H1iii / 16B03 / 16A04/ 14A23: GFR

16B03: Exam Report

Describe the factors that determine glomerular filtration rate (GFR) in the kidney (70% of marks). Outline methods by which GFR can be measured (30% of marks).

57% of candidates passed this question.

Good answers included a description of Starling forces acting at the glomerular basement membrane. A description of the local and systemic factors influencing each component was expected.

It was expected candidates would discuss autoregulation of GFR & RBF, tubuloglomerular feedback, and integrated responses the body uses to keep GFR steady.

Confusion about the nature of induced effects on afferent or efferent arteriolar dilation and constriction limited marks for some candidates. Many failed to mention the effects of mesangial surface area, Bowmans space pressure or serum protein content.

Candidates were expected to outline the methods of GFR estimation. Better responses described the rationale behind the use and limitations. Creatinine clearance, inulin and nuclear medicine techniques all scored marks. Some candidates made no attempt at this section and missed the opportunity to score marks. Estimates of CrCl/GFR [eGFR by formulae such as Cockcroft Gault, and serum Cr] are not measurement of GFR.

16A04: Exam Report

Discuss the factors that influence filtration across the glomerular basement membrane.

38% of candidates passed this question.

It was expected this answer would involve discussion about membrane structure, the unique blood vessel structure (afferent and efferent arterioles allowing a high net pressure to be maintained) and Starlings forces all influencing ultrafiltation. Better answers included comment on mesangial cells contraction to decrease surface area ( caused by angiotensin 2). Details regarding molecular weight cut offs (> 7000 Da are not filtered freely) gained additional credit.

14A23: Exam Report

What is the Glomerular Filtration Rate (GFR)? Discuss the physiological factors that can influence it.

40% of candidates passed this question.

Generally this question was well answered. Almost all answers gave the correct value for GFR

Better  answers  discussed  the  physiological  factors  affecting  each  force  (hydrostatic  and osmotic) across the membrane in a stepwise logical manner.

Some answers discussed the control of renal blood flow; this was not expected and therefore was not rewarded.

H1iii / 16B03 / 16A04 / 14A23: Describe the factors that determine GFR (70 marks). Outline methods by which GFR can be measured (30 marks) Discuss the factors that influence filtration across the glomerular basement membrane What is GFR? Discuss the physiological factors than can influence it

Glomerular Filtration Rate

  • GFR = the volume of plasma filtered by the kidneys per minute → normally 125mL/min
  • Renal blood flow = 1.2L/min
      • 45% = HCt, ∴55% = plasma

∴RENAL PLASMA FLOW = 0.55 x 1.1L/min = 600mL/min

∴ of the 600mL entering glomeruli:

    • 125mL/min goes into Bowman’s space
    • 475mL/min goes to Eff. Arterioles → peritubular caps
  • This ratio (RBF:RPF) is KA FILTRATION FRACTION
  • Ultrafiltration = passive movement of protein free fluid from glom caps → Bowmans’ Capsule

↓

Generation of ultrafiltrate is one of the key functions of the kidney

Determinants of GFR

  • Rate of filtration of any capillary determined by:
    • NET FILTRATION PRESSURE
    • TOTAL SA
    • PERMEABILITY OF FILTRATION MEMBRANE

∴ RATE OF FILTRATION = PERMEABILITY x SA x NFP

Permeability x SA = Kf (filtration coefficient)

NFP = (Glomerular cap hydrostatic P – glomerular cap oncotic P)–(Bowman’s capsule hydrostatic P–Bowman’s capsule oncotic P) 

Permeability

  • Filtration barrier of Renal Corpuscle is formed by 3 layers:
    1. CAPILLARY ENDOTHELIUM
    2. BM
    3. BOWMAN’S CAPSULE EPITHLIUM

1) Cap Endothelium

  • Fenestrated
  • Freely permeable H2O, small solutes <7000Da
  • Impermeable to cells (RBC, WBC, platelets)
  • Has negatively charged glycoproteins ∴limits filtration of large anionic proteins
  • Synthesises vasoactive substances → NO (VD) & ET-1 (VC)

2) Basement Membrane

  • Covers endothelial cells
  • Negatively charged proteins
  • Main role is to filter based on charge

3) Bowman’s Capsule Epithelium

    • Covered by PODOCYTES
    • FILTRATION SLIT DIAPHRAGMS
    • Size selective filtration
    • Stops proteins & macromolecules passing into Bowman’s space (i.e. albumin is 70,000Da ∴should not appear in glomerular filtrate)

∴Glomerular Filtrate contains amino acids, electrolytes, glucose in same [  ] as plasma

  • Glomerular filtrate should NOT contain cells & large molecular weight proteins

Surface Area

  • Depends on no. of functioning nephrons
  • This ↓with ↑age

Net Filtration Pressure

NFP = (PGC – πGC) – (PBC – πBC)

  • NFP is the sum of hydrostatic + oncotic pressures resulting from protein
  • On either side of the capillary wall are 4 pressures → 2 HYDROSTATIC & 2 ONCOTIC
  • KA STARLING’S FORCES

PGLOM CAP

  • Hydrostatic P of caps is high
  • Minimal ↓along length of caps because large cross sectional area of glomeruli results in v. small resistance to flow
  • HYDROSTATIC P of GC is determined by Arterial P & resistance of Aff. & Eff. Arterioles
  • ∆ arterial P will ∆ PGC in same direction, but because of autoregulation this effect is minimal
  • Aff. ↑ resistance = ↓PGC = ↓GFR
  • Eff. ↑ Resistance = ↑PGC = ↑GFR

ΠGLOM CAP

  • Entering capillaries πGC = πplasma
  • ΠGC ↑along length of caps because large amounts of protein free fluid are being filtered out
  • ↑πGC = ↓NFP

PBC

  • Tubules constantly carry fluid away from Bowman’s capsule
  • ∴PBC is v. low & often negligible/excluded from NFP equation
  • Only of importance in pathology → i.e. obstruction to tubule outflow → ↑PBC → ↓NFP

ΠBC

  • Should be zero
  • Any protein in BC will ↑filtration

Mean NFP = 17mmHg

↓

Which produces the 180L/day of glomerular filtrate

  • The glomerulus is a v. specialised capillary bed
    • 2 sets of arterioles (afferent & efferent)
    • 2 sets of capillaries (glomerular & peritubular)
  • Resistance of aff. & eff. arterioles is usually equal → allows glom caps to operate at higher pressures than other cap beds → high glom P is essential for filtration
  • Peritubular capillaries are between the eff. Arteriole & veins → ∴low capillary pressure → essential for tubule reabsorption

Regulation of GFR

  • GFR = Kf x NFP
  • In health Kf is constant
  • ∴GFR is regulated by regulating NFP, mainly through their effect on RBF → the two are inextricably linked

→ Renal autoregulation

→ Neuronal regulation

→ Hormonal regulation

1) Renal Autoregulation

  • Between MAP 70 – 170 RBF remains constant to protect GFR 125mL/min
  • 2 mechanisms:

1) Myogenic Mechanism

  • Afferent & efferent arterioles contain smooth m.
  • ∆ transmural P stimulates smooth m.
  • ↑arterial P = ↑transmural P → smooth m. contraction
  • ∴afferent VC → maintain RBF & GFR constant

2) Tubuloglomerular Feedback

  • Macula Densa → specialised cells in wall of thick asc. LoH as it passes b/w afferent & efferent arterioles
  • ↑renal perfusion = ↑GFR → ↑[NaCl] in tubule lumen → detected by Macula Densa → produce adenosine → A1 receptor of aff. arterioles VC → restore GFR

Neuronal Regulation

  • Aff. & eff. arterioles are innervated by symp n. fibres of ANS
  • Basal symp tone is minimal
  • But altering the resistance of these vessels greatly affects NFP by H-P equation
Q
  • Radius of vessels to power of 4 directly ∝ to flow through the vessel
    • Afferent VC → ↓PGC → ↓GFR
    • Afferent VD → ↑PGC → ↑GFR
    • Efferent VC → ↑PGC → ↑GFR
    • Efferent VD → ↓PGC → ↓GFR
  • & eff. tone are autoregulated between MAP 70 – 170mmHg
  • Also affected by hormones

Hormonal Regulation

  • Main hormonal control of GFR is via AII
  • Juxtaglomerular apparatus is a distinct part of nephron → it is where Thick Asc. LoH passes in b/w aff. & eff. arteriole
  • Contains GRANULAR CELLS which synthesise, store & secrete RENIN
  • RENIN secretion stimulated by ↓BP, ↓Na+ sensed by Macula Densa, SNS stimulation
  • AII is one of the most powerful VC’s
  • VC of vessels to ↑RBF
  • But intense efferent VC → ↑NFP → ↑GFR
  • AII also ↑aldosterone & ↑ADH secretion to ↑blood vol & maintain GFR

GFR Measurement

  • Properties of an indicator substance
  1. Stable → not metabolised/degraded/physiologically reactive
  2. Non-toxic
  3. Easy to measure
  • Use of clearance to measure GFR
    • RENAL CLEARANCE = the volume of plasma completely cleared of a substance by the kidney per unit of time
Clearance

(CLEARANCE = UV/P)

  • So renal clearance can be used to measure GFR if a substance measured only reflects filtration
  • ∴it will have to:
    1. Freely filtered at renal corpuscles
    2. Not reabsorbed
    3. Not secreted
    4. Not synthesised by tubules

Inulin = a polysaccharide that fits above description

  • Problem with inulin:
    • Not naturally occurring in body
    • Delivered by an IV infusion until reaches steady state
    • You need a urine collection over a fixed time whilst it is at SS

Creatinine

  • It is a lesser substitute
  • Formed from muscle creatine
  • Released into blood at constant rate ∴not fluctuating over 24hrs
  • Of the criteria, it does not meet 1 because it is secreted by tubules

∴provides small OVERESTIMATE of GFR

  • Creatinine varies with muscle bulk

∴corrected for age, weight, sex by COCKROFT-GAULT equation

  • There is also a non-linear relationship between serum creatinine & creatinine clearance
  • Renal function ↓50% before a significant ↑CrT plasma is seen