A Newly Recognized Endemic Region of CKD of Undetermined Etiology (CKDu) in South India—“Tondaimandalam Nephropathy”

Abstract

Introduction:
Chronic kidney disease (CKD) is being increasingly recognized as a public health problem in India. The entity of CKD of undetermined etiology (CKDu) is increasingly being reported globally. Here we describe the burden of CKDu in a heretofore undescribed population in South India.

Methods:
We prospectively enrolled all patients with CKD referred to the nephrology department in an observational registry. We analyzed their sociodemographic and clinical features over 4 years. The diagnosis of CKD and its etiology was determined using predefined criteria. Geolocalization of CKD patients was performed. Subsequently, CKD screening was conducted in a village located in an area of CKDu clustering.

Results:
A total of 2424 patients were analyzed; the median age was 52 years and 75.3% were male. Seventy-five percent had advanced CKD. CKDu was the most common (51.7%) etiologic category. This is the highest proportion of CKDu reported among all published CKD studies to date from India. The clinical and demographic profile of this patient population match that of CKDu patients reported from Sri Lanka and Central America, where CKDu is endemic. A clustering of cases of CKDu was noted in specific districts using a geographic information system software. Screening of 447 people in an outreach program at a village located in an area identified to have clustering of CKDu showed a CKD prevalence of 19%.

Conclusion:
We report a previously unrecognized endemic area of CKDu among the underprivileged population engaged in agricultural labor in coastal southeastern India in the states of Tamil Nadu and Puducherry (Tondaimandalam) in India.

Full text

A Newly Recognized Endemic Region
of CKD of Undetermined Etiology (CKDu)
in South India—“Tondaimandalam
Nephropathy”
Sreejith Parameswaran
1
, P. Krishnankutty Rinu
2
, Sitanshu Sekhar Kar
2
,
Kotteyen Thazhath Harichandrakumar
3
, Thottyplackel Devassiya James
2
,
Puthenpurackal Sivan Pillai Priyamvada
1
, Satish Haridasan
1
, Sumit Mohan
4
and
Jai Radhakrishnan
4
1
Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry,
India;
2
Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research
(JIPMER), Puducherry, India;
3
Department of Medical Biometrics and Informatics, Jawaharlal Institute of Postgraduate Medical
Education and Research (JIPMER), Puducherry, India; and
4
Division of Nephrology, Columbia University Medical Centre,
New York, USA
Introduction: Chronic kidney disease (CKD) is being increasingly recognized as a public health problem in
India. The entity of CKD of undetermined etiology (CKDu) is increasingly being reported globally. Here we
describe the burden of CKDu in a heretofore undescribed population in South India.
Methods: We prospectively enrolled all patients with CKD referred to the nephrology department in an
observational registry. We analyzed their sociodemographic and clinical features over 4 years. The
diagnosis of CKD and its etiology was determined using predefined criteria. Geolocalization of CKD pa-
tients was performed. Subsequently, CKD screening was conducted in a village located in an area of CKDu
clustering.
Results: A total of 2424 patients were analyzed; the median age was 52 years and 75.3% were male.
Seventy-five percent had advanced CKD. CKDu was the most common (51.7%) etiologic category. This is
the highest proportion of CKDu reported among all published CKD studies to date from India. The clinical
and demographic profile of this patient population match that of CKDu patients reported from Sri Lanka
and Central America, where CKDu is endemic. A clustering of cases of CKDu was noted in specific districts
using a geographic information system software. Screening of 447 people in an outreach program at a
village located in an area identified to have clustering of CKDu showed a CKD prevalence of 19%.
Conclusion: We report a previously unrecognized endemic area of CKDu among the underprivileged
population engaged in agricultural labor in coastal southeastern India in the states of Tamil Nadu and
Puducherry (Tondaimandalam) in India.
Kidney Int Rep (2020) 5, 2066–2073; https://doi.org/10.1016/j.ekir.2020.08.032
KEYWORDS: chronic interstitial nephritis; chronic kidney disease; CKDu; India; public health
ª2020 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Chronic kidney disease is an increasingly common
cause of morbidity and mortality across the
world.
1
Although diabetes mellitus and hypertension
account for much of the CKD burden in most countries,
there are regions where a surprisingly high incidence
of CKD that remains unexplained has been reported.
2
These CKD clusters, often referred to as CKD of unde-
termined etiology or chronic interstitial nephritis in
agricultural communities, appears to predominantly
affect underprivileged populations engaged in farm
labor in tropical climates in places such as Sri Lanka
and several Central and South American countries such
as Ecuador, Nicaragua, El Salvador, Guatemala and
Panama.
3
More recently, kidney disease clusters similar
to these countries has also been reported from parts of
India, especially from the coastal districts of the state of
Andhra Pradesh.
4
As a tertiary care medical center,
many patients with CKD exhibiting characteristics of
CKDu seek treatment at our center located in South
Correspondence: Sreejith Parameswaran, no. 5348, Department of
Nephrology, Super Specialty Block, JIPMER Campus, Dhanvantari
Nagar PO, Puducherry 605006, India. E-mail: sparameswaran@
outlook.com
Received 25 August 2020; accepted 26 August 2020; published
online 15 September 2020
2066 Kidney International Reports (2020) 5, 2066–2073
CLINICAL RESEARCH

India and we attempted to define their clinical char-
acteristics and explore whether a similar burden of
CKDu exist in our region as well.
METHODS
In the first phase (hospital-based registry) of the study,
an observational registry was established (CKD Regis-
try) for all patients with CKD who presented to the
nephrology outpatient clinic at our institution in the
year 2014. Data of all consecutive incident adult pa-
tients with CKD per Kidney Disease: Improving Global
Outcomes (KDIGO) criteria presenting to the renal
clinic was entered prospectively in the registry.
Data of all enrolled patients between January 1, 2015,
and December 31, 2018, were analyzed as part of this
study.
The following definitions were used for identifica-
tion of the possible etiology of CKD in our cohort.
Diabetes mellitus, identified using American Diabetes
Association (ADA) criteria for fasting and postprandial
blood glucose levels or if the patient was receiving
hypoglycemic agents, was presumed to be the cause of
CKD when present (diabetic kidney disease). CKD was
attributed to hypertensive nephrosclerosis if the pa-
tient had documented systemic hypertension for >5
years before the diagnosis of CKD or with severe hy-
pertension (requiring more than 2 antihypertensives or
blood pressure >160/100 mm Hg) at any time in the
absence of other causes of CKD. Chronic glomerulone-
phritis was diagnosed if kidney biopsy showed
glomerulonephritis or if a patient with CKD had a
history of long-standing edema and/or proteinuria
>þþ or >1.5 g/d. The diagnosis of chronic tubu-
lointerstitial disease was made either on histology or
based on a compatible history, the presence of ves-
icoureteral reflux, and/or recurrent urinary tract
infection. Obstructive uropathy and cystic disease
were diagnosed if there were confirmatory findings
seen on imaging studies. The diagnosis of renovascular
disease was from Doppler study or angiography. Kid-
ney disease in association with specific“syndromes”
was diagnosed by characteristic clinical findings, fam-
ily history, and laboratory abnormalities. A diagnosis
Table 1. Association of sociodemographic factors with CKD
Characteristics
CKDu,
n
(%)
(
n
[1254)
CKD from other causes,
n
(%)
(
n
[1170)
Total,
n
(%)
(
N
[2424)
Statistical significance
(
P
value)
Age, yr, median 52 52 52 (18–87)
Gender
Female 325 (25.9) 275 (23.5) 600 (24.8) 0.17
Male 929 (74.1) 895 (76.5) 1824 (75.2)
Education
No formal education 684 (54.7) 543 (46.8) 1227 (50.9) 0.001
Primary school 256 (20.5) 245 (21.1) 501 (20.8)
Secondary school 237 (18.9) 273 (23.5) 510 (21.2)
Graduate 64 (5.1) 83 (7.2) 147 (6.1)
Postgraduate 10 (0.8) 16 (1.4) 26 (1.1)
Total 1251 1160 2411
Income
<5000 802 (64.1) 773 (66.3) 1575 (65.2) 0.04
5000–20,000 431 (34.5) 363 (31.1) 794 (32.9)
>20,000 18 (1.4) 30 (2.6) 48 (2)
Total 1251 1166 2417
Occupation
Agriculture 403 (59.4) 350 (48.2) 753 (53.6) <0.001
Homemaker 65 (9.6) 75 (10.3) 140 (10)
Professional 44 (6.5) 82 (11.3) 126 (9)
Student 7 (1) 12 (1.7) 19 (1.4)
Other jobs 56 (8.2) 82 (11.3) 138 (9.8)
Not working 104 (15.3) 125 (17.2) 229 (16.3)
Total 679 726 1405
CKD, chronic kidney disease; CKDu, CKD of undetermined etiology.
Table 2. Etiologic profile of chronic kidney disease patients
attending the tertiary care center, 2015–2018
Etiology Patients
n
(%)
Diabetic nephropathy 525 (21.66)
Hypertensive nephropathy 349 (14.40)
Chronic glomerulonephritis 182 (7.51)
Cystic disease 20 (0.83)
Obstructive uropathy 67 (2.76)
Undetermined 1254 (51.73)
Others 27 (1.11)
Total 2424
S Parameswaran et al.: Tondaimandalam Nephropathy CLINICAL RESEARCH
Kidney International Reports (2020) 5, 2066–2073 2067

of CKDu was made, as a diagnosis of exclusion, in the
absence of any of these potential identifiable causes of
CKD and when the blood pressure was less than 160/
100 mm Hg or if the patient required only 2 or fewer
antihypertensive drugs. All patients underwent imag-
ing of the kidneys by ultrasonography to assess kidney
size. Kidney biopsy was performed only in patients
with nondiabetic CKD with kidney size >9 cm.
Contact information of the patients, including postal
address and mobile numbers, demographic and socio-
economic profile, and clinical and laboratory data were
collected. Using the address, geolocalization of the pa-
tients was done using a geographic information system
(GIS) software (QGIS) to determine if there was any
geographic clustering of CKDu.
In the second phase, a voluntary medical camp for
CKD screening was conducted in a village identified to
be in a geographic area with large number of CKDu
cases in the district of Villupuram. All adults in the
village were offered testing for CKD on a voluntary
basis, with the participation of a local NGO. De-
mographic, socioeconomic, and clinical data were
collected using a predefined form, and blood and urine
samples were collected for measuring hemoglobin,
random blood glucose, serum creatinine, and urine al-
bumin (dipstick). On a second visit to this village after
3 months, the estimated glomerular filtration rate was
rechecked to confirm the diagnosis of CKD in those
individuals with low estimated glomerular filtration
rate at the first screening.
Proportions were used to summarize categorical
variables. Mean (SD) was used to summarize contin-
uous variables. Data entry and statistical analysis was
done using EpiData, version 3.1, and SPSS, version 22,
respectively. A Pvalue <0.05 was used as the
threshold for statistical significance. The study was
approved by the institute ethics committee.
RESULTS
A total of 2424 patients with CKD were recruited in the
first phase of the study (hospital-based registry). The
patients were predominantly (75.3%) male with a me-
dian age of 52 years (Table 1). Most patients, >75%,
were in advanced CKD stages (i.e., 4 and 5).
Figure 1. Districts in Tamil Nadu state from where majority of patients were enrolled on the chronic kidney disease (CKD) registry and the
distribution of cases.
CLINICAL RESEARCH S Parameswaran et al.: Tondaimandalam Nephropathy
2068 Kidney International Reports (2020) 5, 2066–2073

Diabetic kidney disease accounted for 21.7%, hy-
pertensive nephrosclerosis 14.4%, chronic glomerulo-
sclerosis 7.5%, and cystic diseases 0.8%. The single
largest diagnostic category was CKD of undetermined
etiology (CKDu), with 51.7% of patients having no
identifiable cause for CKD (Table 2).
The geographic region where the patient lived is
depicted in Figure 1 and Table 3.Morethanhalf
(56%) of the patients were from the districts of
Villupuram and Cuddalore in the state of Tamil
Nadu. Nearly 50% of affected individuals, on
whom information was available on employment,
reported working either in farming (53.6%) or
other blue-collar jobs. Rice paddy, sugarcane, and
groundnut were the predominant crops cultivated
by the patients engaged in farming. Approximately
two-thirds (65.2%) of individuals with CKD re-
ported a family income of less than 5000 (US$77)
per month.
The characteristics of patients with a diagnosis of
CKDu were compared with those of patients with CKD
from identifiable causes (Tables 4 and 5). CKDu
comprised a significantly higher proportion of kidney
disease among farmers and other farm-related laborers
compared with other causes of CKD. In addition, the
proportion of CKDu patients was significantly higher
among the uneducated population, and the proportion
of CKDu patients was significantly higher in the lower-
income group compared to those with higher incomes.
There were no significant differences between CKDu
and non-CKDu categories regarding age and gender
distribution.
Table 3. Districtwise distribution of patients (Tamil Nadu and Puducherry)
District
CKDu,
n
(%)
CKD from other causes,
n
(%)
Total,
a
n
(%)
Population of the District (2011 Census)
in hundred-thousands
% of OPD patients at JIPMER
from the same district
Villupuram 404 (40.8) 268 (29.8) 672 (35.6) 34.59 37.2
Cuddalore 199 (20.1) 186 (20.7) 385 (20.4) 26.1 15
Puducherry 89 (9) 125 (13.9) 214 (11.3) 12.44 17
Tiruvannamalai 58 (5.9) 60 (6.7) 118 (6.2) 24.64 13
Ariyalur 63 (6.4) 29 (3.2) 92 (4.9)
Kanchipuram 17 (1.7) 18 (2) 35 (1.9)
Nagapattinam 13 (1.3) 22 (2.4) 35 (1.9)
Thanjavur 13 (1.3) 13 (1.4) 26 (1.4)
Salem 9 (0.9) 15 (1.7) 24 (1.3)
Others 124 (12.5) 163 (18.1) 287 (15.2)
Total
a
989 899 1888
CKD, chronic kidney disease; CKDu, CKD of undetermined etiology; OPD, outpatient department; JIPMER, Jawaharlal Institute of Postgraduate Medical Education and Research.
a
Native district is available for only 1888 patients.
Table 4. Distribution of comorbid conditions in the study papulation
Comorbidities, treatment
expense, and CKD stage CKDu,
n
(%) CKD from other causes,
n
(%) Total,
n
(%)
P
value
Hypertension <0.001
Present 672 (53.9) 936 (83.1) 1608 (67.8)
Absent 574 (46.1) 191 (16.9) 765 (32.2)
Total 1246 1127 2373
CVD <0.001
Present 180 (18) 211 (26.1) 391 (21.6)
Absent 821 (82) 597 (73.9) 1418 (78.4)
Total 1001 808 1809
Expense of treatment borne by <0.001
Self 799 (64.1) 911 (78.7) 1710 (71.1)
Employer 57 (4.6) 32 (2.8) 89 (3.7)
Insurance 5 (0.4) 6 (0.5) 11 (0.5)
Other 385 (30.9) 209 (18) 594 (24.7)
Total 1246 1158 2404
Stages of CKD <0.001
Stage 1 43 (3.4) 55 (4.7) 98 (4)
Stage 2 17 (1.4) 14 (1.2) 31 (1.3)
Stage 3 234 (18.7) 160 (13.7) 394 (16.3)
Stage 4 314 (25.1) 238 (20.4) 552 (22.8)
Stage 5 644 (51.4) 701 (60) 1345 (55.6)
Total 1252 1168 2420
CKD, chronic kidney disease; CKDu, CKD of undetermined etiology; CVD, cardiovascular disease.
S Parameswaran et al.: Tondaimandalam Nephropathy CLINICAL RESEARCH
Kidney International Reports (2020) 5, 2066–2073 2069

Approximately one-fourth of the study participants
(24%) were being conservatively managed for CKD,
with diuretics, antiemetics, oral hematinics, antihy-
pertensives, and other symptomatic measures, without
renal replacement therapy. One-fifth of the study par-
ticipants were undergoing renal replacement therapy
(19.6%). Among the CKD patients who had a glomer-
ular filtration rate of less than 8 ml/min, 54 patients
(7%) were not receiving renal replacement therapy.
Figures 1 and 2depict the geographical distribution
of patients with CKD and CKDu from the state of Tamil
Nadu. Sixty-two percent of patients hailed from the
districts of Villupuram, Cuddalore, Thiruvannamalai,
and Kancheepuram, and 11.3% were from the Pudu-
cherry district of the union territory of Puducherry.
CKDu accounted for more than 40% of CKD patients
from these districts, with the highest proportion of
CKDu observed in Villupuram and Ariyalur districts
(Table 3). There was apparent clustering of CKDu in
certain taluks (a smaller administrative unit of a district
in India) within the district of Villupuram (Figure 3).
Residents of Nainakuppam village (Ulundurpet
Taluk, Villupuram district, Tamil Nadu), a region
where a large number of patients with CKDu were
identified, were screened for CKD as part of an outreach
effort. Among the 983 inhabitants of the village, 670
were older than 18 years. Of these, 447 individuals
participated in the CKD screening program. Eight
percent were hypertensive, 6.8% were diabetic, and
19% (n ¼85) had an estimated glomerular filtration
rate of <60 ml/min (19%). Based on glomerular filtra-
tion rate criteria, 19% of individuals had CKD. Only 7
individuals were aware of their kidney disease before
Table 5. Proteinuria
Urine protein
CKDu,
n
(%)
CKD from other causes,
n
(%)
Total,
n
(%)
Nil 98 (21.1) 60 (9.4) 158 (14.3)
Trace 90 (19.4) 47 (7.4) 137 (12.4)
þ137 (29.5) 120 (18.8) 257 (23.3)
þþ 140 (30.1) 155 (24.3) 295 (26.7)
þþþ 0 191 (29.9) 191 (17.3)
þþþþ 0 66 (10.3) 66 (6)
Total 465 639 1104
CKD, chronic kidney disease; CKDu, CKD of undetermined etiology.
Figure 2. Distribution of chronic kidney disease (CKD) of undetermined etiology (CKDu) patients from the districts of Tamil Nadu in the CKD
registry.
CLINICAL RESEARCH S Parameswaran et al.: Tondaimandalam Nephropathy
2070 Kidney International Reports (2020) 5, 2066–2073

the screening program. None of them had urinary
symptoms or edema.
DISCUSSION
The relatively high proportion of CKDu among the CKD
patient population from the geographical area studied
suggests that CKDu is endemic in that region and has
not been previously reported. We found that CKDu
was the largest etiologic category among incident pa-
tients with CKD at our institution. CKDu was diagnosed
in 51.7% of patients, and this is the highest proportion
of CKDu reported among all studies from India thus far.
We used the WHO SEARO consensus definition of
CKDu
5
in the study. This definition uses a blood
pressure >160/100 mm Hg as an exclusion criterion for
CKDu. If the blood pressure criterion is not used, the
proportion of CKD where etiology could not be iden-
tified increases to 74%. Along with this observation
from the registry data, the high prevalence of CKD
found in the village where CKD screening was under-
taken strengthens our suspicion of the endemic nature
of CKD in this region. The prevalence of CKD was
found to be 19% in the village, higher than most CKD
prevalence estimates for India
6,7
and similar to the
prevalence reported from the Uddanam region in
Andhra Pradesh
8
and from endemic areas in Sri Lanka.
3
The only prior study that examined the etiology of
CKD from our geographical region in India did so
from a large urban center (Chennai) in 1993.
9
This
study, using hospital data along with clinical and
laboratory criteria to define etiologic categories of
CKD, reported “chronic interstitial nephritis”to be
the most common cause of CKD (27.9%). However,
there are important differences between their report
and our current study. In the earlier study, 70.7% of
the patients reported a high socioeconomic status,
compared to only 2% in our cohort. Chronic inter-
stitial nephritis accounted for a significantly higher
proportion of CKD in the lower-income group
compared to the higher-income group (38.25% vs.
25.11%) in the prior study, which is consistent with
the findings in our sample.
Although estimates on the regional differences in the
proportion of CKDu in the CKD population is not
available from India, a high incidence of CKDu has
been reported from the coastal areas of the state of
Figure 3. Geolocalization of CKD of undetermined etiology (CKDu) patients in the districts of Villupuram (TN) and Puducherry (Puducherry),
showing clustering in certain regions.
S Parameswaran et al.: Tondaimandalam Nephropathy CLINICAL RESEARCH
Kidney International Reports (2020) 5, 2066–2073 2071

Andhra Pradesh.
8
We found that the clinical charac-
teristics of our patient population was comparable with
the characteristics of CKDu patients from endemic areas
in Sri Lanka and Central and South America as well as
Uddanam in Andhra Pradesh, India. The patients were
mostly from an underprivileged background, were
engaged in farm labor or other forms of labor requiring
significant physical activity, working in hot and humid
climate, had shrunken echogenic kidneys with minimal
proteinuria, and often presented with advanced CKD,
with presumably minimally symptomatic or asymp-
tomatic early stages (Table 6). The geographical areas
where our patients belong have a tropical arid climate,
with average ambient temperatures during the summer
of 30 C–41 C and during winter of 30 C–35 C, with
high humidity round the year. This region shares cli-
matic, cultural, and possibly genetic characteristics
with Uddanam, Andhra Pradesh, and regions of Sri
Lanka where CKDu is endemic. The Uddanam area is
located 1100 km north of Tamil Nadu, on the eastern
coast of the Indian peninsula.
On the basis of our observations, we believe that the
burden of CKD and CKDu in this region is much higher
than currently appreciated. The patients enrolled in
our CKD registry likely represent only a fraction of
patients with CKD in this region. Only those patients
referred for specialized nephrology care reach our
center, and patients also seek treatment from other
well-established centers offering kidney care in this
region. This hypothesis coupled with the fact that one-
fifth individuals sampled in one village had CKDu
suggests the possibility that there is a higher preva-
lence of CKDu in the region. Almost 80% of patients in
the CKD registry presented in advanced stages of CKD.
In contrast, the patients detected to have early stages of
CKD during the screening program in the village were
asymptomatic. It appears that the kidney disease is
asymptomatic in the earlier stages, leading to the dis-
ease going undetected till advanced stages of CKD. We
believe that these observations of possible high burden
of CKD in the community, asymptomatic earlier stages
of the disease and presentation in advanced stages of
kidney failure are all compelling reasons to establish a
community-based CKD surveillance and prevention
program in this region.
Our study has several strengths. Our registry
employed a rigorous approach of data collection and
diagnosis adjudication by using predefined clinical
criteria for defining the cause of CKD. Initial spatial
clustering noted among patients presenting to the
Table 6. Clinicoepidemiologic features of major globally reported regional nephropathies
Mesoamerican nephropathy Sri Lankan nephropathy Uddanam nephropathy
Tondaimandalam nephropathy,
Tamil Nadu, India
Geographic
region
Rural, low-altitude, and coastal regions of
Nicaragua and El Salvador mainly and to some
extent Costa Rica and Guatemala
Rural, North Central Province Rural, low-altitude, coastal belt
in the eastern Indian state of
Andhra Pradesh with tropical
arid climate
Rural, low-altitude, northern coastal
districts of Tamil Nadu, India, with
tropical arid climate
Latitude and
longitude
13.794185N, 88.896530E 7.8731N, 80.7718E 15.9129N, 79.7400E 11.1271N, 78.6569E
Epidemiology Widely reported; cross-sectional community-
based, and prospective cohort studies; variable
prevalence based on sex and occupation
Cross-sectional community-based studies;
point prevalence of CKD varies from 5.1% to
16.9% in the endemic region based on
persistent albuminuria as the diagnostic
criterion
Cross-sectional community-
based study; CKD point
prevalence in the endemic area
close to 50% (unpublished
estimates)
Previously not reported
Occupations
affected
Sugarcane, cotton, and subsistence farming;
fishing, mining, brick workers
Rice paddy and chena farming (vegetable and
other crops)
Cashew nut, coconut, and rice
paddy farming
Rice paddy, sugarcane, peanut
farming; laborers engaged in herding
animals, construction work
Age Age range: 20–50 yr Age range 40–50 yr; prevalence increases with
age
Age range 30–60 yr Age range 40–50 yr
Sex M >F (3.4:1) M >F (1.3:1) M >F(—)M>F (4:1)
Clinical features Silent but progressive GFR decline; low-grade
proteinuria (0.1 g/d); nephrotic syndrome rare;
urinary sediment is bland; variable progression
to ESRD; limited access to RRT
Slow progression, long asymptomatic period;
bland urinary sediments; low-grade proteinuria
(0.1 g/d); shrunken kidneys; elevated urinary
biomarkers of tubular damage in early disease
Bland urine sediment, low-
grade or absent proteinuria,
information on progression not
available at present
Clinical presentation in advanced
stages of CKD possibly because of
asymptomatic earlier stages; low-grade
or absent proteinuria; bilateral small
kidneys
Risk factors
implicated
Male sex; increasing age; hypertension; family
history of CKD; sugarcane, banana farming (in
men only); mining/subsistence farming;
NSAIDs, heavy metals, and agrochemical
exposure (inconsistent)
Chena farmer; family history of CKD; use of
traditional medications; ayurvedic medication
use; cadmium exposure; pesticide use
Male sex; increasing age;
agricultural job
Underprivileged socioeconomic status,
farm-related labor, advancing age,
male sex
Histopathologic
features
Chronic tubulointerstitial disease with secondary
glomerular and vascular damage; occasional
global glomerulosclerosis from possible
glomerular ischemia
Chronic tubulointerstitial fibrosis with
nonspecific interstitial inflammation; rare
glomerular collapse and sclerosis with fibrous
intimal thickening and arteriolar hyalinosis
Tubular atrophy and interstitial
fibrosis mainly with secondary
glomerular and vascular
changes
Not studied
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; NSAIDs, nonsteroidal anti-inflammatory drugs; RRT, renal replacement therapy.
CLINICAL RESEARCH S Parameswaran et al.: Tondaimandalam Nephropathy
2072 Kidney International Reports (2020) 5, 2066–2073

clinic was confirmed by a community-based CKD
screening program in the region suspected to be
experiencing the case clustering that found a CKD
prevalence of 19%.
There are some limitations of our study. The primary
data collection relied on a hospital-based registry that
may not be representative of the population at large.
With respect to geolocalization, comparison with
distant districts or even other neighboring states may
have experienced similar clustering of CKDu in these
geographical regions, but such comparative data were
not available. The addresses of patients had informa-
tion only up to the village or town level address and
not street addresses. The screening of a single village
was based on voluntary participation in a medical camp
and hence may have its inherent limitations in terms of
sampling bias.
Further studies in the form of community-based
studies with systematic stratified sampling are needed
to confirm high burden of CKD from CKDu in this region
and the possible factors contributing to the high CKD
burden. We propose that all medical institutions caring
for patients with kidney disease in the state of Tamil
Nadu should maintain a CKD registry and all cases of
CKD should be reported, including the home address
and etiology of CKD. This will allow identification of
regions with clustering of CKD in the state of Tamil Nadu
and in turn will facilitate establishing a community-
based CKD surveillance and prevention program in re-
gions with high CKD burden. The surveillance program
should be coupled with studies on environmental fac-
tors that might be contributing to the high prevalence of
CKDu in the region. It is also possible that there are
other, yet unrecognized regions with clustering of CKD
(CKD hot spots) in India. Implementing a similar strategy
in other parts of the country may identify such regions,
and we believe there is a strong case for establishing a
comprehensive national CKD registry in India
(Supplementary Table S1).
10
In conclusion, we found a high prevalence of CKDu
in the southeastern coastal districts of India, in the
states of Tamil Nadu and Puducherry, similar to the
Uddanam region of Andhra Pradesh that is approxi-
mately 1100 kilometers further north. The geographical
area of the state of Tamil Nadu and Puducherry to
which our patients belong roughly corresponds to the
historical region referred to as “Tondaimandalam,”
11
and hence we propose the name “Tondaimandalam
Nephropathy”for this entity. Further large-scale pro-
spective studies are needed to improve our under-
standing of the factors contributing to the remarkably
high prevalence of chronic kidney disease in this rural
socioeconomically underprivileged region in South
India.
DISCLOSURE
All the authors declared no competing interests.
ACKNOWLEDGMENTS
The JIPMER Renal Registry was funded by the Interna-
tional Society of Nephrology, Belgium, under the Sister
Renal Center program between JIPMER, Puducherry, India,
and Columbia University Medical Center, New York, USA.
The CKD screening program in Nainakuppam village was
organized with funds and logistic support from Tamil Nadu
Chief Minister’s Comprehensive Health Insurance Scheme
(TNCMHIS), Health and Family Welfare Department,
Government of Tamil Nadu, India, and the TNCMCHIS
program office, JIPMER, Puducherry.
SUPPLEMENTARY MATERIAL
Supplementary File (Word)
Table S1. Proposed strategy for identifying and studying
CKD hot spots.
REFERENCES
1. Whelan E. The global epidemic of chronic kidney disease: a
call for action. Occup Environ Med. 2016;73:499–500.
2. Abraham G, Varughese S, Thandavan T, et al. Chronic kidney
disease hotspots in developing countries in South Asia. Clin
Kidney J. 2016;9:135–141.
3. Jayasumana C, Orantes C, Herrera R, et al. Chronic interstitial
nephritis in agricultural communities: a worldwide epidemic
with social, occupational and environmental determinants.
Nephrol Dial Transplant. 2017 01;32:234–241.
4. Ganguli A. Uddanam nephropathy/regional nephropathy in
India: preliminary findings and a plea for further research. Am
J Kidney Dis. 2016;68:344–348.
5. Advancing CKDu research in Sri Lanka. Available at: http://
origin.searo.who.int/srilanka/advancing-ckdu-research-in-sri-
lanka/en/. Accessed February 9, 2020.
6. Agarwal SK, Dash SC, Irshad M, et al. Prevalence of chronic
renal failure in adults in Delhi, India. Nephrol Dial Transplant.
2005;20:1638–1642.
7. Singh AK, Farag YMK, Mittal BV, et al. Epidemiology and risk
factors of chronic kidney disease in India—results from the
SEEK (Screening and Early Evaluation of Kidney Disease)
study. BMC Nephrol. 2013;14:114.
8. Tatapudi RR, Rentala S, Gullipalli P, et al. High Prevalence of
CKD of Unknown Etiology in Uddanam, India. Kidney Int Rep.
2018;4:380–389.
9. Mani MK. Chronic renal failure in India. Nephrol Dial Trans-
plant. 1993;8:684–689. discussion 683.
10. Caplin B, Yang CW, Anand S, et al. The International Society
of Nephrology’s International Consortium of Collaborators on
Chronic Kidney Disease of Unknown Etiology: report of the
working group on approaches to population-level detection
strategies and recommendations for a minimum dataset.
Kidney Int. 2019;95:4–10.
11. Tondaimandalam. Available at: https://en.wikipedia.org/wiki/
Tondaimandalam. Accessed February 9, 2020.
S Parameswaran et al.: Tondaimandalam Nephropathy CLINICAL RESEARCH
Kidney International Reports (2020) 5, 2066–2073 2073