MED 204: Kidney Function Measurement

• The lecture is about measurement of kidney function
• The course code is MED 204
• The lecturers are Prof Triona Ni Chonghaile & Dr. Patrick Walsh
• The date is February 2025

Learning Outcomes

• Define the concept of clearance and calculate clearance values in appropriate units
• Explain clearance in comparing renal handling of substances
• Recall methods of measuring glomerular filtration rate (GFR) using clearance and experimental estimation
• Outline components of urinalysis
• Define glucosuria and proteinuria

Why Renal Clearance Matters

• Assessing renal function is why it is important
• Kidney disease symptoms can include hypertension, edema, bloody urine (hematuria), or be asymptomatic
• GFR must be measured, not directly, but indirectly via clearance

Recapping Glomerular Filtration

• Plasma entering glomerulus is filtered into Bowman's capsule
• Filtered plasma is approximately 20%, which equates to about 180 liters/day
• Filtrate flows through the tubular system, valuable substances are reabsorbed into peritubular plasma
• Glomerular capillary blood pressure drives glomerular filtration

Forces Involved in Glomerular Filtration

• Glomerular capillary blood pressure favors filtration, magnitude 55 mmHg
• Plasma-colloid osmotic pressure opposes filtration, magnitude 30 mmHg
• Bowman's capsule hydrostatic pressure opposes filtration, magnitude 15 mmHg
• The net filtration pressure is the difference between favoring and opposing forces; 55 - (30 + 15) = 10 mmHg

Renal Assessment and Urine Formation

• Ultrafiltration occurs
• Blood is filtered in the glomerular capillaries to create tubular filtrate
• The rate of filtration is the glomerular filtration rate (GFR)
• Reabsorption is the process where filtrate is absorbed back into the blood
• Secretion occurs as substances secrete from the blood into the filtrate

Renal Assessment and Clearance

• The processes involved in urine formation determine the amount of substance in urine
• Renal function can be assessed by measuring the excretion rate of a substance related to its plasma concentration
• Clearance of the substance is this value

Understanding Renal Clearance

• Renal clearance is measured in milliliters of plasma cleared of a substance per minute
• Cs [mL/min] is the symbol and unit of measurement of renal clearance
• Renal clearance is the volume of blood plasma which a particular waste is completely removed from in one minute
• Clearance is substance specific

Clearance Formula

• The general formula: Cs = (Us x V) / Ps
• U represents the concentration of the substance in urine (mg/mL)
• V represents the volume of urine excreted per minute (mL/min)
• P represents the concentration of the substance in plasma (mg/mL)
• Clearance is measured in mL/min
• Direct relationships: ↑[Us] → ↑Cs, ↑V → ↑Cs
• Inverse relationship: ↑[P] → ↓Cs

Measuring Glomerular Filtration Rate (GFR)

• GFR measures the rate at which plasma is filtered at the glomerular capillaries to become tubular filtrate
• GFR is an index of renal function
• Clearance is used to measure GFR
• Decreased GFR is often a sign of renal disease

Necessities for Measuring GFR

• A substance should be filtered freely at the glomerulus to measure GFR
• It should also not be reabsorbed from the filtrate; must not be secreted nor metabolized by tubular cells
• Should not interrupt with kidney function and be easily measured
• The substance needs to enter the tubular filtrate through filtration only and then flow through the tubules and exit in the urine

Inulin Clearance & GFR Measurement

• GFR can be measured using inulin renal clearance
• Inulin is filtered into the tubular filtrate and then flows through the tubules and exits in the urine
• The rate inulin enters the filtrate must be equal to the rate it enters the urine

Inulin Formulae

• Rate of inulin entry into the filtrate: Pin x GFR
• Rate of inulin entry into the urine: Uin x V
• Pin x GFR = Uin x V
• GFR = (Uin x V) / Pin
• Pin = plasma inulin concentration
• Uin = urine inulin concentration
• V = volume of urine excreted/min

Creatinine Clearance

• As inulin does not occur organically in the body, it must be administered intravenously
• Because it must be administered intravenously, it is not commonly used to measure GFR clinically
• In the clinical setting, creatinine, which is a substance produced in the body, may be used to measure estimated GFR (eGFR)

Understanding Creatinine

• Creatinine facilitates ATP production in energy-dependent tissues like muscle and brain
• Liver synthesizes it from arginine (1g/day) + 1g dietary intake
• It is phosphorylated in skeletal muscle and the brain
• Important as an energy source and for quick bursts of anaerobic energy

Creatinine Specifics

• Creatinine forms spontaneously from phosphocreatine
• The constant synthetic rate is approximately 2% of creatine levels per day
• Plasma quantity is based on muscle
• Removed from the blood by glomerular filtration and tubular secretion

Creatine and Renal Filtration

• Increased plasma creatinine is seen when renal filtration is deficient
• Kidney function can be measured by creatine clearance in urine

Accuracy of Creatinine Clearance

• Creatinine does not perfectly meet the criteria for a substance to measure eGFR
• A small quantity of creatinine is secreted into the tubule from the blood
• The error caused is canceled out by another error from the estimation of plasma creatinine

Errors in Creatinine Clearance Cancelled Out

• The fact that some creatinine is secreted into the filtrate results in creatine that enters without filtration
• Term "U" is erroneously high, and Cs = (Us x V) / Ps
• The method for estimating the concentration of plasma creatinine also detects another compound
• "P" is erroneously high, and the errors cancel each other, commonly used for measurement

Clearance Values

• Clearance for both inulin and creatinine is approximately 120 ml/min

Clinically Estimating GFR

• Measuring GFR by measuring creatinine clearance requires assessing creatinine in both plasma and urine
• Mathematical tools can be used to estimate creatinine clearance from the measurement of plasma creatinine only

Clinical Estimation Details

• Clearance must take the patient's age and weight in to account
• Creatinine comes from the breakdown of creatine in muscles
• The amount the plasma/day depends on skeletal muscle mass which depends on age
• Creatinine release into the plasma is constant per day

Estimated GFR Statistics

• 20 to 29 years of age has an average eGFR of 116
• 30 to 39 years of age has an average eGFR of 107
• 40 to 49 years of age has an average eGFR of 99
• 50 to 59 years of age has an average eGFR of 93
• 60 to 69 years of age has an average eGFR of 85
• 70+ years of age has an average eGFR of 75

Estimating GFR

• Creatinine clearance is measured
• The following information is needed:
• Gender
• Age
• Weight
• The best practice model is the Chronic Kidney Disease Epidemiology Collaboration (CDK-EPI 2009)
• GFR can be found with: GFR = 141 × min (Scr/K, 1)α × max(Scr/к, 1)-1.209 × 0.993Age × 1.018 [if female]
• Scr is equal to creatinine in mg/dl

Clearance Statistics: Different Substances

• Comparing clearance of filtered substances with that of inulin reveals the renal handling
• Substances absorbed and filtered has a rate of less than inulin, such as glucose or urea
• Urine levels may be indicators of plasma levels / threshold
• Substances that are greater filtered than insulin has a rate that's higher than what's secreted, for example para-amino-hippuric acid (PAH)

PAH Measurement

• Para-amino-hippuric acid (PAH) is both freely filtrable and nonreabsorbable
• All PAH is secreted by the organic anion secretory pathway in the proximal tubule, which escaped from filtration
• This means this substance is completely removed from the kidneys

Clearance Types

• Case 1: freely filtered, not absorbed, not secreted
• Renal clearance = normal GFR (e.g. Inulin, 125 ml/min)
• Case 2: freely filtered, fully reabsorbed, not secreted:
• Renal clearance = 0 ml/min (e.g. glucose, amino acids)
• Case 3: freely filtered, not absorbed, fully secreted
• Renal clearance = renal plasma flow (625 ml/min) (e.g. para aminohippuric acid (PAH))
• Case 4: freely filtered, slightly reabsorbed, not secreted
• Renal clearance < GFR (e.g. urea (~ 65 ml/min))

GFR and the Kidney

• Evaluating the extent and nature of renal disease depends on knowing GFR
• Renal disease can be generally indicated by a fall in GFR
• A reduction of GFR indicates disease, whilst an increase indicates recovery

Causes of Acute Kidney Injury

• Altered blood supply causes an injury, for example - hemorrhage, heart failure, hypotension
• Damage due to toxins/inflammation, for example - Glomerulonephritis, tubular necrosis
• Urinary tract abnormalities like Urethral obstruction – prostate enlargement or stones
• Assess acute kidney injury using Urea plus electrolyte and/or Sodium, Potassium, Chloride, Bicarbonate, Urea, or Creatinine

GFR Estimations

• The relationship between plasma urea concentration and creatinine estimates
• When renal failure occurs, GFR ↓ and plasma urea ↑

Urine Overview

• Urine is sterile, clear, and amber in color, with a pH of 5.0-6.0
• It is 93-97% water
• 1.2L is roughly expelled from the body

Urine Composition

• Chemical composition:
• 95g/100ml water
• 2g/100ml urea
• 0.6g/100ml sodium chloride
• 0.18g/100ml sulfate
• 0.15g/100ml potassium
• 0.12g/100ml phospate
• 0.1g/100 creatine
• 0.05g/100ml ammonia
• 0.03g/100 uric acid
• 0.015g/100ml calcium
• 0.01g/100ml magnesium
• Volume or composition is affected by diets, drugs, or renal disorders

Urinalysis Summary

• Analysis of urine by physical, chemical, and microscopic means to test for the presence of disease and drugs
• Urinalysis was first carried out in 4000BC
• Involves checking the appearance, concentration, and content of urine
• Diagnoses conditions like Diabetes, UTIs, kidney disorders, liver disorders, and even cancer

Visual Examination

• Hydration level and what substances may be present can be indicated with a visual exam
• Color ranges from pale yellow to dark amber, and unusual colors are caused by dehydration, medications, disease, etc.
• Clarity is rated as clear, cloudy or turbid, and cloudiness arises from mucus, sperm, prostatic fluid, bacteria or blood

Urinalysis Chemicals

• Chemicals are analyzed via test strips with chemicals impregnated into them
• Color indicates the amount of a substance
• Tests check the following:
• Bilirubin
• Glucose
• Haemoglobin
• Ketones
• Nitrite
• pH
• Urobilinogen
• Protein
• Esterases
• Chemical examination is often a precursor to more complicated microscopic examinations

Glucose Relationship

• Glucosuria is when glucose is in the urine
• It is a result of glomerular filtration having more glucose than the renal tubule can reabsorb
• This is when there is above 25 mg/dl glucose in fresh urine

Microscopic Analysis

• Indicates Bacteria and microorganisms, which points to infections
• Microscopic Analysis finds Red blood cells (UTI, renal damage)
• Microscopic Analysis also indicated White blood cells (UTI)
• Epithelial cells indicates inflammation or potentially cancer
• Hyaline Casts are particles made of coagulated mucoprotein released by tubule cells that are usually clear
• Microscopic analysis finds Crystals that can cause kidney stones

Proteinuria Levels

• Increased protein in the urine is Proteinuria
• Proteinuria is caused by foamy urine & or it being diagnosed with a dipstick test
• Caused by three mechanisms
• Glomerular - caused by disease and scarring. In the scenario the glomeruli allows xs protein
• Overload - Large amounts of filterable protein in the tubes that the body can't process/overwhelming -Tubular- PCT has a low reabsorption rate in the PCT

Benign Proteinuria

• Benign (functional) proteinuria
• Proteinuria happens only when standing and isn't detectable in the morning
• Cause is unknown and not associated with future issues