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Chronic Interstitial Nephritis in Agricultural Communities (CINAC)
Introduction
Chronic interstitial nephritis in agricultural communities (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.[1] However, the incidence and prevalence of CINAC have reached epidemic proportions. Predominantly, CINAC affects young men but has also been occasionally reported in women and adolescents in countries such as El Salvador, Guatemala, Nicaragua, and Costa Rica in Central America, Egypt in Africa, and Sri Lanka and India in Asia.[2]
This form of CKD of nontraditional causes has been reported from several world regions and has similar clinical and epidemiological characteristics.[3][4] It is known by various names, such as Central American nephropathy, Salvadoran agricultural nephropathy, Mesoamerican nephropathy, Uddanam endemic nephropathy (India), or CKD of unknown etiology (CKDu) in Srilanka.[5] The term chronic interstitial nephritis in agricultural communities (CINAC) was proposed to describe the disease holistically.[4]
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.[6]
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 three times more than females.[7]
Etiology
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Etiology
The etiology of chronic interstitial nephritis in agricultural communities 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, a form of CKD 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, their occupations expose them to multiple toxic substances, many of which have been outlawed in other countries.[8] 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.
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.[9] These toxins could be present in the air, soil, water, and/or food. Additionally, exposure to a toxin can be modified by climate, topography, and soil use. Lifestyles, working conditions, and impurities in drinking water could determine the route of exposure.[10] 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 it has not been studied yet. Circulation of toxic agents in the blood is subject to renal elimination, which may become compromised in a state of recurrent dehydration in farmworkers. Some studies report that elevated levels of fluoride and vanadium in the environment could be associated with an increasing prevalence of CINAC.[11]
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.[12][13]
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, non-steroidal anti-inflammatory drugs, dehydration, and nephrotoxic medicinal plants.[14]
Another hypothesis for the etiology of CINAC is recurrent dehydration.[15] Repeated dehydration events have been proposed to cause sub-clinical rhabdomyolysis, effects of hyperuricosuria and hyperuricemia, activation of the aldose reductase-fructokinase reaction in the kidney, and vasopressin effects.[16][17][18] 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 four weeks does not induce the dysmorphic lysosomes identified in patients with CINAC.
More studies need to be done; nonetheless, it appears from indirect observations that CINAC is the pathologic expression of a toxic insult.[19]
Epidemiology
Twenty years after reporting the first case, chronic interstitial nephritis in agricultural communities is a significant public health issue in many countries, such as Central America, Sri Lanka, etc. It is estimated that the North Central Province (NCP) in Sri Lanka has more than 60000 estimated cases and more than 20000 annual deaths. The available CINAC statistics from hospital records reveal a steady rise in cases from 2000 to 2015. Between 2000 and 2002, the underlying cause of kidney failure was not found in 82% of CKD cases seen at Anuradhapura teaching hospital.[20] The World Health Organization (WHO) study group reported a slightly higher age-standardized prevalence of CINAC in women than men but observed that more advanced CINAC was seen more commonly in men.[21] This is in line with the well-known higher prevalence of advanced CKD among men, as noted in many studies.[22]
Many epidemiological studies have shown CKD prevalence in farming communities. Less than half of them have diabetes mellitus or hypertension, males predominate, and kidney damage begins in the early stages of life. While the disease predominantly affects men, other community members, such as women, children, and adolescents in these farming communities, are also affected whether they work on the farms or not. This increased prevalence of CKD has been observed in farming communities both in highlands and lowlands.[23][24]
Additionally, it has been demonstrated that in these farming communities, pesticides and heavy metals (cadmium and arsenic) are present in well water, floors in homes, and farmlands (more concentrated in crop areas). Farmers that contaminate their clothes with pesticides (due to lack of protection) provide additional exposure to the family, especially to women who wash family clothing. In the United States, a cohort of 55,580 male licensed pesticide applicators showed a significant association between chronic pesticide exposure and the risk for chronic kidney disease.[25]
An epidemic of CKD not linked with conventional risk factors has been observed in places like India, Japan, Central America, and Sri Lanka.[26] In India, numerous cases have been diagnosed among coconut and paddy farmers.
In Central America, increasing numbers of CKD cases and increased CKD-associated mortality have been noted over the last two decades, especially in El Salvador and Nicaragua. The Pan American Health Organization has reported CKD-specific mortality rates (per 100 000 population) as follows: Nicaragua: 42.8; Guatemala: 13.6; El Salvador: 41.9; and Panama: 12.3.
Pathophysiology
Chronic interstitial nephritis in agricultural communities is one of the causes of chronic kidney disease of unknown etiology, which is generally more frequently seen in certain agricultural communities, as described above. Regarding the underlying pathophysiology of CINAC, two triggers have been proposed: toxic exposure in agricultural communities and heat stress with repeated episodes of dehydration causing recurrent acute kidney injury leading to CKD.[19]
It is plausible that heat stress is an important contributor to the perpetuation of CINAC but is unlikely to be the sole 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 calcineurin inhibitors (CNI) acquire similar lesions in their proximal tubule cells. There is documented CNI effect of some herbicides and insecticides (paraquat, glyphosate, and pyrethroids). These findings strongly suggest a toxicologic etiology for the presence of CINAC.[19]
Roncal-Jimenez et al. pointed out that recurrent dehydration may lead to renal injury by activating the polyol pathway, causing the production of endogenous fructose in kidneys that subsequently induces renal injury through metabolism by fructokinase. Fructose is nontoxic; however, fructokinase metabolizes it to generate uric aid, nephrotoxic oxidants, and inflammatory mediators. The major area where fructokinase is abundantly expressed is in the proximal tubules. Recurrent dehydration leads to repeated aldose reductase stimulation, causing fructose generation in the proximal tubules, resulting in tubular injury and inflammation. In some instances, agricultural laborers commonly use fructose-containing beverages for rehydration. A recent animal study revealed pathology suggestive of CINAC, such as elevated serum creatinine, renal inflammation, proximal tubular injury, and fibrosis after repeated exposure to heat-induced dehydration. Interestingly, this pathology was not observed in fructokinase-deficient mice. Additionally, another animal study reported that access to sufficient and clean water during the period of dehydration could protect the kidney.[18]
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 of 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.[19]
Environmental/occupational toxic exposure is more credible as the main driver of this epidemic.[27] Genetic susceptibility was identified as a risk factor for CINAC using a genome-wide association study (GWAS) in Sri Lanka.[28]
Histopathology
Histologic findings in chronic interstitial nephritis in agricultural communities 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.[29][30][31]
The predominant pattern shows chronic tubulointerstitial nephritis with argyrophilic granules (identified as lysosomes) in enlarged proximal tubular cells associated with varying degrees of epithelial simplification and tubular atrophy and luminal cell fragment shedding with or without a tubulointerstitial expansion (inflammation, edema, fibrosis).[32]
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 two or more clusters of 3 lysosomes that have intra-lysosomal aggregates.[32]
History and Physical
The clinical picture of chronic interstitial nephritis in agricultural communities is similar in many areas. CINAC progresses slowly but at a varying pace based on the level of exposure to agrochemicals/herbicides and/or contaminated water. In the majority of cases, there are no symptoms at the beginning of the disease.[8] Some general symptoms reported at the outset are arthralgia, asthenia, muscle cramps, decreased libido, and faintishness.[33] Proteinuria is rare and moderate. Renal function tests reveal polyuria accompanied by hyperphosphaturia, hypermagnesuria, hypernatriuria, hyperkaliuria, and hypercalciuria.[34]
Urinary symptoms include the following:
- Nocturia
- Dysuria
- Post-void dribbling
- Hesitancy
- Foamy urine
Symptoms appear as early as stage 2 CKD, and the frequency and intensity of symptoms progress as the disease advances. However, at times decreased urine stream, hesitancy, and dysuria are evident from the start.
Patients may also present with extrarenal symptoms when different organs and systems are also affected, while others show no sign of damage.
- Cardiovascular system: blood pressure is either normal or mildly elevated, and electrocardiogram (ECG) is mostly normal. The cardiac stress test, pressor response, and echocardiogram are normal in most cases, whereas mild diastolic dysfunction can be noted. CINAC patients in El Salvador showed few abnormalities of the aortoiliac and carotid arteries but significant tibial artery abnormalities.[33]
- Peripheral arteries: Doppler ultrasound describes a few abnormalities of the carotid and aortoiliac arteries; most of the damage is seen in the tibial arteries. The most common tibial lesion has been reported to be wall irregularities.
- Nervous system: tendon reflex abnormalities are seen in the early stages and sensorineural hearing loss. Both heavy metals and organic solvents are observed to cause sensorineural hearing loss.[35]
- Eyes: fundoscopic examination, intraocular pressure, and visual field tests are normal in most patients, suggesting that these patients do not have significant microvascular damage as in diabetic or hypertensive retinopathy.
Evaluation
There are many ways to narrow down differentials and establish a diagnosis of chronic interstitial nephritis in agricultural communities. The following is the list of investigations needed to diagnose CINAC:
Laboratory Evaluation
Laboratory studies include complete blood count (CBC), comprehensive metabolic panel (CMP), magnesium level, total urine protein, urine sodium range, urine potassium range, urine magnesium range, 24-hour urine, urine protein-creatinine ratio, and urine tubular proteins. The sediment neither shows significant abnormalities nor dysmorphic erythrocytes in the urine assessment. Loss of electrolytes in the early stage, low to mild proteinuria (<1 g), and high levels of beta 2 microglobulin are found.[36][37]
Electrolytes: low concentrations of sodium, potassium, chlorine, and magnesium in the blood; nevertheless, blood osmolality remains normal.
Acid-base imbalance: metabolic alkalosis is predominant, starting as early as stage 2 CKD.
Imaging
Kidney ultrasound reveals an increased echogenicity, decreased cortical-medullary ratio, and irregular margins.[4] Renal Doppler ultrasound shows preserved blood flow in renal and segmental arteries and the renal parenchyma. Bladder ultrasound shows no abnormalities, and prostate ultrasound is normal without masses or other lesions.
Cardiological Evaluation
Electrocardiogram, echocardiogram, Doppler ultrasound of the leg, and carotid doppler test might be warranted in patients varying from one case to another.
Renal Evaluation
Renal function tests, biopsy with immunofluorescence, electron microscopy, and light microscopy could be carried out to establish the diagnosis.
Neurological Evaluation
Electromyography and nerve conduction studies may be needed.
Treatment / Management
Early detection and prevention of further deterioration of kidney function is the cornerstone of therapy in chronic interstitial nephritis in agricultural communities. The most important early step is to move the patient away from agrochemical contact. In addition, supportive care with fluids and electrolytes, adequate hydration, and correction of electrolyte abnormalities are important in early-stage management. Once chronic kidney disease has developed, the patient is generally managed on the lines of chronic kidney disease secondary to other causes. In the final stage of chronic kidney disease, renal replacement therapy should be implemented.
The recent findings suggestive of a lysosomal inclusion body tubulopathy are of great interest to those trying to find therapeutic options to slow down or eliminate the renal damage. It has been argued that despite these findings, oxidative stress might play a key role and that anti-oxidants could be a pertinent treatment option, such as Vitamin C and E.[38]
CINAC prevention measures can include establishing reverse osmosis plants to purify the water and lessen the exposure to possible nephrotoxins via drinking water.[39]
Poor awareness and agrochemical handling practices lead to occupational exposure; hence focusing on farming practices, lifestyle, agrochemical handling, and awareness of health effects could prevent this disease.
Differential Diagnosis
The following is a list of differentials that merit consideration when dealing with a patient having features suggestive of chronic interstitial nephritis in agricultural communities:
- Analgesic nephropathy
- Aristolochic acid nephropathy
- Balcan endemic nephropathy
- Lithium poisoning
- Lead poisoning
- Cadmium poisoning
- Hyperuricemia and urate nephropathy
- Nephropathy secondary to sarcoidosis
- Nephropathy secondary to calcineurin inhibitors
Prognosis
The prognosis of chronic interstitial nephritis in agricultural communities depends on the degree of renal dysfunction (GFR reduction) at the time of diagnosis and treatment options for the underlying condition. It also depends on the patient's past medical history, comorbidity, and general health. The progression of renal dysfunction is relatively rapid, with end-stage renal disease occurring over 4 to 10 years.[19] A study reported excess CKD mortality primarily in Guanacaste lowlands, and the increasing rates in Guanacaste population in hot and dry lowland counties with sugarcane were consistent with an occupational component.[40]
Complications
In patients with chronic interstitial nephritis in agricultural communities, older patients are more susceptible to complications. Delays in diagnosis and treatment worsen the condition. Renal insufficiency is a common manifestation that ultimately progresses to end-stage renal disease. The inflammatory interstitium is completely replaced by fibrosis, and severe degeneration of tubular epithelial cells induces irreversible renal impairment necessitating early renal dialysis and renal transplantation. Some complications are neurologic (reflex alterations in the early stage), auditive (hypoacusis), and vascular lesions in the lower limbs.[4]
Deterrence and Patient Education
Chronic interstitial nephritis in agricultural communities 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 using 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 essential 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 acute kidney injury.
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.
Enhancing Healthcare Team Outcomes
Chronic interstitial nephritis in agricultural communities is a complex disease that develops in susceptible individuals working in agriculture. The hypothesized causal factors can be minimized and may be preventable. Therefore, it is critical to have an interprofessional collaboration and multidisciplinary/interprofessional approach that seeks to strengthen health services, workforce training, health technology, medical surveillance, and increase medication supply with international cooperation. As a relatively recently recognized condition, interprofessional communication between clinicians (MDs, DOs, NPs, and PAs), specialists, nursing staff, and pharmacists is crucial because some team members may not be familiar with the disease or how to monitor and treat it. Therefore, additional training may be necessary for providers who come onto the case management team, and all members must understand the condition, monitor patient progress, and document their findings and observations so everyone managing the case can have access to current and accurate patient data. This interp[professional approach will help drive better outcomes. [Level 5]
Media
(Click Image to Enlarge)
CINAC case 1 Contributed by Cynthia Nast, MD Renal Pathology Cedars Sinai
References
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