Endemic nephropathies

Introduction

Chronic kidney disease (CKD) is a worldwide public health problem affecting approximately 10% to 13% of the population in developed countries, where diabetes mellitus and hypertension are the leading causes of CKD. In developing countries, the percentage of patients with CKD not caused by diabetes or hypertension is considerably higher than in developed countries. The higher proportion of CKD in these countries could be the result of unrecognized endemic nephropathies that are localized to specific geographic locations and related to environmental factors, such as local toxins in food or drinking water. An early recognized example of this was the finding of an increased incidence of interstitial nephritis with papillary necrosis among workers in the fine-watch industry who ingested excess amounts of phenacetin-containing analgesics in their workplaces. Meanwhile, Balkan endemic nephropathy was recognized for many years as a geographically localized entity that was often associated with urothelial carcinoma. A wide variety of etiologies, including heavy metals, viruses, and fungal toxins, were postulated. Aristolochic acid (AA) was implicated as the etiologic agent in so-called Chinese herb nephropathy and more recently as the causative agent in Balkan nephropathy. Ochratoxins can enter the food chain through the meat of animals fed improperly stored grain; in Tunisia, this has been associated with a chronic interstitial nephropathy of unknown cause. In Sri Lanka, a CKD of unknown etiology has been linked to drinking hard water from shallow wells containing polyvalent metallic cations and possibly contaminated with agricultural chemicals, including the herbicide glyphosate. A high prevalence of CKD in male agricultural workers in Central America has been noted, where it has been suggested that severe cyclic dehydration and salt depletion in the hot environment are the major risk factors.

Selected reading

• Wernerson A, Wijkström J, Elinder CG. Update on endemic nephropathies. Curr Opin Nephrol Hypertens. 2014;23:232-238.

Aristolochic acid nephropathy (chinese herb nephropathy, balkan endemic nephropathy)

Aristolochic acid nephropathy (AAN) describes any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing aristolochic acid (AA), as in some Chinese herb preparations, or by the presence of environmental contaminants in food, as occurs in Balkan endemic nephropathy. AAN is extremely widespread throughout the world, especially in Asia.

Chinese herbal medicines that contain AA have been associated with acute kidney failure, often rapidly progressing to near end-stage renal disease. A chronic progressive interstitial nephritis located principally in the cortex, starting in the superficial region, is present with extensive interstitial fibrosis and tubular atrophy with few inflammatory cells ( Figs. 6.1 and 6.2 ). The disease progresses rapidly to end-stage renal disease. Balkan nephropathy is a slowly progressive disease that is only recognized in the late stages of renal insufficiency. Patients show tubular proteinuria and may also have glycosuria. The renal pathology of patients with Balkan nephropathy, who also have a high incidence of urothelial carcinoma, is essentially identical to the findings of so-called Chinese herbal nephropathy , which suggests a common etiology. Previous studies from the endemic areas of Balkan nephropathy showed that plants containing AA were growing in wheat fields and that the plant seeds contaminated the wheat flour harvested in those areas. Further studies of tissue and urine in patients with AAN have shown that AA is the likely causative agent.

AA targets the proximal tubular epithelium, resulting in toxic tubular necrosis. AA forms adducts with DNA, particularly in proximal tubules. Organic anion transporters expressed in the proximal tubules are postulated to play a role in the particular susceptibility of this part of the nephron to the toxic effects of AA. The DNA adducts are irreversible and also cause the upper urothelial carcinomas that develop in patients with AAN. Bilateral nephrectomies have, therefore, been suggested for AAN patients because of the high risk for developing this cancer, which is a major cause of death in AAN. Decrease of urinary neutral endopeptidase (NEP), a marker of intact brush borders, is an early abnormality in AAN and becomes undetectable once AAN patients reach end-stage kidney disease. Screening for a decrease in NEP has been suggested in endemic areas to diagnose AAN.