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Chronic Kidney Disease of Unknown Origin:

An emerging occupational disease?

Sally Moyce, RN PhD March 2018

Disclosures

u I have no disclosures to report.

Objectives

• 1. Describe differences between Chronic Kidney Disease (CKD)

and Chronic Kidney Disease of Unknown Origin (CDKu).

• 2. Explore the global dimensions of CKDu.
• 3. Investigate evidence regarding a possible etiology of CKDu.
• 4. Present an agenda for future research and treatment.

Central America India Sri Lanka Photo credits: La Isla Foundation India

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Chronic Kidney Disease

u Gradual loss of kidney function u Reduced eGFR u Risk factors:

u DM u HTN u Obesity u Advanced Age

Chronic Kidney Disease of Unknown Origin

► Decline in eGFR leading to kidney failure and

death

► High rate of mortality ► Middle aged patients (30s-50s) ► No history of HTN or DM ► Males > Females ► Poor, rural areas ► Predominant occupation: agriculture ► Histology studies:

• Proximal tubular damage (v. glomerular)
• Mild-moderate tubular atrophy
• Interstitial inflammation

► Urine:

• Central America: Low grade proteinuria/albuminuria
• Sri Lanka: Persistent albuminuria

Wijkstrom et al., 2013

Chronic Kidney Disease of Unknown Origin

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Global Dimensions of CKDu Global Dimensions of CKDu

► Central America

• Mortality rates 4x global rates
• Honduras: 25 deaths/100,000
• Nicaragua: 26 deaths/100,000
• El Salvador: 52 deaths/100,000

Global Dimensions of CKDu

► Sri Lanka

• Leading cause of death – 20,000

deaths in last decade

• Endemic districts
• Anuradhapura 15%
• Polonnaruwa 20%
• Badulla 23%

► India

• Andhra Pradesh – 15%

Jayatilake et al, 2013

Etiology

► Barriers to identification

• No standard definition
• Geographic differences in

distribution and detection

• Delays in diagnosis due to

poor access to heath care

• Differences in measurement
• f risk factors

► Potential causes

• Occupational
• Behavioral
• Geographical
• Physiological

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Frequency of measured exposures from systematic review (Lunyera et al, 2015)

Occupational Exposures

• 1. Pesticides
• 2. Heavy metals
• 3. Heat strain/volume depletion
• 4. Strenuous labor

Agrochemicals/Pesticides

► Common agricultural occupational

exposure

► Interstitial nephritis related to pesticide

exposure

► Many pesticides known nephrotoxins,

especially organochlorine insecticides (e.g. propanil)

► Some evidence of pesticides in

drinking water in affected communities

Photo: Julie Potyraj

Organochlorines in India

Median serum levels OCPs (range) OCP Healthy Group CKD Group CKDu Group α HCH 0.7(0.002-1.66) 1.26 (0.34-3.15) 1.68 (0.12-4.26) Aldrin 1.6 (0.002-2.15) 1.96 (0.002-3.12) 2.15 (0.002-3.18) β-endosulfan 1.3 (0.002-2.65) 0.84 (0.002-1.54) 2.38 (0.65-4.28) p, p-DDE 2.6 (0.002-3.54) 1.54 (0.29-2.64) 2.94 (0.68-4.58) Ghosh et al (2017)

►Case-control study in Delhi (n=300) ►Median serum levels of OCPs ►Increased OCP associated with CKDu

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Organochlorines in India

Median serum levels OCPs (range) OCP Healthy Group CKD Group CKDu Group α HCH 0.7(0.002-1.66) 1.26 (0.34-3.15) 1.68 (0.12-4.26) Aldrin 1.6 (0.002-2.15) 1.96 (0.002-3.12) 2.15 (0.002-3.18) β-endosulfan 1.3 (0.002-2.65) 0.84 (0.002-1.54) 2.38 (0.65-4.28) p, p-DDE 2.6 (0.002-3.54) 1.54 (0.29-2.64) 2.94 (0.68-4.58) Ghosh et al (2017)

►Case-control study in Delhi (n=300) ►Median serum levels of OCPs ►Increased OCP associated with CKDu

Heavy Metals

u Heavy metals damaging to kidneys u Effect of agrochemicals may be exacerbated by “hard” water u Linked to tubulo-interstitial disease u Iron-deficiency may increase risk u Increased cadmium levels in CKDu patients in

Sri Lanka (Jayatilake et al, 2013)

Heat Strain/Volume Depletion

► Sugarcane harvesting in Central America ► Chena agriculture in Sri Lanka ► Increased prevalence in lowland, coastal regions ► Evaporative cooling → volume depletion → decreased

kidney perfusion

Heat Exposure in Central America

u Comparison of agricultural workers at sea level and 500 meters above sea

level

u Male workers at sea level had higher prevalence of CKDu than those at

elevation

eGFR<60 mil/min/1.73m2 Workers at sea level 18% Workers at 500 masl 2%

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Prevalence of elevated serum creatinine by sex and age (Peraza et al, 2012)

Strenuous Labor in California

California Heat Illness Prevention Study (PI Marc Schenker, UC Davis)

► Investigation of acute kidney injury (AKI) in 300 California farm workers ► After a single day of work, AKI in 12% of sample ► AKI related to heat exposure, not volume depletion ► AKI associated with 4.5 odds ratio for those paid by the piece

Association of heat strain and volume depletion and AKI (Moyce et al, 2017)

10 20 30 40 50 60 70 80 90 100

No Heat Strain Heat Strain No body mass change Gained body mass Lost <1.5% Lost ≥1.5% No AKI AKI Association of piece-rate work with AKI in California farm workers (Moyce et al, 2017)

Obesity Volume depletion Hypertension Age Yrs in farm work Heat strain Female sex Diabetes Piece-rate 2 4 6 8 10 12 1

Odds of AKI with Heat Strain and Volume Depletion (n=283)

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Multi-Factorial Etiology: Occupational?

Uric acid and chronic kidney disease (Johnson et al, 2013)

Multi-Factorial Etiology: Other Sources?

u Heat exposure + volume depletion

+ social/economic factors + behavioral factors + family history + environmental risks + ???

Future Research

► Standardize case definition of CKDu ► Standardize exposure measurements

• Workload
• Heat exposure
• Volume depletion
• Agrochemical exposure
• Heavy metal exposure

► Focus on AKI and biomarkers pre- and post-work shift or harvest

season

► Global collaboration among researchers

Future Treatment

► Increase access to health care for early

detection and dialysis

► Safe and fair labor practices ► Re-assignment of financial resources to

poorest, rural areas

► Protection of drinking water

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Summary

u CKDu prevalence increasing on global scale u Potential for disease among agricultural workers in United States u Etiology likely multi-factorial but related to heat and volume

depletion

u Improved worker safety essential to combat disease

Questions? Comments?

Sally Moyce, RN PhD Assistant Professor Samuel Merritt University smoyce@samuelmerritt.edu

Question 1

A barrier to the identification of the etiology of CKDu includes which of the following:

A.

Early detection and diagnosis

B.

Lack of standardized case definition

C.

Easily traceable exposures

D.

International attention to problem

Question 2

The most likely cause of CKDu is

A.

Pesticides

B.

Heat strain

C.

Strenuous labor

D.

Multiple causes

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Question 3

u The physician suspects CKDu in which of the following patients who

presents with decreased eGFR?

A.

A 65 year old African American

B.

A 52 year old diabetic patient

C.

A 37 year old immigrant farm worker

D.

A 61 year old subsistence farmer

Select References

u

Ghosh, R., Siddarth, M., Singh, N., Tyagi, V., Kare, P. K., Banerjee, B. D., ... & Tripathi, A. K. (2017). Organochlorine pesticide level in patients with chronic kidney disease of unknown etiology and its association with renal

• function. Environmental health and preventive medicine, 22(1), 49.

u

Lunyera, J., Mohottige, D., Von Isenburg, M., Jeuland, M., Patel, U. D., & Stanifer,

• J. W. (2015). CKD of uncertain etiology: a systematic review. Clinical Journal of

the American Society of Nephrology, CJN-07500715.

u

Moyce, S., Mitchell, D., Armitage, T., Tancredi, D., Joseph, J., & Schenker, M. (2017). Heat strain, volume depletion and kidney function in California agricultural workers. Occup Environ Med, 74(6), 402-409.

u

Peraza, S., Wesseling, C., Aragon, A., Leiva, R., García-Trabanino, R. A., Torres, C., ... & Hogstedt, C. (2012). Decreased kidney function among agricultural workers in El Salvador. American Journal of Kidney Diseases, 59(4), 531-540.

u

Wijkström, J., Leiva, R., Elinder, C. G., Leiva, S., Trujillo, Z., Trujillo, L., ... & Wernerson, A. (2013). Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central

• America. American Journal of Kidney Diseases, 62(5), 908-918.

u

Valcke, M., Levasseur, M. E., da Silva, A. S., & Wesseling, C. (2017). Pesticide exposures and chronic kidney disease of unknown etiology: an epidemiologic

• review. Environmental Health, 16(1), 49.