Chronic kidney disease of unknown etiology and the effect of multiple-ion interactions.

High incidence of chronic kidney disease of unknown etiology (CKDU) prevalent in many countries (e.g., Sri Lanka, equatorial America) is reviewed in the context of recent experimental work and using our understanding of the hydration of ions and proteins. Qualitative considerations based on Hofmeister-type action of these ions, as well as quantitative electrochemical models for the Gibbs free energy change for ionpair formation, are used to explain why (1) fluoride and water hardness due to magnesium ions (but not due to calcium ions) and similarly (2) cadmium ions in the presence of suitable pairing ions can be expected to be more nephrotoxic, while arsenite in the presence of fluoride and hardness may be expected to be less nephrotoxic. No synergy of arsenic with calcium hardness is found. The analysis is applied to a variety of ionic species that may be found in typical water sources to predict their likely combined electrochemical action. These results clarify the origins of chronic kidney disease that has reached epidemic proportions in the North Central Province of Sri Lanka as being most likely due to the joint presence of fluoride and magnesium ions in drinking water. The conclusion is further strengthened by a study of the dietary load of Cd and other toxins in the affected regions and in the healthy regions where the dietary toxin loads and lifestyles are similar, and found to be safe especially when the mitigating effects of micronutrient ionic forms of Zn, Se, as well as corrections for bioavailability are taken into account. The resulting etiological picture is consistent with the views of most workers in the field who have suspected that fluoride and other ions found in the hard water stagnant in shallow household wells were the major causative factors of the disease. Similar incidence of CKDu found in other hot tropical climates is likely to have similar origins.