Global dimensions of chronic kidney disease of unknown etiology (CKDu): a modern era environmental and/or occupational nephropathy?

Diabetes and hypertension are the predominant risk factors for chronic kidney disease (CKD) globally. Infectious diseases resulting in glomerulonephritis are also important in low-income countries [1, 2]. However, in the past two decades, a severe form of CKD has been reported in individuals without these risk factors. CKD of unknown etiology (CKDu) affects adults in their third to fifth decade and is often fatal due to disease progression and lack of dialysis or transplant options in the involved geographic areas. CKDu has been reported in Sri Lanka, several Central American countries, the state of Andhra Prakesh in India and the El-Minia Governorate in Egypt. The results of a joint Sri Lankan and World Health Organization (WHO) funded study focused on identification of risk factors for CKDu in Sri Lanka was recently published in this journal [3]. Subsequent correspondence, highlighting the range of risk factors under consideration, illustrates the complexity of this endeavor [4, 5]. Despite the comprehensive exposure assessment of Jayatilake and colleagues, and prior work in Sri Lanka and Central America, the name CKDu remains appropriate because the etiology is still unknown. Consideration of the similarities and differences in CKDu in the four regions in which it has been reported to date may be useful in the effort to determine causality and develop prevention strategies. Therefore, the table included in this manuscript compares and contrasts the currently available information on CKDu. Importantly, there is no global definition for this disease. Furthermore, levels of proteinuria and albuminuria tend to be low in Central America [6], however the case definition in Sri Lanka was based on persistent albuminuria defined as an albumin–creatinine ratio ≥30 mg/g in an initial urine sample and at a repeat visit [3]. Therefore, the data below utilize the criteria for CKDu of the authors in each publication. Given the limited information about CKDu in the affected areas, particularly in Andhra Pradesh and Egypt, it is not clear that the etiology of the kidney disease is the same in all locations. Different risk factors have been emphasized; altitude and occupational risks factors have received more attention in Central America whereas extensive chemical monitoring was recently reported in Sri Lanka [3]. Moreover, case ascertainment in Sri Lanka has relied much more on proteinuria whereas, in Central America, both urine dipstick and serum creatinine have been used in case identification. Data on magnitude remains extremely limited. However, as shown in the table, a number of similarities are present. The disease is characterized by substantial morbidity and mortality, resulting in death in young and middle aged adult patients, and absence of known causes of CKD such as diabetes and hypertension (or at least severe hypertension as the blood pressure inclusion criteria in the Sri Lankan study was less than 160/100 [3]). Men seem to be more at risk, at least for the most severe disease, and very poor rural areas are most affected with agricultural work being the dominant occupation. Poverty with lack of access to health care makes determining clinical characteristics of CKDu difficult. Even determining when the outbreaks actually started is challenging; CKDu may have been present for a significant period of time but not identified due to absence of diagnostic testing. Furthermore, many of these areas have recently seen a transition from earlier deaths from infectious diseases to deaths from non-communicable diseases in the setting of longer life spans which provides time for CKD to develop and progress. Few studies have reported on urinary findings in CKDu patients. However, in described clinical presentations, typical patients present with a bland urine sediment and minimal proteinuria (Table 1). Recent studies have measured levels of kidney early biological effect markers in urine [7, 8]. The results are consistent with proximal tubular damage and may be useful in future work to identify CKDu at earlier stages and to determine etiology. Information on renal pathology has also been very limited to date. The two studies reporting biopsy results from patients with CKDu in El Salvador both found interstitial fibrosis with varying degrees of tubular atrophy, essentially proportional to stage of CKD. Both series also reported non-specific glomerular damage. Whether this is secondary to a primary tubulointerstitial process or represents a primary glomerular disease or could be due to recurrent ischemia of the glomerular capillaries, such as from dehydration or concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), remains unknown. Wijkstrom et al. concluded that the biopsy results from Central America did not resemble any other common kidney disease [9]. Importantly, these findings are similar to those described in CKDu from Sri Lanka [10–12]. It would be very useful to have additional information on pathology, including at earlier stages of the disease process. Table 1 Comparisons of Key Characteristics Among Areas with Reported CKDu