Transcript Genitourinary Pathophysiology

Genitourinary Pathophysiology
Randall L. Tackett, Ph.D.
Overview
•
•
•
•
•
•
•
Anatomy and functions of the system
Nephron
Homestatic functions
Tests of renal function
Effects of aging
Renal failure
UTIs
Anatomy of Renal and Urologic System
Figure 34-1
Functions of the Kidney
•
•
•
•
Balance solute and water transport
Excretion of metabolic waste products
Conserve nutrients
Regulation of acid and base balance
Endocrine Functions of Kidney
• Renin – Blood pressure and fluid
regulation
• Erythropoietin – RBC production
• 1,25-dihydroxyvitamin D3 – Calcium
• Gluconeogenesis
– Severe fasting
– From amino acids
Nephron
• Functional unit of the kidney
• Approximately 1.2 million nephrons in
each kidney
• Multicomponent tubular structure lined
by epithelial cells
– Formation of urine
– Secretion/reabsorption
Glomerulus
• Tuft of capillaries contained in Bowman’s
capsule
• Main site where filtration of blood occurs
• All components of blood are filtered
except:
– Blood cells
– Plasma proteins with MW > 70,000
Juxtaglomerular Apparatus
• Composed of
– Juxtaglomerular cells (renin)
– Macula densa (sodium)
• Controls
– Renal blood flow
– GFR
– Renin secretion
Components of the Nephron
Figure 34-3
Renal Blood Flow
• Kidneys receive 20% to 25% of CO
• Glomerular filtration rate (GFR)
– Filtration of plasma/unit of time
– GFR is directly related to renal blood flow
• Between arterial pressures of 80-180
mmHg, local mechanisms
(autoregulation) renal blood flow and
thus, GFR constant
Control of Renal Blood Flow
• Autoregulation
– Myogenic mechanism
– Tubuloglomerular feedback
• Neural regulation
• Renin-AII system
• Atrial natriuretic peptide
Stimulants of the Renin-AII System
• Reduced blood pressure
• Decreased sodium concentration in distal
tubule
• SNS stimulation
Renin-AII System
Figure 28-33
Nephron Function
• Major function is to form a filtrate of
protein-free plasma (ultrafiltration)
• Regulates filtrate to maintain
– Body fluid volume
– Electrolyte composition
– pH
Regulation of Filtrate
• Tubular reabsorption
• Tubular secretion
Glomerular Filtrate Composition
• Protein-free
• Electrolytes
• Organic molecules
– Glucose
– Creatinine
– Urea
Glomerular Filtration
Permeability of substances crossing the
glomerulus is determined by:
• Molecular size
• Electrical charge
Major Function of Nephron Segments
Figure 34-11
Concentration/Dilution of Urine
• Involves a countercurrent exchange mechanism
– Fluid flows in opposite directions through parallel
tubes
– Concentration gradient causes fluid to be exchanged
across parallel pathways
• The longer the tube the greater the
concentration gradient
• Loop of Henle serves as the multiplier of the
concentration gradient
Concentration/Dilution of Urine
• Efficiency of water conservation is related to
length of loops of Henle
– Longer the loops, the greater the ability to
concentrate urine
• Urea
–
–
–
–
Product of protein metabolism
One of the major constituents of urine
Approximately 50% is excreted, 50% is recycled
Contributes to osmotic gradient in kidney
Concentration/Dilution of Urine
• Antidiuretic hormone
– Controls final concentration of urine
– Secreted from the posterior pituitary
– Increases water permeability of distal tubule
and the collecting ducts
– Can be a cause of oliguria
Acid-Base Balance
• Distal tubule of kidney regulates acidbase balance
– Secretes hydrogen into tubule
– Reabsorbs bicarbonate
• Buffers in tubular fluid combine with
hydrogen ion, allowing more hydrogen
ion to be excreted
Acid-Base Balance
• Phosphate and ammonia represent
important renal buffers
– Phosphate is filtered at glomerulus
– 75% is reabsorbed, remainder is available as
a renal buffer
• Hydrogen ion combines with phosphate
to form a negatively charged molecule
which makes it lipid insoluble
Acid-Base Balance
• Ammonia is not ionized and is lipid
soluble
• Ammonia creates a concentration
gradient
– Diffuses into renal tubular fluid to combine
with hydrogen to form ammonium ion
– Ammonium is eliminated in urine
Acid-Base Balance
• Renal buffering also requires CO2
• Carbonic anhydrase catalyzes the formation of
hydrogen ion and bicarbonate ion
• Hydrogen is secreted from tubular cell and
buffered in the lumen by ammonia and
phosphate
• Bicarbonate is generated which contributes to
plasma alkalinity
• Hydrogen is excreted in urine
Renal Function and Aging
• Linear decrease in renal blood flow
– Due to change in renal vasculature and
perfusion
– Reduction in numbers of nephrons
• Nephron loss accelerates between 40 and
80 yrs of age
• By 75 yrs of age, functional nephrons are
reduced 30% to 50%
Renal Function and Aging
• Decreased ability to concentrate urine
• Reabsorption of glucose, bicarbonate and
sodium is less efficient
• Age-related decline in renal activation of
vitamin D decreases calcium absorption
in the intestines
Renal Function and Aging
• Response to acid or base load is delayed
and prolonged
• Alteration of drug response
Tests of Renal Function
•
•
•
•
Clearance
Plasma creatinine concentration
Blood urea nitrogen (BUN)
Urinalysis
Renal Clearance
• Determines the amount of a substance
cleared from the blood by the kidneys per
unit of time
• Permits an indirect measure of:
–
–
–
–
GFR
Tubular secretion
Tubular reabsorption
Renal blood flow
Clearance and GFR
• GFR provides best estimate of functional
renal tissue
• Criteria for test substance to measure
GFR:
– Stable plasma concentration
– Freely filtered at glomerulus
– Not secreted, reabsorbed or metabolized by
the tubules
Clearance and GFR
• Inulin (a fructose polysaccharide) meets
these criteria and is used to evaluate GFR
• GFR can be calculated by:
GFR (ml/min) = Uinulin x Volume
Pinulin
Clearance and GFR
• Use of inulin requires constant infusion to
maintain stable plasma level
• An alternative to inulin is creatinine
– Produced by muscle
– Released into blood at a relatively constant
rate
– Freely filtered at glomerulus but small
amount is secreted by tubules (leads to
overestimation of GFR)
Clearance and GFR
• Overestimation of GFR with creatinine is
within tolerable limits
• Only one blood sample required with
creatinine plus a 24 hr urine
Clearance and Renal Blood Flow
• Renal plasma and blood flow can be
estimated using para-aminohippurate
(PAH)
• PAH is filtered at the glomerulus and the
remainder is secreted into the tubules in
one circulation through the kidneys
Plasma Creatinine Concentration
• Plasma creatinine is stable when GFR is stable
• Creatinine produced at a constant rate as a
product of muscle metabolism
• When GFR decreases, plasma creatinine
increases proportionately
• More important for monitoring chronic renal
failure – plasma creatinine requires 7-10 days
to stabilize when GFR declines
Blood Urea Nitrogen (BUN)
• BUN reflects
– GFR
– Urine concentrating capacity
• BUN increases as GFR decreases but
varies with altered protein intake
• BUN increases in states of dehydration
and renal failure
Urinalysis
• Non-invasive and economical
• Evaluates
–
–
–
–
–
–
–
Color
Turbidity
Protein
pH
Specific gravity
Sediment
Supernatant
Urinalysis
• Turbidity increases when formed
substances (crystals, cells, casts) are
present
• Foaming is the result of protein or bile
pigments
• pH
– Alkaline after meals
– Acidic upon awakening
Urinalysis
• Specific gravity is the estimated solute
concentration in the urine
– Can be affected by state of hydration
• Urine sediment – microscopic exam
– Cells, casts, crystals, bacteria
• RBCs
Urinalysis
• Casts (cellular precipitates)
– Red cell casts suggest bleeding
– White cell casts suggest inflammation
– Epithelial casts indicate tubular
degeneration or necrosis
• Crystals
– Can indicate inflammation, infection or
metabolic disorder
Urinalysis
• WBCs
– Pyuria
– Indicative of UTI
• Other measures (dipstick tests)
– Glucose
– Bilirubin
– Hemoglobin
• Drugs
Renal Failure
• Renal insufficiency
– GFR approximately 25% of normal
– Serum creatinine and urea mildly elevated
• Renal Failure
– Significant loss of renal function
• End-stage renal failure
– Less than 10% of renal function
Renal Failure
• Can be acute or chronic
• Reversible or irreversible
• Rapid or slow progression
Uremia
• Syndrome of renal failure
• Elevated blood urea and creatinine levels
• Represents consequences of renal failure
– Retention of toxins and wastes
– Deficiency states
– Electrolyte disturbances
Azotemia
• Refers to increased serum urea levels
• Creatinine serum levels are often also
increased
• Caused by renal insufficiency or failure
Azotemia vs Uremia
• Often incorrectly used interchangably
• Both terms represent the accumulation of
nitrogenous waste products in the blood
Acute Renal Failure (ARF)
• Abrupt reduction in renal function with
elevated BUN and plasma creatinine
• Usually, but not always, associated with
oliguria
– Urine output less than 30 ml/hr or 400 ml/d
• Usually reversible if diagnosed and
treated early after onset
Classification of ARF
• Prerenal
• Intrarenal
• Postrenal
Classification of ARF
Table 35-9
ARF: Clinical Manifestations
Clinical progression occurs in three
phases:
1. Oliguria
2. Diuresis
3. Recovery
ARF: Oliguria
• Begins within 1 day
• Can last from 1-3 weeks depending on
severity of insult
• Anuria is uncommon
• 10%-20% of patients have nonoliguric
failure
• Urine output may vary but BUN and
plasma creatinine increase
Mechanisms of Oliguria
Figure 35-11
ARF: Diuresis
• Renal function begins to recover
• Diuresis is progressive
• Tubules are still damaged
– Sodium and potassium are lost in urine
– Risk for hypokalemia
– Volume depletion (3-4 L/d) may occur
ARF: Recovery
• Plasma creatinine provides an index of
renal function
• Return to normal may take 3-12 months
• Approximately one-third of patients do
not have full recovery of normal GFR or
tubular function
Chronic Renal Failure
• Symptomatic changes usually do not
become evident until renal function
declines to less than 25% of normal
• Proposed theories of the adaptive
response
– Location of damage
– Intact nephron
– Hyperfiltration
Location of Damage
• Location of damage predicts symptoms
• Tubular interstitial disease damages tubular or
medullary portions of the nephron resulting in:
– Renal tubular acidosis
– Sodium wasting
– Difficulty in concentrating/diluting urine
• Vascular or glomerular damage results in:
– Proteinuria
– Hematuria
Intact Nephron Theory
• Loss of nephron mass causes remaining
nephrons to increase function
• Constant rate of excretion is maintained
in the presence of declining GFR
– Major end products in urine are similar to
that in normal patients
– Abnormal amounts of protein, RBCs, white
blood cells and casts
Hyperfiltration Theory
• Continued long-term exposure to
increased capillary pressure and flow
results in progressive failure of intact
nephrons
• Loss of GFR
Factors Contributing to the
Pathophysiology of Renal Failure
•
•
•
•
•
•
Creatinine and urea clearance
Sodium and water balance
Phosphate and calcium balance
Hematocrit
Potassium balance
Acid-base balance
Creatinine and Urea
• Creatinine is constantly released from muscle
and excreted by glomerular filtration
• Amount of creatinine produced equals the
amount filtered and excreted
• If GFR falls, plasma creatinine level increases
• This relationship allows plasma creatinine
concentration to serve as an index of
glomerular function
Creatinine and Urea
• Clearance of urea is similar to that of
creatinine except:
– Urea is filtered and reabsorbed
– Urea varies with state of hydration and diet
• If protein intake and metabolism are
constant, plasma levels of urea increase
as GFR decreases
Sodium and Water Balance
• Sodium levels must be regulated within
narrow limits
• In chronic renal failure, sodium load
delivered to remaining nephrons is
greater than normal
• Increased excretion is accomplished by
decreased reabsorption
Sodium and Water Balance
• Nephron has difficulty conserving sodium
when GFR decreases below 25%
– Obligatory loss of 20-40 mEq of sodium per
day occurs
• If dietary intake is less than above,
sodium deficits and volume depletion
occurs
• Loss of urea can induce osmotic diuresis
Sodium and Water Balance
• As GFR is reduced, the ability to
concentrate and dilute urine is lost
• Individual nephrons can maintain water
balance until GFR declines to 15% to
20% of normal
Potassium
• Excretion is related primarily to distal
tubular secretion and is mediated by:
– Aldosterone
– Na/K ATPase
• Tubular secretion increases until oliguria
occurs
• Large losses of potassium can occur
through the bowel
Potassium
• Once oliguric, patients are very prone to
hyperkalemia especially with:
– Salt substitutes
– Potassium-sparing diuretics
– Volume depletion
• At end-stage renal failure, total body
potassium can increase and become life
threatening
Acid-Base Balance
• Intake of normal diet produces 50 to 100
mEq of hydrogen per day
• Hydrogen is normally excreted in urine
and combined with phosphate and
ammonia
• In early failure, pH is maintained by an
increased rate of acid excretion and
bicarbonate reabsorption
Acid-Base Balance
• Metabolic acidosis begins to occur when GFR
decreases by 30% to 40% due to:
– Decreased ammonia synthesis
– Decreased bicarbonate reabsorption
• Phosphate buffers remain effective until late
stages of failure
• Bicarbonate levels stabilize at end-stage failure
because hydrogen is buffered by anions from
bone
Phosphate and Calcium Balance
• Changes in acid-base balance affect
phosphate and calcium
• In early failure, phosphate excretion
decreases and plasma phosphate levels
increase due to decreased GFR
• Elevated plasma phosphate binds calcium
producing hypocalcemia
Phosphate and Calcium Balance
• Decreased calcium stimulates the release
of parathyroid hormone which releases
calcium from bone and enhances urinary
phosphate secretion
• Phosphate and calcium levels return to
normal
• Incremental losses of GFR decreases
effectiveness of parathyroid hormone
Phosphate and Calcium Balance
• When GFR declines to 25% of normal,
parathyroid hormone is no longer
effective in maintaining serum phosphate
• Persistent reduction of GFR and
hyperparathyroidism results in:
– Hyperphosphatemia
– Hypocalcemia
– Dissolution of bone
Phosphate and Calcium Balance
Hypocalcemia and bone disease are
accelerated by:
• Impaired synthesis of 1,25 vitamin D3
• Lack of vitamin D reduces intestinal
absorption of calcium and impairs
resorption of phosphate and calcium
from bone
Hematocrit
• Anemia is common in chronic failure
• Due to inadequate production of
erythropoietin
Proteins
• Proteinuria and a catabolic state
contribute to the negative nitrogen
balance
• Proteinuria can independently cause
renal damage by promoting
inflammation and fibrosis
Systemic Effects of Uremia
• Skeletal
• CVS
• Neurologic
• Endocrine
Bone inflammation
Hypertension, pulmonary
edema
Encephalopathy,
neuropathy
Growth retardation,
osteomalacia
Systemic Effects of Uremia
• Hematologic
• GI
• Immunologic
• Reproductive
Anemia
Anorexia, ulcers, GI
bleeding
Increased infections
Sexual dysfunction,
menstrual
abnormalities
Urinary Tract Infections (UTIs)
• Usually due to bacteria
• At risk groups
–
–
–
–
–
Premature newborns
Prepubertal children
Sexually active women
Elderly men and women
Diaphragm and spermatocide users
Urinary Tract Infections (UTIs)
• Diagnosed by culture of specific oraganisms
• Usually due to retrograde movement of
causative organism
• Can occur anywhere along the urinary tract
• Usually involve gram-negative organisms
• Gram-positive organisms less common cause
Urinary Tract Infections (UTIs)
Protection against UTIs include:
• Micturition
• Low pH and presence of urea in urine are
bacteriocidal
• Uterovesical junction closes during bladder
contraction to prevent urine reflux
• Longer urethra and prostatic secretion
decrease the risk of infection in men
Consequences of UTIs
•
•
•
•
Infection
Renal and ureter damage
Inability to conserve sodium and water
Inability to excrete potassium and
hydrogen ion
• Increased risk of dehydration and
metabolic acidosis
Types of UTIs
• Cystitis
• Nonbacterial cystitis
• Acute or chronic pyelonephritis
Cystitis
• Inflammation of bladder
• Most common site of UTI
• More common in women
– Shorter urethra
– Proximity of urethra to anus
– Bacterial contamination from vaginal
secretions
Cystitis
• Most common infecting organisms
–
–
–
–
–
E coli
Klebsiella
Proteus
Pseudomonas
Staphylococcus
• Introduction of bacteria and an environment
that promotes bacterial growth are common
factors
Cystitis
• Many patients are asymptomatic
• Symptoms include
– Increased urinary frequency and urgency
– Dysuria
• Hematuria, cloudy urine and flank pain
represent more serious symptoms
Non-bacterial Cystitis
• Women with symptoms of cystitis but
negative urine cultures
• More common in women 20-30 yrs of age
• Referred to as ‘urethral syndrome’
• Caused by inflammed or infected
microscopic paraurethral glands located
in the distal third of the urethra
Interstitial Cystitis
• Persistent and chronic form of
nonbacterial cystitis
• Occurs primarily in women
• May be due to an autoimmune response
Acute Pyelonephritis
• Infection of the renal pelvis and
interstitium
• Causative organism is usually bacterial
but may involve fungi or viruses
• Common risk factors
– Urinary obstruction
– Urine reflux
Common Causes of Pyelonephritis
•
•
•
•
•
•
Kidney stones
Vesicoureteral
Pregnancy
Neurogenic bladder
Instrumentation
Female sexual trauma
Acute Pyelonephritis
• Most common in women
• Responsible organism
– E coli
– Proteus
– Pseudomonas
• Infection occurs through ascension along
ureters
Acute Pyelonephritis
• Onset of symptoms is acute with fever
• May be difficult to differentiate from
cystitis by clinical symptoms
• Specific diagnosis is established by urine
culture
Chronic Pyelonephritis
• Persistent or recurrent autoimmune
infection
• Inflammation and scarring evident
• More likely to occur in patients with
obstructive pathologic conditions
Chronic Pyelonephritis
• Elimination of bacteria with normal
urine flow is prevented
• Progressive inflammation results in
fibrosis and scarring
• Urine concentrating ability is impaired
• Can lead to chronic renal failure
Chronic Pyelonephritis
• Early symptoms are often minimal
• May include hypertension
• May be similar to acute pyelonephritis
Summary
• Kidneys are involved in a number of processes
which are important for maintenance of
homeostasis
• Age-related changes in renal function can have
profound effects and alters the patient’s
response to drugs
• Renal pathology produces predictable changes
in patients which are associated with
alterations in homeostasis