683
Yugoslavia, Bulgaria, and Romania. It is a region of generally high humidity and high rainfall. No local peculiarities in geology have been described. Important information is provided by the incidence of Balkan nephropathy in individuals
of
move into or out of the endemic area. A hisof residence in the affected area for at least 15 tory is usual, accounting for the development of years nephropathy among incomers from disease-free regions who settle in the endemic areas and for the rarity of the disease among people who left the endemic areas when young. The pathology of Balkan nephropathy is equally unusual. The major renal lesion is one of progressive tubular destruction and interstitial and capsular fibrosis.1-6 Gross renal atrophy results. The tubular damage is seen principally in the lower parts of the proximal convoluted tubule and the changes in loop of Henle. The status of glomerular 4 6-8 Balkan nephropathy is disputed.3 They were as tubular the originally regarded secondary to lesions and the interstitial fibrosis. Recent work8 suggests a more distinct glomerular component in the disease process, with local deposition of immune complexes. The central importance of the tubular lesions in Balkan nephropathy is, however, emphasised by the results of renal function tests. 1-4 910 The first detectable abnormality is tubular proteinuria, shown by an increase in urinary &bgr;2-microglobulin and changes in electrophoretic patterns. Defects in acidification and ammonia and urea excretion follow, then alterations in p-aminohippurate clearance and glycosuria culminating in a falling glomerular filtration-rate and renal decoxnpensation. Overt proteinuria, detected by routine tests, is a late feature of the disease, and tests for early tubular proteinuria are essential. Estimations of urinary &bgr;2-microglobulin and urine electrophoresis have proved valuable in epidemiological surveys in the endemic areas. In the course of such investigations some patients have begun to have tubular proteinuria while others have shown an oscillating pattern with tubular proteins appearing only between October and February-an observation which could have important setiological implications. One final piece of information has to be added to the pathology.1 2411 12 About a third of patients dying of Balkan nephropathy in Bulgaria and Yugoslavia have papillomas and/or carcinomas of the renal pelvis, ureter, or bladder. The tumours are sometimes multiple and some-
who
Balkan
Nephropathy
THE natural history of Balkan (endemic) nephropathy is one of the most fascinating topics in renal medicine. 1-5 A consensus view of some of the salient features may be summarised as follows. The
clinical picture is one of progressive renal failure, insidious in onset and usually unaccompanied by salt retention or hypertension. The disease occurs principally between the ages of 30 and 60 and is very rare below 20 or above 70. Females predominate (2/1) in the younger age-groups but later the sex difference is lost. Survival-times range from a few months to nearly 10 years with approximately half the patients dying in 2 years. A family history of Balkan nephropathy is found in about 1 in 5 cases in the endemic area. The disease is rural rather than urban, and most of the patients are connected with farming. There is no association with socioeconomic status, nutrition, or hygiene. The incidence of Balkan nephropathy within the endemic area is variable, but levels as high as 10% of the population have been claimed for some villages with perhaps 30% of individuals showing symptomless proteinuria. Clustering of cases in certain parts of villages, even in individual houses, has been described. The endemic area is situated at an altitude of 300 to 500 metres and lies in the vicinity of the Danube and its tributaries in adjacent parts
Hall, P. W., Dammin, G. J., Griggs, R. C., Fajgelj, A., Zimonjic, B., Gaon, B. Am. J. Med. 1965, 39, 210. 7. Craciun, E. C., Rosculescu, I. ibid. 1970, 49, 774. 8. Apostolov, K., Spasić, P., Bojanic, N. Lancet, 1975, ii, 1271. 9. Hall, P. W., Piscator, M., Vasiljević, M., Popovic, N. Q. Jl Med. 1972, 41,
6. 1. International
Symposium on Endemic Nephropathy (edited by Bulgarian Academy of Sciences, Sofia, 1965.
2. Lancet, 1966, i, 304. 3. The Balkan Nephropathy
(edited by G.
A.
E. W. Wolstenholme and
Puchlev).
J. Knight).
London, 1967. 4. Second International
Symposium on Endemic Nephropathy (edited by Puchlev). Bulgarian Academy of Sciences, Sofia, 1974. 5. Austwick, P. K. C. Proc. R. Soc. Med. 1975, 68, 219. A.
385. 10. Hall, P. W., Vasiljević, M. J. Lab. clin. Med. 1973, 81, 897. 11. Marković, B. Isr. J. med. Sci. 1972, 8, 540. 12. Chernozemsky, I. N., Stoyanov, I. S., Petkova-Bocharova, T. K., J. Cancer, 1977, 19, 1.
et
al. Int.
684
times bilateral. A proportion of these tumour patients, and of "healthy" individuals from the same geographical area, have raised serum &bgr;2-microglobulin levels." The search for aetiological agents in Balkan nephropathy has focused on possible local factors. Studies of several trace elements in the soil and water, and in tissues from patients with the disease, have proved inconclusive: the trace elements in question include lead, copper, zinc, uranium, barium, cadmium, arsenic, fluorine, cobalt, and chromium.1 3The disease existed before the advent of synthetic agrochemicals. There is no evidence to implicate bacteria such as &bgr;-haemolytic streptococci, Leptospira ieterohaemorrhagiae, and brucellae. Claims have been made for arborviruses and a coronavirus.8 Reviewing the subject in 1967, BARNES3 drew attention to the possible role of nephrotoxic fungi occurring as contaminants on foodstuffs, a notion which gained support from the later observations of AUSTWICK and SMITH.14 These workers reported a statistically significant correlation in three endemic areas between variation in the late-summer and autumn rainfall and the number of local deaths from Balkan nephropathy during the succeeding two years-the first clear association between a local environmental factor and the disease. They also described heavy fungal contamination of local foodstuffs, particularly by Penicillium verrucosum var. cyclopium and Fusarium spp. Attempts to demonstrate mycotoxins were unsuccessful but in a new investigation, reported this week on p. 671, one strain of P. verrucosum var. cyclopium induced striking renal tubular lesions when force-fed to rats for only 20 days. The lesions, located in the pars recta and junctional zone of the proximal convoluted tubule, are closely similar to the tubular changes in many patients with Balkan nephropathy ; 1-4 6 and at
present
they
seem to
provide
an
acceptable experi-
mental model for the disease. It is clearly a model rather than the model, and other nephrotoxin-producing fungi may be involved in the human disease as well as additional (non-fungal) setiological agents; one important mycotoxin which should be explored in more detail is ochratoxin A.15 16 A stumbling-block is the discrepancy between the wide distribution of the fungus and the apparently narrow distribution of the disease, though it is possible that Balkan nephropathy is waiting to be discovered outside South Eastern Europe-for instance, in Africa. A useful exercise would be to
review some of the variations in certain features of Balkan nephropathy reported from the different endemic areas; small variations in epidemiology might reflect variations in aetiological agents. Many possibilities are opened up by this work. The chemists and biochemists will want to characterise the putative nephrotoxin and establish its mode of action on the proximal tubular epithelium, The pathologists will be interested in the further evolution of the tubular changes and, above all, in the possible relation between Balkan nephropathy and renal-tract tumours. The very recent demonstration 12 of close similarities between Balkan nephropathy and urothelial tumours with respect to geographical clustering, age, and sex within the Vratza district is of particular interest. Most importantly, the case for implicating fungi in the aetiology of Balkan nephropathy seems to have been strengthened. More information is obviously required about P. verrucosum var. cyclopium and the other nephrotoxin-producing fungi which are almost certainly present in the endemic areas; but it would not be premature to reinforce measures aimed at preventing the local contamination of foodstuffs by potentially lethal fungi.
Hypertension in the Elderly THREE months ago JACKSON and his colleagues’I reported on six previously healthy patients aged between 64 and 84 admitted to hospital within a few days of starting hypotensive medication. In each case a large fall in blood-pressure was associated with severe but mainly reversible consequences such as actual or near loss of consciousness. The subsequent correspondencez-5 has focused on several interrelated problems common to much of present medical practice. Is there an increased risk associated with hypertension in the elderly and is this risk reversible with therapy? At what cost in iatrogenic disease might some increase in survival be purchased, and can the labour and expense of detecting and treating symptomless hypertension in this age-group be justified in social and economic terms? Raised diastolic and systolic pressures are very common in old age and much of the argument that they can be ignored is based on the thesis that what is common must be normal and therefore safe, on descriptions of hypertensives who have reached a
Jackson, G., Pierscianowski, T. A., Mahon, W., Condon, J. R. Lancet, 1976. ii, 1317. 2. Barlow, D. T. C. ibid, 1977, i, 89. 3 Fairman, M. ibid. p. 200. 4. Jackson, G, Pierscianowski, T. A., Mahon, W., Condon, J. R. ibid. p. 367. 5 Jones, J. V., Graham, D. I. ibid, p. 425. 6. Tudor Hart, J. Jl R. Coll. gen. Practnrs, 1975, 25, 160. 7. Wedgwood, J. Br. med. J. 1973, iii, 622. 1.
13. 14.
Sattler, T. A., Dimitrov, Ts., Hall, P. W. Lancet, 1977, i, 278. Austwick, P. K. C., Smith, L. P. in Second International Symposium on Endemic Nephropathy (edited by A. Puchlev); p. 262. Bulgarian Academy of Sciences, Sophia, 1974. 15. Krogh, P., Axelsen, N. H., Elling, F., et al. Acta path. microbiol. scand. A 16.
1974, suppl. 246. Krogh, P., Elling, F., Hald, B., et al. ibid. 1976, 84,
215.
Yugoslavia, Bulgaria, and Romania. It is a region of generally high humidity and high rainfall. No local peculiarities in geology have been described. Important information is provided by the incidence of Balkan nephropathy in individuals
of
move into or out of the endemic area. A hisof residence in the affected area for at least 15 tory is usual, accounting for the development of years nephropathy among incomers from disease-free regions who settle in the endemic areas and for the rarity of the disease among people who left the endemic areas when young. The pathology of Balkan nephropathy is equally unusual. The major renal lesion is one of progressive tubular destruction and interstitial and capsular fibrosis.1-6 Gross renal atrophy results. The tubular damage is seen principally in the lower parts of the proximal convoluted tubule and the changes in loop of Henle. The status of glomerular 4 6-8 Balkan nephropathy is disputed.3 They were as tubular the originally regarded secondary to lesions and the interstitial fibrosis. Recent work8 suggests a more distinct glomerular component in the disease process, with local deposition of immune complexes. The central importance of the tubular lesions in Balkan nephropathy is, however, emphasised by the results of renal function tests. 1-4 910 The first detectable abnormality is tubular proteinuria, shown by an increase in urinary &bgr;2-microglobulin and changes in electrophoretic patterns. Defects in acidification and ammonia and urea excretion follow, then alterations in p-aminohippurate clearance and glycosuria culminating in a falling glomerular filtration-rate and renal decoxnpensation. Overt proteinuria, detected by routine tests, is a late feature of the disease, and tests for early tubular proteinuria are essential. Estimations of urinary &bgr;2-microglobulin and urine electrophoresis have proved valuable in epidemiological surveys in the endemic areas. In the course of such investigations some patients have begun to have tubular proteinuria while others have shown an oscillating pattern with tubular proteins appearing only between October and February-an observation which could have important setiological implications. One final piece of information has to be added to the pathology.1 2411 12 About a third of patients dying of Balkan nephropathy in Bulgaria and Yugoslavia have papillomas and/or carcinomas of the renal pelvis, ureter, or bladder. The tumours are sometimes multiple and some-
who
Balkan
Nephropathy
THE natural history of Balkan (endemic) nephropathy is one of the most fascinating topics in renal medicine. 1-5 A consensus view of some of the salient features may be summarised as follows. The
clinical picture is one of progressive renal failure, insidious in onset and usually unaccompanied by salt retention or hypertension. The disease occurs principally between the ages of 30 and 60 and is very rare below 20 or above 70. Females predominate (2/1) in the younger age-groups but later the sex difference is lost. Survival-times range from a few months to nearly 10 years with approximately half the patients dying in 2 years. A family history of Balkan nephropathy is found in about 1 in 5 cases in the endemic area. The disease is rural rather than urban, and most of the patients are connected with farming. There is no association with socioeconomic status, nutrition, or hygiene. The incidence of Balkan nephropathy within the endemic area is variable, but levels as high as 10% of the population have been claimed for some villages with perhaps 30% of individuals showing symptomless proteinuria. Clustering of cases in certain parts of villages, even in individual houses, has been described. The endemic area is situated at an altitude of 300 to 500 metres and lies in the vicinity of the Danube and its tributaries in adjacent parts
Hall, P. W., Dammin, G. J., Griggs, R. C., Fajgelj, A., Zimonjic, B., Gaon, B. Am. J. Med. 1965, 39, 210. 7. Craciun, E. C., Rosculescu, I. ibid. 1970, 49, 774. 8. Apostolov, K., Spasić, P., Bojanic, N. Lancet, 1975, ii, 1271. 9. Hall, P. W., Piscator, M., Vasiljević, M., Popovic, N. Q. Jl Med. 1972, 41,
6. 1. International
Symposium on Endemic Nephropathy (edited by Bulgarian Academy of Sciences, Sofia, 1965.
2. Lancet, 1966, i, 304. 3. The Balkan Nephropathy
(edited by G.
A.
E. W. Wolstenholme and
Puchlev).
J. Knight).
London, 1967. 4. Second International
Symposium on Endemic Nephropathy (edited by Puchlev). Bulgarian Academy of Sciences, Sofia, 1974. 5. Austwick, P. K. C. Proc. R. Soc. Med. 1975, 68, 219. A.
385. 10. Hall, P. W., Vasiljević, M. J. Lab. clin. Med. 1973, 81, 897. 11. Marković, B. Isr. J. med. Sci. 1972, 8, 540. 12. Chernozemsky, I. N., Stoyanov, I. S., Petkova-Bocharova, T. K., J. Cancer, 1977, 19, 1.
et
al. Int.
684
times bilateral. A proportion of these tumour patients, and of "healthy" individuals from the same geographical area, have raised serum &bgr;2-microglobulin levels." The search for aetiological agents in Balkan nephropathy has focused on possible local factors. Studies of several trace elements in the soil and water, and in tissues from patients with the disease, have proved inconclusive: the trace elements in question include lead, copper, zinc, uranium, barium, cadmium, arsenic, fluorine, cobalt, and chromium.1 3The disease existed before the advent of synthetic agrochemicals. There is no evidence to implicate bacteria such as &bgr;-haemolytic streptococci, Leptospira ieterohaemorrhagiae, and brucellae. Claims have been made for arborviruses and a coronavirus.8 Reviewing the subject in 1967, BARNES3 drew attention to the possible role of nephrotoxic fungi occurring as contaminants on foodstuffs, a notion which gained support from the later observations of AUSTWICK and SMITH.14 These workers reported a statistically significant correlation in three endemic areas between variation in the late-summer and autumn rainfall and the number of local deaths from Balkan nephropathy during the succeeding two years-the first clear association between a local environmental factor and the disease. They also described heavy fungal contamination of local foodstuffs, particularly by Penicillium verrucosum var. cyclopium and Fusarium spp. Attempts to demonstrate mycotoxins were unsuccessful but in a new investigation, reported this week on p. 671, one strain of P. verrucosum var. cyclopium induced striking renal tubular lesions when force-fed to rats for only 20 days. The lesions, located in the pars recta and junctional zone of the proximal convoluted tubule, are closely similar to the tubular changes in many patients with Balkan nephropathy ; 1-4 6 and at
present
they
seem to
provide
an
acceptable experi-
mental model for the disease. It is clearly a model rather than the model, and other nephrotoxin-producing fungi may be involved in the human disease as well as additional (non-fungal) setiological agents; one important mycotoxin which should be explored in more detail is ochratoxin A.15 16 A stumbling-block is the discrepancy between the wide distribution of the fungus and the apparently narrow distribution of the disease, though it is possible that Balkan nephropathy is waiting to be discovered outside South Eastern Europe-for instance, in Africa. A useful exercise would be to
review some of the variations in certain features of Balkan nephropathy reported from the different endemic areas; small variations in epidemiology might reflect variations in aetiological agents. Many possibilities are opened up by this work. The chemists and biochemists will want to characterise the putative nephrotoxin and establish its mode of action on the proximal tubular epithelium, The pathologists will be interested in the further evolution of the tubular changes and, above all, in the possible relation between Balkan nephropathy and renal-tract tumours. The very recent demonstration 12 of close similarities between Balkan nephropathy and urothelial tumours with respect to geographical clustering, age, and sex within the Vratza district is of particular interest. Most importantly, the case for implicating fungi in the aetiology of Balkan nephropathy seems to have been strengthened. More information is obviously required about P. verrucosum var. cyclopium and the other nephrotoxin-producing fungi which are almost certainly present in the endemic areas; but it would not be premature to reinforce measures aimed at preventing the local contamination of foodstuffs by potentially lethal fungi.
Hypertension in the Elderly THREE months ago JACKSON and his colleagues’I reported on six previously healthy patients aged between 64 and 84 admitted to hospital within a few days of starting hypotensive medication. In each case a large fall in blood-pressure was associated with severe but mainly reversible consequences such as actual or near loss of consciousness. The subsequent correspondencez-5 has focused on several interrelated problems common to much of present medical practice. Is there an increased risk associated with hypertension in the elderly and is this risk reversible with therapy? At what cost in iatrogenic disease might some increase in survival be purchased, and can the labour and expense of detecting and treating symptomless hypertension in this age-group be justified in social and economic terms? Raised diastolic and systolic pressures are very common in old age and much of the argument that they can be ignored is based on the thesis that what is common must be normal and therefore safe, on descriptions of hypertensives who have reached a
Jackson, G., Pierscianowski, T. A., Mahon, W., Condon, J. R. Lancet, 1976. ii, 1317. 2. Barlow, D. T. C. ibid, 1977, i, 89. 3 Fairman, M. ibid. p. 200. 4. Jackson, G, Pierscianowski, T. A., Mahon, W., Condon, J. R. ibid. p. 367. 5 Jones, J. V., Graham, D. I. ibid, p. 425. 6. Tudor Hart, J. Jl R. Coll. gen. Practnrs, 1975, 25, 160. 7. Wedgwood, J. Br. med. J. 1973, iii, 622. 1.
13. 14.
Sattler, T. A., Dimitrov, Ts., Hall, P. W. Lancet, 1977, i, 278. Austwick, P. K. C., Smith, L. P. in Second International Symposium on Endemic Nephropathy (edited by A. Puchlev); p. 262. Bulgarian Academy of Sciences, Sophia, 1974. 15. Krogh, P., Axelsen, N. H., Elling, F., et al. Acta path. microbiol. scand. A 16.
1974, suppl. 246. Krogh, P., Elling, F., Hald, B., et al. ibid. 1976, 84,
215.
