Introduction to the kidney: regulation of sodium & glucose. Dr Nick Ashton Senior Lecturer in Renal Physiology Faculty of Biology, Medicine & Health

Transcription

1 Introduction to the kidney: regulation of sodium & glucose Dr Nick Ashton Senior Lecturer in Renal Physiology Faculty of Biology, Medicine & Health

2 Objectives Overview of kidney structure & function Glomerular filtration rate Regulation of sodium Regulation of glucose

3 Gross Anatomy

4 Functions of the Kidney Maintenance of ECFV Sodium and water Acid-base balance Excretion of metabolic waste Urea, creatinine Endocrine secretion Renin-angiotensin system Erythropoietin Vitamin D

5 The Nephron 1. Filtration 3. Secretion 2. Selective reabsorption

6 Blood Supply

7 Renal blood flow Cardiac output = 5 litres / min Kidneys receive 20 % = 1 litre / min RBF times > other organs RBF exceeds O 2 requirements of kidneys RBF not regulated metabolically

8 Glomerulus

9 Glomerular filtration rate GFR = K f [P GC - (P BC + GC )] K f = filtration coefficient P GC = glomerular capillary hydrostatic pressure favours filtration GC = glomerular capillary oncotic pressure opposes filtration P BC = Bowman's capsule hydrostatic pressure opposes filtration

10 Glomerular filtration rate GFR = K f [P GC - (P BC + GC )] GFR = K f [55 - ( )] GFR = K f 10 mmhg GFR = 20% RPF = 125 ml/min = 180 L/day = 60 times plasma volume

11 Autoregulation Maintenance of RBF and GFR despite changes in systemic pressure sleep exercise chronic disease e.g. hypertension, renal artery stenosis

12 Autoregulation Afferent arteriole Efferent arteriole Glom. capillary pressure RBF GFR

13 Autoregulation - mechanisms Myogenic vascular smooth muscle responds to stretch by vasoconstricting Tubuloglomerular feedback distal tubular flow regulates vasoconstriction

14 Arterial pressure Glomerular pressure & plasma flow -ve Plasma colloid osmotic pressure -ve Glomerular filtration rate Proximal and loop reabsorption -ve Glomerulotubular balance Proximal to distal tubular flow Early distal tubule: flow related Osm, [NaCl] Preglomerular resistance Afferent arteriole constriction Macula densa: (i) sensor mechanism (ii) transmitter Tubuloglomerular feedback

15 Measurement of GFR Concept of renal clearance Ux V Px Ux = urinary conc. of x V = urine volume per unit time Px = plasma conc. of x Volume of plasma which is cleared of substance x per unit time

16 Freely filtered Not reabsorbed The ideal marker of GFR Not secreted Markers of GFR Creatinine: used clinically but affected by diet, gender, age, ethnicity GFR (ml/min/1.73 m 2 ) = 175 x [serum creatinine ( mol/l) x ] x [age] x [1.212 if black] x [0.742 if female] 51 Cr-EDTA 125 I-iothalamate 99m Tc-DTPA Inulin: gold standard Cystatin C: the (clinical) future? Excreted in urine

17 Sodium reabsorption along the nephron = 1.5 Kg salt per day = 9 g salt per day

18 Why regulate sodium? Plasma [Na + ] determines Extracellular fluid volume Arterial blood pressure Less expensive than active water transport Linked to most other renal transport processes e.g. glucose reabsorption

19 Bulk reabsorption vs fine Proximal tuning 67% Na + reabsorbed PCT Loop of Henlé 25% Na + reabsorbed DCT Distal & collecting duct 8% Na + reabsorbed

20 Late proximal Urine Blood Cl - anion K + ~ Na + NHE-1 Na + H + NHE-3 H + SLC9A1 Na + SLC9A3 Cl -

21 Late distal / collecting duct Urine ENaC Na + ~ K + Blood Na + Aldosterone K + K + Slow (24-48hrs) genomic effect

22 Glucose transport Solute carrier family SLC5 Sodium-linked co-transporters SGLT1 - transports 1 glucose: 2 Na SGLT2 - transports 1 glucose: 1 Na GLUT gene family Facilitated diffusion GLUT1 GLUT2

23 Urine Early proximal Low-affinity high-capacity K + ~ Blood Na + Glucose Na + SGLT2 GLUT2 Glucose GLUT1 Glucose Na + Late proximal SGLT1 High-affinity low-capacity Glucose K + ~ Na +

24 Urine Early proximal Low-affinity high-capacity K + ~ Blood Na + Glucose Na + SGLT2 GLUT2 Glucose GLUT1 Glucose Na + Late proximal SGLT1 High-affinity low-capacity Glucose K + ~ Na +

25 Glucose excretion: T m Fasting glucose ~ 5 mmol/l and GFR = 125 ml/min Filtered glucose = 5 x = 0.63 mmol/min Transport maximum (T m ) ~ 1.25 mmol/min Plasma glucose ~ 10 mmol/l What happens to Steve? Glucose = 12 mmol/l and GFR = 125 ml/min Filtered glucose = 12 x = 1.5 mmol/min Loss of glucose in the urine

26 Glucose transport splay splay Kidney International 2011:79:S1-6

27 What happens to Ada? Glucose = 22 mmol/l and GFR = 22 ml/min Filtered glucose = 22 x = 0.48 mmol/min Transport maximum (T m ) ~ 1.25 mmol/min yet dipstick +ve for urine Single nephron GFR Splay uraemic toxins Loss of glucose in the urine

28 Gluconeogenesis in the kidney Gluconeogenesis 20% glucose production Cortex 300% increase in diabetes lactate pyruvate oxaloacetate phosphoenol pyruvate triose phosphatases glucose lactate pyruvate phosphoenol pyruvate triose phosphatases glucose Medulla Glycolysis

29 Filtration High volume Summary Selective on the basis of size & charge Reabsorption Selective, allowing excretion of waste and foreign substances Based on active transport of sodium Glucose Normally 100% reabsorption Glucosuria occurs when Tm exceeded e.g. in diabetes