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

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  (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 10 cm long, 5.5 cm in width and about 3 cm thick, weighing 150 grams. Together, kidneys weigh about 0.5% of a person’s total body weight. The kidneys are “bean-shaped” organs, and have a concave side facing inwards (medially). On this medial aspect of each kidney is an opening, called the hilum, which admits the renal artery, the renal vein, nerves, and the ureter.

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

2. Efferent vessel

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,[citatioeeded] 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 40 cm long and 4 mm in diameter. Passing from the renal pelvis out of the hilus and down to the bladder. The ureter carries urine from the kidneys to the bladder by means of peristalsis.

• 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

• Wilms tumor

• Renal cell carcinoma

• 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

• Acute renal failure

• Chronic 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: 1 quart = 960 ml, 1 liter = 1000 ml,

4 quarts. = 1 gallon. Remember to cancel units and you will have no problem.

Now, what we have just calculated is the amount of water that is removed from the blood each day – about 180 liters per day. (Actually it also includes other chemicals, but the vast majority of this glomerular filtrate is water.) Imagine the size of a 2-liter bottle of soda pop. About 90 of those bottles equals 180 liters! Obviously no one ever excretes anywhere near 180 liters of urine per day! Why? Because almost all of the estimated 43 gallons of water (which is about the same as 180 liters – did you get the right answer?) that leaves the blood by glomerular filtration, the first process in urine formation, returns to the blood by the second process – reabsorption.

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 178 liters per day – are reabsorbed back into the bloodstream from the proximal tubules because the physical forces acting on the water in these tubules actually push most of the water back into the blood capillaries. In other words, about 99% of the 180 liters of water that leave the blood each day by glomerular filtration returns to the blood from the proximal tubule through the process of passive reabsorption.

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 iutrition and are commonly used iutritional 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 2030, in some developing regions of the world, water demand will exceed supply by 50%. Water plays an important role in the world economy, as it functions as a solvent for a wide variety of chemical substances and facilitates industrial cooling and transportation. Approximately 70% of the fresh water used by humans goes to agriculture.

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 OH^– from water, then reaction of OH^– with CO₂ (catalysed by carbonic anhydrase) to produce HCO3^–. Either way, the end result is the same.

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 OH^– to produce bicarbonate. The HCO₃^– crosses the basolateral membrane via a Na⁺-HCO₃^– symporter. This symporter is electrogenic as it transfers three HCO₃– for every one Na+. In comparison, the Na⁺-H⁺ antiporter in the apical membrane is not electrogenic because an equal amount of charge is transferred in both directions.

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