Kidney Disease Of Unknown Etiology Research Articles

Oligonephronia: another piece in the CKDu jigsaw?

Rates of chronic kidney disease of unknown etiology are high in Aguascalientes, Mexico. Kidneys of adolescents are small by ultrasonography, compatible with oligonephronia, whereas proteinuria and higher estimated glomerular filtration rates and blood pressures among those with relatively higher kidney volumes probably flag relatively greater degrees of compensatory hypertrophy. Glomerulomegaly and podocytopathy, and later segmental glomerulosclerosis in biopsies, suggest a cascade driven by nephron deficiency. Better measures of glomerular number and volume should improve understanding, facilitate risk assessment, and guide interventions.

Comment on “Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka”

Comment on “Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka”

Response to Comment on “Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka”

Response to Comment on “Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka”

Rebuttal to Comment on “Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka”

Rebuttal to Comment on “Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka”

Economic Feasibility of Reverse Osmosis (RO) Water Treatment Plants: A Case Study from Dimbulagala, Polonnaruwa, Sri Lanka

Social wellbeing is strongly linked with economic feasibility when it needs to attain with the technological advancements. Installation of Reverse Osmosis (RO) water treatment plants have been considered as a promising solution to provide clean water for human consumption, especially in the areas where the CKDu (chronic kidney disease of unknown etiology) prevails. At present, over 2,000 RO treatment plants were installed in the dry zone of Sri Lanka, yet economic feasibility for operation and maintenance of RO plants has not been assessed so far. The present study was intended to identify economic feasibility of operation and maintenance of RO plants. Investigations were carried out in six community RO plants which provided drinking water for over 17,000 people which accounts for 20% of total population in Dimbulagala Divisional Secretariat over a period of 12 months. Six in-depth interviews and questionnaire survey were caried out with RO plant operators. The operational cost per production of cubic meter of filtered water was computed by considering electricity consumption bills. The maintenance costs and service charges were also obtained from the records available with RO plant operators. The results found that the average electricity consumption to produce 1 cube of filtered water is approximately 9kWh and cost is LKR 734 (based on 2021 rates). The average water selling price ranged between LKR 1.00-2.50 per liter. The average monthly income generation from one RO plant is approximately between LKR 561- 875 per cube of filtered water and it largely depended on the type of water source, climatic conditions. It was found that the income generated from RO plants was sufficient enough to cover the operation cost (monthly electricity bill) and for the subsequent maintenance and service charges whenever required. It can be concluded that the use of RO treated water is an economically viable option to provide portable drinking water. 
 Keywords: CKDu, Economic sustainability, Drinking water, Purification cost

Seasonal sensitivity of groundwater dissolved organic matter in recognition of chronic kidney disease of unknown etiology: Optical and molecular perspectives

Chronic kidney disease of unknown etiology (CKDu) has aroused a great concern due to its widespread prevalence in many developing countries. Dissolved organic matter (DOM) has been proved to be associated with CKDu in groundwater. However, the responses of their association to abiotic influencing factors like seasonal variation are not carefully disclosed. Herein, we revealed the seasonal variation of DOM in CKDu related groundwater (CKDu groundwater) and control group (non-CKDu groundwater) collected from Sri Lanka during the dry and wet seasons by excitation-emission matrix spectroscopy and Fourier transform ion cyclotron resonance mass spectrometry. In both CKDu and non-CKDu groundwaters, the input of exogenous DOM during wet season improved the degree of humification and molecular weight of DOM, while oxidative processes during the dry season increased the ratios of oxygen to carbon (O/C). Furthermore, compared with non-CKDu groundwater, more DOM with high O/C enriched in CKDu groundwater during the dry season, indicating stronger oxidative processes in CKDu groundwater. It may result in the enrichment of carboxyl group and induce the enhanced leaching of CKDu-related Si and F−. The receiver operating characteristic (ROC) analysis showed that the CKDu-recognition ability of most optical and molecular indicators was susceptible to seasonal factors and their recognition abilities were stronger in the wet season. The linkage between DOM and CKDu was affected by seasonal factors through the occurrence, mobility, degradation, and toxicity of typical organic molecules (e.g., C17H18O10S). The study provides a new insight into screening pathogenic factors of other endemic diseases related to organic molecules.

Intranasal Administration of Sugarcane Ash Causes Chronic Kidney Disease in Rats.

Background. Silica nanoparticles found in sugarcane ash have been postulated to be a toxicant contributing to chronic kidney disease of unknown etiology (CKDu). However, while the administration of manufactured silica nanoparticles is known to cause chronic tubulointerstitial disease in rats, the effect of administering sugarcane ash on kidney pathology remains unknown. Here we investigate whether sugarcane ash can induce CKD in rats. Methods. Sugarcane ash was administered for 13 weeks into the nares of rats (5 mg/day for 5d/week), and blood, urine and kidney tissues were collected at 13 weeks (at the end of ash administration) and in a separate group of rats at 24 weeks (11 weeks after stopping ash administration). Kidney histology was evaluated, and inflammation and fibrosis (collagen deposition) measured. Results. Sugarcane ash exposure led to the accumulation of silica in the kidneys, lungs, liver and spleen of rats. Mild proteinuria developed although renal function was largely maintained. However, biopsies showed focal glomeruli with segmental glomerulosclerosis, and tubulointerstitial inflammation and fibrosis that tended to worsen even after the ash administration had been stopped. Staining for the lysosomal marker, LAMP-1, showed decreased staining in ash administered rats consistent with lysosomal activation. Conclusion. Sugarcane ash containing silica nanoparticles can cause CKD in rats.

A pragmatic approach to selective genetic testing in kidney transplant candidates

IntroductionAdvances in the field of genetic testing have spurred its use in transplantation. Potential benefits of genetic testing in transplant nephrology include diagnosis, treatment, risk stratification of recurrent disease, and risk stratification in potential donors. However, it is unclear how to best apply genetic testing in this population to maximize its yield. We describe our transplant center's approach to selective genetic testing as part of kidney transplant candidate and donor evaluation.MethodsTransplant recipient candidates were tested if they had a history of ESRD at age <50, primary FSGS, complement-mediated or unknown etiology of kidney disease, or had a family history of kidney disease. Donors were tested if age <35, were related to their potential recipients with known genetic susceptibility or had a first-degree relative with a history of kidney disease of unknown etiology. A targeted NGS gene panel of 385 genes was used. Clinical implications and downstream effects were monitored.ResultsOver 30% of recipients tested within the established criteria were positive for a pathogenic variant. The most common pathogenic variants were APOL1 high-risk genotypes as well as collagen 4-alpha-3, -4 and -5. Donor testing done according to our inclusion criteria resulted in about 12% yield. Positive test results in recipients helped with stratification of the risk of recurrent disease. Positive test results in potential donors guided informed decisions on when not to move forward with a donation.DiscussionIntegrating targeted panel genetic testing into a kidney transplant clinic in conjunction with a selective criteria for testing donors and recipients ensured a reasonable diagnostic yield. The results had implications on clinical management, risk stratification and in some cases were instrumental in directing downstream changes including when to stop the evaluation process. Given the impact on management and transplant decisions, we advocate for the widespread use of genetic testing in selected individuals undergoing transplant evaluation and donation who meet pre-defined criteria.

Growth Hormone Receptor and PCSK9 Define a New Paradigm in the Initiation and Development of Chronic Kidney Disease as Revealed by Exome Sequencing on Illumina Platform

Chronic kidney disease is a combination of many vascular diseases involving mutations of many genes. Hypertension diabetes and atherosclerosis are the most common causes of kidney disease, with hypertension causing just over a quarter of all cases of kidney failure and diabetes causing one-third of them. Other much less common conditions that can cause CKD include inflammation, infections, genetic factors, or longstanding blockage to the urinary system (such as enlarged prostate or kidney stones). In many cases, the causes remained unknown, albeit the manifestation of the diseases with clear phenotypes and biochemical profiles. Heredity and genetic determinants play major roles in the initiation, development, and establishment of CKD. Kidney disease phenotypes can be dissected into many underlying causing candidates’ genes and many molecular genetics approaches are striving to lift the veil on this nagging disease. Recent studies using genetic testing have demonstrated that Mendelian etiologies account for approximately 20% of cases of kidney disease of unknown etiology. CKD is known to be plagued with many genes mutations like mutation in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and mutations in MYH9 and APOL1 genes, COL4A3, COL4A4, and COL4A5 genes playing important roles in the CKD picture. Genetic testing has modernized and revolutionized many areas of medical practices and diagnosis of many diseases and the field of nephrology is not an exception. The advance in Next-generation Sequencing, including whole exome sequencing has proven to be a powerful tool in personalized medicine and for potential noninvasive decryption for biomarkers in kidney disease thereby paving the way for better diagnostic purposes. In this regard, we run whole exome sequencing on whole blood genomic DNA from CKD patients. Bioinformatics analysis led us to uncover a total of more than 3000 single nucleotide polymorphisms (SNPs). To sort out these flurries of targeted SNPs, we undertook filtration using an R-algorithm in combination with the diseases association Clinvar database. This approach led us to 12 combined diagnostic missense variants scattered on different chromosomes. Combined missense reduction after FDR filtration with a Cellrate of 0.75 generated two missense variants located on PCSK9 and GHR genes on chromosomes 1 and 5 and lastly, reduction variants after Filtration by spliced region bring us to a single SNP located on the PCSK9 gene.

Efficacy of Reverse Osmosis in Reducing Chronic Kidney Disease of Unknown Etiology in Sri Lanka: A Narrative Review 

There has been an epidemic of Chronic Kidney Disease of Unknown Etiology (CKDu) affecting the agricultural communities in Sri Lanka, spanning three decades. The main pathological finding has been chronic interstitial nephritis. This narrative review focuses on the efficacy of Reverse Osmosis (RO) technology in purifying water and its impact in reducing CKDu. PubMed, Cochrane and Google Scholar were used to search for peer-reviewed articles from 2000 to 2023. The themes that emerged from the literature review were validated through the opinions of key informants and subject matter experts.There were anecdotal, as well as some research evidence to indicate that RO-treated water is efficacious in preventing and slowing down the progression of CKDu. This relationship needs further investigation with well-designed prospective studies. The literature review also revealed many social, technical and environmental issues related to the use of RO machines. Despite the potential benefits of RO machines, these issues must be resolved in order to prevent serious problems in the future.In conclusion, this review underscores the need for further research, interventions and regulatory measures related to the use of RO machines to reshape the CKDu trajectory in Sri Lanka.

Investigating the microcosm to illuminate the macrocosm: Creating an integrated pathway to investigate chronic kidney disease of unknown aetiology in Sri Lanka

No abstract available

Chronic kidney disease of unknown aetiology in Africa: A review of the literature.

During the last two decades, an epidemic of a severe form of chronic kidney disease (CKD) unrelated to traditional risk factors (diabetes and hypertension) has been recognized in low- to middle-income countries. CKD of unknown aetiology (CKDu) mainly affects young working-age adults, and has become as an important and devastating public health issue. CKDu is a multifactorial disease with associated genetic and environmental risk factors. This review summarizes the current epidemiological evidence on the burden of CKDu and its probable environmental risk factors contributing to CKD in Africa. PubMed/Medline and the African Journals Online databases were searched to identify relevant population-based studies published in the last two decades. In the general population, the burden of CKD attributable to CKDu varied from 19.4% to 79%. Epidemiologic studies have established that environmental factors, including genetics, infectious agents, rural residence, low socioeconomic status, malnutrition, agricultural practise and exposure to agrochemicals, heavy metals, use of traditional herbs, and contaminated water sources or food contribute to the burden of CKD in the region. There is a great need for epidemiological studies exploring the true burden of CKDu and unique geographical distribution, and the role of environmental factors in the development of CKD/CKDu.

Dilemma of chronic kidney disease of unknown origin

Over the past two decades, cumulative increases in the prevalence of chronic kidney disease (CKD) have been observed in selected geographic areas in several countries. The etiology of this CKD cannot be attributed to known or traditional causes or risk factors, and the term chronic kidney disease of unknown etiology (CKDu) has been used to describe this entity. These regional endemic nephropathies are commonly known as CKD of unidentified cause (CKDu) or CKD of nontraditional etiology (CKDnt) and, more recently, Chronic interstitial nephritis of agricultural communities (CINAC). Unlike the traditional causes of CKD (i.e., Hypertension, Diabetes, chronic glomerulonephritis, etc), CKDu has been associated with agricultural and arid regions. Also, the socioeconomic state of those regions is key. This review addresses the present status of the knowledge for different aspects of this regional health problem as well as summarizes available evidence on the risk factors, epidemiology, clinical features, diagnosis, treatment, and prevention of CKDu. It will also highlight the reasons why Africa should be concerned about this condition. Using the keywords “Africa, CKD of unknown origin,” a literature search was conducted on PubMed, Scopus, and Google Scholar, focusing on the research published between 2000 and 2022. Results from the literature show that predisposition to heat stress and dehydration, subclinical rhabdomyolysis, toxins from alcoholic beverages, agrochemicals, and heavy metals all result in acute kidney injury, and repeated exposures to these factors can then cause CKDu. Earlier studies in Sri Lanka nephropathy by Nanayakkara and his team in 2014 identified that a genetic variant of SLC13A3 (sodium-dependent dicarboxylate transporter member 3) is associated with CKDu. Later research conducted in 2015 discovered KCNA10 (a voltage-gated potassium channel) also as a gene implicated in CKDu; these genetic variances were discovered to be common among the populace suffering from kidney diseases, hence suggesting that, people with these genes have a high risk of developing kidney disease. Predisposition to heat stress and dehydration, subclinical rhabdomyolysis, and toxins from alcoholic beverages, agrochemicals, and heavy metals all results in acute kidney injury, and repeated exposures to these factors can then cause CKDu. Also, certain genes have been found to be associated with CKDu.

A Case for Amorphous Silica Nanoparticle Exposure in the Development of Chronic Kidney Disease of Unknown Etiology

A Case for Amorphous Silica Nanoparticle Exposure in the Development of Chronic Kidney Disease of Unknown Etiology

CKD is the Major Cause of Death in Uddanam: A Population-Representative Study Using Smart Verbal Autopsy

IntroductionUddanam is an agricultural area with a high burden of chronic kidney disease of unknown aetiology (CKDu). Despite reports of many deaths due to CKD in the lay press, the exact contribution of CKD to deaths remains uncertain as most deaths occur outside medical care. MethodsWe used SmartVA automated verbal autopsy (VA) tool to ascertain the cause-specific mortality fractions amongst a 2419 subject-strong general population cohort in Uddanam between 2018-2022. VA interviews were conducted twice with the family members of the deceased. ResultsA total of 133 deaths were recorded, giving a crude death rate of 5.5%, 10 times higher than that recorded in national surveys. CKD was responsible for 45% of all deaths, followed by ischemic heart disease (15%) and respiratory disease (6%). ConclusionThis study confirms CKD as the leading cause of mortality in this high CKD burden area and provides crucial data for public health decision-making and resource allocation.

Heavy metal contamination in rice, pulses, and vegetables from CKDu-endemic areas in Cuttack district, India: a health risk assessment

Introduction: Chronic kidney disease of unknown aetiology (CKDu) is an emerging public health concern in India. The present study was carried out to investigate the concentrations of potentially toxic heavy metals (Cd, Pb, Ni, Cr, Hg, and As) in locally grown food crops (rice, pulses, and vegetables) in CKDu prevalent areas of Cuttack district, India.Methods: Exposure risks from food crops were analysed, including estimated daily intake, hazard quotient, hazard index, and carcinogenic risk.Result: The overall heavy metal concentrations in the crop samples were in the following order: Pb>Ni>Cd>Cr>As>Hg. The mean concentration of heavy metals in different crops were as follows, ranked from highest to lowest: spinach, rice, okra, mustard, potato, carrot, tomato, green gram, black gram. A statistical multivariate analysis revealed that the primary sources of Cd, Pb, Ni, Cr, Hg, and As in crop samples were both natural and human activities. For lead, target hazard quotient (THQ) values in rice were greater than 1, indicating significant noncarcinogenic health risks to both adults and children.Discussion: While the majority of the crop samples had Pb levels below the permissible level (10−5), the target carcinogenic risk of Cd was higher than the USEPA threshold value (10−4), showing a cancer risk to adults and children. This study concluded that long-term intake of locally grown food crops may produce a significant health risk to the local inhabitants, and that of regular heavy metal monitoring is strongly recommended in this region.

Single and combined effect of fluoride and hardness of drinking water on nephrotoxicity: <em>in-vivo</em> study using Wistar rats as an animal model

Drinking water in areas with a high prevalence of chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka is known to have high concentrations of fluoride and hardness. The present study evaluated the individual and combined effects of water hardness and fluoride on potential nephrotoxicity, using Wistar rats as an animal model. Thirty-five Wistar rats were randomly assigned into five groups (n=7). Test groups F, H, RL, and RH were given de-ionized water containing 1.5 mg/L fluoride, 200 mg/L hardness, 1.5:200 mg/L fluoride: hardness, and 5:800 mg/L fluoride: hardness respectively, while control group C was given de-ionized water. Body weight and daily water consumption were measured. Serum creatinine, urine creatinine, and urinary biomarker KIM-1 were analyzed. Histopathological changes in the kidneys were observed. There were no significant differences in body weights (p>0.05) while daily water consumption was reduced significantly in the test groups RL and RH (p<0.05). A significant increment in serum creatinine in the RL and RH groups (p<0.05), and a significant reduction in urine creatinine in the F, H, RL and RH groups (p<0.05), were recorded compared to the control. However, the highest magnitude of the effect on serum creatinine and urine creatinine was recorded in the RL group. Significant increment in KIM-1 levels were recorded in the RH group (p<0.05) while the RH group indicated a more rapid increment from the 28th day. When considering histopathology, renal tubular changes were observed in the test groups. The individual and combined effects of water hardness and fluoride may contribute to the aetiology of CKDu in Sri Lanka. 

Screening Charity Recipients: Health Philanthropy, Medical Diagnosis, and Kidney Disease Prevention in Sri Lanka

Over the last several decades, epidemics of chronic kidney disease of unknown aetiology (CKDu) have appeared in Mesoamerica, North Africa, and South Asia. Drawing on 14 months of ethnographic fieldwork in a CKDu-affected village in Sri Lanka, I explore how one CKDu ‘hotspot’ came into being following population screening interventions by a community development organisation, a philanthropic foundation, and a university research group. While the production of test results proved vital to the mobilisation of further research and public health resources for the community, this ethnography reveals philanthropy could be seen to have shaped by screening as much as screening was seen to have influenced by philanthropy. The example of medical screening and philanthropic interventions in Ginnoruwa illustrates how bioindicators of failing kidney function became a key metric for demarcating the community into populations of the deserving (or not so deserving) poorly, which in turn helped to create the pattern of disease prevalence and concentration that led to the community being designated a ‘hotspot’. In Ginnoruwa, philanthropy and screening did not operate independently but constituted a novel hybrid, which I refer to as ‘philanthropic science’.

Concentration and Distribution of Toxic and Essential Elements in Traditional Rice Varieties of Sri Lanka Grown on an Anuradhapura District Farm.

Toxic heavy metals have been the focus of many investigations into chronic kidney disease of unknown aetiology (CKDu) within Sri Lanka. It has been hypothesised that exposure to nephrotoxic arsenic, cadmium and lead could play a role in the development of CKDu, and these metals have previously been found in unsafe concentrations in Sri Lankan rice. Traditional varieties of Sri Lankan rice remain popular due to their perceived health benefits, but their uptake of trace and toxic heavy metals remained unexplored. Here, we report a one-time, cross-sectional dataset on the concentrations of essential and toxic elements present in eleven samples of polished and unpolished traditional rice varieties, all regularly grown and sold in the Anuradhapura district, a CKDu hotspot. All rice was sourced from the same farm, with the exception of one store bought sample grown on another, unidentified farm. Cadmium concentrations varied significantly between varieties, and potentially unsafe concentrations of cadmium were detected in the store-bought sample (Suwadel, 113±13 μg kg-1). Elemental imaging of the grains revealed lead to be stored mainly in the rice bran, which is removed during polishing, while cadmium was distributed in the edible portion of the grain. Essential elements were generally higher in the traditional rice varieties than those reported for non-traditional varieties and are a potential source of trace elements for nutrient-deficient communities. The concentration of selenium, an element that plays a protective role in the kidneys, was too low to provide the minimum recommended intake. The methods developed in this study could be applied to a more comprehensive study of elemental uptake of rice under controlled growing conditions.

Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka

Glyphosate and Fluoride in High-Hardness Drinking Water Are Positively Associated with Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka