Outline of Renal Physiology

Volume

1 rev. 200117.01

Renal Physiology Outline for Medical Students legroj.net

Dr. Legier V. Rojas

Essential Concepts IMPORTANT: This OUTLINE of RENAL PHYSIOLOGY is a compendium of topics needed in the first contact with the renal physiology. This outline includes basic elements in chapters. It was decided to do it as an e-book for easy reading. Remember that this outline is only a summary not a textbook.

Bibliography Recommended Medical Physiology – Principles of Clinical Medicine by Rhoades & Bell, 4th Ed. Part VI: Renal Physiology and Body Fluids Chapter 22: Kidney Function (pgs. 399-426) Chapter 23: Regulation and Fluid and Electrolytes (pgs. 427- 450) Chapter 24: Acid-Base Homeostasis (pgs.451-470) https://amzn.to/2oRKxZh Complimentary • Koeppen BM. & Stanton BA. (2013) Renal Physiology. 5th edition. Mosby.

• Vander’s Renal Physiology, (2018) 9th edition, by Douglas C. Eaton, John P. Pooler • Costanzo LS. (2019) BRS (Board Review Series) Physiology. Seventh edition. Walters Kluger.

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Website See complimentary material in the “legroj” website: http://www.legroj.net

Renal Physiology and Acid-Base Lectures Schedule (2020)

January 17, 2020

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Table of Contents (Click on the title. Each title is linked to the topic)

Renal Physiology ____________________________________________________ 0 Renal Physiology Lectures and Exam Schedule ____________________________ 2 Table of Content ____________________________________________________ 3 Body Fluids ________________________________________________________ 4 The Kidney: functional anatomy ________________________________________ 6 GFR & Clearance ____________________________________________________ 8 The relationship between PAH clearance ________________________________ 21 Tubular Transport Mechanism ________________________________________ 22 Regulation of Effective Circulating Volume and NaCl Balance________________ 29 Regulation of Potassium Balance ______________________________________ 33 Regulation Calcium and Phosphate Balance _____________________________ 38 Diuretic Action_____________________________________________________ 44 Index ____________________________________________________________ 44 Normal Laboratory Values ___________________________________________ 56 Traditional Units REFERENCE RANGE ___________________________________ 56 REFERENCE INTERVAL _______________________________________________ 56 Table conversions __________________________________________________ 56

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Body Fluids Objectives Upon completing this lecture the student should be able to answer the following questions

1. How the body fluid compartments differ with respect to their volumes and ionic composition?

2. What are the driving forces responsible for movement of water across cell membranes and the capillary wall?

3. How do the volumes of the intracellular and extracellular compartments change under various pathological conditions?

The required basic concepts are:

a. b. c. d.

Molarity and equivalence Osmotic pressure Osmolarity and osmolality Tonicity and Osmoticity

Guide of subjects: 1. Physicochemical Properties of the Electrolyte in Solution: Molarity and equivalence, Osmosis and Osmotic Pressure, Tonicity, Osmoticity, Oncotic Pressure, Specific Gravity 2. Volume of the Body Fluid Compartments Total Body Water (TBW) = 0.6 x Body weight Intracellular Fluid (ICF) = 0.4 x Body weight Extracellular Fluid (ECF) = 0.2 x Body weight Interstitial Fluid (ISF) = 0.15 x Body weight Plasma (P) = 0.05 x Body weight 3. Composition of the Body Fluid Compartments: ECF (in mEq/Lt): 145 Na+, 4 K+, 5 Ca++, 105 Cl-, 25 HCO3-, 2 Pi; pH=7.4 ICF (in mEq/Lt): 12 Na+, 150 K+, 0.001 Ca++, 5 Cl-, 12 HCO3-, 100 Pi; pH=7.1 Plasma Osmolality = 2[Na+]P + [glu]/18 + [BUN]/2.8 4. Fluid Exchange between Body Fluids Compartments.

Capillary Fluid Exchange: Fluid Movement = Kf [(Pc-Pi)-(c - i)] Filtration Coefficient (Kf) Hydrostatic Pressures (Pc, Pi) Oncotic Pressures (c, i) Cellular Fluid Exchange:

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Osmotic pressures ICF, ECF, and water.

Addition of Isosmotic NaCl to the ECF, other insulting conditions, etc.

Darrow-Yannet diagrams, handle of body fluids under imbalance.

Key words: Molarity, Equivalence, Osmosis, Osmotic pressure, van’t Hoff law, Osmolarity and osmolality, Oncotic pressure, Tonicity, Osmoticity, Specific gravity, effective and ineffective osmole, total body water, intracellular fluid, extracellular fluid, Interstitial fluid, Plasma, capillary fluid exchange, Starling Forces, Capillary filtration coefficient (Kf), cellular fluid exchange. Darrow-Yannet Diagrams.

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The Kidney: functional anatomy Objectives Upon completing this lecture the student should be able to answer the following questions

1. Which structure in the renal corpuscle are filtration barriers to plasma proteins?

2. What is the physiologic significance of the juxtaglomerular apparatus?

3. What are the nephron types?

4. How the nephron structural segments are organized to supply an efficient function?

The required basic description are:

a. What the blood vessels supply the kidney? b. What nerve innervates the kidney? c. How the urinary bladder stores urine and eliminates it from the body?

Guide of subjects: 1. Structure of Kidney: Gross Anatomy: Cortex, Medulla.

Nephrons.

Renal Pyramids. Pelvis.

Major and Minor calyces.

Urinary Bladder.

Interlobar, Arcuate, Interlobular Arteries.

Afferent and efferent arterioles.

Glomerulus.

2. Ultrastructure of the Nephron: Renal Corpuscle.

Glomerullar capillaries.

Bowman’s Capsule Proximal Tubule.

Henle’s loop Descending and Ascending Thin Limb.

Thick Ascending Limb.

Macula Densa.

Distal Tubule.

Cortical, Outer Medullary and Inner Medullary Collecting Duct.

3. Superficial and Juxtamedullary Nephrons: Characteristics.

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4. Renal Corpuscle in detail: Epithelial cells (Podocytes).

Visceral and Parietal Layers.

Bowman’s Space.

Filtration Barrier.

Endothelial Cells.

Basement Membrane.

Podocytes Foot Processes.

Glycoprotein.

Filtration Slits.

Mesangium Mesangial Cells.

Mesangial Matrix.

5. The Juxtaglomerular Apparatus in detail: Macula Densa of the Thick Ascending Limb.

Extraglomerular Mesangial cells.

The Renin-Producing Granullar Cells of the afferent and efferent arterioles.

6. Innervations of the Kidney: Sympathetic nerve (orig. celiac Plexus).

Adrenergic fibers.

Key words: Cortex. Nephrons. Pelvis. Major and Minor calyces. Urinary Bladder. Glomerular Capillaries. Peritubular Capillaries.

Glomerulus. Henle’s loop. Collecting Duct System. Bowman’s Space. Superficial Nephrons. Vasa Recta. Filtration Slits.

Filtration Barriers. Mesangial Cells. Juxtaglomerular Apparatus. Renal Corpuscle. Proximal Tubule. Distal Tubule.

Bowman’ Capsule. Macula densa. Ultrafiltration. Mesangium. Podocytes.

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GFR & Clearance

Objectives Upon completing this lecture the student should be able to answer the following questions

1. How can the concepts of mass balance be used to measure the Glomerular Filtration Rate (GFR) and Renal Blood Flow (RBF)?

2. Why can Inulin Clearance and Creatinine Clearance be used to measure the Glomerular Filtration Rate (GFR)?

3. Why can p-aminohippuric acid (PAH) clearance be used to measure Renal Plasma Flow (RPF)?

4. What are the factors that determine which molecules cross the Glomerulus and enter the Bowman’s space?

5. Why do loss negative charges on the glomerulus result in proteinuria (loss of protein in the urine)?

6. What Starling Forces are involved in the formation of the Glomerular ultrafiltrate and how do changes in each force affect the GFR? 7. What are Autoregulation of Renal Blood Flow (RBF) and GFR and which factors are responsible for autoregulation?

8. What hormones regulate RBF? 9. Why do hormones influence RBF despite autoregulation?

The three major mechanisms of the kidney Ultra-filtration occurs in the renal glomerulus. Most substances are separated from the blood plasma, with the exception of cells and large proteins.

Reabsorption of useful substances from the glomerular filtrate occurs in the renal tubules.

Secretion occurs directly into the renal tubule for elimination in the urine of additional substances.

Structures and properties of glomerular Membrane The filtration barrier: filtration barrier of the glomerular capillaries consists of three major elements.

Endothelial cells: line the inside of the glomerular capillary.

Basement membrane of the capillary itself.

Epithelial cells or podocytes containing foot process projections that lie on the outside of the capillary in the urinary space of Bowman’s capsule.

The layers of the filtration barrier are up to 1000 times more porous than other capillaries, and exclude only large substances, such as cells and large proteins, primarily by size and charge.

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The endothelium: The nuclei of the endothelial cells are usually found in an area of the basement membrane that is attached to the mesangium. The remainder of each cell is distributed around the inner wall of glomerular capillary. The endothelial cell cytoplasm becomes quite thin and contains ~100 nm pores called fenestrae. Thin single membranes, possibly of a protein-polysaccharide film, cover these fenestrae. These are highly permeable, and do not pose a significant barrier to the movement of even large molecules Basement Membrane: The basement membrane of the glomerular capillary consists of Fig. 3.1. Cellular components of the renal glomerulus

Fig. 3.2. Glomerulus schematic diagram

three layers, but these layers do not contain pores. In the middle of the basement membrane is a dense inner layer called the lamina densa. The lamina densa separates two thinner layers, the lamina rara interna, next to the capillary lumen, and the lamina rara externa next to the urinary space. The lamina densa is made of type IV collagen, which selectively filters molecules between the fibers based on molecular size. The lamina rara layers contain heparin-sulfate, a polyanionic molecule that may act as a charge barrier to molecules such as negatively charged proteins.

Epithelium, cell types: Two types of epithelial cells are found within the urinary space of Bowman’s capsule. The first of these are the parietal epithelial cells that line the inside of the capsule. These cells are not part of the filtration barrier. The second type of epithelial cells is the visceral epithelial cells or podocytes, which are the largest of the cells in the glomerulus. Extending from the main cell body of the podocytes are primary processes from which pedicels or foot processes extend and actually contact the lamina rara externa of the basement membrane. Additional pedicels also arise from secondary and tertiary processes.

Epithelium filtration slits: The distance between pedicels in the normal glomerulus is approximately 25 nm (25x10-9 m). This region is referred to as a slit pore or filtration slit. A thin membrane covers the area of the slit pore, but does not offer much resistance to filtered substances. This membrane is similar to the membrane seen across the pores in the fenestrated glomerular endothelial cells. Pedicels from one cell are seen on many different capillary basement membranes. The

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adjacent pedicels from any one podocyte alternate with the pedicels arising from different cells.

Renal Clearance Definition and Calculation:

The clearance (C) of a substance (N) is defined as the volume of plasma that is completely depleted of N by the kidneys per unit time, usually in minutes. Clearance can be calculated from the amount of N excreted in urine (UN x V) in one minute over the concentration of N in the plasma (PN).

In the formula CN is clearance of substance N, UN is the concentration of N in the urine (mg/ml); V is the volume of urine produced per minute (ml/min) also denominated urine flow rate; and PN is the concentration of N in the plasma (mg/ml). Knowing this, the amount of N (mg) excreted in the urine per minute is the product of U N and V. The clearance of the substance N (CN) is the “virtual� volume of plasma completely cleared of N per unit of time.

The virtual volume: The calculation of the clearance of a substance is based on the assumption that the plasma could be completely cleared of that substance in one passage through the kidney. This is not usually the case. Some amount of most substances remains in the plasma as the blood leaves the kidney. The calculation of clearance tells us the virtual volume of plasma cleared of the substance by assuming that the plasma delivers all of the substance in one passage.

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Renal Clearance: Relationship to Glomerular Filtration Clearance (C) values are not only determined by the amount of a substance filtered by the glomerulus, but also include the amount secreted by the tubules minus the amount reabsorbed by the tubules. For this reason every substance has a clearance value uniquely representing its filtration, reabsortion, and secretory properties. Where no secretion or resorption of the filtered substance occurs, clearance of that substance may be used to determine the glomerular filtration rate (GFR). The GFR is defined as the volume of plasma filtered by all the glomeruli in a given period of time. In the normal adult male, the GFR is equal to ~125 ml/min.

In the normal adult female the GFR is 10% less. At this GFR, ~180 L of fluid are filtered in 24 h. Urine output, however, is only about 1 L per day. From these values it may be assumed that 99% of the glomerular filtrate is reabsorbed by the renal tubules.

Characterization of the Glomerular Filtration Rate The GFR depends of the same factors that contribute to filtration across the glomerular capillary wall (see Equation) and studied in the Cardio Lectures. These elements are essentially the same as that affecting movement across the other capillary in the body (Starling Forces) previously defined.

GFR = K f (PGC − PBS ) − (GC − BS ) Where: Kf Coefficient of ultrafiltration PGC Glomerular capillary hydrostatic pressure PBS Bowman’s space hydrostatic pressure GC Glomerular capillary oncotic pressure BS Bowman’s space oncotic pressure Measure of GFR For a substance that has the same concentration in both the glomerular filtrate and plasma, and that is neither secreted nor reabsorbed by the renal tubules. The amount of that substance excreted in the urine per minute must equal the amount of that substance filtered (filter load) by the glomerulus per minute (GFR). This is expressed in next formula:

GFR = UN 

V PN

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Amount filtered = Amount excreted Amount filtered = GFR x PN (Filtered Load) Amount excreted = (UN) x V (Excretion Load) Inulin infusion: As a necessary requirement the substance used to evaluate and/or calculate GFR must meet certain criteria.

A) After injection the substance must be found in equal concentration in plasma and glomerular filtrate.

B) The substance must be neither secreted nor reabsorbed by the renal tubules.

C) The substance must be nontoxic, nor metabolized, and easily measured.

The carbohydrate INULIN meets all these conditions. However, their limitations are that it is not very easy to measure and, to give accurate result, it must be infused constantly to establish a stable plasma concentration and rate of excretion.

D) Creatinine is used to estimate The GFR in clinical practice.

Factors affecting the GFR Renal Blood flow and Hydrostatic pressure GFR is not affected by plasma concentration but is affected by the rate of blood flow through the kidney (Fig.3.3, Table 3-1).

Changes in glomerular capillary hydrostatic pressure due to changes in systemic blood pressure or arteriolar constriction (both afferent and efferent) Fig.3-3. Starling forces involved in glomerular also alter GFR. Increased ultrafiltration hydrostatic pressure within Bowman’s capsule, due to conditions such as kidney edema or ureter obstruction, can also alter GFR significantly.

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Table 3.1 Forces involved in Filtration in the Nephron Afferent end of glomerular capillary (mm Hg) Forces favoring filtration Glomerular capillary hydrostatic pressure 60 Bowman’s capsule oncotic pressure 0 total 60 Forces opposing filtration Bowman’s capsule hydrostatic pressure Glomerular capillary oncotic pressure total

15 21 36

Efferent end of glomerular capillary (mm Hg) 58 0 58

15 33 48

Avg. glomerular filtration Pressure = 24 mm Hg.

Plasma protein concentration: GFR can be affected by conditions that alter plasma protein concentration (Pr) changes the plasma colloid osmotic pressure or oncotic pressure. Disease such as hypoproteinemia, resulting from malnutrition or liver diseases (producing impaired protein production) can affect GFR. Conditions producing dehydration increase Pr due to loss of water from the ECF. The augment in plasma Pr hinders glomerular capillary filtration rate (GFR).

Filtration Coefficient Kf Kf depends on the glomerular capillary permeability and the glomerular capillary area. Changes in permeability of glomerular capillary occur in both natural and diseases states, such as diabetes mellitus. Permeability changes can affect GFR by changing the filtration coefficient, Kf. Glomerular capillary area is regulated primarily by the mesangial cells containing myofilaments that can contract and relax and therefore influence the capillary surface area by opening and closing the glomerular capillaries. Two hormones; antidiuretic hormone and angiotensin II, are capable of causing mesangial cell to contract and thus reduce filtration surface area and Kf.

Renal Blood Flow (RBF) The blood flow through both kidneys of the average adult male equals slightly more than 20% of the total cardiac output, or approximately 1200 ml/min. This large blood flow clearly is not related to the metabolic needs of the kidneys but is a function of the major roles that kidneys play in regulating blood volume and the plasma concentration of ions and other solutes. From this 20% of the cardiac output 90% of the renal blood flow is distributed to the cortex region and the remaining 10% to the medulla: 8% distributed to the outer medulla and 2% inner medulla.

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Perfusion Pressure and Vascular Resistance Renal Blood Flow (RBF) depends of the pressure difference between the afferent arteriolar and efferent arteriolar and of the vascular bed (P), and the vascular resistance of that bed (R).

Q = RBF =

P R

Fick Principle in measuring RBF The amount of a substance removed from the circulation by the kidney per unit time is equal to the difference between the arterial and venous concentrations of the substance times the blood flow. RBF can be calculated measuring the amount of a given substance excreted by the kidney and dividing this value by the arteriovenous difference in the amount of this substance. The substance should be not sequestered, manufactured, or metabolized by the kidney.

X URINE = ( X A  − X V ) RBF

RBF =

XURINE (X A  − X V )

Clearance of PAH Para-aminohippuric acid (PAH): PAH is a substance that is both filtered and secreted but not reabsorbed or metabolized by the kidneys.

The Effective Renal Plasma Flow (ERPF): ERPF can be estimated using PAH at low doses. PAH at low doses has an extraction ratio of about 90% after a single passage through the kidneys. This means that approximately 90% of PAH is removed from the blood. The clearance of PAH

ActualRBF =

ERBF ExtrationRatio

measures what is called Effective Renal Plasma Flow (ERPF).

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That means that an RPF measure with PAH is a fraction of the total RPF that perfuse functional portions of the nephron. Once ERPF is measured by the PAH clearance the Actual Renal Blood Flow can be calculated from the relationship:

RBF =

RPF (1 − Htc )

Filtration Fraction The Filtration Fraction (FF) is the percentage of plasma volume that is filtered through the glomerular capillary membrane to become glomerular filtrate.

FF represents about 20% of the plasma volume passing through the kidneys (180 L/day).

The average adult produces a urine volume of 1 to 2 L in the same period. This means that greater than 99% of the filtrated must be reabsorbed by the tubules.

Evaluating FF: To calculate the FF it is necessary to know the renal plasma flow (RPF), and the GFR. Renal plasma flow is determined by measuring the clearance of PAH.

FF =

GFR RPF GFR is calculated by inulin clearance RPF is calculated by PAH clearance

Autoregulation of Renal Blood Flow The kidney, like many other organs, exhibits autoregulation over a fairly broad range of arterial pressures.

Autoregulation: Is defined as the ability of an organ, in this case the kidney, to maintain blood flow (Q) during changes in perfusion pressure (P).

To maintain Q the P in the vascular resistance should be change according to the relationship discussed earlier.

The kidney auto regulates in the range between 80-180 mm Hg. The meaning is that GFR remain relatively unchanged over the same range in pressure.

The arteriolar resistance considerably changes GFR. An increase in the afferent vascular resistance tends to reduce glomerular capillary hydrostatic pressure, while a reduction in the afferent vascular resistance tends to increase glomerular capillary hydrostatic pressure. This occurs because the glomerular capillaries are downstream from the resistance

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change. An increase in the efferent vascular resistance tends to increase glomerular capillary hydrostatic pressure, while a reduction in the efferent vascular resistance tends to decrease glomerular capillary hydrostatic pressure.

Mechanism responsible for Autoregulation: Those mechanisms are not clearly delineated. A mechanism resides entirely in the kidney and is not dependent on circulating hormones or neurogenic factors. A second mechanism resides in the mechanical properties of the smooth muscle.

Mechanism: Current evidence supports a role for two possible mechanisms by which afferent arteriolar resistance changes may vary with changes in perfusion pressure.

Myogenic mechanism.

This mechanism is based in the observations that smooth muscle contract in response to stretch. As blood vessel increase in size in response to pressure increases, the smooth muscle cells of the vasculature contract. This prevents a major increase in vascular wall tension in response to an increase in pressure, which could cause a rupture of the vessel.

Tubuloglomerular mechanism.

This mechanism is based on the premise that a change in perfusion pressure causes cells of the macula densa to secrete a vasoconstrictor substance. This, in turn, feeds back and alters afferent arteriolar vascular resistance. The macula densa detects changes in perfusion pressure by detecting changes in distal tubule NaCl concentration. The action of the vasoconstrictor substance on the afferent arteriolar vascular resistance is responsible for maintaining hydrostatic pressure within normal limits. The substance that alters vascular resistance in this proposed mechanism is closely related to the autoregulation of GFR. The effector mechanism may be adenosine or even a metabolite or arachidonic acid. Nitric oxide (NO), a vasodilator produced by the macula densa, may also play a role in the tubuloglomerular feedback, but is not essential to autoregulation.

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The nervous and endocrine regulation of RBF, Table 3-2. Major factors that influence GFR and RBF Stimulus

Effect on GFR

Effect on RBF

Sympathetic nerves

 ECV, shear stress





Angiotensin II Endothelin

 ECV, renin Shear stress, AII, Bk, epinephrine









Vasodilators: Prostaglandins

 ECV, shear stress, AII

NC



Nitric oxide

Shear stress, ACh, His, Bk, ATP

Bradyquinin

PG, ACE

 

 

Vasoconstrictors:

Fig.3-4. Examples of interaction of Endothelial cells with smooth muscle and mesangial cells

The Sympathetic Renal Nervous System: The renal arteries and arterioles are richly innervated by sympathetic fibers that secrete Norepinephrine at their terminals.

Renal sympathetic nerve stimulation increases renal vascular resistance in both afferent and efferent arterioles. This increased resistance decreases RBF. Because the action is on both afferent and efferent resistance, the effect on glomerular hydrostatic pressure, and therefore GFR, is not as great as the effect on Renal Plasma Flow (RPF). In general, sympathetic activity decreases the hydrostatic pressure in the glomerular capillaries and reduces GFR, but the reduction in GFR is less than the reduction in RPF. The main effects will be increases the Filtration Fraction (FF).

Action of vasoactive substances on the Renal Blood Flow (RBF) Many vasoactive substances also alter renal vascular resistance and, therefore, RBF. Examples are antidiuretic hormone (ADH), angiotensin II (AII), and various paracrine, in particular the prostaglandins (PGs).

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Effects of Angiotensin II (AII) AII is the most potent vasoconstrictor released in the body. It affects most vascular smooth muscle, including both afferent and efferent renal arterioles, to increase renal vascular resistance and reduce RBF. In general, renal efferent arterioles are more responsive to the AII than are the afferent arterioles. The initial net effect is on GFR, increasing the rate of filtration. Later on the administration of AII results in a decrease in GFR despite the differential effect on efferent and afferent arterioles, mainly because AII on the mesangial cells.

Mesangial effects of AII: The observed decrease of GFR in AII is due to the effect of AII on renal mesangial cell function. Mesangial cells constrict in response the AII producing a decreased Filtration Coefficient (Kf). It is this effect on Kf that accounts for the overall decrease in GFR. As a generalization, elevated levels of AII lead to increase vascular resistance and subsequent reduction in RBF, as well as a net decrease in GFR. The filtration Fraction (FF) increased simply because the fall in GFR is less than the fall in RPF

The action of ADH Extremely high doses of ADH have vasoconstrictor activity on many areas of vascular smooth muscle, including the afferent and efferent renal arterioles.

There is considerable debate about the importance of ADH in normal day-to-day influences on renal vascular resistance because of the doses required to elicit measurable changes in resistance. Under pathological conditions, such as hemorrhage and shock, ADH release from posterior pituitary is sufficient to elevate plasma ADH to level that causes vasoconstriction. Additionally, administration of ADH in high dose contracts glomerular mesangial cells to reduce the Kf of glomerular capillaries. The net effect, therefore, of ADH is to increase renal vascular resistance and contract mesangial cells thereby reducing GFR and RBF and, therefore, ADH can cause an increase in FF.

The action of prostaglandins Several prostaglandins affect renal vascular resistance. PGE2 and PGI2, are vasodilators that act primarily on the afferent arterioles. Other prostaglandins, such as TXA2, act as vasoconstrictors. The physiological role of these prostaglandins in regulation RBF is not fully understood. These prostaglandins are produced within the kidney and act directly on renal arteriolar smooth muscle.

Guide of subjects: 1. Mass Balance Concept: Mass Excreted = Mass Filtered – Mass Reabsorbed + Mass Secreted.

2. Renal Clearance: Concept: = CX = (UX · V) / PX

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4.

5.

6.

7.

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Mass Balance Concept.

Glomerular Filtration Rate (GFR): Clearance of Inulin.

Characteristics of Inulin.

Mass Balance.

Mass Excreted = Mass Filtered – Mass Reabsorbed + Mass Secreted.

(If Mass Reabsorbed = 0 and Mass Secreted = 0) CIN = GFR. UIN x V = GFR x PIN. Creatinine Clearance.

Relationship between Creatinine Plasma Concentration (PCR) and GFR. Filtration Fraction (FF): FF = GFR/RPF Renal Plasma Flow (RPF): Clearance of p-aminohippuric acid (PAH).

Mass Balance.

Mass Excreted = Mass Filtered – Mass Reabsorbed + Mass Secreted.

(If Mass Reabsorbed = 0 and Mass Secreted = “max”) CPAH = RPF. UPAH x V = RPF x PPAH. Effective Renal Plasma Flow (ERPF).

Renal Blood Flow (RBF).

RBF = RPF / (1-Htc) Glomerular Filtration: Determinant of Ultra filtrate Composition.

Dynamics of Ultrafiltration.

Starling Forces.

GFR = Kf [(PGC – PT) – (GC - T)] Changes in afferent and efferent arteriolar resistance.

Changes in Renal arteriolar Pressures.

Renal Blood Flow: Q = P/R. Relationships between RBF and GFR vs Arterial Blood Pressure Autoregulation Myogenic mechanism.

Tubuloglomerular Feedback.

Regulation of RBF and GFR. Sympathetic nerves.

Angiotensin II Prostaglandins.

Nitric Oxide (NO).

Endothelin.

Bradykinin

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8. Relationship between selective Changes in the resistance of either the afferent arteriole or efferent arteriole on RBF and GFR. 9. Major Hormones that influence GFR and RBF. Key words and concepts Clearance, Mass Balance, Inulin Clearance, Glomerular Filtration Rate (GFR), Creatinine, Creatinine Clearance, Filtration Fraction, p-aminohippuric acid (PAH), PAH Clearance, Renal Plasma Flow (RPF), Effective Renal Plasma Flow (ERPF), Hematocrit (Htc), Renal Blood Flow (RBF), Autoregulation, Starling Forces, Myogenic Mechanism, Tubuloglomerular Feedback, Sympathetic Nerves, Angiotensin II, prostaglandins, NO, endothelin, Bradykinin, and Adenosine.

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The relationship between PAH clearance and RPF is idealized.

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Tubular Transport Mechanism Objectives Upon completing this lecture the student should be able to answer the following questions

1.

2.

3.

4.

5.

6.

7.

The required basic concepts are:

a. b.

What the three processes are involved in the production of Urine?

What is the composition of the normal Urine?

What transport mechanisms are responsible for NaCl reabsorption by the nephron? Where are they located along the nephron?

How Water reabsorption “coupled” to NaCl reabsorption in the Proximal Tubule?

Why does the thick ascending limb of Henle’s loop reabsorb solutes, but not water?

What is the Glomerular balance, and what is its physiological importance?

What are the major hormones that regulate NaCl and water reabsorption in the kidneys? What is the nephron site of action of each hormone?

Mechanism of solute transport in the cellular membrane.

Starling Forces across the peritubular capillaries.

Urine Formation Plasma Ultrafiltration in the glomerulus.

180 L/day, but less than 1% is excreted in the urine.

By the reabsorption and secretion renal tubules modulates the volume and composition of the urine.

Water and solutes suffer Reabsorption from the ultra-filtrate.

Selected solutes are Secreted into the tubular fluid.

General principles of membrane transport.

Three mechanisms can be used: passive, active and endocytosis. Ion movement can be passive or active, whereas all water movement is passive. Remember terminology and concepts: passive transport (diffusion), solvent drag, facilitated diffusion, uniport, coupled transport, symport, antiport, secondary active transport, transport active, endocytosis.

General principles of transepithelial solute and water transport.

Tight junctions held renal cells to remain together. Between cells exist a lateral space denominated the intercellular space. Tight junction separates the apical membranes from the basolateral membranes.

Common Names used from Cell’s Membranes separated by tight junction Membrane inside the tubule Apical Luminal Tubular

Membrane outside the tubule Basolateral Contraluminal Contratubular

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In the nephron a substance can be flow out the tubular fluid (reabsorption) or inside the tubular fluid (secretion).

That movement can be occurring by the so-called transcellular pathway or between cells the so-called paracellular pathway (Fig. 41).

The transcellular pathway uses the two membrane of the cell. Those membranes are asymmetrical in terms of its transporter-molecule constituents.

Na+ reabsorption by the proximal tubule is a good example of transport by the transcellular pathway.

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Fig. 4-1. Routes for fluids and solutes movements in cells lining the tubules in the nephron.

NaCl, other solutes, and water reabsorption along the nephron Nephrons reabsorb 25,000 mEq/day of NaCl and 179 L/day of water.

Proximal tubule: reabsorb approximately 67% of filtered water, Na+, Cl-, K+ and other solutes, including glucose, amino acids.

The key element is the (Na+-K+)-ATPase in the basolateral membrane, because the reabsorption of every substance, including water is linked in some manner to this transporter.

Na+ reabsorption: transcellular Na+ reabsorption is produced by different mechanism in the segments early, and late of the proximal tubule. In the early segment is reabsorbed primarily with HCO3-, glucose, amino acid, Pi, lactate. In the late segment Na+ reabsorption is produced mainly with Cl-. Paracellular Na+ reabsorption occurs in the late proximal tubule is drive by Cl-. 17,000 of the 25,000 mEq of the NaCl filtered each day are reabsorbed in the proximal tubule (~67% filtered load).

Water reabsorption: In the proximal tubule 67% of the filtered water is reabsorb.

The driving force for water reabsorption is the trans-tubular osmotic gradient established by solute reabsorption. Water moves across the tight junction and the proximal tubular cells.

Protein reabsorption: Proteins that are filtered are also reabsorbed in the proximal tubule. Degradation of some proteins occurs in the proximal tubule, and proteins and fragments suffer endocytosis. Inside the cell fragments and proteins are degraded to amino acid by enzymes. Amino acids leave the cell across the

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basolateral membrane and are returned to the blood. Proteinuria (appearance of protein in the urine) is frequently observed with kidney disease.

Henle’s loop: 25% the filtered load of NaCl, and K+, is reabsorbed in the loop of Henle.

This reabsorption occurs almost exclusively in the thick ascending limb. In the Henle’s loop 15% of the water filtered is reabsorbed. This reabsorption occurs almost exclusively in the descending limb. The ascending limb is impermeable to water.

The key element of solute reabsorption by the thick ascending limb is the (Na+K+)-ATPase in the basolateral membrane; similar to the proximal tubule the reabsorption of every substance, including water is linked in some manner to this transporter.

The increased salt transport by the thick-ascending limb increases the magnitude of the positive voltage in the lumen and that voltage is an important driving force for the absorption of several cations including Na+, K+ and Ca++ across the paracellular pathway.

Because the thick ascending limb is impermeable to water, reabsorption of NaCl and other solutes reduces the osmolality of tubular fluid to less than 150 mOsm/kg water.

Distal tubule and collecting duct: 7% of the filtered load of NaCl is reabsorbed in the distal tubule. In that segment K+ and H+ are secreted in a variable amount (8-17%) and water reabsorption depends of the ADH plasma concentration.

In the early distal tubule segment Na+, Cl- and Ca++ are reabsorbed and like the thick ascending limb this segment is water-impermeable. NaCl entry across the apical membrane depends of the Na+-Cl- symporter. Na+ leaves the cell via (Na+K+)-ATPase and Cl- by diffusion across ion-channels.

Two cell types, principal cells and intercalated cells, compose the late distal tubule and the collecting duct. Principal cells reabsorb Na+ and water and secrete K+ intercalated cells secrete either H+ (reabsorb HCO3-) or HCO3- and are therefore important in regulating acid-base balance. Intercalated cells also reabsorb K+.

Regulation of NaCl and water reabsorption: Following table summarize each hormone, major stimulus, the site of action and the effect on the transport.

Hormones that regulates NaCl and water reabsorption Hormone

Major stimulus

Nephron site of action

Effect on transport

Angiotensin II PT  Renin  NaCl & water reabsorption Aldosterone TAL, DT?, CD  Angiotensin II,  [K+]p  NaCl & water reabsorption Atrial Natriuretic Peptide (ANP).

CD  BP,  ECV  NaCl & water reabsorption Urodilantin.

CD  BP,  ECV  NaCl & water reabsorption Sympathetic Nerves (Norepinephrine) PT, TAL, DT/CD  ECV  NaCl & water reabsorption Dopamine PT  ECV  NaCl & water reabsorption ADH DT, CD  POSM,  ECV  water reabsorption Abbreviations: PT=Proximal tubule, TAL=Tick Ascending Limb, DT=Distal Tubule, CD=Collecting Duct,

Angiotensin II: is one of the most potent hormones that stimulate NaCl and water reabsorption in the proximal tubule. A decrease in the extracellular fluid volume activates the renin-angiotensin-aldosterone system, increasing the angiotensin II concentration.

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Aldosterone: Synthesized in adrenal cortex. Aldosterone stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop and the distal tubule and collecting duct. Angiotensin II and increased [K+] level in the plasma stimulates the aldosterone secretion.

Atrial Natriuretic Peptide (ANP; 28 aa) and Urodilantin (32 aa): are codified by the same gene and have similar amino acid sequence. ANP is secreted by the cardiac atria and an increase in blood pressure and an increase in the extracellular fluid volume stimulate its secretion.

ANP decrease the peripheral resistance and enhance urinary NaCl and water excretion. ANP inhibits NaCl reabsorption by the medullary portion of the collecting duct, inhibit ADH-stimulated water reabsorption across the collecting duct and inhibits the ADH secretion from the posterior pituitary.

Urodilantin (U) is secreted by the distal tubule and collecting duct and is not present in the systemic circulation. U Is stimulated by a rise in blood pressure and an increase in the extracellular volume.

U secretion inhibits NaCl and water reabsorption across the medullary portion of the collecting duct. U is a more potent natriuretic and diuretic hormone than ANP. Sympathetic nerves release Norepinephrine and other catecholamine epinephrine released from the adrenal medulla, stimulates NaCl and water reabsorption by the proximal tubule, thick ascending limb of Henle’s loop, distal tubule, and collecting duct. Activation of sympathetic nerves is produced i.e. after hemorrhage.

Dopamine (D) is release from dopaminergic nerves in the kidneys and may be also synthesized by cells of the proximal tubule. D action is opposite to Nor-epinephrine and epinephrine. D secretion is stimulated by an increase in the ECV and its secretion directly inhibits NaCl and water reabsorption in the proximal tubule.

ADH antidiuretic hormone is the most potent hormone that regulates water balance. ADH is secreted by the posterior pituitary in response to an increase in plasma osmolality or a decrease in the ECV. ADH increases the permeability of the collecting duct to water.

Starling Forces regulates NaCl and water reabsorption Could you explain that?

Glomerulotubular balance: The importance of starling forces in regulating solutes and water reabsorption is underscore by the glomerulo-tubular balance (GT balance).

Spontaneous changes in GFR markedly alter the filtered load of sodium (FL = GFR x PNa). However spontaneous changes in GFR do not alter the Na + balance. The reason is that the GT balance.

Small changes in GFR could potentially lead to massive changes in Na+ excretion, if it were not for the phenomenon called glomerulotubular balance. GT-balance refers to the fact that when body Na+ balance is

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normal, Na+ and water reabsorption increase in parallel with an increase in GFR and FL of Na+. A constant fraction of FL of Na+ and water is reabsorbed from the proximal tubule despite variation in GFR. GT-balance reduces the impact of GFR changes on the amount of Na+ and water excreted in the urine.

Mechanism responsible for GT-balance are: Starling forces and Filtered load of glucose and amino acids.

Guide of subjects: 1. General Principles of Membrane Transport: Passive. (Down an electrochemical gradient, no energy requirement) Diffusion.

Facilitated Diffusion.

Channels.

Uniport.

Coupled Transport: antiport or symport Solvent drag.

Active. (Against an electrochemical gradient (requires direct input of energy).

Includes endocytosis.

2. General principles of Transepithelial Solute and Water Transport: Proximal Tubule Transcellular Pathway.

Paracellular Pathway.

NaCl, Solutes and Water reabsorption along the Nephron.

Na+ reabsorption.

Other solutes: HCO3-, Glucose, Cl-, Pi, Amino acids, Lactate.

Water reabsorption Comparative proportion of NaCl reabsorption along the nephron.

Comparative proportion of water reabsorption along the nephron.

Protein reabsorption.

Organic Anion and Organic Cations Secretion.

Henle’s Loop Ascendant Limb.

NaCl, K+, Ca++, HCO3-.

Tubular reduction in osmolality.

Descendent Limb.

Water reabsorption.

Distal tubule and Collecting Duct Early Distal Tubule Reabsorption of NaCl and Ca++

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Thiazide Diuretic (inh. Reab. NaCl) Last Segment of Distal Tubule and Collecting Duct Principal Cells Reabsorption of NaCl. Water reabsorption (f(ADH)) K+ Secretion Intercalated Cells.

Acid Base Balance: Secretion of either H+ or HCO3-.

K+ reabsorption.

3. Regulation of NaCl and Water Reabsorption: Hormones and Neurotransmitter that regulates NaCl and Water reabsorption Angiotensin II. Aldosterone.

Atrial Natriuretic Peptide (ANP).

Urodilantin.

Sympathetic Nerves.

Dopamine.

ADH Starling Forces Glomerulo-Tubular balance Filter Load of Glucose and AA Key words: Reabsorption. Secretion. Passive Diffusion. Facilitated Transport. Uniport, Symport, and Antiport.

Secondary active Transport. Active Transport. Endocytosis. Solvent Drag. Coupled Transport. Tight Junction. Lateral intercellular Space. Transcellular Pathway. Paracellular Pathway. Water Reabsorption is secondary to the solute transport. Glomerulo-tubular Balance. Starling Forces. Atrial natriuretic Peptide (ANP) and Urodilantin. Sympathetic nerves. Renin-Angiotensin-Aldosterone-System. Dopamine.

Antidiuretic Hormone.

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The osmolar clearance is:

It is possible to partition the total urine output in two hypothetical compartments: a. One contain all urine solutes and has an osmolality equal to that of plasma, and b. The volume of solute-free water c.

Free water clearance “water that is free of all solute� is calculated as:

When urine diluted is produced, Cwater is positive indicating that solute freewater is excreted from the body.

When concentrated urine is produced, Cwater is negative, indicating that solute free-water is retained in the body.

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Regulation of Effective Circulating Volume and NaCl Balance Objectives Upon completing this lecture the student should be able to answer the following questions

1.

2.

Why do changes in Na+ balance alter the volume of the ECF? What is the Effective Circulating Volume (ECV)? How is influenced by changes in Na+ balance, and how does it influence renal Na+ excretion?

3.

What is the mechanism by which the body monitors the Effective Circulating Volume (ECV)?

What are the major signals acting on the kidney to alter their excretion of Na+?

How do changes in Effective Circulating Volume (ECV) alter Na+ transport in each of the various portions of the nephron, and how do these changes in transport regulate renal Na+ excretion?

What are the roles mechanism involved in the formation of edema, and what role do the kidneys play in this process?

4.

5.

6.

The required basic concepts are:

e. f. g. h.

Tubular cellular transport and permeability properties.

Body Volumes and compartments Filtered Load.

Nephron Segmental Na+ Reabsorption.

The important point is that the kidneys alter their excretion of Na+ in response to changes in the effective Circulating Volume ECV rather than extra-cellular fluid ECF Volume per se.

The Effective Circulating Volume (ECV) is not a measurable and distinct Body Fluid Compartment; rather than, it is related to the adequacy of tissue perfusion. To understand the role of renal Na+ excretion in regulating the ECF volume it is necessary to consider the ECV concept. In a normal individual ECV varies according the volume of the Extracellular Fluids (ECF) however, the relation it is not maintained under some pathological conditions.

Guide of subjects: 1. The regulation of NaCl and Osmolality of the ECF: Solutes and Osmolality of the ECF Relationships between mechanism of Na+ balance and Osmolality Compensatory mechanism of Osmolality ADH Thirst Route of NaCl Excretion Kidneys Regulating the ECF volume.

Regulating the Na+ excretion.

Feedback to the Kidneys in ECF expansion or contraction

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2. The Concept of ECV: Relationships between NaCl and ECF volume.

Mobile (able to Perfuse) vs Static Volumes.

What sensors detect?

ECV and the Na renal excretion are positively related.

Low Na excretion (contrary Natriuresis).

Congestive heart failure Low cardiac output and ECF high.

Sensed by the Body as decreased ECV. Response: to increase ECV Kidney retains NaCl. Consequence: the ECF expand (Edema).

Conclusion: For normal individual the terms “ECV” and “ECF volume” can be, and quite often are, interchanged. However, it is the ECV, especially under certain pathological conditions (e.g. congestive heart failure), that determines renal NaCl excretion.

3. ECV Volume Sensors: ECV sensors Vascular baroreceptor (these are the most sensitive sensors) Low Pressure Baroreceptors (LPB). Send messages to hypothalamic and medullar regions, via afferents fibers of vagus nerve. Their activity modulates both Sympathetic nerve activity and stimulates ADH secretion.

In general 5-10% in blood volume and pressure are necessary.

LPB in Wall of Cardiac Atria and in addition ANP LPB in Pulmonary Vasculature High Pressure Baroreceptors (HPB). Send messages to hypothalamic and medullary regions, via afferent fibers of vagus and glossopharyngeal nerves. Action is on the Sympathetic nerves and ADH secretion.

HPB in the Carotid Sinus.

HPB in the Aortic Arch.

Juxtaglomerular apparatus of the Kidneys. Particularly the afferent arteriole responds directly to changes in pressure. Renin-AII system.

Central Nervous System.

Hepatic.

4. Volume Sensor Signals: Signals Involved in the control of renal NaCl and Water Excretion Renal Sympathetic Nerves ( activity =  NaCl excretion)  GFR  Renin secretion  NaCl reabsorption: TP, thick ascending limb of Henle loop and CD Renin-Angiotensin-Aldosterone ( secretion =  NaCl excretion)

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 AII levels stimulate PT NaCl reabsorption.  Aldosterone levels in thick ascending limb of Henle loop and CD.  ADH secretion Atrial Natriuretic Peptide (ANP): ( secretion =  excretion)  GFR.  Renin secretion  Aldosterone secretion  NaCl and Water reabsorption by the CD. Urodilatin also.  ADH secretion and inhibition of ADH action on the CD ADH ( secretion =  H2O excretion)  H2O absorption by the CD 5. Control of Na+ excretion with normal ECV (Euvolemia) In euvolemia: Mass balance in NaCl (NaCl intake = NaCl excretion) Response to step increases and decreases in NaCl intake.

[NaCl] and Body weight.

During Transition Positive NaCl Balance Negative NaCl Balance Regulation of NaCl excretion Na+ Filtered Load: FL = GFR x [Na+]P = 180 lt/day x 140 mEq/lt = 25,200 mEq/day Na+ excretion = 1% => 252 mEq/day Segmental Na+ reabsorption Fix: Proximal Tubule (PT) 67% Henle’s loop (HL) 25% Distal Tubule (DT) 4% Mechanism to maintain constant the rate of Na delivered to the CD Autoregulation of GFR Filtered Load (FL) Glomerulo-tubular Balance Regulated: (enough to balance excretion and intake) Collecting Duct (CD) is the main segment 0-4% Aldosterone (Na reabsorption) ANP Urodilantin Sympathetic nerves 6. Control of Na+ excretion with increased ECV: Integrated Response to expansion of the Effective Circulating Volume (ECV) GFR increase

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Reduction of sympathetic nerve activity Decreasing of Na Reabsorption in PT Reduction of sympathetic nerve activity Decreasing of Na Reabsorption in CD Increased FL Decreasing of Na Reabsorption in PT (GT-Balance does not occur) Low ADH High ANP High urodilantin 7. Control of Na+ excretion with decreased ECV: The integrated response to contraction of the Effective Circulating Volume (ECV) have similar mechanism but opposite to indicate in 6.

8. Edema and the Role of the Kidneys: Edema definition: Is the accumulation of excess fluid within the ISF. Starling Forces.

PC  = (+). C  = (+) Lymphatic obstruction (+) Capillary Permeability (+) Edema detected clinically (swelling of ankles) The kidneys must retain NaCl and water.

The source of fluid is P to ISF Decrease in Blood Pressure prevents P to ISF fluid.

But NaCl and water retention replenishes the P volume.

Steps involved in the development of edema resulting from an increase in venous pressure (e.g. During heart failure) Key words and Concepts: Effective Circulating Volume (ECV). Natriuresis. ECV volume sensors.

Baroreceptors. Sympathetic nerves. ANP. Urodilantin. Juxtaglomerular apparatus. Renin-angiotensinaldosterone system. Angiotensinogen. Angiotensin-converting enzyme. Antidiuretic hormone (ADH).

Euvolemia. Positive and negative Na balance. Glomerulotubular balance (GT balance). Starling forces.

Expansion of ECV. Contraction of ECV. Edema.

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Regulation of Potassium Balance

Objectives Upon completing this lecture the student should be able to answer the following questions

1.

2.

3.

4.

5.

6.

The required basic concepts are:

How does the body maintain K+ homeostasis?

What is the distribution of K+ within the body compartments? Why is this distribution important?

What are the hormones and factors that regulate plasma K+ levels? Why is this regulation important?

How do the various segments of the nephron transport K+, and how does the mechanism of K+ transport by these segments determine how much K+ is excreted in the urine?

Why are the distal tubule and collecting duct so important in regulating K+ excretion?

How do plasma K+ levels, aldosterone, ADH, tubular fluid flow rate, and acid-base balance influence K+ excretion? i. j. k.

Tubular cellular transport and permeability properties.

Body Volumes and compartments.

Filtered Load.

Guide of subjects: 1. K+ Homeostasis: Total Body K+ is 50 mEq/Kg of Body weight = 3500 mEq / Ind. 70 Kg Normal conditions: 98% is intracellular.

[K+ ] intracellular is 150 mEq/lt 2 % is extracellular.

[K+ ] extracellular is 4 mEq/lt Hyperkalemia [K+ ] extracellular is >5 mEq/lt Hypokalemia [K+ ] extracellular is <3.5 mEq/lt K+ intracellular/extracellular (Na+-K+)-ATPase RMP Threshold 2. Internal K+ distribution: Diet 100 mEq of K+/day (approx. 33 mEq per meal). Absorbed by the Gastro-intest. T. 33 mEq/14 lt (14 lt = ECF) = 2.4 mEq/lt = ď &#x201E;K+ Homeostasis during K+ increase: Fast Regulation: K+ is uptake by cells (muscle, liver, bone, and RBC).

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Hormonal control increase (Na+/K+)-ATPase activity (acute) or numbers of pumps (chronic): Insulin (few minutes) It is the most important Epinephrine (few minutes) Activates 2 adrenergic receptors Aldosterone (approx. 1 hr) High (primary aldosteronism).Hypokalemia Low (Addison’s Disease). Hyperkalemia Slow Regulation: Renal Excretion (approx. 6 hrs. after the insult).

Tubular Hormonal Renal action of Aldosterone Homeostasis during K+ decrease Inhibition of the hormonal control occurs.

Factors that alters the K+ balance: Acid-Base Balance: Metabolic Acidosis increase plasmatic [K+] • Addition HCl or H2SO4 more important than organic acid: lactic acid, acetic acid, Keto acid.

• Low pH promotes H+ movement into cells.

Metabolic Alkalosis decrease plasmatic [K+] Respiratory Ac-Bas. Disorders have no effect on [K+]p Plasma Osmolality Hyperosmotic plasma Increase plasmatic K+. Related cell volume.

Hyposmotic plasma Decrease plasmatic K+. Related cell volume.

Cell Lysis Hyperkalemia Exercise Muscle K+ release 3. K+ excretion by the kidneys: The kidneys play the main role in maintaining K+ balance. Excrete 90-95% of K+ ingested in the diet.

Stool and Sweat (loss 5-10%) Potassium secretion (blood→ Distal Tubular DT and Collecting Duct CD, fluid).

In normal diet, approx. urinary K+ excretion is 15% of the amount filtered.

Balance Fix: PT: reabsorb 67% of K+ filtered Henle’s loop: reabsorb 20% K+ filtered.

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Variable: DT and CD: secretion and/or reabsorption.

4. Cellular mechanism of K+ transport by the Distal Tubule and Collecting Duct: Distal Tubule and Collecting Duct Principal Cells Secretion occurs in Two steps: • K+ uptake to the cell by Basolateral membrane (Blood → principal cell) • K+ diffusion to the tubular fluid (principal cell → tubular fluid.

Factor that control the rate of K+ secretion: • The (Na+-K+)-ATPase activity • The driving force (apical membrane gradient) • The K+ permeability of the apical membrane.

5. Regulation of K+ secretion by the Distal tubule (DT) and Collecting Duct (CD): Physiological regulators: Plasma K+ Hyperkalemia: • Stimulates (Na+-K+)-ATPase activity that increases the K+ gradient across the apical membrane.

• Increase apical K+ permeability.

• Increase Aldosterone secretion • Increase the flow rate of tubular fluid by inhibiting NaCl and water reabsorption (PT) that stimulates the K+ secretion by the DT and CD. Hypokalemia (low diet or diarrhea): • Inhibit (Na+-K+)-ATPase activity that reduces the K+ gradient across the apical membrane.

• Decrease apical K+ permeability.

• Reduce Aldosterone secretion • Reduce the flow rate of tubular fluid by activates NaCl and water reabsorption (PT) that inhibit the K secretion by the DT and CD. Aldosterone Chronic elevation (24h or longer): Principal Cell (DT and CD) Increase the amount of (Na+-K+)-ATPase Increase the driving force (apical membrane) K+ crossing the apical membrane.

• Direct action on DT and CD • ECF expansion • Normal tubular flow

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Produced by Hyperkalemia and AII (from R-A system) Inhibit by Hypokalemia and ANP Acute elevation (over hours) Principal Cell (DT and CD) Increase the activity of (Na+-K+)-ATPase.

K+ excretion does not increase by: • Increased Na reabsorption • Decreased Tubular flow reabsorption • Decreased K+ secretion

by

Water

Antidiuretic Hormone Principal cell CD Increase the electrochemical driving force (apical membrane) By stimulating Na+ uptake Depolarize the apical membrane ADH does not change K+ secretion ADH decrease tubular fluid Water reabsorption Decrease K+ secretion 6. Factors that perturb K+ excretion: Flow of tubular fluid (ftf).

Increase in ftf (diuretic treatment, ECF volume expansion).

Stimulates K+ secretion in minutes. Because diuretic drugs increase the flow of tubular fluid through the DT and CD they also enhance urinary K+ excretion.

Decrease in ftf (ECF volume contraction cause by hemorrhage, severe vomiting, or diarrhea) Reduces K+ secretion by the DT and CD. Increase in ftf is more effective than K+ ingestion in to increase K+ secretion.

Mechanism: • ftf changes the driving force for K+ in the apical membrane.

• Na+ reabsorption increases the Na+-K+ ATPase activity that increase K+ secretion Acid-Base Balance.

Acute alteration (minutes to hours) Alkalosis: increases K+ secretion • Activates the (Na+-K+)-ATPase activity. Increase [K+] ICF and the driving force for K+ exit across the apical membrane.

• Increase the K+ permeability of the apical membrane.

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Acidosis: decreases K+ secretion • Inhibits the (Na+-K+)-ATPase activity. Reduces [K+] ICF and the driving force for K+ exit across the apical membrane.

• Reduces the K+ permeability of the apical membrane.

Metabolic acidosis effect is time dependent Several days (chronic): urinary K+ excretion is stimulated.

Because decrease water and NaCl reabsorption by PT by inhibiting the (Na+-K+)-ATPase activity. ftf augment in DT and CD. Several minutes (Acute): urinary excretion is reduced.

7. Summary of interaction among hormones and factors that influence K + secretion by the DT and CD: Rate of urinary excretion depends on: Simultaneous change in hormone levels, Acid-base balance Tubular fluid flow (ftf) ftf frequently is the most powerful

Key words and Concepts: Hyperkalemia. Hypokalemia. Internal K+ balance, Insulin, Epinephrine. Plasma osmolality. Acid-base balance. External K+ balance. Cellular mechanism of K+ secretion by the DT and CD. Hormone and factors regulating K+ excretion. Aldosterone. ADH. Plasma [K+]. Tubular fluid flow (ftf) rate.

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Regulation Calcium and Phosphate Balance

Objectives Upon completing this lecture the student should be able to answer the following questions

1.

2.

3.

4.

5.

6.

The required basic concepts are:

What is the physiological importance of Ca2+, HPO42- , H2PO4- , and Pi? How does the body maintain Ca2+ and Pi homeostasis?

What is the relative importance of the kidney versus the gastrointestinal tract and bone in maintaining plasma Ca2+ and Pi levels?

What hormones and factors regulate plasma Ca2+ and Pi levels?

What are the cellular mechanisms responsible for Ca2+ and Pi reabsorption along the nephron?

What hormones regulate renal Ca2+ and Pi excretion? l. Tubular cellular transport and permeability properties. m. Body Volumes and compartments. n. Filtered Load.

Guide of subjects: The kidneys, in conjunction with the gastrointestinal tract and bone, play the major role in maintaining plasma Ca2+ and Pi levels.

Calcium: 1. Calcium ion: Process involved: Bone formation, cell division and growth, blood coagulation, hormone-response coupling, synaptic transmission.

Localization: Bone 99% ICF 0.9 % ECF 0.1 %: Plasma [Ca2+] 10 mg/dl (2.5 to 5 mEq/lt) • Hypocalcemia: increase excitability (tetany, muscular spasm).

• Hypercalcemia: decrease excitability, cardiac arrhythmias, lethargy, disorientation, and even death.

• 55% plasmatic calcium is available to be filtered.

• 50% ionized, 45% bound plasma Pr (albumin) and 5% is complexed by several anions (HCO3-, citrate, Pi, SO42-) • Acidosis: increase % ionized • Alkalosis: decrease % ionized 2. Overview Calcium homeostasis: A. The total amount of Ca2+ in the body

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Ingest calcium is about 1000 mg/day 800 mg/day feces, escapes to be absorbed in the intestinal track.

200 mg/day excreted in the urine Gastrointestinal absorption (200 – 600 mg/day) Active carrier-mediated transport Stimulates by Calcitriol, a metabolite of vitamin D3 In Calcitriol reabsorption increase from 200 to 600 mg/day Excreted by the kidneys (about 200 mg/day) B. The distribution of Ca2+ between bone and ECF compartments.

Parathyroid Hormone (PTH) Parathyroid glands Hypocalcemia (low plasma [Ca2+]) stimulates PTH release that: Stimulates bone resorption Increase calcium reabsorption by the kidneys Stimulates calcitriol production Hypercalcemia (high plasma [Ca2+]) inhibits PTH secretion.

Calcitriol Hypocalcemia (low plasma [Ca2+]) stimulates calcitriol production and mediated by an increase in PTH and decrease in plasma Pi. Calcitonin Parathyroid glands Hypercalcemia stimulates secretion. Calcitonin decrease plasmatic Ca2+ by: Stimulates bone formation: deposition of calcium in the bone.

3. Ca2+ transport along the Nephron: Reabsorption 99% of filtered (ionized and complexed) PT reabsorbs 70 % Henle’s loop 20%. Mainly the thick ascending limb.

DT 9% CD <1% 4. Cellular mechanism of Ca2+ reabsorption: Proximal Tubule (PT): Transcellular 20% Calcium diffusion across the apical membrane into the cell Calcium channels (CaCH) Active extrusion across the basolateral membrane Ca2+-ATPase 3Na+-Ca2+ antiporter Paracellular 8% Tight junctions (solvent drag) Henle’s loop (Thick Ascending Limb, TAL) Transcellular Calcium diffusion across the apical membrane into the cell

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Calcium channels (CaCH) Active extrusion across the basolateral membrane Ca2+-ATPase 3Na+-Ca2+ antiporter Paracellular Tight junctions Na+ reabsorption and parallel Ca2+, because the electric potential (lumen-positive transepithelial voltage) Distal Tubule (DT) Transcellular (exclusively) Calcium diffusion across the apical membrane into the cell Calcium channels (CaCH) Active extrusion across the basolateral membrane Ca2+-ATPase 3Na+-Ca2+ antiporter Although Na+ and Ca2+ reabsorption are in parallel exception is produced during thiazide usage. Thiazide inhibits Na+ reabsorption in the DT and stimulates Ca2+ reabsorption.

5. Regulation of Urinary Ca+2 excretion: PTH (most powerful control) Responsible to maintain Ca2+ homeostasis • Stimulates Ca2+ reabsorption by kidneys (i.e. reduces Ca excretion).

• Although inhibit NaCl reabsorption in the PT and therefore Ca, PTH dramatically stimulates Ca reabsorption thick ascending limb (TAL) of Henle’s loop and DT. Calcitonin Reduces the blood Ca2+, reduces tubular reabsorption and increase their excretion. Its importance in humans has not been as well established.

Calcitriol Stimulates Ca2+ reabsorption by thick ascending limb (TAL) of Henle’s loop and DT. Less important than PTH. Disturbance of Calcium excretion Plasmatic Pi increased i.e. dietary PTH elevates Decrease Ca2+ excretion Plasmatic Pi decreased i.e. dietary PTH reduces Increase Ca2+ excretion ECF volume Affect Proximal Tubule (PT) NaCl and fluid reabsorption Contraction of the ECF Enhance Ca2+ reabsorption (Ca2+ excretion declines) Expansion of the ECF Reduce Ca2+ reabsorption (Ca2+ excretion increases)

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pH disturbance: Acidosis Increase Ca2+ excretion Alkalosis Decrease Ca2+ excretion Phosphate 1. Phosphate ion: Process involved: Pi is an important component of DNA, RNA, ATP and intermediates of metabolic pathways.

Also is major constituent of bone Urinary Pi is an important buffer (titratable acid) for the maintaining of the acidbase balance Localization: Bone 85% ICF 14 % ECF 0.03 %: Plasma [Pi] 4 mg/dl (2.5 to 5 mEq/lt) Protein bound 10% 2. Overview of Pi Homeostasis: Intake 800 â&#x20AC;&#x201C; 1500 mg/day Amount of Pi in the body Relative amount of Pi absorbed by the gastrointestinal tract.

Active Passive Increase if the Pi dietary increases.

It is stimulated by calcitriol.

Pi homeostasis Amount excreted by the kidneys. The kidneys play a vital role in maintaining Pi homeostasis.

Increase in plasma Pi increase Pi filtered that increases urinary Pi. Therefore plasma Pi decreases.

Amount in Bone, ICF and ECF. Distribution of Pi between the ICF and the ECF compartments Regulated by PTH, Calcitriol and Calcitonin in parallel to calcium regulation Regulates Pi distribution between bone and ECF PTH and Calcitriol ICF Pi release increases plasma Pi

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Calcitonin Bone formation, decreases plasma Pi. 3. Pi transport along the Nephron: Reabsorption 90% of filtered (ionized and complexed) PT reabsorbs 80 % Transcellular Route • Pi uptake across the apical membrane by the 2Na+-Pi symport mechanism.

• Pi exists across the basolateral membrane by a Pi-anion antiporter.

DT 10% Excretion 10% of filtered 4. Regulation of Urinary Pi excretion: Hormone and factors that influencing urinary Pi excretion Increase excretion (PT) Increase in PTH (most important) Pi loading ECV expansion Acidosis Glucocorticoids Decrease excretion (PT) (most important) Decrease in PTH Pi depletion ECV Contraction Alkalosis Growth Hormone 5. Mechanism associated: Mechanism of PTH Increase AMPc production.

Inhibit Pi reabsorption by the Pi. Therefore increase Pi excretion.

Mechanism of Pi loading independent of PTH Pi dietary intake modulates Pi transport Modulating Pi transport rate of each 2Na+-Pi symporter.

Increasing the number of transporters.

Mechanism of ECV Volume expansion and contraction Increase and decrease Pi excretion respectively Indirect. Involve PTH Acid-Base balance Acidosis: increase Pi excretion

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Alkalosis: decrease Pi excretion Glucocorticoids (Gluc) Gluc increase Pi excretion Increase of delivery in DT and CD by inhibit Pi reabsorption in PT. DT and CD secrete more H+ and generate more HCO3Growth Hormone Decrease Pi excretion.

6. Integrative Action of PTH, Calcitriol, and Calcitonin on Ca2+ and Pi Homeostasis: PTH Major stimulus for PTH Hypocalcemia Effects of PTH Stimulates bone resorption (release from bone) of Ca2+ and Pi Increase urinary Pi excretion Decrease urinary Ca2+ excretion Stimulates production of Calcitriol Calcitriol Major stimulus for Calcitriol PTH mediated by Hypocalcemia Effects of Calcitriol: The effect net is to increase plasma [Ca2+] and Pi Stimulates Ca2+ and Pi absorption by the intestine Stimulates Ca2+ and Pi release from bone Decrease Ca2+ and Pi excretion by the kidneys.

Calcitonin Major stimulus for calcitonin Increase in [Ca2+] plasmatic Effects of Calcitonin Block bone resorption Stimulates bone calcium deposition Key words and Concepts: Ca2+ homeostasis. Pi homeostasis. PTH. Calcitriol. Calcitonina. Hipocalcemia.

Hypercalcemia. Regulation of renal Ca2+ excretion. Pi homeostasis. Vitamin D3.

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Diuretic Action

Objectives Upon completing this lecture the student should be able to answer the following questions

1.

2.

What effects do diuretics have on Na+ handling by the kidney?

Why do diuretics decrease the volume of the Extracellular Fluid (ECF) and the Effective Circulatory Volume (ECV)?

3.

What mechanisms are involved in delivering diuretics into the lumen of the nephron?

What is the primary nephron site where each class of diuretics acts, and what is the specific membrane transport protein affected?

What are the effects of the various classes of diuretics on the renal handling of K+, Ca2+, HCO3-, Pi, and solute-free water?

4.

5.

The required basic concepts are:

o. p.

Tubular cellular transport and permeability properties.

Body Volumes and compartments.

Guide of subjects: Diuretics are drugs that cause an increase in Urine Output (diuresis).

This diuresis is different that produced after Large Volume of Ingested Water in which solute excretion is not increased.

Diuretics Common Mode of Action: Inhibition of Na+ reabsorption by the nephron: Natriuresis involving diuresis.

1. General Principles of Diuretic action: Process involved: Primary action is increase the Na+ excretion Modify ECF volume and consequently the ECV When they are administered?

Clinical situation where the ECF is expanded.

Factor to be consider: The nephron segment where the Diuretic acts The response of distal segments to the site of action of the diuretic.

The delivery of sufficient quantities of the diuretic to its site of action.

The volume of the ECF and ECV. 2. Diuretics: Sites of action of Diuretics Osmotic diuretics Acts along the PT and thin descending limb of Henleâ&#x20AC;&#x2122;s loop.

Carbonic anhydrase inhibitors PT.

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Loop diuretics Acts along the thick ascending limb of Henle’s loop Thiazide Diuretics Early portion of the DT K-sparing diuretics Acts in the late portion of the DT and the cortical CD. Magnitude of diuresis: Is determined by the diuretic site of action.

Magnitude of Natriuresis.

3. Response of more distal Nephron Segments: When a diuretic inhibits Na+ reabsorption at one site, it causes an increased delivery of Na+ and water to more distal segments.

The function of these more distal segments and their ability or inability to handle this increased load ultimately determines the overall effect of the diuretic on urinary excretion.

4. Adequate delivery of Diuretics to their site of action: Magnitude of effects depends on: Adequate amount of drug to their action’s sites.

Diuretics act from the lumen of the nephron Exceptions: Aldosterone inhibitors (acts intracellularly) and Carbonic anhydrase inhibitors (luminal and intracellular) Diuretics are ultra-filtered or secreted (by the organic anion and organic cation secretory system (PT) 5. Volume of the ECF and ECV: Normal: If ECV decreases GFR is reduced Filtered Load of Na+ is reduced.

Na+ reabsorption in the PT is enhanced When a diuretic is administered If ECV is decreased GFR is reduced Filtered Load of Na+ is reduced.

Delivery of a smaller amount of Na+ to DT Low natriuresis. (Action is reduced) Effect of long-term diuretic therapy on renal Na+ excretion If intake of Na+ is fixed Natriuresis is short-lived (transient response), because Na+ excretion by the diuretic

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Reduced ECV (body weight decrease) Low GFR Increase Na+ PT reabsorption (recovery) Reaches the steady state (several days) Steady State Individual are in steady state (Na+) Diuretics administration Disrupts this balance Increase excretion transiently (acute phase) Set a new the steady state (chronic phase) ECV is reduced (before diuretic administration) 6. Mechanism of action of Diuretics: Osmotic Diuresis: Diuretics that inhibit the reabsorption of solute and water by altering osmotic driving forces along the nephron. Specific membrane transporters are not inhibited. They simply affect the transport across the cells of the nephron through the generation of an osmotic pressure gradient. Example are mannitol (sugar); in diabetes mellitus, glucose; and patient with renal diseases, urea.

Example, Mannitol: Is Ultra-filtered Do not reabsorbed, stay inside the tubular lumen.

Inhibit the tubular fluid reabsorption in segments where water is permeable (PT, descending thin limb of Henleâ&#x20AC;&#x2122;s loop).

Its concentration will increase along the tubular segments Increasing natriuresis.

Natriuresis is about 10% of the filtered load.

Carbonic Anhydrase Inhibitors: Reduce Na+ reabsorption acting on the Carbonic Anhydrase (CA). CA is abundant in the PT. CA is critical for HCO3- reabsorption by the PT. CA is located inside cells and in the apical membrane. CA facilitates the formation of H+ and HCO3- from CO2 and H2O. Bicarbonate exits the cells by the basolateral membrane and return to the blood. H+ is secreted into the tubular fluid in where combines with the HCO3- filtered to produce H2CO3. This is rapidly is hydrolyzed to CO2 and H2O by the CA located in the apical membrane, facilitating their reabsorption.

CA inhibitors Significantly reduces the HCO3- reabsorption Low H+ secretion Na+-H+ antiporter (apical membrane) is reduced by low H+ Na+ reabsorption is reduced Natriuresis 1/3 of Na reabsorption in the PT is related to HCO3- reabsorption CA inhibition is expected causes a large increase in Na+ excretion.

Natriuresis 5-10% of the filtered load

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Loop Diuretics (LD): LDs are organic anions that enter the tubular lumen by glomerular filtration and via secretion by the organic anion secretory system of the PT. They inhibit the Na+ reabsorption by the thick ascending limb of Henle’s loop by blocking the Na+-K+2Cl- symporter located in the apical membrane of these cells. They eliminate the countercurrent multiplication. Examples are furosemide, bumetanide, and ethacrynic acid.

LDs impair the kidney’s ability to dilute and concentrate urine.

LDs are the most potent diuretics available.

Natriuresis is 20-25 % of the filtered load.

Thiazide Diuretics: are organic anions that enter the tubular lumen by glomerular filtration and via secretion by the organic anion secretory system of the PT. They act to inhibit Na+ reabsorption in the early portion of the DT by blocking the Na+-Cl- symporter in the apical membrane.

Thiazide reduces the ability to dilute the urine maximally Natriuresis is 5-10% filtered load.

K-Sparing Diuretics: act on the regions where occurs K+ secretion, mainly in the late portion of the DT and cortical CD. K-sparing diuretics have the ability to inhibit K+ secretion by these regions.

Class of K-Sparing diuretics • Antagonize the aldosterone’s action on the principal cells of the CD, example spironolactone.

• Block the entry of Na+ into the principal cells through the Na+-selective channels in the apical membrane, example amiloride and triamterene.

Amiloride and triamterene are organic cations that enter the tubular lumen by glomerular filtration and via secretion by the organic cation secretory system of the PT. Aldosterone Increase the number of (Na+-K+)-ATPase in the basolateral membrane.

Na+ entry to the cell increases and its movement by the basolateral membrane is elevated. Increase Na+ reabsorption.

K+ blood to lumen movement is increased.

Aldosterone antagonist Reversed effects Mechanism:

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Amiloride and triamterene interact directly with the Na+ channels in the apical membrane of the principal cells and block the Na + entry.

7. Effects of diuretics on the excretion of water and other solutes: Together the Na+ handling along the nephron, diuretics also influence the handling of water and other solutes.

Solute free water depends on: • The normal functions of the nephron, particularly the thick ascending limb.

• The delivery of adequate solute to Henle’s loop.

• The maintenance of a hyperosmotic medullary interstitium (reabsorption of solute free water only).

Inhibition of thick ascending limb reabsorption by loop diuretics result in inhibition of both CH2O and TCH2O. Thiazide diuretics impair urine dilution and thus reduce CH2O. Osmotic diuretics increase the ability to the kidney to produce either CH2O or TCH2O. K+ handling Diuretic use to increase the excretion of K+ (hypokalemia) Inhibition of Na+ and water reabsorption increases tubular fluid rate.

Stimulates K+ secretion Diuretic Action in the Na+ balance Decrease ECV Aldosterone secretion Stimulates K+ secretion.

K-Sparing diuretics Prevents the increase in K+ excretion caused by other diuretics.

Are given in combination with those other diuretics to prevent or to minimize the development of hypokalemia.

HCO3- handling CA inhibitors Inhibits the HCO3- reabsorption Increase the HCO3- excretion Develop metabolic acidosis Filtered load of HCO3- is reduced Less HCO3- available to reabsorption Decrease effectively of CA inhibitors

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Loop and Thiazide diuretics Can induce metabolic alkalosis Because the low ECV Na+ is more avidly reabsorbed in the PT HCO3- is reabsorbed with Na+ Because low ECV Aldosterone secretion Stimulates H+ secretion in the intercalated cells of the CD K-Sparing diuretics Can induce metabolic acidosis Inhibit secondarily H+ secretion.

Ca2+ and Pi handling: All diuretic can significantly alter Ca2+ handling except KSparing diuretics Osmotic diuretics and CA inhibitors Inhibit the Na+ and water reabsorption in the PT Reduce the Ca2+ reabsorption.

Increase the Ca2+ excretion Loop diuretics Change the transepithelial potential Increase the Ca2+ excretion by the paracellular pathway.

Significant effect overall Ca2+ balance Used to treat hypercalcemia However hypercalcemia can occur with their longterm use. Because ECV is decreased.

Thiazide diuretics Cells of the DT reabsorb 9% of the filter load Process: Passive moment via channels in apical and extrusion from the cells in the basolateral membrane: Ca2+ ATPase and 3Na+-Ca2+ antiporter.

Thiazide diuretics inhibit NaCl entry to the cell and cause the MP hyperpolarize Open time of Ca-channels increase Electrochemical gradient increase Stimulates Ca2+ reabsorption Reduce Ca2+ excretion Key words and Concepts: Natriuresis. Steady State. Organic anion and organic cation secretory system.

Osmotic diuretics. Carbonic Anhydrase diuretics. Loop diuretics. Thiazide diuretics. K-Sparing diuretics.

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Micturition Definition: The periodic complete emptying of the bladder, under voluntary control. Micturition is a spinal reflex facilitated and inhibited by higher brain centers.

Exception: during infancy.

Ureters function: (ureters enter the base of the bladder obliquely, forming a flat “valve” the passively prevents the reflux of urine) Urine collected in the pelvis of the kidneys passes through the ureters by: • Gravity in erect position • Contraction of the muscle layers of the ureters (peristaltic contraction).

• Necessary to overcome the gradual increase in tension in the wall of the bladder as urine accumulates in it.

• Peristaltic waves appear to originate in the muscle.

• The waves are modified by: • The action of splanchnic nerves via renal plexus to upper portions of the ureter, and via the hypogastric plexus to the lower portions (excitatory nerves).

• The inferior mesenteric plexus. Send inhibitory fibers to the ureters.

• Afferent sensory fibers (excruciating pain is felt on the passage of calculi through the ureters).

• The peristaltic waves occur at a frequency of 1 to 5 per min. These contractions move the urine from the renal pelvis to the bladder, when it enters in spurts synchronous with each wave.

The Bladder • Consist in a balloon and a cylinder (the neck extending into the urethra).

• Smooth muscle Sheet of muscles in form of a web-work that extended down into the urethra as the muscular wall.

• The wall of the urethra contain elastic connective tissue • Both smooth muscle and the elastic tissue exert a continuous tension in an autonomous manner.

• Normal bladder: completely empty at the end of micturition • The intra-vesical pressure is equal to the intra-abdominal pressure.

• Tone is adjusted, as the bladder is filling.

• A minimal change in the intravesical pressure occurs at a wide range of intravesical volumes.

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When the bladder is distended with fluid, the smooth muscle fibers are stretched, which causes them to contract, thus increasing their tension.

Cystometric: • A cystometrogram is the relationship between the volume of fluid in the bladder and the pressure in the bladder.

• Shows the relationship between filling and pressure development.

• Segments of the cytometrogram: • Ia: Initial filling of the bladder.

• Ib: as the filling continues (up to about 300 ml there is very little increase in pressure.

• Between 150 to 200 ml there is a first desire to void • Between 300 to 350 ml there is a sensation of discomfort.

• Laplace relationship for a sphere (P= 2T/R). As the filling continues tension in the wall increase but so does the radius. Therefore the pressure rises very little. At higher volumes the tension increases more rapidly than the radius, thus increasing the pressure by a considerable amount.

• I: the intravesical pressure rises more steeply between 350 to 400 ml. To these volumes, there is an extreme urgency to void associated with bladder contractions.

• II: pressure developed as micturition begins.

Tonic contraction of the bladder muscular begins.

Prevention of urine leaking out the bladder: • Resistance offered principally by the upper 3 cm of the bladder neck and urethra. The neck of the bladder is sometime viewed as the internal sphincter.

• The external sphincter is composite by skeletal muscle. This tissue keep the urethra compressed so that the lumen is collapsed to prevent urine flowing out the bladder fundus at low or moderated pressure.

• Striated muscle around the urethra (urogenital diaphragm and levator ani) can aid in preventing urinary incontinence particularly when the bladder is full and the person has an urgent desire to urinate. This striated muscle is of secondary importance in that they increase the efficacy of the urinary sphincter but cannot substitute for it. The striated muscle serves to interrupt urination.

Micturition is the act of voiding the contents of the bladder

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Micturition occurs before this volume (bladder content) is reached. Proprioceptive (stretch and tension) receptors in the bladder send out afferent impulses responsible for the sensation of distension and the desire to urinate.

At higher volumes the tension also rises because of tonic contractions of the bladder musculature. Voluntary control can be exerted until the intravesical pressure increases to about 100 cm H2O, at which point involuntary micturition begins. If micturition is unduly postponed a feeling of fullness, then discomfort and finally pain results. The latter sensation is transmitted to the cortex via the lateral spinothalamic tracts. Under these conditions, voiding is inhibited by cortical impulses blocking the discharge of spinal center.

During micturition the perineal muscle and the external urethral sphincter relax. The detrusor muscle contracts and urine passes out though the urethra.

Initiation of micturition seems to involve relaxation of the muscle of the pelvic floor, which may cause a downward pull on the detrusor so that it starts to contract.

Innervation of the micturition reflex: • Parasympathetic pelvic nerves which function to maintain tonus of the bladder.

• Sympathetic hypogastric nerves whose role is not well understood.

• Somatic pudendal nerves, which mediate impulses that, contract the striated musculature of the external sphincter.

• Afferent fibers run chiefly in the pelvis nerves, although they are found in the hypogastric and pudendal nerves.

•

Sequence: • Active contraction of the detrusor muscle of the bladder is reflexly elicited when bladder volume reaches threshold level, which is about 150 ml in the human bladder.

• This reflex may be inhibited or facilitated by higher centers of the CNS. • For micturition to occur the bladder must contract and sphincters must relax.

• External sphincter opens reflexly due to inhibition of impulses from the pudendal nerves.

This inhibition of external sphincter tone originates as part of the total micturition reflex from receptor endings located in the bladder wall itself.

• The internal sphincter is forced open by the contraction of the detrusor, and although it is sympathetically innervated, it is not reflexly opened.

•

Higher control: • It is well know that bladder function and micturition can be controlled voluntarily and impulses arising in various areas of brain can modulate the micturition reflex.

• Facilitator areas: • Anterior pontine area • Lateral reticular areas of medulla.

• Posterior hypothalamus • Inhibitory areas • Midbrain • Cerebellum

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Index

A Acid-Base, 34, 36, 42 Acidosis, 34, 37, 38, 41, 42 ADH, 18, 24, 25, 27, 29, 30, 31, 32, 33, 36, 37 Aldosterone, 24, 25, 27, 30, 31, 34, 35, 37, 45, 47, 48, 49 Alkalosis, 34, 36, 38, 41, 42, 43 Amiloride, 47, 48 angiotensin II, 13, 17, 24 Angiotensin II, 17, 18, 19, 20, 24, 25, 27 apical membranes, 22 Ascending Thin Limb, 6 Atrial Natriuretic Peptide, 24, 27, 31 autoregulation, 8, 15, 16 Autoregulation, 8, 15, 16, 19, 20, 31 B basolateral membranes, 22 Bibliography, 1 Body Fluid, 4, 29 Body Fluids, 4 Bowman’s capsule, 8, 9, 12, 13 Bowman’s Capsule, 6 C CA inhibitors, 46, 48, 49 Calcitonin, 39, 40, 41, 42, 43 Calcitriol, 39, 40, 41 Calcitrol, 43 Calcium, 38, 39, 40 Carbonic anhydrase inhibitors, 44, 45 Clearance, 8, 10, 11, 18, 19, 20 Coefficient of ultrafiltration, 11 compartments, 4, 28, 29, 33, 38, 39, 41, 44 Creatinine, 8, 19, 20 cystometrogram, 51

Effective Renal Plasma Flow, 14, 19, 20 Extracellular Fluid (ECF), 4 F Fick Principle, 14 filtered load, 23, 24, 25, 46, 47 Filtered Load, 29, 31, 33, 38, 45 filtration, 5, 6, 8, 9, 11, 13, 18, 47 Filtration Fraction, 15, 19, 20 Free water clearance, 28 G GFR, 8, 11, 12, 13, 15, 16, 17, 18, 19, 20, 25, 26, 30, 31, 45, 46 Glomerular Filtration, 8, 11, 19, 20 glomerulo-tubular balance, 25 Glomerulus, 6, 7, 8, 9 H Henle’s loop, 6, 7, 22, 24, 25, 31, 34, 39, 40, 44, 45, 46, 47, 48 hydrostatic pressure, 11, 12, 13, 15, 16, 17 Hypercalcemia, 38, 39, 43 Hyperkalemia, 33, 34, 35, 36, 37 Hypocalcemia, 38, 39, 43 Hypokalemia, 33, 34, 35, 36, 37 I Interstitial Fluid (ISF), 4 Intracellular Fluid (ICF), 4 Inulin, 8, 12, 19, 20 INULIN, 12 J juxtaglomerular, 6 Juxtaglomerular apparatus, 30 K

D Distal Tubule, 6, 7, 26, 27, 31, 35, 40 Diuretic, 27, 44, 48 Diuretics, 44, 45, 46, 47 E ECV, 17, 24, 25, 29, 30, 31, 32, 42, 44, 45, 46, 48, 49 Edema, 30, 32 effective Circulating Volume, 29

K+ homeostasis, 33 K-sparing diuretics, 45 M Micturition, 50, 51, 52 N natriuresis, 45, 46

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Objectives, 4, 6, 8, 22, 29, 33, 38, 44 oncotic pressure, 11, 13 osmolality, 4, 5, 24, 25, 26, 28, 37 Osmotic diuretics, 44, 48, 49

R reabsortion, 11, 22, 23, 24, 25, 26, 27, 30, 31, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49 Renal Blood Flow, 8, 13, 14, 15, 19, 20 Renin, 7, 24, 27, 30, 31, 32 RPF, 8, 15, 17, 18, 19, 20, 21

P PAH, 8, 14, 15, 19, 20, 21 paracellular, 23, 24, 49 pelvic nerves, 52 Phosphate, 38, 41 Pi excretion, 38, 42, 43 Pi uptake, 42 Plasma (P), 4 Podocytes Foot Processes, 7 Potassium, 33, 34 Principal Cell, 35, 36 prostaglandines, 17 prostaglandins, 18, 20 Proteinuria, 24 Proximal Tubule, 6, 7, 22, 26, 31, 39, 40 PTH, 39, 40, 41, 42, 43 pudendal nerves, 52

S secretion, 11, 22, 23, 25, 30, 31, 34, 35, 36, 37, 39, 46, 47, 48, 49 Secretion, 8, 22, 26, 27, 35 Starling Forces, 5, 8, 11, 19, 20, 22, 25, 27, 32 T Thiazide, 27, 40, 45, 47, 48, 49 Thick Ascending Limb, 6, 7 Total Body Water (TBW), 4 transcellular, 23 triamterene, 47, 48 U urine flow rate, 10 Urodilantin, 24, 25, 27, 31, 32

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Normal Laboratory Values Traditional Units REFERENCE RANGE

SI Units REFERENCE INTERVAL

Arterial Blood Gases PCO2 PO2 pH

33 – 45 mm Hg 75 – 105 mm Hg 7.35 – 7.45

4.4 – 5.9 kPa 10.0 – 14.0 kPa [H+] 36-44 nmol/lt

Serum Electrolytes Na+ ClK+ HCO3Ca2+ Pi

135 – 147 mEq/lt 95 – 105 mEq/lt 3.5 – 5.0 mEq/lt 22 – 28 mEq/lt 8.4 – 10.2 mg/dl 3.0 – 4.5 mg/dl

135 – 147 mmol/lt 95 – 105 mmol/lt 3.5 – 5.0 mmol/lt 22 – 28 mmol/lt 2.1 – 2.8 mmol/lt 1.0 1.5 mmol/lt

Serum Proteins Total Albumin Globulin

6.0 - 7.8 g/dl 3.5 – 5.5 g/dl 2.3 – 3.5 g/dl

60 – 78 g/lt 35 - 55 g/lt 23 – 35 g/lt

0.6 – 1.2 mg/dl 70 – 110 mg/dl 7 – 18 mg/dl

53 – 106 mol/lt 3.8 – 6.1 mmol/lt 1.2 – 3.0 mmol/lt

275 – 295 mOsm/kg H2O

275 – 295 mOsm/kg H2O

97-137 ml/min 140-197 lt/day 88-128 ml/min 127-184 lt/day

97-137 ml/min 140-197 lt/day 88-128 ml/min 127-184 lt/day

Other Serum Constituents Creatinine Glucose (fasting) Urea Nitrogen (BUN) Serum Osmolality

Creatinine Clearance Male Female

Table conversions Time

Hours

Min

Seconds

1 day

24

1,440

68,400