MPP II 2.4 - RENAL PHYSIOLOGY I

• Lecture #14 covered Renal Physiology I, presented on Wednesday, February 12th.
• The presenter was Julia M. Hum, Ph.D.

Learning Objectives

• Identify the main structures of the kidney's anatomy and relate them to their function within renal physiology
• Explain the four basic steps that lead to urinary excretion
• Describe the blood supply of the kidney
• Label the main components of the nephron and describe their role in relation to filtration
• Compare and contrast the types of nephrons
• Describe the forces at play in control of GFR
• Recognize the principle regulators of GFR and the mechanisms by which they regulate GFR
• Interpret the three methods of assessing renal function

Importance of Renal Physiology

• Most hospitalized patients need water management and electrolyte adjustments
• Renal function predominantly influences long-term blood pressure regulation
• Management of hypertension necessitates understanding renal function
• Chronic kidney disease's prevalence represents a significant clinical challenge
• Managing chronic kidney disease requires navigating a diverse range of co-morbidities
• About 15% of the U.S. population has chronic kidney disease
• High blood pressure and diabetes are the two main causes of CKD
• CKD often goes undetected during early stages
• Medicare spends $50 billion to treat CKD
• There exists potential for new therapeutic kidney disease strategies

Kidney Anatomy

• The hilum consists of the renal artery, vein, lymphatics, nerve supply, and ureter.
• The two major regions of the kidney are the cortex and medulla
• Renal pyramids reside within the medulla

Kidney Workflow

• Kidneys clean blood by extracting all components except plasma proteins, then selectively reintroducing desired ones
• The nephron is the interface between Bowman's capsule and vasculature
• Four main activities that affect kidney function:
• Filtration: Blood transforms into filtrate, excluding plasma proteins
• Reabsorption: Introducing molecules from the existing filtrate back into the blood
• Secretion: Additional waste products or excess substances from the blood are drawn into the ultra filtrate and turned into urine
• Excretion: Expulsion of the final urine
• Filtration can be described as throwing everything but the kitchen sink onto the street

Kidney Bloodflow

• Renal blood flow normally constitutes ~22% of cardiac output
• Renal arteries branch into interlobar, arcuate, and then interlobular arteries before progressing into afferent arterioles leading to glomerular capillaries.
• Peritubular capillaries include interlobular, arcuate, and interlobar veins along with the renal vein.
• These capillaries are where reabsorption and secretion transpire
• Nephrons need well-perfused microvasculature
• Since nephrons are well perfused with microvasculature there can be many micro-ischemic events that alter kidney function
• Decreases to GFR can be caused by aging and microischemic events
• Flow within the peritubular capillary network runs opposite to ultrafiltrate flow
• Filtrate and blood travel in opposing directions

Glomerular and Peritubular Capillary Networks

• Nephrons intake blood at high pressure using leaky blood vessels
• Plasma filtrate is directed for the recovery of vital constituents
• The peritubular network reabsorbs filtered fluid
• The filtrate ends as urine

Nephron makeup

• Each kidney contains from 800,000 to 1 million nephrons; new nephrons cannot regenerate
• After age 40, the number of functional nephrons decreases by 10% every 10 years
• Each nephron contains a glomerulus and tubule
• The glomerulus comprises tufts of glomerular capillaries and facilitates substantial filtration
• Tubules consist of long structures that filter fluid into urine

Glomerulus specifics

• Branching glomerular capillaries form a complex network that maintains high hydrostatic pressure at 60 mm Hg
• Bowman's capsule encloses the glomerulus to receive filtered glomerular fluid
• Next in the capsule you’ll find the proximal tubule from the cortex of the kidney
• Inside the medulla you’ll find the loop of Henle
• Which then sends fluids descending and ascending back to the cortex
• End of thick ascending limb becomes the macula densa within the distal tubule
• Macula densa has specialized epithelial cells and supports nephron function
• Macula densa monitors ultrafiltrate flow rate
• Feedback from the macula densa helps constrict or dilate vessels to maintain constant ultrafiltrate movement

Distal Tubule specific

• Also known as the renal cortex
• Composed of a connecting tubule and a cortical collecting duct
• Receives ultrafiltrate, after which its content is more dilute than in the proximal tubule
• Roughly 250 gathering ducts can be found
• Each duct gathers urine from 4,000 nephrons
• The first portion of the nephron tubule to respond to hormones inside the Distal Tubule

Nephron types

• Juxtamedullary nephrons account for 10% of blood flow
• Superficial nephrons account for 90% of blood flow

Understanding the GFR

• Starling Forces govern filtration and depend on the blood's forces on the membrane
• Take into account hydrostatic molecular diffusion in osmotic pressure
• GFR measures net fluid flow across capillary walls in mL/min
• To calculate GFR, fluid hydrostatic pressure (60 mm Hg) is needed
• From there the numbers can be manipulated to determine net filtration pressure
• Hydrostatic pressure is the force exerted by blood against the vessel walls
• Osmotic pressure is the potential for water to diffuse into a solution

Normal vs bad GFR

• The fact that someone has GFR alone doesn't necessarily mean they have CKD
• If they have an age-related decline however, that would be something to look into
• GFR declines, along with age, can increase the likelihood of CKD
• Remember protein in urine may signify preeclampsia or other underlying issue
• Protein isn’t wanted in ultrafiltrate, so you have to ensure a good connection on these

Starling forces in kidney

• PGC is always higher than πGC in the kidneys
• Three step molecular filter creates a cell and protein free plasma ultrafiltrate
• Capillary endothelial cells come first
• Then there is a thick glomerular basement membrane
• Lastly is the filtration slit diaphragm
• GFR’s are affected by PGC

Forces Favoring Glomerular Ultrafiltration

• PGC = capillary hydrostatic pressure which favors filtration
• πĜC: colloid osmotic pressure which favors fluid retention
• Fluid moves toward the region where the water concentration is lower

What affects Glomerulus

• PGC (influenced by aortic or renal arterial pressure) is the main factor affecting GFR
• Changes in efferent/afferent (arteriolar resistance) also factor
• Body size increases GFR, age decreases it

Arterioles control filtration

• Afferent arteriole constriction reduces filtration (less GFR)
• Dilation increases pressure and GFR (more filtration)
• Efferent arteriole constriction backs up pressure and increases GFR
• Dilation lets blood escape and decreases GFR
• Pressure from filtrate is related to GFR

Bloodflow and GFR

• Vasoconstriction of afferent arterioles decreases
• Vasodilation increases
• Vasoconstriction of efferent arterioles increases
• Vasodilation will decrease

GFR principle regulators

• The three principle regulators of GFR are renal autoregulation, hormonal regulation, and neural regulation

Renal Autoregulation

• Provides constant internal blood pressure and GFR despite changes in systemic arterial pressure
• Vascular autoregulation maintains appropriate RBF for GFR and urine formation

Tubuloglomerular Feedback

• A mechanism regulates RBF and GFR through the juxtaglomerular apparatus (JGA)
• This apparatus is further separated into the renal tubule, mesangial and the efferent and afferent areterioles
• Macula densa monitors the rate of tubular flow
• It can assess sodium as a rate of flowing

Tubuloglomerular Feedback Mesangial Cells

• Has both a communication pathway as well as gap junctions

Tubuloglomerular Feedback Afferent artierole specifics

• Adenosine receptor
• Upon binding, causes constriction
• Granular cells
• Produce renin

3 main hormonal controls

• Constrict, dilate, or prevent dilation

Central ANS controls

• Renal blood flow is controlled by the ANS, proportionate relative to firing levels
• Sympathetic nerve fibers innervate afferent and efferent arterioles
• Under normal circumstances sympathetic stimulation has little to no effect on GFR
• It is important when the brain is ischemic and there is hemmoraging

Assessing renal function by..

• Measuring filtration rate to determine glomerular filtration function.
• Glomerular filtration rate
• Creatinine Clearance.

Clearance in Assessing Renal Function

• The amount of plasma fully clearing any substance over a specific frame
• While plasma flows at ~625 mL/min, the volume normally filtered is 20%, (~125 mL/min)
• Expressed as rate, e.g., Cx=100 ml/min.
• Cx varies by the compound assessed, providing renal function insight in contexts, like homeostasis, disease or similar processes
• Calculation for clearance: Cx = Ux * V/Px
• Ux = the compound's urinary concentration
• Px = the compound's plasma concentration
• V = the flow of urine

Glomerular Filtration Rate

• Inulin "gold standard.” for renal assessment
• Composed as a plant fructose polymer.
• Inulin crosses filtration w/o interference, and moves through tubules as normal and as urine, without issue, so it doesn't stay in the body
• However it takes an unrealistic long time to steadily apply inulin for clinical purposes.
• A similar calculation applies: GFR = Cin = Uin * V/Pin
• Clearance calculation based on inulin provides reliable filtration info
• Still time consuming and takes a while to set up

Creatinine

• Requires infusions to get to appropriate levels with blood draws
• Creatinine is freely filtered and not reabsorbed, and the most commonly known measurement with very easy to do
• Creatinine is and endogenous compound
• Can also produce close estimates like with GFR
• It’s clearance is imperfect however
• Absolute creatinine values = insight.

Explore long-term blood pressure regulation and essential steps in urine production. Understand the clinical significance of renal physiology, challenges in chronic kidney disease (CKD), and age-related kidney function decline. Address structural changes due to chronic hypertension.