CKD-UO in Lanka: A disease in search of a cause

Parallel studies in animals are important. Chronic kidney disease in animals in locations where human are affected may lend support to a fungal cause. ‘Porcine nephropathy’due to citrinin/ ochratoxin was described by Krogh et al in the 1970s.

The Chronic Kidney Disease of ‘Unknown’ Origin (CKD-UO) has been detected in Sri-Lanka since the mid- 1990s, initially in the north central province (NCP) but now also noted elsewhere. It has been variously termed CKD-mfo (multi-factorial origin), chronic agrochemical nephropathy and chronic interstitial nephritis of agricultural communities (CINAC).

Chronic kidney diseases due to ‘non-traditional’ causes have been described as Itai-Itai in Japan or cadmium and Balkan endemic nephropathy-( BEN) due to Aristolochic acid. The causes of Meso- American nephropathy ( MeN) in Central America, ‘ Udhanam nephropathy’ in Andhra Pradesh in India and CKD- UO in Sri Lanka are still under study.

The epidemiology, (‘who, where and when’) and the clinical features of CKD-UO in Sri Lanka are known. Most patients have been residents in the NCP for more than five years, suggestive of synergism, a cumulative effect, continuous exposure to the causative agent, accumulation of a critical level of a kidney toxin or progression of the process that triggers the mechanism leading to decline of kidney function.

This ‘ disease susceptibility’ may be genetic and/or environmental. Many patients have been identified at the time of diagnosis, hence the importance of screening.

Causes studied and considered include the quality and composition of water, contamination of water and soil (by micro-organisms and toxins, metals/trace elements, ‘agro-chemicals’), snakebite envenoming, alcohol intake, food and methods of cooking, smoking, betel chewing, strenuous labour, medicines etc.

As a cause is unknown, a ‘relook’ at CKD (UO) may be prudent with regard to ‘how, why and what’ of CKD which are the remaining questions to be answered while several factors need consideration. 1. 2. Adult diseases may originate in the foetal stage ( Barker hypothesis) and it is known that origins of the chronic kidney disease can be in early life by ‘ developmental programming’. Adverse events affecting the developing kidneys (such as maternal malnutrition) can lead to a reduced number of functioning kidney units called ‘ nephrons’ at birth -- ‘nephron endowment’. Low nephron endowment was considered to predispose to high blood pressure and renal disease (Brenner hypothesis). One of the reasons for variations of estimates of CKD prevalence within and between countries is using a fixed threshold for the rate of formation of urine (known as GFR). Thus Glassock et al highlight the importance of ‘ accurate diagnosis of true chronic kidney disease’ taking into account multiple variables. Smaller kidney size at birth in South Asian babies is considered to predispose to increased risk of adult kidney disease ( Roderick et al). Therefore definitions of CKD and analysis of comparative studies worldwide need consideration of several factors including ethnicity. As a family history of chronic kidney disease is a known risk factor for CKD(UO)-Sri Lanka, can it be a genetic disease? MYH9-Related Disease (MYH9RD) is a cause of glomerular CKD apart from Diabetes mellitus in African- Americans. ‘Clustering of cases’ in affected areas in Sri Lanka has been noted. Can this be a result of ‘ autosomal dominant tubulo- interstitial kidney diseases’( ADTKD) due to genetic mutations affecting at least four genes or due to common exposure to environmental causes? APOL1 gene variants have also been noted in cases of CKD in some parts of the world. In some endemic kidney diseases, the adult offspring of an affected mother have been noted to develop small kidneys and protein leak 3. 4. 5. 6. 7. into urine. Discovery of a genetic cause will have obvious implications for renal transplantation. Why is the disease now noted outside the NCP? Is it due to migration of susceptible individuals, spread of a vector/ toxin or micro- organism or exposure to the same cause as in the NCP? Should kidney tissue, in addition to microscopic evaluation, be analysed for causes such as toxins, micro-organisms and DNA damage as in Balkan Nephropathy? Chronic kidney disease after heat-stroke has been reported in South African miners. It seems necessary to study enzyme pathways and uric acid-induced kidney damage related to such Heat Stress Nephropathy ( HSN) as that reported in Central America. Can it be a microbial agent which has a long incubation period accounting for the delay in manifestations? Has rodent contamination of crops been adequately studied? Is it due to the emergence of new disease- causing organisms? The occurrence of Hanta viral infection in the US and Vibrio cholerae variants in Asia were considered to have developed as a result of ‘environment distress syndrome’ caused by change to ecology (Epstein). Could CKD-UO be an ‘enterogenic (bowel related) nephropathy’? Products of intestinal bacterial action produce 8. chemicals such as p-cresyl sulphate and indoxyl sulphate that are associated with progression of kidney damage and study of this ‘colo-renal’ (gut-kidney) axis is warranted (Evenepoel et al). The bowel bacteria (‘ gut microbiome’) may be affected both by environmental causes and antibiotics. It might be useful to study the bowel bacteria of those affected and not affected by CKD. Additionally, the widespread use of antibiotics may be contributory to disrupting bowel bacteria which reduce oxalic acid formation, thereby contributing to urinary stone formation Research needs to look into s eve r a l p l a n t s / h e r b s. Aristolochic acid from Aristolochia (‘ Sapsanda’Sinhala,’Isvaramuli’-Tamil) is implicated in Balkan kidney disease which has features similar to CKD-UO (SL). Acute renal damage has been shown with Solanum nigram (called ‘ kalukammeriya’) and this needs investigation for potential chronic kidney effects. Star fruit-’ Kamaranka’, ( Averrhoea carambola) is a known cause of ‘ oxalate nephropathy’ in patients with pre- existing chronic kidney disease and is now known to cause chronic nephritis. Vitamin C and nuts are sources of oxalate which need investigation. Some herbal medicines contain Pyrrolizidine alkaloids which are nephro- toxic. Mushroom species such as Cortinarius contain Orellanine (causing acute and chronic kidney disease-Orellanus syndrome), and therefore potential exposure to toxic mushrooms needs further assessment. Inhalation exposure to fungi and Aflatoxin contamination of food need to be studied further. Food additives such as cinnamaldehyde have shown time and dose dependant kidney toxicity in animal studies in India. Miscellaneous causes need scrutiny. ‘Silica nephropathy’ needs research as industries involving silica are widespread in the country ( glass, sand, cement etc). Application of methyl salicylate and menthol to heated skin has been reported to cause persistent kidney disease and merits study. Medication for gastritis and pain relieving medicine (analgesics) need further investigation. Cyanobacterial contamination of dialysis water caused ‘Caruaru syndrome’ in Brazil, characterised by liver and neurological damage and its potential kidney toxicity in humans needs study. 10. Parallel studies in animals are important. Chronic kidney disease in animals in locations where human are affected may lend support to a fungal cause. ‘Porcine nephropathy’due to citrinin/ochratoxin was described by Krogh et al in the 1970s. 11. Snake-bite envenoming is considered an exclusion criterion for the study of CKD-UO(SL) but as it is a significant risk factor for the development of CKD-UO, the interpretation of 9.

this data needs to be clarified. 12. ‘ IgG- 4 related disease ( IgG- 4 RD) and ‘ Karyomegalic Interstitial Nephtitis’ ( KIN) are well recognised causes of chronic kidney disease which need investigation in Sri Lanka. The latter known to be associated with fungal contamination and DNA damage in countries such as Tunisia. 13. Possible contamination of soil, water or food by heavy metals in electronic waste material (‘ e- waste’) and Bisphenyl-A (BPA) used in the plastic industry and known to be associated with protein leak into urine warrant investigation. There is no conclusive proof or evidence as to the cause of CKD ( UO) in Sri Lanka. As is quite appropriately being addressed currently, the quality of water needs to be scrutinised and standards maintained as it is vital for the good health in general. There needs to be strong advocacy for climatic and ecological monitoring and checking of use of agrochemicals. Proper use of protective gear for farmers and manual labourers too plays an important role in maintaining general health of workers.

CKD-UO in SL impacts heavily on the health of the population and on the economy. The aim of well- designed studies needs be one of ‘ converting CKD of Unknown Origin to CKD of Known origin’. If a cause or causes were to be discovered, preventive measures can then be implemented and intensified and treatment tailored accordingly through health education and health policy decisions with national guidelines and protocols. ‘ Inter- disciplinary research’ to explore all possible ‘un-explored causes’ and analysis of data from other countries which have kidney disease similar to that in Sri Lanka seem the way forward to solving this mystery of ‘CKD of undetermined origin’. (S.N. Arseculeratne is Emeritus Professor, Faculty of Medicine, University of Peradeniya and G. Arseculeratne is a Consultant

Dermatologist)

There is no conclusive proof or evidence as to the cause of CKD (UO) in Sri Lanka.