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Chronic kidney disease of undetermined aetiology: tens of thousands of premature deaths, yet too much remains unknown

Chronic kidney disease of undetermined aetiology: tens of thousands of premature deaths, yet too... INTRODUCTION Tens of thousands of working-age adults have been dying from unexplained end-stage renal disease (ESRD) in Central America and South Asia. As the cause of this chronic kidney disease (CKD) remains unknown, the condition(s) (a unified aetiopathology has not been confirmed) has been termed ‘CKD of undetermined aetiology’ (CKDu). ‘CKD of non-traditional aetiology’, ‘chronic interstitial nephritis in agricultural communities’, ‘Mesoamerican nephropathy’, ‘Sri Lankan agricultural nephropathy’ and ‘Uddanam nephropathy’ are also used, but here we use the term CKDu. The first reports of CKDu, almost 20 years ago, were based on observations of an excess of working-age adults from agricultural communities in El Salvador and Sri Lanka receiving dialysis, but without a diagnosis explaining their ESRD [1, 2]. Available population-level data now support a high prevalence of renal dysfunction in the absence of known risk factors in Central America and South Asia [3–5], but the global extent of the problem remains unclear (Figure 1). Lack of access to renal replacement therapy (RRT) in many affected areas means that death from ESRD is common. FIGURE 1 Open in new tabDownload slide Countries affected by CKDu. Countries where there is population-based evidence of CKDu (red) are in Central America (Pacific coastal regions of El Salvador and Nicaragua) and South Asia (north central Sri Lanka and northern coastal Andhra Pradesh, India). There have also been reports of CKDu (gold) in Cameroon, Costa Rica, Egypt, Guatemala, Honduras, Mexico, Panama, Saudi Arabia, Sudan, Thailand and Tunisia. FIGURE 1 Open in new tabDownload slide Countries affected by CKDu. Countries where there is population-based evidence of CKDu (red) are in Central America (Pacific coastal regions of El Salvador and Nicaragua) and South Asia (north central Sri Lanka and northern coastal Andhra Pradesh, India). There have also been reports of CKDu (gold) in Cameroon, Costa Rica, Egypt, Guatemala, Honduras, Mexico, Panama, Saudi Arabia, Sudan, Thailand and Tunisia. DEFINITION Although Kidney Disease: Improving Global Outcomes criteria can be used to identify CKD, defining CKDu is challenging, as it rests primarily on excluding the known causes of disease using clinical and biochemical criteria (as imaging and histopathology are often inaccessible) [6]. The use of the term CKDu has generally been restricted to individuals with renal impairment of unknown cause from agricultural and/or socioeconomically deprived populations with a high reported prevalence of CKD [often based on a single estimated glomerular filtration rate (eGFR) measurement] in the absence of common identifiable aetiologies (e.g. diabetes or glomerulonephritis, as evidenced by heavy proteinuria and/or hypertension). It is not typically used to describe sporadic cases of ESRD without a diagnosis in high-income countries. Even using simple criteria, identifying CKDu can be problematic, as accessing accurate eGFR testing may be difficult in many low-income settings. Furthermore, both the distribution of normal kidney function and the validity of eGFR equations developed elsewhere are unknown in many populations impacted by CKDu. CLINICAL FEATURES CKDu typically presents with asymptomatic renal impairment without associated hypertension or heavy proteinuria. Hyperuricaemia is prominent in established disease and ‘chistata’ (dysuria) is described in Central America [3]. The histological pattern is similar between regions, showing interstitial fibrosis, tubular atrophy and glomerulosclerosis, without immune complex or crystal deposition [7]. There is a male preponderance. In Central America, CKDu often (but not exclusively) affects young adult sugarcane workers [3] and the decrease in eGFR can be dramatic [8], whereas in Sri Lanka, the condition occurs more commonly in middle age [4]. Recently a febrile illness with acute kidney injury (AKI) has been reported in populations at risk of CKDu in both Sri Lanka and Nicaragua [9]. Biopsies during these episodes demonstrate a non-granulomatous acute interstitial nephritis (AIN). Although some patients with this presentation progress to chronic renal impairment, there is currently inadequate evidence that this syndrome is a necessary precursor of CKDu. AETIOLOGY Candidate causes of CKDu include metabolic responses to heat/dehydration, environmental factors (agrochemicals, metals, phyto/mycotoxins), infection and drugs/alcohol, but identifying causal factors in observational studies has proven challenging. There is currently insufficient evidence to support any single cause of disease, and an as yet overlooked factor may be responsible. The lead hypotheses are discussed below. Heat/dehydration It has been proposed that strenuous manual labour in hot conditions without adequate hydration leads to repeated tubular injury and subsequent fibrosis. Injury from heat and volume depletion could be exacerbated by myoglobin release from muscle and/or urate crystalluria, and studies have demonstrated an increase in serum creatinine across a sugarcane cutting shift [10]. However, whether these changes represent creatinine generation or excretion, are transient or sustained and/or are a marker of an underlying lack of reserve in those with pre-existing subclinical CKD is unclear. Seasonal decreases in eGFR have also been proposed to support an occupational cause of disease. However, similar annual variation in kidney function is also observed in populations not at risk of CKDu. Agrochemicals Poisoning by pesticides (e.g. organophosphates) can lead to AKI, raising the possibility of an alternative occupational cause of CKDu. Although there is evidence from the USA that those working with agrochemicals are at increased risk of ESRD, reports from Central America have found that pesticide applicators do not exhibit excess renal dysfunction [3]. Metals A number of metals have historically been responsible for clusters of CKD, but most studies of likely candidates, including cadmium, lead and arsenic, conducted in CKDu regions have not identified higher levels in those with renal dysfunction [3, 4]. Infection Reports of non-granulomatous AIN in at-risk populations raise the possibility of an infective aetiology. Studies of leptospira have demonstrated no excess seropositivity in those with renal impairment in Central America. However, other organisms of known (e.g. hantavirus) or unknown (e.g. flaviviruses) nephrotropism are endemic in areas impacted by CKDu. MANAGEMENT Avoidance of nephrotoxic drugs Although there is no evidence to support nephrotoxic drugs (non-steroidal anti-inflammatory drugs, aminoglycosides) as primary causes of CKDu, use of these agents is widespread and avoidance should be advised in those with established renal dysfunction. Allopurinol Laboratory findings in CKDu have led to the suggestion that urate lowering may be useful in ameliorating progressive renal dysfunction. There have been no clinical trials, but allopurinol has been used in affected regions. Water, rest, shade Labour conditions in areas impacted by CKDu, specifically in Central America, are often brutal. Although measures to improve work conditions are obviously to be supported, there is currently no evidence that such interventions prevent CKDu. RRT RRT provision places a huge strain on health systems in affected regions. Access remains far from universal and, anecdotally, outcomes, particularly with peritoneal dialysis in Central America, are poor. CONCLUSION CKDu leads to premature loss of life at an unprecedented scale in agricultural communities in low- and middle-income countries. Such a burden of disease is unlikely to have been neglected for so long had it been occurring in high-income settings. As the cause remains unclear, only methodologically robust studies, conducted in partnership with affected communities and local investigators, will provide data on the geographical distribution, insights into pathogenesis and a scientific basis for urgently needed preventative interventions. FUNDING B.C. reports grants from the Colt Foundation and the UK Medical Research Council. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Garcia Trabanino R , Aguilar R , Reyes Silva C et al. Nefropatía terminal en pacientes de un hospital de referencia en El Salvador . Rev Panam Salud Publica 2002 ; 12 : 202 – 206 Google Scholar Crossref Search ADS PubMed WorldCat 2 Lanerolle R , Kudalugoda Arachchi J , Nanayakkara S. Demographic characteristics of end stage renal disease in Sri Lanka . J Ceylon Coll Physicians 2000 ; 33 : 3 WorldCat 3 Correa-Rotter R , Wesseling C , Johnson RJ. CKD of unknown origin in Central America: the case for a mesoamerican nephropathy . Am J Kidney Dis 2014 ; 63 : 506 – 520 Google Scholar Crossref Search ADS PubMed WorldCat 4 Wanigasuriya K. Update on uncertain etiology of chronic kidney disease in Sri Lanka’s north-central dry zone . MEDICC Rev 2014 ; 16 : 61 – 65 Google Scholar PubMed WorldCat 5 O'Callaghan C , Shivashankar R , Anand S et al. Prevalence of and risk factors for chronic kidney disease of unknown aetiology in India: secondary data analysis of three population-based cross-sectional studies . BMJ Open 2019 (in press) WorldCat 6 Caplin B , Wang C-W , Anand S et al. The International Society of Nephrology’s International Consortium of Collaborators on Chronic Kidney Disease of Unknown Etiology: report of the working group on approaches to population-level detection strategies and recommendations for a minimum dataset . Kidney Int 2019 ; 95 : 4 – 10 Google Scholar Crossref Search ADS PubMed WorldCat 7 Wijkström J , Leiva R , Elinder CG et al. Clinical and pathological characterization of mesoamerican nephropathy: a new kidney disease in Central America . Am J Kidney Dis 2013 ; 62 : 908 – 918 Google Scholar Crossref Search ADS PubMed WorldCat 8 González-Quiroz M , Smpokou E , Silverwood R et al. Decline in kidney function among apparently healthy young adults at risk of Mesoamerican nephropathy . J Am Soc Nephrol 2018 ; 29 : 2200 – 2212 Google Scholar Crossref Search ADS PubMed WorldCat 9 Fischer RSB , Vangala C , Truong L et al. Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy . Kidney Int 2018 ; 93 : 753 – 760 Google Scholar Crossref Search ADS PubMed WorldCat 10 García-Trabanino R , Jarquín E , Wesseling C et al. Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador – a cross-shift study of workers at risk of Mesoamerican nephropathy . Environ Res 2015 ; 142 : 746 – 755 Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Chronic kidney disease of undetermined aetiology: tens of thousands of premature deaths, yet too much remains unknown

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Publisher
Oxford University Press
Copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
ISSN
0931-0509
eISSN
1460-2385
DOI
10.1093/ndt/gfz014
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See Article on Publisher Site

Abstract

INTRODUCTION Tens of thousands of working-age adults have been dying from unexplained end-stage renal disease (ESRD) in Central America and South Asia. As the cause of this chronic kidney disease (CKD) remains unknown, the condition(s) (a unified aetiopathology has not been confirmed) has been termed ‘CKD of undetermined aetiology’ (CKDu). ‘CKD of non-traditional aetiology’, ‘chronic interstitial nephritis in agricultural communities’, ‘Mesoamerican nephropathy’, ‘Sri Lankan agricultural nephropathy’ and ‘Uddanam nephropathy’ are also used, but here we use the term CKDu. The first reports of CKDu, almost 20 years ago, were based on observations of an excess of working-age adults from agricultural communities in El Salvador and Sri Lanka receiving dialysis, but without a diagnosis explaining their ESRD [1, 2]. Available population-level data now support a high prevalence of renal dysfunction in the absence of known risk factors in Central America and South Asia [3–5], but the global extent of the problem remains unclear (Figure 1). Lack of access to renal replacement therapy (RRT) in many affected areas means that death from ESRD is common. FIGURE 1 Open in new tabDownload slide Countries affected by CKDu. Countries where there is population-based evidence of CKDu (red) are in Central America (Pacific coastal regions of El Salvador and Nicaragua) and South Asia (north central Sri Lanka and northern coastal Andhra Pradesh, India). There have also been reports of CKDu (gold) in Cameroon, Costa Rica, Egypt, Guatemala, Honduras, Mexico, Panama, Saudi Arabia, Sudan, Thailand and Tunisia. FIGURE 1 Open in new tabDownload slide Countries affected by CKDu. Countries where there is population-based evidence of CKDu (red) are in Central America (Pacific coastal regions of El Salvador and Nicaragua) and South Asia (north central Sri Lanka and northern coastal Andhra Pradesh, India). There have also been reports of CKDu (gold) in Cameroon, Costa Rica, Egypt, Guatemala, Honduras, Mexico, Panama, Saudi Arabia, Sudan, Thailand and Tunisia. DEFINITION Although Kidney Disease: Improving Global Outcomes criteria can be used to identify CKD, defining CKDu is challenging, as it rests primarily on excluding the known causes of disease using clinical and biochemical criteria (as imaging and histopathology are often inaccessible) [6]. The use of the term CKDu has generally been restricted to individuals with renal impairment of unknown cause from agricultural and/or socioeconomically deprived populations with a high reported prevalence of CKD [often based on a single estimated glomerular filtration rate (eGFR) measurement] in the absence of common identifiable aetiologies (e.g. diabetes or glomerulonephritis, as evidenced by heavy proteinuria and/or hypertension). It is not typically used to describe sporadic cases of ESRD without a diagnosis in high-income countries. Even using simple criteria, identifying CKDu can be problematic, as accessing accurate eGFR testing may be difficult in many low-income settings. Furthermore, both the distribution of normal kidney function and the validity of eGFR equations developed elsewhere are unknown in many populations impacted by CKDu. CLINICAL FEATURES CKDu typically presents with asymptomatic renal impairment without associated hypertension or heavy proteinuria. Hyperuricaemia is prominent in established disease and ‘chistata’ (dysuria) is described in Central America [3]. The histological pattern is similar between regions, showing interstitial fibrosis, tubular atrophy and glomerulosclerosis, without immune complex or crystal deposition [7]. There is a male preponderance. In Central America, CKDu often (but not exclusively) affects young adult sugarcane workers [3] and the decrease in eGFR can be dramatic [8], whereas in Sri Lanka, the condition occurs more commonly in middle age [4]. Recently a febrile illness with acute kidney injury (AKI) has been reported in populations at risk of CKDu in both Sri Lanka and Nicaragua [9]. Biopsies during these episodes demonstrate a non-granulomatous acute interstitial nephritis (AIN). Although some patients with this presentation progress to chronic renal impairment, there is currently inadequate evidence that this syndrome is a necessary precursor of CKDu. AETIOLOGY Candidate causes of CKDu include metabolic responses to heat/dehydration, environmental factors (agrochemicals, metals, phyto/mycotoxins), infection and drugs/alcohol, but identifying causal factors in observational studies has proven challenging. There is currently insufficient evidence to support any single cause of disease, and an as yet overlooked factor may be responsible. The lead hypotheses are discussed below. Heat/dehydration It has been proposed that strenuous manual labour in hot conditions without adequate hydration leads to repeated tubular injury and subsequent fibrosis. Injury from heat and volume depletion could be exacerbated by myoglobin release from muscle and/or urate crystalluria, and studies have demonstrated an increase in serum creatinine across a sugarcane cutting shift [10]. However, whether these changes represent creatinine generation or excretion, are transient or sustained and/or are a marker of an underlying lack of reserve in those with pre-existing subclinical CKD is unclear. Seasonal decreases in eGFR have also been proposed to support an occupational cause of disease. However, similar annual variation in kidney function is also observed in populations not at risk of CKDu. Agrochemicals Poisoning by pesticides (e.g. organophosphates) can lead to AKI, raising the possibility of an alternative occupational cause of CKDu. Although there is evidence from the USA that those working with agrochemicals are at increased risk of ESRD, reports from Central America have found that pesticide applicators do not exhibit excess renal dysfunction [3]. Metals A number of metals have historically been responsible for clusters of CKD, but most studies of likely candidates, including cadmium, lead and arsenic, conducted in CKDu regions have not identified higher levels in those with renal dysfunction [3, 4]. Infection Reports of non-granulomatous AIN in at-risk populations raise the possibility of an infective aetiology. Studies of leptospira have demonstrated no excess seropositivity in those with renal impairment in Central America. However, other organisms of known (e.g. hantavirus) or unknown (e.g. flaviviruses) nephrotropism are endemic in areas impacted by CKDu. MANAGEMENT Avoidance of nephrotoxic drugs Although there is no evidence to support nephrotoxic drugs (non-steroidal anti-inflammatory drugs, aminoglycosides) as primary causes of CKDu, use of these agents is widespread and avoidance should be advised in those with established renal dysfunction. Allopurinol Laboratory findings in CKDu have led to the suggestion that urate lowering may be useful in ameliorating progressive renal dysfunction. There have been no clinical trials, but allopurinol has been used in affected regions. Water, rest, shade Labour conditions in areas impacted by CKDu, specifically in Central America, are often brutal. Although measures to improve work conditions are obviously to be supported, there is currently no evidence that such interventions prevent CKDu. RRT RRT provision places a huge strain on health systems in affected regions. Access remains far from universal and, anecdotally, outcomes, particularly with peritoneal dialysis in Central America, are poor. CONCLUSION CKDu leads to premature loss of life at an unprecedented scale in agricultural communities in low- and middle-income countries. Such a burden of disease is unlikely to have been neglected for so long had it been occurring in high-income settings. As the cause remains unclear, only methodologically robust studies, conducted in partnership with affected communities and local investigators, will provide data on the geographical distribution, insights into pathogenesis and a scientific basis for urgently needed preventative interventions. FUNDING B.C. reports grants from the Colt Foundation and the UK Medical Research Council. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Garcia Trabanino R , Aguilar R , Reyes Silva C et al. Nefropatía terminal en pacientes de un hospital de referencia en El Salvador . Rev Panam Salud Publica 2002 ; 12 : 202 – 206 Google Scholar Crossref Search ADS PubMed WorldCat 2 Lanerolle R , Kudalugoda Arachchi J , Nanayakkara S. Demographic characteristics of end stage renal disease in Sri Lanka . J Ceylon Coll Physicians 2000 ; 33 : 3 WorldCat 3 Correa-Rotter R , Wesseling C , Johnson RJ. CKD of unknown origin in Central America: the case for a mesoamerican nephropathy . Am J Kidney Dis 2014 ; 63 : 506 – 520 Google Scholar Crossref Search ADS PubMed WorldCat 4 Wanigasuriya K. Update on uncertain etiology of chronic kidney disease in Sri Lanka’s north-central dry zone . MEDICC Rev 2014 ; 16 : 61 – 65 Google Scholar PubMed WorldCat 5 O'Callaghan C , Shivashankar R , Anand S et al. Prevalence of and risk factors for chronic kidney disease of unknown aetiology in India: secondary data analysis of three population-based cross-sectional studies . BMJ Open 2019 (in press) WorldCat 6 Caplin B , Wang C-W , Anand S et al. The International Society of Nephrology’s International Consortium of Collaborators on Chronic Kidney Disease of Unknown Etiology: report of the working group on approaches to population-level detection strategies and recommendations for a minimum dataset . Kidney Int 2019 ; 95 : 4 – 10 Google Scholar Crossref Search ADS PubMed WorldCat 7 Wijkström J , Leiva R , Elinder CG et al. Clinical and pathological characterization of mesoamerican nephropathy: a new kidney disease in Central America . Am J Kidney Dis 2013 ; 62 : 908 – 918 Google Scholar Crossref Search ADS PubMed WorldCat 8 González-Quiroz M , Smpokou E , Silverwood R et al. Decline in kidney function among apparently healthy young adults at risk of Mesoamerican nephropathy . J Am Soc Nephrol 2018 ; 29 : 2200 – 2212 Google Scholar Crossref Search ADS PubMed WorldCat 9 Fischer RSB , Vangala C , Truong L et al. Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy . Kidney Int 2018 ; 93 : 753 – 760 Google Scholar Crossref Search ADS PubMed WorldCat 10 García-Trabanino R , Jarquín E , Wesseling C et al. Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador – a cross-shift study of workers at risk of Mesoamerican nephropathy . Environ Res 2015 ; 142 : 746 – 755 Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Nov 1, 2019

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