Kidneys at Work

Episode 1: Overview

Episode 1: Overview

The chemistry of the blood must be carefully controlled. Major players in this control are the kidneys which remove unwanted and harmful metabolites and foreign molecules from the blood and regulate the concentrations of the blood's electrolytes. Kidney: Anatomy, Renal Artery, Vein and Nerves – To effect this function kidneys receive about 20% of the blood flow. They filter about 10% of this with each passage at a normal rate of about 120ml/minute. Filtration is effected by nephrons of which there may be about 1 million, per kidney at birth, though the number can vary more than tenfold. The filtration is dependent on the number of functional nephrons and declines as they are lost to damage and disease. Nephrons contain a glomerulus where filtration occurs with the filtrate fed into a tubular structure were re-absorption occurs (including 99% of the sodium and water) before the urine is passed into a collecting duct. The collecting ducts join together to ultimately form the ureter which passes the urine down to the bladder. Kidney: Histology of the Nephron and Glomerulus

Blood Supply Blood supply to the kidneys enters via the renal artery and leaves via the renal vein with extensive branching and rejoining in between.

. Ultimate branching of the arterial system occurs at the individual nephron where an afferent arteriole branches into the glomerular capillaries which then rejoin to exit the glomerulus via an efferent arteriole. The efferent arteriole then re-branches to form the peritubular capillaries which receive the re-absorbed components from the nephron and nourish and oxygenate the surrounding cells. Sequential rejoining of vessels then occurs to accomplish exit of the blood via the renal vein.

Nephron Structure

The nephron consists of a capsule enclosing the glomerulus and feeding the filtrate into the tubular structure. Kidney: Histology of Renal Tubules – https://www.urology-textbook.com The tubular structure contains four segments, each of which may be considered to have sub-segments. In order from the capsule the four segments are:

      1. A convoluted segment, the Proximal Convoluted Tubule
      2. One straight side of a U-shaped structure, the Descending Loop of Henle
      3. The other side of the loop, the Ascending Loop of Henle
      4. Another convoluted segment, the Distal Convoluted Tubule

Importantly, the convolutions of the Distal Convoluted Tubule take it past the entrance to the capsule where it contacts the juxtaglomerular apparatus which regulates the function of the nephron by action on the afferent and efferent arterioles. With the aid of the juxtaglomerular apparatus, each individual nephron has the possibility to change the filtration performance in the glomerulus, depending on the urine analysis in its distal tubule. The tubule then continues into the collecting duct which joins with ducts from other tubules to ultimately form the ureter to carry urine to the bladder. Kidney: Physiology of the Glomerular Filtration Rate – https://www.urology-textbook.com

There is a connecting tubule (CNT) which joins the distal convoluted tubule into a collecting duct. The CNT provides an additional source of feedback to its own glomerulus by anatomical association with the afferent arteriole. This new cross-talk pathway between renal tubule and glomerulus can cause dilatation of the afferent arteriole and increased GFR in response to high sodium reabsorption in the connecting tubule.

Episode 2: The Juxtaglomerular Apparatus.

The following is largely abstracted from Wikipedia.

The Juxtaglomerular apparatus has three types of cells:

Juxtaglomerular Cells, Macula Densa Cells, and Lacis Cells

The Juxtaglomerular cells secrete renin into the glomerular arterioles in response to:

Beta1-adrenergic stimulation (adrenaline and noradrenaline via cAMP)

Decrease in renal perfusion pressure (detected directly by the juxtaglomerular cells)

Decrease in NaCl (sodium chloride) absorption in the Macula Densa (often due to a lowered GFR, causing slower filtrate movement through the proximal tubule and so more time for reabsorption thus resulting in a lower NaCl concentration by the time the filtrate reaches the Macula Densa).

Macula densa cells are part of the distal tubule. They sense high NaCl concentration in the distal tubule to secrete a paracrine vasopressor which acts on the adjacent afferent arteriole to decrease GFR, as a tubuloglomerular feedback loop. Specifically, excessive filtration (high GFR) at the glomerulus or inadequate Na uptake in the proximal tubule / thick ascending loop of Henle brings fluid with an abnormally high concentration of Na to the distal convoluted tubule. Na/Cl-co-transporters move Na/Cl into the cells of the macula densa which lack sufficient basolateral Na/K-ATPases to excrete the additional Na. Hence, osmolarity in the cell increases and water flows in, causing the cell to swell. This allows leakage of ATP which is subsequently converted to adenosine. Adenosine vasoconstricts the afferent arteriole and vasodilates (to a lesser degree) the efferent arteriole so decreasing GFR. Additionally, adenosine inhibits renin release in JG cells. Also, when macula densa cells detect higher concentrations of Na and Cl they inhibit Nitric Oxide Synthetase (NOS) (decreasing renin release) with an unknown pathway.

A decrease in GFR, allowing more time for re-absorption, leads to less solute in the tubular lumen. As the filtrate reaches the macula densa, the cells detect the lower concentrations of Na and Cl and upregulate NOS. NOS generates nitric oxide (NO) which stimulates the formation of prostaglandins. These prostaglandins diffuse to the JG cells to activate a prostaglandin receptor which activates adenylate cyclase to raise cyclic-AMP (cAMP) levels. cAMP augments renin release. The activated VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. interferes with the action of cAMP by binding to CREB ( cAMP response element binding protein).

The efferent arterioles are constricted by the vasoconstrictive effect of renin release, while the afferent arterioles are vasodilated by prostaglandins and NO. Dilation of the afferent arteriole and constriction of the efferent arteriole increases filtration pressure in the glomerulus and raises GFR. As a consequence of the constriction of the efferent arteriole, the blood supply to the peritubular cells can be diminished. The resulting anoxia can promote erythropoietin (EPO) production and so RBC formation: but can be damaging to the cells in the area.

The lacis cells are mesanglial structural cells in the glomerulus that under normal conditions serve as anchors for the glomerular capillaries. The mesangial cells within the glomerulus communicate with mesangial cells outside the glomerulus (extraglomerular mesangial cells), and it is the latter cells that form part of the juxtaglomerular apparatus. They are connected with glomerular mesangial cells via gap junctions. The lacis cells contain actin and myosin, allowing them to contract when stimulated by renal sympathetic nerves, which may provide a way for the sympathetic nervous system to modulate the actions of the juxtaglomerular apparatus. The latest thinking is that in times of great sympathetic discharge [i.e. during periods when the blood pressure is low, e.g. from blood loss], mesangial contraction reduces the surface area of the glomerulae, thus reducing glomerular filtration and saving excess fluid from being lost into the urine. In addition, extraglomerular mesangial cells are strategically positioned between the macula densa and the afferent arteriole, and may mediate signalling between these two structures.

Episode 3: Tubular Re-absorption

The following is largely abstracted from this Urology-textbook

1. Sodium, Chloride and Fluids

Proximal Tubule and the Descending Loop of Henle In the proximal tubule, two thirds of the primary urine volume is reabsorbed along with electrolytes. Electrolyte re-absorption leads to the water re-absorption with help of the leaky intercellular spaces of the proximal tubule epithelium. The solvent drag enables the paracellular absorption of water and chloride due to electrolyte concentrations between the tubular lumen and the renal interstitium. The driver of sodium transport is the basolateral sodium-potassium-pump ( the Na/K-ATPase) which exchanges 3Na+ out for 2K+ plus 1 proton (H+) in.. On the luminal side of the proximal tubular epithelium, Na+ enters the cell via co-transport with glucose, galactose, phosphate, sulfate or amino acids, or antiport (exchange ) with protons. The reabsorption of HCO3 is linked to the sodium re-absorption and proton secretion with help of a luminal and intracellular carbonic anhydrase.

Ascending part of Henle Loop. The thick ascending loop (TAL) of Henle is impermeable to water and transports electrolytes into the interstitium of the kidney, producing a high osmotic pressure of the interstitium. 30% of the filtered sodium is reabsorbed using a luminal Na-K-2Cl-cotransport mechanism. he energy for this re-absorption derives from the basolateral sodium-potassium pump. The effective prevention of a passive water flow by watertight tight junctions leads to a high osmotic pressure in the renal medulla. The urine at the end of the TAL is hypotonic. Furosemide inhibits the Na-K-2Cl cotransporter and leads to a massive natriuresis and loss of potassium, calcium and magnesium.

Distal tubule Active sodium transport occurs via a thiazide-sensitive Na-Cl-co-transporter; about 10% of the filtered sodium is reabsorbed in the distal tubule. Thiazides inhibit the sodium re-absorption in the distal tubule and lead to a mild diuresis without loss of calcium (calcium-sparing diuretic). This occurs in the first half of the distal tubule. The second half and the connecting tubule is more similar to the connecting ducts.

Collecting Ducts

The permeability of the collecting ducts for water lead to a concentration of the urine up to fivefold the osmolarity of the plasma. This permeability is regulated with ADH (antidiuretic hormone, or Vasopressin). ADH causes the incorporation of additional water channels (aquaporins) into the luminal membrane. The high osmotic pressure of the renal medulla is the responsible force for the urine concentration. ADH can control 10% of the primary urine volume, thus can regulate the diuresis between 1–20 l/d. In the absence of ADH, the permeability of the collecting ducts for water is low and the urine will not be concentrated. A deficiency of ADH secretion leads to diabetes insipitus, a disorder with massive diuresis and excessive thirst.

Additional Na+ re-absorption takes place in the collecting ducts via luminal Na channels (epithelial sodium channel or ENaC). The energy for the Na+ re-absorption derives from the basolateral sodium-potassium pump. Aldosterone regulates the Na+ and water reabsorption and potassium (K+) secretion by upregulating ENaC and the sodium-potassium pump. It also upregulates in the large intestine. ENaC can be inhibited by amiloride, a potassium-sparing diuretic. Trimethoprim in the anti-bacterial,Bactrim, has a similar effect.

Episode 4:Tubular Re-absorption

The following is largely abstracted from further down the page in this Urology-textbook

2. Potassium, Calcium and Phosphate

Other Components

Potassium re-absorption by the kidney 60–70% off the filtered potassium (K+) is reabsorbed in the proximal tubule. Here there is no specific K+-transporter, re-absorption is managed with the absorption of water (solvent drag). 25–35% of the filtered K+ is reabsorbed in the loop of Henle with the Na-K-2Cl-cotransport mechanism. 5–15% of the filtered K+ reaches the distal nephron. Here K+ level is adjusted by the actions of the Principal Cells and the Intercalating Cells in the distal tubule and collecting ducts. They effect exchange of Na+ re-absorption for K+ excretion, and proton (acid) excretion in exchange for K+re-absorption. Aldosterone, produced in response to angiotensin II and high K+, has major role in promoting these exchanges.

Renal Calcium Re-absorption 60% of the filtered calcium is reabsorbed in the proximal tubule with the paracellular absorption of water (solvent drag). Additionally, there are active transport mechanisms.

Renal Phosphate Re-absorption Phosphate is completely filtered, 80–90% of the phosphate is rreabsorbed in the proximal tubule. With high phosphate concentrations in serum, the phosphate re-absorption becomes saturated and phosphate is excreted until phosphate concentration is normalised. An increased phosphate concentration is the stimulus for the parathyroid hormone release and leads to phosphate excretion, calcium phosphate deposition into the bone and lowers the serum calcium.

Proton Excretion and Acid-Base Homeostasis The renal excretion of protons is a major factor in the acid-base homeostasis; mechanisms are the phosphate excretion, ammonia excretion and re-absorption of bicarbonate in the proximal tubule. In the intercalating cells of the distal tubule and the collecting duct, protons can be re-absorbed from, or excreted into, the lumen via an H+-ATPase, ultimately in exchange for K+ .

Phosphate dissociates in the blood to 80% in HPO42-. In the renal tubules, this secondary phosphate binds a proton and the result is H2PO41-. The newly formed primary phosphate cannot be reabsorbed and with the help of phosphate excretion, a proton is eliminated.

The ammonium excretion can be 10-fold increased in case of acidosis. NH3 is formed in the kidney by deamination of glutamine by the tubular cells and can diffuse into the tubular lumen. In the renal tubules, NH3 binds a proton to form NH4+, which cannot be reabsorbed. Ammonia formation is inhibited by high potassium which thus favors the development of acidosis.

Glomerular filtered bicarbonate is reabsorbed in the proximal tubule via the following mechanism: the filtered HCO3- and secreted H+ from the tubular cell (Na+/ H+exchanger) forms with the help of luminal carbonic anhydrase H2CO3, which dissociates to CO2 and H2O. The CO2 enters easily into the tubule cell and binds with OH- (remnants of the H+ secretion) to bicarbonate (HCO3-). With the help of the Na+/HCO3–cotransporter in the basal membrane, bicarbonate is returned into the blood. In the case of alkalosis, bicarbonate can be secreted to balance the acid-base homeostasis.

Urea Transport of the Kidney About 50 g of urea are filtered per day, of which approximately 25–40 g are excreted in the urine. The reabsorption of urea (proximal tubule, collecting ducts) and active secretion of urea (Henle loop) leads to a urea circulation between the lumen of the nephron and renal medulla, which is an important element of the renal urine concentration. Urea is freely filtered, 50% is reabsorbed in the proximal tubule with the re-absorption of water (solvent drag). Urea is secreted in the thin ascending limb of Henle loop, so significant amounts of urea reach the distal nephron. In the collecting ducts, urea is reabsorbed together with water. These mechanisms enable the formation of a high-osmolar urea gradient in the renal medulla, which is important for the renal urine concentration. If the absorption of urea (and water) is stopped in the collecting duct, the osmolarity of the medulla decreases and the concentration mechanisms collapse.

Uric acid transport of the kidney Uric acid is filtered completely and is partially absorbed in the proximal tubule. In addition, uric acid is secreted in the proximal tubule. Uric acid is has a good solubility in form of sodium urate. To prevent calcium urate crystals in the course of the urine concentration, various complexing agents such as calcium citrate, calcium-binding proteins and mucopolysaccharides are necessary.

Mechanism of the Urine Concentration In the case of water deficiency, the human kidney can concentrate the urine up to 4 times the plasma osmolarity of 290 mosmol/l. With antidiuresis, the daily urine volume is 0.5–1 l. A compllex countercurrent system, which includes the Henle loops, Vasa recta and collecting ducts, generates a hypertonic renal medulla of 1200 mosmol/l. The high osmolarity of the renal medulla enables a urine concentration with a urine osmolarity up to these values.The motor of the renal countercurrent system and the urine concentration is the active NaCl re-absorption in the watertight luminal cells of the thick ascending loop (TAL) of Henle, leading to an increase in osmolarity of the renal interstitium. Another mechanism of the high osmolarity of renal medulla is the reabsorption of urea (proximal tubule, collecting ducts) and active secretion of urea (Henle loop).

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