Physiology of kidneys.
Uropoesis.
Role of kidneys in keeping
homeostasis
Renal physiology (Latin rēnēs, "kidney") is the
study of the physiology of the kidney. This encompasses all functions of the
kidney, including reabsorption of glucose, amino acids, and other small
molecules; regulation of sodium, potassium, and other electrolytes; regulation
of fluid balance and blood pressure; maintenance of acid-base balance; the
production of various hormones including erythropoietin, and the activation of
vitamin D
Much of
renal physiology is studied at the level of the nephron, the smallest
functional unit of the kidney. Each nephron begins with a filtration component
that filters blood entering the kidney. This filtrate then flows along the
length of the nephron, which is a tubular structure lined by a single layer of
specialized cells and surrounded by capillaries. The major functions of these
lining cells are the reabsorption of water and small molecules from the
filtrate into the blood, and the secretion of wastes from the blood into the
urine.
This
illustration demonstrates the normal kidney physiology. It also includes
illustrations showing where some types of diuretics act, and what they do.
Proper function
of the kidney requires that it receives and adequately filters blood. This is
performed at the microscopic level by many hundreds of thousands of filtration
units called renal corpuscles, each of which is composed of a glomerulus and a
Bowman's capsule. A global assessment of renal function is often ascertained by
estimating the rate of filtration, called the glomerular filtration rate (GFR).
Functions
of the kidney[edit]
The
functions of the kidney can be divided into three groups: secretion of hormones,
gluconeogenesis and extracellular homeostasis of pH and blood components. The
nephron is the functional unit of the kidney.
Secretion of hormones
Secretion
of erythropoietin, which regulates red blood cell production in the bone
marrow.
Secretion
of renin, which is a key part of the renin-angiotensin-aldosterone system.
Secretion
of the active form of vitamin D (calcitriol) and prostaglandins.
Gluconeogenesis
The
kidney in humans is capable of producing glucose from lactate, glycerol and
glutamine. The kidney is responsible for about half of the total
gluconeogenesis in fasting humans. The regulation of glucose production in the
kidney is achieved by action of insulin, catecholamines and other hormones.
Renal gluconeogenesis takes place in the renal cortex. The renal medulla is
incapable of producing glucose due to absence of necessary enzymes.
The
body is very sensitive to its pH. Outside the range of pH that is compatible
with life, proteins are denatured and digested, enzymes lose their ability to
function, and the body is unable to sustain itself. The kidneys maintain
acid-base homeostasis by regulating the pH of the blood plasma. Gains and
losses of acid and base must be balanced. Acids are divided into "volatile
acids" and "nonvolatile acids". See also titratable acid.
The
major homeostatic control point for maintaining this stable balance is renal
excretion. The kidney is directed to excrete or retain sodium via the action of
aldosterone, antidiuretic hormone (ADH, or vasopressin), atrial natriuretic
peptide (ANP), and other hormones. Abnormal ranges of the fractional excretion
of sodium can imply acute tubular necrosis or glomerular dysfunction.
Mechanisms
Diagram showing the basic physiologic
mechanisms of the kidney
The
kidney's ability to perform many of its functions depends on the three
fundamental functions of filtration, reabsorption, and secretion, whose sum is
renal excretion.
Urinary
excretion rate = Filtration rate – Reabsorption rate + Secretion rate
Filtration
The blood is
filtered by nephrons, the functional units of the kidney. Each nephron begins
in a renal corpuscle, which is composed of a glomerulus enclosed in a Bowman's
capsule. Cells, proteins, and other large molecules are filtered out of the
glomerulus by a process of ultrafiltration, leaving an ultrafiltrate that
resembles plasma (except that the ultrafiltrate has negligible plasma proteins)
to enter Bowman's space. Filtration is driven by Starling forces.
The
ultrafiltrate is passed through, in turn, the proximal convoluted tubule, the
loop of Henle, the distal convoluted tubule, and a series of collecting ducts
to form urine.
Reabsorption
Tubular
reabsorption is the process by which solutes and water are removed from the
tubular fluid and transported into the blood. It is called reabsorption (and
not absorption) because these substances have already been absorbed once
(particularly in the intestines).
Reabsorption
is a two-step process beginning with the active or passive extraction of
substances from the tubule fluid into the renal interstitium (the connective
tissue that surrounds the nephrons), and then the transport of these substances
from the interstitium into the bloodstream. These transport processes are
driven by Starling forces, diffusion, and active transport.
Indirect reabsorption
In some
cases, reabsorption is indirect. For example, bicarbonate (HCO3-) does not have
a transporter, so its reabsorption involves a series of reactions in the tubule
lumen and tubular epithelium. It begins with the active secretion of a hydrogen
ion (H+) into the tubule fluid via a Na/H exchanger:
In the
lumen
The H+
combines with HCO3- to form carbonic acid (H2CO3)
Luminal
carbonic anhydrase enzymatically converts H2CO3 into H2O and CO2
CO2
freely diffuses into the cell
In the
epithelial cell
Cytoplasmic
carbonic anhydrase converts the CO2 and H2O (which is abundant in the cell)
into H2CO3
H2CO3
readily dissociates into H+ and HCO3-
HCO3- is
facilitated out of the cell's basolateral membrane
Hormones
Some
key regulatory hormones for reabsorption include:
aldosterone,
which stimulates active sodium reabsorption (and water as a result)
antidiuretic
hormone, which stimulates passive water reabsorption
Both
hormones exert their effects principally on the collecting ducts.
Secretion
Main
article: Clearance (medicine)
Tubular
secretion is the transfer of materials from peritubular capillaries to renal
tubular lumen. Tubular secretion is caused mainly by active transport.
Usually only
a few substances are secreted. These substances are present in great excess, or
are natural poisons.
Many drugs
are eliminated by tubular secretion. Further reading: Table of medication
secreted in kidney
Measurement
of renal function
A simple
means of estimating renal function is to measure pH, blood urea nitrogen,
creatinine, and basic electrolytes (including sodium, potassium, chloride, and
bicarbonate). As the kidney is the most important organ in controlling these values,
any derangement in these values could suggest renal impairment.
There are
several more formal tests and ratios involved in estimating renal function:
Renal blood
flow
From
Wikipedia, the free encyclopedia
(Redirected from Renal plasma flow)
Jump to: navigation, search Parameter Value
renal blood
flow RBF=1000 ml/min
hematocrit HCT=40%
renal plasma
flow RPF=600 ml/min
filtration
fraction FF=20%
glomerular
filtration rate GFR=120 ml/min
urine flow
rate V=1 mL/min
Sodium Inulin Creatinine PAH
SNa=150
mEq/L SIn=1 mg/mL SCr=0.01 mg/ml SPAH=
UNa=710
mEq/L UIn=150 mg/mL UCr=1.25 mg/mL UPAH=
CNa=5 mL/min CIn=150 ml/min CCr=125 mL/min CPAH=420
ml/min
ER=90%
ERPF=540 ml/min
In the
physiology of the kidney, renal blood flow (RBF) is the volume of blood
delivered to the kidneys per unit time. In humans, the kidneys together receive
roughly 22% of cardiac output, amounting to 1.1 L/min in a 70-kg adult male.
RBF is closely related to renal plasma flow (RPF), which is the volume of blood
plasma delivered to the kidneys per unit time.
While the
terms generally apply to arterial blood delivered to the kidneys, both RBF and
RPF can be used to quantify the volume of venous blood exiting the kidneys per
unit time. In this context, the terms are commonly given subscripts to refer to
arterial or venous blood or plasma flow, as in RBFa, RBFv, RPFa, and RPFv.
Physiologically, however, the differences in these values are negligible so
that arterial flow and venous flow are often assumed equal.
In anatomy, urinary system, the kidneys filter
wastes (such as urea)
from the blood
and excrete them, along with water, as urine. The medical field
that studies the kidneys and diseases of the kidney is called nephrology
(nephro- meaning kidney is from the Ancient Greek
word nephros; the adjective renal meaning related to the kidney is from Latin rēnēs,
meaning kidneys).
In humans, the kidneys are located in the posterior
part of the abdomen.
There is one on each side of the spine;
the right kidney sits just below the liver, the left below the diaphragm and adjacent to the spleen. Above
each kidney is an adrenal gland (also called the suprarenal gland). The asymmetry
within the abdominal cavity caused by the liver results in the right kidney
being slightly lower than the left one while the left kidney is located
slightly more medial.
The kidneys are retroperitoneal,
which means they lie behind the peritoneum,
the lining of the abdominal cavity. They are approximately at the
vertebral
level T12 to L3. The upper parts of the kidneys are partially protected by the
eleventh and twelfth ribs,
and each whole kidney is surrounded by two layers of fat (the perirenal and
pararenal fat) which help to cushion it. Congenital absence of one or both
kidneys, known as unilateral or bilateral renal
agenesis can occur.
Organization
Above
each human kidney is one of the two adrenal
glands.
In a normal human adult, each kidney is about
The outer portion of the kidney is called the renal cortex,
which sits directly beneath the kidney's loose connective tissue/fibrous capsule.
Deep to the cortex lies the renal medulla, which is divided into 10-20 renal
pyramids in humans. Each pyramid together with the associated overlying
cortex forms a renal lobe. The tip of each pyramid (called a papilla)
empties into a calyx,
and the calices empty into the renal pelvis.
The pelvis transmits urine to the urinary
bladder via the ureter.
Blood
supply
Each kidney receives its blood supply
from the renal artery, two of which branch from the
abdominal aorta.
Upon entering the hilum of the kidney, the renal artery divides into smaller
interlobar arteries situated between the renal papillae. At the outer medulla,
the interlobar arteries branch into arcuate arteries, which course along the
border between the renal medulla and cortex, giving off still smaller branches,
the cortical radial arteries (sometimes called interlobular arteries).
Branching off these cortical arteries are the afferent arterioles supplying the
glomerular capillaries, which drain into efferent arterioles. Efferent
arterioles divide into peritubular capillaries that provide an extensive blood
supply to the cortex. Blood from these capillaries collects in renal venules
and leaves the kidney via the renal vein. Efferent arterioles of glomeruli
closest to the medulla (those that belong to juxtamedullary nephrons) send branches
into the medulla, forming the vasa recta. Blood supply is intimately linked to
blood pressure.
Nephron
Parts of
the kidney: 1. Renal pyramid
3. Renal
artery
4. Renal
vein
5. Renal hilum
6. Renal
pelvis
7. Ureter
8. Minor
calyx
9. Renal
capsule
10. Inferior renal capsule
11. Superior renal capsule
12. Afferent vessel
13. Nephron
14. Minor
calyx
15. Major
calyx
16. Renal
papilla
17. Renal
column
The basic functional unit of the kidney is the nephron,
of which there are more than a million within the cortex and medulla of each
normal adult human kidney. Nephrons regulate water and solute within the cortex
and medulla of each normal adult human kidney. Nephrons regulate water and
soluble matter (especially electrolytes) in the body by first filtering
the blood under pressure, and then reabsorbing some necessary fluid and
molecules back into the blood while secreting other, unneeded molecules. Reabsorption
and secretion are accomplished with both cotransport and countertransport mechanisms established in
the nephrons and associated collecting ducts.
Collecting duct system
The fluid flows from the nephron into the collecting duct system. This segment of the
nephron is crucial to the process of water conservation by the organism. In the
presence of antidiuretic hormone (ADH; also called
vasopressin), these ducts become permeable to water and facilitate its
reabsorption, thus concentrating the urine and reducing its volume. Conversely,
when the organism must eliminate excess water, such as after excess fluid
drinking, the production of ADH is decreased and the collecting tubule becomes
less permeable to water, rendering urine dilute and abundant. Failure of the
organism to decrease ADH production appropriately, a condition known as syndrome of inappropriate ADH
(SIADH), may lead to water retention and dangerous dilution of body fluids,
which in turn may cause severe neurological damage. Failure to produce ADH (or
inability of the collecting ducts to respond to it) may cause excessive
urination, called diabetes insipidus (DI).
A second major function of the collecting duct system is
the maintenance of acid-base homeostasis.
After being processed along the collecting tubules and
ducts, the fluid, now called urine, is drained into the bladder
via the ureter,
to be finally excluded from the organism.
Excretion of
waste products
The kidneys excrete a variety of waste products produced by metabolism,
including the nitrogenous wastes: urea (from protein catabolism) and uric acid
(from nucleic acid metabolism).
Homeostasis
The kidney is one of the major organs involved in
whole-body homeostasis. Among its homeostatic functions are acid-base balance,
regulation of electrolyte concentrations, control of blood volume,
and regulation of blood pressure. The kidneys accomplish these
homeostatic functions independently and through coordination with other organs,
particularly those of the endocrine
system. The kidney communicates with these organs through hormones
secreted into the bloodstream.
Acid-base balance
The kidneys regulate the pH, by eliminating H ions
concentration called augmentation mineral ion concentration, and water
composition of the blood.
By exchanging hydronium
ions and hydroxyl ions, the blood plasma is maintained by the kidney at
a slightly alkaline pH of 7.4. Urine, on the other hand, is acidic at pH 5 or
alkaline at pH 8.
The pH is maintained through four main protein
transporters: NHE3 (a sodium-hydrogen exchanger), V-type H-ATPase (an isoform
of the hydrogen ATPase),
NBC1 (a sodium-bicarbonate cotransporter) and AE1 (an anion exchanger which
exchanges chloride for bicarbonate). Due to the polar alignment of cells in the
renal epithelia NHE3 and the H-ATPase are exposed to the lumen (which is essentially
outside the body), on the apical side of the cells, and are responsible for excreting
hydrogen ions (or protons). Conversely, NBC1 and AE1 are on the basolateral
side of the cells, and allow bicarbonate ions to move back into the
extracellular fluid and thus are returned to the blood plasma.
Acid–base homeostasis is the part of human homeostasis
concerning the proper balance between acids and bases, also called body pH. The
body is very sensitive to its pH level, so strong mechanisms exist to maintain
it. Outside the acceptable range of pH, proteins are denatured and digested,
enzymes lose their ability to function, and death may occur.
Acids and bases
Acid–base imbalance occurs when a significant insult
causes the blood pH to shift out of the normal range (7.35 to 7.45). In the
fetus, the normal range differs based on which umbilical vessel is sampled (umbilical
vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.18 to
7.38). An excess of acid in the blood is called acidemia and an excess of base
is called alkalemia. The process that causes the imbalance is classified based
on the etiology of the disturbance (respiratory or metabolic) and the direction
of change in pH (acidosis or alkalosis). There are four basic processes:
metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory
alkalosis. One or a combination may occur at any given time.
Blood
pressure
Sodium ions are controlled in a homeostatic process
involving aldosterone
which increases sodium ion absorption in the distal convoluted tubules.
When blood pressure becomes low, a proteolytic enzyme
called Renin
is secreted by cells of the juxtaglomerular apparatus (part of the
distal convoluted tubule) which are sensitive to pressure. Renin acts on a
blood protein, angiotensinogen, converting it to angiotensin I
(10 amino acids). Angiotensin I is then converted by the Angiotensin-converting enzyme (ACE) in the
lung capillaries to Angiotensin II (8 amino acids), which stimulates the
secretion of Aldosterone by the adrenal cortex, which then affects the kidney
tubules.
Aldosterone stimulates an increase in the reabsorption of
sodium ions from the kidney tubules which causes an increase in the volume of
water that is reabsorbed from the tubule. This increase in water reabsorption
increases the volume of blood which ultimately raises the blood pressure.
Plasma
volume
Any significant rise or drop in plasma
osmolality is detected by the hypothalamus,
which communicates directly with the posterior pituitary gland. A rise in
osmolality causes the gland to secrete antidiuretic hormone, resulting in water reabsorption
by the kidney and an increase in urine concentration. The two factors work
together to return the plasma osmolality to its normal levels.
Hormone secretion
The kidneys secrete a variety of hormones,
including erythropoietin, urodilatin, renin and vitamin D.
Secretion of hormones
Secretion of erythropoietin, which regulates red blood
cell production in the bone marrow.
Secretion of renin, which is a key part of the
renin-angiotensin-aldosterone system.
Secretion of the active form of vitamin D (calcitriol)
and prostaglandins.
Erythropoietin, also known as erythropoetin or
erthropoyetin (/ɨˌrɪθrɵˈpɔɪ.ɨtɨn/, /ɨˌrɪθrɵˈpɔɪtən/, and /ɨˌriːθrɵ-/) or EPO, is a glycoprotein hormone
that controls erythropoiesis, or red blood cell production. It is a cytokine
(protein signaling molecule) for erythrocyte (red blood cell) precursors in the
bone marrow. Human EPO has a molecular weight of 34 kDa.
Also called hematopoietin or hemopoietin, it is produced
by interstitial fibroblasts in the kidney in close association with peritubular
capillary and tubular epithelial tubule. It is also produced in perisinusoidal
cells in the liver. While liver production predominates in the fetal and
perinatal period, renal production is predominant during adulthood. In addition
to erythropoiesis, erythropoietin also has other known biological functions.
For example, it plays an important role in the brain's response to neuronal
injury. EPO is also involved in the wound healing process.
When exogenous EPO is used as a performance-enhancing
drug, it is classified as an erythropoiesis-stimulating agent (ESA). Exogenous
EPO can often be detected in blood, due to slight differences from the
endogenous protein, for example, in features of posttranslational modification.
Erythropoietin
Function
Primary role in red blood cell production
Erythropoietin is an essential hormone for red cell
production. Without it, definitive erythropoiesis does not take place. Under
hypoxic conditions, the kidney will produce and secrete erythropoietin to
increase the production of red blood cells by targeting CFU-E, proerythroblast
and basophilic erythroblast subsets in the differentiation. Erythropoietin has
its primary effect on red blood cell progenitors and precursors (which are
found in the bone marrow in humans) by promoting their survival through
protecting these cells from apoptosis.
Erythropoietin is the primary erythropoietic factor that
cooperates with various other growth factors (e.g., IL-3, IL-6,
glucocorticoids, and SCF) involved in the development of erythroid lineage from
multipotent progenitors. The burst-forming unit-erythroid (BFU-E) cells start
erythropoietin receptor expression and are sensitive to erythropoietin.
Subsequent stage, the colony-forming unit-erythroid (CFU-E), expresses maximal
erythropoietin receptor density and is completely dependent on erythropoietin
for further differentiation. Precursors of red cells, the proerythroblasts and
basophilic erythroblasts also express erythropoietin receptor and are therefore
affected by it.
Additional nonhematopoietic roles
Erythropoietin has a range of actions including
vasoconstriction-dependent hypertension, stimulating angiogenesis, and inducing
proliferation of smooth muscle fibers. It can increase iron absorption by
suppressing the hormone hepcidin.
EPO also affects neuronal protection during hypoxic
conditions (stroke, etc.). Trials on human subjects are not yet reported; if
proven to be a viable treatment of heart attack and stroke patients, it could
improve the outcome and quality of life. The reasoning behind such a proposal
is that EPO levels of 100 times the baseline have been detected in brain tissue
as a natural response to (primarily) hypoxic damage.
Multiple studies have suggested that EPO improves memory.
This effect is independent of its effect on hematocrit. Rather, it is
associated with an increase in hippocampal response and effects on synaptic connectivity,
neuronal plasticity, and memory-related neural networks.EPO may also be an
effective treatment for depression.
Mechanism of
action
Erythropoietin has been shown to exert its effects by
binding to the erythropoietin receptor (EpoR).
EPO is highly glycosylated (40% of total molecular
weight), with half-life in blood around five hours. EPO's half-life may vary
between endogenous and various recombinant versions. Additional glycosylation
or other alterations of EPO via recombinant technology have led to the increase
of EPO's stability in blood (thus requiring less frequent injections). EPO
binds to the erythropoietin receptor on the red cell progenitor surface and
activates a JAK2 signaling cascade. Erythropoietin receptor expression is found
in a number of tissues, such as bone marrow and peripheral/central nervous
tissue. In the bloodstream, red cells themselves do not express erythropoietin
receptor, so cannot respond to EPO. However, indirect dependence of red cell
longevity in the blood on plasma erythropoietin levels has been reported, a
process termed neocytolysis.
Synthesis and regulation
Erythropoietin levels in blood are quite low in the
absence of anemia, at around 10 mU/ml. However, in hypoxic stress, EPO
production may increase a 1000-fold, reaching 10,000 mU/ml of blood. EPO is
produced mainly by peritubular capillary lining cells of the renal cortex,
which are highly specialized, epithelial-like cells. It is synthesized by renal
peritubular cells in adults, with a small amount being produced in the
liver.Regulation is believed to rely on a feedback mechanism measuring blood
oxygenation. Constitutively synthesized transcription factors for EPO, known as
hypoxia-inducible factors, are hydroxylated and proteosomally digested in the
presence of oxygen.
Medical uses
Main article: Epoetin alfa
Erythropoietins available for use as therapeutic agents
are produced by recombinant DNA technology in cell culture, and include
Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in
treating anemia resulting from chronic kidney disease, inflammatory bowel
disease (Crohn's disease and ulcer colitis) and myelodysplasia from the
treatment of cancer (chemotherapy and radiation), but include boxed warnings of
increased risk of death, myocardial infarction, stroke, venous thromboembolism,
tumor recurrence, and other severe off-target effects.
Renin
Also known as an
angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin
system (RAS)—also known as the renin-angiotensin-aldosterone axis—that mediates
extracellular volume (i.e., that of the blood plasma, lymph and interstitial
fluid), and arterial vasoconstriction. Thus, it regulates the body's mean arterial
blood pressure.
Renin
Renin-angiotensin
system
The
renin-angiotensin system, showing role of renin at bottom.
The renin enzyme circulates in the blood stream and
breaks down (hydrolyzes) angiotensinogen secreted from the liver into the
peptide angiotensin I.
Angiotensin I is further cleaved in the lungs by
endothelial-bound angiotensin-converting enzyme (ACE) into angiotensin II, the
most vasoactive peptide.[4][5] Angiotensin II is a potent constrictor of all
blood vessels. It acts on the smooth muscle and, therefore, raises the
resistance posed by these arteries to the heart. The heart, trying to overcome
this increase in its 'load', works more vigorously, causing the blood pressure
to rise. Angiotensin II also acts on the adrenal glands and releases Aldosterone,
which stimulates the epithelial cells in the distal tubule and collecting ducts
of the kidneys to increase re-absorption of sodium and water, leading to raised
blood volume and raised blood pressure. The RAS also acts on the CNS to
increase water intake by stimulating thirst, as well as conserving blood
volume, by reducing urinary loss through the secretion of Vasopressin from the
posterior pituitary gland.
The normal concentration of renin in adult human plasma
is 1.98-24.6 ng/L in the upright position.
Function
Renin activates the renin-angiotensin system by cleaving
angiotensinogen, produced by the liver, to yield angiotensin I, which is
further converted into angiotensin II by ACE, the angiotensin-converting enzyme
primarily within the capillaries of the lungs. Angiotensin II then constricts
blood vessels, increases the secretion of ADH and aldosterone, and stimulates
the hypothalamus to activate the thirst reflex, each leading to an increase in
blood pressure.
Renin is secreted from kidney cells, which are activated
via signaling from the macula densa, which responds to the rate of fluid flow
through the distal tubule, by decreases in renal perfusion pressure (through
stretch receptors in the vascular wall), and by sympathetic nervous stimulation,
mainly through beta-1 adrenoceptor activation. A drop in the rate of flow past
the macula densa implies a drop in renal filtration pressure. Renin's primary
function is therefore to eventually cause an increase in blood pressure,
leading to restoration of perfusion pressure in the kidneys.
Renin can bind to ATP6AP2, which results in a fourfold
increase in the conversion of angiotensinogen to angiotensin I over that shown
by soluble renin. In addition, renin binding results in phosphorylation of serine
and tyrosine residues of ATP6AP2.
The level of renin mRNA appears to be modulated by the
binding of HADHB, HuR and CP1 to a regulatory region in the 3' UTR.
Genetics
The gene for renin, REN, spans 12 kb of DNA and contains
8 introns.It produces several mRNA that encode different REN isoforms.
Model organisms
Ren1 knockout mouse phenotype
Characteristic Phenotype
Model organisms have been used in the study of REN
function. A knockout mouse line, called Ren1Ren-1c Enhancer KO was
generated.[15] Male and female animals underwent a standardized phenotypic
screen to determine the effects of deletion. Twenty four tests were carried out
on mutant mice and two significant abnormalities were observed. Homozygous
mutant animals had a decreased heart rate and an increased susceptibility to
bacterial infection. A more detailed analysis of this line indicated plasma
creatinine was also increased and males had lower mean arterial pressure than
controls.
Clinical applications
Renin inhibitor
An over-active renin-angiotension system leads to
vasoconstriction and retention of sodium and water. These effects lead to
hypertension. Therefore, renin inhibitors can be used for the treatment of
hypertension.This is measured by the plasma renin activity (PRA).
In current medical practice, the
renin-angiotensin-aldosterone-System's overactivity (and resultant
hypertension) is more commonly reduced using either ACE inhibitors (such as
ramipril and perindopril) or angiotensin II receptor blockers (ARBs, such as
losartan, irbesartan or candesartan) rather than a direct oral renin inhibitor.
ACE inhibitors or ARBs are also part of the standard treatment after a heart
attack.
The differential diagnosis of kidney cancer in a young
patient with hypertension includes juxtaglomerular cell tumor (reninoma),
Wilms' tumor, and renal cell carcinoma, all of which may produce renin.
Measurement
Further information: Plasma renin activity
Renin is usually measured as the plasma renin activity
(PRA). PRA is measured specially in case of certain diseases that present with
hypertension or hypotension. PRA is also raised in certain tumors. A PRA
measurement may be compared to a plasma aldosterone concentration (PAC) as a
PAC/PRA ratio.
Calcitriol increases blood calcium levels ( [Ca2+] ) by
promoting absorption of dietary calcium from the gastrointestinal tract and
increasing renal tubular reabsorption of calcium thus reducing the loss of
calcium in the urine. Calcitriol also stimulates release of calcium from bone
by its action on the specific type of bone cells referred to as osteoblasts,
causing them to release RANKL, which in turn activates osteoclasts.
Calcitriol acts in concert with parathyroid hormone (PTH)
in all three of these roles. For instance, PTH also indirectly stimulates
osteoclasts. However, the main effect of PTH is to increase the rate at which
the kidneys excrete inorganic phosphate (Pi), the counterion of Ca2+. The
resulting decrease in serum phosphate causes Ca5(PO4)3OH to dissolve out of
bone thus increasing serum calcium. PTH also stimulates the production of
calcitriol (see below).
Many of the effects of calcitriol are mediated by its
interaction with the calcitriol receptor, also called the vitamin D receptor or
VDR. For instance, the unbound inactive form of the calcitriol receptor in
intestinal epithelial cells resides in the cytoplasm. When calcitriol binds to
the receptor, the ligand-receptor complex translocates to the cell nucleus,
where it acts as a transcription factor promoting the expression of a gene
encoding a calcium binding protein. The levels of the calcium binding protein
increase enabling the cells to actively transport more calcium (Ca2+) from the
intestine across the intestinal mucosa into the blood.
The maintenance of electroneutrality requires that the
transport of Ca2+ ions catalyzed by the intestinal epithelial cells be
accompanied by counterions, primarily inorganic phosphate. Thus calcitriol also
stimulates the intestinal absorption of phosphate.The observation that
calcitriol stimulates the release of calcium from bone seems contradictory,
given that sufficient levels of serum calcitriol generally prevent overall loss
of calcium from bone. It is believed that the increased levels of serum calcium
resulting from calcitriol-stimulated intestinal uptake causes bone to take up
more calcium than it loses by hormonal stimulation of osteoclasts. Only when
there are conditions, such as dietary calcium deficiency or defects in
intestinal transport, which result in a reduction of serum calcium does an
overall loss of calcium from bone occur.
Calcitriol also inhibits the release of
calcitonin,[citation needed] a hormone which reduces blood calcium primarily by
inhibiting calcium release from bone.(The effect of calcitonin on renal
excretion is disputed.)
he prostaglandins are a group of lipid compounds that are
derived enzymatically from fatty acids and have important functions in the
animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon
ring.
They are mediators and have a variety of strong
physiological effects, such as regulating the contraction and relaxation of
smooth muscle tissue. Prostaglandins are not endocrine hormones, but autocrine
or paracrine, which are locally acting messenger molecules. They differ from
hormones in that they are not produced at a discrete site but in many places
throughout the human body. Also, their target cells are present in the
immediate vicinity of the site of their secretion (of which there are many).
The prostaglandins, together with the thromboxanes and
prostacyclins, form the prostanoid class of fatty acid derivatives, a subclass
of eicosanoids.
The abbreviation for "prostaglandin" is PG;
specific prostaglandins are named with a letter (which indicates the type of
ring structure) followed by a number (which indicates the number of double
bonds in the hydrocarbon structure). For example, prostaglandin E1 is
abbreviated PGE1 or PGE1, and prostaglandin I2 is abbreviated PGI2 or PGI2. The
number is traditionally subscripted when the context allows, but as with many
similar subscript-containing nomenclatures, the subscript is simply forgone in
many database fields that can store only plain text (such as PubMed
bibliographic fields), and readers are used to seeing and writing it without
subscript.
Function
There are currently ten known prostaglandin receptors on
various cell types. Prostaglandins ligate a sub-family of cell surface
seven-transmembrane receptors, G-protein-coupled receptors. These receptors are
termed DP1-2, EP1-4, FP, IP1-2, and TP, corresponding to the receptor that
ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).
The diversity of receptors means that prostaglandins act
on an array of cells and have a wide variety of effects such as:
cause constriction or dilation in vascular smooth muscle
cells
cause aggregation or disaggregation of platelets
sensitize spinal neurons to pain
induce labor
decrease intraocular pressure
regulate inflammatory mediation
regulate calcium movement
control hormone regulation
control cell growth
acts on thermoregulatory center of hypothalamus to
produce fever
acts on mesangial cells in the glomerulus of the kidney
to increase glomerular filtration rate
acts on parietal cells in the stomach wall to inhibit
acid secretion
brain masculinization (in rats at least) (ref :
http://www.jneurosci.org/content/33/7/2761.full.pdf+html)
Prostaglandins are potent but have a short half-life
before being inactivated and excreted. Therefore, they send only paracrine (locally
active) or autocrine (acting on the same cell from which it is synthesized)
signals.
Pronephros
During approximately day 22 of human gestation,
the paired pronephroi appear towards the cranial end of the intermediate
mesoderm. In this region, epithelial cells arrange themselves in a series of tubules
called nephrotomes
and join laterally with the pronephric
duct, which does not reach the outside of the embryo. Thus the
pronephros is considered nonfunctional in mammals because it cannot excrete
waste from the embryo.
Mesonephros
Each pronephric duct grows towards the tail of the
embryo, and in doing so induces intermediate mesoderm in the thoracolumbar area
to become epithelial tubules called mesonephric tubules.
Each mesonephric tubule receives a blood supply from a branch of the aorta,
ending in a capillary tuft analogous to the glomerulus
of the definitive nephron. The mesonephric tubule forms a
capsule around the capillary tuft, allowing for filtration of blood. This
filtrate flows through the mesonephric tubule and is drained into the
continuation of the pronephric duct, now called the mesonephric duct or Wolffian duct. The nephrotomes of the
pronephros degenerate while the mesonephric duct extends towards the most caudal
end of the embryo, ultimately attaching to the cloaca. The mammalian mesonephros is similar to the
kidneys of aquatic amphibians and fishes.
Metanephros
During the fifth week of gestation, the mesonephric duct
develops an outpouching, the ureteric bud, near its attachment to the
cloaca. This bud, also called the metanephrogenic diverticulum, grows
posteriorly and towards the head of the embryo. The elongated stalk of the
ureteric bud, the metanephric duct, later forms the ureter. As the
cranial end of the bud extends into the intermediate mesoderm, it undergoes a
series of branchings to form the collecting duct system of the kidney. It
also forms the major and minor calyces
and the renal pelvis.
The portion of undifferentiated intermediate mesoderm in
contact with the tips of the branching ureteric bud is known as the
metanephrogenic blastema. Signals released from the ureteric bud induce the
differentiation of the metanephrogenic blastema into the renal tubules.
As the renal tubules grow, they come into contact and join with connecting
tubules of the collecting duct system, forming a continuous passage
for flow from the renal tubule to the collecting duct. Simultaneously,
precursors of vascular endothelial cells begin to take their position at the
tips of the renal tubules. These cells differentiate into the cells of the
definitive glomerulus.
Terms
Microscopic
shot of the renal cortex.
Microscopic
shot of the renal medulla.
- renal
capsule: The membranous covering of the
kidney.
- cortex: The outer
layer over the internal medulla. It contains blood vessels, glomeruli
(which are the kidneys' "filters") and urine
tubes and is supported by a fibrous matrix.
- hilus:
The opening in the middle of the concave medial border for nerves and
blood vessels to pass into the renal sinus.
- renal
column: The structures which support the
cortex. They consist of lines of blood vessels and urinary tubes and a
fibrous material.
- renal
sinus: The cavity which houses the renal
pyramids.
- calyces: The
recesses in the internal medulla which hold the pyramids. They are used to
subdivide the sections of the kidney. (singular - calyx)
- papillae:
The small conical projections along the wall of the renal
sinus. They have openings through which urine passes into the
calyces. (singular - papilla)
- renal
pyramids: The conical segments within the internal
medulla. They contain the secreting apparatus and tubules and are also
called malpighian pyramids.
- renal
artery: Two renal arteries come from the aorta,
each connecting to a kidney. The artery divides into five branches, each
of which leads to a ball of capillaries. The arteries supply (unfiltered)
blood to the kidneys. The left kidney receives about 60% of the renal
bloodflow.
- renal
vein: The filtered blood returns to
circulation through the renal veins which join into the inferior vena cava.
- renal
pelvis: Basically just a funnel,
the renal pelvis accepts the urine and channels it out of the hilus into
the ureter.
- ureter: A
narrow tube
- renal
lobe: Each pyramid together with the
associated overlying cortex forms a renal lobe
Diseases and disorders
Congenital
- Congenital hydronephrosis
- Congenital obstruction of
urinary tract
- Duplicated ureter
- Horseshoe kidney
- Polycystic kidney disease
- Renal
dysplasia
- Unilateral small kidney
Acquired
- Diabetic nephropathy
- Glomerulonephritis
- Hydronephrosis
is the enlargement of one or both of the kidneys caused by obstruction of
the flow of urine.
- Interstitial nephritis
- Kidney
stones are a relatively common and particularly painful
disorder.
- Kidney tumors
- Lupus
nephritis
- Minimal change disease
- In nephrotic syndrome, the glomerulus has been damaged so that a
large amount of protein in the blood enters the urine.
Other frequent features of the nephrotic syndrome include swelling, low
serum albumin, and high cholesterol.
- Pyelonephritis
is infection of the kidneys and is frequently caused by complication of a urinary tract infection.
- Renal
failure
THE FORMATION OF URINE
FIGURATION, REABSORPTION, AND SECRETION
Every one of us depends on
the process of urination for the removal of certain waste products in the body.
The production of urine is vital to the health of the body. Most of us have
probably never thought of urine as valuable, but we could not survive if we did
not produce it and eliminate it. Urine is composed of water, certain
electrolytes, and various waste products that are filtered out of the blood
system. Remember, as the blood flows through the body, wastes resulting from
the metabolism of foodstuffs in the body cells are deposited into the
bloodstream, and this waste must be disposed of in some way. A major part of
this "cleaning" of the blood takes place in the kidneys and, in
particular, in the nephrons, where the blood is filtered to produce the urine.
Both kidneys in the body carry out this essential blood cleansing function.
Normally, about 20% of the total blood pumped by the heart each minute will
enter the kidneys to undergo filtration. This is called the filtration
fraction. The rest of the blood (about 80%) does not go through the
filtering portion of the kidney, but flows through the rest of the body to
service the various nutritional, respiratory, and other needs that are always
present.
For
the production of urine, the kidneys do not simply pick waste products out of
the bloodstream and send them along for final disposal. The kidneys' 2 million
or more nephrons (about a million in each kidney) form urine by three precisely
regulated processes: filtration, reabsorption, and secretion.
Filtration
Urine
formation begins with the process of filtration, which goes on
continually in the renal corpuscles . As blood courses through the glomeruli, much
of its fluid, containing both useful chemicals and dissolved waste materials,
soaks out of the blood through the membranes (by osmosis and diffusion) where
it is filtered and then flows into the Bowman's capsule. This process is called
glomerular filtration. The water, waste products, salt,
glucose, and other chemicals that have been filtered out of the blood are known
collectively as glomerular filtrate. The glomerular filtrate consists primarily
of water, excess salts (primarily Na+ and K+), glucose,
and a waste product of the body called urea. Urea is formed in
the body to eliminate the very toxic ammonia products that are formed in the
liver from amino acids. Since humans cannot excrete ammonia, it is converted to
the less dangerous urea and then filtered out of the blood. Urea is the most
abundant of the waste products that must be excreted by the kidneys. The total
rate of glomerular filtration (glomerular filtration rate or GFR)
for the whole body (i.e., for all of the nephrons in both kidneys) is normally
about 125 ml per minute. That is, about 125 ml of water and dissolved
substances are filtered out of the blood per minute. The following calculations
may help you visualize how enormous this volume is. The GFR per hour is:
125 ml/min X 60min/hr= 7500
ml/hr.
The
GFR per day is: 7500 ml/hr X 24 hr/day = 180,000 ml/day or 180 liters/day.
Now, see if you can calculate
how many gallons of water we are talking about. Here are some
conversion factors for you to consider:
Now,
what we have just calculated is the amount of water that is
removed from the blood each day - about
Blood
is a bodily fluid in animals that delivers necessary substances such as
nutrients and oxygen to the cells and transports metabolic waste products away
from those same cells.
In
vertebrates, it is composed of blood cells suspended in blood plasma. Plasma,
which constitutes 55% of blood fluid, is mostly water (92% by volume), and
contains dissipated proteins, glucose, mineral ions, hormones, carbon dioxide
(plasma being the main medium for excretory product transportation), and blood
cells themselves. Albumin is the main protein in plasma, and it functions to
regulate the colloidal osmotic pressure of blood. The blood cells are mainly
red blood cells (also called RBCs or erythrocytes) and white blood cells,
including leukocytes and platelets. The most abundant cells in vertebrate blood
are red blood cells. These contain hemoglobin, an iron-containing protein,
which facilitates transportation of oxygen by reversibly binding to this
respiratory gas and greatly increasing its solubility in blood. In contrast, carbon
dioxide is almost entirely transported extracellularly dissolved in plasma as
bicarbonate ion.
Vertebrate
blood is bright red when its hemoglobin is oxygenated. Some animals, such as
crustaceans and mollusks, use hemocyanin to carry oxygen, instead of
hemoglobin. Insects and some mollusks use a fluid called hemolymph instead of
blood, the difference being that hemolymph is not contained in a closed
circulatory system. In most insects, this "blood" does not contain
oxygen-carrying molecules such as hemoglobin because their bodies are small
enough for their tracheal system to suffice for supplying oxygen.
Jawed
vertebrates have an adaptive immune system, based largely on white blood cells.
White blood cells help to resist infections and parasites. Platelets are
important in the clotting of blood. Arthropods, using hemolymph, have hemocytes
as part of their immune system.
Blood
is circulated around the body through blood vessels by the pumping action of
the heart. In animals with lungs, arterial blood carries oxygen from inhaled
air to the tissues of the body, and venous blood carries carbon dioxide, a
waste product of metabolism produced by cells, from the tissues to the lungs to
be exhaled.
Medical
terms related to blood often begin with hemo- or hemato- (also spelled haemo-
and haemato-) from the Greek word αἷμα (haima) for
"blood". In terms of anatomy and histology, blood is considered a
specialized form of connective tissue, given its origin in the bones and the
presence of potential molecular fibers in the form of fibrinogen.
Functions
Blood
performs many important functions within the body including:
Supply
of oxygen to tissues (bound to hemoglobin, which is carried in red cells)
Supply
of nutrients such as glucose, amino acids, and fatty acids (dissolved in the
blood or bound to plasma proteins (e.g., blood lipids))
Removal
of waste such as carbon dioxide, urea, and lactic acid
Immunological
functions, including circulation of white blood cells, and detection of foreign
material by antibodies
Coagulation,
which is one part of the body's self-repair mechanism (blood clotting after an
open wound in order to stop bleeding)
Messenger
functions, including the transport of hormones and the signaling of tissue
damage
Regulation
of body pH
Regulation
of core body temperature
Hydraulic
functions
Reabsorption
Tubular
reabsorption is the process by which solutes and water are removed from the
tubular fluid and transported into the blood. It is called reabsorption (and not
absorption) because these substances have already been absorbed once
(particularly in the intestines).
Reabsorption is
a two-step process beginning with the active or passive extraction of
substances from the tubule fluid into the renal interstitium (the connective
tissue that surrounds the nephrons), and then the transport of these substances
from the interstitium into the bloodstream. These transport processes are
driven by Starling forces, diffusion, and active transport.
Indirect
reabsorption
In some cases,
reabsorption is indirect. For example, bicarbonate (HCO3-) does not have a
transporter, so its reabsorption involves a series of reactions in the tubule
lumen and tubular epithelium. It begins with the active secretion of a hydrogen
ion (H+) into the tubule fluid via a Na/H exchanger:
In the lumen
The H+ combines
with HCO3- to form carbonic acid (H2CO3)
Luminal carbonic
anhydrase enzymatically converts H2CO3 into H2O and CO2
CO2 freely
diffuses into the cell
In the
epithelial cell
Cytoplasmic carbonic
anhydrase converts the CO2 and H2O (which is abundant in the cell) into H2CO3
H2CO3 readily
dissociates into H+ and HCO3-
HCO3- is
facilitated out of the cell's basolateral membrane
Hormones
Some key
regulatory hormones for reabsorption include:
aldosterone,
which stimulates active sodium reabsorption (and water as a result)
antidiuretic
hormone, which stimulates passive water reabsorption
Both hormones
exert their effects principally on the collecting ducts.
Reabsorption, by definition, is the
movement of substances out of the renal tubules back into the blood capillaries
located around the tubules (called the peritubular copillaries).
Substances reabsorbed are
water, glucose and other nutrients, and sodium (Na+) and other ions.
Reabsorption begins in the proximal convoluted tubules and continues in the
loop of Henle, distal convoluted tubules, and collecting tubules (Figure 3).
Let's discuss for a moment the three main substances that are reabsorbed back
into the bloodstream.
Large
amounts of water - more than
The
nutrient glucose (blood sugar) is entirely reabsorbed back
into the blood from the proximal tubules. In fact, it is actively
transported out of the tubules and into the peritubular capillary
blood. None of this valuable nutrient is wasted by being lost in the urine.
However, even when the kidneys are operating at peak efficiency, the nephrons
can reabsorb only so much sugar and water. Their limitations are dramatically
illustrated in cases of diabetes mellitus, a disease which causes the amount of
sugar in the blood to rise far above normal. As already mentioned, in ordinary
cases all the glucose that seeps out through the glomeruli into the tubules is
reabsorbed into the blood. But if too much is present, the tubules reach the
limit of their ability to pass the sugar back into the bloodstream, and the
tubules retain some of it. It is then carried along in the urine, often
providing a doctor with her first clue that a patient has diabetes mellitus.
The value of urine as a diagnostic aid has been known to the world of medicine
since as far back as the time of Hippocrates. Since then, examination of the
urine has become a regular procedure for physicians as well as scientists.
Sodium
ions (Na+) and other ions are only partially reabsorbed from the
renal tubules back into the blood. For the most part, however, sodium ions are actively
transported back into blood from the tubular fluid. The amount of
sodium reabsorbed varies from time to time; it depends largely on how much salt
we take in from the foods that we eat. (As stated earlier, sodium is a major
component of table salt, known chemically as sodium chloride.) As a person
increases the amount of salt taken into the body, that person's kidneys
decrease the amount of sodium reabsorption back into the blood. That is, more
sodium is retained in the tubules. Therefore, the amount of salt excreted in
the urine increases. The process works the other way as well. The less the salt
intake, the greater the amount of sodium reabsorbed back into the blood, and
the amount of salt excreted in the urine decreases.
Renal
glucose reabsorption is the part of renal physiology that deals with the
retrieval of filtered glucose, preventing it from disappearing from the body
through the urine.
If
glucose is not reabsorbed by the kidney, it appears in the urine, in a
condition known as glucosuria. This is associated with diabetes mellitus.
Selective
Reabsorption of glucose is achieved by a combination of processes.
Firstly,
the glucose in the proximal tubule is co-transported with sodium ions into the
proximal convoluted tubule walls. Some (typically smaller) amino acids are also
transported in this way. Once in the tubule wall, the glucose and amino acids
diffuse directly into the blood capillaries along a concentration gradient.
This blood is flowing, so the gradient is maintained. Lastly, sodium/potassium
ion active transport pumps remove sodium from the tubule wall and the sodium is
put back into the blood. This maintains a sodium concentration gradient in the
proximal tubule lining, so the first step continues to happen.
Renal
protein reabsorption is the part of renal physiology that deals with the
retrieval of filtered proteins, preventing them from disappearing from the body
through the urine.
Almost
all reabsorption takes place in the proximal tubule. Only ~1% is left in the
final urine.
The
proteins cross the apical membrane by endocytosis. They are subsequently
degraded in lysosomes. The remaining free amino acids are transported across
the basolateral membrane by amino acid transporters.
Renal
oligopeptide reabsorption is the part of renal physiology that deals with the
retrieval of filtered oligopeptides, preventing them from disappearing from the
body through the urine.
Almost
all reabsorption takes place in the proximal tubule. Practically nothing is
left in the final urine. Longer oligopeptides, such as angiotensi nand
glutathioneare degraded by enzymes on the brush border, while shorter ones,
such as carnosine, are transported across the apical membrane as a whole by the
PepT 1 transporter, and degraded inside the proximal tubule cell.
Amino
acids are biologically important organic
compounds made from amine (-NH2) and carboxylic acid (-COOH) functional groups,
along with a side-chain specific to each amino acid. The key elements of an
amino acid are carbon, hydrogen, oxygen, and nitrogen, though other elements
are found in the side-chains of certain amino acids. About 500 amino acids are
known and can be classified in many ways. Structurally they can be classified
according to the functional groups' locations as alpha- (α-), beta-
(β-), gamma- (γ-) or delta- (δ-) amino acids; other categories
relate to polarity, pH level, and side chain group type (aliphatic, acyclic,
aromatic, containing hydroxyl or sulfur, etc.) In the form of proteins, amino
acids comprise the second largest component (after water) of human muscles,
cells and other tissues.Outside proteins, amino acids perform critical roles in
processes such as neurotransmitter transport and biosynthesis.
Amino
acids having both the amine and carboxylic acid groups attached to the first
(alpha-) carbon atom have particular importance in biochemistry. They are known
as 2-, alpha-, or α-amino acids (generic formula H2NCHRCOOH in most cases
where R is an organic substituent known as a "side-chain"); often the
term "amino acid" is used to refer specifically to these. They
include the 22 proteinogenic ("protein-building") amino acids which
combine into peptide chains ("polypeptides") to form the building
blocks of a vast array of proteins. These are all L-stereoisomers
("left-handed" isomers) although a few D-amino acids
("right-handed") occur in bacterial envelopes and some
antibiotics.Twenty of the proteinogenic amino acids are encoded directly by
triplet codons in the genetic code and are known as "standard" amino
acids. The other two ("non-standard" or "non-canonical")
are pyrrolysine (found in methanogenic organisms and other eukaryotes) and
selenocysteine (present in many noneukaryotes as well as most eukaryotes). For
example, 25 human proteins include selenocysteine (Sec) in their primary
structure,[10] and the structurally characterized enzymes (selenoenzymes)
employ Sec as the catalytic moiety in their active sites. Pyrrolysine and
selenocysteine are encoded via variant codons; for example, selenocysteine is
encoded by stop codon and SECIS element.Codon–tRNA combinations not found in
nature can also be used to "expand" the genetic code and create novel
proteins known as alloproteins incorporating non-proteinogenic amino acids.
Many
important proteinogenic and non-proteinogenic amino acids also play critical
non-protein roles within the body. For example: in the human brain, glutamate
(standard glutamic acid) and gamma-amino-butyric acid ("GABA",
non-standard gamma-amino acid) are respectively the main excitatory and inhibitory
neurotransmitters;hydroxyproline (a major component of the connective tissue
collagen) is synthesised from proline; the standard amino acid glycine is used
to synthesise porphyrins used in red blood cells; and the non-standard
carnitine is used in lipid transport.
9
of the 20 standard amino acids are called "essential" for humans
because they cannot be created from other compounds by the human body, and so
must be taken in as food. Others may be conditionally essential for certain
ages or medical conditions. Essential amino acids may also differ between
species.
Because
of their biological significance, amino acids are important in nutrition and
are commonly used in nutritional supplements, fertilizers, and food technology.
Industrial uses include the production of drugs, biodegradable plastics and
chiral catalysts.
Renal
urea handling is the part of renal physiology that deals with the reabsorption
and secretion of urea. Movement of large amounts of urea across cell membranes
is made possible by urea transporter proteins.
Urea
allows the kidneys to create hyperosmotic urine (urine that has more ions in it
- is "more concentrated" - than that same person's blood plasma).
Preventing the loss of water in this manner is important if the person's body
must save water in order to maintain a suitable blood pressure or (more likely)
in order to maintain a suitable concentration of sodium ions in the blood
plasma.
About
40% of the urea filtered is normally found in the final urine, since there is
more reabsorption than secretion along the nephron.
It
is regulated by antidiuretic hormone, which controls the amount reabsorbed in
the collecting duct system and secreted into the loop of Henle
Renal
reabsorption of sodium (Na+) is a part of renal physiology. It uses Na-H antiport,
Na-glucose symport, sodium ion channels (minor). It is stimulated by
angiotensin II and aldosterone, and inhibited by atrial natriuretic peptide.
It
is very efficient, since more than 25,000 mmoles/day of sodium is filtered into
the nephron, but only ~100 mmoles/day, or less than 0.4% remains in the final
urine.
Water
is a chemical compound with the chemical formula H
2O. A water molecule contains one oxygen and
two hydrogen atoms
connected
by covalent bonds. Water is a liquid at standard ambient temperature and
pressure, but it often co-exists on Earth with its solid state, ice, and
gaseous state (water vapor or steam). Water also exists in a liquid crystal
state near hydrophilic surfaces.
Water
covers 71% of the Earth's surface, and is vital for all known forms of life.On
Earth, 96.5% of the planet's water is found in seas and oceans, 1.7% in
groundwater, 1.7% in glaciers and the ice caps of Antarctica and Greenland, a
small fraction in other large water bodies, and 0.001% in the air as vapor, clouds
(formed of solid and liquid water particles suspended in air), and
precipitation. Only 2.5% of the Earth's water is freshwater, and 98.8% of that
water is in ice and groundwater. Less than 0.3% of all freshwater is in rivers,
lakes, and the atmosphere, and an even smaller amount of the Earth's freshwater
(0.003%) is contained within biological bodies and manufactured products.
Water
on Earth moves continually through the water cycle of evaporation and
transpiration (evapotranspiration), condensation, precipitation, and runoff,
usually reaching the sea. Evaporation and transpiration contribute to the
precipitation over land.
Safe
drinking water is essential to humans and other lifeforms even though it
provides no calories or organic nutrients. Access to safe drinking water has
improved over the last decades in almost every part of the world, but
approximately one billion people still lack access to safe water and over 2.5
billion lack access to adequate sanitation.There is a clear correlation between
access to safe water and GDP per capita.However, some observers have estimated
that by 2025 more than half of the world population will be facing water-based
vulnerability. A recent report (November 2009) suggests that by
Secretion
Now, let's describe the third
important process in the formation of urine. Secretion is the
process by which substances move into the distal and collecting tubules from
blood in the capillaries around these tubules (Figure 3). In this respect,
secretion is reabsorption in reverse. Whereas reabsorption moves substances out
of the tubules and into the blood, secretion moves substances out of the blood
and into the tubules where they mix with the water and other wastes and are
converted into urine. These substances are secreted through either an active
transport mechanism or as a result of diffusion
across the membrane. Substances secreted are hydrogen ions (H+), potassium ions
(K+), ammonia (NH3), and certain drugs. Kidney tubule secretion plays a crucial
role in maintaining the body's acid-base balance, another example of an
important body function that the kidney participates in.
The organs involved in regulation of external acid-base balance
are the lungs are the kidneys.
The lungs are important for excretion of carbon dioxide (the
respiratory acid) and there is a huge amount of this to be excreted: at least
12,000 to 13,000 mmols/day.
In contrast the kidneys are responsible for excretion of the
fixed acids and this is also a critical role even though the amounts involved
(70-100 mmols/day) are much smaller. The main reason for this renal importance
is because there is no other way to excrete these acids and it should be
appreciated that the amounts involved are still very large when compared to the
plasma [H+] of only 40 nanomoles/litre.
There is a second extremely important role that the kidneys play
in acid-base balance, namely the reabsorption of the filtered bicarbonate.
Bicarbonate is the predominant extracellular buffer against the fixed acids and
it important that its plasma concentration should be defended against renal
loss.
In acid-base balance, the kidney is responsible for 2 major
activities:
·
Reabsorption of filtered bicarbonate: 4,000 to
5,000 mmol/day
·
Excretion of the fixed acids (acid anion and
associated H+): about 1 mmol/kg/day.
Both these processes involve secretion of H+ into the
lumen by the renal tubule cells but only the second leads to excretion of H+
from the body.
The renal mechanisms involved in acid-base balance can be
difficult to understand so as a simplification we will consider the
processes occurring in the kidney as involving 2 aspects:
·
Proximal tubular mechanism
·
Distal tubular mechanism
Proximal Tubular Mechanism
The
contributions of the proximal tubules to acid-base balance are:
·
firstly, reabsorption of bicarbonate which is filtered at the
glomerulus
·
secondly, the production of ammonium
Bicarbonate Reabsorption
Daily
filtered bicarbonate equals the product of the daily glomerular filtration rate
(180 l/day) and the plasma bicarbonate concentration (24 mmol/l). This is 180 x
24 = 4320 mmols/day (or usually quoted as between 4000 to 5000 mmols/day).
About
85 to 90% of the filtered bicarbonate is reabsorbed in the proximal tubule and
the rest is reabsorbed by the intercalated
cells of the distal tubule and collecting ducts.
The
reactions that occur are outlined in the diagram. Effectively, H+
and HCO3- are formed from CO2 and H2O in a
reaction catalysed by carbonic anhydrase. The actual reaction involved is
probably formation of H+ and
The
H+ leaves the proximal tubule cell and enters the PCT lumen by 2
mechanisms:
·
Via a Na+-H+ antiporter (major route)
·
Via H+-ATPase (proton
pump)
Filtered
HCO3- cannot cross the apical membrane of the PCT cell. Instead it
combines with the secreted H+ (under the influence of brush border
carbonic anhydrase) to produce CO2 and H2O. The CO2
is lipid soluble and easily crosses into the cytoplasm of the PCT cell. In the
cell, it combines with
The
basolateral membrane also has an active Na+-K+ ATPase
(sodium pump) which transports 3 Na+ out per 2 K+ in.
This pump is electrogenic in a direction opposite to that of the Na+-HCO3-
symporter. Also the sodium pump keeps intracellular Na+ low which sets
up the Na+ concentration gradient required for the H+-Na+
antiport at the apical membrane. The H+-Na+ antiport is
an example of secondary active
transport.
The
net effect is the reabsorption of one molecule of HCO3 and one
molecule of Na+ from the tubular lumen into the blood stream for
each molecule of H+ secreted. This mechanism does not lead to the
net excretion of any H+ from the body as the H+ is
consumed in the reaction with the filtered bicarbonate in the tubular lumen.
[Note:
The differences in functional properties of the apical membrane from that of
the basolateral membranes should be noted. This difference is maintained by the
tight junctions which link adjacent proximal tubule cells. These tight
junctions have two extremely important functions:
Gate function: They limit access of luminal
solutes to the intercellular space. This resistance can be altered and this
paracellular pathway can be more open under some circumstances (ie the ‘gate’
can be opened a little).
Fence function: The junctions maintain different
distributions of some of the integral membrane proteins. For example they act
as a ‘fence’ to keep the Na+-H+ antiporter limited to the
apical membrane, and keep the Na+-K+ ATPase limited to
the basolateral membrane. The different distribution of such proteins is
absolutely essential for cell function.
The
4 major factors which control bicarbonate reabsorption are:
·
Luminal HCO3- concentration
·
Luminal flow rate
·
Arterial pCO2
·
Angiotensin II (via decrease in cyclic AMP)
An
increase in any of these four factors causes an increase in bicarbonate
reabsorption. Parathyroid hormone also has an effect: an increase in hormone
level increases cAMP and decreases bicarbonate reabsorption.
The
mechanism for H+ secretion in the proximal tubule is described as a
high capacity, low gradient system:
The
high capacity refers to the large amount (4000 to 5000 mmols) of H+
that is secreted per day. (The actual amount of H+ secretion is 85%
of the filtered load of HCO3-).
The
low gradient refers to the low pH gradient as tubular pH can be decreased from
7.4 down to 6.7-7.0 only.
Though
no net excretion of H+ from the body occurs, this proximal mechanism
is extremely important in acid-base balance. Loss of bicarbonate is equivalent
to an acidifying effect and the potential amounts of bicarbonate lost if this
mechanism fails are very large.
Ammonium Production
Ammonium
(NH4) is produced predominantly within the proximal tubular cells.
The major source is from glutamine which enters the cell from the peritubular
capillaries (80%) and the filtrate (20%). Ammonium is produced from glutamine
by the action of the enzyme glutaminase. Further ammonium is produced when the
glutamate is metabolised to produce alpha-ketoglutarate. This molecule contains
2 negatively-charged carboxylate groups so further metabolism of it in the cell
results in the production of 2 HCO3- anions. This occurs
if it is oxidised to CO2 or if it is metabolised to glucose.
The
pKa for ammonium is so high (about 9.2) that both at extracellular and at
intracellular pH, it is present entirely in the acid form NH4+.
The previous idea that lipid soluble NH3 is produced in the tubular
cell, diffuses into the tubular fluid where it is converted to water soluble NH4+
which is now trapped in the tubule fluid is incorrect.
The
subsequent situation with ammonium is complex. Most of the ammonium is involved
in cycling within the medulla. About 75% of the proximally produced ammonium is
removed from the tubular fluid in the medulla so that the amount of ammonium
entering the distal tubule is small. The thick ascending limb of the loop of
Henle is the important segment for removing ammonium. Some of the interstitial
ammonium returns to the late proximal tubule and enters the medulla again (ie
recycling occurs).
An
overview of the situation so far is that:
·
The ammonium level in the DCT fluid is low because of removal
in the loop of Henle
·
Ammonium levels in the medullary interstitium are high (and
are kept high by the recycling process via the thick ascending limb and the
late PCT)
·
Tubule fluid entering the medullary collecting duct will have
a low pH if there is an acid load to be excreted (and the phosphate buffer has
been titrated down.
If
H+ secretion continues into the medullary collecting duct this would
reduce the pH of the luminal fluid further. A low pH greatly augments transfer
of ammonium from the medullary interstitium into the luminal fluid as it passes
through the medulla. The lower the urine pH, the higher the ammonium excretion
and this ammonium excretion is augmented further if an acidosis is present.
This augmentation with acidosis is 'regulatory' as the increased ammonium
excretion by the kidney tends to increase extracellular pH towards normal.
If
the ammonium returns to the blood stream it is metabolised in the liver to urea
(Krebs-Henseleit cycle) with net production of one hydrogen ion per ammonium
molecule.
Urination, formally called micturition, is
the process of disposing urine from the urinary
bladder through the urethra to the outside of the body. Children usualy call Urination
Pee - Pee. The process of urination is usually under voluntary control. When
control over urination is lost or absent, this is called urinary incontinence. Oliguria
refers to a low urine output; anuria refers to absent or almost absent urine output. Urinary
retention refers to the inability to deliver urine through the
urethra to the external environment.
Urine is usually a shade of yellow, due to the color of
bodily wastes disposed through urination. However, with a high concentration of
water in the urine, it can become almost clear. Likewise, if an individual is
dehydrated, their urine will have a dark yellow, almost brown discoloration.
Urinary system
The micturition reflex is activated when the
urinary bladder wall is stretched; it results in urination. This reflex occurs
in the spinal cord,
specifically in the sacral region that is modified by the higher centers in the
brain: the pons and cerebrum. The presence of urine in the bladder stimulates
the stretch receptors, which produces action
potential.
Mechanism of urination
The action potentials are carried by sensory neurons to
the sacral segments of the spinal cord through the pelvic nerves and the
parasympathetic fibers carry the action potentials to the urinary bladder in
the pelvic nerves. This causes the wall of the bladder to contract. In
addition, decreased somatic motor action potentials cause the external urinary
sphincter, which consists of skeletal muscle, to relax. When the external
urinary sphincter is relaxed urine will flow from the urinary bladder when the
pressure there is great enough to force urine to flow through the urethra. The
micturition reflex normally produces a series of contractions of the urinary
bladder.
Action potentials carried by sensory neurons from stretch
receptors in the urinary bladder wall also ascend the spinal cord to a
micturition center in the pons and to the cerebrum. Descending potentials are
sent from these areas of the brain to the sacral region of the spinal cord,
where they modify the activity of the micturition reflex in the spinal cord. The
micturition reflex, integrated in the spinal cord, predominates in infants. The
ability to voluntarily inhibit micturition develops at the age of 2-3 years,
and subsequently, the influence of the pons and cerebrum on the spinal
micturition reflex predominates. The micturition reflex integrated in the
spinal cord is automatic, but it is either stimulated or inhibited by
descending action potentials. Higher brain centers prevent micturition by
sending action potentials from the cerebrum and pons through spinal pathways to
inhibit the spinal micturition reflex. Consequently, parasympathetic
stimulation of the urinary bladder is inhibited and somatic motor neurons that
keep the external urinary sphincter contracted are stimulated.
The pressure in the urinary bladder increases rapidly
once its volume exceeds approximately 400-500 ml, and there is an increase in
the frequency of action potentials carried by sensory neurons. The increased
frequency of action potentials conducted by the ascending spinal pathways to the
pons and cerebrum results in an increased desire to urinate.
Voluntary initiation of micturition involves an increase
in action potentials sent from the cerebrum to facilitate the micturition
reflex and to voluntarily relax the external urinary sphincter. In addition to
facilitating the micturition reflex, there is an increased voluntary
contraction of abdominal muscles, which causes an increase in abdominal
pressure. This enhances the micturition reflex by increasing the pressure
applied to the urinary bladder wall.
Evaluation of Zymnytskyi and Nechyporenko test results
To conduct a Zymnytskyi
test, patient has his urine collected in separate portions every three
hours during day and night (8 portions together). Afterwards, the volume (may
vary from 50 to 300ml) and relative density are measured in every portion. By
adding all volumes we estimate the daily diuresis. Usually, day-time
diuresis exceeds the night-time one twice. If the highest urine density,
at least in one portion, is not lower then 1,018 , it means that the
concentration function of kidneys is not affected. Standart nutritional and
liquid intake diet have to be maintained in order to conduct the test.
Nechiporenko test focuses on counting a number of cell-elements
(erythrocytes, leucocytes) in a certain amount of urine. A middle portion of usually
morning urine is examined. First of all, pH is measured (base pH may cause a
partial cell destruction). Urine is centrifuged on 3000 rounds/min. speed for 3
minutes. Then the top layer is spilled out, leaving 0,5 ml (if there is little
precipitate left) or 1 ml (if there is
much precipitate) and cell elements are counted. Normal values are: leucocytes
(WBC) – up to 4*106 /l; erythrocytes – up to 2*106/l.
References:
1. Review of Medical Physiology // W.F.Ganong. – 24th edition, 2012.
2. Textbook of Medical
Physiology // A.C.Guyton, J.E.Hall. – Eleventh edition, 2005.
3.
Physiology // V.M.Moroz, O.A. Shandra. – Vinnytsia. – Nova khyha Publishers,
2011