Mesoamerican nephropathy vs CKDu in Thailand CKDu in Thailand Chagriya Kitiyakara MBBS FRCP Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok
Talk outline Criteria for CKDu Thailand CKDu Data from National Health Examination surveys V (2015) Selected risk factors for CKDu in Thailand Data from CKDNET
CKD of unknown etiology (CKDu) • A new form of severe CKD without common underlying factors: diabetes, hypertension, or glomerulonephritis • Most data from Central America and South Asia:-epidemic proportions mainly in men from agricultural communities and laborers • Biopsy shows predominantly chronic tubulointerstitial disease • Clinical criteria highly variable: • Different criteria in different parts of the world- some only include age<70 or Age <60
Meso America Sri Lanka Suspected • CKD as measured by eGFR <60 or albuminuria • eGFR < 60 or albuminuria > 30 mg/g Presence of > 30 mg/g Exclusion of • Age < 60 years • ? (Age>70) • Diabetes • Diabetes (self reported or diagnosed • Self reported hypertension in clinic) • Self reported • Hypertension on treatment or BP Autoimmune, hematologic or hereditary >=160/100 on two measurements kidney disease • Proteinuria > 2 g/day
Meso America Sri Lanka Probable • A suspect case with CKD on repeat • A suspect case with CKD on repeat testing Presence of testing performed 12 weeks later Exclusion of -- • Ultrastructural abnormalities on ultrasound Confirmed • Clinical suspicion of other known causes of Presence of CKD • Diabetes based on fasting plasma glucose < Exclusion of 126 mg/dL. • Hematuria No ultrastructural abnormalities on histopathological features consistent with kidney Ultrasound CKDu on the biopsy Bx not required • Autoimmune,GN hematologic, urologic or hereditary kidney disease • Repeated exposure to contrast
ISN: International Consortium of Collaborators on Chronic Kidney Disease of Unknown Etiology (i3C) proxy definition for suspected CKDu: 1) A single measurement of eGFR <60 (CKD-EPI) using standardized creatinine 2) Exclusion of diabetes or hypertension, or heavy proteinuria. 3) Did not specify age cut-off -Substantial proteinuria or hematuria should prompt workup for other forms of kidney disease -In endemic areas, CKDu should be considered in DM and HTN without evidence of end-organ damage
CKDu in Thailand • Previous studies show that Thailand has among the highest level of CKD in the world • Some reports show high CKD prevalence in selected areas with toxin exposure • No CKDu data at the national level
Prevalence and causes of CKD and CKD of unknown etiology in Thailand: National Health Examination V Survey Study Objectives To evaluate the prevalence, regional distribution and risk factors of CKD and CKDu in a nationally representative adult general population of Thailand using data from National Health Exam Survey V (2014) Sci Rep. 2021 Nov 1;11(1):21366. doi: 10.1038/s41598-021-00694-9.
NHES Team and Funding Ramathibodi Hospital, Mahidol University, Bangkok Wichai Aekplakorn MD, PhD (PI) Nareemarn Neelapaichit, PhD Anchalee Chittamma PhD Chiang Mai University, Chiang Mai PI: Prof Wichai Aekplakorn Suwat Chariyalertsak, MD, DrPH Funding Khon Kaen University, Khon Kaen • The Bureau of Policy and Strategy, Ministry of Public Health Pattapong Kessomboon, MD, PhD • Thai Health Promotion Foundation • National Health Security Office, Thailand. Prince of Songkla University, Songkhla • Ramathibodi Hospital, Mahidol University. Sawitri Assanangkornchai MD, PhD Chulalongkorn University, Bangkok Surasak Taneepanichskul, MD, MMed NHES Study Group
Stage 1: Provinces: 21 Methods:NHES V - 2014 5 provinces in 4 regions + Bangkok Stage 2: Districts • 2-3 per province Stage 3: Enumeration Areas • 12 urban, 12 rural from each province • Total 540 EA (120/region) • Multi-stage random sampling Stage 4 • Non-institutionalized registered Samples :31,700 Thai population OP96S017 • Interviews and examinations at community centers
Kidney function assessment • Serum Creatinine at Ramathibodi-Enzymatic method standardized to IDMS- SRM • CKD-EPI equation for non-black (Recommended for Thais and ISN I3N) • Proteinuria: Dipstick >=1+ positive
CKD definitions • Proxy CKD: Single eGFR and proteinuria measurement • Staging by KDIGO • eGFR<60: proxy for CKD 3-5 • CKDu1: Age <70 + eGFR< 60 and no hypertension, no DM • CKDu2: Age 70 + CKDu1 and proteinuria<2+ • CKD prevalence: probability weighted for the registered 2014 Thai population stratified by age, sex, area of residence (urban/rural), geographic region
Characteristics Parameters Total (n=17329) Age (years) Women (%) 47.1 ±14.6 Rural area (%) 52.0 Diabetes (%) 55.1 Hypertension (%) 9.8 Creatinine 28.5 eGFR (ml/min/1.73m2) 0.82 ±0.36 99 ±22.1 Sci Rep. 2021 Nov 1;11(1):21366. doi: 10.1038/s41598-021-00694-9.
CKD1-5 by stage Sci Rep. 2021 Nov 1;11(1):21366. doi: 10.1038/s41598-021-00694-9.
CKDu2 slightly less than CKU1 Sci Rep. 2021 Nov 1;11(1):21366. doi: 10.1038/s41598-021-00694-9.
Prevalence by Age and Sex 40 38 30 12 10 25 Men Prevalence % 10 Women Prevalence % 87 20 65 15 10 9 4 2 2 0 0.05 0.3 0.2 0.4 0 0.1 0.3 0.7 0.9 3 2 3 0.9 0.4 0.6 0.9 20-39 40-49 50-59 60-69 2 ≥70 20-39 40-49 50-59 60-69 ≥70 <70 eGFR<60 <70 CKDu2 eGFR<60,DM-HT-Prot≤1+
Estimated numbers of adults with CKD in Thailand Men and Women Women Men CKD1-5 3.91 CKD1-5 2.28 1.62 eGFR<60 2.39 eGFR<60 1.51 0.88 CKDu1 0.32 CKDu1 0.2 0.11 CKDu2 0.31 CKDu2 0.2 0.11 01234 5 0 0.5 1 Million1.5 2 2.5 Estimates based on Thai National Census data in 2014 based on Million 48,152,153 adults (age ≥20) CKD1-5, eGFR>60 in Age>20; CKDu in Age20-70 (Men, 22,940,105; Women, 25,212,048)
CKD by region (All Adults) eGFR<60 CKDu2 All Age Age<70 Sci Rep. 2021 Nov 1;11(1):21366. doi: 10.1038/s41598-021-00694-9.
Population-based CKD studies in Thailand Study Year N Age Creat Equation CKD1-5 eGFR<60 NE Author InterAsia 2000 5146 Method more Ref >35 Jaffe MDRD- NA 13.8 Yes PerkovicV et al. Kidney Int 2008 Standardized to NHANES serum NHES 3 2004 3117 >15 Jaffe MDRD NA 8.9 Yes Ongajyooth L BMC Neph 2009 Thai-SEEK 2007 3459 >18 Jaffe MDRD 8.6 Yes Ingsathit A IDMS NDT 2010 CKD-EPI 15.9 6.5 NHES V 2014 17,329 >20 Enz CKD-EPI 8.7 5.3 Yes Present study IDMS
CKDu Prevalence Global Country Year N Age Location Sex CKDu Author Ref ratio Nicaragua 2009 1,096 20-60 5 villages Men 18% eGFR<60 Cecilia Torres 3x Am J jKId 2010 SriLanka 2017 4803 >18 Anuradhapur (Rural) Men 6% Thilanga Ruwanpathirana 3X BMC Pub Health 2019 India 2010-14 12,500 >20 Mixed Urban Men 1.6% O’Callaghan-Gordo Thailand 2014 and rural 1.5x (up to 4.8 in BMC open 2019 rural %) 14,437 20-70 National Women 2x 0.6 % Present study survey S 0.6 % BKK 0.7% NE 1.6% NE rural 1.9%
Risk Factors eGFR<60 Age<70 CKDu2 OR (95% CI) OR (95% CI) Age (per 10 year) CKDu1 3.52 OR (95% CI) 3.39 Women (Men=reference) (3.42-3.62) (3.23-3.55) 3.35 Diabetes (Y vs N) 1.65 (3.42- 3.50) 2.41 (1.17-2.32) (1.49-3.89) Hypertension (Y vs N) 2.41 1.67 (1.49-3.89) na Gout (Yes vs No) (1.32-2.10) na na Kidney Stones (Y vs N) 2.34 (2.01-2.72) na 4.06 Painkillers (Regular vs Less) (2.65- 6.23) 5.58 3.77 Rural (Urban = reference) (4.43-7.02) (2.43-5.84) 6.72 (4.43-10.19) Laborer/Agriculture 2.86 6.33 (Other occupations= reference) (2.18-3.75) (4.24- 9.46) 2.86 BMI (18.5-24.9 =reference) (1.23-6.66) <18.5 1.84 2.67 (1.26-2.69) (1.16-6.13) 1.88 25-29.9 (1.32-2.68) 1.16 1.66 >=30 (0.98-1.37) (1.19-2.32) 1.45 (1.02-2.05) Current smoking 0.93 1.54 (Non-smoker=reference) (0.77-1.12) (1.08- 2.20) 1.94 Cardiovascular disease (Y vs N) (1.12-3.38) 1.56 1.86 Herbal medications (Y vs N) (1.04-2.36) (1.07-3.21) 0.96 (0.64-1.44) 0.79 0.95 (0.65-0.97) (0.65-1.39) 0.69 (0.35- 1.37) 0.95 0.65 (0.72-1.26) (0.33-1.28) 1.36 (0.85- 2.18 1.14 1.34 (0.82-1.58) (0.85- 2.14) 1.16 (0.46- 2.95) 1.26 1.11 (0.90-1.77) (0 .44- 2.76) 0.68 0.89 0.79
Sci Rep. 2021 Nov 1;11(1):21366. doi: 10.1038/s41598-021-00694-9.
Age Under 60 GFR<60 CKDu2 odds ratio (95% CI) factors odds ratio (95% CI) 1.97 (0.96-4.04) female (male=reference) 1.13 (0.75-1.69) 1.06 (1.02-1.09) age (year ) 1.07 (1.04-1.10) 2.43(1.32-4.48) rural 1.39 (1.01-1.91) diabetes 2.54 (1.78-3.65) 6.27 (3.21-12.25) hypertension 3.07 (2.36-4.01) 10.68 (6.15-18.52) history of gout 7.87 (5.32-11.65) 5.62 (1.68-18.86) 0.56 (0.32- 1.01) history of urinary stone 4.19 (2.98- 5.92) taking pain killers 2.09 (0.93-4.70) 2.50 (1.24- 5.06) 0.76 (0.38- 1.55) Taking herbs 0.75 (0.56- 1.015) 0.62 (0.26-1.46) BMI status (18.5-24.9) =reference) 1.44 (0.75-2.78) Omitted <18.5 2.33 (1.28- 4.24) 0.98 (0.63- 1.52) 25-29.9 0.56 (.39- 0 .83) >=30 0.71 (0.47- 1.06) smoking (Non smoker=reference) current smoker 1.16 (0.72- 1.86) history of CVD 0.57 (0.31-1.04) Labor/Agri 0.78 (0.58- 1.04)
Selected risk factors and CKD in Thailand Male versus female sex (males much more common in most countries) Rural or agricultural risks Heat Pesticides and herbicides Cadmium (other metals) Analgesics Gout Stones
Proportion in agriculture and non-agriculture labor
Thai agriculture by age group
Employment in agriculture, female (% of female employment) in Thailand was reported at 28.2 % in 2020, according to the World Bank
Agrochemicals in Thailand In 2012-2016, Thailand was number one in the world in use of chemicals in agriculture. Most common herbicide: glyphosate (43 %), 2,4-D, butachlor, and paraquat/gramoxone. Most common insecticide: abamectin (60 percent), chloropyrifos, carbofuran, and cypermethrin On 22 October 2019, National Hazardous Substances Committee (NHSC) changed paraquat, glyphosate (\"Roundup\"), and chlorpyrifos from Type 3 toxic substances to Type 4, effectively prohibiting their production, import, export, or possession. Revised: Restricted allowance of glyphosate only on six major crops: corn, cassava, sugarcane, rubber, oil palms, and fruit. Not permitted in watershed areas and other sensitive ecological zones, and farmers must submit proof of use including the type of crops and the size of their farms when purchasing glyphosate.
Association of pesticide use and kidney impairment in Lamphun Province A cross-sectional study in 59 farmers using pesticides for at least 1 year and aged between 40 and 59 years. Excluded known CKD, DM and HTN + occupationally exposed to industrial chemicals Most of the farmers used glyphosate (74.5%) and paraquat (50.8%) for weed control on the fields before, during, and after harvesting Patthawee Mueangkhiao. Environmental Science and Pollution Research (2020) 27:12386–12394
Existing studies provide scarce evidence for an association between pesticides and regional CKDu epidemics but, given the poor pesticide exposure assessment in the majority, a role of nephrotoxic agrochemicals cannot be conclusively discarded.
Stones Clin J Am Soc Nephrol 10: 2023–2029, November, 2015 Nephrolithiasis and CKD, Kummer et al.
Marked regional variation in CKDu associated with stone in Thailand Prevalence CKDu2 with stones Hx : NHES 5 (2014) 0.3 0.25 0.22 0.21 0.25 0.2 0.15 0.1 0.03 0.04 0 0.05 0.03 0 All All Rural Urban N C NE S BKK
NSAID in healthy individuals Effects of NSAID ( excluding phenacetin )on CKD development in healthy subjects controversial Large epidemiologic studies have mixed results on association between chronic NSAID use and CKD among initially healthy individuals: Country Design Drugs Groups Risk Refs Physicians' Prospective NSAID >2500 Healthy men NSAID no increase Kurth T, Am J Kidney in serum Creat Dis. 2003. Health Study cohort vs none or (N=11,000) over 14yrs rare USA Prospective NSAID Healthy No effect of NSAID cohort Nurses on GFR Curhan GC, Arch (n=1700) Intern Med. 2004 Hong Kong Retrospecti NSAID eGFR>60 Ibuprogen HR=1.12 Wan CJASN ve cohort Coxib Database CoxibHR= 3 ieGFR<60 GFR decline >30%
Pain killer use in NHES 5
Gout/Hyperuricemia Known to be associated with prevalent and incident CKD Experimental studies show mechanisms of direct kidney injury preventable by uric lowering agents Human studies of uric lowering agents have not demonstrated clear effects on CKD development ? In CKDU is uric acid/gout a cause or a marker of tubular dysfunction???
Cadmium and risk of CKD in endemic areas with industrial contamination Mae Sot District, Tak Province, northwestern Thailand, paddy fields are irrigated with the water leached from zinc mines Samples of sediment, paddy soil and rice grown in these fields contained markedly elevated cadmium levels Witaya SwaddiwudhipongWitaya The Southeast Asian journal of tropical medicine and public health 46(1):133-142, 2015
Witaya SwaddiwudhipongWitaya The Southeast Asian journal of tropical medicine and public health 46(1):133-142, 2015
Research translation to prevent and reduce chronic kidney disease: lessons learn from the CKDNET, a quality improvement project in Northeast Thailand CKDNET ..Chronic Kidney Disease Prevention in the Northeast of Thailand Sirirat Anutrakulchai, MD. PhD.
CKD screening and related risks (n=2,205) Ubolratana Nam Phong Don Chang Khok Samran Nong Songhong
CKD criteria either one of the following criteria for 3 months or longer: 1) eGFR < 60 ml/min/1.73 m2, (IDMS-Creat, CKD-EPI non black) or 2) presence of any kidney damage; UACR ≥ 30 mg/g in two consecutive samples; (Microalbumin) Ultrasonography -one of the following chronic kidney conditions and structural abnormalities: - parenchymatous change of kidney, renal stones, complex cysts and polycystic disease (excluding simple cysts), small kidney size (<8.5 cm.) with parenchymal change, presence of hydronephrosis, tumor in the kidneys, unilateral kidney (post nephrectomy, renal agenesis or renal atrophy), Urine RBC ≥ 3-5 cells/HPF
Stage 1 7.3 % CKDNET Stage 2 9.0 % (n=2,205) 2017-2019 Stage 3 8.8 % Stage 4 1.4 % • 5.6% of total CKD 1-5 cases, were Stage5 0.3 % classified as CKD by abnormal ultrasound findings alone without any CKD 1-5 HTN 52% overall other CKD criteria 26.8 % HTN without DM 24% DM 35.8% • Repeating eGFR x2 decreased CKD 3-5 from 12% to 10.5% No HTN, No DM= 40.2 % • Repeating UACR decreased prevalence CKD 3-5 from 17% to 12% 10.5 %
Variables CKD Non-CKD P value (n=592) (n=1,613) 0.011 Smoking habits No 427 (72.1) 1,263 (78.3) 0.020 Quit 78 (13.2) 168 (10.4) Till now 87 (14.7) 182 (11.3) 0.377 0.009 Total DOC and Total NSAID use, n (%) 389 (65.7) 957 (59.3) 0.709 Never used 112 (18.9) 344 (21.3) 0.425 Used to take 312 (19.3) 0.646 Still taking 91 (15.4) 296 (18.4) 0.070 99 (16.7) 2,054 ± 964 0.010 Herbal use, n (%) 1,933 ± 932 4.2 ± 4.6 Drinking water, mL/day (mean ± SD) 4.1 ± 4.2 9.2 ± 8.0 0.638 Salt intake, g/day (mean ± SD) 9.5 ± 7.0 5.0 ± 5.4 Fish sauce intake, ml/day (mean ± SD) 4.8 ± 9.7 8.6 ± 9.5 MSG intake, g/day (mean ± SD) 9.5 ± 10.5 Fermented fish sauce intake, ml/day) 1,028 (63.7) 387 (65.4) 160 (9.9) Alcohol consumption, n (%) 79 (13.3) 425 (26.4) Do not drink Used to drink 126 (21.3) 990 (61.4) Continued drinking 163 (10.1) 381 (64.4) 460 (28.5) Use of herbicide 50 (8.5) Never Have used 161 (27.2) Still using
Table S8: Factors associated with CKD stage 3-5 (excluding anemia and hemoglobin variables in the models) Factors Model 2 p-value Adjusted OR Age (every 1-year increase) <0.001 Male (95% CI) 0.004 Low monthly income (<10,000 Baht) 0.778 Less education (none plus primary school) 1.15 (1.12-1.18) 0.711 Unemployed status 2.31 (1.30-4.11) 0.561 Smoking habits 0.87 (0.32-2.33) 0.88 (0.43-1.77) 0.160 No 1.13 (0.74-1.73) 0.570 Quit Till now 1 0.945 NSAID use 0.59 (0.28-1.23) 0.413 Never used 1.24 (0.59-2.60) Used to take 0.649 Still taking 1 0.009 Alcohol consumption 0.98 (0.60-1.61) 0.761 Do not drink 0.81 (0.48-1.35) 0.046 Used to drink <0.001 Currently drinking 1 <0.001 Drinking water (every increase of 500 ml a day) 0.86 (0.45-1.66) <0.001 Underweight (BMI <18.5 kg/m2) 0.44 (0.24-0.82) 0.98 (0.89-1.09) 0.149 DM 2.02 (1.01-4.03) 0.011 HT without DM Hyperuricemia 3.12 (2.04-4.76) 2.14 (1.44-3.20) Leukocytosis 9.74 (6.66-14.2) Hyperlipidemia 1.47 (0.87-2.46) 0.61 (0.41-0.89)
Conclusions • CKDu rates may also depend on classification (eGFR<60 and/or albuminuria, age cut-off, other methods e.g. USS, other inclusion/exclusion criteria) • Standardization of criteria will be useful for comparisons between regions • CKDu rates in Thailand vary in different regions/locations, but overall are typically less than in hot spot areas (e.g. Mesoamerica) • Northeast region of Thailand likely have the highest rates • Risk factors for CKDu in Thailand may include: rural areas, farmers, painkiller use, stones, hyperuricemia/gout • Sex as CKDu risk has varied in different studies (NHES V vs CKD-NET)
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