The are distributed at the cortex and medulla.

The functions of the kidney are
vital to life and are regulated by the endocrine system by hormones such as antidiuretic
hormone (ADH), aldosterone, and parathyroid hormone (PTH). The important
functions that the kidneys serve including: (1)

1.     
Filtration and excretion of metabolic waste
products

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2.     
Regulation of necessary electrolytes, fluid,
and acid-base balance

3.     
Controlling reabsorption of water and
maintaining intravascular volume ,also kidneys reabsorb glucose, amino acids

4.     
Stimulation of red blood cell (RBC) production.

5.     
Regulation of blood pressure via the
renin-angiotensin-aldosterone system,

6.      Hormonal
functions via erythropoietin, calcitriol, and vitamin D activation.

The kidney is considered as the
most important organ for the excretion of water soluble drugs and/or their
metabolites in to the urine. (2)

Nephrons are urine-producing functional
structures of the kidney (1) which are distributed at the cortex and
medulla. A normal human kidney contains 800,000 to 1.5 million nephrons.
(3) Each nephron is composed of (Figure 1):

 

·       The renal
corpuscle (Bowman capsule): containing the glomerulus.

·       The Proximal
convoluted tubule (PCT), located in the renal cortex.

·       loop of Henle
(LOH) :descending limb and ascending limb located in renal medulla

·       The distal
convoluted tubule.

·       Collecting duct

 

 

Figure
(1): structure of the nephron

Two general classes of nephrons are:

·        
Cortical nephrons have
their loop of Henle in the renal medulla near its junction with the renal
cortex.

·        
Juxtamedullary
nephrons have their the loop of Henle deep in the renal
medulla.(5)

1.1.2. Renal blood
supply (6)           

      Normally, the kidneys receive 1,000 to
1,250 mL/min of blood in the adult person which is about 25% of the cardiac
output (COP). This amount far exceeds that needed to provide the kidney’s
intrinsic oxygen requirement but ensures optimal clearance of all wastes and
drugs from the body. Essentially, all blood passes through glomeruli, and about
10 % of renal blood flow is filtered (a glomerular filtration rate GFR of 125
mL/min in the normal adult). The basal normal blood flow is 3 to 5 mL/min/g of
tissue, greater than in most other organs.

The vascular structure of the renal cortex is
complex.  The renal artery enters the kidney at the hilum, where it
divides into five interlobar arteries, each an end artery. The afferent
arterioles, which arise from the interlobular arteries, divide within the
cortical tissue to form the glomerular capillary network. The capillaries then
reunite to form the efferent arterioles. Vessels from the efferent arterioles
supply the proximal and distal tubules and portions of the loops of Henle and
the collecting ducts. The juxtaglomerular apparatus is between the afferent and
efferent arterioles (Figure 2) and the macula densa, a specialized group
of cells which are located in the distal convoluted tubule. The point at
which the afferent arterioles enter the glomerulus and the efferent arteriole
leaves it, the tubule of nephron return back to touch the arterioles of the
glomerulus of the same nephron from which it exists. At this position, thick
ascending limb of loop of Henle, there is a specific modified region of tubular
epithelium called the Macula densa.

1.1.3.
Factors contributing to renal ischemia/reperfusion (7)

Simply
the term ischemia means that there is a deficient blood supply to tissues due
to obstruction of arterial blood inflow.

The
body is able to adapt to a reduction in blood flow to a certain level, but when
delivery of oxygen and nutrient sub­strates becomes inadequate, cellular injury
leads to organ dysfunction.

The Kidney is considered as one of the most susceptible body organs to
ischemia. Renal parenchymal oxygenation is graded with the highest oxygen
levels noted in the cortex, medium levels in the outer medulla, and the lowest
levels in the papillae. As a consequence, cortical cells are the most sensitive
to ischemia, while cells in the outer medulla can shift to oxygen-independent
metabolism making them less sensitive to a hypoxic environment. Inner medullary
and papillae cells use predominantly glucose to generate ATP via anaerobic
glycolysis. Thus, these regions demonstrate a reduced sensitivity to ischemia.
(12)

Reperfusion
could paradoxically induce and exacerbate tissue injury and necrosis.

Renal ischemia/reperfusion injury (IRI)(13,14)
results from a generalized or localized impairment of oxygen and nutrient
delivery to, and waste product removal from, cells of the kidney.(15)
There is a mismatch of local tissue oxygen supply and demand and accumulation
of waste products of metabolism. As a result of this imbalance, the tubular
epithelial cells undergo injury and, if it is severe, death by apoptosis and
necrosis (acute tubular necrosis ATN), with organ functional impairment of
water and electrolyte homeostasis and reduced excretion of waste products of
metabolism. (15). There are major clinical settings or medication
use which may lead to deposition of ischemia reperfusion injury 🙁 7, 11)

·     
Acute renal failure caused by medications for
the  treatment of hypertension,
especially with angiotensin converting enzyme inhibitors (ACEIs)

·     
Progressive azotemia

·     
Acute pulmonary edema

·     
Renal transplantation.

·     
Vasoconstrictive drugs

·     
Cyclosporine use

·     
Tacrolimus use

·     
Overuse of NSAIDs

·     
Radiocontrast agents

·     
Hypotension linked to sepsis or blood
loss after surgery and trauma.

·     
Renal vascular diseases

1.1.4. Cellular changes during
ischemic acute kidney injury (AKI)

1.1.4.1. Endothelial dysfunction (17)

Endothelial cells contribute to:

·     
Vascular tone

·     
Vascular permeability

·     
Participate in  coagula­tion and regulation of blood flow to
local tissue beds

·     
Modulation of
inflammation

     . Here we will discuss the changes that
occur in the endothelium during ischemic injury