CVR course III: diabetes and vascular disease Renal handling of salt & systemic consequences

Liffert Vogt November 12, 2018 Homeostasis

Osmoregulation Volume regulation What is osmoregulation?

• Principal osmoles in blood: ✔Sodium, chloor, urea, glucose, bicarbonate

✔Osmoregulation is linked to the waterbalance

✔Osmolality vs osmotic pressure (urea and glucose don’t contribute to osm. pressure)

✔Too much water: hyponatremia ✔Too less water: hypernatremia Osmoregulation linked to water balance What is volume regulation?

• Effective circulating volume

✔Volume regulation is linked to sodium balance

✔Too much sodium: edema ✔Too less sodium: volumedepletion Volume regulation linked to sodium balance Volume regulation

• How much (in mL) the plasma volume will expand after infusion of 1 Liter NaCl 0.9% (isotonic)?

• And what about the effective circulating volume? Body ((%) of body weight) Extracellular volume blood volume interstitial volume regulation contraction or expansion space adequate tissue perfusion Adding NaCl, water and isotonic NaCl: effect on plasma and sodium and extra and intracellular volume

NaCl 3% H2O Isotonic Saline Plasma Na - ExtraCF volume Urine Na IntraCF volume - The in the regulation of the effective circulating volume

• GFR is regulated within narrow margins and remains constant until MAP < 70-80 mmHg

• Regulation of the effective circulating volume occurs by influencing the reabsorption of Na+ and H2O Local tissue perfusion

regional hypoperfusion ¯ vasodilation ¯ blood pressure decrease ¯ renal NaCl and fluid retention ¯ effective circulating volume - sum of all tissueperfusions ¹ bloodvolume Regulation effective circulating volume

volume regulation ¯ osmoregulation via plasma Na+ center ADH release in hypothalmus Regulation plasma osmolality

plasma osmolality ­

stimulation thirst stimulation ADH-secretion center ¯ ¯ drinking water retention in collecting duct ­ a decreased effective circulation volume also leads to ADH-secretion Other systems involved in the regulation of the effective circulating volume • Baroreceptors

• RAAS, especially in the presence of absolute or relative hypovolemia Role of baroreceptors

effective volume decreases ¯ decrease cardiac output and BP ¯ baroreceptor stimulation ¯ increased sympathetic tone ¯ increased tubular Na+ reabsorption ¯ increase in effective circulating volume Role of hormones

• Angiotensin II - general - tonus vas efferens ­ - stimulates secretion - stimulates synthesis

• Aldosteron - Na+ retention - K+ excretion

• Atrial natriuretic peptide + - increases urinary Na and H2O excretion - direct vasodilator

Osmoregulation

Sinke AP, Deen PMT. Faseb 2011 Osmoregulation Regulation ADH

Rennke & Denker Renal Pathophysiology 3rd Edition Concentrating and diluting capability

• Urine osmolality: 50 mosmol/kg 1400 mosmol/kg

• Regulation: Henle’s loop collecting duct (ADH) Aquaporines and aldosterone in the principal cell

+

- ANP Overview: note that osmoregulation is not strictly separated from volume regulation

• High serum sodium – water depleted ADH, • Low serum sodium – water excess thirst, osmoles

• Volume overloaded – too much sodium RAAS en • Volume depleted – too less sodium ANP Textbook view on volume and sodium handling

2 compartment model • Extracellular volume (ECV) • Intracellular volume High sodium – high BP

SBP

• PURE study in 17 countries • Including >100,000 subjects • Kawasaki formula used • Spot morning urine sample • Sodium excretion 4.9 g/d DBP

Mente A et al. N Engl J Med 2014;371:601-611. Salt sensitivity • Elderly • African Americans • Obese • Diabetic patients • Users of antihypertensive drugs – RAASi • CKD patients • Proteinuria patients Sodium intake around the world

Northern Japan Tibet Southern Japan USA Germany Italy Spain Malta Finland UK Holland Denmark Iceland Inuit Yanomami

0 10 20 30 grams/day Renal hemodynamics and renal autoregulation

n Physiology of renal hemodynamics n Its role in renal damage Physiology

“The kidney is essentially a bunch of specialized blood vessels” Physiology

• Renal blood flow plm 1 L / min

• Renal extraction oxygen very low (6 %)

• Renal blood flow is high to serve

• Glomerular filtration is hemodynamically driven

• Glomerular filtration plm 200 L / d

• Daily urine production plm 1.5 -2 L / d Glomerular capillary pressure is quantitatively the main determinant of GFR

Afferent arteriole

Pgc can be regulated with high precision by presence of both a pre- and a post-capilary sphincter. Presence of a post-capillary sphincter, the efferent arteriole, is unique to the kidney Blood pressure in the renal vascular bed

Efferent arteriolar tone allows maintenance of glomerular pressure despite filtration of fluid

120 100 80 60 mmHg 40 20 0

a renalis afferent efferent glomerulus peritubular The Starling forces governing glomerular filtration

Net filtration gradient (max plm 13 mmHg)

Pgc Small change in Pcg: Pgc large effect on total filtration gradient

Pb Pb Renal vascular resistance, renal blood flow, and filtration

n Renal blood flow (RBF) determined by:

n Perfusion pressure

n Total renal vascular resistance (afferent + efferent) (Ohm’s law)

n Filtration (GFR) determined by

n Renal plasma flow (RPF) and balance afferent-efferent tone (glomerular pressure)

n Proportion of RPF that is filtered (filtration fraction: GFR/RPF) provides estimate of glomerular pressure in man Regulation of filtration pressure

n Afferent vascular tone n Autoregulation – myogenic n Tubuloglomerular feedback n Efferent vascular tone n Angiotensin-II dependent Regulation of filtration pressure

n Afferent vascular tone n Autoregulation (myogenic) n Keeps filtration pressure constant over wide range BP n Keeps GFR constant n Protects glomerulus against hypertensive damage n Tubuloglomerular feedback n Adapts filtration to keep distal sodium delivery within certain limits n Efferent vascular tone n Angiotensin-II dependent n Tubuloglomerular feedback

GFR increases ¯ increased Cl- delivery in ¯ constriction vas afferens and mesangium ¯ GFR decreases Macula densa and juxtaglomerular cells Autoregulation bij afferent arteriole

200

150 GFR 100 ERPF 50

0

40 80 120 160 Constant filtration pressure over wide renal perfusion range of BP pressure mmHg Regulation of filtration pressure

n Afferent vascular tone n Autoregulation – myogenic n Tubuloglomerular feedback n Efferent vascular tone n Angiotensin-II dependent n Ensures sufficient filtration pressure notwithstanding filtration of fluid from the glomerular capillaries n Crucial for maintenance of filtration during low renal perfusion pressure. n Also determines pressure in peritubular capillaries downstream – and thus modifies starling forces for tubular sodium reabsorption Effects of altered afferent tone on renal plasma flow en GFR

n Flow & GFR change in parallel: filtration fraction unchanged

Pgc ß GFR ß, ERPF ß, FF =

PgcÝ GFR Ý, ERPF Ý, FF = Effects altered efferent tone on renal plasma flow & GFR

n Different effect on flow and GFR: change in filtration-fraction vasoconstriction

PgcÝ GFR Ý, RPF ß, FF Ý

vasodilation

Pgc ß GFR ß, RPF Ý, FF ß Mechanisms of hyperfiltration/hyperperfusion: afferent dysfunction> glomerular hypertension Hemodynamic mechanisms of hyperfiltration: afferent dysfunction increases renal vulnerability to high blood pressure

Afferent arteriole Glomerular capillary

Efferent arteriole Diabetes (Obesity) ( loss) Increased efferent tone Impaired afferent Increased glomerular autoregulatory pressure control pressure Hemodynamic mechanisms of hyperfiltration: afferent dysfunction increases renal vulnerability to high blood pressure Angiotensin II

Afferent arteriole Glomerular capillary

Efferent arteriole Diabetes (Obesity) (Nephron loss) Increased efferent tone

Capillary damage elicits Increased glomerular protein leakage pressure Diabetic nephropathy: pathogenesis

Typical biphasic course of GFR: early hyperfiltration followed by sharp drop GFR

175

Glomerular filtration rate (ml/min) 150

125

100 Micro- Macro- albuminuria albuminuria

75 0 5 10 15 20

Mogensen Duration of diabetes Glomerular hyperfiltration: also DM II

GFR RBF

Newly diagnosed NIDDM (110) 117 ±22 534 ±123

Control subjects (32) 95 472 ±70# ±12# Vora Kidney Int 1992;41:829-35

NIDDM after improving metabolic control (76) 112 ±21 523 ±113

Vora Diabetologia 1993;36:734-40. Renal conditions in man where glomerular hypertension is likely to contribute to renal damage n Diabetic nephropathy n Obesity-induced renal damage n Oligonephromegaly n Substantial loss of renal mass n Hypertension in african-americans n High sodium intake The achieved blood pressure is the main predictor of renoprotection across different studies

MAP (mm Hg) 95 98 101 104 107 110 113 116 119 0 -2 r = 0.69; P <0.05 GFR -4 (mL/min/year) -6 Untreated -8 hypertension

-10 -12 -14 Parving HH et al. Br Med J. 1989 Maschio G et al. N Engl J Med. 1996* Viberti GC et al. JAMA. 1993 Bakris GL et al. Kidney Int. 1996 Klahr S et al. N Eng J Med. 1993* Bakris GL. Hypertension. 1997 Hebert L et al. Kidney Int. 1994 GISEN Group. Lancet. 1997* Lebovitz H et al. Kidney Int. 1994 Bakris AJKD