CLINICAL PHARMACY II
CHP233
PATHOPHYSIOLOGY II
Course Description
• Provide a thorough knowledge of the
pathology of various conditions that
produce alteration in human physiology.
• Get a baseline knowledge of its
application in other subject of pharmacy
such as pharmacotherapy and clinical
practice.
Objectives
• Describe the etiology of the human diseases.
• Outline the mechanisms leading to the
disease.
• Correlate pathophysiology to clinical
manifestations in diseases.
Textbooks and
References
1. Pocket companion to pathologic basis
of disease: by Robbins and Cotran. (7th
edition).
2. Pathophysiology: clinical Concepts of
Disease Process: By Sylvia Price and
Lorraine Wilson. (5th edition).
3. Essentials of Pathophysiology for
Pharmacy: by Martin Zdanowicz.
Lectures/Practical (week)
• Sunday: → 11-12 AM (1 hour)
• Monday: → 8-11AM (3 hours)
Course Contents
1.
2.
3.
4.
5.
6.
Urinary tract disorders
Gastrointestinal disorders
Endocrine system disorders
Musculoskeletal disorders
Pulmonary disorders
Neurological and psychological disorders
Evaluation
Quiz 1 week 6…….15 points
Quiz 2 week 12 …….15 points
Practical Ex. week 14……20 points
Activities and attendence…….10 points
Final Ex………..40 points
Urinary System
Dr. amal abd el moneim
Gross Anatomy
• Consist of six organs
 Kidneys (2)
 Ureters (2)
 Urinary bladder
 Urethra
 Right slightly lower than
left due to space occupied
by liver
• Retorperitoneal (lie
between the peritoneum
and body wall) at the level
Surface anatomy of the
Kidney
12 cm
3cm
6 cm
• Each kidney is bean-shaped
and weight about 160g and
measures 12cm long by 56cm wide and 2.5-3cm thick
• Lateral surface convex,
medial surface concave and
has a slit called the hilum
where it receives the renal
artery, vein, ureter and
lymphatic vessels
Internal Structure of the
Kidney
• Cortex: the outer
granular layer (containing
many corpuscles)
• Medulla: the inner layer
that is formed of renal
pyramids ending with a
papilla and separated by
renal columns from the
cortex
• Pelvis: expanded proximal
ureter
Renal papilla
Microscopic structure of the Kidney
• Each kidney contains 1.2
million functional units
called nephrons
• A nephron consist of two
principal parts
• Renal corpuscle(glomerulus) where the
blood plasma is filtered
• Renal tubule- processes
the filtrate into urine
• Renal Corpuscle
contains:
– Bowman’s capsule
• Part of collecting
system
– Glomerulus
• Afferent arteriole
• Efferent arteriole
• Renal Tubules
1. Proximal convoluted
tubule
2. Loop of Henle
3. Distal convoluted tubule
4. Collecting tubule
Two Types of Nephrons
Cortical and Juxtamedullary Nephrons
• Cortical Nephrons (85%)- nephrons
close to the kidney surface
• Have shorter nephron loops that dip
only slightly into the outer medulla
before turning back (Forming standered
urine)---- the blood flow through cortex
is rapid
• Juxtamedullary nephron (15%)nephrons close (juxta) to the medulla
• Have very long loops that extend to the
apex of the renal pyramid
• Responsible for maintaining the
osmolality and acid-base balance
(concentereted urine due to ADH) in
addition to blood filteration ----- the
blood flow in medulla is slow
The renal corpuscle
composed of glomerulus and Bowman’s capsule
• Consist of a ball of capillaries called a
glomerulus enclosed in a twolayered glomerular (Bowman’s)
capsule
• The parietal layer is a simple
squamous epithelium.
• The visceral layer consist of cells
called podocytes wrapped around
the capillaries.
• The fluid that filters from the
glomerular capillaries, called
glomerular filtrate, collects in the
capsular space between the
parietal and visceral layer and then
flows into the renal tubule.
Juxtaglomerular (JG) Apparatus
• Glomerular Filteration pass
through three barriers:
1. Capillary endothelium
2. Basement membrane
3. Glomerular epithelium (visceral layer
of Bawman’s capsule) slit pores
between pedicles of bodocytes.
• Juxtaglomerular Apparatus =
Macula densa + JG cells (smooth
muscle fibers from afferent
arterioles).
• Macula densa monitors BP through
renin release, also macula densa
produce erythropoietin.
Blood supply to the kidney
Receives 20% of the cardiac output
Control of blood pressure
Urine collection
• From each renal papilla
, collecting ducts
collect the urine and
released it into minor
calyx then to major
calyx then to renal
pelvis to ureter
ureter
• Are muscular retroperitoneal
tubes that extends from
kidney to the urinary bladder at
the angle Trigone.
• The mucosa has transitional
epithelium that is continuous
with that of the pelvis and
bladder
• Urine stretches tube causing
the muscularis ms. to contract
in paristaltic waves, milking
urine down to the bladder
Nephrolithiasis (stone)
• It occurs when the urine becomes
too concentrated and substances
crystallized.
• The symptoms arise when stones
begin to move down ureter causing
an intense pain.
• Kidney stones may formed in the
pelvis or calyces of the kidney or in
the ureter.
Urinary Bladder
• Retroperitoneal.
• Have internal wrinkles (rugae)
that permit expansion (capacity ~
1L)
• Trigone: is area at the base
delinated by openings of ureters
and urethera without muscle
• It has internal (involuntary) and
external sphincter (voluntary).
• Its muscularis, called the detrusor
muscle,
• The mucosa has transitional
epithelium
Female urethra
• It extended from the base of the
bladder to the vestibula (3 – 5 Cm)
• External urethral sphincter is
voluntary at the pelvic floor.
• UTIs (esp. E.coli)
Male urethra
Male: 18 – 20 Cm
1. Prostatic urethra: from the base of the
bladder through the prostatic gland
2. Membranous urethra: between the
prostatic gland and the penis base
3. Penile (spongy ) urethra: traverses penis
to orifice
Major kidney functions
1. Regulation of:
Body fluid osmolarity and volume
Electrolyte balance
Acid-base balance
Blood pressure
2. Excreation of:
Metabolic product
Foreign substances (pesticides, chemicals, )
3. Secretion of:
Erythropoitin
1,25-dihydroxy vitamin D3 (activation of vitamin D)
Renin
Prostaglandin
Nephron Functional
Mechanisms
1. Filtration (from
glomeruli).
2. Reabsorption (from
renal tubules).
3. Secretion (from the
blood directly to the
tubules).
4. Excretion (elimination
from the body).
Nephron function
1. Filtration: (the first step in urine
•
•
•
•
formation)
It is bulk transport of fluid from blood to kidney
tubules ( isosmotic filtrate which is free from blood
cells and protein ).
Result of hydraulic pressure (i.e. increased water
content of filterate)
GFR = 180 L/day.
The higher molecular weight of plasma constituent,
the lower the rate of its filtration e.g. serum albumin
and hemoglobin in comparison with glucose or
Glomerular Filtration
• The mechanism of filtration is Bulk Flow
• Direction of movement: from glomerular
capillaries to capsular space
• Driving force: pressure gradient (net filtration
pressure; NFP)
• Types of pressure that affect the filtration:
 Favoring force: Capillary Blood Pressure (BP)
 Opposing force: blood colloid osmotic pressure
(COP) and Capsule Pressure (CP).
Glomerular Filtration Forces
Glomerular filtration rate
(GFR)
• Amount of filtrate produced in the kidneys
each minute is 125 mL/min. = 180 L/day.
• Factors that alter filtration pressure and
change GFR, include:
 Increased renal blood flow--------increased GFR
 Decreased plasma protein------increased GFR
causes edema.
 Hemorrhage -----------------decreased capillary BP
decreased
GFR regulation: adjusting
blood flow
• GFR should be finely controlled to avoid excessive loss of
fluid or decreased filtration with subsequent increased
accumulation of waste products.
• GFR is regulated through three mechanisms:
1. Renal autoregulation (renin -Ang. -Aldosterone)
2. Neural regulation: (sympathetic)
3. Hormonal regulation (ADH, NO, Endothellin,
Prostaglandin E2 and prostacyclins)
All these mechanisms adjust renal blood pressure and
resulting blood flow.
Measurement of GFR
1. Inulin:
(it is polysaccharides from Dhalia plant)
Freely filterable at the glomerulus.
Does not bind to plasma proteins.
Biologically inert.
Non-toxic , neither synthesized nor metabolized
in kidney.
Neither absorbed nor secreted.
Does not alter renal function.
Can be accurately quantified.
Low concentration are enough (10-20 mg/100 ml
plasma) and taken by injection.
Measurement of GFR
2- CREATININE:
End product of muscle creatine metabolism
Used in clinical sitting to measure GFR but
less accurate than inulin method (because 10
% secreated from renal tubules).
Serum Creatinine
(0.6 to 1.2 mg/dL)
• Creatinine is a break-down product of creatine
phosphate in muscle, and
• Creatinine is usually produced at a constant rate by the
body (depending on muscle mass).
• Is mainly filtered by the kidney, though a small amount is
actively secreted.
• There is no tubular reabsorption of creatinine.
• If the filtering of the kidney is deficient, blood levels rise
• Measuring Serum Creatinine is a simple test and it is the
most commonly used indicator of renal function.
• A rise in blood creatinine levels is observed only with
marked damage to functioning Nephrons.
• Therefore, this test is NOT suitable for detecting
early stage kidney disease.
• A better estimation of kidney function is given by the
creatinine clearance test
The Typical Reference Ranges
0.5 to 1.0 mg/dL for Women
0.7 to 1.2 mg/dL for Men
• Female has less serum level of creatinine than male.
• Elderly persons, on the other hand, may have less serum level
of creatinine than the adult.
• In patients with malnutrition, severe weight loss, and long
standing illnesses the muscle mass tends to diminish over time
and, therefore, their creatinine level may be lower than
expected for their age.
Creatinine Clearance
• Creatinine clearance which represents the
rate at which creatinine is removed from the
body by the kidneys
• Roughly approximates the
GFR.
• Its value is given in units of milliliters per
minute.
• Normal Range for male
75-125 ml/min
Nephron function
2- Reabsorption: it is the process of
returning filtered material ( 99 % of what
filtered) to the bloodstream.
May involve transport proteins.
Normally glucose is totally reabsorbed.
Two pathways of reabsorption:
1. Transcellular pathway (I.e. through the cell
membrane)
2. Paracellular transport (i.e. through junctions
between cells)
Nephron function
3-Secretion:
Material secreted to lumen of the kidney
tubules from blood.
Active transport (usually) of toxins and foreign
substances (e.g. saccharine and some drugs as
penicillin).
Nephron function
4- Excretion:
loss of fluid from the body in form of urine
Amount excreted = (amount filtered + amount
secreted) - amount of solute reabsorbed
An overview of urine formation
1. Podocytes
2. Bawman’s space
3. Proximal tubules
4. Loop of Hennel
5. Distal tubules
6. Collecting duct.
7. Renal caylex
8. Renal pelvis
9. Ureter
10. urethera
Urine concentration and dilution
• Importance:
• When there is excess water in the body and body
fluid osmolarity is reduced; the kidney can excrete
urine with an osmolarity as low as 50 mosm/Liter ( a
concentration that is only about one six the
osmolarity of normal extracellular fluid).
• conversely, when there is a deficient of water and
extracellular fluids osmolarity is high, the kidney can
excrete urine with a concentration of about 1200 to
1400 mosm/Liter ( 4-5 times the osmolarity of
normal extracellular fluid).
Requirements for forming a
concentrated or diluted urine
1. The controlled secretion of antidiuretic
hormone (ADH), which regulates the
permeability of the distal tubules and
collecting ducts to water.
2. A high osmolarity of the renal medullary
interstitial fluid, which provides the
osmotic gradient necessary for water
reabsorption to occur in the presence of high
The Counter-Current Mechanism
Produces a Hyperosmotic Renal
Medullary Interstitium
Hyperosmotic gradient in the
renal medulla interstitium
The role of ADH:
There is a high osmolarity of the renal medullary
interstitial fluid, which provides the osmotic
gradient necessary for water reabsorption to
occur.
Whether the water actually leaves the collecting
duct (by osmosis) is determined by the hormone
ADH.
Osmoreceptors by the hypothalamus detect the
low level of water (high osmolarity), to send an
impulse to the pituitary gland which releases
ADH into the bloodstream.
ADH makes the wall of the collecting duct more
permeable to water.
Regulation of Renin Secretion
1. Renal mechanism:
 Tension of the afferent artery (stretch
receptor).
 Macula densa (stimulated by the content of
Na ions in the distal convoluted tubule)
1. Nervous mechanism: sympathetic nerve
2. Humoral mechanism: E, NE, PGE2, PGI2
Micturation control
Micturition, or urination, is the act of emptying
the bladder.
1. As urine accumulates, distention of the bladder
activates stretch receptors, which trigger spinal
reflexes, resulting in storage of urine.
2. Voluntary initiation of voiding reflexes results in
activation of the micturition center of the pons,
which signals parasympathetic motor neurons that
stimulate contraction of the detrusor muscle and
relaxation of the urinary sphincters.
Kidney functions that changed
with age:
1.
2.
3.
4.
Decline in the number of functional nephrons
Reduction of GFR
Reduced sensitivity to ADH.
Problems with the micturation reflex.
Some important facts
• Kidney may sustain 90 % loss of
nephrons and still not show apparent
symptoms.
• 2-4 % of population only have 1 kidney.
ALTERATIONS OF KIDNEY
STRUCTURE &
FUNCTION IN DISEASE
Renal failure
• Renal failure or kidney failure (formerly
called renal insufficiency) describes a
medical condition in which the kidneys fail to
adequately filter toxins and waste products
from the blood.
• Renal disease can be categorized either by:
1. The site of the lesion (eg, glomerulopathy vs
tubulointerstitial disease) or by
2. The nature of the factors that have led to kidney
disease (eg, immunologic, metabolic, infiltrative,
infectious, hemodynamic, or toxic).
BUT, the most appropriate classification is to first
categorize the cause of the patient's renal failure as
prerenal, intrarenal, or postrenal and then to
subdivide each of these categories according to
specific causes and anatomic locations
Major causes of kidney disease
1. Prerenal disease (renal hypoperfusion)
True volume depletion
Gastrointestinal, renal, or sweat losses or
bleeding
Heart failure
Hepatic cirrhosis (including the hepatorenal
syndrome)
Nephrotic syndrome (particularly after diuretic
therapy for edema)
Hypotension
Nonsteroidal anti-inflammatory drugs
Bilateral renal artery stenosis (particularly after therapy
with an angiotensin-converting enzyme inhibitor)
Major causes of kidney disease
2- Intrarenal disease
Vascular disease
Acute
Vasculitis
Malignant hypertension
Thromboembolic disease
Chronic
Nephrosclerosis
Glomerular disease
Glomerulonephritis
Nephrotic syndrome
Tubular disease
Acute
Acute tubular necrosis
Multiple myeloma
Hypercalcemia
Uric acid nephropathy
Chronic
Polycystic kidney disease
Medullary sponge kidney
Interstitial disease
Acute
Pyelonephritis
Interstitial nephritis (usually druginduced)
Chronic
Pyelonephritis (due primarily to
vesicoureteral reflux)
Analgesic abuse
Major causes of kidney disease
3- Postrenal disease
Obstructive uropathy
Prostatic disease
Malignancy
Calculi
Congenital abnormalities
Intrarenal disease
 Because intrarenal diseases leading to
direct damage to the Nephron and
interstitial tissues of the kidney, intrarenal
causes considered to be the most
important factor for the development of
renal failure.
Structure of the Glomerulus
Glomerulonephritis (GN)
(Bright’s disease)
 It is a group of diseases that result in inflammation
and injury of the glomeruli (mainly through
immunologic reaction).
 This diseases disrupt the capillary membrane and
causes proteinuria, hematuria, oliguria, edema,
hypertension and azotemia (the presence of
nitrogenous waste in the blood).
Normal glomerular membrane
Damaged glomerular membrane
 Two types of immune mechanisms leading to
glomerular diseases:
1.
Injuries result from reaction of antibody with fixed glomerular
antigen (e.g. SLE)
2. Injuries result from circulating antigen-antibody complexes that
become trapped in the glomerular membrane (e.g. poststreptococcal
infection).
• Both leading to complement activation and leukocyte
recruitment and glomerular damage.
Glomerulonephritis (GN)
•
The main types of glomerulonephritis:
1. Nephritic syndrome: it is group of diseases that
produce proliferative inflammatory responses ( i.e.
increase the cellular component of the glomeruli
with leukocyte infiltration) that increase the
permeability of the glomerular capillary membrane
leading to loss of RBCS and protein in urine.
2. Nephrotic syndrome: it is group of diseases that
increase the permeability of the glomerular capillary
membrane leading to massive loss of only protein in
urine.
Nephritic syndrome:
 It is characterised by hematuria with red cell cast,
decreased GFR, azotemia, oliguria and hypertension.
 It is provoked by group of diseases that produce
proliferative inflammatory responses ( i.e. increase
the cellular component of the glomeruli e.g.
endothelium, podocytes and mesengial cells).
 This inflammation leading to escape of RBCS and
protein in urine.
 There are two types :
1.Acute proliferative GN
2.Rapidly progressive GN
Acute proliferative GN
Acute post-infectious glomerulonephritis
• It is diffused proliferative injury caused by trapping of
immuncomplex after infection with group A B-hemolytic
streptococcai, staph. Infection, mumps, measles, or chicken box,
HBV, HCV.
• The reaction leading to proliferation in the endothelial cells of the
glomeruli with leukocyte infilteration and escaping of RBCs and
protein.
• It occurs in children and young adult.
• Clinical manifestation: by hematuria with red cell cast (cola-like
urine), decreased GFR (due to loss of protein), azotemia, oliguria,
edema in face and hand due to Na and water retention
(aldosterone secretion)and hypertension (renin release).
• Diagnosis: elevated antistreptolysin O
• The condition may resolved spontaneously especially in children.
Rapidly progressive (Crescentic) GN
subacute GN
• It is subacute severe focal proliferative inflammation in the glomeruli
with formation of crescent shaped structure that obliterating the
Bawman’s capsule (These are produced in part by proliferation of
the parietal epithelial cells of Bowman's capsule in response to
injury and in part by infiltration of monocytes and macrophages).
• It is provoked by number of immunologic diseases e.g. SLE and
Goodpasture’s syndrome (antibodies (IgG) formed against the
basement membrane of the glomeruli and alveoli).
• it is characterized by rapid and progressive loss of renal function
with features of the nephritic syndrome, often with severe oliguria
and (if untreated) death from renal failure within weeks to months.
• Treatment: immunosuppresive drugs after plasma electrophoresis
(to remove antibodies).
Chronic Glomerulonephritis
• Slowly progressive diffused glomerular destruction
(oblitration) from long standing GN.
• chronic GN develops insidiously and is discovered only late in
its course, after the onset of renal insufficiency.
• It is characterized by polyuria or oliguria, proteinuria,
hypertension, progressive azotemia and death from uremia.
• The kidneys become contracted with progressive destruction
in all structures inside “end-stage kidney” Within 2-40 ys.
• Hemodialysis or renal transplantation may delay the rate of
disease progression.
Nephrotic syndrome
 It is the disease which affect the integrity of the glomerular capillary
membrane that increased its permeability leading to massive loss of only
protein in urine (>3.5 gm/day), hypoalbuminemia, generalized edema
(termed anasarca) and hyperlipidemia (reflex increase in the lipoprotein
synthesis by the liver) and lipiduria.
N.B.
At the onset there is little or no azotemia, hematuria, or hypertension.
Etiology:
1. Primary (i.e. changes in the kidney): usually occur in children
focal and segmental glomerulosclerosis (FSGS
minimal-change disease (MCD).
membranous nephropathy
membranoproliferative GN
2. Secondary (i.e. Caused by systemic diseases) e.g. diabetes, amyloidosis,
and SLE. It occur mainly in adults.
Minimal-Change Disease (Lipoid
Nephrosis)
• Also called foot-process disease. (most common
nephrotic syndrome in children).
• is characterized by glomeruli that have a normal
appearance by light microscopy but show diffuse
flattened podocyte foot processes when viewed with
the electron microscope without any evidence of
immunologic reaction.
• Respond well to corticosteroides
• Prognosis well.
Focal and Segmental
Glomerulosclerosis
• It is characterised by sclerosing or prliferation in
local area of the glomeruli due to idiopathic GN or
sometimes SLE, Goodpasture’s disease.
• Prognosis with drug is good (50% respond)
Membranous GN
• Membranous nephropathy (MN) is caused by an
autoimmune response against an unknown renal
antigen; it is characterized by granular subepithelial
deposits of antibodies with GBM thickening and loss
of foot processes but little or no inflammation.
• The disease is often resistant to steroid therapy. And
progress to End-stage renal failure.
Membranoproliferative
Glomerulonephritis
• It is characterized by both deposition of immune
complex under the basement membrane with
hyperproleferation of glomerular cells either
primarily or secondary to other disease.
• The prognosis is bad “developed End-stage renal
failure” .
Tubulointerstitial Diseases
Tubulointerstitial Diseases
1. Tubulointerstitial Nephritis : involving
Acute pyelonephritis (bacterial infection)
Chronic pyelonephritis (back pressure and scare
formation)
Drug-induced interstitial nephritis (hypersensitivity
immune reaction e.g. antibiotics or PG inhibition with
ischemic damage e.g. anti-inflammatory agents)
2. Acute Tubular Necrosis (ATN)
Tubulointerstitial Diseases
• It is a group of inflammatory diseases of the kidneys
that primarily involve the interstitium and tubules.
• Mainly it is due to infection so it is called
(pyelonephritis) that affect the pelvis and kidney
parenchyma.
• If it is due to secondary disease or drug it is called
Tubulointerstitial Nephritis
Tubulointerstitial Nephritis
1. Acute pyelonephritis:


1.
2.
3.
It is a common suppurative inflammation of the kidney and the renal
pelvis, which is caused by bacterial infection (mainly E.coli, other
important organisms are species of Proteus, Klebsiella, Enterobacter, and
Pseudomonas).
Pathogenesis:
Transmission of infection in ascending order from lower UTI (most
common) or from bloodstream (less common).
In the presence of renal obstruction or ureterovesciular reflux (UVR), the
infected urine make backward pressure on the bladder, ureter, pelvis then
the kidney leading to infection of the kidney.
The kidney become swollen with multiabscess on its surface, and PMNs
infilteration in the renaltubules and interstatium tissue leading to its
destruction and cast formation.
• Risk factors for development of acute pyelonephritis:
1.
2.
3.
4.
5.
6.
7.
•
Urinary obstruction (stone, neoplasma, prostatic hyperplasia….)
Female gender (short urethra, near anus)
Pregnancy (mechanical pressure)
Vesicouretral reflux
Catheterization.
Metabolic diseases (DM, GOUT….)
Immunosuppressive drugs.
It is characterized by :
 chills, fever, and malaise, loin pain.
 Urinary findings include pyuria and bacteriuria.
 bladder and urethral irritation (dysuria, frequency, urgency).
 It is diagnosed mainly by “pus cells” in urine
 90% of the cases respond well to antibiotic therapy.
Chronic Pyelonephritis and Reflux
Nephropathy
• It is a morphologic entity in which predominantly
interstitial inflammation and scarring of the renal
parenchyma is associated with grossly visible scarring
and deformity of the pelvicalyceal system either due
to prolonged obstruction or reflux infection.
• The clinical manifestation may still non-obviuos until
deteriorated to renal failure.
Acute Tubular Necrosis (ATN)
• ATN is characterized morphologically by damaged tubular epithelial cells
and clinically by acute suppression of renal function.
• It is the most common cause of acute renal failure.
• It may be developed secondary to diseases that produced marked
hypotension and shock. The pattern of ATN associated with shock is called
ischemic ATN. A second pattern, called nephrotoxic ATN which is developed
secondary to nephrotoxic drugs (e.g. gentamycin) or organic solvents and heavy
metals.
• Clinical manifestation:
1.
2.
3.
The initiation phase: slight decline in urine output with a rise in serum
creatinine.
The maintenance phase : marked oliguria.
The recovery phase: steady increase in urine volume, reaching as much as
about 3 L/day until renal tubules return to its normal function again.
Renovascular diseases
1. Hypertension with nephrosclerosis:
• Hypertension: it is sustained elevation of the
blood pressure above the acceptable level
(>140/90 mmHg).
• Nephrosclerosis: pathologic change in the renal
blood vessels as a result of hypertension leading
to chronic renal failure.
• N.B.: hypertension may leading to
nephrosclerosis and vice versa (i.e. Renal vascular
damage may leading to secondary HTN. through
renin-ang.-aldosterone system).
Hypertension with nephrosclerosis:
• Essential HTN may be Benign ( slowly progressive)
and Malignant ( rapidly progressing HTN with end
organ damage).
• Therefore, nephrosclerosis may be Benign or
Malignant.
1. Benign nephrosclerosis: Progressive, chronic renal damage
associated with benign hypertension; characterized by hyaline
arteriolosclerosis (especially afferent arterioles) and
narrowing of vascular lumens with resultant cortical atrophy.
2. Malignant nephrosclerosis: Acute renal injury associated
with malignant hypertension; arteries and arterioles show
fibrinoid necrosis and hyperplasia of smooth muscle cells;
petechial hemorrhages on the cortical surface.
Renovascular diseases
2- renal artery stenosis:
• It is atherosclerosis of the renal arteries causing rapidly
progressing HTN.
• Pathogenesis: unilateral or bilateral renal artery stenosis
leading to renal ischemia, activation of renin-angiotensinaldosterone system and finely causing progressive HTN.
• N.B. :
1. Unilateral renal artery stenosis leading to nephrosclerosis of the
other kidney.
2. The treatment of the developed HTN with ACEIs may leading to
renal failure.
3. Treatment of renal artery stenosis is mainly by surgical method.
Renovascular diseases
3- Thrombotic microangiopathies:
• Disorders characterized by fibrin thrombi in
glomeruli and small vessels resulting in acute renal
failure
• CAUSES:
1. Childhood hemolytic uremic syndrome is caused by
endothelial injury by an E. coli toxin;
2. Thrombotic thrombocytopenic purpura is caused
by defects in von Willebrand factor leading to
excessive thrombosis, with platelet consumption.
Acute renal failure (ARF)
“ it is an acute, reversible, rapidly decline in renal function
(GFR) sufficient to increase blood levels of nitrogenous
wastes (azotemia) and impair fluid and electrolyte
balance”.
• Persons with acute renal failure often are asymptomatic, and
the condition is diagnosed by observation of elevations in blood
urea nitrogen (BUN) and creatinine.
• Acute renal failure, although it causes an accumulation of
products normally cleared by the kidney, is a reversible
process if the factors causing the condition can be corrected.
Causes of Acute Renal Failure
e.g. NSAID, ACEIs
Pathogenesis of acute renal failure
Sloughing and necrosis of tubular epithelial cells leading to obstruction and increased
intraluminal pressure, which reduces glomerular filtration. Afferent arteriolar
vasoconstriction, caused in part by tubuloglomular feedback, results in decreased
glomerular capillary filtration pressure. Tubular injury and increased intraluminal
pressure cause fluid to move from the tubular lumen into the interstitium (backleak).
Ischemia or nephrotoxin
Decreased
renal blood
flow
Tubular cell
damage
Glomerular
damage
Deccreased
glomerular
blood flow
Increased
NaCL delivery
to macula
densa
Tubular
obstruction
Decreased
GFR
Backleak of
filterate
Decreased
glomerular
ultrafilteration
Clinical Course of acute renal failure
• The course of acute renal failure can be divided into three phases:
1. Initiating phase (oliguric phase< 400 mL/day): which lasts
hours or days, is the time from the onset of the precipitating event
(e.g., ischemic phase of prerenal failure or toxin exposure) until
tubular injury occurs.
* It is accompanied with azotemia, fluid and electrolyte
disturbance.
2.
Diuretic phase (2-3 weeks): it begin when the urine output
increase to more than 400 mL /day.
* it is caused by osmotic diuretic effect of high level of BUN and
serum creatinine. Also, impaired ability of the recovered tubules
to concentrate urine which leading to loss of fluid and electrolyte.
Clinical Course of acute renal failure
3- The recovery phase (after 1 year): is the period
during which repair of renal tissue takes place. Its
onset usually is heralded by a gradual increase in
urine output and a fall in serum creatinine
Treatment of acute renal failure
1. Treatment of underlying cause .
2. Continuous monitoring of fluid and electrolyte.
3. Adequate caloric intake to reduce the breakdown of
protein that increase BUN.
4. Control of infection with non-nephrotoxic
antibiotic.
5. Dialysis until the renal function restored.
CHRONIC RENAL FAILURE
“It is slowly progressive and irreversible
destruction of kidney structures over a period
of years”
Chronic Renal Failure
pathophysiology
There are two theories for the development of renal
failure:
1. All nephrons are diseased with different degrees, or
2. Nephrons are progressively destroyed while the
remaining intact nephrons become hypertrophyed
to carry the entire load of the kidney with increased
the urine flow rate until a point of destruction of
most nephrons with appearance of signs of kidney
failure.
Causes of chronic renal failure
(stages)
1. Tubulointerstatial diseases e.g. chronic pyelonephritis.
2. Chronic glomerulonephritis.
3. Renovascular diseases e.g. renal artery stenosis, benign
and malignant nephrosclerosis.
4. Connective tissue diseases e.g. Systemic Lupus
Erythematosis.
5. Congenital renal diseases e.g. polycystic kidney diseases.
6. Metabolic disorders e.g. DM, gout, hyperparathyroidism.
7. Toxic nephropathy e.g. NSAIDs abuse.
8. Postrenal obstructive causes e.g. calculi, and tumors.
Clinical Course of chronic renal
failure (stages)
• The progression of chronic renal failure usually
occurs in four stages:
1. Diminished renal reserve,
2. Renal insufficiency,
3. Renal failure, and
4. End-stage renal disease
Clinical Course of chronic renal failure
(stages)
1. Diminished Renal Reserve:
• Diminished renal reserve occurs when the GFR drops to
approximately 50% of normal.
• The serum BUN and creatinine levels still are normal, and no
symptoms of impaired renal function are evident.
2. Renal Insufficiency:
• Renal insufficiency represents a reduction in the GFR to 20%
to 50% of normal.
• During this stage, azotemia, anemia, and hypertension appear.
• As nephrons are destroyed, the remaining nephrons
compensate for those that are lost by filtering more solute
particles and water from the blood ( polyuria).
Clinical Course of chronic renal failure
(stages)
3. Renal Failure:
• Renal failure develops when the GFR is less than 20% of normal.
• At this point, the kidneys cannot regulate volume and solute
composition, and edema, metabolic acidosis, and hyperkalemia
develop.
4. End-Stage Renal Disease (ESRD):
• End-stage renal disease (ESRD) occurs when the GFR is less than
5% of normal.
• It is characterized by a reduction in renal capillaries and scarring in
the glomeruli. Atrophy and fibrosis are evident in the tubules. The
mass of the kidneys usually is reduced.
• At this phase of treatment with dialysis or transplantation is
necessary for survival.
End-Stage Renal Disease (ESRD) or
uremic syndrome
“i.e. urine in blood”
End-Stage Renal Disease (ESRD)
• End-stage renal disease (ESRD) occurs when the GFR is less than
5% of normal.
• Different physiologic functions may be imbalanced:
Biochemical changes
1. Metabolic acidosis:
 Normally, The kidneys regulate blood pH by eliminating
hydrogen ions produced. This is achieved through hydrogen
ion secretion, sodium and bicarbonate reabsorption, and the
production and elimination of ammonia and phosphate.
 In chronic renal failure, these mechanisms become impaired,
(i.e. phosphate and ammonia retained, while HCO3decreased) and metabolic acidosis results.
 With progressive renal failure, CaCO3 from bone may be
used to balance the excess H+.
2. Potassium imbalance:
 Approximately 90% of potassium excretion is through the
kidneys.
 In polyuric stage, hypokalemia may developed.
 In ESRD, hyperkalemia may be aggravated especially with
metabolic acidosis (due to shift of K+ from the cells to ECF)
leading to fatal arrhythmia.
3. Sodium imbalance:
 Sodium and water are eliminated through the kidneys.
 In polyuric stage, hyponatremia may developed.
 In ESRD, hypernatremia may be developed leading to edema,
hypertension and CHF.
4. hypermagnesemia:
 In ESRD, hypermagnesemia may be developed especially with
laxative administration (e.g. milk of magnesia).
5. azotemia:
 In ESRD, accumulation of nitrogenous toxins (e.g. BUN,
creatinine, phenolic compounds, amines…….).
6. hyperurecemia:
 Hyperurecemia may developed leading to deposition of urate
crystals in joints and kidney (stone formation).
Genitourinary changes
 Polyuria followed by oliguria and finally anuria.
 Excessive loss of protein in urine with granular cast
formation.
 Sterility and loss of libido for both male and female.
Cardiovascular changes
 Hypertension, CHF (due to Na+ and water retention),
pericarditis (due to accumulation of toxins) and arrhythmias
(due to K+, H+ accumulation).
Respiratory changes
 Pulmonary congestion (butterfly appearance), deep inspiration
(Kussmaul’s respiration), dyspnea on exertion.
 Pneumonitis (lung infection).
Hematologic problems
 Normochromic, normocytic anemia due to:
o Erythropoietin defeciency.
o Reduced RBCs life span due to biochemical abnormalities
(hemolysis).
o Excessive blood loss (due to hemodialysis)
o Iron defeciency and vit. B12 defeciency (due to impaired
absorption in uremic patients).
o Pallor, fatigue, nosebleeds and dyspnea on exertion may
developed.
Hematologic problems
 Infection with hypothermia may developed inspite normal WBCs
count; due to:
o Reduced chemotaxis and delayed hypersensitivity due to
toxin accumulation.
o Poor nutrition.
o Pulmonary edema.
o Using catheters.
o Using corticosteroids and immunosuppressive agents.
Cutaneous problems
 Yellow, dry, scaly skin (due to accumulation of urinary pigments).
 Thin, brittle hair and nail.
 Uremic pruritis, not removed with treatment (due to deposition
of Ca++) and sometimes uremic frost (due to urea deposition).
Gastrointestinal abnormalities
 Anorexia, nausea and vomiting.
 Weight loss.
 Metallic taste and ammonia odour of mouth (due to splitting
of urea into ammonia by saliva).
 Stomatitis and ulceration of small and large intestine with
excessive bleeding.
 Infection with hepatitis C during dialysis.
Dietary changes
1. Protein should be restricted to avoid azotemia.
2. Carbohydrates and fats: hyperglycemia (due to decreased
tissue sensitivity to insulin), and hypertriglycridemia.
Neuromuscular abnormalities
1. Central nervous system: memory defects,
lethargy, confusion , coma and astrexis
(flapping tremors). Dialysis may leading to
brain edema and dementia.
2. Peripheral neuropathy: numbness
(paresthesias) of foot and hand due to
damage of myelin sheath by uremic toxins.
Calcium and skeletal disorders
(renal osteodystrophy)
There ate three types of lesions may developed:
1. Osteomalacia or rickets (60 %): due to deficiency of
bone mineralization caused by deficiency of vit. D3 (active
form) and Ca++ absorption.
2. Osteitis fibrosa (30 %): due to osteoclastic resorption of
bone and replacement by fibrous tissue in a localized parts
(secondary hyperparathyroidism may be involved).
3. Osteosclerosis (10%): it is an alternating bands of
decreased and increased bone density in the vertebral
column.
With finally deposition of calcium in soft tissue e,g.
in the sclera of the eye.
Treatment of ESRD
1. Conservative treatment.
2. Dialysis.
3. Transplantation.
Diagnostic Procedures in
Renal Diseases
Diagnostic Procedure in
Renal Diseases
1. BIOCHEMICAL METHODS.
2. MORPHOLOGIC METHODS.
Biochemical Methods
• Many serious renal diseases do not produce symptoms until
renal function is significantly impaired.
• Therefore, tests for detection of renal function is important.
1. Chemical examination of urine:
A) proteinuria:
* normally (< 150 mg/dl excreted in urine, mainly albumin)
* in renal failure (> 150 mg/dl)
* Dipstick test used for examination of urine.
* grading from 0 to +4 indicate the amount of protein in
urine (accurate).
 Disadvantages:
1. Early morning samples are more concentrated.
2. False-positive in women that has contaminated urine with
vaginal secretion.
3. Screening for large MW protein only.
4. Laboratory 24-hr urine collection is more accurate.
 Source of urine protein (proteinuria):
1. Functional e.g. from heavy exercise or fever.
2. Overflow that is caused by overproduction of abnormal
protein e.g. Bence Jones protein in multiple myeloma.
3. Glomerular e.g. in GN: that help the large, negatively charged
molecules to pass freely through the glomeruli.
4. Tubular e.g. chronic pyelonephritis (reflux nephropathy) or
ATN.
Biochemical Methods
B) Hematuria:
 The dipstick test is easy and accurate method for screening and
follow up of occult blood in urine followed by microscopic
examination of urine.
 Ex. UTI, stone, trauma, or GN.
c) Hydrogen ion concentration:
 Normal urine pH (4.5 – 8.0) , but due to breakdown of food and
body tissues; the urine become slightly acidic.
 Diurnal urine pattern means: alkaline tide (i.e. raised pH after
meal) followed by acidic tide: (i.e. fall in pH during sleep due to
hypoventilation)
 Different factors which may affect urine pH:
1. Food: protein diet causing acidic urine, while vegetable diet
causing alkaline urine.
2. Metabolic acidosis: acidic urine.
3. Urinary tract infection: alkaline urine.
4. Renal tubular acidosis and hypokalemia: alkaline urine.
 Conditions in which the change in urine pH is useful:
1. Stones that are formed in acidic urine: e.g. calcium oxalate and
urate, alkalinization of urine with NaHCO3 or ingestion of food
that alkalinized urine (milk or vegetables) and high fluid intake
help in dissolution of these calculi.
2. Stones that are formed in alkaline urine: e.g. calcium phosphate
(triple phosphate), acidification of urine with drugs or ingestion
of food that acidify urine (meat) and high fluid intake help in
dissolution of these calculi.
 Test for urine pH (Dipstick test):
 Precautions:
1. Fresh urine is collected (to avoid splitting of urea into ammonia which
inturn alkalinize urine).
2. Remove the strip immediately to avoid washing of the reagent.
3. Compared the strip with standard one in daylight.
D) Specific gravity:


1.
2.
3.
4.
5.
Urinometer is used to measure the concentration of urine (osmolality)
which reflect the ability of the kidney to concentrate urine>
Method:
Calibrate with water at 16 C
Fill the cylinder with urine.
Put the urinometer.
Read the measure
True sp.gr. Corrected for the temperature (i.e. add 0.001 for each temp.
above 3C OR subtract 0.001 for each temp. below 3C)
 There is a specific correlation between sp,gr. and osmolality
 Normal urine sp.gr.= 1.010 which increased by concentration
of urine an decreased by dilution of it.
 Glucose increase the sp.gr. While urea decrease it.
Biochemical Methods
2. Glomerular filtration rate:
• Less accurate method than inulin in detection of renal
function but more safe.
A) Creatinine clearance test:
 End product of tissue catabolism which is excreted mainly via
glomeruli and not reabsorbed.
 Serum creatinine level= 0.7-1.5 mg/dl (male>female).
 Method:
• Collect 24-hr urine and detect creatinine.
• Take 1 serum sample of blood during 24-hr. and detect
serum creatinine.
• Calculate creatinine clearance= UxV/P
B) Serum creatinine and BUN:
 Increased their level indicate decreased GFR (azotemia).
 Serum creatinine is more accurate “ constant ms mass” than
BUN “ affected by dprotein in diet and endogenous protein
catabolism”
3. Tubular function test:
 The main function of renal tubules are reabsorption and
secretion which is controlled by hormones and concentration
gradient.
 For measurement of proximal tubular function:
 Phenolsulfophthalein excretion test (PSP).
 Para-aminohipurate excretion test (PAH).
 For measurement of distal tubular function:
 Concentration & dilution test, acidification and Na
conservation test.
A) PSP excretion test:
 It is non-toxic dye excreted mainly via tubules.
 Method:
1.The patient should ingest 3 cups of water 30’ before injection
of dye.
2.The patient should empty the bladder 15’ after injection.
3.Collect the urine in 1 L volumetric flask then add 5 ml NaOH
4.The pink color developed compared with standard.
5.Normally, the intensity of the color indicate the amount of dye
eliminated.
B) PAH excretion test:
 It is substance that is filtered by GFR and secreted through
tubules.
 It is indicator of the renal plasma flow if it is eliminated
completely.
C) Concentration and dilution of urine:
 concentration urine test: (by measurment of sp.gr. With water

1.
2.
3.
restriction)
Method:
Eat normal diet and restrict water after 6 PM. (diuretic should be avoided).
Collect urine at the next 6,7,8 AM.
One specimen should have sp.gr.> 1.003.
 dilution urine test:
1.
2.
3.
Drink 1 L water over 30’ .
Collect the urine in the next 3 hr.
One specimen should have sp.gr. < 1.003.
 Disadvantages;
1. Nausea and vomiting may interfere with the dilution test.
2. The ability to concentrate or dilute urine lost with kidney diseases,
hepatic diseases and CHF.
D) Urinary acidification test:
 Used to measure the amount of acid eliminated via kidney.
 Used for diagnosis of acute tubular acidosis.
 Method:
1. Collect urine for 2 days.
2. NH4CL taken orally for 3 days with continuous urine
collection.
3. Continuous measurement of pH within 5 days.
4. NH4+ splitted in the body and liberate H+ which
eliminated through the tubules.
5. In renal tubular acidosis: the tubules failed to eliminate the
acid load (pH > 5.3)
E) Na conservation test:
 Urine is normaly Na+ free.
 In renal failure (chronic pyelonephritis): loss of Na+ and water
decrease the plasma volume, decrease GFR)
 It is used to evaluate the amount of salt required to be taken
or restricted in diet.
Morphologic Methods
1. Microscopic examination of urine:
 The freshly collected urine, centrifuged and the deposits
suspended in 0.5 ml urine and examined microscopically.
 The normal deposits: contained few cast from vagina, urinary
tract, few RBCs, few WBCs.
 The abnormal deposits are: bacteria, casts, RBCs, WBCs.
 Casts indicate damage of the tubular cells.
 Different casts: red cell casts (GN), white cell casts
(pyelonephritis), fatty casts (nephrotic syndrome), granular
casts (ESRD).
 Cylindruria: excessive cast production which indicate renal
diseases.
Morphologic Methods
2- Bacteriologic examination of urine;
 Normally urine is sterile.
 Bacteria is detected in UTI.
 Method:
1. Collect the midstream urine after washing the external
genitalia.
2. Within 30’ make 2 tests:
 Culture and sensitivity test:
inoculation of urine into agar plate and incubated for 24
hr then count the colonies and the specific antibiotic.
• Urinary test strip:
detect nitrite developed with Gm –ve infection.
3- Radiologic examination:
A) Intravenous pyelogram:
1. Plain radiogram of the abdomen is taken.
2. IV injection of contrast media.
3. Radiograph is taken at:
 5’ for visualization of cortical lesions
 15’ for visualization of calyx, pelvis, ureter abnormality
 45’ for visualization of bladder abnormalities.
4. The test is C.I. in ESRD
5. Advantages:
• detect the shape, size and position of the kidney
• Detect the kidney ability to concentrate or dilute dye.
• Detect any disease or abnormalities.
6. Retrograde pyelogram can be used to ensure the results.
B) Renal ultrasonography:
 It depends on the reflection of ultrasound applied on the
abdomen using sonogram.
 Uses:
1. To distinguish solid tumor from fluid-filled cyst.
2. Used in ESRD when IVP is contraindicated.
3. Detect the accurate kidney size, and abnormalities.
4. Evaluation of any complication to renal transplantation.
5. Help in introduction of needle in renal biopsy.
C) Renal radionuclide imaging:
 injection of radioactive material then use gamma camera to
detect the lesions.
E.g. renovascular diseases.
D) Computed tomography (CT):
 Can be used to visualized all urinary system and detect lesions
e.g. stones, neoplasm, thrombosis using ionized radiation.
E) Magnetic resonance imaging (MRI):
 More accurate and detailed method without application of
ionized radiation (as in CT) or radiocontrast media (as in
pyelogram).
F) Renal arteriogram:
 Catheter is introduced from the femoral artery to the
abdominal aorta to renal artery with injection of the contrast
media.
 Used for detection of arterial stenosis, kidney patchy necrosis
in chronic pyelonephritis. But the risk of hypersensitivity may
developed.
G) Renal biopsy:
 The patient lies on abdominal sandbag and help the
kidney to protruded backward.
 Using needle, specimen is collected and examined
microscopically for any diffused renal diseases
 This technique is accompanied with life-threatening
bleeding.