Genitourinary Pathophysiology

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Genitourinary Pathophysiology

• Randall L. Tackett, Ph.D.

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Overview

• Anatomy and functions of the system
• Nephron
• Homestatic functions
• Tests of renal function
• Effects of aging
• Renal failure
• UTIs

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Anatomy of Renal and Urologic System
Figure 34-1
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Functions of the Kidney

• Balance solute and water transport
• Excretion of metabolic waste products
• Conserve nutrients
• Regulation of acid and base balance

5
Endocrine Functions of Kidney

• Renin Blood pressure and fluid regulation
• Erythropoietin RBC production
• 1,25-dihydroxyvitamin D3 Calcium
• Gluconeogenesis
• Severe fasting
• From amino acids

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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

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Glomerulus

• Tuft of capillaries contained in Bowmans capsule
• Main site where filtration of blood occurs
• All components of blood are filtered except
• Blood cells
• Plasma proteins with MW gt 70,000

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Juxtaglomerular Apparatus

• Composed of
• Juxtaglomerular cells (renin)
• Macula densa (sodium)
• Controls
• Renal blood flow
• GFR
• Renin secretion

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Components of the Nephron
Figure 34-3
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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

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Control of Renal Blood Flow

• Autoregulation
• Myogenic mechanism
• Tubuloglomerular feedback
• Neural regulation
• Renin-AII system
• Atrial natriuretic peptide

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Stimulants of the Renin-AII System

• Reduced blood pressure
• Decreased sodium concentration in distal tubule
• SNS stimulation

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Renin-AII System
Figure 28-33
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Nephron Function

• Major function is to form a filtrate of
  protein-free plasma (ultrafiltration)
• Regulates filtrate to maintain
• Body fluid volume
• Electrolyte composition
• pH

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Regulation of Filtrate

• Tubular reabsorption
• Tubular secretion

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Glomerular Filtrate Composition

• Protein-free
• Electrolytes
• Organic molecules
• Glucose
• Creatinine
• Urea

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Glomerular Filtration

• Permeability of substances crossing the
  glomerulus is determined by
• Molecular size
• Electrical charge

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Major Function of Nephron Segments
Figure 34-11
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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

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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

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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

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Acid-Base Balance

• Distal tubule of kidney regulates acid-base
  balance
• Secretes hydrogen into tubule
• Reabsorbs bicarbonate
• Buffers in tubular fluid combine with hydrogen
  ion, allowing more hydrogen ion to be excreted

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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

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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

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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

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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

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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

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Renal Function and Aging

• Response to acid or base load is delayed and
  prolonged
• Alteration of drug response

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Tests of Renal Function

• Clearance
• Plasma creatinine concentration
• Blood urea nitrogen (BUN)
• Urinalysis

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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

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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

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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

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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)

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Clearance and GFR

• Overestimation of GFR with creatinine is within
  tolerable limits
• Only one blood sample required with creatinine
  plus a 24 hr urine

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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

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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

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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

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Urinalysis

• Non-invasive and economical
• Evaluates
• Color
• Turbidity
• Protein
• pH
• Specific gravity
• Sediment
• Supernatant

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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

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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

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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

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Urinalysis

• WBCs
• Pyuria
• Indicative of UTI
• Other measures (dipstick tests)
• Glucose
• Bilirubin
• Hemoglobin
• Drugs

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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

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Renal Failure

• Can be acute or chronic
• Reversible or irreversible
• Rapid or slow progression

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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

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Azotemia

• Refers to increased serum urea levels
• Creatinine serum levels are often also increased
• Caused by renal insufficiency or failure

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Azotemia vs Uremia

• Often incorrectly used interchangably
• Both terms represent the accumulation of
  nitrogenous waste products in the blood

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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

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Classification of ARF

• Prerenal
• Intrarenal
• Postrenal

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Classification of ARF
Table 35-9
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ARF Clinical Manifestations

• Clinical progression occurs in three phases
• Oliguria
• Diuresis
• Recovery

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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

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Mechanisms of Oliguria
Figure 35-11
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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

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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

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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

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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

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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

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Hyperfiltration Theory

• Continued long-term exposure to increased
  capillary pressure and flow results in
  progressive failure of intact nephrons
• Loss of GFR

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Hematocrit

• Anemia is common in chronic failure
• Due to inadequate production of erythropoietin

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Proteins

• Proteinuria and a catabolic state contribute to
  the negative nitrogen balance
• Proteinuria can independently cause renal damage
  by promoting inflammation and fibrosis

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Systemic Effects of Uremia

• Skeletal Bone inflammation
• CVS Hypertension, pulmonary edema
• Neurologic Encephalopathy, neuropathy
• Endocrine Growth retardation, osteomalacia

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Systemic Effects of Uremia

• Hematologic Anemia
• GI Anorexia, ulcers, GI bleeding
• Immunologic Increased infections
• Reproductive Sexual dysfunction, menstrual
  abnormalities

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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

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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

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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

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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

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Types of UTIs

• Cystitis
• Nonbacterial cystitis
• Acute or chronic pyelonephritis

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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

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Cystitis

• Most common infecting organisms
• E coli
• Klebsiella
• Proteus
• Pseudomonas
• Staphylococcus
• Introduction of bacteria and an environment that
  promotes bacterial growth are common factors

85
Cystitis

• Many patients are asymptomatic
• Symptoms include
• Increased urinary frequency and urgency
• Dysuria
• Hematuria, cloudy urine and flank pain represent
  more serious symptoms

86
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

87
Interstitial Cystitis

• Persistent and chronic form of nonbacterial
  cystitis
• Occurs primarily in women
• May be due to an autoimmune response

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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

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Common Causes of Pyelonephritis

• Kidney stones
• Vesicoureteral
• Pregnancy
• Neurogenic bladder
• Instrumentation
• Female sexual trauma

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Acute Pyelonephritis

• Most common in women
• Responsible organism
• E coli
• Proteus
• Pseudomonas
• Infection occurs through ascension along ureters

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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

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Chronic Pyelonephritis

• Persistent or recurrent autoimmune infection
• Inflammation and scarring evident
• More likely to occur in patients with obstructive
  pathologic conditions

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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

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Chronic Pyelonephritis

• Early symptoms are often minimal
• May include hypertension
• May be similar to acute pyelonephritis

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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 patients
  response to drugs
• Renal pathology produces predictable changes in
  patients which are associated with alterations in
  homeostasis