Environmental toxin-induced acute kidney injury

Abstract

Human beings are exposed to various potentially toxic agents and conditions in their natural and occupational environments. The kidney, due to its concentrating ability and excretory function, is highly vulnerable to the effects of environmental toxins. Identifying the precise cause and mechanisms of environmentally induced renal injury remains a challenge for which various scientific disciplines need to be involved. Investigations in this field are confronted with the apparent infinite types of toxins, their mutual interaction, handling/metabolization by the body, ways of exposure, etc. Although interdisciplinary efforts and persistence are required to identify, mechanistically unravel and tackle environmental toxin–induced pathologies, research eventually pays off in ameliorated working/living conditions and development of preventive/therapeutic strategies. This review was compiled to particularly emphasize the need for a maintained awareness of environmental threats in general and those targeting the kidney. Different mechanisms of renal toxicity are illustrated and discussed, thereby focusing on three types of environmental toxins, namely aristolochic acid, melamine and heavy metals.

aristolochic acid, heavy metals, melamine, nephropathy

Introduction

Human beings are continuously exposed to various potentially harmful conditions and agents, both in their natural and occupational environments. Environmental causes of health issues can be physical (e.g. high temperature, dehydration), biological (e.g. bacteria/viruses) or chemical (organic/inorganic). Being responsible for maintaining body homeostasis and waste management, the kidneys are an important primary target of these hazards and thus are highly vulnerable to their toxic effects [1]. In particular, environmental toxins, to which we are unintentionally exposed via oral, inhalational or transdermal routes, are a common yet underappreciated cause of kidney injury. The high vulnerability of the kidney can be explained by its main physiological features, such as the highest blood flow per 100 g tissue, the largest endothelial surface by weight, highly active multiple metabolizing enzyme systems, the high concentration of filtered chemicals in tubular fluid adjacent to tubular cells, protein unbinding of chemical compounds in the tubules and further intrarenal biotransformation of chemicals. Two major mechanisms inducing renal toxicity are (i) proximal tubular cell damage occurring due to extensive cellular uptake of toxins by both apical and basolateral transport systems and (ii) extensive tubular crystal formation due to the kidney’s concentrating capacity. In this review we deal with these two different mechanisms of toxicity by focusing on three different types of environmental toxins, namely aristolochic acid, melamine and heavy metals.

Aristolochic acid nephropathy

In 1993, a group of Belgian women who had ingested slimming pills containing powdered root extracts of Chinese herbs presented urothelial malignancy concomitant with a rapidly progressive tubulointerstitial nephritis and fibrosis leading to end-stage renal disease (ESRD) [2–5]. This so-called Chinese-herb nephropathy (CHN) showed great clinical and histopathological similarities with a chronic tubulointerstitial kidney disease that was reported for the first time in the 1950s and was only seen in the Balkan area of Southeastern Europe and for this reason was termed Balkan Endemic Nephropathy (BEN) [6–8]. Rigorous investigations identified aristolochic acid (AA), a chemical compound (i.e. nitrophenanthrene carboxylic acid) commonly found in the Aristolochiaceae plant family, as the causative nephrotoxic agent in both these pathologies [9–14]. CHN appeared to be the dramatic consequence of substituting roots of the harmless Stephaniatetrandra with the AA-rich Aristolochiafangchi in herbal preparations, which was due to the fact that both plants share the same name, Pin Yin [4, 15, 16]. BEN most likely is the result of environmental exposure to seeds of Aristolochiaclematitis, a weed commonly found in Balkan meadows and crop fields, which can commingle with grain during harvesting and contaminate wheat flour for home-baked bread [8, 10–14, 17]. After the identification of AA as the common causal factor in CHN and BEN, any renal disease following AA exposure is now commonly recognized as aristolochic acid nephropathy (AAN).

Epidemiology

The true global, let alone country-specific, incidence and prevalence of AAN is unknown. This lack of up-to-date epidemiological data is largely due to the absence of a consensus definition, unavailability of diagnostic criteria and tools and the limited awareness of this disease. Since the publication of the Belgian cases index, several cases and case series from around the world (Europe [4, 18–22], USA [23], Australia [24], Japan [25], Korea [26], China [27, 28], Taiwan [28] and Hong Kong [29]) have been and are still reported, indicating that AAN is a global problem (Figure 1). Although the use of Aristolochia spp. and herbs that can be mistaken for them in herbal treatments have now been prohibited in many countries, there is evidence that large-scale exposure to AA continues and that the incidence is much higher than previously thought [28, 30–32]. Particularly in Asia, numerous ingredients known or suspected to contain AA are still used in traditional medicine. Warned by the severe and prolonged nephrotoxicity of AA, Chinese nephrologists started collecting histories of medication use from patients with chronic kidney disease (CKD) as routine clinical practice, especially from those presenting idiopathic chronic tubulo-interstitial nephropathy. In this way, over the years, thousands of AAN patients have been diagnosed and are still followed in the long term [27, 33]. Additionally, in Taiwan a longitudinal analysis conducted on a random cohort of 200 000 patients from the data of the National Health Insurance (NHI) between 1997 and 2003 revealed that up to 40% of the population are likely to have been prescribed AA-containing herbal products [34], thus indicating AAN is a potentially devastating public health problem. Furthermore, AA containing species are known to be used in many regions where AAN has not yet been officially reported and diagnosis is not yet part of routine clinical practice, including Africa, South America and the Indian subcontinent [4, 35].

Fig. 1.

CHN/AAN is a rapidly progressive interstitial nephritis leading to ESRD and urothelial malignancy that was originally reported in Belgium in the context of the intake of slimming pills containing powdered Chinese herbs (Aristolochia fangchi). (A) Countries with reported cases of CHN/AAN around the world. (B) Masson’s trichrome staining shows the deposition of extracellular matrix in blue/green. (C) Example of a traditional mixture of Chinese herbs.

With respect to BEN, which is geographically confined to families living near tributaries of the Danube River in Bosnia, Bulgaria, Croatia, Romania and Serbia [7, 36], the estimated prevalence of the use of AA ranges between 2% and 10% [37]. Based on a more profound screening, the idea has been put forward that even the suspected cases need to be included, by which the prevalence increases up to 20% in endemic areas [37]. The rather wide range of variation greatly depends on the precise region and country [37–41] in which the data were gathered. Overall, at least 25 000 people have been identified as suffering from BEN [42].

Pathophysiology

Based on multiple regression analysis, it is clear that the cumulative dose of AA determines the onset and rate of decline in renal function and the degree of renal insufficiency [27, 43]. Even after cessation of the exposure, progression of renal failure is generally relentless. Acute AAN may progress to ESRD within 1 month and is often observed in patients having continuously ingested a high dose during a short period of time [44]. Generally, development of ESRD takes longer (months to years) and is associated with either a consistent or intermittent intake of a low dose of AA for a long period of time [45]. The slowest rate of renal functional decline is typically observed in patients with BEN, where progression to complete renal failure can take up to 15–20 years [46] due to relatively low exposure [17].

On a pathological level, AAN causes two main distinct health problems that are either carcinogenic or degenerative/fibrotic in nature. In the upper urinary tract, AAN induces typical multifocal urothelial atypia and transitional cell carcinoma, whereas in the kidney it induces cortical tubular atrophy and extensive interstitial fibrosis [15, 47]. The exact pathophysiological mechanisms by which AA initiates its pathological features are not fully understood. However, with respect to malignancy it has been established that AA is metabolically activated {i.e. nitroreduction by microsomal and cytosolic enzymes [48–50] to a cyclic N-acylnitrenium ion that is able to covalently bind the purine bases (adenine, guanine)} leading to the formation of DNA adducts [51]. These DNA adducts, termed aristolactams, are mutagenic and typically lead to AT→TA transversions. Whereas in rodent AAN models these mutations typically affect the H-ras proto-oncogene [52], in urothelial carcinomas isolated from AAN patients the tumour suppressor gene p53 appeared to be particularly affected by a specific AAG→TAG mutation [14, 53, 54]. Nonetheless, given the gene targets, it is highly likely that aristolactams drive urothelial tumourigenesis [55].

How AA exerts its proximal epithelial cytotoxic effects and thereby induces tubular atrophy is not yet fully understood. However, the mechanisms involved in AA toxicity appear to converge to apoptosis [56–58]. From in vivo and in vitro experiments it is clear that AA can enter the cell via organic anion transporters (OATs) [59–62], resulting in defective activation of anti-oxidative enzymes, mitochondrial damage, impaired regeneration of proximal tubular epithelial cells (i.e. cell cycle S-phase arrest) [63, 64], endoplasmic reticulum and mitochondrial stress, activation of the caspase pathway and apoptosis [65, 66] (Figure 4). Furthermore, AA is able to impair receptor mediated endocytosis of low molecular weight proteins (e.g. albumin, beta2-microglobulin) via decreased megalin expression [67]. Given the typical formation of aristolactam DNA adducts it is highly likely that injury to and/or breakage of the DNA strand is causing these cytotoxic effects in addition to the carcinogenic effects [63, 67]. Why injury to the upper urinary tract urothelium turns malignant whereas injury to proximal epithelial cells leads to apoptosis and cortical atrophy remains to be clarified.

Another major renal histopathological feature of AA toxicity is tubulointerstitial fibrosis (Figure 1). Whereas fibrosis might ensue as an inherent consequence of proximal epithelial cell injury/death [68], there are indications that AA, as a toxin, might directly induce extracellular matrix deposition via multiple signalling pathways that often converge to increased transforming growth factor beta (TGF-β) expression, a major pro-fibrotic cytokine. Rui et al. [69] demonstrated in a human proximal epithelial cell line that AA is able to induce overexpression of TGF-β1 and that this overexpression is mainly mediated by the Jun N-terminal kinase signalling pathway. Also, a recent study made clear that AA-injured kidneys loose phosphate tensin homologue (PTEN) expression both in the epithelium and the interstitium [70]. This PTEN downregulation induces expression of pro-fibrotic genes via SMAD3-, p53- and Akt-dependent pathways and appears to facilitate TGF-β-induced gene expression and apoptosis. In addition, AAN has been shown to present G2/M cell cycle arrest, a pathological feature closely linked to the development of fibrosis [71]. Overall, it is clear that the numerous pathways associated with the development of AA-induced fibrosis are also involved in cell injury, dedifferentiation, proliferation and apoptosis. Therefore it remains an ongoing and daunting task to pinpoint the exact (obviously multipathway) mechanism by which AA affects gene expression and specifically initiates its fibrosis-stimulating action. It is likely that new studies focusing on miRNAs and epigenetic modifications might open new avenues in unravelling mechanisms underlying the development of AAN [64, 72, 73].

Treatment

Until recently there has been no well-established therapeutic regimen for the treatment of AAN. In the mid-1990s, glucocorticosteroid treatment of AAN patients with mild renal injury revealed that patients who had received steroids had a slower progression to ESRD as compared with untreated patients [74]. More recently it was reported that low-dose steroid therapy reversed or delayed the progression of severe chronic AAN [75]. As most patients progress to ESRD, however, there is usually a need for renal replacement therapy, i.e. dialysis or kidney transplant. However, given the high malignant potential, care must be taken to minimize future development of upper urinary tract cancers by performing prophylactic bilateral nephro-ureterectomies and aggressive cancer surveillance [76].

Melamine-induced nephropathy

What is melamine and where is it used?

Melamine is an organic base that is commercially synthesized from urea with cyanic acid as an intermediate step. Melamine contains 67% nitrogen by mass (Figure 2). Depending on the process by which it is purified, melamine may contain a number of structurally related by-products, including cyanuric acid, ammeline and ammelide (Figure 2). In the gastrointestinal tract these compounds are produced by microbial degradation of melamine through sequential hydrolysis, thereby replacing either one, two or three amino groups.

Fig. 2.

Structure formula of melamine and its analogues.

Melamine is produced for the synthesis of melamine formaldehyde resin, a very durable thermosetting plastic. Melamine also has fire-retardant properties and is used as insulation, soundproofing material and as a major component in Pigment Yellow 150.

It is also worth mentioning that melamine is a metabolite of the pesticide cyromazine. Melamine, because of its high nitrogen content, was used in fertilizers in the 1950s and 1960s, however, it is much more expensive and less effective compared with other common nitrogen fertilizers, such as urea. In the past, melamine has been used as a non-protein nitrogen source in cattle food, but because of its slow hydrolysis in ruminants, it is now categorized as ineffective.

Why is melamine added to food?

Melamine is illegally added to food to falsely boost apparent protein levels. Standard methods, such as the Kjeldahl and Dumas tests, estimate protein levels by measuring the nitrogen content. Hence these tests can overestimate the protein content if nitrogen-rich compounds such as melamine are added. Thus the addition of 1 g of melamine to 1 L of milk falsely increases the protein content (normal content in milk ±3.0%). When melamine is dissolved at room temperature, 3.1 g of melamine can be dissolved in 1 L water without forming precipitate, thereby falsely increasing the protein content by 1.2%, which ultimately may lead to an overestimation of the milk's protein content of 30%.

Toxicity of melamine: results from animal studies leading to safe guidelines for melamine content of foods

The LD50 (i.e. the dose of a compound that results in the death of 50% of the tested animals) of melamine in rats was found to be 3.2 g/kg body weight (bw) [77]. Acute toxicity of melamine is mainly localized in the kidney, as was seen during a study performed in sheep: animals receiving lethal oral doses of melamine (single 100 g dose or daily doses of 25–50 g over 7–9 days) suffered from acute kidney injury (AKI) with elevations in blood urea and creatinine preceding death [78]. Post-mortem analysis identified renal tubular crystals as the potential cause of the renal failure. Animals chronically exposed to melamine suffer from urinary crystal formation as well: dogs receiving a 3% melamine diet for 1 year showed crystalluria and proteinuria/haematuria [79]. Actually, consequences of renal tubular crystals and renal stone formation are the commonly reported problems of animals that are affected by melamine overload [80, 81].

In order to provide safety guidelines for melamine content in food [82], the US Food and Drug Administration (FDA) provided a tolerable daily intake (TDI) of 0.63 mg/kg bw, based on the no observed adverse effect level (NOAEL) of 63 mg/kg bw in rats and an uncertainty factor of 100 for interspecies differences. By introducing an additional uncertainty factor of 10 (among other things because of immature kidney function in young children), the TDI was later decreased to 0.063 mg/kg bw. Using other calculations based on animal data, both the World Health Organization and European Food Safety Authority (EFSA) came to a TDI of 0.2 mg/kg bw, which is between the two values of the US FDA.

Outbreak of melamine toxicity in cats and dogs

In 2007 it was reported in North America that numerous dogs and cats were suffering from AKI [83]. This outbreak was associated with ingestion of melamine-contaminated pet foods and was associated with a very high mortality rate, which, along with melamine, could be attributed to the presence of another toxic compound, the melamine analogue cyanuric acid [84].

A study in cats investigated the toxic effects of cyanuric acid and melamine and revealed that the toxic dietary dose of melamine was reduced to one-fifth (from 1% to 0.2% in the diet) if co-administrated with cyanuric acid (0.2%) [85]. Analysis of the urine and renal tissue of affected cats revealed the presence of crystals containing both melamine and cyanuric acid. Melamine can interact with the isomeric form of cyanuric acid during the formation of melamine cyanurate (Figure 3), which in turn explains the increased stone formation and toxicity [84].

Fig. 3.

Hydrogen-bonded interaction between melamine and cyanuric acid/uric acid.

Outbreak of melamine toxicity in humans

In spite of many reports describing melamine toxicity in animals, an outbreak of melamine-induced renal stones was reported in Chinese children <3 years of age in September 2008 [86, 87]. The outbreak was associated with the consumption of milk powder containing melamine at concentrations as high as 2.6 g/kg [88]. In total, 52 857 children received treatment for consumption of melamine-contaminated milk. AKI occurred in 2.5% of the cases and mortality was recorded in four cases [89, 90]. It is also important to mention that currently it is not clear to what extent cases of nephrolithiasis without clinically overt AKI in these children may lead to CKD in the future. Analysis of the stone composition in humans exposed to melamine-contaminated milk mainly demonstrated the presence of melamine and uric acid [88, 89]. Currently we hope for no further outbreaks of melamine toxicity in the future, however, ambient exposure to lower concentrations because of widespread melamine use is possible. A recent manuscript in the Journal of the American Society of Nephrology reported on increases in serum and urinary melamine concentrations in workers in melamine tableware manufacturing factories in Taiwan. More importantly, those urinary increases in melamine concentration were positively associated with urinary markers of renal tubular damage [91].

Mechanism of melamine nephrotoxicity

While investigating melamine excretion in rats it became clear that 90% of an administered dose of melamine is excreted in the urine within 24 h [92]. During renal excretion, melamine precipitates in the distal tubules as green radial crystals that could be visualized on haematoxylin and eosin–stained kidney sections originating from cats and dogs having eaten melamine-contaminated pet food [84, 85]. Distal tubular crystals in some animals induced distal tubular obstruction and necrosis, resulting in AKI in those animals. Other animals suffered from CKD characterized by the presence of tubular crystals that were partially overgrown by tubular epithelial cells, interstitial inflammation and fibrosis.

Fig. 4.

Mechanisms involved in the uptake and action of aristolochic acid, melamine and the heavy metals Cd, Pb and Hg along the nephron. Adapted from Barbier et al. [111] with permission.

Interestingly, as melamine in rats has a relative low toxicity profile (toxicity defined as the development of urolithiasis) and a relatively high LD50 of 3161 mg/kg bw [77], one should not expect that melamine alone could induce renal crystal deposition when extrapolating these results to cats, dogs and humans. This discrepancy can be explained by the co-precipitation of melamine with another compound. During the outbreak in cats and dogs [84], melamine co-precipitated with cyanuric acid (the food was co-contaminated with cyanuric acid for unknown reasons), while in human infants the co-precipitant was uric acid [88, 89] present at relatively high concentrations in the urine of young infants [82]. Figure 3 shows the interactions between melamine and cyanuric acid/uric acid.

At present, it is not clear whether the tubular and interstitial damage seen in melamine-affected kidneys is induced solely because of physical obstruction by precipitated or adhered crystals (Figure 4) or by a direct toxic effect of melamine. In vitro studies using renal epithelial cell lines of different species showed that a direct toxic effect of melamine is unlikely [93]. It is possible that other pathological findings induced by melamine, such as urinary bladder and ureteral transitional cell carcinomas as reported in male rats, are the result of stone formation as well [77, 94]. Research dealing with the mechanisms of melamine toxicity in recent years has also focused on lower and longer-term melamine–cyanuric acid exposure rather than high-dose acute toxicity. These studies revealed that young male rats are more prone to develop renal toxicity induced by melamine–cyanuric acid compared with older and female rats and that melamine–cyanuric acid toxicity is reversible [95]. Furthermore, it was reported that urinary markers of renal tubular damage can be used as early markers of renal damage induced by melamine–cyanuric acid [96, 97].

Treatment of melamine nephropathy

Data on the treatment of melamine nephropathy are scarce. A study in 47 children with melamine-induced urolithiasis and AKI revealed successful treatment in 9 patients who underwent conservative treatment (including intravenous fluid infusion, use of diuretics, urine alkalization and urethral catheterization), in 31 children after retrograde ureteral catheterization, in 4 patients treated with ureterolithotomy and in 1 patient after percutaneous nephrostomy (98).

Metal-induced nephropathy

General considerations

Exposure to toxic metals is one of the oldest occupational and environmental chemical risks causing adverse health effects. Cadmium (Cd), lead (Pb) and to a lesser extent mercury (Hg) are widespread occupational and environmental toxins. Human exposure can occur due to activities such as mining, melting, soldering, welding, plating, recycling of metals, fossil fuel combustion and industrial applications [99–105]. Exposure to metals may occur through inhalation, ingestion or skin penetration. In an occupational setting, inhalation is the most important exposure route [99–101]. An important route of exposure that should not be neglected is the inhalation of tobacco smoke [106–108]. Metals do not biologically break down. As a consequence, the metal resides in the body until it is excreted. During this period, metal compounds can be transformed into other more or less toxic substances, e.g. through protein binding or binding to other ligands [109].

The chemical form (i.e. species) may influence the toxicokinetics and toxicodynamics of metals. Factors that influence metal speciation include (i) carrier-mediated processes for specific metal species (Pb), (ii) valence state (Hg), (iii) particle size (Pb and Cd), (iv) the nature of metal-binding ligands (Pb), (v) the presence of the metal as an organic versus inorganic species (Pb and Hg) and (vi) biotransformation of metal species (Pb and Hg) [110]. With respect to renal handling, the proximal tubule is a central player in metal toxicity for the vast majority of metals. This is particularly due to its bulk reabsorbing activity.

The mechanisms involved in the uptake of Cd, Pb and Hg along the nephron have been elegantly described by Barbier et al. (Figure 4) [111, 112]. In the proximal tubule, several transporters of essential metals are involved in the uptake of free forms of Cd, Pb and Hg [e.g. zinc transporter 1 (ZnT1), ZRT/IRT-like protein (ZIP) and ATP-binding cassette (ABC) protein] [113]. Furthermore, after conjugation with metallothionein and glutathione (GSH), these metals can also be reabsorbed by endocytosis or by transport of Cys conjugates through the Na⁺ amino acid co-transporter after degradation of GSH by the brush border enzyme γ-glutamyltransferase. In the distal tubule or connecting ducts, divalent metal transporter 1 (DMT1) and stretch-activated channels (SACs) could play an important role in the uptake of ionized forms of Cd, Pb and Hg. DMT1 is probably a major transporter of metals in the loop of Henle. Paracellular pathways may also participate in metal transport along the proximal tubule and the loop of Henle.

The exact cellular processes underlying the metal-induced nephrotoxicity are not yet fully understood. Growing attention is directed towards the effect of metals on the oxidative status of cells and the production of reactive oxygen species (ROS) as well as their effect on cellular antioxidant defences such as superoxide dismutase (SOD) and glutathione peroxidase (GPX) [99, 101, 103, 114–121]. Oxidative stress can cause disruption of cellular macromolecules such as DNA, proteins and lipids [122–124].

The extent to which and how metals interact with each other remains a relatively unexplored field [125]. Several epidemiological studies have underlined that isolated environmental and occupational exposure to a single metal rarely occurs and is often combined with exposure to other metals [101, 126–129]. As reviewed by Choudhury and Mudipalli [129], research on the effect of combined exposure to metals on the kidney in humans is scarce. Similarities in kidney target areas and mechanisms of injury raise concerns regarding the possible nephrotoxicity of combined exposure to metals [99, 130]. In this respect, the recent finding that co-exposure to Pb increases the renal response to low levels of Cd in metallurgy workers is worth mentioning [100].

Cadmium

Occurrence and exposure

Cadmium, discovered by the German chemist Friedrich Strohmeier in 1817 [131], is a highly toxic and carcinogenic metal that is widely distributed in the environment. Mounting evidence from populations exposed to low or moderate levels points to Cd as a risk factor for a broad spectrum of health conditions, including cardiovascular, kidney and bone disease [132, 133]. Being a by-product of mining, melting and refining of Zn, Pb and Cu ores, the industrial production of Cd started in the 1930s. The use of Cd in consumer products (e.g. pigments, batteries, coatings and plastic stabilizers) increased dramatically until the 1970s and 1980s, resulting in widespread soil contamination from industrial releases, fuel combustion and Cd-containing phosphate fertilizers. Soil contamination by Cd is a major environmental health problem because leafy and root vegetables and grains concentrate the metal from soil, providing a major pathway for exposure through diet and tobacco [134–136]. Ambient air and dust can also contribute to Cd exposure, particularly in urban areas and in the vicinity of industrial sources and waste sites [137]. Public health policies such as tobacco control, air pollution reduction and hazardous waste remediation, have resulted in significantly decreased Cd exposure in developed countries. Nevertheless, additional public health efforts and efforts to reduce the levels of Cd in air, soils and food are critical to further prevent Cd exposure in the general population, especially since studies of National Health and Nutrition Examination Survey (1999–2008) data revealed that exposure to Cd at the current reduced levels is associated with cardiovascular, bone and kidney disease.

Absorption and distribution

As described by Johri et al. [101] Cd is absorbed from the gastrointestinal tract by DMT1. Following absorption, Cd primarily binds to serum albumin, the form in which it is transported to the various parts of the body, mainly the liver. Within the liver, intracellular Cd dissociates from albumin and released Cd ions induce the synthesis of metallothionein, which results in an increasing proportion of liver Cd being bound to metallothionein. The Cd–metallothionein complex is then slowly released back into the circulation.

Renal handling/toxicity

During the phase when plasma Cd is bound to albumin, there is only limited uptake of Cd by the kidney. The Cd–metallothionein complex, because of its low molecular weight, is freely filtered through the glomerulus and reabsorbed by the proximal tubule [101, 131, 116, 138]. Cd upregulates metallothionein production in the liver and kidney to limit the toxicity of free Cd²⁺. However, when the capacity of the proximal tubule to produce metallothionein is exhausted, progressive tubular cell damage may occur due to an increased uptake/intracellular concentration of Cd²⁺ [101, 112].

Renal Cd toxicity is primarily characterized by dysfunction of the proximal tubule, evidenced by polyuria and increases in the urinary excretion of glucose, amino acids, electrolytes (particularly Na⁺, K⁺ and Ca²⁺) and low molecular weight proteins. Prozialeck and Edwards [139], in an excellent review, put forward an elegant model of Cd-induced proximal tubule injury. Following accumulation of Cd in the proximal tubule, epithelial cell function may be affected, involving mild oxidative stress, disruption of cellular signalling cascades and alterations in cell adhesion. With mild injury, damage may be repaired through an autophagic response. However, if the injury is more severe, apoptosis and/or autophagic cell death can occur and repair processes will be inadequate, which ultimately results in necrosis of the proximal tubule cells [140].

Renal pathology

Data on pathologic findings in chronic Cd nephrotoxicity are scarce. One example can be found in itai-itai disease, named after the excruciating pains (Jap. itai = Eng. it hurts) in the spine and joints that were associated with severe Cd poisoning in Japan in the early 20th century. Kidneys in cases of itai-itai disease were red-brown, had a granular surface and were decreased in size. Microscopically there was extensive tubular atrophy and interstitial fibrosis. Inflammatory cells were present in small numbers. Some degree of glomerular sclerosis was present. Others investigating the renal pathology in patients exposed to either Cd fumes or pigments failed to show significant histological changes that might be due to differences in exposure and hence differences in the quantity of Cd in renal tissue [141–143].

Treatment

None of the chelation therapies have thus far been approved for clinical use in Cd toxicity. Balanced iron intake has proven effective in reducing the bioavailability of Cd present in the intestine by reducing its absorption (144).

Lead

Occurrence and exposure

Lead exposure/toxicity was a common problem among Romans >2000 years ago. Exposure to Pb is still an important environmental risk factors and in the year 2010 was estimated to account for 0.6% of the global disease burden [145]. Due to the elimination of Pb in gasoline, Pb-based paints and Pb pipes in homes, a significant reduction in blood Pb levels has been observed in recent decades [145, 146]. While cases of acute Pb poisoning have become rare, continuous exposure to low levels of Pb is still a public health issue in industrialized countries. Lead exposure leading to acute Pb poisoning or chronic health effects remains a significant public health problem in low- and middle-income countries, particularly because regulatory policies are lacking [147].

Once Pb is contained in dust and soil, it does not dissipate, biodegrade or decay, which means that it becomes a long-term source of Pb exposure, particularly in children. The mode for Pb transmission from contaminated soil to children is by hand to mouth (pica) and it was reported in a very recent review that elevated blood Pb levels of children living near landfills were closely associated with increased soil Pb levels and toxic effects, including adverse outcomes such as encephalopathy or even death [148].

Absorption and distribution

Corporeal handling of Pb is much less understood [99, 116, 149, 150]. Following absorption, Pb is transported to the blood plasma and within minutes is transferred to the erythrocytes where it is primarily bound to haemoglobin. Only ±6% circulates in the plasma from where it is distributed to the soft tissues (e.g. kidney), teeth and the skeleton, which contains up to 95% of the total Pb burden.

Renal handling/toxicity

Circulating Pb bound to low molecular weight proteins (<1% of the total) is filtered freely through the glomerulus and partially reabsorbed by the proximal tubule [116]. Following Chaumont et al. [151] it is likely that Pb is reabsorbed by the proximal tubule as a low molecular weight complex protein similar to the Cd–metallothionein complex. Cellular toxicity of Pb is complex and may develop via different pathways. First, exposure to Pb may induce oxidative stress, thereby initiating a cascade of events that may lead to vascular resistance and high blood pressure. Second, free radicals may be generated that activate nuclear factor κß and inflammation. Third, Pb may interfere with Ca-dependent enzymatic reactions and the induction of apoptosis. These various pathways can ultimately lead to the development of renal injury [116].

Renal pathology

Renal pathology in ‘chronic’ Pb nephropathy is characterized by granular contracted kidneys with a reduced number of functioning nephrons with multifocal tubular atrophy and dilatation and arteriolar and interstitial fibrosis. Glomeruli are normal and arteries and arterioles show medial thickening and luminal narrowing, probably related to hypertension. This renal pathology differs from that seen in ‘acute’ Pb nephropathy, which is consistently associated with acid-fast intranuclear inclusions in proximal epithelial cells. These intranuclear inclusion bodies consist of a Pb–protein complex and may be seen in tubular epithelial cells in the urinary sediment during acute poisoning [152].

Treatment

The most commonly used therapeutic strategy for Pb poisoning is chelation therapy to promote metal excretion. Chelators such as CaNa₂EDTA and meso-2,3-dimercaptosuccinic acid (DMSA) have been reported to have protective effects against Pb toxicity. However, CaNa₂EDTA can cause renal toxicity (particularly at the proximal tubule), especially with repeated high doses and in subjects with a previous history of kidney damage. Moreover, because of its relative lack of specificity, co-excretion of other essential metals such as zinc, iron and manganese may occur and continuous monitoring of these metals is warranted [153].

Mercury

Occurrence and exposure

Mercury is used in gold mining to extract gold from ore by forming ‘amalgam’—a mixture composed of approximately equal parts of Hg and gold. Approximately 15 million people, including ∼3 million women and children, participate in artisanal small-scale gold mining in developing countries and 37% of global air emissions of Hg are produced by this activity [154]. Exposure to Hg can cause various adverse health effects in humans. The nervous system and the kidneys are especially sensitive to Hg toxicity [114, 155, 156]. The three key determinants of Hg toxicity are the chemical form one is exposed to (i.e. mercury vapour versus inorganic versus organic compounds), the route of exposure and the dose [157].

Absorption and distribution

Once absorbed, Hg may undergo several metabolic transformations through oxidation, reduction, methylation and demethylation processes. The distribution of Hg in the body after exposure essentially depends on the binding form of the absorbed Hg: inorganic Hg salts are predominantly deposited in the kidney, while exposure to metallic Hg vapour or methylmercury increases the Hg concentration in the brain. Normally the highest Hg concentrations are found in the kidney followed by the liver, spleen and brain [158, 159].

Renal handling/toxicity

Renal accumulation of inorganic Hg was found to occur mainly in the convoluted and straight segments of the proximal tubule [160]. Mercury–thiol conjugates of GSH are considered the principal entity involved in the uptake of Hg at the proximal tubule [161]. Regarding its uptake, studies suggest the involvement of different transporters operating at the luminal and basolateral membrane (162). At the luminal surface, transport of Hg appears to occur through the luminal membrane as a conjugate of L-cysteine, such as dicysteinylmercury, via one of the amino acid transport systems, while at the basolateral membrane, transport of mercuric conjugates of GSH and/or cysteine takes place through OAT1 and OAT3 [163–165]. It has been hypothesized that Hg binding to sulphydryl groups on proteins, which are extensively present in the S3 part of the proximal tubule, is responsible for the characteristic S3 segment Hg-induced cellular dysfunction and death, resulting in the well-known Hg-induced nephrotoxicity [163].

Renal pathology

Chronic Hg poisoning results in kidneys of normal or slightly decreased size. Initially, interstitial oedema, inflammatory infiltration with lymphocytes and tubular cell changes such as necrosis, flattening of epithelium and desquamation of epithelial cells are present [166–168]. Later, there is progressive loss of tubules and interstitial fibrosis [166]. Glomerular pathology is limited to membranous nephropathy [168].

Treatment

Mercury intoxications were previously treated with dimercaprol, also called British antilewisite (BAL) and d-penicillamine. However, dimercaprol is itself toxic, with a narrow therapeutic range and serious side effects, including nephrotoxicity, hypertension and brain deposition of inorganic as well as organic Hg. In view of this, BAL is now considered to be contraindicated [169]. The efficacy of d-penicillamine in the removal of Hg is rather poor and use of the compound is contraindicated in renal failure. Data from several case and cohort reports present increasing evidence for the safe use of DMSA and d,l-2,3-dimercapto-1-propanesulfonic acid (Dimaval or DMPS) in the treatment human poisoning by various Hg compounds [170].

Conclusion

It is clear that our bodies are continuously challenged by environmental toxins and that the kidney, due to its concentrating ability and excretory function, very often is affected. Since our kidneys play a crucial role in maintaining body homeostasis, i.e. providing a balanced ionic composition, volume, pH and osmolality of our body fluid, renal injury often has far-reaching clinical consequences. In contrast to the majority of disease aetiologies, identifying the precise cause and mechanism of environmentally induced renal injury remains a daunting task involving many scientific disciplines, as evidenced above. Investigations in this field are particularly challenged by the apparent infinite types of toxins, their mutual interaction and handling/metabolization by the body. With the recent development of ‘-omics’, in particular metabolomics, and chemical profiling research tools, this process is likely to speed up in the future. Although a group effort and persistence are required to identify and tackle environmental toxin–induced renal pathologies, research eventually pays off in ameliorated working/living conditions, the development of treatments or, at least, an increased general awareness of particular environmental threats to the kidney. An important driving factor herein is the fact that environmental toxins are a preventable cause of kidney disease.

Conflict of interest statement

None declared.