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PHYSIOLOGY 03028 WEEKS 8 AND 9: DETAILS ALONG THE NEPHRON 3/9/00

Cormack, Ch. 7; Guyton and Hall, Chs. 25-31; Michael and Rovick, Units 7, 10, 11;

van Wysberghe and Cooley, Cases 22-24

W. Crone (303 FTZ, 629-7439, cronewil@hvcc.edu, http://www.hvcc.edu/academ/faculty/crone/index.html)

NOTE: 2nd lecture test will cover through the material that we cover Monday, March 13

(which should be everything in this handout)

FILTRATION:

Glomerular capillaries are fenestrated to allow the passage of ultrafiltrate. There is a net filtration pressure of only 10 mm Hg because of balancing hydrostatic and oncotic pressures (what are they?). The main filtration barrier seems to be the basal lamina (basement membrane) of the capillaries, although as mentioned on Monday, the slits between the cytoplasmic extensions of the podocytes seems to have an effect as well.³ Proteinuria: disruption of this (-) charged protein barrier.

Glomerular filtration rate (GFR): volume of filtrate produced by kidneys per minute: 115 ml/min (female) and 125 ml/min (male), or up to 180 L/day. With total blood volume at 5.5 L, this means the blood is filtered every 40 minutes, so must return a lot of that fluid to the blood.

Afferent/efferent arterioles determine the rate of blood flow into the glomerulus, so vasoconstriction/vasodilation of them can control GFR: e.g., sympathetic innervation on the arterioles, or tubuloglomerular feedback from the macula densa of the proximal portion of the DCT. The macula densa cells sense changes in volume delivered to them (or at least changes in [NaCl]). They can lead to dilation of the afferent arteriole, increased renin production, and angiotensin II constriction of the efferent arteriole as ways of creating this feedback.³

To measure GFR, we need to find a product that is neither reabsorbed nor secreted, such that the amount excreted per minute in urine should be equal to the amount filtered per minute in the glomeruli. Example: inulin (a plant fructose polymer) ideally, and creatinine often used clinically (slightly secreted muscle metabolism creatine waste product).¹

quantity of inulin filtered = U X V (U: inulin concentration in urine; V: rate or volume/time of urine formation), or quantity filtered per minute.

creatinine clearance (our clinical GFR equivalent) = (U X V)/P (P: plasma concentration)

Creatinine levels are tightly linked to GFR levels, and so when there is a sudden decrease in GFR, e.g., acute renal failure, there will be a rise in blood creatinine levels. A definition of acute renal failure: a rise in creatinine of 0.5 mg/dL/day and a rise in blood urea nitrogen of 10 mg/dL/day for several days.⁴ normal values: creatinine: 0.6 - 1.2 mg/dL and BUN: 8 - 22 mg/dL

REABSORPTION (especially in the PCT):

Most of the water and salt of the filtrate is reabsorbed in the PCT. The water reabsorption is osmotic, following the active extrusion of sodium chloride from the tubule into the peritubular capillaries. At the start, the glomerular ultrafiltrate has the same osmolality as plasma (about 290 mOsm), and remains at that level throughout the PCT. An approximating formula which demonstrates that sodium is the primary osmolal agent:⁴

plasma osmolality = 2 X [Na⁺] + [glucose (mg/dL)]/18 + [BUN (mg/dL)]/2.8

The driving force of reabsorption is the active transport of Na⁺ from the filtrate to the peritubular blood. The simple cuboidal epithelial cells that make up the PCT walls have lots of active sodium pumps on their basal and lateral sides, setting up a gradient in the cell that favors the passage of Na⁺ from the lumen of the PCT to the epithelial cells and then out. This also sets up an electrical gradient, which encourages Cl^- to accompany the Na⁺ out into the interstitial fluid. With all of these osmotic particles leaving (and with the apical surface of the PCT epithelial cells permeable to water), water then also leaves the PCT lumen to interstitial fluids, and is eventually reabsorbed by the peritubular capillaries. This takes care of about 2/3 of the salt and water in the glomerular ultrafiltrate.

amino acids and glucose: reabsorbed in the PCT thanks to facilitated diffusion driven by a sodium contransporter. Generally, this carrier-mediated transport is not saturated. But glycosuria can occur when plasma glucose concentration reaches 180-200 mg glucose/100 ml blood in diabetes mellitus. All of this extra glucose in the tubule lumen is an osmotic load that will increase urine output: the polyuria of diabetes.

ACTIONS IN THE LOOP OF HENLE:

Ascending limb of the loop of Henle described first (since more active processes occurring here in the cells of the thick segment of the ascending loop): Na⁺, K⁺, Cl^- diffuse from the filtrate in the lumen into the ascending limb cells (ratio of 1:1:2) via an electrocally neutral Na-K-2Cl cotransporter. The ascending limb cells then use their sodium pumps to get Na⁺ across their basolateral membranes. Cl^- follows because of electrical attraction, and some K⁺ diffuses back into the filtrate in the lumen of the ascending limb.

The walls of the ascending limb of the loop of Henle are impermeable to water. With the salt being pumped out of it, the fluid in the tubule is hypoosmotic (100 mOsm) as it reaches the distal convoluted tubule (DCT). Deep down in the medulla, though, it can reach 1,200-1,400 mOsm, or quite hyperosmotic, so somehow that the salt being pumped out of the ascending limb of the loop of Henle is accumulating in the tissue fluid of the medulla, along with a collection of urea from the medullary collecting duct.³

In contrast to the ascending limb, the descending limb of the loop of Henle does not actively transport salt, but is permeable to water. With the surrounding interstitial fluid hyperosmotic, the water of the filtrate is drawn out of the descending limb and enters peritubular capillaries. The ascending/descending limbs of the loop of Henle are close to each other, allowing for a countercurrent mechanism, with a positive feedback mechanism. As the ascending limb extrudes more salt, the more concentrated the fluid heading down the descending limb becomes, because of the countercurrent multiplier system. For this to work:

1. the majority of the salt from the ascending limb needs to remain in the medulla
2. the water that is exiting the descending limb must be taken up by blood vessels leaving the area

These goals are accomplished by the vasa recta, or peritubular capillaries that form capillary loops around the long loops of Henle of the (juxtamedullary) nephrons. Briefly, salts and solutes like urea diffuse into blood as the blood descends to the medulla in the vasa recta, but then diffuse out of the ascending capillaries into the descending capillaries, a countercurrent exchange. Note: the main source of urea here is the medullary collecting duct, as it is very permeable to urea and the thick ascending limb to the cortical collecting duct isn't.

About 90% of filtered Na⁺, K⁺ is reabsorbed in PCT and loop of Henle. The final amounts of Na⁺, K⁺ in urine is dependent on the DCT and the cortical region of the collecting duct, thanks to…

THE DCT: MAJOR SITE OF ALDOSTERONE FUNCTION

Aldosterone, a mineralcorticoid secreted by adrenal cortex, regulates renal absorption of Na⁺ and secretion of K⁺. Under the influence of aldosterone, K⁺ is secreted from peritubular blood to the later part of the DCT and cortical collecting duct. The two main stimulations of aldosterone are:³

1. renin-angiotensin system
2. potassium ion concentrations

THE COLLECTING DUCT: MAJOR SITE OF ADH FUNCTION

After the DCT, the tubular fluid goes to the collecting ducts. As the collecting ducts head down through this hypertonic medullary territory, the walls of the collecting duct are permeable to water. Water osmoses out and is taken away by capillaries to the general circulation (so that there's little diluting of the medullary interstitial fluid). The rate at which the water osmoses out of the collecting duct is dependent on how permeable to water the walls of the collecting duct are, and that permeability is dependent on anti-diuretic hormone, ADH. ADH is secreted by the posterior pituitary in response to increased blood osmolality sensed in the hypothalamus.

diabetes insipidus: due either to CNS disease at hypothalamus (central diabetes insipidus) or renal disease (nephrogenic diabetes insipidus): dilute urine in the face of hypernatremia, without ADH secretion.

ACID-BASE ISSUES:

Not all acid-base issues can be handled by the lungs. For example, protein metabolism produces nonvolatile acids. As a result, the kidneys help to regulate the blood pH by excreting H⁺ in the urine and reabsorbing bicarbonate. Kidneys usually reabsorb most of filtered bicarbonate and excrete H⁺, so normal urine is slightly acidic. But, the membranes of the tubule cells facing the lumen of the tubules are impermeable to bicarbonate. So an indirect approach involving carbonic anhydrase allows for the reabsorption of bicarbonate in the proximal tubule:

HCO₃^- + H⁺ --> H₂CO₃ --> CO₂ + H₂O and its application in the PCT cells.

So in a metabolic acidosis, bicarbonate blood levels (normal 21-26 mEq/L) are low, and are high in a metabolic alkalosis. Think about how this equation can be"driven" in one direction or the other depending on what is in excess/deficit. With the CO₂ diffusing across into a PCT cell, carbonic acid can be reconstituted there and the hydrogen ion put back into the lumen via a Na⁺/H⁺ antiport.

Active secretion of H⁺ ions can occur as well in the intercalated cells of the DCT. These use a H⁺ ATPase to pump the ions out actively.³

A nephron has trouble producing a very acidic urine (pH < 4.5). For more acid to be excreted, the acid must be buffered.

Phosphates and ammonia provide the means for excreting most of the H⁺ in the urine. Phosphate is filtrated in, and ammonia is produced in tubule cells by deamination of amino acids. Hence, the luminal H⁺ can be buffered by two means even as the bicarbonate is mostly reabsorbed:

H⁺ + HPO₄^2- --> H₂PO₄^- and H⁺ + NH₃ --> NH₄⁺

metabolic acidosis: addition of acid to body, with decreased [HCO₃^-].

metabolic alkalosis: increased [HCO₃^-]

anion gap = [Na⁺] - ([HCO₃^-] + [Cl^-]), usually 8-12 mEq/L

Table of acidosis/alkalosis situations:¹

Acidosis with a widened anion gap: there is an offending substance that dissociates into a H⁺ ion (hence the acidosis), and an accompanying anion (hence, the wider anion gap), e.g., aspirin overdose, methanol poisoning, lactic acidosis, diabetic ketoacidosis.

Acidosis with a normal anion gap (hyperchloremic acidosis): loss of bicarbonate from either kidney or GI tract. The bicarbonate loss is balanced by a [Cl^-] rise in serum, e.g., diarrhea or renal tubular acidosis.⁴

ELECTROLYTE CONCERNS, PART I:

SODIUM:

Hyponatremia, [Na⁺] < 135 mEq/L or 135 mmol/L, is a common disorder of body fluid and electrolyte balance in hospitalized adults, e.g., increased sodium loss, vomiting, diarrhea, burns, diuretics. So loss of ECF, stimulating thirst (more water intake), and ADH secretion, less water excretion. Symptoms of lethargy, fatigue, seizures, and coma are from brain cell swelling as plasma osmolality falls.²

Types of hyponatremia could include:³

hypernatremia: sodium levels > 145 meq/L. Always is associated with hypertonicity. Fluid shift out of cells, so increased thirst, sticky mucus membranes, and ADH secretion in order to compensate. Can have:

"Third spacing" refers to a shift of ECF fluids from its intravascular to its interstitial compartment, and so functionally not contributing to circulation. More generally, volume contraction means a decrease in ECF, while volume expansion means an increase in ECF volume. As examples, an isosmotic diarrhea will decrease ECF volume, but not lead to a fluid shift from the ICF. High sodium intake can change the ECF osmolarity, so that water will shift from the ICF to ECF to compensate.¹

POTASSIUM: Major considerations with potassium levels are:²

hypokalemia: K⁺ < 3.5 mEq/L. This increases the gradient across excitable membranes, and thus leads to hyperpolarization, so muscle weakness and prolonged cardiac depolarization. Major causes include: diet, diuretics, aldosterone excess, etc.²

hyperkalemia: K⁺ > 5 mEq/L. This decreases that membrane gradient, and so more likely to set off depolarizations, e.g., cardiac arrhythmias. Major causes include: renal failure, aldosterone deficit, etc.²

1. LS Costanzo, Physiology [Saunders Text and Review Series] (WB Saunders, Philadelphia, 1998), pp. 213, 216.
2. BE Gould, Pathophysiology for the Health-Related Professions (WB Saunders, Philadelphia, 1997), pp. 76-85..
3. AC Guyton, JE Hall, Textbook of Medical Physiology, 9th ed. (WB Saunders, Philadelphia, 1996), pp. 308, 321, 328, 352, 395, 961.
4. JA Shayman, Renal Pathophysiology (JB Lippincott, Philadelphia, 1995), pp. 4, 84-85, 136.

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