Journal of Kidney

Risk Factor Distribution among Subjects with Declined Estimated Glomerular Filtration Rate in Areas Endemic to Chronic Kidney Disease of Unknown Aetiology of Sri Lanka

Author info »

Introduction

The chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka is an endemic nephropathy marked by progressive tubulointerstitial damage in kidneys [1]. The disease has emerged endemic in North Central, Uva and certain other provinces in Sri Lanka [2,3] and is enigmatic with the uncertainty over the causal factors involved. The medically relevant risk factors pertaining to CKD [4] do not appear to explain the disease development in the endemic areas of the country. The disease associates factors such as notable confinement to a geoclimatic region namely the dry zone of the island and to a particular socioeconomic stratum of the society. First emerged in 1990s, the disease has been predominantly seen in paddy farming communities with greater occurrence among males. A range of other demographic factors such as exposure to agrochemicals, contaminated drinking water, and genetic predisposition, as well as exposure to heavy metals [5] have been received the attention as causal but the issue remains without a finality. For this reason, the disease is termed CKD of unknown aetiology (CKDu) and more recently as CKD of multifactorial origin (CKDmfo) in Sri Lanka [6]. It implies aetiology beyond the medically established CKD risk factors. It is thus important that the contribution of both medically established and other suspected risk factors of the disease development be assessed in endemic areas.

The clinically pertinent risk factors of CKD have been listed by the National Kidney Foundation, USA [4]. Accordingly, initiation risk factors (IRF) may induce the kidney damage while progression risk factors (PRF) aggravate the already initiated disease. The rationale is that a history of an initiation risk factor may suggest a causal relation hence aetiology to the subsequent CKD of the individual. The approach may distinguish between CKDu fraction among total CKD in the areas affected as the former may not associate such history. The recognition of locally important CKD precursors and thereby the individuals at increased risk of renal disease potentially allows directed disease alleviation at community level by prior intervention. PRF management and treatment to modifiable risk factors may improve the wellbeing of the patients by compromising disease progression towards end stage renal disease (ESRD). These approaches in long run will ease the economic burden of the consequent public health expenditure. In this context, risk factor distribution among chronic kidney disease patients in the affected areas deserves attention.

Methods

Two cross sectional studies were conducted in Padaviya (PDV, 2016-2017), and Girandurukotte/ Mahiyanganaya (GK/MH, 2017- 2018) in North Central and Uva provinces respectively. The areas are known to be endemic to CKDu with high disease prevalence as compared to the rest of the country. The studies collected spot urine, whole blood and risk factor data from volunteer subjects to span all CKD stages and a control group with sufficient renal health. The subjects were subsequently sorted using estimated glomerular filtration rate (eGFR; mL/min per 1.73 m2) and urine albumin to creatinine ratio (UACR, mg/g) into CKD/CKDu and control groups as mentioned below in this section. Delineation between CKD and CKDu remains obscure in individual medical records and in local medical practice, thus a tendency to designate the disease as CKD/CKDu occurs [7]. Similarly, the study presumably involved CKD and CKDu cases and attempted to assess and compare between two using the history of initiation risk factors. Study areas were comparable in the contexts of climate, subculture and socioeconomics as the subjects were predominantly from rural paddy farming communities supported by irrigation water.

In Padaviya, patients undergoing treatments for chronic kidney disease at the renal clinic of the district hospital, and individuals who were presumably of renal health from the same general area participated in the study. The latter constituted the endemic control. Total subject participation was 178 (all male, age range: 36-79 yrs). The study also included a nonendemic control group from Padalangala (PDL) in Sabaragamuwa province which is geographically non-contiguous to the North Central Province. The area was not considered as CKDu endemic. In Girandurukotte and Mahiyanganaya, participants were either suspected or diagnosed CKD/ CKDu patients identified during community screening program conducted by the Renal Disease Prevention and Research Unit (RDPRU) of the Ministry of Health, Nutrition and Indigenous Medicine, Sri Lanka. An endemic control group with apparently good renal health was constituted from the general population of the area. Total subject participation was 172 (gender: random, age range: 19-86 yrs).

Subject participation was on volunteer basis following verbal and informed consent. Only males were recruited in PDV and PDL where as both males and females were involved randomly in GK/ MH. Serum creatinine (mg/dL), urine albumin (mg/L) and urine creatinine (mg/dL) were measured by standard methods of clinical determination in compliance with respective producer-manuals and quality control (QC) standards at laboratories of Padaviya hospital (PDV samples), Padaviya and Venus Hospital (GK/MH samples), Polonnaruwa. Estimated glomerular filtration rate (eGFR; mL/ min per 1.73 m2) was determined using serum creatinine. For the purpose, chronic kidney disease epidemiology collaboration (CKDEPI) equation was used. Urine albumin to creatinine ratio (UACR mg/g) which is unaffected by urine concentration was estimated as the ratio of urine albumin to urine creatinine.

Subjects were verified and sorted into the CKD stages and control group in both studies using renal dysfunction markers, eGFR and UACR, in agreement with Stevens and Levin [8]. Briefly, the subjects were assigned to disease progression stages, G1,G2,G3a,G3b,G4 and G5 when they were within eGFR ranges of >89, 60-89, 45-59, 30-44, 15-29 and <15 respectively. However, subjects were confirmed to be at G1 or G2 only if they further had a UACR at or greater than 30. Individuals having an eGFR greater than or equal to 90 with UACR equal to or lower than 29 were considered to be with adequate renal health hence in the control. Provisional G2 subjects with eGFR equal to or lower than 29 were excluded from the study as their renal status was inconclusive with the dysfunction markers employed in the study. Finally, stages G1 through G5 were merged as total CKD and considered against respective control groups.

The study followed the established CKD risk factors (traditional risk factors) of each individual participant as put forward by the National Kidney Foundation of USA [4]. The risk factor data were collected by an authorized medical practitioner as answers to a questionnaire through subject interview. Subjects were gently cross-examined for verification and elimination of recall bias. Diabetes mellitus, hypertension, autoimmune diseases, systemic infections such as malaria and leptospirosis, urinary tract (UT) infections, urinary stones, lower UT obstructions, cardiovascular diseases, dyslipidemia, liver diseases, drug toxicity, snake bites, family history of kidney disease and history of acute kidney disease were considered as initiation risk factors (IRF) when those existed prior to initial diagnosis of the disease. Diabetes mellitus, high blood pressure, and smoking were considered as progression risk factors (PRF) if those emerged after diagnosis. Questionnaire also spanned demographic risk factors (nontraditional risk factors) suspected to be implicated in CKDu development in the areas, such as education, occupation and domestic water source.

Ethical clearance for the studies, RP/2015/04 dated November 02, 2015 and RP/2017/03 dated July 07, 2017, was obtained from the ethical review committee at the Faculty of Medicine, General Sir John Kotelawala Defence University, Sri Lanka.

Statistical analyses

Risk factor prevalence was compared between control and CKD groups using Chi square goodness of fit test. The hypothesis tested was, ‘the occurrence of the IRF between CKD and non CKD groups was not different’. The test was conducted independently for each risk factor. The expected values were estimated according to McHugh [9]. Statistical significance (p<0.05) suggested a known aetiology hence CKD rather than CKDu with regard to the IRF considered. Complementarily, odds ratio (OR) was determined with 95% confidence interval for IRF, and demographic factors. Odds>1 at p<0.05 pointed to an association.

Results

The study followed medical (traditional) and demographic (nontraditional) risk factors pertaining to the chronic kidney disease in two areas endemic to the chronic kidney disease of unknown aetiology in North Central and Uva provinces of Sri Lanka. In both areas, substantial percentage of CKD subjects reported IRF that existed prior to medical diagnosis (Table 1 and Figure 1). However, IRF prevalence was higher among healthy subjects as well. In Padaviya (PDV), about 92% of the CKD affected had IRF as compared to 85.7% in the endemic control group from the same area while in the nonendemic control group from PDL had IRF in 71.4% of the subjects. In GK/MH, 69.5% reported IRF among the CKD affected while its endemic control group reported 41.7% (data not shown).

Figure 1: Initiation risk factors that existed prior to the development of chronic kidney disease in subjects of CKDu endemic areas of Sri Lanka. Data were obtained by interview n=152, and 131 in Padaviya, and Girandurukotte/ Mahiyanganaya respectively CKD subjects were identified as G1, G2, G3a, G3b, G4 and G5 by eGFR >89, 60-89, 45-59, 30-44, 15-29 and <15 respectively. Then, G1 or G2 were confirmed when UACR ≥ 30. eGFR ≥ 90 with UACR ≤ 29 was considered healthy and excluded. G2 with eGFR ≤ 29 were excluded as their renal status was inconclusive. Stages G1 through G5 were subsequently merged as total CKD (Stevens and Levin, 2013).

Table 1: Risk factor distribution pertaining to chronic kidney disease development in CKDu endemic Padaviya, and Giandurukotte/ Mahiyanganaya areas of Sri Lanka

Chi square analyses showed that CKD development statistically associated only with hypertension (p<0.01) in GK/MH and with systemic infections (p<0.01), urinary tract infections (p<0.05) and family history of kidney disease (p<0.05) in PDV as IRF (Table 2). Odds Ratio estimation (Table 3) confirmed that likelihood of CKD development increased with systemic infections (p<0.01) and urinary tract infections (p<0.05) in PDV and with hypertension (p<0.01) in GK/MH. Majority of IRF studied however were not associated with CKD development. Occurrence of hypertension at GK/MH was 38.2% among total CKD (data not presented). In PDV, systemic infections predominantly malaria, family history of kidney disease and urinary tract infections were reported by 79.6%, 28.2% and 48.6% CKD subjects respectively. On the other hand, 3.5% and 14.5% of CKD patients did not report any IRF of the study in PDV and GK/MH respectively. These percentage occurrences represent CKD cases excluding control subjects. Major fraction of CKD patients had one or more progression risk factors (PRF). Diabetes mellitus, hypertension and smoking habit occurred among 48.6% and 44.2% of the total CKD in PDV and GK/MH respectively with hypertension as the most common (PDV, 26.06% and GK/MH, 32.06%). About 2.7% of CKD subjects had two PRF each in PDV (data not shown).

Table 2: Association of initiation risk factors with chronic kidney disease in CKDu endemic areas of Sri Lanka

Table 3: Odds of chronic kidney disease development with risk factors in CKDu endemic areas of Sri Lanka

The odds of CKD development was greater among males, the subjects with lesser education, and among the subjects who utilized dug-well water for drinking (Table 3). Risk also increased among field farmers by occupation and with agrochemical usage. All the enhanced risks were statistically significant (p<0.001). The risk of CKD rendered by unemployment was 27% lesser compared to those with employment with true population effect between 13-57%.

Conclusion

The results indicate that the disease chronic kidney development in both PDV and GK/MH areas may not be explained by traditional risk factors alone, and certain non-traditional risk factors such as education level, occupational application of agrochemicals, and domestic usage of dug-well water appeared to be influencing it. Feasibility for enhanced patient wellbeing occurs in the endemic areas via PRF management.

Acknowledgement

Field support from Renal Disease Prevention and Research Unit, Ministry of Health, Nutrition and Endogenous Medicine is appreciated. Work envisaged in the paper was supported by the Ministry of Science, Technology and Research, Sri Lanka and by the National Science Foundation, Sri Lanka via the research grants, MSTR/TRD/AGR/RD/01 and RPHS/2016/CKDu/04 respectively.

References

1. 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;17:213-221.
2. Jayasekara JM, Dissanayake DM, Adhikari SB, Bandara P. Geographical distribution of chronic kidney disease of unknown origin in North Central Region of Sri Lanka. Ceylon Med J. 2013;58:6-10.
3. Rajapakse S, Shivanthan MC, Selvarajah M. Chronic kidney disease of unknown etiology in Sri Lanka. J Occup Environ Health. 2016;22:259-264.
4. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67:2089-2100.
5. Gifford FJ, Gifford RM, Eddleston M, Dhaun N. Endemic nephropathy around the world. Kidney Int Rep. 2017;2:282-292.
6. Wimalawansa SJ. Escalating chronic kidney diseases of multi-factorial origin in Sri Lanka: Causes, solutions, and recommendations. Environ Health Prev Med. 2014;19:375.
7. Ranasinghe AV, Kumara GW, Karunarathna RH, De Silva AP, Sachintani KG, Gunawardena JM, et al. The incidence, prevalence and trends of chronic kidney disease and chronic kidney disease of uncertain aetiology (CKDu) in the North Central province of Sri Lanka: An analysis of 30,566 patients. BMC Nephrol. 2019;20:338.
8. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: Synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158:825-830.
9. Silva Junior GB, Pinto JR, Barros EJ, Farias GM, Daher ED. Kidney involvement in malaria: An update. Revista do Instituto de Medicina Tropical de São Paulo. 2017;59.
10. Yang C. Leptospirosis renal disease: emerging culprit of chronic kidney disease unknown aetiology. Nephron. 2018;138:129-136.
11. Athuraliya NTC, Abeysekera TDJ, Amerasinghe PH, Kumarasiri R, Bandara P. Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka. Kidney Intl. 2011;80:1212–1221.
12. Wickremasinghe AR, John RJP, Wanigasuriya KP. Chronic kidney disease of unknown aetiology in the north central province of Sri Lanka: trying to unravel the mystery.Ceylon Med J. 2011;56:143-146.
13. Jayasumana C, Paranagama P, Agampodi S, Wijewardane C, Gunatilake S. Drinking well water and occupational exposure to herbicides is associated with chronic kidney disease, in Padavi-Sripura, Sri Lanka. Environ Health. 2015;14:6.
14. Rango T, Jeuland M, Manthrithilake H, McCornick P. Nephrotoxic contaminants in drinking water and urine, and chronic kidney disease in rural Sri Lanka. Sci Total Environ. 2015;518:574-585.
15. Chandrajith R, Dissanayake CB, Ariyarathna T, Herath HMJMK, Padmasiri JP. Dose-dependent Na and Ca in fluoride-rich drinking water- another major cause of chronic renal failure in tropical arid regions. Sci Total Environ. 2011;409:671-675.
16. Wasana HMS, Aluthpatabendi D, Kularatne WMTD, Wijekoon P, Weerasooriya R. Drinking water quality and chronic kidney disease of unknown aetiology (CKDu): Synergic effects of fluoride, cadmium and hardness of water. Environ Geochem Health. 2016;38:157-168.
17. Chandrajith R, Nanayakkara S, Itai K, Aturaliya TNC, Dissanayake CB. Chronic kidney diseases of uncertain aetiology (CKDue) in Sri Lanka: Geographic distribution and environmental implications. Environ Geochem Health. 2011;33:267-278.
18. Soni RK, Weisbord SD, Unruh ML. Health-related quality of life outcomes in chronic kidney disease. Curr Opin Nephrol Hypertens. 2010;19:153-159.