Balkan endemic nephropathy is a non—inflammatory tubulointerstitial lesion of the renal parenchyma in people living in endemic regions of the Balkans. It is manifested by asthenic syndrome, lower back pain, pallor and copper tinge of the skin, xanthochromia, macrohematuria, polyuria, polydipsia. It is diagnosed with the help of general and biochemical blood tests, urine, ultrasound, MRI, CT, MSCT of the kidneys, general and excretory urography, nephroscintigraphy, histological examination of the biopsy. Patients are recommended symptomatic antianemic, anti-ischemic, detoxification, renal replacement therapy, kidney transplantation.
ICD 10
N15.0 Balkan nephropathy
Meaning
Balkan endemic nephropathy (BEN) was first described as Yugoslav nephritis in 1942. In 1956, there were reports of the detection of renal pathology with a similar clinical picture in residents of Bulgarian and Romanian villages. BEN was recognized as an independent nosological unit by WHO experts in 1964. Most cases of non-inflammatory tubulointerstitial nephritis have been reported in residents of rural areas of the Balkan peninsula (Bulgaria, Bosnia and Herzegovina, Romania, Serbia, Slovenia, Croatia) located on the tributaries of the Danube. The incidence in the foci reaches 30-33%. All endemic territories are located on plains surrounded by hills or in rivers, alternating with non-endemic regions. The main contingent of patients are 30-60-year-old rural residents. Up to 40-45 years, women suffer twice as often as men, later this difference is leveled. In urban residents, children and adolescents, the disease is usually not detected. Emigrants from the Balkan countries rarely get sick when they leave early. In immigrants, BEN can develop after 15-20 years of living in the hearth.
Causes
The etiology of the disease has not been definitively established. Specialists in the field of urology and nephrology are developing several theories of the origin of pathology, each of which is partially confirmed by statistical data and observation results. For the final determination of the causes of kidney damage in the inhabitants of the Balkan region, more extensive studies are required. Presumably, the etiological factors of endemic nephropathy may be:
- Infectious agents. According to the authors of the viral and prion theories of the occurrence of Balkan tubulointerstitial nephropathy, a chronic progressive course with a long asymptomatic period corresponds to signs of a slow infection. Indirect confirmation of the infectious genesis of the disease is the isolation of cytopathogenic agents from the biological substrates of patients and the possibility of infection of laboratory animals (guinea pigs, rats). The causative agent of BEN has not yet been established, but the role of bacteria in the development of an endemic form of nephropathy has already been completely excluded.
- Nephrotoxic mycotoxins. The theory that endemic Balkan nephropathy is a chronic ochratoxicosis is quite convincing. Ochratoxin A is considered as the main nephrotoxin, which is produced by some mold fungi and enters the human body with flour products from contaminated grain. The main arguments in favor of the mycotoxic origin of the disease are the detection of an increased concentration of ochratoxin in the blood of residents of endemic areas and the similarity of pathomorphological changes with nephrological pathology in animals suffering from ochratoxicosis.
- Aristolochic acid. The theory of American scientists connects the development of Balkan nephropathy with the use of products contaminated with seeds of clematis kirkazon. This weed, which massively affects wheat fields of endemic territories, contains aristolochic acid, which has carcinogenic and nephrotoxic properties. In support of the theory, data on the development of “herbal Chinese nephropathy” in Belgian patients who took herbal preparations with kirkazone were used. The theory does not explain the absence of endemia in other regions where this plant is common.
- Pliocene lignites. Deposits of Pliocene lignites, the youngest variety of brown coal in the Balkans, have been identified in most endemic territories. They include aromatic amines that provoke the occurrence of uroepithelial cancer. Since such lignites have a loose structure, they are easily eroded by water and fall into drinking wells of farms and rural settlements. The frequent development of squamous cell carcinoma of the ureters and pelvis in the Balkan regions with a high incidence of nephropathy indirectly confirms the common etiology of these diseases, but lignites were not detected in all endemic areas.
- The genetic factor. Since the endemic variant of nephropathy often has a family character, some researchers have expressed ideas about the role of hereditary predisposition. In their opinion, the inherited mutation increases the sensitivity of the renal mesenchyma to the action of nephrotoxic modifying factors. It is possible that BEN is the result of dysembriogenetic disorders, leading to a decrease in the number of nephrons and a decrease in the functional reserve of the kidneys. The argument in favor of the genetic theory was the identification of changes in the 3rd chromosome in patients.
The role of environmental factors in the occurrence of endemic renal pathology is studied separately. In samples of soil, drinking water, local food, elevated concentrations of certain ions that have a nephrotoxic effect (vanadium, cadmium, manganese, copper, lead, chromium, etc.) are determined, some of which are found in large quantities in the biological tissues of deceased patients. The mechanism of development of nephropathy with an imbalance of minerals and their dangerous combinations have not yet been established. In addition, some urologists consider BEN as a variant of primary amyloidosis.
Pathogenesis
Although the mechanism of development of the Balkan endemic tubulointerstitial nephropathy is still being clarified, scientists have managed to compile a fairly complete picture of the pathomorphological changes occurring in the kidneys. The most likely trigger for the disorder is the expression of a mutated gene or DNA modification under the influence of a long-term effect of a possible provoking factor (ochratoxin A, aristolochic acid, virus, prion, aromatic amines, etc.). Autoimmune mechanisms can play an essential role in the formation of sclerotic processes.
The nephrons are usually the first to be affected: their basement membrane thickens, the mesangium of the glomeruli expands. At the same time, there are hydropic dystrophic changes in the epithelium of the proximal tubules, which are subsequently aggravated by thickening, hyalinization, and stratification of the basement membrane. The active growth of the interstitial connective tissue leads to the development of extracellular and perivascular sclerosis, which increases due to ischemia of the renal parenchyma against the background of thickening of the vessel walls, fibrosis of their intima and asymmetric narrowing of the lumen. The processes of fibrosis, sclerosis, hyalinization of the stroma, atrophy of most of the proximal tubules and part of the glomeruli end with severe nephrosclerosis with a decrease in kidney size by 2.5-4 times to 40-70 g.
Symptoms
The symptoms increase slowly, at the initial stages they are characterized by non-specificity. Usually, patients with Balkan nephropathy note weakness, fatigue, loss of appetite, minor pain in the lumbar region. Subsequently, uncomfortable sensations increase, periods of heaviness and dull pain in the lower back are replaced by painful attacks. The skin becomes pale, sometimes with a copper tinge, gradually turns yellow on the palms and soles. As nephropathy progresses, exercise intolerance, thirst, increased diuresis, dryness and insufficient turgor of the skin appear. Possible redness of urine due to the presence of red blood cells (macrohematuria). Edema is extremely rare. 20% of patients develop arterial hypertension.
Complications
Due to an early violation of erythropoietin synthesis, endemic nephropathy is complicated even at preclinical stages by normal or hypochromic anemia, leading to hypoxia of the brain, myocardium, other organs and tissues. Residents of the Balkan region suffering from kidney damage are 100 times more likely than those living in other territories to develop highly differentiated transitional cell cancer of the pelvis and ureters. This malignant neoplasm is detected in almost 40% of patients with BEN, and in 10% of patients the tumor process is bilateral. When an infection is attached, pyelonephritis may occur. In some cases, nephrolithiasis develops. The outcome of Balkan nephropathy is severe renal failure, leading to death from uremia with toxic multiple organ disorders.
Diagnostics
When making a diagnosis, the duration of residence in an endemic area, the dynamics of the increase in the clinical picture, and the data of laboratory and instrumental examination are taken into account. Diagnostic search is aimed both at verifying the disease and assessing the functional viability of the tubular apparatus. Diagnosis of Balkan endemic nephropathy at the latent stage of the disease is usually difficult. In such patients, the importance of the geographical criterion increases significantly. The most informative research methods are:
- General urinalysis. It is characterized by a decrease in the specific gravity of urine below 1003, tubular proteinuria up to 1 g / day with the release of mainly low-molecular β2—microglobulin, and in the later stages – α1-, α2-, β-, γ-globulins, microhematuria. Glucose is often detected in the collected material.
- Blood test. An early diagnostic sign of BEN is anemia. In patients, the total level of erythrocytes and hemoglobin decreases, with hypochromic hematopoiesis, the color index (CI) decreases. The content of leukocytes, the ratio of their types, ESR are usually not changed.
- Biochemical blood analysis. Insufficiency of the filtering function of glomeruli is detected at a late stage of nephropathy. The serum concentration of creatinine, uric acid, urea nitrogen, macronutrients increases. Violation of renal filtration is confirmed by a Rehberg breakdown.
- Nephrological complex. Already at the pre-azotemic stage of BEN, the level of excretion of amino acids in the urine increases, the excretion of ammonium and uric acid is disrupted. With the development of renal insufficiency, the content of creatinine, urea, potassium, sodium, calcium, phosphorus in the urine changes.
- Ultrasound of the kidneys. Echographic examination is more indicative at the terminal stages of endemic nephropathy: the kidneys are symmetrically reduced in size, have a homogeneous structure, and do not contain calcinates. If necessary, ultrasound can be supplemented with an overview radiography, CT, MSCT, MRI of the kidneys.
- Histology of the renal biopsy. In the obtained material, signs of dystrophy and atrophy of the proximal tubules, edema of the interstitial tissue and endothelium of the stroma capillaries are determined, single macrophages are detected. In the later stages, the morphological picture of tubulointerstitial sclerosis prevails.
Excretory urography, nephroscintigraphy can be performed to assess the filtering ability of the kidneys. Endemic Balkan nephropathy is differentiated with chronic glomerulonephritis, pyelonephritis, analgesic drug nephropathy, cystinosis, intoxication nephropathy due to poisoning with mercury, lead salts, cadmium. According to the indications, a urologist or a nephrologist attracts an oncologist, a toxicologist, a therapist to examine the patient.
Treatment
Etiotropic therapy of the disease is not offered. Medical tactics are aimed at correcting symptoms, nephroprotection, and reducing the progrediency of BEN. To reduce the load on the kidneys, it is recommended to give up hard physical work, sufficient rest, limiting the consumption of salt, protein products, water (taking into account the stage of Balkan nephropathy). Depending on the severity of clinical manifestations and the presence of complications, symptomatic therapy is carried out, including:
- Antianemic agents. Iron preparations, folic acid, erythropoietins, and anabolic steroids can be used to stimulate hematopoiesis. Patients with severe anemia are sometimes transfused with erythrocyte mass.
- Anticoagulants and antiplatelet agents. Improving the rheological properties of blood and renal blood flow can reduce ischemia and slow down fibrosis somewhat. In the terminal stages, medications of this group are not used due to increased bleeding.
- Detoxification. At the initial stage, enterosorbents, antiazotemic phytopreparations are used. With increasing renal insufficiency, patients are transferred to replacement therapy (hemodialysis, peritoneal dialysis, hemofiltration, etc.).
- Kidney transplantation. Donor kidney transplantation is a radical method of treatment of Balkan nephropathy in the terminal stages. According to the results of observations, there were no cases of recurrence of the disease in the transplanted kidney.
Prognosis and prevention
Pathological processes in the kidneys that occur with endemic nephropathy are irreversible and, in the absence of medical care, lead to death within 5-10 years from the moment of the appearance of clinical symptoms of the disease. About half of patients die in the first 2 years after the diagnosis of BEN. Due to the ambiguity of etiopathogenesis, prevention is difficult. As possible measures to prevent the development of uropathology, it is proposed to move the inhabitants of endemic foci to other territories as early as possible, to exclude closely related marriages of representatives of families in which Balkan nephropathy was detected. A possible positive role can be played by improving the environmental situation: high-quality water filtration, the fight against clematis-like kirkazone, fungal damage to grain crops, control of contamination of food with ochratoxin A. Secondary prevention is aimed at screening urological control of contingents from the risk group.