Renal Pathophysiology I

1. Renal Pathophysiology I Review of Renal Function Role of the Kidneys in Maintaining Blood Volume and Pressure

2. Main Functions of Kidneys • Regulation of Blood Volume and Pressure • (focus of today’s lecture) • Regulation of Plasma Composition • (focus of Lecture 2) • Elimination of Wastes • (focus of Lecture 3) • Excretion of foreign chemicals • Endocrine functions

3. Role of Kidneys in Disease • Innocent bystanders in other problems or pathologies • Most often, kidneys help solve these problems • Sometimes the kidney can contribute to problems • Often damaged by other disease processes • Indicator of disease elsewhere in the body

11. From: Physiology of the Kidney and Body Fluids” by R.F. Pitts.

12. Glomerular Filtration Rate (GFR) • Good indicator of renal function • Declines with age, but large safety factor • Significance of changes: • Moderate changes in GFR provide information to kidney about blood volume • A significant fall in GFR causes substances that are normally eliminated by the kidneys to remain in the blood = renal failure

13. GFR Declines with Age http://www.kidney.org/PROFESSIONALS/kdoqi/guidelines_ckd/Gif_File/kck_f9.gif

14. Determinants of GFR • Rate of filtration = hydraulic permeability x surface area x net filtration pressure. or: • Rate of filtration = Kf x net filtration pressure. • The forces that deterine the net filtration pressure are the same Starling Forces that affect all capillaries: • Capillary hydrostatic pressure, interstitial hydrostatic pressure, capillary oncotic pressure, interstitial oncotic pressure

16. These determinants can change with injury or disease • Diabetes – deposition of extracellular matrix material decreases Kf. • Obstruction of kidney tubule (due to inflammation or scarring) will Increase PBS, which will decrease GFR • Autoimmune diseases such as lupus (SLE) involves production of immune complexes that can damage the glomerulus, ultimately decreasing the Kf.

17. Regulation of GFR • Changes in MAP change renal blood flow • Changes in contraction of renal arterioles can shift the GFR.

19. Regulation of Renal Blood Flow:Tubuloglomerular Feedback Macula densa cells sense Chloride delivery to distal tubule A decrease in chloride delivery triggers local response that dilates the afferent arteriole, helping to raise GFR towards normal. Works in reverse as well: More chloride constricts afferent arterioles

20. Regulation of Sodiumand Blood Volume

21. What is the connection between sodium and blood volume? • Sodium is freely filtered at the glomerulus • About 65% is reabsorbed in the proximal tubule • Another 25% is reabsorbed in the loop of Henle • Most of the remaining 10% is reabsorbed in the distal convoluted tubule and collecting duct. • Less than 1% winds up in the urine • The reabsorption of water follows the reabsorption of sodium, down the osmotic gradient.

23. Sodium Balance Decrease Na+ in urine increased blood volume increase blood pressure

24. Regulation of Sodium Excretion • Most important sensors are ones that detect blood pressure, both inside (the juxtaglomerular apparatus) and outside (the arterial baroreceptors). • The controlled variable is the amount of sodium excreted in the urine.

25. Regulation of Sodium Excretion • Two Hormone Systems Involved: • Renin/Angiotensin/Aldosterone • Atrial Natriuretic Peptide (ANP)

26. Renin • Made by juxtaglomerular cells • An enzyme that splits angiotensinogen to form angiotensin I. Angiotensin I (AI) is then converted to angiotensin II (AII) in the lungs via angiotensin converting enzyme (ACE) • Stimuli for release include sympathetic nerve activity, decreased intrarenal BP, decreased delivery of Na+ and Cl- to macula densa

27. Secrete renin

29. Actions of Angiotensin II • Release of Aldosterone • Vasoconstriction • Release of ADH (antidiuretic hormone) • Stimulation of Thirst

30. Aldosterone • Steroid hormone made by adrenal cortex. • Controls activity and/or number of Na+/K+/ATPase pumps in distal tubules and collecting ducts. • Increased aldosterone leads to increased reabsorption of Na+ and water (assuming distal tubules and collecting ducts are permeable to water, which is under the control of ADH). • Release triggered by angiotensin II, and by high extracellular K+ (more on this later).

31. Aldosterone alters the expression of this enzyme

32. Atrial Natriuretic Peptide • Made by atria of the heart • Release triggered by increased stretch of atria (indicating increased blood volume) • Actions include: • Dilates glomerular afferent arterioles, increasing GFR. • This increases the amount of sodium filtered, thereby increasing sodium excretion • Inhibits Na+ reabsorption in collecting ducts

34. Plasma Osmolarity Posm= 2 x [Na+(mEq/L)]p + [glucose (mg/dl)]/18 + [urea (mg/dl)]/2.8 • Plasma osmolarity is normally about 295 mOsm/L • Sodium, which is normally between 135-145 mEq/L accounts for most of the osmolarity of the blood. • We’ll talk about the rest of what’s in the blood later. • Generally, a rise in plasma osmolarity indicates dehydration. We’ll discuss exceptions later.

35. Regulation of Osmolarity • Osmolarity is sensed by osmoreceptors in hypothalamus • Controlled variables: • Urine volume and osmolarity • Thirst and fluid consumption

36. Urine Volume and Osmolarity is Largely Regulated by ADH • ADH = Antidiuretic Hormone = Vasopressin • Actions of ADH: • Increases reabsorption of water in the distal tubules and collecting ducts. • Contraction of arteriolar smooth muscle throughout the body, increasing TPR

37. (ADH release)

38. Mechanism of ADH Action • Distal tubules and collecting ducts are normally nearly impermeable to water. • In presence of ADH, they become permeable, allowing water to move out of the tubule, down its osmotic gradient. • Depending of levels of ADH, the osmolarity of urine can be very high (around 1400 mOsm) or low (100 mOsm). • Likewise the volume of the urine can be high or low.

39. Stimuli for ADH Release • An increase in plasma osmolarity (as little as a 2% change) • A decrease in blood volume (need about 10% change to trigger release). Sensed by atrial volume receptors and arterial baroreceptors • Angiotensin II • Certain drugs (nicotine, narcotics) • Inhibited by alcohol

40. Vasopressin = ADH

41. Vasopressin = ADH Also: Alcohol inhibits ADH release

42. Control of Thirst

43. Thirst centers Vasopressin = ADH drinking Return of plasma Volume to normal

44. decreased plasma volume i decreased venous, atrial and arterial pressures l m increased ADH release stimulation of thirst centers in brain i i increased permeability of increased drinking distal tubules and collecting ducts l i l decreased water excretion l m l return of plasma volume towards normal

45. Common Scenario: Hemorrhage Cardiovascular responses help, but cannot correct loss of blood volume

46. Immediate Responses: When plasma volume falls, GFR falls, too Less sodium and water is excreted The reflex increase in sympathetic nerve activity augments this effect.

48. ADH is release in response to the fall in BP. It helps retain water and also triggers thirst Thirst centers Vasopressin = ADH drinking Return of plasma Volume to normal

50. When can this response go wrong? • If there is no true fall in blood pressure, just a decrease in blood flow to the kidney. This could occur if there is atherosclerosis of the renal artery, or an anatomic malformation of this blood vessel • If there is heart failure, blood pressure is low due to failing heart, not blood loss.