Renal system
Each of two kidneys consists of 8-10 conical pyramids having their bases in the cortex and their apices project toward the pelvis. Each pyramid consists of outer cortex and inner medulla.-Each pyramid pours its urine into a minor calyx.
-Every 2-3 calyces unite to form a major calyx.-Major calyces unite to form the renal pelvis.
-Renal pelvis leads urine through the ureter which emerges through the hilum of kidney.
-At the hilum also, renal artery enters and renal vein leaves
-Two ureters pour into single urinary bladder from which urethra emerges.
Renal blood supply
About 25% of the resting cardiac output ﴾1.25 L\min﴿ supplies the 300 grams of renal tissue with much greater flow to the cortex ﴾97%﴿ than to the medulla.-The renal artery gives off segmental arteries which divide into interlobar branches. Interlobar arteries pass between the renal pyramids and curve to run between the cortex and medulla as arcuate arteries.
-Arcuate arteries give off interlobular branches ﴾radial arteries or medullary rays﴿.
-Interlobular arteries give off afferent arterioles which enter Bowman's capsule and supply renal glomerular capillaries.
-Efferent arterioles collect the remaining blood inside renal glomerular capillaries and leave Bowman's capsule to give off peritubular capillaries which collect blood that is reabsorbed from renal tubules.
-Peritubular capillaries either pour directly into the interlobular veins, or indirectly into vasa recta and then into interlobular veins.
-Interlobular veins run along interlobular arteries, hence they pour into arcuate, interlobar, segmental and, lastly, renal veins.
Nephrons
The structural and functional unit of kidney is called nephron. There are two types of nephrons: cortical nephrons and juxtamedullary nephrons. More than one million nephrons are present in each kidney. They are composed of the following structures:-Glomerulus which is a globular tuft of capillaries supplied by afferent arteriole and drained by efferent arteriole and enclosed inside tightly sealed Bowman's capsule. Blood that is filtered inside the glomerulus is transferred from Bowman's capsule to the renal tubules.
-The first segment of renal tubules is the proximal tubule which starts as a tortuous tubule called proximal convoluted tubule ﴾PCT﴿ or called pars convoluta.
-Proximal convoluted tubule then straightens to be called the proximal straight tubule ﴾PST﴿ or called pars recta.
-At the junction between outer and inner stripes of outer medullary zone starts the thin descending limb of Henle's loop ﴾tDHL﴿
-Henle's loop turns back to become the thin ascending limb of Henle's loop ﴾tAHL﴿
-Henle's loop thickens at the junction between the inner and outer medullary zones to be referred to as ascending limb of Henle's loop ﴾TAHL﴿.
-Henle's loop enters the cortex again as distal tubule.
-The distal tubule passes between the afferent and efferent arterioles of the same nephron making with the afferent arteriole a special contact called juxtaglomerular apparatus ﴾JGA﴿.
-The distal tubule, then, continues as distal convoluted tubule ﴾DCT﴿.
-Distal convoluted tubules of several nephrons unite as collecting tubules.
-Collecting tubules pour in larger collecting tubes.
-Collecting tubes become cortical collecting ducts.
-They then enter the medulla as medullary collecting ducts.
-Medullary collecting ducts end in main duct of renal pyramid to supply the minor calyx,etc.
Glomerular capillary membrane
It is composed of three layers: The single layer of capillary endothelial cells lies on basement membrane and covered by the visceral layer of Bowman's capsule which is called podocytes.The endothelial layer is fenestrated such that even some plasma proteins ﴾but not cells﴿ can pass through its fenestrae. Yet; the proteins can not exit the basement membrane despite its very high permeability ﴾ more than 100 times the permeability of other capillary membranes in human body﴿. Other filtered materials and ions, however can pass easily through the membrane and the slit pores between the feet of podocytes.
Functions of kidney
Regulation of extracellular fluid (ECF)volume and osmolarityRegulation of body fluids composition
Regulation of blood pressure
Regulation of acid-base balance
Regulation of bone metabolism by regulation of excretion of calcium and phosphate ions and formation of active the form of vitamin D (1, 25 dihydroxycholecalcipherol)
Production of erythropoietin hormone
Excretion of various metabolic waste products, drugs, toxic substances and poisons.
Renal clearance
When certain amount of substance ﴾x﴿ is cleared away from plasma and excreted in urine, it is called renal clearance of that substance ﴾Cx ﴿.Not all of the substance filtered from glomerular capillaries appears in urine, instead; some of this substance may be reabsorbed back to the blood via peritubular capillaries, while additional amounts of the same substance may be secreted from tubular cells to tubular lumen to appear in urine.
So: Cx = GFR TR + TS
where GFR is the glomerular filtration rate of xTR is the tubular reabsorption of x
TS is the tubular secretion of x
Glomerular filtration rate ﴾GFR﴿
Glomerular filtration is passive non-selective process. When renal plasma flows from afferent to efferent arterioles, about 20% of its contents is filtered by glomerular filtration from glomerular capillaries to Bowman's capsule. This is called the filtration fraction ﴾FF ﴿
GFR = renal plasma flow ﴾ RPF ﴿* FF
GFR = RPF * 20%
RPF = renal blood flow ﴾ RBF ﴿* (1-hematocrit)
= 1250 ml\min * 0.5
GFR = 625 ml\min * 20% = 125 ml\min
Hence, about 180 liters of plasma are filtered by renal glomeruli every day. But, about 179 liters are reabsorbed by renal tubules back to the circulation and only about 1 liter is excreted as urine every day.
Measurements of GFR and RBF
A substance used to measure GFR and RBF must fulfill the following requirements:1. It must not be toxic.
2. It must not be stored, or metabolized by kidney.
3. It must not be produced, secreted or reabsorbed by renal tubules.
4. It must not affect GFR or RBF by itself.
Measurement of GFR
Endogenous substance like creatinine or exogenous substance like inulin fairly fulfills most of the previously mentioned requirements to measure GFR.GFR = Cin = Uin * V / Pin
Where Cin = Clearance of inulin
Uin = Urinary concentration of inulin
V = Urine flow
Pin = Plasma concentration of inulin
Measurement of RBF
Measurement of RBF can be calculated after measurement of RPF as follows: RBF = RPF / (1-hematocrit)RPF can be measured by measurement of clearance of (x) substance that is completely 100% extracted from plasma and excreted in urine during its passage from afferent to efferent arterioles (extraction ratio = 1.0).
RPF = Cx / Ex
Where Cx is clearance of x
Ex is extraction ratio of x
But Ex is 1.0
So RPF = Cx
Such substance (x) is not found yet. But, there is another substance called paraaminohippuric acid (PAH) that is about 90% extracted, so, its extraction ratio is said to be 0.9 (EPAH = 0.9).
RPF = CPAH / EPAH
= CPAH / 0.9Factors affecting GFR
The following equation summarizes some factors influencing GFRGFR = Kf * (net ultrafiltration pressure)
= Kf * (PG + ΠB – PB - ΠG)
= Kf * (60 + 0 – 18 - 32) respectively
= Kf * (+10 mmHg)
Where Kf is ultrafiltration coefficient which is the effective ultrafiltration surface area multiplied by glomerular capillary permeability
PG is glomerular capillaries' hydrostatic pressure
ΠB is osmotic pressure of colloids inside Bowman's capsule
PB is hydrostatic pressure inside Bowman's capsule
ΠG is osmotic pressure of colloids inside glomerular capillaries
The latter four factors are called Starling forces
Other factors affecting GFR are:
-RBF: when RBF increases GFR also increases
-FF: when FF increases GFR also increases
-Vasoconstriction of afferent arterioles decreases GFR (decreased PG)
-Slight vasoconstriction of efferent arterioles increases GFR (increased PG)
-Severe vasoconstriction of efferent arterioles decreases GFR (increased ΠG)
Control of GFR
Control of GFR is by one or more of the followings:Sympathetic nervous activity
Hormones and autacoids
Autoregulation
Plasma levels of amino acids and glucose
1- Sympathetic nervous activity: Strong sympathetic activity decreases GFR e.g., in severe hemorrhage and in cerebral ischemia while the role of parasympathetic (vagal) innervations is yet unknown.
2- Hormones and autacoids: Hormones are small chemical substances that are secreted from endocrine glands and transported by blood to work at distant organs while autacoids are chemical substances that are secreted and act locally.
Adrenaline (epinephrine), nor-adrenaline (nor-epinephrine), angiotensin II, aspirin and endothelin decrease GFR.
Nitric oxide, prostaglandin and bradykinin increase GFR
3- Autoregulation: Two regulatory processes are encountered in the regulation of GFR:
Juxtaglomerular feedback mechanism: Juxtaglomerular apparatus (JGA) consists of specific distal convoluted tubular epithelial cells called macula densa (which contains osmoreceptors that are sensitive to any increase or decrease in concentration of NaCl) in close contact with specific smooth muscle cells in the wall of afferent arterioles called Juxtaglomerular cells.
When GFR is decreased; tubular flow slows down resulting in increased tubular reabsorption of NaCl. This will decrease NaCl near the osmoreceptors of macula densa. Macula densa will send impulses to the JG cells to relax resulting in vasodilatation of afferent arterioles. This will increase blood flow to the glomerular capillaries which will in turn increase GFR.
The reverse occurs when GFR is increased; tubular flow quickens resulting in decreased tubular reabsorption of NaCl. This will increase NaCl near the osmoreceptors of macula densa. Macula densa will send impulses to the JG cells to contract resulting in vasoconstriction of afferent arterioles. This will decrease blood flow to the glomerular capillaries which will in turn decrease GFR. Renin is also produced by JG cells in response to any increase in GFR or RBF which will result in production of angiotensin I and then angiotensin II to decrease GFR and RBF.
Myogenic mechanism: Increased RBF that causes increase in GFR; is at the same time the cause of distension of afferent arterioles and stretch of smooth muscles lining their walls. This stretch results in myogenic contraction of these smooth muscles leading to vasoconstriction of afferent arterioles and decreased RBF and GFR.
4- Plasma levels of amino acids and glucose: This mechanism depends on the fact that tubular reabsorption of amino acid and glucose is unlimited and so, when plasma levels of amino acids and glucose increase; tubular reabsorption will also increase resulting in decreased amounts of NaCl near the osmoreceptors of macula densa. Macula densa will send impulses to the JG cells to relax resulting in vasodilatation of afferent arterioles. This will increase blood flow to the glomerular capillaries which will in turn increase GFR.
Tubular reabsorption
-It is a highly selective process that may be passive or active.-Some substances are completely reabsorbed like amino acids and glucose.
-Some substances are mostly reabsorbed like bicarbonates and some other electrolytes.
-Some other substances are mostly reabsorbed in the presence of specific factors like hormones but their reabsorption is reduced when these hormones are reduced or absent like water reabsorption which is increased in the presence of antidiuretic hormone, and sodium ions reabsorption which is increased in the presence of aldosterone and\or angiotensin II hormones.
-Many substances are reabsorbed along with other substances like chloride ions which follow sodium ions, and sodium chloride salt which follows water.
-Some substances are 50% reabsorbed (and 50% excreted) like urea.
-Some other substances are about completely excreted like creatinine and some drugs and poisons.
There is a glomerulotubular balance such that when GFR increases; tubular reabsorption also increases. But this is not eternal; in reality, the active transport processes of reabsorption may be saturated when the tubular lumen is overloaded with filtered substances. The maximum tubular load of certain substance above which an active transport process of tubular reabsorption is saturated and reabsorption is ceased is called transport maximum (Tm) of that substance.
The maximum plasma concentration of certain substance above which this substance starts to appear in urine is called renal threshold of that substance which equals Tm/GFR
Transport maximum of glucose (TmG) is about 325 mg/min and its ideal renal threshold is 325/125 = 2.6 mg/ ml = 260 mg/100 ml
But the actual renal threshold for glucose is about 180 mg/100 ml and this difference may be due to that not all of renal tubules have the same Tm and that some of the filtered glucose molecules before Tm bypass reabsorption.
Control of tubular reabsorption
1-Sympathetic control: Sympathetic activity leads to increase in tubular reabsorption of sodium ions.2- Hormonal activity:
A- Aldosterone: Secreted from adrenal cortex and acts on principal cells of distal tubules to increase reabsorption of sodium ions and excretion of potassium ions. It increases permeability of luminal membrane to sodium ions and stimulates sodium- potassium pump in basolateral membrane. Adrenal insufficiency (Addison's disease) results in excessive sodium loss and potassium retention while adrenal hyperactivity (Cushing syndrome) results in sodium retention and potassium depletion.B- Angiotensin II: Produced by the lungs from angiotensin I this in turn produced in the liver from angiotensinogen or called renin. Renin is formed in kidneys as mentioned. Angiotensin acts directly (or indirectly after stimulation of aldosterone) to increase sodium ions reabsorption.
C- Antidiuretic hormone (vasopressin): This is produced from posterior pituitary gland and it acts on distal and collecting tubules and ducts to increase water reabsorption and urine concentration.
D- Atrial natriuretic peptide (ANP): Produced by cardiac atria in response to any increase in blood volume and acts especially on collecting ducts to decrease sodium and water reabsorption and so, increase urine excretion to restore normal blood volume.
E- Parathyroid hormones: Produced by parathyroid glands and act especially on thick ascending limbs of Henle's loops (and distal convoluted tubules) to increase calcium and magnesium ions reabsorption and decrease phosphate reabsorption.
Renal regulation of ECF osmolarity
Normal ECF osmolarity is about 280-300 mosm\L and it is mostly dependant on sodium ions concentration (142 mEq\L). Normal daily sodium ions intake must equals its daily output = 10-20 mEq.Na+ intake ECF volume Blood pressure
Angiotensin II Baroreceptors
Na+ excretion Pressure natriuresis Brain stem
Aldosterone Na+ reabsorption Sympathetic activity
Plasma osmolarity (Posm) in healthy subjects is calculated from plasma sodium concentration (PNa+)
Posm = 2.1 * PNa+
But, in patients with renal diseases, plasma concentrations of other substances like urea and glucose are also calculated.
When Posm decreases; kidneys excrete large amounts of diluted urine (down to 50 mosm\L) while when Posm increases; kidneys excrete small amounts of highly concentrated urine (up to 1200 mosm\L). The human body must get rid of not less than 600 mosm of metabolic wastes per day. So, it is very necessary to excrete not less than 0.5 liters of highly concentrated urine daily.
600 mosm\day
= 0.5 L\day this is the minimum obligatory urine volume
1200 mosm\L
According to this equation, when kidney losses its ability to produce concentrated urine; the minimum obligatory urine volume will increase resulting in excessive loss of body fluids (a disease called diabetes insipidus).
According to the same equation, excessive intake of hyperosmotic fluids like sea water will seriously increase the Posm and, thence, the minimum obligatory urine volume even with the maximum renal capability of urine concentration resulting in death from dehydration due to excessive loss of body fluids. The ability of kidney for concentration of urine requires the presence of hyperosmotic medulla created by countercurrent mechanism and urea recirculation in concert with ADH.
Countercurrent mechanism
-The descending and ascending limbs of Henle's loop and vasa recta run a long distance parallel, counter and in close proximity to each other carrying solutes toward medulla and water toward systemic circulation resulting in hyperosmotic medulla.-Descending limbs of Henle's loop are called countercurrent multipliers
because they continuously bring new NaCl to medulla while ascending vasa recta are called countercurrent exchangers because they continuously draw back water from medulla to the systemic circulation.
-The major bulk of tubular reabsorption of water and solutes (about 65%) occurs in proximal tubules. So, tubular fluid reaches the thin segments within its original osmolarity (300 mosm\L).
-About 15% of water reabsorption occurs in tDHL which is carried back to the systemic circulation via ascending vasa recta. But tDHL is impermeable to solutes which stay within thin segment not reabsorbed. So, tubular fluid reaches the ascending limbs highly hyperosmotic (1200 mosm\L).
-Starting from tAHL, all the following segments are impermeable to water in absence of ADH but very little amounts of solutes are passively reabsorbed in tAHL. So, tubular fluid reaches the following segment still hyperosmotic (900 mosm\L).
-The major active reabsorption of electrolytes occurs in TAHL (about 30%) which is mainly due to 1Na+-2Cl-1K+ active cotransport process which works against as much as 200 mosm\L concentration gradient. So, tubular fluid reaches distal tubules hypoosmotic (100 mosm\L).
-The remaining reabsorption processes of electrolytes (about 5%) occur in distal segments.
-The net result is hyperosmotic medulla which favors further water reabsorption (about 19%) from collecting ducts in the presence of ADH and only about 1% of filtered water is excreted in urine. While in absence of ADH, about 20% of filtered water is excreted.
Urea recirculation
Recirculation of urea is responsible for about 40% of the process of urine concentration when urea is reabsorbed from medullary colleting tubules to the medullary interstitium to be secreted again from the tubular cells of thin segments to their lumen where the cycle is repeated again and again.
Body control of ECF osmolarity
Osmoreceptors-ADH feedbackThirst center in brain stem
Salt appetite center in brain stem
Osmoreceptor cells lie in anterior hypothalamus and are sensitive to any increase in Na+ concentration and send signals to supraoptic nuclei which stimulate the posterior pituitary gland to increase secretion of ADH (vasopressin) that increases water reabsorption. Vasopressin secretion is also stimulated by decreased blood volume, decreased blood pressure, nausea, vomiting, morphine and nicotine. Vasopressin secretion is inhibited by increased blood volume, increased blood pressure and alcohol intake.
Increased osmolarity also stimulates the thirst center in brain stem to increase the desire for water intake and also to increase secretion of ADH. Thirst center is also stimulated by decreased ECF volume, decreased blood pressure, angiotensin II and dryness of mouth, pharynx and esophagus while it is inhibited by decreased ECF osmolarity, increased ECF volume, increased blood pressure and gastric distension.
Decreased osmolarity stimulates salt appetite center in the brain stem to increase the desire for salt intake.
Renal regulation of blood volume and pressure
Blood volume is kept constant despite the tremendous changes in fluids intake from 0.1th to 10 times normal due to:Small increase in blood volume results in large increase in cardiac output.
Small increase in cardiac output results in large increase in blood pressure
Small increase in blood pressure results in large increase in urine excretion which immediately hinders and reverses the raising blood volume and pressure.
Acute increase in blood pressure is balanced by direct increase in Na+ excretion due to increase in GFR and decrease in Na+ reabsorption with increase in Na+ leak back to the tubular lumen. Pressure induced increase in Na+ excretion is called pressure natriuresis which is always accompanied by pressure diuresis (pressure induced increase in urine excretion).
Chronic increase in blood pressure is balanced by decrease in angiotensin II production which results in decrease in Na+ reabsorption directly or indirectly by decreasing aldosterone production from adrenal cortex.
Body regulation of acid-base balance
Any change in hydrogen ions concentration [H+] will affect all cellular and body functions due to its effects on many reactions. Normal [H+] in ECF is only 0.00000004 mol\L, so; it is better to use pH (which is log [H+] = 7.4).
Nobody can survive more than hours when pH raises to 8.0 or falls to 6.8 (more or less than normal by 0.6). Regulation of [H+] is by one or more of the following systems: Chemical acid-base buffer systems in body fluids, respiratory and renal regulation of acid-base balance.
a. Buffer systems are:
Bicarbonate buffer system: It is the most important buffer system in ECF. The following reaction occurs when [H+] is increased:H+ +HCO3 → H2CO3 → H2O + CO2......(CO2 to be expired by the lungs)
While when [OH-] is increased, the following reaction occurs:OH + H2CO3 → H2O + HCO3............( HCO3 to be excreted by kidneys)
The power of dissociation constant (pK) for bicarbonate system is 6.1 and accordingly, Henderson-Hasselbalch equation states that:pH = 6.1 + log [HCO3]\0.03 PCO2
When HCO3 decreases; pH is decreased and there will be metabolic acidosisWhen PCO2 increases; pH is decreased and there will be respiratory acidosis
When HCO3 increases; pH is increased and there will be metabolic alkalosis
When PCO2 decreases; pH is increased and there will be respiratory alkalosis
Phosphate buffer system: It is important buffer system in intracellular and renal tubular fluids. Its pK is 6.8 and the following reaction occurs when [H+] increases:
H+ + HPO42 → H2PO4
When [OH] is increased the following reaction occurs:
OH + H2PO4 → HPO42 + H2O
Protein buffer systems: Are the most available intracellular buffer systems but also work extracellularly. One of the most important protein buffers is hemoglobin in red blood cells.H+ + Hb → HHb
Ammonium buffer system: Is the last choice buffer system in renal tubules when bicarbonate and phosphate buffer systems are saturated. Ammonium is formed from metabolism of glutamine inside renal tubular cells. The following reaction occurs when [H+] increases:H+ + NH3 → NH4+
When [OH-] is increased the following reaction occurs:OH + NH4+ → NH4OH
b. Respiratory regulationRespiratory regulation of acid-base balance is via stimulation or inhibition of the respiratory center in the brain stem by the central chemosensitive areas which are bilateral aggregations of neurons beneath the ventral surface of medulla that are sensitive to changes in H+ and PCO2. The result is hyper- or hypo- ventilation respectively.
Double normal alveolar ventilation reduces PCO2 and raises pH from 7.4 to 7.63 while 1\4th normal alveolar ventilation raises PCO2 and reduces pH to 6.95 because pH is inversely related to PCO2 according to Henderson-Hasselbach equation.
c. Renal regulation:
Occurs by excretion of acidic or alkaline urine. Normally, daily renal secretion of H+ is about 4400 mmol. Bicarbonates system buffers 4320 mmol in renal tubules and the other 80 mmol are buffered by phosphates and then ammonium buffer systems. Most of renal tubular cells utilize secondary active transport to secrete H+ like Na+-H+ antiport, but the intercalated cells of distal tubules utilize primary active transport called proton pump.
Diuretics
Diuretics are substances that increase urine excretion which mostly involves water and electrolytes. They are given as medications in case of increased ECF volume especially those accompanying edema and increased blood pressure. They are classified according to their mode of action into:Osmotic diuretics: Acting basically on proximal tubules by increasing tubular fluid osmolarity to inhibit water and electrolytes reabsorption. Examples are urea, mannitol, sucrose…
Loop diuretics: Strong diuretics acting on TAHL by blocking 1Na+2Cl1K+ secondary active cotransport resulting in severe decrease in reabsorption of these electrolytes with suppression of countercurrent mechanism. Examples are furosemide, ethacrynic acid, bumetanide…
Thiazides: Acting on early distal tubules by blocking Na+-Cl cotransport decreasing their reabsorption. Example is chlorothiazide.
Carbonic anhydrase inhibitors: Acting on proximal tubules and intercalated cells of distal tubules by inhibition of enzyme carbonic anhydrase resulting in decreasing bicarbonate reabsorption and H+ secretion. This will decrease Na+-H+ antiport and, consequently, decrease Na+ reabsorption. Example is acetazolamide (diamox)
Competitive aldosterone inhibitors: Acting on cortical collecting tubules by competing with aldosterone and blocking its receptors resulting in decreasing Na+-K+ antiport which results in decreasing Na+ reabsorption. Example is spironolactone (K+ sparing)
Na+ channels blockers: Acting on collecting tubules by blocking Na+ channels resulting in decreasing Na+ reabsorption which also indirectly spares K+ by decreasing the availability of Na+ for Na+-K+ antiport. Examples are amiloride, triametrene…