renal - DOC by linzhengnd


									Describe the functional anatomy of the kidneys and to explain the physiology of
renal blood flow



The Nephron
Functional unit = nephron = tubule + glomerulus

Approximately 1.3 million nephrons / kidney


      glomerulus is a 200 um diameter structure formed by the invagination of a tuft
       of capillaries into the dilated, blind end of the nephron (Bowman's capsule).
      The capillaries are supplied by an afferent arteriole and drained by a slightly
       smaller efferent arteriole
      There are two cellular layers separating the blood from the glomerular filtrate
       in Bowman's capsule: the capillary endothelium and the specialized
       epithelium of the capsule that is made up of podocytes overlying the
       glomerular capillaries. These layers are separated by a basal lamina. The
       endothelium of the glomerular capillaries is fenestrated, with pores that are
       70-90 nm in diameter.

      Stellate cells called mesangial cells are located between the basal lamina and
       the endothelium. Role : (1) contractile and play a role in the regulation of
       glomerular filtration (2) They also secrete various substances, take up
       immune complexes, and are involved in the production of glomerular disease.

      Functionally, the glomerular membrane permits the free passage of neutral
       substances up to 4 nm in diameter and almost totally excludes those with
      diameters greater than 8 nm. The total area of glomerular capillary
      endothelium across which filtration occurs in humans is about 0.8 m 2.


     The PCT is about 15 mm long and 55 um in diameter. Its wall is made up of a
      single layer of cells that interdigitate with one another and are united by apical
      tight junctions. Between the bases of the cells, there are extensions of the
      extracellular space called the lateral intercellular spaces. The luminal edges of
      the cells have a striate brush border.

     The proximal tubule terminates in the thin segment of the descending limb of
      the loop of Henle, which has an epithelium made up of attenuated, flat cells.
      The total length of the thin segment of the loop varies from 2 to 14 mm. It
      ends in the thick segment of the ascending limb, which is about 12 mm in
      length. The cells of the thick ascending limb are cuboid. They have numerous
      mitochondria, and the basilar portions of their cell membranes are extensively

     The thick ascending limb of the loop of Henle reaches the glomerulus of the
      nephron from which the tubule arose and passes close to its afferent arteriole
      and efferent arteriole. The walls of the afferent arterioles contain the renin-
      secreting juxtaglomerular cells. At this point, the tubular epithelium is modified
      histologically to form the macula densa. The juxtaglomerular cells, and the
      macula densa, are known collectively as the juxtaglomerular apparatus

     The distal convoluted tubule is about 5 mm long. The distal tubules coalesce
      to form collecting ducts that are about 20 mm long and pass through the renal
      cortex and medulla to empty into the pelvis of the kidney at the apexes of the
      medullary pyramids. The epithelium of the collecting ducts is made up of
      principal cells (P cells) and intercalated cells (I cells). The P cells, are
      involved in Na+ reabsorption and vasopressin-stimulated water reabsorption.
      The I cells, are concerned with acid secretion and HCO3- transport. The total
      length of the nephrons, including the collecting ducts, ranges from 45 to 65

Blood Vessels
      Interlobular arteries  afferent arterioles  glomerular capillary tuft  efferent
       arteriole (technically a portal system)  peritubular capillaries  interlobular
      Glomerular capillaries are the only capillaries in the body that drain into
      The efferent arterioles from the juxtamedullary glomeruli drain not only into a
       peritubular network but also into vessels that form hairpin loops (the vasa
       recta). These loops dip into the medullary pyramids alongside the loops of
       Henle. The descending vasa recta have a nonfenestrated endothelium that
       contains a facilitated transporter for urea, and the ascending vasa recta have
       a fenestrated endothelium, consistent with their function in conserving solute.
      The volume of blood in the renal capillaries at any given time is 30-40 mL.

Lymphatics - The kidneys have an abundant lymphatic supply that drains via the
thoracic duct into the venous circulation in the thorax.


      The renal capsule is thin but tough. If the kidney becomes edematous, the
       capsule limits the swelling, and the tissue pressure (renal interstitial pressure)
       rises. This decreases the glomerular filtration rate and is claimed to enhance
       and prolong the anuria in acute renal failure.

Innervation of the Renal Vessels

      The renal nerves travel along the renal blood vessels
      Sympathetic: postganglionic sympathetic efferent fibers. sympathetic
       preganglionic innervation comes primarily from the lower thoracic and upper
       lumbar segments of the spinal cord. The sympathetic fibers are distributed
       primarily to the afferent and efferent arterioles, the proximal and distal tubules,
       and the juxtaglomerular cells. In addition, there is a dense noradrenergic
       innervation of the thick ascending limb of the loop of Henle.
      Parasympathetic: cholinergic innervation via the vagus nerve, but its function
       is uncertain
      Renal afferents presumably mediate a renorenal reflex by which an increase
       in ureteral pressure in one kidney leads to a decrease in efferent nerve
        activity to the contralateral kidney, and this decrease permits an increase in its
        excretion of Na+ and water.

Blood Flow

In a resting adult, blood flow: 1.2-1.3 L/min (~ 25% of CO)

Measuring Renal blood flow:

       Direct method: Electromagnetic flow meters
       Clearance methods based on Fick principle:
            o Flow = amount of substance taken up per unit time / arterio-venous
                difference for the substance across the kidney
           o Since the kidney filters plasma, the calulcated flow is the renal plasma flow
           o Criteria for indicator used - Any excreted substance whose concentration in
               arterial and renal venous plasma can be measured and if it is not
               metabolized, stored, or produced by the kidney and does not itself affect
               blood flow.
           o Renal plasma flow can be measured by infusing p-aminohippuric acid (PAH)
               and determining its urine and plasma concentrations. Extraction ratio of PAH
               is is high (~0.9), hence the negligible venous levels, which can be ignored.
               Therefore "renal plasma flow" can be calculated by dividing the amount of
               PAH in the urine by the plasma PAH level only. The value obtained should be
               called the effective renal plasma flow (ERPF) to indicate that the level in renal
               venous plasma was not measured. In humans, ERPF averages about 625
Pressure in Renal Vessels

      When the mean systemic arterial pressure is 100 mm Hg, the glomerular capillary
       pressure is about 45 mm Hg. The pressure drop across the glomerulus is only 1-3 mm
       Hg, but there is a further drop in the efferent arteriole.
      The pressure in the peritubular capillaries is about 8 mm Hg
      The pressure in the renal vein is about 4 mm Hg

Regulation of the Renal Blood Flow

      Dopamine is made in the kidney and causes renal vasodilation and natriuresis.
      Angiotensin II exerts a greater constrictor effect on the efferent arterioles than on
       the afferent.
      Prostaglandins increase blood flow in the renal cortex and decrease blood flow in
       the renal medulla.
      Acetylcholine also produces renal vasodilation.
      A high-protein diet raises glomerular capillary pressure and increases renal blood
      Renal blood flow is decreased during exercise and, to a lesser extent, on rising from
       the supine position.
      Functions of the Renal Nerves
           o Stimulation of the renal nerves increases renin secretion by a direct action of
               released norepinephrine on β1-adrenergic receptors on the juxtaglomerular
               cells and it increases Na+ reabsorption, probably by a direct action of
               norepinephrine on renal tubular cells. The physiologic role of the renal nerves
               in Na+ metabolism is also unsettled.
           o Strong stimulation of the sympathetic noradrenergic nerves to the kidneys
               causes a marked decrease in renal blood flow. Norepinephrine constricts the
               renal vessels particularly interlobular arteries and the afferent arterioles. This
               effect is mediated by α1-adrenergic receptors and to a lesser extent by
               postsynaptic α2-adrenergic receptors.
      Auto regulation of Renal Blood Flow
           o Renal autoregulation is present in denervated and in isolated, perfused
               kidneys but is prevented by the administration of drugs that paralyze vascular
               smooth muscle.
           o It is probably produced in part by a direct contractile response of the smooth
             muscle of the afferent arteriole to stretch. NO may also be involved.
           o At low perfusion pressures, angiotensin II also appears to play a role by
             constricting the efferent arterioles, thus maintaining the GFR. This is believed
             to be the explanation of the renal failure that sometimes develops in patients
             with poor renal perfusion who are treated with drugs which inhibit
             angiotensin-converting enzyme.

Regional Blood Flow & Oxygen Consumption

      The main function of the renal cortex is only filtration of large volumes of blood
       through the glomeruli, hence renal cortical blood flow is relatively great and oxygen
       extraction is low.
      Cortical blood flow is about 5 mL/g of kidney tissue/min, PO2 of cortex is 50mmHg
      Arterio-venous oxygen difference for the whole kidney is only 14 mL/L
      In the medulla, blood flow is about 2.5 mL/g/min in the outer medulla and 0.5
       mL/g/min in the inner medulla. However, metabolic work is being done, particularly
       to reabsorb Na+ in the thick ascending limb of Henle, so relatively large amounts of
       O2 are extracted from the blood in the medulla. The PO2 of the medulla is about 15
       mm Hg. This makes the medulla vulnerable to hypoxia if flow is reduced further. NO,
       prostaglandins, and many cardiovascular peptides in this region function in a
       paracrine fashion to maintain the balance between low blood flow and metabolic

Describe glomerular filtration and tubular function

Formation of Glomerular Filtrate

The filtration barrier within the glomerulus is the interface between the blood and the external
3-step process: through fenestrae in the glomerular-capillary endothelial layer, through the
basement membrane, and finally through slit diaphragms between podocyte foot processes.

Size and charge of particles effect their filterability


       Free filteration of solutes < 7000 d (small ions, glucose, urea, amino acids)
       Total exclusion of plasma albumin (molecular weight of approximately 66,000 d),
        however, glomerular filtrate does contain extremely small quantities of albumin
       For molecules with a molecular weight ranging from 7000 and 70,000 d, the amount
        filtered becomes progressively smaller as the molecule becomes larger.

Electrical charge:

       Surfaces of all the components of the filtration barrier contain fixed polyanions,
        which repel negatively charged macromolecules during filtration.
       Negatively charged macromolecules are filtered to a lesser extent, and positively
        charged macromolecules to a greater extent, than neutral molecules.
       Negative charges in the filtration membranes act as a hindrance only to
        macromolecules, not to mineral ions or low-molecular-weight organic solutes. Thus,
        chloride and bicarbonate ions, despite their negative charge, are freely filtered.

Direct Determinants of GFR

Rate of filtration = hydraulic permeability x surface area x NFP

Because it is difficult to estimate the area of a capillary bed, a parameter called the filtration
coefficient (Kf) is used to denote the product of the hydraulic permeability and the area

NFP or Net Filtration Pressure depends on 2 oncotic forces and 2 hydrostatic forces called
starling forces:

NFP = (PGC –πGC) – (PBC –πBC)

PGC : glomerular capillary hydraulic pressure

πBC : oncotic pressure of fluid in Bowman's capsule

PBC : hydraulic pressure in Bowman's capsule

πGC : oncotic pressure in glomerular capillary plasma

Because there is normally little protein in Bowman's capsule, πBC may be taken as zero and
not considered in our analysis. Accordingly, the overall equation for GFR becomes

GFR = Kf *(PGC – PBC –πGC)
Summary of Direct GFR Determinants and Factors That Influence Them

Direct determinants of GFR: GFR         Major factors that tend to increase the
= Kf (PGC – PBC –πGC)                   magnitude of the direct determinant
Kf                                 1. ↑ Glomerular surface area (because of relaxation
                                        of glomerular mesangial cells)
                                        Result: ↑GFR
PGC                                1. ↑ Renal arterial pressure
                                   2. ↓ Afferent-arteriolar resistance (afferent dilation)
                                   3. ↑ Efferent-arteriolar resistance (efferent
                                        Result: ↑GFR
PBC                                1. ↑ Intratubular pressure because of obstruction of
                                        tubule or extrarenal urinary system
                                        Result: ↓GFR
πGC                                1. ↑ Systemic-plasma oncotic pressure (sets πGC at
                                        beginning of glomerular capillaries)
                                   2. ↓ Renal plasma flow (causes increased rise of πGC
                                        along glomerular capillaries)
                                        Result: ↓GFR
Estimated Forces Involved in Glomerular Filtration in Humans

Forces                              Afferent end of glomerular Efferent end of glomerular
                                    capillary (mm Hg)          capillary (mm Hg)
1 Favoring filtration               60                              58
hydraulic pressure, PGC
2 Opposing filtration               15                              15
 a Hydraulic pressure in
Bowman's capsule, PBC
 b Oncotic pressure in              21                              33

glomerular capillary,          GC

3 Net filtration pressure (1 – 2) 24                                10

Measuring GFR

GFR can be measured by measuring the clearance of a substance (x) that is freely filtered through
the glomeruli and neither secreted nor reabsorbed by the tubules, nontoxic and not metabolized by
the body.


UX = concentration of X in urine

V. = urine flow per unit of time

PX = concentration in plasma

Commonly used substances to measure GFR

       Inulin, a polymer of fructose with a molecular weight of 5200 is extensively used to measure
       Radioisotopes such as 51Cr-EDTA

Tubular function

The relative proportions of filtration, reabsorption, and secretion determine the amount
excreted of a particular substance
Average Values for Several Substances Handled by Filtration and Reabsorption

Substance Amount filtered per day            Amount excreted        % reabsorbed
Water, L     180                             1.8                    99.0
Sodium, g    630                             3.2                    99.5
Glucose, g 180                               0                      100
Urea, g      56                              28                     50

Metabolism by the Tubules

      Extraction of organic nutrients from the glomerular filtrate or peritubular capillaries
       and metabolizing them as dictated by the cells' own nutrient requirements
      Synthesis of ammonium from glutamine
      Production of bicarbonate

Transport mechanisms:

Routes of transport:

      1 -step paracellular route: substance goes around the cells
      2-step transcellular route: (more common) - substance goes through the cells across the
       apical membrane facing the tubular lumen and across the basolateral membrane facing the
       interstitium. Occur through channels and transporters

Mechanisms of transport:

      Diffusion – across chemical or electrical gradient. Accounts for all kinds of transport across
       paracellular route and endothelial barrier. Substances that are lipid soluble, such as the
       blood gases or steroids, can diffuse directly through the lipid bilayer.
      Primary active transport: these are ATPase pumps which generate energy from hydrolysis of
       ATP and pump one or more solutes against their electro-chemical gradient. Eg Na-K Atpase
       which transport 3 sodium ions out and 2 potassium ions in to cell for every ATP molecule
      Secondary active transport: transport of solute against its electrochemical gradient requires
       energy which is produced by movement of another solute ‘down’ its gradient as in
       secondary active transport.
      Uniporter – facilitated diffusion of single solute species through the membrane. Eg- GLUT
       family of proteins that permit, in the kidney's proximal tubule epithelial cells, glucose to
       move from the cytosol across the basolateral membrane into the interstitium
      Symporter - move 2 or more solute species in the same direction across a membrane eg
       SGLT protein family, that co-transport sodium and glucose. An important symporter in the
       proximal tubule is a so-called NBCe transporter, which moves 3 bicarbonate ions and 1
       sodium ion per transport cycle
      Antiporter - move 2 or more solute species in opposite directions across a membrane. Eg. -
       NHE protein family – move Na into the cell and protons out of cells
      Receptor mediated endocytosis or transcytosis: usually a protein, binds to a site on the
       apical surface of an epithelial cell, and then a patch of membrane with the solute bound to it
       is internalized as a vesicle in the cytoplasm. Subsequent processes then degrade the protein
       into its constituent amino acids, which are transported across the basolateral membrane
       and into the blood.

Osmolality: The ability of solutes to lower the concentration of water is called osmolality. It
is a function both of the concentration of solutes and the kind of solutes. For example,
proteins are better than sugars, and sugars are better than small ions, at lowering the
concentration of water. Osmolality is expressed in units of osmoles per kilogram of water (or,
more commonly, milliosmoles per kilogram). Osmolality is often called osmotic pressure.
Osmolality and osmotic pressure have the same meaning; they are just expressed in different
units (1 mOsm/kg = 19.3 mm Hg of osmotic pressure). The osmotic pressure resulting from
the proteins only (ignoring everything else) is called the colloid osmotic pressure or oncotic
pressure. Colloid osmotic pressure is a component of the Starling forces governing filtration
and absorption across endothelial layers. In other barriers, specifically the epithelial lining of
the renal tubules, solute permeabilities are generally lower than water permeability.
Therefore, all solutes contribute to driving a water flux. Here, all of the osmolality, not just
the component resulting from proteins, is important. The osmolarity is simply the sum of the
molar concentrations of all solutes without regard to kind. Fortunately, when osmolality is
measured (milliosmoles per kilogram of water) and osmolarity is calculated from solution
ingredients (milliosmoles per liter), the results are usually within 10% of each other. The
difference between osmolality and osmolarity is illustrated in the case of physiological saline
(0.9% NaCl, or 154 mmol/L NaCl). This solution is commonly used as a hospital infusion
solution because it matches the normal osmolality of human plasma (280–290 mOsm/kg).
The osmolarity of this solution is 154 + 154 = 308 mOsm/L, but when measured, the
osmolality is 287 mOsm/kg.

Transport Mechanisms in Reabsorption

      Most of the transport in kidney is reabsorption
      The glomerular filtration and proximal tubule re-absorption is approximately iso-osmolar i.e.
       the water and solute move across membrane is equal proportions. The reabsorption in more
       distal tubules is not iso-osmolar
      Most of the solute reabsorbed in the proximal tubule consists of sodium and the anions that
       must accompany the sodium to maintain electroneutrality: mostly chloride and bicarbonate.
      Water diffuses along with solutes as the proximal tubule epithelium is very permeable to
      Starling forces of hydrostatic pressure and osmotic pressure govern absorption of solute and
       water from the interstitium in to the peri-tubular capillaries. Osmotic pressure is more
       important than hydrostatic pressure because - It requires a hydrostatic pressure gradient of
           19.3 mm Hg to act as an equivalent driving force as an osmotic gradient of 1 mOsm/kg, and
           the hydrostatic pressure difference is usually not more than 5–8 mm Hg.
          The total volume of interstitial space is only 4% of the total cortical volume, and the vascular
           volume is a little higher.
          Estimated Forces Involved in Movement of Fluid from Interstitium into Peritubular
           Capillaries (early part) are as follows:

Forces                                                                                       mm Hg
1 Favoring uptake
 a Interstitial hydraulic pressure, PInt                                                     3

 b Oncotic pressure in peritubular capillaries, πPC                                          33
2 Opposing uptake
 a Hydraulic pressure in peritubular capillaries, PPC                                        20
 b Interstitial oncotic pressure, πInt                                                       6

3 Net pressure for uptake (1 – 2)                                                            10

Steps involved in reabsorption of solute and water through trans-cellular and para-cellular route:


4 steps:

          Step 1: Active extrusion of sodium via Na-K ATPase from the cell to the interstitium leaving
           low conc. Of Na within the cell
          Step 2: Low conc. In the cell causes diffusion of Na from the lumen into the cell down the
           conc. Gradient. Movement of anions parallel Na movement to maintain electrical neutrality.
          Step 3: Accumalation of sodium and anions in the interstitium produces osmotic gradient
           from lumen to the interstitium which drives diffusion of water
          Step 4: Bulk movement of accumulated solutes and water from the interstitum to the peri-
           tubular capillaries based on starling forces

As the solutes and water move from the lumen to the interstitium, the luminal conc. Of solutes that
are not transported via trans-cellular route increases. The increasing conc. Of these solutes drives
there diffusion down conc. gradient via para-cellular route. Eg urea, Cl-, K+, Ca+, Mg+ . Glucose is
never transported through para-cellular route

Limits on absorption: Tm and gradient limited systems

There are upper limits to the speed with which any given solute can be reabsorbed from the tubular
lumen to capillary blood.

Transport mechanisms can be classified by the properties of these limits as either (1) tubular
maximum-limited (Tm) systems or (2) gradient-limited systems

       Tubular maximum-limited (Tm) systems: Tm systems reach an upper limit because the
        transporters moving the substance become saturated; any further increase in solute
        concentration does not increase the rate at which the substance binds to the transporter
        and thereafter moves through the membrane. Limiting rate is property of the transporter.
       Gradient-limited systems: Gradient-limited systems reach an upper limit because the tight
        junctions are leaky, and any significant lowering of luminal concentration relative to the
        interstitium results in a leak back into the lumen as fast as the substance is transported out.
        Limiting rate is property of the permeability of the epithelial monolayer regardless of the
        maximal rate of the transport protein

Explain the counter-current mechanisms in the kidney

The Countercurrent Mechanism

       A countercurrent system is a system in which the inflow runs parallel to, counter to, and in
        close proximity to the outflow. This occurs for both the loops of Henle and the vasa recta in
        the renal medulla.
       Medullary osmotic gradient: Medulla is almost iso-osmotic near corticomedullary junction
        and hyperosmotic near papillary tip
            o Medullary osmotic gradient is an important urine concentrating mechanism of
            o Medullary osmotic gradient is ‘produced’ by operation of the loops of Henle as
                countercurrent multipliers and ‘maintained’ by the operation of the vasa recta as
                countercurrent exchangers
       Counter current multiplier action of loop of henle:
            o Depends on two important features of loop of henle: (i) active transport of Na+ and
                Cl- out of its thick ascending limb (TAL), (ii) the high water permeability of its thin
                descending limb (TDL)
            o Steps:
                      TAL pumps out Na & Cl out into interstitium relative to water making
                         interstitium hyperosmotic
                      Relatively hypo-osmotic fluid enters the TDL from proximal tubule as a result
                       the water moves out into interstitium and the tubular fluid equilibrates with
                       the hyperosmotic interstitium down the TDL
                    Movement of water out of TDL into medullary interstitium decreases solute
                       conc. in the interstitum and increases the solute conc. within the tubule and
                       hence increases solute conc. gradient across the TAL which inturn promotes
                       more solute transport into the interstitum
                    Hence, hypotonic fluid flows out into the distal tubule, and isotonic and
                       subsequently hypertonic fluid flows into the TAL.
                    The process keeps repeating, and the final result is a (i) Hyperosmotic
                       medullary iterstitum and (ii) Increasing gradient of osmolality from the top
                       to the bottom of the loop.
                    The greater the length of the loop of Henle, the greater the osmolality that
                       can be reached at the tip of the pyramid. This is because of additional length
                       of thin ascending limb which is impermeable to water but allows passive
                       diffusion of Na and CL contributing to additional counter current
      Counter current exchange action of vasa recta
          o Maintains the medullary osmotic gradient
          o The solutes diffuse out of the vessels conducting blood toward the cortex and into
              the vessels descending into the pyramid.
          o Conversely, water diffuses out of the descending vessels and into the fenestrated
              ascending vessels.
          o Therefore, the solutes tend to recirculate in the medulla and water tends to bypass
              it, so that hypertonicity is maintained. The water removed from the collecting ducts
              in the pyramids is also removed by the vasa recta and enters the general circulation.
          o Countercurrent exchange is a passive process

Outline the endocrine functions of the kidney

The endocrine functions of the kidney can be classified into three categories:
    Production of hormones by the kidney
      Hormones produced in the circulation as a final result of enzymes released by the
      Hormones which have their site of action on the kidney

The hormones produced by the kidney are:
    1,25 dihydroxycholecalciferol (or calcitriol, the active form of vit D: a hormone
       produced from a vitamin precursor). The final step in producing the active form of
       this hormone is the hydroxylation reaction which occurs in the cells of the proximal
       tubule. The reaction is catalysed by a mitochondrial enzyme, 1a-hydroxylase.
   • Erythropoietin - glycoprotein hormone. Stimulation for production - renal
       hypoxaemia. Site of production - endothelial cells of the peri-tubular capillaries
   • prostaglandins

Enzymes released by the kidney which initiate reactions leading to the production and/or
release of hormones are:
    • Secretion of the enzyme renin which initiates reactions leading to the production of
       angiotensin II (from the plasma protein angiotensinogen) and the release of
       aldosterone (from the adrenal cortex).
    • Secretion of kallikrein leading to the production of bradykinin in the circulation

Hormones which have their site of action on the kidneys are:
   • antidiuretic hormone (ADH)
   • aldosterone
   • calcitriol
   • parathormone (PTH)
   • atrial natriuretic peptide - produced in the right atrium - prominent natriuretic
     effects on the kidney. Stimulation – increase in blood volume causing atrial stretch.
     The ANP receptors have guanylate cyclase activity which is activated by binding of
     ANP. Activation of these receptors on the glomerular mesangial cells results in
     relaxation of these cells and an increase in GFR. Other actions of ANP are: (1)
     inhibition of release of ADH, (2) decreased release of aldosterone, (3) inhibition of
     vasoconstrictor actions of angiotensin II

Describe the role of the kidneys in the maintenance of acid/base balance

Normal Contributions of Tubular Segments to Renal Hydrogen Ion Balance

Proximal tubule
 Reabsorbs most filtered bicarbonate (normally about 80%)*
 Produces and secretes ammonium
Thick ascending limb of Henle's loop
 Reabsorbs second largest fraction of filtered bicarbonate (normally about 10–15%)*
Distal convoluted tubule and collecting-duct system
 Reabsorbs virtually all remaining filtered bicarbonate as well as any secreted bicarbonate
(Type A intercalated cells)*
 Produces titratable acid (Type A intercalated cells)*
 Secretes bicarbonate (Type B intercalated cells)

* Processes achieved by hydrogen ion secretion.

The mechanism by which bicarbonate is reabsorbed involves the tubular secretion of hydrogen ions

An enormous amount of hydrogen ion secretion occurs in the proximal tubule, with additional
secretion in the thick ascending limb of Henle's loop and collecting-duct system(Type A intercalated

Predominant proximal tubule mechanism for the secretion of hydrogen ions that result in
reabsorption of bicarbonate. Hydrogen ions are secreted via an Na-H antiporter (member of
the NHE family). Bicarbonate is transported into the interstitium via an Na-HCO3 symporter
(member of the NBC family):

Predominant collecting tubule mechanisms in Type A intercalated cells for the secretion of
hydrogen ions that result in formation of titratable acidity. The apical membrane contains H-
ATPases that transport hydrogen ions alone or in exchange for potassium. (c.a., carbonic
General mechanism for reabsorption of filtered bicarbonate. A secreted hydrogen ion
combines with a filtered bicarbonate to form CO2 and water in the lumen, catalyzed by
extracellular carbonic anhydrase present in the cell brush border. The CO2 and water formed
in this process simply mix with the existing quantities of those substances. The bicarbonate
generated intracellularly is transported into the interstitium and then back into peritubular
Tubulo-glomerular balance for bicarbonate re-absorption: When there is an increased filtered load
of bicarbonate, the proximal tubule automatically reabsorbs more. This is due to the decrease in free
hydrogen ion concentration in the lumen of the proximal tubule when delivery of bicarbonate is
increased. This decrease provides a natural driving force to increase the rate of the apical Na-H

Renal Excretion of Acid and Base

The kidneys achieve base balance by two ways: (1) allow some filtered bicarbonate to pass through
to the urine and (2) secrete bicarbonate via Type B intercalated cells in the cortical collecting duct. In
essence, the Type B intercalated cell is a "flipped-around" Type A intercalated cell. The overall
process achieves the disappearance of a plasma bicarbonate and the excretion of a bicarbonate in
the urine, with resulting acidification of the plasma and alkalinization of the urine.

      Hydrogen ion excretion on phosphate buffer
      Hydrogen ion excretion on ammonium

Hydrogen ion excretion on phosphate buffer

Divalent phosphate (base form) that has been filtered and not reabsorbed reaches the collecting
tubule, where it combines with secreted hydrogen ions to form monovalent phosphate (acid form)
and is then excreted in the urine. The bicarbonate entering the blood is new bicarbonate, not merely
a replacement for filtered bicarbonate. (ATP, adenosine triphosphate; c.a., carbonic anhydrase.)
in contrast to the reabsorption of bicarbonate, the secreted hydrogen ion remains in the tubular
fluid, trapped there by the buffer, and is excreted in the urine.

Neither filtration of hydrogen ions nor excretion of free hydrogen ions make a significant
contribution to hydrogen ion excretion. First, the filtered load of free hydrogen ions, when the
plasma pH is 7.4, is less than 0.1 mmol/day. Second, there is a minimum urinary pH—approximately
4.4—that can be achieved. This corresponds to a free hydrogen ion concentration of 0.04 mmol/L.
With a typical daily urine output of 1.5 L, the excretion of free hydrogen ions is only 0.06 mmol/day,
a tiny fraction of the normal 50–100 mmol ingested or produced every day. unreabsorbed divalent
phosphate available for buffering is roughly 40 mmol/day. In other words, the kidneys can excrete
hydrogen ions, using the phosphate buffer system, at rate of about 40 mmol/day.

Hydrogen ion excretion on ammonium

Quantitatively, more hydrogen ions can be excreted by means of ammonium than organic buffers

In the liver following reaction takes place:
Glutamine released from the liver is taken up by proximal tubule cells, both from the lumen (filtered
glutamine) and from the renal interstitium. The cells of the proximal tubule then convert the
glutamine back to bicarbonate and NH4+. In essence, the proximal tubule reverses what the liver has
done. The NH4+ is secreted by the Na-H antiporter into the lumen of the proximal tubule,4 and the
bicarbonate exits into the interstitium and then into the blood

The ammonium ion produced from glutamine in the proximal tubule cells is reabsorbed in the thick
ascending limb and enters the medullary interstitium. The medullary interstitium is impermeable to
ammonium ion but not to ammonia (the dissociation product of ammonium). Ammonia is freely
permeable through the epithelial cells and diffuses into the tubular lumen. Once in the lumen, it
recombines with hydrogen ion secreted by hydrogen ATPases. Once the ammonia combines with
hydrogen ion, the ammonium is trapped in the lumen and is excreted. This excretion of ammonium
removes 1 hydrogen ion equivalent from the body. Because the original reaction that generated
ammonium also generates a bicarbonate, the overall nephron handling of glutamine excretes 1
hydrogen ion and returns 1 bicarbonate to the blood. Because glutamine production can be
stimulated by acidosis, the metabolism of glutamine and subsequent excretion of ammonium and
return of bicarbonate to the blood is an effective way to counteract excessive ingestion or
production of acids in the body
Homeostatic Control of the Processes That Determine Renal Compensations for Acid Base
      1. Glutamine metabolism and NH4+ excretion are increased during acidosis and
         decreased during alkalosis. The signal is unknown.

      2. Tubular hydrogen ion secretion is:
 a.        Increased by the increased blood PCO2 of respiratory acidosis and decreased by the
          decreased PCO2 of respiratory alkalosis.

 b.        Increased, independently of changes in PCO2, by the local effects of decreased
          extracellular pH on the tubules; the opposite is true for increased extracellular pH.

Renal threshold for bicarbonate excretion is 27-28 mmol/l.

(additional points in the acid base chapter)

Describe the role of the kidneys in the maintenance of fluid and electrolyte

Sodium absorption

           Mainly an active transcellular process driven by Na-K ATPase which work on the basolateral

            Tubular segment                               % Na absorbed
            Proximal                                      65
            Ascending thin and thick limb                 25
            DCT                                           5
            Collecting duct                               5
            <1% appears in urine

Chloride reabsorption

Reabsorption is passive via paracellular pathway and active via transcellular pathway

Directly or indirectly coupled with reabsorption of Na hence location and % reabsorption is similar to

Critical transport step for CL is from lumen to cell. The transport process in the luminal membrane
must achieve a high enough intracellular high chloride conc. to cause downhill CL- movement across
basolateral membrane

Water reabsorption

Tubular segment                                       % water absorbed
Proximal segment                                      65%
Descending thin limb of henle                         10%
Collecting duct                                       5% (During water loading)
                                                      >24% (during dehydration)

The segments of renal tubule fall into 3 categories with regard to water permeability :

    (i)        Luminal membrane of the proximal tubule and descending thin limb of henle always
               have a very high permeability
    (ii)       Luminal membrane of ascending limbs of henle loop and luminal membrane of DCT are
               always relatively water impermeable
    (iii)      Water permeability of the luminal membrane of the collecting duct system is intrinsically
               low but can be regulated

The kidney can produce maximal urinary conc. of 1400 mosm/kg

The sum of urea, sulphate, phosphate, other waste products and small no. of non waste ions
excreted each day normally averages approx 600mosm/day

Therefore the minimal volume of water in which this mass of solute can be dissolved is ~
600mmol/1400mosm/L = 0.43L/day which is known as the obligatory water loss

Tubular mechanisms of water and electrolyte exchanges:


 The entire proximal tubule is the major site for reabsorption of salt and water. The proximal
convoluted tubule is the major site for reabsorption of glucose, amino acids, and other important
organic substances and the major site for reabsorption of bicarbonate. The proximal straight tubule
is the major site for secretion of organic acids and bases (including drugs). Because of the large
amount of hydrogen ion transported (on the sodium-hydrogen antiporter) and the large amount of
base equivalents transported (as part of chloride reabsorption), the presence of the enzyme
carbonic anhydrase (both in the cell interior and on the luminal surface) is important for normal
transport. Ammonium produced and secreted here is important for maintaining acid-base balance.


The major transporter in the thick ascending limb is the Na-K-2Cl symporter (NKCC), which is the
target for inhibition by loop diuretics like furosemide and bumetanide. The apical membranes have a
very low water permeability. In addition to NKCC, the cells contain an Na, H antiporter and
potassium channels that recycle potassium from the cell interior to the lumen. Besides transcellular
routes, some sodium and calcium also move paracellularly in response to the lumen positive
potential. The thick ascending limb cells are the point in the nephron at which salt is separated from
water so that water and salt excretion can be controlled independently. Defects in NKCC, the
recycling potassium channel, and the basolateral chloride channel lead, respectively, to the 3
different types of Bartter's syndrome. Ammonium ion (produced in the proximal nephron) is
reabsorbed here as part of normal acid-base balance. Besides the thick ascending limb cells, the thin
descending limb cells apparently have no active transport with passive water reabsorption, with
little or no NaCl reabsorption and passive entry (secretion) of urea into tubule. In the thin ascending
limb in juxtamedullary nephrons, there is also apparently no active transport, but the apical
membranes are relatively impermeable to water and urea, and NaCl reabsorption is passive.

The apical membrane contains the Na-Cl symporter (NCC), which is the target for inhibition by
thiazide diuretics. There is also some sodium reabsorption via apical sodium channels (ENaCs). The
DCT is also the major site for regulated reabsorption of Ca via apical Ca channels (under control of
parathyroid hormone [PTH] and basolateral Na-Ca exchanger). A defect in NCC leads to Gitelman's


The principal cells are the major cell type in the CCD. Sodium absorption is via apical sodium
channels (ENaC). Activity of ENaC is controlled by the hormone aldosterone. Potassium secretion is
via potassium channels and is driven by a concentration gradient and potential gradient. Water
resorption is via aquaporin 2, the activity of which is controlled by the antidiuretic hormone (ADH).
Some chloride reabsorption is passive via the paracellular pathway

type A intercalated cell is responsible for active secretion of acid as hydrogen ion via an H-ATPase
and at least 2 isoforms of H-K-ATPase. The H-K-ATPase is also involved in potassium balance.
Bicarbonate is returned to blood secondary to H+ secretion (isohydric cycle). The acid secretion
responds to aldosterone


Type B intercalated cell, is responsible for active secretion of base as HCO3– (isohydric cycle). H+ is
returned to blood secondary to bicarbonate secretion (isohydric cycle). The relative numbers of type
A and type B cells depend on an individual's acid-base status. Type B cells are relatively rare in
individuals whose diet contains any significant amount of animal protein.
Describe the role of the kidneys in the maintenance of osmolality

Independent control of total body sodium balance requires specific hormonal mechanism

Renal control of sodium balance involves two broad mechanisms (1) pressure natriuresis and
dieresis which cannot control water and sodium independently (2) hormonal mechanism which can
control sodium and water balance separately and occurs in the distal part of nephron

Hormones involves:

      Under normal physiological state, Aldosterone plays most important role in sodium balance.
      In certain pathophysiological states other hormones such as natriuretic peptide, and ADH
       play imp role
      Other hormones:
           o Cortisol, estrogen, growth hormone, thyroid hormone and insulin increase
           o Glucagon, progesterone and parathyroid hormone decrease absorption


Response to decreased blood pressure:

      SHORT TERM RESPONSE: baro-receptor mediated vascular response
      INTERMEDIATE RESPONSE: renal mediated release of rennin, and production of AGII  re-
       inforces short term responses
      LONG TERM RESPONSE: circulating AG II stimulate adrenal cortex  aldosterone diffuses
       into the cells of the principal cells of the distal nephrons to combine with the
       mineralocorticoid receptor  complex reallocates in the nucleus and acts as a transcription
        factor leading to release of mRNA which leads to increase number of the luminal sodium
        channel and baso-lateral Na-K ATPase  ↑total body sodium and blood volume
       In the complete absence of aldosterone only 2% of sodium is excreted as the main site of
        absorption is the proximal tubules. Given the total glomerular sodium filtrate of
        26100mmol/L (GFR * pNa = 180 * 145 ), 2% is 522 mmol
       Regulation of plasma aldosterone:

Natriuretic peptides:

       ANP and BNP
       Source is atria
       Stimulation is atrial wall stretch
       Action of natriuretic peptides:
             o   Vascular: relaxes afferent arteriole increasing filtration
             o   Tubular:
                     Direct: act on medullary collecting duct to inhibit Na absorption
                     Indirect: inhibit release of rennin and action of angiotensin II


       Increases permeability of cortical and medullary collecting ducts to water
       Increases sodium absorption


2 major sites:

       Sodium independent distal nephron  determined mainly by ADH
       Sodium dependent proximal nephron  mechanism to regulate ECF volume in response to
        blood pressure

ADH is peptide produced by the hypothalamic nuclei – supraoptic and paraventricular nuclei

Most important input for ADH  cardiovascular baro-receptors and hypothalamic osmoreceptors

Osmo-receptor are more sensitive than baro-receptor hence osmoreceptor influence predominate
over that of baro-receptor

Describe the role of the kidney in the handling of glucose, nitrogenous products
and drugs


      Normally, all the filtered glucose is reabsorbed in the proximal tubule.
      This involves removing glucose from the tubular lumen along with sodium via a
       sodium-dependent glucose symporter (SGLUT) across the apical membrane of
       proximal convoluted tubule epithelial cells, followed by its exit across the basolateral
       membrane into the interstitium via a GLUT uniporter.
      The tight junctions do not manifest significant permeability to glucose. Hence there is
       no back-leak as the luminal concentration falls.
      SGLUT symporter is a rate limiting transporter, and is a Tm-limited system hence
       abnormally high filtered loads overwhelm the reabsorptive capacity (exceed the Tm).
       This occurs when plasma glucose rises above roughly 300 mg/dL (Tm ~ 375 mg/min)
       and little glucose begins to spill into the urine. Any glucose not reabsorbed is an
       osmole in the tubule that has consequences for water reabsorption.
Proteins and Peptides

      Small and medium-size proteins (eg, angiotensin, insulin) are filtered in considerable
      Small amount of large plasma proteins does make it through eg. For albumin, (the
       plasma protein of highest concentration in the blood), the concentration in the filtrate
       is normally about 10 mg/L, or roughly 0.02% of the plasma albumin concentration
       (50 g/L)
      Proximal tubule is capable of taking up filtered albumin and other proteins. Although
       they are transported intact out of the lumen into the epithelial cells, are degraded into
       their constituent amino acids before being transported into the cortical interstitium.
      The initial step for the uptake of larger proteins is endocytosis at the luminal
       membrane. This energy-requiring process is triggered by the binding of filtered
       protein molecules to specific receptors on the luminal membrane. Therefore, the rate
       of endocytosis is increased in proportion to the concentration of protein in the
       glomerular filtrate until a maximal rate of vesicle formation, and thus the Tm for
       protein uptake, is reached. The pinched-off intracellular vesicles resulting from
       endocytosis merge with lysosomes, whose enzymes degrade the protein to low-
       molecular-weight fragments, mainly individual amino acids. These end products then
       exit the cells across the basolateral membrane into the interstitial fluid, from which
       they gain entry to the peritubular capillaries.
      Endocytic process is easily saturable
      Total filtered protein = GFR x concentration of protein in filtrate = 180 L/day x 10
       mg/L = 1.8 g/day. Almost all the filtered protein is taken up, so that the excretion of
       protein in the urine is normally only 100 mg/day.
      The kidneys are major sites of catabolism of many plasma proteins, specifically
       including polypeptide hormones. Decreased rates of degradation occurring in renal
       disease may result in elevated plasma hormone concentrations.
      Very small peptides, such as angiotensin II, are handled differently than larger
       proteins. The very small peptides are completely filterable at the renal corpuscles and
       are then catabolized mainly into amino acids within the proximal tubular lumen by
       peptidases located on the luminal plasma membrane. The amino acids are then
       reabsorbed by the same transporters that normally reabsorb filtered amino acids.


Importance: It is both a waste substance that is eliminated to maintain nitrogen balance and a
necessary factor in controlling water balance.

Urea is produced continuously by the liver as an end product of protein metabolism.

The production rate increases on a high-protein diet and decreases during starvation, but
production never stops.

The normal level in the blood is quite variable (3 mmol/L–9 mmol/L), reflecting variations in
both protein intake and renal handling of urea.

Plasma urea concentration is usually expressed as blood urea nitrogen (BUN) in units of
mg/dl. Each molecule of urea contains 2 atoms of nitrogen, so 1 mmol of urea contains 2
mmol of nitrogen, with a combined weight of 28 mg. Thus, the normal levels of plasma urea
are expressed as BUN values ranging from 8.4 mg/dL to 25.2 mg/dL. We use units of
millimoles per liter because we can then directly convert to osmolality.

As a molecule, urea is small (molecular weight, 60 d), is water soluble, and is freely filtered.
Because of its highly polar nature, it does not permeate lipid bilayers, but a set of uniporters
(the UT family) transport urea in various places in the kidney and in other sites within the
body (particularly red blood cells). Because urea is freely filtered, the filtrate contains urea at
a concentration identical to that in plasma.

As water is reabsorbed in the proximal tubule, urea becomes concentrated within the lumen,
it is driven passively through the leaky tight junctions. By the time the tubular fluid enters the
loop of Henle, about half the filtered urea has been reabsorbed, and the urea concentration
has increased to a little more than its value in the filtrate

The interstitium of the medulla has a considerably higher urea concentration than plasma and
the concentration increases from the outer to the inner medulla, and its peak value in the inner
medulla depends on hydration status and levels of ADH. The medullary urea concentration is
greater than in the tubular fluid entering the loop of Henle favouring urea secretion into the
lumen. The tight junctions in the loop of Henle are no longer permeable, but the epithelial
membranes of the thin regions of the Henle loops express urea uniporters which permit
secretion of urea. the urea secreted from the medullary interstitium into the thin regions of the
loop of Henle replaces the urea previously reabsorbed in the proximal tubule. Thus, when
tubular fluid enters the thick ascending limb, the amount in the lumen is at least as large as
the filtered load. Because about 80% of the filtered water has now been reabsorbed, the
luminal urea concentration is now several times greater than in the plasma. Beginning with
the thick ascending limb and continuing all the way to the medullary collecting ducts, the
luminal membrane urea permeability (and the tight junction permeability) is essentially zero.
Therefore, a large amount (roughly the filtered load or more) of urea is still within the tubular
lumen and flowing from the cortical into the medullary collecting ducts. The concentration is
now much greater than in the plasma. As tubular fluid flows in the collecting-duct system
from cortex to medulla, additional water is reabsorbed. Thus, luminal urea concentration rises
even more and can easily reach 50 times greater than in plasma. Therefore, urea is reabsorbed
a second time. In fact, this reabsorbed urea is the source of urea that is secreted into the loop
of Henle. Finally, the result is that half the original amount of filtered urea passes into the
final urine, an amount that, over the long term, must match hepatic production of urea if the
body is to remain in balance for urea.

Drug metabolism by the kidney

Although the liver plays a dominant role in drug metabolism, this review demonstrates that
the kidney is metabolically active in the biotransformation
of drugs.Almost all phase I and Phase II pathways occur in the kidney. The figure shows the
enzyme location in the kidney for drug metabolism
Fig. below shows the possible pathways that may result during renal metabolism of a drug. Entry across either
the brush border (BBM) or the basolateral membrane (BLM) is accompanied by biotransformation of the drug
(A 5 organic anion; C 5 organic cation) to a metabolite (B or D, respectively). The metabolite may then move in
the direction of reabsorption or secretion/excretion. In the upper section of the left panel, an organic anion such
as salicylic acid can exchange with a-ketoglutarate across the BLM in a tertiary active transport step dependent
on sodium a-ketoglutarate cotransport. Glycination of salicylic acid to e.g., salicyluric acid (indicated as B)
provides a compound that more readily enters the urine. Other possibilities are that A remains unmetabolized
and is simply excreted as the administered drug; or B could be a different metabolite that is more likely to be
reabsorbed. The lower left hand panel depicts reabsorption of an organic anion that may occur by anion
exchange across the BBM as well as through cotransport with sodium. For example, pyrazinoate is
cotransported into the tubule cell with sodium and is returned to the blood as pyrazinoate. Biotransformation of
A to B could lead to a metabolite with a predominant pathway of either reabsorption or secretion. The right hand
panel depicts possible pathways for disposition of organic cations. In the upper right of the panel an organic
cation such as meperidine enters the renal tubule cell along its electrochemical gradient. It may be
biotransformed to meperidine N-oxide (D), a more polar compound that enters the tubule fluid. Unmetabolized
meperidine may exchange for a proton across the BBM or the metabolite may follow a reabsorptive route such
as would be the case for the demethylated normeperidine. The lower half of the right hand panel depicts an
organic cation (C), such as isoproterenol that can be reabsorbed across the BBM in exchange for a proton. Upon
entry into the cell catechol-O-methyl transferase activity produces methylated isoproterenol that moves back
into the blood. Some of the isoproterenol may itself cross the BLM and/or a more polar metabolite could enter
the tubule fluid
Describe the physiological effects and clinical assessment of renal dysfunction

(physiological effects of ARF and CRF best given in guyton pg 406 onwards)

Syndromes                                    Important Clues to Diagnosis                 Findings That Are Common
Acute or rapidly progressive renal failure   Anuria                                       Hypertension, hematuria
                                             Oliguria                                     Proteinuria, pyuria
                                             Documented recent decline in GFR             Casts, edema
Acute nephritis                              Hematuria, RBC casts                         Proteinuria
                                             Azotemia, oliguria                           Pyuria
                                             Edema, hypertension                          Circulatory congestion
Chronic renal failure                        Azotemia for >3 months                       Hematuria, proteinuria
                                             Prolonged symptoms or signs of uremia        Casts, oliguria
                                             Symptoms or signs of renal osteodystrophy    Polyuria, nocturia
                                             Kidneys reduced in size bilaterally          Edema, hypertension
                                             Broad casts in urinary sediment              Electrolyte disorders
Nephrotic syndrome                           Proteinuria >3.5 g per 1.73 m2 per 24 h      Casts
                                             Hypoalbuminemia                              Edema
Asymptomatic urinary abnormalities           Hematuria
                                             Proteinuria (below nephrotic range)
                                             Sterile pyuria, casts
Urinary tract infection                      Bacteriuria >105 colonies per milliliter     Hematuria
                                             Other infectious agent documented in urine   Mild azotemia
                                             Pyuria, leukocyte casts                      Mild proteinuria
                                             Frequency, urgency                           Fever
                                             Bladder tenderness, flank tenderness
Renal tubule defects                         Electrolyte disorders                        Hematuria
                                             Polyuria, nocturia                           “Tubular” proteinuria
                                             Symptoms or signs of renal osteodystrophy    Enuresis
                                             Large kidneys
                                             Renal transport defects
Hypertension                                 Systolic/diastolic hypertension              Proteinuria
Nephrolithiasis                      Previous history of stone passage or           Hematuria
                                     removal                                        Pyuria
                                     Previous history of stone seen by x-ray        Frequency, urgency
                                     Renal colic
Urinary tract obstruction            Azotemia, oliguria, anuria                     Hematuria
                                     Polyuria, nocturia, urinary retention          Pyuria
                                     Slowing of urinary stream                      Enuresis, dysuria
                                     Large prostate, large kidneys
                                     Flank tenderness, full bladder after voiding

Tests for proximal and distal tubular function

Several proximal tests are available.

1.     About 30 g of plasma albumin passes through the glomerular barrier each day. Fortunately,
       most of this albumin is absorbed through the brush border of the proximal tubules by
       pinocytosis. Inside the cell the protein molecule is digested into amino acids, which are then
       absorbed by facilitated diffusion through the basolateral membrane. Proteins derived from
       proximal tubule cells, such as ß2-microglobulin, are reabsorbed by the proximal tubules. If this
       protein is demonstrated by urine electrophoresis, a proximal reabsorption defect is present.
       This is also the case, when generalized aminoaciduria is present.
2.     Glucosuria in the absence of hyperglycaemia indicates a proximal reabsorption defect of
       glucose, since all glucose is reabsorbed before the fluid reaches the end of the proximal tubules
       in the normal state.
3.     The lithium clearance. Lithium clearance used as a measure of the proximal reabsorption
       capacity in the nephron. The lithium ion, Li+, is filtered freely across the glomerular barrier, and
       its concentration in the ultrafiltrate is equal to that in plasma water. Lithium carbonate is used
       in the treatment of manic phases (catecholamine over-reaction) of manic depressive psychosis.
       A plasma concentration of 0.5-1 mM provides enough Li+ to block membrane receptors on the
       neurons involved for catecholamine binding. Li+ is reabsorbed isosmotically in the proximal
       tubules together with water and Na+. The amount of Li+ that leaves the proximal tubules (pars
       recta) is equal to its excretion rate in the final urine. This is because there is practically no
       reabsorption or secretion of Li+ distal to this location. Accordingly, a large lithium clearance
       depicts a low proximal lithium reabsorption, and thus a poor proximal tubular function at a
       given GFR. Normally, the passage fraction of Li+ is 0.25-0.3 at the end of the proximal tubules
       and almost the same fraction passes into the urine.
4.   Hypokalaemia combined with normal or increased renal K+ -excretion suggests a defective
     proximal K+ -reabsorption.
5.   Secretion across the proximal tubules (PAH clearance).

Tests of distal tubular function:

1.   Renal concentrating capacity is easily estimated as osmolalities in morning plasma and urine.
     Normal plasma osmolality ranges over 275-290 mOsmol per kg, and a urine osmolality above
     600 mOsmol per kg suggests an acceptable renal concentrating capacity (more accurate is a
     standardized water deprivation test).
2.   Inability to lower urine pH below 5.3 despite a metabolic acidosis is indicative of distal renal
     tubular acidosis (ie, a bicarbonate reabsorption defect). This is a rare inherited condition with
     failure of bicarbonate reabsorption in the distal tubules and the collecting ducts. The metabolic
     acidosis is instituted by the oral intake of 100 mg ammonium chloride per kg and confirmed by
     a pHa less than 7.35 with a negative base excess and [bicarbonate] below 21 mM.
3.   NaCl reabsorption in the early part of the distal tubule dilutes the tubular fluid, because this
     segment is impermeable to water. Thiazide diuretics inhibit the Na+-Cl- symporter protein that
     causes a measurable increase in NaCl excretion and in diuresis

Stix testing with dipstics

Routine stix testing for blood, glucose, protein etc. is necessary for the clinical evaluation of renal
patients. Reagent strips for red blood cells are extremely sensitive. Even a trivial bleeding from a
small capillary results in a positive answer indicating the presence of a few red cells. In such cases
microscopy is necessary. Microscopy of fresh urine reveals red cells in cases of bleeding from the
urinary tract, and red-cell casts in cases of kidney bleeding as in glomerulonephritis.

Since the concentration threshold in urine for most reagent strips is 150 mg albumin per litre (l),
there is no reaction to the normal albumin concentration of 20 mg l-1. Even 50-100 mg of protein is
often excreted daily due to the upright posture and exercise.
An early sign of diabetic glomerular leakage or nephropathy is microalbuminuria, which is defined as
an albumin concentration of 50-150 mg per l of urine, and measured by radioimmunoassay (RIA).

Some laboratories measure the Tamm-Horsefall glycoprotein, which is secreted from the cells of the
thick ascending limb of Henle, and thus a normal constituent of urine.

Bacteria in the urine produce nitrite from the urinary nitrate, and dipsticks easily demonstrate the
nitrite. Urinary tract infection also results in white blood cells in the urine, and more than 10 cells
per µl are abnormal.
Describe the process of tuboglomerular feedback

General: Tuboglomerular feedback relates the reflex arc by which the macula densa
influences afferent arteriolar tone in order to ensure constant tubular fluid flow through
the nephron. Collectively, both form the JGA
Macula Densa
- Located within the wall of the ascending Loop of Henle/early DCT
- Close to the renal arterioles
- Controls tone of afferent arteriole via release of vasoactive substances
o Adenosine (vasoconstrictor) → via α1 receptor activation
o NO (vasodilator)
- Release of vasoactive substances determined by Na+ content of tubular fluid in
Explain the physiological process which cause oliguria in response
to hypovolaemic shock

General: Hypovolaemic shock is a state whereby the body is unable to meet the
metabolic demands of tissue (delivering O2, substrates / removing wastes) due to
inadequate intravascular (circulating) volume. 1° depletion in H2O & Na.
Characterised by:
      ↓tendency for VR →→ ↓CO

Depending on the cause of hypovolaemic shock ECF osmolality may be isoosmolar
(haemorrhage) or hyperosmolar (dehydration)

Compensatory Mechanism: Oliguria (<0.5ml/kg/hr (<25ml/hr) urine production)
Aim of Oliguria: Retain H2O, Na+
Detection Systems
Osmoreceptors (Normal: 280-295mosm/L)
      Most sensitive detector (1-2% change osmolality) → activation compensation

High pressure baroreceptors (aortic arch, carotid sinus):
- 10-15% depletion intravascular vol (>4L TBW depletion)
- ↓SNS inhibition
o RAA activation
o ↓GFR
o Maintain MAP
Low pressure baroreceptors volureceptors (great vessels, RA):
     ~10% intravascular depletion
     ↓inhibition posterior pituitary → ↑ADH release

Intra-renal baroreceptors
       ↓MAP → ↓renal perfusion pressure → ↓GFR
       ↑renin release JGA → RAA activation

Macula Densa (JGA) tuboglomerular feedback
- ↓Na/Cl content tubular fluid → MD → release NO → dilate afferent arteriole →
maintain GFR
o MAP <70mmHg autoregulation fails (myogenic mechanism / tuboglomerular
feedback cannot maintain constant GFR)

Effector Mechanisms
- Nonapeptide produced in post pituitary after stimulation by hypothalamus
- Effects:
o Vascular: bind V1 receptors vascular smooth muscle → constriction
o Renal: bind V2 receptors CD → ↑cAMP → inserts aquaporins CD
o Renal: ↑ADH-urea transporters → ↑urea reabsorption → ↑renal medullary
interstitial osm (contributes 50% interstitial osmolality)
        Result: ↑concentrating ability kidney, ↑H2O reabsorption

- ↑activity with ↓MAP
- Effects:
o Central: Stimulation thirst centre

       Effect: ↑input, correct deficit
       o CV: ↑HR, ↑SV → ↑CO
       o ↑SVR
       Effect: Attempt to ↑MAP, VR
       o Renal: Constriction afferent/efferent arterioles (α1 receptors)
       o ↓Kf
       Effect: ↓GFR, conserve H2O, Na+
       o Renal: ↑renin release JGA granular cells (β1 receptors)
       Effect: RAA activation

RAA System
- Renin released (above) → cleaves angiotensinogen → ATI –lungs (ACE) → ATII /
ATIII –adrenal cortex→ Aldosterone release
- ATII (ATIII ↓potent):
o Peripheral: ↑SVR by ATII binding AT1R → direct constrictor
        Effect: Attempt ↑MAP
        o Renal: constrict efferent > afferent arteriole
        Effect: ↓GFR part of autoregulation
        o Renal: ↑Na/H2O reabsorption PCT (AT1R)
        Effect: Retain H2O, Na+
        o Central: Stimulation hypothalamus, posterior pituitary
        Effect: Thirst, ↑ADH release
        - Aldosterone:
        o Renal: ↑H2O, Na+ reabsorption DCT/CD → aldosterone receptor principal
        Effect: ↑Na/H2O absorption, ↑K elimination

List the hormones that regulate tubular reabsorption and describe their action and site of
 Hormone               Trigger                           Site of Action         Action
 Angiotensin II        Release of renin from JGA via     1° aff < eff           Vasoconstriction
                       SNS stimulation (β1 receptors),   arterioles             → ↓GFR
                       local baroreceptor (↓stretch)     Direct effect on       ↑Na+ reabsorption
                                                         PCT                    ↑Aldosterone
                                                         Adrenal                release
                                                         HyTh                   Thirst, ↑ADH
 Aldosterone           ↑ATII, ↑K+ plasma, ACTH; prodn    CD → induces           Principal cells →
                       in adrenal cortex (zona           prodn of Na,K-         ↑K+ excretion/Na+
                       glomerulosa)                      ATPase                 absorption
                                                         (basloateral) & K      Type A cells →
                                                         channels (luminal)     ↓H+ secretion (↓K
 ADH (vasopressin)     → Post pituitary 2° stim n by     CD cAMP -              ↑H2O reabsorpn
                       hypothalamus (↑osmolarity,        mediated insertion     ↑urea reabsorpn
                       ↓MAP)                             of ‘aquaporins’        → ↑medullary
                                                         into duct              osmolarity
                                                         membranes              Stimulates K+
                                                                                secn/Na+ absorpn
 ANP                   ↑atrial stretch                   Constrict efferent /   ↑GFR
                                                         dilate afferent        ↓ATII /
                                                         arteriole / ↑Kf        ↓Aldosterone
                                                         Inhibit RAA            ↓thirst / ↑urine
                                                         system                 Inhibits Na+
                                                         ↓ADH                   reabsorpn (likely
                                                         CD                     only a very small
 PTH                   ↓[Ca2+]extracellular              PCT                    ↓phosphate
                       β-adrenergic stimn                Late DCT               absorpn
                                                                                ↑Ca2+ reabsorpn
                                                                                (↑Mg, H as well)

Outline the mechanisms by which the kidney maintains potassium homeostasis
General: K+ is 1° intracellular cation
       Plasma conc 2 – 5 mmol/L

Normal range is important
      Cell membrane functioning (especially cardiac)

- Glomerular filtration K = 5 x 180 = 900 mmol/day
- Most filtered K is reabsorbed → this rate is fixed
o 55% PCT
o 30% AscLoH
- Also secreted into tubules → main method of regulation
- Urinary K conc not affected by primary changes in body Na or water

Distal Convoluted Tubules (& cortical CD)
1. Principal Cells →Secrete K
- With normal dietary intake → net effect is K excretion; ↓K → net effect is absorption
- Main determinants:
o Plasma K → ↑K directly stimulates basolateral Na/KATPase
o Aldosterone → also stimulated by ↑K
       Induces production basolateral Na/KATPase
       ↑production K channels in luminal membrane → movement is down conc
    gradient therefore ↑tubular flow rate → ↑K excretion
       o Plasma pH → low H directly stimulates basloateral NA/KATPase
       2. Type A Intercalated cells → reabsorb K
       - Medullary CD always reabsorbs K

Outline a physiological basis of classifying diuretics related to their site of action
Diuretics are therapeutic agents that increase the production of urine. Diuretics are
employed to enhance the excretion of salt and water in cases of cardiac oedema or arterial
hypertension. The so-called natriuretics inhibit tubular Na+-reabsorption, but since the
secretion of K+ and H+ is also increased, the patient must have compensatory treatment.
The sites of action for different groups of diuretics are shown in Fig.
   Carboanhydrase inhibitors (eg, acetazolamide): act on the carboanhydrase (CA) in
    the brush borders and inside the cells of the proximal tubules. Inhibition of the
    metallo-enzyme reduces the conversion of filtered bicarbonate to carbon dioxide. As
    a result, there is a high concentration of bicarbonate and sodium in the tubular fluid
    of the proximal tubules. Up to half of the bicarbonate normally reabsorbed is
    eliminated in the urine causing a high urine flow and a metabolic acidosis. Thus,
    these inhibitors are diuretics. They are mainly used in the treatment of open-angle
    glaucoma (ie, an intraocular pressure above 22 mmHg). Acetazolamide promotes the
    outflow of the aqueous humour and probably diminishes its isosmotic secretion.

   Loop diuretics (bumetanide and furosemide): inhibit primarily the reabsorption of
    NaCl in the thick ascending limb of Henle by blocking the luminal Na+-K+-2Cl--
    symporter. The reabsorption of NaCl, K+ and divalent cations is reduced, and also
    the medullary hypertonicity is decreased. Hereby, the distal system receives a much
    higher rate of NaCl, water in isotonic fluid, and K+. The overall result is an increased
    excretion of NaCl, water, K+ and divalent cations. The patient’s plasma- [K+] should
    be checked regularly.

   Thiazide diuretics (bendroflurazide, hydrochlorothiazide): act on the early part of
    the distal tubule by inhibiting the (Na+- Cl-)-symporter. They increase K+ excretion
    by increased tubular flow rate. Thiazide and many other diuretics are secreted in the
    proximal tubules. This secretion inhibits the secretion of uric acid, so thiazide is
    contraindicated by gout.

   Potassium-sparing diuretics (eg, amiloride): inhibit Na+-reabsorption by inhibition
    of sensitive Na+-channels in the principal cells of the distal tubules and collecting
    ducts. Hereby, they reduce the negative charge in the lumen and thus the K+-
    secretion. Amiloride causes natriuresis and reduces urinary H+- and K+-excretion

   Aldosterone-antagonists (eg, spironolactone) compete with aldosterone for
    receptor sites on principal cells. As aldosterone promotes Na+-reabsorption and H+/
    K+ -secretion, aldosterone-antagonists cause a natriuresis and reduce urinary H+ -
    and K+ -excretion. Aldosterone-antagonists are weak potassium-sparing diuretics,
    mainly used to reduce K+ -excretion caused by thiazide or loop diuretics.
      Angiotensin-converting-enzyme (ACE)-inhibitors (captopril, enapril and lisinopril)
       reversibly inhibit the production of angiotensin II, reduce systemic blood pressure,
       renal vascular resistance and K+ -secretion. ACE-inhibitors promote NaCl and water
       excretion. ACE-inhibitors increase RBF without much increase in GFR, because of a
       decrease in both afferent and efferent arteriolar resistance. The development of
       diabetic nephropathy can be markedly delayed by early reduction of blood pressure
       with ACE-inhibitors and by careful diabetic management.

      Osmotically active diuretics are substances such as mannitol and dextrans. These
       substances retard the normal passive reabsorption of water in the proximal tubules.
       Osmotic therapy with mannitol is used in the treatment of cerebral oedema.
       Mannitol is a hexahydric alcohol related to mannose and an isomer of sorbitol.
       Mannitol passes freely through the glomerular barrier and has hardly any
       reabsorption in the renal tubules. Its presence in the tubular fluid increases flow
       according to the concentration of osmotically active particles, which inhibit
       reabsorption of water. The high flow of tubular fluid means that the excretion of Na+
       is great - despite the rather low Na+ concentration. Mannitol may help to flush out
       tubular debris in shock with acute renal failure, but the results are controversial.
       Dextrans (ie, polysaccharides) have a powerful osmotic and diuretic effect. - The
       larger, molecules (macrodex) are seldom used as volume expanders during shock
       because of allergic reactions.

describe the pharmacology of mannitol, loop diuretics, thiazides, aldosterone
antagonists, other potassium-sparing diuretics and carbonic anhydrase inhibitors



 Class            Osmotic diuretic
 Presentation     20% mannitol bottles 100ml/500ml

 MOA              The proximal tubule and descending limb of Henle's loop are freely permeable to
                  water. mannitol is filtered by the glomerulus but not reabsorbed causes water to
                  be retained in these segments and promotes a water dieresis
                  The major site of action of osmotic diuretics is the loop of Henle.

                  By extracting water from intracellular compartments, osmotic diuretics
                  expand the extracellular fluid volume, decrease blood viscosity, and inhibit
                  renin release. These effects increase RBF, and the increase in renal
                  medullary blood flow removes NaCl and urea from the renal medulla, thus
                  reducing medullary tonicity. Under some circumstances, prostaglandins
                may contribute to the renal vasodilation and medullary washout induced by
                osmotic diuretics. A reduction in medullary tonicity causes a decrease in the
                extraction of water from the DTL, which, in turn, limits the concentration of
                NaCl in the tubular fluid entering the ATL. This latter effect diminishes the
                passive reabsorption of NaCl in the ATL. In addition, the marked ability of
                osmotic diuretics to inhibit reabsorption of Mg2+, a cation that is reabsorbed
                mainly in the thick ascending limb, suggests that osmotic diuretics also
                interfere with transport processes in the thick ascending limb. The
                mechanism of this effect is unknown.
                Osmotic diuretics are used to increase water excretion in preference to sodium
                excretion. This effect can be useful when avid Na+ retention limits the response
                to conventional agents. It can be used to maintain urine volume and to prevent
                anuria that might otherwise result from presentation of large pigment loads to
                the kidney (eg, from hemolysis or rhabdomyolysis).
                Osmotic diuretics alter Starling forces so that water leaves cells and reduces
                intracellular volume. This effect is used to reduce intracranial pressure in
                neurologic conditions and to reduce intraocular pressure before ophthalmologic
                procedures. A dose of 1–2 g/kg mannitol is administered intravenously.
                Intracranial pressure, which must be monitored, should fall in 60–90 minutes.

Renal           Effects on Urinary Excretion. Osmotic diuretics increase the urinary excretion
                of nearly all electrolytes, including Na+, K+, Ca2+, Mg2+, Cl-, HCO3 -, and

                Effects on Renal Hemodynamics. Osmotic diuretics increase RBF by a variety
                of mechanisms. Osmotic diuretics dilate the afferent arteriole, which increases
                PGC, and dilute the plasma, which decreases PGC. These effects would increase
                GFR were it not for the fact that osmotic diuretics also increase PT. In general,
                superficial SNGFR is increased, but total GFR is little changed

adverse         Mannitol is rapidly distributed in the extracellular compartment and extracts
effects         water from cells. Prior to the diuresis, this leads to expansion of the extracellular
                volume and hyponatremia. This effect can complicate heart failure and may
                produce florid pulmonary edema. Headache, nausea, and vomiting are commonly
                observed in patients treated with osmotic diuretics.
                Excessive use of mannitol without adequate water replacement can ultimately
                lead to severe dehydration, free water losses, and hypernatremia. As water is
                extracted from cells, intracellular K+ concentration rises, leading to cellular losses
                and hyperkalemia. These complications can be avoided by careful attention to
                   serum ion composition and fluid balance.


 Absorption       Poorly absorbed, which means that they must be given parenterally.

 Metabolism       Mannitol is not metabolized

 Excretion        excreted by glomerular filtration within 30–60 minutes, without any important
                  tubular reabsorption or secretion.


loop diuretics
The two prototypical drugs of this group are furosemide and ethacrynic acid
      Bumetanide
      Ethacrynic acid
      Furosemide
      Torsemide


 Class            Loop diuretic
 Presentation      Oral: 20, 40, 80 mg tablets; 8, 10 mg/mL oral solutions

                   Parenteral: 10 mg/mL for IM or IV injection

 MOA                              +   +
                  Inhibitor of Na -K -2Cl- symport in TAL (mechanism unknown)
                  increase the delivery of solutes out of the loop of Henle
                  This symporter captures the free energy in the Na+ electrochemical
                  gradient established by the basolateral Na+ pump and provides for
                  "uphill" transport of K+ and Cl- into the cell.
                  Also inhibit Ca2+ and Mg2+ reabsorption in the thick ascending limb by
                  abolishing the transepithelial potential difference that is the dominant
                driving force for reabsorption of these cations.

Use             acute pulmonary edema, other edematous conditions, and acute hypercalcemia.
                Other indications for loop diuretics include hyperkalemia, acute renal failure, and
                anion overdose.
Dose            20-80mg
Renal           Effects on Urinary Excretion. Owing to blockade of the Na+-K+-2Cl-
                symporter, loop diuretics increase urinary excretion of Na+ and Cl-
                profoundly (i.e., up to 25% of the filtered load of Na+). Abolition of the
                transepithelial potential difference also results in marked increases in
                the excretion of Ca2+ and Mg2+. Also has weak carbonic anhydrase-
                inhibiting activity  increase the urinary excretion of HCO3 - and
                phosphate. increase the urinary excretion of K+ and titratable acid.
                This effect is due in part to increased delivery of Na+ to the distal
                tubule. Other mechanisms contributing to enhanced K + and H+
                excretion include flow-dependent enhancement of ion secretion by
                the collecting duct, nonosmotic vasopressin release, and activation of
                the renin-angiotensin-aldosterone axis. Acutely, loop diuretics
                increase the excretion of uric acid
                By blocking active NaCl reabsorption  interfere with a critical step in
                the mechanism that produces a hypertonic medullary interstitium
                block the kidney's ability to concentrate urine during hydropenia. Also,
                since the thick ascending limb is part of the diluting segment,
                inhibitors of Na+-K+-2Cl- symport markedly impair the kidney's ability
                to excrete a dilute urine during water diuresis.

                Effects on Renal Hemodynamics. If volume depletion is prevented
                by replacing fluid losses, inhibitors of Na+-K+-2Cl- symport generally
                increase total RBF and redistribute RBF to the midcortex. The
                mechanism of the increase in RBF is not known but may involve
                prostaglandins. Loop diuretics block TGF by inhibiting salt transport
                into the macula densa so that the macula densa no longer can detect
                NaCl concentrations in the tubular fluid. Therefore, unlike carbonic
                anhydrase inhibitors, loop diuretics do not decrease GFR by
                activating TGF. Loop diuretics are powerful stimulators of renin
                release. This effect is due to interference with NaCl transport by the
                macula densa and, if volume depletion occurs, to reflex activation of
                the sympathetic nervous system and to stimulation of the intrarenal
                baroreceptor mechanism. Prostaglandins, particularly prostacyclin,
                may play an important role in mediating the renin-release response to
                loop diuretics.
CVS             Loop diuretics, particularly furosemide, acutely increase systemic
                venous capacitance and thereby decrease left ventricular filling

adverse        By inhibiting salt reabsorption in the TAL, loop diuretics increase delivery to the
effects        collecting duct. Increased delivery leads to increased secretion of K+ and H+ by
               the duct, causing hypokalemic metabolic alkalosis. This toxicity is a function of
               the magnitude of the diuresis and can be reversed by K+ replacement and
               correction of hypovolemia.
               Loop diuretics occasionally cause dose-related hearing loss that is usually
               reversible. It is most common in patients who have diminished renal function or
               who are also receiving other ototoxic agents such as aminoglycoside antibiotics.
               Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is
               caused by hypovolemia-associated enhancement of uric acid reabsorption in the
               proximal tubule. It may be prevented by using lower doses to avoid development
               of hypovolemia.
               Magnesium depletion is a predictable consequence of the chronic use of loop
               agents and occurs most often in patients with dietary magnesium deficiency. It
               can be reversed by administration of oral magnesium preparations.

Interactions    (1) aminoglycosides (synergism of ototoxicity caused by both drugs),
               (2) anticoagulants (increased anticoagulant activity), (3) digitalis
               glycosides (increased digitalis-induced arrhythmias), (4) lithium
               (increased plasma levels of lithium), (5) propranolol (increased
               plasma levels of propranolol), (6) sulfonylureas (hyperglycemia), (7)
               cisplatin (increased risk of diuretic-induced ototoxicity), (8) NSAIDs
               (blunted diuretic response and salicylate toxicity when given with high
               doses of salicylates), (9) probenecid (blunted diuretic response), (10)
               thiazide diuretics (synergism of diuretic activity of both drugs leading
               to profound diuresis), and (11) amphotericin B (increased potential for
               nephrotoxicity and toxicity and intensification of electrolyte
Absorption     Oral bioavailability ~ 60%
Distribution   bound extensively to plasma proteins, delivery of these drugs to the
               tubules by filtration is limited. However, they are secreted efficiently
               by the organic acid transport system in the proximal tubule and
               thereby gain access to their binding sites on the Na+-K+-2Cl- symport
               in the luminal membrane of the thick ascending limb
Metabolism     T1/2~1.5 hours. 35% metabolized mainly in the kidney by glucoronide
Excretion      65% excreted renally in intact form

Three main drugs – hydrochlothiazide, indapamide, metolazone

 Class           thiazide
 Presentation    Oral: 12.5 mg capsules; 25, 50, 100 mg tablets; 10, 100 mg/mL solution

 MOA             Thiazide diuretics inhibit the Na+-Cl- symporter in DCT. In this regard,
                 Na+ or Cl- binding to the Na+-Cl- symporter modifies thiazide-induced
                 inhibition of the symporter, suggesting that the thiazide-binding site is
                 shared or altered by both Na+ and Cl-
                 Mutations in the Na+-Cl- symporter cause a form of inherited
                 hypokalemic alkalosis called Gitelman's syndrome
 Use             (1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic
                 hypercalciuria, and (4) nephrogenic diabetes insipidus
 Dose            25–100 mg as a single dose or in two divided dose

 Renal           Effects on Urinary Excretion. moderately efficacious because
                 approximately 90% of the filtered Na+ load is reabsorbed before
                 reaching the DCT. weak inhibitor of carbonic anhydrase, an effect that
                 increases HCO3 - and phosphate excretion and probably accounts for
                 their weak proximal tubular effects. Increase the excretion of K+ and
                 titratable acid. Acute administration of thiazides increases the
                 excretion of uric acid. However, uric acid excretion is reduced
                 following chronic administration. May cause a mild magnesuria.
                 Since inhibitors of Na+-Cl- symport inhibit transport in the cortical
                 diluting segment, thiazide diuretics attenuate the ability of the kidney
                 to excrete a dilute urine during water diuresis. However, since the
                 DCT is not involved in the mechanism that generates a hypertonic
                 medullary interstitium, thiazide diuretics do not alter the kidney's
                 ability to concentrate urine during hydropenia.

                 Effects on Renal Hemodynamics. In general, inhibitors of Na+-Cl-
                 symport do not affect RBF and only variably reduce GFR owing to
                 increases in intratubular pressure. Since thiazides act at a point past
                 the macula densa, they have little or no influence on TGF.

adverse         These toxicities are similar to those observed with loop diuretics
                Hyperglycemia may occur in patients who are overtly diabetic or who have even
                mildly abnormal glucose tolerance tests. The effect is due to both impaired
                pancreatic release of insulin and diminished tissue utilization of glucose.
                Hyperglycemia may be partially reversible with correction of hypokalemia.
                Thiazides cause a 5–15% increase in total serum cholesterol and low-density
                lipoproteins (LDL). These levels may return toward baseline after prolonged use.
                Hyponatremia is an important adverse effect of thiazide diuretics. It is due to a
                combination of hypovolemia-induced elevation of ADH, reduction in the diluting
                capacity of the kidney, and increased thirst. It can be prevented by reducing the
                dose of the drug or limiting water intake.
                ALLERGIC REACTIONS
                The thiazides are sulfonamides and share cross-reactivity with other members of
                this chemical group. Photosensitivity or generalized dermatitis occurs rarely.
                Serious allergic reactions are extremely rare but do include hemolytic anemia,
                thrombocytopenia, and acute necrotizing pancreatitis.
                OTHER TOXICITIES
                Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase
                inhibitors may occur. Impotence has been reported but is probably related to
                volume depletion

Interactions    may diminish the effects of anticoagulants, uricosuric agents used to
                treat gout, sulfonylureas, and insulin and may increase the effects of
                anesthetics, diazoxide, digitalis glycosides, lithium, loop diuretics, and
                vitamin D. The effectiveness of thiazide diuretics may be reduced by
                NSAIDs, whether nonselective or selective COX-2 inhibitors, and bile
                acid sequestrants (reduced absorption of thiazides). Amphotericin B
                and corticosteroids increase the risk of hypokalemia induced by
                thiazide diuretics.

                A potentially lethal drug interaction warranting special emphasis is
                that involving thiazide diuretics and quinidine. Prolongation of the QT
                interval by quinidine can lead to the development of polymorphic
                ventricular tachycardia (torsades de pointes) owing to triggered
                activity originating from early after-depolarizations
Absorption      Oral bioavailabilty ~ 70%
 Metabolism      T1/2 7.5 hrs. Secreted into the proximal tubule by the organic acid
                 secretory pathway to gain access to luminal side of Na+-Cl- symporter
 Excretion       Renal route of excretion


aldosterone antagonists


 Class           aldosterone antagonists

 Presentation    Oral: 25, 50, 100 mg tablets

 MOA             Epithelial cells in the late distal tubule and collecting duct contain
                 cytosolic MRs that have a high affinity for aldosterone. Aldosterone
                 enters the epithelial cell from the basolateral membrane and binds to
                 MRs; the MR-aldosterone complex translocates to the nucleus, where
                 it binds to specific sequences of DNA (hormone-responsive elements)
                 and thereby regulates the expression of multiple gene products called
                 aldosterone-induced proteins (AIPs). the net effect of AIPs is to
                 increase Na+ conductance of the luminal membrane and sodium
                 pump activity of the basolateral membrane. Consequently,
                 transepithelial NaCl transport is enhanced, and the lumen-negative
                 transepithelial voltage is increased. The latter effect increases the
                 driving force for secretion of K+ and H+ into the tubular lumen.

                 Drugs such as spironolactone and eplerenone competitively inhibit
                 the binding of aldosterone to the MR. Unlike the MR-aldosterone
                 complex, the MR-spironolactone complex is not able to induce the
                 synthesis of AIPs. Since spironolactone and eplerenone block the
                 biological effects of aldosterone, these agents also are referred to as
                aldosterone antagonists. MR antagonists are the only diuretics that do
                not require access to the tubular lumen to induce diuresis.
Use             most useful in states of mineralocorticoid excess or hyperaldosteronism (also
                called aldosteronism), due either to primary hypersecretion (Conn's syndrome,
                ectopic adrenocorticotropic hormone production) or to secondary
                hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic
                syndrome, or other conditions associated with diminished effective intravascular
                volume). Use of diuretics such as thiazides or loop agents can cause or
                exacerbate volume contraction and may cause secondary hyperaldosteronism. In
                the setting of enhanced mineralocorticoid secretion and excessive delivery of Na +
                to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of
                either type may be used in this setting to blunt the K+ secretory response.
Renal           Effects on Urinary Excretion. The effects of MR antagonists on
                urinary excretion are very similar to those induced by renal epithelial
                Na+-channel inhibitors. However, unlike that of the Na+-channel
                inhibitors, the clinical efficacy of MR antagonists is a function of
                endogenous levels of aldosterone. The higher the levels of
                endogenous aldosterone, the greater are the effects of MR
                antagonists on urinary excretion.

                Effects on Renal Hemodynamics. MR antagonists have little or no
                effect on renal hemodynamics and do not alter TGF.
Other           Spironolactone has some affinity toward progesterone and androgen receptors
                and thereby induces side effects such as gynecomastia, impotence, and menstrual
                irregularities. Therapeutic concentrations of spironolactone block ether-a-go-go-
                related gene channels, and this may account for the antiarrythmic effects of
                spironolactone in heart failure. High concentrations of spironolactone have been
                reported to interfere with steroid biosynthesis by inhibiting cytochrome P450
                steroid hydroxylases.

Side effects/   HYPERKALEMIA
adverse         Unlike other diuretics, K+-sparing diuretics can cause mild, moderate, or even
effects         life-threatening hyperkalemia (Table 15–2). The risk of this complication is
                greatly increased by renal disease (in which maximal K+ excretion may be
                reduced) or by the use of other drugs that reduce renin ( blockers, NSAIDs) or
                angiotensin II activity (angiotensin-converting enzyme inhibitors, angiotensin
                receptor inhibitors). Since most other diuretic agents lead to K+ losses,
                hyperkalemia is more common when K+-sparing diuretics are used as the sole
                diuretic agent, especially in patients with renal insufficiency. With fixed-dosage
                combinations of K+-sparing and thiazide diuretics, the thiazide-induced
                hypokalemia and metabolic alkalosis are ameliorated. However, owing to
                variations in the bioavailability of the components of fixed-dosage forms, the
                thiazide-associated adverse effects often predominate. Therefore, it is generally
                preferable to adjust the doses of the two drugs separately.
                 By inhibiting H+ secretion in parallel with K+ secretion, the K+-sparing diuretics
                 can cause acidosis similar to that seen with type IV renal tubular acidosis.
                 Synthetic steroids may cause endocrine abnormalities by actions on other steroid
                 receptors. Gynecomastia, impotence, and benign prostatic hyperplasia have all
                 been reported with spironolactone. Such effects have not been reported with
                 ACUTE RENAL FAILURE
                 The combination of triamterene with indomethacin has been reported to cause
                 acute renal failure. This has not been reported with other K+-sparing diuretics.
                 KIDNEY STONES
                 Triamterene is only slightly soluble and may precipitate in the urine, causing
                 kidney stones.


 Absorption      Oral bioavailabilty ~ 65%,
 Distribution    highly protein-bound
 Metabolism      T1/2~ 1.6 hrs. metabolized extensively (even during its first passage
                 through the liver), undergoes enterohepatic recirculation. active
                 metabolite of spironolactone, canrenone, has a half-life of
                 approximately 16.5 hours, which prolongs the biological effects of
 Excretion       biliary


carbonic anhydrase inhibitors



 Side effects/




other potassium-sparing diuretics

To top