Environmental fluoride exposure and implications on potential pediatric kidney health risks: an approach with urinary biomarkers.

BACKGROUND: Environmental fluoride exposure at elevated levels is potentially linked to kidney injury, and may contribute to chronic kidney disease of uncertain etiology (CKDu) as a risk factor. However, this link remains unclear, and examining the risk of kidney damage from early life fluoride exposure may provide important insights. Hence, this study aimed to investigate associations of fluoride exposure with pediatric kidney health in CKDu impacted and unimpacted communities in Sri Lanka. METHODS: Considering the geographical variations in environmental fluoride, climate, and prevalence of CKDu, four study groups were established within selected education zones in CKDu-endemic dry zone regions (D-En), and CKDu-nonendemic regions within the dry (D-NE), wet (W-NE), and intermediate (I-NE) climatic zones. The study population included 922 school students (11-18 years of age). Participants in each group were divided into four subgroups based on quartiles of respective urinary fluoride (UF) distribution for comparison of urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and albumin-creatinine ratio (ACR). RESULTS: UF levels in participants particularly in CKDu endemic dry zone regions were significantly high compared to the other regions. Significantly high median urinary NGAL (in D-NE) and ACR (in D-EN, and W-NE) levels were observed in subgroups of higher UF quartiles. Albuminuria was not particularly identified in subjects with high UF excretion. Urinary KIM-1 showed no significant variation across the UF quartile subgroups. Linear regression identified weak associations of UF with kidney injury biomarkers. CONCLUSIONS: Fluoride exposure is particularly high in CKDu-endemic dry zone communities. As implied by kidney injury biomarkers, a strong link between fluoride exposure and pediatric kidney health was not evident at the observed exposure levels in the study regions.

Environmental heat exposure and implications on renal health of pediatric communities in the dry climatic zone of Sri Lanka: An approach with urinary biomarkers.

Prolonged heat exposure during outdoor physical exertion can result in adverse renal health outcomes, and it is also supposed to be a driver of chronic kidney disease of uncertain etiology (CKDu) in tropical regions. School students are more likely to experience high heat exposure during outdoor sports practices, and the current knowledge on potential renal health outcomes associated with heat exposure carries many knowledge gaps. Hence, the present study aimed to perform biomarker-based assessment of the likelihood of pediatric renal injury focusing the communities in the dry climatic zone in Sri Lanka, where it prevails relatively harsh climate and high prevalence of CKDu. School students who engaged in regular outdoor sports practices (high-heat exposure), and an age-matched control of students who did not engage in sports practices (low-heat exposure) from four educational zones: Padavi Sripura (N = 159) and Medirigiriya (N = 171), Uhana (N = 165) and Thanamalwila (N = 169) participated in this cross-sectional study representing CKDu endemic and non-endemic regions. Effective temperature (ET), wet-bulb globe temperature (WBGT), heat index (HI) and humidex were used for comparison of thermal comfort in the environment. The intensity of environmental heat measured by thermal comfort indices showed no significant difference (p > 0.05) among the study regions. Urinary kidney injury molecule (KIM-1) and albumin-creatinine ratio (ACR) in participants with high heat exposure did not differ significantly from those in the control groups in the four study zones, where urinary neutrophil gelatinase-associated lipocalin showed substantial differences in some groups. Irrespective of heat exposure, increased KIM-1 excretion was observed (p < 0.01) in participants of CKDu endemic regions compared to those in non-endemic areas. Within the context of our findings, there is no plausibly strong evidence to establish potential association of heat exposure with the likelihood of developing renal injury or abnormal renal outcomes in dry zone school students in Sri Lanka.

Exploring the Utility of Urinary Creatinine Adjustment for KIM-1, NGAL, and Cystatin C for the Assessment of Kidney Function: Insights from the C-KidnEES Cohort.

Normalization of urinary biomarkers of kidney injury is a common practice in clinical and research settings to account for variations in urine concentration, and urinary creatinine is often used as a reference. However, to date, there is no consensus on the adjustment of urinary biomarkers with creatinine, and both absolute and creatinine-adjusted biomarker levels are adopted for making interpretations of kidney health. Hence, the present study aimed to investigate the associations of urinary creatinine with three widely used kidney injury biomarkers, KIM-1, NGAL, and cystatin C, to validate the applicability of urinary creatinine as a reference for normalization. A cross-sectional study was performed with 2100 students, 10-18 years of age in the Children's Kidney Environmental Exposure Study (C-KidnEES) cohort established in Sri Lanka. As identified in linear regression analyses, normalization of urinary KIM-1, NGAL, and Cys-C to urinary creatinine did not result in significant under-adjustment or over-adjustment to the absolute urinary concentrations, giving no specific rationale for creatinine adjustment. Hence, absolute urinary concentrations of the above biomarkers can be adopted for the characterization of subclinical kidney injury in adolescents in community studies where early morning urine sampling is practiced. However, for spot urine samples, consideration of both absolute and creatinine-adjusted biomarker levels would be a better approach.

Urinary cystatin C: pediatric reference intervals and comparative assessment as a biomarker of renal injury among children in the regions with high burden of CKDu in Sri Lanka.

BACKGROUND: Cystatin C (Cys-C) is an emerging biomarker of renal diseases and its clinical use, particularly for screening the communities affected by chronic kidney disease of unknown etiology (CKDu), is hindered due to the lack of reference intervals (RIs) for diverse ethnic and age groups. The present study aimed to define RIs for urinary Cys-C (uCys-C) for a healthy pediatric population in Sri Lanka and in turn compare the renal function of the residential children in CKDu endemic and non-endemic regions in Sri Lanka. METHODS: A cross-sectional study was conducted with 850 healthy children (10-17 years) from selected locations for reference interval establishment, while a total of 892 children were recruited for the comparative study. Urine samples were collected and analyzed for Cys-C, creatinine (Cr) and albumin. Cr-adjusted uCys-C levels were partitioned by age, and RIs were determined with quantile regression (2.5th, 50th and 97.5th quantiles) at 90% confidence interval. RESULTS: The range of median RIs for uCys-C in healthy children was 45.94-64.44 ng/mg Cr for boys and 53.58-69.97 ng/mg Cr for girls. The median (interquartile range) uCys-C levels of children in the CKDu endemic and non-endemic regions were 58.18 (21.8-141.9) and 58.31 (23.9-155.3) ng/mg Cr with no significant difference (P = 0.781). A significant variation of uCys-C was noted in the children across age. CONCLUSIONS: Notably high uCys-C levels were observed in children with elevated proteinuria. Thus, uCys-C could be a potential biomarker in identifying communities at high risk of CKDu susceptibility.

Interventional nephrology and vascular access practice: A perspective from South and Southeast Asia.

South and Southeast Asia is the most populated, heterogeneous part of the world. The Association of Vascular Access and InTerventionAl Renal physicians (AVATAR Foundation), India, gathered trends on epidemiology and Interventional Nephrology (IN) for this region. The countries were divided as upper-middle- and higher-income countries as Group-1 and lower and lower-middle-income countries as Group-2. Forty-three percent and 70% patients in the Group 1 and 2 countries had unplanned hemodialysis (HD) initiation. Among the incident HD patients, the dominant Vascular Access (VA) was non-tunneled central catheter (non-TCC) in 70% of Group 2 and tunneled central catheter (TCC) in 32.5% in Group 1 countries. Arterio-Venous Fistula (AVF) in the incident HD patients was observed in 24.5% and 35% of patients in Group-2 and Group-1, respectively. Eight percent and 68.7% of the prevalent HD patients in Group-2 and Group-1 received HD through an AVF respectively. Nephrologists performing any IN procedure were 90% and 60% in Group-2 and Group 1, respectively. The common procedures performed by nephrologists include renal biopsy (93.3%), peritoneal dialysis (PD) catheter insertion (80%), TCC (66.7%) and non-TCC (100%). Constraints for IN include lack of time (73.3%), lack of back-up (40%), lack of training (73.3%), economic issues (33.3%), medico-legal problems (46.6%), no incentive (20%), other interests (46.6%) and institution not supportive (26%). Routine VA surveillance is performed in 12.5% and 83.3% of Group-2 and Group-1, respectively. To conclude, non-TCC and TCC are the most common vascular access in incident HD patients in Group-2 and Group-1, respectively. Lack of training, back-up support and economic constraints were main constraints for IN growth in Group-2 countries.

Peritoneal dialysis: Status report in South and South East Asia.

BACKGROUND: Peritoneal dialysis (PD) as a modality of kidney replacement therapy (KRT) is largely underutilized globally. We analyzed PD utilization, impact of economic status, projected growth and impact of state policy(s) on PD growth in South Asia and Southeast Asia (SA&SEA) region. METHODS: The National Nephrology Societies of the region responded to a questionnaire on KRT practices. The responses were based on the latest registry data, acceptable community-based studies and societal perceptions. The representative countries were divided into high income and higher-middle income (HI & HMI) and low income and lower-middle income (LI & LMI) groups. RESULTS: Data provided by 15 countries showed almost similar percentage of GDP as health expenditure (4%-7%). But there was a significant difference in per capita income (HI & HMI -US$ 28 129 vs. LI & LMI - US$ 1710.2) between the groups. Even after having no significant difference in monthly cost of haemodialysis (HD) and PD in LI & LMI countries, they have poorer PD utilization as compared to HI & HMI countries (3.4% vs. 10.1%); the reason being lack of formal training/incentives and time constraints for the nephrologist while lack of reimbursement and poor general awareness of modalities has been a snag for the patients. The region expects ≥10% PD growth in the near future. Hong Kong and Thailand with 'PD first' policy have the highest PD utilization. CONCLUSION: Important deterrents to PD underutilization were lack of PD centric policies, lackadaisical patient/physician's attitude, lack of structured patient awareness programs, formal training programs and affordability.

Impact of National Economy and Policies on End-Stage Kidney Care in South Asia and Southeast Asia.

BACKGROUND: The association between economic status and kidney disease is incompletely explored even in countries with higher economy (HE); the situation is complex in lower economies (LE) of South Asia and Southeast Asia (SA and SEA). METHODS: Fifteen countries of SA and SEA categorized as HE and LE, represented by the representatives of the national nephrology societies, participated in this questionnaire and interview-based assessment of the impact of economic status on renal care. RESULTS: Average incidence and prevalence of end-stage kidney disease (ESKD) per million population (pmp) are 1.8 times and 3.3 times higher in HE. Hemodialysis is the main renal replacement therapy (RRT) (HE-68%, LE-63%). Funding of dialysis in HE is mainly by state (65%) or insurance bodies (30%); out of pocket expenses (OOPE) are high in LE (41%). Highest cost for hemodialysis is in Brunei and Singapore, and lowest in Myanmar and Nepal. Median number of dialysis machines/1000 ESKD population is 110 in HE and 53 in LE. Average number of machines/dialysis units in HE is 2.7 times higher than LE. The HE countries have 9 times more dialysis centers pmp (median HE-17, LE-02) and 16 times more nephrologist density (median HE-14.8 ppm, LE-0.94 ppm). Dialysis sessions >2/week is frequently followed in HE (84%) and <2/week in LE (64%). "On-demand" hemodialysis (<2 sessions/week) is prevalent in LE. Hemodialysis dropout rates at one year are lower in HE (12.3%; LE 53.4%), death being the major cause (HE-93.6%; LE-43.8%); renal transplants constitute 4% (Brunei) to 39% (Hong Kong) of the RRT in HE. ESKD burden is expected to increase >10% in all the HE countries except Taiwan, 10%-20% in the majority of LE countries. CONCLUSION: Economic disparity in SA and SEA is reflected by poor dialysis infrastructure and penetration, inadequate manpower, higher OOPE, higher dialysis dropout rates, and lesser renal transplantations in LE countries. Utility of RRT can be improved by state funding and better insurance coverage.

Chronic interstitial nephritis in agricultural communities: a new perspective on etiology, diagnosis and mechanism.

Chronic interstitial nephritis in agricultural communities is a devastating kidney disease with a globally increasing prevalence. Its cause is unknown. Two predominant etiologies are hypothesised: recurrent episodes of dehydration and exposure to environmental toxins, such as agrochemicals and metals. In this review, we summarise arguments on: 1) why heat stress/dehydration is an unlikely cause of this disease and 2) why chronic interstitial nephritis in agricultural communities is to be considered a toxin-induced nephropathy. Mechanistically, we provide arguments for a putative role of pesticides on the one hand, and the calcineurin pathway on the other hand, both of which require further investigation. Finally, we summarise several important perspectives for research on chronic interstitial nephritis in agricultural communities.

Aetiology, practice patterns and burden of end-stage kidney disease in South Asia and South-East Asia: A questionnaire-based survey.

AIM: There is paucity of data on the epidemiology of end-stage kidney disease (ESKD) from South Asia and South-East Asia. The objective of this study was to assess the aetiology, practice patterns and disease burden and growth of ESKD in the region comparing the economies. METHODS: The national nephrology societies of the region; responded to the questionnaire; based on latest registries, acceptable community-based studies and society perceptions. The countries in the region were classified into Group 1 (High|higher-middle-income) and Group 2 (lower|lowermiddle income). Student t-test, Mann-Whitney U test and Fisher's exact test were used for comparison. RESULTS: Fifteen countries provided the data. The average incidence of ESKD was estimated at 226.7 per million population (pmp), (Group 1 vs. Group 2, 305.8 vs. 167.8 pmp) and average prevalence at 940.8 pmp (Group 1 vs. Group 2, 1306 vs. 321 pmp). Group 1 countries had a higher incidence and prevalence of ESKD. Diabetes, hypertension and chronic glomerulonephritis were most common causes. The mean age in Group 2 was lower by a decade (Group 1 vs. Group 2-59.45 vs 47.7 years). CONCLUSION: Haemodialysis was the most common kidney replacement therapy in both groups and conservative management of ESKD was the second commonest available treatment option within Group 2. The disease burden was expected to grow >20% in 50% of Group 1 countries and 78% of Group 2 countries along with the parallel growth in haemodialysis and peritoneal dialysis.

The Utility of Novel Renal Biomarkers in Assessment of Chronic Kidney Disease of Unknown Etiology (CKDu): A Review.

Chronic Kidney Disease (CKD) is a globally prevalent non-communicable disease with significant mortality and morbidity. It is typically associated with diabetes and hypertension; however, over the last two decades, an emergence of CKD of unknown etiology (CKDu) has claimed thousands of lives in several tropical agricultural communities. CKDu is associated with gradual loss of renal function without initial symptoms until reaching complete kidney failure and eventually death. The most impacted are young adult males of lower socio-economic strata. Since the disease progression can be successfully attenuated through early detection, the development of superior screening and management measures is of utmost importance. In contrast to the conventional biomarkers, novel biomarkers with improved sensitivity and specificity are being discussed as promising tools for early diagnosis of the disease. This review summarizes emerging novel biomarkers used in assessing CKD and discusses the current utility and diagnostic potential of such biomarkers for CKDu screening in clinical settings of different communities impacted by CKDu. Our goal is to provide a framework for practitioners in CKDu impacted regions to consider the use of these novel biomarkers through this synthesis. The increased use of these biomarkers will not only help to validate their diagnostic power further and establish potential prognostic value but may also provide critical insights into sites and mechanisms of renal damage.

Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy.

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.

CKD of Unknown Etiology (CKDu) in Sri Lanka: A Multilevel Clinical Case Definition for Surveillance and Epidemiological Studies.

Emergence of a new form of chronic kidney disease (CKD) of unknown etiology (CKDu) during the last 2 decades has resulted in considerable morbidity and mortality among the agricultural community residing in the north central region of Sri Lanka. A 3-level epidemiological case definition to identify CKDu in Sri Lanka was developed and published by the Ministry of Health in November 2016. The Sri Lanka Society of Nephrology (SLSON) refined the definition through a consensus of experts using a systematic approach in August 2017. An initial consultative meeting with the participation of 31 experts, including nephrology specialists, experts on primary care and epidemiology, and policy and university academics with long-standing experience in CKDu research, was held to identify the gaps in the existing definition. Following the meeting, a facilitator conducted 2 rounds of remote consultations using the Delphi method to obtain consensus of the participants on suggestions to improve the existing case definition. The process was initiated in August 2017 and was completed in April 2018 and resulted in the participants agreeing to a refined multilevel clinical case definition for CKDu to be used in surveillance and epidemiological studies. This article describes the process used and development of this new case definition for CKDu in Sri Lanka.

Kidney Diseases in Agricultural Communities: A Case Against Heat-Stress Nephropathy.

The beginning of the 21st century has seen the emergence of a new chronic tubulo-interstitial kidney disease of uncertain cause among agricultural communities in Central America and Sri Lanka. Despite many similarities in demography, presentation, clinical features, and renal histopathology in affected individuals in these regions, a toxic etiology has been considered mainly in Sri Lanka, whereas the predominant hypothesis in Central America has been that recurrent acute kidney injury (AKI) caused by heat stress leads to chronic kidney disease (CKD). This is termed the heat stress/dehydration hypothesis. This review attempts to demonstrate that there is sparse evidence for the occurrence of significant AKI among manual workers who are at high risk, and that there is little substantial evidence that an elevation of serum creatinine < 0.3 mg/dl in previously healthy people will lead to CKD even with recurrent episodes. It is also proposed that the extent of global warming over the last half-century was not sufficient to have caused a drastic change in the effects of heat stress on renal function in manual workers. Comparable chronic tubulo-interstitial kidney disease is not seen in workers exposed to heat in most tropical regions, although the disease is seen in individuals not exposed to heat stress in the affected regions. The proposed pathogenic mechanisms of heat stress causing CKD have not yet been proved in humans or demonstrated in workers at risk. It is believed that claims of a global warming nephropathy in relation to this disease may be premature and without convincing evidence.

Novel mutation in the SLC12A3 gene in a Sri Lankan family with Gitelman syndrome & coexistent diabetes: a case report.

BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessively inherited salt-wasting tubulopathy associated with mutations in the SLC12A3 gene, which encodes for NaCl cotransporter (NCC) in the kidney. CASE PRESENTATION: In this report, we describe two siblings from a Sri Lankan non-consanguineous family presenting with hypokalaemia associated with renal potassium wasting, hypomagnesemia, hypocalciuria and hypereninemic hyperaldosteronism with normal blood pressure. Genetic testing showed that both were homozygotes for a novel missense mutation in exon 10 of the SLC12A3 gene [NM_000339.2, c.1276A > T; p.N426Y], which has not previously been reported in the literature in association with GS. Their mother was a heterozygous carrier for the same mutation. The father was not alive at the time of testing. This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS. Interestingly both siblings had young onset Diabetes with strong family history. CONCLUSION: These findings have implications in providing appropriate genetic counseling to the family with regard to the risk associated with inbreeding, the detection of carrier/presymptomatic relatives. It further expands the known spectrum of genotypic and phenotypic characteristics of Gitelman syndrome.

Arterial stiffness &Sri Lankan chronic kidney disease of unknown origin.

Chronic kidney disease (CKD) is common and independently associated with cardiovascular disease (CVD). Arterial stiffness contributes to CVD risk in CKD. In many developing countries a considerable proportion of CKD remains unexplained, termed CKDu. We assessed arterial stiffness in subjects with Sri Lankan CKDu, in matched controls without CKD and in those with defined CKD. Aortic blood pressure (BP), pulse wave velocity (PWV) and augmentation index (AIx) were assessed in 130 subjects (50 with CKDu, 45 with CKD and 35 without CKD) using the validated TensioMed™ Arteriograph monitor. Brachial and aortic BP was lower in controls than in CKDu and CKD subjects but no different between CKDu and CKD. Controls had a lower PWV compared to subjects with CKDu and CKD. Despite equivalent BP and renal dysfunction, CKDu subjects had a lower PWV than those with CKD (8.7 ± 1.5 vs. 9.9 ± 2.2 m/s, p < 0.01). Excluding diabetes accentuated the differences in PWV seen between groups (controls vs. CKDu vs. CKD: 6.7 ± 0.9 vs. 8.7 ± 1.5 vs. 10.4 ± 1.5 m/s, p < 0.001 for all). Sri Lankan CKDu is associated with less arterial stiffening than defined causes of CKD. Whether this translates to lower cardiovascular morbidity and mortality long term is unclear and should be the focus of future studies.