Chronic kidney disease of unknown
etiology
Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
(CKDu) is an increasing health concern in
Sri Lanka
Sri Lanka (, ; si, ශ්රී ලංකා, Śrī Laṅkā, translit-std=ISO (); ta, இலங்கை, Ilaṅkai, translit-std=ISO ()), formerly known as Ceylon and officially the Democratic Socialist Republic of Sri Lanka, is an ...
.
CKDu is recognized as
chronic kidney disease without the usual associated causative factors.
The first cases of CKDu were reported in Sri Lanka's
North Central Province (NCP). Chronic kidney disease (listed under diseases of the urinary tract), was identified as the 8th leading cause of in-hospital mortality in Sri Lanka, and the leading cause of death in
Anuradhapura
Anuradhapura ( si, අනුරාධපුරය, translit=Anurādhapuraya; ta, அனுராதபுரம், translit=Aṉurātapuram) is a major city located in north central plain of Sri Lanka. It is the capital city of North Central ...
and
Polonnaruwa
Poḷonnaruwa, ( si, පොළොන්නරුව, translit=Poḷonnaruva; ta, பொலன்னறுவை, translit=Polaṉṉaṟuvai) also referred as Pulathisipura and Vijayarajapura in ancient times, is the main town of Polonnaruwa Dis ...
in 2016.
This rise in mortality coincided with the increasing cases of CKDu seen across the country.
Studies have shown an estimated 70,000 CKDu patients in high risk areas.
Various possible causes for CKDu in Sri Lankans have been investigated, including poisoning from
metal
A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typicall ...
s,
cyanobacteria
Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...
toxins,
agrochemical
An agrochemical or agrichemical, a contraction of ''agricultural chemical'', is a chemical product used in industrial agriculture. Agrichemical refers to biocides ( pesticides including insecticides, herbicides, fungicides and nematicides) an ...
s, and
heat stress
Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...
, but no definite causes have been identified.
There have been several other geographic areas in which CKDu has emerged, such as
Africa
Africa is the world's second-largest and second-most populous continent, after Asia in both cases. At about 30.3 million km2 (11.7 million square miles) including adjacent islands, it covers 6% of Earth's total surface area ...
,
Central America
Central America ( es, América Central or ) is a subregion of the Americas. Its boundaries are defined as bordering the United States to the north, Colombia to the south, the Caribbean Sea to the east, and the Pacific Ocean to the west. ...
(see
Mesoamerican nephropathy
Mesoamerican nephropathy (MeN) is an endemic, non-diabetic, non-hypertensive chronic kidney disease (CKD) characterized by reduced glomerular filtration rate (GFR) with mild or no proteinuria and no features of known primary glomerular diseases. M ...
), and
Asia
Asia (, ) is one of the world's most notable geographical regions, which is either considered a continent in its own right or a subcontinent of Eurasia, which shares the continental landmass of Afro-Eurasia with Africa. Asia covers an area ...
.
Due to similar signs and symptoms of CKDu in these areas, CKDu is also referred to as Chronic Interstitial Nephritis in Agricultural Communities.
Geographic distribution
CKDu is most common in Sri Lanka's NCP,
but cases also have been identified in some parts of Eastern, Central, and North Western provinces. The affected villages are located in the dry zone of the country where it rains only a few months a year.
Demographics
A combination of poverty and lack of access to
healthcare
Health care or healthcare is the improvement of health via the prevention, diagnosis, treatment, amelioration or cure of disease, illness, injury, and other physical and mental impairments in people. Health care is delivered by health profe ...
has made clinical diagnosis of CKDu difficult.
The majority of patients are of low
socioeconomic status and live in agricultural areas, or are involved in farming.
Although it also occurs in females and youth, the majority of CKDu patients are males between 17 and 70 years of age.
High numbers of CKDu cases are individuals in their most productive working age (30 – 60 years), creating a negative economic impact in affected areas.
Within the NCP and its bordering villages, a 15-20% prevalence of CKDu has been reported.
Timeline
1990 - CKDu first reported in Sri Lanka's dry zones.
2009 - Sri Lanka's Ministry of Health and The
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
conducted a study to determine the etiology of CKDu
with the goal of developing preventative strategies.
2016 - A case definition for CKDu was developed and published by Sri Lanka's Ministry of Health to help identify CKDu in
Sri Lanka
Sri Lanka (, ; si, ශ්රී ලංකා, Śrī Laṅkā, translit-std=ISO (); ta, இலங்கை, Ilaṅkai, translit-std=ISO ()), formerly known as Ceylon and officially the Democratic Socialist Republic of Sri Lanka, is an ...
.
Disease overview
CKDu is characterized by a lack of common risk factors (e.g.
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
and
hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
)
normally associated with Chronic Kidney Disease.
This disease manifests itself as asymptomatic at first, with a slow progression until later stages, when it becomes irreversible.
The most common symptoms include:
fatigue, panting, lack of appetite,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, and
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
.
CKDu typically results in death due to low access to
dialysis and
organ transplant
Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transpo ...
technology.
Annual deaths are estimated at around 1,400 based on medical and clinical observations.
Affected kidneys exhibit a toxic etiology called
tubulointerstitial nephritis
Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules ...
.
Possible causes
The concentration of CKDu cases in the NCP suggests multiple risk factors - including a combination of nephrotoxins - that may be responsible for the prevalence of this disease.
Potential causes include dehydrating working conditions, genetic susceptibility, and various lifestyle factors.
Although one single causative factor has not been identified as the source of CKDu, occupational and environmental causes have been identified as the main reason for the prevalence of the disease.
Possible environmental exposures include:
Drinking water
The lack of surface water in the dry zone of Sri Lanka has led many people in the NCP to rely mainly on
groundwater
Groundwater is the water present beneath Earth's surface in rock and soil pore spaces and in the fractures of rock formations. About 30 percent of all readily available freshwater in the world is groundwater. A unit of rock or an unconsolidate ...
in dug and tube
well
A well is an excavation or structure created in the ground by digging, driving, or drilling to access liquid resources, usually water. The oldest and most common kind of well is a water well, to access groundwater in underground aquifers. The ...
s.
An estimated 87% of the population in dry zone regions use and consume groundwater.
Elevated
fluoride levels and distribution patterns in potable water have been detected in the drinking water of CKDu prevalent areas.
Fluoride is an important causal component of CKDu due to its tendency to accumulate in the kidneys.
Additionally, studies have shown that there may be a possible link between
water hardness
Hard water is water that has high mineral content (in contrast with "soft water"). Hard water is formed when water percolates through deposits of limestone, chalk or gypsum, which are largely made up of calcium and magnesium carbonates, bicarbo ...
, fluoride concentration, and CKDu prevalence.
Therefore, drinking water quality might be a significant contributing factor to the disease; several villages that have implemented drinking water regulations seemed to have lower cases of CKDu.
Exposure to metals
The widespread use of
agrochemical
An agrochemical or agrichemical, a contraction of ''agricultural chemical'', is a chemical product used in industrial agriculture. Agrichemical refers to biocides ( pesticides including insecticides, herbicides, fungicides and nematicides) an ...
s in Sri Lanka has led some researchers to study various
heavy metals
upright=1.2, Crystals of osmium, a heavy metal nearly twice as dense as lead">lead.html" ;"title="osmium, a heavy metal nearly twice as dense as lead">osmium, a heavy metal nearly twice as dense as lead
Heavy metals are generally defined as ...
found within these chemicals as potential causes of CKDu in afflicted regions.
The significant differences in between wet and dry cycles in the dry zone can influence the
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
of heavy metals.
People can be exposed to these metals through water and diet.
Heavy metals can induce the synthesis of
Metallothionein
Metallothionein (MT) is a family of cysteine-rich, low molecular weight (MW ranging from 500 to 14000 Da) proteins. They are localized to the membrane of the Golgi apparatus. MTs have the capacity to bind both physiological (such as zinc, copp ...
proteins, which are responsible for metal detoxification in the body. Heavy metal-induced
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
plays a role in renal toxicity and injury to the
proximal tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. It can be further classified into the proximal convoluted tubule (PCT) and the proximal strai ...
s. It is possible that a combination of reactions between heavy metals and water hardness might be contributing to the prevalence of CKDu.
Specific metals of concern include:
* ''
Cadmium
Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, silvery-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Like zinc, it demonstrates oxidation state +2 in most of ...
:'' A known nephrotoxic environmental toxin reported to impair kidney function following exposure.
Low levels detected in drinking water in CKDu affected areas.
* ''
Arsenic
Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, but ...
:'' Combined with water hardness, has been shown to cause kidney damage through
calcium arsenate
Calcium arsenate is the inorganic compound with the formula Ca3(AsO4)2. A colourless salt, it was originally used as a pesticide and as a germicide. It is highly soluble in water, in contrast to lead arsenate, which makes it more toxic. The min ...
crystal formation.
Low levels detected in drinking water in CKDu affected areas.
* ''
Aluminum
Aluminium (aluminum in American and Canadian English) is a chemical element with the symbol Al and atomic number 13. Aluminium has a density lower than those of other common metals, at approximately one third that of steel. It has ...
:'' Concern if combined with fluoride into aluminum-fluoride
complexes, which could potentially move through
biological membrane
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the ce ...
s easier than aluminum and fluoride can individually.
Low levels detected in drinking water in CKDu affected areas, but other potential sources include poor quality aluminum pots which can leach out aluminum during cooking.
Mitigation considerations
Due to the unknown etiology of CKDu, funding for the clinical care of affected populations and continued research is important.
Some preventative suggestions based on proposed risk factors for CKDu include drinking only treated and spring water,
regulated safety protocol for agrochemicals,
and improved work practices to prevent
dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
.
References
{{Reflist
Kidney diseases
Health in Sri Lanka