Glyphosate has been termed a ‘once-in-a-century herbicide’ due to its incredible impact on weed management and the crop production industry. Research states that glyphosate degrades relatively quickly in soil once it has been sprayed. However, glyphosate and its metabolites can possibly persist in soil, plant tissues, and water under certain conditions for a lot longer than postulated. Research has suggested that glyphosate may reach groundwater, surface water, and other nontarget sites through processes such as leeching and surface runoff.

Now, for the past couple of decades, tens of thousands of people living in rural Sri Lanka have suffered kidney failure due to unknown causes, also termed CKDu. Reports show similar incidences of this kidney disease popping up in tropical farming communities throughout the world; the identified possible culprit…

Glyphosate

Glyphosate is the active compound found in Roundup, the most widely used herbicide in the world. Roundup is a glyphosate-based herbicide used to control weeds and other pests. It is supposed to break down in a few days; however, when glyphosate encounters other trace metal ions, such as magnesium and calcium, glyphosate-metal ion complexes can be formed. These complexes have been found to persist for seven years in water and 22 years in soil. Those affected by CKDu are usually from the most vulnerable and underserved populations.

glyphosate and renal disease

Roundup Ingredient Connected to Epidemic Levels of Chronic Kidney Disease | Duke Pratt School of Engineering

It has been proposed that glyphosate’s cumulative mechanism of toxicity in humans may be through its unique ability to substitute for glycine, a coding amino acid, during protein synthesis. Recent papers show detailed descriptions of strong glycine dependencies in proteins linked to various diseases relating glyphosate substitution for glycine during protein synthesis as a possible contributing cause of diabetes, obesity, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), autism, multiple sclerosis and prion diseases, anencephaly, CKDu, and gout.

Glyphosate’s Synergistic Toxicity in Combination with Other Factors as a Cause of Chronic Kidney Disease of Unknown Origin – PMC (nih.gov)

CKD has become a global epidemic. This major health issue is observed in the rice paddy farming areas of Sri Lanka and has become the subject of many scientific and political debates over the last decade. Sri Lanka has seen a doubling of this disease every 4-5 years since it was first identified in the mid-1990s.  Health workers have also reported the prevalence of CKDu in Mexico, Nicaragua, El Salvador, and the state of Andhra Pradesh in India. In 2009, the Sri Lankan Ministry of Health introduced criteria for the case definition of CKDu.

These included:

  • (1) No past history of, or current treatment for diabetes mellitus or chronic and severe hypertension, snake bites, urological disease of known etiology
  •  or glomerulonephritis.
  • (2) Normal glycosylated haemoglobin levels (HbA1C ˂ 6.5%).
  • (3) Blood pressure ˂160/100 mmHg untreated or ˂140/90 mmHg on up to two antihypertensive agents.

Glyphosate, Hard Water and Nephrotoxic Metals: Are They the Culprits Behind the Epidemic of Chronic Kidney Disease of Unknown Etiology in Sri Lanka? – PMC (nih.gov)

What is Chronic Kidney Disease of Unknown Etiology (CKDu)

CKDu refers to a form of CKD that is not associated with common risk factors such as;

  •   Hypertension.
  •   Diabetes.
  •   Glomerulonephritis.

It typically affects individuals who do not have a history of diabetes, high blood pressure or any other primary KD.

Not surprisingly, there is a shortage of data on CKDu. However, the Indian CKD Registry showed that CKDu is the second-most common underlying cause of CKD (16.0%) after diabetic nephropathy (31.3%).

Causes of CKDu

There are varied causes for CKDu that are associated with different environments and occupational exposure.

These include;

  •   Heat stress
  •   Dehydration
  •   Agrochemicals (pesticides, herbicides, fertilizers)
  •   Heavy metals (cadmium, lead, arsenic, etc.)
  •   Water sources
  •   Infection

Risk Factors Associated with CKDu

  1. Arsenic and cadmium in the water
  2. Male sex
  3. Being a farmer
  4. Using and spraying pesticides without personal protective equipment (PPE)
  5. Drinking well water
  6. Dehydration
  7. Extreme physical exertion
  8. Heat stress
  9. Agrochemical exposure
  10. Nephrotoxic drugs such as aristolochic acid
  11. Smoking
  12. Alcohol made with local traditional methods
  13. Infections
  14. Snake bites
  15. Family history of CKD

 

Source via Chronic kidney disease of unknown aetiology: A comprehensive review of a global public health problem – Rao – 2023 – Tropical Medicine & International Health – Wiley Online Library

CKDu is similar to the end stage of CKD. Microscopic analysis of renal tissues of patients with CKDu has shown tubulointerstitial disease. A kidney biopsy study of sugar cane workers in Nicaragua confirmed that CKDu comes with glomerular and tubulointerstitial damage, glomerulosclerosis, and chronic glomerular ischemia.

Symptoms Associated

  •   Fatigue
  •   Panting
  •   Lack of appetite
  •   Nausea
  •   Sleep disturbance
  •   Exhaustion
  •   Weight loss

Unfortunately, it is a life-threatening disease due to late recognition and rapid disease progression and has become a silent killer for most patients. The primary feature of CKDu is fibrosis in kidney tubules and interstitials with glomerular and vascular damage at different stages of the disease process.

Rising of a global silent killer: critical analysis of chronic kidney disease of uncertain aetiology (CKDu) worldwide and mitigation steps | Environmental Geochemistry and Health (springer.com)

Chronic Kidney Disease of Unknown Origin: A Mysterious Epidemic – PMC (nih.gov)

Glyphosate: Its Environmental Persistence and Impact on Crop Health and Nutrition – PMC (nih.gov)

Chronic kidney disease of unknown aetiology: A comprehensive review of a global public health problem – Rao – 2023 – Tropical Medicine & International Health – Wiley Online Library

Source via:  Chronic Kidney Disease of Unknown Origin: A Mysterious Epidemic – PMC (nih.gov)

 

What is glyphosate?

Glyphosate is the most widely used herbicide in the world. It is a non-selective systemic biocide with broad-spectrum activity. It was introduced in 1974 to control weeds in agricultural production fields. Numerous commercial formulations contain this compound, and herbicide formulations containing this active ingredient represent approximately 60% of the global market for non-selective herbicides. Approximately 600,000 to 750,000 tons of glyphosate are used each year, and it is estimated that its use will increase, reaching between 740,000 and 920.000 tons by 2025.

Glyphosate linked to kidney disease

Glyphosate targets and inhibits a key enzyme involved in synthesising essential amino acids in plants. Its mechanism of action involves its ability to block the shikimic acid pathway. Glyphosate inhibits the enzyme 5-enolpyruvilshikimate-3-phosphate synthase (EPSPS), a step in the shikimate pathway. The shikimic pathway is responsible for the biosynthesis of aromatic amino acids such as tryptophan, tyrosine and phenylaniline. These amino acids are essential for protein synthesis and plant growth.

The EPSPS enzyme catalyses a key step within this pathway, combining shikimate-3-phosphate with phosphoenolpyruvate (PEP) to produce 5-enolpyruvylshikimate-3-phosphate. This is necessary for aromatic amino acid production.

Glyphosate mimics PEP and binds to the active site of EPSPS, preventing the enzyme from functioning properly. This cascade of events leads to an accumulation of shikimate-3-phosphate and a depletion of aromatic amino acids, slowing plant growth and leading to plant death. When the EPSPS enzyme is blocked, plants can not produce the essential compounds they rely on to survive. Over time, these plants will wither and die.

While the shikimate pathway is involved in the synthesis of aromatic amino acids in plants, fungi, and some microorganisms, it is absent in animals. Many investigations on glyphosate toxicity in animals have suggested the low toxicity of this compound, but adverse effects were only observed after exposure to relatively high doses. This led to the conclusion that glyphosate-based herbicides (GBH) did not pose a health risk to animals and humans.

Toxic Effects of Glyphosate on the Nervous System: A Systematic Review – PMC (nih.gov)

How is Glyphosate Degraded in the Environment?

Glyphosate degradation in the environment is primarily driven by microbial activity. Microorganisms such as bacteria and fungi in the soil play a major role in the degradation process. Soil microbes break down glyphosate for the use of carbon, nitrogen and phosphorus. Its persistence is thought to be low to moderate, although this is considered to be quite variable. Some of the following factors influence its biodegradation;

  •   Physico-chemical
  •   Biological properties
  •   Soil composition

Glyphosate: Its Environmental Persistence and Impact on Crop Health and Nutrition – PMC (nih.gov)

However, studies show that due to improper application and excessive spray, glyphosate has been observed in aquatic and terrestrial environments. Studies show glyphosate has been detected in soil, crop products, animals that feed on crop products, humans and fresh water.

Source via Glyphosate: Its Environmental Persistence and Impact on Crop Health and Nutrition – PMC (nih.gov)

Ground Water Consumption & Heavy Metals

A large field study published in Environmental Science and Technology Letters on September 13, 2023, looked at the wells supplying drinking water to the Sri Lankan communities. They found that in certain agricultural areas, the high, dry climate and its geological formations create perfect conditions for hard water.  In these regions, CKDu has reached epidemic levels. As many as 10% of children aged 5-11 years old show signs of early onset kidney damage.

The team sampled over 200 wells across four regions in Sri Lanka. Researchers found significantly higher levels of the herbicide in 44% of wells within the affected areas versus just 8% of those outside them. They also found increased levels of vanadium and fluoride linked to kidney damage. Researchers concluded that the high use of glyphosate worldwide should serve as a serious warning when considering the risk of long-term exposure to glyphosate.

groundwater contamination, kidney and renal disease

Another study showed glyphosate contamination in CKDu-affected areas; glyphosate sediment was detected in all sediment samples. A study based in Argentina found up to 67 μg/kg of glyphosate in 80% of collected rain samples. It is also thought that those living in CKDu-affected areas may be ingesting more glyphosate through their consumption of locally grown food as well as imported foods such as red lentils. In addition, water hardness has also been described as a risk factor in CKDu.

Farmers’ urine has been found to contain glyphosate after spraying this pesticide, with higher levels found in those not wearing PPE. Studies found that the use of glyphosate was associated with five-times higher odds of developing CKDu compared to those without exposure to glyphosate.

It has been proposed that glyphosate forms stable complexes with metals such as magnesium, calcium, cadmium, strontium, and arsenic, all present in hard water. These metals can act as carriers of these toxins to the kidney, leading to renal proximal tubular injury.


Source via Glyphosate, Hard Water and Nephrotoxic Metals: Are They the Culprits Behind the Epidemic of Chronic Kidney Disease of Unknown Etiology in Sri Lanka? – PMC (nih.gov)

Glyphosate’s Synergistic Toxicity in Combination with Other Factors as a Cause of Chronic Kidney Disease of Unknown Origin – PMC (nih.gov)

Chronic kidney disease of unknown aetiology: A comprehensive review of a global public health problem – Rao – 2023 – Tropical Medicine & International Health – Wiley Online Library

Testing and Screening

Screening tests should include serum creatinine (by a standardised assay) and urine dipstick and/or urine albumin creatinine ratio (UACR). To avoid misdiagnosis, repeat measurements at least three months apart should be done. Cystatin C was found to be the most sensitive functional marker for the detection of CKDu when compared to serum creatinine and UACR; however, its high cost limits its use. A potential role of urinary proteome profiling for early diagnosis of CKDu has also been suggested.

Chronic kidney disease of unknown aetiology: A comprehensive review of a global public health problem – Rao – 2023 – Tropical Medicine & International Health – Wiley Online Library

The use of harmful pesticides and fertilisers not only has a detrimental effect on the environment but is also one of the drivers of CKDu and the CKDu epidemic. There is a clear need to educate farmers about the negative impact of these farming practices. If handling and using these chemicals, the use of PPE is a must and implementation of safe methods of disposal of empty pesticide containers/bottles and fertiliser bags is also essential. Glyphosate has been banned in several countries, and its use is restricted in others.

While glyphosate is effective for weed control, its persistence in the environment and potential for bioaccumulation, particularly in regions with hard water, exacerbate the risk of CKDu. CKDu is a complex disease involving multiple environmental, occupational, and possible genetic factors, indicating glyphosates may not be the sole cause. However, it is a driving cofactor in susceptible populations. Further research is needed into the long-term health effects of glyphosate. Stricter regulatory controls on its use and safer agricultural practices are required, especially in vulnerable communities.

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