Renal lecture notes

From Biol557

• started here on 03/22/10.

Contents 1 Kidney I Structure and function overview 1.1 Functions of the kidney 1.2 Adrenal glands 1.3 Kidney cross-section 1.4 Kidney bloodflow 1.5 Renal nephrons 1.6 Renal capsule = glomerulus and the capsule that contains it 1.7 Glomerular nephritis 1.8 Post-filtrate formation 1.9 Renal epithelial cells 1.10 Distinguishing features of epithelial cells in various segments 1.11 Renal nerves and lymphatic vessels 1.12 Renal blood flow at nephron level 1.13 Juxtaglomerular apparatus 1.14 Blood flow of the kidney 2 =Formation of urine 2.1 Glomerular filtration 2.1.1 Filtration coefficient 2.1.2 Net filtration pressure 2.1.2.1 Glomerular hydrostatic pressure 2.1.2.2 Blood colloital osmotic pressure 2.1.3 =Capsular hydrostatic pressure 2.1.4 Systemic blood pressure and glomerular blood pressure 2.2 Regulation of GFR 2.2.1 Intrinsic controls 2.2.2 Renin / angiotensin / aldosterone 2.2.3 Sympathetic nervous system 2.2.4 Other factors 2.3 Tubular reabsorption 2.3.1 Characteristics of carrier-mediated transporters 2.3.2 Specific example of carrier mediated transport: Glucose 2.3.3 Specific example of carrier mediated transport: amino acids 2.3.4 Protein transportation 2.4 Transport characteristics of various tubule segments 2.4.1 Comparison of proximal and distal 2.4.2 Henle 2.4.3 Distal tubule and cortical collecting duct

Kidney I Structure and function overview

Functions of the kidney

• It eliminates metabolic wates products like creatin, creatinine, and urea, as well as uric acid.
• It also does lots of other stuff:
  • It controls the amount of water in the body and therefore regulates blood volume and therefore pressure.
  • The kidney also regulates the circulating electrolyte balance.
    • This is closely linked to regulation of water retention.
  • It regulates acid / base.
    • We'll have a whole lecture on this at the end of this section because the lungs are highly involved also.
  • Production of specific hormones and enzymes
    • This includes bone morphogens
    • Prostaglandins can mediate vascular diameter; they also do lots of stuff in the kidney.
    • Kallikrein and prostaglandins are important for transport phenomenons.
      • These two are generated where they are needed and cleared quickly.
    • IGF1 is important during kidney development. It is not all that important in adults unless a kidney is removed or diseased. If you remove the kidney, then remaining kidney will produce IGF1. IGF1 is involved in renal hypertrophy. The remaining kidney will grow in size.
  • Specialized metabolic function (a catch-all phrase)
    • Conversion of vitamin D to active from.
    • The kidney can also generate ammonia from aas.
    • It can synthesize glucose from non-carbohydrate sources. Not a usual function; only under duress.
    • It can inactivate small hormones by filtering them out and not reabsorbing them.

Adrenal glands

• These sit right on top of the kidneys.
• There are two types: the medulla (inner) and the cortex (outer) parts.
• The medulla generates norepi and epi.
• The cortex generates two classes of steroid hormones:
  • Glucocorticoids:
    • Involved in lots of intermediary metabolism.
  • Metalocorticoids
    • Adlosterone is most important. It controls renal function.

Kidney cross-section

• No you don't have to know all bits and pieces. Know:
  • The cortex versus the medulla. This is important for understanding how nephrons work.
  • The striations are the individual tubules of the nephrons.
    • There are about 1 million (half a million per kidney).

Kidney bloodflow

• This is a gross oversimplification.
• There is an artery and vein coming in. They surround the tubular networks. There is lots of branching because each tubule has its own vein and artery.
• The kidney receives a quarter of the cardiac output.
  • This comes out to 1200 ml per minute in an adult male.
• Everything the kidney does depends on the first filtration of the blood.

Renal nephrons

• Nephrons cannot regenerate so if we lose them from ischemia or something, they cannot be regenerated.
  • If you have damage to a nephron, you can repair it.
• We have lots of spares, so we can (and will) lose thousands throughout life.
• One will have normal function of the kidneys with only 1/3 the nephrons with which we start.
• Upon donation of a kidney, the remaining kidney will hypertrophy.
  • The nephrons will get larger, not proliferate.
  • This will restore about 80% of function.
• The kidney filters the blood, then the filtrate which contains small molecular weight things and water, and the nephron will selectively reabsorb stuff.
  • What isn't reabsorbed is urine.
• The overall structure of the nephtron:
  • The blood supply comes into the glomerular capillary bed.
  • Then there is the tubule and the collecting duct.
  • First we'll talk about the filtering unit and then of the tubule and collecting duct.

Renal capsule = glomerulus and the capsule that contains it

• There are two capillary beds in the kidney.
• The first capillary bed occurs in each of the glomeruli.
• This first capillary bed is a filtration system.
• The blood comes in through the afferent arteriole toward the efferent arteriole (A before E).
  • The afferent arteriole is larger in diameter than the efferent arteriole. This puts pressure on the filtering unit which drives water and low-molecular weight compounds out of the blood supply into the capsular space.
• The filtration unit is very specialized:
  • The first filtration level is the endothelial cells.
    • The fenestrations of the endothelial cells are negatively charged to repel proteins (which are generally positively ch,arged) so that the slits don't get clogged.
    • These will let about anything except cells go through.
    • That is why you have to have the charge because you don't want all the proteins to clogg.
  • The second filtration level is the basemement membrane on which the endothelial cells sit (the deep membrane).
  • The last specialization are the podocytes. They sit on the outside of the capillary and have feet that interact with other podocytes to form very small slits (filtration slits). These give the most selective (smallest) filter.

Glomerular nephritis

• When you lose the selectivity of filtration (allowing larger molecular weight components to enter the filtrate), there is no way to reabsorb those large things.
  • Thus you will see proteins and such in the urine.
• This is usually caused by autoimmune disorders.
  • This can occur during streptococcus infections, especially because the antibodies genreated in response can clog the filter.
• When you start filtering out proteins:
  • the tubule can become blocked because the filtrate can become very viscus
  • the proteins are removed from the blood such that osmotic pressure drops, thus causing adema throughout the body (look for adema in renal disorders).
    • Once adema starts, one requires dialysis.
  • Note that we all excrete proteins in the urine some times; it is not always indicative of disease.

Post-filtrate formation

• The filtrate enters the capsule and enters the tubule and on to the proximal convoluted tubule, loop of henle, distal convoluted tubules, and collecting duct.
  • We distinguish between these four parts because different things occur in each.
• Nephrons come in two varieties:
  • Cortical nephrons
    • 80-90% is in the cortex.
    • Just a small part of the loop drops into the medulla.
  • Juxtamedullary nephrons
    • The loop drops all the way down into the urine.
    • These are the nephrons that generate concentrated urine.

Renal epithelial cells

• All the segments are lined with epithelial cells but they are not all the same.
  • The nature of the epithelial cells in each segment that determines the function of the segment.
• The apical surface of the epithelial cells is the side that face in toward the lumen of the tube. Therefore the basolateral side is the opposite.
• Tight junctions between the epithelial cells keep filtrate and blood from flowing together between the cells.
• Secretion is from the blood to the lumen. Absorption is from the lumen into the blood. It is all relative to the blood.
• The apical membrane of these epithelial cells has lots of microvilli to increase surface area.

Distinguishing features of epithelial cells in various segments

• What transporter are present and on which membrane do they reside.
  • Depending on which membrane you put this on will determine whether you have a secretory or excretory cell.
  • For example: sodium-potassium ATPase is always found on the basolateral membrane. So if you're moving filtrate from the lumen into the blood, you put a sodium channel on the apical surface and put an Na-K ATPase on the basolateral membrane. This way, the sodium will flow down it's gradient into the cell and then be pumped out.
  • There are a couple of exceptions.
• What can go through the junctional complexes - tight versus leaky epithelia:
  • In the proximal tubule, lots of water and some ions transport across the juction (a leaky epithelial) but in the distal it is very tight, nothing gets by.
• The size and shape of the cells.
  • These characteristics will dominate what it can do.
  • Podocytes are a type of epithelial cell.
  • The cells that line the capsule are inert and simply keep the filtrate in the capsule.
  • The proximal tubule cells are thick with lots of microvilli and mt. 70-90% of what is reabsorbed from the filtrate into the blood occurs in the proximal tubules.
  • The cells of the loop of henle are thinner, with fewer microvilli. They have a very specialized function. They move water in one area and move sodium / chloride in another area.
  • The distal tubule (which contains the juxtoglomerular apparatus, where the distal tubule interacts with the afferent arteriole) and the collecting duct have quite large cells with few microvilli because most everything that will be reabsorbed has been reabsorbed. In this section there is hormonal control over what will be reabsorbed.
    • Once in the collecting duct there are two types of cells. Those with microvilli handle acids / bases.
  • All this is just to say that the size and shape helps dictate function.

Renal nerves and lymphatic vessels

• There are lots of nerves which can serve to change diameter of afferent vessel.
• There are lymphatics to drain.

Renal blood flow at nephron level

• There is a boatload of branching because there are lots of little vessels that surround the tubule.
• The efferent arteriole starts after the glomerulus and splits into many branches that surround the tuble and then join together to flow into the venous system.
  • The branches that surround the tubules are called the tubular capillary bed and is the second of the two capillary beds.
  • This bed does all that we would expect, like exchange oxygen, etc.
• The capillaries that surround the juxtamedullary nephronic loops are called the vasa recta.

Juxtaglomerular apparatus

• This is where the distal tubule is in direct contact with the afferent arteriole.
• At the point of contact, the epithelial cells of the distal tubule are called macula densa and the smooth muscle cells that surround the tubule are called granular cells.
• The macula densa are osmosensors so they can sense the osmolarity of the filtrate in this late stage of the nephron (after most stuff has been reabsorbed). They can secrete factors that will affect constriction or dilation of the afferent vessel. Constriction reduces blood flow and thus there is less filtrate. Dilations causes increased blood flow and increased filtration.
• In the efferent arterioles, the cells are called granular cells. When these cells are stimulated by systemic factors, they secrete renin into the blood supply. This will affect cells throughout the whole body. For now, know that it has a systemic affect and that the overall affect is vasoconstriction and salt and fluid retention.
  • We'll review this often.

Blood flow of the kidney

• About 1200 ml / minute.
• About 10% of the blood volume becomes the initial filtrate.
  • This works about to 120 ml / min or 170 liters / day.
  • But we don't pee that much.
  • The entire plasma volume is filtered about 60 times per day.
• The filtrate is mostly water along with anything under 10k MW, including ions, aas, sugars, metabolic wastes, etc.
  • Albumin is about 60K MW and Hb is about 40K MW.
• The formation of the filtrate is nonselective. However, our reabsorption is selective.
• We can either reabsorb stuff or secrete stuff through the epithelial cells of the nephron.
  • We are particularly interested in secreting acids.

=Formation of urine

• started here on 03/24/10.
• Today we'll go over some of the control mechanisms.
  • We'll save tubular secretion for next lecture, we'll cover the other two today.

• Three mechanisms:
  • Glomerular filtration
    • relatively nonselective
  • Tubular reabsorption
  • Tubular secretion

• passed out exams.
• stopped here on 03/22/10.

Glomerular filtration

• The glomerular filtration rate is about 170 liters / day in a normal, healthy adult.
• This can tell us some about kidney function.
  • Like if nephrotoxic drugs are having effects on the blood.
• There are two major parameters that control the filtration rate:
  • The filtration pressure (net is summed up over all nephrons)
  • The nature of the filtration membrane (the three layered membraneous structure we talked about last time).

Filtration coefficient

• This is a coefficient that describes how much can get through the membrane.
• It is inversely proportional to the resistance.
• It is directly proportional to the surface area (all the capillaries put together).
• Things that affect filtration coefficient are generally associated with disease states because this doesn't change much in healthy adults:
• Any disease states that change one of the three membranes (especially the basement membrane or the podocytes), there will be a change.
  • Fibrosis on the membranes can decrease the coefficient.
• Any disease state that changes the surface area will decrease the coefficient.
  • Like loss of nephrons or loss of capillary beds.

Net filtration pressure

• This can be changed minute to minute.
• If the pressure goes up, there will be more filtrate generated.
• This pressure is a function is still a function of all the things of other capillary beds plus a new one:
  • Glomerular blood hydrostatic pressure: just like normal hydrostatic pressure, but much higher; pushes stuff out of the blood.
  • Blood colloital osmotic pressure: keeps stuff in the blood.
  • Capsular hydrostatic pressure: analogous to interstitial hydrostatic pressure (which is discounted in other capillary beds of the body because it is so low); this force will keep things in the blood.
• Net pressure is about 10 mmHg pushing stuff out of the blood.
• Net filtration pressure = glomerular hydrostatic pressure - blood colloital osmotic pressure - capsular hydrostatic pressure.
  • This makes sense becuase glomerular hydrostatic pressure wants to drive fluid out of the blood and into the filtrate and the other two want to keep fluid in the blood.

Glomerular hydrostatic pressure

• The only difference than with other capillary beds is that the pressure is about twice as high.
• This is because the efferent arteriole is smaller than the afferent arteriole diameter.

Blood colloital osmotic pressure

• Same thing as when we talked about it before (about 30 mmHg).
• It depends on the osmotic pressure of the blood.
• Let's say you have a large decrease in plasma protein (liver failure, saline administration, etc.).
  • This will drive the net filtration up because the force keeping fluid in the blood will decrease.
• Let's say you get dehydrated.
  • This will drive the net filtration down because the osmotic pressure will go up and hold more fluid into the blood.

=Capsular hydrostatic pressure

• About 15 mmHg.

Systemic blood pressure and glomerular blood pressure

• The glomerular hydrostatic pressure is not directly affected by the blood pressure in the body.
  • That is, whether the systemic blood pressure is between 80 and 180 mmHg, it won't directly affect the afferent arteriole pressure.
• There will be an affect, though, it will come through the CNS.
• We don't want these two blood pressures directly linked because then our filtration rate would be directly linked with normal activities like standing up.

Regulation of GFR

Intrinsic controls

• These are intrinsic to the kidney system.
• This includes the myogenic system in which stretching of the smooth muscle cells causes contraction back to the original size which maintains the GBP.
• Second is the tubuloglomerular feedback mechanism: this is the feedback provided by the juxtamedullary apparatus.
  • In this mechanism, the cells are called macula densa cells.
  • They sense changes in osmolarity then give off chemicals that affect the neighboring vessels.
    • When they sense high salt they secrete factors that increase diameter of the afferent arteriole which will decrease the diamter and therefore decrease GFR.

Is this right?

Renin / angiotensin / aldosterone

• The beginning of the cascade is the release of renin.
  • A severe drop in blood pressure (like, below 80), the granular cells (in the blood vessels) will sense this and will release their granules which contain renin directly into the blood stream.
  • Macula densa cells can also release chemicals that will cause the release of renin.
  • The sympathetic nervous system can also cause the release of renin.
  • Note that these all have to do with low blood pressure, low osmolality, or sympathetic stimulation.
• Everything renin does causes an increase of salt and fluid retention.
• Because renin is in the blood, it is systemic.

Is renin released into the afferent or efferent arteriole?

• Renin converts angiotensinogen (normally in blood, made by liver) to angiotensin I.
• ACE converts angiotensin I to angiotensin II in the lungs.
  • ACE = angiotensin converting enzyme.
  • ACE is in the lungs.
  • ACE inhibitors decrease blood pressure by targeting ACE.
• Angiotensin II causes the release of aldosterone by the adrenal cortex.
  • Aldosterone is a steroid hormone that causes sodium retention in the kidney.
• Angiotensin II causes the release of ADH in hypothalamus and stimulates thirst elsewhere in the brain.
  • ADH causes water reabsorption in the kidney.

Is there some automaticity for water / sodium retention?  What happens if you activate aldosterone but don't have ADH release?
*While aldosterone has only a direct effect on sodium, but when sodium enters, the osmolality increases and therefore water is absorbed, also.

• If you have a tumor that causes ADH release causes very high blood pressure.

Sympathetic nervous system

• Let's say there is a heart attack and the blood pressure decreases.
• Baroreceptors detect it which causes constriction at afferent arterioles which will decrease GFR.
• Epi can also cause a decrease in GFR via constriction of afferent arterioles because you don't want to be burning ATP on filtration when trying to outrun a lion.
• Note that the afferent arteriole is innervated, not the afferent.

Other factors

• We don't need to know all these; she'll explain them on the test if she uses it.
• There are lots of localized factors that can affect what is going on in the kidney.

Tubular reabsorption

• Possible control mechanisms:
  • Osmotic gradients:
    • In the proximal tubules where there is lots of flow, the removal of water is driving by osmotic gradients.
  • Concentration gradients:
    • For something like glucose these differences will be important.
  • The presence of transporters:
    • If you don't have the transporter in the epithelial cell, then it won't be reabsorbed.
    • As an example, no transporters for the drugs we take, thus they are eliminated by the kidney and we have to take 500 mg every four hours.
      • So if the drug is somehow reabsorbed, don't give the normal does.
  • Activation of transporters
    • They may be there but are not activated.
  • Hormonal stimulation
  • Metabolic energy
    • This isn't usually a limiting factor, though, the kidney does use lots of energy so in disease states it can matter.
• Glomerular filtration is non-selective.
• Tubular reabsorption is very selective; even sodium and chloride use different transporters.
• Active transport requires energy.
• Passive reabsorption but does require a transporter (for our discussion of the nephron).
• A pump is something that uses energy and moves things across the concentration gradient.
• A channel allows a specific molecule to move down its concentration gradient.
• A co-transporter (aka symporters): transport two or more species in the same direction.
• An antiporter uses two components in opposite directions.
  • Think sodium-hydrogen exchanger.

Characteristics of carrier-mediated transporters

• They have specificity regarding the species they transport.
  • They won't transport things even if they are similar in size or charge.
• Directionaliy
  • Most will only go one direction.
• Polarity
  • They are found only in one of the two membranes (apical or basal).
• There can be multiple transporters in the same cell.
  • There can be three different chloride channels in the same cell and they may be regulated differently.
• Different segments of the kidney have different transporters.
  • This is what makes the sections of the tubule different.
• Carriers can be saturated.
  • Best example is glucose.

Specific example of carrier mediated transport: Glucose

• Once you've bound all the carriers, you can't move any more.
• In a normal state, all the glucose in the filtrate can be reabsorbed.
• However, if the filtrate has 2 or 3 times as much glucose then there may not be enough transporters to move it all back into the blood.
• Glucose transporters are only found in the proximal tubules.
• The glucose transporter is a symporter; it moves both glucose and sodium.
  • It is a secondary active transporter because it harnesses the energy of the sodium gradient (which wants to move sodium into the cell) to move glucose against its concentration gradient.
  • On the basal side of the cell, the sodium is being pumped out via an ATP-dependent pump to maintain the low sodium levels.
  • Also on the basal membrane is a glucose channel that allows glucose to flow down its concentration gradient from inside the cell into the blood.

Specific example of carrier mediated transport: amino acids

• Most amino acid transporters are also sodium-linked symporters that rely on the sodium gradient for energy.
• We want to keep our amino acids.

Protein transportation

• If protien gets into the filtrate there are not transporters so it will show up in the urine.
• We all have some, but it rises in deases sates.
• Missed the diseases.

Transport characteristics of various tubule segments

• There things distinguish regions:
  • Size and shape of cells
  • What can get through junctions
  • Proteins of ...?

Comparison of proximal and distal

• Transport capacity:
  • Proximal reabsorbs in bulk.
    • Most stuff is along gradient.
    • Most stuff reabsorbed is reabsorbed here.
  • Distal tubule
    • Because water has been reabsorbed things must be moved up concentration gradient.
• Electrical characteristics:
  • Proximal: ?
  • Distal tubule: nothing leaks across
• Control of transport:
  • Proximal: gradients and transporters
  • Distal: hormonal control

• What is transporterd:
  • Proximal:
    • 70% of water
    • 70% of sodium
    • All organics
  • Henle
    • 10% of water
    • 20% of sodium
    • Ascending loop cannot absorb water but you can get rid of sodium and chloride.
  • Distal and collecting duct:
    • 9% of sodium
    • 19% of water
    • It is this last 9 and 19% that controls homeostasis.

Henle

• There is a triple cotransporter that moves chloride, potassium, and sodium into cell from filtrate.
  • The sodium is moved into the blood.
  • Cl and K+ are moved into blood via a cotransporter.
  • The potassium is recycled through the sodium potassium atpase. Once it gets high, the luminal membrane potassium channel is opened and it flow back into the filtrate.
• Lasis, a class of diuretics, target the triple co-transporter, thus inhibiting it and generating more urine because water won't follow reabsorption after chloride and sodium are reabsorbed.

Where is the energy burned for this whole process?

Distal tubule and cortical collecting duct

• It is in this area that aldosterone works.
• There is a luminal sodium channel which is increased in expression by aldosterone.
• Then sodium flows into the cell, it is then pumped out by na/k atpase into the blood.
• Then potassium is increased in cell and secreted via a potassium channel on the luminal surface.
• Note that aldosterone is only controlling a very small part of the nephron, a very small amount of the sodium reabsorption by the kidney, but a very important part.
• There are also intercalated cells

• stopped here on 03/24/10.