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

4. The Burden of Kidney Disease • In 2008, nearly 550,000 people were being treated for end stage renal disease. • Of these, about 70% were on dialysis. • Most are treated at dialysis centers, typically 3 times per week, about 4 hours each time. • Cost = $77,000 per patient per year • All Americans who need dialysis are covered by Medicare, regardless of age

5. Major Causes of Renal Disease • Diabetes: 205,724 cases per year • Hypertension: 133,537 • Glomerulonephritis: 83,268 • Cystic kidney: 26,094 • Urologic disease: 13,065 • All other: 86,294

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

14. 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

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

16. 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 determine 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

18. 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.

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

21. Regulation of Renal Blood Flow: Tubuloglomerular Feedback Macula densa cells sense Na+ and Cl - delivery to the distal tubule When BP drops, Na+ and Cl – delivery drop A decrease in Na+ and Cl – delivery dilates the afferent arteriole, helping to raise GFR towards normal. Works in reverse as well: More Na+ and Cl – constricts afferent arterioles

22. Regulation of Sodiumand Blood Volume

23. 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.

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

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

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

28. 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

30. Secrete renin

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

32. 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).

33. Aldosterone alters the expression of this enzyme

34. 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

36. 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, at least that’s what your kidney thinks. We’ll discuss exceptions later.

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

38. 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

39. (ADH release)

40. 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.

41. 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

42. Vasopressin = ADH

43. Vasopressin = ADH Also: Alcohol inhibits ADH release

44. Control of Thirst

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

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

47. 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. Aldosterone decreases sodium excretion, which helps retain water

49. 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. Another example of fluid loss: