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Chronic kidney disease of uncertain etiology in Sri Lanka is a possible sequel of interstitial nephritis!:

  • faculty of Medicine university of Peradeniya sri lanka

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Introduction: The majority of published data on chronic kidney disease of uncertain etiology (CKDu) is on asymptomatic patients who were detected in screening programs. The clinicopathological profile of a group of patients presenting with acute symptoms and renal dysfunction from CKDu endemic regions in Sri Lanka was studied. Methods: 59 patients > 10 years of age with backache, feverish fatigue feeling, dysuria, joint pain, or dyspepsia, singly or in combination with elevated serum creatinine (> 116 and > 98 µmol/L for male and females, respectively) were included in the study. Those patients who had normal-sized kidneys were biopsied after excluding clinically detectable causes for renal dysfunction. Histology was scored with activity and chronicity indices. These patients' urinary sediment and inflammatory markers were checked. Patients were stratified into three groups based on duration of symptom onset to the time of biopsy. The natural course of the disease was described using serial mean serum creatinine and histological activity as well as chronicity indices in these 3 groups. Results: These patients' mean age, occupation, and sex ratio were 44 (9) years, 57 farmers, and male : female 55 : 4, respectively. Mean serum creatinine at biopsy was 143.8 (47.9) µmol/L. Elevated inflammatory markers and active urine sediment were reported. Histology was compatible with an interstitial nephritis with a mixture of acute and chronic tubulointerstitial lesions and glomerular scarring. In the natural course of an acute episode of CKDu, serum creatinine and histological activity were reduced while histological chronicity increased. Conclusion: CKDu may be preceded by an acute episode of tubulointerstitial nephritis (TIN).
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©2016 Dustri-Verlag Dr. K. Feistle
ISSN 0301-0430
DOI 10.5414/CNP86S115
e-pub: July 29, 2016
Correspondence to
Dr. Zeid Badurdeen
Centre for Education
Research and Training
on Kidney Diseases
(CERTKiD), Faculty of
Medicine, University of
Peradeniya, Sri Lanka
Key words
symptomatic CKDu –
– tubulointerstitial
nephritis – natural
Chronic kidney disease of uncertain etiology in
Sri Lanka is a possible sequel of interstitial
Clinicopathological prole of symptomatic, newly-diagnosed CKDu
Zeid Badurdeen1, Nishantha Nanayakkara1,4, Neelakanthi V.I. Ratnatunga1,2,
Abdul W.M. Wazil4, Tilak D.J. Abeysekera1, Premil N. Rajakrishna4,
Jalitha P. Thinnarachchi4, Ranjith Kumarasiri3, Dulani D. Welagedera4,
Needika Rajapaksha4, and Adambarage P.D. Alwis4
1Centre for Education Research and Training on Kidney Diseases (CERTKiD),
2Department of Pathology, 3Department of Community Medicine, Faculty of
Medicine, University of Peradeniya, Peradenya, and 4Renal Transplant and
DialysisUnit, Teaching Hospital, Kandy, Sri Lanka
Abstract. Introduction: The majority of
published data on chronic kidney disease of
uncertain etiology (CKDu) is on asymptom-
atic patients who were detected in screening
programs. The clinicopathological prole
of a group of patients presenting with acute
symptoms and renal dysfunction from CKDu
endemic regions in Sri Lanka was studied.
Methods: 59 patients > 10 years of age with
backache, feverish fatigue feeling, dysuria,
joint pain, or dyspepsia, singly or in combi-
nation with elevated serum creatinine (> 116
and > 98 µmol/L for male and females, re-
spectively) were included in the study. Those
patients who had normal-sized kidneys were
biopsied after excluding clinically detectable
causes for renal dysfunction. Histology was
scored with activity and chronicity indices.
These patients’ urinary sediment and inam-
matory markers were checked. Patients were
stratied into three groups based on duration
of symptom onset to the time of biopsy. The
natural course of the disease was described
using serial mean serum creatinine and his-
tological activity as well as chronicity in-
dices in these 3 groups. Results: These pa-
tients’ mean age, occupation, and sex ratio
were 44 (9) years, 57 farmers, and male :
female 55 : 4, respectively. Mean serum cre-
atinine at biopsy was 143.8 (47.9) µmol/L.
Elevated inammatory markers and active
urine sediment were reported. Histology was
compatible with an interstitial nephritis with
a mixture of acute and chronic tubulointer-
stitial lesions and glomerular scarring. In the
natural course of an acute episode of CKDu,
serum creatinine and histological activity
were reduced while histological chronicity
increased. Conclusion: CKDu may be pre-
ceded by an acute episode of tubulointersti-
tial nephritis (TIN).
Chronic kidney disease of uncertain eti-
ology (CKDu) is an alarming environmental
nephropathy among agricultural communi-
ties in the tropical climates of the world [1].
CKDu is prevalent among the paddy cultivat-
ing farmers in the North Central region of Sri
Lanka [2]. CKDu in Sri Lanka is described as
an asymptomatic, insidious, and slowly pro-
gressive nephropathy, predominately affect-
ing young males [3]. The changes in hydro-
geochemical environment, agrochemicals,
aristolochic acid, and ochratoxins have been
the most studied causative agents in CKDu
Sri Lanka [4]. Previous studies have reported
interstitial brosis and tubular atrophy with-
out signicant interstitial inammation and
glomerular sclerosis as signicant histologi-
cal features in asymptomatic CKDu patients
of Sri Lanka [5, 6].
The clinical presentation of CKDu was
either asymptomatic subnephrotic range pro-
teinuria detected on population screening or
presenting with symptoms of end-stage renal
failure (ESRF). The physicians in CKDu en-
demic regions had observed in the recent past
that apparently healthy individuals presented
with acute symptoms associated with renal
dysfunction. This research was designed to
Clinical Nephrology, DOI 10.5414/CNP86S115
Badurdeen, Nanayakkara, Ratnatunga, et al. S2
study the clinicopathological prole of those
acutely ill, symptomatic patients with renal
dysfunction in CKDu endemic regions.
This prospective study was conducted in
the Nephrology and Transplant Unit at the
Teaching Hospital Kandy and Department of
Pathology, Faculty of Medicine, University
of Peradeniya. Informed written consent was
obtained from each patient. Ethical approval
for this study was taken from the Ethical Re-
view Committee of the Faculty of Medicine,
University of Peradeniya (2012/EC/54 dated
Previously healthy males and females
from the CKDu endemic North Central re-
gion in Sri Lanka, aged > 10 years present-
ing to a renal clinic with recent onset of
backache, feverish fatigue feeling, dysuria,
joint pain, and dyspepsia, either singly or in
combination, were tested for serum creati-
nine levels. Those patients who had persis-
tently elevated serum creatinine (> 116 and
> 98 µmol/L for male and females) for up to
2 weeks were recruited for the study. Those
with clinically identiable causes for the
renal dysfunction and small-sized kidneys
were excluded. Serial serum creatinine was
measured from symptom onset to the time
of biopsy. Renal biopsy was done after ob-
taining informed consent within 90 days of
symptom onset. Serum calcium, phosphate,
uric acid, white blood cell count (WBC),
erythrocyte sedimentation rate (ESR), C-re-
active protein (CRP), urine for bacterial cul-
ture, urine deposit for microscopy, and sulfo-
salicylic acid test for proteins were done at
the time of biopsy.
Parafn sections of the biopsies were ex-
amined with routine and special stains. Di-
rect immunouorescence staining was done
to detect immune complexes of IgG, A, and
M, and complement. Those with no evidence
of immune complex mediated glomerular
disease and no other identiable primary or
secondary renal pathology were followed up.
The renal lesions were scored 0, 1, 2, 3; if
there was no lesion up to 30%, 30 – 60%, and
> 60% area affected, respectively. The dis-
ease activity index (AI) was scored as a sum
of interstitial lymphocyte inltration and tu-
bulitis (0 – 6) and chronicity index (CI) as a
sum of glomerular sclerosis, tubular atrophy,
interstitial brosis, and periglomerular bro-
sis (0 – 12). Patients were placed into one of
3 groups based on duration of symptom on-
set to the time of biopsy. 28 patients between
1 and 30 days, 10 patients between 31 and 60
days, and 8 patients between 61 and 90 days
after onset of symptoms were biopsied and
assigned to groups 1, 2, and 3, respectively.
The clinicopathological data were ex-
pressed with mean, standard deviation (SD),
and percentages. In the dened 3 groups, the
serial changes of serum creatinine on a linear
graph and activity and chronicity scores to-
gether on a separate bar chart were plotted.
All statistical procedures were performed
using SPSS version 20 (IBM, Armonk, NY,
The demographic and clinical character-
istics of 59 symptomatic CKDu patients are
shown in Table 1. The salient pathological
lesions as a percentage of total number of
biopsies observed were interstitial lympho-
cyte inltration (ILI) 96.7%, tubulitis (TU)
81.4%, glomerular sclerosis (GS) 81.4%,
interstitial brosis (IF) 88.1%, tubular atro-
phy (TA) 93.2%, and periglomerular brosis
(PGF) 42.4%. The semiquantitative scores
Table 1. The clinical and demographic characteristics of 59 symptomatic
CKDu patients.
Parameters Description
Mean age, SD 44(9) years
Male : female 55 : 4
Farmer : other jobs 57 : 2
Mean systolic blood pressure, SD 122 (15) mmHg
Mean diastolic blood pressure, SD 79 (10) mmHg
Mean serum creatinine, SD 143.8 (47.9) ref: 53 – 116 µmol/L
Mean serum calcium, SD 2.3(0.2) ref: 2.2 – 2.7 mmol/L
Mean serum phosphate, SD 1.3(0.5) ref: 0.81 – 1.45 mmol/L
Mean uric acid, SD 6.4(1.9) ref: 3.5 to 7.2 mg/dL
Urine protein (sulfosalicylic acid test) 80% cases trace or Nil
20% cases 1+ and 2+
Microscopic hematuria 20.7% cases RBC > 3/HPF (positive)
Pyuria 48.6% cases WBC > 5/HPF (positive)
Erythrocyte sedimentation rate (ESR) 65.6% cases > 20 mm/hour
C-reactive protein (CRP) 48.5% cases > 10 mg/L
SD = standard deviation; RBC = red blood cells; WBC = white blood cells;
HPF = high power eld.
Acute episode of CKDu in Sri Lanka S3
of salient histological lesions of symptom-
atic CKDu as a percentage of total number
of patients is shown in Table 2.
The mean serum creatinine decline was
observed serially from 189 to 153 µmol/L
in group 1, from 179 to130 µmol/L and 130
to 129 µmol/L in group 2, and from 171 to
123 µmol/L and 123 to 158 µmol/L and 158
to 148 µmol/L in group 3 (Figure 1a). The
mean histological activity scores of groups 1,
2, and 3 were 3.4, 2.7, and 2.75, respectively
(Figure 1b). The mean histological chronic-
ity scores of groups 1, 2, and 3 were 4.17,
4.50, and 5.75, respectively (Figure 1b).
In our study, > 90% symptomatic patients
were male farmers with a mean age of 44
years. A CKDu epidemiological study in the
North Central region of Sri Lanka has report-
ed that the majority of the diagnosed CKDu
cases were asymptomatic, > 90% farmers
with a mean age 54 years, detected in screen-
ing programs [7]. Conversely, acute symp-
tomatic CKDu is presenting at a younger age
than asymptomatic CKDu.
Michael et al. [8] have reported arthralgia
45%, rash 21%, fever 30%, loin pain 21%,
and dysuria 15% as presenting symptoms
of patients with acute tubulointerstitial ne-
phritis (TIN). However, none of the acute
symptomatic CKDu patients presented with
typical clinical features of TIN like fever and
rash or oligo anuria [9]. Subnephrotic range
proteinuria, hematuria, sterile pyuria, and
elevated inammatory markers observed in
these patients were compatible with the clin-
ical prole of TIN [10].
The dominant histological features in
asymptomatic CKDu patients in Sri Lanka
were interstitial brosis and tubular atrophy
without signicant interstitial inamma-
tion and glomerular sclerosis. Wijetunga et
al. [6] has reported tubulitis as a feature in
just 1% of asymptomatic CKDu cases. The
salient histological lesions observed in acute
symptomatic CKDu were signicant inter-
stitial inammation and wide-spread tubuli-
tis in the background of brosis and tubular
We described the natural course of an
acute episode of interstitial nephritis in Fig-
ure 1. We propose that this acute episode of
interstitial nephritis is followed by residual
scarring as the possible pathological process
Table 2. The semiquantitative scores of salient histological lesions of symptomatic CKDu as a percent-
age of total number of patients.
Histological lesions Percentages of scores
“0” scores “1” score “2” score “3” score
Interstitial lymphocyte inltration (ILI) 3.3% 43.5% 35.5% 17.7%
Tubulitis (TU) 19.4% 33.9% 24.2% 22.6%
Glomerular sclerosis (GS) 22.6% 50.0% 16.1% 11.3%
Interstitial brosis (IF) 12.9% 35.5% 46.8% 4.8%
Tubular atrophy (TA) 8.1% 35.5% 51.6% 4.8%
Peri-glomerular brosis (PGF) 58.1% 35.5% 4.8% 1.6%
Figure 1. The change of mean serum creatinine, mean histological activity, and chronicity scores of 3
groups of patients in relation to duration of symptom onset to point of biopsy. a: the serial mean serum
creatinine; b: the mean histological activity and chronicity scores.
Badurdeen, Nanayakkara, Ratnatunga, et al. S4
that leads to CKDu. This acute episode could
be either the rst episode or one of multiple
We described for the rst time the clini-
copathological prole of a group of patients,
the majority being young healthy male farm-
ers presenting with acute symptoms and re-
nal dysfunction from CKDu endemic North
Central region of Sri Lanka. Their biomarker
prole was compatible with an early CKD
with evidence of systemic inammation.
Histology is compatible with a signicant
interstitial inltrate, tubulitis, and brosis in
the absence of primary glomerular disease.
We described an acute episode of TIN in
these symptomatic CKDu patients. We rec-
ommend keeping these symptomatic patients
in endemic regions under surveillance for
early detection of CKDu. Further studies are
recommended targeting this specic group to
identify the etiology and possible interven-
We acknowledge the staff of the Nephrol-
ogy and Renal Transplant Unit, Teaching
hospital, Kandy and staff of renal sentinel
clinics in the North Central region of Sri
Lanka. We thank H.M.N.D. Herath, Depart-
ment of Pathology, Faculty of Medicine, Per-
adeniya for the preparation of histological
slides. Finally, we thank Rusiru Hemage and
Yashoda Somarathne of CERTKiD, Faculty
of Medicine, Peradeniya for their technical
support in manuscript preparation.
Conict of interest
All the authors declared no competing
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... 10 The main histological features in Sri Lankan CKDu are tubular atrophy (TA), interstitial fibrosis (IF), and periglomerular fibrosis (PGF) in the absence of or with a mild degree of interstitial mononuclear inflammatory cell infiltration and tubulitis. 11,12 The electron microscopic analysis of relatively early stages of CKDu cases from patients in Central America revealed mild wrinkling of the glomerular basement membrane and subendothelial edema with segmental effacement of podocyte foot processes. 13 Partial tubular cell degeneration was also observed. ...
... 5,[23][24][25] In contrast, in Sym-CKDu, widespread tubulitis and plasma lymphocytic cellular infiltrate were reported in Sri Lanka and Central America. 11,13 Because Sym-CKDu was proposed as the early phase of the disease, 11 clinical, biochemical, and light and electron microscopic evaluations were performed in this study to identify typical abnormalities in early disease. ...
... 5,[23][24][25] In contrast, in Sym-CKDu, widespread tubulitis and plasma lymphocytic cellular infiltrate were reported in Sri Lanka and Central America. 11,13 Because Sym-CKDu was proposed as the early phase of the disease, 11 clinical, biochemical, and light and electron microscopic evaluations were performed in this study to identify typical abnormalities in early disease. ...
Full-text available
Introduction Although the investigation of chronic kidney disease of uncertain etiology (CKDu) has identified many possible influencing factors in recent years, the exact pathomechanism of this disease remains unclear. Methods In this study, we collected 13 renal biopsies from patients with symptomatic CKDu (Sym-CKDu) from Sri Lanka with well-documented clinical and socioeconomic factors. We performed light microscopy and electron microscopic evaluation for ultrastructural analysis which was compared to 100 biopsies from German patients with 20 different kidney diseases. Results Of the Sri Lankan patients, most were men (12/13), frequently employed in agriculture (50%), and showed symptoms such as feverish feeling (83.3%), dysuria (83.3%), and arthralgia (66.6%). Light microscopic evaluation using activity and chronicity score revealed that cases represented early stages of CKDu except for two biopsies which showed additional signs of diabetes. Most glomeruli showed only mild changes, such as podocyte foot process effacement on EM. We found a spectrum of early tubulointerstitial changes including partial loss of brush border in proximal tubules, detachment of tubular cells, enlarged vacuoles, and mitochondrial swelling associated with loss of cristae and dysmorphic lysosomes with electron-dense aggregates. None of these changes occurred exclusively in Sym-CKDu, however they were significantly more frequent in these cases than in the control cohort. Conclusion In conclusion, our findings confirm the predominant and early alterations of tubular structure in CKDu that can occur without significant glomerular changes. The ultrastructural changes do not provide concrete evidence of the cause of CKDu but were significantly more frequent in Sym-CKDu compared to the controls.
... [15] Numerous studies have been carried out in Sri Lanka investigating trace elements and mineral composition of groundwater and soil environment concerning the CKDu endemicity. [14,16,17] However, the influence of geo-climatic factors on CKDu has not been adequately addressed. Therefore, this study aimed to investigate the underlying causes for spatial endemicity of CKDu in Sri Lankan, concerning geo-climatological and anthropological factors. ...
... We selected only males of the most affected age group of CKDu for the study. [11,16] However, there were no distinguishable differences regarding agrochemical usage, dominant livelihood, and socioeconomic status between these two communities. ...
Full-text available
Background: Chronic kidney disease of unknown etiology (CKDu) is a critical health issue among farming communities of the dry zone in Sri Lanka. Aims and Objectives: This study was conducted to identify the possible anthropological, biochemical, and geo‑environmental characteristics of CKDu, comparing an affected and nonaffected community. Materials and Methods: Serum creatinine (SC) levels were measured and estimated glomerular filtration rate values were calculated in both communities based on a stratified sampling method. Anthropological data, such as population structure, farming behavior, and poverty statistics, were obtained from the respective government officials. Geo‑climatic data including elevation, monthly average temperature, rainfall, humidity, ultraviolet intensity, and sunshine hours were obtained for study areas. Results: The most striking difference between the two communities is significantly high SC in male individuals between the age categories of 40–60 in the CKDu endemic area in comparison to nonendemic participants in the same age category from the nonendemic area. Conclusion: Significant differences were observed in migration, drinking water sources, and hot humid environment between the two studied regions.
... In general, cases are seen in community screening programs, while symptoms appear with the end-stage renal failure. Currently, CKDu is diagnosed using serum creatinine as a surrogate marker (> 96 mmol/dL in females and 116 mmol/dL in males) with only mild proteinuria (albumin/creatinine ratio ≥ 30 mg/g) (Badurdeen et al. 2016). Nevertheless, this method is ineffective for detecting early-stage cases because serum creatinine rises late in kidney disease histories. ...
Full-text available
Quality of drinking water has become a significant concern with chronic kidney disease of uncertain aetiology (CKDu), particularly in the dry zone regions of Sri Lanka. In this study, groundwaters consumed by biopsy-proven CKDu patients were assessed for identifying possible hydrogeochemical risk factors because histopathological observations are still considered the best method for identifying CKDu cases. Major anions, cations, and 22 trace elements in groundwater were measured in addition to dissolved organic carbon (DOC) and its isotope ratios (expressed as δ13CDOC). Variations of groundwater quality were monitored monthly in five selected wells. The data were compared with a non-endemic region with a similar climatic and socio-economic background. Groundwater used by CKDu cases is predominantly of the Ca–Mg–HCO3 type. Over 88% of the samples showed excess hardness, while 44% showed high fluoride (F−) contents (> 0.60 mg/L). These two parameters are noticeably different compared to groundwater from non-endemic regions with similar geoenvironmental backgrounds. The dissolved organic carbon (DOC) content varied from 0.06 to 0.30 mmol/L with a mean value of 0.15 mmol/L in CKDu wells. In most cases, known nephrotoxic trace elements such as As, Pb, Cd, and U were found to be lower than 0.01 µg/L. Seasonally, F− and Si4+ (as H4SiO4) content fluctuated, even though monsoon rain inputs did not seem to alter the geochemical composition. Principal component analysis (PCA) indicated that the dissolution of aquifer minerals and ion exchange processes are most likely responsible for the groundwater geochemistry in the study terrain. This study highlights the importance of F−, hardness (Ca2+ + Mg2+), and Si4+ in groundwaters of CKDu-related tropical terrains. The synergetic impact of these parameters needs further systematic studies, ideally combined with animal models, to unravel the aetiological mechanisms of CKDu.
... Meanwhile, we hypothesize recurrent episodes of AIN could lead to irreversible damage and CKDu. Hence, CKDu is a sequel of AINu, and subclinical leptospirosis is a competitive candidate to be the etiology of CKDu [20]. ...
Full-text available
Purpose: Chronic kidney disease of uncertain etiology (CKDu) is an environmental nephropathy in which the etiological factors are yet uncertain. Leptospirosis, a spirochetal infection that is common among agricultural communities, has been identified as a potential etiology for CKDu beyond environmental nephropathy. Although CKDu is a chronic kidney disease, in endemic regions, an increasing number of cases are reported with features suggestive of acute interstitial nephritis without any known reason (AINu), with or without background CKD. The study hypothesizes that exposure to pathogenic leptospires is one of the causative factors for the occurrence of AINu. Method: This study was carried out using 59 clinically diagnosed AINu patients, 72 healthy controls from CKDu endemic region (endemic controls [ECs]), and 71 healthy controls from CKDu non-endemic region (non-endemic controls [NECs]). Results: The seroprevalence of 18.6, 6.9, and 7.0% was observed in the AIN (or AINu), EC, and NEC groups, respectively, from the rapid IgM test. Among 19 serovars tested, the highest seroprevalence was observed at 72.9, 38.9, and 21.1% in the AIN (AINu), EC, and NEC groups, respectively, by microscopic agglutination test (MAT), particularly for serovar Leptospira santarosai serovar Shermani. This emphasizes the presence of infection in AINu patients, and this also suggests that Leptospira exposure might play an important role in AINu. Conclusion: These data suggest that exposure to Leptospira infection could be one of the possible causative factors for the occurrence of AINu, which may lead to CKDu in Sri Lanka.
... CKDu is primarily a chronic interstitial disease which may have resulted from acute or subacute, lowgrade recurrent interstitial nephritis [15][16][17]. Episodes of acute interstitial nephritis (AIN) have been clearly demonstrated in the endemic populations of Sri Lanka and Nicaragua, demographics and pathology of these nephropathies are similar [18][19][20]. It is thought that immunomodulatory therapy is likely to decelerate the fibrotic process and hence the severity of irreversible kidney damage [21,22]. ...
Full-text available
Background Patients presenting with acute interstitial nephritis (AIN) of unknown aetiology, probably the earliest presentation of chronic kidney disease of unknown aetiology (CKDu), have been treated with oral prednisolone and doxycycline by physicians in Sri Lanka. This trial assessed the effectiveness of prednisolone and doxycycline based on eGFR changes at 6 months in patients with AIN of unknown aetiology. Method A randomized clinical trial with a 2 × 2 factorial design for patients presenting with AIN of unknown aetiology ( n = 59) was enacted to compare treatments with; A-prednisolone, B-doxycycline, C-both treatments together, and D-neither. The primary outcome was a recovery of patients’ presenting renal function to eGFR categories: 61–90 ml/min/1.73m ² (complete remission– CR) to 31–60 ml/min/1.73m ² (partial remission– PR) and 0–30 ml/min/1.73m ² no remission (NR) by 6 months. A secondary outcome was progression-free survival (not reaching < 30 ml/min/1.73m ² eGFR), by 6–36 months. Analysis was by intention to treat. Results Seventy patients compatible with a clinical diagnosis of AIN were biopsied for eligibility; 59 AIN of unknown aetiology were enrolled, A = 15, B = 15, C = 14 and D = 15 randomly allocated to each group. Baseline characteristics were similar between groups. The number of patients with CR, PR and NR, respectively, by 6 months, in group A 3:8:2, group B 2:8:3 and group C 8:5:0 was compared with group D 8:6:1. There were no significant differences found between groups A vs. D ( p = 0.2), B vs. D ( p = 0.1) and C vs. D ( p = 0.4). In an exploratory analysis, progression-free survival in prednisolone-treated (A + C) arms was 0/29 (100%) in comparison to 25/30 (83%) in those not so treated (B + D) arms, and the log-rank test was p = 0.02, whereas no such difference found ( p = 0.60) between doxycycline-treated (B + C) arms 27/29 (93%) vs those not so treated (A + D) arms 27/30 (90%). Conclusion Prednisolone and doxycycline were not beneficial for the earliest presentation of CKDu at 6 months. However, there is a potential benefit of prednisolone on the long-term outcome of CKDu. An adequately powered steroid trial using patients reaching < 30 ml/min/1.73m ² eGFR by 3 years, as an outcome is warranted for AIN of unknown aetiology. Trial registration Sri Lanka Clinical Trial Registry SLCTR/2014/007, Registered on the 31st of March 2014.
... Recently, a subcategory of patients has been reported from these at-risk areas for CKDu in Nicaragua and Sri Lanka. 4,5 There was tubulitis and significant interstitial cell infiltrate in the background of glomerular sclerosis, tubulointerstitial fibrosis and tubular atrophy in their biopsies, compatible to acute interstitial nephritis. CKDu patients with acute lesions (CKDu-A) subsequently transform into commonly encountered CKDu patients with chronic features (CKDu-NA), 6 or to a distinct subclinical phenotype (CKDu-S) with normal renal functions, besides irreversible histologic changes. ...
... More recent studies highlighted as well the role of arsenic and the association between urinary herbicide level and biomarkers of kidney injury (165,166). In 2016, a series of kidney biopsies in 59 patients with CKDu in Sri Lanka revealed chronic tubulointerstitial lesions with glomerular scarring (163). In 2017, de Silva et al. performed mixed methods research and revealed an association of CKDu with the poorest of the poor marginalized social category in agricultural settlements (164). ...
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In many cases the social determinants of health need to be assessed through their interaction with environmental factors. This review looks at the impact of physical location and occupation of individuals on their kidney health. It examines the effect of living at high altitude on kidney function and the relationship between extreme cold or hot temperatures and the incidence of kidney injury. It reviews as well the many occupations that have been linked to kidney disease in high-income and low-and-middle-income countries. As a conclusion, this overview proposes preventive recommendations that could be individualized based on weather, altitude, socio-economic level of the country and occupation of the individual.
... Written informed consent was obtained from the participants before the data collection of the study. Since the disease is dominant among male farmers and the highest prevalence was reported in the age group of 30-60 years, [5,12] only that group was selected using a stratified random sampling technique. Three hundred participants from the Wilgamuwa region and 150 participants from the Hanguranketha region were included in the study. ...
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© 2022 Environmental Disease | Published by Wolters Kluwer - Medknow 47Comparison of biochemical characteristics between anendemic and a nonendemic area for CKDu Sri LankaA. Medagedara1,2, Pasan Hewavitharane1, Rohana Chandrajith3, Hemalika T. K. Abeysundara4,R. O. Thatil5, S. Thennakoon6, Buddhisha Mahanama1, N. Weerasuriya7, A. Thilakarathne7,Nishantha Nanayakkara11Center for Research, National Hospital, Kandy, Sri Lanka, 2Department of Fundamentals of Nursing, Faculty of Nursing,University of Colombo, 3Department of Geology, Faculty of Science, University of Peradeniya, 4Department of Statistics and ComputerSciences, Faculty of Science, University of Peradeniya, 5Department of Crop Sciences, Faculty of Agriculture,University of Peradeniya, 6Department of Community Medicine, Faculty of Medicine, University of Peradeniya,7Provincial Director of Health Services, Central Province, Sri LankaIntroduction: Chronic kidney disease with uncertain etiology (CKDu) was first recognized in the 1990s inSri Lanka. Considering the distribution of CKDu in the country, clusters of endemic and nonendemic areascan be identified. This study was carried out to compare the biochemical characteristics between CKDuendemic and nonendemic areas in Sri Lanka.Materials and Methods:A cross‑sectional study was carried out among randomly selected males between theage category of 30 and 60 years in selected villages of Wilgamuwa (endemic) and Hanguranketha (nonendemic),located in the dry and wet zone, respectively.Results: The total participation percentage from the endemic area was 74.7% (224 out of 300 invitees). Outof 150 participants invited from the nonendemic area, only 100 participated in the study cohort. There wasa striking difference between the two areas in serum creatinine levels (P = 0.001). When considering thebehavioral patterns of the two study areas, the main occupation was farming and there was no significantdifference between the behaviors of the people in the selected areas. A significant number of participants(n = 31, 13.8%) from the endemic area had high serum creatinine levels with a mean of 109 μmol/L(standard deviation [SD] = 66.41) (normal: 90–116 μmol/L). Whereas, in the nonendemic area, only 3 (3%)participants had elevated creatinine levels with a mean value of 85.41 μmol/L (SD = 18.78). A significantdifference was observed in the two groups in the mean values of serum creatinine levels (P = 0.001). Themean value of random blood sugar (RBS) was 113.56 mg/dL (SD = 44.38) and 119.10 mg/dL (SD = 50.48)in endemic and nonendemic areas, respectively. There was no significant difference between the meanvalues of RBS (P = 0.2). The mean serum cholesterol was slightly higher in Wilgamuwa (119.26 mg/dl,SD = 45.31) compared to Hanguranketha (189.02 mg/dl, SD = 45.09). However, that was not statisticallysignificant (P = 0.6) (7) (PDF) Comparison of biochemical characteristics between an endemic and a nonendemic area for CKDu Sri Lanka. Available from: [accessed Aug 08 2022].
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Over the past 30 years, climate change has taken one of the leading places among the ten main causes of death due to natural disasters. Rising temperatures have been shown to increase emergency department admissions for a wide range of kidney diseases, including acute kidney injury (AKI), chronic kidney disease, kidney stones, and urinary tract infections. The occupational effect of heat stress is also associated with AKI, which can quickly progress to acute kidney failure with high mortality. The basis of the pathogenetic mechanisms of heat-induced AKI is a decrease in the circulating blood volume and electrolyte disturbances due to increased perspiration. Water evaporation from the surface of the skin contributes to dehydration with an increase in serum osmolarity. In response to this, vasopressin is activated, the specific gravity of urine increases, and the amount of urine decreases. The glomerular filtration rate progressively decreases. Hypokalemia develops, which changes to hyperkalemia within 12 hours. Tubular endothelium is damaged, which leads to microthrombosis of afferent and efferent renal arteries, the development of an inflammatory response, and exhaustion of the renal interstitium. Possible rhabdomyolysis and myoglobinemia with subsequent tubular obstruction worsen existing kidney damage. According to the leading mechanism of damage, there are two types of acute heat damage to the kidneys: classical rhabdomyolysis and acute interstitial nephritis. Although modern medical advances have contributed to the development of effective treatment and management strategies (rapid cooling, extracorporeal detoxification methods, etc.), mortality in kidney damage due to general overheating has decreased slightly over the past decades. For health care and industry researchers, it is necessary to identify the harmful occupational conditions that lead to heat stress nephropathy and to develop certain occupational safety strategies.
A kidney disease of unknown cause is affecting up to 20% of men living in agricultural communities recognized to be hotspots, among them Nicaragua, El Salvador, Guatemala, and Sri Lanka. The disease often manifests in the third or fourth decade of life. Kidney biopsy indicates that the major finding is chronic tubulointerstitial nephritis in a majority of patients, although a subset may also present with symptoms of dysuria or fever and have acute interstitial nephritis on histology. In this chapter we review the epidemiology, pathology, and prominent hypotheses regarding potential causes of this mysterious kidney disease. We also provide a brief overview of ongoing population and occupational cohorts conducting promising investigations and/or interventions to prevent the disease.
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The aim of the study was to identify the epidemiology of chronic kidney disease of uncertain etiology in Sri Lanka. A cross-sectional study was carried out by analyzing health statistics, and three cohort studies were conducted (n = 15 630, 3996, and 2809) to analyze the demographic information, age-specific prevalence, etiology, and stage of presentation. We screened 7604 individuals for chronic kidney disease of uncertain etiology. The results showed that the male:female ratio was 2.4:1, the mean age of patients was 54.7 ± 8 years, 92% of the patients were farmers, and 93% consumed water from shallow dug wells. Familial occurrence was common (36%). The prevalence of chronic kidney disease in different age groups was 3% in those aged 30-40 years; 7% in those aged 41-50 years, 20% in those aged 51-60 years, and 29% in those older than 60 years. Chronic kidney disease of uncertain etiology was diagnosed in 70.2% of patients, while 15.7% and 9.6% were due to hypertension and diabetic mellitus, respectively. The majority of patients were stage 4 (40%) at first presentation, while 31.8% were stage 3 and 24.5% were stage 5. Stage 1 and 2 presentation accounted for only 3.4%. Low prevalence of CKDU was noticed (1.5%) among those who consumed water from natural springs. Prevalence was highest among males, rice farming communities, and those presenting at later disease stages.
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ABSTRACT In recent years, Central America, Egypt, India and Sri Lanka have reported a high prevalence of chronic kidney disease of unknown etiology in agricultural communities, predominantly among male farmworkers. This essay examines the disease’s case definitions, epidemiology (disease burden, demographics, associated risk factors) and causal hypotheses, by reviewing published findings from El Salvador, Nicaragua, Costa Rica, Sri Lanka, Egypt and India. The range of confirmed chronic kidney disease prevalence was 17.9%–21.1%. Prevalence of reduced glomerular filtration (<60 mL/min/1.73 m2 body surface area) based on a single serum creatinine measurement was 0%–67% men and 0%–57% women. Prevalence was generally higher in male farmworkers aged 20–50 years, and varied by community economic activity and altitude. Cause was unknown in 57.4%–66.7% of patients. The dominant histopathological diagnosis was chronic tubulointerstitial nephritis. Associations were reported with agricultural work, agrochemical exposure, dehydration, hypertension, homemade alcohol use and family history of chronic kidney disease. There is no strong evidence for a single cause, and multiple environmental, occupational and social factors are probably involved. Further etiological research is needed, plus interventions to reduce preventable risk factors.
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To study the early pathological changes in renal lesions of asymptomatic patients with kidney diseases, with no definite aetiology living in regions endemic for chronic kidney disease of unknown etiology (CKDUe). Design Retrospective study. Regions endemic for CKDUe in and around the North Central Province of Sri Lanka. Two hundred and eleven asymptomatic patients living in endemic regions detected with renal disease by screening for proteinuria using the dipstick method. Those with long standing hypertension, diabetes mellitus, histological diagnosis of primary glomerular diseases, immunocomplex mediated diseases or renal lesions secondary to systemic diseases were excluded. Renal lesions were divided into seven histological categories depending on the pathological changes: Category 0: no detectable changes. Category 1: Interstitial fibrosis ± mild interstitial inflammation ± tubular atrophy; no glomerulosclerosis. Category 2: Interstitial fibrosis ± mild interstitial inflammation ± tubular atrophy; glomerulosclerosis. Category 3: Moderate or severe interstitial fibrosis, interstitial inflammation and tubular atrophy ± glomerulosclerosis; Category 4: Interstitial inflammation ± tubular atrophy ± glomerulosclerosis; no interstitial fibrosis. Category 5: The prominent change is interstitial inflammation with tubulitis. Category 6: Severely scarred kidney. Histological categories were compared with calculated glomerular filtration rates and age of the patients. Number of cases in histological categories 0 to 6 were: 7 (3.3%), 71 (33.6%), 53 (25.1%), 63 (29.9%), 0, 2 (0.9%) and 15 (7.1%) respectively. The mean glomerular filtration rate was >90 ml/min in patients in category 0 and 1 and declined progressively in categories 2 and 3. Apart from category 0, all had interstitial fibrosis and in category 1, 62 (87.3%) had interstitial fibrosis without inflammation. Severity of interstitial inflammation increased from category 1 to 3. The early disease among asymptomatic patients is characterized by interstitial fibrosis without significant interstitial inflammation and glomerular sclerosis with preserved glomerular function. Although the role of interstitial inflammation in the initiation of the disease is not clear, it appears to have a role in the progression of the disease.
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Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury (AKI) for which early treatment improves prognosis. The recent increase in prevalence has not been reflected in the literature. The aim of our study was to analyse all native kidney biopsies performed from 1994 to 2009 and included in the Spanish Registry of Glomerulonephritis with a histological diagnosis of ATIN. We assessed the prevalence of ATIN, associated clinical syndromes and urinary sediment abnormalities. We divided the population into two groups according to age: adults (15-65 years) and elderly patients (>65 years). We collected a total of 17 680 native kidney biopsies from 120 hospitals in Spain. The overall prevalence of ATIN was 2.7%. When the analysis was restricted to patients with AKI, the prevalence increased to 12.9%. During the 16 years of follow-up, there was a significant increase in prevalence (from 3.6% in the first 4 years to 10.5% in the last 4 years), which was more marked among elderly patients (from 1.6 to 12.3%). The most common clinical manifestations were AKI, microscopic haematuria, non-nephrotic proteinuria, leucocyturia and arterial hypertension, which were more frequent in the elderly. The prevalence of ATIN has increased in recent years, especially in patients aged >65 years. This could be due to an increase in drug-associated ATIN, which would justify early renal biopsy to identify ATIN and reduce the probability of progression to chronic kidney disease. Although, our data are not able to corroborate this fact.
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Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.
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end-stage renal disease, analgesic-induced tubulointerstitial nephritis, urinary tract obstruction, hyperuricemia, nephrocalcinosis, lead nephropathy, sarcoid nephropathy, acute drug-induced tubulointerstitial nephritis
Acute interstitial nephritis (AIN) is an important and common cause of acute kidney injury, particularly in hospitalized patients. The classic presentation of AIN includes fever, rash, arthralgias, eosinophilia, and acute kidney injury. While renal biopsy is considered the gold standard for diagnosis, the clinical presentation of fever and rash along with laboratory evidence of peripheral blood eosinophilia, eosinophiluria, and low-grade proteinuria strongly suggest the diagnosis. Histologically, interstitial inflammation with interstitial edema and tubulitis is the hallmark of interstitial nephritis. The most common causative factors are drugs, infections, and certain immune-mediated disorders. Discontinuation of the offending agent is considered the mainstay of therapy while the use of corticosteroids to hasten renal recovery may be beneficial. The role of interstitial nephritis in the pathogenesis of chronic kidney disease and end-stage renal disease is increasingly recognized, further emphasizing the importance of its early diagnosis and timely treatment.
Epidemics of chronic kidney disease not attributable to common causes have recently been observed in Central America and Asia. Since the etiology is unclear, the disease is often known by terms such as chronic kidney disease of unknown etiology. There is growing evidence that risk factors include rural agricultural work and agrochemical exposure. The disease should be renamed chronic agrochemical nephropathy to highlight the most likely etiology and draw attention to the condition. KEYWORDS Chronic kidney diseases/etiology; renal insufficiency, chronic/etiology; kidney failure, chronic/etiology; agrochemicals/adverse effects; pesticides/adverse effects; nephropathy; occupational exposure; environmental exposure; environmental health.
The global prevalence of chronic kidney disease (CKD) of uncertain etiology may be underreported. Community-level epidemiological studies are few due to the lack of national registries and poor focus on the reporting of non-communicable diseases. Here we describe the prevalence of proteinuric-CKD and disease characteristics of three rural populations in the North Central, Central, and Southern Provinces of Sri Lanka. Patients were selected using the random cluster sampling method and those older than 19 years of age were screened for persistent dipstick proteinuria. The prevalence of proteinuric-CKD in the Medawachchiya region (North Central) was 130 of 2600 patients, 68 of 709 patients in the Yatinuwara region (Central), and 66 of 2844 patients in the Hambantota region (Southern). The mean ages of these patients with CKD ranged from 44 to 52 years. Diabetes and long-standing hypertension were the main risk factors of CKD in the Yatinuwara and Hambantota regions. Age, exceeding 60 years, and farming were strongly associated with proteinuric-CKD in the Medawachchiya region; however, major risk factors were uncertain in 87% of these patients. Of these patients, 26 underwent renal biopsy; histology indicated tubulointerstitial disease. Thus, proteinuric-CKD of uncertain etiology is prevalent in the North Central Province of Sri Lanka. In contrast, known risk factors were associated with CKD in the Central and Southern Provinces.
Endemic occurrence of chronic kidney disease with unknown etiology is reported in certain parts of the north central dry zone of Sri Lanka and has become a new and emerging health issue. The disease exclusively occurs in settlements where groundwater is the main source of drinking water and is more common among low socio-economic groups, particularly among the farming community. Due to its remarkable geographic distribution and histopathological evidence, the disease is believed to be an environmentally induced problem. This paper describes a detailed hydrogeochemical study that has been carried out covering endemic and non-endemic regions. Higher fluoride levels are common in drinking water from both affected and non-affected regions, whereas Ca-bicarbonate type water is more common in the affected regions. In terms of the geochemical composition of drinking water, affected households were rather similar to control regions, but there is a large variation in the Na/Ca ratio within each of the two groups. Fluoride as shown in this study causes renal tubular damage. However it does not act alone and in certain instances it is even cytoprotective. The fine dividing line between cytotoxicity and cytoprotectivity of fluoride appears to be the effect of Ca(2+) and Na(+) of the ingested water on the F(-) metabolism. This study illustrates a third major cause (the other two being hypertension and diabetes) of chronic kidney diseases notably in tropical arid regions such as the dry zone of Sri Lanka.