Kidney Chapter 5 - KOII_WS2324_C05_Kidney PDF

Chapter 5 Kidney Dr.-Ing. Sebastian Jansen Lecture Series: Künstliche Organe II Content 2 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney Artificial Organs - Kidney Anatomy & Physiology Kidney anatomy – Position & Shape a pair of kidneys; between 12th thoracicand 3rd lumbar ve...

Chapter 5 Kidney Dr.-Ing. Sebastian Jansen Lecture Series: Künstliche Organe II Content 2 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney Artificial Organs - Kidney Anatomy & Physiology Kidney anatomy – Position & Shape a pair of kidneys; between 12th thoracicand 3rd lumbar vertebrae; bean shaped with the convex side directed outwards; roughly; of red/brown color – Size & Weight 4 cm thick, 7 cm wide, and 11 cm long (4711); 150 – 180 grams Kidneys Position and schematic of the kidneys 3 Artificial Organs - Kidney Anatomy & Physiology Kidney function – Filtering & Excretion of water-soluble metabolic products (urea, uric acid, potassium, creatinine) and drugs or toxins – Regulation water (affects blood pressure & volume) and electrolyte content (osmolarity); Acid-base balance (pH-value) Kidneys – Hormon secretion Renin (blood pressure regulation); EPO, Vitamin D3, … – Receives 20% of cardiac output Position and schematic of the kidneys 4 Artificial Organs - Kidney Anatomy & Physiology Kidney structure – The medulla consists of 10 – 12 renal pyramids – A renal lobe consists of a pyramid with the respective cortex section – Within a lobe, the nephron is the functional unit (total of 1.2 mio.) Renal cortex Renal medulla (10-12 pyramids) Renal artery (from aorta) Renal vein (into vene cava) Ureter Schematic and image of the cross-section of a kidney 5 Artificial Organs - Kidney Anatomy & Physiology Kidney structure – The medulla consists of 10 – 12 renal pyramids Renal lobe Nephron Renal corpuscle – A renal lobe consists of a pyramid with the respective cortex section – Within a lobe, the nephron is the functional unit (total of 1.2 mio.) – A nephron consists of a corpuscle and a tubulus 6 Artificial Organs - Kidney tubulus Structure of the kidney Anatomy & Physiology Kidney structure – A corpuscle consists of the Bowman-capsule and the glomerulum Glomerulus proximal tubule distal tubule Bowman-capsule – Blood enters the corpuscle via the artery, is filtered, and exits it via the vein cortex medulla – The course of the veins are in direct proximity of the following tubules system Artery Vein Loop of Henle Urine Collecting duct Schematic of a nephron unit (left) and further course of the veins beyond the corpuscle (right) 7 Artificial Organs - Kidney Anatomy & Physiology – The filtrate from the glomerulum is called primary urin (180 l/day) – From the primary urin, water and other valuable substances are re-absorbed until ca. 1.5 l/day actual urin is excreted Glomerulus (glomerular filtration rate) 50 – 100 nm distal tubule Bowman-capsule 10 l/day Artery 1500 l/day 1.5 l/day cortex – A total of 1500 l/day of blood is pressed through the filter (50 – 100 nm) in the glomerulum. The glomerular filtration rate is ca. 180 l/day proximal tubule 180 l/day medulla Kidney structure Vein Loop of Henle Urinecollecting duct The nephron and average values of overall filtration rates 8 Artificial Organs - Kidney Glomerular filtration Anatomy & Physiology 1. Active (pressure) squeezing of blood from the glomerulus into the Bowman-capsule 2  primary urine: water and substances dissolved in blood plasma (glucose, urea & salts, no proteins) 1 2. Active (energy consumption) transport of glucose & sodium back into tissue and blood (capillaries) 4 Tubular reabsorption  Build-up of concentration gradient in tissue and capillaries 5 3 3. Passive (osmosis) backflow of 80% of the primary urinary water from the tubules into the blood vessels in the descending (water-permeable) tubule.  re-absorption of water due to osmotic pressure 4. Active (energy consumption) transport of salts and nutrients in the (water-impermeable) distal tubule  Build-up of concentration gradient 1 2 4 3 5. Passive (osmosis) outflow of water in the collecting pipe, further reabsorption of salts  Final water & electrolyte regulation 9 Artificial Organs - Kidney Mechanisms of re-absorbtion 5 Anatomy & Physiology Kidney regulation – Regulation of water & electrolyte Water quantity normally extremely constant (+/- 0.22% of body-weight); sodium level extremely constant; Kidney is major player in water regulation, mainly by:  RAAS: Renin-Angiotensin-Aldosteron-System  ADH: Antidiuretic hormone  … – Regulation of acid-base balance (pH-value) pH-value: 7.4 +/- 0.04; Kidney is part of the regulation system;  Reabsorption of bicarbonate – Regulation of blood pressure  Through water regulation (RAAS, ADH) 10 Artificial Organs - Kidney Anatomy & Physiology Blood pressure (baroreceptor cells) Renin-Angiotensin-Aldosterone-System (RAAS) – Juxtaglomerular apparatus Cells measure blood pressure in arteriole and Na+ concentration in urine. Decrease of blood pressure and/or of Na+ concentration induces release of Renin Juxtaglomerular apparatus Renin containing cells Maculla densa concentration Na+ Distal tubule Schematic of the juxtoglomerular apparatus 11 Artificial Organs - Kidney Anatomy & Physiology Renin-Angiotensin-Aldosterone-System (RAAS) – Juxtaglomerular apparatus Cells measure blood pressure in arteriole and Na+ concentration in urine. Decrease of blood pressure and/or of Na+ concentration induces release of Renin – Renin transfers Angiotensinogen into Angiotensin I which is transferred to Angiotensin II by ACE. Angiotensin II induces vasoconstriction and a release of Aldosterone. Aldosterone induces an increased reabsorption of water and Na+ beyond the distal tubule Blood pressure (baroreceptor cells) Angiotensinogen Renin Angiotensin I ACE Angiotensin II Vasoconstriction Aldosterone release Blood pressure Water reabsorption Na+ reabsorption Regulatory scheme (simplified) of the RAAS 12 Artificial Organs - Kidney Na+ in harn Anatomy & Physiology Antidiuretic hormone (ADH) – Stimuli ADH is expressed by the hypothalamus due to increasing osmolarity in the plasma (osmotic sensitive cells in the hypothalamus) and/or due to a decreasing blood-pressure (baroreceptor cells in right atrium and aorta) – Effect in kidney The Urine-collecting duct is impermeable to water without ADH. ADH makes the duct permeable and increases water-reabsorption in this part of the tubule Selvarajan RS, Rahim RA, Majlis BY, Gopinath SCB, Hamzah AA. Ultrasensitive and Highly Selective Graphene-Based Field-Effect Transistor Biosensor for AntiDiuretic Hormone Detection. Sensors (Basel). 2020 May 6;20(9):2642. doi: 10.3390/s20092642 13 Artificial Organs - Kidney Impact of ADH on water-regulation in the kidney as explained by Selvarajan et al. Anatomy & Physiology Regulatory effect on the acid-base balance – Lung The CO2 generated by the cells is quickly formed to carbonic acid and further on to H+-proton and bicarbonate (HCO3-). This process is reversed in the lungs and the CO2 is excreted (by breathing). Usually, the metabolic CO2 generation is completely excreted by the lungs Generated by metabolism Excreted by lung – Kidney The kidney further regulates the balance by the ability to excrete H+-protons and reabsorb bicarbonate (HCO3-) Regulation of acid-base balance through tubuli and lung 14 Artificial Organs - Kidney Anatomy & Physiology Regulatory effect on the acid-base balance – HCO3- reabsorption The cells in the proximal tubule are able to reabsorb the primarily excreted bicarbonate (HCO3-), which fulfills important pH-buffer functions. – In case of acidosis, the cells are also able to excrete H+ protons in exchange of a Na+ ion – In case of alkalosis, this process including the reabsorption is decreased and more bicarbonate is excreted (so less bicarbonate can buffer protons in the extracellular matrix) Regulation of acid-base in the proximal tubule by excretion of H+ protons and reabsorption of bicarbonate 15 Artificial Organs - Kidney Anatomy & Physiology Kidney parameters – Renal blood flow (RBF) Blood flow through the kidneys (1000 ml/min) => ~550 ml/min plasma flow through kidneys (RPF) – Glomerular filtration rate (GFR) Primary urine produced by the glomerular capillaries per time. Standard values are gender-specific and agedependent (♂ 95–145 ml/min; ♀ 75–125 ml/min). 16 Artificial Organs - Kidney Anatomy & Physiology Kidney parameters – Renal blood flow (RBF) Blood flow through the kidneys (1000 ml/min) => ~550 ml/min plasma flow through kidneys (RPF) – Glomerular filtration rate (GFR) Primary urine produced by the glomerular capillaries per time. Standard values are gender-specific and agedependent (♂ 95–145 ml/min; ♀ 75–125 ml/min). – Sieving coefficient (S) Ratio of concentration in filtrate to concentration in plasma Glomerulum 𝑐𝑝𝑟𝑖𝑚𝑎𝑟𝑦 𝑢𝑟𝑖𝑛𝑒 𝑆= 𝑐𝑝𝑙𝑎𝑠𝑚𝑎 General 𝑐𝑓𝑖𝑙𝑡𝑟𝑎𝑡𝑒 𝑆= 𝑐0 S=0: S=1: 17 Artificial Organs - Kidney no filtration free filtration Anatomy & Physiology Retention capacity of the glomerulus (Sieving coefficient) Substance Molecular weight (Da = g/mol) Radius (Å = 0.1 nm) Sieving coefficent (-) Water 18 1,0 1,0 Urea 60 1,6 1,0 Glucose 180 3,5 1,0 Sucrose 342 4,4 1,0 Inulin 5 500 14,6 0,98 – 1,0 Myoglobin 17 000 19,5 0,75 Ovalbumin 43 000 28,5 0,22 Hemoglobin 68 000 32,5 0,03 Albumin 69 000 35,5 0,001 Medizinische Universität Wien 18 Artificial Organs - Kidney Molecular weight > 10000 Da are increasingly hindered when passing through the membrane Anatomy & Physiology Kidney parameters – Renal blood flow (RBF) Blood flow through the kidneys (1000 ml/min) => ~550 ml/min plasma flow through kidneys (RPF) – Glomerular filtration rate (GFR) Primary urine produced by the glomerular capillaries per time. Standard values are gender-specific and agedependent (♂ 95–145 ml/min; ♀ 75–125 ml/min). – Sieving coefficient (S) Ratio of concentration in filtrate to concentration in plasma – Fractional Excretion (FE) Percentage of a substance‘s matter flow in the final urine compared to the matter flow in the primary urine 19 Artificial Organs - Kidney 𝐹𝐸 = FE=0: FE=1: FE=5: 𝑛ሶ 𝑓𝑖𝑛𝑎𝑙 𝑢𝑟𝑖𝑛𝑒 𝑛ሶ 𝑝𝑟𝑖𝑚𝑎𝑟𝑦 𝑢𝑟𝑖𝑛𝑒 complete reabsorption in tubule no reabsorption or secretion complete secretion of a substance (plasma is completely free afterwards) Anatomy & Physiology Kidney parameters – Renal blood flow (RBF) Blood flow through the kidneys (1000 ml/min) => ~550 ml/min plasma flow through kidneys (RPF) – Glomerular filtration rate (GFR) Primary urine produced by the glomerular capillaries per time. Standard values are gender-specific and agedependent (♂ 95–145 ml/min; ♀ 75–125 ml/min). – Sieving coefficient (S) Ratio of concentration in filtrate to concentration in plasma – Fractional Excretion (FE) Percentage of a substance‘s matter flow in the final urine compared to the matter flow in the primary urine – Clearance (C) Plasma volume-flow that is completely cleared (theoretical) 20 Artificial Organs - Kidney 𝑐𝑢𝑟𝑖𝑛𝑒 𝐶= ∙𝑄 𝑐𝑝𝑙𝑎𝑠𝑚𝑎 𝑢𝑟𝑖𝑛𝑒 𝐶𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 = 0.05 ∙ 100 𝑚𝑙/𝑚𝑖𝑛 0.1 𝐶𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 = 50 𝑚𝑙/𝑚𝑖𝑛 Also: 𝐶 = 𝐹𝐸 ∙ 𝐺𝐹𝑅 Anatomy & Physiology Kidney parameters – Example: Sodium (Na+) RPF = 550 ml/min  RBF = 1000 ml/min  RPF = 550 ml/min SNa = 1  GFR = 125 ml/min GFR= 125 ml/min  QUrine = 1.5 l/day = 1.04 ml/min  SNa = 1 (free filtration)  FENa = 1% (physiologically)  CNa = 168 𝑚𝑚𝑜𝑙/𝑙 140 𝑚𝑚𝑜𝑙/𝑙 99% Na-reabsorption FENa = 1% ∙ 1.04 𝑚𝑙/𝑚𝑖𝑛 = 1.25 ml/min Artificial Organs - Kidney cNa = 140 mmol/l 𝑛ሶ Na = 17,5 mmol/min (= 1% GFR) The FE of sodium is a clinical indicator for acute kidney failure. It is determined by 24h collection of urine (=> cNA and QUrine) and measurement of cNa in plasma (SNa = 1) and an estimation of GFR (see next slide) 21 cNa = 140 mmol/l 𝑛ሶ Na = 77 mmol/min Qurine = 1.04 ml/min 𝑛ሶ Na = 0,175 mmol/min cNa = 168 mmol/l Anatomy & Physiology Kidney parameters Metabolic residue from muscle activity – Example: Creatinine (Cr)  RBF = 1000 ml/min RPF = 550 ml/min  RPF = 550 ml/min  GFR = 125 ml/min  QUrine = 1.5 l/day = 1.04 ml/min  SCr = 1 (free filtration)  FECr = 100% (physiologically) SCr = 1 GFR= 125 ml/min FECr = 100% 1.327 𝑔/𝑙 The C of creatinine is clinically used to estimate GFR (FECr = 100%). It is determined by 24h collection of urine (=> cCr and QUrine) and measurement of cCr in plasma (SCr = 1). Artificial Organs - Kidney cCr = 11 mg/l 𝑛ሶ Na = 1.38 mg/min (= 100% GFR)  CCr = 0.011 𝑔/𝑙 ∙ 1.04 𝑚𝑙/𝑚𝑖𝑛 = 125 ml/min 22 cCr = 11 mg/l 𝑛ሶ Cr = 6.05 mg/min Qurine = 1.04 ml/min 𝑛ሶ Cr = 1.38 mg/min cCr = 1.327 g/l No Cr-reabsorption No Cr-Secretion Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 23 Artificial Organs - Kidney Pathophysiology Kidney failure – Acute failure Sudden and usually reversible kidney failure  Pre-renal: e.g. insufficient blood flow through the kidney due to blockage of the vessel (thrombus, tumor, high fluid losses, heart insufficiency)  Intra-renal: e.g. tubular necrosis, intoxication  Post-renal: e.g. kidney stones – Chronic failure slowly degrading, irreversible kidney failure      24 Diabetes Hypertension Glomerulonephritis Polycystic kidney disease Other (congenital, …) Artificial Organs - Kidney Polycystic kidneys Pathophysiology Diagnostic options – Laboratory     Creatinine level (↑ @ 50% kidney damage) Creatinine clearance (=> GFR) Urea (↑ @ 75% kidney damage) Electrolytes, … – Imaging  Ultrasound (kidney stones, tumor, cysts)  CT-Scan (vessel diagnostic, tumors)  MRI-Scan (vessel diagnostics, tumors) – Biopsy  Proof of glomerulonephritis – Scintigraphy Imaging of functional tissue, estimate of RBF, GFR, … 25 Artificial Organs - Kidney CT Scan of cystic kidney (upper) and MRI of kidney stone (lower) Therapies Treatment options – Acute failure Medication and treatment according to the underlying cause of the acute renal failure; temporal dialysis (Artificial kidney) might be needed – Chronic failure No cures for chronic kidney failure. Replacement of kidney / kidney function necessary  Transplantation  Chronic dialysis Patient on dialysis 26 Artificial Organs - Kidney Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 3.1 Historic Milestones 3.2 Dialysis Techniques 3.3 Dialyzer 3.4 Dialysate 3.5 Cannulation 3.6 Pump 27 Artificial Organs - Kidney Dialysis - Basics Basic principles used in kidney / dialysis: – Adsorption Chemical, physical or electrostatic bonding of substances to another surface – Filtration Convective filtering of solved / unsolved substances through a filter membrane by hydraulic forces (pressure gradients) Membrane (permeable) Principle of filtration 28 Artificial Organs - Kidney Dialysis - Basics Basic principles used in kidney / dialysis: – Adsorption Chemical, physical or electrostatic bonding of substances to another surface – Filtration Convective filtering of solved / unsolved substances through a filter membrane by hydraulic forces (pressure gradients) Membrane (permeable) – Diffusion Uniform distribution of molecules due to the random Brownian molecular motion (temperature dependent) Principle of diffusion 29 Artificial Organs - Kidney Dialysis - Basics Basic principles used in kidney / dialysis: – Adsorption Chemical, physical or electrostatic bonding of substances to another surface – Filtration Convective filtering of solved / unsolved substances through a filter membrane by hydraulic forces (pressure gradients) Membrane (semi-permeable) – Diffusion Uniform distribution of molecules due to the random Brownian molecular motion (temperature dependent) – Osmosis Osmotic pressure due to concentration differences in a semi-permeable membrane 30 Artificial Organs - Kidney Δp Principle of osmotic pressure Dialysis - Basics Basic idea behind dialysis: – Selective membrane The dialyzer membrane is designed to hold back valuable substances (e.g. proteins, cells) and to let pass water-soluble waste products / toxins into a dialysate solution Selective membrane – Forces Forces that drives the excretion of the waste products and toxins are filtration diffusion and osmosis or a combination – With or without pressure difference The principle is thinkable with or without a pressure difference over the membrane and hence a fluid loss on the blood side Excretion of substances into dialysate Principle of dialysis 31 Artificial Organs - Kidney Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 3.1 Historic Milestones 3.2 Dialysis Techniques 3.3 Dialyzer 3.4 Dialysate 3.5 Cannulation 3.6 Pump 32 Artificial Organs - Kidney Dialysis - Milestones Dialyze machine by Haas 1913 1924 Vividiffusion by Abel et al. 33 Artificial Organs - Kidney Dialyzer by Möller 1945 1950 Drum kidney by Kolff Hollow fiber dialyzer by Stewart 1956 Travenol Dialyze machine 1966 Dialysis - Milestones Dr. Abel (1913) – Dialyze system Developed in Baltimore (USA); Tubes with a semipermeable membrane made from collodion, a cellulose based material were used; The group performed animal trials Dr. Haas (1924) – First treatment of patient with acute failure Took place in Giessen (Germany); Haas also used cellulose-based materials for the membrane; Patients temporarily improved but the overall effect is not sufficient => patients still died from the kidney failure; He discovered the possibility of excreting water from the patients (ultrafiltration) Dialyzer of Abel (upper) and Haas (lower) 34 Artificial Organs - Kidney Dialysis - Milestones Dr. Kolff (1945) – First survival of a patient with acute failure in a hospital in the Netherlands; a big disadvantage of the system was that water could not be excreted from the patients (necessary for lung-edema or hypertension) Patient treated with the “drum kidney” of Dr. Kolff 35 Artificial Organs - Kidney Dialysis - Milestones Dr. Kolff (1945) – First survival of a patient with acute failure in a hospital in the Netherlands; a big disadvantage of the system was that water could not be excreted from the patients (necessary for lung-edema or hypertension) Dr. Möller (1950) – First clinical effective therapy in Germany Eight models were built and the treatment time was reduced from 13 hours to 8 hours Travenol standard kidney (1956) – Standardized dialysis treatment by a company later known as Baxter Travenol Co; Acceptance also due to better cannulation techniques 36 Artificial Organs - Kidney Möller dialyzer (left) and Travenol dialyze machine (right) Dialysis - Milestones Dr. Stewart (1966) – First hollow fiber membrane dialyzer Significant progress in treatment quality due to large membrane area; also due to improving cannulation techniques and shunt techniques First hollow fiber dialyzer by Stewart (upper) and modern dialyzer (lower) 37 Artificial Organs - Kidney Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 3.1 Historic Milestones 3.2 Dialysis Techniques 3.3 Dialyzer 3.4 Dialysate 3.5 Cannulation 3.6 Pump 38 Artificial Organs - Kidney Dialysis Techniques Basic components of modern dialysis: – Membrane dialyzer Device with a selective membrane through which blood and dialysate are directed – Dialysate Fluid with a specific composition that allows for the blood purification – Cannulation Vascular access allowing for regular use Erythrocytes Proteins Purifed blood Dialyzer Pump Blood from vein Principle of dialysis Artificial Organs - Kidney Urea Dialysate – Pumps Pumps are needed to overcome the pressure loss in the dialyzer 39 Salts Dialysis Techniques Hemoperfusion Dialysator Heparin Heparin Blutleckdetektor – An Adsorber is filled with a micro-pourous substance (e.g. activated carbon) that filters toxic substances in blood through adsorption UF-Kontr. – Used for specific toxins (e.g. drug abuse, medication overdose, …) Entgasung Blood Blutpumpe pump Patient Patient Bypass – Blood flow: ca. 300 ml/min Art. pressure art. Druck Adsober UF Ven. pressure ven. Druck – Also used in combination with a dialysis LF-Kontr. Heizung Proportionierung AirLuftdetektor detector Klemme clamp Exemplary scheme of a hemoperfusion setup HD1 S.Stiller 40 Artificial Organs - Kidney Dialysis Techniques Hemoperfusion – An Adsorber is filled with a micro-pourous substance (e.g. activated carbon) that filters toxic substances in blood through adsorption – Blood flow: ca. 300 ml/min – Used for specific toxins (e.g. drug abuse, medication overdose, …) – Also used in combination with a dialysis Exemplary Adsorber cartridges for hemoperfusion 41 Artificial Organs - Kidney Dialysis Techniques Hemofiltration Blood leakage Blutleckdetektor detector – Convective transport of the watersoluble toxins through the dialyzer membrane Hemofilter Heparin Heparin BlutBlood pumpe pump Ultrafiltration UF pump Pumpe – Large fluid loss is compensated with a substitute Art. pressure art. Druck Patient Patient ven. Ven. pressure Druck HF Dialyzer – Blood flow rate: ca. 300 ml/min – Intermitted mode and Continuous mode (CRRT); Typical filtration rate: 25 ml/kg h – Post-dilution (shown here) vs predilution Pump UF-Kontr. Substitute fluid Artificial Organs - Kidney Air detector Luftdetektor clamp Klemme Balance Körpergewicht - 42 Heating Heizung HF1 S.Stiller Exemplary scheme of a hemodialysis setup Dialysis Techniques Hemodialysis Waste Blood Blutpumpe pump UF-Kontr. Dialysate pump Entgasung UF UF Purified water Dialysate concentrate Conductivity LF-Kontr. measurement AirLuftdetektor detector Klemme clamp Proportioning Proportionierung Exemplary scheme of a hemodialysis setup Artificial Organs - Kidney Ven. pressure ven. Druck Degassing Heizung Heating 43 Patient Patient Bypass Balance – Ultrafiltration only used to excrete water from patient (edema, hypertension) – Blood flow: ca. 200 - 300 ml/min; Dialysate flow: ca. 400 - 600 ml/min Art. pressure art. Druck Dialysator Heparin Heparin LF/HF Dialyzer Bypass – Diffusive transport of the water-soluble toxins through the dialyzer membrane Blood leakage Blutleckdetektor detector HD1 S.Stiller Dialysis Techniques Hemodiafiltration Entgasung – Filtration rate: ca. 25 ml / kg h (e.g. 2 l/h) ProportioHeating nierung Purified water Dialysate concentrate – Transmembrane pressure (TMP): max. 300 mmHg Dialysate pump Proportioning UF pump UF-Kontr. Bypass – Blood flow: > 300 ml/min Blood Blutpumpe pump Balance Degassing Heating Heizung AirLuftdetektor detector Klemme clamp Exemplary scheme of a hemodiafiltration setup Artificial Organs - Kidney ven. Ven. pressure Druck Conductivity LF Meas. Balance Körpergewicht 44 Art. pressure art. Druck High-flux Heparin Heparin Dialysator HF Dialyzer Bypass – Combination of both worlds; diffusive excretion supported by convective excretion Blood leakage Blutleckdetektor detector Waste Patient Patient Dialysis Techniques Hemodiafiltration – Combination of both worlds; diffusive excretion supported by convective excretion – Blood flow: > 300 ml/min – Filtration rate: ca. 25 ml / kg h (e.g. 2 l/h) – Transmembrane pressure (TMP): max. 300 mmHg Dialysis machine 45 Artificial Organs - Kidney Dialysis Techniques Hemodiafiltration Advantages Disadvantages Increased Clearance The additional convective excretion increases the clearance rates especially for middle sized molecules Impact of patient’s hemodynamic The additional filtration rate can de-stabilize the hemodynamic of the patient Stress on erythrocytes / other cells The transmembrane pressure can damage erythrocytes and other cells Stress on canulation (shunt) Due to the increased flow rate and lower arterial pressure 46 Artificial Organs - Kidney Dialysis Techniques Dialysis in numbers: – ca. 80.000 patients in Germany – 3 treatments a week for 4-5 hours – About 250 ml of blood volume extracorporeal – 100 – 150 Liters of dialysate per treatment – 40.000 € per patient per year – About 3 billion € total costs in Germany Dialysis center 47 Artificial Organs - Kidney Dialysis Techniques Peritoneal dialysis – Peritoneum used as a semi-permeable membrane (1 – 2 m²) The peritoneum 48 Artificial Organs - Kidney Dialysis Techniques Peritoneal dialysis – Peritoneum used as a semi-permeable membrane (1 – 2 m²) – Fresh dialysate solution is infused into the Abdomen (2 – 3 liters) Fresh dialysate – Blood is cleared from water-soluble toxins by diffusion – To excrete water from the patient, glucose is mixed into the dialysate. The peritoneum is impermeable to glycose and water is excreted by osmosis Infusion of fresh dialysate into the peritoneum 49 Artificial Organs - Kidney Dialysis Techniques Peritoneal dialysis – Peritoneum used as a semi-permeable membrane (1 – 2 m²) – Fresh dialysate solution is infused into the Abdomen (2 – 3 liters) – Blood is cleared from water-soluble toxins by diffusion Utulized dialysate – To excrete water from the patient, glucose is mixed into the dialysate. The peritoneum is impermeable to glycose and water is excreted by osmosis – The utilized and enriched dialysate is drained 4 to 6 hours later and a new cycle starts Draining of used dialysate 50 Artificial Organs - Kidney Dialysis Techniques Peritoneal dialysis (PD) in numbers – 8% of dialysis patients in Germany – Performance of peritoneum decreases over a few years => switch to hemodialysis necessary – Continuous PD 4 times a day, self-managed dialysate change – Automated PD a machine infuses over night 10 – 12 liters dialysate automatically. Over day no extra dialysis is needed Dialysis at home using the peritoneal dialysis 51 Artificial Organs - Kidney Dialysis Techniques Peritoneal dialysis (PD) 52 Advantages Disadvantages No intervention in the circulatory system The heart is not overloaded, cannulation in blood stream is not required Depends on individual peritoneum performance The transport properties of the peritoneum are individual Patients with heart insufficiencies can be treated Because of no intervention in the circulatory system Protein loss Peritoneum is permeable for proteins. Loss must be compensated for by a special diet Independence from dialysis center Perfect for working patients or for patients who go on vacation Risk of peritonitis Cannulation is entry-port for pathogenic germs Artificial Organs - Kidney Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 3.1 Historic Milestones 3.2 Dialysis Techniques 3.3 Dialyzer 3.4 Dialysate 3.5 Cannulation 3.6 Pump 53 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Design Requirements – Selectivity of the membrane  Permeable for salts / small molecules  Impermeable for proteins  Potentially high ultrafiltration rate – High membrane surface area – Low priming volume Ultrafiltration: 2 – 100 nm – General hemocompatibility Fibers in a modern hollow-fiber membrane dialyzer 54 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Design of Dialyzer – Hollow fiber structure A bundle of hollow membrane fibers are put in a housing and sealed. Blood flows through the fibers and dialysate flows around the fibers; Similar to oxygenators (but in oxygenators, blood is outside the fibers and the gas flows inside!); High surface to volume ratio (surface area up to 2 m²; up to 10.000 fibers) Fibers in a modern hollow-fiber membrane dialyzer 55 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Design of Dialyzer – Hollow fiber structure A bundle of hollow membrane fibers are put in a housing and sealed. Blood flows through the fibers and dialysate flows around the fibers; Similar to oxygenators (but in oxygenators, blood is outside the fibers and the gas flows inside!); High surface to volume ratio (surface area up to 2 m²; up to 10.000 fibers) – Plate membrane structure Membrane plates that separate the blood and dialysate; higher priming volume; lower membrane area (less efficient); but: lower pressure loss (no pump needed) Plate dialyzer by Kiil 56 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Selectivity of dialyzer membrane – Materials Historically, cellulose-based materials were used which lack good biocompatibility; A modified cellulose-based material - Cellulose Triacetate – with good biocompatibility is still used today. Additionally, synthetic materials (Polysulfone, Polyethersulfone) are used (hydrophobic) – Sizes The hollow fibers typically have 300 µm in diameter with a 5 – 40 µm wall-thickness. The priming volume of the fibers are about 30 – 160 ml – Mechanical stability For ultrafiltration, a pressure difference above the membrane needs to be withstood (TMP: max. 300 mmHg) Microscopic images of symmetric and asymmetric membrane structures 57 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Selectivity of dialyzer membrane – Low-Flux vs. High-Flux High-Flux dialyzer are more permeable to medium-sized molecules than Low-Flux dialyzers; Thus, the clearance of these substances is improved. Some studies suggests a superiority of High-Flux over Low-Flux due to an incomplete removal of uremic toxins in Low-Flux. – Trade-off High permeability (high effectivity) but retention of vital proteins and molecules Sieving coefficients for exemplary dialyzers 58 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Selectivity of dialyzer membrane – Molecular weight cut-off (MWCO) For characterization of the selectivity of the dialyzer membrane. Typically, the molecular weight where 90% are retained (S = 10%) – Only for rough orientation Values are dependent on operation parameter. Selectivity is based on diffusion speed. Even larger molecules can diffuse through membrane after a long time 10% Sieving coefficients for exemplary dialyzers 59 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Countercurrent flow mode – Countercurrent flow mode Dialyzers today are operated in countercurrent flow mode Dialysate Blood Countercurrent flow principle in a dialyzer 60 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Countercurrent flow mode – Countercurrent flow mode Dialyzers today are operated in countercurrent flow mode – Constant concentration gradient The countercurrent flow mode results in a (nearly) constant concentration gradient over the length of the dialyzer. Cocurrent flow mode decreases clearance of smaller molecules about 10%. By Cruithne9 - Own work, CC BY-SA 4.0 https://commons.wikimedia.org/w/index.php?curid=57612048 61 Artificial Organs - Kidney Comparison of concentration gradients in cocurrent and countercurrent flow Design of Artificial Kidney - Dialyzer High membrane surface area Low priming volume – Small circular fibers Typical diameters: about 300 µm Up to 10.000 fibers => surface area ≈2 m² – Fibers are packed into housing Dialysate must be distributed equally to all fibers to avoid dialysate channeling (portions of dialysate that pass dialyzer without contact to the membrane) – Priming volume Hollow fibers provides excellent volume to surface ratio; priming volume ≈ 100 – 130 ml Bundle of dialyzer fibers 62 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Biocompatibility – Biocompatible materials Fibers: cellulose triacetate, polysulfone, … Housing: Polycarbonate – Hemocompatible flow Design to avoid unphysiological flow (high shear rates, stagnation zones); Special focus on blood inlet and outlet – Trade off High membrane surface area vs. minimum artificial surface contact for blood – Coatings Heparin coatings available (but heparin is commonly given by infusion) 63 Artificial Organs - Kidney Advertising image of lateral blood inlet in a dialyzer Design of Artificial Kidney - Dialyzer Manufacturing – Fiber bundle Packing of fibers in housing; fibers are sealed at the end to avoid inflow of potting material – Potting Potting material (Polyurethan) is injected by potting caps, distributed (by centrifugal forces) and hardened – Cutting Potting caps are removed and the potting is cut open Fiber bundle (sealed) Potting (centrifuge) Cutting (opening of fibers) Final cap assembly – Final assembly Final caps are assembled Different manufacturing steps for dialyzer 64 Artificial Organs - Kidney Design of Artificial Kidney - Dialyzer Exemplary membrane datasheet (Fresenius) TMP: max. 300 mmHg 65 Artificial Organs - Kidney Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 3.1 Historic Milestones 3.2 Dialysis Techniques 3.3 Dialyzer 3.4 Dialysate 3.5 Cannulation 3.6 Pump 66 Artificial Organs - Kidney Design of Artificial Kidney - Dialysate Dialysate - Composition Dialysate composition in acetate and bicarbonate dialysis compared to normal values in serum 67 Artificial Organs - Kidney Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 3.1 Historic Milestones 3.2 Dialysis Techniques 3.3 Dialyzer 3.4 Dialysate 3.5 Cannulation 3.6 Pump 68 Artificial Organs - Kidney Design of Artificial Kidney - Cannulation Design Requirements – Vascular access – Sufficient blood flow Blood flow > 200 ml/min must be provided – Regular vascular access required (dialysis treatment typically 3 times a week) – Others Low complication rates, … Vascular access for hemodialysis 69 Artificial Organs - Kidney Design of Artificial Kidney - Cannulation Sufficient blood flow – Problem: Arteries would provide for sufficient blood flow but are deep embedded in tissue and a superficial access is not possible; Veins are well accessible but cannot provide for sufficient blood flow (4x more veins than arteries in wrist); Solution is the arteriovenous shunt – Arteriovenous shunt Surgical procedure that connects the artery to the vein. => Increased blood flow in wellaccessible vein. Vein expands due to the increased blood pressure and remodeling of vessel wall occurs (arterialization). Shunt is prepared several month before first dialysis session (time to heal and remodel) 70 Artificial Organs - Kidney Expansion due to increased pressure Mixed blood (A-V) Vein Artery Principle of arteriovenous shunt / fistula Design of Artificial Kidney - Cannulation Sufficient blood flow – Synthetic grafts for arteriovenous shunts Shunt with native vessels should be preferred (lower complication rates, no artificial materials) From Dialysis Synthetic shunt graft Vein – Indications for artificial shunts If native veins are no longer suitable for shunting (failed AV-fistula, exhausted superficial veins); Bypass of blocked shunts Artery To Dialysis Connection of a synthetic shunt 71 Artificial Organs - Kidney Design of Artificial Kidney - Cannulation Sufficient blood flow – Synthetic grafts for arteriovenous shunts Shunt with native vessels should be preferred (lower complication rates, no artificial materials) – Indications for artificial shunts If native veins are no longer suitable for shunting (failed AV-fistula, exhausted superficial veins); Bypass of blocked shunts – Several options A synthetic graft offers a variety of options for a arteriovenous shunt Different possible A-V connections using a synthetic graft 72 Artificial Organs - Kidney Design of Artificial Kidney - Cannulation Cannulas - Requirements – Low traumatization / pain Low sliding resistance, low surface roughness, special design of catheter tips „Back-eye“ – „Back-eye“ Opening on the back-side of the needle to prevent suction to vessel wall – Low flow resistance Mainly depends on diameter (Hagen-Poiseuille): Trade-off of small trauma vs low resistance Flow Viscosity Length 𝑉ሶ ∙ 𝜂 ∙ 𝑙 Δ𝑝 = 𝜋 ∙ 𝑟4 Pressure loss Radius Cannulas for dialysis 73 Artificial Organs - Kidney Design of Artificial Kidney - Cannulation Areal puncture Cannulation techniques – Areal puncture Repeated puncturing in a narrow area is not recommended due to the risk of aneurysms Rope ladder Buttonhole Standard cannula – Rope ladder Widely distributed punctures (1.5 inch apart) with alternating location – Buttonhole Using the exact same puncture every time; formation of scar tissue around the puncture channel. Less pain if buttonhole channel is carefully prepared and used. After ≈10 cannulations, a buttonhole cannula can be used (lower trauma); 2 – 3 buttonholes may be created for alternation on consecutive days 74 Artificial Organs - Kidney Buttonhole cannula Different puncture strategies (upper); principle of rope ladder puncture (lower) Design of Artificial Kidney - Cannulation Cannulation - Complications – Acute and chronic complications Acute complications occure within first hours / days of the shunting; Chromic complications are due to extensive use; Cannulation is the weak point of dialysis – Thrombosis / Bleeding Thrombus formation and bleeding are common complications. Require surgical intervention – Infections Infections due to repeated cannulation – Hematoma / Aneurysm Weakening of vessel walls due to repeated puncturing can result in aneurysms. Subcutaneous bleeding can result in hematoma Complications of AV-fistula cannulation: venous aneurysm (upper) and infections (lower) 75 Artificial Organs - Kidney Design of Artificial Kidney - Cannulation Single needle dialysis – Principle Blood is taken and returned in a batchwise process through a single needle cannulation – Less traumatization A single needle induces less traumatization of the shunt – Less effectivity Studies show that the clearance using single needle is roughly half of double needle clearance rates Principle of single needle dialysis 76 Artificial Organs - Kidney Design of Artificial Kidney - Cannulation Central venous access – Shaldon catheter Shaldon catheter is frequently used in ICU patients for permanent vascular access; two lumen catheter – Chronic hemofiltration In case of ICU patients, hemofiltration can be performed continuously using a Shaldon catheter – Acute hemodialysis In case of a acute, reversible kidney failure, the central venous access can be used for hemodialysis Shaldon catheter for chronic vascular access 77 Artificial Organs - Kidney Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Kidney 3.1 Historic Milestones 3.2 Dialysis Techniques 3.3 Dialyzer 3.4 Dialysate 3.5 Cannulation 3.6 Pump 78 Artificial Organs - Kidney Dialysis Techniques Pumps in dialysis Heparin High-flux pump Heparin Dialysator Blutleckdetektor – Blood pump – Dialysate pump BlutBlood pumpe pump Degassing Entgasung pump Bypass – Ultrafiltration pump – Heparin pump art. Druck Dialysate pump Proportionierung ven. Druck – Substitute pump LF – Degassing pump UF pump UF-Kontr. Heizung Substitute pump Körpergewicht Pumps used in dialysis setups 79 Artificial Organs - Kidney Luftdetektor Klemme Patient Patient Dialysis Techniques Pumps in dialysis – Roller pumps Pump induces rotating occlusion on a tube; prone to some hemolysis, but possibility to use pre-assembled tubing systems; volume-driven (not pressure driven); blood flow directly dependent from rotating speed tube roller occlusion wall Commonly used as blood pump, dialysate pump, substitute pump, ultrafiltration pump Principle of roller pump 80 Artificial Organs - Kidney Dialysis Techniques Pumps in dialysis – Rotational pumps Pressure driven pump. Commonly used as degassing pump – Syringe pumps Piston pump using standard syringes; Commonly used for anticoagulation (heparin pump) Exemplary syringe pump 81 Artificial Organs - Kidney Dialysis Techniques Dialysis machines Monitor Single needle pump Blood pump Dialyzer Bypass Heparin pump Dialysate concentration Bubble detector Arterial pressure Arterial & venous temperature Exemplary dialysis machine (Fresenius 5008) 82 Artificial Organs - Kidney Substitute pump Venous clamp