Chinese Herbs Nephropathy(CrCl 46 ml/min)

Analgesic Nephropathy(CrCl 39 ml/min)

Chronic 5-ASA Tubulo-Int. Nephritis (CrCl 25 ml/min)

Balkan Endemic Nephritis(CrCl 15 ml/min)

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Aristolochic acid associated nephropathy:Aristolochic acid associated nephropathy:PathologyPathology

Michel Depierreux et al - 1994

Extrarenal manifestations:• Aortic insufficiency• Peritoneal fibrosis• Periureteral fibrosis

The clinical and pathological manifestations of aristolochic The clinical and pathological manifestations of aristolochic acid nephropathy:acid nephropathy:Report of 58 casesReport of 58 cases

•• Acute tubular necrosisAcute tubular necrosisAcute tubular necrosisAcute tubular necrosis

•• Tubular dysfunction Tubular dysfunction –– degeneration atrophy degeneration atrophy –– R.T.A., R.T.A., Fanconi syndromeFanconi syndrome

•• Chronic aristolochic acid nephropathyChronic aristolochic acid nephropathy

Chen W et al: Zhonghua Yi Xue ZA Zhi 81: 1101-1105, 2001

Aristolochic acid associated Aristolochic acid associated nephropathy: nephropathy: PharmacologyPharmacology

Structure activity relationships of AA analogues: toxicity in Structure activity relationships of AA analogues: toxicity in l d i h li l lll d i h li l ll ii d h i i ld h i i lcultured epithelial cells cultured epithelial cells –– nitronitro-- and methoxygroup criticaland methoxygroup criticalBalachandran P et al: Kidney Int 67: 1797Balachandran P et al: Kidney Int 67: 1797--1805, 20051805, 2005

Studies on pharmacodynamic characteristics of AA I in ratsStudies on pharmacodynamic characteristics of AA I in ratsSu T et al: Zhonghuo Zhong Yao Za Zhi 29: 676Su T et al: Zhonghuo Zhong Yao Za Zhi 29: 676--681, 2004681, 2004

•• oral administrationoral administration

•• highest concentration in liver and kidneyhighest concentration in liver and kidney

•• partial metabolism in the liver and accumulation in the kidneypartial metabolism in the liver and accumulation in the kidney

Aristolochic acid associated Aristolochic acid associated nephropathy:nephropathy: Mechanism (1)Mechanism (1)

A i t l hi id i d h i lA i t l hi id i d h i lAristolochic acids induce chronic renal Aristolochic acids induce chronic renal failure with interstitial fibrosisfailure with interstitial fibrosisin saltin salt--depleted ratsdepleted rats

Debelle FD et al: JASN 13: 431Debelle FD et al: JASN 13: 431--436, 2002436, 2002

Rabbit model:Rabbit model:Cosyns JP et al:Cosyns JP et al:Cosyns JP et al:Cosyns JP et al:Chronic aristolochic acid toxicity Chronic aristolochic acid toxicity in rabbits: A model of Chinese in rabbits: A model of Chinese herbs nephropathy?herbs nephropathy?Kidney Int 59: 2164Kidney Int 59: 2164--2173, 20012173, 2001

Aristolochic acid associatedAristolochic acid associatednephropathy: nephropathy: Mechanism (2)Mechanism (2)

cont

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The reninThe renin--angiotensin system blockade angiotensin system blockade does not prevent renal interstitial fibrosis does not prevent renal interstitial fibrosis induced by aristolochic acidsinduced by aristolochic acids

Debelle FD et al: Kidney Int 66: 1815Debelle FD et al: Kidney Int 66: 1815--25, 200425, 2004

Dexfenfluramine does not enhance aristolochic Dexfenfluramine does not enhance aristolochic acid nephrotoxicity in ratsacid nephrotoxicity in rats

Debelle FD et al: Arch Toxicol 77: 218Debelle FD et al: Arch Toxicol 77: 218--225, 2003225, 2003

Aristolochic acid nephropathy: A worldwide problemAristolochic acid nephropathy: A worldwide problem

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Debelle FD et al, Kidney Int 74: 158-169, 2008

Aristolochic acid associatedAristolochic acid associatednephropathy:nephropathy: Physiopathology (1)Physiopathology (1)

Aristolochic acid impedes endocytosis and Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cellsinduces DNA adducts in proximal tubule cells

Lebeau C et al: Kidney Int 60: 1332, 2001Lebeau C et al: Kidney Int 60: 1332, 2001

Control

10 µmol AA

20 µmol AA

20 µmol AA+ 24h recovery

ControlControl 15 µM CdCl15 µM CdCl22

0.1% DMSO0.1% DMSO 20 µM AA20 µM AA

Control

10 µmol AA20 µmol AA20 µmol AA

+ 24h recovery

ControlControl 15 µM CdCl15 µM CdCl22

0.1% DMSO0.1% DMSO 20 µM AA20 µM AA

Aristolochic acid associatedAristolochic acid associatednephropathy:nephropathy: Physiopathology (2)Physiopathology (2)

Aristolochic acid impedes endocytosis and Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cellsinduces DNA adducts in proximal tubule cells

Lebeau C et al: Kidney Int 60: 1332, 2001Lebeau C et al: Kidney Int 60: 1332, 2001

Expression of megalin and exposure to aristolochic acid in OK cells: immunoblot analysis

Aristolochic acid associated Aristolochic acid associated nephropathy: nephropathy: Physiopathology (3)Physiopathology (3)

Synergetic effect of monocyteSynergetic effect of monocyte--chemotactic proteinchemotactic protein--1 and AA 1 and AA on transdifferentiation of human tubular epithelial cells on transdifferentiation of human tubular epithelial cells in in vitrovitro

Zheng F et al: Zhanghua Nei Ke Za Zhi 39: 831Zheng F et al: Zhanghua Nei Ke Za Zhi 39: 831--4, 20004, 2000

AAAA--induced apoptosis in LLCinduced apoptosis in LLC--PK1 cells and amelioration PK1 cells and amelioration of the apoptotic damage by calcium antagonistsof the apoptotic damage by calcium antagonists

Gao R et al: Chin Med J 113: 418Gao R et al: Chin Med J 113: 418--424, 2000424, 2000

Patients with AA nephropathy: mast cell infiltration Patients with AA nephropathy: mast cell infiltration ––proliferation of myofibroblastproliferation of myofibroblast

Wu Y et al: Hum Exp Toxicol 24: 1Wu Y et al: Hum Exp Toxicol 24: 1--7, 20057, 2005

Aristolochic acid associatedAristolochic acid associatednephropathy:nephropathy: TreatmentTreatment

•• Cortisone treatment Cortisone treatment –– unsuccessfulunsuccessful----successfulsuccessfulVanherweghem JL et al: Lancet 341: 387Vanherweghem JL et al: Lancet 341: 387--91, 1993,Am J Kidn Dis 27:209,9691, 1993,Am J Kidn Dis 27:209,96

Eff f l di E1 i h i f i l hiEff f l di E1 i h i f i l hi•• Effects of prostaglandin E1 in the progression of aristolochic Effects of prostaglandin E1 in the progression of aristolochic acid nephropathy: slowing of the progression (6 months)acid nephropathy: slowing of the progression (6 months)

Chin Med Sci J 20: 67Chin Med Sci J 20: 67--69, 200569, 2005

long dan xie gan wan long dan xie gan wan –– contains aristolochic acidcontains aristolochic acid

•• Chemoprotective effect of five drugs on renal interstitial fibrosis Chemoprotective effect of five drugs on renal interstitial fibrosis induced by an aristolochi acidinduced by an aristolochi acid--containing chinese herb in ratscontaining chinese herb in rats

Zhu S et al: Am J Nephrol 25: 23Zhu S et al: Am J Nephrol 25: 23--29, 200529, 2005

Simvastatin: shows a protective effect on development of renal fibrosis Simvastatin: shows a protective effect on development of renal fibrosis induced by Mu Tong (an aristolochic acidinduced by Mu Tong (an aristolochic acid--containing chinese herb)containing chinese herb)

•• TransgeneTransgene--derived hepatocyte growth factor attenuates reactive derived hepatocyte growth factor attenuates reactive fibrosis in aristolochic acid nephrotoxicityfibrosis in aristolochic acid nephrotoxicity

Okada H et al: Nephrol Dial Transplant 18: 2515Okada H et al: Nephrol Dial Transplant 18: 2515--23, 200323, 2003

possible therapeutic effect of lowpossible therapeutic effect of low--dose HGFdose HGF

Urothelial carcinoma associated with the use of a Chinese Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)herb (Aristolochia fangchi)

““ The prevalence of urothelial carcinoma among patients with endThe prevalence of urothelial carcinoma among patients with end--stage stage chinesechinese--herb nephropathy (caused by aristolochia species) is high”herb nephropathy (caused by aristolochia species) is high”

Mean duration of use and total doses of components of weight-reducing pills and levels of aristolochic acid–related DNA adducts

Nortier JL et al: New Engl J Med 342: 1686-92, 2000

Mild urothelial atypia Moderate urothelial atypia Severe urothelial atypia

Aristolochic acid associated nephropathy: Aristolochic acid associated nephropathy: UrotheliumUrothelium

2752

J-P Cosyns et al: Am J Kidney Dis 33: 1011-17, 1999

Aristolochic acid associated nephropathy:Aristolochic acid associated nephropathy:Urothelial carcinoma in situUrothelial carcinoma in situ

2752

J-P Cosyns et al: Am J Kidney Dis 33: 1011-17, 1999Overexpression of p53 protein

Chinese Herbs: Stromal InvasionChinese Herbs: Stromal Invasion

2752 SI

J-P Cosyns et al: Am J Kidney Dis 33: 1011-17, 1999

Chinese Herbs: Papillary Transitional Cell CarcinomaChinese Herbs: Papillary Transitional Cell Carcinoma

2752 PT

J-P Cosyns et al: Am J Kidney Dis 33: 1011-17, 1999

Urothelial carcinoma associated with the use of a Chinese Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)herb (Aristolochia fangchi)

Autoradiograms of DNA adducts in renal tissue Autoradiograms of DNA adducts in renal tissue from two patients with chinesefrom two patients with chinese--herb nephropathyherb nephropathy

Nortier JL et al: New Engl J Med 342: 1686-92, 2000

Aristolochic acid and the etiology of endemic (Balkan) Aristolochic acid and the etiology of endemic (Balkan) nephropathy nephropathy

HPLC MS and Quant. P32 postlabeling

DNA adducts found in renal cortex of patients with BEN

“signature”

mutation

Grollmann AP et al: PNAS 104: 12129-34, 2007

p53 mutational spectra in transitional cell carcinomas

AA adducts and mechanism of toxicity ???

Activation of p53 Promotes Renal Injury in AcuteActivation of p53 Promotes Renal Injury in AcuteAristolochic Acid (AA)NephropathyAristolochic Acid (AA)NephropathyLi Zhou,*† Ping Fu,* Xiao R. Huang,†‡ Fei Liu,*† Kar Li Zhou,*† Ping Fu,* Xiao R. Huang,†‡ Fei Liu,*† Kar Neng Lai,† and Hui Y. Lan†‡Neng Lai,† and Hui Y. Lan†‡

•• AA induced dephosphorylation of STAT3 and the subsequentAA induced dephosphorylation of STAT3 and the subsequent•• . AA induced dephosphorylation of STAT3 and the subsequent . AA induced dephosphorylation of STAT3 and the subsequent activation of p53 and TEC apoptosis.activation of p53 and TEC apoptosis.

•• In contrast, overexpression of STAT3, p53 inhibition, or p53 In contrast, overexpression of STAT3, p53 inhibition, or p53 knockdown with small interfering RNA all knockdown with small interfering RNA all attenuated attenuated AAAA--induced TEC apoptosis.induced TEC apoptosis.

•• These results suggest that AA induces TEC death These results suggest that AA induces TEC death via via apoptosis by dephosphorylation of STAT3 and posttranslational apoptosis by dephosphorylation of STAT3 and posttranslational p p y p p y pp p y p p y pactivation of p53, supporting the hypothesis that :activation of p53, supporting the hypothesis that :

•• p53 promotes renal injury in acute AAN.p53 promotes renal injury in acute AAN.

Li Zhou et al JASN 21: 31 – 41 ; 2010

Activation of p53 promotes renal injury in Activation of p53 promotes renal injury in acute aristolochic acid nephropathyacute aristolochic acid nephropathy

AA induced acute AAN at day 4 is yprevented in p53 KO mice

Li Zhou et al JASN 21; 31-41 ; 2010

Urothelial carcinoma associated with the use of a Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)Chinese herb (Aristolochia fangchi)

Rik f t f th li l iRiks factors for urothelial carcinoma in patients with end-stage Chinese herb nephropathy

Nortier JL et al: New Engl J Med 342: 1686-92, 2000

Aristolochic acid nephropathy: A worldwide Aristolochic acid nephropathy: A worldwide problemproblem

Chinese herb/AAN and /Balkan endemic nephropathy:the two faces of Janus?

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Debelle FD et al, Kidney Int 74: 158-169, 2008

Aristolochic acid induces proximal tubule apoptosis Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation and epithelial to mesenchymal transformation

Representative photomicro-graphs and time courseof the semiquantitative score of N-cadherin and Jones membrane staining

Pozdzik AA et al:Kidney Int 73: 595-607, 2008

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3022

Historical HennaHistorical Henna

Bangladesh 12th C. AD

Morocco

Knossos 1600 BC

Catherine Cartwright Jones

Persia 15th C. AD

Knossos 1600 BC

TakaoutTakaout: Hair Dye: Hair Dye

Natural Takaout El Beldia(Tamaris Orientalis) (Morocco).

•• NaturalNatural plantplant•• NoNonn toxictoxic•• RareRare•• Black dye hairBlack dye hair

Takaout Roumia(Paraphenylene diamine) (Soudan).

•• CC66HH44(NH(NH22))22

•• MineralMineral•• HighHighlyly toxictoxic•• Free sellingFree selling•• Black dye hairBlack dye hair•• Cosmetic agentCosmetic agent•• FilmsFilms

Poisoning with hairPoisoning with hair--dye containing dye containing paraphenylene diamine paraphenylene diamine

Renal failureRenal failure

•• Acute:Acute:•• IngestionIngestion

•• Suicidal attemptSuicidal attempt

•• Chronic:Chronic:•• Skin contactSkin contact

•• Focal glomerulosclerosisFocal glomerulosclerosisFocal glomerulosclerosisFocal glomerulosclerosis

Suliman SM et al: Saudi J Kidney Dis Transplant 6: 286-289, 1995

Takaout RoumiaTakaout Roumia(Paraphenylene diamine)(Paraphenylene diamine)

Intoxication due to massive topical use (Sudan).

Paraphenylene diamine intoxicationParaphenylene diamine intoxication

Glomerular (A) and tubular (B-D) lesions. H&E staining.

A. Glomerular swelling and hypercellulari-ty. B. Inflammatory cells are present around eosinophilic intraluminal material (arrow) Someeosinophilic intraluminal material (arrow). Some tubular epithelial cytoplasm is attenuated. C. Tubular basement membrane is distinct in some areas. D. Intraluminal inflammatory cells are seen with a small proteinaceous casts. The tubular basement membrane is indistinct.

Nephrotoxicity due to Chronic Paraphenylene Diamine (Hair Dye)Nephrotoxicity due to Chronic Paraphenylene Diamine (Hair Dye)

Hamdouck M Abdelraheem et al Aslam Kidney Center Khartoum Hamdouck M Abdelraheem et al Aslam Kidney Center Khartoum SudanSudan

•• 72 hairdressers ,Henna tattoo designers (mean age 40.3 72 hairdressers ,Henna tattoo designers (mean age 40.3 72 hairdressers ,Henna tattoo designers (mean age 40.3 72 hairdressers ,Henna tattoo designers (mean age 40.3 years) with chronic contact with PPDyears) with chronic contact with PPD

•• Duration of exposure varied from 1 to 21 years.Duration of exposure varied from 1 to 21 years.

•• Albuminuria 26.4%, haematuria 41.1%, anaemia 28.8% , Albuminuria 26.4%, haematuria 41.1%, anaemia 28.8% , hypertension 29.4% . hypertension 29.4% .

•• In eleven of the participants to this study renal funtion In eleven of the participants to this study renal funtion impairment was detected. 1.6impairment was detected. 1.6--26 mg /dl26 mg /dl

•• Chronic PPD exposure may cause renal dammage related Chronic PPD exposure may cause renal dammage related to duration and type of PPD used . to duration and type of PPD used .

•• Renal lesion is characterized by prominent interstitial Renal lesion is characterized by prominent interstitial fibrosis and tubular atrophy.fibrosis and tubular atrophy.

Different features of Chinese Herb NephropathyDifferent features of Chinese Herb Nephropathyand Balkan Endemic Nephritisand Balkan Endemic Nephritis

Chinese Herb Nephropathy Balkan Endemic Nephritis

Rate of progression rapid very slowKidney survival 2 years (17%) over 20 yearsExtrarenal manifestations

Aortic insufficiency documented in 40% not describedPeritoneal fibrosis described not foundPeriureteral fibrosis described not found

Urinary deposit aseptic leukocyturia, 40% scarce depositGross morphology

Kidney atrophy asymmetric, 54% symmetricOutline irregular, 31% smooth

Kidney morphology extensive interstitial fibrosisand loss of tubular structures interstitial fibrosis

DB Balkan 1

Kidney syndromes from alternative medicines (1):Kidney syndromes from alternative medicines (1):

•• Acute tubular necrosisAcute tubular necrosis•• Traditional African medicine: toxic plantsTraditional African medicine: toxic plants

((Securidaca longepedunculata, Euphorbia matabalensis, Crotalaria laburnifolia, Securidaca longepedunculata, Euphorbia matabalensis, Crotalaria laburnifolia, Heliotropium, Symphytum, Senecio plants, Callilepsis laureola, Atractylis gummifera, Heliotropium, Symphytum, Senecio plants, Callilepsis laureola, Atractylis gummifera, Cape aloesCape aloes) or adulteration by dichromates) or adulteration by dichromates

Colson CR & De Broe ME, 2005

Cape aloesCape aloes) or adulteration by dichromates) or adulteration by dichromates

•• Sri Lankan traditional Ayuverdic pharmacopoeia: toxic plantsSri Lankan traditional Ayuverdic pharmacopoeia: toxic plants((Crotalaria species, Cassia auriculata, Hollarrhena antidysentericaCrotalaria species, Cassia auriculata, Hollarrhena antidysenterica))

•• Asian rural areas: raw carp bileAsian rural areas: raw carp bile

•• Saudi Arabia: raw sheep bileSaudi Arabia: raw sheep bile

•• China: China: Taxus celebricaTaxus celebrica

•• Hydrazine sulfateHydrazine sulfate

•• Mentha spicataMentha spicata

•• Chi h b t i t d ith i (Chi h b t i t d ith i (Ni H Chi h t PiNi H Chi h t Pi ))•• Chinese herbs contaminated with arsenic (Chinese herbs contaminated with arsenic (Niu Huang Chieh tu Pien,…Niu Huang Chieh tu Pien,…))

•• Morocco: Morocco: Takaout roumiaTakaout roumia (paraphenylenediamine, PPD)(paraphenylenediamine, PPD)

•• Sudan: henna adulterated with PPDSudan: henna adulterated with PPD

•• CantharidinCantharidin

•• Chelation therapy with EDTAChelation therapy with EDTA

3360

Kidney syndromes from alternative medicines (2)Kidney syndromes from alternative medicines (2)•• Proximal tubulopathy (Fanconi’s syndrome)Proximal tubulopathy (Fanconi’s syndrome)

•• Glycyrrhiza speciesGlycyrrhiza species (herbal cough mixtures, (Chinese) herbal teas, gancao, Boui(herbal cough mixtures, (Chinese) herbal teas, gancao, Boui--ougiougi--toutou

•• Chinese herbs contaminated with cadmiumChinese herbs contaminated with cadmium

•• Distal tubular toxicityDistal tubular toxicity•• Germanium Germanium

Colson CR & De Broe ME, 2005

•• Acute interstitial nephritisAcute interstitial nephritis•• Traditional African medicine: toxic plantsTraditional African medicine: toxic plants (Cape Aloes)(Cape Aloes)

•• Peruvian medicinePeruvian medicine (Uno degatta)(Uno degatta)

•• China: Taxus celebricaChina: Taxus celebrica

•• Chinese herbs adulterated with non steroidal antiChinese herbs adulterated with non steroidal anti--inflammatory drugs:inflammatory drugs: (Tung (Tung Shueh pills) Shueh pills)

•• Hypericum, ledumHypericum, ledum

•• Analgesic nephropathy,Papillary necrosisAnalgesic nephropathy,Papillary necrosis•• Willow barkWillow bark (Salix species)(Salix species)

•• Chinese herbs adulterated with non steroidal antiChinese herbs adulterated with non steroidal anti--inflammatory drugs inflammatory drugs (indomethacine, diclofenac, mefenamic acid, phenylbutazone): (indomethacine, diclofenac, mefenamic acid, phenylbutazone): Chuifong Chuifong Tuokuwan, Tung ShuehTuokuwan, Tung Shueh pills, otherpills, other

•• HypertensionHypertension•• Glycyrrhiza speciesGlycyrrhiza species (herbal cough mixtures, (Chinese) herbal teas, gancao, Boui(herbal cough mixtures, (Chinese) herbal teas, gancao, Boui--

ougiougi toutou3360

Kidney syndromes from alternative medicines (3)Kidney syndromes from alternative medicines (3)•• Kidney stonesKidney stones

•• Ephedra containing herbal preparations (Ephedra containing herbal preparations (Ma huang, Ma huang, dietary supplements dietary supplements containing ephedra alkaloids)containing ephedra alkaloids)

•• Cranberry juice (oxalate)Cranberry juice (oxalate)

•• With cadmium contaminated Chinese herbsWith cadmium contaminated Chinese herbs

•• Urinary retentionUrinary retentionNiNi D iD i (S bi(S bi l bi)l bi) 66

Colson CR & De Broe ME, 2005

•• Niger: Niger: Datura speciesDatura species (Sobi(Sobi--lobi) lobi) [[5656]]

•• Chinese herbs: Chinese herbs: Rhodondendron molle, Rehmania glutinosa, Carthamus tinctorius, Rhodondendron molle, Rehmania glutinosa, Carthamus tinctorius, Atropa belladona, Hyoscyamus niger, Datura speciesAtropa belladona, Hyoscyamus niger, Datura species

•• Acute interstitial nephritisAcute interstitial nephritis•• Traditional African medicine: toxic plantsTraditional African medicine: toxic plants (Cape Aloes)(Cape Aloes)

•• Peruvian medicinePeruvian medicine (Uno degatta)(Uno degatta)

•• China: Taxus celebricaChina: Taxus celebrica

•• Chinese herbs adulterated with non steroidal antiChinese herbs adulterated with non steroidal anti--inflammatory drugs:inflammatory drugs: (Tung (Tung Shueh pills) Shueh pills)

•• Hypericum, ledumHypericum, ledum

•• Chronic tubuloChronic tubulo--interstitial nephritis with fibrosisinterstitial nephritis with fibrosis•• Chinese herbs containing Aristolochia sp.: Belgian slimming regimen, Mokutsu, Chinese herbs containing Aristolochia sp.: Belgian slimming regimen, Mokutsu,

BouiBoui

•• China: Jia Wey Guo Sao pills (herbal mixture, no aristolochia) China: Jia Wey Guo Sao pills (herbal mixture, no aristolochia)

•• Urinary tract carcinomaUrinary tract carcinoma3360

Chronic kidney disease of unknown Chronic kidney disease of unknown etiology in Sri Lankaetiology in Sri Lanka

•• Slow, progressive, asymptomatic developmentSlow, progressive, asymptomatic development

•• Age less than 20 years at startAge less than 20 years at start

•• Men working in agricultureMen working in agriculture

•• ESRF 40ESRF 40--60 yrs60 yrs

•• AnaemiaAnaemia

•• Bilateral small kidney, loss of corticoBilateral small kidney, loss of cortico--medullary medullary diff ti ti R l bi t b t h fib idiff ti ti R l bi t b t h fib idifferentiation.Renal biopsy ,tub atrophy,fibrosis.differentiation.Renal biopsy ,tub atrophy,fibrosis.

•• Hypertension is not prevalentHypertension is not prevalent

•• Ochratoxin excluded, cadmium;other environm toxin???Ochratoxin excluded, cadmium;other environm toxin???

Chronic kidney disease of unknown etiologyChronic kidney disease of unknown etiologyin Sri Lankain Sri Lanka

Teaching hospital Teaching hospital Anuradhapua Anuradhapua -- ↑↑ of of deaths to CKDdeaths to CKD

Anual health bulletin Anual health bulletin 2005: 19802005: 1980--20052005doubling of doubling of genitourinary system genitourinary system diseasesdiseases

Mortality due to renal Mortality due to renal causes:causes:

VanumijaVanumija firstfirst

AnuradhapuraAnuradhapura 3th3thAnuradhapuraAnuradhapura 3th3th

PolonnarunaPolonnaruna 4th4th

JaffinaJaffina 6th6th

National task forceSecretary Ministry of Health, Country Representative WHO and others

Technical Steering committee International

OrganigramOrganigram

advisory committee

Lead investigatorsof main studies

---------------------------Central database management

(Imperial College/WHO HQ)

advisoryboard

Project field officer

collection of samples• renal biopsy • post mortem tissues

environmental studies

• epidemiological survey• case control studies• diet studies