2. Over 90% of the blood supplying the renal tissue is directed to
the cortex, suggesting that metabolism in this area is aerobic
whereas the medulla, with only at most 10% of the blood
supply, is mainly anaerobic.
The pathways that operate in these areas reflect the oxygen
availability, that is cortical cells oxidize glucose, fatty acids and
ketone bodies, whereas the renal medulla, being relatively
oxygen deficient, relies on anaerobic glycolysis and so produces
a significant amount of lactate. It is this compound that
contributes to the body’s ability to synthesize glucose via renal
gluconeogenesis.
3. • Normally, it is the liver which contributes most glucose to the
body via gluconeogenesis and in usual feeding/fasting cycles,
kidney-derived lactate accounts for only about 10% of the
gluconeogenic substrates. However, in times of starvation, this
proportion rises significantly and the kidney becomes a net
glucose provider.
• Oxidative catabolism of glucose, fatty acids produces acetyl-
CoA which enters the Krebs TCA cycle. Generation of reduced
coenzymes by isocitrate dehydrogenase, 2-oxoglutarate
dehydrogenase, succinate dehydrogenase, and malate
dehydrogenase supports mitochondrial oxidative
phosphorylation and much of the ATP so generated is used to
drive the active transport mechanisms involved with tubular
function.
6. The classification of calcitriol (vitamin D3) as a
vitamin is erroneous because the active
molecule is synthesized in vivo by a process
which usually provides an adequate amount to
ensure correct calcium homeostasis.
The final step in the biosynthesis of calcitriol
(also known as 1,25 cholecalciferol or 1,25(OH)2
D3 or dihydroxy vitamin D3) occurs in
mitochondria of the proximal tubules.
7. 1. The precursor, 7-dehydrocholesterol is converted by a non-
enzymatic reaction to cholecalciferol (calciol). This reaction
occurs in skin exposed to sunlight due to irradiation by UV-B
light at a wavelength of about 300 nm.
2. Cholecalciferol is transported via carrier proteins to the liver
where hydroxylation at carbon-25 occurs in a reaction
catalysed by a microsomal cytochrome P450 hydroxylase to
form calcidiol.
3. This compound travels to the kidney attached to specific
binding proteins, where another cytochrome P450 enzyme,
mitochondrial 1-a-hydroxylase, introduces a second hydroxyl
group in to the molecule to form the active calcitriol.
8.
9.
10. The two hydroxylase enzymes can also utilize the plant-
derived steroid, ergocalciferol, (vitamin D2) as a
substrate.
The final product is biologically active and so food
manufacturers often fortify their products with
ergocalciferol to prevent the occurrence of vitamin D
deficiency and consequent rickets in childhood or
osteomalacia in adults.
11. • In addition to 1-α-hydroxylase, the kidney also
possesses a 24-hydroxylase which uses calcidiol as
substrate; the product of the reaction, 24,25
dihydroxy D3, is biologically inactive.
• This represents an important control point in the
pathway. The activity of the 1-a-hydroxylase is
promoted by calcium ions and the action of PTH
acting via a G-protein/cAMP cascade. However,
calcitriol itself simultaneously induces the 24-
hydroxylase and suppresses 1- α -hydroxylase
creating an effective feedback loop (Figure below).
12.
13. Calcitriol’s action primary function is in regulating
plasma calcium concentration.
The other hormone of note synthesized by kidney
(by interstitial fibroblasts in the kidney) is
erythropoietin (EPO) , a glycosylated peptide
hormone (molecular weight approximately 50 000),
which promotes red blood cell formation and is
secreted in response to poor oxygen perfusion
(hypoxia) of the kidney.
This, along with the control of blood pressure via the
RAA system illustrates the importance of the kidney
in regulating aspects of the blood vascular system
16. Chemical Composition
• Water accounts for about 95% of urine volume; the remaining 5% consists of solutes. The
largest component of urine by weight, apart from water, is urea,which is derived from the
normal breakdown of amino acids.
• Other nitrogenous wastes in urine include uric acid (an end product of nucleic acid
metabolism) and creatinine (a metabolite of creatine phosphate, which stores energy for
the regeneration of ATP and is found in large amounts in skeletal muscle tissue).
• Normal solute constituents of urine, in order of decreasing concentration, are urea, Na, K,
PO43–, SO42–, creatinine, and uric acid.
• Much smaller but highly variable amounts of Ca2, Mg2, and HCO3– are also present in
urine.
• Unusually high concentrations of any solute, or the presence of abnormal substances such
as blood proteins, WBCs (pus), or bile pigments, may indicate pathology
21. Why test renal function?
To asses the functional capacity of kidney
Early detection of possible renal impairment.
Severity and progression of the impairment.
Monitor response to treatment
Monitor the safe and effective use of drugs which
are excreted in the urine
22. Functions of kidney
1) Maintenance of homeostasis:
• The kidneys are responsible for the regulation of
water, electrolyte & acid-base balance in the
body.
2) Excretion of metabolic waste products:
• The end products of protein & nucleic acid
metabolism are eliminated from the body.
• These include urea, creatinine, creatine, uric
acid, sulfate & phosphate.
23. 3) Retention of substances vital to body:
• The kidneys reabsorb several substances of
biochemical importance in the body e.g.
glucose, amino acids etc.
4) Hormonal functions:
• The kidneys also function as endocrine organs
by producing hormones.
24. In kidney synthesis:
1) Erythropoietin:
• A peptide hormone, stimulates hemoglobin
synthesis and formation of erythrocytes.
2) 1,25-Dihydroxycholecalciferol (calcitriol):
• The active form of vitamin D is finally produced in
the kidney.
• It regulates calcium absorption from the gut.
25. 3) Renin:
• A proteolytic enzyme liberated by kidney,
stimulates the formation of angiotensin II which,
in turn, leads to aldosterone production.
• Angiotensin II & aldosterone are the hormones
involved in the regulation of electrolyte balance.
26.
27. Formation urine
• Nephron is the functional unit of kidney.
• Each kidney is composed of approximately one million
nephrons.
• Nephron, consists of:
Bowman's capsule (with blood capillaries)
proximal convoluted tubule (PCT)
loop of Henle
distal convoluted tubule (DCT)
collecting tubule.
28.
29. • The blood supply to kidneys is relatively large.
• About 1200 ml of blood (650 ml plasma) passes
through the kidneys, every minute.
• About 120-125 ml is filtered per minute by the
kidneys and this is referred to as glomerular
filtration rate (GFR).
30. • With a normal GFR (120-125 ml/min), the
glomerular filtrate formed in an adult is about 175-
180 litres/day, out of which only 1.5 litres is
excreted as urine.
• More than 99% of the glomerular filtrate is
reabsorbed by the kidneys.
• Urine formation basically involves two steps-
glomerular filtration and tubular reabsorption.
31. 1) Glomerular filtration:
• This is a passive process that results in the
formation of ultrafiltrate of blood.
• The glomerular filtrate is almost similar in
composition to plasma
32. 2) Tubular reabsorption:
• The renal tubules (PCT, DCT and collecting
tubules) retain water and most of the soluble
constituents of the glomerular filtrate by
reabsorption.
• This may occur either by passive or active
process.
33. Kidney function tests may be divided into 4
groups.
1) Glomerular function tests:
• All the clearance tests (inulin, creatinine, urea)
are included in this group.
2)Tubular function tests:
• Urine concentration or dilution test, urine
acidification test.
34. 3) Analysis of blood/serum:
• Estimation of blood urea, serum creatinine, protein and
electrolyte are useful to assess renal function.
4) Urine examination:
• Routine examination of urine - volume, pH, specific
gravity, osmolality and presence of certain abnormal
constituents (proteins, blood, ketone bodies, glucose
etc).
36. Clearance tests
• Clearance is defined as the volume of plasma that
would be completely cleared of a substance per
minute.
• In other words, clearance of a substance refers to the
milliliters of plasma which contains the amount of
that substance excreted by kidney per minute.
37.
38.
39. Creatinine clearance tests
• Creatinine is an excretory product derived from
creatine phosphate.
• The excretion of creatinine is rather constant and
is not influenced by body metabolism or dietary
factors.
• Creatinine is filtered by the glomeruli and only
marginally secreted by the tubules.
40. • Creatinine is the end product of catabolism of creatine
phosphate.
• Free creatinine is a waste product of creatine metabolism, is
present in all body fluids and secretions.
• It is freely filtered by the glomerulus.
• There is a slight increase after the meal and especially after
the meat in the diet because a small amount is present in the
meat.
• There is a very little effect by the liver function.
• Creatine phosphate is used in the contraction of skeletal
muscles, by providing the energy.
• Creatinine is the waste product formed in the muscles from
high energy compound creatine phosphate.
41.
42.
43. • Creatinine clearance may be defined as the
volume (ml) of plasma that would be completely
cleared of creatinine per minute.
Procedure:
• In the traditional method, creatinine content of a
24 hr urine collection and the plasma
concentration in this period are estimated.
44. • The creatinine clearance (C) can be calculated as
follows:
U = Urine concentration of creatinine.
V = Urine output in ml/min (24 hr urine
volume divided by 24 x 60)
P = Concentration of creatinine.
U x V
______
P
C =
45. Reference values:
• The normal range of creatinine clearance is
around 120-145 ml/min.
• These values are slightly lower in women.
• Serum creatinine normal range:
• Adult male: 0.7-1.4 mg/dl
• Adult female: 0.6-1.3 mg/dl
• Children: 0.5-1.2 mg/dl
46. • Diagnostic importance:
• A decrease in creatinine clearance value (<75 %
normal) serves as sensitive indicator of a decreased
GFR, due to renal damage.
• It is useful for early detection of impairment in
kidney function.
47. Urea clearance tests
• Urea is the end product of protein metabolism.
• After filtered by the glomeruli, it is partially
reabsorbed by the renal tubules.
• Urea clearance is less than the GFR and it is
influenced by the protein content of the diet.
• Urea clearance is not as sensitive as creatinine
clearance.
48. • Urea clearance is defined as the volume (ml) of plasma
that would be completely cleared of urea per minute.
• It is calculated by the formula:
Cm=Maximum urea clearance.
U = Urea concentration in urine (mg/dl).
V = Urine excreted per minute in ml.
P = Urea concentration in plasma.
U x V
______
P
Cm =
49. Diagnostic importance:
• A urea clearance value below 75 % of the normal is
serious, since it is an indicator of renal damage.
• Blood urea level is found to increase only when the
clearance falls below 50% normal.
• Normal level of blood urea: 20-40 mg/dl
50. Causes for increased blood urea
1) Pre-renal conditions:
• Dehydration: Severe vomiting, intestinal
• obstruction, diarrhea, diabetic coma, severe burns,
fever and severe infections.
2) Renal diseases:
• Acute glomerulonephritis
• Nephrosis
• Malignant hypertension
• Chronic pyelonephritis
51. 3) Post-renal causes:
• Stones in the urinary tract
• Enlarged prostate
• Tumors of bladder
4) Medications:
• Acetaminophen
• Aminoglycosides
• Diuretics.
52. Decreased Blood Urea:
• Urea concentration in serum may be low in late
pregnancy, in starvation, in diet grossly deficient in
proteins and in hepatic failure.
53. Uremic syndrome
• It is the terminal manifestation of renal failure.
• A group of toxins contribute to this situation.
• Increased uric acid causes uremic pericarditis.
55. Urine concentration tests
• This is a test to assess the renal tubular function.
• It is a simple test and involves the accurate
measurement of specific gravity which depends on
the concentration of solutes in urine.
• A specific gravity of 1.020 in the early morning
urine sample is considered to be normal.
56. Osmolality and specific gravity
• The osmolality of urine is variable.
• In normal individuals, it may range from 500-1,200
milliosmoles/kg.
• The plasma osmolality is around 300
milliosmoles/kg.
57. What is this test?
• This test measures the concentration (osmolality) of
particles in your urine.
• It finds out whether your electrolyte balance is
normal and whether your kidneys are working as
they should.
58. • Measurement of urine osmolality will also help to
assess tubular function.
59. • Test results may vary depending on your age, gender, health history,
the method used for the test, and other things. Your test results may
not mean you have a problem.
If your results are higher than normal, you may have one of these
conditions:
• Dehydration
• Too much sugar in your urine (glycosuria)
• Adrenal problems
• Liver cirrhosis, if you also have low urine sodium
• High-protein diet
61. Analysis of blood (or serum)
• Estimation of serum creatinine and blood urea are useful.
• These tests are less sensitive than the clearance tests.
• Serum creatinine is a better indicator than urea.
62. • Urine examination:
• The volume of urine excreted, its pH, specific
gravity, osmolality, the concentration of abnormal
constituents (such as proteins, ketone bodies,
glucose and blood) may help to have some
preliminary knowledge of kidney function.
63. Proteinuria
Glomerular proteinuria:
• The glomeruli of kidney are not permeable to
substances with molecular weight more than
69,000 and plasma proteins are absent in normal
urine.
• When glomeruli are damaged or diseased, they
become more permeable and plasma proteins may
appear in urine.
64.
65. • The smaller molecules of albumin pass through
damaged glomeruli more readily.
• Albuminuria is always pathological.
• Large quantities of albumin are lost in urine in
nephrosis.
• Small quantities are seen in urine in acute
nephritis, strenuous exercise and pregnancy.
66. Micro-albuminuria
• It is also called minimal albuminuria .
• It is identified, when small quantity of albumin
(30-300 mg/day) is seen in urine.
67. • Micro albuminuria is an early indication of
nephropathy in patients with diabetes mellitus and
hypertension.
• All diabetics and hypertensive should be screened for
microalbuminuria.
• It is an early indicator of onset of nephropathy.
68. Overflow proteinuria
• When small molecular weight proteins are
increased in blood, they overflow into urine.
• E.g, hemoglobin having a molecular weight of
67,000 can pass through normal glomeruli and if it
exists in free form (as in hemolytic conditions),
hemoglobin can appear in urine (hemoglobinuria).
69. Hemoglobinuria occurs when the cause is outside
the urinary tract there is intravascular hemolysis
and the reticuloendothelial system cannot store
or metabolize free Hb.
– This occurs particularly in the dilute and alkaline
urine.
This free Hb has filtered through the glomeruli
and passes into urine = called Hemoglobinuria.
Hemoglobinuria may also occur due to
lysis of RBC in the urinary tract.
– In case of intravascular hemolysis of RBCs, no RBCs
are seen in the urine. Only there is hemoglobinuria.
Hematuria is the presence of intact RBCs in
urine.
70.
71. Normal
Normally Hemoglobin is not a presence in the urine.
Hemoglobinuria is seen in:
• Incompatible blood transfusion.
• Poisons like a mushroom, and snake bite.
• Malaria.
• Hemolytic disorders like sickle cell anemia,
thalassemia, glucose-6-phosphate dehydrogenase
deficiency.
• Paroxysmal hemoglobinuria.
• Fava beans sensitivity.
• Disseminated intravascular coagulopathy.
• Fever side effects and infections.
73. • Loop diuretics are diuretics that act at the ascending limb of
the loop of Henle in the kidney. They are primarily used
in medicine to treat hypertension and edema often due
to congestive heart failure or chronic kidney disease.
• Loop diuretics are 90% bonded to proteins and are secreted
into the proximal convoluted tubule through organic anion
transporter 1 (OAT-1), OAT-2, and ABCC4. Loop diuretics act on
the Na+-K+-2Cl− symporter (NKCC2) in the thick ascending
limb of the loop of Henle to inhibit sodium, chloride and
potassium reabsorption. This is achieved by competing for the
Cl− binding site.
74. The cells of the macula densa are sensitive to the concentration of sodium chloride
in the distal convoluted tubule. A decrease in sodium chloride concentration
initiates a signal from the macula densa that has two effects: (1) it decreases
resistance to blood flow in the afferent arterioles, which raises glomerular
hydrostatic pressure and helps return the glomerular filtration rate (GFR) toward
normal, and (2) it increases renin release from the juxtaglomerular cells of the
afferent and efferent arterioles, which are the major storage sites for renin.
75. • Loop diuretics also inhibits NKCC2 at macula
densa, reducing sodium transported into
macula densa cells.
• This stimulates the release of renin, which
through renin–angiotensin system, increases
fluid retention in the body, increases the
perfusion of glomerulus, thus
increasing glomerular filtration rate (GFR).
