2 - Nephrology

Question 1

What is the GFR calculated?

Answer 1

GFR is defined as the clearance of Inulin. However, clinically it is estimated by the creatine clearance. This estimation becomes inadequate at <30ml/min.
GFR = (Uin)x(F)/(Pin)

Question 2

Hos is Renal Blood Flow determined?

Answer 2

RBF is estimated from the clearance of PAH (para aminohippurate). Since it is almost perfectly excreted, the clearance approximates the plasma flow.
To get blood flow from plasma flow->
RBF = Renal Plasma Flow/(1-hematocrit)

Question 3

Describe the autoregulation of GFR.

Answer 3

GFR and RBF is maintained almost constant across arterial pressure changes from 75-160mmHg via 2 mechanisms:

1) Myotonic -> changes in stretch of the afferent arteriole causes a corresponding change in contraction/dilation. This changes resistance and controls GFR.
2) Tubulo-Glomerular Feedback -> JGA senses changes in volume/NaCl and causes a compensatory change in Renin release and constriction/dilation of the afferent arteriole smooth muscle

Question 4

Discuss Na/H2O transport in the PCT.

Answer 4

The Na/H+ Exchanger (NHE3) is a facilitated transport for Na into the cell, and H+ out.
NHE3 is trafficked to apical membrane in response to Angiotensin II.
Na is also used to resorb Glucose, Amino Acids and Phosphate.
**the low intracellular Na concentration is maintained by the Na/K ATPase Pump
Water flows into the cell (following Na) via APQ1 that is constantly present in both membranes.

Question 5

Discuss Na/H2O transport in the TAL.

Answer 5

Na/K/2Cl Cotransporter (NKCC2) uses the Na gradient to resorb Cl and K into the cell.
NKCC2 are increased via ADH.
K is prevented from building up within the cell via the ROMK channel in the apical membrane.
**the low intracellular Na concentration is maintained by the Na/K ATPase Pump
H2O follows Na via bulk diffusion.

Question 6

Discuss Na/H2O transport in the DCT.

Answer 6

Na/Cl Cotransporter (NCC) uses the Na gradient to resorb Cl.
NCC increase in response to aldosterone.
**the low intracellular Na concentration is maintained by the Na/K ATPase Pump
H2O follows Na via simple diffusion.

Question 7

Discuss Na/H2O transport in the Collecting Duct.

Answer 7

Na is transported via the Epithelial Na Channel (ENaC).
ENaC respond to both ADH and Aldosterone.
**the low intracellular Na concentration is maintained by the Na/K ATPase Pump
H2O is transported across the apical membrane via AQP1, which are transported there in the presence of ADH.
AQP2/3 transport H2O across the basolateral membrane.

Question 8

Describe the renal control of Na.

Answer 8

1) Neural Reflex(short) -> changes in arterial volume/pressure cause both a cardiovascular reflex to change cardiac output, but also stimulates renal sympathetics, causing constriction/dilation of afferent arteriole
2) Hormonal Control (long) -> aldosterone promotes increased Na resorption via stimulation of the Na/K ATPase, NCC and ENaC.

Question 9

What stimulates the release of Renin?

Answer 9

1) Renal sympathetic nerves -> response to changes in stimulation of systemic baroreceptors
2) Intrarenal baroreceptors -> JGA is sensitive to changes in volume
3) Macula Densa -> these cells are sensitive to changes in NaCl concentration and direct JGA to secrete Renin

Question 10

What is the impact of Atrial Natriuretic Factor?

Answer 10

ANF is released from the cardiac atria in response to distention. This inhibits Na resorption, thus excreting more water.
ANF acts to increase GFR and Medullary Blood Flow and decrease/inhibit Renin release and Aldosterone. Each of these play a role in Na excretion, which in turn drives H2O excretion.

Question 11

How is H2O excretion regulated within the Kidney?

Answer 11

While H2O typically “follows” Na, control is exerted at the Collecting Duct via ADH stimulation of APQ1 channels.
ADH->APQ1 transport -> H2O resorption disproportionate to Na -> urine concentration

Question 12

What stimulates ADH secretion?

Answer 12

Secreted from the pituitary via;

1) Systemic Baroreceptors -> increases in volume cause DECREASED ADH, causing more dilute urine/more excreted H2O
2) Osmoreceptors -> cells in the hypothalamus that produce ADH are directly sensitive osmolarity and control ADH secretion (more sensitive mechanism)

Question 13

How is K concentration controlled in the Kidney?

Answer 13

K is freely filtered, and resorbed in the PCT (85%) and TAL (20%). This largely constant, so the excreted K concentration is driven by the excretion in the DCT and CCD.
Aldosterone is the primary regulator of K through stimulation of Na/K ATPase in the Principle Cells of the CCD, followed by passive diffusion to tubule via ROMK channel.
K concentration is sensed by the cells of the adrenal cortex to stimulate Aldosterone secretion.

Question 14

What are the functions of the Intercalated Cells of the Collecting Duct?

Answer 14

IC Cells control Acid-Base balance. Both have a H+ ATPase and HCO3-/Cl Cotransporter, but on different membranes.
Type A -> organized for H+ secretion with H ATPase on the apical membrane
Type B -> organized for HCO3- secretion with HCO3-/Cl Cotransporter on the apical membrane
They also contain a H/K ATPase which are only active in severe K deficiency.

Question 15

Describe the renal control of Ca++.

Answer 15

~40% of body Ca remains bound to proteins in the plasma and is unfiltered. The filtered Ca is resorbed in the PCT (60%), LofH (30%) and DCT (9%).
Resorption is controlled via PTH which stimulates Ca uptake in the LofH and DCT.

Question 16

Describe the renal control of Phosphate.

Answer 16

Most of the phosphate is resorbed in the PCT (60%) and DCT(20%). Resorption is controlled by PTH:

1) increases bone resorption of phosphate and Ca, increasing load on Kidney and increasing excretion
2) decreases Tm of phosphate, decreasing capacity for resorption

Question 17

Describe the renal control of Mg++.

Answer 17

Most of body Mg++ is intracellular(99%). While 25% is resorbed in the PCT, ~65% is resorbed in the TAL through paracellular transport via channels through the tight junctions.

Question 18

What is the difference between Obligatory and Facultative Water Resorption?

Answer 18

Obligatory reabsorption -> in the PCT which does not take part in the formation of dilute vs concentrated urine
Facultative Reabsorption -> in the distal portion of the nephron, this reabsorption is controlled to determine urine concentration

Question 19

What is osmolar clearance? What is free water clearance?

Answer 19

Osmolar -> portion of a given osmotic solute that is excreted
Free Water -> value representing the extent of concentration of the urine/H2O removal

Question 20

Describe the Countercurrent Multiplier.

Answer 20

The progressive concentration of the tubular filtrate within the Loop of Henle leads to the development of a intersitial medullary gradient which is essential for water retention in the Collecting Duct.
Since the TAL is impermeable to water, as the Na is actively resorbed into the interstitium a gradient develops. This gradient causes a concentration of the filtrate in the descending limb, which in turn adds to the interstitial gradient.
This results in a progressively increasing concentration within the Loop of Henle, finally producing a hypotonic solution at the DCT.

Question 21

Describe the Countercurrent Exchanger.

Answer 21

This refers the course of the vasa recta in the maintenance of the interstitial medullary gradient. By rapidly removing excess solutes and H2O, this exchanger reduces the required rate of the multiplier

Question 22

Describe urea transport in the kidney.

Answer 22

Unlike the active transport of Na in the formation of the concentrated urine, urea transport is passive. In the Inner Medulla Collecting Duct, Urea flows out into the interstitium along its osmolar gradient. Then resabsorbed in the LofH, it repeats the cycle. This causes serial concentration of Urea until it excedes the gradient in the collecting duct (~350mOsm).
Urea concentration within the medullary contributes almost 40% to the osmolality of the intersitium. This greatly aids in the urine concentration in the LofH and collecting duct.

Question 23

What are the three major mechanisms of pH control in the Kidney?

Answer 23

1) Secretion of H -> NHE3 in the PCT(85%), TAL and DCT transport H to the tubule; driven by CO2->H2CO3->HCO3- + H+ in epithelial
2) Resorption of HCO3- -> “transport” in the PCT(85%) is through the promotion of the dissociation of H2CO3 within the epithelial cell -> tubule HCO3- reacts with H+ from NHE3, which drives H equilibrium to the right and promotes more intracellular H+ (and HCO3-) formation -> Na+/HCO3- then diffuse to blood
3) Production of new HCO3- -> CO2 within the blood diffuses into epithelium and promotes formation of H2CO3->H+ and HCO3- -> HCO3- and Na+ then diffuse back into blood
New HCO3- is also produced from the breakdown of Glutamine into NH4+ in the PCT.

Question 24

What is the role of intercalated cells in pH control?

Answer 24

Type A -> secrete H+ via H+ ATPase; this is buffered by HPO4– and NH3
Type B -> secrete HCO3-

Question 25

What is the significance of the phosphate and ammonia buffers in controlling pH?

Answer 25

-combination of excess H+ with phosphate and ammonia produce new bicarbonate ions which can be added to the blood with Na+

Question 26

Describe the renal correction of alkalosis.

Answer 26

In alkalosis, higher concentrations of HCO3- (vice H2CO3) is filtered and comparatively less CO2 is present, therefore less H+ is formed. This results in excretion of NaHCO3 and a shift in the bicarbonate buffer -> correcting alkalosis.

Question 27

Describe the renal correction of acidosis.

Answer 27

In acidosis, the rate of H+ secretion raises greater than the filtration of HCO3-. The H+ combines with one of the buffers (phosphate or ammonia) in the filtrate and is excreted. When this happens, HCO3- is formed in the epithelium and a Na+ is absorbed. These then diffuse together into the blood, raising the HCO3- concentration and lowering the H+ -> correcting the acidosis.

Question 28

What are the four “types” of pH imbalance in the body?

Answer 28

HCO3-/H+ Ratio:
Metabolic = bicarb imbalance
Respiratory = pCO2/H+ imbalance
Metabolic Acidosis - low bicarb
Respiratory Acidosis - high pCO2
Metabolic Alkalosis - high bicarb
Respiratory Alkalosis - low pCO2

Question 29

What are some common causes of pH imbalance?

Answer 29

Respiratory Acidosis/Alkalosis:
-hyper/hypoventilation 
Metabolic Acidosis:
-renal tubular acidosis
-diarrhea
-diabetes mellitus
-CRF
Metabolic Alkalosis:
-excessive aldosterone
-excessive vomiting

Question 30

What is an Anion Gap? What is the clinical significance?

Answer 30

Gap = [Na+] - ([HCO3-] +[Cl-])
Expected ~ 8-16mEq/L
Acts as a useful tool when diagnosing metabolic acidosis:
Increased Gap-> diabetes, lactic acidosis, CRF, aspirin/methanol/ethylene glycol poisoning
Normal Gap-> diarrhea, RTA

Question 31

How do you read an In Vivo Nomogram?

Answer 31

These represent the typical clinical presentations (+/- 2SD) of acidosis/alkalosis.  If patient's pH, [HCO3-] and pCO2 lie outside a shaded area this suggests a mixed acid-base disorder. 
Intersection of bands = Normal Range
Clockwise starting at "12"-> 
Acute/Chronic Met Alkalosis, 
Chr Respiratory Acidosis, 
Ac Resp Acid, 
Ac/Chr Met Acid
Ac Resp Alk