used, but are usuallyaccompanied by side effects such as infection, cardiovascular disease,and even death.



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The Human Kidney Replacement Unit (HKRU), or the implantableartificial kidney (IAK) is an artificial hemocatharsis type hemophoresisdevice designed in compliance with the sciences of hemorheologyis,assisted with internal artificial intelligence and sensors, for precisehomeostasis, hemoperfusion and osmoregulation. This device is more

patient friendly in every respect than the best dialyzing units andprocesses in use anywhere in the world today. The HKRU will bedescribed in detail later in this report but to better understand theHKRU 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, measuringaround 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 sideof 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 45gallons (180 liters) each day to filter out about 2 quarts of wasteproduct and extra water in the urine. They removing excess mineralsand wastes such as creatinine and urea. They regulate thecomposition of the blood by keeping the relative concentrations of suchinorganic ions as sodium, phosphorus, and chloride in the blood

plasma at a nearly constant level. The kidneys help regulate the body’scalcium/vitamin D activation as well as performing all the otheressential regulations described in detail in the following text.Potassium for instance, is controlled very carefully by the kidneys, forproper functioning of the nerves and muscles, particularly those of theheart.Blood Urea Nitrogen (BUN) is a waste product produced in the liver asthe end product of protein metabolism (or degradation). Duringdigestion, protein is broken down to amino acids. Amino acids containnitrogen, 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 intothe blood and is removed in the filtrate. Filtrate, extracted from theblood in the Bowman’s capsule in the renal corpuscle of the kidney, iscomposed of water, ions e.g. sodium, potassium, chloride), glucose andsmall 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 energystoring molecule, produced largely from muscle breakdown and isproportional to the muscle mass. High values, especially with highBUN levels, may indicate problems with the kidneys. Uric Acid isexcreted in the urine. High values are also associated with kidney

problems. Phosphorus is largely stored in bone, and is regulated bythe 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 vitaminD, which maintains calcium for bones and for normal chemicalbalance in the body.

When the kidneys are functioning properly and the concentration of anion in the blood, and hence in the glomerular filtrate exceeds itskidney threshold value, the excess in the filtrate is not reabsorbed butis released in the urine thus maintaining near constant levels, thesame is so with excess protein. This is done by sophisticatedmechanisms of osmosis, reverse osmosis and ion exchange filtration.

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

SECTION 3: Diseases That Cause Kidney Failure

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



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pressure, even when their blood pressure is only mildly elevated. Infact , 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, mostkidney diseases attack the nephrons, causing them to loose theirfiltering capacity. Chronic renal failure is characterized by progressivedestruction of the nephrons. As stated above, the most commoncauses of kidney disease are diabetes and high blood pressure. Othercauses are glomerulonephristis, inherited and congenital kidneydiseases such as polycystic kidney disease (PKD), and some arecaused by poisons and trauma. Diabetes is a disease that keeps thebody from using glucose (sugar) as it should. If glucose stays in theblood instead of breaking down, it can act like poison and damage the

nephrons in the kidneys. High blood pressure can also damage thesmall blood vessels in your kidneys nephrons. The damaged vesselscannot filter poisons from your blood as they should.If the problems worsen and renal function drops below 10 to 15percent “end stage renal disease”, the person cannot live long withoutdialysis or transplantation.

Glomerulonephristis and glomerulosclerosis are broad terms thatinclude different forms of damage to the kidneys glomeruli.Glomerulonephritis is the inflammation of the membrane tissue in thekidney that serves as a filter, separating wastes and extra fluid from

the blood. Several different types of kidney diseases are groupedtogether 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 ordiabetes is responsible.

Diabetic Nephropathy is a glomerular disease that can actually beplaced in two categories: a systemic disease and a sclerotic disease,because specific damage done to the kidneys is associated withscarring, or sclerosis of the glomeruli. In addition to scarring thekidney, 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 differentcauses, both can lead to end stage renal disease.

Diabetes Mellitus both diabetes mellitus and the un related diabetesinsipidus result in the excretion of large volumes of urine, and canlead 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 certainfoods. 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 producedby the pancreas. When a person does not make enough insulin, or the

body does not respond to the insulin that is present, the body cannotprocess glucose, and it builds up in the bloodstream. High levels of glucose in the blood or urine lead to a diagnose of diabetes. Bothtypes of diabetes can lead to kidney disease.

Type 1 Diabetes: Only about 1 in 20 people with diabetes has type 1diabetes, known as insulin-dependent diabetes mellitis. (IDDM) People with type I diabetes must receive daily insulin injections. Type 1diabetes is more likely to lead to kidney failure. About 40 percent of people with type 1 develop severe nephropathy and kidney failure bythe age of 50. Some develop kidney failure before the age of 30.

Type 2 Diabetes: About 95 percent of people with diabetes have type2 diabetes, once known as noninsulin-dependent diabetes mellitus(NIDDM) Many people with type 2 diabetes do not respond normally totheir own or to injected insulin, a condition called insulin resistance. Type 2 diabetes occurs more often in people over the age of 40. Thedeterioration that characterizes kidney disease of diabetes takes placein and around the glomeruli. Early in the disease, the filteringefficiency diminishes, and important proteins in the blood are lost inthe urine. Later in the disease, the kidneys lose their ability to removethe waste products creatinine and urea from the blood. The final stage

is kidney failure in which the glomerular filtration rate drops to lessthan 10 milliliters per minute.

Nephrogenic Diabetes Insipidus: The kidneys produce a large volumeof dilute urine because they fail to respond to antidiuretic hormoneand are unable to concentrate urine. There are also two types of diabetes insipidus in existance. In nephrogenic diabetes insipidus, thekidneys do not respond to antidiuretic hormones, so they continue toexcrete a large amount of dilute urine. In the other type, the pituitarygland fails to secrete antidiuretic hormone. Nephrogenic diabetesinsipidus may be hereditary. The gene that causes the disorder is

recessive and carried on the X chromosome, so usually only malesdevelop symptoms. However, females who carry the gene can transmitthe disease to their sons.

Glomerular Disease can sometimes develop rapidly after an infectionin 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 thekidneys, but an infection may stimulate the immune system and bringon sudden symptoms of swelling (edema), reduced urine output(oliguria), and blood in the urine (hematuria). High blood pressurefrequently accompanies reduced kidney function in this disease which

can escalate into kidney failure.

Glomerulosclerosis: The following categories can overlap; that is adisease might belong to two or more categories In several scleroticconditions, another systemic disease like Lupus Erythematosus (SLE),or Lupus Nephritis, which is the name given to the kidney disease isalso responsible for scarring. This condition occurs whenautoantibodies form, or are deposited in the glomeruli, causinginflammation. Ultimately, the inflammation may create scars,stimulated by molecules called growth factors which may be made byglomerular 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 glomerulardisease 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 bloodprotein; and edema, swelling in parts of the body. With furtherdeterioration, glomerular filtration will be insufficient to remove wasteproducts such as creatinine, which is a waste product created by thenormal breakdown of muscle during activity. With ESRD the creatininelevel (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 seehow fast the kidneys remove creatinine from the blood and ismeasured as milliliters per minute (mL/min), done from a 24-hourcollection of urine. The patient is said to have advanced clinicalnephropathy when the glomerular filtration rate has decreased to lessthan 75 milliliters per minute, and total kidney failure when theglomerular 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 clearanceaccurately. BUN is blood urea nitrogen. ( a deciliter of normal bloodcontains 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 otherproteins in the urine exceeds 200 micrograms per minute. Albuminacts like a sponge drawing extra fluid from the body into the bloodstream, where the fluid would normally be removed by the kidneys, but

seeping into the urine at this rate causes the blood to loses its capacityto absorb extra fluid from the body, thus causing excessive swelling inthe body. This condition is called uremia. Without dialysis, uremia willlead to seizures, or coma and will ultimately result in death.

Diseased kidneys do not produce enough of the hormoneerythropoietin (EPO) which stimulates the bone marrow to producethe proper number of red blood cells to carry oxygen to vital organs inthe body. When EPO is below ??? the patient is diagnosed withanemia.

Patients with ESDR generally, are unable to maintain theconcentration of electrolytes such as the positive (+) cations sodium,calcium, potassium and magnesium, and the negative (-) anionschloride, bicarbonate, phosphate and sulfate, thus preventing thenormal system equilibrium, known as homeostasis. The rate of fluidintake in the body is governed by thirst, and the rate of excretion isgoverned by an antidiuretic hormone (ADH) also called vasopressin,made in the hypothalamus, a gland in the base of the brain and storedin the pituitary gland. With ESDR, the kidneys ability to respond toADH is impaired and cannot concentrate the urine by returning theexcess water to the bloodstream.

Systemic Lupus Erythematosus (SLE): Systemic LupusErythematosus has the ability to occur in almost any system of thebody. People with SLE develop antibodies against their own tissue which attacks self-tissue like a foreign invader. The disease has nocure and more women develop SLE than men. Current theories linkthe development of lupus with hereditary and environmental factors,some of which include stress, infections and certain medications andchemicals. Kidneys are frequently affected by SLE and this can becritical because there are no outward symptoms of kidney failure untilit is too late. In SLE, DNA may appear outside the cells, floating in the

blood serum. In these cases the immune system produces largenumbers of antibodies to the DNA, called anti-DNA-one of theindications of SLE. When these antibodies combine with their target,the result is an immune complex Sometimes these complexes cannotbe removed from the blood by normal body processes, and they aretrapped 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 becaused by drugs, heavy metal poisoning, or an autoimmune disease,such as Systemic Lupus Erythematosus or Sjogrens syndrome. Threetypes exist, each producing slightly different symptoms. When bloodpotassium levels are low, neurologic problems may develop, including

muscle weakness, diminishing reflexes, and even paralysis. Kidneystones may develop, causing damage to kidney cells and leading tochronic kidney failure.

Renal Glycosuria: or Glucosuria, is a condition in which glucose(sugar) is excreted into the urine, despite normal or low glucose levelsin the blood. When blood is filtered through the kidneys, glucose isremoved along with many other substances. The filtered fluid passersthrough the network of tubules in the kidney, where it is reabsorbedand returned to the bloodstream, and unwanted substances excreted

in the urine, but with renal glucosuria, glucose will be excreted intothe urine despite normal glucose levels in the blood.

Cystinuria: an inherited defect of the kidney tubules, causingexcretion of amino acid-cystine into the urine, causing cystine stonesin the urinary tract. People with this disorder must have inherited twoabnormal genes, one from each parent.

Fanconi’s Syndrome: a rare disorder of the tubule function thatresults in excess amounts of glucose, bicarbonate, phosphates, andcertain amino acids in the urine.

Vitamin D-Resistant Rickets: a rare disorder is nearly alwayshereditary, passed as a dominant gene that is carried on the Xchromosome. This defect causes a kidney abnormality that allowsphosphate to be excreted into the urine, resulting in low bloodphosphate levels.

Hartnup diaease: a rare hereditary disorder that occurs when aperson inherits two recessive genes for the disorder, one from eachparent. The disease affects how the body processes amino acids, whichare building blocks of proteins.

Bartter’s Syndrom: is a disorder in which the kidneys over-excreteelectrolytes (potassium, sodium, and chloride), resulting in low bloodlevels of potassium (hypokalemia) and high blood levels of thehormones aldosterone and renin. The levels of sodium chloride and water in the blood become low. The body tries to compensate byproducing more aldosterone and rennin. These hormones reduce thelevels of potassium in the blood.



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

Polycystic Kidney Disease: a hereditary disorder in which manycysts form in both kidneys; the kidneys grow larger but have lessfunctioning kidney tissue. Chronic infection, a frequent problem, can worsen the kidney failure. About half of those with this disease havehigh blood pressure at time of diagnosis.

Medullary Cystic Disease: a disorder in which kidney failure developsalong with cysts deep within the kidneys. A person starts to produceexcessive amounts of urine because the kidneys don’t respond toantidiuretic hormone which normally signals the kidneys toconcentrate 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 kidneytissue to appear spongy. A person with this disorder is prone todevelop painful kidney stones, blood in the urine and kidneyinfections.

Alport’s Syndrome: (hereditary nephritis), a hereditary disorder in which kidney function is poor, blood is present in the urine, anddeafness and eye abnormalities sometimes occur. This disorder is

caused by a defective gene on the X chromosome, but other factorsinfluence 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 thedefect) and usually develop kidney failure. Symptoms are blood in theurine, and the urine may also contain varying amounts of protein, white blood cells, and casts (small clumps of material ) of varioustypes, which are visible under a microscope.

Nail-Patella Syndrome: a rare hereditary disorder of the connectivetissue 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 boneX-rays and a biopsy of the kidney tissue.

Without the critical technological breakthrough of a Human KidneyReplacement Unit like the one being developed here, persons with endstage renal disease will have to undergo either dialysis or a kidneytransplant (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 tocomplications caused by toxic wastes and fluid build-up in the body. The amount of time left to live depends on the condition of the patientand the amount of kidney function left.

The design intent of the Human Kidney Replacement Unit is tomake it as compact as possible, and incorporate into the logic asmany natural kidney functions as scientifically feasible, unlikehemodialysis 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 dialysisis not only grossly inconvenient but basically it just removes toxinsfrom the blood, and does not regulate the chemical composition of theblood, 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 notavailable, dialysis is necessary to help rid your body of harmful wastessuch as urea , extra salt and extra water, all of which are removedfrom the blood. Doctors suggest dialysis when kidney failure iscausing 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 avery high blood potassium concentration (hyperkalemia).

Hemodialysis is a treatment method that uses a machine, having aspecial blood filter or semipermeable membrane called a dialyzer. 85%of all dialysis is performed with this technique. The other 15% of thecases use a method known as peritoneal dialysis, which uses theperson’s own peritoneum as the semipermeable membrane. Dialysis isperformed three times a week with the treatments lasting from 3 to 5hours. Before regular dialysis is begun, a site on the body must be

chosen for vascular access, where the blood will be removed andreturned during dialysis. There are several kinds of accesses, one of which is arteriovenous (AV) fistula, which is said to be the bestapproach, but if the patient has small veins that won’t developproperly into a fistula, vascular access can be achieved using asynthetic tube implanted under the skin in the arm. The tube becomesan artificial vein that can be used repeatedly for needle placement. ASubclavian 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 theneck, 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. ExtracorporealCircuit, carries the patients blood from the access to the dialyzer, andback to the access. The circuit includes the arterial line, blood pump,heparin infusion pump, dialyzer, venous line, and monitors for bloodflow, pressure, and air/foam detectors.

Most dialyzers (filtering cartridges) are constructed of a styrenebutadine cylinder filled with up to 11,000 cellulose hollow fibers eachhaving an internal diameter of approx 200-300 microns.Blood flows through the center of the fibers, dialysate which is watercontaining blood ionic substances such as sodium, potassium, and

calcium in required concentrations, flows in a countercurrent directionoutside the fibers, sometimes in cross flow direction across fibers. Thedialysate is continually replaced as waste products build up to preventreduction in concentration gradient and diffusion rate. It is alsoimportant for the pH of dialysate to be within an acceptable range.Bicarbonate-buffered dialysate should have a pH of 7.3. Normal bodypH ranges from 7.35 to 7.45, slightly alkaline.

Dialyzer First-Use Syndrome is a group of symptoms that may occurshortly after beginning dialysis with a new cellulose dialyzer that isinsufficiently 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 ethyleneoxide gas or bits of cellulose remaining in the dialyzer aftermanufacturing. Re-processing a cellulose dialyzer can also reduce theincidence of FUS by removing ethelyne oxide and cellulose bits; acoating of blood protein remaining in the dialyzer after dialysis alsomakes the reprocessed dialyzer more biocompatible—unless thecoating is removed by bleach during reprocessing.

Vitamins are substances that the body needs for normal growth andhealth. Dialysis removes vitamins B12, folic acid, and pyridoxin,

which promote good blood cell growth and maturity.Haemofiltration requires membranes with large pores to remove middlesized 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, inmedium sized dialyzers the ultrafiltration coeffient is 60mL/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 isabout 192.6 mL/min, and the Creatinine clearance is 248.6 mL/min. These values sound favorable, but the immediate side effects, oradverse reactions patients with ESRD have are; hypertension,hypotension, headaches and nausea. Other complications include

blood loss, blood overheating, hemolysis, excessive filtration withelectrolyte imbalance. Shortness of breath with wheezing, respiratoryarrest, itching, hives, edema, hypertension above baseline, elevatedpulse rates and arrhythmia can also result.

Long term side effects of dialysis: Patients, after being on dialysisfor long periods, such as several years, develop medical problems frombone, 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 liquidmatrix 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 sixcatagories which are: (1) inorganic ions and salts; (2) plasma proteins:(3) organic nutrients; (4) nitrogenous waste products; (5) specialtransported products; (6) dissolved gasses. The cations (positivelycharged 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 , chlorideand bicarbonate are the most abundant. There are also carbohydrates(HCO3), glucose and traces of other sugars-- amino acids-- otherorganic 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 plasmaabove. The formed elements suspended in the whole blood are of three major types. Red blood corpuscles “cells” (erythrocytes), whiteblood cells (leukocytes), and the platelets, which are small disc shapedbodies 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 ahematopoietic stem cell.

Red blood cells (RBC’s) or (+red corpuscles) make up 40-45percent of one’s blood. They are biconcave disc-shaped bodies that

resemble cells without nucli, mitochondria and golgi apparatus andother subcellular organelles, especially in the mature cells which arelacking many of the characteristics of living cells. In adults RBC’s areformed in the red bone marrow, which fills the interior of the upperends of the long bones and the shafts of flat bones like those in theskull, ribs and pelvis. RBC’s arise from normally necleated, rapidlydividing connective-tissue cells of the bone marrow. The normalsurvival time for RBC’s is 120 days, then the old worn out cells areengulfed by phagocytic cells of the liver, spleen and lymph nodes.RBC’s contain a molecule called hemoglobin (Hb, 3.8% heme and96.2% globin with a molecular weight of 64.450, a globulin protein

composed of four independent polypeptide chains. Each of the fourchains enfolds a complex prosthetic group called heme, which has aniron atom at its center. Each molecule of hemoglobin contains fouriron atoms, and each iron atom can bind with one molecule of oxygen(Hb+402). This is called oxyhemoglobin, and is how blood gets itsbright red color. Oxygen is carried in the red blood cells by beingpicked up in the capillaries of the lungs and released in the capillariesof the systemic circulation system and absorbed by the body’s cellsalong with food in the blood which was processed by the digestivesystem into smaller components such as proteins, fats, andcarbohydrates. Hemoglobin has an affinity for oxygen due to the

influence of pH, because H+ ions act as negative allosteric modulatorsfor hemoglobin. CO2 produced as metabolic waste by cells , isabundant 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 95percent of the carbon dioxide (C02) generated in tissues back to thelungs where it is released into the air. Hemoglobin also regulates localvariation in blood pressure, by carrying a nitric oxide, a gas thatrelaxes the blood vessel walls.

White blood cells (leukocytes) fight infection, but are less numerousthan red ( the ratio between the two is around 1 to 700). There arethree types: granulocytes, lymphocytes and monocytes. There are, inturn, three kinds of granulocyte: neutrophis, eosinophils andbasophils. 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 immunesystem, B lymphocytes produce antibodies, which destroy foreign



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bodies. There are inflammatory T cells that recruit macrophages andneutrophils to the site of infection. Cytotoxin T lymphocytes (CTLs)that kill virus-infected and, perhaps, tumor cells. Helper T cells thatenable the production of antibodies by B cells. Although bone marrowis 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 othertissues where they encounter antigens, continue to divide by mitosisand mature into fully functional cells.

Monocytes leave the blood and become macrophages, large phagocyticcells that engulf foreign material (antigens) that enter the body, anddead and dying cells in the body.

Neutrophils squeeze through the capillary walls and into infectedtissue where they kill the invaders (e.g. bacteria)d then engulf the

remnants by phagocytosis.

Platelets are small fragments produced from megakaryocytes andblood normally contains 150,000 to 450,000 platelets per microliter. If this value should drop much below 50,000 microliters, there is adanger of uncontrolled bleeding. This shows the essential role thatplatelets have in blood clotting.

Influencing Blood Pressure: The Blood pressure in the body dependson 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 bloodpressure, (3) the circulating blood volume- the higher the circulatingblood volume, the more the heart muscle gets stretched by theincoming blood. The kidney influences blood pressure by; (1) Causingthe arteries and veins to constrict, (2) increasing the circulating blood volume.



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Specialized cells are located in a portion of the distal tubule locatednear 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 bloodpressure and the increase in Na is relayed to them by the maculadensa cells. The jaxtaglomerular cells then release an enzyme calledrenin. Renin converts another protein from the blood calledangiotensin into antiotensin ll. Angiotensin ll causes blood vessels tocontract. The increased blood vessel constrictions elevate the bloodpressure.

How the Kidneys Increase the Circulating Blood Flow; Angiotensinll stimulates the adrenal gland to secrete a hormone called

aldosterone. Aldosterne stimulates more Na reabsorption in the distaltubule, and water gets reabsorbed along with the Na. The increasedNa and water reabsorption from the distal tubule reduces urine outputand increases the circulating blood volume. The increased bloodvolume helps stretch the heart muscle and causes it to generate morepressure with each beat, thereby increasing blood pressure. Theactions taken by the kidney to regulate blood pressure are especiallyimportant during traumatic injury, when they are necessary tomaintain 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 becomesticky and adhere to collagen, they bind fibrinogen and release ADPand thromboxan A2 which recruit and activate still more platelets inthe blood. Although blood clotting is desirable when we get into anaccident, cardiovascular problems arise when blood clotsinappropriately in blood vessels or the chambers of the heart. Doctorsuse mild blood thinning agents, or platelet inhibition to prevent theseblood clots. Clotting is inhibited by Aspirin (acetylsalicylic acid), Ticlid(ticlodipine), Plavix (clopidogrel). Platal (cilostazol), Persantin(dipyridamol), Anyurane (sulfinpyrazone) and three Intravenous agentscalled Rheopro (abciximab), Integrilin (eptifibatide) and Aggrastat

(tirofiban). Nitrates. Vitamin E and Ginko Biloba also have mildantiplatelet effects.

Blood clotting (coagulation): The science that causes blood to clotboth inside and outside the human body is thoroughly researched inthis project, in order to design in the safeguards necessary to preventthis type of phenomenon from occurring inside the Human KidneyReplacement Unit, thyis will avoid the use of Heparin which is a



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

Blood clotting is the body’s normal response to a bleeding injuryMost blood clots dissolve back into the blood when the body hashealed the vessel, but if the clot does not dissolve it can be potentiallydangerous. Some types of blood clots are: Thrombus, which is ablood clot that forms along the wall of the heart or a blood vessel andslows the blood flow, unless it continues to enlarge enough to blockthe blood flow altogether. An Embolus is a clot that forms in one areaof the body, and travels through the blood stream to lodge in anothervessel. Emboli, are more dangerous because they can cause a suddenblockage 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 andcalcium ions (Ca2+) (blood banks use a chelating agent to bind thecalcium so blood will not clot in the bag) and about a dozen otherprotein clotting factors which circulate in the blood as inactiveprecursors. They are activated by proteolytic cleavage, which becomesactive proteases, for other factors in the system.

Examining the processes of blood clotting: Damaged cells display asurface protein called tissue factor (TF). Tissue factor binds toactivated Factor 7. The TF-7 heterodimer is a protease with two

substrates—Factor 10 and Factor 9. Factor 10 binds and activatesFactor 5. This heterodimer is called prothrombinase because it is aprotease that converts prothrombin (also known as factor ll) tothrombin. Thrombin has several different activities. Two of them are:proteolytic cleavage of fibrinogen (aka “Factor I”) to form: solublemolecules of fibrin and a collection of small fibrinopeptides, activationof Factor 13 which forms covalent bonds between the soluble fibrinmolecules converting them into an insoluble meshwork, the clot.

Amplifying the clotting process: The TF-7 complex (which startedthe process) also activates Factor 9. Factor 9 binds to Factor 8, a

protein that circulates in the blood stabilized by another protein, VonWillebrand Factor (vWF). This complex activates more Factor 10. Asthrombin is generated, it activates more Factor 5, Factor 8, and Factor11, and Factor 11 amplifies the production of activated Factor 9.

Function of the Human Kidney Replacement Unit (HKRU)



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Before we get into the function of the HKRU, we need to reviewhow 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 occurimmediately after the blood enters the glomerular capillaries of theBowmans capsule (or renal corpuscle) through the efferent arteriolelocated in the kidney cortex. Here, whole blood containing 40 to 50 %formed elements and 50 to 60% percent plasma, enters the glomerularcapillaries..

From the plasma, the heart forces the filtrate of water, containingions, and waste products of urea and creatinine along with dissolvedsubstances and other small molecules like sodium, phosphorus andpotassium, 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 aretoo large to filter through the membrane to any degree, and will moveon in the blood-stream.

The filtrate leaves the lumen of the bowmans capsule (approximately170 liters per day) and moves into the lumen of the nephron wheresmall molecules such as ions, glucose and amino acids get reabsorbedinto the bloodstream from the filtrate.

Specialized proteins called transporters are located on themembranes of the various cells of the nephron. These transportersgrab the small molecules from the filtrate as it flows by. Eachtransporter 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, whilefewer ones are spread out through other segments.

Some transporters require energy, usually in the form of adenosinetriphosphate (active transport), while others do not (passive transport).Water gets reabsorbed passively by osmosis in response to the buildupof reabsorbed Na in spaces between the cells that form the walls of thenephron.

Other molecules get reabsorbed passively when they are caught up inthe flow of water (solvent drag). Reabsorption of most substances is



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

Two major factors affect the reabsorption process: (1)

Concentration of small molecules in the filtrate- The higher theconcentration, the more molecules are reabsorbed. There is only afixed number of transporters for a given molecule present in thenephron, so there is a limit to how many molecules the transporterscan grab in a given period of time. (2) Flow rate affects the timeavailable 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 25percent of filtered Na. The Distal tubule reabsorbs 8 percent of filteredNa, 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 thecapsule, into the proximal convoluted tubule system of the nephron. The proximal convoluted tubule, the loop of Henle, and the distalconvoluted tubule are encapsulated in a dense network of capillariesbranching from the other arteriole leaving the Bowmans capsule,carrying the blood in which the filtrate was removed. The capillariesunite 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 convolutedtubule, then through the long loop of Henle, then through the distalconvoluted tubule, and finally into the collecting tuble, which runsfrom the cortex through the medulla to the renal pelvis. On the way, water leaving the tubles by osmosis, as well as ions and smallmolecules actively transported out of the tubules, can be reabsorbedby 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 theblood. When water must be removed, all that is not absorbed byosmosis is pumped by active ions, with water following. In this casethe pumps are in the convoluted tubules and ascending limb of theloop of Henle. Two kinds of ion –Na+ and Cl- ions are the crucialsolutes for controlling water in living tissue. By the action of ionicpumps, some 75 percent of the solutes and the water that follows them



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are removed from the filtrate in the proximal convoluted tubule andreabsorbed by the capillary network. The remaining filtrate passes intothe loop of Henle, where fine tuning of the filtrate concentration andvolume 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 thelumen. Now, as the filtrate moves up the other side (ascending limb),Na and Cl are reabsorbed, but water is not, setting up a concentrationdifference in NaCl along the length of the loop with the highestconcentration 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 alldiffuse passively back into the descending limb, to produce a cycling of some of the ions from ascending limb to tissue fluid to descendinglimb to ascending limb to tissue fluid, and so on). The result is that asalt-ion concentration gradient is maintained in the tissue fluid along

the loop, with the concentration lowest in the outer part of the kidneycortex where the convoluted tubules are located, and highest in themedulla, where the tip of the loop of Henle is located. The wall of theascending limb of the loop is impermeable to water, since water doesnot diffuse out of the tubule as the salt ions are moved out. When theurine dilute enters the collecting tubule, water is allowed to moves bypassive osmossis from the dilute urine in the tubule to thesurrounding hypertonic tissue fluid, until the final urine may becomeessentially isotonic with highly concentrated tissue fluid in the innerregion of the medulla. Whether the collecting tuble finally releasesdilute 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 pituitarygland, 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 canpass 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 endingsof these osmoreceptors are located in the posterior pituitary gland and

secrete ADH. The human body requires at least 500 mg of sodiumper day but the average American ingests between 2,300 to 6,900mg 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 secreteADH. If the Na concentration of the blood is low, they do not secreteADH. In reality, there is always some very low level of Adh secretedfrom the osmoreceptors.



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The more water absorbed in the blood reduces the Naconcentration. The reduced Na concentration in blood reduces theamount of Filtered Na in the kidney’s glomerulus where all the Na isreabsorbed with some of the water. The reduced Na is sensed by theosmoreceptors, therefore not much ADH is secreted and not much

water is reabsorbed in response to the Na concentration gradient setup by the loop of Henle. The excess water is excreted in the urine andthe 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) bya chemical mixture of hydrogen ions and sodium bicarbonate, which isproduced by the carbon dioxide (CO2) formed in the cells as abyproduct of many chemical reactions. The CO2 enters the blood inthe capillaries, where red blood cells contain an enzyme calledcarbonic anhydrase that helps combine CO2 and water (H2O) to form

carbonic acid (H2CO3) quickly. The carbonic acid formed then rapidlyseparates into hydrogen ions (H+) and bicarbonate ions (HCO3). Thisreaction can also proceed in the reverse direction, whereby sodiumbicarbonate plus hydrogen ions yields carbon dioxide and water.CO2+H2O--- H2CO3-H++HCO3. The correct pH is maintainedby keeping the ratio of hydrogen ion to bicarbonate in the bloodconstant. If acid (hydrogen ion) is added to the blood, the bicarbonateconcentration will be reduced, altering the pH concentration of theblood

Diets rich in meats provide acids to the blood when digested. Diets

rich in fruits and vegetables make our blood alkaline because they arerich in bicarbonates. Exercising muscles produce lactic acid thatmust be eliminated from the body or metabolized. High altitudes andrapid breathing makes our blood alkaline. In contrast, certain lungdiseases that block the diffusion of oxygen can cause the blood to beacidic.

The kidneys can correct any imbalance by removing excess acid(hydrogen ions) or bases (bicarbonate) in the urine and restore thebicarbonate concentration in the blood to normal. The kidney cellsproduce 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 thenephron. Also, bicarbonate ions get produced and secreted into theblood. In the lumen of the nephron, filtered bicarbonate combines with secreted hydrogen ions to form carbon dioxide and water (carbonanhydrase is also present on the luminal surface of the kidney cells).



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Whether the kidney removes hydrogen ions or bicarbonate ions inthe urine depends upon the amount of bicarbonates filtered in theglomerulus from the blood relative to the amount of hydrogen ionssecreted by the kidney cells. If the amount of filtered bicarbonate isgreater 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 filteredbicarbonate, then hydrogen ions will be lost in the urine.

If the Kidneys Are Working Properly, with an acid diet hydrogenions are added to the blood by breaking down a meat-rich dietcombined with bicarbonate in the blood to form carbon dioxide and water. This reaction reduces the bicarbonate concentration and thepH in the blood and this decreased bicarbonate concentration in theblood 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 fromthe kidney cells into the blood was equal to the hydrogen ion secretedinto the lumen and greater than the filtered load of bicarbonate fromthe blood- therefore, the blood has a net gain of bicarbonate. Thisprocess continues to loose hydrogen ions in the urine and gainbicarbonate in the blood until the concentrations of hydrogen (pH) andbicarbonate ions in the blood are restored to normal.

An Alkaline Diet: Bicarbonate added to the blood from fruit orvegetable-rich diet combines with hydrogen ions to form carbondioxide and water. This reaction reduces the hydrogen ionconcentration and increases the pH. The increased bicarbonateconcentration increases the amount of bicarbonate filtered in theglomerulus. The filtered bicarbonate exceeds the amount of hydrogenion secreted by the kidney cells, and excess bicarbonate is lost in theurine. The amount of bicarbonate secreted from the kidney cells intothe blood was equal to the hydrogen ions secreted into the lumen andless than the filtered load of bicarbonate from the blood, therefore, theblood has a net loss of bicarbonate. This process continues to lose

bicarbonate in the urine and reduce the bicarbinate in the blood untilthe concentrations of hydrogen (pH) and bicarbonate ions in the bloodare restored to normal. A solution with a pH above 7 is alkaline, orbase; a solution with a pH below 7 is acid. A solution with a pH of 7.0is neutral. Normal body pH ranges between 7.35-7.45, slightlyalkaline.



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In the nephrons; water is not the only substance reabsorbed into theadjacent capillaries. In a normal healthy person all the glucose,almost all the amino acids, and most all the salt ions are alsoreabsorbed and returned to the blood. Much of this reabsorptioninvolves active transport, and thus energy expenditure by the tubule

cells. To recap “the kidney functions by forcing out of the blood in theglomerulus most molecules small enough to pass through the pores,and then reabsorbing into the capillaries surrounding the convolutedtubules and loop of Henle only what is to be saved”. Most substanceshave a kidney threshold level. If the concentration of a substance inthe blood exceeds its kidney threshold level, the excess is notreabsorbed from the filtrate by the capillaries but is instead excreted inthe urine. Glucose has a high threshold level, but if the blood-sugarlevel is abnormally high, as it is in diabetics, sugar appears in theurine. The kidneys help regulate the composition of the blood bykeeping 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 theglomerular filtrate, exceeds its kidney threshold value, the excess isexcreted in the urine.

Potassium is the primary positive ion within the cells, where 98percent of the 120 grams is found. Potassium along with sodium, regulates the water balance and acid-base balance in the blood andtissue. 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 totalpotassium. The red blood cells contain 420 mg., which is why a redblood cell level is a better indication of an individuals potassium statusthan 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, orabout 0.8-1.5 grams per 1,000 calories consumed. The averageAmerican diet includes from 2-6 grams per day.

Some common problems that have been associated with low potassiumlevels include hypertension, congestive heart failure, cardiacarrythmias, fatigue, depression and mood swings. People whoconsume 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 sodiumand potassium balance is as finely tuned as those of calcium and



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phosphorus, or calcium and magnesium. Potassium is absorbed fromthe small intestines, at about 90 percent absorption. Most excesspotassium is eleminated in the urine and some in sweat. The adrenalhormone aldosterone stimulates elimination of potassium by thekidneys

Kidneys and Calcium; As stated, the body stores calcium in thebones, yet maintains a constant level in the blood. If the bloodcalcium level falls, the parathyroid glands in your neck release aharmone called parathyroid hormone. This increases calciumreabsorption from the distal tuble of the nephron to restore the bloodcalcium level. Parathyroid hormone also stimulates calcium releasefrom bone and calcium absorption from the intestine. In addition toparathyroid hormone, the body also requires vitamin D to stimulatecalcium absorption from the kidney and intestine. Vitamin D isfound in milkproducts. A precursor to vitamin D (cholecalciferol) is

made in the skin and processed in the liver. However, the final stepthat converts an inactive form of cholecalciferol into active vitamin Doccurs in the proximal tubule of the nephron. Once activated, vitaminD stimulates calcium absorption from the proximal tubule and fromthe intestine, threby increasing blood calcium levels.

Kidney stones are often caused by problems in the kidney’sability to handle calcium. In addition, the kidney’s role inmaintaining blood calcium is important in the bone diseaseosteoporosis that afflicts many elderly people, especially women.

All Implantable Artificial Kidney (IAK) Functions will be similar tothose of healthy kidneys, processing around 170 liters of blood filtrateper day from the patients whole blood, taken from Iliac artery. Here,the blood will undergo the same processes, or stages in the orderoccuring in the nephrons of real kidneys. These are Ultra-filtration,Selective Reabsorption and Tubular Excretion. The IAK has manyadvantages over dialysis, a few which are, patients with kidney failure will not have to remain at home, in town, spending three days a weekin dialysis centers, but instead, will be able to commute to work, workharder, stay longer if needed and travel for long duration’s, just likepeople with healthy kidneys. Another important feature is that the

HKRU patient will feel much better by not suffering the side effectsassociated with dialysis.

In the HKRU/IAK; there are a total of 20 membranes, 12 reverseosmossis membranes for ultra-filtration, and 8 osmossis membranesfor re-absorption. Before attempting to understand how themembranes in the HKRU function, the reader should review the nextfew pages on membrane technology.



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

fluid.

Membranes Thickness and Pore Sizes: Membranes are normallyabout 150 um thick. Membrane pore size is the average diameter of individual pores in a membrane. Although some manufacturers reportpore diameters in precise terms, the pores are rarely perfectlyspherical. In some applications the largest pore size is more criticalthan the average size. Most laboratory and medical applications call formembrane filters that are generally less than 0.1 mm thick with aprecise pore size.

Particles Separated by Membrane filtration are normally smallerthan 100 micron in diameter- a particle range between 0.1 and 1micron is not uncommon. Actually, the proper name for what we aredoing here is “sieving”, where large particles are separated fromsmaller ones. Filtration on the other hand, by definition is the removalof practically all particles from a solution.

Although membrane manufacturing processes have strict tolerances,pore size is usually determined statistically by the average dimensionof the smallest particle that will pass through it.

Pore-Size Ratings reflect performance rather than actual pore sizeand are expressed as nominal or absolute. A nominal rating meansthat some predetermined proportion of particles, usually 98% areretained. A membrane/filter with an absolute rating should retain100% of the particles larger than its reported pore size. There is noabsolute method to determine pore size or even the exact properties of a membrane. Only through testing can manufacturers be certain thata specific filter membrane is proper for certain applications.

Membrane pore sizes can range from atomic dimensions (<10angstroms to 100+ microns. Several standardized tests are available

to determine pore size. The bubble point test evaluates performanceunder aqueous conditions. However, the bubble test cannot be usedfor hydrophobic membranes, as they do not wet evenly. The waterintrusion pressure method calculates pore size based on pressureneeded to force water through the filter. Pore size is calculated frommeasurements of capillary force, pressure, and water height. Themethod is described in ASTM F316. Only through testing can



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manufacturers be certain that a specific filter membrane is proper fortheir application.

The majority of membranes are made of cellulose esters formed bysubstituting hydroxyl groups with the appropriate reactive groups. For

example, in the two most ubiquitous forms, cellulose nitrate andcellulose acetate, the hydroxyl group is interchanged with the nitrogroup and acid anhydride or acid chloride, respectively. Other commonmembrane filter materials include vinyl, nitrile, nylon, polypropylene,and polytetra-fluoroethylene (PTFE or Teflon). Cellulose esters,plastics and Teflon are generally hydrophobic which hinders filtrationof aqueous solutions. Most membranes are treated with wettingagents, such as glycerol, Tween, and Triton X-100, which allow waterto flow freely.

Membranes created for reverse osmossis (RO) and ultrafiltration

and nanofiltration (NF) are generally coatings of thin verry poruspolymer, or plastic applied to a backing material. Since membranefiltration deals with very small partacles, electric charge can greatelyaffect filter effeciency and performance. When wet, most filters have anegative charge. At neutral pH, most cells, viruses andmacromolecules also exhibit a negative charge. The repulsion of likecharges can overcome electrostatic attraction and van der Waals forcesneeded to absorb small particles into the membrane, leading to lessthan optimal performance. For sterilization purposes, asbestos isoften chosen because of its high positive charge when wet. Raising theionic strength of the solution can also reduce negative charge.

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

Chemical compatibility; of the cellulose esters, cellulose nitrile is theleast tolerant of organic solvents. Cellulose acetate behaves similarilyto cellulose nitrate but is resistant to alcahals.

Some Companies specializing in membrane filters are Britishfounded Whatman, Inc. (Fairfield Nj). DBCD, Inc. (webster Texas). Palland Gelman Companies have merged. Millipore has teamed withAmicon and Tylan.Gradipore is an Australian Company specializing in blood purifyingfilters.



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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 rapidadsorption of plasma proteins onto the surface of dialyzer membranes

is one of the initial events that occur at the start of hemodialysis. Thetype of protein adsorbed varies between different membranes and mayinfluence biocompatability, which has been linked to activation of several metabolic pathways including alternate pathway of complement, interleukins, coagulation, kallikrein and eicosanoidpathways.

Blood Clotting Caused By Artificial Surfaces (Membrane):

The Chemistry that initiates normal Blood Clotting Is Describedin Section (Four Page 17). The relevance of the activation of

coagulation is really and issue of practical performance of therapy. Inaddition to biocompatibility, clotting is affected by several factorsincluding flow stagnation, rough surfaces, charge on surface andshear force. Implantation of anticoagulants on membranes couldeliminate this problem but is not available for practical use.

The interaction of blood with materials is central in thethrombogenic response obtained in extracorporeal circulation. Thrombin generation is determined through activation of bloodcoagulation, platelet activation, trauma to thr blood, blood flow, anduse of anticoagulants. It is important to note that artificial surfaces

interact with the hemostatic system wiyhout the benrfit of theprotective roles provided by the endothelium, and even without anyadditional trigger factors, artifical surfaces will alter the normalhaemostatic balance in favor of thrombogenesis.

Following the initial and rapid adsorption of plasma proteins ontothe material, activation of coagulation and plateletadhesion/aggregation occur, leading to thrombin generation andformation of fibrin. Activation of coagulation is thought to betriggered at the level of the contact system. This is a complex processcomprising 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 processesoccurring in extracorporeal circulation, especially the effects of variable flow conditions and shear stresses and air/blood interfaceson platelet adhesion, aggregation and release of platelet contents.



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It has been demonstrated that activation of coagulation was morepronounced with polyacrylonitrile membrane than cellulose acetateeven though the reverse was true for complement activation. Thus, when criteria of biocompatability are defined in order to choose adialysis membrane, it is important to take into account several

parameters.

First Use Syndrome: Anaphylaxis (type 1 hypersensitivity is asyndrome including one or more of the following life threateningresponses: 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 orleukotrienes: this mediator release may be due to immunological ornon-immunological mechanisms.

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

medical equipment that cannot withstand heat sterilization. There issignificant scientific evidence that ETO can haptenize human proteinssuch as human serum albumin (HAS), thus rendering the allergenETO-HAS. Approximately two-thirds of patients who experienceddialysis anaphylaxis have IgE against ETO-HAS, whereas only about5% of those without anaphylaxis have IgE against ETO-HAS.

Generally, not just in the kidneys but throughout the body, thereare four processes by which molecules move across biologicalmembranes. The first mode of transport affects ions, which are smallelectrically charged atoms or molecules (e.g. Na+or K+ or Cl-or Ca++).

Because of their charges they cannot freely diffuse across thephospholipid portion of cell membranes and their movement iscatalyzed or facilitated by transport proteins, called ion channels. These proteins do not use energy to change their conformation but areeither ‘gated’ by ligands (hormones, neurotransmitters, neuclotides],voltage ( transmembrane potential), or osmotic pressure differenceacross the membrane (a sensitivity for pressure also called mechano-sensitivity). Once channels provide an open pore conformation, ionsdiffuse in one direction determined by the electrochemical potentialacross the membrane. Ion channels or transporters do not controlthe direction of ion flux, but simply provide a pathway exhibiting an

ion selective property (e.g. discriminating positive from negativecharges). The electrochemical potential is called driving force andconsists of two components: the membrane potential (positive ionsflow towards the negatively charged side of the cell membrane, mostlythe cytoplasmic side), and the chemical potential (ion or concentrationgradient, where one side has more ions than the opposite side). Moreions will flow from the higher toward the lower concentration than inthe opposite direction.



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Second, aquaporins, a specialized class of proteins promote thediffusion of water across membranes. Although water has a highpermeability across lipid membranes, and can pass through ionchannels while they are open (along with ions, called flux coupling),

aquaporins are membrane proteins selective for water (and sometimesglycerol). Aquaporins are found in most membranes that are involvedin physiological homeostasis, salt (electrolyte) metabolism, and waterretention and secretion. Water and salt permeability are a majorregulatory mechanism for metabolic processes. Diarrhea and asthmaare two examples where mutations, toxins and/or auto-immuneprocesses disturb homeostasis.

Third, glucose is a major source of metabolic energy. It isprocessed 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 glucoseconcentration (chemical potential) that controls directionality of flux,not the facilitator. Carbohydrates do not carry electrical charges. Insome cases however, glucose transport is coupled to ion flux(symporters and antiporters) and it is the ion gradient and thus themembrane potential which pushes glucose to flow against its ownconcentration gradient (called pumping). These human glucosetransporters are compared to bacterial glucose uptake systems thatuse feedback signaling pathway where the level of chemical energy iscoupled 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 metabolitesamong 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 moleculessubsequently bind to receptors in the cytoplasm or nucleus of the cell.Examples are glucocorticoids, cholesterol derived hormones thatregulate carbohydrate metabolism through the control of geneexpression activity.

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



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Molecules usually contain two atoms. Those containing the samekind of atoms are molecules of elements, and molecules formed by theunion of different kinds of atoms are molecules of compounds. If theformula of a compound is known, the atomic weights can be used tocalculate the formula weight of that compound. The molecular weight

may be calculated from the molecular formula of the substance: it isthe sum of the atomic weights of the atoms making up the molecule.For example, water has the molecular formula H2O, indicating thatthere are two atoms of hydrogen and one atom of oxygen in amolecule 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 differentmolecules. For H2O, the H-O-H bond angle is about 104.5 degreesand the H---O bond distance is 1.0 angstrom (100 picometers = 100pm). The molecular weight of a substance is the sum of the atomic weights of all the atoms present in the molecule. If the substance isrepresented 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 10individual cartridges. The cartridges are arranged in pairs in theIHKRU; one cartridge on each side of each of the five blood chambers.or cavities cut through the skeletal frame. The first three centerchambers in are pressurized to the normal blood pressure. The lasttwo center chambers are osmosis cavities. The five chambers arelined up in series, with communication between them via narrow tallslots through the dividing wall separating the five chambers.

As the whole blood flowing at the rate of approximately 125ml/min or 45 gallons (180 liters) each day, containing all thesubstances, leaves the tube extending from the iliac artery to theentrance of the first of five center chambers in the IHKRU, positiveblood pressure in the center (renal) chambers forces-out only apercentage of the bloods total water content, per time spent in therenal chamber; however, the entire blood volume gets filteredapproximately 20 to 25 times each day by the process of reverse



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osmosis (RO). Water, which has an Atomic Mass Unit (AMU) of 18.015, is one of the smaller molecules in the blood, but lager thanHydrogen with an amu of 2.016. These, along with Sodium with anamu 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 membraneslocated in cartridges on either side of the first blood chamber. Waterand molecules smaller than 60 amu will continue on through thesecond membrane in the two cartridges, out into collecting areas.Molecules larger than Urea at 60.06 amu will not pass through thesecond (outer-most) membranes in the first cartridges and will bechanneled out special drain ports to a waste collecting area. Duringfiltration some molecules are caught in solvent drag with the water asthey pass through the membrane pores and enter the chambers; also,some of the molecules are drawn through the membranes byspecialized protein transporters. The higher the concentration of the

substance, the greater the amount of filtrate, or the greater thefiltration rate, the more substance gets filtered.

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

The reabsorption of most substances is related to the reabsorptionof Na, either directly, via sharing a transporter, or indirectly viasolvent drag, which is set up by the reabsorption of Na. Glucose isreabsorbed by a transporter that also transports sodium (Na).(Diffusion is the movement of molecules from an area of highconcentration to an area of lesser concentration across a permeablemembrane 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 differencesand the permeability of the membranes

By the time the blood reaches the osmosis/diffusion chamber, theblood is transporting mostly larger molecules. Since the bloodpressure inside and the filtrate on the outside of the injectionmembranes are now near equal pressures, dynamic diffusion occursand some of the water, sodium, calcium flows from the region wherethey are highly concentrated to a the region where they are lessconcentrated, until a state of equilibrium is reached. Diffusion occurs



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when a system is not at equilibrium. Osmosis is the diffusion of liquidmolecules across a semipermeable membrane.

Rate of Diffusion (Ficks’ Law)

The rate of a substance across a membrane is related to theconcentration 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 largerthan calcium, which is 40.08 amu. glucose, urea, creatinine, saltions, amino acids etc. The formed elements, red blood cells, whiteblood cells and platelets, along with the plasma protein molecules aretoo large to be filtered out here and will travel on in the blood stream.

The minutely thicker blood leaves the first central chamber andenters 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. Alsofrom 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 afterleaving the first central chamber.

All the filtrate collected in the urinary spaces of certain wasteremoval membranes of the second chamber, will be recycled from thebottom of the collection chambers, or urinary space, to the topthrough 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 concentratedurine 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 areseparated. As the blood with the formed elements and plasma proteinleaves the pressurized chamber.



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Changes of the concentration at two different planes of a vessel dueto the time-dependence of diffusion (C1: concentration I, x0: covereddistance 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,X

1 - X

o is the distance between them. Since the concentrationdecreases with growing distance has the concentration gradient anegative value. If the formula is applied to any small distance then thevalues 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 lawof diffusion. It states that a substance diffuses in the direction thateliminates its concentration gradient dc I dx at a rate proportional tothe 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 calledthe 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 / ( C1 – C2 /X1 Xo)

(C1 – c 2 /21 x 1 - Xo) is called the concentration gradient. D is thediffusion 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 longones. It is the square of the distance that has an influence on the

formula and it is proportional to the available area. Diffusion isimportant when regulating the molecular movements within cells orbetween neighboring cells.



IMPLANTED

ARTIFICIAL KIDNEY

implantable kidney

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