CURRENT Occupational and Environmental Medicine (Lange Medical Books), 5th Edition

26. Renal Toxicology

German T. Hernandez, MD

Rudolph A. Rodriguez, MD

In the United States, 594,374 patients were treated for end-stage renal disease (ESRD) in the year 2010 at a yearly cost of well over $47 billion. Both the number of patients and the associated costs continue to grow annually. The etiology of the kidney injury in a significant percentage of these patients is never fully elucidated, and the diagnosis of renal disease of occupational origin is rarely considered. The true incidence of chronic kidney disease secondary to occupational and environmental exposures in the United States is unknown. However, these exposures represent potentially preventable causes of chronic kidney disease. Even if occupational and environmental exposures account for only a small percentage of the causes of ESRD in the United States, the significant morbidity, mortality, and costs associated with renal replacement therapy potentially could be prevented.

The kidney is especially vulnerable to occupational and environmental exposures. Approximately 20% of the cardiac output goes to the kidneys, and a fraction of this then is filtered; this is represented by the glomerular filtration rate (GFR). The GFR is normally 125 mL/min, or 180 L/d. Along the nephron, this filtrate is largely reabsorbed and then concentrated and acidified. Thus, occupational and environmental toxins can be highly concentrated in the kidney, and as the pH of the filtrate changes, some toxins can exist in certain ionic forms. These factors help to explain the pathophysiologic mechanisms involved in certain toxins. For example, lead and cadmium cause much of their renal ultrastructural damage in the proximal tubule, where two-thirds of the filtered load is reabsorbed.

Following relatively high-dose exposure to certain organic solvents, metals, or pesticides, acute kidney injury may develop within hours to days. The renal lesion usually is acute tubular necrosis. The clinical picture usually is dominated by the extrarenal manifestations of these exposures, and if the other organ systems recover, renal recovery is the rule. Chronic kidney disease (CKD) or ESRD also may develop after certain exposures. The renal lesion in these cases usually is chronic interstitial nephritis, and lead nephropathy is a prime example. However, glomerular lesions are also seen after selected exposures such as to organic solvents or silicosis; in general, glomerular lesions after occupational or environmental exposures are very uncommon.

The renal evaluation of patients thought to have renal disease associated with an environmental or occupational exposure should be guided by the history, physical examination, and clinical presentation of the renal disease. The time course will separate acute from chronic kidney disease. In acute kidney injury, the urine sediment usually is diagnostic of acute tubular necrosis. Most chronic kidney diseases associated with exposure to agents such as lead or cadmium present with chronic interstitial nephritis characterized by tubular proteinuria (usually less than 2 g/24 h) and a urine sediment usually lacking any cellular elements. A nephritic urine sediment is suggestive of a proliferative renal lesion and has been associated with only a few exposures, such as to organic solvents. The nephrotic syndrome, characterized by more than 3.5 g protein per 24 hours, edema, and hypercholesterolemia, is also associated with exposure to some heavy metals, including mercury.

Monitoring workers for the possible renal effects of occupational exposures is very difficult because of the lack of sensitive and specific tests of renal injury. Serial measurement of traditional tests such as creatinine or blood urea nitrogen (BUN) is inadequate because these tests do not become abnormal until significant renal damage has occurred. Tests for use in adult studies correlate with the site of possible damage. Some of these tests detect possible glomerular injury (eg, urine albumin), proximal tubule damage (eg, retinol-binding protein, N-acetyl-β-D-glucosaminidase, and alanine amino peptidase), and distal tubule injury (eg, osmolality). Most of these tests were designed to detect early renal tubular damage. Unfortunately, their use is limited by many factors; for instance, some are unstable at certain urine pHs, others return to normal levels within a few days of the exposure despite renal damage, and others exhibit large interindividual variations. Most important, unlike micro-albuminuria, which is able to predict future nephropathy in type 1 diabetes, the predictive value of these newer tests has not been validated. More long-term studies are needed before these newer renal tests can be used routinely to monitor renal injury in the workplace.

The Kidney Disease Improving Global Outcomes (KDIGO) CKD work group has published clinical practice guidelines for the evaluation and management of chronic kidney disease. These guidelines suggest classifying patients with chronic kidney disease based on cause, one of five estimated GFR categories, and one of three categories of albuminuria. Lower GFR and higher levels of albuminuria are associated with an increased risk of CKD progression and the development of complications.

ACUTE KIDNEY INJURY

A large number of occupational and environmental toxins can cause acute renal injury, usually after high-dose exposure. Although the extrarenal manifestations of the particular toxic exposure usually dominate the clinical presentation and course, the characteristics and time course of the acute kidney injury are very similar in all exposures. In the vast majority of cases, acute tubular necrosis is the renal lesion that develops. Hours to days after the exposure, the acute tubular necrosis is manifested by decreased urine output, usually in the oliguric range of less than 500 mL/d. The urinalysis typically is diagnostic of acute tubular necrosis, with renal tubular cells, muddy brown granular casts, and little or no protein. Red blood cells, white blood cells, or casts of either cell type are not typically seen with acute tubular necrosis and their presence suggests a glomerulonephritis instead. Increases in BUN and creatinine and electrolyte abnormalities develop as expected in acute kidney injury, and patients may require dialysis until the renal function recovers. After 1–2 weeks, recovery from acute tubular necrosis usually is heralded by the onset of a diuresis.

Hemodialysis and/or hemoperfusion have almost no role in accelerating the clearance of occupational and environmental toxins. For these techniques to be effective, toxins must have a low apparent volume of distribution and molecular weight, a low affinity for plasma proteins, and low tissue-binding properties. For example, charcoal hemoperfusion can result in almost complete removal of circulating paraquat, but because of high tissue binding, only small amounts of total-body paraquat are removed. Consequently, hemoperfusion does not affect the prognosis in paraquat poisoning. These extracorporeal techniques are effective only after a few intoxications, which include certain alcohols, salicylate, lithium, and theophylline.

ACUTE KIDNEY INJURY CAUSED BY HEAVY METALS

Significant exposure to any of the divalent metals—chromium, cadmium, mercury, and vanadium—is capable of producing acute tubular necrosis. Of these metals, the only one encountered in industrial settings in high enough concentrations to produce acute tubular necrosis with notable frequency is cadmium. Exposure to cadmium in toxic amounts is usually through inhalation, and the classic history of exposure is that of workers welding cadmium-plated metals. Welders exposed to cadmium fumes present with coughing and progressive pulmonary distress leading to adult respiratory distress syndrome. Kidney injury occurs rapidly in the form of acute tubular necrosis. Severe exposure is capable of producing bilateral cortical necrosis.

ACUTE KIDNEY INJURY CAUSED BY ORGANIC SOLVENTS

In the occupational setting, the lungs are the most common route of absorption of hydrocarbons. Inhaled hydrocarbons then quickly pass into the pulmonary circulation. Transcutaneous absorption is also an important route of absorption for solvents. Organic solvents are lipophilic and therefore are distributed in highest concentration in the fat, liver, bone marrow, blood, brain, and kidneys.

1. Halogenated Hydrocarbons

image Carbon Tetrachloride

Carbon tetrachloride (CCl4) is used as an industrial solvent and as the basis for manufacture of fluorinated hydrocarbons. It was once used as a household cleaning agent and as a component of fire extinguisher fluid under the brand name Pyrene.

After acute exposure, patients typically present with confusion, somnolence, nausea, and vomiting. Mucous membrane irritant effects, such as burning eyes, may occur, although some workers may be symptom-free for several days following exposure and then present with complaints of vomiting, abdominal pain, constipation, diarrhea, and in some cases fever. Physical findings may be compatible with the acute abdomen at this stage of illness, and many patients have been improperly subjected to laparotomy for that reason.

After 7–10 days of illness, there may be a decline in urine output even to the point of anuria. Patients with carbon tetrachloride intoxication usually show signs of prerenal azotemia, as demonstrated by a low urinary sodium excretion, and if ischemic acute tubular necrosis does not supervene, the prerenal azotemia may improve after volume repletion. If the hepatotoxicity is severe, patients also may develop hepatorenal syndrome.

image Other Aliphatic Halogenated Hydrocarbons

Other aliphatic halogenated hydrocarbons are nephrotoxic, some to a greater and some to a lesser degree than carbon tetrachloride. Ethylene dichloride (C2H4Cl2) is used as a solvent for oils, fats, waxes, turpentine, rubber, and some resins; as an insecticide and fumigant; and in fire extinguishers and household cleaning fluids. It is slightly less potent than carbon tetrachloride as a renal toxicant but causes far greater central nervous system toxicity. Ingestion or heavy inhalation may produce acute tubular necrosis similar to that encountered with mercury poisoning.

Chloroform (CCl3H) is more nephrotoxic than carbon tetrachloride and produces proximal tubule cell damage in animal models. Trichloroethylene (C2HCl3) has a number of industrial uses and also has been used as an anesthetic agent. Acute kidney injury has followed inhalation of this agent and has occurred in persons using it as a solvent for cleaning. Although it is partially unsaturated, it has toxic effects comparable with those of carbon tetrachloride and chloroform.

Tetrachloroethane (1,1,2,2-tetrachloroethane, C2H2Cl4) is an excellent solvent for cellulose acetate and is by far the most toxic of the halogenated hydrocarbons. Vinylidene chloride (1,1-dichloroethylene, C2H2Cl2) is a monomer used in the manufacture of plastics and is not used as a solvent. Its toxicology is similar to that of carbon tetrachloride.

Ethylene chlorohydrin (2-chloroethyl alcohol, C2H4 ClOH) is used as a solvent and as a chemical intermediate. It is far more toxic than any of the other aliphatic halogenated hydrocarbons. Unlike the others, it penetrates the skin readily and is absorbed through rubber gloves. Its mechanism of toxicity is not well understood.

2. Nonhalogenated Hydrocarbons as a Cause of Acute Kidney Injury

image Dioxane

Dioxane is a cyclic diether; it is colorless, has only a faint odor, and is freely soluble in water. The vapor pressure of dioxane is quite low, so respiratory overexposure is rare. Although dioxane is less toxic than the halogenated hydrocarbons, toxicity can be insidious, and large amounts can be inhaled without warning. Injury may become apparent hours after exposure.

Clinically, patients present with anorexia, nausea, and vomiting. Jaundice is uncommon. In fatal cases, clinical presentation may resemble an acute abdominal emergency. Urine output decreases on about the third day of illness.

image Toluene

There are several reports of acute kidney injury occurring with toluene inhalation (glue sniffing); most case reports describe reversible acute tubular necrosis, with a few reports documenting acute interstitial nephritis. However, metabolic acidosis associated with toluene abuse has been well documented. The two mechanisms involved are overproduction of hippuric acid and reduction of excretion of net acid (primarily NH4+) in some abusers. Sodium and potassium depletion also occurs commonly in these patients.

image Alkyl Derivatives of Ethylene Glycol

The principal derivatives of ethylene glycol used commercially are the monoethyl ether (Cellosolve), the monomethyl ether (methyl Cellosolve), and the butyl ether (butyl Cellosolve). The three compounds are similar pharmacologically, with increasing toxicity in the order listed above. All can be absorbed through the skin or lungs, as well as through the gastrointestinal tract. These agents are irritants of skin and mucous membranes and act as central nervous system depressants, with resulting symptoms of headache, drowsiness, weakness, slurred speech, staggering gait, and blurred vision. The renal injury caused by these ethers is not related to the oxalic aciduria caused by the parent compounds, which are dialcohols.

image Phenol

Phenol (carbolic acid) causes local burns and may be absorbed both through the lungs and transdermally. Although phenol causes severe local burns, systemic symptoms also may occur. These include headache, vertigo, salivation, nausea and vomiting, and diarrhea. In severe intoxication, urinary albumin excretion may be increased. Red cells and casts are found in the urine. The potentially disastrous consequences of transdermal absorption should not be underestimated.

Patients may present with hypothermia, which is followed by convulsions. The urine may be dark, and oliguria may develop. Phenol is metabolized to hydroquinone, which, when excreted in the urine, may be oxidized to colored substances, causing the urine to change to green or brown (carboluria). Prolonged exposure has been reported to result in proteinuria.

image Pentachlorophenol

Pentachlorophenol is used as a preservative for timber and as an insecticide, herbicide, and defoliant. It is readily absorbed through the skin. In addition to causing acute kidney injury, pentachlorophenol causes a hypermetabolic state, with hyperpyrexia and vascular collapse. Workers exposed to pentachlorophenol in clearly subtoxic doses may present with reversible decreased proximal tubular function as manifested by reduced tubular resorption of phosphorus. When these workers are reexamined after a 21-day vacation, renal function—both GFR and proximal tubular function—returns to normal.

image Dinitrophenols & Dinitro-o-Cresols

These agents have been used as pesticides and herbicides. After absorption, they uncouple oxidative phosphorylation. Fatal hyperpyrexia has been reported. Although patients develop acute kidney injury, it is not known whether this is a direct effect of the agents or secondary to the metabolic consequences, such as myoglobinuria.

ACUTE KIDNEY INJURY CAUSED BY UNIDENTIFIED PESTICIDES

Exposure, Pathogenesis, & Clinical Findings

A reduction in GFR, as well as tubular reabsorption of phosphate suggestive of mild proximal tubular dysfunction, has occurred in some agricultural workers. Changes in tubular function and in GFR rate occur in conjunction with depression of serum cholinesterase, suggesting that organophosphates may be responsible for these changes in renal function.

In an ethically questionable study, prisoners in a New York State prison were fed carbaryl. This pesticide is similar in action to the organophosphates, and the prisoners likewise demonstrated a decrease in GFR and tubular resorption of phosphate. There is no evidence that structural damage occurs after exposure to any of these agents.

Organic mercurials are used as fungicides. Absorption of these agents in agricultural workers has been reported to lead to nephrotic syndrome in the case of methoxymethyl mercury silicate, and a dose-dependent increase in the urinary excretion of γ-glutamyl transpeptidase has been reported in the case of phenyl mercury, indicating a direct nephrotoxic effect of this class of compounds.

ACUTE KIDNEY INJURY CAUSED BY ARSINE

image Exposure

Arsine (AsH3) is a heavy gas and is the most nephrotoxic form of arsenic. It is produced by the action of acids on arsenicals, usually during coal or metal-processing operations. Exposure to arsine may be insidious because even as simple an operation as spraying water on metal dross may liberate arsine. Arsine is also used in the semiconductor industry. It may be shipped over long distances with a potential for public health disasters because arsine is an extremely toxic gas.

image Clinical Findings

Arsine is primarily hemotoxic and is a potent hemolytic agent after acute or chronic exposure. The first signs of poisoning are malaise, abdominal cramps, nausea, and vomiting. This may take place immediately or after a delay of up to 24 hours. Renal failure results from acute tubular necrosis secondary to hemoglobinuria.

image Treatment & Prognosis

Acute tubular necrosis may be delayed by treatment with hydration and mannitol. However, red blood cell exchange and plasma exchange have been used to prevent further hemolysis. Recovery from acute tubular necrosis induced by arsine may not be complete, and there is evidence that residual interstitial nephritis may result.

ACUTE KIDNEY INJURY CAUSED BY PHOSPHORUS

Ingestion of only a few milligrams of elemental yellow phosphorus may produce acute hepatic and acute renal necrosis. Chronic exposure may result in proteinuria, although the kidney is not the primary organ affected by phosphorus.

BALKAN-ENDEMIC NEPHROPATHY AND THE CENTRAL AMERICAN EPIDEMIC OF CHRONIC KIDNEY DISEASE

The prototypical renal disease associated with an environmental exposure is Balkan-endemic nephropathy (BEN), which is now considered a form of aristolochic acid nephropathy. BEN highlights the difficulties involved in identifying specific toxins that may cause renal disease. In the late 1950s, BEN was first described as an interstitial nephropathy associated with urinary tract tumors. It is endemic to rural areas along the Sava, Danube, and Morava rivers in Serbia, Croatia, Bosnia-Herzegovina, Bulgaria, and Romania. It strikes predominantly farm workers in the fifth to sixth decades. Most victims have resided for at least 20 years in villages where the disease is endemic, and children are not affected.

Patients present with abnormalities of tubular function, including renal tubular acidosis, glycosuria, and hyperuricosuria with hypouricemia. Proteinuria is usually less than 1 g/d, which is consistent with the absence of glomerular disease. Not all patients with chronic kidney disease will progress to ESRD. Renal pathology includes interstitial fibrosis and periglomerular fibrosis; there is no inflammatory component, and glomeruli are normal. Papillary transitional-cell cancer is seen in 30–40% of patients with BEN. Anemia seems to be disproportionate to the degree of renal failure in these patients.

Many etiologies had been proposed to account for BEN. Both lead and cadmium were excluded as possibilities. Aristolochic acid is a known renal toxin and has been found in flour obtained from wheat contaminated with the seeds of Aristolochia clematis in areas of endemicity. In addition, aristolochic acid DNA adducts have been found in the kidney tissue of patients from endemic regions. Aristolochic acid exposure is now thought to be the cause of BEN (see “Aristolochic Acid Nephropathy/Analgesic Nephropathy” below).

There appears to be an epidemic of chronic kidney disease across Central America that disproportionately affects men who work in lower altitudes. The clinical manifestations include minimal proteinuria, slow progression, and small echogenic kidneys on ultrasound imaging. Agricultural workers in low altitudes seem to be particularly at risk for this form of CKD. The etiology has been identified, and potential causes include volume depletion with repeated episodes of heat-related acute kidney injury, toxins (agro-chemicals, heavy metals, aristolochic acid, and medications), infections, and genetic causes. Dialysis and transplantation is not an option for many in Central America and therefore many of these men die an early death due to chronic kidney disease. Efforts are underway by many groups to identify the etiology of the CKD in this region.

ARISTOLOCHIC ACID NEPHROPATHY & ANALGESIC NEPHROPATHY

When evaluating patients suspected of having renal disease associated with environmental or occupational exposures, it is very important to exclude herbal and analgesic nephropathy. Both commonly present with chronic interstitial nephritis, as do most occupationally related renal disease. Aristolochic acid nephropathy (previously known as Chinese herb nephropathy) was first described in 1991; physicians in Belgium noted an increasing number of young women presenting with ESRD following exposure to Chinese herbs at a weight-reduction clinic. The renal pathology and the association with papillary transitional-cell cancer are very similar to the renal findings in BEN. In fact, aristolochic acid was the common denominator found in the weight-reduction formulas. Cases of aristolochic acid nephropathy now have been reported worldwide, and aristolochic acid exposure in rat models produced similar renal lesions as in humans. Aristolochic acid DNA adducts have been demonstrated in the kidney tissue of patients with aristolochic acid nephropathy. Most other herbal remedies are safe, but adulteration of these herbal remedies is not uncommon. The common contaminants that may cause renal disease include botanicals (eg, aristolochic acid), synthetic drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], and diazepam), and heavy metals (eg, lead and cadmium). Renal dysfunction as a consequence of NSAIDs and selective cyclooxygenase-2 inhibitors may present in three different forms. The most common form is hemodynamic kidney injury after the loss of prostaglandin-mediated afferent arteriolar vasodilatation. This then leads to afferent arteriolar vasoconstriction in patients with preexisting volume depletion. Both classes of drugs also can cause acute kidney injury secondary to acute interstitial nephritis, which usually is accompanied by nephrotic-range proteinuria. Both forms of kidney injury are reversible after discontinuation of the offending drug, although the kidney injury as a consequence of interstitial nephritis is usually more severe and may require dialysis support. The third form of renal dysfunction is papillary necrosis, which is not reversible and which occurs after many years of high doses of NSAIDs. Papillary necrosis occurs more commonly after chronic phenacetin use. Phenacetin is no longer available in the United States. It is controversial whether chronic acetaminophen use causes papillary necrosis.

In addition to NSAIDs and aristolochic acid, herbal remedies may contain heavy metals, such as lead, cadmium, or mercury; the renal disease associated with these metals is discussed in the following sections.

CHRONIC KIDNEY DISEASE

CHRONIC KIDNEY DISEASE CAUSED BY LEAD

Although organic lead, which was widely used as an additive to gasoline in the past, is not nephrotoxic, its combustion products are. At one time, lead was released into the environment at a rate of approximately 60 million kg/y as inorganic lead through the combustion of gasoline. Its environmental fate is unknown. Lead can be absorbed from the gastrointestinal tract or the lungs. Gastrointestinal absorption is approximately 10% in adults and 50% in children. Within 1 hour of absorption by the gut, lead is concentrated in bone (90%) and kidneys. The biologic half-life ranges from 7 years to several decades.

Although Lanceraux described the link between lead exposure and small contracted kidneys in 1863, the modern awareness of lead nephropathy originated with the Australian experience. Acute lead poisoning in childhood was very common in Queensland between 1870 and 1920, when lead paint was still being used. Twenty years later, a follow-up study of children hospitalized for acute lead poisoning found that more than 30% of these children had chronic nephritis, hypertension, or proteinuria. Gouty arthritis was noted in approximately 50% of patients. Epidemiologic data in the United States also confirm the link between overt lead exposure and chronic kidney disease, hypertension, and gout.

Experimental models of lead nephropathy found that administration of continuous high-dose lead to rats over a 1-year period resulted in a significant reduction in GFR, and the renal pathology revealed the characteristic proximal tubule intranuclear inclusions that are prominent early in human lead nephropathy. After 6 months of lead exposure, focal tubular atrophy and interstitial fibrosis appeared, and after 12 months, enlarged, dilated tubules were noted. Chelation of lead with dimercaptosuccinic acid (DMSA) resulted in an increase in GFR in rats, but the tubulointerstitial disease did not reverse. Continuous low-level lead exposure in rats did not produce significant changes in renal function and produced only mild alterations in renal morphology after 12 months.

Many studies have noted an approximate incidence of gout of 50% among subjects with lead nephropathy. The possible mechanisms of saturnine gout include decreased renal clearance of uric acid, crystallization at low urate concentrations, and lead-induced formation of guanine crystals. Human studies have found that patients with gout and chronic kidney disease have significantly higher urinary lead excretion after chelation than do either subjects with gout and normal renal function or subjects with CKD and no gout. These findings implicate lead as the cause of both the gout and the CKD in these patients.

Acute lead intoxication is associated with hypertension, but the relationship between chronic lead exposure and hypertension remains controversial in the setting of mounting evidence. Despite the continued decline in lead exposure in the US population, a significant association between relatively low blood lead levels and hypertension remains among Mexican Americans and African Americans in the United States. Many large population studies have found a direct correlation between blood lead levels and zinc protoporphyrin and blood pressure. The possible mechanisms linking lead and hypertension include increased intracellular calcium, inhibition of the Na+, K+-adenosine triphosphatase (ATPase) system, direct vasoconstriction, and alterations in the rennin-angiotensin-aldosterone axis.

Human studies also have investigated the role of lead in the association of hypertension and CKD. Early studies in patients with overt lead exposure, hypertension, and CKD have implicated lead as a cause of both the renal insufficiency and hypertension. However, these studies included patients with high-level lead exposure, including those with moonshine consumption. There is growing evidence that low-level lead exposure is associated with chronic kidney disease among certain populations.

Data from the Normative Aging Study and the National Health and Nutrition Examination Surveys suggest that low-level lead exposure may be associated with impaired renal function among veterans, and adults and adolescents in the general US population. A more recent Swedish case-control study of subjects with low-level exposure to lead found an association between increasing blood lead levels and the risk of ESRD.

Small studies from Taiwan recently have reported low-level environmental lead exposure as an independent risk factor for renal disease progression among patients with diabetic and nondiabetic CKD. Furthermore, intravenous chelation therapy with ethylenediaminetetraacetic acid (EDTA) seems to ameliorate the decline in renal function when compared with placebo in the same Taiwanese patients with diabetic and nondiabetic CKD. Despite these findings, lead exposure as an independent risk factor for CKD progression has not received further attention.

image Presentation

The classic presentation for lead nephropathy is chronic kidney disease accompanied by a history of hypertension and gout. However, the diagnosis of lead nephropathy also should be considered in patients with chronic kidney disease and low-grade proteinuria, even without gout or significant hypertension. The urinalysis usually reveals 1+ to 2+ proteinuria but is otherwise normal, without cells or cellular casts. Twenty-four-hour urine collection usually has non-nephrotic-range proteinuria in the range of 1–2 g, and renal ultrasonography typically shows small, contracted kidneys. Renal biopsy reveals nonspecific tubular atrophy, interstitial fibrosis, and minimal inflammatory infiltrates, and the arteriolar changes are indistinguishable from nephrosclerosis and appear even in patients with lead exposure and no history of hypertension. Electron microscopy shows mitochondrial swelling and increased numbers of lysosomal dense bodies within proximal tubule cells; intranuclear inclusion bodies usually are present in the early stages of lead exposure but often are absent after chronic exposure or after lead chelation.

image Diagnosis

The diagnosis is considered after documenting significant lead exposure. Whole blood lead levels are not useful unless elevated because low whole blood lead levels do not exclude chronic lead exposure. The EDTA lead mobilization test correlates well with bone lead levels. One gram of EDTA is given intravenously or 2 g of EDTA with lidocaine are given intramuscularly in two divided doses 8–12 hours apart, and urine is then collected for 72 hours in patients with chronic kidney disease or for 24 hours in patients with normal renal function. Early studies in patients with overt lead exposure demonstrated that a total excretion greater than 600 μg lead chelate over 3 days was indicative of significant lead exposure. Studies of patients in Taiwan with low-level lead exposure raise the possibility that a total lead chelate excretion as low as 20–599 μg may be significant. Tibial K x-ray fluorescence measurements also correlate well with bone lead levels and, if available, should replace the EDTA mobilization test.

image Treatment

Overt lead nephropathy is one of the few preventable renal diseases. Whether renal function improves with treatment is controversial, but in some patients treatment has resulted in a modest improvement in GFR or, at the minimum, a slowing of the progression of the renal insufficiency even with low-level exposure. In addition, lead chelation treatment has led to increased urate excretion, which might have an impact on the management of gout in these patients. For patients with overt lead nephropathy, treatment consists of continued EDTA injections thrice weekly, with the goal of normalizing the urinary lead chelate.

Among patients with nondiabetic chronic kidney disease and low-level lead exposure (urine lead chelate excretion between 80 and 599 μg), treatment is continued with weekly intravenous infusions of 1 g EDTA until the urine lead chelate decreases to below 60 μg. The oral lead chelator DMSA is currently being studied and should replace EDTA as the treatment of choice for lead exposure. However, the safety and efficacy of chronic DMSA and EDTA in patients with moderate to severe renal insufficiency have not been well studied, and these agents should be used with caution in these patients.

CHRONIC KIDNEY DISEASE CAUSED BY CADMIUM

Cadmium, which is found primarily as cadmium sulfide in ores of zinc, lead, and copper, accumulates with age, having a biologic half-life in humans in excess of 10 years. In the United States, the use of cadmium doubled every decade in the twentieth century because of its common use in the manufacture of nickel-cadmium batteries, pigments, glass, metal alloys, and electrical equipment.

Between 40% and 80% of accumulated cadmium is stored in the liver and kidneys, with one-third in the kidneys alone. Cadmium is also a contaminant of tobacco smoke, and in the absence of occupational exposure, accumulation is substantially greater in smokers than in nonsmokers. Nonindustrial exposure is primarily via food; only approximately 25% of ingested cadmium is absorbed. “Normal” daily dietary intake varies between 15 and 75 mg/d in different parts of the world, although only a small fraction of this amount (0.5–2.5 mg/d) is absorbed. The cadmium body burden of a 45-year-old nonsmoker in the United States is approximately 9 mg, whereas in Japan the total is approximately 21 mg. Although clinical disease has been recognized among the general population in Japan, this has not been the case in the United States, where cadmium generally has been regarded as an exclusively industrial hazard. This may represent a failure to assign the correct cause to conditions commonly regarded as the result of aging.

After exposure to cadmium, the blood concentration rises sharply but falls in a matter of hours as cadmium is taken up by the liver. In red blood cells and soft tissues, cadmium is bound to metallothionein, which is a low-molecular-weight polypeptide. This cadmium-metallothionein complex is filtered at the glomerulus, undergoes endocytosis in the proximal tubule, and is later degraded in the lysosomes. The adverse effects of cadmium on the proximal tubule are probably mediated by unbound cadmium, which can interfere with zinc-dependent enzymes.

The principal target organs for cadmium toxicity after chronic low-dose exposure are the kidneys and lungs. Once a critical concentration of 200 μg/g of renal cortex is achieved, the renal effects, such as Fanconi syndrome, become evident. Hypercalciuria with normocalcemia, hyperphosphaturia, and distal renal tubular acidosis all contribute to the osteomalacia, pseudofractures, and nephrolithiasis seen in certain patients. Many of the symptoms usually originate from the increased calcium excretion that accompanies the renal tubular dysfunction. Ureteral colic from calculi is seen in up to 40% of patients subjected to industrial exposure. Itai-Itai (“ouch-ouch”) disease is a painful bone disease associated with pseudofractures in Japan, and it is attributed to local cadmium contamination of food staples by polluted river water. The possible causes of osteomalacia include a direct effect of cadmium on bone, diminished renal tubular reabsorption of calcium and phosphate, and increased parathyroid hormone and the subsequent decreased hydroxylation of vitamin D.

The role of cadmium in the induction of chronic interstitial nephritis is controversial. A study of 1021 workers with low-level cadmium toxicity found that early kidney damage evidenced by tubular proteinuria was evident at levels thought to be safe by World Health Organization health-based limits. Although some studies demonstrate subtle declines in GFR or an increase in odds ratios of ESRD in cross-sectional studies, few studies demonstrate an increase incidence of severe chronic kidney disease. However, workers should be monitored closely. Renal cadmium toxicity should be suspected in patients with low-molecular-weight proteinuria, urinary calculi, multiple tubular abnormalities, and a urine cadmium concentration greater than 10 μg/g of urine creatinine. There is no definitive treatment as no chelating agent is effective in removing cadmium from the body. Supportive treatment with removal from the source of exposure and treatment of osteomalacia, if present, should be initiated.

CHRONIC KIDNEY DISEASE CAUSED BY MERCURY

image Exposure

Occupational mercury poisoning usually results from inhalation of metal fumes or vapor, although toxicity has been reported after exposure to oxides of mercury, mercurous or mercuric chloride, phenylmercuric acetate, mercuric oxide, and mercury-containing pesticides. Divalent mercury is quite nephrotoxic when ingested, it accumulates in the proximal tubule, and can produce acute kidney injury in doses as low as 1 mg/kg. Although acute tubular necrosis will result after administration of mercuric chloride (HgCl2), such exposures occur either rarely or not at all as occupational hazards.

The two forms of renal disease resulting from mercury toxicity are acute tubular necrosis and nephrotic syndrome. In humans, acute tubular necrosis develops after ingestion of 0.5 g HgCl2, and in rats, HgCl2is used routinely to produce an experimental model of acute tubular necrosis. There also have been sporadic case reports of nephrotic syndrome after mercury exposure. These may be idiosyncratic reactions, and accordingly, occupational studies have not been able to find an association between mercury exposure and proteinuria. Membranous nephropathy, minimal-change disease, and anti–glomerular basement membrane antibody deposition all have been reported following mercury exposure.

Mercuric chloride can induce membranous nephropathy in certain rat strains. Before the development of the basement membrane immune deposits seen in membranous nephropathy, an autoimmune glomerulonephritis with linear immunoglobulin G (IgG) deposits along the glomerular capillary wall is first seen, but no pulmonary hemorrhage develops as seen in the Goodpasture syndrome. A T-cell-dependent polyclonal B-cell activation is responsible for the IgG deposits. As in humans, removal from mercury exposure, which can be in vapor or injections, results in reversal of the proteinuria in the rat models.

image Diagnosis

The clinical presentation in patients with acute tubular necrosis is usually dominated by the extrarenal manifestations of mercury toxicity. When the history of mercury exposure is available, the diagnosis of acute tubular necrosis from mercury toxicity is not difficult. On the other hand, it is more difficult to attribute glomerular disease such as membranous nephropathy to mercury exposure. Although elevated blood and urine mercury concentrations are consistent with significant exposure, these concentrations do not correlate with renal disease. Spontaneous resolution of the proteinuria following removal from the source of mercury exposure is consistent with mercury-mediated glomerular disease.

image Treatment

The mainstay of treatment is removal from the source of mercury exposure and chelation with the parenteral agent British anti-Lewisite (dimercaprol BAL) or with oral dimercaptosuccinic acid (succimer, DMSA). BAL is given as an initial dose of up to 5 mg/kg intramuscularly, followed by 2.5 mg/kg twice daily for 10 days. Succimer is given at a dose of 10 mg/kg by mouth every 8 hours for 5 days. In severe cases of mercury toxicity with anuric acute kidney injury, the use of hemodialysis with the prefilter infusion of DMSA has been reported to increase the removal of inorganic mercury.

CHRONIC KIDNEY DISEASE CAUSED BY BERYLLIUM

image Exposure

Beryllium is encountered in the manufacture of electronic tubes, ceramics, and fluorescent light bulbs, as well as in metal foundries. Because its absorption through the gut is very poor, beryllium’s principal route of entry into the body is by inhalation.

image Clinical Findings

The main manifestation of berylliosis is as a systemic granulomatous disease involving primarily the lungs, as well as the bone and bone marrow, the liver, the lymph nodes, and many other organs. Kidney damage occurs not as an isolated finding but only in conjunction with other forms of toxicity. In the kidneys, berylliosis can produce granulomas and interstitial fibrosis. Beryllium nephropathy is associated with hypercalciuria and urinary tract stones. Renal stone disease is common in berylliosis and may occur in up to 30% of patients. Parathyroid hormone levels are depressed, and the presumed mechanism of hypercalciuria is increased calcium absorption through the gut similar to that encountered in sarcoidosis. Hyperuricemia is also characteristic of beryllium nephropathy.

CHRONIC KIDNEY DISEASE CAUSED BY URANIUM

It is unclear whether uranium is responsible for significant occupationally related renal disease in humans. Uranium can cause acute kidney injury in experimental models, and the pathologic changes are consistent with acute tubular necrosis. During the Manhattan Project, acute tubular necrosis occurred in men working on the atomic bomb. Whether uranium can cause chronic kidney disease remains controversial. Although previous studies of Gulf War veterans exposed to depleted uranium and workers in a uranium-refining plant did reveal an increase in urinary β2-microglobulin excretion, the studies did not document decreased renal function, and the urinary β2-microglobulin levels were still in the normal range.

CHRONIC KIDNEY DISEASE CAUSED BY SILICOSIS

Silicosis is a form of pneumoconiosis associated with pulmonary exposure to silica. Heavy exposure can result in a generalized systemic disease resembling collagen-vascular disease, such as systemic lupus erythematosus. Inhalation of silica may trigger an autoimmune response in sensitive individuals; in fact, the occurrence of positive antinuclear antibody and antineutrophil cytoplasmic autoantibodies is increased in patients with silicosis.

The possible association of silica and glomerulonephritis is suggested by animal studies, case-control studies, and multiple case reports. Animals experimentally exposed to silica developed acute interstitial nephritis with deposition of silica in the kidney. This fact led to speculation that silica may contribute to analgesic nephropathy as a result of the widespread use of silicates in analgesic preparations. Certain studies have found that patients with silicosis have a high prevalence of albuminuria, impaired renal function, and glomerular abnormalities at autopsy. The reported cases of possible silica-associated glomerular disease include glomerular proliferation with occasional crescents, subendothelial and membranous deposits, and tubular degeneration. The renal silica content was elevated in most of the patients in whom it was measured. Interestingly, not all patients reported to have possible silica-associated nephropathy had pulmonary disease. A recent population-based case-control study found a positive association between occupational silica exposure and chronic kidney disease.

CHRONIC KIDNEY DISEASE CAUSED BY ORGANIC SOLVENTS

Solvent exposure may occur in many industries where there is use of paints, degreasers, and fuels, including the petrochemical and aerospace industries. There have been a number of intriguing case reports over the last 40 years of anti–glomerular basement membrane antibody–mediated glomerulonephritis occurring after solvent exposure. However, it remains unclear whether the solvent exposure is truly causal in these cases. Membranous nephropathy also has been reported after long exposure to mixed organic solvents. Twenty-five case-control studies have investigated hydrocarbon exposure and renal disease, and although most of these studies have major limitations, 20 found an increased odds ratio between solvent exposure and a variety of renal diseases. Animal studies show that solvents can cause acute renal damage at high doses, and only mild chronic renal changes have been produced with chronic low-dose exposure. There are no animal models for immunologic renal disease caused by solvents.

It is clear that solvent exposure at high doses may lead to acute kidney injury as a consequence of acute tubular necrosis, and substantial evidence supports that solvent exposure is associated with glomerulonephritis. However, solvent exposure is common, and glomerulonephritis is rare, which suggests that if the association does exist, certain host factors are necessary for this idiosyncratic reaction to develop.

CHRONIC KIDNEY DISEASE CAUSED BY CARBON DISULFIDE

image Exposure History & Clinical Findings

Carbon disulfide is used in the manufacture of rayon and neoprene tires. A number of renal disorders are reported, along with accelerated atherosclerosis. The latter may affect the renal circulation and lead to renal dysfunction, hypertension, proteinuria, and renal insufficiency. The renal effects of carbon disulfide probably are a direct result of its atherogenic effect and not related to direct nephrotoxicity. However, there is a case report of a worker with long-term high-level exposure who did develop ESRD and focal segmental glomerular sclerosis.

REFERENCES

Chen KH: Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens. Am J Kidney Dis 2012;60:530 [PMID: 22721929].

Ghahramani N: Silica nephropathy. Int J Occup Environ Med 2010;1:108 [PMID: 23022796].

Gökmen MR: The epidemiology, diagnosis, and management of aristolochic acid nephropathy. Ann Intern Med 2013;158:469 [PMID: 23552405].

Karami S: Occupational exposure to dusts and risk of renal cell carcinoma. Br J Cancer 2011;104:1797 [PMID: 3111161].

Li SJ: Mercury-induced membranous nephropathy. Clin J Am Soc Nephrol 2010;5:439 [PMID: 20089494].

Pennemans V: The association between urinary kidney injury molecule 1 and urinary cadmium in elderly during long-term, low-dose cadmium exposure. Environ Health 2011;10:77 [PMID: 21888673].

Sommar JN: End-stage renal disease and low level exposure to lead, cadmium and mercury. Environ Health 2013;12:9 [PMID: 23343055].

Vupputuri S: Occupational silica exposure and chronic kidney disease. Ren Fail 2012;34:40 [PMID: 22032652].

Weiner DE: The Central American epidemic of CKD. Clin J Am Soc Nephrol 2013;8:504 [PMID: 23099656].

 image SELF-ASSESSMENT QUESTIONS

Select the one correct answer to each question.

Question 1: The kidney

a. is especially vulnerable to occupational and environmental exposures

b. receives about half the cardiac output

c. reabsorbs and dilutes filtrate

d. prevents development of toxins in ionic forms

Question 2: Acute kidney injury

a. occurs only after high-dose exposure

b. always develops as acute tubular necrosis

c. leads to a decrease in BUN and creatinine

d. may require dialysis until the renal function recovers

Question 3: Chronic kidney disease (CKD)

a. is rarely in the form of chronic interstitial nephritis

b. does not include lead nephropathy

c. does not follow exposures to organic solvents

d. is characterized by tubular proteinuria

Question 4: Balkan-endemic nephropathy (BEN)

a. is a form of aristolochic acid nephropathy

b. is an interstitial nephropathy associated with urinary tract infections

c. strikes farm workers at all ages

d. affects children living on farms

Question 5: Lead nephropathy

a. is an acute kidney disease accompanied by a history of hypertension and gout

b. should not be considered in patients who do not have gout or hypertension

c. ultrasonography typically shows small, contracted kidneys

d. reveals no tubular atrophy on renal biopsy

Question 6: Overt lead nephropathy

a. is one of the few preventable renal diseases

b. treatment has no impact on the management of gout

c. treatment consists of continued EDTA injections once weekly

d. treatment is continued until urine lead chelate is below 20 μg

Question 7: Cadmium

a. primarily affects the kidneys and liver

b. renal effects include the Fanconi syndrome

c. symptoms usually result from the increased calcium excretion that accompanies the glomerular injury

d. causes ureteral colic from calculi in most patients subjected to industrial exposure

Question 8: Silicosis

a. can result in a generalized systemic disease resembling collagen-vascular disease

b. is the most common cause of systemic lupus erythematosus

c. decreases the occurrence of positive antinuclear antibody

d. has no effect on the occurrence of antineutrophil cytoplasmic autoantibodies

Question 9: The epidemic of chronic kidney disease in Central America

a. primarily affects automobile factory workers

b. is caused by heavy metals

c. disproportionately affects agricultural workers at lower, warm weather altitudes

d. is a form of aristolochic acid nephropathy

Question 10: Toluene inhalation (glue sniffing)

a. is a cause of nephrotic syndrome

b. may lead to the development of respiratory acidosis

c. is a cause of renal tubular acidosis

d. is associated with Fanconi syndrome



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