Session 7 Flashcards
Describe the epidemiology of UTIs briefly
Recognised frequent in general practice (1-3% of all consultations) and are the commonest type of hospital-acquired infection.
Infections occur in both sexes and at all ages, but are commonest in females (1-3% in adult women) and at the extremes of age.
• Up to 50% of all women may suffer from sympatomatic UTI at some time in their life.
While many infections are mild, renal infections may lead to long term renal damage and the urinary tract is the commonest source of life-threatening Gram-negative bacteraemia.
Gram-negative rods e.g. E.coli is very common
Describe the different clinical syndromes of lower UTIs
[*] Several clinical syndromes are recognised, the commonest being lower UTI of the bladder (cystitis – inflammation of the bladder)
- Bacterial cystitis: frequency and dysuria (painful micturition – difficulty passing urine, stinging/burning pain) often with pyuria (urine contains pus) and haematuria (urine contains blood)
- Abacterial cystitis: as above but without ‘significant bacteriuria’ (presence of bacteria in urine) e
- Prostatitis (inflammation of the prostate): fever, dysuria, frequency with perineal and low back pain
- Lower UTI clinical symptoms and signs: sometimes low grade fever, dysuria, frequency, ugency
Describe the different clinical syndromes of upper UTIs
- Acute pyelonephritis: symptoms of cystitis plus fever and loin pain
- Chronic interstitial nephritis: renal impairment following chronic inflammation – infection could be one of the many causes
- Upper UTI (pyelonephritis) clinical symptoms and signs: fever, loin/back pain, referred pain from kidneys normally on side, may have dysuria and frequency. SYSTEMIC ILLNESS PRESENTATION
[*] Upper UTI (pyelonephritis) may result from haematogenous or ascending routes of infection.
What is Asymptomatic Covert Bacteriuria?
Asymptomatic: covert bacteriuria – detected only by culture, important in children and pregnancy. There is increased risk in pregnant mothers of acute pyelonephritis and premature babies. However quite a few elderly people commonly present with asymptomatic bacteriuria and they do not require treatment (no symptoms).
What is the worst possible clinical syndrome?
Septiceaemia +/- shock (could be fatal)
How is the normal urinary tract protected?
[*] The normal urinary tract is protected from infection by a variety of defence mechanisms:
- Foremost is the regular flushing during voiding which removes organisms from the distal urethra
- Between voiding such organisms may ascend the urethra and hence infection is commoner in females, because the urethra is comparatively short.
- Antibacterial secretions in the urine and urethra
What are Host Factors to consider in UTIs?
- Shorter urethra: more infections in females (bacteria are predominantly bowel flora – migrated and can ascend up the urethra and into the bladder)
- Obstruction (which disrupts the flow of urine – disrupts clearance mechanism): enlarged prostate, pregnancy, stones, tumours, uterine prolapse in older women. Urinary stasis increases the risk of developing a UTI.
- Neurological: incomplete emptying, residual urine (urine is left behind in the bladder => pathogens have the capacity to colonise in bladder)
- Ureteric reflux: ascending infection from bladder especially in children – the backwards flow of urine carries bacteria up to the bladder.
What are Bacterial Factors to consider?
- Faecal flora: potential urinary pathogens colonise periurethral area
- Adhesion: fimbriae and adhesions allow attachment to urethral and bladder epithelium
- K antigens: allow some E. coli to resist host defences by producing polysaccharide capsule. Capsule is slime like and helps organism evade some of the host’s immunological mechanisms.
- Haemolysis: damage membranes and cause renal damage
- Urease: produced by some bacteria e.g. proteus which breaks down urea creating a favourable environment for bacterial growth (using urea as part of its nutritional support)
What are sites and causes of urinary tract obstruction?
[*] Sites and Causes of Urinary Tract Obstruction:
- Ureteropelvic junction: calculi
- Ureter: Calculi, calcium, retroperitoneal fibrosis
- Bladder: neuropathic bladder
- Vesicoureteric junction: calculi
- Bladder neck: hypertrophy
- Prostate: benign prostatic hyperplasia, calcium
- Urethra: stricture (e.g. associated with urethral or bladder surgery in the past)
What is the most common pathogen in a UTI?
[*] Most common pathogen is E.coli (part of the coliforms which part of enterobacteriaeceae)– gram negative rods. Others are proteus (gram negative) and enterococci (gram positive)
Young women and hospitalised patients may also develop a UTI due to coagulae-negative staphylococci e.g. Staph. Saprophyticus. This is due to increased risk factors such as catheterisation (biofilms)
Describe the appropriate clinical and laboratory investigations used to diagnose UTI briefly
[*] Urine specimens must be collected carefully to minimise contamination. The first portion of voided urine is discarded and a midstream urine specimen collected.
[*] If there is a delay in examination, urine specimens should be refrigerated or collected in containers with boric acid to prevent bacterial multiplication in transit
[*] Some clinicians and laboratories use screening methods to exclude urinary infection.
[*] Dipstick tests are available for the detection of blood, leukocyte esterase (indicating white blood cells) and nitrite (indicating the presence of nitrate-reducing bacteria).
[*] Laboratory investigations may include microscopy for white and RBCs and squamous epithelial cells.
How would you distinguish bacteriuria/contamination?
[*] Distinguishing between bacteriuria/contamination: The number of bacterial colonies cultured from urine specimens is estimated to give a bacterial count. Kass defined the term significant bacteriuria as >10^5 (>100,000) colony forming units (cfu) of a single organism per ml of urine however this figure cannot be applied to all clinical situations and counts must be interpreted with caution.
- Single specimen 80% predictive
- ? role in cystitis, men and children.
What does the interpretation of culture results depend on?
[*] The interpretation of culture results depends on clinical details (symptoms, previous antibiotics), nature and quality of specimen, delay in culture and species isolated.
- Clinical details – symptoms and previous antibiotics (is it a recurruring problem? If patient had a recent UTI, recent antibiotics could give false negatives)
- Quality of specimen
- Delays in culture
- Microscopy (if available) however organisms may have multiplied after collection (false positive)
- Organism(s) isolated
What is meant by Sterile Pyuria?
[*] Repeat specimens may be required with low bacterial counts, evidence of contamination or so called ‘sterile pyruria’ – pus (white blood cells) in the urine without bacterial growth. This may be caused by
- Prior antibiotic
- Urethritis (chlamydia or gonococci)
- Vaginal infection or inflammation
- Fastidious organisms (controversial significance) – they require specialized environments to grow in due to complex nutritional requirements
- Tuberculosis
- Appendicitis (appendix stuck on bladder)
- Chemical inflammation
[*] Where tuberculosis is considered, three early morning urine specimens should be collected for culture.
Explain about asymptomatic bacteriuria in older people?
- Benign condition
- High prevalence in older people especially elderly females
- Generally have associated pyuria – hence will have ‘positive’ dip stick test therefore do not ‘routinely’ dispstick/culture
- Not associated with increased risk of morbidity/mortality
- Leads to unnecessary antibiotics treatment (the doctors make the mistake of thinking patient has UTI – give antibiotics needlessly, increasing the selective pressure for resistance)
- Only requires action in pregnancy and urology surgery
What is urethral syndrome?
[*] About 50% of women who present with the clinical features of cystitis do not have positive urine cultures – a condition known as abacterial cystitis or ‘urethral syndrome’. The aetiology of this condition is controversial but explanations include
- Infection with low counts of bacteria
- Infection with fastidious organisms not detected on routine culture
- Sexually transmitted infections e.g. Chlamydia => urethritis (urethral ifnlammation
- Non-infective inflammation e.g. chemical, mechanical, physical
- Vaginal infection/inflammation
[*] The other 50% women have significant bacteriuria.
What is an Uncomplicated UTI? What is a Complicated UTI?
[*] UNCOMPLICATED UTI: In healthy women of child-bearing age who have 1st time presentation and are otherwise systemically well, – no need to culture urine – infection indicated by nitrite/leucocyte esterase dispstick testing
[*] Culture urine in ‘complicated UTI’ i.e. pregnancy, treatment failure, suspected pyelonephritis, complications, male, paediatric
Describe Specimen Collection
- MSU (midstream urine specimen) – cleansing not required in women. This can only be done in compliant patients e.g. not small children. The first part of the stream of urine flushes out bacteria colonising skin and urethra – to reduce contamination (we’re more interested in bacteria in the bladder) – do not want to culture normal flora of skin and urethra.
- Clean catch in children – no antiseptic
- Collection bag (20% false positives). It can be difficult to collect samples from small children, so an adhesive bag can be placed over their genitals. This gives a false positive rate of 20%
- Catheter sample (aspirate relatively recently passed urine – sample taken not from the bag but by using a needle up a special tube in the catheter)
- Supra-pubic aspiration (needle through anterior abdominal wall, only done in desperate circumstances when other methods have not been successful, RARE)
- Transportation: 4 degrees C +/- boric acid (to stop organisms multiplying - stops bacterial division to keep the sample representative of the collection time)
What is meant by Screening?
[*] Screening: near patient (bedside tests)
Turbidity (visual inspection: urine is normally clear or slightly yellow but cloudiness can be caused by increased white blood cells)
Dipstick testing:
- Leucocyte esterase (marker for inflammation – indicates presence of WBCs)
- Nitrite (indicates presence of Nitrate reducing bacteria)
- Haematuria (sometimes visible but small amounts of blood not always visible – many reasons, can’t diagnose UTI)
- Proteinuria (indication of potential kidney damage that may be part of infection – many reasons, can’t diagnose UTI)
Describe the sensitivity and specificity of Dipstick testing, and when is Dipstick testing useful and not useful?
- Highly sensitive if both leukocyte and nitrite is positive (but doesn’t necessarily mean bacterial infection – levels could be raised due to other reasons)
- Highly specific if both leukocyte and nitrite negative (definitely can exclude UTI)
- Less specific if only one is positive (should send for MSU collection and culture).
- Sensitivity = [true positives] / [true positives + false negatives]
- Specificity = [true negatives] / [true negatives + false positives]
[*] Dipstick testing:
Useful to exclude UTI
- In children >3 years
- Men with mild/non-specific symptoms
- Elderly/institutionalised women
Not useful
- Acute uncomplicated UTI in women
- Men with typical/severe symptoms
- Catheterised patients (often have positive results even if they don’t have an infection)
- Older patients without features of infection (asymptomatic bacteriuria common) – no point in investigating them as no need to give them unnecessary antibiotics
What is the fractional excretion of Na+?
[*] Fraction excretion (FE) of Na is usually <1%. Diuretics increase the FE of Na.
Describe tubular reabsorption of Na+ in the late DCT and CD
[*] Tubular reabsorption of Sodium (part 2 – and secretion of potassium); by the Principal cells in the late distal tubule and collecting duct
- Na-K-ATPase in basolateral membrane
- Na+ enters via ENaC
- Na+ reabsorption favours K+ secretion by creating a lumen negative potential – favours the movement of K+ from principal cell to lumen
- K+ secreted through K+ channels
- Aldosterone increases expression of Na-K-ATPase, ENaC and K+ channels
- Diuretics blocking Na+ channels also reduces K+ secretion (unless they are K+-sparing)
What are the different ways in which diuretics work?
By Direct action on cells to block Na+ transporters in the apical (luminal) membrane
- Loop Diuretics act on Loop of Henle by blocking Na-K-2-Cl cotransporter
- Thiazide diuretics act on the early Distal Tubule by blocking Na-Cl cotransporter
- K+ sparing diuretics act on Late DT and CD by blocking ENaC channels
All are secreted into lumen in PCT
Act from within the lumen on transporters
By antagonising the action of aldosterone
- Aldosterone acts on principal cells of Late DT and CD (increases Na+ reabsorption via ENaC)
- Aldosterone antagonists – competitive inhibition of aldosterone receptor (decreased Na+ reabsorption)
By Modification of Filtrate Content – Osmotic diuretics
- Small molecules freely filtered at glomerulus
- Not reabsorbed
- Increase osmolarity of filtrate
- Decreased water and Na+ reabsorption throughout tubule
By inhibiting activity of enzyme – carbonic anhydrase inhibitors.
How Carbonic Anhydrase Inhibitors work?
- Most Na+ ion reabsorption occurs in the PCT however, carbonic anhydrase inhibitors, the only class of diuretic drugs that acts on the proximal tubule are not particularly potent. This is because they inhibit Na and HCO3- reabsorption rather than NaCl reabsorption, as there is less HCO3- in the glomerular filtrate, there is a reduced effect on Na+ ion reabsorption
- Plasma HCO3- concentration declines during chronic use of these drugs because of the increased urinary excretion of HCO3-, further limiting the diuretic potency of carbonic anhydrase inhibitors
- They inhibit action of carbonic anhydrase in brush border and PCT cell.
- Carbonic anhydrase inhibitors e.g. acetazolamide increase excretion of bicarbonate with accompanying Na+, K+ ions and water resulting in an increased flow of an alkaline urine and metabolic acidosis.
- These agents, although not now used as diuretics, are still used in the treatment of glaucoma to reduce the formation of aqueous humour and also in some unusual types of infantile epilepsy.
- Urinary loss of bicarbonate depletes extracellular bicarbonate, and the diuretic effect of carbonic anhydrase inhibitors is completely self-limiting.
- NB: carbonic anhydrase inhibitors are not currently used as diuretics.
Describe Loop Diuretics
[*] Loop diuretics e.g. furosemide, bumetanide are the most powerful diuretics, capable of causing the excretion of 15-25% of filtered Na+ ions. Their action is often described as ‘torrential urine flow’. They act on the thick ascending limb, inhibiting the NaKCC carrier in the apical membrane by combining with its Cl- binding site.
- 25% of filtered Na+ absorbed via Na-K-2Cl transporter in Loop of Henle
- The K+ carried across apical membrane drifts back into the lumen via K+ channels which creates a positive lumen potential, which helps to drive absorption of the positively charged ions Ca2+ and Mg2+.
- Loop diuretics are secreted into lumen in the proximal tubule (via organic anion pathway) and travel downstream to act at the Loop of Henle)
- Very potent diuretics as 25-30% of filtered sodium reabsorbed in Loop of Henle so segments beyond have limited capacity to reabsorb the resulting flood of Na and water
- Used in heart failure – diuretic effect by decreasing afterload and preload through vaso and venodilatation of vascular smooth muscle.
- In Acute Pulmonary Oedema, Furosemide is given IV for rapid action. (rapid action is largely due to venodilatation)
- Loop diuretics are used to treat fluid retention and oedema in: nephrotic syndrome, renal failure, cirrhosis of liver (spironolactone preferred, Loop diuretics added if necessary)
- Impairs calcium absorption in the loop of Henle (useful in treatment of hypercalcaemia to induce urinary excretion of calcium – IV fluids given together with furosemide). Impairs Ca2+ reabsorption because once the NaKCC transporter is blocked, lumen potential is more negative therefore drive for Ca2+ and Mg2+ reabsorption is impaired.
Describe the action of thiazide diuretics
[*] Thiazide diuretics acting on the early distal tubule:
- Sodium reabsorbed via Na-Cl-Cl transporter which Thiazide diuretics block
- Unlike in loop of Henle, blocking Na+ absorption increases Ca2+ absorption
- Thiazide diuretics e.g. Bendroflumethiazide, are secreted into lumen in PCT. Travel downstream to act at DCT to increase Na+ (and H2O) loss in urine.
- Reduces Ca2+ loss in urine (as thiazide diuretics increase Ca2+ absorption)
- Less potent diuretics than loop diuretics – only 5% of sodium reabsorption inhibited therefore ineffective in renal failure
- Widely used in hypertension (vasodilatation) => ECF volume reduction
- Higher incidence of hypokalaemia
Describe diuretics acting on the late DCT
[*] Diuretics acting on late distal tubule and collecting duct (and their effect on potassium secretion)
- Potassium sparing diuretics e.g. Amiloride
- Aldosterone antagonists: e.g. Spironolactone (acts via intracellular Aldosterone receptors)
- Both are mild diuretics affecting only 2% of Na+ reabsorption
- Both types reduce Na+ channel activity
- Both reduce the loss of potassium (‘potassium-sparing diuretics)
- Both can produce life threatening hyperkalaemia – especially if used with ACE inhibitors, K+ supplements or in patients with renal impairment.
Describe K+ secretion in the Distal Tubule and Collecting Duct
[*] K+ secretion in distal tubule and collecting duct is a passive process driven by electrochemical gradient for K+ between principal cell and lumen. Rate of K+ secretion depends on
- Concentration gradient for K+ secretion which depends on ICF [K+} and [K+] concentration in tubular fluid (CHEMICAL GRADIENT)
- Sodium absorption: inward movement of Na+ ion creates a favourable lumen negative potential for K+ secretion (ELECTRICAL GRADIENT)
