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Giles Kisby GE Y1 Renal

Renal:

Spring Term:

LECTURES:Learning Outcomes – Year 1 (2014) Spring Term:Exam questions will be set in standard SBA (single best answer) and EMQ (extended matching question) formats. The SBA and EMQ formats will be well known to you, and further details are provided on Blackboard.

LECTURES Lecture 1: Kidney structure and histology Lecture 2: Approaches to assessing kidney function Lecture 3: Renal blood flow and regulation Lecture 4: Renin Angiotensin system Lecture 5: Water loading states Lecture 6: The lone Englishman lost in the Sahara Lecture 7: Acid base balance – physiology Lecture 8: Acid base balance – illustrations from the critically ill patient’s physiology Lecture 9: Renal causes of hypertension Lecture 10: Erythropoetin Lecture 11: Sodium and potassium handling Lecture 12: Clinical scenarios (electrolytes) Lecture 13: When the kidneys are lost Lecture 14: Clinical demonstration: video and meeting with a renal patient Lecture 15: Renal physiology scenarios Lecture 16: Overview of kidney function and dysfunction Lecture 17: Predict the consequences of loss of endocrine functions of the kidney Lecture 18: Control of calcium and phosphate; vitamin D, PTH

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and the kidney

The main goal of this course is to help you develop a sound understanding of how the renal system achieves the vital functions of controlling fluid and electrolyte balance, its role in control of blood pressure and as part of the endocrine system - and how these functions are perturbed in disease. The course has been designed to develop and present core material from a clinical perspective. The primary goal is to equip you with the knowledge base to apply basic renal science to clinical practice in the later years of your course, recognizing that the practice of renal medicine, and fluid and biochemical management in all patients, is integrally related to the physiological processes you will cover over this term. We also hope to instill a finer appreciation of the scientific intricacies of the renal system. The course is structured in three overlapping themes: Theme one covers functional anatomy and histology. In the second theme, the essentials of fluid and electrolyte balance are understood through lectures on physiology and illustrations from clinical pathology. Theme three explores the consequences to normal physiology ‘when things go wrong’ in disease states. At the end of the course, you will be able to: 1) Describe the structural organisation of the kidneys and urinary tract at the system and cellular levels. 2) Explain the physiological mechanisms by which the various components of the kidney produce and regulate the composition of urine. a) Define Renal Clearance and Glomerular Filtration Rate and explain in principle how these may be measured in patients 3) Understand the principal renal mechanisms responsible for homeostasis of water, electrolytes, pH, glucose and urea in the extracellular fluid. a) Appreciate the centrality of water in the control of cell volume, blood pressure and metabolism b) Understand the physiological implications of dehydration and how the body responds to it c) Understand the physiological implications of water loading states and how the body responds to them d) Understand the intracellular and extracellular balance of sodium and potassium ions including how and why the gradients are maintained. e) Understand why maintenance of appropriate pH is important physiologically 4) Understand how renal mechanisms contribute to the control of blood pressure. 5) Describe the sites and mechanism of action of the main classes of diuretics. 6) Use the knowledge of kidney function and roles to: a) Understand how the body responds to overload and deficiencies of sodium and

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potassium, including the pathological features found in each situation. b) Determine the implications of sodium and potassium abnormalities in a number of different clinical scenarios. c) Identify several clinical scenarios in which acid-base balance is disrupted. d) Describe how the body deals with acid-base abnormalities in a number of different situations. - 2 -7) Outline the principal causes of acute and chronic renal failure.a) Show awareness of the clinical features people may develop in acute and renal failure. b) Outline the possible ways of managing these patients. c) Show awareness of the different modalities of renal replacement therapy.

LECTURES Lecture 1: Kidney Structure and Histology Dr Ruth Tarzi, (r.tarzitiimperial.ac.uk) To understand the gross anatomy of the kidney To be aware of its principal relations to other structures To understand the basic structure of the glomerulus at a cellular level To appreciate how this structure controls its filtering function To know the component parts of the nephron and the basic function of each part To understand the sampling and handling issues related to taking a medical renal biopsy • To understand the purpose of the medical renal biopsy • To be able to recognise in a renal biopsy some of the possible deviations from the norm Lecture 2: Approaches to assessing renal function Dr Peter Hill (peter.hill4tinhs.net) To understand the physiological functions of the kidney To understand how kidney function can be measured To understand methods for measuring or estimating glomerular filtration rate To understand how to assess urea and creatinine readings in renal disease states To know how to assess proteinuria and haematuria Lecture 3: Renal blood flow and regulation Dr Nish Arulkumaran, (n.arulkumarantiimperial.ac.uk) To learn about the anatomical and physiological concepts underlying the renal vasculature and perfusion, To provide insights into the intrinsing and extrinsic mechanisms involved in regulation of renal blood flow To gain understanding on pathophysiology of renal vascular impairmen Lecture 4: Renin-angiotensin system and control of blood pressure Dr Nish Arulkumaran (n.arulkumarantiimperial.ac.uk) To learn about the blood pressure: what it does to/for the body, how do we measure it RAS system - components and roles, therapeutic targets

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Pathophysiology of hypertension and renal involvement Lecture 5: Drinking yourself to death: water loading states Dr Ruth Tarzi (r.tarzitiimperial.ac.uk) Understand the principal mechanisms responsible for the homeostasis of serum sodium, osmolality and total body water content. Understand the functions of antidiuretic hormone. Understand the physiological implications of water loading and how the body responds to it. - 4 - Understand the causes and consequences of pathological water loading states e.g.syndrome of inappropriate ADH secretion, primary polydipsia, secondary hyperaldosteronism. Lecture 6: The lone Englishman lost in the Sahara Desert. Dr Jeremy Levy (j.levytiimperial.ac.uk) To understand how the body handles water and what can go wrong. To understand how to interpret blood results in this context and how disorders of water balance might be managed. Much of the body is water. Water allows solutes to remain dissolved, and changes in body water can cause changes in solute concentrations. Physiological processes require tight control of solute concentrations, and hence water distribution is also tightly regulated. Control of body water is mainly through the kidneys. The proximal tubule reabsorbs 70% of water filtered together with salt, but cannot change the concentration of urine (iso-osmolar reabsorption). The loop of Henlé in the kidney allows humans to make dilute urine, while the distal tubule and collecting ducts act to make concentrated urine, through the action of ADH (or Vasopressin). Humans can change the concentration of their urine over a very wide range. ADH is the key hormone controlling water balance, but many others affect water homeostasis via actions on salt and water (eg cortisol, thyroxine, atrial natriuretic peptide). Excess water leads to solute dilution (eg hyponatraemia) whilst water deprivation leads to solute concentration (eg hypernatraemia). Both these states can cause severe problems. Both can also be caused by bad doctoring, as well as by hormone dysfunction, drugs, behaviour etc. Dehydration (in its true form loss of water only) leads to increased concentration of solutes, and reduction of both extracellular and intracellular volume. Dehydration is a very potent stimulus to ADH release, which should minimise further water loss through the kidneys by increasing the reabsorption of water in the distal tubules – less water is excreted in the urine. If this does not happen and water loss is not corrected, dehydration leads to death. Under- or over-activity of the hormone systems controlling water balance can lead to over or under-hydration, and various electrolyte disturbances. Excess ADH leads to water retention and hyponatraemia, while too little ADH leads to diabetes insipidus and dehydration. The rennin-angiotensin system is also crucial in control of water balance via the effects of angiotensin II and aldosterone on sodium handling

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and vasoconstriction. It is important to identify the cause of disturbance in patients physiology in order that the correct action can be taken to remedy the situation – if water is missing, water needs replacing alone; if salt is lost, salt needs replacing. Lecture 7: Acid-Base balance – physiology Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk) Lecture and relevant articles will be made available on Blackboard Lecture 8: Acid Base Balance – illustrations from the critically ill patient’s physiology Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk) Cases will be provided on the day of the lectures - 5 -Lecture 9: Renal causes of hypertension Dr Peter Hill (peter.hill4tinhs.net) Understand the pathological consequences of uncontrolled hypertension Appreciate when to suspect secondary hypertension and know causes of secondary hypertension To be aware of imaging modalities to investigate renovascular hypertension To be aware of treatment options for renovascular hypertension To be aware of therapeutic approaches to treating primary and secondary hypertension Lecture 10: Erythropoeitin Dr Peter Hill (peter.hill4tinhs.net) To be aware of the physiological functions of erythropoetin and its regulation To understand the consequences of dysregulation of the HIF axis To be aware of the therapeutic uses of erythropoetin To understand the approach to managing anaemia in renal disease Lecture 11: Sodium and potassium handling Dr Elaine Clutterbuck (Elaine.clutterbucktiimperial.nhs.uk) To understand the factors affecting sodium and potassium balance. a) the levels are regulated, and the role of the kidneys b) that there is a close relationship between – sodium and water homeostasis, and between potassium and hydrogen ion balance. To outline some of the clinical conditions associated with an imbalance of sodium / potassium a) their symptoms, signs and immediate management

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Lecture 12: Discussion of clinical scenarios Dr Damien Ashby (d.ashbytiimperial.ac.uk) Lecture 13: When the kidneys are lost Dr Damien Ashby (damien.ashbytiimperial.nhs.uk) Understand the pathophysiology and treatment of end stage renal disease Lecture 14: Clinical demonstration : video and meeting with renal patient Dr Liz Lightstone (l.lightstonetiimperial.ac.uk) Understand how kidney failure impacts on patients’ lives Understand the practicalities involved in dialysis and transplantation Lecture 15: Renal Physiology – clinical scenarios Dr Jeremy Levy (j.levytiimperial.ac.uk) Cases for self-directed learning will be made available on Blackboard Lecture 16: Overview of kidney function and dysfunction with respect to learning objectives of the course Dr Damien Ashby (damien.ashbytiimperial.nhs.uk) Lecture 17*: Predict the consequences of loss of endocrine functions of the kidney Professor Karim Meeran (k.meerantiimperial.ac.uk) - 6 -Lecture 18*: Control of calcium and phosphate: vitamin D, PTH and the kidney; Professor Karim Meeran (k.meerantiimperial.ac.uk) * These two lectures will be given in the Pathology (Part 2) Course where they sit more appropriately.

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LECTURES:07/01/14: Introduction to the kidney: anatomy and histology: Ruth Tarzi

Los (from booklet): To understand the gross anatomy of the kidney To be aware of its principal relations to other structures To understand the basic structure of the glomerulus at a cellular level To appreciate how this structure controls its filtering function To know the component parts of the nephron and the basic function of each part To understand the sampling and handling issues related to taking a medical renal biopsy • To understand the purpose of the medical renal biopsy • To be able to recognise in a renal biopsy some of the possible deviations from the norm

Los (from Slides):o To understand the gross anatomy of the kidneyo To be aware of its principal relations to other structureso To understand the basic structure of the glomeruluso To appreciate how this structure controls its filtering functiono To know the component parts of the nephrono To understand the role of the renal biopsy in diagnosis of kidney disease

Notes:

- Basic anatomy:o Kidneys are at T11-L2 on left; kidneys are T12-L3 on righto Kidneys are 11-13cm longo Pathway of urine after kidney:

Urine collects in central portion (pelvis) By the time it reaches this point, urine is in its final state

Drains into ureters (on on each side)

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Collects in bladder Excreted by (single) urethra

o Renal parenchyma = Cortex and medullao Approximately 1 million filtering units; the nephrons

o Glomerulus: the network of capillaries at the filtering site: Blood enters a capillary tuft by afferent arteriole Under high pressure, cells and proteins retained within capillary lumen Much of fluid phase pushed out of blood vessel across specialised filtration

structure

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Endothelial cell layer with pores Glomerular basement membrane Epithelial cells (= podocytes) with slit membranes

Blood leaves glomerulus by efferent arteriole Filtrate passes into Bowman’s capsule

o Bowman's capsule: surrounds the glomerulus and performs the first filtration stepo Nephron: Nephron is the basic structural and functional unit of the kidney; ie

includes the blood vessels as well as the bowman’s capsule etc of each unito Glomeruli are in cortex with the loop of henle travelling into the medulla; ie

glomeruli are a part of the nephrono The Bowman's capsule is a cup-like sac at the beginning of the tubular component of

a nephron in the mammalian kidney that performs the first step in the filtration of blood to form urine. A glomerulus is enclosed in the sac. Fluids from blood in the

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glomerulus are collected in the Bowman's capsule (i.e., glomerular filtrate) and further processed along the nephron to form urine.

o Nephrons join collecting ducts to take urine out through medulla into pelviso Mesangial cells regulate blood flow through the capillaries and contribute towards

the support of the capillaries Ie capillaries held together by mesangial cells with podocytes on the other

surfaces of the capillaries to mediate filtration (holding back large molecules such as proteins, and passing through small molecules such as water, salts, and sugar) out to the filtered region (bowman’s space)

- The nephron:o 1. Afferent arteriole:

ANP increases flow ATII, sympa, ADH decrease blood flow

o 2. Glomerulus: Small molecules (HCO3-, Cl-, Na+, K+, etc) and water exit; proteins kept in

blood (podocyte damage can therefore give proteinurea and hypoalbuminaemia)

Endothelium has large pores: fluid, dissolved solutes, and plasma proteins all are filtered across this layer of the glomerular capillary barrier. On the other hand, the pores are not so large that blood cells can be filtered.

Basement memb: The multilayered basement membrane does not permit filtration of plasma proteins and, therefore, constitutes the most significant barrier of the glomerular capillary.

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Podocytes: Because of the relatively small size of the filtration slits formed by the podocytes, the epithelial layer (in addition to the basement membrane) also is considered an important barrier to filtration.

Another feature of the glomerular barrier is the presence of negatively charged glycoproteins. These fixed negative charges are present throughout the barrier: on the endothelium, basement membrane, on the podocytes / epithelium.

Nb Regardless of their charge, small solutes are freely filtered across the glomerular barrier. However, for large solutes such as plasma proteins, the charge does affect filtration.

o 3. Proximal convoluted tubule: [the major reabsorbtion site] 2/3 water and 2/3 Na ions passing are reabsorbed [both same rate so

remains isotonic]; brush border cell microvilli aid water resorbtion 100% AAs and gluc reabsorbed (unless undiagnosed diabetic; the

transporters can become saturated if v. high gluc conc) [secondary active transport]

o 4. Descending loop of henle: [concentration occurs] Permeable to water but not NaCl and urea Decends to medulla At bottom osmolarity equalised with surrounding medullary interstitum:

however tubular fluid mainly NaCl whereas medullary interstitum mainly urea

o 5. Ascending Limbs of the loop of henle: Thin asc limb

Impermeable to water, permeable to NaCl and urea: NaCl moves out, urea moves in

Volume and osmolarity unchanged Thick asc limb:

Impermeable to water AND urea; NaCl actively reabsorbed into the interstitum so tubular fluid hyposmotic by the end of the limb

o 6. Distal convoluted tubule:

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At early part: Aldosterone acts here to increase NaCl reabsorbtion; at late part: ADH is able to act; in ADH absence will just give further dilution making further hypoosmotic but in ADH presence water exits too

Impermeable to water unless ADH present (ie ADH inserts porins). Impermeable to urea; NaCl actively reabsorbed into the interstitum so tubular fluid increasingly hyposmotic

Aldosterone acts here to increase NaCl reabsorbtion Juxtaglomerular cells in the afferent arteriole at the region of the Distal

convoluted tubule secrete RENIN (ie then its downstream effects etc) in response to:

(1) Renal hypoperfusion, (2) Sympathetic nerve stimulation (3) Reduced NaCl delivery to tubule lumen at macula densa

(caused by reduced GFR/filtrate volume) macula densa: an area of closely packed specialized cells lining the wall of

the distal convoluted tubule which form a part of the juxtaglomerular apparatus (sensitive to NaCl)

o 7. Collecting ducts: Cortical collecting duct acts exactly as the Distal convoluted tubule Medullary collecting duct reabsorbs NaCl actively as prev but is slightly more

permeable to water and urea, even without ADH present (small amount of urea enters tubular fluid, small amount of water reabsorbed)

ADH affects water permeability and is required for sufficient water reabsorbtion

ADH also affects urea permeability here; will give knock on effect of allowing greater water reabsorbtion via changing the osmotic gradient; the urea will ultimately re-enter the tubule at the thin asc limb again but via this mech greater concentration is facilitated

o 8. Efferent arteriole: [ie from glomerulus] Proteins not filtered so high conc protein here; this allows for the extensive

water reabsorbtion that occurs as prev described Mechanical pressure difference also occurs due to blood having slowed at

glomerulus therefore via starling equation any water reabsorbtion will be encouraged compared to otherwise

Constriction of efferent arterioles gives increased glomerular filtration rate due to increased pressure at glomerular capillaries; eg ATII constricts efferent more than afferent arteriole so inc GFR (efferent arteriole more sensitive to ATII; serves to maintain GFR when ATII is constricting the afferent arteriole)

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- The nephrono Modulates the contents of filtrateo Depending on body’s needs varies

Volume of fluid excreted Amount of salt excreted

o Major points of control Glomerular filtration Counter-current multiplier (Loop of Henle) Anti-diuretic hormone’s effects (water reabsorption) Renin-angiotensin-aldosterone system (salt retention)

- The renal biopsyo For patient:

Provide the cause of the patient’s disease Indicate what treatment the patient requires

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Provide information on likely outcome eg. recovery of renal function vs need for long term dialysis

o Sample fixed in paraffin and sections taken for inspection Light microscopy

Need to examine the biopsy at multiple levels for thorough assessment

Immunohistology Often stain for antibody components to demonstrate areas of

immune activity Immunofluorescence

o Performed by applying fluorescent labelled antibodies to frozen sections

o Visualised on a fluorescence microscope Immunoperoxidase

o Uses paraffin sectionso Primary antibodies are identified using an antibody

amplification step with a coloured end product Electron microscopy

May showo Deposition of immune complexeso Deposition of other abnormal substances e.g. amyloid

[amyloidosis refers to a variety of conditions wherein normally soluble proteins become insoluble and are deposited in the extracellular space of various organs or tissues, disrupting normal function]

o Abnormalities of intrinsic glomerular structure eg the thickening of diabetes

Pathologies:- Glomeruli

o Inflammationo Scarringo Infiltrationo Major manifestations are due to either:

Failure to filter an adequate amount of blood so that waste products are not excreted

Failure to maintain barrier function leading to loss of protein and/or blood cells in the urine

o Many glomerular diseases are caused by deposition of immunoglobulins in the glomerulus

Therefore biopsies are stained for IgA, IgG, IgM and complement

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Immune complexes are composed of a lattice-work of antibody and antigen

May become deposited in the glomerulus and lead to an inflammatory response

Deposition at subendothelial sites will give greatest inflam due to close proximity to blood and therefore are worst location;

also can occur at mesangial cells (eg IgA nephropathy) or at subepithelial cells (ie on the podocyte side not the

mesangial side) Antigens in immune complexes may be:

endogenous (autoantigens) – e.g. lupus exogenous e.g. derived from response to infective organisms

Microscopic Haematuria Most patients will have either:

o IgA nephropathy Mesangial proliferation IgA deposition at the mesangial cells Mesangial electron dense deposits (ie the immune

complexes)o Thin membrane disease

Normal glomeruli by light and immunomicroscopy Thin membranes on electron microscopy [thinning

of the basement membrane (ie the blood/tubular fluid interface) of the glomeruli in the kidneys]

Nephrotic syndrome the 'filters' in the kidney become 'leaky' and large amounts of

protein leak from your blood into your urine Caused by breakdown of the normal glomerular filtration barrier;

Barrier depends on the integrity of the glomerular basement membrane and podocytes; possible causes of breakdown of barrier:

o Damage to podocyte focal / segmental glomerulosclerosis minimal change disease

loss of podocyte foot processes, vacuolation, and the appearance of microvilli.

o Immune deposits membranous nephropathy light chain deposition disease

o Others advanced diabetic nephropathy [Marked thickening

of basement membrane (and mesangial increase) in diabetes]

renal amyloid deposition Symptoms:

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o Severe proteinuriao Hypoalbuminaemiao Oedema (due to effect of low blood prot on starling

equation)o Hyperlipidaemia (the low blood prot causes inhibition of

certain enzymes that would otherwise lower blood lipid levels)

- Tubules - Acute tubular necrosis

o Inflammationo Scarringo Acute lesions: acute tubular necrosis / injury: one of the below stimuli

gives loss of polarity of tubule cells

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apoptosis&necrosis and sloughing into lumen to give lumen obstruction result is cause failure of glomerular filtrationif insult removed the tubules recover [dedifferentiation prolif differentiation]

Ischaemic eg hypovolaemic shock

Toxic (drugs, eg cisplatin, myoglobin in rhabdomyolysis)

Immunological eg secondary to glomerulonephritis

o Chronic lesions: tubular atrophy Due to imflam at tubules or secondary to imflam elsewhere in kidneys tubular atrophy is an Indication of permanent nephron loss; correlates

with irreversible loss of function

- Interstitiumo Acute examples

Oedema Inflammatory cell infiltration Haemorrhage

o Chronic: interstitial fibrosis

- Vesselso Narrowingo Inflammation

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08/01/14: Approaches to assessing renal function: Dr Peter Hill

Los (from booklet):Lecture 2: Approaches to assessing renal function Dr Peter Hill ([email protected]) To understand the physiological functions of the kidney To understand how kidney function can be measured To understand methods for measuring or estimating glomerular filtration rate To understand how to assess urea and creatinine readings in renal disease states To know how to assess proteinuria and haematuria

Notes:- Overview:

o Review of anatomy and physiological functions of the kidneyo How to measure kidney functiono Measuring glomerular filtration

GFR assessments and introduction to CKDo Assessing the urineo Applying renal function tests in renal disease

- Kidney Functions o Filtration and excretion of waste productso Electrolyte homeostasiso Hormone production

Erythropoietin For red blood cell production

1,25 Calcitriol [ie activation of vit D via providing the 2nd hydroxylation] For calcium, phosphate and bone metabolism

o Blood pressure control via renin/angiotensin/aldosterone axis prostagladins and bradykinin

o Acid Base homeostasis

- Nephron diagram:

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- Glomerulus:o 20% of cardiac output reaches the kidney (1200ml/min)o Allows filtration of small and molecules but acts of a barrier to larger molecules.o Also limits filtration based on charge with cations filtered more freelyo Creates ultra-filtrate:

Ultrafiltrate is made by pressure differences between the afferent and efferent arterioles.

By increasing vasoconstriction of efferent arteriole there is an increase in upstream pressure and thus increases UF

o To exit the blood components must pass through the three layers of cells within a glomerulus:

Endothelial Cells with fenestrations Glomerular Basement Membrane Epithelial Cells/Podocytes

The epithelial cells are attached to the GBM by discrete foot processes.

The pores between the foot processes (slit pores) are closed by a thin membrane called the slit diaphragm, which functions as a modified adherens junction

o Other functions include Phagocytosis Endocrine Synthesis of vasoactive and inflammatory meditiators

- Proximal Convoluted Tubuleo Main function is reabsorbtion

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o Most of the volume of the fitrate solution is reabsorped here; 55-60% of filtrate is reabsorbed here

70% of filtered sodium chloride and water 90% of filtered bicarbonate Excretes Ammonia Resorption of amino acids and glucose (100% unless untreated diabetic;

system overwealmed)o Three steps:

entry into the cell across the luminal membrane, movement across the basolateral membrane into the intercellular space, and uptake by the peritubular capillary.

- Loop of Henleo Concentrating machinery: max concentration at bottom of the loop then begins to

become less concentrated again as NaCl resorbed]o The term "counter-current" is also used in descriptions of the Loop of Henle - and

refers to the tubular fluid flowing in opposite directions along the descending and ascending limbs

o Descending limb Permeable to water Less permeable to Na+ and Cl-

Ie water moves outo Thin Ascending Limb

Impermeable to water Highly permeable to Na and Cl, and somewhat permeable to urea

loss of NaCl from the tubular fluid greatly exceeds the gain in urea [ie as ascends the conc of the fluid starts to fall from its peak at the bottom]

Ie Na and Cl are resorbedo Thick Ascending Limb

Reabsorbs NaCl from the tubular fluid via a different transport process from that of the thin ascending limb of Henle.

Acts in similar way to Distal Convoluted Tubule. Where furosemide = frusemide acts (Na-K Cl symporter is inhibited)

- Distal Tubuleo Ie DCT and Collecting ducto Fine tuning occurso Some Na and Cl resorptiono Urinary acidificationo Calcium excretion: dep on PTHo Ongoing urine concentratingo Potassium Secretion: dep on electrochem grado ADH acts here to increase salt and water resorption

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o Thiazides act here

- Measuring Kidney Function1. Glomerular Filtration 2. Tubular Reabsorption 3. Tubular Secretion4. Hormone production (EPO and vitamin D)5. Urine Production.

o Glomerular Filtration Most common test of kidney function Determines the clearance of a substance from the plasma Does not determine the cause for kidney disease Glomerular Filtration Rate

Sum of the filtrate rates of all functioning nephrons Normal 120-130ml/min/1.73m2

Depends on age, sex and body size Variable between nephrons and between people Reduced GFR means loss of filtering capacity and accumulation of

waste products No direct measurement Estimated from urinary clearance of an ideal filtration marker from

the plasma per unit timeo Clearance = U * V

PP = plasma concentration of markerU = urinary concentration of markerV = urine flow rate

o Inulin – best molecule we have so far Fructose polymer Freely filtered solute Non-toxic Not secreted or reabsorped by the kidney Not metabolised by the kidney Infuse inulin, then collect regular blood and urine

samples over several hours for GFR assessment [ie to gain U, V, P readings]; BUT IMPRACTICAL SO RARELY USED

o Creatinine best endogenous substance so far Product of metabolism of creatine and

phosphocreatine in skeletal muscle

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Usually constant muscle turnover for an individual [BUT a person with more muscle will have a higher baseline creatine level] [nb heavier means prob has more muscle]

Freely filtered and not reabsorped but there is tubular secretion

tends to over estimate GFR because of tubular secretion

CON: Creatine level poorly sensitive to GFR: spike in endogenous production of Creatinine (thus allowing its use to measure GFR) only comes when there is established kidney failure!! (actually want sensitivity at start of kidney damage instead!)

Alternatively: Cystatin C; an endogenous cysteine protease inhibitor

Basic equation:

Creatine variables other than kidney damage: muscle mass, age, sex, race; these variables can be added to make more complex equations: [give accurate predictions]

Cockcroft Gault eq MDRD - Modified Diet in Renal Disease

Equationso Urea: [less good]

Product of nitrogen metabolism Small molecule freely filtered by kidney Variable production rate depending on protein intake, liver function, tissue

breakdown Approx 50% may be reabsorped by the tubules

Alternatively: measure using radioisotopic methods:

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o Closely correlate with inulin clearanceo Given as a single boluso Measure decay in serial blood testo BUT:

Expensive Radioactivity used

o Eg radiolabelled EDTA (51 Cr labelled diethylenediaminetetra-acetate)

used widely in clinical practice (Transplant donors, to accurately assess GFR when administering chemotherapy

o Eg Iothalamate; o eg Iohexol

- Other renal function tests o urine

Appearance If supernatant is clear but urine looked red at the outset likely

haematuria Red / Brown

o – myoglobinuria or haemoglobinuriao – food dyes or beetroot ingestiono – porphyria o – rifampicin

White o – pyuria [white cells in urine], phosphate crystals, chyluria

Black o due to hemoglobinuria , alkaptonuria,

Microscopy An undervalued but useful resource Infection [RBCs stacked up can indicate nephritis] rouleaux Crystals [antifreeze crystals in attempted suicide] Casts [granular protein casts in nephrotic syndrome]

Urinalysis – dipstick analysis Concentration [taken early morning so not diet/drinking dependant] pH Glucose Proteinuria

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o Indicates glomerular permeability or lose of reabsorption of filtered proteins

o But can be a benign variant (Orthostatic proteinuria)o Primarily detects albumin but not other proteins eg

immunoglobulin light chains. o Highly specific, but not very sensitive for the detection of

proteinuria; it becomes positive only when protein excretion exceeds 300 to 500 mg/day.

o Can be used to detect microalbuminuria, the earliest clinical manifestation of diabetic nephropathy

o Likely to reflect some underlying glomerular disease Primary renal lesion (focal glomerulosclerosis or

membranous nephropathy or another glomerulonephritis)

secondary (diabetic nephropathy or myeloma) secondary to a systemic disorder such as congestive

heart failure. Haematuria

o Macroscopic vs microscopico Bleeding anywhere in renal tract – glomerulus to external

urethral meatuso Common causes

Infection Stones Malignancy Glomerulonephritis Myoglobinuria

o Blood: Low Ca level of blood would indicate poor hydroxylation of vit D by

kidney Anaemia can be due to Erythropoietin Deficiency from kidney

o In anaemia the kidney is more hypoxic than otherwise so HIFs generated at kidney leading to greater erythropoietin (EPO) production to lead to replacement RBCs being synthesised

o [nb also:, transfusions will give high Fe levels which can cause kidney failure]

Poor kidney function can give acidosis as the tubular fluid is more acidic than blood (ie so if not removed the blood will be more acidic)

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- Renal Failure (GFR used to follow/investigate)o Renal Failure definitions

Acute – rapid loss of GFR and tubular function over hours to days Chronic – sustained loss of GFR and tubular function over longer period –

months.

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08/01/14: Renal blood flow and regulation: Nish

Arulkumaran

Los (from booklet): To learn about the anatomical and physiological concepts underlying the renal vasculature and perfusion, To provide insights into the intrinsic and extrinsic mechanisms involved in regulation of renal blood flow To gain understanding on pathophysiology of renal vascular impairment

Notes:

- Pressure and Flow are required to perfuse organso • Pressure is determined by:

the volume of blood within the vascular bed (regulated by kidneys) and the compliance of the vessel wall (regulated by kidneys)

o • Flow is determined by heart rate and contractility and blood volume (regulated by kidneys)

- The kidney Controls blood volume & composition: o 1. Controls Red blood cell production

– Secretion Of the hormone erythropoietin o 2. Maintains Volume of the circulation

– Excretion Of sodium and watero 3. Maintains Tonicity and composition of plasma

– Excretion Of acid and other electrolytes/substances

- Kidney blood flow:o Only tissue to have arterioles either side of a capillary bedo Afferent: high pressure; main control of blood flow occurs hereo Efferent arterioles: low pressure; constriction allows GFR to be maintained even if

OVR RPF is decreased (ie even if wanting to excrete less still want to maintain filtering; events elsewhere will change amount of fluid reabsorbed/lost)

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o >20% of cardiac output goes to kidney; any blood loss etc therefore will give major disruption at the kidney

Cortex 90%, Medulla 10% To ensure:

1. Adequate Blood filtration 2. Effective other renal processes: (absorption, secretion, excretion)

o Blood flow regulation is achieved mainly by alterations in vessel diameter (poiseuille eq shows this is the most effective method)

o Regulation of renal blood flow [in addition myogenic stretch feedback occurs] 1. Autocrine and paracrine [extensive autoregulation occurs - cf ]

• Nitric Oxideo Produced by endotheliumo • Causes vasodilation: decreases vascular resistanceo • Systemically: reduces blood pressureo • Locally: Maintains renal blood flowo • Maintains basal state of vasodilatation in healtho • Lost in presence of vascular inflammatory diseases

– Smoking – Hypertension – Hypercholesterolemia – Diabetes – Systemic inflammatory conditions – Reactive oxygen species production

• Adenosineo The macula densa signals via adenosine – cf

• Prostaglandinso Vasoactive autocoids synthesized from fatty acids by

Cyclooxygenaseo Inhibited by NSAIDso Most are vasodilatorso Important role in haemorrhage: production stimulated to

counter the sympa and ATII effects which would otherwise give a damaging decrease in RPF and GFR

o PGE2 and PGI2 produced locally at the kidney Dopamine

o At low levels gives dilation at renal arterioles thus serving similar function to prostaglandins

• bradykinino Peptide which stimulates NO and prostaglandin production o – Broken down by angiotensin converting enzyme (ACE)

• endothelino Vasoconstrictor – important in acute BP changes

2. Neural • Sympathetic tone

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o More alpha1 receptors on afferent arterioles than efferent so gives decrease in RPF and GFR.

o Ie in hypotension the cardiovascular system with attempt to raise systemic BP even at the cost of blood flow to the kidneys

3. Hormonal • Angiotensin II

o Low levels: high RPFo High levels: decrease in RPF but GFR maintainedo In the kidneys, ATII constricts glomerular arterioles, having a

greater effect on efferent arterioles than afferent. o As with most other capillary beds in the body, the

constriction of afferent arterioles increases the arteriolar resistance, raising systemic arterial blood pressure and decreasing the blood flow.

o However, the kidneys must continue to filter enough blood despite this drop in blood flow, necessitating mechanisms to keep glomerular blood pressure up.

o To do this, angiotensin II constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing glomerular pressure.

o The glomerular filtration rate(GFR) is thus maintained, and blood filtration can continue despite lowered overall kidney blood flow.

o Because the filtration fraction has increased, there is less plasma fluid in the downstream peritubular capillaries. This in turn leads to a decreased hydrostatic pressure and increased oncotic pressure (due to unfiltered plasma proteins) in the peritubular capillaries. The effect of decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries will facilitate increased reabsorption of tubular fluid.

o There is actually some contradictions with Costanzo saying Low levels: increase in GFR; (& prob tiny dec to RPF); High levels: decrease in GFR and RPF.

• Vasopressin • Catecholamines

o Noradrenaline, adrenalineo Parallel sympathetic activation

ADH and Atrial/Brain Natriuretic Peptides released in response to changes in blood volume

o Changes in blood flow are sensed by juxtaglomerular apparatus Modulates release of renin and vasoactive substances which act locally and

systemically

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– Vascular tone (especially afferent and efferent arterioles) – Renal salt and water retention

o Note the proximity of the glomeruli and juxtaglomerular apparatus inc ascending limb of loop of henle/start of distal convoluted tubules where the macula densa is

- Renal autoregulation: Autoregulation protects glomeruli from changes in BP; preserves RBF and circulating volume given changes to systemic BP; simultaneously preserves renal excretion/GFR

o 1. Myogenic hypothesis: Inc arterial pressure stretches the blood vessels This gives reflex contraction of smooth muscle in the walls of the vessels;

stretch activated Ca channels are activated Increased resistance to bloodflow results thus preventing a rise to RPF

o Tubuloglomerular feedback Increased renal arterial pressure gives inc RPF and GFR Due to starling equation there will be a greater delivery of solute and water

to the tubules Macula densa is sensitive to the NaCl concentration (ie elevated once the

water has left; will also be raised if there is a problem with sodium reuptake) and signals for vasoconstriction of the afferent arterioles

RPF and GFR then will return to normal Specifically:

Apical Na-K-2Cl cotransporters move sodium into the cells of the macula densa.

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The macula densa cells do not have enough basolateral Na/K ATPases to excrete the sodium, so the cell's osmolarity increases.

Water flows into the cell to bring the osmolarity back down, causing the cell to swell.

When the cell swells, a stretch-activated non-selective anion channel is opened on the basolateral surface. [pannexin channels]; ATP escapes through this channel and is subsequently converted to adenosine.

Adenosine vasoconstricts the afferent arteriole via A1 receptors and vasodilates (to a lesser degree) efferent arterioles via A2 receptors, which decreases GFR.

Also, adenosine inhibits renin release in JG cells via A2 receptors on JG cells using a Gi pathway.

- If renal perfusion drops: Systemic responses:

Control of systemic blood volume [RAS – cf]o Salt and water retention

Systemic Vascular responses [RAS – cf]o Inc Perfusion pressure

Autoregulation: the myogenic and tubuloglomerular feedback will shut off to inc

perfusion Local vascular responses

Renal arteriolar vasodilation: prostaglandins give vasodilation at afferent arterioles [eg PG synthesis stimulated at kidneys if hypotension/haemorrhage; note that the same stimuli trigger sympa, PG synth and ATII]

ATII at low level so gives vasoconstriction mainly at efferent arteriole

OVR result is GFR being maintained Drugs may interfere with this local regulation:

o Eg NSAIDs counter prostaglandin action and ACEi counters ATII action

o Dangerous in low pressure states eg: – Dehydration – Heart failure – Sepsis – Postoperative recovery

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At very low pressures a threshold is reached and renal regulation is insufficient to maintain blood pressure; this threshold can be increased (ie bad) in various disease states to give normotensive renal failure [note: here are talking of autoregulation (ie the myogenic and tubuloglomerular feedback will shut off to inc perfusion) but is actually including the other mechanisms eg local proastaglandin and ATII effects that also will try to raise the pressure]

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o If renal perfusion rises: [systemic hypertension]: Pressure diauresis can occur: increased salt and water loss due to increase in

RPF Autoregulatiory systems give return to baseline: Renal blood flow constant

across physiological range of hydration and blood pressure

- Note that autoregulation for preservation of GFR occurs in the healthy state but in disease eg haemorrhage the SNS may signal for dec GFR to prevent loss of fluid (at the cost of filtration; therefore creatinine levels will increase). Prostaglandins help to reduce the magnitude of any such drop. ATII acts to reduce RPF without reducing GFR.

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08/01/14: Blood pressure & the Renin-Angiotensin System : Nish Arulkumaran

Los (from booklet): To learn about the blood pressure: what it does to/for the body, how do we measure it RAS system - components and roles, therapeutic targets Pathophysiology of hypertension and renal involvement

Notes:

- Highly compliant arteries give accumulation of potential energy (and therefore lower systolic pressure) and then release of the potential pressure during diastole (and therefore increased diastolic pressure than otherwise)

- Low compliance arteries ie stiff arteries will give systolic hypertension and a wide pulse pressure (due to both an increased systolic pressure and decreased diastolic pressure).

o Diabetes, hypertension, atherosclerosis and renal failure all result in arteries becoming calcified and therefore less compliant

o The low pressure in diastole is bad as it is this period in which the heart gets its blood supply

- Hypertension: o Retinopathy: haemorrhage/edema in eyeo LV hypertrophy: working against high resistance; will give poorer fillingo Vessel hypertrophy: impaired kidney flow / renal artery stenosis; kidney will

interpret as hypotension and so give damaging feedback responses; renal failure may occur

o Increases stroke risk: prob via causing intracranial haemorrages and shear stresses in vessels

o RAS activation due to renovascular disease is the primary mechanism for hypertension

o is most effectively treated with RAS blockade WILL RESULT IN SHORT TERM REDUCTION OF GFR – If renal function very poor may lead to renal failure – Better long term renal outcomes if tolerated

o Patients with heart failure, hypertension or renal disease (especially diabetes) should be on ACEIs / ARBs unless contraindicated

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o Essential hypertension is the form of hypertension that by definition, has no identifiable cause [contributors: Genetic – Diet (Salt) – BMI – Exercise – alcohol – Age – Smoking]

o Secondary hypertension is a type of hypertension which by definition is caused by an identifiable underlying secondary cause [Renal disease is the commonest cause]

- RAS is activated when renal perfusion/function is impaired o – Shock o – Renal artery stenosiso – Intrinsic renal diseases: diabetes, glomerulonephritis

- The three cellular components of the JGA are the:o 1. Macula densa of the distal convoluted tubule

Senses any increase in the NaCl concentration in the distal tubule and secretes a locally active vasopressor (adenosine) which acts on the adjacent afferent arteriole to decrease glomerular filtration rate (GFR).

Nb this signalling was detailed prevo 2. smooth muscle cells of the afferent arteriole known as juxtaglomerular cells

(=granular cells) They secrete renin in response to: – Beta1 adrenergic stimulation – Decrease in renal perfusion pressure (detected directly by the granular

cells) – Decrease in NaCl concentration at the macula densa as signalled via PGs

(not via adenosine for RAS stim)o 3. extraglomerular mesengial cells

Produce EPO (erythropoietin)

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- Renin is secreted by at least 2 cellular pathways: o A constitutive pathway for the secretion of prorenin o A regulated pathway for the secretion of mature renin

- Angiotensinogen

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• No enzymatic activity • Produced constitutively by the liver and released into the circulation • Substrate for cleavage by RENIN to give ANGIOTENSIN I (the N-terminal 12 amino acids)

- Angiotensin I• 12 amino acid peptide

– Produced by cleavage of angiotensinogen by renin• No intrinsic activity• Substrate for ANGIOTENSIN CONVERTING ENZYME (ACE)• ACE is made by the pulmonary and renal endothelium • Cleavage by ACE produces the 10-- amino acid peptide ‐ ANGIOTENSIN II; The active hormone• ACE also breaks down bradykinin

- Angiotensin II• 10 amino acid peptide• Host of actions• All tend to INCREASE blood pressure

• Systemic Vasoconstriction– Increases blood pressure

• Renal vasoconstriction – Efferent>afferent arteriole– Protects glomerular filtration pressure – Reduces medullary blood flow thereby reducing hydrostatic pressure in pericapillary tubules (therefore increased reabsorbtion)

• Salt retention – Stimulates proximal tubular Na+/H+ exchange– Stimulates aldosterone release from adrenal gland

• Water retention and thirst – Stimulates release of ADH from pituitary

• Cleaved by angiotensinases located in red blood cells to form less active cleavage products • Half life is ~30s in the circulation

- Angiotensin III• Angiotensin III has 40% of the pressor activity of angiotensin II but has 100% of the aldosterone producing activity

- Aldosterone• Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex • Aldosterone is produced in response to an increase in the plasma concentration of Angiotensin III, angiotensin II, ACTH (Adrenocorticotropic hormone), and K+

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• Aldosterone exerts its effects via the mineralocorticoidreceptor (MR) and the resultant activation of specific amiloride-sensitive sodium channels (ENaC) and the Na/K ATPase pump.

Acting on the nuclear mineralocorticoid receptors (MR) within the principal cells of the distal tubule and the collecting duct of the kidney nephron, it upregulates and activates the basolateral Na+/K+ pumps, which pumps three sodium ions out of the cell and two potassium ions into the cell.

This results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine (lumen of collecting duct).

Aldosterone upregulates epithelial sodium channels (ENaCs), increasing apical membrane permeability for Na+

• This results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine (lumen of collecting duct).

- RAS system acts to maximise glomerular filtration pressure – Vasoconstriction: Systemic and renal (efferent>afferent arterioles)– Proximal sodium resorption (ATII)– Distal sodium resorption (aldosterone)– Water resorption and thirst (ADH)

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• β blockers (usually end in -- olol)‐– Renin release is increased by sympathetic stimulation

• Renin inhibitor (Aliskiren) cleavage of angiotensinogen by renin

• Angiotensin Converting Enzyme Inhibitors (ACEIs)– End in “-- pril”‐– Block production of angiotensin II– Also inhibit breakdown of bradykinin (dry cough; bradykinin sensitises pulmonary receptors)

• Angiotensin II receptor blockers– End in “-- sartan”‐– Block vasoconstriction and release of aldosterone/ADH

• Spironolactone – Antagonises aldosterone–ie downstream of RAS

When to block RAS • Hypertension from any cause • Heart failure • Intrinsic renal disease (PROTEINURIA)

– Commonly associated with intraglomerular hypertension– All proteinuric patients should be on ACEI/ARB unless contraindicated

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• Renovascular disease (~ renal artery stenosis: but don’t use ACEi)

When NOT to block RAS• Acute illness/haemodynamic stress – GFR critically dependent on RAS when haemodynamics are compromised (ie w after heavy bleed etc)• RAS Blockade will reduce GFR by up to 15% – If renal function very poor RAS blockade can precipitate need for dialysis• Hyperkalaemia – Reduced aldosterone will impair K+ excretion • Persistent cough with ACEI -- > ARB ‐

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14/01/14: Water and dehydration: Jeremy Levy

Los (from booklet: are in the below format there!):“To understand how the body handles water and what can go wrong. To understand how to interpret blood results in this context and how disorders of water balance might be managed. Much of the body is water. Water allows solutes to remain dissolved, and changes in body water can cause changes in solute concentrations. Physiological processes require tight control of solute concentrations, and hence water distribution is also tightly regulated. Control of body water is mainly through the kidneys. The proximal tubule reabsorbs 70% of water filtered together with salt, but cannot change the concentration of urine (iso-osmolar reabsorption). The loop of Henlé in the kidney allows humans to make dilute urine, while the distal tubule [assuming ADH absence; otherwise further dilution of urine occurs here] and collecting ducts act to make concentrated urine, through the action of ADH (Vasopressin). Humans can change the concentration of their urine over a very wide range. ADH is the key hormone controlling water balance, but many others affect water homeostasis via actions on salt and water (eg cortisol [inc A/NA sensitivity for a1 & b1 signalling at kidney], thyroxine [increases GFR; prob via inc cardiac output], atrial natriuretic peptide). Excess water leads to solute dilution (eg hyponatraemia) whilst water deprivation leads to solute concentration (eg hypernatraemia). Both these states can cause severe problems. Both can also be caused by bad doctoring, as well as by hormone dysfunction, drugs, behaviour etc.

Dehydration (in its true form loss of water only) leads to increased concentration of solutes, and reduction of both extracellular and intracellular volume. Dehydration is a very potent stimulus to ADH release, which should minimise further water loss through the kidneys by increasing the reabsorption of water in the distal tubules – less water is excreted in the urine. If this does not happen and water loss is not corrected, dehydration leads to death.

Under- or over-activity of the hormone systems controlling water balance can lead to over or under-hydration, and various electrolyte disturbances. Excess ADH leads to water retention and hyponatraemia, while too little ADH leads to diabetes insipidus (see below) and dehydration. The rennin-angiotensin system is also crucial in control of water balance via the effects of angiotensin II and aldosterone on sodium handling and vasoconstriction.

It is important to identify the cause of disturbance in patients physiology in order that the correct action can be taken to remedy the situation – if water is missing, water needs replacing alone; if salt is lost, salt needs replacing.”

From slides:• To understand the physiological control of water and circulating blood volume.• To understand how this can go wrong• To be able to interpret blood biochemistry correctly and manage states of dehydration

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Notes:

- Solute distribution:o OVR osmolarity inside and out of cells will be the same and is typically 290mmol/l [is

very tightly controlled; little variance] K is the main contributor inside cells Na is the main contributor outside cells

o By comparison urine osmolarity varies greatly: 50-1500mmol/L

- What would happen if ..o You give a person intravenous hypertonic saline?

Blood pressure increases due to both the fluid itself and the movement of water out of cells

Through time bp returns to normal as kidneys etc respondo You give intravenous normal saline?

BP increases due to the fluid vol added Through time bp returns to normal as kidneys etc respond Detailed answer (see next lec for some explaination):

isotonic fluid ingestion, no change in osmolarity intravascular volume baroreceptor stimulation and macula densa sodium renin

secretion renal sodium loss ANP and BNP secretion renal sodium and water loss

o You give intravenous 5% dextrose solution? Is the closest thing to pure water that can be added; pure water would give

cell bursting at area of entry and of RBCs, dextrose is quickly metabolised but at least gives a small delay/buffer to allow for fluid to move out of blood not at a dangerous rate

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BP will inc but quickly fall as fluid exits to cells; later kidneys start removing the fluid altogether

- Furosemide:o Blocks NaKCl2 pump of thick ascending limbo therefore reduced resorbtion of Na to kidney medulla [nb loop makes urine dilute

by reabsorbing salt; then distal tubule and collecting ducts act to make concentrated urine]

o therefore Na gradient is not established which would otherwise allow for extensive concentration of the urine / resorbtion of water later in the tubules (also drives the water resorbtion that is occurring on the descending limb of the loop too)

o therefore acts as a diauretic (is a loop diauretic)

- Ie: The loop of Henlé in the kidney allows humans to make dilute urine, while the distal tubule [assuming ADH absence; otherwise further dilution of urine occurs here] and collecting ducts act to make concentrated urine, through the action of ADH (Vasopressin).

o Distal Tubule [here are assuming ADH not present] Active solute reabsorption – last 2 – 3 % Urine maximally dilute (50 mosmol/kg)

o Collecting Duct ADH sensitive; If no ADH – CD is water insensitive hence dilute urine In presence of ADH – water is reabsorbed

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- AVP = ADH = vasopressin = arginine vasopressino Nonapeptide (9 aas) synthesised by hypothalamus and secreted from posterior

pituitaryo Effects:

Direct vasoconstrictor NaCl reabsorption in TAL loop of Henle Water retention in collecting ducts Receptor binding activates cAMP which stimulates water channel (aquaporin

2) incorporation into apical membraneo Osmoceptors (at hypothalamus) sense change in serum osmolality NOT Nao Osmoceptors are sensitive:

1% ECF osmolality ADH release (eg fluid deprivation) and thirst 1% ECF osmolality ADH release (eg water ingestion) and thirst supression

o Non-osmotic stimuli for ADH release include: [eg in surgery body may retain fluid even if serum is very dilute]

stress, hypoxia, pain, volume depletion [also: MDMA = ecstasy - cf]

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- Renin-angiotensin-aldosterone system:apopt

[nb therefore if are on such drugs and are dehydrated will be unable to vasoconstrict to restore kidney perfusion (and also unable to inc blood pressure of any blood still going to kidney)]

- ANPo Polypeptide released from cardiac myocytes (mainly the atria) [small amount from

other body areas entirely!]

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o Increases urinary excretion of Na and water [increases flow at afferent arteriole and decreases it at efferent arteriole]

o Inhibits Na resorption by collecting duct by inhibiting ENaCo Inhibits renin production and aldosterone secretiono Vascular smooth muscle relaxation is stimulated

- Dehydration causes: o Burnso Cholerao Diarrhoeao Heat/exerciseo Diauretic useo Untreated Diabetes insipidus o Untreated Diabetes mellitus [nb Hyperglycaemia causes severe dehydration;

Glucose is a potent osmolite]

- Dehydration effects:o 1% weight loss

– thirsto 2% weight loss

– more thirst, vague discomfort, loss of appetiteo 3-4% weight loss

– increased blood red cell concentration, lethargy, apathy, nausea, emotional instability

o 6% weight loss – tingling limbs, heat exhaustion, increased body temp

o 8% weight loss – dizziness, confusion, delerium

o 20% weight loss – death

- Clinical features of dehydrationo Postural hypotension, o Tachycardia [heart struggling to find enough blood to pump around body]o low skin turgor,

To determine skin turgor, the health care provider grasps the skin on the back of the hand, lower arm, or abdomen between two fingers so that it is tented up. The skin is held for a few seconds then released.

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Skin with normal turgor snaps rapidly back to its normal position. Skin with decreased turgor remains elevated and returns slowly to its normal position

o sunken eyes, o dry mouth, o thirst

- Biochemical features of dehydrationo Serum osmolality higho Serum Na usually higho Serum K / Mg / Ca – high/low or normalo Serum urea higho Hb high

- Treatment:o Give back the lost fluid

– if true dehydration – water !– if salt and water – saline!

- Diabetes insipidus (DI) o Is a condition characterized by excessive thirst and excretion of large amounts of

severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine.

o Dilute urine despite elevated serum osmolality; Patients may produce 10 –15 litres urine per day

o Central (lack of secretion) or nephrogenic (failure to respond) to ADH (AVP)o Differential diagnosis is psychogenic polydipsia

Any of a range of mental disorders leading to obsessive / over-drinking

- Diabetes mellituso Glucose is a potent osmoliteo Hyperglycaemia causes severe dehydration

o Typical diabetic readings: Low Na: normal mass diluted by the glucose

drawing water out of cells

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High K: ketoacidosis is pushing K+ out of cells and lack of insulin pushing K+ into cells!!

Urea 15 mmol/l [high because of increased renal reabsorption of urea mediated by ADH in turn triggered by high blood osmolarity]

Glucose 50 mmol/l [high directly because of the diabetes]

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14/01/14: Water loading states: Dr Ruth Tarzi

Los (from booklet): Understand the principal mechanisms responsible for the homeostasis of serum sodium, osmolality and total body water content. Understand the functions of antidiuretic hormone. Understand the physiological implications of water loading and how the body responds to it. Understand the causes and consequences of pathological water loading states e.g.syndrome of inappropriate ADH secretion, primary polydipsia, secondary hyperaldosteronism.

Notes:

- Summary:o Water Balance is a critical homeostatic function.o Movement of water between compartments is regulated by osmotic pressure

provided by solutes.o Plasma osmolarity is tightly regulated by thirst and the secretion of ADH leading to

renal water reabsorption.o Sodium balance is maintained by the renin/angiotensin aldosterone system and

ANP/BNP.

- MDMA = ecstasy effects:o Sympathomimetic

Tachycardia Sweating Pyrexia

o Induces Serotonin release Psychological effects

o Also: Hyper-pyrexia: abnormally high fever Rhabdomyolysis causing Acute Renal Failure

Ie breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream kidney problems

Disseminated Intravascular Coagulation Long term pyschopathology associated with degeneration of serotoninergic

neuroneso Secretion of ADH is caused by ecstasy:

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Is a form of syndrome of inappropriate antidiuretic hormone secretion or SIADH

ie failure to excrete water If associated with very high fluid intake too then:

Water overload Diluted serum (hyponatraemia) Cerebral Oedema

o Acute hyponatraemia : With rapid hyponatremia, water moves down osmotic gradient into the CSF and brain causing cerebral oedema.

o Chronic hyponatraemia: brain volume expansion leads to loss of water and osmolytes from brain and new equilibrium with lower extracellular sodium concentration.[but may die before the solutes have been able to exit the brain]

- Water/osmolarity balanceo Water accounts for 50-60% total body weight;

[Total body water is controlled to within <1-2%] 2/3 total body water is intracellular 1/3 total body water is extracellular

o Osmolarity vs Osmolality Osmolarity = measure of solute concentration per volume (mOsm/litre of

solution). Osmolality = measure of solute concentration per kg of solvent (mOsm/kg). For our purposes these are virtually the same.

o Calculating plasma osmolality Calculated plasma osmolality = (2 x Na) + glucose + urea = about 290

mOsmoles/l. True osmolarity can be measured in the biochemistry lab and usually does

not deviate more than +2 to -2 from the calculated. Causes of an osmolal gap – difference between calculated and true

osmolality:o With metabolic acidosis

Ethanol Ketones Lactic acids Renal failure Ethylene glycol (antifreeze) Paraldehydes

o Without metabolic acidosis Ethanol Mannitol or sobitol infusion

o Regulation:

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OSMORECEPTORS in the hypothalamus; Can sense changes in plasma Osmolarity of <1% Sensing possible due to absent BBB at hypothalamusa. After water load (ie drinking), plasma osmolarity fallsb. Detected by Hypothalamic osmoreceptorsc. Reduced thirstd. Reduced ADH secretion

BARORECEPTORS of circulatory system: respond to hypovolaemia 8-10% change; ie much less sensitive than

the osmoreceoptors Control levels of:

– Angiotensin II [gives inc level]– Relaxin [gives inc level]– ANP [gives dec level]

- ADHo nonopeptideo Synthesized in the supraoptic nucleus of the hypothalamus.o Secretory granules migrate down the suprahypophyseal tract and are stored in the

posterior pituitary from where they are secreted.o Stimuli for secretion:

(1) OSMOTIC REGULATION: Increasing Plasma Osmolarity detected by hypothalamic osmoreceptors (linear relationship; sensitive)

Effects: ADH secretion and thirst:o Basal ADH receptors exist to detect ADH (ie blood side)o Aquaporin-2 inserted into the luminal surfaceo Long term effect: increased Aquaporin 2 synthesis tooo RESULT: Reabsorption of water from filtrate

(2) VOLUME REGULATION: Decreased intravascular volume (non-linear relationship; less sensitive)

Sensors: o Pressure receptors in carotid sinus and left atrium

(baroreceptors), and afferent arteriole (juxta glomerular apparatus).

Effectors: o Renin-Angiotensin System

(retain sodium; ie used if vol dec)o Atrial and ‘Brain’ Natriuretic Peptides

(lose sodium; ie used if vol inc)o RESULT: This system principally functions to regulate renal

sodium excretion; ie then the water will follow the Na to give the required volume change

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- Example: Man on a marathon in humid climate; not drinking; will lose both water and salt so osmoreceptors will not be triggered but the baroreceptors will be:

o (1) REDUCED carotid sinus baroreceptor stimulation leading to reduced parasympathetic tone (tachycardia and vasoconstriction).

o (2) Reduced NaCl delivery to the macula densa and reduced stretch in the afferent arteriole, leading to INCREASED renin secretion.

o (3) Reduced atrial stretch – reduced ANP secretion.o (4) NB ADH will only be released if plasma osmolarity goes up or severe

hypovolaemia (8-10%).

- Example: Eating crisps and drinking beer in a bar: INCREASED circulating volumeo Carotid and atrial baroreceptor stimulation induces INCREASED atrial natriuretic

peptide secretiono Natriuretic peptides oppose the renin-angiotensin system

Induce renal sodium loss Reduces plasma renin activity

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o Natriuresis results in loss of body water Ie have to bring the Na back to body to regain the water but are trying to get

rid of the Na

- Water Overloaded States o (1)Inability to secrete excess water

- Syndrome of inappropriate ADH secretion Non-physiological (ie abnormal) release of ADH Water retention Reduced plasma osmolarity [ie must have this on test readings for it

to be SIADH [if not given this directly can still work it out by the equation: Plasma osmolarity = 2 x (Na) + urea + glucose]

Ecstasy induced ADH secretion may be fatal because of the speed of secretion and amount of water drunk.

Causes of SIADH: (see also endo notes)o CNS Disorderso Drugs eg MDMA ie ecstasyo Pulmonary Disorders: pneumoniao Cancer

Treatment of SIADHo Treatment (and diagnosis) of the underlying precipitanto Treatment of the effects of ADH

Treat quickly if effects of ADH excess arose quickly Treat slowly if effects of ADH excess arose slowly

Rapidly correcting hyponatraemia in chronic situations risks demyelinating brain injury as water leaves the brain down an osmotic gradient.[Brain adapts to chronic hyponatraemia by loss of salts. Over-rapid correction of serum sodium leads to loss of water and brain shrinkage]

Most cases, and if in doubt, treat slowly with fluid restriction

- Primary polydipsia Inappropriate ingestion of water (10-20L per day!) Results in reduced plasma osmolarity Usually associated with psychiatric conditions Kidney has a high capacity to excrete urine but if this is exhausted

then hyponatraemia will occur.

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o (2) Primary Renal Salt Retention and Secondary Water Retention [all will prob result in oedematous states; Inability to secrete excess water won’t give edema as RAS not activated and proteins remain in blood]

- Renal Failure Inabilty to excrete salt and water loads due to reduced GFR.

- Nephrotic syndrome [can lead to RAAS activation] In nephrotic syndrome serum albumin is low because it is able to

exit at nephrons and leave the body; this leads to low plasma oncotic pressure, giving fluid leakage into tissues and in turn inappropriate activation of RAS due to low BP [actually have plenty of fluid, just is in the wrong place]

[ie sufficient filtering at kidney is occurring, is just that protein is also leaving]

- Heart Failure [can lead to RAAS activation] (1) reduced cardiac output increases venous pressure, so increased

hydrostatic pressure pushing fluid out of vessels, reducing circ vol and activates RAS;

(2) reduced renal perfusion also activates RAS - Liver Failure [can lead to RAAS activation]

Liver cirrhosis increases portal venous pressure so favouring fluid moving into ascites rather than travel through liver and circ system RAS activation

Liver failure reduces serum albumin, reduces oncotic pressure so fluid not retained in capillary, so effective circulating volume reduced, activates RAS

- Example: lung cancer

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o Inappropriate ADH secretion from his Ca lung. His urine osmolarity is higher than the plasma osmolarity, even though he is hyponatraemic. His reduced level of consiousness is due to cerebral oedema.

- Example: prostate cancer

o Although he is hyponatraemic, he does not have SIADH as his osmolarity is HIGH.o He is appropriately concentrating his urine.o He has renal failure secondary to bladder outflow obstruction (prostate cancer),

leading to primary salt retention and a high urea. His concentrated plasma and low potassium are likely due to diuretic use.

30/01/14: Acid-Base Balance: Doris Doberenz

Los (from booklet):Lecture 7: Acid-Base balance – physiology Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk) • Lecture and relevant articles will be made available on Blackboard

Los (from slides):

• Homeostatic principles: • maintenance of hydrogen ion concentration and electric neutrality

• Different conceptual principles of explaining acid base abnormalities:• Traditional: H+ and Bicarbonate (Henderson-Hasselbalch) vs. physicochemical

(Stewart)• Physiological consequences of acidosis and alkalosis for the whole body• Principles of acid-base production, buffering, transport, elimination and compensation

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• Definition of pH, Standard Bicarbonate, Base excess and deficit• Common acid base disturbances and causes

• Metabolic acidosis:• Hyperkalaemia• Lactic acidosis (shock and liver failure)• Ketoacidosis

• Starvation• Diabetes

• Loss/decrease of Sodium Bicarbonate• gut (diarrhoea)• kidneys: RF• hyperchloraemia

• Metabolic alkalosis • common association with: hypochloraemia, hypokalaemia

• Respiratory acidosis: high production and/or reduced respiratory elimination of CO2

• Causes of reduced ventilation• airways, lungs• Brain• Nervous system and neuromuscular junction• Muscle

• Respiratory alkalosis: • reduced production of CO2 and/or• Hyperventilation

• hypoxia, high altitude• Mechanical (over)ventilation

• Systematic approach to evaluating acid base abnormalities:• History, drugs, fluids• Examination• Blood pH ?acidosis/?alkalosis• pCO2: ?respiratory cause or compensation• Bicarbonate/base excess/deficit: ?metabolic cause/compensation• Other blood and urine tests (Na, K, Cl, renal and liver function, lactate,

ketones, urine dipsticks

Notes:

- Acid-Base Balance: important homeostatic and physico-chemical principleso Maintenance of normal hydrogen ion concentration/pH

For optimal cellular function (enzymatic reactions, transmembrane ion transport pumps etc) Acidaemia effects:

Systemic vasodilation [tissue autoregulation]

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Sympathoadrenal activation: tachycardia, increased cardiac output [“reflex tachy”]

More O2 release from Hb / Increased tissue O2 delivery High blood potassium as it moves out of cells in exchange for H+

ions moving into cells [ hyperkalemia gives cardiac dysarrthmias and cardiac arrest]

o Bradycardia risk (K+ is outside the cell so hyperpolarised membrane)

o Tall T waveso smaller P waves o widening of the QRS complex

Direct negative inotropic effect (“K+ will dec ionotropy as it is by blocking K+ site that Dijoxin increases ionotrophy”)

Insulin resistance [ diabetes] (“insulin prob triggered to encourage K+ uptake by cells as this is one of its functions”)

Alkalaemia effects: Systemic + cerebral vasoconstriction (“brain etc assumes O2 is

high”) Reduced cardiac output (prob due to arrhythmias) Less O2 release from Hb / Decreased O2 delivery Low blood potassium as it moves into cells in exchange for H+ ions

moving out of cells: hypokalemia:o Tachycardia risk (K+ in the cell so less negative memb

potential BUT repolarisation will take longer)o Arrhythmiaso flattened or inverted T waves, o ST depression o wide PR intervalo prolonged QT interval

Ionized hypocalcaemia, as calcium binding to plasma proteins increased

Traditional Henderson-Hasselbalch relevant here: (focus: pH control) Bicarbonate and pCO2 govern acid/base balance Henderson-Hasselbalch equation:

pH = 6.1 + log [HCO3-]paCO2 x SCO2

[ie paCO2 x SCO2 = PP * solubility = [H2CO3]]o Maintenance of electrical neutrality (positive ions = negative ions)

In any watery solution, and in any body compartment the sum of all positively charged ions must equal the sum of all negatively charged ions

e.g. [Na+] + [H+] = [Cl-] + [OH-] Strong cations (eg Na+ in blood) drive H+ out and OH- in (to blood) Strong anions (eg Cl- in blood) drive H+ in and OH- out (of blood)

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[ie the H+ and OH- fill the gap in charge as above] A more complete equation:

o [SID] + [H+] – [WA-] - [HCO3-] – [CO32-] – [OH-] = 0o Where SID = strong ion difference

Ie (Na+ + K+ + Ca++ + Mg++) – (Cl- + SO42- + Lactate-)

Normally 40 – 44 meq(+)o Also: WA = Weak acids/bases (~buffers):

mainly albumin and phosphoric acid/phosphate Stewart’s approach relavant here:

new quantitative/ physico-chemical approach Focus on Electroneutrality Dissociation of water and concentration of H+ (pH) and HCO3- (=OH-

+ CO2) are dependent variables of:o pCO2o Strong ion difference (in plasma/ECF mainly [Na+] – [Cl-])o [weak acids] (mainly proteins, eg albumin and phosphate)o Ie HCO3- resorption will be upregulated if Cl- or HCO3- level

falls and downregulated if Cl- or HCO3- level rises as a means to keep anion level constant

- Note:o Red meat and cheese contribute to acidic conditions in body: one of the effects of

academia is insulin resistance therefore such foods may contribute to diabeteso Most acid-base disorders are treated by reversal of the cause

- Physiologic acidso Cellular metabolism constantly produces:

‘Volatile’ acid (13–15 000 mEq/d) = CO2 (CO2 + H2O H2CO3 HCO3- + H+) from aerobic metabolism/cellular respiration (Krebs cycle)

‘Non-volatile’ acids (20 – 70 mEq/day) Lactic acid (anaerobic glucose metabolism)

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Sulphuric, phosporic and and uric acid from protein and nucleic acid metabolism

Free fatty acids, ketoacids (fat metabolism)

- How does the body deal with acid-base challenges and maintain homeostasis?o 1. Bufferingo 2. Transport (often by buffers!)

Blood proteins (Haemoglobin, Albumin) Carbonic-acid-bicarbonate system (CO2 + H2O H2CO3 HCO3- + H+)

[early PCT]o 3. Elimination:

pulmonary (CO2) renal (H+), coupled with generation of HCO3-

o 4. Compensation Respiratory / metabolic, mainly (but not only) via Carbonic-acid-bicarbonate

system: [Pulmonary elimination]

(CO2 + H2O H2CO3 HCO3- + H+) [Renal elimination/generation]

= Metabolic-respiratory link In a state of dynamic balance Maintenance of normal physiological pH ~ 7.4 requires maintenance

of 20:1 relationship between bicarbonate and carbon dioxide component as can be proven via the HH equation

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Lungso In metabolic acidosis: inc CO2 removal by hyperventilationo In metabolic alkalosis: dec CO2 removal by hypoventilation

Kidney o In metab. or resp. acidosis:

inc excretion of H+ (& Cl-) [nb excretion of H+ is coupled to retention of HCO3-] and inc generation HCO3-

o In metab. or resp. alkalosis: dec excretion of H+; this gives inc net urinary loss of

filtered HCO3- instead and dec Generation of HCO3-

o Lactate metabolism to CO2 and H2O using H+ and generating HCO3-

o Glutamine metabolism NH4+ excretion HCO3- generation

o Nb the strong control of blood pH by kidney means that there is a wide urine pH range as these compensations are made:

Urine pH range: 4.5 – 8.5 Liver

o Lactate metabolism: gluconeogenesis using H+ and generating HCO3- for

titration of peripheral H+ from lactic acido Urea formation generating H+:

titrating HCO3- from metabolism of neutral and alkaline amino acids

BUT excess H+ from acid amino acids; ie generating H+

Ie therefore this is decreased in acidosis CO2+2NH4 CO(NH2)2 + H2O + 2 H+ + Urea

o Glutamine generation using H+ (increased in acidosis)

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- pHo pH change by 1 = [H+] change x 10 o Small decimal changes in pH mean relatively large changes in [H+] o pH range compatible with life: 6.8 – 7.8 o normal range: 7.37 - 7.45 o veins are more acidic than arteries

- Standard bicarbonateo Concentration of bicarbonate in a sample of blood under ‘standard’ conditions:

Temp 37˚ pCO2 of 5.3 kPa (= 40 mmHg)

o i.e. normalized respiratory conditions, to eliminate changes in bicarbonate resulting from patient respiration; thus assessing only the metabolic component of acid-base balance

o Normal range 21 – 27 mmol/l < 21 mmol/l: metabolic acidosis > 27 mmol/l: metabolic alkalosis

- Base excess and deficito more accurate assessment of metabolic component of acid-base status than

standard bicarbonateo Compared to Standard Bicarbonate, takes not only carbonic-acid-bicarbonate but

also other blood buffer systems into account (haemoglobin, albumin and phosphate; often abnormal in sick patients)

o Base excess: Amount of strong acid that would have to be added to produce normal pH 7.4 in sample

Base excess > + 2 mmol/l: metabolic alkalosiso Base deficit: Amount of strong base that would have to be added to produce normal

pH 7.4 in sample Base deficit more negative than - 2 mmol/l: metabolic acidosis

- Lactate o Normal <2mmol/l

- Metabolic acidosis: common causeso 1.Addition of acid

(overwhelming buffers and metabolic elimination) OR (addition of acid anions leading to rise in H+ to maintain electric

neutrality) Lactic acidosis / ketoacidosis etc Examples:

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Diabetes mellitus Starvation (including hospital starvation!) Poisoning with external acid substances and their metabolites:

o Salicylateo Ethylenglycol (anti-freeze) o Methanolo Ethanol (formic acid as metabolite)

o 2. Sodium Bicarbonate loss Gastrointestinal (diarrhoea, fistulae) Renal: renal tubular acidosis: failure of the kidneys to appropriately acidify

the urine; HCO3- will be lost instead (see also kidney failure below)o 4. Hyperchloraemia

As blood chloride rises, blood hydrogen ion rises and bicarbonate falls (to maintain electric neutrality)

Eg can cause by giving (‘Normal’ Saline, containing 154 mmol/l Cl!; v high)o 5. Renal failure:

Decreased elimination of ‘fixed renal acid anions Sulphate (SO42-) and Phosphate (PO43-)

Reduced net renal H+ removal and HCO3- regenerationo Hyperkalaemia

- Metabolic acidosis investigations:o Blood lactate o Blood chloride o Urinanalysis (dipstick)

?Ketoacidosis (starvation or diabetes) Ketones (can also be measured in blood) Glucose (high in diabetes, absent in starvation; therefore can be

used to distinguish the two) ?Renal failure

Blood creatinine (and creatinine clearance) Urine pH (with acid blood urine pH should be < 5) Specific gravity (low as failing kidney can’t concentrate urine) Protein, Blood

- Metabolic Alkalosiso Raised pH from raised HCO3- [though as below seems to also encompass other

causes]o Causes:

H+ loss

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Loss of gastric acid (and Na+) from severe vomiting or excessive gastric tube drainage

Increased HCO3- commonly due to hypochloraemia from diuretics (loss of Cl-

compensated by increased Bicarbonate anion to maintain electric neutrality

Bicarbonate administration H+ shift into cells

Ie A rise in the serum pH (decrease in H+ concentration) will result in a shift of H+ out of the cell and potassium into the cell. Hypokalaemia

Low chloride commonly due to renal chloride loss from diuretics metabolic

alkalosiso Compensation: Pulmonary CO2 retention by hypoventilation (gain in volatile acid)

(maintenance of ~20:1 relationship between HCO3- and CO2)

- Respiratory Acidosiso Increase in CO2 (volatile acid) [ie as below is not just due to breathing issues; is any

mech via CO2 changes: tissue acidosis

increased production (sepsis, hyperthermia/fever, hyperalimentation)

decreased removal by perfusion blood acidosis/acidaemia

decreased removal by ventilation o due to pathology in:

Central nervous system (brain, spinal cord) Peripheral nervous system/neuromuscular junction Respiratory muscles Airways Lungs/cardiorespiratory system

o Due to: too little mechanical ventilation

o Metabolic/renal compensation: Increased excretion of H+ (e.g. as NH4+Cl-) retention/production of HCO3-

- Respiratory Alkalaemia/Alkalosiso Increased pH from excessive respiratory loss of CO2 (volatile acid) (hyperventilation) o Causes;

Primary: anxiety, pain, stress

Response to hypoxia,

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eg. high altitude, pathological hypoxia Mechanical hyperventilation

o Compensation: Increased renal HCO3- excretion and H+ retention (gain of metabolic acid), i.e. reduced standard bicarbonate and base deficit (maintenance of ~20:1 relationship between HCO3- and CO2)

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30/01/14: Acid-Base Balance Clinical Cases: Doris Doberenz

Los (from booklet):Lecture 8: Acid Base Balance – illustrations from the critically ill patient’s physiology Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk) • Cases will be provided on the day of the lectures

Los (from slides):[no Los]

Notes: [use these cases/examples on slides as rev test: ie understand all the example numbers]

- Misc:o 'drip and suck' - consisting of a IV fluids (drip) and nasogastric tube to decompress

the bowel (suck) [gastric aspiration]o Drugs for asthma can give heart effects cardiac arresto Case 1: abdominal pain & acidosis:

Was thought to be due to gut ischaemia but was just starvingo Case 2: COPD, acidosis:

metabolic acidosis exacerbation by too little mechanical ventilation [patient requires a high RR]

o Case 3: asthma: Drugs for asthma can give heart effects cardiac arrest BOTH resp and

metabolic (due to ischaemia) acidosiso Case 4:

Persistent vomiting, unable to tolerate food metabolic alkylosis Very anxious/nervous, breathing fast resp alkylosis

o Case 5: heavy smoking and chronic lung disease resp acidosis previous stroke, associated with fits lactic acidosis low blood glucose (1 mmol/l) ketoacidosis

o Case 6: In Intensive Care on mechanical ventilation with aim to keep arterial

carbon dioxide low normal (to help control brain blood volume and brain pressure: ie brain constricts as thinks there is high O2 availability) resp alkylosis

Then given intravenous Normal Saline strong acidosis exaserbated by low HCO3 from the prev situation

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06/02/14: Clinical scenarios (electrolytes): Dr Damien Ashby

Los:- THERE ARE NO LOS; THIS LEC IS PROB JUST FOR PRACTICE / REINFORCEMENT OF INFO

COVERED ELSEWHERE ON THE COURSE

Notes:

- Normal Na = 135 – 145- Normal K = 3.5 – 5.5

o Ie this dilute K+ in serum means that K+ is relatively unaffected by addition of water to the ECF (will stay in normal range) whereas the Na level will be more significantly reduced in terms of magnitude of reduction so hyponatremia can occur

- Conc of Na determines the amount of water in the extracellular space:o ADH ~ ICF

Ie are moving water which is then mostly distributed to the intracellular spaces (because have not changed Na level)

However will be some expansion of ECF too thus a hyponatremia is observed (see below ectopic ADH); hypokalemia will not be caused for the reason given above

o Aldosterone ~ ECF Ie are moving water and Na so the water will be retained in the ECF because

are not changing the Na conc so there will not be a reason for shift to ICF Note that aldosterone is not only regulated by RAS system but by the K+

level too: Aldosterone stimulated by: potassium levels going too high, if there is less blood flow to your kidneys, or if your blood pressure falls

- Note that cerebral edema is a problem with high ICF whereas all other edemas are a problem with high ECF

o Ie ADH hypersecretion can cause cerebral edema but not peripheral edema- Note that can be ECF depleted and poor renal perfusion but with high blood pressure; ie the

high BP is trying to correct the renal perfusion- Note dextrose water replaces ICF and saline replaces ECF

- Case 1o Low BP, dirrhoea, oligourea

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o = ECF depletion; give Na rich fluid

- Case 2o Edema, Heart attack recently, high BPo = Ras activation due to low renal perfusion pressure caused by the low cardiac

output due to the heart attack

- Case 3:o Lung mass, head problems (prob encephalopathy), low Nao = ADH secreting lung tumour giving hyponatremia (but not hypokalemia for the

reason given prev) and cerebral edema (an ICF edema)

- Case 4 o Vomiting, high K, pigmented skino = NOT CAUSED BY THE VOMITING; THIS IS IN FACT A SYMPTOMo = Addisons: low aldosterone so low K+ excretion. Vomiting / nausea is a symptom of

Addisons (specifically of hyperkalemia). Skin pigmentation caused by the high ACTH

- Case 5o Patient on loop diauretic, stroke, high BP, high Nao = must have been on floor a while before found so is dehydrated giving

hypernatremia, exacerbated by the frusimide. High BP as when you do not drink adequate water the body will compensate by retaining sodium but at same time the persistent dehydration will lead the body to gradually ‘close' some of the capillary beds. This leads to increased pressure places on arteries and a rise in blood pressure.

- Case 6o High Na, skull fracture, confused, seizures, polyurico = fracture gives pituitary damage and therefore loss of ADH release. Low ADH

(Diabetes insipidus) gives the polyuria and therefore H2O depletion causing cerebral contraction; symptoms of which include confusion and seizures

o Give fluid with high water content (eg 5% dextrose) [ie dextrose water replaces ICF]

- Case 7:o Collapse, high K+, low BP, oligourea, pelvic mass, low pulseo = renal failure due to bladder blockage causing urinary retention (the mass) and

giving reduced K+ excretion (unresponsive to aldosterone). High K+ give the low pulse and low BP due to disruption at heart

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06/02/14: When the kidneys are lost: Dr Damien Ashby Los (from booklet):

- Understand the pathophysiology and treatment of end stage renal disease

Notes:

Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds (such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds) in the blood. [ie all of which occurs in renal failure]

In turn results in inflammation of the visceral and parietal pericardium [ie pericarditis]Note that creatine does not increase proportionately with kidney failure; only high for

extreme failure

- Kidney failure effects:o Oedema [ie kidneys fail to remove excess fluid from body: DON’T PUT RF PATIENTS

ON A DRIP!]o high K [reduced K+ excretion (unresponsive to aldosterone!)]

tall T waves loss of P waves broad QRS bradycardia acidosis

o nausea [hyperkalemia gives nausea]o pericarditis [see above]o encephalopathy [due to the high levels of toxins in the blood]o anaemia: are not making EPO; therefore administer synthetic EPOo bone damage: A build-up of phosphates in the blood that diseased kidneys cannot

filter out may cause Bone damageo Altered cardiovascular disease risks:

Raised risks of arterial calcification disease higher cholesterol levels associated with improved CV disease risk

- Treatment: [which favoured depends on personal aspects of that patient / preference and whether are young enough for the temporary inc in mortality rate exhibited by transplant op to be worth the risk]

o Dialysis:[Associated with high mortality rates even in the young]

Peritoneal dialysis Fill peritoneal space with fluid; leave for diffusion exchange to occur

then keep replacing Hemodialysis

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Either via fistula [vein/artery shunt that gives a high flow vessel that is suitable for the frequent needle penertations for dialysis]

Or a line: flexible tube, which is put into one of the veins just below the neck, and held securely in place by a cuff under the skin. Ie used repeatedly without removal between dialysis events

Fluid accumulates in interval between dialysis events so follow weight changes and correct at dialysis

o Transplant raised demand but constant donation levels; long waiting times; tissue

typing immune suppression

corticosteroids calcineurin inhibitors

o eg cyclosporine antiproliferative agents

o eg azathioprine monoclonal antibodies

complications - early vein thrombosis ureteric obstruction rejection

complications - late opportunistic infections

o CMVo fungal

cancers: inc risk;o skino lymphoma

chronic graft failure

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06/02/14: Sodium and Potassium Handling: Dr E. J. Clutterbuck

Los (from slides/booklet):- To understand

o the factors affecting sodium and potassium balance o How the levels are regulated, and the role of the kidneyso that there is a close relationship between

sodium and water homeostasis,

potassium and hydrogen ion balance.- To outline some of the clinical conditions associated with an imbalance of sodium /

potassium o Their symptoms, signs and immediate management.

Notes:

Sodium:- Sodium handling: Summary

o Sodium and water homeostasis are interlinkedo Potassium and Hydrogen take part in exchangeo Fluid distribution between cells and ECF

depends on osmotic differences which are usually due to sodium concentration

o Aldosterone is most important factor in Na regulation controlled by RAS - responds to renal blood flow

- Na is mainly regulated by kidney ie kidney = regulator of ECF volume- Sodium loss

o GI Tract Potent source of Na loss if vomit / diarrhoea: ~100-130mmol/litre

o Skin insensible losses = sweat: ~30mmol Na/day

o Urine Wide regulation but relatively non-existant losses when necessary;

Na excretion regulates Na balance: 3-200mmol/day [ie If sodium-free diet - urine losses can reduce to 3mmol/day]

- Sites of sodium reabsorption

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o Proximal tubule 65% Basolateral membrane Active Na / K exchange pump Pumps Na out of cell

in exchange for K; Keeps intracellular [Na] low Then Na in tubular lumen can enter cell passively down concentration

gradient Other mechanisms for Na entry through lumen side:

o Co-transport - amino acids, glucose, PO4o Exchange transport - Na / H antiporter

In this way Na reabsorbtion is coupled to HCO3 reabsorption: The H+ once in lumen gives CO2 from HCO3 which can then diffuse into the tubule cell and reform HCO3 for transport to blood and H+ for the cycle to repeat

Subsequently water follows. As other solutes and water leave the lumen, Chloride concentration rises;

Chloride moves down conc gradient via paracellular pathwayo Loop of Henle: Thick Ascending Limb: 25%

Cl=rate limiting; Loop diuretics compete Cl (eg frusemide)

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o Distal tubule and collecting duct 9-10% Distal convoluted tubule

Basolateral Na/K pumpo provides energyo keeps cell [Na] low for Na / Cl co-transport on lumen side

Thiazide diuretics inhibit NaCl reabsorption

Cortical collecting duct Here is the main point of regulation; ie is via aldosterone level basolateral active Na pump

o Na entry via lumen channels creates -ve lumen potentialo This drives K secretion and /or Cl paracellular reabsorption

Aldosterone generated by renin release from JGA on stimulation by:

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o stretch receptors in afferent arteriole wall (ie blood volume low renin release)

o cardiac/arterial baroreceptors: adrenergic nerveso fall in lumen Cl in macula densa

aldosteroneo increases tubular sodium reabsorption

increases number of Na channels Drives the Na pump Increases K influx to cell on blood side Increases K efflux into lumen [ie can cause

hypokalaemia & alkalosis]

- Non-aldosterone factors affecting sodium excretiono Changes in glomerular filtration rate

V Low GFR decreases Na excretion Low GFR reduces sodium presented to prox tubule ie Nearly all reabsorbed

o Changes in renal blood flow Low tubular flow increases prox tubule reabsorption

o Changes in plasma oncotic pressure in tubule blood vessels Haemoconcentration increases prox tubule reabsorption

- Hypernatraemia (high [Na])o Usually water deficit - NOT sodium excesso Cellular dehydration

thirst, confusion, comao Other causes:

Inappropriate secretion of excess aldosterone

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Primary aldosteronism (Conn’s syndrome) benign adenoma of adrenal cortex water excess, high BP, hypokalaemia, high plasma bicarbonate early: low urinary sodium; late: tubular damage rise urinary Na

Secondary aldosteronism liver disease, Nephrotic, Protein malnutrition reduced renal blood flow: hypertension, renal artery stenosis cardiac failure

- Hyponatraemia (low [Na])o Usually water overload - NOT sodium loss: must assess volume status firsto Subtypes:

1) GI Fluid loss with water replacement [ie Sodium losses usually isotonic (GI Tract) then replaced by water

diarrhoea, vomit, sweat, burns – then drink water iatrogenic - excess dextrose replacement fluids

2) Failure of homeostasis Addisons disease (absence of aldosterone) Kidney tubule dysfunction

o pyelonephritis, analgesic nephropathyo recovery from Acute tubular necrosis (ATN), post-

obstructive uropathyo Results in cellular overhydration: Effects:

headache, nausea/vomit, cramps, confusion, fits o Pseudo-hyponatraemia:

other osmotic agents attract water and therefore dilute sodium eg diabetic : glucose eg renal failure: urea

o Factitious hyponatraemia: Sodium measured mmol / l plasma hyperlipidaemia / hyperproteinaemia replaces plasma water [though if just

serum looked at then the Na level will be fine]o Treatment; [Never correct more than 6mmol/l in 6hrs; Vaptans often overcorrect]

Hypovolaemic Hyponatraemia: Replace salt and water; but not too suddenly: (increase

[Na]<6mm/l/day) o Normal saline (140mm/l)o Dioralyte (60mm/l Na, 20mm/l K, 90mm/l glucose)

Normovolaemic Hyponatraemia: SIADH: treat the disease

Hypervolaemic Hyponatraemia : diuretics (to remove extracellular sodium), water restrict (1l), ACEI

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- Na and volume loss (ie is not hyponatremia)o plasma volume reduced - dizzy, faint, tachycardia, low BP (postural drop)o reduced interstitial volume

thirsty, nausea no oedema, sunken eyes, dry mucosa

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Regulation of Potassium

- Potassium handling: Summaryo Mainly intracellularo Regulated by kidney

degree of re-secretion by distal tubular cells subservient to control of body Na and hydrogen aldosterone

o Changes usually due to changes in total body K shift between ICF and ECF

o Hypo- / Hyper-kalaemia can be life-threatening

- [K] change due to change in total body K or shift in K in / out of large intracellular pool- Longterm K homeostasis controlled by renal K excretion governed by aldosterone- Things that inc K+ uptake at body cells:

o Insulin, o b antagonists o shift potassium into cells

- Things that dec K+ uptake at body cells:o Acidosis,o hyperosmolarity,o cell lysis o shift potassium out of cells

- Effects of inc ECF [K]:o Fall in membrane potential, lower threshold for excitation (nerve, muscles)

- Intake - foods: 60-80mmol / dayo Output o colonic fluid (rich in K) 10 mmolo sweat 10 mmol o ie output is therefore primarily urine [regulated by aldosterone] ~ 60 mmol / day

Urine losses depend upon: amount of Na available for exchange amount of H and K in distal tubule / coll ducts

(H competes with K) aldosterone level (causes Na retention / K loss)

- Movement at kidney:o Glomerular filtrate 700 mmol / day

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o proximal tubule ~100% reabsorptiono distal tubule - principle cells re-secreted (ie via Na exchange)

Na/K ATPase maintains high ICF K K diffusion to lumen Na diffusion from lumen negative lumen potential/gradient gives

further K diffusion to lumen Aldosterone (stimulated by [K] rise)

increases Na and K channels drives Na/K ATPase

o medullary collecting duct - intercalated cells Acidify urine; Pump H against conc gradient out of cells to lumen (& makes

fresh bicarbonate for release to blood)) [ie H pumped out by intercalated cells diminishes the negative gradient so K+ not secreted]

Luminal Active K pump reabsorbs K

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- Ie K secretion is determined by:o priority of Na reabsorption [at principle cells]; and H secretion [at intercalated cells]o although: [K] stimulates aldosterone K secretion

- Hypokalaemiao Loss of total body K

GI losses vomit, diarrhoea, surgical fistula

Kidney diuretics, renal disease, Cushings syndrome / steroids [MR receptor

overlap], increased aldosterone productiono Shift from ECF into cells

primary alkalosis (H leaves cells to correct alkalosis, K shifts into cells in exchange)

use of insulin (drives glucose into cells, takes K)o Symptoms:

weakness, tetany (alkalosis reduces Ca ionisation) ecg changes: ST depression, flat T; arrhythmia, acid urine, high plasma bicarbonate (may lag behind a few days)

o Therapeutic Potassium Repletion Don’t overshoot

Not too fast (arrhythmias) no more than 40mmol per hour If not fluid overloaded / normal kidney function

give in normal saline 20-40mmol KClper litre NB correcting acidosis - will induce hypokalaemia

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ie remember to consider K replacement diabetic ketoacidosis: fluids/insulin : K falls

- Hyperkalaemiao False hyperkalaemia:

Taken from vein being infused with potassium Haemolysis / Cell breakdown

small needle, traumatic puncture delayed analysis /prolonged storage high platelets, high leucocytes

Lab error Familial pseudohyperkalaemia (uncommon genetic disorder)

o Increased total body K increased intake - food, drugs, IV fluids renal disease (unable to secrete eGFR<15-20ml/min / Aldosterone

deficiency adrenal dysfunction (addisons disease +volume depletion ) low renin due to JGA damage- DM Blockage of renin - angiotensin stimulus to aldosterone

o ACEInhibitors; ARBlockers; Aliskiren Inhibition of action on distal tubule

o Competitive inhibitor: Spironolactone Inhibition of Na transport in distal tubule

o Amiloride , triamtereneo Increased total body Ko Shift of K from Cells to ECF

severe systemic metabolic acidosis K exchanges for H

insulin deficiency (reduced uptake by cells) cellular damage (release of K)

Rhabdomyolysis, tumour lysis syndrome, severe burns Drugs – succinylcholine,Bblockers, digoxin toxicity

o May be multifactorial Diabetic, hypertensive, heart failure, renal failure Drugs: ACEinhibitors, ARblockers, spironolactone

o Drugs causing Hyperkalaemia Alter transmembrane potassium movement

B blockers, digoxin, mannitol, glucoose Potassium containing agents

Iv K fluids, salt substitutes, herbal meds, blood, Reduce aldosterone secretion

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ACEI, ARB, NSAIds, heparins, antifungals (fluconazole), CNI: Cyclosporin / tacrolimus

Block aldosterone bind to mineralocorticoid R Spironolactone, epleronone

Inhibit epithelial sodium channel Amiloride, triamterene, trimethoprim, pentamidine

o Hyperkalaemia potentially Life-threatening: weak, irritable, paraesthesiae ecg changes K>6.5 (tall T, flat P, wide QRS) arrythmia- cardiac arrest if >7.5-8mmol/l

o Treatment Stabilise membrane potential:

Achieve using iv Calcium Shift into cells: iv Glucose / insulin

Nb 10u actrapid WITH 50ml glucose 50% [ie doctors often get this wrong]

Correct acidosis: Ie use Sodium Bicarbonate

Chelate: Use Calcium resonium

Diuretics / If Renal failure - call dialysis unit!

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13/02/14: Renal Physiology – clinical scenarios: Dr Jeremy Levy

Los (from slides/booklet): No actual Los and said in class not examinable (prob as is quite clinical) but worth doing scenarios as brings knowledge together and the pattern recog will prob be useful for the exams:

Notes:

- Normal:o Na: 135-145o Osmolality: 280-295

- You foolishly decide to take part in the Marathon des Sables – running 150 km across the Sahara in 6 days, carrying your food and emergency kit weighing 9 Kg. On the third day you lose you water bottle soon after starting, but continue running all day. You crawl into camp that afternoon rather the worse for wear. = Hyperosmotic volume contraction

- Serum sodium and osmolality: Loss of water greater than loss of salt (amount of salt in sweat is less than in

blood : sweat is a hypotonic solution) Higher than norm: eg Na might be 150-160 mmol/l and osmolality 300-310

mosm/mol (Normal= 280-295) Note that high salt is due to both the net loss of water in sweat and

the increased Na reabsorbtion at kidneys to try to hold onto what water body still has

Water and salt are lost from the serum (intravascularly) so water then moves from cells to the blood and is further lost. Leading to total body water depletion.

- blood pressure: For moderate dehydration BP remains normal but in very severe/prolonged

cases such as this the homeostatic systems are overwealmed and BP drops (once BP systems maximally active the BP falls with volume)

If is normal will likely be sensitive to stresses; eg postural hypotension; if stand up vasoconstriction etc is usually required to maintain the BP but is already maximal so BP falls (and person may also faint)

- physiological processes that have kept you more or less alive:

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Dehydration ADH release from posterior pituitary stimulates reabsorption of water + vasoconstricts

Mech of Dehydration ADH release:o Secretion in response to reduced plasma volume is activated

by pressure receptors in the veins, atria, and carotids.o Secretion in response to increases in plasma osmotic

pressure is mediated by osmoreceptors in the hypothalamus.

o Secretion in response to increases in plasma CCK is mediated by an unknown pathway.

o JGA Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body.

Aside: ADH secretion inhibitors:o Ethanol (alcohol) reduces the secretion of AVP o Atrial natriuretic peptide inhibits AVP secretion

Kidneys produce renin angiotensin II powerful vasoconstrictor and stimulates production of aldosterone which increases water reabsorption (and ADH as mentioned above)

Inhibition of ANPo Urine:

low urine sodium, (as want to retain Na to allow retention of water) high osmolality (as still must get rid of waste products to a degree but low

water excretion) low urine volume / low micturition: will lead to an increase in waste

products in blood (eg urea reabsorbtion somewhat increased to help retain H2O) but is NOT renal failure as is fully reversible; but may progress to ATN / RF with continued low perfusion etc. Note that creatinine is still cleared; serum Cre only inc at late RF (reduced clearance and inc production due to ischaemia)

- A 25 year old woman is admitted to hospital for the birth of her first baby. After a prolonged labour she requires a caesarian section, and the baby is safely delivered. Blood test on the next day show:= Hyperosmotic volume contraction

Serum Na 149 mmol/l (135-145) [High] Serum potassium 5.0 mmol/l (3.5-5) [slightly high] Serum urea 8 mmol/l (2.5 – 6.7) [high]

o Results analysis: Dehydration due to hard labour / sweat, blood loss high sodium, high

urea potassium hard to interpret:

is concentrated due to the dehydration but also excreted in exchange for Na to greater degree at kidney as high Na wanted to retain the H2O

therefore K+ doesn’t generally change unless severely dehydrated

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Give IV dextrose solution to replace volume

- 48 hours later she is noted to be semi conscious, barely rousable, with a new divergent squint of her eyes. Blood tests show:

Serum Na 105 mmol/l (135-145) – very low Serum potassium 3 mmol/l (3.5-5) Serum urea 3 mmol/l (2.5 – 6.7)

o Explanation:o Water overloaded:

encouraged to drink lots given too much fluids by IV Pain gives central ADH stim ( sympa ADH secretion) and via kidney (

sympa JGA renin/RAS ADH secretion) Analgesics (opiates) give central ADH stim

o Rapid fall in Na has led to central pontine myelinolysis Occurs when dehydrated then overhydrated Nerve demylination at pons area (only) occurs potentially fatal mech not clear; seems to be due to the rapid Na shifts either way across

memb as Na moves in when dehydrated then out when overhydrated causing the demylination

- Distinguish between a patient with primary polydipsia (drinking too much from psychiatric illness) causing polyuria, and a patient with true polyuria from diabetes insipidus.

o Fluid deprivation test: fluid deprive and those with DI will not be able to concentrate their urine but polydipsic individuals will

o Include hourly weight and urine volume / Na / osmolality: Eg polydipsic gives conc urine and maintains weight Eg cheating poydypsic would give dilute urine instead of concentrated but

would not lose weight!o Note that no treatments are really available to help vs nephrogenic DI in terms of

cure; can only give thiazide diuretics

- Cholera

- How does cholera cause diarrhoea? Bacteria which releases a toxin that binds irreversibly to small bowel

epithelium. Toxin taken up into cells and stimulates cAMP production.

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Inhibits absorption of NaCl in villus cells, stimulates chloride secretion in crypt cells

leading to massive loss of isotonic electrolyte solution. Improves in a few days as gut replenishes and bacteria are lost but must

maintain hydration of patients: water, NaCl until infection passes- Why do people die from dehydration? What actually kills them?

Intravascular water loss hypovolaemia loss of perfusion to major organs

Concentrated intravascular solution dehydrates cells: shrink and contract Loss of perfusion to muscles increases lactic acid production acidotic:

enzymes do not work Brain shrinks: attached to the inside of the skull stretches venous sinus

bleeding- Why do patients with dehydration sometimes get renal failure?

Blood pressure falls reducing blood flow to the kidneys and hence their ability to function. Recovers with hydration, but over too long will lead to ATN / RF

- A 21 year old woman has become tired and lethargic and gone to her GP. She is found to have a BP of 110/60 and weighs 50 Kg. She has weak muscles globally (due to low potassium).

- Some investigations show: Serum Na 138 mmol/l [normal]Serum K 2.2 mmol/l [low]Serum Urea 10 mmol/l [high]

- How would you decide if she was intravascular volume depleted?; BP is low but may be normal for her!:

o Test for postural hypotension. If volume depleted will not be able to compensate when stands vasoconstriction is maximally activated

o look for weak pulse but tachyo look for low JVPo Skin turgor [Decreased skin turgor/elasticity is a late sign in dehydration]o dry mouth

- Possible causes of this scenario:o Diuretic abuse fits perfectly; look for diauretic presence in urineo Possibly vomiting (e.g. bulimia)

potassium wouldn’t likely drop so much but is possible due to alkylosis giving H+ movement out of cells in exchange for K+ and dehydration giving RAS stim for inc Na retention at cost of K+ at kidney via aldosterone

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o Not Conn’s [aldosterone-producing adenoma]: causes hypokalaemia but hypertension not hypotension!

o Not Simmond’s syndrome = Sheehan syndrome: pituitary infarct; panhypopituitarism; would not be walking into the GP

o Severe diarrhoea; This can cause either a metabolic acidosis or a metabolic alkalosis: Metabolic acidosis tends to be associated with acute infective diarrhoea eg

cholera. The problem is an excessive loss of bicarbonate in the diarrhoeal fluid.

Diarrhoeas which are caused by predominantly colonic pathology may cause a metabolic alkalosis: this includes chronic diarrhoeas due to ulcerative colitis, colonic Crohn’s disease and chronic laxative abuse.[ie these latter examples could be the solution due to alkylosis giving H+ movement out of cells in exchange for K+ and dehydration giving RAS stim for inc Na retention at cost of K+ at kidney via aldosterone]

nb- Bulimia: vomiting- Anorexia: not eating

- Irbesartan is an angiotensin receptor blocker- Losartan is an angiotensin receptor blocker

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13/02/14: Overview of kidney function and dysfunction with respect to learning objectives of the course Dr Damien Ashby

Los (from slides/booklet):

Notes:

See requested slides to practice with

- Steroid drugs adrenals stop making steroids so if drug removed will get addison’s (low aldosterone) etc

- Septic shock low BP low flow causing lactic acidosis- Nb Ti/Tii RF as possible causes of electrolyte imbalances- Pulmonary embolism does not show up on CXR esp if acute

o Gives cough and chest paino Gives type I resp failure hyperventilation acute resp alkylosis o [nb there are many other causes for hyperventilation than anxiety!]

- Too high heparin/warfarin can give blood in stools (nb they are cleared renally so RF high circ conc blood in stools!]

- Renovascular disease = renal artery stenosis: o lack of bloodflow will cause the kidney to shrinko the kidney will activate RAS dueto its low blood flow!

- RRT = renal replacement therapy = dialysis of transplantation- RF gives nausea due to electrolyte imbalance / toxin buildup loss of appetite may then

explain further disruptions- Cachexia (wasting syndrome) is long term result of anorexia- “BM” = blood glucose test! (was just the name of the company making the tests)- Normal anion gap <12; abnormal if lactate / ketones etc

o = ([Na+] + [K+]) − ([Cl−] + [HCO3−])- Reasons for normal anion gap but metabolic acidosis:

o Surgical urinary diversion to gut (urine Cl absorbed in bowel excrete HCO3 to compensate acidosis) (creat low)

o RF (creat high)o Overcompensated Na replacement (consider if known Dr input)

- Renal cysts show on Xray; are benign- Calyces shrink and contract through time randomly; benign; seen on x ray- Hyperkalemia: bradycardia, flat p waves, broad QRS, tall T waves

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28/02/14: CONTROL OF CALCIUM AND PHOSPHATE: VITAMIN D, PTH AND THE KIDNEY: Prof Karim Meeran

Los (from Booklet): All of the below:1. Predict the consequences of loss of endocrine functions of the kidney 2. Control of calcium and phosphate: vitamin D, PTH and the kidney To explain the mechanisms of calcium homeostasis To understand the importance of a fixed calcium level on nerve and muscle function To understand the effects of vitamin D, PTH on calcium homeostasis. To list the causes of hypercalcaemia and hypocalcaemia To understand the clinical effects of hypercalcaemia and hypocalcaemia To compare and contrast osteoporosis and osteomalacia To understand the metabolism and activation of vitamin D

*Please note that this topic can be examined in either exam, as it forms part of both the Renal course and the Pathology course. Notes: [nb netters images/book may be useful]

- Vitamin D:o Animal products / supplements / from our skin: Vitamin D3 cholecalciferol;

not hydroxylated at 1 or 25 position; only at inherent 3 positiono Plant products / supplements: Vitamin D2 ergocalciferol;

not hydroxylated at 1 or 25 position; only at inherent 3 positiono 25 – vit D

Generated by vit D - 25 hydroxylase in the liver 100% of any absorbed vitamin D from gut is hydroxylated This is the stored and measured form of vitamin D

o 1,25 – vit D Generated by 1 alpha hydroxylase in kidney Rarely, this enzyme can be expressed in lung cells of sarcoid tissue Called calcitriol as now has three OH groups

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- Calcium:o Parathyroid hormone

when calcium low, PTH rises. PTH causes:

movement of calcium from bone increased calcium activation of renal 1 alpha hydroxylase increased calcium via vit D

o this is the rate determining step in activation of vit D and therefore is the step that needs to be regulated

o Causes of hypercalcaemia Primary hyperparathyroidism (ie high PTH giving high Calcium in the

plasma): Bones : pain / fractures Extra calcium gets stuck in kidneys nephrocalcinosis and Kidney

stones Causes psychiatric symptoms ie moans Causes abdominal pain and constipation ie groans

Cancer with bone metastases Distinguish from primary hyperparathyroidism by PTH level; cf

Overactive active vitamin D production Eg due to sarcoidosis:

o A disease involving abnormal collections of inflammatory cells (granulomas) that can form as nodules in multiple organs.

o Frequently causes an increase in vitamin D production outside the kidney, namely inside the immune cells found in the granulomas the condition produces

Check vitD levelo Investigations of high calcium

Serum calcium Serum PTH (high or normal suggest hyperparathyroidism; Low PTH suggests

cancer) Vitamin D levels CXR (sarcoidosis; ie frequently causes an increase in vitamin D production

outside the kidney, namely inside the immune cells found in the granulomas the condition produces)

o Hypoparathyroidism: Eg no parathyroid glands

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Give calcitriol to allow gut Ca uptake but must also give Ca supplements as will still not get the physiological release of Ca from bones that occurs in normal person

o CLINICAL SIGNS of a low calcium [Chronic calcium deficiency results in loss of calcium from bone in order to

maintain circulating calcium] Trousseau’s sign (~ carpopedal spasm) Chvostek’s sigh Convulsions Laryngeal spasm

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- Metabolic bone disease (don’t confuse these with osteoarthritis):o Osteoporosis [= things that will affect all aspects of bone (so not vit D deficiency!!)]

Normal serum calcium and phosphate and PTH, ALP may be raised esp if one of the sudden causes

Bone slowly lost after age 20 Residual bone normal in structure; is just loss of bone mass ie the bones just

become thinner (bone loss but with a normal calcium) Causes of osteoporosis:

Bed bound Space: weightlessness Low testosterone / oestrogen for any reason (inc Menopause) Hyperthyroidism Cushing’s Malnutrition Old age Cirrhosis (due to the harmful effects of substances such as bilirubin

and bile acids or the toxic effect of alcohol or iron on osteoblasts) Ketoacidosis (the acidosis thins the bones)

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o Osteomalacia = secondary hyperparathyroidism (“due to low vit D or diet / preg / other tumours(!)”)

Bone is demineralized; ie Ca:protein ratio in bone will decrease Low serum calcium and phosphate Caused by lack of Ca:

Diet:o Lack of Ca in diet

vitamin D deficiency giving failure to gain Ca from diet:o Renal failure; hydroxylation function losto Anticonvulsants induce breakdown of vitamin Do Lack of sunlighto Chappatis (phytic acid); in Asian diet, chelates vit D in gut

Pregnancy:

o PTHrP: Physiological role at bone is in causing sacrifice of mother’s bone via paracrine mech to provide Ca for building child skeleton during pregnancy

Case history:

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Low calcium, low phosphate High PTH High alkaline phosphatase (a marker of bone breakdown/turnover;

is generated in osteoblasts) = OSTEOMALACIA!

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o Paget’s disease Bone has increased turnover

ie Increased osteoblasts (synth) and osteoclasts (deg) ie high breakdown and high synth; initially is net thinning then net

thickening Bone pain High alkaline phosphatase Normal serum calcium and phosphate and PTH Case history:

Very high alkaline phosphatase and bone pain = Paget’s disease!

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26/03/14: Renal causes of hypertension: Dr Peter Hill

Los (from Booklet):

Lecture 9: Renal causes of hypertensionDr Peter Hill ([email protected]) Understand the pathological consequences of uncontrolled hypertension Appreciate when to suspect secondary hypertension and know causes of secondary hypertension To be aware of imaging modalities to investigate renovascular hypertension To be aware of treatment options for renovascular hypertension To be aware of therapeutic approaches to treating primary and secondary hypertension

Notes:

- Nb the majority of studies have reported a higher prevalence and significantly higher mean blood pressure levels among both Afro-Caribbean populations

- Hypertension is a risk factor for:o Strokeo Cardiovascular Disease [ie MI / angina]o Heart Failureo Left Ventricular Hypertrophy

- Clinical values:o OPTIMAL

120/80 or lesso NORMAL

120-129/80-84o HIGH NORMAL

130-139/85-89o HYPTENSION

140+/90+ Nb diurnal variation in BP is lost in hypertension too

- Primary vs Secondary hypertension:

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o Primary = essential hypertension = no specific individual cause The vast majority of cases Contributing factors:

– Familial – overweight – Increased salt intake – high alcohol intake – black population.

o Secondary = Hypertension with a discernable cause Secondary causes:

Renal [reduced filtration/excretion will give hypertension]o – Intrinsic Renal disease eg Glomerulonephritiso – Chronic kidney diseaseo NB ACEi/ARB CAN be used in these patients: these drugs

help by giving just a small drop in GFR (ie in this situation the GFR is not highly reliant on RAS system) thereby reducing the workload on the kidneys and therefore helping avoid ischaemic effects by reducing oxygen demands

Renovascular Disease = RAS [gives hypertension due to RAAS activation]

o Renal Bruit on auscultation bruit ("rushing" sound) on affected side due to renal

artery stenosiso Creatinine rise after starting ACEi or ARB: DO NOT USE

THESE IN THESE PATIENTS: use CCBs or stent the RASo Unequal sized kidneys: kidney with RAS is smallero RAS caused by:

Atherosclerosis May be widespread through body or just at

renal artery Often associated with peripheral vascular

disease (PVD): obstruction of large arteries not within the coronary, aortic arch vasculature, or brain.

Fibromuscular dysplasia Affects young women non-atherosclerotic, non-inflammatory

vascular disease that causes abnormal growth within the wall of an artery; tight loops of vessel obstruct flow

Can affect any arterial bed: here are referring to renal artery effects

Causes hypertension, transient ischemic attack and stroke

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Hypertension Via smooth muscle hypertrophy (nb

myogenic theory)o Doesn’t just cause hypertension: Ischaemic Atrophy or

Ischaemic glomerulopathy of the kidneys Vascular Disease

o – Coarctation: ie narrowing of arteries in peripheral vasculature to give increase to blood pressure

Endocrine causeso – Cushings diseaseo – Conn’s syndrome/ Hyperaldosteronism

Low Potassium, high sodium values Sudden onset pulmonary oedema due to the water

retention]o – Phaeochromocytoma

Drugso – Alcoholo – Nasal decongestant (adrenaline is active agent)o – Cocaineo – OCPo – NSAIDSo – Corticosteroids

Sleep Apnoea hypertension o Thought to be due to nocturnal hypoxia or hypercapnia

provoking responses to give daytime hypertension

- Imaging modalities to investigate renovascular hypertension:o Digital subtraction angiography: is Xray and contrast basedo Magnetic Resonance Angiography: is MRI

Gadolinium contrast: Gives toxicity if patient has renal failure; ie poor clearance gives

Nephrogenic systemic fibrosis (NSF), also known as nephrogenic fibrosing dermopathy (NFD) [is a disease of fibrosis of the skin and internal organs caused by gadolinium exposure]

Can’t see Fibromuscular Dysplasia very wello CT Angiography

Not as good as Magnetic Resonance Angiography: Less good resolution Very good at picking up fibromuscular dysplasia

o Doppler Ultrasound Compare systolic velocities in aorta and renal artery

o Captopril Renogram Use a maker of glomerular filtration

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Compare images before and after captopril (an ACEi): in renal artery stenosis see fall in GFR in stenosed kidney due to its dependence on the RAS system

- Hypertension treatments: [secondary has lower NICE target BP than does essential hypertension]

o Life Style changes: Weight loss Regular exercise Avoidance of excess alcohol salt smoking caffeine

o Drugs: Young (<55yrs)

ACEi/ARB is first line Older (>55yrs) or afro-Caribbean

CCB or thiazide is first line BUT NOT ABLE TO USE ACEi/ARB IF RENAL ARTERY STENOSIS Alpha blockers (doxazocin) if urinary symptoms [will aid relaxation of the

bladder as well as drop the BP]o Surgery:

Angioplasty alone / Angioplasty with sten>ng Eg if treatment not working Eg if malignant hypertension (eg haemorrages being caused in eyes or brain) Eg if want to be able to use ACEi to treat another disease Eg effective at straightening the loops of Fibromuscular dysplasia

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26/03/14: Erythropoeitin: Dr Peter Hill

Los (from Booklet):

Lecture 10: ErythropoeitinDr Peter Hill ([email protected]) To be aware of the physiological functions of erythropoetin and its regulation To understand the consequences of dysregulation of the HIF axis To be aware of the therapeutic uses of erythropoetin To understand the approach to managing anaemia in renal disease Notes:

- HIF = Hypoxia Inducible Factoro Is a transcription factoro EPO gene HRE = hypoxic response element binds HIF to upregulate EPOo Is constitutionally expressed but is inactivated in normoxia due to the presence of

O2 AND Fe allowing hydroxylation which gives ubiquitination which gives degradation of the HIF

o Effects: Angiogenesis / Vascular endothelial growth

VEGF, iNOS, HO-1 pH regulation

Carbonic anhydrase production [ie prob to counter any acidity] Cell Proliferation, differentiation & Viability

IGF-2 TGF-β3

Blood Cell Production EPO

Iron metabolism Transferrin production [is a iron-binding blood plasma glycoprotein]

Glucose metabolism Glucose Transporters Glycolytic Enzymes

o Pathology: ALL THESE GIVE INC ERYTHROCYTOSIS Loss of HIF Hydroxylase enzyme leads to increased erythrocytosis [“Chuvash

Polycythaemia”] Mutation in HIF2 alpha subunit gives increased erythrocytosis with

pulmonary hypertension

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von Hippel Lindau Syndrome: failure of the degradation pathway: result is a cancer syndrome predisposing to a variety of malignant and benign tumors of the eye, brain, spinal cord, kidney, pancreas, and adrenal glands

- EPOo Is a glycoprotein growth factor with Fe cofactoro Produced in the kidney (>90%) and liver (<10%)

Made by fibroblasts in kidney produced by interstitial fibroblasts in the kidney in close

association with peritubular capillary and tubular epithelial tubule = from Juxtatubular Interstitial Cells = from extraglomerular mesangial cells

Made by stellate cells in the liver o Stimulates erythropoiesis:

Acts via JAK / STAT signalling at erythropoietin receptor (EpoR) Promotes red blood cell survival by protecting immature RBC cells from

apoptosis.

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EPO uses iron as a co factor‐ so need to ensure adequate stores: nb renal pateints have poor storage capacity of Fe so must really iron overload them

o Other effects: vasoconstriction and hypertension stimulating angiogenesis proliferation of smooth muscle fibers

o EPO synth is stimulated by renal hypoxia: Anaemia stimulates EPO production by acting as a hypoxic stimulus

o Kidney is a relatively hypoxic environment making it ideal to be the regulator of EPO level

o Clinical use: Has replaced transfusions as a means of maintaining RBC / Hb level in

dialysis patients [ie renal patients that are not making the EPO themselves so will have low RBC / Hb]

Transfusions gave viral diseases such as Hepatitis B, decreased transplant success due to sensitisation of the patient to possible kidney transplants and Iron Overload Syndromes

o However is useful to give EPO immediately with a new transplant to help protect against ischaemic injury

Slows progression of renal failure: prob via countering renal hypoxia without giving inc workload of increase Fe clearance requirement

In fact EPO varients are often used instead called ESA’s = erythropoiesis stimulating agents, which act for longer period at the EPO receptor: eg Darbepoeitin, Micera

Note that less drug used than would give normalisation because has been shown to give increase CVD / stroke risk though the exact mechanism is not clear

Use in cancer:

Cancer patients often have low RBC levels but use of EPO in such cases has been shown to enhance the oncogenic progression in the body

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Unwanted events: ESA use can stimulate the production of antibodies vs the EPO

receptor thereby making the patient transfusion dependant for new RBC source

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Tutorial notes:

- EMQ ans: Countercurrent in loop of henle has steep longitudinal gradient and shallow transverse gradient

- Kidney is NOT erythropoietic!- ADH acts at collecting duct not DCT- UTA1 protein performs the urea reabsorbtion at collecting duct in response to ADH

- Na2ClK cotransporter is secondary active transport- ADH and oxytocin differ by 2x AA- Lack of FVIII gives haemophillia A therefore can give people ADH to help stimulate FVIII

production- Nb if there is an “all of the above” option then if two of the others are true then that MUST

be the correct answer regardless of the other options- THIAZIDES HAVE A VASODILATION EFFECT; IS ARGUEABLY MORE IMPORTANT THAN THEIR

EFFECT ON REDUCING SALT REUPTAKE IN LOWERING BLOOD PRESSURE- K+ sparing diuretics have diuretic effect but key action is in inducing hyperkalemia to help

counter effect of coadministered diurectics- Loop diuretics give hypocalcaemia- Differentials (all some similarities): DM vs diuretic vs lithium poisoning vs primary polydipsia

vs DI- Kf is the rate constant for the GFR equation: is affected by:

o Surface area at glomeruluso Integrity of glomerulus o The negative charge of albumin in blood (esp for cations)

- Adenosine vasoconstricts the afferent arteriole via A1 receptors in response to macula densa sensing high Na in tubules

- Causes of glomerulonephritis:o SLEo Goodpasture’so Streptococcal infection leading to macrophage activation at kidneyo Berger’s disease = “IgA nephropathy”

deposition of the IgA antibody in the glomeruluso UTIo Alport

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- Fanconi’s syndromeo Disturbance of PCT function (glucose, amino acids, bicarbonate etc are passed into

the urine)o Will present with hypokalemia (prob due to changed electrochem gradient)

- Bartter syndromeo Autosomal recessiveo Na2ClK cotransporter is mutatedo Hypokalemia and alkylosis will result with risk of hypotension

- Addisonso Low Na high K

- Liddle’s Syndromeo Activating ENaC mutationo Hypertension is the resulto Nb ENaC = epithelial sodium channel upregulated by aldosterone and inhibited by

amiloride- Conn’s

o Primary hyperaldosteronismo High Na, low K, low renin

- RASo Secondary hyperaldosteronism

o High Na, low K, high renin- Alport

o A renal disease that is associated with deafness

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Constanzo notes:

- the cells of the proximal convoluted tubule are unique in having an extensive development of microvilli, called a brush border, on their luminal side.

- The superficial cortical nephrons have their glomeruli in the outer cortex. These nephrons have relatively short loops of Henle, which descend only into the outer medulla. The juxtamedullary nephrons have their glomeruli near the corticomedullary border.

- The glomeruli of the juxtamedullary nephrons are larger than those of the superficial cortical nephrons and, accordingly, have higher glomerular filtration rates. The juxtamedullary nephrons are characterized by long loops of Henle that descend deep into the inner medulla and papilla and are essential for the concentration of urine.

- renal artery segmental arteries interlobar arteries arcuate arteries interlobular arteries the first set of arterioles, the afferent arterioles the first capillary network, the glomerular capillaries, ultrafiltration occurs second set of arterioles, the efferent arterioles, peritubular capillaries, (mainly juxtamedullary nephrons: vasa recta present: solutes and water are reabsorbed, a few solutes are secreted), (mainly superficial cortical nephrons: kidney epithelial cells are supplied with blood) small veins renal vein.

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- Water accounts for 60% of body weight- Approximately two-thirds of total body water is in the ICF, and about one-third is in the ECF

(plasma + interstitial fluid). - 60% of body weight is water, 40% of body weight is ICF, and 20% of body weight is ECF. - The percent of blood volume occupied by red blood cells is called the hematocrit, which

averages 0.45 or 45% and is higher in males (0.48) than in females (0.42).- volumes of the body fluid compartments are measured by the dilution method:

o mannitol cannot cross cell membranes, and it will be distributed in ECF but not in ICF. Thus, mannitol is a marker for ECF volume.

o Isotopic water (e.g., D2O) will be distributed everywhere that water is distributed, and thus isotopic water is used as a marker for total body water

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- The volume of a body fluid compartment:o Depends on the amount of solute it contains. o For example, the volume of the ECF is determined by its total Na (and its

accompanying anions which together with it will form NaCl and NaHCO3- The normal value for osmolarity of the body fluids is 290 mOsm/L- Solutes such as NaCl and NaHCO3 and large sugars such as mannitol are assumed to be

confined to the ECF compartment because they do not readily cross cell membranes. o For example, if a person ingests a large quantity of NaCl, that NaCl will be added

only to the ECF compartment and the total solute content of the ECF will be increased.

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- Disturbances:o Isosmotic volume contraction

Diarrhea burn

o Hyperosmotic volume contraction = more water lost than salt = hyperosmotic ECF is left at end = no change to haemocrit

Sweating fever diabetes insipidus

o Hypoosmotic volume contraction = less water lost than salt = hypoosmotic ECF is left at end = ICF will increase!!

Adrenal insufficiencyo Isosmotic volume expansion

Infusion of isotonic NaClo Hyperosmotic volume expansion

High NaCl intakeo Hyposmotic volume expansion = no change to haemocrit

SIADH; For example, if an extra 3 L of water is reabsorbed by the collecting ducts, 1 L will be added to the ECF and 2 L will be added to the ICF (because ECF constitutes one-third and ICF constitutes two-thirds of the total body water).

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- Clearance:o By definition, renal clearance is the volume of plasma completely cleared of a

substance by the kidneys per unit timeo the units of clearance are volume per unit time (e.g., mL/min; L/hour; L/day)o renal clearance is the ratio of urinary excretion ([U]x * V ) to plasma concentration

(ie have to account for both amount removed but also the amount remaining to know how many units of volume have been completely cleared by having removed that volume of the substance):

o renal clearance of albumin is approximately zero because, normally, albumin is not filtered across the glomerular capillaries

o renal clearance of glucose is also zero as Glucose is filtered and then completely reabsorbed

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o Inulin , a fructose polymer, is freely filtered across the glomerular capillaries, but it is neither reabsorbed nor secreted; therefore, its clearance measures the glomerular filtration rate (GFR).

o Filtration fraction: The filtration fraction is that fraction of the RPF that is filtered across the

glomerular capillaries. The value for the filtration fraction is normally about 0.20, or 20%. That is, 20% of the RPF is filtered, and 80% is not filtered.

o Net Resorbtion vs net Secretion:

- RBF: The kidneys receive about 25% of the cardiac outputo RBF follows Q = ΔP/R.o The major mechanism for changing blood flow (RBF; eg in response to

haemorrhage) is by changing arteriolar resistance. (nb here are wanting to change RBF; below will later see autoregulation which keeps RBF constant with physiological systemic pressure changes)

o Resistance is provided mainly by the arterioles, however, there are two sets of arterioles, the afferent and the efferent. Therefore in the kidney changing blood

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flow can be accomplished by changing afferent arteriolar resistance and/or efferent arteriolar resistance

o Sympathetic nervous system and circulating catecholamines. Both afferent and efferent arterioles are innervated by sympathetic nerve

fibers that produce vasoconstriction by activating a1 receptors. However, because there are far more a1 receptors on afferent arterioles,

increased sympathetic nerve activity causes a decrease in both RBF and GFR.

Thus, the cardiovascular system will attempt to raise arterial pressure even at the expense of blood flow to the kidneys.

o Angiotensin II. Angiotensin II is a potent vasoconstrictor of both afferent and efferent

arterioles. However, the efferent arteriole is more sensitive to angiotensin II than the

afferent arteriole Low levels of angiotensin II produce an increase in GFR by constricting

efferent arterioles (ie think of as for mild / severe haemorrhage will need to reduce RBF to send blood elsewhere but want to maintain GFR if possible to avoid toxicity),

This protective effect of ATII in maintaining BP and GFR in haemorrhage is lost in ACEi use so a bleed not only gives low BP to rest of body but at kidney will get low BP/RBP without maintenance of a normal GFR

high levels of angiotensin II produce a decrease in GFR by constricting both afferent and efferent arterioles (ie just think of as for very serious haemorrhage will want to lower the GFR to maintain every bit of fluid possible).

The juxtaglomerular cells secrete renin in response to: Beta-1 adrenergic stimulation Decrease in renal perfusion pressure (detected directly by the

granular cells) Decrease in NaCl concentration at the macula densa (ie is sensing

the tubule lumen), often due to a decrease in glomerular filtration rate, resulting in slower filtrate movement through the proximal tubule and, thus, more time for reabsorption. [here the signalling is via adenosine which will also give some direct vasoconstriction]

Gives increased reabsorbtion at the proximal tubule [acts at the Na/H exchanger]

o Prostaglandins. Several prostaglandins (e.g., prostaglandin E2 and prostaglandin I2) are

produced locally in the kidneys and cause vasodilation of both afferent and efferent arterioles.

The same stimuli that activate the sympathetic nervous system and increase angiotensin II levels in hemorrhage also activate local renal prostaglandin production.

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Thus, prostaglandins modulate the vasoconstriction produced by the sympathetic nervous system and angiotensin II (Unopposed, this vasoconstrictioncan cause a profound reduction in RBF, resulting in renal failure.)

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit synthesis of prostaglandins and, therefore, interfere with the protective effects of prostaglandins on renal function following a hemorrhage.

- Autoregulation (Renal arterial pressure can vary from 80 to 200 mm Hg, yet RBF will be kept constant; nb as prev in haemorrhage if drops v low then changes to RBF may need to be made to save body at cost of kidney)

o Myogenic hypothesis. The myogenic hypothesis states that increased arterial pressure stretches

the blood vessels, which causes reflex contraction of smooth muscle in the blood vessel walls and consequently increased resistance to blood flow

o Tubuloglomerular feedback. Tubuloglomerular feedback is also a mechanism for autoregulation

explained as follows: When renal arterial pressure increases, both RBF and GFR increase.

The macula densa uses the composition of the tubular fluid as an indicator of GFR. A large sodium chloride concentration is indicative of an elevated GFR, while low sodium chloride concentration indicates a depressed GFR.

Sodium chloride is sensed by the macula densa by an apical Na-K-2Cl cotransporter. Detection of elevated sodium chloride levels triggers the basolateral release of ATP from the macula densa cells, causing a drop in GFR, mediated by constriction of the afferent arteriole.

- Ultrafiltration: (also neg glycoproteins throughout help to repel proteins)o Endothelium: no real barrier to filtration

All but cells can pass througho Basement membrane:

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Proteins cannot pass througho Epithelial cells = podocytes; attached to basement membrane by foot processes:

Also some prot blocking

o Starling equation: The oncotic pressure of Bowman’s space, which is analogous to interstitial

fluid, is considered to be zero, since filtration of protein is negligible. The only pressure that changes along the afferent arteriole is πGC, the

oncotic pressure of glomerular capillary blood. As fluid is filtered out of the glomerular capillary, protein is left behind, and the protein concentration and pGC increase. By the end of the glomerular capillary, pGC has increased to the point where the net ultrafiltration pressure becomes zero.

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Causes of low GFR: ACEi (see prev) Changes in πGC are produced by changes in plasma protein

concentration. o Thus, increases in plasma protein concentration produce

increases in πGC, which decrease both the net ultrafiltration pressure and GFR.

o On the other hand, decreases in plasma protein concentration (e.g., nephrotic syndrome, in which large amounts of protein are lost in urine) produce decreases in πGC, which increase both net ultrafiltration pressure and GFR.

Changes in PBS can be produced by obstructing urine flow (e.g., ureteral stone or constriction of a ureter).

o For example, if the ureter is constricted, urine cannot flow through that ureter to the bladder, causing urine to back up in the kidney. Consequently, hydrostatic pressure in the nephrons will increase as far back as Bowman’s space, producing an increase in PBS. An increase in PBS decreases the net ultrafiltration pressure, thereby decreasing GFR.

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Glucose:- Glucose moves from tubular fluid into the cell on the Na+/glucose cotransporter (called

SGLT; sodium-glucose linked transporter; is secondary active transport) in the luminal membrane. Two Na ions and one glucose bind to the cotransport protein.

- On the basolateral side GLUT 1 and GLUT 2 mediate the transfer of glucose by facilitated diffusion

- PAH: EXAMPLE OF SECRETIONo para-aminohippurateo the substance used to measure RPF. o PAH is an organic acid that is both filtered across glomerular capillaries and secreted

from peritubular capillary blood into tubular fluid.- Urea: EXAMPLE OF PASSIVE REABSORBTION:

o Urea is freely filtered across the glomerular capillaries, and the concentration in the initial filtrate is identical to that in blood (i.e., initially, there is no concentration difference or driving force for urea reabsorption). However, as water is reabsorbed along the nephron, the urea concentration in tubular fluid increases, creating a driving force for passive urea reabsorption

o The urea from the collecting duct passively enters the medullary interstial fluid and diffuses into the loop of henle. As it passes back up the ascending limb of the loop of henle and reabsorption of other ions occurs the urea becomes even more concentrated. This recirculation can occur several times and steadily increases urea

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concentration in the medullary tissue until equilibrium is reached. The overall aim of this recirculation is to excrete a high concentration of urea in very little water.

- WEAK ACIDS AND BASES—Example of NON-IONIC DIFFUSION o Eg salicylic acid (HA) and its conjugate base, salicylate (A)

At acidic urine pH, HA predominates, there is more “back-diffusion = resorbtion” from urine into blood, and the excretion (and clearance) of salicylate is decreased.

At alkaline urine pH, A- predominates, there is less “back-diffusion = resorbtion” from urine to blood, and the excretion (and clearance) of salicylate is increased.

o Ie recall pharma aspirin (salicylic acid is the active metabolite of aspirin) can make urine alkaline to increase excretion

[ie y axis is just clearance but given per unit GFR here as this would also affect OVR clearance]

- Sites of Na reabsorbtion: o See image below: this is the reason for the potency order being loop>thiazide>K

sparing

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- Sites of K+ resorption:

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- PROXIMAL CONVOLUTED TUBULEo PTH inhibits Na/phosphate cotransport [recall from endo notes that PTH inhibits

Na/phosphate cotransport PROXIMAL CONVOLUTED TUBULE: ie at NaPi IIa]o Angiotensin II stimulates Na-H exchanger on lumen side [ie stimulates Na

reabsorption and H excretion which is coupled to bicarbonate reabsorption]o Ie as below the Na/H exchanger and HCO3- transport are reflecting carbonic

anhydrase activity on lumen side (to give CO2 passage inside) and CA activity inside the cell to give H & HCO3- for these transport events

o Note that once Na passes out Cl- will follow via paracellular mech as lumen becomes more negatively charged; see below pic

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[ie whole carbonic anhydrase system is at early PCT]

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- Thick Ascending Limbo Note that ADH stimulates Na-K-2Cl cotransport out of tubules but prob is a minor

effect as should be equating ADH effects as movements of H2O onlyo loop diuretics

are anions that attach to the Cl-binding site of the Na -K-2Cl cotransporter as on prev diagram loop diauretics will therefore have the capacity to block

up to 25% of Na reabsorption Na is extruded from the cell by the Na-K ATPase Cl and K diffuse through channels in the basolateral membrane, down their

respective electrochemical gradients. Small amount of K recycles back to lumen to make the system electrogenic;

helps drive Ca and K reabsorption further down lumen

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- Early Distal tubule:o Is the site of Ca reabsorption stimulated by PTHo Thiazide diuretics bind to the Cl site of the electroneutral Na –Cl cotransportero Cl diffuses through channels in the basolateral membrane

[ie NaCl entry!!]

- Late distal tubule and collecting ducts:o The principal cells

are involved in water and urea reabsorption (stimulated by ADH ie at principal cells)

are involved in Na reabsorption (stimulated by aldosterone) and K secretion (stimulated by aldosterone)

The K permeability and the size of the electrochemical gradient for K are higher in the luminal membrane; therefore, most of the K diffuses across the luminal membrane rather than being recycled across the basolateral membrane into the blood.

The single most important principle for understanding the factors that alter K+ secretion is that the magnitude of K secretion is determined by the size of the electrochemical gradient for K across the luminal membrane.

Effect of diet (&visa versa): high K+ diet: The ingested K enters the cells (aided by the insulin response to a meal) and raises the electrochemical driving force for K secretion across the luminal membrane and so the ingested K is excreted into the urine.

Aldosterone: increases electrochemical gradient to favour K+ exit to urine via increasing NA/K pump activity

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Acid-base disturbances: alkalosis increases K secretion, and acidosis decreases K secretion (ie due to the universal H/K exchanger on cells including at principal cells

Diuretics: [is by increasing the intracellular K concentration and by decreasing the luminal K concentration]

o Loop diuretics and thiazide diuretics inhibit Na reabsorption “upstream” to the site of K secretion (in the thick ascending limb and in the early distal tubule, respectively), thereby delivering more Na to the principal cells. When more Na is delivered to the principal cells, more Na enters the cells across the luminal membrane, and more Na is extruded from the cells by the Na-K ATPase. Simultaneously, more K is pumped into the cells, which increases the intracellular K concentration and increases the electrochemical driving force for K secretion.

o A second factor contributing to the increased K secretion is the increased flow rate produced by these diuretics. When the flow rate through the late distal tubule and collecting duct increases, the luminal K concentration is diluted, which increases the driving force for K secretion.

o Loop diuretics (but not thiazide diuretics) also cause increased K excretion by inhibiting Na-K-2Cl cotransport and, as a result, K reabsorption in the thick ascending limb

Luminal anions. The presence of large anions (e.g., sulfate and HCO3) in the lumen of the distal tubule and collecting duct increases K secretion. Such nonreabsorbable anions increase the electronegativity of the lumen, thereby increasing the electrochemical driving force for K secretion

ARE NOT WHRE THIAZIDES ACT K–sparing diuretics (ie counter aldosterone K+ loss to compensate for K+

loss caused by diauretics acting elsewhere): Amiloride and triamterene bind to the luminal membrane Na

channels and inhibit the aldosterone induced increase in Na reabsorption.

Spironolactone (aldosterone-antagonist but can also be classed as a potassium-sparing diuretic), prevents aldosterone (also is steroid-based) from entering the nucleus of the principal cells

o The α-intercalated cells are involved in K reabsorption in exchange for H+ in the condition of a low

K diet (prob a minor physiological event) at separate transporter the cells are involved in H+ secretion driven by

aldosterone

o The principal cells:

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o The α-intercalated cells:

- Na regulation:o Sympathetic nerve activity (inc filtering)

Sympathetic activity is activated by the baroreceptor mechanism in response to a decrease in arterial pressure

Causes: vasoconstriction of afferent arterioles and therefore reduced GFR

( inc Na retained) increased proximal tubule Na reabsorption due to the slower flow in

the tubules ( inc Na retained) o Atriopeptin (ANP) [and brain natriuretic peptide (BNP)] (inc filtering)

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ANP is secreted by the atria in response to an increase in ECF volume Causes:

vasodilation of afferent arterioles, vasoconstriction of efferent arterioles, increased GFR ie greater gross Na/H2O filtered; subsequent

reabsorbtions are just percentages so greater OVR gross losses decreased Na reabsorption in the late distal tubule and collecting

ducts (prob due to the reduced RBF giving reduced refreshing of blood)

o Starling forces in peritubular capillaries (dec reuptake) increases in ECF volume dilute πc (ie reduced oncotic pressure) and

therefore inhibit proximal tubule Na reabsorptiono Renin-angiotensin-aldosterone system (dec reuptake)

Activated in response to decreased arterial pressure

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- Potassium regulation:o Causes of K+ Shift Out of Cells / Hyperkalemia

Insulin deficiency (due to acidosis and because insulin usually directly stim K uptake due to having just had meal)

b2-Adrenergic antagonists (dec K/Na pump action) a-Adrenergic agonists (just learn) Acidosis / Exercise (H/K exchanger at all cells) Cell lysis: K+ is an intracellular ion! Hyperosmolarity (ie of ECF)

If the osmolarity of ECF is increased, water will flow from ICF to ECF because of the osmotic gradient. As water leaves the cells, the intracellular K concentration increases, which then drives the diffusion of K from ICF to ECF.

(A simpler way of visualizing the mechanism is to think of water flow from ICF to ECF as “dragging” K with it.)

o Causes of K+ Shift into Cells / Hypokalemia Insulin b2-Adrenergic agonists (inc K/Na pump action) a-Adrenergic antagonists (just learn) Alkalosis (H/K exchanger at all cells) Hyposmolarity

Reverse mech to above; water moving into cells will dilute the K+ present there thereby setting up grad for more to move in

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- Phosphate regulation:o Only Phos unbound to plasma proteins is ultrafiltrateableo reabsorption is accomplished by an Na-phosphate cotransporter in the luminal

membrane of the proximal convoluted and straight tubule cellso The relatively high level of phosphate excretion is physiologically important because

unreabsorbed phosphate serves as a urinary buffer for H+

- Calcium regulation:[loop diuretics give risk of hypocalcaemia BUT risk of hypercalcaemia with thiazides!!]

o Only Ca unbound to plasma proteins is ultrafiltrateableo Ca2 reabsorption is tightly coupled to Na reabsorption in the proximal tubule and

loop of Henle; DHTK mech for this but think of as the Na pulling the Ca through with it: consequence is that if body / drugs are trying to expel Na at these locations

Ca will be excreted at high levels too eg loop diuretics give risk of hypocalcaemia

o Only in the distal tubule is the reabsorption of Na and Ca dissociated: ie drugs / physiology act independently on the two ions here: in fact the

reverse relationship exists!: thiazides which INHIBIT Na reuptake will

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STIMULATE Ca reabsorbtion (ie risk of hypercalcaemia with thiazides): By lowering the sodium concentration within the distal tubule epithelial cells, thiazides increase the activity of the Na+/Ca2+ antiporter on the basolateral membrane to transport more Ca2+ into the interstitium.

PTH gives inc Ca reabsorbtion at distal tubule but will not affect Na uptake

- Magnesium regulation:o Main site of reabsorption is the thick ascending limbo Frusemide will inhibit Mg reabsorption at thick ascending limb

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- ANTIDIURETIC HORMONE:- As described in the preceding section, ADH has three actions on the renal tubule [but note

that the hormone does have other effects; see endocrinology for full detail]:o (1) It increases the water permeability of the principal cells of the late distal tubule

and collecting ducts. o (2) It increases the activity of the Na-K-2Cl cotransporter of the thick ascending limb,

thereby enhancing countercurrent multiplication and the size of the osmotic gradients to aid water retention.

o (3) It increases urea permeability in the inner medullary collecting ducts (principal cells; UT-A1 transporters), enhancing urea recycling and therefore giving greater urea concentration in urine and eventual excretion in a smaller volume of water

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[nb ADH is acting at V2 receptors]

Summary- Total body water is distributed between ICF and ECF. As percentages of body weight, 60% is

total body water, 40% is ICF, and 20% is ECF. ECF consists of plasma and interstitial fluid. Volumes of the body fluid compartments are measured by dilution of marker substances.

- ECF and ICFosmolarity are always equal in the steady state. When there is a disturbance of body fluid osmolarity, water shifts across cell membranes to re-establish the equality of ECF and ICF osmolarity. These shifts produce changes in ECF and ICF volume. Renal clearance is the volume of plasma cleared of a substance per unit time and is determined by its renal handling. Substances with the highest clearances are both filtered and secreted. Substances

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with the lowest clearances either are not filtered or are filtered and subsequently reabsorbed. Inulin is a glomerular marker whose clearance equals the GFR.

- RBF is autoregulated over a wide range of arterial pressures by changes in the resistance of the afferent arterioles. Effective RPF is measured by the clearance of PAH, and RBF is calculated from the RPF.

- GFR is determined by the permeability of the glomerular capillary barrier (Kf) and the net ultrafiltration pressure. Net ultrafiltration pressure is the sum of three Starling pressures across the glomerular capillary: PGC, pGC, and PBS. If any of the Starling pressures change, net ultrafiltration pressure and GFR are altered.

- Reabsorption and secretion modify the ultrafiltrate that is produced by glomerular filtration. The net reabsorption or secretion rate of a substance is the difference between its filtered load and its excretion rate. Glucose is reabsorbed by a Tm limited process: When the filtered load of glucose exceeds the Tm, then glucose is excreted in the urine (glucosuria). PAH is secreted by a Tm-limited process.

- Na reabsorption is greater than 99% of the filtered load and occurs throughout the nephron. In the proximal tubule, 67% of the filtered Na is reabsorbed isosmotically with water. In the early proximal tubule, Na is reabsorbed by Na-glucose cotransport, Na –amino acid cotransport, and Na-H exchange. In the late proximal tubule, NaCl is reabsorbed. ECF volume expansion inhibits proximal tubule reabsorption, and ECF volume contraction stimulates it. In the thick ascending limb of the loop of Henle, a water-impermeable segment, 25% of the filtered Na is reabsorbed by Na-K-2Cl cotransport. Loop diuretics inhibit the Na-K-2Cl cotransporter. In the distal tubule and collecting ducts,8%of the filtered Na is reabsorbed. In the early distal tubule, the mechanism is Na-Cl cotransport, which is inhibited by thiazide diuretics. In the late distal tubule and collecting ducts, the principal cells have aldosterone-dependent Na channels, which are inhibited by K-sparing diuretics.

- K balance is maintained by shifts of K across cell membranes and by renal regulation. The renal mechanisms for K balance include filtration, reabsorption in the proximal tubule and thick ascending limb, and secretion by the principal cells of the late distal tubule and collecting ducts. Secretion by the principal cells is influenced by dietary K aldosterone, acid-base balance, and flow rate. Under the conditions of low K intake, K is reabsorbed by a-intercalated cells of the distal tubule.

- Body fluid osmolarity is maintained at a constant value by changes in water reabsorption in the principal cells of the late distal tubule and collecting duct. During water deprivation, ADH is secreted and acts on the principal cells to increase water reabsorption. During water drinking, ADH secretion is suppressed, and the principal cells are impermeable to water.

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BONUS info:

- To investigate diabetes mellitus biopsy: use electron microscopy to look for glomerular basement membrane (GBM) thickening

o Diabetes causes Glomerulosclerosis: refers to a thickening and hardening (scarring) of the glomerulus

- Mesangial cells are specialized smooth muscle cells and are one contributor to control of GFR

- Extraglomerular mesangial cells: the fibroblasts that secrete EPO are in amongst these cells

- the kidney consists of three main layers: the cortex, medulla (together called the parenchyma) and pelvis

- imaging is used to investigate pre-renal and post-renal problems but not renal problems

- renal problems: Light microscopy, electron microscopy and immunohistochemistry are the three major modalities for investigating renal problems ie post-biopsy

- to investigate immune complexes: all three modalities can be used but only light microscopy for larger deposits

- despite Costanzo diagram K+ is regulated in the distal tubule

- Total glomerular filtrate is 180 litres per day in a healthy individual

- In cases of reduced blood pressure local nitric oxide and prostaglandins are released in the renal arteries to allow maintenance of renal blood flow over a range of blood pressures

- Gitelman syndrome: This mild disease is caused by inactivation of the sodium chloride co-transporter of the distal convoluted tubule

- Cells on lumen side of nephrons can be called parietal cells: eg Aldosterone increases numbers of sodium channels on parietal cells of the cortical collecting duct

- Acute renal failure:

o Pre-renal failure and acute tubular necrosis contributes towards >80% of cases of ARF.

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Common causes of pre-renal failure (40-70%) include renal hypoperfusion (Reduction of renal blood flow).

ATN (10-50%) is the damage to renal tubular cells by immune reactions or nephrotoxins, for example antibiotics and radiological contrasting agents.

o Heart problem is a common trigger via pre renal failure mech: Renal hypoperfusion is the leading cause of ARF. commonly caused by

congestive heart failure, cirrhosis and renal artery stenosis.o Pulmonary oedema is a common complication of ARF (prob via failure of excretion

of fluid), and both can be caused by congestive heart failure or sepsis. o Impaired potassium excretion is commonly observed in ARF patients, which leads to

elevated serum potassium level, i.e. hyperkalaemia.

- Hyperkalaemia: intravenous calcium can be used to correct the condition [think of as giving Ca to stop the K+ induced bradycardia]

- Pseudohypoaldosteronism

o is a condition that mimics hypoaldosteronism. However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback inhibition.

o there are two independent forms of PHA with different inheritance patterns: T1: Renal form with autosomal dominant inheritance exhibiting salt loss

mainly from the kidneys thiazide unresponsive T2: multi-system form with autosomal recessive form exhibiting salt loss

from kidney, lung, and sweat and salivary glands thiazide responsive

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