LECTURE 2 ON RENAL PHYSIOLOGY



LECTURE 2 ON RENAL PHYSIOLOGY

12 November 2001

First lecture covered the anatomy and normal function of the kidney, specifically the functions of each part of the nephron. This lecture covers the interaction of the renal system with the rest of the body.

NEUROHUMORAL CONTROL

A number of hormone systems affect the kidneys function, especially regarding management of plasma volume:

ADH AntiDiuretic Hormone, also known as Vasopressin

Makes collecting tubule permeable to water so urine is concentrated

Makes blood vessels constrict to increase blood pressure.

Secreted by the posterior Pituitary gland .

Regulated very tightly by serum sodium concentration/osmolality (+/- 3 %)

Regulated less tightly by stretch/BP receptors (+/- 10 %)

RENIN-ANGIOTENSIN- ALDOSTERONE

This system is initiated by the kidney sensing a relative decrease in perfusion or oxygenation, upon which the kidney (juxtaglomerular apparatus) releases Renin. Renin is an enzyme which converts Angiotensinogen to Angiotensin I, a potent vasoconstrictor. AT-I is converted by Angiotensin converting Enzyme (ACE) to Angiotensin II, another more potent vasoconstrictor, which has two effects. AT-II raises the BP by vasoconstriction, and stimulates the Zona Glomerulosa of the Adrenal gland to release Aldosterone. Aldosterone is a hormone which promotes sodium retention by the kidney and expands the plasma volume. ACE inhibitors such as captopril, enalapril and others can be useful in the treatment of certain conditions where angiotensin is pathologic; such as congestive heart failure and hypertension associated with kidney disease.

CONCEPT OF EFFECTIVE ARTERIAL BLOOD VOLUME (EABV)

In addition to blood pressure and blood volume, the body is able to sense perfusion as well. There are a number of conditions in which total body water is very high and the patient has edema, yet perfusion to essential organs is relatively reduced, so both the ADH and R-A-S systems are activated.

These conditions are the following:

Congestive Heart Failure

Liver failure (cirrhosis)

Nephrotic syndrome

Pregnancy

Severe anemia

In most of these conditions, Renin and aldosterone levels are very high even though there can be marked amounts of edema. ADH is usually stimulated by the reduced relative EABV, resulting in hyponatremia.

FLUID COMPARTMENTS

Total body water (TBW) = 0.6 * weight in KG

TBW consists of 3 main compartments:

Intracellular 2/3 of total, or about 28 liters, main ion is potassium

Interstitial fluid 1/4 of total, or about 10.5 L, main extracellular ion is Sodium

Plasma volume 1/12 of total, or about 3.5 L.

Pathologic conditions associated with derangements of these:

A. Inappropriate ADH secretion results in low sodium concentration because of increased total body water, relative to sodium which may or may not be increased. Inappropriate ADH secretion occurs in conditions where the EABV is low, or in certain lung or brain conditions when ADH production is increased. May swell, may not.

B. CHF, hypothyroid disease, and renal failure result in expansion of extracellular fluid by different mechanisms, resulting in edema.

C. Hypertension is often the result of increased plasma volume, which can be caused by renal disease, increased salt intake, excessive Aldosterone secretion.

POTASSIUM

This is the major intracellular cation.

Average daily potassium intake is about 1 mEq/kg/day, or about 70 mEq daily.

This amount must be excreted daily to maintain balance. Excretion is mainly through the kidney and GI tract. (diuretics and diarrhea can lead to hypokalemia).

The serum concentration of potassium is tightly regulated, and disorders can result in muscle weakness and cardiac arrhythmias.

K+ varies according to the following:

Aldosterone, which stimulates excretion in the distal tubule. Blocked by spironolactone.

Epinephrine, which shifts K+ out of cells

Insulin, which shifts K+ into cells

Acid-Base status, the more acidic, the more K+ shifts out of cells in exchange for H+

Osmolality.

Renal handling of potassium:

Glomerulus Prox Tubule Loop of Henle Distal Tubule Collecting tubules

filtered 2/3 reabsorbed 20% reabsorbed Variable, depending on the above.

Diuretic site of: Thiazides Lasix, Bumex Thiazides

action Acetazolamide Demedex Spironolactone

CALCIUM AND PHOSPHATE

Important ions for bone formation, muscle action, energy transfer (ATP), and multiple other metabolic functions.

As a result of their importance, there is a very complicated regulating system:

a. Parathyroid Gland secretes Parathyroid Hormone (PTH) which raises Calcium level.

b. Thyroid Gland secretes calcitonin, which antagonizes PTH

c. Vitamin D is made by the skin, activated by the lungs and kidneys, to raise calcium level.

d. Acid base status plays a role, as the bone serves as a buffer for chronic acidosis

e. Intake is regulated by PTH, Vitamin D, Dietary sources, and uptake is linked to other nutrients.

f. The majority of Calcium is protein bound

g. Phosphate is another major intracellular ion.

h. Excretion is regulated by PTH, Vitamin D, and requires normal renal function.

ACID BASE

Normal human pH 7.3 to 7.5 equivalent to about 40 nanoMole/L or 0.0017 mEq of total free H+.

This compares to 2000 mEq of sodium in solution in the body.

Acid base regulation:

A) metabolism generates 32,000 mEq/day, which is converted to H2O in the cells.

B) 16,000 mMoles of CO2 are generated in cellular respiration and must be transported to the lung without causing significant drop in serum pH

C) 70 mEq of acid is generated and must be removed to the kidneys for excretion

D) Buffer system carries H+

- RBC's (hemoglobin)

- Proteins

- Bicarbonate in ratio of 1 part dissolved CO2 to 20 parts HCO3

- The anion gap is a measure of buffer capacity, excess gap can be considered to represent

potential bicarbonate.

E) Excretion

- lung blows off CO2 and hence traps H+ as H2O

- Kidney

- Lumenal Carbonic anhydrase in proximal tubule to reclaim filtered bicarb

- basolateral CA in distal tubule to generate gradient for H+ out of blood/into cell so extra H+ can be excreted in high pCO2 conditions

- PO4 and SO4 provide a small amount of buffering in urine

- NH3 conversion to NH4+Cl- (ammonia to ammonium chloride) provides a huge

sink for H+

- production of NH4Cl is determined by the intracellular pH. This is important in

the case of severe hypokalemia, where H+ shifts into cells so potassium can come

out into the extracellular fluid - the ECF is rendered alkalotic while the

ICF is acidotic, so a patient with hypokalemia and apparent metabolic alkalosis will

secrete an acid urine.

EQUATIONS

The basis for these relationships is the Henderson-Hasselbach equation:

pH = 6.1 + log (HCO3/0.3pCO2)

rearranged to a linear relationship:

H+ = 24 (pCO2/HCO3)

This relationship is based on the chemical reaction:

CO2 + H2O H2CO3 H+ + HCO3-

CA

which is mediated by CA Carbonic Anhydrase.

CA inhibitors such as acetazolamide are used for various conditions; most commonly Glaucoma, but also in mountain climbers to prevent altitude sickness. These agents block the action of carbonic anhydrase mostly in the kidney, resulting in trapping of bicarbonate in the urine, resulting in production of a metabolic acidosis which can be dangerous if the patient is not monitored regularly.

ANEMIA

The kidney is also responsible for the production of Erythropoietin (EPO or EPOGEN, Arenesp) which is a hormone that turns on bone marrow production of Red Blood Cells. As the kidney looses function, its ability to produce EPO fails as well, resulting in anemia. This usually becomes an issue when the kidney is working at less than 30 % of normal (GFR < 30). When the Hematocrit falls to less than 30 %, Erythropoietin can be given as an injection (similar to insulin) usually once or twice a week, to improve the anemia and the fatigue that goes with it.

CASES TO REVIEW

1. In a 35 year old woman an adenoma of her left adrenal gland produces high levels of Aldosterone. She experiences retention of Sodium by the kidneys, and develops hypertension and swelling of the ankles. However, after several days, sodium excretion increases to its previous level (excretion = intake). When the adenoma is removed surgically, sodium excretion increases (excretion > intake) for a few days but then returns to normal (intake = output).

Delineate the mechanisms involved in these Aldosterone induced changes in sodium excretion.

2. A 65 year old man has a heart attack, and afterwards complains of fatigue, shortness of breath, and swelling of the ankles. On physical exam he is found to have distended neck veins, and pitting edema of the ankles. Crackles are heard over the bases of the lungs. He is afebrile, pulse is 90, and the BP is 110/70. Labwork shows the following:

Sodium 130 Normal 135-147

Potassium 3.8 Normal 3.5-4.9 mEq/L

Bicarbonate 23 Normal 22-28

Creatinine 1.1 Normal 0.8-1.2 mEq/L

A. Is the extracellular fluid volume in this patient above or below normal?

B. Is the effective arterial blood volume (EABV) above or below normal?

C. Is the kidney retaining or dumping sodium in this patient? What Evidence on physical exam supports your conclusion? Is the kidney retaining water? How?

D. What is the mechanism for developing hyponatremia in this patient?

The physician treating this patient prescribes a loop diuretic (lasix), and digoxin (which helps the heart contract stronger). Repeat labwork shows the following:

Sodium 135 Normal 135-147

Potassium 3.1 Normal 3.5-4.9 mEq/L

Bicarbonate 30 Normal 22-28

Creatinine 1.8 Normal 0.8-1.2 mEq/L

E. What effect will the lasix have on his extracellular fluid volume?

F. What is the mechanism for development of hypokalemia in the patient now?

G. What is the significance of the elevated creatinine?

H. What type of acid-base disturbance does this man have now?

Clinicopathologic correlates:

STRUCTURE: FUNCTION: PATHOLOGY:

ENDOTHELIAL CELL makes vessel KAWASAKI'S

GBM molecular sieve GOODPASTURE'S

EPITHELIAL CELL charge selectivity MINIMAL CHANGE

MESANGIUM makes GBM BERGER'S, DIABETES

BOWMAN'S CAPSULE

TUBULES

PROXIMAL reabsorbs solutes RTA, STONES, WASTING

LOOP OF HENLE reabsorbs water ISOSTHENURIA

THICK ASCENDING LIMB ACUTE TUBULAR reabsorbs sodium NECROSIS

DISTAL adjusts H,K,Na RTA, STONES

COLLECTING reabsorbs water DIABETES INSIPIDUS

INTERSTITIUM supports tubules and ALLERGIC concentration gradient INTERSTITIAL NEPHRITIS

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