International Journal of Scientific and Technical Research in Engineering (IJSTRE) www.ijstre.com Volume 3 Issue 2 ǁ March 2018. A comprehensive review of Chronic Kidney Disease of Unknown Etiology Adoni Fernando1, Nivethika Sivakumaran1* 1(Undergraduate Department of Biomedical Science, International College of Business and Technology, No. 36, De Kretser Place, Bambalapitiya, Sri Lanka) ABSTRACT : This review was written to provide a comprehensive summary of the suggested etiologies of Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka. In this review, Chronic Kidney Disease (CKD) is explained in detail and its known etiologies are discussed. CKDu is defined and its epidemiology is discussed, with the compilation of statistic from over 15 research papers through the years 2000 to present. KEYWORDS: Chronic agrochemical nephrology, Chronic Kidney Disease, Chronic Kidney Disease of multifactorial origin, Chronic Kidney Disease of unknown etiology, Chronic interstitial nephritis of agricultural communities ABBREVIATIONS: CKDu: Chronic kidney disease of unknown etiology, CKD: Chronic Kidney Disease, CKDmfo: Chronic Kidney Disease of multifactorial origin, CINAC: Chronic Interstitial Nephritis in Agricultural Communities, NCP: North Central Province (of Sri Lanka), CRF: Chronic Renal Failure, CRD- Chronic Renal Disease, GFR- Glomerular Filtration Rate, NFK- National Kidney Foundation (USA), KDQOI- Kidney Disease Quality Outcome Initiative, ESRD- End Stage Renal Disease, BMI- Body Mass Index, NSAID- Non Steroidal Anti Inflammatory Drug, DDT- Dichlorodiphenyltrichloroethane, Cd- Cadmium, Pb- Lead, U- Uranium, N- Nitrogen, K- Potassium I. INTRODUCTION Chronic kidney disease (CKD) is defined as kidney damage or a decreased glomerular filtration rate. CKD is characterized by progressive destruction of renal mass, with irreversible sclerosis and loss of nephrons over a period of time, depending on the underlying etiology. Diabetes, hypertension and different forms of glomerular nephritis are known etiologies of CKD [1]. The rising prevalence of non-infectious diseases such as diabetes mellitus and hypertension suggests that CKD incidence will continue to rise [2]. Over the last two decades, the epidemic of a new strain of CKD of unknown etiology in rural farming communities of Sri Lanka, has elevated the concern of the disease. This new strain has been observed to be endemic in agricultural and rural regions. CKDu may also be referred to as CKD of multifactorial origin (CKDmfo), chronic agrochemical nephrology (CAN) or chronic interstitial nephritis of agricultural communities (CINAC) [3]. The disease is prevalent especially in the North Central Province (NCP). It is observed in mainly the dry regions that may utilize irrigation methods for farming. It disproportionately affects males of poor socio-economic background and workers of paddy farming [4, 5]. In Sri Lanka there is an estimated affected population of 400,000 people and death toll of around 20,000 people. CKDu is not exclusive to Sri Lanka, and many cases of CKD of unknown etiology have been reported in different parts of the world; e.g., Costa Rica [6], India [7], Egypt [8], Nicaragua [9], and more. However, in Sri Lanka, there is limited knowledge on the exact prevalence and geographical distribution of CKDu at this time. Even with the suggestion of many etiologies, the limited supporting evidence means that the exact cause of the disease is still unknown. Water contamination is a popular suggestion, but the evidence supporting the claim is insufficient. The role of environmental exposure to high concentrations of nephrotoxicants (such as, Cd, Pb, and U), which may accumulate and cause functional and structural damage in renal tissue, is a weighty hypothesis Manuscript id. 631855358 www.ijstre.com Page 38 A comprehensive review of Chronic Kidney Disease of Unknown Etiology [10]. Farming and the use of fertilizer or other agrochemicals are also considered risk factors [11, 12]. High levels of as exposure is also suggested to be an etiological factor in CKDu [13]. Water used for consumption is thought to be a major source of contaminants that lead to CKD. The contaminants may seep into water from the natural environment (geological sources), but the intensive use of agrochemicals to increase the production of agricultural resources is also a significant possibility of water contamination. The local water bodies may be polluted with seepage from irrigation or farming, especially those that lay close to fields used for cultivation. A systematic assessment of water quality is therefore needed, in order to understand risk related to exposure and assess the potential health effects [14]. This review attempts to provide a comprehensive understanding of CKDu and its prevalence in Sri Lanka. It attempts to document the possible etiologies of CKDu, put forward by research throughout the year 1997 to present. The endemic regions in North Western Province of Sri Lanka is shown in Fig.1. Polpithigama is identified as a high risk geographic area for CKDu (Screening Guidelines Chronic Kidney Disease Sri Lanka 2017 Epidemiology Unit Ministry of Health, 2017). Nikawewa has a high prevalence of the disease and has two specialized nephrology units, catering to CKD patients. Figure 1. Nephrology units and satellite clinics for kidney diseases in Sri Lanka (Daily News, 2017) II. CHRONIC KIDNEY DISEASE Chronic Kidney Disease is recognized as a global public health problem. The disease is coined from the kidneys functions progressively diminishing over time due to the progressive damage of the renal mass. CKD is also known as Chronic Renal Failure (CRF), Chronic Renal Disease (CRD) and Chronic Kidney Failure (CKF). CKD can be defined as structural or functional anomalies of the kidneys or a decreased glomerular filtration rate (GFR), persisting for a period of three months, (<60 ml/min or 1.73 m2). Manuscript id. 631855358 www.ijstre.com Page 39 A comprehensive review of Chronic Kidney Disease of Unknown Etiology 2.1. Functions of the kidneys The main functions of the kidneys are; filtration of waste products and excess water from blood to be excreted through urine, regulation of blood pressure, production of erythropoietin (important for formation of red blood cells, and maintaining balance of salts and chemicals in bloodstream at the right level(NFK, www.kidney.org). CKD is a slowly progressing disease, and often goes unnoticed and underdiagnosed. It is usually asymptomatic until histopathological features such as tubulointestitial fibrosis and tubular atrophy, observed in renal biopsies. Usually when the signs and symptoms manifest, the disease has reached to a severity, for which the cure is a kidney transplant, without which there is a 100% mortality rate. The conditions of a CKD patient irreversibly worsen over time. 2.2. Stages of CKD CKD is diagnosed based on definition of the Kidney Disease Quality Outcome Initiative (KDQOI) of the National Kidney Foundation (NFK). The functional damage of kidneys can be assessed by GFR, and the disease can be classified into 5 stages such as, stage 1: Kidney damage with normal or increased GFR (>90 mL/min /1.73 m2), stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2), stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2), stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2), and stage 5: Kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis). CKD is usually detected when the kidneys function drops to 25% of normal kidney function, whereas symptoms appear when the function plummets to 1/10th of the normal level. Each kidney has approximately one million nephrons, the functional unit of kidney, which filter wastes from the body. The human body can maintain the normal GFR, even when there is a gradual destruction of the nephrons. This happens by mechanisms to compensate for the loss, such as hypertrophy of renal tissue and hyper filtration by the surviving nephrons. This occurs regardless of the underlying etiology of the CKD, and allows blood to be filtered and the plasma solutes to be cleared as it would in normal conditions. When GFR decreases to 50% of normal, the level of plasma solutes such as creatinine and urea show a significant increase. The creatinine in plasma will be approximately double that of normal, when GFR drops to 50%; i.e., when the plasma creatinine reaches 1.2 mg/dL from the baseline value of 0.6 mg/dL, it represents halving of the functional nephron mass, although it is still within the defined reference range. 2.3. Known etiologies of Chronic Kidney Disease Certain common chronic diseases can lead to chronic kidney disease. These diseases can damage the renal tissue permanently causing damage and giving rise to CKD. 2.3.1. Diabetes mellitus CKD was thought to develop as a result of diabetes and was known as "diabetic nephropathy". The elevated levels of blood glucose leads to an increased strain on the nephrons of the kidneys when filtering blood. It is estimated that moderate to severe CKD is found in 15-23% of patients that have a history of diabetes [15]. 2.3.2. Hypertension High blood pressure is a leading cause of CKD globally. Hypertension damages the blood vessels and may lead to a reduced blood flow to kidneys. The elevated pressure can also damage the nephrons assisting renal damage. More than 50% of the CKD patients suffer from hypertension (High Blood Pressure and Chronic Kidney Disease www.kidney.org National Kidney Foundation’s Kidney disease outcomes Quality initiative, n.d.). Diabetes mellitus and hypertension are the identified major etiologies of CKD. In addition, Tubulointerstitial disease has been seen to have a strong link to CKD in Sri Lanka. There has been a significant prevalence of CKD observed in toxic nephropathies due to tubulointerstitial disease. There are a few identified causes of tubulointerstitial disease such as heavy metals, radiation nephritis, chronic hyperkalemia, chronic hypercalcemia, etc. [16]. Progressive kidney diseases that lead to CKD may also be caused by proteinuria, systemic hypertension, elevated nephrotoxins or decreased perfusion, smoking, uncontrolled diabetes, illegal drug abuse, physical injury, and many more.