Nephron

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      • The kidneys act as endocrine organs, releasing renin, erythropoietin, and1,25-dihydroxy-vitamin D3 into the circulation.(MCQ)
      • Blood from renal arteries is delivered to the glomeruli
      • At one fifth of cardiac output, this is the highest tissue-specific blood flow (MCQ)
      • The amount of a substance excreted by the kidney is determined by the amount filtered by the glomerulus less the amount absorbed plus the amount secreted
      • Renal Anatomy
        • The kidneys are located in the retroperitoneum.
        • The human kidney is multilobed and grossly divided into a cortex and a medulla.
        • The basic functional unit of the kidney is the nephron
          • The nephron is composed of a long, thin tubule that is closed at one end
          • (Bowman’s capsule).
          • Bowman’s capsule surrounds a high-pressure capillary network, the glomerulus.
          • Together, Bowman’s capsule and the glomerulus serve as a filtration unit, which forms the glomerular filtrate that enters the tubule.
        • The tubular fluid generated by glomerular filtration is modified by reabsorption and secretion across the epithelial cells that form the tubule wall.
          • Net movement of water or solutes from the tubular lumen into the interstitium is referred to as tubular reabsorption.
          • Net transport of substances from the interstitium to the lumen is called secretion.
      • Each nephron has its own blood supply, which is composed of two arterioles and two capillary systems in series
        • The first capillary system is a high-pressure capillary glomerulus
          • It favors filtration
          • It is the source of the tubular fluid.
        • peritubular capillary system
          • After passing through the afferent arteriole, the glomerulus, and the efferent arteriole, the blood enters the peritubular capillary system
          • It is  alow-pressure system that favors reabsorption.
      • There are two types of nephrons
        • cortical (about 85%). (MCQ)
        • juxtamedullary (15%).
        • Cortical nephrons
          • have short loops of Henle with peritubular capillaries
          • Peritubular capillaries differ depending on their association with different nephrons.
        • Juxtamedullary nephrons
          • have long loops of Henle and vasa
          • The vasa recta are long narrow capillary tubules that have a great resistance to blood flow. (MCQ)
        • A portion of the arterial plasma leaves the glomerulus (ie, the product of filtration) to form the protein-free tubular fluid.
        • The remaining arterial plasma enters the peritubular capillary system or vasa recta.
      • The renal tubule consists of the
        • proximal convoluted tubule
        • the loop of Henle
        • the distal convoluted tubule
        • collecting duct that carries the final urine to the renal pelvis and ureter.
      • Renal Blood Flow and Glomerular Filtration
        • Approximately 25% of cardiac output supplies the kidneys, which account forabout 1% of body mass. (MCQ)
        • The high blood flow is necessary to generate the large hydrostatic pressure re- sponsible for the formation of glomerular ultrafiltrate.
        • Most of the renal blood flow goes to the cortex, where the glomeruli are located. (MCQ)
        • Autoregulation of Renal blood flow
          • Renal blood flow remains constant over a wide range of arterial pressures.
          • autoregulation is accomplished by increases in afferent arteriolar resistance.
      • Renal handling of p-aminohippuric acid (PAH)
        • an example of active secretion by a transport-maximum (Tm)-limited mechanism. (MCQ)
        • PAH is foreign to the body and is excreted by filtration plus secretion.
        • The active secretory mechanism is located on the basolateral membrane ofthe proximal convoluted tubule.
        • The PAH carrier issaturableand is inhibited by the drug probenecid.
        • The transport of PAH increases linearly with the concentration of PAH
        • (PPAH) until the delivery of PAH to the peritubular capillaries increases to the point where Tm is attained
        • Secretion of PAH then becomes constant (TmPAH) and equals about 80 mg/min/1.73 m2 in a young male adult. (MCQ)
        • Because PAH is actively secreted in the proximal tubular segment, the TmPAH is a measure of the functional mass of proximal tubules. (MCQ)
      • Renal plasma flow
        • Renal plasma flow can be measured by the Fick method. (MCQ)
        • Most of the arterial plasma entering the kidneys perfuses the proximal tubular segment.
        • Arterial plasma flow entering the kidneys splits into two parallel paths
        • Onepath perfuses the proximal tubular segment used for urine production (ie, secretory tissue),
        • Other path keeps the tissue alive, perfuses inert tissue.
        • These facts are used to develop the Fick method for measuring total renal plasma flow using PAH as the marker
        • Under steady-state conditions
          • PAH entering kidneys/min = PAH leaving kidneys/min

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      • PAH clearance can be used to measure renal plasma flow. (MCQ)
      • If it is assumed that the kidneys can remove all of the PAH from arterial
      • plasma, then the venous plasma concentration of PAH would be 0, and the Fick equation would be equal to the clearance of PAH:

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        • Why CPAH is is about 90% of total RPF but not 100% of total RPF
          • Because a fraction of arterial plasmadoes not perfuse nephrons but rather perfuses inert tissue, the venous plasma concentration of PAH is not 0.
          • PvPAH concentration is about 10% of PaPAHwhen PPAH levels are low.
          • Thus, if CPAH is measured when PPAH levels are low, it is about 90% of total RPF
          • CPAH measures effective renal plasma flow (ERPF)
          • Total renal plasma flow is designated as RPF.
        • Glomerular filtration rate
          • The rate at which tubular fluid is produced is termed the glomerular filtration rate (GFR)
          • Normally GFR = 120–125 mL/min (MCQ)
          • The driving force for glomerular filtration is the net ultrafiltration pressure,which always favors fluid movement out of the capillaries.
          • The glomerulus is a high-pressure capillary system, and the peritubularcapil- lary system (as well as the vasa recta) is a low-pressure system.
          • Thus, the GFRcan be related to Starling’s forces:

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hydrostatic pressures (Pgc)

colloid osmotic pressure (p gc)

 

        • Variables that influence GFR include
          • Hydrostatic pressures in the glomerulus and Bowman’s capsule
          • Oncotic pressures in the glomerular plasma and filtrate
          • Permeability of glomerular barriers
          • Surface area available for filtration
          • Negative electrical charge on filtered solutes (which hinders filtration)
          • Renal blood flow
        • In the glomerulus, hydrostatic pressures (Pgc) provide the driving force for fil- tration
        • Starling’s forces are also responsible for reabsorption across the peritubular capillary endothelium.
        • Because tubular filtrate is virtually protein free, proteins are concentrated in the glomerulus, and colloid osmotic pressure (p gc)increases as blood flows through the glomerulus
        • As p gcrises and meets the hydrostatic pressure, filtration equilibrium (ie, where net filtration pressure is 0) is attained.
        • An increase in blood flow through the glomerulus increases the GFR because it increases the distance over which filtration occurs before equilibrium is reached.
        • Clearance
          • Clearance is defined as the volume of arterial plasma required to produce the amount of substance X excreted in the urine per minute

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  • where
    • Cx =clearance of X (mL/min)
    • Ux =urine concentration of X (mg/mL)
    • Px =arterial plasma concentration of X (mg/mL) V = urine flow (mL/min)
  • Clearance is usually measured in the steady state
  • If a substance is present in arterial plasma but is not excreted (Ux = 0), then the clearance of that substance is 0. (MCQ)
  • If a substance is secreted into the tubular fluid (eg, a foreign substance), then it cannot be excreted at a rate faster than it is presented to the kidneys via the renal arteries (ie, clearance cannot exceed renal plasma flow).
  • If a substance X is freely filterable and is not secreted or reabsorbed by the tubules, then the clearance of X can be used to measure the GFR.
  • Thus, the GFR for substance X is identical to its clearance:

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  • The GFR of a particular substance can be measured by the clearance method as long as the substance satisfies the following criteria. (MCQ)
    • The substance should be freely filtered (ie, not bound to plasma protein)
    • It should not be reabsorbed or secreted.
    • It should not be stored or metabolized by the kidneys
    • It should be nontoxic.
    • It should not alter the GFR.
    • It should be easily measurable in plasma and urine.
  • A substance that meets the criteria for measurement of the GFR is inulin, a fructose extracted from dahlia roots.

 

Creatinine clearance (Ccr)

In general, Ccr overestimates the GFR by 15–20% because the GFR decreases with age but Pcr remains constant due to decreased muscle mass.

 

Consider the following example of a GFR calculation:

A 72-kg patient has a urine volume of 2.88 L/24 h. The Ucr is 0.9 mg/mL, and the Pcr is0.8 mg/100 mL.

      • Filtration fraction (FF)(MCQ)
        • fraction of renal plasma volume (RPF) that is filtered at the glomerulus
        • FF = GFR RPF
        • RPF = RBF (1− Hct),(MCQ)

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        • Normally 20% of the RBF is filtered, and the remainder flows into the peritubular capillary.(MCQ)
        • An increase in FF causes an increased protein concentration in peritubular capillary blood.
        • Increased postglomerular resistance increases FF and vice versa.
        • Renal blood flow (RBF) can be calculated from the RPF if the hemat-
        • ocrit (Hct, %) is known:

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        • The GFR increases when glomerular capillary pressure is increased and decreases when glomerular capillary pressure is decreased.
        • Alterations in preglomerular and postglomerular renal vascular resistance influence RBF, GFR, and FF
      • Transport Mechanisms of Nephron Segments
        • Proximal Tubule
          • Loose tight junctions make the proximal tubule water permeable.
          • The bulk of filtered small solutes is absorbed.
            • 60% of filtered Na+,Cl, K+, Ca2+, and H2O is absorbed(MCQ)
            • 90% of filtered HCO3is absorbed.(MCQ)
          • All filtered glucose and amino acid (100%)  is absorbed.(MCQ)
          • Phosphate transport is regulated by parathyroid hormone.(MCQ)
          • Osmolaritydoes not change due to passive reabsorption of water.

Consequences of independent isolated constrictions or dilationsof the afferent and efferent arterioles.

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      • Loop of Henle
        • The volume of fluid reaching the loop of Henle is about one third of the originally filtered volume.
        • The descending limb is water permeable, increasing the osmolarity of the tubular fluid.
        • The ascending limb is impermeable to water,decreasing the tubular fluid osmolarity.
          • This segment is known as the diluting segment because hypotonic fluid leaves.
        • Mg2+ reabsorption occurs in the loop of Henle.(MCQ)
        • The Na+-K+-Cl2cotransporter is located here and is affected by loop di-uretics (eg, furosemide).(MCQ)
        • Flow through the loop of Henle is relatively slow, allowing the kidney tomaintain a high medullary osmolarity.(MCQ)
      • BARTTER SYNDROME
        • CharacterizedbyNa+,K+,andClwasting.(MCQ)
        • The primary defect is in Clreabsorption in the ascending limb of the loop of Henle,(MCQ)
        • It leads to decreased tonicity of the interstitium and an inability to concentrate urine.
        • Reninand aldosterone levelsareincreased(MCQ)
        • bloodpressureremainslow.(MCQ)
        • Symptoms include polyuria (excessive urination), nocturia (nighttime urination), developmentaldelay, and dehydration.
        • Thesyndromeresultsinhypokalemicmetabolicalkalosis(MCQ)
        • TreatmentisaimedatconvertingK+balancebyoralpotassiumsupplementation.(MCQ)
      • Distal Nephron
        • The distal convoluted tubule and the collecting duct reabsorb variable amounts of water depending on circulating levels of antidiuretic hormone (ADH) and aldosterone.
        • ADH
          • stimulates increased water permeability in the distal convoluted tubule and the collecting duct(MCQ)
          • makesthe tubular fluid isosmotic with the ISF.(MCQ)
        • Aldosterone increases Na+ reabsorption andK+ secretion.(MCQ)
        • These hormones regulate (MCQ)
          • K+ excretion
          • final urinary concentrations of K+, Na+, and Cl.
        • Two main cell types are present in the distal nephron.
          • Principal cells are involved with Na+ and water transport.(MCQ)
          • Intercalated cellssecrete H+ and reabsorb K+.(MCQ)
        • These processes allow the kidney to secrete dilute or concentrated urine as necessary to maintain homeostasis.
        • The early distal convoluted tubule is the site of action of thiazide diuretics, which inhibit the Na+-Clcotransporter.(MCQ)
      • Regulation of NaCl Excretion
        • Because sodium salts are the predominant extracellular solutes, total body sodiumdetermines extracellular fluid volume. Thus, any change in the amount of sodium in the body affects the regulation of ECF.
        • The primary regulatory systems that respond to changes in body fluid volume are the
          • sympathetic nervous system
          • renin-angiotensin-aldosterone system
          • atrialnatruretic factor (ANF
          • ADH or vasopressin.
        • The sympathetic nervous system
          • hasstretch receptors on blood vessels suchas vena cava, cardiac atria, and pulmonary vessels.
          • A decreased firing rate in the afferent nerves from these volume recep-tors increases sympathetic outflow from cardiovascular medullarycenters.
          • Increased renal sympathetic tone leads to salt reabsorption and activa-tion of the renin-angiotensin system.(MCQ)
        • Aldosterone secretion is controlled by the renin-angiotensin system
          • Granular cells in the wall of renal afferent arterioles, which are part of thejuxtaglomerular apparatus, release renin(MCQ)
          • renin is an enzyme that converts angiotensinogen from the liver to angiotensin I.(MCQ)
          • Renin production is controlled by three mechanisms
            • Decreased sodium chloride delivery past macula densa cells in the thick ascending limb of the loop of Henle increases renin release.(MCQ)
            • Baroreceptors in the wall of the afferent arteriole respond to pres- sure, stretch, or shear stress by increasing renin release.
            • Stimulation of Beta-adrenergic receptors on the juxtaglomerular granular cells stimulates renin release.(MCQ)
            • Factors influencing renin secretion.
              • Inhibitory factors(MCQ)
                • Increased Na+ and Cl– reabsorption across macula densa
                • Increased afferent arteriolar pressure
                • Angiotensin II
                • Vasopressin
              • Stimulatory factors(MCQ)
                • Increased sympathetic