Chronic interstitial nephritis in agricultural communities is a new form of chronic kidney disease; its etiology is not linked to diabetes, hypertension, glomerulopathies, or other known causes of renal diseases. It had reached epidemic proportions in Central America, Sri Lanka, and other tropical countries. It was reported mainly in young men, occasionally women, and adolescents. The causes are potentially preventable, and to avoid the high morbidity associated with this condition, it must be promptly diagnosed and treated. This activity reviews the epidemiological characteristics, clinical features, histopathological findings, and management of an interprofessional team of chronic interstitial disease in agricultural communities.
Review the epidemiological characteristics of CINAC.
Describe the etiology and clinical features of CINAC.
Outline the histopathological findings in CINAC patients
Explain the management of CINAC by an interprofessional team.
CINAC is a new form of chronic kidney disease (CKD) with its own etiopathogenesis; not related to other well-known causes of CKD such as diabetes, hypertension, and glomerulopathies. However, the incidence and prevalence of CINAC have reached epidemic proportions. CINAC affects predominantly young men, occasionally women and adolescents in Central America, Sri Lanka, and other tropical countries.
This form of CKD of nontraditional causes has been reported from several world regions and has similar clinical and epidemiological characteristics. It is known by a variety of names. In Central America, the disease was named “Meso-American Nephropathy” (MeN), whereas in Sri Lanka, “CKD of unknown etiology” (CKDu) was the preferred terminology. The term chronic interstitial nephritis in agricultural communities (CINAC) was proposed to describe both entities.
CINAC affects people working in the agricultural sectors of these regions, which are described as CINAC endemic areas.
The socio-economic and occupational determinants such as poverty, exposure to toxic agrochemicals, and hot tropical climates correlate with clinical characteristics that help make the diagnosis. The disease most frequently occurs in men and affects women, children, and adolescents who live in these farming communities. In endemic regions, CINAC is noted even in those who do not work in agriculture.
In fact, according to The Pan American Health Organization, Nicaragua and El Salvador have CKD-related estimated mortality rates of 42.8 and 41.6 deaths per 100,000, respectively, which is fourfold higher than any other country. In El Salvador, CKD is the second most common cause of death in young men, with males affected at three times the rate of females.
The etiology of CINAC remains unknown. A disease with unusual clinical behavior would also be expected to have unusual risk factors, etiologies, and pathophysiologic mechanisms. Chronic kidney disease (CKD) is traditionally etiologically associated with diabetes mellitus and hypertension in most cases and, to a lesser degree, with primary or secondary kidney diseases.
However, there is a form of CKD that affects agricultural communities in endemic and epidemic proportions. It is found particularly among male farmers, presents at a young age, and affects a proportionately lower number of non-farming women and adolescents. In addition, this form is associated with functional changes and biomarkers of kidney damage among children in these communities. These characteristics suggest risk factors associated with the environment in these communities and the occupations of their residents, implying several etiologic factors working in conjunction with a predominant one.
Residents in these agricultural communities are exposed to the same risk factors as the world’s general population. Additionally, due to their occupations, they are exposed to multiple toxic substances in multiple agrochemicals, many of which have been outlawed in other countries. These chemicals are used in large quantities, mixed and applied without personal protective gear, and over prolonged workdays. Working conditions include elevated ambient temperatures and intense physical activity with suboptimal hydration, among others.
One hypothesis might be that disease is associated with toxic agents (heavy metals ab, chemicals, or microbial substances) in the environment from either natural or artificial sources. These toxins could be present in the air, soil, water, food, or combinations of the above. Additionally, exposure to a toxin can be modified by climate, topography, soil use. Lifestyles, working conditions, and impurities in drinking water could determine the route of exposure. A patient may have exposure to the toxin via inhalation, ingestion, or skin contact. Therefore, exposure exists on a spectrum, from high-level through repeated exposures affecting primarily farmers to low-level through chronic exposure affecting the general population. In both cases, genetic susceptibility could be a conditioning factor but has not been studied yet. Circulation of toxic agents in the blood is subject to renal elimination, which may be compromised in a state of recurrent dehydration in farmworkers.
It is hypothesized that the toxins cause direct tubular cell toxicity. Secondary tubular damage occurs due to alterations of the renal blood flow due to environmental conditions.
Additional factors that make the farmworkers and surrounding communities vulnerable to kidney damage are low birth weight, infectious diseases such as malaria, diabetes, hypertension, obesity, smoking, excessive alcohol consumption, and non-steroidal anti-inflammatory drugs nephrotoxic medicinal plants.
The etiology of CINAC is multifactorial. However, the nature of the toxin has not been identified to date.
A multifactorial etiopathogenesis is proposed with nephrotoxicity due to toxic agents as its central axis.
Repeat events of dehydration have been proposed as a cause of CINAC. However, in hotter areas where agrochemicals are rarely or never used, CINAC is absent. In addition, experiments in rats demonstrated that dehydration/heat stress over 4 weeks does not induce the dysmorphic lysosomes identified in patients with CINAC.
The dysmorphic lysosomes seen ubiquitously in biopsies of CINAC patients are only occasionally seen in patients who had calcineurin inhibitor toxicity because of cyclosporine. However, Dysmorphic lysosomes are also noted in some other disorders, such as Fabry’s disease. In Fabry’s disease, the lysosomal enzyme alpha-galactosidase A is deficient with the resultant accumulation of undegraded globotriaosylceramide.
Whatever the toxin may be in CINAC, the lysosomal enzymes are unable to degrade IT. Till we study further, it appears from indirect observations that CINAC is CINAC is the pathologic expression of a toxic insult.
Many epidemiological studies have shown CKD prevalence in farming communities ranges from 15% to 21%, with a 9% to 13% prevalence of chronic kidney failure (CKF). Less than half of them have DM or HTN, males predominate, and kidney damage begins in the early stages of life. While the disease predominates in men, women, children, and adolescents who live in these farming communities are also affected whether they work as farmers or not. This increased prevalence of CKD has been observed in farming communities both in highlands and lowlands.
Additionally, it has been demonstrated that in these farming community’s pesticides, and heavy metals (cadmium and arsenic) are present in well water, floors in homes, and farmlands (more concentrated in crop areas); Domestic exposure can occur not only with the application on the lands but also from pesticide storage in household facilities. Farmers that contaminate their clothes with pesticides (due to lack of protection) provide an additional source of exposure to the family, especially for women who wash family clothing. In the United States, a cohort of 55,580 male licensed pesticide applicators showed a significant association between chronic exposure to pesticides and risk for ESRD.
Two triggers have been proposed: toxic exposure in the agricultural communities and heat stress with repeated episodes of dehydration causing recurrent acute kidney injury leading to CKD. It is plausible that heat stress is an important contributor to the perpetuation of CINAC but is unlikely to be the main driving force because CINAC is absent in very hot areas such as Cuba, Myanmar, and Northern Sri Lanka, where agrochemicals are rarely used. The identical clinical and pathologic phenotype of CINAC in different locations supports the involvement of common pathophysiological pathways. The patients treated with CNIs, acquire similar lesions in their proximal tubule cells. The documented CNI effect of some herbicides and insecticides (paraquat, glyphosate, and pyrethroids) suggests a pathway leading to the striking similarity of PT lesions in these 2 forms of toxic nephropathy. These findings strongly suggest a toxicologic etiology for the presence of CINAC.
One hypothesis for the damage could be the continued farmers' exposure to toxic substances without protection during the spraying at high temperatures that cause vasodilation and opening the skin pores, causing an increment in the absorption and selective damage to the different organs, leading to reflex disorders, sensorineural hearing loss, and Chronic Kidney Disease.
An environmental/occupational toxic exposure is more credible as the main driver of this epidemic. Genetic susceptibility was identified as a risk factor for CINAC by using a genome-wide association study (GWAS) in Sri Lanka.
Histologic findings in CINAC cases from different regions of the world are similar. There is 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 muscular hypertrophy, smooth muscle vacuolization, and intimal proliferation within arteries and arterioles.
The predominant pattern shows chronic tubulointerstitial nephritis with enlarged proximal tubular cell argyrophilic granules (identified as lysosomes) associated with varying degrees of epithelial simplification and tubular atrophy luminal cell fragment shedding with or without tubulointerstitial expansion (inflammation, edema, fibrosis).
Electron microscopy: Confirmatory diagnosis is established in the presence of enlarged (>1.2 mm) dysmorphic lysosomes containing electron-dense aggregates. In the absence of enlarged lysosomes, the diagnosis should be suspected if there are 2 or more clusters of 3 lysosomes that have intra-lysosomal aggregates
History and Physical
General symptoms: In the early stages of CKD, patients report general symptoms such as arthralgia, asthenia, decreased libido, cramps, and fainting.
Urinary symptoms: micturition impairments are common: nocturia, dysuria, post-void dribbling, hesitancy, and foamy urine. Symptoms appear as early as stage 2 CKD, the frequency and intensity of symptoms progress as the disease advances. At times decreased urine stream, hesitancy, and dysuria are evident from the start.
Extrarenal symptoms: different organs and systems are also affected, while others show no sign of damage.
Cardiovascular system: blood pressure is either normal or mildly elevated, electrocardiogram (ECG) is mostly normal. The cardiac stress test, pressor response, and echocardiogram were normal in most cases, whereas mild diastolic dysfunction can be noted.
Peripheral arteries: Doppler ultrasound describes few abnormalities of the carotid and aortoiliac arteries; most of the damage is seen in tibial arteries. The most common tibial lesion has been reported to be wall irregularities.
Nervous system: tendon reflex abnormalities are seen in early stages, as well as sensorineural hearing loss.
Eyes: fundoscopic examination, intraocular pressure, and visual field tests were normal in most patients. Suggesting that these patients do not have significant microvascular damage as in diabetic or hypertensive retinopathy.
Laboratory studies include complete blood count (CBC), comprehensive metabolic panel (CMP), magnesium level, urine total protein, urine sodium range, urine potassium range, urine magnesium range, 24-hour urine, urine protein-creatinine ratio, urine tubular proteins. In the Urine assessment, the sediment shows no significant abnormalities nor dysmorphic erythrocytes. Loss of electrolytes in the early stage, low to mild proteinuria (<1 g), and high levels of Beta 2 microglobulin (NGAL and NAG) are founded.
Electrolytes: low concentrations of sodium, potassium, chlorine, and magnesium in the blood; nevertheless, blood osmolality remains normal.
Acid-base balance: metabolic alkalosis is predominant, starting as early as stage 2 CKD.
Kidney ultrasound reveals an increased echogenicity, decreased cortical-medullary ratio, and irregular margins. Renal Doppler ultrasound shows preserved blood flow in renal and segmental arteries and renal parenchyma. Bladder ultrasound shows no abnormalities, and prostate ultrasound is normal without masses or other lesions.
Electrocardiogram, echocardiogram, doppler ultrasound of the leg, and carotid doppler test.
Renal function tests, biopsy with immunofluorescence, electron microscopy, and light microscopy.
Electromyography and nerve conduction studies.
Treatment / Management
Early detection, prevention of further deterioration of kidney function is the cornerstone of therapy. The most important early step is to move away from the patient from agrochemist contact.
Supportive care with fluids and electrolytes, adequate hydration, and correction of electrolyte abnormalities are important in early-stage management.
In the final stage of chronic kidney disease, renal replacement therapy should be implemented.
Aristolochic acid nephropathy
Balcan endemic nephropathy
Hyperuricemia and urate nephropathy
Nephropathy secondary to sarcoidosis
Nephropathy secondary to calcineurin inhibitors
Depends on the degree of renal dysfunction (GFR reduction) at the time of diagnosis as well as on treatment options for the underlying condition.
Some of the complications are neurologic (reflex alterations in the early stage), auditive (hypoacusis), vascular lesions in the lower limbs.
Deterrence and Patient Education
CKD in agricultural workers calls for careful health education. The occupational health team can play important roles in recognizing kidney disease risks among agricultural workers, advocating for prevention strategies such as the use of pesticides according to federal regulations, use of PPE, shade, rest, and water supply to prevent heat stress, dehydration, and volume depletion.
Occupational and community health teams should assess work, and it is important to identify patient occupation, provide guidance in the management of pain to prevent overuse of NSAIDs, educate patients on the potential risks of self-treatment with antibiotics for urinary symptoms, and encourage them to seek professional care to decrease the risk of AKI.
CKD screening in high-risk patients based on their medical and occupational history should include the history of prior occupation such as farm work, type of crops, spraying of pesticides, and sugar cane cutting.
Pearls and Other Issues
We report a case of CINAC with typical histological findings on kidney biopsy slides for the purpose of illustration.
A 40-year-old man with more than 10 years of agricultural work and abnormal electrolytes for 5 years. He does not have diabetes or hypertension and has a serum creatinine of 2.05 mg/dL with normal serum albumin and negative HIV and hepatitis serology.
Microscopic findings: The specimen for conventional light microscopy, studied with hematoxylin and eosin, periodic acid-Schiff, periodic acid-methenamine silver, and Masson's trichrome stained sections, consists of skeletal muscle, fat, connective tissue, and renal cortex with medulla. There are 10 glomeruli, 1 of which is globally sclerotic. Four glomeruli have moderate capillary wall corrugation, 7 glomeruli have periglomerular fibrosis, and 1 glomerulus is moderately enlarged. No hypercellularity,
Glomerular inflammation, segments of sclerosis, or crescents are evident. There is approximately 45% cortical tubular atrophy with interstitial fibrosis, with moderate mononuclear predominant inflammation associated with the fibrosis. There is minor tubular inflammation focally, and no neutrophils are in the tubular lumina. Scattered preserved and atrophic proximal tubular cells have large irregular silver positive granules. Arteries and arterioles have moderate to severe muscular hypertrophy, and arteries have mild intimal fibrosis. Immunofluorescence microscopy is performed on frozen sections, with appropriate controls, stained with fluoresceinated antisera to human IgG, IgA, IgM, C1q, C3, albumin, fibrin, and kappa, and lambda immunoglobulin light chains and is graded on a scale of 0-4+. Each frozen section consists of a corticomedullary junction and medulla with a single glomerulus, which fails to stain for any immune reactants. Arteriolar walls stain for C3 (3+).
Tubular casts stain for IgA (4+), IgM (2+), and kappa (4+), and lambda (4+) light chains. The remaining immune reactants are negative. The specimen for electron microscopy, studied first by light microscopy of methylene blue-stained one-micron thick sections, consists of fat, capsule, and renal cortex containing 18 glomeruli. Nine glomeruli are globally sclerotic, some in the subcapsular region. Glomeruli overall are normal, 5 have periglomerular fibrosis, and 4 have moderate capillary wall corrugation. No hypercellularity, segments of sclerosis, or crescents are evident.
There is approximately 40% tubular atrophy with interstitial fibrosis, and 80% of the scarred areas have heavy mononuclear inflammation. There are thickened tubular basement membranes involving approximately 20% to 25% of the preserved tubules. No neutrophils are evident. Arteries and arterioles have moderate muscular hypertrophy. Ultrastructural study of 5 glomeruli reveals predominantly normal to segmental mild thickening of glomerular basement membranes and the normal trilaminar appearance.
There is approximately 70% to 75% podocyte foot process effacement, and few podocytes have large cytoplasmic lipid globules. There are no electron-dense (immune complex) deposits in any location. Endothelial cells have preserved fenestrate and no tubuloreticular inclusions. The tubular and interstitial changes are confirmed. There are clusters of rounded to slightly dysmorphic small lysosomes containing electron-dense aggregates. There also are larger (>1.2 microns) dysmorphic proximal tubular lysosomes containing dispersed electron-dense aggregates.
Enhancing Healthcare Team Outcomes
CINAC is a complex disease that develops in susceptible individuals working in agriculture. The hypothesized causal factors can be minimized and may be preventable. It is of critical importance to have an intersectoral collaboration and multidisciplinary approach that seeks to strengthen health services, workforce training, increase medication supply, health technology, and medical surveillance with international cooperation.
(Click Image to Enlarge)
CINAC case 1
Contributed by Cynthia Nast, MD Renal Pathology Cedars Sinai
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