renal

Describe the functional anatomy of the kidneys and to explain the physiology of

renal blood flow









THE NEPHRON









FUNCTIONAL ANATOMY







The Nephron

Functional unit = nephron = tubule + glomerulus



Approximately 1.3 million nephrons / kidney



Glomerulus:



 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.







Tubule:



 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

invaginated.







 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

mm.







Blood Vessels

 Interlobular arteries  afferent arterioles  glomerular capillary tuft  efferent

arteriole (technically a portal system)  peritubular capillaries  interlobular

veins.

 Glomerular capillaries are the only capillaries in the body that drain into

arterioles.

 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.







Capsule



 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

mL/min.

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

flow.

 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

needs.



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

world.

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



Size:



 Free filteration of solutes 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:







PROXIMAL TUBULE



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.









THICK ASCENDING LOOP OF HENLE



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.

DISTAL CONVOLUTED TUBULE



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

syndrome.









CORTICAL COLLECTING DUCT: PRINCIPLE CELLS



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

CORTICAL COLLECTING DUCT: INTERCALATED CELLS TYPE A



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









CORTICAL COLLECTING DUCT: INTERCALATED CELLS TYPE B



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

absorption

o Glucagon, progesterone and parathyroid hormone decrease absorption







ADH



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



ADH:



 Increases permeability of cortical and medullary collecting ducts to water

 Increases sodium absorption







WATER EXCRETION:



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



THIRST AND SALT APPETITE:

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

and drugs



Glucose



 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

quantities.

 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.



Urea



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

Hyperlipidemia

Lipiduria

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

Casts

Azotemia

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

ascLoH

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

↓MAP



Depending on the cause of hypovolaemic shock ECF osmolality may be isoosmolar

(haemorrhage) or hyperosmolar (dehydration)



Compensatory Mechanism: Oliguria (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 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

cells

Effect: ↑Na/H2O absorption, ↑K elimination



List the hormones that regulate tubular reabsorption and describe their action and site of

action

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

release

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

reabsorpn)

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

role)

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)



Kidney

- 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



mannitol



Physicochemical

Structure







Class Osmotic diuretic

Presentation 20% mannitol bottles 100ml/500ml



Pharmacodynamics

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.

Use TO INCREASE URINE VOLUME

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).

REDUCTION OF INTRACRANIAL AND INTRAOCULAR PRESSURE

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.





Dose

Renal Effects on Urinary Excretion. Osmotic diuretics increase the urinary excretion

of nearly all electrolytes, including Na+, K+, Ca2+, Mg2+, Cl-, HCO3 -, and

phosphate.



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

CVS

CNS

Respiratory

Other



Side effects/ EXTRACELLULAR VOLUME EXPANSION

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.

DEHYDRATION, HYPERKALEMIA, AND HYPERNATREMIA

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.







Interactions



Pharmacokinetics

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



Distribution

Metabolism Mannitol is not metabolized





Excretion excreted by glomerular filtration within 30–60 minutes, without any important

tubular reabsorption or secretion.



Evidence









loop diuretics

The two prototypical drugs of this group are furosemide and ethacrynic acid

 Bumetanide

 Ethacrynic acid

 Furosemide

 Torsemide



Frusemide

Physicochemical

Structure









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



Pharmacodynamics

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

pressure

CNS

Respiratory

Other



Side effects/ HYPOKALEMIC METABOLIC ALKALOSIS

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.

OTOTOXICITY

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.

HYPERURICEMIA

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.

HYPOMAGNESEMIA

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.

ALLERGIC & OTHER REACTIONS







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

imbalance).

Pharmacokinetics

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

conjugation.

Excretion 65% excreted renally in intact form



Evidence

Thiazides

Three main drugs – hydrochlothiazide, indapamide, metolazone

Hydrochlothiazide

Physicochemical

Structure









Class thiazide

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



Pharmacodynamics

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.

CVS

CNS

Respiratory

Other



Side effects/ HYPOKALEMIC METABOLIC ALKALOSIS AND HYPERURICEMIA

adverse These toxicities are similar to those observed with loop diuretics

effects IMPAIRED CARBOHYDRATE TOLERANCE

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.

HYPERLIPIDEMIA

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

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

Pharmacokinetics

Absorption Oral bioavailabilty ~ 70%

Distribution

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



Evidence









aldosterone antagonists



SPIRONOLACTONE

Physicochemical

Structure









Class aldosterone antagonists



Presentation Oral: 25, 50, 100 mg tablets







Pharmacodynamics

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.

Dose

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.

CVS

CNS

Respiratory

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.

HYPERCHLOREMIC METABOLIC ACIDOSIS

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.

GYNECOMASTIA

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

eplerenone.

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.







Interactions



Pharmacokinetics

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

spironolactone.

Excretion biliary



Evidence









carbonic anhydrase inhibitors



Physicochemical

Structure

Class

Presentation

Pharmacodynamics

MOA



Use

Dose

CVS

CNS

Respiratory

Other



Side effects/

adverse

effects

Interactions



Pharmacokinetics

Absorption

Distribution

Metabolism



Excretion



Evidence









other potassium-sparing diuretics