Chronic kidney disease (CKD) has become a public health concern over the last several years. It is a major problem, with some developed countries spending around 3% of their annual health-care budget on management every year (1). Before the SARS-CoV-2 pandemics, the reported prevalence at the international level was 13.4%, and around 4 to 7 million people at end-stage renal disease (ESRD) who needed replacement therapy (2).

According to the scientific community the most remarkable risk factors for CKD are diabetes and hypertension. However, some other risk factors should be taken into account such as: HIV-associated nephropathy, viral infections (dengue) or break-bone fever, malaria, leishmaniasis, leptospirosis and others (1). Research from 2015 reported that more than a million deaths, and around 19 million disabilities were related to reduced glomerular filtration rates secondary to cardiovascular diseases (1, 3, 4). Inflammation is another well-studied condition related to CKD. Some authors have described that an inflammatory stage could work as a maladaptive and uncontrolled disorder in CKD patients and is associated with cardiovascular disease (5–7).

The unknown etiology CKD has been reported as a global phenomenon including uncommon risk factors such as: dehydration, leptospirosis, heat stress, water quality and others (8). However, the number of uncommon causes of CKD has not been limited, especially due to changes in global health after the SARS-CoV-2 pandemics. Their long term effects on kidney health are not known at the moment, and several years shall pass after gaining enough knowledge about it.

In Mexico, the problem is not minor. The prevalence of albuminuria in children in some rural areas is reported to be over 40% and the frequency of deaths secondary to ESRD is near 15 per 1,000 among adult inhabitants (9). Other studies in Mexican rural areas have reported similar results (10, 11). As previously mentioned, the number of unknown ESRD causes are several but not reported at all.

This study aims to report on the non-traditional risk factors for CKD progression to ESRD using a scoping review methodology.

The methodology described by Arksey and O’Malley (12) was used performing an extensive review of the information. The literature review question was defined using key words included in MESH terms from PubMed, which was the only source for information. The key words that were included were: end-stage renal disease, end-stage kidney disease, end-stage renal failure, chronic kidney failure, chronic renal failure, non-traditional, unknown, causes, diabetes and hypertension; applying Boolean operators. The information was not limited with regard to time. The number of articles resulting from the previously mentioned key word combination was 707. Key words and number of hints are described in Supplementary Table S1.

A total of 46 manuscripts were reviewed. Selection criteria included: The English language, the full text, and quantitative observational studies (cross-sectional, case–control and cohort studies) in the adult population. Reviews, clinical trials, case reports, qualitative and studies including children were not included for review.

The review and selection of manuscripts were performed during a 4-month period by pairs. The selected manuscript was systematized in an excerpt matrix (worksheet) that included: the lead author, year and place, objective, study design, sample, variables, statistical analysis, and results. Supplementary Table S2 summarizes the characteristics of the studies included.

As diabetes and hypertension are mainly the most common ESRD risk factors, and all manuscripts which included such topics were excluded. Studies performed on children were also excluded.

As previously mentioned, diabetes mellitus and hypertension are the most common risk factors for ESRD. However, in several cases, the etiology is unknown (13–17). Globally, ESRD is a public health concern affecting people’s quality of life. In order to carry out some strategies to prevent its harmful effects on the health of young adults, all possible risk factors must be well documented. The non-traditional ESRD risk factors are depicted based on six categories.

End Stage Renal Disease is a major concern for public health at a global level. As it can be seen, non-traditional risk factors are numerous and have different etiologies. The main risk factors reported globally have already been described (diabetes and hypertension). However, risk factors should be classified according to geographical and economic conditions. CKD screening has been recommended as a cost-effective strategy in high-risk patients allowing starting early management of the prevention of progression and identification of specific conditions. These types of early actions that work as preventive medicine are considered as the key for better public health practices that provide some opportunities for improved patient access to better attention and improved outcomes (52). Screening costs may vary depending on the country. In developed countries (high income) the cost per year is estimated between 50,000 to 150,000 USD. In Mexico the cost for a basic blood and urine tests is around 25 to 250 USD (53). This type of screening is good enough to detect early kidney damage in every patient including groups of people that are looking for an annual medical checkup. In 2014, Komenda et al. reported a worldwide review regarding costs of proteinuria and glomerular filtration rate in different groups of patients including the general population, diabetics, and hypertensive patients. The reported cost was between $100,253 to $109,912 USD. The authors concluded that CKD screening is cost-effective in patients with identifiable risk factors (54).

Although there is an idea of how to counteract ESRD for these two most common causes, it is a matter of concern that in many of the studies the etiology of the disease is still not clear. Consequently, there is insufficient knowledge regarding how to contribute with a solution.

This health problem, as previously mentioned, has an impact on everyone, but specifically in Mexico there are endemic areas of the disease, such as Jalisco and Aguascalientes, which have high incidences in children, adolescents, and young adults (55, 56).

It is important for health professionals to attend to these patients from early detection since the costs in the different levels of care for kidney patients are high, aside from how significantly their quality-of-life decreases, both for patients and their family members involved in the process (57–59).

For those individuals that have been diagnosed with ESRD, it must be considered that their disease will last a lifetime, so they will have to search for some other replacement medical treatments that are currently available, such as: peritoneal dialysis, hemodialysis and transplantation (60, 61). In Mexico, those who have social security through insurance policies associated with their school or work will have access to one of the first two treatments (61). However, access to a kidney transplant will be influenced by the search for a donor by the kidney patient himself/herself, which often complicates this process, since a living donor must be found among his/her own relatives or acquaintances, instead of a search for a cadaveric donor, as is commonly done in other countries (61, 62).

In Mexico, receptor candidates for kidney transplant, need to perform a series of studies and a biopsy to determine the cause of kidney failure and the current damage to the kidney (56, 61). This practice is expensive, but it could contribute to the problem that has developed when this paper was written, in order to identify some causes that have been neglected, which are important in the development of ESRD. The public health system should propose alternatives that help to identify these factors that would undoubtedly assist in explaining a portion of this great problem (58).

Lastly, it’s important to mention the role of diagnosis before kidney transplantation. As previously mentioned, living kidney donors are at risk of ESRD (incidence 11.7 per 10,000) (50), and several times the cause can be prevented based on medical history data such as family members with diabetes, hypertension, and other CKD risk factors. Candidates to become living kidney donors must be studied in depth to avoid diabetes and other chronic causes related to kidney disease. Several reports have shown the importance of graft biopsies for prognosis in children and adults (60, 63–65). However, information about kidney biopsy as a diagnostic tool before transplantation is scarce. The same applies to medical programs that propose the probability of graft loss secondary to that of primary diseases, or other factors such as follow-ups and attachment therapy issues. In 2012, Sellarés et al. reported that non-attachment therapy was the cause of renal transplant failure in 26 of 315 patients. Antibody-mediated rejection and T cell-mediated rejection represented 18 and 9% of kidney graft failure, respectively (66). Recurrent glomerulonephritis is reported in 10 to 20% after kidney transplantation and around 50% have a graft lost. Even follow up is in long term, the cause is generally unknown and represents the third most common cause of graft failure (67). It is clear that kidney transplant programs worldwide are ambitious, and their main intention is to improve patients’ lives. However, some programs are focused on numbers only. Several kidney transplant programs must restate the way in which they will act. Public policy transfer cannot be applied in the same way in different countries. Although there are international guidelines for kidney transplant protocols (68), local guidelines must be adapted in order to improve selection criteria and to avoid short term complications and a second transplant.

The aim of this review was to find as much information as possible in order to show a general panorama of non-traditional causes for CKD progression. However, the information about the topic is extensive and dynamic. Although we have tried to be as exhaustive as possible, there are several non-traditional causes for CKD that are not included in this paper. Perhaps, the number of unknown causes of CKD is beyond the modern knowledge and ready to be studied in future reviews.

End Stage Renal Disease is an international major concern for public health. The number of deaths per year is alarming and is increasing gradually, owing to an increasing prevalence of diabetes mellitus and other cardiovascular diseases. Epidemiological transition in developing countries should be taken into account since infectious diseases, environmental exposures, and other risk factors for ERSD increase the burden of disease. This fact affects not only public health policy. In general terms, the problem has the capability to seriously affect public policy at several levels. It is necessary to put the issue on the table and add it to the public agenda in order to find multidisciplinary solutions.

DC-G and ES-D: conceptualization, project administration, and writing-original draft preparation. ES-P, RC, AR-d-A, MG-G, and RM-d-P: investigation and writing-review. ES-D: editing. All authors participated directly in the manuscript, the investigation, writing the original draft preparation, the writing of the review, and read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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