Istifanus Bala Bosan

Professor of Medicine/Nephrology
Ahmadu Bello University Zaria
Hon. Consultant Physician/Nephrology
Ahmadu Bello University Teaching Hospital
Shika - Zaria
BACKGROUND
CKD a rising global health burden

CKDu reported in epidemic proportions in South Asia and

Central America

 Among the poor communities especially farmers, and those who

work in the hot sun without adequate access to clean drinking
water.

 So far reported only in the tropics and subtropical countries

 Described in Central America as MesoAmerican Nephropathy

and Uddhanam Nephropathy in South Asia

 Aetiology not attributable to DM, HTN or any known cause of

Kidney damage
 DEFINITION
No acceptable global definition

Term – Uncertain, Unknown, Undetermined origin are

used interchangeably

A diagnosis of exclusion

Central America use Urine dipstick and serum creatinine

in case identification while South Asia use Proteinuria as
assessed by ACR >30mg/g
2013 Pan American Health Organisation, US CDC &
prevention and Latin American Society of nephrology and
hypertension developed guidelines for defining CKDu
CKD as defined by KDIGO work group
Under 60 years of age
No DM, Hypertension or other common causes of Kidney
disease

2016 Sri Lankan MOH dev. Epidemiologic definition of

CKDu modified twice by the Sri Lankan Society of
Nephrology but no concensus on criteria for diagnosis
outside kidney biopsy.
Histology
 Tubulointerstitial changes
 Tubular atrophy
 Interstitial mononuclear cell infiltration
 Interstitial fibrosis

 Glomerular changes have also been described

 Glomerular hypertrophy
 Global glomerulosclerosis
 Glomerular ischaemia and
 Thickened Bowman’s capsule
 Effacement of foot processes and vacuolation of podocyte
cytoplasm

Generally accepted CKDu is asymptomatic and

slowly progressive
Hypertension and oedema are late features
 Staging
Stage 1 – Persistent proteinuria (ACR >30mg/g with eGFR
≥90mls/min/1.73m2

Stage 2 – Persistent proteinuria with eGFR = 60

-89mls/min/1.73m2

Stage 3 – Persistent proteinuria with eGFR = 30 –

59mls/min/1.73m2

Stage 4 - Persistent proteinuria with eGFR < 30 –

59mls/min/1.73m2
When to suspect CKDu
Uraemia with
Minimal or absent proteinuria
No haematuria
Normal HbA1C, normal BP
No HIV, snake bite, GN or other urinary tract disease
Progressive shrinking of kidneys on ultrasound
Chronic tubulointerstitial nephropathy on biopsy
Tubulointerstitial fibrosis ± interstitial mononuclear
cell infiltration and non specific glomerular damage
EPIDEMIOLOGY
 Global disease burden report in 2016
 CKD deaths moved to 11th position
 Crude prevalence of CKD moved from 147.6 in 1990 to 275.9/million in2016
 Attributed to rising Diabetes Mellitus and Hypertension

 CKDu – described in 1994 in Sri Lanka

 2002 – Pacific coastal central American farming communities

 2012/13 - Sri-Lanka – clustering of CKD in rural farming communities

 Later – India, North and West Africa

 There are similarities and differences in prevalence and aetiological factors

between different populations and different regions

 Valid prevalence estimates are not available due to the absence of multicenter
random population surveys and standardized data.
South Asia
 Investigating the prevalence and causative agents of CKDu, Nihal
Jayatilake et al(2013)
 Samples from food, water, soil and agrochemicals

 Analysed for heavy metals –Arsenic, Cadmium, lead, selenium

 Prevalence found was 16.9% in females and 12.9% in males however,

the males had more severe disease and the severity increased with
increasing age. The risk was higher in those cultivating vegetables
 Urinary Cadmium and Arsenic were at levels that could cause kidney
damage
 Food items in endemic CKDu areas contained Cadmium and Lead
above reference levels
 Pesticide residues were above reference values

 Serum Selenium levels were low in persons with CKDu suggesting

protective role
Central America
Risk factors are mainly occupational

Male agric workers doing strainous out door labour in

hot climate causing dehydration leading eventually to
CKD

Elevated rates of CKDu in other occupations like

brickmaking and construction workers

Increased rates in areas that do not grow sugarcane or

vegetables
Sub Saharan Africa
Tanzania
Malawi
Nigeria
Usman S (2018) – rising cases of CKD in Yobe
Suleman MM (2019) – CKDu in Northern Yobe, Nigeria
Babagana-Kyari M (2022) – CKDu epidemics in
Northern Yobe State, the missing research gap
Ongoing research in North East Nigeria on select
populations including biopsies
Ongoing community surveys by the team in Ibadan
Any role for ISN?
ISN working group on CKDu

Portal for tracking on going research on CKDu

?ISN grants for research on CKDu

CLINICAL FEATURES
The common clinical features of CKDu are impaired
kidney function in the absence of diabetes, primary
glomerular nephritis, or structural abnormality.

mainly affects male rural agricultural workers.

Found in tropical and subtropical countries mainly in

Central America and South Asia.

Asymptomatic but hypertension or oedema occur in

late stages
AETIOLOGY
The actual cause is unknown

Several risk factors have been implicated and are

being studied in several parts of the world

Factors are heterogenous and vary from region to

region in type and emphasis by researchers

Factors are not standardized and limited in geography

Frequency of measured exposures from studies across different regions. (A) Exposures measured in studies from all
regions; (B) exposures measured in studies from South Asia; (C) exposures measured in studies from Central America.
Five most frequently studied risk
factors
South Asia
Central America Heavy metal
Age contamination
Sex (Men) Occupation (Farming)

Heat stress Agrochemical use

Occupation (Farming) Family history of CKDu

Agrochemical use Tobacco smoking

 Review of Literature
CKDu Aetiology: A systematic review (Joseph Lunyera, 2016)
Identified 1607 articles
Only 26 qualified for final inclusion (case-controlled studies)
11 South Asia, 8 Central America and 7 others
A comparative review: CKDu research conducted in
Central America and South Asia (Jennifer Hoponick Redmon, 2021)
Identified – Asia 82 peer reviewed and 55 field studies
- Central America 65 peer reviewed and 34 field studies
Both groups found out the focus of:-
South Asia - Drinking water, heavy metals and agrochemicals
Central America - Heat stress /Dehydration and Agrochemicals
Other Observations about CKDu
Researchers in India did not find Age, sex, education,
employment in Agric, use of pesticides, smoking and
alcohol consumption as significant contributors to
CKDu.
A cross-sectional analysis of data from Urban and
rural population in Northern Peru, found low
prevalence of low eGFR (as surrogate for CKDu)
Tumbes a coastal agricultural settlement in central
America has very low prevalence of CKDu although
they have similar living/working conditions as their
counterparts in areas with high prevalence
 Tumbes Andhra El Salvador Egypt Sri Lanka Nicaragua
Pradesh/Udd (coastal El-Sharkia
anam region)

Population 240,590 14,807 238,244 8,017,894 21,358,975 206,264

Urbanicity 94.1% (urban) 24% (urban) 67% (urban) 77% (urban) 77% 81.6% (urban)
(urban)

Climate Arid and Hot tropical Tropical Arid Tropical Tropical

subtropical

Humidity 76% 70–90% 62–100% Over 90% 70–95% 65–80%

Precipitation 131.4 mm 1067 mm 13 to 155 mm 4 mm (no rain 200 mm 181 mm
season)

Temperature 21–40 °C 34.3 °C 23–35 °C 32.6 °C 36 °C 35 °C

Average annual 25.3 °C 31.5 °C 26 °C 26.2 °C 27 °C 32.5 °C
temperature

Altitude Sea level 60–70 m 90 m 4–8 m 81 m 109 m

Agriculture Rice, lime, Rice coconuts Sugarcane Cotton Chena, rice Banana,
banana and cashew cultivations sugarcane

Pesticide Paraquat, Organochlorid Paraquat Cadmium, nickel Glyphosate Pyrethroids

methomyl es and mercury and
90SP chlorpyrifos

Metal Arsenic Silica Arsenic, Cadmium Cadmium Aluminum,

contamination cadmium arsenic, lead
 Andhra El Salvador Egypt Sri Nicaragua
Tumbe Pradesh/ (coastal El- Lanka
s Uddanam region) Sharkia
Leptospira 0.02– 61.8% – 49.7% 53% 36%
5%

Hypertension 26.9% 38.5–615% 30% – 26% 22%

rates

Type 2 10.3% 7.2–30% 8.8% – 8.6% 10%

diabetes
mellitus

CKDu < 1% 1.6–4.8%, 25% 17.7% 15–21% 19%

up to 60%
MECHANISM
Exertion Dehydration Heat stress
Rhabdomyolysis Frequent subclinical hypovolaemia

Cortical aldose reductase activation Vasopressin

Hyperuricaemia
Fructose prod. And Metabolism
(Proximal tubular activity)
Fructose
RAAS activation
Oxidative stress
Inflammation
Endothelial dysfunction NSAIDS
Glomerular hypertension Agrochemicals
Ischaemia Heavy metals
Tubulointerstitial damage Nephrotoxins

CKD
Damage due to dehydration
 Frequent subclinical hypovolaemia
 Dehydration
 Hyperosmolarity
 Rhabdomyolysis
 Blood thickening
 Hyperuricaemia
 Inflammation
 Tubulointerstitial damage
 Activation of Vasopressin, RAAS and
aldose reductase in the proximal
tubules  Tubular proteinuria (β2
macroglobulinuria)
 Conversion of Glucose to fructose
 No oedema, no hypertension
 Metabolism by fructokinase

 Oxidative tissue injury

Prevention of CKDu
Causal factors are yet to be identified but several risk
factors are known so prevention programmes can be
organized around these:-
Provision of clean water for drinking and domestic use
Appropriate disposal of Nickel batteries, plastics, etc.
Regulate the use of herbicides/insecticides
Increase awareness of the dangers of NSAIDs and
unspecified herbs
Good welfare support for affected families
Key points
CKDu Epidemics occur agricultural communities in
tropical and subtropical countries
Several risk factors have been identified but differ
between regions and countries
It is yet to be established whether CKDu is a single
disease entity or a conglomeration of diseases caused
by different combinations of factors
Yet to have a global standardized definition
Multiple risk factors recognized in areas of high prevalence of CKDu may
also be found in areas with low prevalence

Genetic influence is a high possibility

Research gaps abound so opportunity should be seized to unravel the
mystery behind this silent epidemic
 References
1. Jennifer Hoponick Redmon, Keith E. Levine, Jill Lebore, James Harrington, A.J. Kondash A
comparative review: CKDu research conducted in Latin America versus Asia. Environmental
Research 2021;192:110270
2. Joseph Lunyera, Dimishika Mohottige, Megan Von Isenburg, Marc Jenland et al. CKD of
uncertain aetiology: A systematic review. Clinical Journal of American Society of Nephrology
2016; vol.2 March
3. Matteo Floris, Nicola Lipori, Andrea Angioi, Gjanfranca Cabiddu, Doloretta Piras et al.
chronic Kidney disease of undetermined aetiology around the world. Kidney and blood
pressure research 2021; 46:142-151
4. Andrea Ruiz-Alejos, Ben Caplin, J. Jaime Miranda and Antonio Bemabe-Ortiz. CKD and
CKDu in northern Peru: a cross-sectional analysis under the DEGREE protocol. BMC
Nephrology 2021:22:37
5. Usman S. (2018) Rising cases of CKD in Yobe trigger concern among stakeholders. Online
publication https://dailypost.ng/2018/11/07 rising-cases-chronic-kidney-disease-yobe-trigger-
concern-among-stakeholders
6. Suleiman MM, Shettima J, Ndahi K, Abdul H, Bala MM, Ummate I and Hussein K. Chronic
Kidney disease of unknown origin in northern Yobe, Nigeria: Experience from a regional
tertiary hospital in North Eastern Nigeria. Borno Medical Journal 2019;16:1-8
7. Babagana-Kyari M, Kazeem M K and Jajere A A. Chronic Kidney disease of Unknown
aetiology (CKDu) epidemics in Northern Yobe State Nigeria: The missing research gap.
African Journal of health, safety and environment 2022; Vol 3(2):31-45