Chronic kidney disease of unknown etiology: a disease related to global warming?

Abstract

Chronic kidney disease (CKD) is increasingly common throughout the world, largely due to the burgeoning epidemics of obesity and diabetes. Not only are diabetic nephropathy and hypertension the two most common causes of end-stage renal disease, but persons with obesity and metabolic syndrome also frequently show early signs of kidney disease well before diabetes and high blood pressure become apparent. Thus, a major focus has been on identifying the underlying mechanisms by which obesity and insulin resistance might predispose to kidney damage. While obesity and diabetes represent the “big behemoth” in the room, there are areas of the world where CKD is rocketing yet these conditions are almost absent. In Central America, for example, an epidemic of CKD is striking agricultural communities from Guatemala to Panama, with some of the hardest hit areas being in Pacifi c coastal communities in Nicaragua and El Salvador. A similar outbreak of CKD is occurring among workers in the rice paddies of northern Sri Lanka. These patients typically are not obese, do not have diabetes and have normal or only mildly elevated blood pressure. They do not show evidence of glomerular disease, as they are non-nephrotic and usually have no blood cells or cell casts in the urine sediment. Renal biopsies usually show extensive kidney scarring, primarily tubulointerstitial, and secondary glomerulosclerosis and glomerular ischemia.[1] Because these patients do not appear to have any of the common causes of CKD, their disease is often described as being of unknown etiology, or labeled for the region they live in, as in Mesoamerican nephropathy. A major effort is now under way to identify the cause of these mysterious diseases. Important discoveries related to past local CKD epidemics have stimulated interest in the possible role of toxins such as agrochemicals, pesticides, silica, or heavy metals in the current epidemics. For example, Aristolochia is now recognized as the etiologic agent for Balkan nephropathy and for Chinese herbs nephropathy. Cadmium contamination of the Jinzu River in Japan in the early 1900s was identifi ed as the cause of the outbreak of itai-itai disease, associated with CKD, proximal tubular injury and hypophosphatemic rickets. While it seems likely that toxins may be involved, our group has focused on another potential driver, which we believe is underappreciated but may play an active role, not only in these emerging epidemics, but also “under the radar” in CKD generally throughout the world. Specifi cally, there is increasing evidence that recurrent dehydration may lead to kidney damage. Evidence for such a mechanism was recently shown in mice, in which recurrent dehydration resulted in mild tubulointerstitial injury with fi brosis.[2]