Balkan endemic nephropathy

INTRODUCTION — Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease associated with a high frequency of urothelial atypia, occasionally culminating in tumors of the renal pelvis and urethra.

Affected patients most commonly reside in Southeastern Europe, including the areas traditionally considered to comprise the Balkans: Serbia, Bosnia and Herzegovina, Croatia, Romania, and Bulgaria. More specifically, BEN is most likely to occur among those living along the confluence of the Danube River, a region in which the plains and low hills generally have high humidity and rainfall. The currently accepted cause of BEN is exposure to aristolochic acid (AA). In contrast to the classic presentation of AA nephropathy, which is characterized by a rapid decline in kidney function (six months to two years), BEN is slowly progressive (10 to 20 years), however, likely related to low-level exposure [1].

This topic reviews BEN. The classic presentation of AA nephropathy is discussed elsewhere. (See "Nephropathy induced by aristolochic acid (AA) containing herbs".)

EPIDEMIOLOGY — The estimated prevalence of BEN in endemic areas ranges between 0.5 to 4.4 percent [2]. It has been suggested that the prevalence would be as high as 20 percent if aggressive screening were to be performed in at-risk populations; a striking observation is that nearly all affected patients were farmers. In some regions in Bosnia, approximately 10 percent of the patients on dialysis have BEN as the cause of end-stage kidney disease (ESKD) [3].

The prevalence of BEN appears to be decreasing. For many decades, the prevalence of BEN remained stable and approximately the same in the majority of endemic areas [4]. However, more recently the number of patients with the diagnosis of BEN in dialysis centers, an indirect measurement of the prevalence of BEN, has decreased in Bosnia Herzegovina and Serbia. For example, according to an annual report on dialysis and kidney transplantation in Bosnia and Herzegovina, the number of BEN patients on kidney replacement therapy decreased from 305 to 148 (79.7 to 42.2 per million people) from 2008 to 2019 [5].

The putative decrease in BEN prevalence over the last few decades may be due to diminished exposure to aristolochic acid (AA), a strong environmental nephrotoxin and carcinogen. AA exposure has decreased because of significant improvement in farming and milling practices and prevention of the contamination of flour. The differences in prevalence observed in different countries could be due to differences in AA exposure, diagnostic criteria and methodology, in case fatality or duration of disease, or in immigration patterns [6].

ETIOLOGY — Over the years, an impressive number of potential etiologic agents and genetic factors have been proposed [7,8]. BEN is most likely caused by chronic exposure to low concentrations of aristolochic acid (AA) [9-11]. AA, a mutagenic and nephrotoxic alkaloid found in the plant Aristolochia clematitis, most likely underlies both Chinese herbal nephropathy and BEN [9,12]. There are striking pathologic and clinical similarities between BEN and the progressive interstitial fibrosis observed in young women who have been on a slimming regimen including Chinese herbs (as well as other agents) (table 1) [12,13]. In addition, using ultrasensitive methods utilizing liquid chromatography and mass spectroscopy, aristolactam-DNA adducts were demonstrated in the kidney cortex of individuals with BEN and in urothelial tumors from individuals from endemic regions [14]. Characteristic A:T→T:A mutations of the TP53 tumor-suppressor gene were also identified in urothelial tumors from residents of BEN-endemic villages. In a follow-up study, aristolactam-DNA adducts were demonstrated in 70 percent of 67 individuals with urothelial tumors who resided in BEN-endemic areas. The aristolactam-DNA adducts were present in 94 percent of individuals who had A:T→T:A mutations in TP53. By contrast, neither the aristolactam-DNA adducts nor A:T→T:A mutations were detected in urothelial tumors of 10 patients residing in nonendemic areas [15,16]. (See "Nephropathy induced by aristolochic acid (AA) containing herbs".)

These clinical, histopathologic, epidemiologic, and toxicologic data suggest that long-term exposure to AA is the etiologic factor in BEN [13,17]. AA nephropathy has been proposed as a more correct term for BEN [13].

Other toxins and environmental exposures that are found in the Balkans and/or are unique to that area have been considered. Many suspect agents and/or general group of compounds or organisms have been implicated, but none have been definitively linked. These include trace elements (lead, cadmium, silica, selenium), viruses, plant toxins, fungi (ochratoxin A, a mycotoxin), and/or aromatic hydrocarbons [18-20].

Ochratoxin A, a mycotoxin which induces oxidative DNA damage and causes nephrotoxicity in experimental models, has been found in much higher levels in the blood and urine of individuals in areas endemic for BEN and affected with BEN [21-23]. However, similarly high exposure occurs throughout the world in farming communities, which are largely free of chronic kidney diseases (CKDs) [23,24].

Polycyclic aromatic hydrocarbons or other toxins leached from coal into the water supply were found in higher levels in affected areas in one study, but a larger study failed to find higher levels of these hydrocarbons or other dissolved organic compounds in the water supply of endemic villages compared with nonendemic villages [25].

Genetic factors — A genetic predisposition to BEN has been proposed by some investigators. Support for this hypothesis includes observations that the disease clearly affects specific families and that some ethnic populations who have lived in the area for generations (such as Roma) do not suffer from BEN. Although a mode of inheritance has not been established, polygenetic inheritance appears to be most plausible.

The reported prevalence of BEN is 3 to 7 percent in the exposed population [26]. Genetically determined interindividual variability may contribute to the risk of developing BEN and urothelial tumors [26]. Polymorphisms that effect susceptibility to BEN and urothelial tumors are likely to be found in genes responsible for the absorption, bioactivation metabolism, detoxification (cytochrome P450-mediated O-methylation), excretion, and transport of AA.

A possible causative gene(s) has not been identified. Candidate genes have been localized to the region between 3q24 and 3q26 [27]. Given the association with bladder cancer, a correlation with mutations in the p53 tumor suppressor gene has also been explored [28]. Whether this gene predisposes to BEN or bladder cancer in these patients is unclear.

A unifying hypothesis may be that BEN develops in genetically predisposed individuals who are chronically exposed to a causative agent found within endemic areas. This possibility was suggested by a study of 100 adult offspring (mean age 49 years) of individuals with BEN who were compared with adults from unaffected families (most of whom were from endemic villages) [29]. Individuals whose mothers had BEN had slightly smaller kidneys and somewhat greater degree of proteinuria, moderately increased albuminuria (formerly called "microalbuminuria"), and beta2-microglobinuria. These individuals probably represent early cases of BEN and suggest a maternal association with BEN risk. Whether this reflects an X-linked genetic factor or exposure to environmental toxins in utero is unproven [30].

However, the following observations are inconsistent with a genetic basis or in utero exposure as a sole explanation for the disease:

●BEN has been observed in individuals who have migrated from nonendemic into endemic areas and in previously unaffected families who have lived for at least 15 years in endemic areas.

●BEN does not develop in individuals who left endemic areas early in life, despite being from previously affected families, or who spent less than 15 years in high-incidence areas.

PATHOLOGY — With early disease, kidney histology reveals cortical focal tubular atrophy, interstitial edema, and peritubular and glomerular sclerosis, with limited mononuclear cell infiltration. Narrowing and endothelial swelling of interstitial capillaries (eg, capillarosclerosis) are also described.

In advanced cases, marked tubular atrophy and interstitial fibrosis develop, along with focal segmental glomerular changes and global sclerosis [31]. As mentioned, there is also an extremely high incidence of cellular atypia and urothelial carcinoma of the genitourinary tract.

CLINICAL FEATURES — BEN is a slowly progressive tubulointerstitial disease that may culminate in end-stage kidney disease (ESKD). Clinical manifestations first appear in patients 30 to 50 years of age; findings prior to the age of 20 years are extremely rare.

One of the first signs of BEN, detected only when prospective monitoring is performed, is tubular dysfunction. This is characterized by increased excretion of low-molecular-weight proteins (such as beta2-microglobulin and neopterin [32]) that are not detected on the urine dipstick for protein [29,33]. Among offspring of patients with BEN who had no clinical kidney abnormalities, 6 percent had elevated beta2-microglobulin levels compared with 1 percent in the control group [29].

Early tubular injury can also lead to renal glucosuria, aminoaciduria, and diminished ability to handle an acid load. Over more than 20 years, there is a progressive decrease in concentrating ability (possibly resulting in polyuria) and in the glomerular filtration rate (GFR). Many patients eventually progress to ESKD. As an example, among 18 patients with BEN followed for a mean of 15 years, six progressed to requiring dialysis [34].

Additional clinical features include:

●Patients are usually normotensive and without edema; hypertension only develops with end-stage disease.

●A normochromic normocytic anemia occurs with early disease, which becomes increasingly pronounced as the disorder progresses.

●Urinary tract infection (UTI) is rarely observed [35].

●The kidneys are usually of normal size early in the course of the disease [36]. A symmetric reduction of kidney size with a smooth outline and normal pelvicaliceal system is subsequently observed with late-stage disease. Intrarenal calcifications are not observed.

●High incidence of transitional cell carcinoma, predominantly of the renal pelvis and ureter, but also involving the urinary bladder, in BEN-endemic areas (2 to 50 percent, which is a 2- to 10-fold higher incidence than in nonendemic areas) [3,37-40]. These tumors are generally superficial and slow growing. (See "Malignancies of the renal pelvis and ureter" and "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder".)

DIAGNOSIS — The diagnosis of BEN is typically considered in a patient with slowly progressive chronic kidney disease (CKD) who is living in or recently moved from an endemic area, particularly if the family history is positive for BEN.

The diagnosis is based upon the presence of some combination of the following findings (table 1):

●Symmetrically shrunken, smooth kidneys without intrarenal calcifications

●Mild tubular proteinuria, hyposthenuria, and glucosuria

●Normochromic hypochromic anemia out of proportion with the decrease in glomerular filtration rate (GFR)

●Urothelial atypia

●A panel of nonspecific histologic findings on kidney biopsy, although a kidney biopsy is not necessary if the above findings are present in a patient from an endemic area or with a positive family history (see 'Pathology' above)

Differential diagnosis — The course and histologic appearance of BEN can resemble that of other chronic interstitial nephropathies, including analgesic nephropathy and Chinese herb nephropathy. The history typically reveals ingestion of the potential causative substance in the latter disorders, and these can be further differentiated from BEN by the absence of a positive family history and the finding of shrunken kidneys with irregular contours on ultrasonography (versus smooth contour) (table 1). (See "Clinical manifestations and diagnosis of analgesic nephropathy" and "Nephropathy induced by aristolochic acid (AA) containing herbs".)

MANAGEMENT — There is no specific treatment for BEN. Therapy is largely supportive, including implementation of strategies to delay progression and manage the complications of chronic kidney disease (CKD). Patients who progress to end-stage kidney disease (ESKD) may be treated with dialysis or kidney transplantation. (See "Overview of the management of chronic kidney disease in adults" and "Indications for initiation of dialysis in chronic kidney disease".)

Given the high incidence of cellular atypia of the genitourinary tract, we advocate surveillance with urine sent for cytology once a year [41]. For patients who are considering or have undergone transplantation, screening with urine cytologies every six months is recommended. (See "Malignancies of the renal pelvis and ureter".)

Whether bilateral native nephroureterectomies are advisable in those who have progressed to ESKD, particularly those undergoing kidney transplantation, is unclear. A similar problem faces patients with Chinese herbal nephropathy. (See "Nephropathy induced by aristolochic acid (AA) containing herbs".)

Implementing public health measures to avoid aristolochic acid (AA) exposure will likely be the most effective way to prevent BEN in countries harboring the disease [42].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY

●Epidemiology – Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease that is most commonly reported in patients who reside in Southeastern Europe. The estimated prevalence is between 0.5 and <5 percent, with most cases reported in farmers. (See 'Introduction' above and 'Epidemiology' above.)

●Etiology – BEN is likely caused by exposure to aristolochic acid (AA). AA nephropathy has been proposed as a more correct term for BEN. (See 'Etiology' above.)

●Pathology – In early disease, kidney histology reveals cortical focal tubular atrophy, interstitial edema, and peritubular and glomerular sclerosis with limited mononuclear cell infiltration. In advanced cases, marked tubular atrophy, interstitial fibrosis, and focal segmental glomerulosclerosis are seen. (See 'Pathology' above.)

●Clinical features – Early clinical manifestations include clinically silent tubular dysfunction (eg, glucosuria, aminoaciduria). More advanced disease leads to decreased concentrating ability and glomerular filtration rate (GFR) and progression to end-stage kidney disease (ESKD). Patients with BEN have anemia out of proportion to the degree of reduced GFR, and they have a high risk of urothelial malignancy. (See 'Clinical features' above.)

●Diagnosis – The diagnosis is typically considered in a patient with slowly progressive chronic kidney disease (CKD) who is living in or recently moved from an endemic area. Clinical findings of tubular dysfunction, anemia disproportionate to GFR, and features on kidney ultrasound support the diagnosis. Kidney ultrasound is normal with early disease; more advanced disease is characterized by a symmetric reduction of kidney size, with a smooth outline and normal pelvicaliceal system, without intrarenal calcifications. (See 'Clinical features' above and 'Diagnosis' above.)

●Management and prevention – Therapy is largely supportive, including strategies to delay progression and manage the complications of CKD. Given the high incidence of cellular atypia of the genitourinary tract, we suggest regular surveillance with urine cytology once or twice per year. Improvements in farming and milling practices and prevention of the contamination of flour by AA most likely help to prevent BEN. (See "Overview of the management of chronic kidney disease in adults" and 'Management' above.)