Eric Yarnell, ND, RH(AHG)

2013

VESICOURETERAL REFLUX

Figure 1 Diagram of the bladder submucosal tunnel

Reference: Cooper 2009Normal Short

Figure 2 International Reflux Grading System

Reference: Cooper 2009

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Figure 7. Grading of vesicoureteral reflux with the International Reflux System.

Reference: Fernbach 2000

©2000 by Radiological Society of North America

EVALUATION

To diagnose VUR:

VCUG: urethral/bladder function assessed, requires catheter

Nuclear cystograph: to assess kidney function and structure

Other assessments:

Kidney/bladder US: to see gross defects

IVP: visualizes entire urinary tract

DMSA scintigraphy: to assess renal scarring

MONITORING

UTI incidence

Blood pressure

Urine creatinine

Urine microalbumin

Renal ultrasound (if no scarring and no UTI x 5 yr, stop monitoring)

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ANTIBIOTIC PROPHYLAXIS?

Increases resistance without decreasing UTI incidence in huge study, n = 74,974 (Conway 2007).

That includes VUR kids (stage 4-5 most likely to get recurrent UTI)

Trial showing no prevention of pyelonephritis or renal scarring in 100 Italian kids with VUR II-V vs. no tx, 4 yr follow-up (Pennesi 2008)

SURGERY?

Indication for referral: VUR III+ with multiple recurrent UTIs, pyelonephritis, or signs of kidney damage

Not superior to medical tx in randomized trial (Smellie 2001)

“It is uncertain whether the treatment of children with VUR confers clinically important benefit. The additional benefit of surgery over antibiotics alone is small at best. Assuming a UTI rate of 20% for children with VUR on antibiotics for five years, nine re-implantations would be required to prevent one febrile UTI, with no reduction in the number of children developing any UTI or renal damage.” (Hodson 2007)

NATURAL TREATMENT PRINCIPLES

Bacterial adhesion inhibitors; probiotics

Immunostimulants, immunomodulators

Urinary tract tonics

Antifibrotics

Treat acute UTIs; if not much better in 24-48 h resort to antibiotics

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Vacciniummacrocarpon

V. ovatum © 2012 G. Maroney, used with permissionV. macrocarpon © 2013 E. Yarnell

CLINICAL TRIAL 1

Japanese children (n=7 boys, 5 girls) with VUR I-IV given 100 ml juice concentrate (“50%”) qd

Controls: 11 boys, 8 girls given cefaclor 5--10 mg/kg

3--27 mon follow-up

UTI (defined as fever, elev CRP, 106 CFU/ml) occurred in 2 pt in each group (not significantly different)

Reference: Nishizaki 2009

CLINICAL TRIAL 2

Italian children n=186, double-blind trial, 1 yr follow-up

Randomized to cranberry juice (“2.8% extract”) or trimethoprim syrup

No difference in UTI rates between groups

Subgroup with high ferulic acid levels in urine did have higher UTI rate. Difference in grain intake, or gut flora?

Ref: Uberos 2012

HO

H3COOH

O

ferulic acid

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CRANBERRY INTERACTIONS

No interaction with cefaclor or amoxicillin in humans (Li 2009)

Sulfamethoxazole-trimethoprim: unknown, unlikely

Nitrofurantoin: unknown, unlikely

Confusing data on warfarin interactions

Safe in pregnancy (Wing 2008)

MISC ADHESION INHIBITORS

Vaccinium vitis-idaea (lingonberry)

Equisetum arvense (horsetail)

Betula pendula (birch)

Galium odoratum (sweet woodruff)

Urtica dioica (nettle) leaf

Herniaria glabra (rupturewort)

Zea mays (corn) stigmata

Elymus repens (couch grass)

Reference: Rafsanjany 2013;

Wojnicz 2012

Betula papyrifera © 2013 E. Yarnell

Mahonia aquifolium

N+

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11

O

O

OCH3

OCH3

M. aquifolium © 2013 E. Yarnell

M. aquifolium © 2013 Heron Botanicals,used with permission

O

OH

HO

O

O

OOH

O

OH

O

berberine

5’-methoxyhydnocarpin

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BERBERINE

In vitro, assembly of fibrimiae by uropathogenic E. coli inhibited by berberine (Sun 1988).

In vitro, blocks biofilm formation by Strep. epidermidis (Wang 2009).

In vitro, inhibits MRSA adhesion, also synergistic with ampicillin and oxacillin, even restoring their efficacy (Yu 2005)

Equisetumarvense

E. arvense © 2013 E. Yarnell

Galiumaparine

Galium spp © 2013 E. Yarnell

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Parietariajudaica

P. judaica © 2013 Heron Botanicals,used with permission

Parietariafloridiana

P. floridiana © 2013 E. Yarnell

Echinaceaangustifolia

E. pa$ida © 2013 E. Yarnell

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Codonopsispilosula(dǎngshēn)党参

C. pilosula © 2013 E. Yarnell

Astragalusmembranaceus(huángqí)黃芪

C. pilosula © 2013 E. Yarnell

Anti-kidney scarring(Lu 1997)

Centellaasiatica

C. asiatica © 2013 Heron Botanicals,used with permission

C. asiatica © 2013 E. Yarnell

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ACUTE UTI TREATMENT

Definition: fever, pyuria, >106 CFU/ml bacteriuria

Rest, no sweets, pungent foods, avoid sugar

Juniperus communis aril tincture 3-10 gtt q2h

Echinacea angustifolia fresh root tincture 2.5 ml (0.5 tsp) q2h

Urtica dioica leaf tea, 0.5-1 cup 4-5 times a day

Reminder: if not significantly better in 24-48 h, antibiotics

CASE STUDY

2-yo white girl, grade I (left), II (right) VUR, good diet/lifestyle, no other health issues

Two confirmed UTIs to date, recovered quickly from both with antibx

Parents prefer no antibx, ND rx cranberry powder and D-mannose

One-year follow-up: one instance of culture-negative UTI-like sx (with pyuria), no need for antibx

REFERENCES

Conway PH, Cnaan A, Zaoutis T, et al. Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA 2007;298(2):179-86.

Cooper CS. Diagnosis and management of vesicoureteral reflux in children. Nat Rev Urol 2009;6(9):481-9.

Fernbach SK, Feinstein KA, Schmidt MB. Pediatric voiding cystourethrography: a pictorial guide. Radiographics 2000;20(1):155-68; discussion 168-71.

Hodson EM, Wheeler DM, Vimalchandra D, et al. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2007;(3):CD001532.

Li M, Andrew MA, Wang J, et al. Effects of cranberry juice on pharmacokinetics of beta-lactam antibiotics following oral administration. Antimicrob Agents Chemother 2009;53(7):2725-32.

Lu Y, Li JZ, Zheng X. Effect of Astragalus Angelica mixture on serum lipids and glomerulosclerosis in rats with nephrotic syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi 1997;17(8):478-80 [in Chinese].

Nishizaki N, Someya T, Hirano D, et al. Can cranberry juice be a substitute for cefaclor prophylaxis in children with vesicoureteral reflux? Pediatr Int 2009;51(3):433-4.

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Pennesi M, Travan L, Peratoner L, et al. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008;121(6):e1489-94.

Rafsanjany N, Lechtenberg M, Petereit F, Hensel A. Antiadhesion as a functional concept for protection against uropathogenic Escherichia coli: in vitro studies with traditionally used plants with antiadhesive activity against uropathognic Escherichia coli. J Ethnopharmacol 2013;145(2):591-7.

Smellie JM, Barratt TM, Chantler C, et al. Medical versus surgical treatment in children with severe bilateral vesicoureteral reflux and bilateral nephropathy: A randomised trial. Lancet 2001;357:1329-33.

Sun D, Abraham SN, Beachey EH. Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli. Antimicrob Agents Chemother 1988;32(8):1274-7.

Uberos J, Fernández-Puentes V, Molina-Oya M, et al. Urinary excretion of phenolic acids by infants and children: a randomised double-blind clinical assay. Clin Med Insights Pediatr 2012;6:67-74.

Wang X, Yao X, Zhu Z, et al. Effect of berberine on Staphylococcus epidermidis biofilm formation. Int J Antimicrob Agents 2009;34(1):60-6.

Wing DA, Rumney PG, Preslicka CW, et al. Daily cranberry juice for the prevention of asymptomatic batteriuria in pregnancy: a randomized, controlled pilot study. J Urol 2008;180:1367–1372.

Wojnicz D, Kucharska AZ, Sokół-Łętowska A, et al. Medicinal plants extracts affect virulence factors expression and biofilm formation by the uropathogenic Escherichia coli. Urol Res 2012;40(6):683-97.

Yu HH, Kim KJ, Cha JD, et al.Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. J Med Food 2005;8(4):454-61.

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