Balkan Endemic Nephropathy

Balkan endemic nephropathy is a chronic tubulointerstitial kidney disease with a high risk of upper urothelial carcinoma. It is confined to rural farming villages along the tributaries of the Danube in Serbia, Bosnia and Herzegovina, Croatia, Bulgaria and Romania.

The disease clusters in families and villages. It affects people who lived in an endemic area for many years, usually from childhood, and appears at age 30 to 60 years. It is not transmitted to people who move away before adolescence.

Prevalence in affected villages has been 2 to 10% of residents, with a lower incidence in recent decades as farming practices changed.

Exposure to aristolochic acid is the best supported cause. The source is seeds of Aristolochia clematitis, a weed that grows in wheat fields and contaminates flour. Ochratoxin A and other environmental toxins are possible contributors.

Upper urothelial carcinoma develops in 30 to 50% of affected people in endemic villages. The lesion is bilateral in about 10%.

Pathophysiology. Aristolochic acid is taken up by proximal tubular cells and forms aristolactam-DNA adducts. It causes tubular atrophy with hypocellular interstitial fibrosis (predominantly in the outer cortex). Urothelial tumours show a mutational signature (A to T transversions in TP53).

• Insidious onset with slowly progressive loss of kidney function over 10 to 20 years, usually without hypertension or oedema.
• Anaemia that appears early and is disproportionate to the level of kidney function.
• Tubular dysfunction: low molecular weight proteinuria, glycosuria, mild albuminuria (under 1 g daily), concentrating defect with polyuria, distal acidosis.
• Small, shrunken kidneys (under 9 cm), bilateral and symmetrical, on ultrasound.
• Painless macroscopic haematuria or flank pain from urothelial tumours of the renal pelvis, ureter or bladder.
• Family history of kidney failure in the village or household.

Red flags

• Haematuria or flank pain in a patient from an endemic area.
• Rapid fall in function or new hypertension.
• Anaemia with haemoglobin under 100 g/L without another cause.
• New masses on ultrasound or filling defects on urography.

• Residence history (at least 10 to 15 years in an endemic village) and family history; no other cause of chronic tubulointerstitial disease.
• Creatinine, eGFR, urea, electrolytes, bicarbonate, haemoglobin, urine microscopy, urine protein:creatinine ratio; urinary beta-2 microglobulin (above 300 microg/g creatinine in early disease).
• Ultrasound: small kidneys with normal or increased echogenicity and cortical thinning.
• Kidney biopsy (when diagnosis is unclear): hypocellular interstitial fibrosis, tubular atrophy, and relative sparing of glomeruli.
• Surveillance for urothelial cancer: urine cytology, cystoscopy and CT or MR urography at the time of diagnosis, then yearly.
• Aristolactam-DNA adducts in tissue where available.

Differential diagnosis

• Aristolochic acid nephropathy from herbal remedies, analgesic nephropathy, hypertensive nephrosclerosis, chronic pyelonephritis, reflux nephropathy, lead and cadmium nephropathy, chronic glomerulonephritis, other causes of small kidneys.

There is no specific treatment; manage progression and screen for cancer.

• Avoid exposure: move children away from endemic exposure, avoid locally grown wheat in affected areas where feasible, and stop herbal products containing Aristolochia.
• Renoprotection: blood pressure below 130/80 mmHg; ramipril 2.5 mg daily increased to 10 mg daily (creatinine and potassium at 1 to 2 weeks; accept a rise up to 30%; stop if potassium exceeds 6.0 mmol/L); sodium under 2 g daily; avoid NSAIDs and contrast.
• Anaemia: iron replacement when ferritin is under 200 microg/L or transferrin saturation is under 20%; epoetin alfa 50 to 100 units/kg three times weekly when haemoglobin is under 100 g/L; target 100 to 120 g/L (avoid above 130 g/L).
• Metabolic acidosis: sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L.
• Mineral and bone disorder: phosphate target 1.1 to 1.7 mmol/L in dialysis, cholecalciferol 50 000 units weekly for 6 to 8 weeks then 800 to 2000 units daily when 25-hydroxyvitamin D is under 50 nmol/L.

Upper urothelial cancer

• Yearly urine cytology, cystoscopy and upper tract imaging; prophylactic nephroureterectomy is considered at kidney failure or transplantation, as the risk of upper tract carcinoma is high (30 to 50%).
• Tumours: nephroureterectomy with bladder cuff excision, with cisplatin based chemotherapy when eGFR is at least 60 (carboplatin based regimens when eGFR is 30 to 59).

Kidney failure. Dialysis at eGFR 5 to 10 with symptoms or complications (Kt/V at least 1.2 on haemodialysis); kidney transplantation after exclusion of urothelial cancer, with continued surveillance on immunosuppression.

Monitoring. Creatinine, eGFR, urine protein:creatinine ratio and haemoglobin every 3 months; cystoscopy and urine cytology yearly; imaging of the upper tract yearly.

Referral and escalation. Nephrology from diagnosis; urology for any haematuria; oncology for tumours.

Special groups

• Residents of endemic villages: screen family members from age 20 to 30 with eGFR, urine and ultrasound.
• Pregnancy: kidney function worsens with advanced disease; stop ACE inhibitors before conception.
• Migrants from endemic regions: same surveillance for cancer for life.