Recurrent / Persistent UTI and

Management of Kidney Stones

Julian Mander RPH Urology

Persistent UTI

Persistent UTI implicates an underlying infective focus, not cleared until the underlying problem is dealt with.

Always the same organism on MSU. MSUs remain positive after treatment and between clinical episodes.

Classically Proteus and infection staghorn stones, classically older females. Infection not cleared unless stone cleared.

In males, commonly persisting prostatic infection, typically not cleared with cephalexin or amoxycillin – use trimethoprim or norfloxacin (or ciprofloxacin) in men.

Recurrent UTI

Recurrent UTI means reinfection, typically with varying or different organisms.

Definition: Three or more MSU documented UTIs within 12 months.

3% of women, uncommon in men.

Urine cleared of bacteria in between clinical episodes c/f persistent UTI not cleared.

Recurrent UTI

1/3 of women with recurrent UTI in adult life had their initial UTI during childhood.

UTIs tend to occur in clusters in those with recurrent UTI.

Predisposing factors are unclear – sexual intercourse in women estrogen deficiency in post menopausal women altering vaginal flora

Role of residual urine poorly studied, assumed that PVR > 100 ml associated with recurrent UTI (?180 ml), but PVR proportional to starting volume and bladders always overfilled for U/S.

Pathophysiology Recurrent UTI

Bacteriuria is common in women, but established UTI/cystitis relatively uncommon – why do some women get recurrent UTI whilst most don’t ?

All bacteria invading the urinary tract activate an inflammatory response in terms of neutrophil infiltration, important to clear the bacteria.

Extent to which different organisms activate the inflammatory response varies markedly, and the relationship of this activation to different disease states is complex.

Deficiency in activation of inflammatory response in some people predisposes them to infection.

Bacterial attachment to mucosa is important, bacteria – host interaction here is important and poorly understood.

Secretor Status

Mendelian dominant inherited characteristic of secretion of water soluble form of antigen immunodominant sugars

- Blood group A: N acetyl-D-galactosamine B: D-galactosamine

Non secretors linked with relative deficiency of certain immunoglobulin classes.

Non secretors have more infections, including UTI’s.

Suggestion that non-secretors have less efficient immune systems

ABO Blood Group Status

Blood group B have 50% greater chance of UTI than non-B group.

Blood group AB also have a higher incidence of UTI.

Absence of anti-B isohaemaglutinin renders individual more susceptible to UTI. Large number of bacteria cross react with anti ABO blood group isohaemaglutinins. These cross reacting antigens vary in their immunogenicity. “B-like” immunogen is particularly antigenic and may increase the naturally occurring isohaemaglutinins, inhibiting bacterial attachment and colonization and increasing susceptibility to compliment.

Humoral Response

Superficial infection results in the formation and release of secretory IgA.

UTI causes a selective and up to four fold increase in IgA secretion.

Some adults with UTI appear to have a defect in the maturation of sIgA.

Superficial vs Intracellular infection – recent work on intracellular infection and the detection of IBCs – intracellular bacterial communities – relevant to clearance of infection and persistent UTIs.

Moving from superficial to intracellular infection is poorly understood, but humoral and subsequent inflammatory response and neutrophil recruitment is thought to be important.

Investigation

MSUs critical for correct management

Ultrasound kidneys and bladder residual (n.b. without bladder overdistension, which will give

artificially elevated PVR – good U.K. study showing PVR proportional to pre void volume)

Cystoscopy usually unnecessary if PVR is OK and patient not had frank haematuria.

MSU tests

Critical in the management of recurrent / persistent UTIs.Irritative LUTS not always UTI! - Interstistial cystitis, lower

ureteric stone, bladder cancer esp CIS.Urinalysis dipstick tests – OK for screening / diagnosis in non

complicated UTI 90% specificity 90% sensitivity.

►Females - if more than one presentation with cystitis within 12 month time frame – DO MSUs.◄

►Males – any presentation with cystitis symptoms – DO MSUs◄

Treatment Persistent UTIs

Remove the source of persisting infection:

Staghorn stones – require complete clearance and follow up.

Clear prostatic infection in men.

Remove foreign bodies – JJ stents, catheters

Treatment Recurrent UTIs

Behavioural modification

Cranberry juice

Probiotics – “Good bacteria”

Antibiotic treatment

Antibiotic prophylaxis

Bacterial vaccines

Behavioural Modification

Avoiding sex works for some women, but strains relationships.

Anal sex probably predisposes men to UTI, but is generally not discussed, and there are no scientific papers discussing this.

General hygiene advice is a waste of time, and makes women feel they have poor hygiene.

Cranberry Juice

Antibacterial action due to aromatization of quinic to benzoic acid in the gut.

Benzoic acid converted to hippuric acid in the liver, excreted in urine.Hippuric acid (Hiprex!) converted to formalin in the bladder in the

presence of acidic urine (Hence Hiprex + NH4Cl or ascorbic acid). Requires high residual volumes. (Kass 1959)

Also said to release organic molecules into urine which block bacterial adherence (pro-anthocyanidins which prevent docking of bacteria on A-type linkage of flavanols). (Analogous to secretion blood gp Antigns)

Some evidence for effectiveness in simple recurrent UTI in women (300ml/day)

Probiotics “Good Bacteria”

(By definition, a probiotic is any substance containing live organisms that, when ingested, have a beneficial effect on the host by altering the body's intestinal microflora)

No evidence that they reduce incidence of UTIs

Lactobacillus preparation and antibiotic associated diarrhea with Rx UTI17% absolute risk reduction in diarrhea associated with antibiotic

administration, and significant reduction in risk of Clostridium difficile infection, in patients given lactobacillus drink – suggested as routine admin to hospital patients > 50 that are receiving antibiotics

Use of probiotic Lactobacillus preparation Hickson et al BMJ 2007; 335 (7610): 80

Antibiotic Resistance

Most commonly associated with multiple courses of full dose antibiotics for recurrent UTIs.

Do not use antibiotics in patient with an indwelling catheter unless they are septicaemic.

Do not use antibiotics in patients with infection stones, unless septicaemic.

Do not use antibiotics in pateints with JJ stent unless MSU positive.

In patient with recurrent UTIs, MSU documentation is vital for assessment of antibiotic sensitivities and resistance.

Antibiotic Treatment

Amoxycillin simply doesn’t work – always recurs (Kincaid Smith) – seems OK with clavulinic acid though.

Urosepsis T > 38 = hospital and I/V antibiotics + renal U/S exclude infected obstructed.

Gentamicin + Amoxycillin (Enterococcus) monitor levels or Timentin

Males – all males with UTI have prostatitis (just (don’t) do PSA!!) – prostatic persistence allegedly due to inactivity Abs in acidic pH prostatic fluid. Trimethoprim or fluoroquinolones (Norfloxacin) best – requires 2 weeks Rx, 4 weeks if recurs. Most commonly older men with Rx Cephalexin failure seen.

Pyelonephritis best at least 2 weeks antibiotics.

Antibiotic Treatment

New work on intracellular infection as cause of complicated UTI.

Diagnosis of IBCs on urine cytology or biopsy with EM.

Most effective intracellular Abs are fluoroquinolones. May explain observed increased efficacy for these drugs – but should be reserved for complicated UTI.

Antibiotic Prophylaxis

Treatment for recurrent UTIs 95% success Use after clearance of UTI with full dose Ab, U/S clear. Prescribe antibiotic pending sensitivities.

Not for catheter (IDC) related infection, or persisting UTI.

Nitrofurantoin most commonly 50 mg before bed (no alteration gut/vaginal flora)

Cephalexin 250 mg

Augmentin Duo

Trimethoprim (150 mg) linked to early multi resistance

Authority prescription for “complicated UTI” on 1800 888333

6 months generally ? 12 months for elderly. Permanent on 6 month rotation for early recurrence or repeated problems. Post intercourse tablet can work.

Bacterial Vaccines

Phase II trial published April 07 in a group of women with 3 or more UTIs in 12 monthsVaginal pessaries containing “Urovac” vaccine contains heat killed bacteria from 10 human

uropathogenic bacteria: 6 strains E coli 1 strain each of Proteus, Morganella, Klebsiella, EnterococcusVaccine with or without boosters. 3 pessaries at weekly intervals with boosters 1 pessary

monthly for 3 months.

72% infection free over 6months in treatment group with boosters vs 30% infection free in placebo group, but placebo group only 3 subjects.

Vaginal Mucosal Vaccine for Recurrent UTI in Women Hopkins et al J Urol 2007; 177:1349

Management of Kidney Stones

Julian Mander

Spontaneous Stone Passage

Most stones will pass spontaneously and don’t require surgical intervention.

80% of 5 mm stones will pass spontaneously.

50% of 8 mm stones will pass spontaneously.

Stones in the lower ureter at presentation more likely to pass than stones in the upper ureter.

Typically episodic pain will be experienced while stone is passing.

Adequate pain relief is important for expectant management – NSAIDs.

Irritative LUTS with stone in lower 1/3 ureter ≠ UTI.

Dissolution of Uric Acid Stones

pKa Uric acid = 5.75 Urine pH 7 80% urate ionizedUrine pH > 7.5, increase Ca deposition on stone -> insolubleRx Sodibic 840 mg qid or Ural sachets one qidRepeat imaging 6 +/- 12 weeksNot dissolved -> surgery

Prevention increase urine output > 2 li / 24 hours allopurinol 300 mg or 100 mg daily ? decrease protein intake 90 gm / 24 hours ? Run urine pH 7

Indications for Surgical Intervention

1. Infected obstructed kidney = surgical emergency

2. Pain uncontrolled despite PR NSAIDS

3. Stone clearly too large to pass > 8mm

4. Significant CRF creatinine >200

5. Solitary kidney – risk obstructive uropathy

Surgical Intervention – JJ Stents

GA + Cystoscopy – low morbidityInitially described late 1970’s, not in common usage until 1980’sInitially no longer than 6 or 12 weeks because of encrustationNow new polymers 6 months, silastic stents 12 months

Risks - septicaemia following insertion infected obstructed - ureteric perforation - misplacement if not done with contrast and II - stent pain 15% unable to tolerate Rx as renal colic NSAIDs - loin pain with voiding - cystitis symptoms - do MSU not dipstick which is always +ve - delays stone passage, but enables future instrumentation

JJ Stents

Surgical Intervention – Rigid Ureteroscopy

Scopes Perez – Castro early 1980’s 12 F Uromat water pressure devices mid 1980’s 7.5 – 8.5 scopes 1990s

Fragmentation EHL probes and U/S probes 1980’s Pneumatic lithoclast probes 1990’s

Risks: - ureteric perforation - ureteric stricture

Use: still best option for lower 1/3 ureteric stones

Rigid Ureteroscope

Surgical Intervention – Flexible Ureteroscopy and Laser

Flexible ureteroscopes 1990’s 7.5 F late ’90s poor durability – 6 week lifespan @ $15,000

Holmium YAG laser 1990’s, prostates initially $120,000 machine 200 micron fibers $800 - $2000

Risks - ureteric strictures - urosepsis and death still with infection staghorns

Failures – narrow UOs - dilators - narrow ureters – pre stent - lower pole access

Flexible Ureteroscopy

Flexible Ureteroscopy Views

Surgical Intervention - ESWL

First treatment Stuttgart 1980Dornier HM3 1983RPH Seimens Lithostar 1991RPH Dornier 2001GA or LAOpaque stones only (U/S guidance available)3000 shocks – treatment about one hourPre stenting – stones > 2 cm - infection stonesRisks – pain passing stone fragments ?late hypertension - obstruction (steinstrasse) +/- infection - renal haemorrhage and kidney loss (beware coagulopathies)Success rates – pelvicalyceal 80% stone free rates

Surgical Intervention – Percutaneous Nephrolithotomy

1970’s Whickham, London – Seldinger technique for renal puncture1982 – 83 Pat Bary RPH pioneered in WAUpper vs Lower pole punctures – upper pole later + supra 11th ribAccess failuresAnatomical failures – parallel punctures, coagulum extractionSingle stage 30F Amplatz dilatation eventuallyFragmentation development – EHL, U/S, pneumatic Lithoclast

Risks – bleeding 7% transfusion rate RPH (Kaye tamponade balloon) - 1/200 kidney lost with each puncture & dilatation - nephrectomy for bleeding occasionally - deaths from urosepsis with infection staghorns - bowel, sleen and liver injuries

PCN

Open Surgery Uretero/Pyelo/Nephrolithotomy

Occasionally pyeloplasty for PUJ obstruction, with pyelolithotomy

Pyelonephrolithotomy for staghorn stones – lost art - splitting kidney on Brodel’s line - Renacidin irrigation - Coagulum pyelolithotomy - renal Xray plate - Gil – Vernet’s plane in pyelolithotomy - clamp and cool kidney

Risks – loss renal function - sepsis - loss kidney

Staghorn Stones

Generally elderly, unfit and infected

Mortality from urosepis

High recurrence rate 15 – 30%

Sepsis not cleared unless stone cleared

Commonest cause of persisting Proteus infection

Surgery - now the most common indication for PCN - “sandwich” with ESWL - ? role of flexi ureteroscopy and laser - ? ESWL de novo – some reports

Staghorn Stones

Pregnancy – Special Case

Concern is preterm labour – with or without interventionGreater concern the earlier the pregnancyXray exposure concerns at all stages, greater in first trimesterNSAIDs unable to use because of ductus closure risks Traditional management: U/S diagnosis hydronephrosis +/- stone manage with U/S alone if small and pain manageable – rare intervention required – do V. Limited IVP - control +5min + 30min ureteroscopic vs open - issues with stents AVOID

Latest: U/S diagnosis followed by immediate flexi ureteroscopy + laser No Xray usage at all Waterson et al Urology 60:383-7 2002

“Metabolic Workup”

Recurent stone former = 2 or more stonesBiochemical stone analysis importantIVP for medullary sponge kidney in Ca Ox stonesSerum calcium, albumin, uric acid repeatedMSU ?UTI ?pH (Type 1 distal RTA fasting urine always pH > 5.3)24 hour urine Calcium Oxalate Uric acid +/- CystinePTH assay in Calcium stone patientsRenal Acid load test for RTA “persisting fasting alkaline urine in

presence of hypercalciuria and CaPO4 stones

Medical Management – Cystine Stones

Inherited defect renal tubular reabsorption 4 amino acids COLA

Autosomal recessive, but some heterozygous have problem

pKa cystine higher than uric acid - increase solubility only at pH > 7.2 - double solubility at pH 7.8

Dissolution - > 2 li urine / 24 hours – best 3 – 4 li !! - pH > 7.8 Kcitrate thought best, but can use NaHCO3 - often not successful

Thiol group donors – D Penicillamine 1.5 gm / day - form cystine-S-penicillamine soluble molecule

? ACE inhibitor - captopril

Medical Management – Infection Stones

MgNH4PO4 = struvite with proteinaceous matrixUrea splitting bacteria, produce urease enzymes, splitting urea to

ammonium, increase urine pH and may provide initial glycocalyx proteinaceous compound.

Urine pH > 7.2 required

Proteus commonly, also some Pseudomonas, Klebsiella, E coliPersisting Proteus UTI is hallmark (esp diabetic Aboriginals – E coli)

Surgery to clear stone, followed by one month full dose bacteriocidal antibiotic, followed by 12 month surveillance with monthly MSUs

? Hemiacidrin irrigation following surgery? Oral urease inhibitors

Medical Management – Calcium Stones

47gm calcium filtered daily, UOP 200 mg Ca/day = > 99% reabsorbed

Tubular transport max exceeded -> hypercalciuria

Ksp need only exceed 15 – 30 minutes to nucleate stone

Concept of heterogenous nucleation

Hypercalciuria Vs Hyperoxaluria - Ionic activity ? Oxalate 10 x more important in CaOx stone formation

Medical Management - Hypercalciuria

Hypercalciuria Absorptive 1. Type 1 hypercalciuric on low Ca diet 2. Type 2 hypercalciuric on normal Ca diet 3. Type 3 hypercalciuric + hyperphosphatemic + low renal tubular reabsorption of phosphorous

Excretive 4. Renal leak hypercalciuria 5. Hyperparathyroidism 6. Hypercalciuria in response to CHO ingestion + sarcoidosis, multiple myeloma, hyperthyroidism, leukemia,

lymphoma, milk – alkali syndrome, Vit D intoxication, immobilization syndrome, renal tubular acidosis

Medical Management – Hypercalciuria

Treatment – Theoretical

Hyperabsorbers – methylcellulose - oral oxalate!

Hyperexcretors - diuresis > 2 li / day - thiazides decrease calcium excretion ? just work through volume – polyuria - all hyperabsorber treatments

Medical Management – Renal Tubular Acidosis

Distal (Type 1) RTA only form stones – mostly Ca PO4 = hyperchloremic acidosis, Buttler Albright syndrome, idiopathic acidosis

Decrease H+ excretion by distal tubule – increase distal tubular K+ excretion to compensate - excessive loss Na, K, Ca in urine - decrease serum Na - decrease ADH - water diuresis - decrease ECFV - increase aldosterone - increase Na, Cl reabsorption by kidney - hypochloremia, hypokalemia, metabolic acidosis with hypercalciuria !

Medical Management – Renal Tubular Acidosis

Diagnosis: Renal acid load test NH4Cl -> urine pH 5

Treatment: Shohl’s solution 98 gm Nacitrate + 140 gm citric acid in 100 ml water Dose 15 ml qid

Medical Management - Hyperoxaluria

Hyperoxaluria Oxalate 10 x ionic activity of Ca or PO4 Endogenous production enzymatic cleavage glyoxalate to oxalic acid + glycine Exogenous gut absorption – chocolate, rhubarb, brocholi (???)

Treatment Oral calcium!!! Dietary modification 24 hour urine output > 2 li / day

Management in Practice – Idiopathic CaOx Stones

Urine output 2 li per 24 hours halves stone production ( induce nocturia )

Thiazide diuretics

? Potassium Citrate

No scientific evidence for dietary recommendations

( N.B. Advice to push oral fluids during renal colic is ill founded – stones shown to pass more rapidly if urine diverted with nephrostomy tube

=> better to reduce fluid intake while passing stone)