1. Information
Check Blackboard for information and Power point slides from lectures
PP slides are in syllabus
Send all class notes to Dr Wall who will forward to lecturer

2. Introduction
Text: Renal Pathophysiology, Helmut Rennke and Bradley Denker, 3rd edition, 2010
Syllabus
Small groups: Group Assignments: attendance strongly encouraged
Blackboard

3. Examinations
Exam questions come from both small group sessions and lectures
Lectures and slides follow textbook

4. Role of the Kidney
Major function of kidney is to maintain homeostasis for a number of solutes and water
Homeostasis maintained despite variations in endogenous production and dietary intake

5. Homeostasis: maintaining total body contents at a stable and normal level, even in the face of changes in dietary intake or endogenous production rate.

6. HOMEOSTASIS Electrolytes: sodium, potassium, chloride
Water (osmolality)
Acid-base: bicarbonate (ECFV buffer)
Minerals: calcium, phosphorus, magnesium
Waste material: urea (protein), creatinine (muscle), uric acid (nucleic acids)

7. Endocrine Functions Erythropoietin
1-alpha hydroxylase to produce 1,25 (OH)2D3
Renin
Paracrine/autocrine functions
a. bradykinin
b. prostaglandin
c. endothelial factors
1. nitric oxide
2. endothelin

8. Blood pressure regulation: the kidney is the critical organ in maintaining normal blood pressure.
homeostasis of sodium and water, maintaining normal extracellular fluid volume.
2) control of the renin – angiotensin – aldosterone axis.
3) production of vasodilatory substances

9. Other Functions of the Kidney
Catabolism of small peptide hormones, such as insulin (decreased nephron mass therefore leads to decreased insulin catabolism and resultant longer circulating half-life of insulin)
Kidney can produce glucose via gluconeogenesis during fasting
Kidney is responsible for elimination of many medications, thus,changes in kidney function will change plasma concentrations of these drugs

10. Concept of Balance
Neutral balance refers to the state in which dietary intake plus endogenous production equals excretion rate of the kidney. In this situation total body contents of the substance remains stable
Positive balance: intake plus endogenous production >renal excretion rate, leading to increased total body content
Negative balance: intake plus endogenous production <renal excretion rate, leading to decreased total body content

11. Mechanism of Kidney Function
Glomerular level:
massive quantities of plasma ultrafiltrate are formed at the glomerulus (180 liters/d)
this requires an enormous blood flow. ~10-20% of total cardiac output
Tubular level:
greater than 99% of glomerular filtrate must be reabsorbed
selective reabsorption and secretion determines urinary excretion rates

12. Glomerular and tubular levels must
operate in concert to achieve normal kidney function (GFR).
Glomerular filtration rate, therefore, is the best index of overall kidney function.
Other kidney functions correlate with GFR

13. Processes Involved in Renal Function
Filtration
Deposition into Bowman’s space of an ultrafiltrate of plasma from glomerular capillary blood
Reabsorption
Transport of water and certain solutes from fluid within the tubules into the peritubular capillaries
Secretion
Addition of certain solutes (but not of water) to the fluid in the tubules from the peritubular capillaries
Excretion
Removal from the body of water and solutes as urine

34. Starling Forces Promoting filtration out of capillary
1. hydrostatic pressure within capillary
2. oncotic pressure within interstitium
Opposing filtration out of capillary
3. oncotic pressure within capillary
4. hydrostatic pressure within interstitium
Net fluid flow in or out of capillary
Determined by the algebraic sum of the Starling forces, and by the filtration coefficient, Kf

36. Glomerular Filtrate Formation
GFR = LpS (P - tau)
Lp = capillary wall permeability
S = glomerular capillary surface area available for filtration
P= hydrostatic pressure gradient between capillary and Bowmans space
tau = oncotic pressure gradient between capillary and Bowmans space

37. Ultrafiltration: Glomerular vs. Other Capillaries
The glomerular system has:
Higher hydrostatic pressure in capillary and little decrease in this pressure along the capillary
Low hydrostatic pressure in Bowman’s space (tubular reabsorption)
Lower oncotic pressure in Bowman’s space (protein-free ultrafiltrate)
Higher Kf (permeability factor)

43. Urine flow rate is not autoregulated
Increased perfusion pressure results in increased urinary flow rate (pressure natriuresis)
Urine flow rate is not a good index of overall kidney function
GFR is the best index of overall kidney function

44. Definitions Filtered load (mg/min) = (Px) x GFR
Filtered load represents the amount of substance in plasma that is filtered at the glomerulus per unit of time
Excretion rate (mg/min) = (Ux) x UFR
Excretion rate represents the amount of the substance excreted into the urine per unit of time

45. Urine flow rate is not autoregulated
Increased perfusion pressure results in increased urinary flow rate (pressure natriuresis)
Urine flow rate is not a good index of overall kidney function
GFR is the best index of overall kidney function

46. Properties of Marker of GFR
Present in plasma at a constant concentration
Freely filtered at the glomerulus
Once filtered, no reabsorption, secretion, synthesis, or metabolism occurs

47. GFR Exogenous example: inulin
Endogenous example: creatinine (~10% secretion, so over-estimates GFR)
Given these properties, the filtered load of inulin is equal to its excretion rate
Pinulin x GFR = Uinulin x UFR
GFR (ml/min) = Uinulin x UFR/Pinulin
GFR is the best overall index of kidney function

48. Renal Clearance
Renal clearance represents the volume of plasma cleared of the substance via elimination into the urine per unit of time
Units = ml/min

49. Renal Clearance Renal clearance = (Ux x UFR)/Px (ml/min)
The renal clearance (ml/min) of any substance cleared by the kidney can be defined as: (Clearance of substance x) = (urine concentration of x) x (urine flow rate)/plasma concentration of x
“UV/P”

50. Clearance Ratio
Clearance ratio: defined as the clearance of the particular substance (Cx) divided by GFR
(Cx/GFR)

51. Clearance Ratio
If clearance ratio =1.0, then the solute is handled like inulin and its renal clearance is equal to GFR
If clearance ratio <1, then this solute is filtered, but reabsorbed (eg, sodium)
If clearance ratio >1, then the solute is filtered, and it is actively secreted from the peritubular capillaries into the tubular fluid (eg, potassium)

52. Clearance Ratio (Cont’d)
If clearance ratio is 0, then either the solute is too large to be filtered (protein) or it is filtered and 100% reabsorbed (glucose and amino acids)

53. Renal Plasma Flow
There is no endogenous substance that can be used to estimate renal plasma flow
Para-aminohippurate (PAH) is an exogenous substance that is filtered and actively secreted such that it is almost completely extracted from the plasma in one pass through the kidney
The clearance of PAH, therefore, is equal to renal plasma flow

54. Filtration Fraction Normal GFR is approximately 120 ml/min
Normal renal plasma flow is approximately 600 ml/min
Filtration fraction (FF) represents the fraction of renal plasma flow which becomes GFR
FF = GFR/RPF = 120/600 = 0.2
Thus, about 20% of renal plasma flow becomes GFR

55. Alterations in Filtration Fraction
Volume depletion results in reduced cardiac output and reduced renal plasma flow. Filtration fraction increases in order to maintain GFR at a constant level. This autoregulatory response involves a vasodilatation of the afferent arteriole and vasoconstriction of the efferent arteriole. The efferent circulation exiting the glomerulus now has a significantly reduced hydrostatic pressure and a markedly increased oncotic pressure. These factors augment reabsorption of solute and water in
the peritubular capillaries, thus helping
preserve volume status.

56. Autoregulation
Whenever autoregulation is occurring, there is enhanced proximal tubular reabsorption
This limits delivery to the distal nephron and favors NaCl and water conservation

57. Alterations in Filtration Fraction
Volume expansion augments cardiac output and increases renal plasma flow. Filtration fraction decreases in order to maintain GFR at a constant level. The efferent circulation exiting the glomerulus has a higher than normal hydrostatic pressure and less increase in oncotic pressure. These factors diminish reabsorption of solute and water in the peritubular capillaries, thus, promoting the excretion of the excess solute and water.

58. Syllabus
See Summary tables concerning hormonal changes, hemodynamic changes, renal tubular changes that occur with alterations in extracellular fluid volume
See syllabus: diuretics