Renal Review

Ana Ivkovic and Rahul Dave

Kidney functions

Primary: water regulation and electrolyte balance--homeostasis The renal system functions to maintain the intravascular volume (of body fluids) Other:

Endocrine: renin, erythropoieten, calcitriol Liver-like fxns: glucose synthesis

Basic Concepts

Excretion = Filtration - Reabsorption + Secretion

Filtration:

Bowmans capsule Reabsorption: Peritubular capillaries Secretion: Peritubular capillaries

Measuring Fluid Compartments

Total Body Water = 60% total body weight

2/3 = ICF
1/4 = Plasma

1/3 = ECF
3/4 = Interstitial Fluid

Total Body Water: varies with fat 20-40-60 Rule ICF high in K and Mg; ECF high in Na, Cl Plasma high in protein; interstitial fluid low in protein-Gibbs Donnan (neg. charged prots attract more pos. charge) Smallest compartment (plasma) most important (intravascular volume that is controlled by kidney)

Osmolarity and Oncotic Pressure

Normal plasma osmolarity = 285-290 mOsm/L Tightly controlled Osmolarity vs. Osmolality
Osmolarity = mmol solute/L solution Osmolality = mmol solute/kg h2O

Reflection coefficient:

0 = ineffective osmolyte (urea, ethanol--freely permeable) 1 = effective osmolyte (Na, K, glucose w/o insulin; draw water)

Oncotic Pressure: the fraction of plasma osmolarity that is due to plasma proteins

Tonicity vs. Osmolarity

Osmolarity

Describes the osmotic properties of a solution Refers to the osmotic effect on the volume of a cell Ex: hypotonic soln--water moves in, cell swell

Tonicity

Isosmotic solns not necessarily isotonic (has to do w/ concept of reflection coefficient--ex of urea solution and RBC)

Darrow-Yanet Diagrams--Think Logically!

All volume disturbances originate in the ECF compartment Changes in the ICF compartment are in response to changes in the ECF hyposmotic contraction refers to the volume of fluid that remains

Volume contractions

Diarrhea, vomiting, loss of blood--isosmotic volume contraction Diaphoresis (sweating), dehydration-hyperosmotic contraction Remember that sweat is hyposmotic Addisons disease (lack of aldosterone)-hyposmotic volume contraction

Volume expansions (rarer)

Isotonic volume expansion (isotonic saline IV): ECF expands, ICF doesnt change Hypertonic volume expansion: ECF osmolarity increases, draws fluid from ICF Hypotonic volume expansion: ECF osmolarity decreases, adds fluid to ICF (examples: psychogenic polydipsia, SIADH)

Renal vascularization

Renal artery --> interlobar artery --> arcuate artery --> interlobular artery--> afferent arteriole* --> glomerular capillaries--> efferent arteriole* --> peritubular capillaries *serial arrangement of arterioles--important!

Juxtamedullary vs. Superficial Nephron

JMN has long Loop of Henle Generates a concentrated urine JMNs are what we lose with age

Renal Clearance and Blood Flow

C.O. = 5.2 L/min RBF = 1.2 L/min (20% of cardiac output) RPF = .66 L/min (plasma = 55% of blood); also equal to the clearance of PAH (filtered and secreted) GFR = Clearance of inulin or creatinine Inulin is filtered but not secreted or reabsorbed Creatinine clearance a slight overestimate of GFR because it is partly secreted (GFR = 0.9 X Ccreatinine) Filtration Fraction = GFR/RPF, normally 20%

PAH

Used to measure RPF Effective RPF = ([U]PAH x V) / [P]PAH = CPAH

Clearance Ratio

CR = Cx/Cin If CR = 1, substance x is only being filtered If CR < 1, substance x is being reabsorbed If CR > 1, substance x is being secreted

GFR:
A.
B.

C.
D. E. F. G.

Is dependent on hydrostatic pressure inside glomerular capillaries Depends on the oncotic pressure inside glomerular capillaries Is equal to the clearance of inulin Under normal conditions, is rarely dependent on the oncotic pressure inside Bowmans space Creatinine is used to calculate it Three of the above All of the above

Starlings Forces of capillary exchange

GFR = Kf (PGC - PBS - GC) Hypoalbuminemia increases GFR PBS: low unless obstruction present (kidney stones increase GFR) Basement membrane has fixed negative charge--> neg. charged prots cant get across --> oncotic pressure in Bowmans space = 0

Contd

Hydrostatic Pressure is high and relatively constant (due to serial arterioles) Oncotic Pressure increases along length of glomerular capillary (as more fluid is filtered out) Filtration occurs upstream while reabsorption occurs downstream Q: why does a low GFR result in increased reabsorption? A: more time to filter --> oncotic pressure increases

AFFERENT AND EFFERENT ARTERIOLES ARE THE MAJOR SITES OF REGULATED RESISTANCE IN THE RENAL VASCULATURE:

Glomerular capillary is unique: 2 sites of vasoconstriction

Autoregulation

Myogenic Mechanism (Bayless): intrinsic reflex mechanism of smooth muscle; increased pressure causes vasoconstriction Tubuloglomerular feedback: macula densa senses increased filtered load of NaCl--> sends signals to afferent arteriole to vasoconstrict, thereby decreasing the filtered load (by decreasing GFR back to normal) Both processes serve to keep RBF and GFR constant

Sympathetic Innervation

There is no parasympathetic input to the kidneys Sympathetic innervation of the afferent and efferent arterioles is the major regulator of RBF and GFR Vasoactive compounds also act on afferent and efferent arterioles: NE, Angiotensin II, Endothelin--> constrict; Ach, NO, PGs, etc --> dilate Low vs. severe sympathetic drive--examples of exercise and hemorrhage

Urine formation

Ultrafiltration of plasma Reabsorption of H2O and solutes from tubular fluid Active and passive processes Transcellular and paracellular (lateral space) transport; latter occurs in proximal tubule due to leaky tight junctions--> ions pass, followed by H2O In collecting duct tight jxns are very tight and do not allow passage of water, proteins, or solutes

Solute Regulation in Nephron Segments

Reabsorption and Secretion along Proximal Tubule

Isosmotic fluid reabsorption Reabsorbs 2/3 of filtered load of Na and water (Aquaporin 1) Highly permeable to H2O; solvent drag of K and Ca Understand TF/P graph

Upper Segment of PT

Na cotransported along with bicarb, glc, amino acids, phosphate (luminal membrane) H+ secreted as counter-transport with Na (luminal membrane) Sodium bicarbonate is reabsorbed (basolateral membrane) Under normal conditions, reabsorption will increase as plasma [gluc] increases Once plasma [gluc] reaches a certain level, all glucose carriers in the PT will be saturated, leaving some glucose behind Tm of SGLT-2 (sodium coupled) is 200g/dl, which is exceeded in diabetics; osmotic diuresis results

Lower Segment of PT

NaCl reabsorbed transcellularly (1/3) and paracellularly (2/3); due to transepithelial voltage Amino Acids and Bicarbonate have been completely reabsorbed Glucose SGLT-1 (2 Sodium coupled) transporters move glucose against higher gradient

Thick Ascending Limb

Reabsorbs 1/4 of filtered Na Has the Na-K-2Cl cotransporter

Inhibited by Furosemide (loop diuretic)

Impermeable to water; tubular osmolarity decreases (diluting segment)--> separation of movement of water and solute Lumen becomes positively charged, causing paracellular transport of Na, K, Ca, and Mg

Early Distal Tubule/Collecting Duct

Also impermeable to water (like TAL) Continues the dilution of urine; the cortical diluting segment Reabsorption of Na/Cl (cotransporter) Inhibited by Thiazide diuretics

Thiazide diuretics unique in that they increase Ca++ reabsorption (Loop diuretics increase Ca++ excretion by diminishing NaK2Cl + lumen effect)

Late Distal Tubule/Collecting Duct: fine tuning

Principal cells--reabsorb Na, H2O, and secrete K+ Impermeable to water, except in presence of ADH (Vasopressin) ADH causes water channels to relocate to apical cell membrane (AQUAPORIN 2) Na (transcellularly) and Cl (paracellularly) are reabsorbed Aldosterone causes an increase in Na absorption and increases K secretion Spironolactone (K-sparing) blocks aldosterone; other K-sparing diuretics (Triamterene, Amiloride) act directly on the Na channel, independent of aldosterone Intercalated cells--secrete H+ through primary active transport

exchange H+ out of cell for K+ into cell; K+ reabsorption possess carbonic anhydrase activity for bicarb reabsorption

Miscellaneous Renal Stuff

Na+, Ca++ are never secreted; rather, fail to reabsorb Prostaglandins released during hypovolemic shock to increase RPF and prevent renal ischemia Aldosterone: promotes Na reabsorption and K secretion (via action on principal cells); also promotes H+ secretion (via action on intercalated cells)-->a link between volume and acid-base regulation Posm = 2[Na] + 2[Glucose] + [BUN] ADH: OSMOREGULATION ALDOSTERONE: Na+/VOLUME REGULATION

Genetic Defects that Target Tenal Transport Mechanisms

Bartters Syndrome: defect in NaK2Cl transporter Gettelmans Syndrome: defect in Na/Cl cotransporter Liddels: defect in ENaC (turned on) Pseudohypoaldosteronism: defect in ENaC (turned off--> Na doesnt get reabsorbed--> volume contraction

Graphs to be familiar with:

WATER BALANCE

Urine flow rate is never zero There is an inverse relationship between urine flow and osmolarity Normal urine osmolarity 600 mOsm/L

Range

= 50 - 1200!! (kidneys can concentrate urine up to 4x the plasma concentration)

Control Mechanisms of Osmoregulation

Osmoreceptors

Increase in plasma osm--> hypothalamus stimulated to release ADH (hypothalamic set point 285 mOsm/L solution) Respond to < 2% change in plasma osmolarity Most important control in osmoregulation Respond to changes in Blood Pressure Require a 15-20% change in BP before activation

Baroreceptors

Disorders of Osmoregulation
Psychogenic Polydipsia, Hypothalamic/Central Diabetes Insipidus: low ADH Nephrogenic Diabetes Insipidus: ineffective ADH (kidney unable to respond to ADH)

Mechanisms to Concentrate Urine

Countercurrent Multiplication--creation of osmotic gradient

Loop of Henle Generates a urine that is concentrated as high as 600 mosm/L

Urea recycling

Medullary Collecting Duct Needed to increase the osmolar gradient from 600 to 1200 mosm/L Kidneys use urea to do osmotic work when in state of antidiuresis

Countercurrent exchange--vasa recta maintains the medullary insterstitial osmotic gradient set up by the countercurrent multiplier

Diuresis vs Antidiuresis

Understand the diagrams on p. 9 Water diuresis: most concentrated urine just before ascending limb and TAL; most dilute at end of CD Antidiuresis: most concentrated in lumen at level of renal papillae (in medulla); most dilute at TAL

SODIUM REGULATION

Renin, Angiotensin, Aldosterone

Renin secretion stimulated by:

Decrease in effective circulating volume (decreased pressure at afferent arteriole) Increase in sympathetic nerve activity Tubuloglomerular feedback (decreased Na load sensed by macula densa, causing renin release) Arteriolar constriction--> increases TPR Increases Aldosterone Increases ADH and thirst

Angiotensin II:

Aldosterone causes:

Na reabsorption at principal cells K secretion in CD

Aldosterone secretion:

Increased by ACTH, Angiotensin II, high plasma [K+], cases of volume contraction Decreased by *ANP* and high plasma Na+ (feedback inhibition)

ANP: OPPOSES RAAS; increases Na+ excretion during cases of volume expansion (cardiac myocytes are stretched)

Note: Na+ alterations do not affect plasma osmolarity, rather they affect the effective circulating volume; H2O homeostasis and ADH determine plasma osmolarity

Aldosterone escape
A protective mechanism during cases of abnormal aldosterone elevation (example of adrenal tumor); system becomes insensitive to aldosterone.

Renal Physiology
Lectures 41 to 48 Rahul Dave (rdave2@uic.edu)

I cant go through everything in detail. Know the handout.

My goal is to make this make sense to you, and orient your studying. Pay attention to major vs minor factors.
Minor doesnt mean less important to study, but helps you keep changes in perspective

You need to memorize the regulation, etc and understand the logic. Its easy to talk yourself into something wrong.

Potassium Balance

K+ distribution and homeostasis

Plasma K is low must be controlled well

Determines membrane potential

Metabolic alkalosis causes hypokalemia (and vice-versa) Rules of thumb: understand mechanisms

Na and K go opposite

K+ Transport K+ Transport

See diagrams in handout for cellular transport pathways in different sections

Regulation of K+
MAJOR FACTORS K+ itself (K promotes its own secretion) Aldosterone (Na+ excr., K+ reabs., H+ excr.) MINOR FACTORS Tubular flow increases secretion ADH no net effect Alkalosis (acute) increases secretion Tubular Na+ increases secretion Insulin Increase reabsorption Epinephrine Decreases secretion (fight/flight)

Diuretics

See diagrams of cell transport pathways

Control of Circulating Volume

Small fraction of TBW cant detect it directly. Also, since detection and changes are indirect, the changes must occur slowly
Measured by BP (myogenic feedback) or [Na+] (tubuloglomerular) Controlled by changing Na+

Volume Sensors & Effectors

Baroreceptors detect pressure Central (Left atrium; carotid sinus)

ADH Na reabs; collecting duct permeability

Pressure: myogenic feedback Na (also K & Cl, maybe): tubuloglomerular

Intrarenal volume sensors

Low ECF volume makes you thirsty Sympathetic overdrive (fight/flight) conserve water & peripheral blood flow

Mechanisms Controlling ECF

Cardiac atria secrete ANP lowers GFR Aortic Arch Baroreceptor Sympathetic system

Macula Densa Renin-Ang-Ald System

Hydrostatic/Oncotic pressure balance Adrenal Cortex hormones like aldosterone

All of these affect Na+ balance!

Calcium and Phosphate Balance

Rules of Thumb: Ca2+

Hitchhiking only takes you so far. But try to understand why & how these are true. In the PCT & TAL: Ca2+ follows Na+ paracellularly In the DCT & CD: Ca2+ is regulated by PTH

Rules of Thumb: PO43Try to understand why & how these are true. In the nephron it undergoes paracellular transport

Controlled by PTH in the proximal tubule

PTH

Absorb (P) from gut & bone to incr. plasma (P) Excrete it in the urine But Ca2+ and PO4 cant be together

Phosphate Trashing Hormone in urine

So if (P) is low, Ca2+ is high, and vice-versa

PTH, not calcitonin, is a major controller of Ca2+.

Vitamin D Synthesis

This is a stupid detail, but winds up being tested sometimes (No promises about Hudson) Vit D is synthesized in liver & Kidney
D (liver) 1-OH-D (kidney) 1,25-OH-D
You need Vitamin D to absorb Ca2+ Think: Vit-D fortified milk

Acid-Base: Basics

Removing Acid or Base

Buffers

Blood Intracellular

seconds minutes

Lung

compensated state

hours days

Kidneys

Net acid excretion counts NH4, Titratable Acid, HCO3

Titratable (weak) acids include lactic acid, ketone bodies, etc. Strong acids are secreted as their Na salts (eg, Na2SO4)

Buffering Mechanisms

[HCO3-] = 24 pH = 6.1 + log = 7.4 0.03 x P-CO2 = 40 Know this and make sure you can calculate it!

Lung Mechanisms

CO2 is an acid and gets blown out by respiration.

So when you sprint, you develop lactic acidosis. This is metabolic acidosis. To get rid of the acid, you hyperventilate and breathe faster.

Kidney Mechanisms
Mainly by HCO3H2O + CO2 CA H2CO3 HCO3- + H+

Kidney: HCO3

Locations: look at cell diagrams Regulation

Proximal tubule: follows Na+ (understand why)

Na/H antiport. Whenever one H+ exits, a tubular HCO3- is used up to neutralize it. Also, to regenerate that H+, a HCO3 is made, which is transported to the blood.

Systemic Acidosis (in PCT, Henle, CD)

Kidney: H+

H+ is usually tied to other ions

In the intercalated cell of collecting duct, there is a ATP-dependent H+ pump that secretes H+ Upregulated by aldosterone

Nitrogen Removal (NH3 or NH4+)

The mechanisms are complicated
Know that H+ acidifies & traps NH3 in the lumen (as NH4+)
K+ also regulates NH4+ production dont worry

(The mechanisms are important if you want to do really well)

Clinical Evaluation of Acid-Base Disorders

the simple way

Q1. Acidosis or Alkalosis?

Remember compensation is never 100%

pH < 7.4 . Acidosis pH > 7.4 . Alkalosis pH = 7.4 .. Youre fine (or mixed)

Metabolic or Respiratory

If its acidosis (or alkalosis) look for the source of acid (or base) HCO3 < 24 HCO3 > 24 metabolic CO2 > 40 CO2 < 40 respiratory

Compensated or Uncompensated?
Check with the formulas Fig 43.23 in Berne & Levy

Im not sure whether he gave you these formulas. If he didnt dont worry.

Check the nomogram

It will tell you acute vs chronic.

Is it Mixed?
Note that HCO3- and CO2 move in opposite directions If they move in the same direction you have a mixed disorder.

Clinical Causes

Metabolic Acidosis: Diabetic ketoacidosis, diarrhea Metabolic Alkalosis: antacid, vomiting (will loose Cl too) Respiratory Acidosis: Hypoventiliation, pulmonary edema Respiratory Alkalosis: Hyperventilation

Cell Diagrams
You can find these in Costanzo, Hudsons H/O or Berne & Levy. Best study tool: Draw these out yourself. Know them cold.

Stone Kidneys are cool .

Good luck .