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Chronic kidney disease of unknown etiology: Case definition for India – A perspective


1 Department of Nephrology, Nanjappa Hospital, Shivamogga, Karnataka, India
2 Department of Nephrology, DaVita Kidney Care, Chennai, Tamil Nadu, India
3 Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Correspondence Address:
YJ Anupama,
Department of Nephrology, Nanjappa Hospital, Shivamogga, Karnataka - 577 201
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijn.IJN_327_18

  Abstract 


Chronic kidney disease of unknown etiology (CKDu) is a form of chronic kidney disease (CKD) that is prevalent in certain rural populations around the world. It is distinct by its clinicopathologic characteristics and has multifactorial etiology, being mostly linked to several environmental toxins. Although the presentation is similar in various regions across the globe, it also differs in subtle ways from region to region. In India too, there have been reports of the disease in several pockets. There is a need for a comprehensive definition to identify the cases accurately to ease clinical diagnosis and facilitate screening of populations in affected areas. This article presents the diagnostic criteria for CKDu proposed in a consensus meeting at Chennai, India, in May 2017.

Keywords: Chronic kidney disease of unknown etiology, diagnostic criteria, India



How to cite this URL:
Anupama Y J, Sankarasubbaiyan S, Taduri G. Chronic kidney disease of unknown etiology: Case definition for India – A perspective. Indian J Nephrol [Epub ahead of print] [cited 2019 Nov 12]. Available from: http://www.indianjnephrol.org/preprintarticle.asp?id=266081




  Introduction Top


Chronic kidney disease (CKD) is an emerging public health problem of global dimensions with a reported prevalence in the range of 11%–13%.[1] The prevalence is on the rise not only in the developed countries but also in the low- and middle-income countries, although precise estimates are not clearly available from these countries. Diabetes mellitus and hypertension are the two most common drivers for CKD in most countries, while it is associated with some ill-defined causes, termed “nontraditional” in some countries.[2]

While the global community is garnering support to tackle the CKD epidemic in urban population, CKD of unknown etiology (CKDu) is being increasingly reported from isolated, predominantly rural locations in several regions across the world.[2] Particularly, CKDu has been reported from Nicaragua, El Salvador, Costa Rica, Sri Lanka, India, Egypt, and Tunisia.[2],[3],[4]


  Definition Top


The understanding of CKDu is hindered by the lack of a precise definition encompassing all the attributes of the disease. In the clinical context, a patient is labelled as CKDu after excluding all the known causes of CKD. There are some common clinical characteristics that define CKDu and differentiate it from some of the known causes of CKD. Across locations reported globally, the disease is seen in young and middle-aged adults, mostly males who are engaged in strenuous work for their livelihood, like agriculture and manual labor. The patients have minimal or no proteinuria. CKDu patients typically are nondiabetic and have either normal blood pressure or are only mildly hypertensive.[2],[5],[6] The disease is progressive leading to stage 5 CKD needing renal replacement therapy over a span of several months. Kidney biopsy, performed in few patients, has revealed varying degrees of tubular atrophy and interstitial fibrosis with inflammatory cells.[7],[8]

Although there is fair degree of overlap in the clinical syndrome across the global locations, there are subtle yet salient differences between the presentations in the different regions. Hence, definition for CKDu requires inclusion of clinical and laboratory criteria which are region-specific. Formulating a definition that is comprehensive and inclusive of all the components of the disease is an arduous task and a consensus has been hard to achieve across nephrology community, public health professionals, and academic researchers.[9] Presently, defining CKDu is a major stumbling block in research involving CKDu and appears to be the Achilles' heel.

The disease begins insidiously and there are few or no symptoms till the disease is fairly advanced. Some of the markers that can identify CKD in early stages are not easily available. With CKDu, most of the early manifestations are associated with tubular abnormalities and alterations in urinary sediment before there is clinically evident proteinuria/albuminuria or a fall in glomerular filtration rate (GFR). There are further difficulties in estimating GFR reliably, and even then by the time there is a definite fall in estimated glomerular filtration rate (eGFR), the disease would be clearly advanced and irreversible. These are some of the problems with diagnosing CKDu.[10]


  Regional Variations Top


The clinical picture of CKDu differs in some subtle ways from region to region.[11] While men in the second or third decade are more commonly affected in Central America, men and women are equally affected in Sri Lanka, where it affects older people in the fourth or fifth decade.[5],[9] Proteinuria is more prominent in Sri Lankan nephropathy. Likewise, in India too, it affects older people, but these patients have minimal or no proteinuria and normal or only mildly elevated blood pressure. Significant differences in the clinical presentation between the regions are given in [Table 1].
Table 1: Key similarities and differences between presentations of CKDu in various regions

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  CKDu in India Top


In India, CKDu was first reported from Uddanam region of Andhra Pradesh state, which includes the coastal regions of Srikakulam district and Chimakurthy Mandal in Prakasam district.[11],[12] As in other epidemic sites reported globally, there are several postulates for the causation of the disease in Uddanam region. Several earlier studies which evaluated the effect of heavy metals or pesticides with CKD in this population failed to show a significant association. The study of water from different sources for trace elements and inorganic ions was carried out in the two districts and the concentrations of different inorganic chemicals were found to be within the permissible limits for drinking water.[13] Later studies revealed that silica is consistently elevated in the groundwater in this area and it is speculated that the CKD is because of direct nephrotoxicity of silica.[14],[15] Strontium is another heavy metal that is found elevated in the groundwater in several villages in this region.[15] In addition, there are reports of CKDu from some regions in Maharashtra, Odisha, and Goa, though not studied to an equivalent extent.[14],[16],[17] Increase in ambient temperature and fall in annual rainfall over time may be additional contributory factors of the kidney disease in these regions.[14] Genetic polymorphisms in enzymes which are involved in the metabolism of organochlorine pesticides are also being studied.[18]


  Case Definition for CKDu – The Indian Perspective Top


In the Indian context, although CKDu is being increasingly seen and reported from multiple places, the identification continues to be based on clinical judgment, by excluding other causes of CKD. The existing literature has broadly characterized the clinical traits of the patients in the epidemic region, while a clear definition to aid CKDu diagnosis as part of surveillance, epidemiological studies, and clinical trials is nonexistent. Thus, there is an urgent need to develop a consensus of defining CKDu in the Indian context. It is imperative to clearly define criteria which could be used to aid systematic clinical, epidemiological, and surveillance studies. For this, the criteria should have high sensitivity, but the tools for the definition should be easily applicable on a large population, cheap, and must be easily available for application in field conditions. A preliminary effort was made to put together opinions of various workers in the field comprising nephrologists, epidemiologists, pathologists, and geneticists in May 2017 at Chennai under the aegis of Indian Society of Nephrology (ISN), Indian Council of Medical Research (ICMR), and Tamilnadu Kidney Research Foundation (TANKER), a Chennai-based nongovernmental organization (see annexure below).


  Annexure Top


Members of CKDu India Consensus Group: From India- Dr Georgi Abraham, Professor of Nephrology, Pondicherry Institute of Medical sciences, Puducherry and Chief Nephrologist, Madras Medical Mission, Chennai; Dr Sanjay K Agarwal, Professor and Head of Nephrology, All India Institute of Medical Sciences, New Delhi; Dr Chacko Korula Jacob, Nephrologist, Bangalore Baptist Hospital, Bengaluru; Dr Raviraju Tatapudi, Chief Nephrologist, GITAM Institute of Medical Sciences and Research, Vishakhapatnam; Dr Manoj Muhrekar, Director, ICMR- National Institute of Epidemiology, Chennai; Dr Tripti Khanna, Scientist F, Indian Council of Medical Research, New Delhi; Dr Prabhdeep Kaur, Scientist E and Head of Division of Noncommunicable Diseases, ICMR- National Institute of Epidemiology, Chennai; Dr Narayan Prasad, Professor of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow; Dr Gangadhar Taduri, Professor of Nephrology, Nizam's Institute of Medical Sciences; Dr Suresh Sankarasubbaiyan, Chief Nephrologist, DaVita Kidney Care, Chennai; Dr Anupama Y J, Consultant Nephrologist, Nanjappa Hospital, Shivamogga, Karnataka; Dr Gopalakrishnan N, Professor of Nephrology, Madras Medical College, Chennai; Dr Santosh Varughese, Professor of Nephrology, Christian Medical college, Vellore; Dr Swarnalatha Gowrishankar, Chief Pathologist, Apollo Hospitals, Hyderabad; Dr Sivakumar V, Chief Nephrologist, Sri Venkateshwara Institute of Medical Sciences, Tirupati; Dr. Raja Karthik, Associate professor, NIMS Hyderabad; Dr. C.Prabhakar Reddy, Associate professor, NIMS Hyderabad; Dr Anil Purty, Professor of Community Medicine, Pondicherry Institute of Medical Sciences, Puducherry; Dr Sharath Babu Geda, Consultant Nephrologist, Vijaya Superspeciality Hospital, Vijaya wada; Dr Thirumavalavan, Consultant Nephrologist, Sri Hospitals, Chennai; Dr J P Tiwari, Professor of Nephrology, Goa Medical College, Goa; Dr Sathya Prkash Manimunda, Scientist D, National Centre for Disease Informatic and Research (NCDIR)-ICMR, Bengaluru. and from Sri Lanka- Dr Chula Herath, Professor of Nephrology, Department of Nephrology and Transplantation, Sri Jayawardenepura General Hospital, Sri Lanka; Dr Nalika Gunawardena, National Professional Officer, World Health Organization Country Office, Colombo, Sri Lanka.

The work groups opted to adopt a similar approach to Pan American Health Organization (PAHO) in terms of stratifying identification into suspected, possible, and definite case [Table 2]. The group proposed mandatory criteria to suspect CKDu and also criteria to exclude other known causes for other forms of CKD. The criteria are simple and can be used for surveillance or screening purposes and can be used in field studies. At the next level, a probable case of CKDu is diagnosed by abnormal eGFR and/or urinary abnormalities persisting for more than 3 months. This stage also includes exhaustive exclusion criteria which makes it more suitable for clinic-based identification of CKDu cases. At the third level are the diagnostic criteria for determining definite case of CKDu, which include application of more advanced tools such as ultrasonography and/or kidney biopsy. This level of diagnosis is more suitable for research studies and clinicopathologic studies where stringent inclusion criteria for recruitment of cases are required. Thus, the components of the definition encompass medical history and diagnostic testing including imaging, urine examination, and biopsy in a graded manner as we climb from a probable to definite case. Such a graded approach will augur well with the feasibility of implementation at various levels of the health system be it a screening camp or surveillance study or even a clinic-based evaluation, even at tertiary centers. The group concluded that these criteria could be a starting point or a guide to selection of cases of CKDu for clinical and epidemiologic studies and that these criteria could be modified in time as further knowledge into the pathogenesis of the disease advanced.
Table 2: Proposed case definition for chronic kidney disease of uncertain etiology in India

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  Conclusion Top


CKDu is increasingly being recognized in certain regions in India. The condition requires further systematic studies and large-scale epidemiologic studies for elucidation of a clear pathogenetic mechanism. Definition of the disease is clearly difficult, given the various presentations in different regions and has proved to be the “Achilles' heel.” Clearly much work needs to be done to unravel the mystery of this disease and needs a concerted multidisciplinary approach.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease – A systematic review and meta-analysis. PLoS ONE 2016;11:e0158765. doi: 10.1371/journal.pone. 0158765.  Back to cited text no. 1
    
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Gifford FJ, Gifford RM, Eddleston M, Dhaun N. Endemic nephropathy around the world. Kidney Int Rep 2017;2:282-92.  Back to cited text no. 2
    
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Almaguer M, Herrera R, Orantes CM. Chronic kidney disease of unknown etiology in agricultural communities. MEDICC Rev 2014;16.  Back to cited text no. 3
    
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Jayatilake N, Mendis S, Maheepala P, Mehta FR. Chronic kidney disease of uncertain aetiology: Prevalence and causative factors in a developing country. BMC Nephrol 2013;14:180.  Back to cited text no. 4
    
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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;63:506-20.  Back to cited text no. 5
    
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Rajapakse S, Shivanthan MC, Selvarajah M. Chronic kidney disease of unknown etiology in Sri Lanka. Int J Occup Environ Health 2016;22:259-64.  Back to cited text no. 6
    
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Wijkström J, Leiva R, Elinder CG, Leiva S, Trujillo Z, Trujillo L, et al. Clinical and pathological characterization of Mesoamerican nephropathy: A new kidney disease in Central America. Am J Kidney Dis 2013;62:908-18. doi: 10.1053/j.ajkd. 2013.05.019.  Back to cited text no. 7
    
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Nanayakkara S, Komiya T, Ratnatunga N, Senevirathna ST, Harada KH, Hitomi T, et al. Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka. Environ Health Prev Med 2012;17:213-21.  Back to cited text no. 8
    
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Weaver VM, Fadrowski JJ, Jaar BG. Global dimensions of chronic kidney disease of unknown etiology (CKDu): A modern era environmental and/or occupational nephropathy? BMC Nephrol 2015;16:145. doi: 10.1186/s12882-015-0105-6.  Back to cited text no. 9
    
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Pan American Health Organization. Epidemic of Chronic Kidney Disease in Agricultural Communities in Central America. Case definitions, methodological basis and approaches for public health surveillance. Available from: http://iris.paho.org/xmlui/handle/123456789/34132. [Last accessed on 2018 Jan 2].  Back to cited text no. 10
    
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Abraham G, Varughese S, Thandavan T, Iyengar A, Fernando E, Naqvi SA, et al. Chronic kidney disease hotspots in developing countries in South Asia. Clin Kidney J 2016;9:135-41.  Back to cited text no. 12
    
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Reddy DV, Gunasekar A. Chronic kidney disease in two coastal districts of Andhra Pradesh, India: Role of drinking water. Environ Geochem Health 2013;35:439-54.  Back to cited text no. 13
    
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Glaser J, Lemery J, Rajagopalan B, Diaz HF, Trabanino RG, Taduri G, et al. Climate change and the emergent epidemic of CKD from heat stress in rural communities: The case for heat stress nephropathy. Clin J Am Soc Nephrol 2016;11:1472-83.  Back to cited text no. 14
    
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Khandare AL, Reddy YS, Balakrishna N, Rao GS, Gangadhar T, Arlappa N. Role of drinking water with high silica and strontium in chronic kidney disease: An exploratory community-based study in an Indian village. Indian J Comm Health 2015;27:95-102.  Back to cited text no. 15
    
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Mascarenhas S, Mutnuri S, Ganguly A. Deleterious role of trace elements – Silica and lead in the development of chronic kidney disease. Chemosphere 2017;177:239-49.  Back to cited text no. 17
    
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Siddarth M, Datta SK, Ahmed RS, Banerjee BD, Kalra OP, Tripathi. Association of CYP1A1 gene polymorphism with chronic kidney disease: A case control study. Environ Toxicol Pharmacol 2013;36:164-70.  Back to cited text no. 18
    



 
 
    Tables

  [Table 1], [Table 2]



 

 
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   Abstract
  Introduction
  Definition
  Regional Variations
  CKDu in India
   Case Definition ...
  Conclusion
  Annexure
   References
   Article Tables

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