Regulation of kidneys work.Regulation of kidneys work.Role of kidneys in Role of kidneys in homeostasis maintenance.homeostasis maintenance.

Balancing role of the kidneyBalancing role of the kidney

• Water balanceWater balance

• Sodium / potassium / chloride intake and Sodium / potassium / chloride intake and excretion balancedexcretion balanced

• Average daily requirements:Average daily requirements:• Water : 25 - 35 ml/kg/dayWater : 25 - 35 ml/kg/day• Sodium : 1 - 1.4 mmol/kg/daySodium : 1 - 1.4 mmol/kg/day• Potassium: 0.7 - 0.9 mmol/kg/dayPotassium: 0.7 - 0.9 mmol/kg/day• Chloride : 1.3 - 1.9 mmol/kg/dayChloride : 1.3 - 1.9 mmol/kg/day

Urine formation results from Glomerular Urine formation results from Glomerular filtration, Tubular reabsorption, and Tubular filtration, Tubular reabsorption, and Tubular secretionsecretion

Urinary excretion rate = Filtration rate – Reabsorption rate + Secretion rateUrinary excretion rate = Filtration rate – Reabsorption rate + Secretion rate

Filtration only

Urine

GFR = C in

Filtration, reabsorption

Urine

C sub. ˂ C in.

C sub. ˃ C in.

Filtration, secretion

Urine

Glomerular Filtration Rate - Glomerular Filtration Rate - DeterminantsDeterminants

This is simplification of Starlings principle for This is simplification of Starlings principle for movement across capillariesmovement across capillaries

Net Filtration = KNet Filtration = Kff NFP NFP KKff is Filtration co-efficient is Filtration co-efficient

Incorporates surface area Incorporates surface area membrane permeability membrane permeability

NFPNFP= = Net filtration pressureNet filtration pressure in mmHg: in mmHg:NFP = Glomerular capillary hydrostatic pressure – NFP = Glomerular capillary hydrostatic pressure – Bowman’s capsule hydrostatic pressure – Glomerular Bowman’s capsule hydrostatic pressure – Glomerular capillary oncotic pressurecapillary oncotic pressure

Glomerular filtration rate (GFR)Glomerular filtration rate (GFR)KKff affected by: affected by:

– Mesangial cell contraction Mesangial cell contraction ↓↓ area area– Causes Causes - angiotensin II- angiotensin II

- ADH- ADH- bradykinin- bradykinin

– Membrane permeability relatively constantMembrane permeability relatively constant

Think about the effects of each of the determinants of net Think about the effects of each of the determinants of net filtration pressure – filtration pressure – GCHPGCHP e.g: if afferent arteriole constriction, efferent arteriole dilatation, e.g: if afferent arteriole constriction, efferent arteriole dilatation,

GCHP falls. This leads to a fall in GFR GCHP falls. This leads to a fall in GFR BCHPBCHP e.g: ureteric obstruction causes e.g: ureteric obstruction causes ↑↑BCHP and BCHP and ↓↓GFRGFRGCOPGCOP e.g: fluid overload with low oncotic pressure - e.g: fluid overload with low oncotic pressure - ↑↑GFRGFR

Net Filtration Pressure along Net Filtration Pressure along glomerulusglomerulus

Drop along capillary due to Drop along capillary due to Decreased glomerular capillary hydrostatic pressureDecreased glomerular capillary hydrostatic pressureIncreased glomerular capillary oncotic pressureIncreased glomerular capillary oncotic pressure

Glomerular capillary NFP:Glomerular capillary NFP:NFP = GCHP – BCHP – GCOPNFP = GCHP – BCHP – GCOP

NumbersNumbers::Afferent end: Afferent end: 24 = 60 - 15 – 2124 = 60 - 15 – 21Efferent end:Efferent end:10 = 58 – 15 - 3310 = 58 – 15 - 33

Factors affecting GFR - Factors affecting GFR - summarysummary

1. Mean Hydrostatic driving force1. Mean Hydrostatic driving force

(pressure in GC-BC)(pressure in GC-BC)

2. K2. Kff (filtration coefficient) (filtration coefficient)

3. Oncotic pressure gradient3. Oncotic pressure gradient

Measuring GFRMeasuring GFRIdeal is Ideal is CLEARANCECLEARANCE of a substance that is freely of a substance that is freely

filtered by the glomerulus but not secreted or filtered by the glomerulus but not secreted or reabsorbed. Also not stored, metabolised in kidney, reabsorbed. Also not stored, metabolised in kidney, not toxic, does not alter GFR and easy to measure.not toxic, does not alter GFR and easy to measure.

INULININULIN is gold standard is gold standardWould need constant infusion to maintain a constant Would need constant infusion to maintain a constant

plasma concentrationplasma concentration

Creatinine – not ideal – formed by muscle, released Creatinine – not ideal – formed by muscle, released at reasonably constant rate, BUT – overestimates at reasonably constant rate, BUT – overestimates GFR by approx 10% due to SECRETION in tubulesGFR by approx 10% due to SECRETION in tubules

Plasma ClearancePlasma Clearance

Plasma clearancePlasma clearance is defined as is defined as the the amountamount of plasmaof plasma that is that is cleared cleared oror “cleansed“cleansed” ” of a particular of a particular substancesubstance inin one minuteone minute. The . The kidneys kidneys will will carry out thiscarry out this clearance process through the use of clearance process through the use of filtrationfiltration, , reabsorptionreabsorption and and secretionsecretion

Filtration will Filtration will directlydirectly affect clearance. affect clearance. As filtration increases, more material As filtration increases, more material will be removed from the blood will be removed from the blood plasma. Reabsorption will plasma. Reabsorption will indirectlyindirectly affect clearance. As reabsorption affect clearance. As reabsorption increases, less material will be increases, less material will be removed from the blood plasma. removed from the blood plasma. Secretion will Secretion will directlydirectly affect affect clearance. As secretion increases, clearance. As secretion increases, more material will be removed from more material will be removed from blood plasma.blood plasma.

Plasma ClearancePlasma Clearance

The formula used to calculate plasma The formula used to calculate plasma clearance is:clearance is:

C = V x U/PC = V x U/P

C C = plasma clearance rate in ml/min= plasma clearance rate in ml/min

VV = urine production rate in ml/min = urine production rate in ml/min

U U = the concentration of a substance in the = the concentration of a substance in the urine in mg/mlurine in mg/ml

PP = the concentration of a substance in the = the concentration of a substance in the plasma in mg/mlplasma in mg/ml

As you track the units in the equation, you will As you track the units in the equation, you will notice that mg/ml cancel out, leaving ml/min. notice that mg/ml cancel out, leaving ml/min.

Let us practice calculating plasma Let us practice calculating plasma clearance using the clearance clearance using the clearance equation. In all your calculations, equation. In all your calculations, assume that the urine production rate assume that the urine production rate (V) is 2 ml/min. Let’s start with the (V) is 2 ml/min. Let’s start with the substance inulin (not insulin!). If after substance inulin (not insulin!). If after a dose of inulin, your urine has 30 a dose of inulin, your urine has 30 mg/ml and your plasma has 0.5 mg/ml mg/ml and your plasma has 0.5 mg/ml of this substance, what is the inulin of this substance, what is the inulin clearance rate? If you got 120ml/min, clearance rate? If you got 120ml/min, you are correct!you are correct!

120 ml/min = 2 ml/min x 30 mg/ml/ 0.5 mg/ml120 ml/min = 2 ml/min x 30 mg/ml/ 0.5 mg/ml

Renal Blood Flow (RBF)Renal Blood Flow (RBF)

Very high – 20% cardiac output at rest, (1200ml Very high – 20% cardiac output at rest, (1200ml blood/min or 600ml of plasma/min). Kidneys blood/min or 600ml of plasma/min). Kidneys <1% body wt<1% body wt

Tightly autoregulated (similar to heart, brain)Tightly autoregulated (similar to heart, brain)Why the high blood flow:Why the high blood flow:

High OHigh O22 consumption – consumption – 6ml/100g/min (C/W heart 8-10, Brain 3.5)6ml/100g/min (C/W heart 8-10, Brain 3.5)Second highest behind heart (per gram tissue)Second highest behind heart (per gram tissue)

Most blood flow and OMost blood flow and O22 consumption goes to consumption goes to cortexcortex

Oxygen extraction quite low – 1.5vol% c/w 5vol% Oxygen extraction quite low – 1.5vol% c/w 5vol% for body as wholefor body as whole

Related mainly to active NaRelated mainly to active Na++ reabsorption and H reabsorption and H++ ATPase pumps. Linked to GFR. (ATPase pumps. Linked to GFR. (↑ GFR ↑ GFR ↑0↑022 consumption.)consumption.)

Regulation of RBFRegulation of RBF

SYSTEMIC and LOCAL (=autoregulation)SYSTEMIC and LOCAL (=autoregulation)

SYSTEMIC effects blood flow to more than just kidneysSYSTEMIC effects blood flow to more than just kidneys

NeuralNeural – sympathetic/noradrenergic – sympathetic/noradrenergicVasoconstrictionVasoconstriction – – ↓ ↓ RBFRBF. Small . Small ↓ GFR (↓ GFR (partially partially

offset by increased oncotic pressure in offset by increased oncotic pressure in glomerular capillaries)glomerular capillaries)

Increased renin secretionIncreased renin secretion (direct effect on (direct effect on 1 1

receptors). Causes angiotensin II release receptors). Causes angiotensin II release Afferent and efferent V/C and also action on Afferent and efferent V/C and also action on mesangial cells mesangial cells ↓ GFR ↓ GFR (but (but ↓ RBF↓ RBF more so more so filtration fraction increases)filtration fraction increases)

Increased sensitivity of juxtaglomerular cellsIncreased sensitivity of juxtaglomerular cells

Humoral Humoral Noradrenaline – V/CNoradrenaline – V/C

Prostaglandins – PGIProstaglandins – PGI22, PGE, PGE22. Cause renal . Cause renal arteriole V/Darteriole V/D

Renin (as per prev page)Renin (as per prev page)

OtherOther – e.g. exercise, diet – e.g. exercise, diet

Renin – Angiotensin systemRenin – Angiotensin system

Autoregulation of RBFAutoregulation of RBF

• MYOGENIC and MYOGENIC and METABOLIC METABOLIC componentscomponents

• Metabolic component Metabolic component here is here is tubuloglomerular tubuloglomerular feedbackfeedback, that also , that also regulates GFRregulates GFR

• RBF relatively constant RBF relatively constant between approx between approx MBPMBP 75 75 and 170 mmHGand 170 mmHG

Reabsorption of sodiumReabsorption of sodium

Mechanisms of Mechanisms of reabsorptionreabsorption