Tubular Structure And Function PDF

Tubular Structure And Function Ahmed Aburima Hull York Medical School, University of Hull Learning Outcomes [Describe the mechanisms of HCO3- and Na+ reabsorption throughout the nephron] [Describe K+ regulation by the kidney] [Describe hormonal action throughout the tubule] [Outline how concentrated...

Tubular Structure And Function Ahmed Aburima Hull York Medical School, University of Hull Learning Outcomes [Describe the mechanisms of HCO3- and Na+ reabsorption throughout the nephron] [Describe K+ regulation by the kidney] [Describe hormonal action throughout the tubule] [Outline how concentrated urine is formed–the counter-current mechanism] HCO3- reabsorption Proximal Convoluted Tubule (PCT) Na+ & H2O reabsorption Osmosis 65% and 25% of Na+ reabsorbed at PCT and loop of Henle, respectively, regardless of hormonal control. When aldosterone concentrations are high, essentially all the remaining filtered Na+ is actively reabsorbed in the distal convoluted tubules and collecting ducts. The amount of Na+ reabsorbed in the tubules is precisely tailored to need, and Na+ is never secreted into the filtrate. Hormonal regulation of Na+ and H2O output Renin Angiotensin Aldosterone Reflex Collecting Ducts Afferent Arterioles Removing Na+ and H2O from Your Blood Atrial natriuretic peptide and B-type natriuretic peptide ANP is made by overstretched atria (cardiomyocytes) BNP is made by overworked ventricles (cardiomyocytes) ANP & BNP dilate afferent arterioles >>> Increase blood flow & filtration ANP & BNP suppress reabsorbing Na+ >>> Na+ and water are lost in the urine, reducing blood volume and decreasing the stretch and workload of the heart Proximal Convoluted Tubule (PCT) glucose reabsorption Osmosis * Kidneys filter approximately 180g of glucose/day from plasma, all of which is reabsorbed (healthy state). * Tubular maximum for glucose (TmG): 260-350mg/min/ 1.73m2 (equivalent to ~200mg/dL glucose in plasma) Proximal Convoluted Tubule (PCT) glucose reabsorption The amount of glucose reabsorbed by the kidneys is equivalent to the amount entering the filtration system. The reabsorption increases with increase in glucose concentration up to approximately 11 mmol/L (~200 mg/dL). At this threshold, the system becomes saturated and the maximal reabsorption rate, the glucose transport maximum (TmG), is reached. No more glucose can be absorbed, and the kidneys begin excreting it in the urine, the beginning of glycosuria Why is glucose found in the urine of patients with uncontrolled DM? Proximal Convoluted Tubule (PCT) K+ reabsorption Regardless of the need, up to 90% of the filtered K+ is reabsorbed at proximal tubules and the thick ascending limb of the nephron loop. Collecting Duct (CD) K+ secretion As a rule, K+ levels in the ECF are sufficiently high that K+ needs to be excreted by the principal cells of the cortical collecting ducts. (At times, the amount of K+ excreted may actually exceed the amount filtered.) When ECF K+ concentrations are abnormally low, the renal principal cells conserve K+ by reducing its secretion and excretion to a minimum. Osmosis Regulation of Urine Concentration and Volume: Osmotic Gradient within the Medulla Regulation of Urine Concentration and Volume: Osmotic Gradient within the Medulla The counter-current mechanism Regulation of Urine Concentration and Volume: Osmotic Gradient within the Medulla Regulation of water output AntiDiuretic Hormone release (a.k.a vasopressin) Regulation of Urine Concentration and Volume: Osmotic Gradient within the Medulla Regulation of water output Aldosterone Hormone release Renal collecting ducts Influence Of Other Hormones (a) Female Sex Hormones: (i) Estrogens are chemically similar to aldosterone and, like aldosterone, enhance NaCl reabsorption by the renal tubules. Because water follows, many women retain fluid as their estrogen levels rise during the menstrual cycle. Estrogens are also largely responsible for the edema experienced by many pregnant women. (ii) Progesterone appears to decrease Na+ reabsorption by blocking the effect aldosterone has on the renal tubules (by competing for the receptors). Thus, progesterone has a diuretic-like effect and promotes Na+ and water loss. (b) Glucocorticoids: Such as cortisol and hydro-cortisol, enhance tubular reabsorption of Na+, but they also promote an increased glomerular filtration rate that may mask their effects on the tubules. However, when their plasma levels are high, the glucocorticoids exhibit potent aldosterone-like effects and promote edema. Recommended Reading Contact details: [email protected] Wolfson Building, Office 508, Ext:6678 Renal Acid-Base Balance Ahmed Aburima Hull York Medical School, University of Hull Learning Outcomes [Explain the concept of acid-base balance] [Describe common buffering systems] [Describe the renal regulation of hydrogen ion / bicarbonate balance] [Explain disturbances in acid-base balance] Acid-Base Balance Blood pH Venous Arterial Acid-Base Balance Blood pH Venous Arterial Acid: substances that donate protons H+ Increase H+ à pH falls á acidity HCl 2 H+ Cl- H+ pH H+ H+ 7 ClCl- ClH+ Cl- As concentration of hydrogen ions increases, pH drops Acid-Base Balance Blood pH Venous Arterial Bases: substances that accept protons H+ Decrease H+ à pH rises â acidity NaOH Na+ OH- H + ClH + ClNa+ OHH + ClH + ClNa+ OHH + ClNa+ OH- 2 7 pH Acids and basis neutralize each other Acid-Base Balance Blood pH Venous Arterial Buffer Systems Buffers prevent major changes in pH Bind with H+ when excess acid present Release H+ if body fluids too basic “Buffers are solutions which can resist changes in pH when acid or alkali is added.” H+ H+ H+ H+ H+ H+ Acid-Base Balance Blood pH Venous Arterial Buffer Systems H+ Concentration in the blood is regulated sequentially by (1) Chemical buffers (2) Respiratory centres (3) Renal system Milliseconds minutes Hours- a day Acids are being created constantly Diet Metabolism CO2 + H2O Fatty acid Amino Acids Cells/Blood Aerobic Lactic/Uric Acid Non-Aerobic Ketone Bodies Buffers: Intracellular proteins, Hb Extracellular fluid HCO3- CO2 + H2O Lungs Urine excretion Kidneys BUFFERING SYSTEMS BUFFERS USED BY THE BUFFERING SYSTEMS Bicarbonate Respiratory System Bicarbonate Phosphate Proteins Blood Bicarbonate Kidneys Phosphate Ammonia Composition of Body Fluids (Electrolytes) Phosphate Buffer System It is mainly an intracellular buffer and a renal tubular buffer. Its concentration in plasma is very low. The phosphate buffer system operates in the internal fluid of all cells. This buffer system consists of dihydrogen phosphate ions (H2PO4-) as hydrogen-ion donor (acid) and hydrogen phosphate ions (HPO42-) as hydrogen-ion acceptor (base). These two ions are in equilibrium with each other as indicated by the chemical equation below. H2PO4- H+ + HPO42- The role of kidneys in maintaining acid-base balance (a) Maintain the concentrations of HCO3- in the body by reabsorption. (b) Regenerate new HCO3- from CO2 when CO2 is in excess in the blood Bicarbonate Buffer system! (a) HCO3- reabsorption Lumen Intercalated cell Na+ 5 H+ Na+ 6 ATP K+ ClHCO3- + H+ 1 H2CO3- 5 ATP Carbonic 2 anhydrase H+ 4 HCO33 Carbonic anhydrase H2O + CO2 Peritibular Capillary Collecting Duct 1 H+ combines with HCO3- in the filtrate, forming H2CO32 H2CO3- splits forming CO2 and H2O, which enter the cell 3 CO2 combines with H2O forming H2CO3-, which quickly splits forming H+ combines with HCO3- 4 HCO3- enters the peritubular capillary 5 H+ is excreted in the filtrate 6 Na+ is expelled from, into ECF - HCO3- is impermeable. - Carbonic anhydrase is present on the surface of Intercalated cells Generation of New Bicarbonate by The Ammonia Buffer system Glutamine metabolism 3 2 4 Peritibular Capillary 1 5 1 Glutamine is metabolised to NH4+ and HCO3- 4 NH4+ is reabsorbed and secreted as NH3 2 HCO3- enters the peritubular capillary 5 NH3 binds H+ and secreted as NH4+ 3 NH4+ is secreted into filtrate Generation of New Bicarbonate by Phosphate 3 2 5 1 4 1 CO2 combines with H2O forming H2CO3- 3 H+ is secreted into the filtrate by H+ ATPase pump 2 H2CO3- splits forming H+ and HCO3- 4 HCO3- enters the peritubular capillary 5 H2OP4- is excreted in the urine Excretion of buffered H+ in PCT - Once HCO3- is used up, any additional H+ will be excreted with urine. - The body continuously introduce new H+ from diet. - Continues H+ secretion >>>> Lower urine pH. - H+ secretion ceases when urine pH falls to 4.5. - Any additional H+ is neutralised in the filtrate. New HCO3- is generated. Buffering Capacity in Body 52% of the buffering capacity is in cells 5% is in RBCs 43% of the buffering capacity is in the extracellular space of which 40% by bicarbonate buffer, 1% by proteins and 1% by phosphate buffer system Alterations to Acid–Base Balance Two major categories Acidosis: H+ increases above normal (pH below 7.35) Alkalosis: H+ decreases below normal (pH above 7.45) Respiratory acidosis Respiratory acidosis is due to an accumulation of CO2 in the blood stream. This pushes the carbonic anhydrase reaction to the right, generating H+: carbonic anhydrase CO2 H2CO3 HCO3(-) + H+ Respiratory alkalosis Respiratory alkalosis is generally caused by hyperventilation, usually due to anxiety. The primary abnormality is a decreased pCO2. Metabolic acidosis Is the gain of acid or the loss of bicarbonate. Cause Usual causes are the generation of ketone bodies in uncontrolled diabetes mellitus, diarrhea (loss of bicarbonate), excess protein consumption (breakdown products are amino ACIDS), or excess alcohol consumption: Can also be caused by ingestion of an acid (aspirin, ethanol, or antifreeze). Exercise creates a milder, transient metabolic acidosis because of the production of lactic acid. Metabolic alkalosis Is due to the gain of base or the loss of acid. The primary abnormality is an increased HCO3. Cause Caused from an increase in bicarbonate in the blood because of ingestion of excess bicarbonate in the form of an antacid (Tums), eating excess fruits (vegetarian diets and fad diets*), loss of acid from vomiting, What would happen if the respiratory system had a problem with ventilation? Respiratory Acidosis and Alkalosis Normal PCO2 fluctuates between 35 and 45 mmHg Respiratory Acidosis (elevated CO2 greater than 45mmHg) Depression of respiratory centers via narcotic, drugs, anesthetics CNS disease and depression, trauma (brain damage) Interference with respiratory muscles by disease, drugs, toxins Restrictive, obstructive lung disease (pneumonia, emphysema) Respiratory Alkalosis (less than 35mmHg- lowered CO2) Hyperventilation syndrome/ psychological (fear, pain) Overventilation on mechanical respirator Ascent to high altitudes Fever What if your metabolism changed? Metabolic acidosis Bicarbonate levels below normal (22mEq/L) Diarrhea (loss of intestinal bicarbonate) Ingestion, infusion or production of more acids (alcohol) Salicylate overdose (aspirin) Accumulation of lactic acid in severe Diabetic ketoacidosis starvation Metabolic alkalosis bicarbonate ion levels higher (greater than 26mEq/L) Excessive loss of acids due to loss of gastric juice during vomiting Excessive bases due to ingestion, infusion, or renal reabsorption of bases Intake of stomach antacids Diuretic abuse (loss of H+ ions) Severe potassium depletion Steroid therapy Compensation for deviation Lungs (only if not a respiratory problem) If too much acid (low pH)—respiratory system will ventilate more (remove CO2) and this will raise pH back toward set point If too little acid (high pH)—respiratory will ventilate less (trap CO2 in body) and this will lower pH back toward set point Kidneys If too much acid (low pH)—intercalated cells will secrete more acid into tubular lumen and make NEW bicarbonate (more base) and raise pH back to set point. If too little acid/excessive base (high pH)- proximal convoluted cells will NOT reabsorb filtered bicarbonate (base) and will eliminate it from the body to lower pH back toward normal. How can the kidneys control acids and bases? Collecting ducts Acidemia H+ Na+ ATP Cl- 4 ATP H+ HCO3- HCO3- + H+ 1 H2CO3- K+ Carbonic anhydrase 2 Carbonic anhydrase H2O + CO2 3 Principal cell H+ Na+ ClHCO3- H+ - HCO3 Carbonic anhydrase H2O + CO2 ATP Peritibular Capillary Na+ H+ Lumen Intercalated cell Peritibular Capillary Lumen Alkalemia Definitions Normal pH is 7.35 - 7.45 Normal C02 is 35 -45 mmHg If this value is abnormal, the patient has respiratory acidosis or alkalosis. Normal HC03 is 22-26 mEq/L If this value is normal, but one of the below values is abnormal, the patient has compensated. If this value is abnormal, the patient has metabolic acidosis or alkalosis Normal O2 Saturation is 80-100 ml/dl If this value is normal in a respiratory pH problem, patient is compensating. Interpreting Arterial Blood Gases (ABG) This blood test is from arterial blood, usually from the radial artery. There are three critical questions to keep in mind when attempting to interpret arterial blood gases (ABGs). First Question: Does the patient exhibit acidosis or alkalosis? Second Question: What is the primary problem? Metabolic? or Respiratory? Third Question: Is the patient exhibiting a compensatory state? Assessment Step 1 Step One: Determine the acid/base status of the arterial blood. If the blood's pH is less than 7.35 this is an acidosis, and if it is greater than 7.45 this is an alkalosis. You may hear nurses or doctors say: "The patient is 'acidotic' or 'alkalotic' Assessment Step 1 If the pH is low, it is acidosis. If it is high, it is alkalosis. Assessment Step 2 Once you have determined the pH, you can move on to determine which system is the 'primary' problem: respiratory or metabolic. To do this, examine the pCO2 and HCO3- levels. Assessment Step 2 If the pCO2 is the only one that is abnormal, it is respiratory. If the HCO3 is the only one that is abnormal, it is metabolic. If they are both abnormal, they are compensating, so we need to evaluate it further. Go to step 3. Assessment Step 3 Determine if the body is attempting to compensate for the imbalance or not. If both CO2 and Bicarbonate are high or both low, the patient is compensating. If one is normal and the other is too high or low, the patient is not compensating. You will never have a case where one is high and one is low. Arterial Blood Gas problems when compensation is present pH Respiratory Acidosis Acid Metabolic Alkalosis Base Metabolic Acidosis Acid Respiratory Alkalosis Base PCO2 HCO3 What makes infants and elderly more susceptible to acid-base imbalance? Infants are at greater risk: - Low volume on lungs (half of adults) - Excessive fluid shift (high rate of fluid intake and output) - High metabolic rate (twice adult rate) - Higher rate of water loss - Inefficiency of kidneys Aged people are at greater risk: - Decrease in total body volume, leads to slow homeostasis - Unresponsive to thirst cues Key Concepts Daily diet and metabolism generates a net increase in acids The kidneys with the lungs maintain the body’s pH by regulating the HCO3-/CO2 buffer pair. The lungs exert an immediate effect by controlling CO2; the kidneys exert a slower effect by controlling HCO3- and H+ concentration. The kidneys maintain acid-base homeostasis by reabsorbing filtered bicarbonate and excepting either bicarbonate or protons depending on the body’s needs. Recommended Reading Contact details: [email protected] Wolfson Building, Office 508, Ext:6678 Recommended Reading Glomerular Structure And Function Ahmed Aburima Hull York Medical School, University of Hull Learning Outcomes [Describe the mechanisms and ultra structure governing filtration and its regulation (Nephrons)] [Describe the concept of auto-regulation] [Describe the Renin-Angiotensin-Aldosterone System (RAAS) and hormonal influences on Glomerular Filtration Rate (GFR)] [Describe how kidney function is assessed] [Distinguish between the syndromes of acute and chronic renal failure and outline their pathogenesis] Functions of Urinary system: Outline (1) Maintain Water Balance. (2) Maintain Salt Balance. (3) Maintain Blood pH. (4) Excretion of metabolic waste products. (5) Other Functions (i) Blood Glucose Regulation - Glucose re-uptake - Gluconeogenesis: conversion of lactate, amino acids and glycerol (triglyceride breakdown products) into glucose and glycogen. (ii) Endocrine gland: Renin > regulates blood pressure and kidney function Erythropoietin > stimulates the production of RBC (ii) Metabolise vitamin D >active form Regions of Urinary system: Outline Kidney structure: outline Rapid weight lose >kidney drop to lower position (Ptosis) Ptosis > Urine buildup in kidney> Hydroneophrosis Kidney structure: outline 1200mL blood (~20% of total blood volume) enters kidneys/ minute> 90% of which perfuses the cortex Nephron structure: outline Nephron types: outline Cortical Nephron (85%) Juxtamedullary Nephron (15%) Nephron structure: outline Nephron structure: outline Increase surface area for Absorption and Secretion High # mitochondria: Energy demand Principal cells: H2O & Na+ balance. Intercalated cells: AcidBase balance Nephron Capillary Beds: outline Venules Arterioles Artery Vein Capillary Bed Portal System Glomerular Capillaries Renal Artery Pertitubular Capillaries Renal Vein Cortical Nephron J.M Nephron Vasa Recta Efferent Glomerular Arterioles Afferent Glomerular Arterioles Urine Formation: Outline (1) Glomerular filtration - A passive process in which hydrostatic pressure forces fluids and solutes through a membrane. (2) Tubular reabsorption - The movement of solutes and water from the lumen of the renal tubule across the epithelial cells and back into the blood. (3) Tubular secretion - The movement of the solutes directly from the blood across the epithelial cells and into the luminal filtrate. Glomerular Filtration: * The amount of fluid (plasma) filtered into Bowman’s space per unit time. * Normal filtration is ~180L of plasma/day> entire plasma volume 60 times a day > 1.5L leaves body as urine. Glomerular Filtration: - A passive process in which hydrostatic pressure forces fluids and solutes through a membrane. - Fenestrated endothelium allow all blood components except blood cells to pass through - Basement membrane prevents plasma proteins entering capsular space - Podocytes prevents macromolecules from traveling further Regulation of Glomerular Filtration: (1) Intrinsic Regulation (Autoregulation): * Autoregulation is the local adjustment of blood flow to individual organs based on their immediate requirements * Suppresses changes in renal blood flow and GFR in response to mean arterial pressure from 80 to 180 mmHg (i) Myogenic mechanism: Reflect the property of the smooth muscle cells to adapt to systemic blood pressure. Decline in systemic BP >> Increase in systemic BP >> Regulation of Glomerular Filtration: (1) Intrinsic Regulation (Autoregulation): * Autoregulation is the local adjustment of blood flow to individual organs based on their immediate requirements * Suppresses changes in renal blood flow and GFR in response to mean arterial pressure from 80 to 180 mmHg Regulation of Glomerular Filtration: (1) Intrinsic Regulation (Autoregulation): (ii) Tubulo-Glomerular feedback Macula Densa (MD) cells respond to filtrate NaCl concentration (which varies directly with filtrate flow rate). When GFR increases, there is not enough time for reabsorption and the concentration of NaCl in the filtrate remains high. MD cells respond to high levels of NaCl in filtrate by releasing vasoconstrictor chemicals (ATP and others) that cause intense constriction of the afferent arteriole, reducing blood flow into the glomerulus. This is drop in blood flow decreases GFR, slowing the flow of filtrate and allowing more time for filtrate processing (NaCl reabsorption). (MD) cells On the other hand, the low NaCl concentration of slowly flowing filtrate inhibits ATP release from MD cells, causing vasodilation of the afferent arterioles. This is allows more blood to flow into the glomerulus, thus increasing GFR. Renin Angiotensin Aldosterone Reflex Angiotensin converting enzyme (ACE) Angiotensin I (active) Angiotensin II (active) Angiotensingen (inactive) Renin Blood pressure Inhibits renin release Aldosterone Plasma Na+ Plasma K+ Juxtoglomular cells (J-G cells) expanded plasma volume Na+ and water retention K+ excretion How kidney function is assessed? Renal Clearance (RC) The volume of the plasma that is cleared of a substance in one minute (ml/min). Glomerular Filtration Rate (GFR) The amount of fluid (plasma) filtered into Bowman’s space per unit time. Normal filtration is ~180L of plasma/day> entire plasma volume 60 times a day > 1.5L leaves body as urine. Renal clearance Renal clearance tests are done to determine the GFR, which allows us to detect glomerular damage and follow the progress of renal disease. The renal clearance rate (C) of any substance, in ml/min, is calculated from the equation C = UV/P where Renal clearance Standardized against a substance that is neither absorbed nor secreted>>> Inulin, a polysaccharide, is completely filtered. When inulin is infused such that its plasma concentration is 1 mg/ml (P = 1 mg/ml), then generally U = 125 mg/ml, and V = 1 ml/min. Therefore, its renal clearance is C = (125 x 1)/1 = 125 ml/min meaning that in 1 minute the kidneys have cleared all the inulin present in 125 ml of plasma. How Kidney Function Is Assessed? Substance X Clearance rate 0 ml/min Compared to Inulin What it means Examples < Inulin Net reabsorption Glucose (healthy individual) 125 ml/min = Inulin Neither reabsorption nor secretion Creatinine* 200 ml/min > Inulin Net Secretion Drug metabolites *Creatinine, which has a C of 140 ml/min, is freely filtered but also secreted in small amounts. It is often used nevertheless to give a “quick and dirty” estimate of GFR because it does not need to be intravenously infused into the patient as does inulin. Kidney Failure Renal Failure Definition A condition in which the kidneys fail to remove metabolic end products from the blood and regulate the fluid, electrolyte, and pH balance of the extracellular fluids Underlying causes Renal disease Systemic disease (Urological defects of nonrenal origin) Types of Renal Failure Acute renal failure Abrupt in onset Often reversible if recognized early and treated appropriately Chronic kidney Failure End result of irreparable damage to the kidneys Develops slowly, usually over the course of a number of years Acute Renal Failure Vs Chronic Kidney Failure Acute Renal Failure Recognized by a significant elevation of serum creatinine within hours or days or by a significant decrease in urine output for more than 6 hours. Elevation of serum creatinine by more than 26.5mmol/L or 0.3mg/dL Elevation of serum creatinine by more than 50% of baseline Urine output less than 0.5mL/Kg BW/day (Oliguria) Chronic Renal Failure Recognized by the presence of structural kidney damage Or a decreased GFR of less than 60mL/min/1,73m2 for more than 3 months. Common Causes of Acute Kidney Disease Pre-renal Cases of Acute Renal Failure Hypovolemia (blood loss) Extremely low blood pressure (shock) Heart failure Decreased renal perfusion due to vasoactive mediators, drugs. Common Causes of Acute Kidney Disease Pos-trenal Cases of Acute Renal Failure Ureteral/bladder obstruction (enlarged prostate/bladder cancer) Kidney/bladder stones Renal Cases of Acute Renal Failure Acute tubular necrosis Prolonged renal ischemia Exposure to nephrotoxic drugs, metals, organic solvents, diagnostic agents Disorders affecting the filtering units (nephrons) of the kidneys (for example, acute glomerulonephritis, tubulointerstitial nephritis Sepsis Common Causes of Chronic Kidney Disease Clinical Manifestations of Chronic Renal Failure Accumulation of nitrogenous wastes Alterations in water, electrolyte, and acid-base balance Mineral and skeletal disorders >>>>imbalances in bone metabolism and increases the risk of a type of bone disease called renal osteodystrophy (defective bone development). Anemia and coagulation disorders Hypertension and alterations in cardiovascular function >>>> thrombotic events or bleeding Gastrointestinal disorders Neurologic complications Disorders of skin integrity Immunologic disorders Altered Drug Metabolism in Kidney Disease CKD and its treatment can interfere with the absorption, distribution, and elimination of drugs Altered drug absorption Antacid treatment Altered metabolism Result of less protein-bound drugs Increased intermediates of drug metabolism Alterations in dosage may be required. Microbiology of the Urinary Tract Dr Dave Hamilton MRCP FRCPath BSc Microbiology York Trust Learning Outcomes 1. Outline the syndromes of urethritis, cystitis and pyelonephritis 2. Describe the epidemiology of urinary tract infections (UTI) 3. Describe the nature of the common organisms causing UTI 4. Describe the diagnostic criteria for UTI 5. Outline the role of antibiotics in the prevention and management of uncomplicated UTI 6. Be enthralled by our immune system Urinary tract infection classification Route of acquisition – Ascending versus haematogenous Site of infection – Involvement of urethra – urethritis (lower) – Involvement of bladder – cystitis (lower) – Involvement of kidney – pyelonephritis (“upper UTI”) Community-acquired versus nosocomial Urinary tract infection - epidemiology How frequent are they? Who gets them? When do they get them? What causes them? Why do get they them? UTI – how frequent are they? Most common bacterial infection seen in primary care (5% of all consultations) About 5% of women each year present to their GP with UTI symptoms. Up to 50% of women, during their lifetime, will suffer from a symptomatic UTI (1 in 5 of these will experience one or more recurrences) Commonest cause of nosocomial infection T Hooton Uncomplicated Urinary Tract Infection,Engl J Med 2012; 366:1028-1031. Who gets UTI and when do they get them? Which bacteria cause UTI? Commonest cause of UTI is Escherichia coli UTI-causing (uropathogenic) E. coli (UPEC) are distinct from other disease causing types e.g. E. coli O157 which are associated with intestinal disease UPEC belong to a restricted number of serotypes They are members of the bacterial flora of the large bowel Resident population of UPEC important in individuals who experience relapsing/recurring UTI M Wilson and L Gaido Laboratory Diagnosis of Urinary Tract Infections in Adult Patients Clin Infect Dis. 2004; 38:1150–8 Other causes of UTI Viruses – Adenoviruses Associated with haemorrhagic cystitis – BK and JC viruses Associated with infection and graft failure in patients following kidney transplants Mycobacterium tuberculosis Parasitic infection – Schistosoma haematobium A Kumar, J Turney, A Brown and M McMahon1 Unusual bacterial infections of the urinary tract in diabetic patients—rare but frequently. lethal. Nephrol. Dial. Transplant. (2001) 16 (5): 1062-1065 Two principal routes of acquisition Ascending – From urethra to bladder (causing cystitis) – From the bladder to the kidney (causing pyelonephritis) Haematogenous – From blood to kidney (causing pyelonephritis or renal abscess) Host defences against UTI Urine flow and micturition Urine chemistry (osmolality; pH; organic acids) Secreted factors – sIgA (secretory IgA) – Lactoferrin: an iron chelator Mucosal defences – Mucopolysaccharides - glucoseaminoglycan – Few receptors Bacterial virulence factors Uropathogenic E. coli – Type 1 fimbriae – Bind to mannose residues on host cells – Associated with cystitiscausing strains Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. O'Brien et al. Curr Opin Infect Dis. 2015 Feb;28(1):97-105 Bacterial virulence factors Uropathogenic E. coli – Type P fimbriae adhere to urinary tract cells – K Antigen – Prevents immune cells phagocytosing the E.coli Both help cause infection, especially of the upper tract - pyelonephritis Risk Factor Explanation Female sex Shorter urethra Urethra opens into introitus Closer to perineum/anus Anatomic abnormality e.g. Congenital abnormalities of urinary tract Diverticula Prostatic hypertrophy Reflux of urine from bladder to kidney Stagnant urine Residual urine after incompleted emptying of bladder Functional abnormality Neurological disorders Spina bifida Multiple sclerosis Incomplete emptying of bladder Requirement for catheterisation Catheterisation Bypasses host defences Acts as foreign body Biofilm formation Pregnancy Dilated ureters Imcomplete bladder emptying Gestatinal glycosuria? Foreign body (e.g. stones) Mucosal damage Bacteria less accessible to host defences Urinary tract surgery/instrumentation Mucosal damage Direct introduction of bacteria into tract Patients may have pre-op infection/bacteriuria Patients frequently catheterized Insertion of foreign bodies e.g. stents Stalenhoef van Dissel, van Nieuwkoop. Febrile urinary tract infection in the emergency room. Curr Opin Infect Dis. 2015 Feb;28(1):106-11 UTI in pregnancy Bacteriuria and lower UTI – Some studies show Associated with lower birth weight Premature delivery Increased perinatal morbidity Increased risk of development of pyelonephritis (in up to 30% of infections) Also associated with prematurity, low birth weight Foetal loss The patient with UTI Cystitis – – – – – Frequency Dysuria Urgency Suprapubic discomfort Fever usually absent or low grade – In infants Failure to thrive Poor feeding – In elderly Signs may be absent Sudden onset of confusion Pyelonephritis – May have symptoms of cystitis – Loin pain – Fever – Rigors – Renal angle tenderness Diagnosis of UTI - Urinalysis Detects High negative predictive value (good at ruling out UTI) – Protein Positive predictive value is lower (some false positive’s) – Blood Nitrite may be falsely negative – Leucocyte esterase – Nitrites – Some bacteria just are – Low numbers of bacteria Leukocyte esterase may be falsely negative – Patient taking antibiotics E.g. cefalexin – High glucose in urine Laboratory diagnosis of UTI – urine microscopy White cells – Presence suggests UTI Epithelial cells – Presence suggests contamination Red cells – In females may be associated with menstruation – Can occur in infection.. – …but may also be seen with stones/tumours Diagnosis of UTI In this real urine result there is a low number of red cells, a high number of white cells (WBC) suggesting infection and a low number of epithelial cells suggesting contamination is unlikely. Diagnosis of UTI In this case E coli has been cultured. Sensitivities to the most useful antibiotics for UTI have been provided. Nosocomial UTI Commonest nosocomial infection May follow urological surgery or instrumentation… But most are associated with urinary catheterisation Urinary catheters Bypass defence mechanisms of lower urinary tract Act as a foreign body Bacterial form biofilm on catheters 5% -10% increase in prevalence of bacteriuria each day the catheter remains in situ Nicolle LE Catheter associated urinary tract infections. Antimicrob Resist Infect Control. 2014 Jul 25;3:23 Catheter-associated UTI prevention What works – Not catheterising the patient – Limit duration of catheterisation – Aseptic insertion – Closed drainage systems – In some patients Ag++-bonded catheters What doesn’t work – Application of soap/antiseptics to urethral meatus – Disinfectants in drainage bag – Antiseptic/antibiotic irrigation of bladder Urinary catheters All catheters eventually get colonised Catheter-associated bacteriuria does NOT require antimicrobials Only treat if the patient has signs/symptoms of infection “Urethral syndrome” As many as 50% of women with clinical features of cystitis have negative urine cultures Explanation – Low counts of bacteria – Fastidious bacterial which do not grow on routine culture media eg ureoplasma – Non-infective inflammation – Sexually transmitted pathogens such as Chlamydia trachomatis Phillip H1, Okewole I, Chilaka V. Enigma of urethral pain syndrome: why are there so many ascribed etiologies and therapeutic approaches? Int J Urol. 2014 Jun;21(6):544-8. 2014 Jan 21. Management of uncomplicated lower UTI Maintain good hydration May resolve spontaneously – 50% in otherwise fit women If antimicrobials indicated – Short courses (3d) are as effective as longer… …and reduce selective pressure for resistance …and may result in fewer side effects Choice of antimicrobials – Depends on local resistance patterns – Agents which achieve high concentrations in urine Antimicrobial Features Trimethoprim Cheap Active against most agents of uropathogens associated with uncomplicated UTI Nitrofurantoin Very high urine concentrations achieved Not active against Proteus species Does not achieve effective concentrations in kidney and should NOT be used if upper tract infection suspected Ampicillin/amoxicillin Should NOT be used empirically high rates of resistance (65-70% in E. coli) Quinolones – e.g. ciprofloxacin NOT indicated for empiric therapy Management of recurrent UTI Women with >3 episodes annually may benefit from antimicrobial prophylaxis – Optimal duration not identified – But 6 month’s Rx often used – “Rotation” of antibiotics – Despite limited evidence Other interventions – Voiding post-intercourse – HRT in post-menopausal women Alternative approach – Self-medication proanthocyanidins Management of recurrent UTI Women with >3 episodes annually may benefit from antimicrobial prophylaxis – Optimal duration not identified – But 6 month’s Rx often used – “Rotation” of antibiotics may help prevent emergence of resistance Other interventions – Voiding post-intercourse – HRT in post-menopausal women Alternative approach – Self-medication proanthocyanidins Management of recurrent UTI Women with >3 episodes annually may benefit from antimicrobial prophylaxis – – – Optimal duration not identified But 6 month’s Rx often used “Rotation” of antibiotics may help prevent emergence of resistance Other interventions – – Voiding postintercourse HRT in postmenopausal women Alternative approach – Self-medication In 2008, the Cochrane review supported cranberry potential use only in recurrent UTI prophylaxis for young women. Even for this indication, further clinical trials (double-blinded, randomized, placebo-controlled) displayed no differences between cranberry consumption and controls. The efficacies in other groups of subjects, such as the elderly or paediatric populations with neurogenic bladder, are even more questionable. Hisano M. Cranberries and lower urinary tract infection prevention. Clinics. 2012 Jun; 67(6): 661–667 Children Send urine sample if temp >38c for >24 hours Clean catch Pad Suprapubic aspirate Children 3 years leukocyte esterase and nitrite Children risk factors poor urine flow history suggesting previous UTI or confirmed previous UTI recurrent fever of uncertain origin antenatally-diagnosed renal abnormality family history of vesicoureteric reflux (VUR) or renal disease constipation dysfunctional voiding enlarged bladder abdominal mass evidence of spinal lesion poor growth high blood pressure. Children Treatment Lower tract: – Amoxicillin, trimethoprin or cephalexin Upper Tract Mild – Co-amoxiclav Upper Tract severe – Cefotaxime or gentamicin < 3 months ‘Fever in the Under 5’s NICE guideline CG160’ Children In children infection may indicate underlying abnormalities of the urinary tract. Imaging may be appropriate. Urinary tract infection in under 16s: diagnosis and management. NICE 2007,CG54. Children Summary UTI are common Upper/lower and simple/complicated Microbial host interactions Diagnosis Treatment Children and catheters [email protected] Very happy to discuss any issues around inection through your learning journey. Kidney Disease and Renal Failure Autumn 2022 Matt Morgan Prof of Renal Medicine and Medical Education Learning Outcomes Explain the concept, clinical presentation and common causes of Chronic Kidney Disease Explain the concept, clinical presentation and common causes of Acute Kidney Injury Explain the concept, clinical presentation and common causes of Nephrotic syndrome Explain the concept, clinical presentation and common causes of Nephritic Syndrome Describe the common complications of loss of renal function Kidney Disease Why do we care about renal disease? It is common It impacts quality of life It reduces life expectancy It is expensive (It is really really really interesting and treating patients with it is very satisfying) This Photo by https://www.flickr.com/photos/joshhough/339013794/ (CC BY-NC-SA 2.0) Learning about kidney disease? Initially kidney medicine can appear complicated and difficult To understand the causes and treatments - break it down into broad topics and key presentations Link causes to what you are learning about how the kidney functions For complications – link it to what the kidney does (ie homeostatic/endocrine functions) and what happens if those things go wrong This Photo by Unknown Author is licensed under CC BY-NC http://www.workplaceconfidence.com/wp-content/uploads/2013/07/confusion-that-costs-money.jpg How should we think about kidney disease? Broad topics (syndromes) Chronic kidney disease Acute kidney Injury Nephritic Syndrome Key presentations Unexplained impaired kidney function Unexplained haematuria and/or proteinuria Nephrotic Syndrome Other rare stuff eg tubular function disorders Problems identified during monitoring of chronic disease Other rarer stuff eg tubular function disorders, familial diseases Measuring Kidney Function Serum creatinine Traditional measure of kidney function Influenced by: Gender, Ethnicity, Age, Body mass, Diet, Exercise Not sensitive to small changes in good function Non-linear relationship between serum creatinine and kidney function http://www.worldcme.com/webpages/members_only/diabetes/case3/graphA1.gif Estimated glomerular filtration rate (eGFR) Calculated from creatinine, age, gender, ethnicity Better reflection of kidney function Best measure for use in stable renal function eGFR =186 x (Creat(micromole/L) / 88.4)-1.154 x (Age(years))-0.203 x 0.742 if female x 1.21 if black YOU DO NOT NEED TO MEMORISE THIS Estimated Glomerular Filtration Rate is the best measure of stable kidney function eGFR Normal eGFR Normal creatinine limit for population Serum creatinine μmol/L Loss of renal function Pulmonary Oedema A Salt and water retention Hyper-reninaemia Increased sodium and water reabsorption Inability to concentrate urine (early) Loss of diurnal rhythm of urine excretion Inability to excrete water load (loss of nephrons) Dilutional hyponatraemia Oedema Hypertension A:FrankGaillard CC-BY-SA 3.0 http://commons.wikimedia.org/wiki/File:Pulmonary_oedema.jpg B: James Heilman MD CC-BY-SA 3.0 http://commons.wikimedia.org/wiki/File:Combinpedal.jpg Pitting Oedema B Renal anaemia Impaired quality of life reduced exercise capacity impaired cognition  risk of Left Ventricular Hypertrophy  CV disease Treated with recombinant erythropoietin Renal Mineral Bone Disease Kidney unable to 1α hydroxylate 25-D3 Reduced calcium absorption Increased PTH release Increased bone demineralisation Reduced phosphate excretion Treated with Phosphate restriction 1α hydroxylated vitamin D Hypertension Multiple mechanisms RAS activation Sodium retention Volume expansion Sympathetic NS activity Endothelial dysfunction Accelerates decline of kidney function Contributes to cardiovascular risk (stroke, MI, heart failure) https://opentextbc.ca/anatomyandphysiology/chapter/25-4-microscopic-anatomy-of-the-kidney/ Anatomy and Physiology by Rice University is licensed under a Creative Commons Attribution 4.0 Excretory function Accumulation of toxic waste products creatinine rises only after significant renal damage retention nitrogenous waste retention of urate retention of phosphate Reduced drug metabolism Opiates Insulin Antibiotics Uraemic frost Madeux B, Pons B, Elkoun K, et al. Postgrad Med J 2016;92:491. Electrolyte abnormalities Hypo/hyperkalaemia Muscle dysfunction, cardiac arrhythmias Hypo/hypernatraemia Neurological dysfunction Hypocalcaemia Cardiac arrhythmias, muscle spasm, paraesthesia By Mikael Häggström, used with permission CC BY-SA https://commons.wikimedia.org/wiki/File:ECG_in_hyperkalemia.svg Metabolic acidosis Metabolic acidosis Increased respiratory drive Feel breathless Chest pain Confusion Bone pain Demineralisation of bone (bone buffering) What can we do? Identify why the kidneys aren’t working properly Stop them getting worse Restore/improve function Treat the complications of lost function Medication Dietary changes Replace kidney function Dialysis Transplantation End of life care Image from ABC of Kidney Disease, 2nd Edition 2013, BMJ Books, Ed. David Goldsmith Renal Transplantation, He M & Taylor J chapter 11 pg 162 Fig 11.6 Chronic kidney disease Chronic Kidney Disease (CKD) Slow progressive loss of renal function – usually irreversible eGFR 26μmol/L increase or 50-100% from baseline 354μmol/L (started