The
human kidneys:
The nephron is a tube; closed at one end, open at the other. It consists of a:
The nephron makes urine by
In 24 hours the kidneys reclaim
The steps:
|
Composition of plasma, nephric
filtrate, and urine (each in g/100 ml
of fluid). These are representative values. The values for salts are
especially variable, depending on salt and water intake. |
|
|||||||
|
Component |
Plasma |
Nephric Filtrate |
Urine |
Concentration |
% Reclaimed |
|
||
Urea
|
0.03 |
0.03 |
1.8 |
60X |
50% |
|
||
|
Uric acid |
0.004 |
0.004 |
0.05 |
12X |
91% |
|
||
|
Glucose |
0.10 |
0.10 |
None |
- |
100% |
|
||
|
Amino acids |
0.05 |
0.05 |
None |
- |
100% |
|
||
|
Total inorganic salts |
0.9 |
0.9 |
<0.9-3.6 |
<1-4X |
99.5% |
|
||
|
Proteins and other macromolecules |
8.0 |
None |
None |
- |
- |
|
||
|
|
|
|
|
|
|
|
||
|
|
||||||||
|
Blood urea nitrogen or Blood urea creatinine |
<=1.25 x Na |
1.26 - 2.5 x Na |
2.6 - 5 x Na |
5 - 10 x Na |
> 10 x Na |
|||
|
Proteinuria |
no change |
1 + |
2 - 3 + |
4+ |
nephrotic
syndrome |
|||
|
Haematuria |
no change |
microscopic |
gross |
gross + clots |
obstructive
uropathy |
|||
As the fluid flows into the loop of Henle, it is approximately isotonic to the blood. Here more sodium ions are pumped out, but water does not follow them. So,
In the distal tubules, more sodium is reclaimed by active transport, and still more water follows by osmosis.
Final adjustment of the sodium and water content of the body occurs in the collecting tubules.
Although 98% of the sodium has already been removed, it is the last 2% that determines the final balance of sodium - and hence water content and blood pressure - in the body. The reabsorption of sodium in the collecting tubules is closely regulated, chiefly by the action of the hormone aldosterone.
The release of ADH (from the posterior lobe of the pituitary gland) is regulated by the osmotic pressure of the blood.
The result:
|
Basic principles of urine formation The goal of urine production is to maintain
the volume and composition of the blood. This requires the elimination of
organic wastes; most importantly ·
urea, ·
creatinine and ·
uric acid. This requires some
accompanying water - but water loss must be kept to a minimum. at the
same time, useful solutes must be resorbed. To accomplish these goals,
the kidney uses three basic mechanisms: a)
glomerular filtration b) tubular
reabsorbtion c) tubular
secretion 2. Glomerular Filtration
(Fig. 26.7) Filtration
occurs within the renal corpuscle, as fluid moves under pressure
across the walls of the glomerular capillaries and into the space within
Bowman's capsule. There are three physical barriers that determine
which materials from the blood will pass into the renal tubules based on the
size of the passages. a) capillary
endothelium (pores) b) basement membrane
(lamina densa) that surrounds the capillaries c) the filtration
slits between the processes of the podocytes all substances go
through except blood cells and most proteins Filtering
capacity is high because: a) long blood
capillaries within glomerulus (high surface area) b) many pores in
capillaries (50x normal) c) blood pressure is
high in capillaries (afferent arteriole has greater diameter than efferent) 3. Filtration pressures
(Fig. 26-10) The tendency for materials to be forced from the capillaries and
into the renal tubules is determined by the net hydrostatic and osmotic
pressures acting on the materials: a)
Glomerular blood hydrostatic pressure (GBHP): this is the blood pressure in the glomerular
capillaries - typically 45-55 mm Hg. It forces materials out of the
capillaries. b) Capsular
hydrostatic pressure (CHP): this
opposing pressure arises from the fluid already within the nephron -
typically 15 mm Hg. The net hydrostatic pressure (GBHP-CHP) will thus be
about 35 mm Hg, and tends to push material out into the nephrons. c) Blood colloid
osmotic pressure (BCOP): although the
net hydrostatic pressure would force fluid and solutes out of the capillaries,
the osmotic pressure exerted by suspended proteins within the plasma tend to
retain water within the capillaries. The magnitude of this pressure will
depend upon the amount of suspended proteins in the plasma - typically 25-30
mm Hg. d) Capsular
colloid osmotic pressure (CCOP): by
contrast, the suspended proteins within the nephron will draw water out of
the capillaries - although this pressure is typically very small (0 mm Hg). e) Net filtration
pressure (NFP) will be determined by the
difference between the net hydrostatic and net colloid osmotic pressures.
This is typically about 10 mm Hg in the direction that would force material
out of the capillaries. NFP
= GBHP - (CHP + BCOP) NFP = 55- (15 +
30) NFP = 10 mm Hg note
that if GHP (blood pressure) drops by only 10 mm Hg, the filtration stops (hemoraging, shock or dehydration) 4. Glomerular filtration rate
(GFR)= amount of filtrate produced each minute This
can be determined using the creatinine clearance test. Normally about 180
liters (50 gal) of filtrate per day!!!!! BUT about 99% resorbed so only
1-2 liters per day of urine The GFR depends
upon blood pressure The GFR is
regulated in several ways depending upon
the needs of the body: a)
autoregulation (Fig. 26.11): the ability
to maintain constant GFR despite changes in systemic arterial pressure;
involves adjustment of diameters of the glomerular arterioles and
capillaries: increase in afferent arterioles and decrease in efferent =
increase in blood pressure: this works through the juxtaglomerular
apparatus b) hormonal
regulation: -
renin/angiotensin II: the
juxtaglomerular apparatus releases renin when renal blood flow declines; this leads to the formation of angiotensin II which
elevates GFR by - constriction
of efferent arteriole - stimulating
reabsorption of Na and water in PCT - triggering release
of ADH = reabsorption of water - triggering release
of aldosterone = increases Na (therefore water reabsorption) - stimulating thirst
-
atrial natriuretic peptide (ANP):
stretching of the atrial walls of the heart leads to release of atrial
natriuretic peptide, which increases GFR - dilation of afferent and constriction of efferent arterioles = increase GFR - also promotes
secretion (thus elimination) of water and Na (natriuretic) c)
neural (autonomic regulation):
sympathetic innervation leads to decreased GFR by constrict of afferent --
thus urine
production decreases significantly during
stress Significance of the kidney's ability to concentrate urine.A. Urine osmolality can range from 60 mosm (dilute urine, the body is in a state of positive water balance) to 1200 mosm (concentrated urine, the body is in a state of negative water balance. B. Definitions: 1. Diruesis: When urine flow is greater than normal ( > 1 ml/min in an adult). a. Osmotic diuresis: Diuresis caused by the presence of extra, non-reabsorbed solute in the tubular lumen. b. Water diuresis: Diuresis caused by a decrease in water reabsorbed from the tubule lumen. 2. Antidiuresis: Urine flow that is less than normal (< 1 ml/min in an adult). 3. Hypoosmotic: Urine with an osmolality less than that of plasma (< 300 mosm). 4. Hyperosmotic: Urine with an osmolality greater than that of plasma (> 300 mosm). C. Concentration or dilution of the urine leads to changes inf plasma osmolality. Changes in osmolality of the plasma and extracellular fluid have significant effects on the volume of the cell (cell shrinkage or swelling). D. Concentration and dilution of the urine leads to alterations in blood volume and, consequently, to changes in cardiac function, blood pressure and perfusion of tissue. E. Concentration or dilution of urine is not a result of active reabsorption or secretion of water. In the renal tubule, the movement of water to areas of high osmolality allows for its passive reabsorption. F. The three components of the urinary concentrating system are: 1. Countercurrent multiplier system of the loop of Henle. 2. Antidiuretic hormone (ADH) and its effects on the permeability of the distal tubule and the collecting duct. 3. Countercurrent exchange system of the vasa recta. II. Countercurrent multiplier system: this system resides in the loop of Henle.A. Significant differences in the properties of the two limbs of the loop of Henle contribute to the generation of an osmotic gradient in the interstitial tissue of the kidney that increases in magnitude from the cortex to the renal papilla. 1. The thin descending limb (TDL) The TDL is very permeable to both water and solute. Therefore, tubular fluid in this nephron segment reaches equilibrium with the interstial tissue during fluid passage 2. The thick ascending limb (TAL) a. The TAL actively pumps NaCl out of the tubule fluid and into the interstitium. b. The TAL is impermeable to water; thus, solute is separated from water which leads to a dilution of the tubular fluid in this nephron segment while the interstitial tissue becomes osmotically concentrated. B. NaCl constitutes a major portion of the corticomedullary interstitial osmotic gradient. However, urea (an end product of protein catabolism) also constitutes a significant portion of this gradient. Most urea is passively reabsorbed by the proximal tubule, but during antidiuresis, urea is reabsorbed by the collecting duct, as well. C. The countercurrent multiplier system generates the corticomedullary osmotic gradient necessary to enhance water reabsorption (figures 1a and 1b). 1. The selective reabsorption of NaCl without water in the TAL results in a hypertonic interstitium. The TAL can reabsorb NaCl to achieve a 200 mosm difference in the fluid at any horizontal plane between the interstitium and the tubular lumen. This pumping of NaCl without water is the single effect that is subsequently multiplied by the countercurrent multiplier system to generate an interstitium that is progressively more osmotically concentrated toward the medulla. 2. Theoretically, the longer the loop of Henle, the greater the magnitude of the osmotic gradient (which enhances the ability to concentrate the urine). 3. The two limbs of the loop of Henle work to generate an osmotic gradient within the medullary region of the kidney and also work to dilute the tubular fluid (urine). Water is not reabsorbed in the loop of Henle! Urine is not concentrated in the loop of Henle! III The distal tubule, the collecting duct, and antidiuretic hormone (ADH)A. If the body's regulatory mechanisms dictate, concentration of urine occurs as the tubular fluid flows through the late distal tubules and the medullary collecting ducts. B. The presence or absence of ADH determines whether the urine is concentrated or dilute. 1. ADH is a small peptide hormone produced in the supraoptic nuclei near the pituitary gland in the brain. ADH is stored and released from neurons in the posterior pituitary (figure 2a and 2b). 2. In the absence of ADH, the final urine osmolality will equal the osmolality of the tubular fluid at the end of the loop of Henle. The osmolality of the urine may even continue to drop as more solute and NaCl is reabsorbed from the late distal tubule and collecting duct. If ADH is absent, the distal tubule and collecting duct are impermeable to water, preventing water movement out of the tubule in response to the hypertonic interstitium (corticomedullary osmotic gradient, figure 3a). 3. If ADH is present, the late distal tubule and collecting duct are permeable to water. Thus, as the tubular fluid traverses these segments (and through the corticomedullary gradient), water will passively diffuse from the tubular lumen into the interstitium. Concentration of the urine is the result. The urine osmolality will vary depending on the plasma levels of ADH (figure 3b). a. ADH attaches to specific receptors on the peritubular membrane of the distal tubule and collecting duct. The increased water permeability is attributed to the physical insertion of water channels into the luminal membrane of these segments (figure 4). b. Attachment of ADH to the basolateral receptors also results in insertion of urea channels into the luminal membrane of the medullary collecting duct, which results in an increased urea permeability in this segment only. Thus, during antidiuresis urea constitutes a greater portion (as much as 40%) of the corticomedullary gradient than during diuresis (10%). IV. Countercurrent exchange system (vasa recta)A. The capillary system that perfuses the medullary region of the kidney is termed the vasa recta. The vasa recta are specialized peritubular capillaries which function in countercurrent exchange. B. Similar to extrarenal capillary beds, the vasa recta serve to deliver various nutrients to the medulla and remove various waste and metabolic products from this area. In addition, the vasa recta are responsible for returning the water reabsorbed by the late distal tubules and collecting ducts to the systemic vasculature. C. The architecture of the vasa recta is very different from the cortical peritubular capillaries. Anatomically, the vasa recta run parallel to the loops of Henle (figure 5a and 5b). If the medullary portion of the kidney was perfused by capillaries that began at the cortical and ended at the medullary regions, the osmotic gradient would quickly wash away (figure 5a). Since the vasa recta enter and exit the renal tissue at the cortex the gradient is not washed out (figure 5b). Blood perfusing the medullary tissue equilibrates with the interstitium so that the gradient is maintained. V. Regulation of water balance (ADH and thirst)A. The basic strategy for maintaining proper water balance is to regulate two elements: water output (regulated in part by ADH) and water input (regulated through the sensation of thirst and the behavioral response to this sensation). B. Secretion of ADH and sensation of thirst are regulated primarily in response to changes in plasma volume and osmolality. 1. Changes in plasma volume are monitored by baroreceptors in the left atrium. In addition, baroreceptors in the carotid sinus and aortic arch monitor arterial pressure. The firing rate of impulses from these baroreceptors to the hypothalamus varies indirectly with changes in plasma volume and arterial pressure. 2. Changes in plasma osmolality are monitored by osmoreceptors near the hypothalamus. The firing rate of impulses from these receptors varies directly with changes in plasma osmolality. C. Normally, ADH release from the posterior pituitary is inhibited. When plasma volume decreases and/or plasma osmolality increases, inhibition is relieved and ADH is released into the blood. 1. Significant increases in plasma ADH are not detected until plasma volume drops by 10%. 2. Changes in plasma osmolality as small as 1% will trigger increases or decreases in plasma ADH. D. When plasma volume and/or arterial pressure decreases and/or plasma osmolality increases, an increase in thirst intensity occurs. |
A. Approximately 50% of the body's Na is in the ECF. (The remaining 50% is in bone. Movement of Na in and out of bone is not closely regulated).
1. Na is the major solute of the
ECF and, thus, is the major contributor to ECF osmolality.
2. The ECF compartment volume is strongly dependent on the plasma Na
concentration.
3. Significant changes in plasma Na concentration can signficantly alter plasma
osmolality to...
a. alter the balance of osmotic
forces across the cell membrane.
b. cause the kidney to reabsorb water.
B. Plasma Na concentration is maintained within a narrow range: 136-146 mEg/L.
C. Na balance is the equilibrium between Na intake and output, i.e. intake = output.
1. Negative Na balance occurs
when output of Na is greater than intake.
2. Postive Na balance occurs when Na intake is greater than output.
A.
Water is passively reabsorbed by the renal tubules in response to an osmotic
gradient between the tubular fluid and the plasma. This osmotic gradient is
established by NaCl and NaHCO3, primarily. Thus, transport of Na
from the tubular fluid to the plasma is required to establish this gradient.
B.
Na and water reabsorption in nephron segments
1.
Early proximal tubule - (figure 1a) Na moves passively across the luminal
membrane down its electrochemical gradient since the low intracellular Na
concentration and the inside negative electrical potential difference favor Na
movement into the cell. Two mechanisms involved in Na entry include: (I)
Na-cotransport with glucose, inorganic phosphate, sulfate, amino acids and
organic acids and (ii) Na/H exchange. Na is actively transported by Na,K-ATPase
across the peritubular membrane to the plasma.
2. Late proximal tubule - (figure 1b) Na cotransport with glucose,
inorganic phosphate, amino acid and organic acid reabsorption is virtually
complete at the end of the early proximal tubule. Thus, Na enters the late
proximal tubule cell passively by Na/H exchange. Peritubular Na transport still
involves Na,K-ATPase.
3. Thin descending limb - Na, Cl and urea are secreted into this segment
down their concentration gradient, rather than reabsorbed.
4. Thin ascending limb - Na and Cl are passively reabsorbed. Water does
not follow since this segment is impermeable to water.
5.Thick ascending limb - (figure 1c) Na enters the cell across the
luminal membrane via the carrier-mediated Na:K:2Cl cotransporter driven by the
electrochemical gradient for Na. (K and Cl transport are uphill). Na,K-ATPase
actively move Na into the peritubular fluid (K and Cl exit passively). This
segment is responsible for reabsorption of 25% of filtered Na.
6. Early distal tubule - (figure 1d) Na enters passively via Na/Cl
cotransport. Na is transported across the peritubular membrane by Na,K-ATPase. This
segment also is water impermeable.
7. Late distal tubule and collecting duct - (figure 1e) Na is passively
reabsorbed down its electrochemical gradient through Na channels. Peritubular
Na transport is by the activity of Na,K-ATPase. The distal tubule and
collecting duct reabsorb 5% and 3%, respectively, of filtered Na. Regulation of
Na reabsorption occurs in these segments.
C.
Na reabsorption by the late distal tubule and collecting duct is stimulated by
aldosterone
1.
Aldosterone is a steroid hormone that is produced and secreted by the adrenal
glands. The adrenal glands are located adjacent to the anterior pole of the
kidney.
2. Angiotensin II, formed through the renin-angiotensin system,
stimulates the release of aldosterone. Angiotensin II is produced during the
conversion of angiotensinogen (released into the plasma from the liver) by
renin (released from the JGA) to angiotensin I. A converting enzyme found in
the lungs and kidneys converts angiotensin I circulating in the blood to
angiotensin II which circulates to the adrenal glands and stimulates
aldosterone secretion.
3. Aldosterone increases Na reabsorption by the late distal tubule and
collecting duct by three mechanisms:
a.
Aldosterone increases luminal membrane permeability to Na.
b. Aldosterone increases the number and/or activity of peritubular membrane
Na,K-ATPase.
c. Aldosterone increase ATP production by the mitochondria to provide more
energy for Na,K-ATPase.
A. Changes in GFR.- Changes in GFR can significantly alter the filtered load of Na because filtered load of Na = (GFR) (Pna). Thus, without compensation, a decrease in GFR would produce Na excess and increased GFR would produce a Na deficit. GFR must be closely regulated to maintain adequate Na and water balance.
B. Review of Starling forces involved in glomerular filtration
GFR = Kf [(Pb - Pc) - (pib - pic)]
In contrast to filtration in extrarenal capillary beds,
glomerular Pb remains constant whereas
C. Single nephron glomerular filtration rate (snGFR) refers to the volume of plasma filtered through a single glomerulus (one glomerular capillary bed) per unit time (usually one minute).
1. Immediate responses to changes in the various determinants of snGFR.
a. Changes in initial glomerular
plasma flow rate (Q): snGFR varies linearly with Q. Changes in Q displace the
point along the glomerular capillary length at which
b. Changes in glomerular capillary hydrostatic pressure: The primary sites for variation in vascular resistance within the kidney is at the afferent and efferent arterioles. Alterations in resistance in either vessel result in alterations in renal blood flow according to the follwing equation:
Figure 4 summarizes the effects
that a change in afferent or efferent arteriolar resistance will have on RBF,
c. Changes in glomerular
capillary oncotic pressure. In theory, snGFR should vary with
d. Changes in filtration coefficient: Changes in Kf effect snGFR. A decrease in Kf decreases GFR.
e. Changes in oncotic pressure in Bowman's capsule: Normally, pic is essentially zero and should not change. However, damage to the glomerular capillary wall and the subsequent leakage of macromolecules into Bowman's space may result in a pathologic increase in pic.
f. Changes in hydrostatic pressure within Bowman's capsule: Pc should remain unchanged normally. Obstruction of the renal tubules or the ureter will increase Pc.
2. Physiological compensation for alterations in Na balance by regulating GFR is accomplished by (i) autoregulation of GFR and (ii) glomerulotubular balance.
a. Autoregulation of RBF and GFR: Over a range of perfusion pressures (80-180 mm Hg) both RBF and GFR remain stable due to inherent properties of the kidney tissue that respond to changes in arterial perfusion pressure. Although not fully understood, one aspect of autoregulation is explained by the equation Q = [[Delta]]P/R. Changes in perfusion pressure, P, must be accompanied by proportional changes in resistance, R, if flow, Q, is to remain constant. The predominant change in resistance occurs in the afferent arteriole. Stretch in the arteriole wall increases P and, hence, increases R. Shortening of the arteriole wall decreases P and, hence, decreases R.
b. Glomerulotubular balance refers to the fact that under normal conditons a constant fraction (67%) of the filtered load of Na is reabsorbed in spite of GFR variations. In fact, glomerulotubular balance allows Na reabsorption to increase (99.09%) with an increase in GFR.
3. The two processes involved in glomerulotubular balance are: (i) changes in the filtration fraction (FF = GFR/RBF) which leads to changes in the peritubular capillary oncotic pressure and (ii) Na-cotransport.
a. Changes in the filtration fraction can result from an increase or decrease in GFR as the initial event. The increases or decreases in GFR are accompanied by increases or decreases, respectively, in Na and water reabsorption so that a constant fraction of the ultrafiltrate (67%) is reabsorbed.
b. Since Na reabsorption is linked to reabsorption of various organic solutes, an increased or decreased filtered solute load (secondary to increased or decreased GFR) will be accompanied by an increased reabsorption of solute and Na (increased Na due to cotransport with solute).
D. Changes in Na intake
1. Changes in GFR - Increased Na intake is accompanied by increased water retention, resulting in expansion of ECF volume. This volume expansion produces a decrease in plasma oncotic pressure and an increased systemic arterial pressure leading to Increased GFR. The increased GFR increases renal Na and water excretion to return ECF to normal.
2. Changes in Na reabsorption - Alterations in Na reabsorption are influenced by many factors, such as
(a)
changes in aldosterone
levels,
(b)
(b) altered levels of angiotensin II,
(c)
(c) changes in
sympathetic tone and catecholamines levels,
(d)
(d) alterations in the
filtration fraction and the consequent changes in plasma oncotic pressure,
(e)
(e) Atrial natriuretic factor (ANF), and
(f)
(f) other natriuretic
hormones
a. For example, increased Na intake would produce
i. Increase in GFR due to
increased ECF volume in direct response to increased plasma Na concentration.
ii. Increased plasma oncotic pressure due to increased plasma Na
iii. Increased arterial pressure (for reasons not completely understood).
b. Increased plasma Na levels will decrease aldosterone secretion, resulting in decreased Na reabsorption from the late distal tubule and collecting duct.
c. The increased blood pressure (from increased plasma Na) leads to an increased in the filtered load of Na which is sensed at the macula densa cells. A decrease in renin release results, and is accompanied by a decrease in angiotensin II. Decreased angiotensin II also decreases aldosterone secretion from the adrenal glands. Decreased aldosterone decreases Na reabsorption in the late distal tubule and collecting duct.
d. An increased plasma volume due to increased Na can trigger physiological compensation through the release of atrial natriuretic factor (ANF).
1. The increase in plasma volume triggers the release of ANF, a peptide hormone from the secretory granules within the atrial muscle cells of the heart.
2. ANF causes diuresis and a decrease in Na reabsorption at the renal tubules by several mechanisms.
a. Inhibiting aldosterone
production at the adrenal gland
b. Inhibiting renin release from the JGA.
c. Inhibiting ADH secretion from the posterior pituitary and inhibiting the
action of ADH at the renal tubule.
d. ANF, thus, reduces Na and water retention which aids to bring plasma volume
back to normal levels e. a role for other natriuretic hormones , like ouabain,
remains to be defined. These ouabain-like agents inhibit the activity of
Na,K-ATPase at the peritubular membrane to decrease Na reabsorption.
6. Morphology of the kidneys.
a. Position of kidneys in body
cavity.
b. Gross shape of the kidneys.
c. Internal anatomy of the kidney.
i. Cortex
ii. Medulla
d. Functional unit of the kidney, the nephron.
i. Renal corpuslce
ii. Proximal tubule
iii. Loop of Henle
iv. Distal tubule
v. Collecting duct
7. Filtration of the plasma.
a. Forces involved in glomerular
ultrafiltration.
b. Selectivity of ultrafiltration
8. Reabsorption of the filtrate.
9. Secretion of materials into the tubule fluid.
10. Concentration and dilution of the urine.
a. Osmotic gradient within the renal medulla.
i. Source of the gradient
b. Role of the collecting ducts.
i. Antidiuteric hormone
ii. Source of the hormone
iii. Sight of action for the hormone
11. Cooling of the body.
a. Physical processes.
i. Radiation
ii. Conduction
iii. Convection
iv. Sweating
b. Dissipation of heat during and after exercise.
(Fig. 2).
note: it follows,
therefore, if you fail to transport a solute (e.g., lactose), then you will
fail to absorb an associated volume of water. This is the basis of "osmotic
diarrhea" (e.g., "lactose intolerance").
Ø Diabetes insipidus
is a rare disorder of water metabolism.
Ø This means
that the balance between how much water or fluid you drink is not balanced with
the fluid you urinate.
Ø Diabetes insipidus
is caused by a lack of, or non-response to, the antidiuretic hormone
vasopressin.
Ø This
hormone controls water balance by concentrating urine.
Ø Patients
with diabetes insipidus urinate too much, so
they need to drink a lot to replace the fluid they lose.
Ø Vasopressin
is made by the cells of the hypothalamus (located in the brain) and is stored
and secreted by another part of the brain called the posterior pituitary gland.
Ø The
antidiuretic hormone is then released into the bloodstream where it causes
tubules within the kidney to reabsorb water. Water that cannot be reabsorbed is
passed out of the body in the form of urine.
Ø Decreased
secretion of vasopressin causes less water to be reabsorbed and more urine to
be formed.
Ø When
vasopressin is present at normal levels, more water is reabsorbed and less
urine is formed. You should not confuse diabetes insipidus
with the metabolic disease, diabetes
mellitus.
Ø Diabetes mellitus is a different disease caused by a lack of,
or an impaired response to, the hormone insulin.
Ø
This hormone is made by the pancreas and helps in
carbohydrate metabolism.
Ø Without
insulin, a person cannot make use of the carbohydrates he or she takes in, such
as sugar.
Ø The
hormone insulin affects sugar so that it can enter the body’s cells and be used
for energy.
Ø When
insulin is insufficient or not present, an abnormally high amount of sugar will
be in the blood and urine
Disease characteristics. Nephrogenic diabetes insipidus (NDI) is characterized by inability to
concentrate the urine, which results in polyuria (excessive urine production)
and polydipsia (excessive thirst). Affected infants usually have poor feeding
and failure to thrive, and have the rapid onset of severe dehydration with an
illness, hot environment, or the withholding of water. Short stature and
secondary dilatation of the ureters and bladder from the high urine volume is
common in untreated patients. Treatment with a very low salt diet and thiazide
diuretics can reduce urine volume by up to 50%.
Diagnosis/testing. The clinical diagnosis of NDI
relies upon demonstration of subnormal ability to concentrate the urine despite
the presence of the antidiuretic hormone, pituitary-derived arginine
vasopressin (AVP). Molecular genetic testing of the AVPR2 gene
(chromosomal locus Xq28) detects about 100% of disease-causing mutations
in individuals with X-linked NDI; molecular genetic testing of the AQP2
gene (chromosomal locus 12q13) detects about 100% of disease-causing
mutations in individuals with autosomal recessive NDI. Such testing is
clinically available.
Genetic counseling. NDI is most commonly inherited
in an X-linked recessive manner (~90% of patients) and can also be inherited in
an autosomal recessive manner (~10% of patients) and in an autosomal dominant
manner (~1% of patients). The risks to sibs and offspring depend upon the mode
of inheritance and the carrier status of the parents, which can be established
in most families using molecular genetic testing. Prenatal testing is
available.
hypothalamic
· psychogenic (water intoxication)
· primary nephrogenic
· secondary nephrogenic
This disorder is characterized by:
It can have several causes:
|
Testing
Used in the Molecular Diagnosis of |
||||
|
% of
Patients |
Genetic
Mechanism |
Test Type
|
Test
Availability |
|
|
X-linked |
AR |
|||
|
~100% |
|
AVPR2 mutations |
Direct
sequencing of AVPR2 gene Mutation scanning |
Clinical |
|
|
~100% |
AQP2 mutations |
Direct
sequencing of AQP2 exons Mutation scanning |
|
There are two types of diabetes insipidus.
While the symptoms of these two disorders are similar, the causes are
different.
Central diabetes insipidus
If you have been diagnosed with central diabetes insipidus, there are some things you should know
about how the disorder is caused and what you and your doctor can do about it.
What causes it?
In central diabetes
insipidus, the antidiuretic
hormone vasopressin is either missing or present at a low level. This low level
or lack of vasopressin is due to a malfunction in the part of your brain, the
posterior pituitary gland, which releases the hormone into your blood-stream.
|
|
Tumour of the pituitary gland. |
|
|
Head injury, with damage to pituitary gland. |
|
|
Brain tumour. |
|
|
Infections, such as meningitis or encephalitis. |
|
|
Haemorrhage in the pituitary gland or in adjacent
structures. |
|
|
Aneurysm. |
What are the symptoms?
|
|
excessive urination (polyuria) which is followed by |
|
|
excessive thirst (polydipsia) |
Ø
Patients with central diabetes insipidus are often extremely tired because they
cannot get enough sleep uninterrupted by the need to urinate. Their urine is
very clear and odourless. These symptoms can appear at any time.
Ø
Because they lose so
much water from urination, they also feel very thirsty. If this disorder is
untreated, they could become seriously dehydrated, and their bodies will not
have enough water to function properly.
Nephrogenic diabetes insipidus
Nephrogenic diabetes
insipidus is much less
common than central diabetes
insipidus. If you have been
diagnosed with nephrogenic diabetes
insipidus, your doctor or
nurse will discuss the disorder and its treatment with you. They will be happy
to answer your questions.
What causes it?
Nephrogenic diabetes
insipidus may be caused by
kidney diseases that make the kidneys unable to respond to vasopressin. While
there is enough vasopressin in the body (unlike in central diabetes insipidus), the kidneys cannot respond to the
hormone’s signal to reabsorb water. The disease may be acquired or inherited by
male children.
What are the symptoms?
The symptoms of nephrogenic diabetes insipidus
are similar to central diabetes
insipidus; that is,
excessive urination (polyuria) followed by excessive thirst (polydipsia).
How is it treated?
The first step in treating this disease is correct
diagnosis. In addition to the medications available, balancing your water or
fluid intake with your urine output is also part of treatment. If this disorder
is untreated, you could become seriously dehydrated, and your body will not
have enough water to function.
The
two most common tests used to diagnose diabetes insipidus
are the following:
|
|
Water
deprivation test/vasopressin test |
||||
|
|
Hypertonic saline infusion
test. |
||||
|
|
Other tests which may be
used are the urine specific gravity test and the serum or urine osmolality
test. |
||||
|
|
Central diabetes insipidus |
Nephrogenic diabetes insipidus |
Diabetes mellitus |
|
||
|
How common
is the disease? |
Uncommon |
Uncommon |
Common |
|
||
|
What causes
the disease? |
The mechanism for
secreting vasopressin malfunctions. |
The kidneys are
unable to respond to the diuretic hormone vasopressin. It is acquired or may
be inherited by male children. |
Enough of the
hormone insulin is not secreted, or the body’s cells do not respond to it.
Heredity, stress, obesity, pregnancy, and drugs can also lead to diabetes mellitus. |
|
||
|
What do
these hormones do and why are they important? |
Vasopressin is a
diuretic hormone that controls water metabolism. It is made in the
hypothalamus (a part of the brain) and is stored and secreted by the
posterior pituitary gland (also in the brain). |
It causes tubules
within the kidney to reabsorb water. Water that is not absorbed is released
as urine. |
Insulin is made in
the pancreas, where it controls carbohydrate metabolism. It controls sugar
(glucose) levels in the body. |
|
||
|
What are the
signs and symptoms of the disease? |
Sudden or gradual
urination of large amounts of clear, colourless fluid, followed by excessive
thirst (polydipsia). Dehydration can occur if fluid balance is not
maintained. |
Same as central diabetes insipidus:
polyuria followed by polydipsia. |
Excessive
urination (polyuria), excessive thirst (polydipsia), excessive appetite
(polyphagia). May be sudden or gradual with no symptoms. Tiredness, weight
gain or loss, skin infections that do not heal. |
|
||
|
What
diagnostic tests can be used to detect the disease? |
Water deprivation
test/ vasopressin test. Hypertonic saline infusion test. |
Water deprivation
test/ vasopressin test. Hypertonic saline infusion test. |
Fast blood sugar- |
|
||
|
What
treatments are used to combat the disease? |
Balance fluid
intake and urine output. Replace antidiuretic hormone, vasopressin, find, if
possible, under-lying brain disease. |
Balance urine
output with fluid intake. Diuretics. |
Correct
sugar/insulin intake. |
|
||
Diabetes insipidus is the excretion
of abnormally large volumes of dilute urine (i.e., greater than 50 ml/kg body
weight in 24 hours with a specific gravity less than 1.010 or osmolality less
than 300 mosmol/kg) [Robertson
1988, Robertson
1995]. In addition to inherited forms of NDI, causes of diabetes insipidus
include:
If you
are treated for central diabetes
insipidus, the condition is usually
corrected by giving synthetic vasopressin. It is administered by placing some
in a small plastic tube and gently blowing the liquid into the nostril where it
is readily absorbed by the tissue of the nose lining. It can also be taken
orally, but the dose required is higher. If you have nephrogenic diabetes insipidus, water pills (thiazide diuretics) may be
pre-scribed by your doctor. You may be confused as to why you need to take
diuretics for this disorder. Thiazide diuretics have been shown to stimulate
the production of a hormone that helps your body retain salt. This added amount
of salt keeps you from losing too much water.
1.
There is no cure for hereditary NDI. Management is
usually best accomplished in consultation with a nutritionist and an
experienced pediatric nephrologist, or endocrinologist, or biochemical
geneticist.
General management. The essence of management is
the provision of free access to drinking water and to toilet facilities.
Infants, who are naturally unable to seek out water according to their thirst,
must be offered water between regular feedings. Children and adults who are
heavy sleepers may need to be awakened at night by a family member or an alarm
clock in order to drink water and to urinate. As long as an individual's thirst
mechanism remains intact and the person is otherwise well, these measures prevent
hypernatremic dehydration. Water restriction is generally contraindicated.
Education of friends, teachers, caretakers, and neighbors, and a willingness to
find creative solutions is helpful.
Polyuria (and thus polydipsia) can be reduced by up to 50%
without inducing hypernatremia by the use of thiazide diuretics (i.e.,
hydrochlorthiazide, chlorthiazide) in standard to high doses. Since these
diuretics cause potassium wasting, serum potassium concentration should be
monitored and supplemental potassium provided in the diet or pharmacologically
as needed. Alternatively, a potassium-sparing diuretic such as amiloride may be
given with a thiazide diuretic. Note that amiloride should not be given without
a thiazide diuretic. Adding amiloride has been shown to be effective in
preventing hypokalemia and seems to have a further beneficial effect on the
urine output in some individuals. The effectiveness of thiazide diuretics in
reducing urine output is maximized with a diet that is very low in salt (300 mg
sodium/day), low in protein (about 2 gm/kg/day), and low in other substances
that increase the osmolar load in the glomerular filtrate. This restricted diet
should be established with the aid of a trained clinical nutritionist, as
supplementation with other nutrients lacking in this restricted diet may be
required.
Non-steroidal anti-inflammatory drugs (NSAID), such as
indomethicin, may also improve urine concentrating ability and reduce urine
output. They have been used individually and in combination with the thiazide
diuretics (with or without amiloride). Because NSAIDs have undesirable effects,
such as gastric and renal tubular damage, and because the incidence of
complications has not been studied in patients with NDI, caution is warranted
in the chronic use of NSAIDs for treatment of NDI.
Therapy is judged to be effective when urine output
declines below a documented baseline in patients with ad libitum water
intake. Objective measurements of 24-hour urine volume are more valuable than
subjective reports of the volume or frequency of voiding, although reduction in
the latter provides a sense of benefit to lifestyle. When thiazide diuretics
therapy is initiated, patients should be informed that a transient increase in
urine output may occur due to salt diuresis. Periodic measurements of serum
sodium concentration help identify unrecognized hyperosmolarity and early
dehydration. Urine output and urine specific gravity are useless as indicators
of hydration status.
2.
Emergency treatment for dehydration. When patients
with NDI present with dehydration or shock, it is essential to establish
whether the deficit is primarily in free water (through water deprivation or
excessive urine, stool, or sweat) or in extracellular fluid (bleeding, fluid
extravasation). The natural tendency of healthcare providers to treat patients
with dehydration with normal saline (0.9% NaCl) is dangerous in patients with
NDI if the deficit is primarily in free water. Acute blood loss or shock may be
treated with isotonic fluid until the blood pressure and heart rate are
stabilized, after which 2.5% dextrose in water is the preferred solution.
Dehydration associated with free water deficit should be treated by gradually
replacing the deficit water as well as ongoing urinary losses. Whenever
possible, rehydration should occur with the oral intake of drinking water. If
administration of IV fluids is required, 2.5 % dextrose in water and/or
quarter-normal saline should be used. If significant hypernatremia is present,
serum sodium concentration should be monitored and the hydration solution
modified to avoid reducing serum sodium concentration faster than one mEq/l per
hour. Rapid increases or decreases in plasma osmolarity can cause seizures, coma,
brain damage, and death.
3.
Special situations. Patients being
prepared for surgery are often denied oral intake for many hours and are
described as having "NPO" (nothing per ora) status. In
patients with NDI, an IV must be provided from the beginning of NPO
status, and the patient's oral intake of water for that period, which is
typically much larger than that of an individual who does not have NDI, should
be given intravenously as 2.5% dextrose in water.
4.
Hydronephrosis, hydroureter, and megacytis. Because
hydronephrosis, dilatation of the urinary tract, and megacystis are known
complications of any form of diabetes insipidus, a renal ultrasound examination
should be performed once the diagnosis of NDI is made and repeated annually.
Treatment involves medical management to reduce urine output and continuous or
intermittent bladder catheterization when significant post-void urinary bladder
residuals are present.
5. Growth and development. Growth and psychomotor development should be monitored in infants and children. Failure to thrive or short stature may result from unsuccessful management or inadequate nutrition related to polydipsia. Children with a history of an episode of severe dehydration, delayed developmental milestones, or a delay in establishing the correct diagnosis and management warrant a formal developmental evaluation and intervention before school age.
Ø
The most obvious effect
of this rare,
Ø
A rare autosomal dominant disorder of renal
epithelial transport that clinically resembles primary hyperaldosteronism with
hypertension and hypokalemic metabolic alkalosis inherited disorder is extremely high blood pressure
(hypertension).
Ø
It is caused by a single mutant allele
(therefore the syndrome is inherited as a dominant trait) encoding the
aldosterone-activated sodium channel in the collecting tubules.
Ø
The defective channel
is always "on" so too much Na+ is reabsorbed and too
little is excreted. The resulting elevated osmotic pressure of the blood
produces hypertension.
Ø
Liddle's work suggested that
people in this family could not maintain the proper balance of salt and water
in the body. Their chemical imbalance created the alarmingly high blood
pressure that is the cardinal feature of what came to be called Liddle's syndrome.
Ø
Thirty-one years after Liddle's seminal observations,
researchers with the Howard Hughes Medical Institute at Yale University led a
team that found the genetic cause at the heart of Liddle's syndrome.
Ø
The group reported in
the November 4, 1994 issue of Cell that an abnormal sodium channel gene
in the kidney causes the body to retain excessive amounts of salt and water,
which leads to high blood pressure.
Ø A
combination of fluid, electrolyte, and hormonal abnormalities characterized by
renal K, Na, and Cl wasting; hypokalemia; hyperaldosteronism; hyperreninemia;
and normal BP.
Ø The
syndrome usually appears in
childhood as a sporadic or familial, usually autosomal recessive, disorder. The
cause is deranged NaCl transport in the ascending thick limb of the loop of
Henle and the distal tubule. K, Na, and Cl wasting contribute to the
stimulation of renin release accompanied by juxtaglomerular cell hyperplasia.
Aldosterone levels are elevated. K depletion is not eliminated by correction of
the hyperaldosteronism. Na wasting results in a chronically low plasma volume
reflected by a normal BP despite high renin and angiotensin levels and by an
impaired pressor response to angiotensin infusion. Metabolic alkalosis often
develops. Platelet aggregation is inhibited. Hyperuricemia and hypomagnesemia
may occur. The kinin-prostaglandin axis is stimulated, and urinary excretion of
prostaglandins and kallikrein is increased.
Ø Affected
children have poor growth rates and appear malnourished. Muscle weakness,
polydipsia, polyuria, and mental retardation may be present.
Ø Bartter's
syndrome is differentiated
from other diseases associated with hyperaldosteronism by the absence of
hypertension (eg, in primary hyperaldosteronism) and edema (eg, in secondary
hyperaldosteronism). In adult patients, bulimia nervosa, vomiting, or
surreptitious diuretic or laxative abuse must be excluded as a cause. In these
conditions, the urinary chloride is usually low (< 20 mmol/L).
Ø K
supplementation plus spironolactone, triamterene, amiloride, an ACE inhibitor,
or indomethacin will correct most features, but no drug completely eliminates K
wasting. Indomethacin 1 to 2 mg/kg/day usually maintains the plasma K level
close to the lower limit of normal
Although urine formation occurs primarily by the filtration-reabsorption mechanism described above, an auxiliary mechanism, called tubular secretion, is also involved.
The cells of the tubules remove certain molecules and ions from the blood and deposit these into the fluid within the tubules. Example: Both hydrogen ions (H+) and potassium ions (K+) are secreted directly into the fluid within the distal tubules. In each case the secretion is coupled to the ion-for-ion uptake of sodium ions (Na+).
Tubular secretion of H+ is important in maintaining control of the pH of the blood.
While we think of the kidney as an organ of excretion, it is more than that. It does remove wastes, but it also removes normal components of the blood that are present in greater-than-normal concentrations. When excess water, sodium ions, calcium ions, and so on are present, the excess quickly passes out in the urine. On the other hand, the kidneys step up their reclamation of these same substances when they are present in the blood in less-than-normal amounts. Thus the kidney continuously regulates the chemical composition of the blood within narrow limits. The kidney is one of the major homeostatic devices of the body.
The human kidney is also an endocrine gland secreting three hormones:
|
The artificial kidney uses the principle of dialysis to purify the blood of patients whose own kidneys have failed.
|
The left portion of the figure ("Dialysis unit")
shows the mechanism used today in artificial kidneys. Small molecules like
urea are removed from the blood because they are free to diffuse between the
blood and the bath fluid, whereas large molecules (e.g., plasma proteins) and
cells remain confined to the blood. The bath fluid must already have had
essential salts added to it to prevent the dangerous loss of these ions from
the blood. Note that blood and bath fluid flow in opposite directions across
the dialysis membrane. This "counter-current" exchange maintains a
diffusion gradient through the entire length of the system. An anticoagulant
is added to the blood so it will not clot while passing through the machine.
The anticoagulant is neutralized as the blood is returned to the patient. |
|
|
Artificial kidneys have proved of great benefit in helping patients of acute
kidney malfunction survive the crisis until their own kidneys resume operation.
They have also enabled people suffering from chronic kidney failure to remain alive,
though at an enormous expense of time (often three sessions of 6 or more hours
per week), money, and psychological well-being. Furthermore, although dialysis
does a good job at removing wastes, it cannot perform the other functions of
the kidney:
The function of the artificial
kidney is to remove
diffusible molecules and ultrafiltration for the removal of water and sodium
chloride from the blood stream. The artificial
kidney is used primarily
for the maintenance of chronic renal failure patients.
The first problem with the early artificial
kidneys and hemodialysis
was the repeated withdrawal of blood from the body with large and cumbersome
needles. As improvements in technology led to the invention of the arteriovenous
shunt, the accessibility of a person's veins was increased. The greatest
problems of the artificial kidney and hemodialysis include
the complexity and size of the machine, the cost and time spent on the
operation of the machine, and the biocompatibility of the machine. Today, there
are artificial kidneys that can be worn around
the neck of a patient, such as the Wearable Artificial Kidney
(WAK). Typically, 6-12 hours are spent a week on the maintenance of the
machines. The smaller machine has a greater cost and requires more operational
maintenance.
People who have survived hemodialysis for over 30 years are an exception.
They appear to have lost body mas and have aged too fast. (Shaldon and Koch,
1995). Hemodialysis needs to be improved, but researchers are still looking for
solutions. One solution would be to look at the biocompatibility of the machine
and see if it needs improvement. The problem of biocompatibility occurs when
the blood enters the dialyzer and is filtered by the membranes. It is the
membrane-blood interaction that brings up the question of biocompatibility. For
more than 20 years, regenerated cellulose has been used as the primary membrane
for dialysis. Research in recent years has focused on improving the cellulose
membranes instead of finding a new substance to use as a membrane. Most
research is done by adding functional groups to either the membrane surface or
to the bulk polymer (Vienken et al., 1995).
In an attempt to solve these problems, a research team at the University of Michigan is experimenting with adding a "Bioreactor unit" to the dialysis unit. The bioreactor consists of many hollow, porous tubes on the inner wall of which is attached a monolayer of proximal tubule cells (derived from pigs). The dialysis bath fluid passes through the lumen of the tubes where molecules and ions can be picked up by the apical surface of the cells. Discharge of essential molecules and ions (as well as hormones) at the basolateral surface of the cells places these materials back in the blood (just as the proximal tubule cells in the nephron normally do). So far, all the testing has been done using dogs, but the results seem promising.
The ideal alternative to long-term dialysis is transplantation of a new kidney. The operation is technically quite easy. The major problems are:
Artificial kidney has helped treat fatal kidney failures on many patients
and it is continuing to upgrade with new bioengineering innovations. However, artificial kidney, or dialyzers face certain
obstacles as the technology is expensive and complex. Dialyzers are support
systems which can not take on the task of a human kidney permanently without great cost. However, dialyzer
treatments in compliant with kidney
transplantation have been very successful in returning a patient to healthy
conditions.
Kidney Transplant:
A patient completing the artificial
kidney treatment, may
receive a kidney from a
live donor or a dead one. The biggest issue in transplantation is compatibility
between the donor and the receiver. Even with many years of experience in kidney transplantation, the issue
of compatibility and rejection of the organ has not been completely resolved.
Since the availability of immunosupressive drugs, the threat of rejection has
minimized somewhat, but with great risk to the patient. In most cases, the
donor is a close relative of the patient as there is greater compatibility and
a higher probability of successful Transplant. If a patient were to receive a
graft from a dead cadaver, the kidney
will need special treatment as it may not start to function immediately after
the transplantation.
Use of immunosupressive drugs was introduced in the 1960's and have improved
greatly over the years. After transplantation, the patient is put into
intensive care in the most isolated room and given immunosupressive drugs. The
drug lowers the possibility of rejection by decreasing the immune responses of
the patient. This will allow easier integration of the graft in the patient's
body. However, lower immune responses means that the patient will be extremely
vulnerable to bacteria and virusses, which greatly increases the risk of
infection and other diseases leading to a complete rejection of the graft,
possibly causing permanent harm to the patient. If a complete rejection was to
occur, there will be no choice but to remove the graft from the patient.
However, it is possible for patient to receive a second graft and even a third
one. Once the graft is removed, the patient can be returned to artificial kidney treatments to await a new
donor.
Artificial Kidney Treatment Issues
A-V fistula
All-natural
Implants
Catheters
Acute
Indwelling ("Buttons") (subclavian)
Needle Options
Two needles (supply upstream)
Double-lumen needle
Single-needle systems
Technical Issues
Recirculation
Blood damage
Pressure loss
Discomfort, hematoma
The human kidney secretes three hormones:
One of the functions of the kidney is to monitor blood pressure and take corrective action if it should drop. The kidney does this by secreting the proteolytic enzyme renin.
All of these actions lead to an increase in blood pressure.
Erythropoietin is a glycoprotein. It acts on the bone marrow to increase the production of red blood cells. Stimuli such as bleeding or moving to high altitudes (where oxygen is scarcer) trigger the release of EPO.
People with failing kidneys can be kept alive by dialysis. But dialysis only cleanses the blood of wastes. Without a source of EPO, these patients suffer from anemia.
Now, thanks to recombinant DNA technology, recombinant human EPO is available to treat these patients. Some of the drugs used to treat AIDS, zidovudine (AZT) for example, cause anemia as a side effect. Recombinant EPO helps AIDS patients cope with this one of the many problems that the disease creates.
Because EPO increases the hematocrit, it enables more oxygen to flow to the skeletal muscles. Some distance runners (and cyclers) have used recombinant EPO to enhance their performance. Although recombinant EPO has exactly the same sequence of amino acids as the natural hormone, the sugars attached by the cells used in the pharmaceutical industry differ from those attached by the cells of the human kidney. This difference can be detected by a test of the athlete's urine.
Recently it has been found that EPO is also synthesized in the brain when oxygen becomes scarce there (e.g., following a stroke), and helps protect neurons from damage. Perhaps recombinant human EPO will turn out to be useful for stroke victims as well.
Calcitriol is 1,25[OH]2 Vitamin D3, the active form of vitamin D. It is derived from
Calciferol in the blood is converted into the active vitamin in two steps:
Calcitriol acts on the cells of the intestine to promote the absorption of calcium from the diet.
Calcitriol diffuses into cells and, if they contain receptors for it (intestine cells do), it binds to the receptor molecules. The receptor-ligand complex now can bind to its response element:
5' AGGTCAnnnAGGTCA 3'
This sequence of nucleotides (n can be any nucleotide) is found in the promoters of genes that are turned on by calcitriol. Once the hormone-receptor complex is bound to its response element, other transcription factors are recruited to the promoter and transcription of the gene(s) begins.
Insufficient calcitriol prevents normal deposition of calcium in bone.
The most common causes are inadequate amounts of the vitamin in the diet or insufficient exposure to the sun.
However, some rare inherited cases turn out to be caused by inheriting two mutant genes for the kidney enzyme that converts 25[OH] vitamin D3 into calcitriol.
Although called a vitamin, calciferol and its products fully qualify as hormones because they are
In response to a rise in blood pressure, the heart releases two peptides:
Both hormones lower blood pressure by
The latter two effects reduce the reabsorption of water by the kidneys. So the volume of urine increases as does the amount of sodium excreted in it.
These effects give ANP and BNP their name (natrium = sodium; uresis = urinate). The net effect of these actions is to reduce blood pressure by reducing the volume of blood in the circulatory system
I. Clinical use of diuretics
A. Diruretics are agents used pharmacologically to produce a natriuresis and diuresis through inhibition of the reabsorption of Na, Cl or both. Diuretics can induce a negative fluid balance and are generally employed clinically in cases of positive fluid imbalances such as edema, associated with congestive heart failure and hypertension.
(i). Classes of diuretics - Diuretics are generally classified by the nephron segment where Na reabsorption is inhibited or the mode of action to produce diuresis.
(a) Loop diuretics impair Na transport in the TAL of the loop of Henle. These diurectics produce their effect by inhibiting the Na:K:2Cl cotransporter.
(b) NaCl cotransport in the distal tubule is inhibited by the thiazide diuretics. These agents also inhibit the activity of the enzyme carbonic anhydrase in the proximal tubule, which indirectly decreases K reabsorption in the distal tubules.
(c) K+ sparing diuretics reduce K+ excretion through inhibition of aldosterone. These diuretics are used to prevent the dangerous hypokalemia induced by other diuretics.
(d) Osmotic diuretics, like mannitol, simply produce an osmotic diuresis. Mannitol, a sugar, is freely filtered by the glomerulus and is not reabsorbed. The presence of this osmotic particle in the lumen of the proximal tubule and loop of Henle inhibits water reabsorption. Na reabsorption is reduced by solvent drag with mannitol and water.
(e) Inhibition of carbonic anhydrase reduces NaHCO3 and NaCl reabsorption by the proximal tubule to produced a modest diuresis. However, the action of diuretics which behave as carbonic anhydrase inhibitors is limited by the loop of Henle reabsorbing the NaCl not reclaimed by the proximal tubule. A second disadvantage is the loss of HCO3- induced by inhibition of carbonic anhydrase results in a metabolic acidosis.
II. Kidney or renal disease
A. Kidney or renal disease can be defined as an impairment of the normal function of the kidneys, but may be clinically undetectable. Because the kidneys have such a large functional reserve (only 10% of 1,000,000 nephrons are required to maintain homeostasis), much kidney or renal disease goes undetected. Renal failure occurs once a renal disease becomes severe enough to produce a clinically detectable loss of GFR and the associated derangements in solute and water balance.
B. Sequelae of Renal disease/failure
1. Proteinuria or increased protein excretion. Minimal proteins normally cross the glomerulus into the tubular fluid. The small amount of protein entering the tubular lumen is reabsorbed. In renal failure, glomerular barrier and tubular reabsorption processes are generally disrupted, resulting in loss of proteins into the urine.
2. Inability to concentrate urine. The loss of functioning nephrons and subsequently the countercurrent mechanism is often disrupted with significant renal disease, resulting in inability to produce a concentrated urine. Production of a large volume of dilute urine, or polyuria occurs. However, in advanced stages of renal failure even the ability to dilute urine is lost and the urine excreted has an osmolality similar to plasma.
3. Uremia. The clinical definition of uremia is an increased serum creatinine or blood urea nitrogen in a patient that is showing clinical signs of illnes. Uremia develops when the byproducts of protein and oxidative metabolism (organic acids, as well as H+ and K+) are not excreted and, hence, not removed from the blood. The accumulation of these toxic substances in the blood is manifest in a variety of symptoms such as diarrhea, vomiting, heart failure (due to low ECF volume), anemia, convulsions, etc.
III. Treatment of renal failure
A. Conservative treatment. The initial treatment of renal failure involves fluid diuresis. Although polyuria, or increased urine volume is associated with renal failure, metabolic byproducts are not removed from the blood. The administration of fluids intravenously will help to increase blood volume and improve renal blood flow so that waste accumulation can be decreased. Since GFR is markedly decreased, the burden imposed on the kidney is reduced by lowering the intake of protein, Na, K, and phosphate to levels which can be handled by the remaining nephrons.
B. Dialysis. In very severe cases of renal failure a more aggressive approach may be required to reduce the symptoms of uremia. In these cases, dialysis, either hemodialysis or peritoneal dialysis are employed. The concept of dialysis is defined as the movement of solutes across a semipermeable membrane. During dialysis, solute transport occurs by passive diffusion, i.e., solute moves from an area of high concentration to low concentration. Water, on the other hand, moves from low to high concentration. Thus, the dialysing solution must be more concentrated than the blood for water removal. Two types of dialysis are employed clinically.
1. Peritoneal dialysis is the most simple and frequently used form of dialysis. The lining of the peritoneal cavity serves as a dialysis membrane. A dialysis catheter is placed in the peritoneal cavity, the dialysis fluid is injected into the cavity through this catheter and left for approximately 30 min to allow solute diffusion from the blood into the dialysis fluid. The catheter is then removed and drained. This procedure is repeated hourly for 36-48 hr.
2. Hemodialysis requires the pumping of blood through an artificial kidney, which is actually a dialyzer with a membrane for solute removal. In this case, the blood of the patient is passed through the dialyzer which removes solute and then transfers the blood back to the patient. Heparin is adminstered to prevent blood clotting during the procedure.
C. Transplantation is the treatment of choice in cases of permanent renal failure and tend to be the most successful of the treatments employed. The surgical procedure can be routinely performed with little difficulty. Donor kidneys are most commonly obtained from unrelated cadavers; however, some donor kidneys are donated from close blood relatives
Hematuria is the presence of blood, specifically red blood cells, in the
urine. Whether the blood is
visible only under a microscope or visible to the naked eye, hematuria is a
sign that something is causing bleeding in the genitourinary tract: the
kidneys, the ureters (tubes that carry urine from the kidneys to the bladder), the prostate gland (in
men), the bladder, or the urethra (tube that carries urine from the bladder out of the body).
Bleeding
may happen once or it may be recurrent. It can indicate different problems in
men and women. Causes of this condition range from non–life threatening (e.g.,
urinary tract infection) to profoundly serious (e.g., cancer, kidney disease).
Therefore, a physician should be consulted as soon as possible.
Types
There are two types of hematuria, microscopic and gross (or macroscopic). In microscopic
hematuria, the amount of blood in the urine is so small that it can be seen only under a microscope. A
small number of people experience microscopic hematuria that has no discernible
cause (idiopathic hematuria). These people normally excrete a higher
number of red blood cells.
In
gross hematuria the urine
is pink, red, or dark brown and may contain small blood clots. The amount of
blood in the urine does not
necessarily indicate the seriousness of the underlying problem. As little as 1
milliliter (0.03 ounces) of blood will turn the urine red.
"Joggers hematuria" results from repeated jarring
of the bladder during jogging or long-distance running. Hematuria that is not
blood related is called pseudohematuria. Excessive consumption of beets,
berries, or rhubarb; food coloring; and certain laxatives and pain medications
can produce pink or reddish urine.
Incidence
Hematuria occurs in up to 10% of the general population.
Causes
Many conditions are associated with hematuria. The most common causes include
the following:
There are rare diseases and genetic disorders that also cause hematuria.
Some of these are:
Symptoms
In many cases, blood in the urine
(gross or microscopic) is the only sign of a disorder. In others, a variety of
symptoms, such as the following, may be present.
Classification
Bleeding is classified by when it occurs during urination, which may indicate
the location of the problem.
Symptoms may indicate the site and/or cause of bleeding:
The physician takes a complete personal and family medical history. The
personal history can provide useful information:
The family history may reveal inherited predispositions to kidney stone
disease, sickle cell anemia, von Hippel-Lindau disease, or another genetic
disorder associated with hematuria.
A thorough physical examination
is performed, with emphasis on the urinary tract, abdomen, pelvis, genitals,
and rectum.
Tests
In cases of suspected microscopic hematuria, a sample of the patient's
midstream urine is applied
to a chemically treated strip. The chemical changes color if blood is in the urine. The intensity of the color
indicates the amount of blood present. This test (called a dipstick test)
is performed in the doctor's office.
A positive result warrants
examination of the urine
under the microscope to look for the presence of cancer cells (urine cytology). A urine culture may be grown to
check for various infections. The tests may be repeated on a 24-hour collection
of the patient's urine, and
a blood chemistry workup may be ordered.
Cystourethroscopy, or
cystoscopy, is performed when the cause of gross or microscopic hematuria
cannot be identified. Local anesthesia is given, and a small, rigid or flexible
fiber-optic instrument is inserted into the urethra. The physician can visually
inspect the urethra, bladder, and prostate through the cystoscope. The
procedure takes about 10 minutes. Some patients experience minor short-term
discomfort with urination or slight spotting of blood over the next couple of
days.
Intravenous pyelogram (IVP) is a
special x-ray procedure in which a colorless dye containing iodine is injected
into a vein in the patient's arm. The dye collects in the urinary system and
provides enhanced contrast for a series of x-rays taken over 30 minutes. This
produces a better image of the kidneys, ureters, and bladder and can reveal
stones, tumors, blockages, and other possible causes of hematuria. After the
procedure, the patient may be asked to go to the bathroom, completely empty
their bladder, and return for a final x-ray.
Patients who previously had an
allergic reaction to intravenous dye or to shellfish should tell their doctor
before undergoing an IVP.
If these tests fail to show the
cause of hematuria, ultrasound or computer-assisted tomography (CAT
scan) may be ordered.
Differential Diagnosis
When no specific cause can be found, bladder and kidney stones, cancer, and
other life-threatening diseases can be ruled out. The possible causes that
remain include conditions that may correct themselves, or the hematuria may be
idiopathic. Men over the age of 50 with no clear diagnosis should have a yearly
PSA (prostate specific antigen) test to screen for prostate cancer
Treatment ranges from antibiotic therapy to surgery, depending on the
underlying cause.
Benign prostate hypertrophy (BPH) may be treated many
ways. Eliminating foods and beverages from the diet and over-the-counter
medications that irritate the prostate and cause it to swell is one option.
Medication (terazosin) is often prescribed to treat BPH. When the condition
does not respond to these measures, surgical removal of all or part of the
gland may be recommended.
Kidney and bladder stones typically require procedures
that remove or break up the stones, as well as measures to prevent their
recurrence.
Kidney disease is treated according to diagnosis. In severe
cases, dialysis may be necessary.
Medications (e.g., quinine, rifampin, phenytoin) that cause
hematuria are discontinued.
Trauma-induced hematuria (e.g., a blow to the kidneys)
is treated according to the severity of the injury, ranging from bed rest and
close clinical observation to surgical repair or, in extreme cases, removal of
the damaged tissue or organ.
Cancerous tumors found in the kidney, ureters, prostate, or
bladder may be treated with radiotherapy, chemotherapy, and surgery.
Urinary tract blockages are treated with correction or
removal of the blockage.
Viral infections of the urinary tract and sexually
transmitted diseases, particularly in women, are treated with medication.
Prognosis
Prognosis differs according to the underlying condition and the patient's
response to treatment.
Thursday, September 06, 2001