Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries—Novel Findings
Round 1
Reviewer 1 Report
This is a complete and updated review of a topic of interest.
Some comments:
In the first paragraph of the introduction they refer to a new form of CKD but the reference is from 2004. Therefore this form does not seem so new. Point 1.3: the authors say that glomerular damage is manifested through proteinuria, this is not entirely true since, in the urine, low molecular weight proteins can be found that cross the glomerular filtration barrier without damage but not they reabsorb in the tubule due to tubular damage. In fact, the early markers mentioned below are proteins of this type (generally). Specify better either the levels of proteinuria or if it is a specific protein (mainly high molecular weight proteins) In deterrence, certain minerals are proposed as possible causes of kidney damage, such as cadmium, my question is whether none of the articles consulted have measured metallothioneins as a confirmation of this theory,Author Response
Reviewer 1 - Journal - Environments (ISSN 2076-3298)
Manuscript ID - environments-660739
Number of Pages - 26
Title: Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries
Authors: Sunil J. Wimalawansa * , Chandra B. Disanayake
Abstract: A new form of chronic tubulointerstitial kidney disease (CKD) not related to diabetes or hypertension appeared during the past four decades in several peri-equatorial and predominantly agricultural countries. Commonalities include stagnation of drinking water sources, harsh climatic conditions with prolonged dry seasons, and rampant poverty and malnutrition. In general, the cause is unknown, so the disease is named CKD of unknown aetiology (CKDu). It is likely caused by a combination of factors; a better term is CKD of multifactorial origin (CKDmfo). Middle-aged malnourished men with more than 10 years of exposure to environmental hazards are the most vulnerable. Over 30 factors have been proposed as causative, but none has been properly tested. Favourable climatic patterns, adequate hydration, and less poverty and malnutrition seem to prevent the disease. With the right conditions, chemical species such as calcium, phosphate, oxalate, and fluoride form intra-renal nanomineral particles initiating CKDmfo. This article examines the key potential causes of CKDmfo and risk factors and vulnerabilities that predispose individuals to the disease. Findings suggest that in addition to drinking water from stagnant sources, more than 10 years of exposure to environmental nephrotoxins and other compounds are needed to contract this fatal disease.
Reviewer Comments:
English language and style
( ) Moderate English changes required
(x) English language and style are fine/minor spell check required
( ) I don't feel qualified to judge about the English language and style
Comments and Suggestions for Authors
This is a complete and updated review of a topic of interest.
Additional comments:
In the first paragraph of the introduction they refer to a new form of CKD but the reference is from 2004. Therefore, this form does not seem so new.
Thank you for pointing out – we have corrected this now.
Point 1.3: The authors say that glomerular damage is manifested through proteinuria, this is not entirely true since, in the urine, low molecular weight proteins can be found that cross the glomerular filtration barrier without damage but not they reabsorb in the tubule due to tubular damage. In fact, the early markers mentioned below are proteins of this type (generally). Specify better either the levels of proteinuria or if it is a specific protein (mainly high molecular weight proteins) In deterrence, certain minerals are proposed as possible causes of kidney damage, such as cadmium, my question is whether none of the articles consulted have measured metallothioneins as a confirmation of this theory,
Cadmium in water has not been reported any studies in Sri Lanka. Neither any other heavy metals. We and others believe that heavy metals is not involved in the causation of CKDmfo in Sri Lanka.
We have expanded the sections of CKDmfo diagnosis section with addition of a new section on measurements of biochemical markers. Metallothionein were included in this section as a separate paragraph in section 2.0.
Submission Date - 20 November 2019
Date of this review - 22 Nov 2019 11:21:56
Author's Reply to the Review Report (Reviewer 1)
Please provide a point-by-point response to the reviewer’s comments and either enter it in the box below or upload it as a Word/PDF file. Please write down "Please see the attachment." in the box if you only upload an attachment.
Reviewer 2 Report
Review comment sheet
1 A brief summary
The paper describes that the authors examined the key potential causes of CKDmfo and risk factors and vulnerabilities that predispose individuals to the disease. Findings suggest that in addition to drinking water from stagnant sources, more than 10 years of exposure to environmental nephrotoxins and other compounds are needed to contract this fatal disease.
This is a very nice paper. However, I have some comments.
2 Overall evaluation
The findings from this paper are excellent and novel regardness of a review.
3 Main problem
This manuscript contained some questions described below.
I think this paper has very interesting, this study contributes to future's clinical medicine largely. I have some questions from a point of view of clinical medicine.
In this paper the authors focused the affect of kidney by various substances.
The investigation of substances that can cause kidney damage is very interesting and includes important details. There is also a reference to urinary biomarkers, and the content is clinical and practical. But we need to prove these changes histopathologically. Please tell us about the findings case reports including in your case or country or animal experiments, especially the findings and images of tubulointerstitial injury from the literature.
Regarding urinary biomarkers, urinary L-FABP is the marker that most quickly reflects tubular injury. I would like to mention this marker. There is literature that another group in Sri Lanka has evaluated tubule
injury due to urine L-FABP. References are listed below.
Reference
Eiichi Sato et al, Urinary excretion of liver-type fatty acid-binding protein reflects the severity of sepsis Renal Replacement Therapy volume 3, Article number: 26 (2017)
J Water Health. 2018 Apr;16(2):212-222. doi: 10.2166/wh.2018.070.
Arsenic, cadmium, lead, and chromium in well water, rice, and human urine in Sri Lanka in relation to chronic kidney disease of unknown etiology.
S Herath HMA et al.
As for kidney damage caused by heavy metals, there is an itai-itai disease due to pollution in Japan, which reports a long-term prognosis. How will Sri Lanka track these kidney damages in the future?
It may be difficult to mention in this paper, but please tell us your suggestions for water quality improvement measures.
Environ Health. 2014 Mar 15;13(1):18. doi: 10.1186/1476-069X-13-18.
Mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium exposure of the polluted Jinzu River basin, Toyama, Japan; a 26-year follow-up.
Maruzeni S, Nishijo M1, Nakamura K, Morikawa Y, Sakurai M, Nakashima M, Kido T, Okamoto R, Nogawa K, Suwazono Y, Nakagawa H.
Author Response
Reviewer 2 - Journal - Environments (ISSN 2076-3298)
Manuscript ID - environments-660739 -- Number of Pages - 26
Title: Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries
Authors: Sunil J. Wimalawansa * , Chandra B. Dissanayake
Abstract: A new form of chronic tubulointerstitial kidney disease (CKD) not related to diabetes or hypertension appeared during the past four decades in several peri-equatorial and predominantly agricultural countries. Commonalities include stagnation of drinking water sources, harsh climatic conditions with prolonged dry seasons, and rampant poverty and malnutrition. In general, the cause is unknown, so the disease is named CKD of unknown aetiology (CKDu). It is likely caused by a combination of factors; a better term is CKD of multifactorial origin (CKDmfo). Middle-aged malnourished men with more than 10 years of exposure to environmental hazards are the most vulnerable. Over 30 factors have been proposed as causative, but none has been properly tested. Favourable climatic patterns, adequate hydration, and less poverty and malnutrition seem to prevent the disease. With the right conditions, chemical species such as calcium, phosphate, oxalate, and fluoride form intra-renal nanomineral particles initiating CKDmfo. This article examines the key potential causes of CKDmfo and risk factors and vulnerabilities that predispose individuals to the disease. Findings suggest that in addition to drinking water from stagnant sources, more than 10 years of exposure to environmental nephrotoxins and other compounds are needed to contract this fatal disease.
Reviewer 2 - Comments:
English language and style
( ) Moderate English changes required
( ) English language and style are fine/minor spell check required
(x) I don't feel qualified to judge about the English language and style
Comments and Suggestions for Authors
1 A brief summary
The paper describes that the authors examined the key potential causes of CKDmfo and risk factors and vulnerabilities that predispose individuals to the disease. Findings suggest that in addition to drinking water from stagnant sources, more than 10 years of exposure to environmental nephrotoxins and other compounds are needed to contract this fatal disease.
This is a very nice paper. However, I have some comments.
Thank you
2 Overall evaluation
The findings from this paper are excellent and novel regardless of a review.
Thank you
3 Main problem - This manuscript contained some questions described below.
I think this paper is very interesting, this study contributes to future's clinical medicine largely. I have some questions from a point of view of clinical medicine.
In this paper the authors focused the effect of kidney by various substances.
The investigation of substances that can cause kidney damage is very interesting and includes important details. There is also a reference to urinary biomarkers, and the content is clinical and practical. But we need to prove these changes histopathologically. Please tell us about the findings case reports including in your case or country or animal experiments, especially the findings and images of tubulointerstitial injury from the literature.
Thank you: We have added a paragraph to describe the histopathological features of this tubulointerstitial renal disease, as a suggested.
Regarding urinary biomarkers, urinary L-FABP is the marker that most quickly reflects tubular injury. I would like to mention this marker.
We have added relevant discussion on biomarkers including the importance of L-FABP in the text.
Eiichi Sato et al, Urinary excretion of liver-type fatty acid-binding protein reflects the severity of sepsis Renal Replacement Therapy volume 3, Article number: 26 (2017)
We have added two paragraphs under the section 1.3.1-biochemical markers to illustrated the points mentioned, including the above reference.
There is literature that another group in Sri Lanka has evaluated tubule injury due to urine L-FABP. References are listed below.
· S Herath HMA et al., Arsenic, cadmium, lead, and chromium in well water, rice, and human urine in Sri Lanka in relation to chronic kidney disease of unknown etiology.
We have included this reference in the same section but they have failed to fing any relationship between L-FABP and heavy metals.
As for kidney damage caused by heavy metals, there is an itai-itai disease due to pollution in Japan, which reports a long-term prognosis. How will Sri Lanka track these kidney damages in the future?
Thank you: Sri Lanka soil water or food do not have excess cadmium and no patient has presented with clinical signs and symptoms of cadmium poisoning. However as suggested we have included itai-itai and references to not this point.
It may be difficult to mention in this paper, but please tell us your suggestions for water quality improvement measures. Environ Health. 2014 Mar 15;13(1):18. doi: 10.1186/1476-069X-13-18.
Now we have attempted to give some discussion related to how water quality can be improved in these dry zonal regions.
Mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium exposure of the polluted Jinzu River basin, Toyama, Japan; a 26-year follow-up.
Maruzeni S, Nishijo M1, Nakamura K, Morikawa Y, Sakurai M, Nakashima M, Kido T, Okamoto R, Nogawa K, Suwazono Y, Nakagawa H.
Submission Date - 20 November 2019
Date of this review - 03 Dec 2019 03:58:07
Author's Reply to the Review Report (Reviewer 2):
Our responses to the reviewer are above under the queries.
Manuscript was markedly improved with additional information to strengthened it, for the benefit of the readers.
Thank you for the constructive comments, allowing us to improve the quality of the manuscript.
Thank you
Professors, Wimalawansa and Dissanayake
Author Response File: 
Author Response.pdf
Round 2
Reviewer 2 Report
Revised Manuscript is well written.
All comments have been addressed.
Improvements in the manuscript have been noted.
