Heavy metal poisoning nephropathy

　　First, Etiology

　　Due to long-term occupational exposure, environmental pollution, accidental ingestion, and the application of heavy metal preparations, heavy metals are absorbed into the body through the digestive tract, respiratory tract, or skin, causing renal injury. After heavy metal protein complexes are filtered by the glomerulus, they are mainly reabsorbed in the proximal tubule, where the protein is decomposed and the heavy metal is released to produce toxic effects. Among other factors related to tubular heavy metal injury, the most important may be the affinity of heavy metals for the kidneys, their half-life, and the inherent toxicity of the heavy metals.

　　Second, Pathogenesis

　　The mechanism of kidney damage caused by heavy metals includes the following three aspects:

　　1. Direct toxic effect:Most heavy metals have a direct toxic effect, which is closely related to the dose. When the urine containing heavy metals flows through the proximal tubule, the proximal tubule cells become the main target organ of heavy metal toxicity. The reabsorption and secretion of the proximal tubule lead to vacuolation,变性 and necrosis of the tubular epithelial cells.

　　2. Immune injury:Certain heavy metals such as mercury and gold can damage renal tissue, causing changes in antigenicity and the production of autoantibodies, leading to immune injury of the glomerulus.

　　3. Renal ischemia:The direct toxic effects of heavy metals cause tubular dysfunction or acute tubular necrosis, or hemolytic uremic syndrome caused by their hemolytic action, which slows down the urinary flow through the macula densa, increases urinary sodium, activates the renin-angiotensin system, leading to renal vasoconstriction, renal ischemia, and causes renal injury through intracellular calcium ion accumulation, phosphatase activation, arachidonic acid product formation, and oxygen free radical production. For example, in cases of lead poisoning, lead is absorbed by the human body with the highest concentration in the kidneys and bones. The concentration of blood lead is consistent with recent lead exposure, while normal blood lead levels do not exclude past lead exposure or increased body lead burden. After lead bound to filterable plasma ligands is filtered by the glomerulus, it is mainly reabsorbed in the proximal tubule. The excretion of lead in the kidneys also occurs through tubular transport. Lead can freely pass through the luminal and basolateral surfaces of the tubular cell membrane. Inside the cytoplasm, lead combines with a protein to form an insoluble metal protein complex, precipitating into the nucleus to form characteristic eosinophilic inclusions visible under an optical microscope. Some of the characteristics of the lead-binding protein mentioned above have been recognized. This protein is rich in glutamic acid, aspartic acid, and glycine. The toxic effect of lead is mainly to block the oxidative phosphorylation of the mitochondria.

　　Alcohol may enhance the nephrotoxicity of lead, and the nephrotoxicity of both may have a synergistic effect. Elevated blood lead levels and multiple tubular dysfunction are observed in patients with chronic alcoholism.

　　Currently, it is believed that potential or symptomatic lead poisoning can develop into chronic renal failure. Epidemiological evidence that strongly supports this understanding includes:

　　(1) Chronic renal failure accounts for a high proportion in the mortality composition of the lead exposure population.

　　(2) The follow-up results of acute lead poisoning children in Queensland, Australia, show that more children died of chronic renal failure.

　　(3) The incidence of chronic renal failure is high in the population drinking illegal whiskey (such as using distillers with a large amount of lead) in the southern United States. However, the results of biological monitoring of occupational lead exposure for several years failed to verify the above evidence. The explanation for the above conflicting research results is that lead toxicity may be exacerbated by other risk factors such as other metals, drugs, alcohol, and individual constitution.

　　Pathophysiological studies suggest that lead also has a hypotensive effect. It is believed that lead can reduce renal perfusion, increase peripheral resistance at the same time; the number of glomerular parietal cells can increase after acute stimulation by lead; and it can cause enhanced α-adrenergic activity. The relationship between lead and arterial hypertension is complex. At present, some people believe that the hypotensive effect of lead may be through a calcium-dependent mechanism. Because the absorption of lead in the diet is related to calcium and phosphorus.

　　The clinical manifestations of heavy metal-induced nephropathy are complex, in addition to typical renal damage, it mainly complicates systemic diseases such as toxic encephalopathy, anemia, jaundice, liver damage, etc. Lead nephropathy often complicates gout, accounting for about 50% of the incidence rate. Early cessation of lead toxicity absorption has a good prognosis. Even after treatment, sequelae such as epilepsy and incomplete mental development often occur after the discovery of brain symptoms. As for lead toxicity潜伏in the bones, it is often easy to enter the blood circulation when infected with diseases such as infection, and recurrence occurs until the heavy lead band on the X-ray bone film disappears, and then there is no danger.

　　I. Renal manifestations

　　1, Pre-renal renal insufficiency:It often occurs before tubular necrosis, and due to the direct or indirect effects of heavy metals, it can cause peripheral circulatory failure, renal vasospasm, and renal insufficiency, which is manifested by decreased glomerular filtration rate, increased serum creatinine and urea nitrogen, but generally normal tubular function.

　　2, Acute tubular necrosis (ATN):Due to direct toxicity of heavy metals, hemoglobin casts can block the tubular lumen, leading to acute tubular necrosis (ATN) due to renal ischemia, which is manifested by acute renal failure and obvious tubular dysfunction, such as decreased urine osmolality, increased urine sodium, and decreased urine specific gravity.

　　3, Chronic tubular dysfunction:This is a common manifestation of chronic nephrotoxicity caused by low-dose heavy metals, mainly characterized by dysfunction of the proximal tubules, and clinical symptoms such as low molecular weight proteinuria, renal glycosuria, aminoaciduria, phosphaturia, and Fanconi syndrome.

　　4, Chronic interstitial nephritis:It is mainly seen in the sequelae of acute poisoning injury or in the late stage of chronic tubular damage, with relatively concealed clinical manifestations. Clinical symptoms include polyuria, increased nocturia, thirst, and often only discovered when chronic renal failure occurs.

　　5. Nephrotic syndrome:It is caused by immune damage to the glomerulus by heavy metals, and it is more common in metals such as mercury, cadmium, and gold. Clinically, it is mainly manifested by large amounts of proteinuria, hypoalbuminemia, and edema or hyperlipidemia, accompanied or not, and normal renal function.

　　II. Extrarenal manifestations

　　The extrarenal manifestations vary with the type of heavy metal, and common ones include headache, fever, stomatitis, gastroenteritis, abdominal pain, pneumonia, pulmonary edema, rash, muscle paralysis, toxic encephalopathy, anemia, jaundice, liver damage, etc.

　　As with chronic lead poisoning, its main clinical feature is a potential, progressive disease that is difficult to detect early through general renal function examination indicators. Lead nephropathy is characterized by reduced renal blood flow, decreased glomerular filtration rate, varying degrees of hypertension, and hyperuricemia. 50% of cases have gout attacks, and some cases have微量albuminuria, hyperkalemia, and tubular acidosis. Urinary sediment is normal. With the tubular degeneration, interstitial fibrosis, and calcification, it slowly progresses to chronic renal failure. It is currently believed that potential or symptomatic lead poisoning can all develop into chronic renal failure.

　　In children and experimental animals with acute lead poisoning, the dysfunction of the proximal tubules is manifested as the classic Fanconi syndrome. In adult chronic lead nephropathy, renal biopsy may show non-specific tubulointerstitial lesions, with interstitial fibrosis, lymphocytic infiltration, tubular atrophy and dilation, vascular lesions, and even severe arteriosclerosis. Non-specific vascular damage is related to the occurrence of hypertension. In the early years of lead poisoning, only a few cases show eosinophilic deposits in the nuclei of proximal tubule cells.

　　Chronic renal failure occurs after long-term exposure to lead, which may not have a history of acute发作 of other lead poisoning symptoms. Factors such as diet, tension, etc., can cause a slow release of bone lead deposition, promoting the progression of renal damage. There is currently no reliable method to predict and determine that lead nephropathy has entered an irreversible stage. The excretion of N-acetylglucosaminidase (NAG) and lysozyme (LYS) in the urine of occupational lead contacts is increased, and it remains higher than normal levels or only slightly reduced after leaving lead contact. The duration of lead exposure is positively correlated with the level of urinary NAG excretion. These results indicate that long-term occupational lead exposure leads to increased urinary enzyme excretion, and persistent lysosomal enzymeuria suggests chronic interstitial tubular damage.

　　Arterial hypertension is common in patients with chronic lead poisoning, long-term exposure to lead workers, chronic renal failure, and other diseases related to arterial hypertension (heart failure, cerebrovascular accidents, etc.), which significantly increases mortality. Experimental studies have confirmed that in patients with chronic renal failure accompanying chronic exposure to low-dose lead, the excretion of lead increases during EDTA mobilization test, while in patients with essential hypertension without chronic renal failure, the lead excretion does not exceed 3.14μmol/24h during EDTA mobilization test. The above studies suggest that lead plays a certain role in the pathogenesis of some essential hypertension.

　　The key to heavy metal poisoning nephropathy is prevention, avoiding contact with various heavy metals that can easily cause acute poisoning of liver and kidney function, which can effectively prevent the occurrence of the disease; once symptoms appear, contact should be stopped immediately. Acute poisoning patients should be washed out immediately,解毒剂 and emergency dialysis treatment should be applied, and efforts should be made to prevent the aggravation of systemic and renal function damage and acute death. Old housing should be washed frequently to avoid children from contacting lead paint and other raw materials containing heavy metals. It is necessary to wash hands frequently; it is necessary to wash hands before meals and before going to bed. Bottles, nipples, and toys should be washed frequently.

　　First, urine examination

　　Proteinuria, namely low molecular weight proteinuria, is the main symptom, and there may be hematuria, hemoglobinuria, and tubular casts. Urine enzymes such as NAG, urinary trace proteins such as RBP, α1-MG, β2-MG, urine calcium, urine phosphorus, urine sugar positivity, aminoaciduria, and alkaline urine may increase.

　　Second, renal function examination

　　The clearance rate of endogenous creatinine is reduced, blood urea nitrogen, creatinine, and uric acid are increased, the nuclear renal map often shows a parabolic renal map, and GFR decreases.

　　Third, biochemical examination

　　There may be hypokalemia, acidosis, hypercalcemia, hyperuricemia, elevated blood SGPT, and increased jaundice index, etc.

　　Fourth, determination of various heavy metal contents

　　Those who have the conditions can make urine aluminum, urine cadmium, urine gold, and other determinations to clarify the types and contents of heavy metal poisoning.

　　Fifth, imaging examination

　　X-ray or B-ultrasound examination can detect renal calcification and renal calculi.

　　Sixth, renal biopsy

　　When acute tubular necrosis occurs due to direct toxic effects and ischemic renal tubular injury, light microscopy shows proximal tubular epithelial cell degeneration, necrosis, lumen dilation, interstitial congestion, edema, and inflammatory cell infiltration around the tubules.

　　When chronic interstitial nephritis occurs, there are a large number of lymphocytes and plasma cells infiltrating the renal interstitium, interstitial fibrosis, dilatation or atrophy of renal tubules; in severe cases, the entire kidney is diffusely fibrotic; renal vessels and glomeruli are affected.

　　When nephrotic syndrome occurs, light microscopy can see membranous or proliferative glomerular changes, and the basement membrane thickens or there are electron-dense deposits on the mesangial surface under electron microscopy. Immunofluorescence suggests IgG, IgM, and C3 granules are deposited in the mesangium or capillary wall.

　　Heavy metal poisoning nephropathy should avoid spicy and irritating foods in diet, and pay attention to eating some soft and easy-to-digest foods during the recovery period, such as congee, noodle soup, and egg custard. Gradually return to normal diet later. It is also necessary to pay attention to light diet, eat less greasy foods, and consume eggs, milk, dairy products, vegetables, fruits, and other foods appropriately, drink plenty of water, drink less alcohol, exercise moderately, and can do physical therapy to improve symptoms.

　　First, treatment

　　1. Treatment principles and methods

　　The key to the treatment of heavy metal poisoning is prevention. Once symptoms appear, immediate cessation of exposure should be done. Acute poisoning patients should be immediately lavaged, detoxifying agents and emergency dialysis treatment should be administered.

　　(1) Immediately leave the scene of poisoning: For different heavy metals, general treatment should be given, such as emergency gastric lavage, changing contaminated clothing, whole-body shower, oral alkaline drugs (sodium bicarbonate 8-12g/d), and intravenous infusion of prednisolone (hydrocortisone) 200-400mg.

　　(2) Detoxification drug application: Depending on the type of heavy metal, calcium disodium EDTA (EDTACa-Na2, calcium disodium EDTA), sodium sulfosuccinate (sodium bisulfite), and sodium dithionate (sodium dithionate) are administered intravenously, which helps to quickly detoxify.

　　(3) Dialysis treatment: In critical cases such as acute renal failure, oliguria or anuria, and hyperkalemia, which threaten life, immediate peritoneal dialysis or hemodialysis treatment is required to quickly remove the toxin.

　　(4) Symptomatic treatment: For the clinical manifestations of heavy metal poisoning, active symptomatic treatment should be carried out, such as alkalinizing urine, correcting anemia, protecting the liver, preventing gastrointestinal bleeding, and providing general supportive therapy.

　　2. Nephrotoxicity and treatment of common heavy metals

　　(1) Mercury: Mercury and its compounds are widely used industrial chemicals, used in various industrial production processes, large quantities of spermicidal contraceptives, fungicides, and disinfectants, etc. At room temperature, mercury is a liquid metal that can exist in the form of metallic mercury, organic mercury, and inorganic mercury. All forms of mercury are nephrotoxic, with inorganic mercury being the most nephrotoxic, especially mercuric chloride. Mercury can enter the body through the respiratory tract, digestive tract, and skin, etc., and metallic mercury vapor is easily absorbed through the lungs. Since the kidneys are the main organ for accumulating and excreting mercury in the body, when the amount of mercury entering the kidneys is too large or too fast, exceeding the detoxification capacity of metallothionein (Metallothionein, MT) in the cytoplasm of renal tubular cells, a large amount of free mercury can accumulate in the kidneys, causing kidney damage. Many studies have explored the possibility of kidney damage caused by mercury. Long-term chronic exposure to mercury and its compounds can lead to subclinical nephrotoxic changes. Exposure to different types of mercury compounds or different exposure times can cause different types of kidney damage. In workers engaged in the production of mercury salts, mild proteinuria, increased BB-50 brush border antigen, and enzymuria were found. Minamata disease (Minamatadisease) was first discovered in Minamata Bay, Japan, and is a disease caused by mercury-containing industrial toxins. Some studies on this disease have shown that mercuric has nephrotoxicity. In 509 infants treated with phenylmercury for antifungal therapy, when the urine mercury level exceeded 220μg/L, the γ-glutamyl transpeptidase level increased in a dose-dependent manner. Two years after discontinuing the drug, the enzyme returned to normal.

　　Acute mercury poisoning can cause gastrointestinal symptoms such as nausea, vomiting, and abdominal pain within a few hours, along with swelling and ulcers of the oral mucosa, and in severe cases, laryngeal edema. Renal damage is mainly characterized by acute tubular necrosis, with symptoms such as oliguria, proteinuria, hematuria, and cast formation in urine, and in severe cases, it may progress to acute renal failure. Chronic mercury poisoning can lead to dysfunction of the proximal tubules, resulting in low molecular weight proteinuria, increased urinary enzymes such as γ-GT, NAG, and increased urinary retinol-binding protein (RBP). Larger doses of mercury can cause glomerular damage, with mild cases presenting with minimal albuminuria and severe cases showing nephrotic syndrome. Under electron microscopy, basal membrane damage or extracellular immune complex deposition can be observed, with fusion of the podocytes.

　　The key to the prevention and treatment of mercury poisoning lies in prevention. Once poisoning is diagnosed, immediate cessation of exposure is required, and mercury chelation therapy with sodium dimercaptopropionate (sodium dithiocarbamate) or sodium dimercaptosuccinate (sodium dithiocarbamate) should be administered. In cases of acute mercury poisoning with acute renal failure, dialysis treatment should be provided, or combined with small-dose medication to promote excretion.

　　(2) Lead: Lead is primarily absorbed through the respiratory and digestive tracts. After entering the blood, lead binds to transferrin and is distributed throughout the body, mainly excreted through the kidneys. Long-term exposure to lead is the main cause of lead-induced renal damage.

　　Acute lead poisoning patients exhibit obvious gastrointestinal symptoms, with abdominal colic being the most prominent, along with toxic liver disease, and may be accompanied by headache, hypertension, and toxic encephalopathy. Renal injury has characteristic pathological changes, namely, swelling and degeneration of the proximal tubules, with intracellular inclusions composed of lead-protein complexes, which can be shed from the cells and excreted in urine, hence the presence of nuclear inclusions in urine.

　　Renal damage is mainly seen in occupational exposure, long-term consumption of food stored in lead containers, and chronic lead poisoning. In addition to abdominal colic, anemia, and peripheral neuropathy, there may be elevated uric acid levels and gouty manifestations. Early kidney manifestations include dysfunction of the proximal tubules, which can be seen as low molecular weight proteinuria, aminoaciduria, diabetes, and phosphaturia. In the late stage, the main manifestations are TIN, with the appearance of interstitial fibrosis, tubular atrophy, renal sclerosis, and ultimately leading to chronic renal failure (CRF).

　　The treatment for lead poisoning involves first removing the source of exposure and stopping contact, usually through intravenous infusion of Na2-Ca-EDTA (calcium disodium EDTA), injection of disodium dithionate (NaDMS) or oral administration of disodium dithionate (DMSA). Treatment for chronic renal failure is the same as general conservative therapy; chelating agents that promote lead excretion are commonly used in clinical practice, such as EDTA, sodium citrate (sodium citrate), and dimercaprol (BAL). Hypertension should be controlled. Symptomatic treatment can be provided for hyperuricemia and gout. Compared to simple EDTA treatment, combined therapy with EDTA infusion and hemodialysis has a very rapid effect on removing lead in acute lead poisoning, but the efficacy of reversing chronic renal damage is not certain.

　　(3) Cadmium: Cadmium poisoning is mainly due to industrial exposure or environmental pollution. Cadmium can be absorbed through the respiratory and digestive tracts, and typical symptoms often occur years after exposure to cadmium. The kidney is a target organ for cadmium, which combines with sulfoprotein to form metallothionein, converting the toxic cadmium ions into relatively stable metallothionein, thereby neutralizing the toxicity. If too much cadmium is ingested, sulfoprotein is exhausted and cannot combine with无毒性的 metallothionein, leading to direct damage to renal tissue.

　　Acute inhalation of large amounts of cadmium oxide smoke can cause chemical pneumonia and pulmonary edema, and severe cases may have liver and kidney damage. Renal changes are often due to dysfunction of the proximal tubules or ARF. Chronic cadmium poisoning mainly damages the kidneys, and clinical manifestations can include low molecular weight proteinuria, aminoaciduria, diabetes, kidney stones, and osteomalacia. In the late stage, interstitial fibrosis of the kidneys can lead to tubular acidosis and chronic renal failure.

　　The treatment of cadmium poisoning is challenging, as chronic renal damage caused by cadmium is often irreversible, and the lesions can progress even after discontinuing exposure. Although thiol chelating agents have a strong affinity for cadmium, the complexes formed are unstable and can accumulate in the kidneys after being reabsorbed by the renal tubules, thereby enhancing their toxic effects, and are therefore listed as contraindicated in cadmium poisoning. Aminocarboxylate chelating agents have little therapeutic effect. In recent years, studies have found that dithiocarbamate salts (dithiocarbamates) can effectively excrete renal cadmium and may become the main drugs for treating cadmium poisoning.

　　(4) Arsenic: Metallic arsenic is insoluble in water and is almost non-toxic. Arsenic trioxide (commonly known as arsenic) and arsenic pentoxide are highly toxic, and organic arsenic also has strong toxicity. Arsenic compounds can cause acute hemolysis in addition to direct toxicity to the kidneys, leading to the formation of a large amount of free hemoglobin that blocks the renal tubules, causing tubular degeneration and necrosis, and the appearance of dark brown urine and oliguria. Severe cases may quickly enter acute renal failure.

　　Acute arsenic poisoning can manifest as severe acute gastrointestinal symptoms, with kidney damage as acute tubular necrosis. Clinically, proteinuria, hematuria, and cast urine may be observed. Chronic arsenic poisoning can lead to tubular dysfunction, causing acute tubular interstitial lesions and chronic renal failure. Some small-scale studies have observed that workers exposed occupationally to arsenic have higher excretion levels of RBP, albumin, β2-microglobulin, and kidney BB-50 brush border antigen in urine compared to the control group.

　　The treatment for arsenic poisoning, in addition to using sodium bis(thiodipropionate) or dimercaptopropanesulfonic acid (sodium dimercaptopropanesulfonate) for arsenic chelation, should also involve early dialysis and blood exchange therapy to improve the condition, and use alkaline drugs to reduce the obstruction of the renal tubules by hemoglobin.

　　(5) Chromium: Acute poisoning is often caused by accidental ingestion or skin contact with high-concentration hexavalent chromium compounds (chromates or dichromates), leading to liver and kidney damage, with clinical manifestations such as liver enlargement, jaundice, liver function damage, oliguria, proteinuria, hematuria, and rapid onset of acute renal failure. Chronic exposed individuals show increased excretion of β2-microglobulin, amino acids, and low-molecular-weight proteins in urine, as well as increased activity of NAG enzyme and γ-GT. The nephrotoxicity of chromates and dichromates has been confirmed in animal experiments, and tubular necrosis has been found in acute chromium poisoning in humans. Epidemiological studies have shown that workers with long-term chronic exposure to chromium have a significantly higher percentage of mild tubular function damage, with abnormal increases in β-uridylic acid hydrolase, total protein, RBP, β2-microglobulin, and kidney BB-50 brush border antigen compared to non-exposed individuals. Individuals with urinary chromium excretion exceeding 15μg/g creatinine have significantly more abnormal values of RBP and BB-50 than those with urinary excretion below 15μg/g creatinine, but the degree of tubular damage is not proportional to the level of urinary chromium excretion. The observed tubular damage in workers exposed to chromium is mainly due to acute poisoning, while tubular damage in workers with long-term chronic exposure to chromium often appears after a considerable period of exposure.

　　Acute poisoning is mainly treated symptomatically and protected for liver and kidney function, and early dialysis treatment can help alleviate chromium poisoning. Sodium thiosulfate and dimercaptopropanesulfonic acid (DMPS) have certain chelating and excretion effects on chromium.

　　II. Prognosis

　　Heavy metal poisoning has an unfavorable prognosis if not discovered and treated early.