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Quest to identify geochemical risk factors associated with chronic kidney disease of unknown etiology (CKDu) in an endemic region of Sri Lanka—a multimedia laboratory analysis of biological, food, and environmental samples

Abstract

The emergence of a new form of chronic kidney disease of unknown etiology (CKDu) in Sri Lanka’s North Central Province (NCP) has become a catastrophic health crisis. CKDu is characterized as slowly progressing, irreversible, and asymptomatic until late stages and, importantly, not attributed to diabetes, hypertension, or other known risk factors. It is postulated that the etiology of CKDu is multifactorial, involving genetic predisposition, nutritional and dehydration status, exposure to one or more environmental nephrotoxins, and lifestyle factors. The objective of this limited geochemical laboratory analysis was to determine the concentration of a suite of heavy metals and trace element nutrients in biological samples (human whole blood and hair) and environmental samples (drinking water, rice, soil, and freshwater fish) collected from two towns within the endemic NCP region in 2012 and 2013. This broad panel, metallomics/mineralomics approach was used to shed light on potential geochemical risk factors associated with CKDu. Based on prior literature documentation of potential nephrotoxins that may play a role in the genesis and progression of CKDu, heavy metals and fluoride were selected for analysis. The geochemical concentrations in biological and environmental media areas were quantified. Basic statistical measurements were subsequently used to compare media against applicable benchmark values, such as US soil screening levels. Cadmium, lead, and mercury were detected at concentrations exceeding US reference values in many of the biological samples, suggesting that study participants are subjected to chronic, low-level exposure to these elements. Within the limited number of environmental media samples, arsenic was determined to exceed initial risk screening and background concentration values in soil, while data collected from drinking water samples reflected the unique hydrogeochemistry of the region, including the prevalence of hard or very hard water, and fluoride, iron, manganese, sodium, and lead exceeding applicable drinking water standards in some instances. Current literature suggests that the etiology of CKDu is likely multifactorial, with no single biological or hydrogeochemical parameter directly related to disease genesis and progression. This preliminary screening identified that specific constituents may be present above levels of concern, but does not compare results against specific kidney toxicity values or cumulative risk related to a multifactorial disease process. The data collected from this limited investigation are intended to be used in the subsequent study design of a comprehensive and multifactorial etiological study of CKDu risk factors that includes sample collection, individual surveys, and laboratory analyses to more fully evaluate the potential environmental, behavioral, genetic, and lifestyle risk factors associated with CKDu.

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References

  1. Abid, S., Hassen, W., Achour, A., Skhiri, H., Maaroufi, K., Ellouz, F., et al. (2003). Ochratoxin A and human chronic nephropathy in Tunisia: is the situation endemic? Human and Experimental Toxicology, 22, 77–84.

  2. Agarwal, S. K. (2005). Chronic kidney disease and its prevention in India. Kidney International, 68, S41–S25.

  3. Allinson, G., Nishikawa, M., Silva, S. S. D., Laurenson, L. J. B., & Silva, K. D.. (2002). Obervations on metal concentrations in tilapia (Oreochromis mossambicus) in reservoirs of South Sri Lanka. Ecotoxicology and Environmental Safety, 51.

  4. Allinson, G., Salzman, S. A., Turoczy, N., Nishikawa, M., Amarasinghe, U. S., Nirbadha, K. G. S., et al. (2009). Trace metal concentrations in Nile tilapia (Oreochromis noloticus) in three catchments, Sri Lanka. Bulletin of Environmental Contamination and Toxicology, 82, 389–394.

  5. Andreu, V., & Gimeno-Garcia, E. (1999). Evolution of heavy metals in marsh areas under rice farming. Environmental Pollution, 104, 271–282.

  6. Athuraliya, N. T. C., Abeysekera, T. D. J., Amerasinghe, P. H., Kumarasiri, R., Bandara, P., Karuaratne, U., et al. (2011). Uncertain etiologies of proteinuric-chronic kidney disease. Kidney International, 80, 1212–1221.

  7. Bandara, J. M. R. S., Senevirathna, D. M. A. N., Dasanayake, D. M. R. S. B., Herath, V., Bandara, J. M. R. P., Abeysekara, T., et al. (2007). Chronic renal failure among farm families in cascade irrigation systems in Sri Lanka associated with elevated dietary cadmium levels in rice and freshwater fish (tilapia). Environmental Geochemical Health.

  8. Bandara, J. M. R. S., Wijewardena, H. V. P., Liyanege, J., Upul, M. A., & Bandara, J. M. U. A. (2010a). Chronic renal failure in Sri Lanka caused by elevated dietary cadmium: Trojan horse of the green revolution. Toxicology Letters, 198, 33–39.

  9. Bandara, J. M. R. S., Wijewardena, H. V. P., & Seneviratne, H. M. M. S. (2010b). Remediation of cadmium contaminated irrigation and drinking water: a large scale approach. Toxicology Letters, 198, 89–92.

  10. Bandara, J. M. R. S., Wijewardena, H. V. P., Bandara, Y. M. A. Y., Jayasooriya, R. G. P. T., & Rajapaksha, H. (2011). Pollution of river Mahaweli and farmlands under irrigation by cadmium from agricultural inputs leading to a chronic renal failure epidemic among farmers in NCP, Sri Lanka. Environmental Geochemistry and Health, 33, 439–453.

  11. Brooks, D. R., Ramirez-Rubio, O., & Amador, J. J. (2012). CKD in Central America: a hot issue. American Journal of Kidney Diseases, 59, 481–484.

  12. Centers for Disease Control and Prevention (CDC). (2012). Childhood Lead Poisoning Prevention Program. What do parents need to know to protect their children? http://www.cdc.gov/nceh/lead/acclpp/blood_lead_levels.htm.

  13. Centers for Disease Control and Prevention (CDC). (2015). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2015 [ http://www.cdc.gov/nchs/nhanes.htm].

  14. Chandrajith, R., Dissanayake, C. B., Ariyarathna, T., Herath, H. M. J. M. K., & Padmasiri, J. P. (2011). Dose-dependent Na and Ca in fluoride-rich drinking water—another major cause of chronic renal failure in tropical and arid regions. Science of the Total Environment, 409, 671–675.

  15. Commission report: joint FAO/WHO Food Standards Programme: Codex Committee on Contaminants in Foods 2011: CF/5 INF/1Fifth Session. The Hague, Netherlands, 21–25 March 2011.

  16. Correa-Rotter, R., Wesseling, C., & Johnson, R. J. (2014). CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy. American Journal of Kidney Diseases, in press.

  17. Cusumano, A. M., & Bedat, M. C. G. (2008). Chronic kidney disease in Latin America: time to improve screening and detection. Clinical Journal of the American Society of Nephrology, 3, 594–600.

  18. Desalegn, B., Nanayakkara, S., Harada, K. H., Hitomi, T., Chandrajith, R., Karunaratne, U., et al. (2011). Mycotoxin detection in urine samples from patients with chronic kidney disease of uncertain etiology in Sri Lanka. Bulletin of Environmental Contamination and Toxicology, 87, 6–10.

  19. Elledge, M. F., Redmon, J. H., Levine, K. E., Wickremasinghe, R. J., Wanigasariya, K. P., & Peiris-John, R. J. (2014). Chronic kidney disease of unknown etiology in Sri Lanka: quest for understanding and global implications. RTI Press: Research Brief.

  20. Fang, Y., Yang, W., Ma, N., Xin, Z., Fu, J., Liu, X., Fang, Y., Mariqa, A. M., Zhu, X., & Hu, Q. (2014). Concentrations and health risks of lead, cadmium, arsenic, and mercury in rice and edible mushrooms in China. Food Chemistry, 147, 147–151.

  21. Garcia-Garcia, G., Gutierrez-Padilla, A. J., Chavez-Iniguez, J., Perez-Gomez, H. R., Mendoza-Garcia, M., Pena, M. d. M. G.-D. l., et al. (2013). Identifying undetected cases of chronic kidney disease in Mexico. Targeting high-risk populations. Archives of Medical Research, 44, 623–627.

  22. Garcia-Trabanino, R., Dominguez, J., Jansa, J. M., & Oliver, A. (2005). Proteinuria and chronic renal failure in the coast of El Salvador. Nefrología, 25, 30–36.

  23. Gorry, C. (2013). Sounding the alarm on chronic kidney disease in farming communities: Maria Isabel Rodriguez MD, Minister of Health, El Salvador. MEDICC Review, 15, 8–10.

  24. Gutierrez-Amavizca, B. E., Orozco-Castellanos, R., Ortiz-Orozco, R., Padilla-Gutierrez, J., Valle, Y., Gutierrez-Gutierrez, N., et al. (2013). Contribution of GSTM1, GSTT1, and MTHFR polymorphisms to end-stage renal disease of unknown etiology in Mexicans. Indian Journal of Nephrology, 23, 438–443.

  25. Huang, Z., Xiao-Dong, P., Wu, P. G., Han, J. L., & Chen, Q. (2013). Health risk assessment of heavy metals in rice to the population in Zhejiang, China. PloS One, 8(9), e75007.

  26. Illeperuma, O. A., Dharmagunawardhane, H. A., & Herarh, K. P. R. P. (2009). Dissolution of aluminum from substandard utensils under high fluoride stress: a possible risk factor for chronic renal failures in the North Central Province. Journal of the National Science Foundation of Sri Lanka, 37, 219–222.

  27. Jankovic, S., Bukvic, D., Marinkovic, J., Jankovic, J., Maric, I., & Djukanovic, L. (2011). Time trends in Balkan endemic nephropathy incidence in the most affected region in Serbia, 1977-2009: the disease has not yet disappeared. Nephrology, Dialysis, Transplantation, 26, 3171–3176.

  28. Järup, L. (2002). Cadmium overload and toxicity. Nephrology, Dialysis, Transplantation, 17(Supp; 2), 35–39.

  29. Jayasekara, J. M. K. B., Dissanayake, D. M., Gunaratne, M. D. N., Sivakanesan, R., & Dissanayake, D. M. T. S. (2013). Prevalence of G6PD deficiency in patients with chronic kidney disease of unknown origin in North Central Region of Sri Lanka: case control study. International Journal of Recent Scientific Research, 4, 455–458.

  30. Jayasumana, M. A. C. S., Paranagama, P. A., Amarsinghe, M. D., Wijewardane, K. M. R. C., Dahanayake, K. S., Fonskea, S. I., et al. (2013). Possible link of chronic arsenic toxicity with chronic kideny disease of unknown etiology in Sri Lanka. Journal of Natural Science Research, 3, 64–73.

  31. Jayasumana, C., Gunatilake, S., & Senanayake, P. (2014). Glyophosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka. International Journal of Environmental Research and Public Health, 11, 2125–2147.

  32. Jayatilake, N., Mendis, S., Maheepala, P., & Mehta, F. R. (2013). Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country. BMC Nephrology, 14, 180–193.

  33. Jayawardana, S.. (2013). ‘Safe limit’ for arsenic. A horrendous myth—GMOA President. The Nation, p. 3.

  34. Jha, V. (2010). Herbal medicines and chronic kidney disease. Nephrology, 15, 10–17.

  35. Kobayashi, E., Suwazono, Y., Dochi, M., Honda, R., & Kido, T. (2009a). Estimation of benchmark rice cadmium doses as threshold values for abnormal urinary findings with adjustment for consumption of Jinzu River water. Bulletin of Environmental Contamination and Toxicology, 83, 102–107.

  36. Kobayashi, E., Suwazono, Y., Dochi, M., Honda, R., & Kido, T. (2009b). Influence of consumption of cadmium-polluted rice or Jinzu river water occurrence of renal tubular dysfunction and/or Itai-Itai disease. Biological Trace Element Research, 127, 257–268.

  37. Laux, T. S., Bert, P. J., Ruiz, G. M. B., Gonzalez, M., Unruh, M., Aragon, A., et al. (2012). Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village. Journal of Nephrology, 25, 533–540.

  38. Long, D. T., Icopini, G., Ganev, V., Petropoulous, E., Havezov, I., Voice, T., et al. (2001). Geochemistry of Bulgarian soils in villages affected and not affected by Balkan endemic nephropathy: a pilot study. International Journal of Occupational Medicine and Environmental Health, 14, 193–195.

  39. McDowell, M. A., Dillon, C., Osterloh, J., Bolger, P. M., Pellizzari, E. D., Montes de Oca, R. M., et al. (2004). Hair mercury levels in U.S. children and women of childbearing age: reference data from NHANES 1999-2000. Environmental Health Perspectives, 112(11), 1165–1171.

  40. Mittal, S., Kher, V., Gulati, S., Agarwal, L. K., & Arora, P. (1997). Chronic renal failure in India. Renal Failure, 19(6), 763–770.

  41. Nanayakkara, S., Komiya, T., Ratnatunga, N., Senevirathna, S. T. M. L. D., Harada, K. H., Hitomi, T., et al. (2012a). Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka. Environmental Health and Preventive Medicine, 17, 213–221.

  42. Nanayakkara, S., Senevirathna, S. T. M. L. D., Karunaratne, U., Chandrajith, R., Harada, K. H., Hitomi, T., et al. (2012b). Evidence of tubular damage in the very early stage of chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka: a cross-sectional study. Environmental Health and Preventative Medicine, 17(109–117).

  43. Nanayakkara, S., Senevirathna, S. T. M. L. D., Abeysekera, T., Chandrajith, R., Ratnatunga, N., Gunarathne, E. D. L., et al. (2014). An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the North Central Region of Sri Lanka. Journal of Occupational Health.

  44. National Toxicology Program, National Institute of Environmental Health Sciences (2012). NTP monograph on health-effects of low-level lead. NIH Publication No. 12–5996. ISSN 2330–1279.

  45. Nordberg, G., Jin, Y., Bernard, A., Fierens, S., Buchet, J. P., Ye, T., et al. (2002). Low bone density and renal dysfunction following cadmium exposure in China. AMBIO(31), 478–481.

  46. O’Donnell, J. K., Tobey, M., Weiner, D. E., Stevens, L. A., Johnson, S., Stringham, P., et al. (2011). Prevalence of and risk factors for chronic kidney disease in rural Nicaragua. Nephrology, Dialysis, Transplantation, 26, 2798–2805.

  47. Occupational Safety and Health Administration, United States Department of Labor (2004). Cadmium. OSHA 3136-06R.

  48. Orantes, C. M., Herrera, R., Almaguer, M., Brizuela, E. G., Hernandez, C. E., Bayarre, H., et al. (2011). Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: Nefrolempa study, 2009. MEDICC Review, 13, 14–22.

  49. Peiris-John, R. J., Wanigasuriya, J. K. P., Wickremasinghe, A. R., Dissanayake, W. P., & Hittarage, A. (2006). Exposure to acetylcholinesterase-inhibiting pesticides and chronic renal failure. Ceylon Medical Journal, 51, 42–43.

  50. Peraza, S., Wesseling, C., Aragon, A., Leiva, R., Garcia-Trabanino, R. A., Torres, C., et al. (2012). Decreased kidney function among agricultural workers in El Salvador. American Journal of Kidney Diseases, 59, 531–540.

  51. Premarathna, H. M. P. L., Hettiarachchi, G. M., & Indrarathne, S. P. (2011). Trace metal concentration in crops and soils collected from intensively cultivated areas of Sri Lanka. Pedologist, 230–240.

  52. Rajapurkar, M. M., John, G. T., Kirpalani, A. L., Abraham, G., Agarwal, S. K., Alemeda, A. F., et al. (2012). What do we know about chronic kidney disease in India: first report of the Indian CKD registry. BMC Nephrology, 13, 10–18.

  53. Redmon, J. H., Elledge, M. F., Womack, D. S., Wickremasinghe, R., Wanigasuriya, K., Peiris-John, R. J., et al. (2014). Additional perspectives on chronic kidney disease of unknown etiology (CKDu) in Sri Lanka—lessons learned from the WHO CKDu population prevalence study. BMC Nephrology, 15, 125–135.

  54. Remuzzi, G., & Horton, R. (2013). Acute renal failure: an unacceptable death sentence globally. The Lancet, 382, 2041–2042.

  55. Roncal-Jimenez, C., Lanaspa, M.,. A., Jensen, T., Sanchez-Lozada, L.,. G., & Johnson, R.,. J. (2015). Mechanisms by which dehydration may lead to chronic kidney disease. Annals of Nutrition & Metabolism, 66(suppl 3), 10–13.

  56. Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: heavy metal nephrotoxicity. Nefrología, 32, 279–286.

  57. Senevirathna, L., Abeysekera, T., Nanayakkara, S., Chandrajith, R., Ratnatunga, N., Harada, K. H., et al. (2012). Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: a cohort study in Medawachchiya, Sri Lanka. Environmental Health and Preventive Medicine, 17, 191–198.

  58. Siddarth, M., Datta, S. K., Ahmed, R. S., Banerjee, B. D., Kalra, O. P., & Tripathi, A. K. (2013). Association of CYP1A1 gene polymorphism with chronic kidney disease: a case control study. Environmental Toxicology and Pharmacology, 36, 164–170.

  59. Siddarth, M., Datta, S. K., Mustafa, M. D., Ahmed, R. S., Banerjee, B. D., Kalra, O. P., et al. (2014). Increased level of organochlorine pesticides in chronic kidney disease patients of unknown etiology: role of GSTM1/GSTT1 polymorphism. Chemosphere, 96, 174–179.

  60. Soderland, P., Lovekar, S., Weiner, D. E., Brooks, D. R., & Kaufman, J. S. (2010). Chronic kidney disease associated with environmental toxins and exposures. Advances in Chronic Kidney Disease, 16, 254–264.

  61. Torres, C., Aragon, A., Gonzalez, M., Lopez, I., Jakobsson, K., Elinder, C.-G., et al. (2010). Decreased kidney function of unknown cause in Nicaragua: a community-based survey. American Journal of Kidney Diseases, 55, 485–496.

  62. United States Environmental Protection Agency (U.S. EPA). (2015). Regional screening levels (RSLs)—generic tables. Risk assessment. Retrieved from http://www.epa.gov/risk/regional-screening-levels-rsls-generic-tables-november-2015.

  63. United States Environmental Protection Agency (U.S. EPA). (2016a). Secondary drinking water standards: guidance for nuisance chemicals. Drinking water contaminants—standards and regulations. Retrieved from https://www.epa.gov/dwstandardsregulations/secondary-drinking-water-standards-guidance-nuisance-chemicals.

  64. United States Environmental Protection Agency (U.S. EPA). (2016b). Table of regulated drinking water contaminants. Your drinking water. Retrieved from http://www.epa.gov/your-drinking-water/table-regulated-drinking-water-contaminants.

  65. United States Geological Survey (USGS). (2013). Geochemical and mineralogical data for soils of the conterminous United States. Retrieved from Reston, VA: http://pubs.usgs.gov/ds/801/pdf/ds801.pdf.

  66. Wang, M. Y., Chen, A. K., Wong, M. H., Qiu, R. L., Cheng, H., & Ye, Z. H. (2011). Cadmium accumulation in and tolerance of rice (Oryza sativa L.) varieties with different rates of radial oxygen loss. Environmental Pollution, 159, 1730–1736.

  67. Wanigasuriya, K. (2012). Aetiological factors of chronic kidney disease in the North Central Province of Sri Lanka: a review of the evidence to-date. Journal of the College of Community Physicians of Sri Lanka, 17, 15–20.

  68. Wanigasuriya, K. P., Peiris-John, R. J., Wickremasinghe, R., & Hittarage, A. (2007). Chronic renal failure in North Central Province of Sri Lanka: an environmentally induced disease. Transactions of the Royal Society of Tropical Medicine and Hygiene, 101, 1013–1017.

  69. Wanigasuriya, K. P., Peiris, H., Ileperuma, N., Peiris-John, R. J., & Wickremasinghe, R. (2008). Could ochratoxin A in food commodities be the cause of chronic kidney disease in Sri Lanka? Transactions of the Royal Society of Tropical Medicine and Hygiene, 102, 726–728.

  70. Wanigasuriya, K. P., Peiris-John, R. J., & Wickremasinghe, R. (2011). Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrology, 12.

  71. Watanabe, Y., Kobayashi, E., Okubo, Y., Suwazono, Y., Kido, T., & Nogawa, K. (2002). Relationship between cadmium concentrations in rice and renal dysfunction in individual subjects of the Jinzu River basin determined using a logistic regression analysis. Toxicology, 172, 93–101.

  72. Wickremasinghe, A. R., Peiris-John, R. J., & Wanigasuriya, K. P. (2011). Chronic kidney disease of unknown aetiology in the North Central Province of Sri Lanka: trying to unravel the mystery. Ceylon Medical Journal, 56, 143–145.

  73. Wijetunge, S., Ratantunga, N. V. I., Abeysekera, D. T. D. J., Wazil, A. W. M., Selvararah, M., & Ratnatunga, C. N. (2013). Retrospective analysis of renal histology in asymptomatic patients with probable chronic kidney disease of unknown aetiology in Sri Lanka. Ceylon Medical Journal, 58, 142–147.

  74. Wijkstrom, J., Leiva, R., Elinder, C. G., Leiva, S., Trujillo, Z., Trujillo, L., et al. (2013). Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America. American Journal of Kidney Diseases, 62, 909–918.

  75. World Health Organization (WHO). (2011). Guidelines for drinking-water quality. Retrieved from http://apps.who.int/iris/bitstream/10665/44584/1/9789241548151_eng.pdf.

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Acknowledgments

The authors wish to thank RTI International for providing the internal Grand Challenge research funds focusing on non-communicable diseases to allow for the drafting of this manuscript in full. We would also like to thank the following RTI employees specifically: Ms. Laura Haines for acting as the primary laboratory analyst, Ms. Ellen Bishop for reference value support, and Ms. Kibri Everett for geographic information systems support. Sample collection was supported by the University of Alabama at Birmingham, International Training and Research in Environmental and Occupational Health program, Grant Number 5 D43 TW05750, from the National Institutes of Health-Fogarty International Center (NIH-FIC).

Author information

Correspondence to Keith E. Levine or Jennifer Hoponick Redmon.

Ethics declarations

The study participant recruitment process, informed consent, and study protocol were approved by the Ethics Review Committee of the Faculty of Medicine, University of Kelaniya. Advance laboratory analyses were completed between November 2013 and March 2014 in blinded fashion with approval from the RTI Institutional Review Board.

Additional information

Keith E. Levine, Jennifer Hoponick Redmon, and Myles F. Elledge contributed equally to this work.

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Levine, K.E., Redmon, J.H., Elledge, M.F. et al. Quest to identify geochemical risk factors associated with chronic kidney disease of unknown etiology (CKDu) in an endemic region of Sri Lanka—a multimedia laboratory analysis of biological, food, and environmental samples. Environ Monit Assess 188, 548 (2016). https://doi.org/10.1007/s10661-016-5524-8

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Keywords

  • CKDu
  • Sri Lanka
  • Non-communicable disease
  • Chronic kidney disease
  • CKD of unknown etiology
  • North Central Province
  • Risk factors
  • Biological media
  • Environmental media
  • CKD of non-traditional causes
  • CKDnT
  • Geochemical
  • Regional laboratory analysis
  • Cadmium
  • Arsenic
  • Lead
  • Mercury
  • Fluoride
  • Metals