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

16. Determinants of GFR or:
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 Sodium and 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. Posm = 2 x [Na+(mEq/L)]p + [glucose (mg/dl)]/18 + [urea (mg/dl)]/2.8
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 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:

51. 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.

52. Heart Failure
Basic problem is a decrease in blood pressure due to insufficient cardiac output.
Kidneys respond as those there has been a hemorrhage – by increasing:
Sympathetic nerve activity
Renin release
ADH release
This response can be maladaptive, as excessive amounts of retained fluid cause peripheral and pulmonary edema.

53. Responses to Heart Failure

54. During heart failure, fluid retention helps a little, but can quickly lead to edema

56. Extra slides – Add as needed

57. Osmoreceptors are located in the hypothalamus

58. The Loop of Henle concentrates the tubular fluid.
Urine concentration depends on the plasma ADH levels.
ADH determines permeabilitiy of distal tubules and collecting ducts to water.

59. Stimuli for ADH release
Increased plasma osmolarity
Decreased plasma volume
Angiotensin II
Certain drugs (incl. nicotine, narcotics)

60. Inhbitors of ADH Release
A decrease in plasma osmolarity
An increase in blood volume
Atrial Natriuretic Peptide (ANP) (also known as atrial natriuretic factor)
Certain drugs (ethanol)

61. Hypovolemia
Hypotension
Normal blood volume
Normal blood pressure
ADH
release
Hypervolemia
hypertension
Plasma osmolarity (sOsm/L)

62. Control of Thirst
Activity of osmoreceptors (increased osmolarity stimulates thirst)
Activity of blood volume receptors and baroreceptors (a decrease in blood volume or pressure stimulates thirst)
Angiotensin II stimulates thirst

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

64. Decrease Na+ in urine increased blood volume increase blood pressure

65. When sodium is reabsorbed, water follows down its osmotic gradient

66. Sensing of plasma sodium is mostly through indirect signals that reflect blood volume and pressure
Baroreceptors inside and outside the kidney:
Carotid baroreceptors
Juxtaglomerular apparatus
Macula Densa – senses delivery and reabsorption of chloride (which generally reflects sodium delivery)

68. Renin/Angiotensin/Aldosterone System

69. Stimuli for Renin Release
Sympathetic nerve activity
Decreased firing of intrarenal baroreceptors
Decreased chloride delivery to macula densa

70. Actions of Angiotensin II
Stimulates release of aldosterone
Potent vasoconstrictor
Stimulates release of ADH
Stimulates thirst

71. Aldosterone alters
the expression of
this enzyme

72. Atrial Natriuretic Peptide (ANP)
Made by the atria of the heart, and released in response to an increase in the stretch of the atria
Actions of ANP
Dilates glomerular afferent arterioles – increase amount of sodium filtered and thereby excreted
Inhibits Na+ reabsorption in collecting tubule

73. Potassium Regulation
Most (55%) of the filtered potassium is reabsorbed in the proximal tubule, another 30% is absorbed in the loop of Henle.
Depending on diet, potassium may be reabsorbed or secreted in the distal convoluted tubule and the cortical collecting duct.

74. Regulation of potassium secretion
Na+/K+/ATPase A high K+ diet enhances update of K+ into the principal cells (the ones that line the tubule)
Aldosterone increases K+ uptake into the principal cells (via Na+/K+/ATPase), and makes the luminal membrane more permeable to K+
K+ secretion is flow dependent – high urine production can lead to K+ deficiency.

75. Aldosterone alters
the expression of
this enzyme

76. Hypertension and the Kidney
Kidney malfunction is implicated in most cases of hypertension (i.e. the kidney should be able to respond to high BP by increasing salt and water excretion).

77. Drugs to treat hypertension often target the kidney
Diuretics act at various points along the renal tubules to increase water loss in the urine
Can lead to potassium depletion
Increases sensitivity to heat stress

78. Blood pressure generally increases with age.

79. Hemorrhage

80. Autotransfusion results from a fall in capillary hydrostatic pressure and helps restore blood volume after fluid loss

82. Vasopressin = ADH

83. Heart Failure
Basic problem is a decrease in blood pressure due to insufficient cardiac output.
Kidneys respond as those there has been a hemorrhage – by increasing:
Sympathetic nerve activity
Renin release
ADH release
This response can be maladaptive, as excessive amounts of retained fluid cause peripheral and pulmonary edema.

84. Responses to Heart Failure

85. During heart failure, fluid retention helps a little, but can quickly lead to edema

86. Normal Plasma Values Substance Plasma Concentration Na+
mEq/L K+
3.5 – 4.5 mEq/L
Cl-
95 – 105 mEq/L
HCO3 -
24 – 32 mEq/L
Glucose
65 – 110 mg/dl (= mmol/L)
Blood urea nitrogen (BUN)
8 – 25 mg/dl

87. Sodium regulation Controlled variable: Sodium excretion in urine
Hormonal systems involved:
Renin/Angiotensin/Aldosterone
Atrial Natriuretic Peptide

90. Sensing of plasma sodium is mostly through indirect signals that reflect blood volume and pressure
Baroreceptors inside and outside the kidney:
Carotid baroreceptors
Juxtaglomerular apparatus
Macula Densa – senses delivery and reabsorption of chloride (which generally reflects sodium delivery)