CPR 2 Β· Lecture 49 Β· PHYS

Renal Clearance

Objectives: PHYS.0330 Β· 0331 Β· 0332 Β· 0333 Β· 0334 Β· 0335 Β· 0336 Β· 0381  |  Recommended reading: Rhoades & Bell, Medical Physiology 6th ed., Chapter 22

Clearance Principle
GFR Measurement β€” Inulin & Creatinine
RPF & RBF Measurement β€” PAH
Renal Handling of Glucose
Plasma Concentration–Clearance Relationships
Fractional Excretion
Free Water Clearance
Appendix / Summary Tables
Clearance Principle PHYS.0330

Definition

Renal clearance is the volume of plasma cleared of a substance by the kidneys per unit time.

Units: mL/min

Cx = (Ux × V̇) / Px
  • Cx = Clearance of substance x (mL/min)
  • Ux = Urine concentration of x (mg/mL)
  • VΜ‡ = Urine flow rate (mL/min)
  • Px = Plasma concentration of x (mg/mL)

Excretion Rate vs. Clearance

Excretion rate = Ux Γ— VΜ‡  β†’ units: mg/min

Clearance = (Ux Γ— VΜ‡) / Px  β†’ units: mL/min

Excretion rate β‰  Clearance. Clearance normalizes by dividing by plasma concentration.

Worked Example

Px = 0.2 mg/mL; Ux = 6 mg/mL; V̇ = 2 mL/min

1. Excretion rate = 6 Γ— 2 = 12 mg/min

2. Clearance = 12 / 0.2 = 60 mL/min

Quantifying Tubular Function

Filtered load = GFR Γ— Pz
Reabsorption = (GFR Γ— Pz) βˆ’ (Uz Γ— VΜ‡)
Secretion = (Uz Γ— VΜ‡) βˆ’ (GFR Γ— Pz)
Excretion = Uz × V̇
Excretion = Filtration βˆ’ Reabsorption + Secretion
Renal Handling Clearance vs. GFR Example
Filtered only, not excreted C = 0 Glucose (normal plasma level)
Filtered, no reabsorption or secretion C = GFR (125 mL/min) Inulin
Filtered + net reabsorption C < GFR Sodium, urea
Filtered + net secretion C > GFR PAH
NEPHRON β€” RENAL HANDLING OF A SUBSTANCE Glomerulus (Bowman's) Afferent art. Efferent art. Tubule (PCT / LOH / DCT) Peritubular Capillaries Urine Filtration Reabsorption Secretion Excretion LEGEND Filtration (Glomerulus β†’ Tubule) Reabsorption (Tubule β†’ Peritubular) Secretion (Peritubular β†’ Tubule) Excretion (Tubule β†’ Urine)
GFR Measurement β€” Inulin & Creatinine PHYS.0331 Β· 0332

Requirements for an Ideal GFR Marker

  1. Freely filtered at the glomerulus
  2. Not reabsorbed or secreted by the tubules
  3. Not synthesized or metabolized by the kidneys
  4. Non-toxic

β†’ If these are met: Excretion rate = Filtration rate, therefore Clearance = GFR

Inulin β€” Gold Standard for GFR

  • Fructose polymer (exogenous)
  • Freely filtered, NOT reabsorbed, NOT secreted, NOT synthesized, non-toxic
  • Meets all ideal GFR marker criteria
GFR = CIn = (UIn × V̇) / PIn = 125 mL/min

Requires IV infusion; not endogenous β†’ impractical for routine clinical use

Creatinine β€” Clinical GFR Estimate

  • End product of muscle metabolism; produced at constant rate
  • Endogenous β†’ no infusion needed
Ccr = (Ucr × V̇) / Pcr

Normal creatinine clearance: 90–140 mL/min

Two errors that cancel:

  1. Creatinine is slightly secreted β†’ ↑ numerator (Ucr Γ— VΜ‡) by ~20%
  2. Colorimetric assay detects other substances β†’ ↑ Pcr (denominator) by ~20%

β†’ Errors cancel β†’ Ccr β‰ˆ GFR βœ“

Worked Example β€” Creatinine Clearance

Given: 24-h urine volume = 600 mL; Pcr = 10 mg/dL; Ucr = 240 mg/dL; BUN = 80 mg/dL (normal 10–20)

Convert V̇: 600 mL/day ÷ (24 × 60 min) = 0.42 mL/min

Ccr = (240 Γ— 0.42) / 10 = 10 mL/min

Normal: 90–140 mL/min β†’ suggestive of renal insufficiency

Steady-state interpretation:

At steady state: Production = Excretion

↓GFR β†’ ↓Creatinine excretion β†’ ↑ Plasma creatinine accumulates

ProductionGFR (L/d)Pcr (mg/L)
1.8 g/d18010
1.8 g/d11160
PLASMA CREATININE vs. GFR (Inverse Relationship) GFR (L/day) Plasma Creatinine (mg/L) 0 30 60 90 120 150 180 0 20 40 60 80 100 120 140 160 Insidious β€” small Ξ” Pcr despite large ↓GFR Steep: small ↓GFR β†’ large ↑ Pcr CKD (GFR ~11 L/d) Normal (GFR ~180 L/d)
Changes in GFR may take days to manifest as detectable changes in plasma creatinine. ↑Muscle mass β†’ ↑Pcr (age/sex differences). Drugs inhibiting tubular secretion of creatinine β†’ ↑Pcr (false elevation).
Creatinine clearance may overestimate GFR in chronic kidney disease (CKD) when GFR is very low, because the relative contribution of secretion to total excretion becomes proportionally larger.
RPF & RBF Measurement β€” PAH PHYS.0335

PAH (Para-amino Hippuric Acid)

  • Organic anion; given by IV infusion
  • Filtered at glomerulus AND rapidly secreted into tubular fluid
  • At low plasma concentrations: almost completely removed from plasma in a single pass
  • β†’ PAH clearance β‰ˆ Renal Plasma Flow (RPF)
RPF = CPAH = (UPAH × V̇) / PPAH
RBF = RPF / (1 βˆ’ Hematocrit)

Worked Example

UPAH = 65 mg/mL; V̇ = 1 mL/min; PPAH = 0.1 mg/mL; Hct = 0.45

RPF = (65 Γ— 1) / 0.1 = 650 mL/min

RBF = 650 / (1 βˆ’ 0.45) = 650 / 0.55 = ~1182 mL/min β‰ˆ 1200 mL/min

ParameterNormal Value
RPF~650 mL/min
RBF~1200 mL/min
GFR~125 mL/min
Filtration fraction (GFR/RPF)~20%
PAH CLEARANCE vs. PLASMA PAH CONCENTRATION Plasma PAH Concentration (mg/dL) Clearance (mL/min) 0 10 20 30 40 50 60 70 80 0 100 200 300 400 500 600 700 CPAH = RPF (~650 mL/min) Tmax exceeded β†’ CPAH falls (renal venous PAH > 0) Progressive fall as Tmax exceeded
Renal Handling of Glucose PHYS.0333 Β· 0334 Β· 0381

Normal Conditions

  • Glucose freely filtered at glomerulus
  • All filtered glucose reabsorbed in PCT
  • Transporters: SGLT2 (early PCT, high capacity), SGLT1 (late PCT), with basolateral GLUT2 / GLUT1
  • Clearance = 0 at normal plasma glucose

Key Thresholds & Values

  • Renal threshold = plasma glucose at which glucosuria begins β‰ˆ 200 mg/dL
  • Tmax = maximum reabsorption rate β‰ˆ 375 mg/min
  • Splay = gradual rather than abrupt transition; caused by nephron heterogeneity (different nephrons have different Tmax values)
Diabetes mellitus: Plasma glucose far exceeds renal threshold β†’ glucose appears in urine (glucosuria) β†’ osmotic diuresis β†’ polyuria and polydipsia.
GLUCOSE HANDLING β€” FILTERED, REABSORBED, EXCRETED Plasma Glucose Concentration (mg/dL) Rate (mg/min) 0 100 200 300 400 500 600 700 800 0 100 200 300 400 500 600 Splay (nephron heterogeneity) Renal Threshold ~200 mg/dL Tmax ~375 mg/min Filtered Reabsorbed Excreted
Plasma Concentration–Clearance Relationships PHYS.0334 Β· 0335

Inulin

Only filtered, no reabsorption or secretion.

β†’ Clearance always = GFR = 125 mL/min (constant, concentration-independent)

PAH

Filtered + secreted. At low concentrations, nearly all PAH is removed β†’ high clearance (~650 mL/min).

As concentration ↑, secretion hits Tmax β†’ clearance progressively falls.

Glucose

Completely reabsorbed at low concentrations β†’ clearance = 0.

Above renal threshold: excretion begins β†’ clearance rises toward GFR.

CLEARANCE vs. PLASMA CONCENTRATION (Inulin, PAH, Glucose) Plasma Concentration (increasing β†’) Clearance (mL/min) 0 125 250 375 500 625 GFR Renal threshold Inulin (C = GFR) PAH (C > GFR β†’ falls) Glucose (C = 0 β†’ rises)
Fractional Excretion PHYS.0332

Definition & Formula

Fractional Excretion (FE) = proportion of the filtered load of a substance that is ultimately excreted in urine.

FEx = (Ux × V̇) / (GFR × Px)

Equivalently, using creatinine as GFR marker:

FENa = (UNa Γ— PCr) / (PNa Γ— UCr) Γ— 100

FENa β€” Distinguishing AKI Causes

FENaInterpretationMechanism
< 1% Prerenal AKI Tubules intact; vigorous Na⁺ reabsorption (↓flow/volume)
1–2% Indeterminate β€”
> 2% Intrinsic/Renal AKI Tubular dysfunction; unable to reabsorb Na⁺ normally

Clinical Scenarios

ConditionFENaTubular FunctionManagement Implication
Normal ~1% Normal β€”
Dehydration / hypovolemia < 1% Intact Volume resuscitation
Heart failure (low CO) < 1% Intact Treat underlying cardiac issue
Acute tubular necrosis (ATN) > 2% Impaired Supportive; avoid nephrotoxins
Glomerulonephritis > 2% Impaired Immunosuppression, dialysis
Free Water Clearance PHYS.0336

Definition & Formulas

Free water clearance (CHβ‚‚O) = volume of solute-free (pure) water saved or excreted by the kidneys per unit time.

CHβ‚‚O = VΜ‡ βˆ’ Cosm
Cosm = (Uosm × V̇) / Posm
  • VΜ‡ = Urine flow rate (mL/min)
  • Cosm = Osmolal clearance (mL/min)
  • Uosm = Urine osmolality (mOsm/kg)
  • Posm = Plasma osmolality (mOsm/kg)

Interpretation

CHβ‚‚OUrine TypeADH LevelKidney Action
= 0 Isosmotic Moderate Urine = plasma osmolality
Positive (+) Dilute (hypoosmotic) Low Excreting excess water
Negative (βˆ’) Concentrated (hyperosmotic) High Conserving water

CHβ‚‚O = +1 mL/min: 1 mL/min of pure water excreted in excess (dilute urine; ↓ADH)

CHβ‚‚O = βˆ’1 mL/min: 1 mL/min of pure water conserved (concentrated urine; ↑ADH)

Free Water Clearance β€” Three Scenarios

ScenarioCH₂OUosm vs PosmADH LevelFlow (V̇ vs Cosm)Interpretation
Isosmotic = 0 Uosm = Posm Moderate V̇ = Cosm No net free water gain or loss
Dilute Urine > 0 (+) Uosm < Posm Low ↓ VΜ‡ > Cosm Excreting excess free water
Concentrated Urine < 0 (βˆ’) Uosm > Posm High ↑ VΜ‡ < Cosm Conserving free water
Appendix β€” Summary Tables
Instructor: Dr. Noah Leton  |  Reference tables for rapid review
Summary Tables PHYS.0330–0336 Β· 0381

Table 1: Clearance of Key Substances

Substance Renal Handling Clearance vs. GFR Normal Clearance Clinical Use
Inulin Filtered only = GFR 125 mL/min Gold standard GFR marker
Creatinine Filtered + secreted (small) β‰ˆ GFR 90–140 mL/min Clinical GFR estimation
PAH Filtered + secreted (near-complete) >> GFR (at low conc.) ~650 mL/min (= RPF) RPF measurement
Glucose Filtered + completely reabsorbed = 0 (at normal conc.) 0 Glucosuria marker (DM)
Sodium Filtered + net reabsorption (99%) < GFR ~1.25 mL/min Volume status, FENa for AKI
Urea Filtered + partial reabsorption < GFR ~50–75 mL/min Renal function, BUN

Table 2: Key Formulas

FormulaNameUse
Cx = (Ux × V̇) / PxClearanceAny substance
GFR = (UIn × V̇) / PInInulin clearance = GFRGold standard
Ccr = (Ucr Γ— VΜ‡) / PcrCreatinine clearance β‰ˆ GFRClinical GFR
RPF = (UPAH × V̇) / PPAHPAH clearance = RPFRenal plasma flow
RBF = RPF / (1 βˆ’ Hct)β€”Renal blood flow
FL = GFR Γ— PxFiltered loadTubular function
FEx = (Ux × V̇) / (GFR × Px)Fractional excretionAKI classification (FENa)
CHβ‚‚O = VΜ‡ βˆ’ CosmFree water clearanceUrine concentration ability
Cosm = (Uosm × V̇) / PosmOsmolal clearance—

Table 3: FENa Interpretation

FENaLikely Cause of AKITubular Function
< 1% Prerenal (hypovolemia, heart failure, renal artery stenosis) Intact
1–2% Indeterminate β€”
> 2% Intrinsic renal (ATN, glomerulonephritis) Impaired