Genes and environment in chronic kidney disease hotspots.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) can cluster in geographic locations or in people of particular genetic ancestries. We explore APOL1 nephropathy and Balkan nephropathy as examples of CKD clustering that illustrate genetics and environment conspiring to cause high rates of kidney disease. Unexplained hotspots of kidney disease in Asia and Central America are then considered from the perspective of potential gene × environment interactions. RECENT FINDINGS: We report on evidence supporting both genes and environment in these CKD hotspots. Differing genetic susceptibility between populations and within populations may explain why causal environmental risk factors have been so hard to identify conclusively. Similarly, one cannot explain why these epidemics of kidney disease are happening now without invoking environmental changes. SUMMARY: Approaches to these CKD hotspots are of necessity becoming more holistic. Genetic studies may help us identify the environmental triggers by teaching us about disease biology and may empower environmental risk factor studies by allowing for stratification of study participants by genetic susceptibility.

Cooking methods employing natural anti-oxidant food additives effectively reduced concentration of nephrotoxic and carcinogenic aristolochic acids in contaminated food grains.

Emerging evidence suggests that aristolochic acids (AA) produced naturally by a common weed Aristolochia clematitis in the cultivation fields is contaminating the food products in Balkan Peninsula and acting as the etiological agent in the development of Balkan endemic nephropathy. In this study, we investigated the combined use of natural anti-oxidative "food additives" and different cooking methods to find a solution for the widespread contamination of AA in food products. The results indicated that the addition of healthy dietary supplements (such as cysteine, glutathione, ascorbic acid, citric acid and magnesium) during cooking, is a highly efficient method in lowering the concentration of AA in the final food products. Because previous observation indicated one of the toxicological mechanisms by which AA exert its toxicity is to induce oxidative stress in internal organs, it is anticipated that these added anti-oxidants will also help to attenuate the nephrotoxicity of AA.

An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature.

The term "aristolochic acid nephropathy" (AAN) is used to include any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing aristolochic acids (AA) as part of traditional phytotherapies (formerly known as "Chinese herbs nephropathy"), or by the environmental contaminants in food (Balkan endemic nephropathy). It is frequently associated with urothelial malignancies. Although products containing AA have been banned in most of countries, AAN cases remain regularly reported all over the world. Moreover, AAN incidence is probably highly underestimated given the presence of AA in traditional herbal remedies worldwide and the weak awareness of the disease. During these two past decades, animal models for AAN have been developed to investigate underlying molecular and cellular mechanisms involved in AAN pathogenesis. Indeed, a more-in-depth understanding of these processes is essential to develop therapeutic strategies aimed to reduce the global and underestimated burden of this disease. In this regard, our purpose was to build a broad overview of what is currently known about AAN. To achieve this goal, we aimed to summarize the latest data available about underlying pathophysiological mechanisms leading to AAN development with a particular emphasis on the imbalance between vasoactive factors as well as a focus on the vascular events often not considered in AAN.

Chronic kidney disease: global dimension and perspectives.

Chronic kidney disease is defined as a reduced glomerular filtration rate, increased urinary albumin excretion, or both, and is an increasing public health issue. Prevalence is estimated to be 8-16% worldwide. Complications include increased all-cause and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline, anaemia, mineral and bone disorders, and fractures. Worldwide, diabetes mellitus is the most common cause of chronic kidney disease, but in some regions other causes, such as herbal and environmental toxins, are more common. The poorest populations are at the highest risk. Screening and intervention can prevent chronic kidney disease, and where management strategies have been implemented the incidence of end-stage kidney disease has been reduced. Awareness of the disorder, however, remains low in many communities and among many physicians. Strategies to reduce burden and costs related to chronic kidney disease need to be included in national programmes for non-communicable diseases.

Aristolochic acid nephropathy: Harbinger of a global iatrogenic disease.

This review constitutes an overview of our investigations of aristolochic acid nephropathy, a chronic kidney disease associated with carcinomas of the upper urinary tract. Our studies began by confirming the hypothesis that chronic dietary poisoning by aristolochic acid was responsible for endemic (Balkan) nephropathy. A unique TP53 mutational signature in urothelial tumors and the presence of aristolactam-DNA adducts in the renal cortex, defined in the course of this research, proved to be robust biomarkers of exposure to this potent nephrotoxin and human carcinogen. Armed with this information, we used molecular epidemiologic approaches and novel mechanistic information to establish the causative role of aristolochic acid in upper urinary tract carcinoma in Taiwan, where one-third of the population had been prescribed herbal remedies containing Aristolochia, and the recorded incidence of upper urinary tract cancers is the highest in the world. As traditional Chinese medicine is practiced similarly in Taiwan and China, it is likely that upper urinary tract carcinomas and their attendant aristolochic acid nephropathy are prevalent in China and other Asian countries where Aristolochia herbs have been used for centuries in the treatment and prevention of disease, creating a potential public health problem of considerable magnitude.

Possible health impacts of naturally occurring uptake of aristolochic acids by maize and cucumber roots: links to the etiology of endemic (Balkan) nephropathy.

Aristolochic acids (AAs) are nephrotoxic and carcinogenic derivatives found in several Aristolochia species. To date, the toxicity of AAs has been inferred only from the effects observed in patients suffering from a kidney disease called "aristolochic acid nephropathy" (AAN, formerly known as "Chinese herbs nephropathy"). More recently, the chronic poisoning with Aristolochia seeds has been considered to be the main cause of Balkan endemic nephropathy, another form of chronic renal failure resembling AAN. So far, it was assumed that AAs can enter the human food chain only through ethnobotanical use (intentional or accidental) of herbs containing self-produced AAs. We hypothesized that the roots of some crops growing in fields where Aristolochia species grew over several seasons may take up certain amounts of AAs from the soil, and thus become a secondary source of food poisoning. To verify this possibility, maize plant (Zea mays) and cucumber (Cucumis sativus) were used as a model to substantiate the possible significance of naturally occurring AAs' root uptake in food chain contamination. This study showed that the roots of maize plant and cucumber are capable of absorbing AAs from nutrient solution, consequently producing strong peaks on ultraviolet HPLC chromatograms of plant extracts. This uptake resulted in even higher concentrations of AAs in the roots compared to the nutrient solutions. To further validate the measurement of AA content in the root material, we also measured their concentrations in nutrient solutions before and after the plant treatment. Decreased concentrations of both AAI and AAII were found in nutrient solutions after plant growth. During this short-term experiment, there were much lower concentrations of AAs in the leaves than in the roots. The question is whether these plants are capable of transferring significant amounts of AAs from the roots into edible parts of the plant during prolonged experiments.

Chronic kidney disease associated with environmental toxins and exposures.

People are exposed to various potentially toxic agents and conditions in their natural and occupational environments. These agents may be physical or chemical, may enter the human body through oral, inhalational, or transdermal routes, and may exert effects on all organ systems. Several well-known as well as lesser known associations exist between chronic kidney disease (CKD) and both environmental agents and conditions, such as heavy metals, industrial chemicals, elevated ambient temperatures, and infections. The effects of these agents may be modulated by genetic susceptibility and other comorbid conditions and may lead to the development of acute and CKD. In this article, we present environmental factors that are associated with CKD.

[Sporadic upper urinary tract urothelial cell carcinomas: identification of interaction between toxic carcinogens and individuals genetic susceptibility]. / Tumeurs des voies excrétrices urinaires supérieures sporadiques: identification de l'interaction entre l'exposition aux carcinogènes environnementaux et la susceptibilité génétique des individus.

Upper urinary tract urothelial cell carcinomas (UUT UCC) are rare sporadic tumors. Recent epidemiologic and molecular data have shown a singular susceptibility of UUT UCCs for specific risk factors. The main exogenic factors involved in UUT UCCs carcinogenesis remain tobacco and occupational exposure (aromatic amines, polycyclic hydrocarbures and chlored solvents). Enzymatic variants of detoxification system may be responsible of carcinogenesis with these toxics. Tumors induced by phenacetine consumption are decreasing since it was banned in the 1970s. Also, acid aristolochic exposure (Balkan nephropathy, Chinese Herb nephropathy) has been demonstrated to specifically induce UUT UCCs. Familial genic polymorphism of detoxification system would explain geographic distribution in endemic areas. In Taiwan, chronic arsenic exposition would constitute the main risk factor of UUT UCC. However, theses mechanisms of carcinogenesis remain unclear. The knowledge of UUT UCC development mechanisms implying toxic detoxification systems is still incomplete. To date, there is a growing body of evidence supporting that the interaction between individual genetic susceptibilities and environmental toxic exposure is a key to explain carcinogenesis in the majority of sporadic UUT UCC occurrence.

Metals and kidney markers in adult offspring of endemic nephropathy patients and controls: a two-year follow-up study.

BACKGROUND: The etiology of Balkan Endemic Nephropathy, (BEN), a tubulointerstitial kidney disease, is unknown. Although this disease is endemic in rural areas of Bosnia, Bulgaria, Croatia, Romania, and Serbia, similar manifestations are reported to occur in other regions, for instance Tunisia and Sri Lanka. A number of explanations have been stated including lignites, aristolochic acid, ochratoxin A, metals, and metalloids. Etiologic claims are often based on one or a few studies without sound scientific evidence. In this systematic study, we tested whether exposures to metals (cadmium and lead) and metalloids (arsenic and selenium) are related to Balkan Endemic Nephropathy. METHODS: In 2003/04 we recruited 102 adults whose parents had BEN and who resided in one of three communities (Vratza, Bistretz, or Beli Izvor, Bulgaria). A control group comprised of 99 adults having non-BEN hospitalized parents was enrolled in the study during the same time. We conducted face-to-face interviews, ultrasound kidney measurements, and determined kidney function in two consecutive investigations (2003/04 and 2004/05). Metals and metalloids were measured in urine and blood samples. To assess the agreement between these consecutive measurements, we calculated intraclass correlation coefficients. Repeated measurement data were analyzed using mixed models. RESULTS: We found that cadmium and arsenic were associated with neither kidney size nor function. Lead had a significant but negligible effect on creatinine clearance. Selenium showed a weak but significant negative association with two of the four kidney parameters, namely creatinine clearance and beta2-microglobulin. It was positively related to kidney length. These associations were not restricted to the offspring of BEN patients. Adding credence to these findings are reports showing comparable kidney effects in animals exposed to selenium. CONCLUSION: The findings of this 2-year follow-up study indicate that metals and metalloids do not play a role in the etiology of Balkan Endemic Nephropathy. Against the assumption in the literature, selenium was not protective but a risk factor. Since comparable associations were observed in animals, future studies are needed to explore whether selenium may have adverse renal effects in humans.

Analyses of DNA adducts formed by ochratoxin A and aristolochic acid in patients with Chinese herbs nephropathy.

Chinese herbs nephropathy (CHN), a unique type of nephropathy has been associated with the intake of weight-reducing pills containing the Chinese herb Aristolochia fangchi. Moreover, an association between the use of A. fangchi and urothelial cancer in CHN patients has been reported indicating that aristolochic acid (AA) the major alkaloid of A. fangchi might be the causal agent. Similarities of CHN to the Balkan endemic nephropathy (BEN) have led to the hypothesis of a common etiological agent for both diseases. Evidence has accumulated that BEN is an environmentally-induced disease strongly associated with the fungal mycotoxin ochratoxin A (OTA). Both, AA and OTA are nephrotoxic and carcinogenic and induce the formation of DNA adducts. As OTA has been suspected as fungal contaminant in the herbal batches used for the preparation of the weight-reducing pills we analysed tissues from CHN patients by the 32P-postlabeling procedure for the presence of DNA adducts related to both OTA and AA exposure. Whereas, AA-specific DNA adducts were detected in all five urinary tract tissues from five patients (total RAL: 32-251 adducts per 10(9) nucleotides), OTA-related DNA adducts were detectable in two kidneys and one ureter only (total RAL: 1.5-3.7 adducts per 10(9) nucleotides). Thus, OTA-related DNA adduct levels were about 50 times lower than AA-DNA adduct levels. In female and male rats that were treated with the slimming regimen in the same way like the CHN patients except that the amount of Chinese herbs was 10 times higher, AA-DNA adducts were found in kidney tissues (total RAL ranging from 51 to 83 adducts per 10(9) nucleotides) but adducts derived from OTA were not observed. These results demonstrate that OTA-related DNA adducts do not play a key role in CHN or CHN-associated urothelial cancer.

Selenium deficiency in Yugoslavia.

Data on selenium (Se) deficiency in Yugoslavia are presented. The results include Se content of soil, cereal crops, and garlic grown in these soils, and human serum and scalp hair from several towns and regions. All data indicate a serious Se deficiency: soil (n = 140), the mean value of 200 +/- 69.6 micrograms/kg Se; wheat, (58) mean = 20.5 +/- 12.4 micrograms/kg; corn, (79) mean = 13.7 +/- 13.6 micrograms/kg; and garlic, (66) mean = 13.7 +/- 17.1 micrograms/kg Se. Analyses of human tissue show a very low Se status of the Yugoslav population: serum, (n = 875) mean = 50.0 +/- 18.0 micrograms/L and scalp hair, (388) mean = 94 +/- 16 micrograms/kg Se. In some regions, Se contents of grain, garlic, and human serum and hair are approaching those in the low-Se belt in China. It is assumed that very low Se status of a human population could be a risk factor in the development of Balkan Endemic Nephropathy (BEN) and in a high incidence of urinary tract tumors (UTT) in endemic areas.

Selenium deficiency and Balkan endemic nephropathy.

Data on selenium (Se) deficiency in Yugoslavia are summarized. These data include the selenium contents of stream sediments, rocks, soils, cereal crops grown in these soils, and human serum and scalp hair from several towns and regions. Analyses of human tissues in Yugoslavia show very low Se concentrations in both endemic and nonendemic areas. In some regions, including those with endemic villages, selenium contents of grains and human serum and hair are extremely low, approaching those in the low-selenium zone in China. According to the biological function of selenium, a very low intake of selenium may be a fundamental underlying condition that would predispose persons to attack by other agents in the development of Balkan endemic nephropathy.