UTI in kidney transplantation recipients 2017h\

1. Kidney Transplantation
Conference
Maj. Chaken Maniyan M.D.
Division of Nephrology, Department of Medicine
Phramongkutklao Hospital
25.4.2017

2. Demographic data
§ผู้ป่ วยหญิงไทยโสด อายุ 21 ปี
§ภูมิลําเนา : เขตลาดพร ้าว กทม.
§อาชีพ : นักศึกษา
§ศาสนาพุทธ
§สิทธิการรักษา : ประกันสุขภาพทัGวหน้า รพ.รร. 6

3. Case Presentation
§ESRD (from Lupus nephritis) S/P CDKT เมษายน 2555
§HbE trait
§Major depressive disorder
§Myoma uteri with ovarian cysts

4. Case Presentation
§2551 :
§Present with RPGN (BUN 102 mg/dL , Cr 4 mg/dL)
kidney biopsy : LN class IV with 20% global sclerosis
§IVCY x 6 cycle à Mycophenolate mofetil (250) 1x2
pc , prednisolone (5) 4 x1 pc
§2552 :Turn ESRD on CAPD
§2553 :Teenage pregnancy with uncontrolled HT à
medical complete abortion
§2554 : refractory infected CAPD (cefazolin +
ceftazidime IP 14 d)à remove TK + shift mode to HD

5. Case Presentation
§เม.ย. 2555 : CDKT (PRA 0 % , HLA 1-2-0)
§Cold ischemic time 24 hr 52 min
§Warm ischemic time 40 min
§Induction regimen : IL-2 Antagonist , MMF,
Methylprednisolone
§Maintenance : MMF, tacrolimus, prednisolone
§กค. 2556 :Avascular necrosis of Right femoral head
S/P Rt.Total hip arthroplasty

6. Case Presentation
§ก.ย. 57 :Acute pyelonephritis (U/C : > 105 E.Coli ได ้
ceftriaxone IV 14 days)
§ US : Myoma uteri with overian cysts (Size 2 cm) with
condyloma accuminata
§พ.ย. 59 : Cr 1.8à 2.1 mg/dL
§ทํา kidney biopsy : Inadequate specimen , 11/13 glomeruli
global sclerosis , no morphologic evidence of acute
rejection seen , C4d negative, Sv40 - negative
§Baseline Cr = 1.7-1.8 mg/dL
§แผนก Pediatric Nephrology ส่งต่อมาเพืGอรักษาต่อเนืGอง

7. Present illness
§ 1 week PTA :
§ มีอาการปวดท ้องน้อย ร่วมกับมีประจําเดือน ปัสสาวะ
แสบขัดบางครัMง แต่ปริมาณปัสสาวะออกเท่าเดิม ไม่
บวม ไม่มีไข ้ทานได ้ไม่อาเจียน ไม่มีตกขาว
§ผู้ป่ วยไปพบแพทย์ทีGรพ. แพทย์แจ ้งว่าสงสัย กระเพาะ
ปัสสาวะติดเชืMอ ได ้รับยา norfloxacin (200) 1x2 o pc
มารับประทาน 5 วัน
§อาการยังไม่ดีขึMน มีปัสสาวะแสบขัดอยู่ รับประทาน
อาหารและนํMาได ้น้อยลง ไม่มีไข ้ไม่มีหนาวสัGน ไม่ปวด
ท ้องน้อย ไม่บวม ไม่มีอาเจียนหรือท ้องเสีย

8. Personal history
§Personal history
§ ปฏิเสธยาลูกกลอน/ยาสมุนไพร/ยาต ้ม/ยาชุด
§ ปฏิเสธดืGมสุรา สูบบุหรีG
§ ไม่มีสัตว์เลีMยงทีGบ ้าน
§ มีแฟน อายุ 21 ปี มี SI บางครัMง ใช ้Condom
§ Family history :
§ ปฏิเสธโรคไตในครอบครัว

9. Current medication
§ MMF (250) 2 tab at 0800 น. , 1 tab at 2000 น.
§ Advagraf (1) 6 tab OD at 0800 น.
§ Prednisolone (5) 1x1o pc
§ CaCO3 (1.5) 1 x1 o ac
§Vitamin D2 (20,000) 1 tab q 10 days
§ Sertraline (50) 1 ½ x 1 o pc
§ Clonazepam (0.5) 1 x 1 o hs
§ Ferrous fumarate (200) 1 x 2 o ac

10. Physical examination
§ V/S: BT 36.6 C, RR 22 /min, BP 128/81 mmHg, HR 70 /min BW 54 .2 kg
§GA:A youngThai woman, alert , follow to command
§HEENT: no pale conjunctivae, anicteric sclera, no thyroid gland enlargement
§LN: not palpable
§CVS: JVP 4 cm above sternal angle , normal S1 S2, no murmur
§Lungs: normal breath sound, crepitation both lower lungs
§Abdomen: mild distension, active bowel sound, soft, not tender, no guarding,
surgical scar at RLQ
§CVA not tender both side
§Extremities : No pitting edema both legs
§ Neuro : good consciousness , follow to command, no facial palsy

11. Problem lists
§ Dysuria with suprapubic pain in CDKT recipient (4 yr.) )
§ ESRD with Lupus nephritis
§ Major depressive disorder
§ HbE trait
§ Myoma uteri with ovarian cyst with condyloma accuminata
§ History of acute pyelonephritis
§ History of refractory infected CAPD
§ History of teenage pregnancy with medical abortion

12. What is provision diagnosis
and initial investigation?

13. Date Hb/Hct WBC PMN/L Plt BUN/Cr UA
23/2/60 8.9/28 19300 87.9/19 323000 28.8/2.6 pH 5.5 SpGr 1020 WBC:Numerous RBC 2-3 Bact :
numerous, Nitrite positive prot neg
Urine gram stain: numerous PMN , Gram negative
bacilli
Laboratory results

14. Date Na K Cl HCO3 Prograf
level
23/2/60 137 3.8 106 18 Advagraf (1) 6 tab , MMF(250) 2-0-1, pred 1x1
Laboratory results

15. Initial management
§CBC, BUN, Cr, electrolyte
§Repeat UA, urine C/S
§Ciprofloxacin (500) 1x2 o pc
§Force oral fluid 2-3 L/d
§Same dose immunosuppressive drugs

16. Date Hb/Hct WBC PMN/L Plt BUN/Cr UA
23/2/60 8.9/28 19300 87.9/19 323000 28.8/2.6 pH 5.5 SpGr 1020 WBC:Numerous RBC 2-3 Bact :
numerous, Nitrite positive prot neg
28/2/60 8.4/26.6 13600 75/19 371000 27.7/2.37 pH 6.5 SpGr 1005 WBC 30-50 RBC 0-1 Bact : few,
Nitrite negative, prot neg
Laboratory results

17. Date Na K Cl HCO3 Prograf
level
23/2/60 137 3.8 106 18 7.2 Advagraf (1) 6 tab , MMF(250) 2-0-1, pred 1x1
28/2/60 138 3.9 104 23 - Advagraf (1) 6 tab , MMF(250) 2-0-1, pred 1x1
Laboratory results

18. Urine CS
§>10^ 5 CFU/mL Escherichia coli
§ PIPERACI/TAZOB. …S
§ AMPICILLIN..... I
§ CEFTRIAXONE.... S
§ CEFTAZIDIME.... S
§ ERTAPENEM...... S
§ TRIMETHO/SULFA. S OXACILLIN...... – S
§ IMIPENEM....... S .
§ CEFOXITIN...... S
§ NORFLOXACIN.... R
§ CIPROFLOXACIN.. R
§ LEVOFLOXACIN... R
§ AMOXICIL/CLAV.. S
§ GENTAMICIN..... S
§ AMIKACIN....... S

19. What is your next management

20. F/U at OPD KT
§ เมืGอวาน มีไข ้สูงหนาวสัGน มีอาเจียน 2 ครัMงเป็นอาหาร และนํMา
, มีอาการปวดท ้องน้อย , ไม่มีปัสสาวะแสบขัด , ไม่มีตกขาว
, ไม่มีถ่ายเหลว
§ปัสสาวะออกเท่าเดิม , ดืGมนํMาวันละ 3-3.5 L/d
§BT 39.8 C, PR 133/min, BP 110/70 mmHg, RR14/m
§PE: Febrile , look fatigue, mild paled conjunctivae
§H/L : unremarkable
§Abd: Soft not tender, CVA negative both , allograft not
tender
§Ext: no edema
§NS :WNL

21. US abdomen
§Small size and increased parenchymal echogenicity of both native kidneys.
§Transplanted kidney shows mild hydronephrosis w/o cause of obstruction.
§No renal stone
§No perinephric collection
§The transplant kidney is 10.3 cm in length and 1.1 cm in thickness.
§Bladder partially distended without definite stone or gross mass.
§Two well-defined heterogeneous hypoechoic lesions in uterus, measuring
4.0x4.0 cm and 1.8x2.2 cm. DDx. myoma uteri or focal adenomyosis.
§2.6x2.2-cm cystic lesion at right adnexa is noted, probably corpus luteal cyst.
§No hydrosalpinx is detected.

22. Date Hb/Hct WBC PMN/L Plt BUN/Cr UA
23/2/60 8.9/28 19300 87.9/19 323000 28.8/2.6 pH 5.5 SpGr 1020 WBC:Numerous RBC 2-3 Bact :
numerous, Nitrite positive prot neg
28/2/60 8.4/26.6 13600 75/19 371000 27.7/2.37 pH 6.5 SpGr 1005 WBC 30-50 RBC 0-1 Bact : few,
Nitrite negative, prot neg
6/3/60 8.9/27.2 8000 75.9/14.8 257,000 29.9/2.42 pH 6.5 SpGr 1008 WBC 0-1 RBC 0-1 Bact : few,
Nitrite negative, prot neg
Laboratory results

23. Date Na K Cl HCO3 Prograf
level
23/2/60 137 3.8 106 18 7.2 Advagraf (1) 6 tab , MMF(250) 2-0-1, pred 1x1
28/2/60 138 3.9 104 23 - Advagraf (1) 6 tab , MMF(250) 2-0-1, pred 1x1
6/3/60 137 4 103 22 4.4 Advagraf (1) 6 tab , MMF(250) 1-0-1, pred 1x1
Laboratory results

24. Treatment
§Admit ward
§Repeat H/C, UA, U/C
§Request US KUB
§BK,CMV viral load
§Consult Gynecologist à R/O PID
§Ertapenem 0.5 gm IV q 24 hr (7 days)
§MMF(250) 1 tab at 09.00, 21.00
§Advagraf (1) 6 tab at 09.00 (prograf level = 4.4)
§Prednisolone (5) 1x1 pc
§Bactrim (400/80) 1x1 o pc
§Hemax 4000 u sc 2 /wk

25. Date Hb/Hct WBC PMN/L Plt BUN/Cr UA
23/2/60 8.9/28 19300 87.9/19 323000 28.8/2.6 pH 5.5 SpGr 1020 WBC:Numerous RBC 2-3 Bact :
numerous, Nitrite positive prot neg
28/2/60 8.4/26.6 13600 75/19 371000 27.7/2.37 pH 6.5 SpGr 1005 WBC 30-50 RBC 0-1 Bact : few,
Nitrite negative, prot neg
6/3/60 8.9/27.2 8000 75.9/14.8 257,000 29.9/2.42 pH 6.5 SpGr 1008 WBC 0-1 RBC 0-1 Bact : few,
Nitrite negative, prot neg
20/4/60 9.7/30.2 6700 78.5/16.8 400,000 23/2.3 pH 5 SpGr 1003 WBC 3-5 RBC 30-50 Bact : few,
Nitrite negative
Laboratory results

26. Date Na K Cl HCO3 Prograf
level
23/2/60 137 3.8 106 18 7.2 Advagraf (1) 6 tab , MMF(250) 2-0-1, pred 1x1
28/2/60 138 3.9 104 23 - Advagraf (1) 6 tab , MMF(250) 2-0-1, pred 1x1
6/3/60 137 4 103 22 4.4 Advagraf (1) 6 tab , MMF(250) 1-0-1, pred 1x1
20/4/60 138 4.6 102 20 5.3 Advagraf (1) 6 tab , MMF(250) 2-0-2, pred 1x1
Laboratory results

27. • UTI is frequent and important complication of kidney
transplantation
• Kidney allograft pyelonephritis may be associated with
bacteremia, metastatic spread, impaired graft function
and even death
• UTI occurs 25 % of KTRs within 1st year of transplant
UTI in
kidney transplantation recipients
Handbook of Kidney Transplantation
Ariza-Heredia EJ,et al. Ann Transplant 2013; 18:195.

28. Definitions
• Asymptomatic bacteriuria :
– >105 CFU/mL without local or systemic symptoms of UTI
• Uncomplicated UTI :
– > 105 CFU/mL with local urinary symptoms, such as dysuria, frequency, or
urgency, but no systemic symptoms
• Complicated UTI
– > 105 CFU/mL on urine culture with fever and either one of the following:
– allograft pain, chills, malaise
– bacteremia with the same organism in urine
– biopsy with findings consistent with pyelonephritis
• Recurrent UTI is ≥ 3 episodes of UTI in one year
Ruth M de Souza et al. Nature Reviews Nephrology , 252-264 , 2008

29. Pathogenesis
• Uropathogenic bacteria ascending from urethra to bladder
• Bacterial virulence structures, such as P fimbriae- promote adhesion
• Absence of sphincter between ureter and native bladder
• Ureteral stents and renal cysts can serve as reservoirs for bacteria
• Transplant pyelonephritis can occur by seeding of kidney from
bloodstream infection or surgical site infection.
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

30. Host factors
Preoperative factors Intraop factors Postoperative factors
Female sex Deceased donor kidney Excessive immunosuppression
Diabetes mellitus Infected donor organ
Graft dysfunction/rejection
Systemic illness treated with
steroids and
Use of a ureteric stent
Infection of native kidney/ureteric
stumps
Urinary tract abnormality
Duplex ureters Instrumentation of urinary tract
Extensive dialysis Prolonged urinary
catheterization
Re-transplantation
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

31. UTI in pediatric recipients
• Urinary tract malformations are more common (up to 25%)
– Vesicoureteric reflux (VUR)
• VUR progressed to pyelonephritis in 84% of cases
– Posterior urethral valves
– Prune belly syndrome
– Cloacal defects
– Reconstructed bladders
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008
Dunn SP et al.. J Pediatr Surg 22: 1095–1099,1987

32. Organism factors
• Gram-neg bacteria accounting > 70% of UTI in KTRs
– Enterococcus sp., E. coli and Enterobacter cloacae are the most common
– E. coli expresses type 1 P fimbriae increase bacterium’s adherence in urothelium
– Pseudomonas sp., Klebsiella sp. And P.mirablis
• Candida albicans are difficult to treat; fungal aggregates can obstruct outflow tract
• BK virus can cause BK nephropathy, typically in high-dose immunosuppression and BK
nephropathy can induce graft dysfuntion.
• Tuberculosis can be contracted by or reactivated in immunosuppressed patients
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

33. CLINICAL MANIFESTATIONS
• Lower urinary tract symptoms (cystitis)
– Frequency
– Urgency
– Dysuria
– Hematuria
– Suprapubic pain
• Upper urinary tract symptoms (pyelonephritis)
– Rigors and/or pyrexia
– Hematuria
– Loin pain in native kidney
– Pain over graft
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

34. CLINICAL MANIFESTATIONS
• Immunosuppressive therapy can mask the clinical manifestations and signs of
infection
• It is difficult to distinguish complicated UTI from acute rejection.
– Fever commonly associated with UTI.
– Tenderness directly associated with complicated UTI.
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

35. Screening
• Screening asymptomatic bacteriuria --> prevent symptomatic UTIs.
• Symptomatic UTIs have been associated with early graft dysfunction
• In order to screen : UA with U/C at 2, 4, 8, 12 wks posttransplant
• No regularly screen for asymptomatic bacteriuria after 3 months
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

36. Diagnosis
• Asymptomatic bacteriuria: Asymptomatic with >105 CFU/mL on U/C
• Uncomplicated and complicated UTI
– > 105 CFU/mL in the presence of associated clinical findings
– Positive leukocyte esterase, nitrites, blood, and protein and urine shows pyuria (> 10 WBC/HPF
of unspun urine)
• Corynbacterium urealyticum should be suspected in chronic UTI with negative U/C
– Alkaline urine (pH >7), pyuria or microscopic hematuria with no other explanation,
– presence of struvite crystals, obstructive uropathy, and encrusting cystitis or pyelitis
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

37. Evaluation after diagnosis
• US KUB for allograft , native kidney and bladder should be done in
– one month after transplantation
– History of nephrolithiasis or
– ≥ 2 episode within same year
• Recurrent UTI with normal US KUB à noncontrast CT of urinary tract (urinary strictures,
stones, and complex cysts. )
• Voiding cystourethrography à identify vesicoureteral reflux.
• Urodynamic studies à identify bladder dysfunction or outflow obstruction
• Cystoscopy à abnormalities in urethra or bladder
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

38. Treatment:
Asymptomatic bacteriuria
• ≤ 3 months after KT à Treatment to prevent symptomatic UTIs (associated with risk of acute allograft
rejection)*
• > 3 months of transplant à No consensus for treatment
– Patients with asx E. coli and Enterococcus bacteriuria suggested that presence of pyuria may be
used to identify benefit from antibiotic treatment compared with bacteriuria but no pyuria☨
• Selection of oral antibiotic based upon the susceptibility pattern of the microorganism.
• Most centers give antibiotics for 5 days.
• Commonly used regimens
– ciprofloxacin 250 mg orally twice daily, amoxicillin 500 mg orally three times daily,
and nitrofurantoin 100 mg orally twice daily
* Lee JR, Bang H, Dadhania D, et al.Transplantation 2013; 96:732.
☨El Amari EB, Hadaya K, Bühler L, et al.. Nephrol Dial Transplant 2011; 26:4109.

40. Treatment: Uncomplicated UTI
• Empirically treat with oral antibiotics
• Initial selection of ATB based local antibiotic resistance patterns and past causative organisms
• Commonly prescribed empiric treatment includes
– Ciprofloxacin 250 mg bid or
– Levofloxacin 500 mg OD
– If Enterococcus species are suspected à amoxicillin 500 mg tid or nitrofurantoin 100 mg bid
• Duration
– ≤ 6 mo after KT : 10-14 days of oral ATB
– > 6 mo after KT : 5-7 days of oral ATB
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

41. Treatment: Complicated UTI
• Empirical IV antibiotics that cover both gram-negative and gram-positive
bacteria.
• Empiric antibiotics adequate coverage against P. aeruginosa, enteric gram-neg
organisms, and Enterococcus species.
• Commonly regimens include
– piperacillin-tazobactam 4.5 g IV every 6 hr or
– meropenem 1 g IV every 8 hr , or
– vancomycin 15 mg/kg IV q 12 hr PLUS cefepime 1 g IV q 8 hr
• Duration : 14-21 days
• Oral ATB substituted for IV once free of symptoms and ATB susceptibilities are
known.
Ruth M de Souza et al. Nature Reviews Nephrology 4, 252-264 , 2008

42. PREVENTION
• Metaanalysis 6 RCTs (N= 545 KTRs) shown DS TMP-SMX prophylaxis à
– lower risk of sepsis and bloodstream infection (RR 0.13)
– lower risk of bacteruria (RR 0.41)
– Not reduce graft loss or mortality
• Most centers continue TMP-SMX for at least 6 months to 1 yr posttransplant
• No consensus for optimal preventive duration for UTI in era of antibiotic
resistance.
Green H et al .. Transpl Infect Dis 2011; 13:441.

43. PREVENTION
• We suggest that all KTRs receive UTI prophylaxis with daily TMP-SMX for at
least 6 months after transplantation. (2B)
• Dose : Single-strength pill (80 mg as trimethoprim) or double-strength pill
(160 mg as trimethoprim) daily or three times per week
• Use of TMP-SMX for first 9 months was associated with statistically significant
decreases in number of any bacterial infection, overall number of UTI and
number of noncatheter UTI.
• Data are not demonstrating clinical benefit beyond first 9 months
American Journal of Transplantation 2009; 9 (Suppl 3): Si–Si

44. Thank you for your attention