Toward a Comprehensive Hypothesis of Chronic Interstitial Nephritis ...

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Toward a Comprehensive Hypothesis of Chronic Interstitial Nephritis in Agricultural Communities pez, l Herrera-Valdes, Miguel Almaguer-Lo Carlos Manuel Orantes-Navarro, Rau pez-Marıń, Xavier Fernando Vela-Parada, Marcelo Hernandez-Cuchillas, Laura Lo and Lilly M. Barba Over the past 20 years, there has been an increase in chronic interstitial nephritis in agricultural communities (CINAC) not associated with traditional risk factors. This disease has become an important public health problem and is observed in several countries in Central America and Asia. CINAC predominantly affects young male farmers between the third and fifth decades of life with women, children, and adolescents less often affected. Clinically, CINAC behaves like a chronic tubulointerstitial nephropathy but with systemic manifestations not attributable to kidney disease. Kidney biopsy reveals chronic tubulointerstitial nephritis with variable glomerulosclerosis and mild chronic vascular damage, with the severity depending on sex, occupation, and CKD stage. The presence of toxicological, occupational, and environmental risk factors within these communities suggests a multifactorial etiology for CINAC. This may include exposure to agrochemicals, a contaminated environment, repeated episodes of dehydration with heat stress, and an underlying genetic predisposition. An understanding of these interacting factors using a multidisciplinary approach with international cooperation and the formulation of a comprehensive hypothesis are essential for the development of public health programs to prevent this devastating epidemic. Q 2016 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Chronic interstitial nephritis in agricultural communities, Chronic kidney disease of unknown causes (CKDu), Pesticides, Dehydration, Heat stress

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iabetes mellitus and hypertension are the two leading causes of CKD across the globe, particularly in the developed world. In developing countries, these wellknown etiologies of CKD can be accompanied or supplanted by other causes of glomerular and tubulointerstitial diseases such as infections or injury due to nephrotoxic drugs, herbal supplements, environmental toxins, and occupational exposure to pesticides. These factors all can contribute to the high burden of CKD in developing nations.1 During the past two decades in certain locations in Latin America and Asia, there has been an increase in the prevalence of CKD affecting agricultural communities, specifically targeting young male agricultural workers who do not have the traditional risk factors of diabetes and hypertension. This recently recognized form of CKD has been termed chronic interstitial nephritis in agricultural communities (CINAC) and has become an important and devastating public health issue, particularly in Central America.2-8 In fact, according to The Pan American Health Organization, Nicaragua and El Salvador have CKDrelated estimated mortality rates of 42.8 and 41.6 deaths per 100,000, respectively, which is fourfold higher than any other country in the world with respect to mortality due to kidney disease. In El Salvador, CKD is the second most common cause of death in men, with males affected at three times the rate of females.9

EPIDEMIOLOGICAL CHARACTERISTICS AND PATHOGENESIS In El Salvador, a number of epidemiological studies have estimated the prevalence of CINAC in farming communities to be between 15% and 21% with a 9% to 13% prevalence of chronic renal failure. Less than half of those affected have diabetes mellitus or hypertension. While the disease predominates in men, it also affects women, children, and adolescents who live in these farming commuAdv Chronic Kidney Dis. 2017;24(2):101-106

nities regardless of whether they work in agriculture, and evidence suggests that the kidney disease may begin in the early stages of life. This increased prevalence of CKD has been observed in farming communities both in the highlands and lowlands of El Salvador, suggesting there may be multiple factors involved.3,10,11 Interestingly, similar findings of CINAC have been reported worldwide, particularly in Sri Lanka, India, and Egypt. The etiology of this epidemic of CKD remains unclear but is thought to include exposure to toxins such as pesticides and herbicides and repeated episodes of dehydration which occur in all affected populations. Other similar risk factors that have been identified in those affected in differing locations include agricultural work, male sex, age, poverty, use of well water, over use of NSAIDs, and histories of snake bites and infections to a more limited degree.12,13 In farming communities, heavy metals (cadmium and arsenic) and pesticides are present in well water, floors in homes, and farmlands and are more concentrated in

From the National Health Institute (INS) and National Renal Health Research Coordinator, Ministry of Health (MINSAL), San Salvador, El Salvador; Nephrology Institute, Havana, Cuba; Division of Clinical Research in Nephrology, Massachusetts General Hospital, Boston, MA; Department of Medicine, Mount Sinai St. Luke’s-West, New York, NY; and Division of Nephrology, Harbor—UCLA Medical Center, Los Angeles, CA. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Carlos Manuel Orantes-Navarro, MD, National Health Institute (INS) and National Renal Health Research Coordinator, Ministry of Health (MINSAL), San Salvador, El Salvador. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2017.01.001

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crop areas. These likely accumulate due to extensive use of birth weight or a genetic predisposition. In Sri Lanka, a pesticides, including those which have been banned in genomewide association study demonstrated an SNP in many developed countries, to improve crop yield. The inthe gene encoding sodium-dependent dicarboxylate transcrease in CKD incidence in Central America began approxporter member 3, which conferred increased risk for imately 20 years ago, concomitant with a significant CINAC with a population attributable fraction of 50% increase in the use of toxic agricultural chemicals such as and odds ratio of 2.3.28 Repeated episodes of dehydration due to inadequate paraquat, glyphosate, triazines, methamidophos, and intake of fluids while engaged in manual labor in a hot humethyl parathion.4,5 The nephrotoxic potential of these compounds is known and has been described in the mid climate have been proposed as a cause of CINAC, and literature.14-19 Pesticide exposure occurs during farmland undoubtedly repeated dehydration may produce kidney application and from pesticide storage in household damage.29 Suggested pathogenetic mechanisms for dehydration-induced kidney injury include activation of facilities. During spraying, farmers may inhale or the aldo reductase-fructokinase pathway in the proximal accidentally ingest pesticides and herbicides, and tubule with subsequent uric acid production resulting their skin may become contaminated with these toxins in proximal tubular injury; this has been replicated in an due to the lack of outer garment protection. There is an experimental model.30,31 There also may be a role of association between self-reported use of carbamate pestirhabdomyolysis.12 Dehydration, caused by inadequate cides in a hot and humid environment with a change in 20 fluid intake in a hot environment, can affect elimination kidney-related biomarkers and a reduction in GFR. In the United States, a cohort of 55,580 male licensed pestiof toxic agents from the blood and increase the concentracide applicators showed a significant association of tion of these agents in the kidney medulla, thus contribchronic exposure to specific pesticides with increased uting to development of kidney injury. While there may risk of developing end-stage kidney disease.21 Further evbe a role for dehydration in this epidemic of CKD, dehydraidence for a role of toxin tion alone cannot explain the exposure is the presence of spectrum of this disease, CLINICAL SUMMARY extrarenal symptoms associwhich affects not only male ated with CINAC including farmworkers, but also men Chronic interstitial nephritis in agricultural communities urinary dribbling, abnorwho are not farmworkers, (CINAC) typically occurs in young to middle age male malities in arteries by ultramen in the same geographic farmworkers in regions of Central America and Asia but sound, myoclonus and region who do not work in also may occur in women and children. sensorineural deafness.22 agriculture, women who are CINAC is a form of tubulointerstitial nephritis and is a major Volcanic soil and other natuemployed and not employed public health crisis in affected countries. ral contaminants such as in agriculture, and school age There are genitourinary, neurologic, and vascular arsenic and hard water also children and adolescents. abnormalities in addition to the kidney disease. may play a role. Although a CLINICAL single metal cannot be linked The pathogenesis of CINAC likely is multifactorial including to CINAC, heavy metals CHARACTERISTICS pesticide exposure, heat stress, dehydration, environhave been found in excessive In the early stages of CINAC, mental contaminants, effects of low socioeconomic status, amounts in the urine of agripatients may be asymptomand genetic susceptibility. cultural workers. Jayasuatic or demonstrate urinary mana and associates5,23 hesitancy, a thin urinary hypothesized that the use of glyphosate, an herbicide stream and dysuria. Symptoms become more common in and strong metal chelater, in conjunction with arsenic CKD 2 and may include genitourinary abnormalities and the consumption of hard water, might be a cause of such as nocturia, dysuria, post void dribbling, hesitancy, kidney disease in Sri Lankan agricultural workers. and foamy urine, as well as systemic symptoms such as arWhen agricultural workers’ clothes become contamithralgias, abnormal tendon reflexes, muscle cramps, asthenated with pesticides, family members subsequently nias, decreased libido, and fainting.22 At this time, there may be exposed, particularly women while laundering also may be polyuria with elevated urinary magnesium, sodium, calcium, and phosphorous, with resulting serum the family clothing.24-26 In affected agricultural communities, family members may be exposed via electrolyte abnormalities including hyponatremia, hypoinhalation or ingestion of these toxins due to kalemia, hypomagnesemia and hypocalcemia, and metacontamination of household items or the surrounding bolic alkalosis. As the disease progresses, these water and soil. In three farming communities in El symptoms progressively intensify with worsening of the Salvador with a significant prevalence of CINAC, kidney disease. Urine analysis typically is unremarkable children and adolescents have been shown to have an or shows mild proteinuria, likely of tubular origin with increased incidence of CKD.10 Ramirez-Rubio and associincreased b2 microglobulin and tubular markers of injury ates27 showed that adolescents in an affected community including KIM-1 and NGAL.22,32,33 Urine culture is in Nicaragua had increased tubular injury associated bionegative. Kidney imaging shows changes of CKD and preserved kidney blood flow. No urinary bladder or markers despite no involvement with agricultural work. Other factors may contribute to childhood CKD in these prostate abnormalities are identified on ultrasound regions such as poor maternal nutrition resulting in low evaluation.22 Adv Chronic Kidney Dis. 2017;24(2):101-106

Comprehensive Hypothesis of CINAC

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As noted above, extrarenal symptoms involving the cardiovascular, peripheral vascular, and nervous systems may be present. Most patients are normotensive or have mildly elevated blood pressure, with a normal EKG and echocardiogram. On cardiac stress testing, patients typically have preserved physical capacity, and few have an abnormal pressor response. Peripheral arterial doppler studies show few abnormalities of the carotid and aortoiliac vessels; however, femoral and particularly tibial arteries demonstrate irregular walls and atherosclerosis.22 Sensorineural hearing loss is a common finding, while fundoscopic examination, intraocular pressure, and visual field testing are normal in the majority of patients, suggesting an absence of significant microvascular damage as is observed with diabetic or hypertensive retinopathy.22

muscular hypertrophy, smooth muscle vacuolization, and intimal proliferation within arteries and arterioles. Interestingly, there are some differences in the extent of interstitial inflammation and glomerular enlargement relative to the type of agricultural work; sugarcane workers demonstrate more tubulointerstitial scarring and inflammation and less glomerular enlargement compared with those working with other crops. Immunofluorescence shows no specific immune deposition in the glomeruli, tubules, or interstitium.34 Electron microscopy has revealed inclusions in proximal tubular epithelium, possibly secondary lysosomes or autophagic vacuoles; however, the pathogenesis of this feature is uncertain as similar structures are associated with quinine administration and their significance is unknown with respect to CINAC.

HISTOPATHOLOGICAL CHARACTERISTICS Histologic findings are similar in cases of CINAC from different geographic areas.34-36 The predominant pattern is of a chronic tubulointerstitial nephritis characterized by tubular atrophy, interstitial fibrosis, and a variable interstitial mononuclear inflammatory infiltrate. There may be associated global glomerulosclerosis, glomerulomegaly, ischemic-appearing glomerular capillary wall corrugation, and features of vascular injury including

PROPOSED CASE DEFINITIONS OF CINAC The epidemic itself is defined as an increase in the number of cases of CKD in agricultural communities, which are characterized by three general conditions: poverty with all its repercussions, unhealthy working conditions, and a contaminated environment. These elements link the disease to deep rooted socioeconomic circumstances.22 This CKD epidemic has a double burden. The first is the presence of well-known traditional causes of CKD (diabetes

DEFINITION OF THE EPIDEMIC Increase in CKD cases across the world in agricultural communi es Affects both sexes (male predominance) Appears early in life Double burden of the disease Known tradi onal causes vs. non-tradi onal causes

Possible case (epidemiological criteria) Pa ent living in an agricultural community with no known history of renal disease Presence of biomarkers of kidney damage Decreased glomerular filtra on rate Probable case (clinical criteria) Primary or secondary causes of kidney disease cannot be iden fied Asymptoma c at early stages of the disease Symptoms: fa gue, cramps, polyuria, nocturia, dysuria, foamy urine, fain ng, joint pain Signs: occasional hypotension, normal fundoscopy, vascular wall irregulari es predominantly of lower limbs, altered neurological reflexes, sensorineural hearing loss Laboratory: low or absent proteinuria, markers of tubular damage, abnormal excre on of electrolytes in urine, hyponatremia, hypokalemia, hypocalcemia and hypomagnesenemia

Confirmed case (histopathological criteria) Chronic tubulo-inters

al nephri s with glomerulosclerosis and mild chronic vascular changes .

Figure 1. To make a confirmed diagnosis of chronic interstitial nephritis in agricultural communities (CINAC), it is necessary to take into account epidemiological, clinical, and histopathological criteria, within the appropriate clinical and geographical context. Adv Chronic Kidney Dis. 2017;24(2):101-106

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mellitus, hypertension, glomerulopathies, and obstructive uropathy) which affect developed and developing countries, with an additional second burden due to as yet undetermined causes which result in a histopathological pattern of chronic tubulointerstitial nephritis impacting those in the targeted areas.2 Examples of cases and their inclusion as part of this epidemic are detailed below. A person who has lived or worked in agricultural communities with no known history of kidney disease and who demonstrates biomarkers of kidney damage in the urine and/or decreased glomerular filtration rate is considered to have a possible case of CINAC based on epidemiology.3,37 Additional information may further the diagnosis to a probable case of CINAC, which adds clinical criteria to the epidemiology. This would encompass a patient with possible CINAC in whom a primary or secondary cause of kidney disease has not been identified and who progresses from an early asymptomatic stage to exhibiting symptoms of fatigue, cramps, polyuria, nocturia, dysuria, foamy urine, fainting, joint pain and/ or signs including occasional hypotension, mild cardiac disorders with predominant lower extremity peripheral

vascular damage, a normal funduscopic examination, altered neurological reflexes, and sensorineural hearing loss. None of these findings should be a consequence of the stage of CKD. Additional findings may include no or minimal proteinuria, the presence of tubular injury markers such as b2 microglobulin, and abnormal urinary electrolyte excretion with associated hyponatremia, hypokalemia, hypomagnesemia, and/or hypocalcemia.3,22 A confirmed case of CINAC fulfills the epidemiological and clinical criteria of CINAC denoted above and in whom a kidney biopsy demonstrates the histopathological pattern of chronic tubulointerstitial nephritis with or without secondary glomerulosclerosis and vascular damage.34 Figure 1 depicts how these case definitions fit within the broad diagnostic spectrum of CINAC from the community level to the individual. COMPREHENSIVE HYPOTHESIS OF CINAC PATHOGENESIS CINAC is a multifactorial disease, predominantly affecting young male farmers, and fewer numbers of nonfarming women, adolescents, and children. The widespread reach of CINAC within farming communities in

Social Determinants of Health: CondiƟons of Poverty Unhealthy ealthyy working worki g condiƟons

Environmental ntal PolluƟon Air

Water

Food

Clothing

Harsh agricultural working conditions

Human behavior Polluted drinking water

Agricultural occupation

Periodic toxic exposure

Indiscriminate use of agrochemicals

Hot and hu humid environment

Heatt stre stress & Dehydration

Direct and indire indirect contact with agrochemicals

Ischemia chem

Entrance ce routes ro Ingestion

High level

Farmers armers s

Concentration ation of toxins in the kidneys s

Skin contact

inhalation

Low level

CHRONIC C C EXPOSURE EXP

NEPHROTOXICITY OTOX Y

Molecular Mo M ecula cell changes c

Chronic kidney Ch ney damage

Genera G General Po opulati Population

Risk Group

CINAC

• Sugar cane cuƩer • Farmer Non-sugar cane cuƩer • Non-farmer that lives or lived in agricultural communiƟes

Low birth weight

Fetal life

Newborn

Gene c factors Family history, Gender Living in the agricultural community

Infant

Toddler

Child

Adolescent

Adult

Elderly

Appears early in life Double burden of the disease Known tradi onal causes & non-tradi onal causes

Figure 2. Several factors play a role in the etiology of chronic interstitial nephritis in agricultural communities (CINAC), with environmental contamination by nephrotoxic agents as the pathogenic trigger. Different levels of exposure to this pollution may predispose susceptible individuals to kidney damage. Superimposed unhealthy working conditions, including dehydration, provide additional risk but cannot explain the epidemic alone. For patients living in these communities, the aggregate injury of long-term exposure to these insults results in the development of CINAC. Adv Chronic Kidney Dis. 2017;24(2):101-106

Comprehensive Hypothesis of CINAC

Central America and Asia suggests the presence of environmental risk factors associated with the occupation of their residents. Those living in these agricultural communities are exposed to the same risk factors as the general population, with additional exposure occupational risks. Environmental natural or man-made toxic agents (heavy metals, pesticides, and chemicals and/or microbial substances) in the air, soil, or water may be subjected to transformation by climate, topography, and soil use.14-17,24,33,36,38 These may spread to the wider farming community via air, water soil displacement, or absorption into the food chain. These toxic agents can then affect a susceptible subject who is exposed to unhealthy lifestyles and harsh working conditions such as dehydration and heat stress. Farmers likely have more concentrated and chronic exposure via drinking water, inhalation, ingestion, or skin contact while working in the fields. The intensity of the exposure may vary, ranging from high level (repeated exposure affecting primarily farmers) to a low level (chronic exposure affecting the general population) leading to repeated episodes of subclinical kidney injury. On a molecular level, toxins can affect the kidney tissue through direct tubular cell toxicity or alterations in intrarenal blood flow producing secondary tubular damage leading to CINAC.14,23 Other factors putting this population at increased risk for CKD include low birth weight, infectious diseases, traditional risk factors, use of NSAIDs, and nephrotoxic medicinal herbs. Finally, there may be genetic susceptibility among the affected populations. A comprehensive hypothesis for the development of CINAC is summarized in Figure 2. CONCLUSIONS The medical and scientific communities recognize CINAC as a public health crisis. The use of the unifying term CINAC in concert with our comprehensive hypothesis of its pathogenesis and proposed case definitions provides a framework for continued collection and analysis of risk factor data. Establishing a set of criteria for public health surveillance in different regions of the world with the same epidemic pattern (eg, El Salvador and Sri Lanka) will allow reporting from differing geographic locations with similar disease patterns.12 It is hoped that identification of multiple potential risk factors will provide public health officials and decision makers opportunities for early identification, intervention, and ultimately prevention of CINAC in socially vulnerable individuals in rural communities. In addition, there are social and environmental implications with regard to human rights in the context of adequate occupational health and safety. CINAC appears to be a complex disease that develops in susceptible individuals working in agriculture or within that environment to a lesser extent. It is of critical importance to have a broad collaboration and multidisciplinary approach that seeks to strengthen health services, work force training, and access to health technology, medications, and medical surveillance through international cooperation. Adv Chronic Kidney Dis. 2017;24(2):101-106

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Adv Chronic Kidney Dis. 2017;24(2):101-106