Balkan nephropathy is clinically silent initially and occurs three times more frequently in women than men. Affected individuals are usually farmers. First symptoms are nonspecific [1], occurring usually after the patient turns 30 years old and consists of weakness, anorexia, nausea, vomiting, headache, dizziness, somnolence, muscular spasms, dyspepsia, pale skin with copper-brown discoloration of the palms and soles, weight loss, episodes of macrohematuria and mild, non-characteristic pain in the lumbar area. Blood pressure remains normal in incipient phases and becomes elevated later during illness evolution. Symptoms of chronic kidney disease (uremic syndrome) become apparent as Balkan nephropathy progresses [2] [3]. Dysuria and fever are absent. Peripheral edema is seldom seen and is due to hydroelectrolytic disturbances. Working capacity is preserved for a long time. Patients with prolonged disease evolution present with urothelial tumors or signs of chronic renal failure: pollakyuria, polydipsia, and nocturia.

• Pain

  Advanced Search: • Use “ “ for phrases o [ “pediatric abdominal pain” ] • Use – to remove results with certain terms o [ “abdominal pain” –pediatric ] • Use OR to account for alternate terms o [teenager OR adolescent ] [msdmanuals.com]

  Crimean-Congo haemorrhagic fever (CCHF) is a tick-borne viral disease with symptoms such as high fever, muscle pain, dizziness, abnormal sensitivity to light, abdominal pain and vomiting. [ecdc.europa.eu]

  […] and consists of weakness, anorexia, nausea, vomiting, headache, dizziness, somnolence, muscular spasms, dyspepsia, pale skin with copper-brown discoloration of the palms and soles, weight loss, episodes of macrohematuria and mild, non-characteristic pain [symptoma.com]

  Analgesic nephropathy is most common in women in the sixth and seventh decades of life who have a history of low back pain, migraine headaches, or other chronic musculoskeletal pain. [emedicine.medscape.com]

  Veale EL, Mathie A (2016) Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan Endemic Nephropathy, is a regulator of K2P channels. Br J Pharmacol 173:1639–52 pmid:26914156 View Article PubMed/NCBI Google Scholar 13. [journals.plos.org]

• Hypertension

  […] and other organ evidence of hypertensive damage (hypertensive retinopathy and left ventricle hypertrophy) [ 9,10 ]. [ndt.oxfordjournals.org]

  In all likelihood, cases of so-called hypertensive kidney disease or hypertensive nephrosclerosis belong in the category of atherosclerotic kidney disease. [emedicine.medscape.com]

  The patients had the following common characteristics: from endemic areas; other renal ailments in the family; copper-yellow skin and orange palms and soles; normochromic anaemia; absence of acute onset, considerable albuminuria, hypertension and oedema [ncbi.nlm.nih.gov]

  The clinical picture that emerges is that of an insidiously progressive nephropathy with severe anemia but with only mild hypertension. [annals.org]

  Hypertension was defined as a systolic blood pressure 140 mm Hg and/or a diastolic blood pressure 90 mm Hg and/or history of hypertension. To identify diabetes, both history of diabetes and serum glucose were used. [sjkdt.org]

• Kidney Failure

  xanthochromia of palms and soles (Tanchev's sign), early hypochromic anemia, absence of proteinuria, and slow progression of kidney failure. [ipfs.io]

  failure N17.0 Acute kidney failure with tubular necrosis N17.1 Acute kidney failure with acute cortical necrosis N17.2 Acute kidney failure with medullary necrosis N17.8 Other acute kidney failure N17.9 Acute kidney failure, unspecified Reimbursement [icd10data.com]

  Unlike most patients with kidney failure, people with the Balkan illness often have healthy blood pressure. [newscientist.com]

  Affected individuals develop kidney damage that slowly progresses over 10 to 20 years to kidney failure. Many people with this condition also develop a type of bladder cancer known as upper urothelial carcinoma (UUC). [rarediseases.info.nih.gov]

• Uremia

  For instance, German doctors documented a large number of deaths from uremia in Serbia in 1915, while in the village of Bistretz (Bulgaria) a disease with the clinical features of BEN was reported in 1910. [uninet.edu]

• Urinary Incontinence

  Focus on today's hot topics in urology, including stress and mixed urinary incontinence; prolapse therapy; therapy for overactive bladder; and targeted therapy for renal cell carcinoma. [books.google.com]

• Incontinence

  Focus on today's hot topics in urology, including stress and mixed urinary incontinence; prolapse therapy; therapy for overactive bladder; and targeted therapy for renal cell carcinoma. [books.google.com]

Tubular type proteinuria involving albumin and β2-microglobulin is initially intermittent and not accompanied by decreased serum protein levels but later becomes permanent. It is usually less than 0.5 g/24 hours. Urine concentration ability is gradually lost and followed by a decrease in the glomerular filtration rate [4] [5]. Urinary sediment detects red, white blood cells [6] and tumor cells if the disease has become complicated by a urothelial tumor [7]. Bacteriuria, glycosuria, enzymuria, and aminoaciduria (hydroxyprolinuria) have been described. Normo- or hypochromic normocytic hypo regenerative anemia is present from the initial stages of the disease and is more severe than expected based on glomerular filtration rate reduction. It is caused by urinary or digestive losses, impaired erythropoietin synthesis, and hemolysis. The erythrocyte sedimentation rate is elevated. Complement, as well as anti-tubular basal membrane and anti-glomerular basal membrane antibodies levels, remain normal. High values of urinary leucine aminopeptidase activity have been described. Tubular dysfunction leads to salt wasting, abnormal ammonia, phosphate and uric acid excretion and urine acidification abnormalities.

Balkan nephropathy progresses in a gradual manner, with several stages. Azotemia is initially absent, then asymptomatic, with stable blood urea nitrogen level and in the end clinically overt.

Ultrasonography reveals progressive, symmetrical kidney atrophy [6] [8] due to sclerosis and high echo density of the renal pelvis and parenchyma. Histology demonstrates the substratum of these findings: interstitial and periglomerular fibrosis, glomerular lesions of the endothelial and mesangial proliferative type or micro cysts. Tubular epithelium may be dystrophic or atrophic, may be affected by hydroprotidic de-generescence or pseudo cystic dilatation. Vascular lesions consist of intimal fibrous hyperplasia or intimal fibrosis and arterial hyalinosis.

Radiography and other imaging methods may reveal carcinomas that usually involve the upper ureter or renal pelvis [9]. Tumors may also be encountered in the urinary bladder, but this is a rare finding. Urography and ascending pyelography, as well as computer tomography scans are useful in tumor diagnosis. Renal biopsy is seldom indicated because patients usually present when the kidneys are already atrophied.

GOAL: Analysis of the incidence of urothelial cancer and outcome of treatment in patients with Endemic Balkan Nephropathy (EN) after renal transplantation. [ncbi.nlm.nih.gov]

There are no known treatments to slow the progression of this disease. [myvmc.com]

Treatment and prognosis As these tumors are bilateral, multiple and of low grade conservative management is the mainstay of treatment 1. Promoted articles (advertising) [radiopaedia.org]

Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy., et al. Nephrol Dial Transplant 29(11):2020-2027, 2014. [medicine.stonybrookmedicine.edu]

Prognosis of Balkan Endemic Nephropathy (BEN) The prognosis of this condition is poor, as those who develop Balkan endemic nephropathy progressive to chronic renal failure over a period of three months to ten years. [myvmc.com]

[…] nephropathy endemic to the littoral regions of the Danube, occurring in the Balkans—Bulgaria, Croatia, Romania, Serbia Etiology Unknown; converging lines of evidence suggest a link to long-term consumption of food contaminated with aristolochic acid Prognosis [medical-dictionary.thefreedictionary.com]

Symptoms and prognosis The disease primarily affects people age 30 to 60 years of age. People moving to endemic areas do not develop the condition until living there for 15 years. [ipfs.io]

Treatment and prognosis As these tumors are bilateral, multiple and of low grade conservative management is the mainstay of treatment 1. Promoted articles (advertising) [radiopaedia.org]

Hypotheses have been advanced over many years to explain the etiology of EN; we are pursuing an earlier, largely ignored and untested hypothesis that seeds of Aristolochia clemantitis contaminate grain used in baking bread, a dietary staple in the endemic [grantome.com]

Using a molecular epidemiologic strategy, we recently established that aristolochic aid (AA) is the etiologic agent responsible for BEN and its associated UUC. [medicine.stonybrookmedicine.edu]

Balkan endemic nephropathy and the associated urinary tract tumours: review on etiological causes, potential role of mycotoxins. Ochratoxin A in human blood in relation to Balkan endemic nephropathy and urinary tract tumours in Bulgaria. [medical-dictionary.thefreedictionary.com]

"Aristolochic acid and the etiology of endemic (Balkan) nephropathy". Proc. Natl. Acad. Sci. U.S.A. 104 (29): 12129–34. doi : 10.1073/pnas.0701248104. PMC 1913550. PMID 17620607. ↑ Julia C. Mead (2007). "Manna from hell". [ipfs.io]

Abstract Endemic Balkan nephropathy (EBN) is a kidney disease of unknown etiology limited to Bulgaria, Rumania and former Yugoslavia. [ncbi.nlm.nih.gov]

Significant epidemiologic features of EN include its occurrence within certain villages; among these villages, only members of certain households are affected. [grantome.com]

Using a molecular epidemiologic strategy, we recently established that aristolochic aid (AA) is the etiologic agent responsible for BEN and its associated UUC. [medicine.stonybrookmedicine.edu]

↑ The Epidemiology, Diagnosis, and Management of Aristolochic Acid Nephropathy: A Narrative Review Annals of Internal Medicine 19 March 2013, Vol 158, No. 6 ↑ Elif Batuman (August 12, 2013). [ipfs.io]

Such an explanation fits most of the existing epidemiological data. [ncbi.nlm.nih.gov]

[…] scientists to understand the main issues of epidemiological study design and analysis. [books.google.com]

This hypothesis is supported by striking similarities between the pathophysiology of EN and the recently recognized syndrome of aristolochic acid nephropathy. Scientists based at the Univ. of Zagreb School of Medicine and Rudjer Boskovic Inst. [grantome.com]

In addition, the renal pathophysiology and histopathology observed in endemic nephropathy most closely resemble the entity known as aristolochic acid nephropathy. [ncbi.nlm.nih.gov]

Although various hypotheses had been advanced to explain the etiology of BEN/UUC none could fully explain the unique epidemiological and pathophysiological features of this disease, and its cause remained a mystery. [medicine.stonybrookmedicine.edu]

Brenner/Rector remains the go-to resource for practicing and training nephrologists and internists who wish to master basic science, pathophysiology, and clinical best practices. [books.google.com]

These results therefore provide further structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2. [journals.plos.org]

A high incidence of urothelial cancer in end-stage BEN patients strongly suggests preventive nephro-ureterectomy in all end-stage patients with BEN treated with either transplantation or dialysis. [ncbi.nlm.nih.gov]

[…] endemic nephropathy is caused by chronic dietary exposure to low concentrations of a toxin called aristolochic acid, which comes from a plant called Aristolochia clematis. [1] [2] [3] Genetics factors may also be involved. [2] [3] There is no specific prevention [rarediseases.info.nih.gov]

Prevention There are no primary preventive measures available for [disease name]. Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3]. [wikidoc.org]

NO SPECIFIC PREVENTION There is no specific prevention or treatment for BEN. Patients who progress to end-stage renal disease may be treated with dialysis or kidney transplantation. [silive.com]

1. Stefanovic V, Cukuranovic R, Miljkovic S, et al. Fifty years of Balkan endemic nephropathy: challenges of study using epidemiological method. Ren Fail. 2009;31:409–418.
2. Djukanović L, Marić I, Marinković J, et al. Evaluation of criteria for the diagnosis of Balkan endemic nephropathy. Ren Fail. 2007;29:607–614.
3. Cukuranovic R, Jovanovic I, Miljkovic S, et al. Hemodialysis treatment in patients with Balkan endemic nephropathy: an epidemiological study. Ren Fail. 2007;29:805–810.
4. Alecković M, Mesić E, Trnacević S, et al. Glomerular filtration rate in examined population of Bosnian Posavina—region of Balkan Endemic Nephropathy. Bosn J Basic Med Sci. 2010;10:S68–S72.
5. Dimitrov P, Tsolova S, Georgieva R, et al. Clinical markers in adult offspring of families with and without Balkan endemic nephropathy. Kidney Int. 2006;69:723–729.
6. Radonić M, Radosević Z. Clinical features of Balkan endemic nephropathy. Food Chem Toxicol. 1992;30(3): 189–192.
7. Stefanovic V, Polenakovic M, Toncheva D. Urothelial carcinoma associated with Balkan endemic nephropathy. A worldwide disease. Pathol Biol. 2011; 59(5): 286–291.
8. Vukelic M, Sostaric B, Belicza M. Pathomorphology of Balkan endemic nephropathy. Food Chem Toxicol. 1992;30(3): 193–200.
9. Vikram R, Sandler CM, Ng CS. Imaging and staging of transitional cell carcinoma: part 2, upper urinary tract. AJR Am J Roentgenol. 2009;192 (6): 1488-1493.