Formula and Failure Melamine and Kidney Disease in Children by rjh17349

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									                               3/16/2009




Formula and Failure:
Melamine and Kidney
Disease in Children
Dr Maury Pinsk
Dr.
Pediatric Nephrologist,
Stollery Children’s Hospital




              ****,




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Objectives
 Review the events leading up to the marketing
 and distribution of melamine-contaminated
 products in world food markets
 Understand the pathophysiology of melamine
 toxicity in the kidney
 Discuss recommendations and supporting
 evidence for screening infants and children
 exposed to melamine-contaminated products




Case
 Chinese immigrant family
 for Canadian Immigration
 physical
 9 month old child
 Not clear if exposed to
 melamine contaminated
 formula
 Child is asymptomatic
 and growing well
 What do you do?




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Your options
 A.
 A renal ultrasound
 B. serum creatinine
 C. urinalysis
 D. urinary melamine level
 E.
 E watch and wait




Sickness in children throughout
Asia related to contaminated
 o ua
formula

 Sept 20-21 2008
   Ministry of Health in China reported 52,857
   children sought medical treatment
     12,900 hospitalized
     4 deaths from kidney failure




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                                                      http://chinadigitaltimes.net




22 dairies in China found to have melamine in
milk
  Ranged from 0.09-2,560 ppm
  Canadian Food Inspection Agency max: 2.5 ppm,
  0.5 ppm for formula
                           p
So how does melamine show up in milk?




             WHO, WEEKLY EPIDEMIOLOGICAL RECORD, NO. 38, 26 SEPTEMBER 2008
        CFIA, http://www.hc-sc.gc.ca/fn-an/securit/chem-chim/melamine/qa-melamine-qr-eng.php#8




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An interest in melamine..
          Anying            company,
 Xuzhou Anying, a Chinese company advertising
 “dust of melamine” as “ESB protein powder” on
 the global market trading website, Alibaba.
 “The latest product, ESB protein powder, which
 is researched and developed by Xuzhou Anying
 Biologic Technology Development Co., Ltd…
                            percent,
 contains protein 160 - 300 percent which
 solves the problem for shortage of protein
 resource,”


   http://www.sciencebase.com/science-blog/melamine-and-kidney-failure.html




An interest in melamine
 Maximum solubility of melamine at RT =
 3.1 g/L
 Can increase protein determination in milk
 by 1.2%
  qu a e o overestimation of protein
 Equivalent to o e es a o o p o e
 content by 30%
                                                          Hau 2009 JASN




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But the truth is…
 Possible implication in North Korean infant deaths 2005
 (North Korean News, Oct 2008)

 Pesticide residues of cyromazine convert to melamine in
 vivo (Joint FAO/WHO Meeting on Pesticide Residues, WHO 2007)
 Common practice to add melamine to livestock feed
 along with sodium nitrite, urea, ammonia, silica,
 potassium nitrate, sodium nitrite, glacial acetic acid,
 activated carbon materials, urea, ammonia, potassium
 nitrate, to improve its nutritional profile and other
 properties of the feed (Epoch Times, Oct 5, 2008)




But the truth is…
 Additive urea to foodstuffs in North America has
 been practiced as recently as 1985
 (http://www.theregister.co.uk/2008/10/06/china_melamin
 e_scare/ )
 The use of melamine in this context contravenes
 international regulations where they exist.




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Sound familiar?…
 Pet food
 contaminated with
 melamine found in
 wheat gluten.
 Wheat gluten often
 contains melamine
 when used in textile
 manufacturing,
 Scheyer (2000)




Menu Foods Recall
 Cianciolo (2008): Clinicopathologic findings in 70
 cats fed contaminated food
   Polydypsia, polyuria, anorexia, dehydration, vomiting
   Azotemia, anemia
   Pathology:
      Acute tubular necrosis
      Interstitial nephritis
      Crystalluria




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What the crystals look like…



    Low power                          1000x




                         SEM
                            www.labservices.uoguelph.ca/urgent.cfm




How safe is melamine?
 (Can I use my renovation tax rebate to save kidneys?)




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Back in the day…




 Doses up to 36 mg/kg had no untoward effect on
 dogs dosed 15 times/7 months
 Bladder stones were noted, but attributed to
 more than 150 bladder catheterizations in that
 period (1 animal).




So is Melamine toxic?
 LD50 =
   3200-3800 mg/kg in rats
   3300-7000 mg/kg in mice
 Rats:
   Nephrolithiasis, interstitial fibrosis
      0.225-0.9% of diet
      >0.45% - bladder transitional cell carcinoma
 Sheep
   >200 mg/kg/d – renal failure, nephrolithiasis
 Cats and Dogs
   1% pure melamine diet = NO renal injury, Puschner
   (2007)




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Melamine disposition in mammals

 No evidence for metabolism
 Mast 1983
    Wistar rats – radiolabelled melamine po
    Vd = TBW, accumulation in the kidney
 Baynes 2008*
    IV administration in weanling pigs
    Low Vd, rapid renal clearance
 Est. blood clearance in 28 hours to achieve safe
 level of melamine (50 mcg/mL) (USDA 2007)




So why are there crystals?




Crystals from affected         Crystals when melamine
      cat urine                added to normal cat urine

                 Not melamine stones?
                                               Ciancolo 2008




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Further data from Menu Food
Recall
 Urine and stone analysis from affected
 dogs and cats showed the presence of
 melamine, along with cyanuric acid in the
 stone material.
 Cyanuric acid can be a breakdown product
    melamine
 of melamine, and is used in the
 manufacture of melamine
 Other sources




Cyanuric acid
 Cyanuric acid is a breakdown product of
 chloroisocyanurates
 Chloroisocyanurates are present in:
   Swimming pool chlorination
   Municipal water treatment
   Dishwasher (
   Di h              hi ) detergents
           h (machine) d t        t
 Also breakdown product of melamine by
 bacteria
   Klebsiella spp. Pseudomonas spp.




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Cyanuric acid toxicity
                           rat, mice,
 Evaluated for toxicity in rat mice and
 dogs
            (Hammond et al., 1986; Hodge et al., 1965)
 a similar spectrum of effects as melamine:
   Diuresis
   At high concentrations bladder calculi
   No indications of renal toxicity or kidney
   tubule precipitates




How dangerous in cyanuric acid?

                                   7.7g/kg
 LD 50 of cyanuric acid in rats is 7 7g/kg
              http://www.cfsan.fda.gov/~dms/melamra.html. May 25, 2007   .
 Considered to be non toxic




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How dangerous in cyanuric acid in
humans?
 Allen (1982): Examined disposition of
 cyanuric acid from consumed pool water in
 5 swimmers
   >98% excretion, complete by 20h, no
   metabolism, no untoward effects
 Dufour (2006)
   Modified methodology to use cyanuric acid to
   calculate amount of ingested pool water
   Kids ingest more than adults (!)




       cyanuric acid           melamine




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Which leads to this…




And now back to the problem
 The Chinese milk contamination was done
 with relatively pure melamine, so cyanuric
 acid not present at outset
 Stones removed from affected children
 were described as soft and “uric acid-like”,
 but not submitted to formal analysis.
 http://www.moh.gov.cn/publicfiles///business/cmsresources/mohyzs/cmsrsdocument/doc2317.doc




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Mechanisms for stones studied
 Lam et al (Cli Chi A t 402 2009)
           (Clin Chim Acta 402:2009)

 Studied 14 patients with stones associated with
 contaminated formula 10 days after cessation of
 formula
 Examined urinary chemistry, including melamine
                    levels.
 and cyanuric acid levels Did not do stone
 analysis.
 Compared stone formers (15) with non stone
 formers (20), all with exposure




Patient characteristics stone
formers
Male               11/15
Asymptomatic       10/15
Symptoms           UTI                    1/7
                   Dysuria                3/7
                   Hematuria              1/7
                   Vomiting               1/7


                               Lam et al (Clin Chim Acta 402:2009)




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Laboratory abnormalities
Elevated creatinine              2/9* (6 unmeasured)
                                 2/9
Elevated urea                    2/9* (6 unmeasured)
Elevated Urine Ca                2/14 (1 unmeasured)
Elevated Urine urate                      5/15
Elevated urine oxalate           1/14 (1 unmeasured)
         < 7.0
Urine pH <= 7 0                          15/15
Elevated urine protein                    3/15
Elevated urine microalbumin               2/15
Elevated B2-microglobulin        2/12 (3 unmeasured)




Comparison with control subjects

     Urine chemistries        OR        95%ile CI           P

 Melamine >7.1 mcg/mmol       7.33     1.29 - 41.65       0.04
Cyanuric acid > 10 mcg/mmol   0.83      0.15 - 4.53       0.82
 Uric acid > 0.9mmol/mmol     4.00     0.93 -17.30        0.12
      Urine pH < 7.0          4.33    0.45 – 42.02        0.38



                              Lam et al (Clin Chim Acta 402:2009)




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No significant difference in urinary calcium,
phosphate, magnesium
No significant difference in proteinuria, of any
sort
Authors correlated stone size with urinary
melamine concentration
Authors concluded that cyanuric acid not
important in stone formation – likely urate.
Stated stones are dissimilar from those obtained
from animal studies…..




Urine from affected infant                Uric acid crystals (human)




   Cyanuric acid + melamine (cat)   Melamine crystals (cat, in vitro)




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So renal failure develops in a few..
 Probably multifactorial, but probably includes effect of
 cyanuric acid
 Obstructive uropathy possible, but more likely ATN
 Also inflammatory effect causing interstitial nephritis
    Concentrating mechanisms lost – polyuria
 Moderated by:
    Hydration status
    Load of melamine
    Lithogenic chemistry of urine (salt, urate, citrate)




So what guidelines have been
published for asymptomatic child?
 American Society of Pediatric Nephrology
    No evaluation
    http://www.aspneph.com/ASPNStatement%20Melamine%20Oct22_cbl%20(3).pdf


 Public Health Agency of Canada
    Serum creatinine and ultrasound
  http://www.phac-aspc.gc.ca/media/cpho-acsp/080928melamine_bkg-eng.php#i

 Canadian Pediatrics Society
    In Press: Buka, I et al Pediatr Child Health 14(4): April 2009




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Recent data (hot off the press)
             (NEJM,
 Wang et al (NEJM Feb 3 2009 online)
 1129 Taiwanese children, Sept 24-Oct 23 2008
 exposed to melamine containing milk products
 Assessed risk factors for complication based on
 reported level of exposure: > 2.5 ppm, 0.05-2.5
 ppm and used control population data




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Application of data to clinical
setting
 Younger children tended to higher incidence of
 stones (not clinically significant)
                 10
                  9
                  8
                                       *
       Age (y)



                  7
                  6
                  5
                  4
                  3
                  2
                  1
                  0
                      Stones          No Stones


                               * p=0.009




Application of data to clinical
setting
 Symptoms did not differentiate those with
 stones
 Prems were at higher risk of stones than
 FT infants
   os children       d ey stones ad o
 Most c d e with kidney s o es had no
 urinary abnormalities




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 Should we do an ultrasound?
         I know the patient was exposed to melamine contaminated food

                 Positive Negative                                 Positive Negative
                   US       US                                       US       US
High exposure         9        35                High exposure        23          98
  > 2.5 ppm                                        > 500 ppm
Low exposure          2       605                Low exposure         19          281
0.05-2.5 ppm                                       <150 ppm


    OR: 77.79 (16.19-373.75)                               OR: 3.47 (1.81-6.65)
           P<0.0001                                             P<0.0001

        (Taiwan, Wang)                                        (Beijing, Guan)


                                                                               NEJM 2009




    Should we do an ultrasound?
     I do NOT know the patient was exposed to melamine contaminated food
                        but the patient has lived in Asia
      Taiwan, Wang               Hong Kong                Beijing, Guan

              Positive    Negative                                    Positive Negative
                US          US                                          US       US

   Any           11         640                          Any            41          380
 Exposure                                              exposure

    No           1          477                           No               8        160
 exposure                                              exposure



        OR 8.20 (1.06-63.72)                                  OR: 2.16 (0.99 – 4.71)

                 P = 0.035                                           P = 0.070
            Incidence: 11:1000       Incidence: 3.7:1000        Incidence: 83:1000
                                                                                   NEJM 2009




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                                 http://chinadigitaltimes.net




My suggestions….
 If the patient is symptomatic has known
 exposure to melamine-contaminated
 product:
   Blood work, US, referral to
   nephrology/urology




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                                             3/16/2009




 If the patient is asymptomatic with known
 exposure to melamine contaminated
 product
   Higher chance of positive US
   What are implications for asymptomatic
   patient with stone?




Your options: Asymptomatic child
with unknown exposure?
 A renal ultrasound ?
 A.
 B. serum creatinine
 C. urinalysis
 D. urinary melamine level
 E.
 E watch and wait




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             3/16/2009




Questions?




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