Fd Chem. Toxic. Vol. 30, No. 3, pp. 183 188, 1992
0278-6915/92 $5.00 + 0.00 Copyright ~,c~1992 Pergamon Press Ltd
Printed in Great Britain. All rights reserved
E P I D E M I O L O G Y OF B A L K A N E N D E M I C N E P H R O P A T H Y S. (~EOVI6, A. HRABAR and M. ~ARI6 Medical Centre. Slavonski Brod; Institute for Public Health of Croatia, Zagreb, and Institute for Medical Research and Occupational Health, University of Zagreb, Croatia Summary--The first outbreak of Balkan endemic nephropathy (BEN) was reported between 1955 and 1957, initially in Serbia and soon afterwards in Croatia and in Bosnia and Herzegovina. The disease appears to be of a focal nature. In Yugoslavia at least six foci are known, generally along major rivers of the Danubian river basin, in areas that have often been flooded in the past and even today suffer from high ground waters. The prevalence rate of the disease is reported to be between 2 and 10%. In the endemic area of Croatia, a systematic survey of "in-the-field' cases of the disease since 1975 has shown a prevalence between 0.5 and 4.4%. When suspected cases are also included the prevalence rises to 20% or more. Specific mortality (based on official statistics) during the period 1957-1984 averaged 1.54%o per annum, but some studies have shown that mortality is actually more than twice as high as this figure. More women are affected than men; women also more frequently die of BEN than men. Lethality is extremely high. A striking feature of BEN is the familial occurrence of the disease. Incidence does not seem to be connected with ethnic group differences. Immigrants into the endemic area may also contract the disease. An increased incidence of malignant tumours of the urinary tract has been recorded in populations living in endemic areas. Epidemiological characteristics suggest that the disease is contracted in the domestic situation, or possibly from other family members. Factors to be considered are food, water or long close contact. It is also possible that the disease is contracted outside the house, in connection with farming activities, since the affected persons are almost exclusively farmers.
Introduction Between 1955 and 1957 the Health Service had to deal with a disease of an endemic nature when, first in Serbia and soon afterwards in Croatia and in Bosnia and Herzegovina, the outbreak was reported of an unusual kidney disease that was marked by strict geographical limits, familial occurrence, a high mortality rate from uraemia, and the fact that it affected primarily the agricultural population. Soon it was learned that the same type of disease also existed in the border regions of the neighbouring countries R o m a n i a and Bulgaria, where it had been established some years earlier. It is not known for certain if the disease had existed before, though there are indications that for some reason the disease intensified in the period 1955-1957.
Geographical distribution and ecological characteristics of the disease focus BEN appears to be of a focal nature. In Bulgaria there are two foci: in one the disease has affected 52 villages, and in the other, close by, four villages (Dotchev, 1973). In R o m a n i a too, two such foci are known, though with fewer affected villages (Bruckner et al., 1965). In Yugoslavia, at least six loci are known and they are located in three of the Yugoslav republics (Bosnia and Herzegovina, Croatia and Serbia), generally along major rivers of the Danubian fiver basin. The regions affected by the disease are chiefly flood-prone flatland, although Abbreviation: BEN = Balkan endemic nephropathy.
in some parts of Serbia and also in Bulgaria hilly, drained areas are involved. The focus of the disease in Croatia (around Slavonski Brod) is exclusively ftatland (88-97 m above sea level), which has often been flooded in the past and even today suffers from high groundwaters. This focus is comparatively well delimited, with the river Sava in the south, Slavonski Brod in the east, the foothills of Dilj G o r a in the north, and the N o v a Gradi~ka Posavlje in the west. In the border villages of the area there have been cases of the disease in the past, but this has not been confirmed by recent research. According to the 1981 census (Authorities of the County of Slovonski Brod), the area has a total of 10,094 inhabitants living in 14 villages. The villages are situated along major country roads and consist mainly of two rows of houses, the number of which varies between 50 and 400 per village. The older houses are built of brick and stand on high foundations (a precaution against floods). Humidity is evident in most of the houses, especially in the winter when the walls become wet right up to the ceiling. In all older houses the attic usually served as the main storeroom for food. Here the farmers used to dry meat, store maize and, because of a lack of separate storage facilities, even wheat. As a result the houses were always infested with rodents. In the farmyard there are one or several outhouses, a well--usually in the front p a r t - - a n d , in the rear part, the toilet and a dunghill. Thickets and copses extend fight down to the villages. On higher ground there are fields and on lower ground there are ponds full of reeds and other marsh plants, surrounded by willow trees, poplars and ash trees. Under a land improvement project, 183
S. (~EOVld et al.
184
Table 1. Endemic nephropathy patients* in percentages by year Year Village
1975
1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989
Kani~a 4.4 1.9 4.1 3.3 2.2 2.0 2.2 1.5 1.6 2.8 1.9 1.7 2.5 1,0 1.4 Bebrina 2.4 -2.6 -1.8 -1.9 -1.9 --1.3 2.6 2.2 Banovci -2.0 -1.2 -1.4 -3.2 -3.9 -2.9 2.2 1.0 ~ume6e -1.1 1.9 -0.7 -0.7 -0.7 . . . . . Brodski Varog 0.8 -0.6 -0.5 -0.8 -1.2 . . . . . *BEN patients are those with proteinuria as shown by sulphosalicyclicacid or LMW test, anaemia and pathological serum creatinine values. which has been in progress for the past 3-4 years, the thickets a n d copses are being cleared a n d large areas of land t u r n e d into fertile ploughland.
Morbidity Morbidity, or the prevalence of BEN, has been presented very differently by different a u t h o r s who have studied the Yugoslav foci of the disease, depending on the m e t h o d s and criteria they used. However, s u m m i n g up these reports, it can be said t h a t prevalence lies somewhere between 2 a n d 10% (Strahinji6 a n d Stefanovi6, 1983). A systematic study of the frequency of the disease in a C r o a t i a n focus was started in 1975, a n d in-thefield medical checks have since been carried out every year d u r i n g the same season. The survey covers five endemic villages: two previously greatly affected, two less affected, and one village with previously only sporadic cases. The entire p o p u l a t i o n a b o v e 3 years of age are invited to undergo e x a m i n a t i o n , a n d between 63 and 86% of the total village p o p u l a t i o n have responded to the invitation. On the basis o f medical history, epidemiological data, purpose-oriented clinical e x a m i n a t i o n a n d l a b o r a t o r y findings, persons are considered to be affected by the disease if they are f o u n d to have p r o t e i n u r i a (established by m e a n s of a sulphosalicylic acid or the low molecular weight protein test), a n a e m i a (men h a e m o g l o b i n < 120 g/litre, w o m e n h a e m o g l o b i n < 113 g/litre) a n d increased creatinine values in the serum ( > 1 3 2 / ~ m o l / litre). Suspected cases are considered to be those persons w h o have p r o t e i n u r i a a n d m a y also have either a n a e m i a or increased creatinine values in the serum. Individuals are eliminated if their history, clinical e x a m i n a t i o n or study of medical d o c u m e n tation indicates t h a t some o t h e r kidney disease is present. In the two previously greatly affected villages (Kani2a, Bebrina) the p r o p o r t i o n of diseased persons has been s h o w n to vary from 0.5 to 4.4% in individual years (Table 1). It should be n o t e d t h a t in Kani2a a slight trend towards a decrease in the n u m b e r o f sick persons has been observed in recent years. In the o t h e r two villages (Banovci, ~ume6e), which were less affected in the past, the trends are quite different. In Banovci the n u m b e r of affected persons evidently grew until 1984, a n d then declined, whilst in ~ume6e it has definitely been decreasing. The fifth village (Brodski Varog) is m a r k e d by a c o n t i n u a t i o n of
h y p o - e n d e m y t h r o u g h o u t the period of study ((~eovi6 1988). The p r o p o r t i o n of sick men to sick w o m e n is 1:1.65. Various reasons have been p u t forward for this observation, such as a greater susceptibility of w o m e n to pyelonephritis d u r i n g pregnancy a n d childbirth, or their greater inclination to m a k e use of health services, However, the latter reason can be eliminated since d u r i n g the o b s e r v a t i o n period, from which the data are derived, practically an equal n u m b e r o f men a n d w o m e n are examined.
et al.,
Specific mortality According to regularly collected data on deceased n e p h r o p a t h i c patients, specific mortality for the entire e n d a n g e r e d Posavlje region a r o u n d Slavonski Brod averaged 1.54 per t h o u s a n d per year d u r i n g the period 1957-1987. However, as in the case of m o r b i d ity, the specific mortality rate varies considerably from village to village, a n d on the basis of this rate the e n d a n g e r e d villages can be placed into three groups. The first g r o u p consists of villages with a specific mortality exceeding 2.0 per t h o u s a n d . They are Kani2a, Berbrina, Pri6ac a n d Slavonski Koba~. The second g r o u p with a mortality rate between 1.0 a n d 1.9 per t h o u s a n d also consists of five villages: Banovci, Lu~ani, ~ume6e, Zbjeg a n d ~ivike, while the third group, with a mortality up to 1.0 per t h o u s a n d , comprises the remaining five villages (Table 2). Special studies aimed at establishing specific mortality have s h o w n that mortality is actually more t h a n twice as high as the average specific mortality of 1.46 (Babug a n d H r a b a r , 1976). A n example o f this is the mortality rate reported for the village of Slavonski Kobag for the period 1958-1972 (Table 3). The differences o b t a i n e d in estimates of specific mortality are u n d e r s t a n d a b l e in view of the difficulties in trying to establish the cause of death, especially in the case of elderly persons suffering from several chronic diseases. A m o n g the diseased persons there are m o r e w o m e n t h a n men (a m e n : w o m e n ratio of 1: 1.58); this Table 2. Specific mortality rates of BEN for the period 1957-1987 Specific mortality per Village 1000 inhabitants Bebrina, Kani;~a, Pri~ac, Slavonski Koba~ />2.0 Banovci, Lu~ani, gume6e, Zbjeg, ~ivike 1.1~1.9 Brodski Varo~, Dubo~ac, Malino, Slobodnica, Stupni6ki Kuti 0.2-0.9
185
Epidemiology of Balkan endemic nephropathy Table 3. Annual mortality rates o f BEN for the period 1958-1972 in the population o f Slavonski Kobag examined in 1958
Death from BEN
Year 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1958-1972
2O
Total no. o f deaths
General mortaity (per 1000)
No.
Specific mortality per 1000 inhabitants
24
13.0 13.1 15.5 13.5 10.8 9.8 9.3 18.9 15.0 10.4 16.0 18.1 21.1 16.9 19.9 14.7
7 10 14 11 7 3 7 18 5 5 14 11 12 9 8 141
3.8 5.5 7.8 6.2 4.0 1.7 4.1 10.6 3.0 3.0 8.6 6.9 7.7 5.8 5.3 5.6
24
28 24 19 17 16 32 25 17 26 29 33 26 30 370
10
I 1957 1960
5
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0
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8
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0278-6915/92 $5.00 + 0.00 Copyright ~,c~1992 Pergamon Press Ltd
Printed in Great Britain. All rights reserved
E P I D E M I O L O G Y OF B A L K A N E N D E M I C N E P H R O P A T H Y S. (~EOVI6, A. HRABAR and M. ~ARI6 Medical Centre. Slavonski Brod; Institute for Public Health of Croatia, Zagreb, and Institute for Medical Research and Occupational Health, University of Zagreb, Croatia Summary--The first outbreak of Balkan endemic nephropathy (BEN) was reported between 1955 and 1957, initially in Serbia and soon afterwards in Croatia and in Bosnia and Herzegovina. The disease appears to be of a focal nature. In Yugoslavia at least six foci are known, generally along major rivers of the Danubian river basin, in areas that have often been flooded in the past and even today suffer from high ground waters. The prevalence rate of the disease is reported to be between 2 and 10%. In the endemic area of Croatia, a systematic survey of "in-the-field' cases of the disease since 1975 has shown a prevalence between 0.5 and 4.4%. When suspected cases are also included the prevalence rises to 20% or more. Specific mortality (based on official statistics) during the period 1957-1984 averaged 1.54%o per annum, but some studies have shown that mortality is actually more than twice as high as this figure. More women are affected than men; women also more frequently die of BEN than men. Lethality is extremely high. A striking feature of BEN is the familial occurrence of the disease. Incidence does not seem to be connected with ethnic group differences. Immigrants into the endemic area may also contract the disease. An increased incidence of malignant tumours of the urinary tract has been recorded in populations living in endemic areas. Epidemiological characteristics suggest that the disease is contracted in the domestic situation, or possibly from other family members. Factors to be considered are food, water or long close contact. It is also possible that the disease is contracted outside the house, in connection with farming activities, since the affected persons are almost exclusively farmers.
Introduction Between 1955 and 1957 the Health Service had to deal with a disease of an endemic nature when, first in Serbia and soon afterwards in Croatia and in Bosnia and Herzegovina, the outbreak was reported of an unusual kidney disease that was marked by strict geographical limits, familial occurrence, a high mortality rate from uraemia, and the fact that it affected primarily the agricultural population. Soon it was learned that the same type of disease also existed in the border regions of the neighbouring countries R o m a n i a and Bulgaria, where it had been established some years earlier. It is not known for certain if the disease had existed before, though there are indications that for some reason the disease intensified in the period 1955-1957.
Geographical distribution and ecological characteristics of the disease focus BEN appears to be of a focal nature. In Bulgaria there are two foci: in one the disease has affected 52 villages, and in the other, close by, four villages (Dotchev, 1973). In R o m a n i a too, two such foci are known, though with fewer affected villages (Bruckner et al., 1965). In Yugoslavia, at least six loci are known and they are located in three of the Yugoslav republics (Bosnia and Herzegovina, Croatia and Serbia), generally along major rivers of the Danubian fiver basin. The regions affected by the disease are chiefly flood-prone flatland, although Abbreviation: BEN = Balkan endemic nephropathy.
in some parts of Serbia and also in Bulgaria hilly, drained areas are involved. The focus of the disease in Croatia (around Slavonski Brod) is exclusively ftatland (88-97 m above sea level), which has often been flooded in the past and even today suffers from high groundwaters. This focus is comparatively well delimited, with the river Sava in the south, Slavonski Brod in the east, the foothills of Dilj G o r a in the north, and the N o v a Gradi~ka Posavlje in the west. In the border villages of the area there have been cases of the disease in the past, but this has not been confirmed by recent research. According to the 1981 census (Authorities of the County of Slovonski Brod), the area has a total of 10,094 inhabitants living in 14 villages. The villages are situated along major country roads and consist mainly of two rows of houses, the number of which varies between 50 and 400 per village. The older houses are built of brick and stand on high foundations (a precaution against floods). Humidity is evident in most of the houses, especially in the winter when the walls become wet right up to the ceiling. In all older houses the attic usually served as the main storeroom for food. Here the farmers used to dry meat, store maize and, because of a lack of separate storage facilities, even wheat. As a result the houses were always infested with rodents. In the farmyard there are one or several outhouses, a well--usually in the front p a r t - - a n d , in the rear part, the toilet and a dunghill. Thickets and copses extend fight down to the villages. On higher ground there are fields and on lower ground there are ponds full of reeds and other marsh plants, surrounded by willow trees, poplars and ash trees. Under a land improvement project, 183
S. (~EOVld et al.
184
Table 1. Endemic nephropathy patients* in percentages by year Year Village
1975
1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989
Kani~a 4.4 1.9 4.1 3.3 2.2 2.0 2.2 1.5 1.6 2.8 1.9 1.7 2.5 1,0 1.4 Bebrina 2.4 -2.6 -1.8 -1.9 -1.9 --1.3 2.6 2.2 Banovci -2.0 -1.2 -1.4 -3.2 -3.9 -2.9 2.2 1.0 ~ume6e -1.1 1.9 -0.7 -0.7 -0.7 . . . . . Brodski Varog 0.8 -0.6 -0.5 -0.8 -1.2 . . . . . *BEN patients are those with proteinuria as shown by sulphosalicyclicacid or LMW test, anaemia and pathological serum creatinine values. which has been in progress for the past 3-4 years, the thickets a n d copses are being cleared a n d large areas of land t u r n e d into fertile ploughland.
Morbidity Morbidity, or the prevalence of BEN, has been presented very differently by different a u t h o r s who have studied the Yugoslav foci of the disease, depending on the m e t h o d s and criteria they used. However, s u m m i n g up these reports, it can be said t h a t prevalence lies somewhere between 2 a n d 10% (Strahinji6 a n d Stefanovi6, 1983). A systematic study of the frequency of the disease in a C r o a t i a n focus was started in 1975, a n d in-thefield medical checks have since been carried out every year d u r i n g the same season. The survey covers five endemic villages: two previously greatly affected, two less affected, and one village with previously only sporadic cases. The entire p o p u l a t i o n a b o v e 3 years of age are invited to undergo e x a m i n a t i o n , a n d between 63 and 86% of the total village p o p u l a t i o n have responded to the invitation. On the basis o f medical history, epidemiological data, purpose-oriented clinical e x a m i n a t i o n a n d l a b o r a t o r y findings, persons are considered to be affected by the disease if they are f o u n d to have p r o t e i n u r i a (established by m e a n s of a sulphosalicylic acid or the low molecular weight protein test), a n a e m i a (men h a e m o g l o b i n < 120 g/litre, w o m e n h a e m o g l o b i n < 113 g/litre) a n d increased creatinine values in the serum ( > 1 3 2 / ~ m o l / litre). Suspected cases are considered to be those persons w h o have p r o t e i n u r i a a n d m a y also have either a n a e m i a or increased creatinine values in the serum. Individuals are eliminated if their history, clinical e x a m i n a t i o n or study of medical d o c u m e n tation indicates t h a t some o t h e r kidney disease is present. In the two previously greatly affected villages (Kani2a, Bebrina) the p r o p o r t i o n of diseased persons has been s h o w n to vary from 0.5 to 4.4% in individual years (Table 1). It should be n o t e d t h a t in Kani2a a slight trend towards a decrease in the n u m b e r o f sick persons has been observed in recent years. In the o t h e r two villages (Banovci, ~ume6e), which were less affected in the past, the trends are quite different. In Banovci the n u m b e r of affected persons evidently grew until 1984, a n d then declined, whilst in ~ume6e it has definitely been decreasing. The fifth village (Brodski Varog) is m a r k e d by a c o n t i n u a t i o n of
h y p o - e n d e m y t h r o u g h o u t the period of study ((~eovi6 1988). The p r o p o r t i o n of sick men to sick w o m e n is 1:1.65. Various reasons have been p u t forward for this observation, such as a greater susceptibility of w o m e n to pyelonephritis d u r i n g pregnancy a n d childbirth, or their greater inclination to m a k e use of health services, However, the latter reason can be eliminated since d u r i n g the o b s e r v a t i o n period, from which the data are derived, practically an equal n u m b e r o f men a n d w o m e n are examined.
et al.,
Specific mortality According to regularly collected data on deceased n e p h r o p a t h i c patients, specific mortality for the entire e n d a n g e r e d Posavlje region a r o u n d Slavonski Brod averaged 1.54 per t h o u s a n d per year d u r i n g the period 1957-1987. However, as in the case of m o r b i d ity, the specific mortality rate varies considerably from village to village, a n d on the basis of this rate the e n d a n g e r e d villages can be placed into three groups. The first g r o u p consists of villages with a specific mortality exceeding 2.0 per t h o u s a n d . They are Kani2a, Berbrina, Pri6ac a n d Slavonski Koba~. The second g r o u p with a mortality rate between 1.0 a n d 1.9 per t h o u s a n d also consists of five villages: Banovci, Lu~ani, ~ume6e, Zbjeg a n d ~ivike, while the third group, with a mortality up to 1.0 per t h o u s a n d , comprises the remaining five villages (Table 2). Special studies aimed at establishing specific mortality have s h o w n that mortality is actually more t h a n twice as high as the average specific mortality of 1.46 (Babug a n d H r a b a r , 1976). A n example o f this is the mortality rate reported for the village of Slavonski Kobag for the period 1958-1972 (Table 3). The differences o b t a i n e d in estimates of specific mortality are u n d e r s t a n d a b l e in view of the difficulties in trying to establish the cause of death, especially in the case of elderly persons suffering from several chronic diseases. A m o n g the diseased persons there are m o r e w o m e n t h a n men (a m e n : w o m e n ratio of 1: 1.58); this Table 2. Specific mortality rates of BEN for the period 1957-1987 Specific mortality per Village 1000 inhabitants Bebrina, Kani;~a, Pri~ac, Slavonski Koba~ />2.0 Banovci, Lu~ani, gume6e, Zbjeg, ~ivike 1.1~1.9 Brodski Varo~, Dubo~ac, Malino, Slobodnica, Stupni6ki Kuti 0.2-0.9
185
Epidemiology of Balkan endemic nephropathy Table 3. Annual mortality rates o f BEN for the period 1958-1972 in the population o f Slavonski Kobag examined in 1958
Death from BEN
Year 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1958-1972
2O
Total no. o f deaths
General mortaity (per 1000)
No.
Specific mortality per 1000 inhabitants
24
13.0 13.1 15.5 13.5 10.8 9.8 9.3 18.9 15.0 10.4 16.0 18.1 21.1 16.9 19.9 14.7
7 10 14 11 7 3 7 18 5 5 14 11 12 9 8 141
3.8 5.5 7.8 6.2 4.0 1.7 4.1 10.6 3.0 3.0 8.6 6.9 7.7 5.8 5.3 5.6
24
28 24 19 17 16 32 25 17 26 29 33 26 30 370
10
I 1957 1960
5
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