Balkan endemic nephropathy (BEN) is chronic irreversible tubulointerstitial nephritis that is diagnosed in agrarian regions of the Balkan (Bosnia and Herzegovina, Bulgaria, Croatia, Romania, and Serbia). BEN has never been documented in children and adolescents, has insidious onset, and is usually diagnosed in the fifth decade with terminal renal failure developing in sixth and seventh decade of life. The disease is also characterized by frequent occurrence of tumours of the renal pelvis and urethers. Majority of endemic villages are located at the alluvial valleys of Danube and its tributary rivers. There have been no significant changes in the geographic distribution of BEN since its first descriptions in 1950s [
Members of Society of Nephrology, Dialysis and Transplantation in Bosnia and Herzegovina have organised screening in one village of Bosanska Posavina, Domaljevac, a known endemic village located near Sava River, between the towns Samac and Odzak. Inhabitants received a general call for health checkup that included history, physical exam, urine dipstick test (Combur-Test Urine test strips, Cobas, Roche) and urine test for microalbuminuria in those with negative proteinuria (Micral-Test, ACCU-CHEK, Roche). Screening was done by nephrologists, medical students, local physicians, and nurses. The checkup completed in 387 inhabitants (around 10% of total village population), between 9 and 91 years old. Over 60% of examinees were women. We divided examinees into two groups: examinees with family burden for BEN and examinees without family burden for BEN. 149 (38.5%) Domaljevac inhabitants reported positive family history of BEN. Few months after the initial screening, we invited subjects with proteinuria or microalbuminuria for additional testing in accordance with the project of early detection of chronic renal disease in high risk groups in Bosnia and Herzegovina [
Urine was examined by dipstick method, for determination of microalbuminuria, creatinine in urine (by kinetic method with alkali picrate in an Architect ci/8200-Abbott Diagnostics, Wiesbaden, Germany), and urinary A1MG (by an immunonephelometric method using Behring Nephelometer II (BN II)-Dade Behring, Marburg, Germany), and A1MG/creatinine ratio was calculated. The cut-off value for A1MG for BEN screening purposes was 10 mg/L, according to the recommendations of International Workshop on Screening, Diagnosis, Classification and Treatment of Endemic (Balkan) Nephropathy [
Using standard biochemical methods, blood levels of creatinine, fasting glucose, cholesterol HDL, LDL, triglycerides, and hemoglobin were determined, with values expressed in SI units. Glomerular filtration rate was estimated (eGFR) in all individuals, using the MDRD formula. Ultrasound examination of kidneys was done by two experienced nephrologists (Logic 3 General Electric device with 3,75 MHz probe), with measurement of length, width, and parenchyma thickness. Average length was calculated by adding length of both kidneys and dividing it by two. Values lower than 100 mm were assumed to be reduced kidney length [
Individuals with known or newly diagnosed diabetes were excluded from further analyses (five with positive BEN family history and seven without). Since it is known that hypertension may alter excretion of A1MG [
Besides descriptive statistics, we used inferential statistics for data analysis. D’Agostino-Pearson test showed that urinary A1MG and A1MG/creatinine ratio did not have normal distribution, while all other variables were normally distributed. Statistical significance of difference in numerical variables between the groups were tested using Mann-Whitney Test (small samples), while differences for nominal variables were tested using Fisher’s exact test (small samples).
Demographic structure of the examined population was similar in both groups (Table
Demographic structure of the examined population.
Positive family history for BEN | Negative family history for BEN | |
---|---|---|
Men | 11 (45.83%) | 13 (41.63%)* |
Women | 13 (54.17%) | 19 (59.37%)* |
Age (median) | 44 yrs | 42.5 yrs* |
Proteinuria, microalbuminuria, A1MG, and kidney size in the examined persons.
Positive family history for BEN ( |
Negative family history for BEN ( |
|
|
---|---|---|---|
Proteinuria ( |
7 (29.17%) | 5 (15.63%)* | 0.403 |
Microalbuminuria ( |
8 (33.33%) | 13 (40.63%)* | 1.0 |
Microalbuminuria (mg/L) |
|
|
0.49 |
Urinary A1MG (mg/L) |
|
|
0.87 |
Kidney length (mm) |
|
|
0.86 |
Cortex width (mm) |
|
|
0.30 |
Table
Average values of urinary A1MG/creatinine ratio were
We also did not find statistically significant difference in frequency of reduced kidney length (less than 100 mm) between these groups.
Diagnosis of BEN in early, asymptomatic stage is challenging. Even when decline in renal function exists, the symptoms and signs of the disease are not specific. Renal biopsy is performed in a very limited number of patients with BEN suspicion and BEN is still diagnosed if agreed diagnostic criteria are met and after excluding other possible renal diseases.
Basic criteria for diagnosis of BEN defined by Danilovic [
This Consensus Statement [
During all these years, different criteria were suggested or added to the accepted diagnostic criteria for BEN, in order to improve the diagnosis of BEN in its early stages. Among others, there were decreased kidney volume and shorter longitudinal diameter of the kidney found on ultrasonography. Anemia, more profound than expected for the given stage of CKD, was considered for a long time as one of the criteria for diagnosing early BEN [
In affected households, both genetically related and non-related family members are at risk, supporting the argument that familial aggregation is more important than heredity [
Considering above mentioned findings, we wanted to compare certain characteristics, including A1MG and the ratio, and see if they differ between apparently healthy individuals with and without family burden for BEN, all living in endemic area, in order to define those characteristics that could be part of the pathophysiological pathway of the disease, which would make them the potential early marker of the disease.
There is a scarce number of previous studies that examined kidney function in detail in the early phases of BEN. Mainly, it was proved that primary lesion in BEN affects the proximal tubule. Radonic and Radosevic in 1992 also described changes in urinary concentrating ability, occurring some time before decease in renal blood flow and GFR [
Proximal tubular dysfunction is main characteristics of BEN. Beta 2 microglobulin (B2MG) was considered as a sensitive marker of tubulopathy for many years, and it was used in screening for BEN [
In our current study, we did not find statistically significant differences neither in median values of A1MG, nor in frequency of elevated values of A1MG between the two groups. Similarly, no statistical difference was found in urine A1MG/creatinine ratio, proteinuria, and microalbuminuria as well as in average blood pressure, hemoglobin level, and haematuria between these two groups. Arsenović et al. had similar findings in their study, with no differences in the frequency of renal function disorders (proteinuria, alpha1-microglobulinuria, urine specific gravity, osmolality, functional excretion of sodium, and tubular phosphate resorption) or anemia between individuals with and without family BEN burden [
Ultrasound kidney measurements in our study showed smaller average values, but still in the normal limits and without any differences between examinees with positive family history of BEN and examinees without family history of BEN. In Bulgaria, in the endemic region of Vratza, it was reported that the average length of kidney in the offspring of BEN patients was significantly smaller than in the other examinees [
Since in our study we did not confirm statistically significant difference in the examined markers between healthy individuals with and without family history for BEN, we considered that these markers are probably not a part of pathophysiological pathway of the disease and are not predictive of risk for BEN. Alterations in these characteristic (increased urinary excretion of A1MG, reduced kidney length and cortex width, etc.) are probably acquired nonspecific indicators of already altered tubular and renal function in affected individuals. On the other hand, B2MG, a known early marker for BEN that we did not evaluate in our patients, could be, according to some authors, more than just a marker and may play a role in the pathogenesis of the disease [
We suggest screening for BEN and CKD in all inhabitants of endemic villages, regardless of family BEN burden. Although inhabitants of BEN villages without family burden for BEN have low risk of developing BEN, their risk is probably higher than that in the population outside BEN areas. These individuals should be included in regular mass screening. The incidence of BEN is underestimated since ESRD represents just the tip of the iceberg. Other stages of CKD caused by BEN represent a greater medical burden. Even though BEN shifted toward older age groups, Dimitrov et al. [
The increased A1MG along with increased albumin excretion in clinically healthy inhabitants of endemic area, found in our and other earlier studies, are markers of early kidney injury but are also responsible for additional adverse effect on kidney function. Thus, in analogy with enhanced secondary preventive measures in diabetics with microalbuminuria, a similar approach should be undertaken in apparently healthy inhabitants of BEN endemic areas with positive proteinuria. By detecting individuals in the early stages of CKD/BEN, we can delay progression and prevent complications by more stringent control of hypertension, dyslipidemia, hyperglycemia, anemia, electrolyte disorders, and acidosis.
In our study, we did not find statistically significant difference in the examined markers between healthy individuals with and without family burden for BEN. We concluded that these markers are not predictive of risk for BEN.
The authors declare that there is no conflict of interests regarding the publication of this paper.