Lithium nephropathy

　　1. Etiology

　　Toxic renal damage caused by lithium treatment over a long period of time.

　　2. Pathogenesis

　　The toxic effect of lithium is related to its inhibition of adenylate cyclase and the reduction of cyclic AMP levels. The reduced cyclic AMP levels are conducive to glycogen synthesis and inhibit glycogenolysis. In addition, lithium also inhibits the protein kinase inhibitor of glycogen synthase and inhibits other enzymes related to glycogenolysis. The aforementioned mechanisms are related to the accumulation of glycogen in the distal tubules and collecting ducts during the treatment with lithium, which then participates in the occurrence of renal histological and functional changes. The pathogenesis is as follows:

　　1. Dysfunction of renal water metabolism

　　It is currently believed that polyuria and thirst caused by lithium may have multiple mechanisms, among which a renal diabetes insipidus is considered to be the main mechanism. This is a damage that occurs in the distal part of the distal tubule and the collecting duct, characterized by impaired sensitivity to endogenous and exogenous vasopressin. One of the mechanisms for this damage is that lithium inhibits the adenylate cyclase, impairing the generation of cAMP caused by vasopressin. However, the impairment of cAMP generation may not be the only mechanism for this toxic effect. In addition, studies in rats have shown that lithium does not change the responsiveness of the isolated perfused papilla to vasopressin, and it suggests that there is a factor in the plasma of rats receiving lithium treatment that can interfere with the action of vasopressin at the receptor sites in the distal renal units.

　　In patients with polyuria and thirst caused by lithium treatment, the generation of non-electrolyte water during water loading is not impaired, but their ability to reabsorb non-solute water under dehydration conditions is significantly reduced. After taking thiazide diuretics, both of the aforementioned symptoms can be alleviated. In the case of nephrogenic diabetes insipidus, thiazide diuretics can produce antidiuretic effect by reducing the transport of water to the distal renal units, which is achieved by natriuretic diuresis, reducing extracellular volume, decreasing glomerular filtration rate, and increasing the reabsorption fraction of sodium and water in the proximal tubules. Thiazide diuretics also increase the reabsorption of lithium, which may cause rapid lithium excretion. The potassium-sparing diuretic Amiloride can reduce polyuria caused by lithium by inhibiting the uptake of lithium by distal tubular cells.

　　2. Uricosuric disorder

　　In addition to the impaired urine concentration ability, severe cases may also have uricosuric disorder in the distal region. Perez et al. reported that the majority of cases of this disease have this disorder, but Donker et al. found only 2 cases among 28 individuals taking lithium who could not reach a pH of 5.4 after acid load, while Coppen et al. did not find any uricosuric dysfunction in 16 individuals taking lithium for 1 to 12.5 years.

　　The study found that as long as the level of bicarbonate in plasma is normal, the excretion fraction of bicarbonate is very small, and the excretion fractions of phosphorus and ammonia in urine are normal, indicating that the uricosuric disorder caused by lithium occurs in the distal rather than the proximal tubules.

　　3. Acute renal failure

　　Acute renal failure can be caused by acute lithium poisoning in both humans and animals. The mechanism involves tubular cell degeneration and necrosis. Evan and Ollerich's research on the ultrastructure of the disease found mitochondrial swelling, expansion of rough endoplasmic reticulum, and expansion of the apical cytoplasm. In the case of acute renal failure caused by lithium poisoning in humans, tubular necrosis occurs.

　　Most scholars' research has not indicated that the duration of lithium treatment is significantly correlated with the degree of functional damage. Some researchers have performed renal biopsies on 7 patients with acute renal failure caused by lithium treatment, and the results showed that the main changes were interstitial fibrosis and focal tubular atrophy. These pathological changes are clearly not related to acute renal failure. Another renal biopsy study observed a group of patients with acute renal failure related to acute lithium poisoning and a group of patients with no acute toxic symptoms who were treated with lithium. The results found that the pathological changes previously considered to be related to acute toxicity, such as interstitial leukocyte infiltration, tubular dilation, and degeneration, were not significantly different between the two groups, while acute ischemic tubular necrosis was not seen in patients with acute renal failure due to acute lithium poisoning.

　　I. Infection

　　The main reason for the decreased resistance to infection in patients with nephrotic syndrome is due to:

　　1. Large amounts of IgG are lost in the urine.

　　2. The deficiency of factor B (component of the alternative complement pathway) leads to defects in the immune调理 role against bacteria;

　　3. During malnutrition, the body's non-specific immune response ability is weakened, causing damage to the body's immune function.

　　4. Large amounts of transferrin and zinc are lost in the urine. Transferrin is essential for maintaining normal lymphocyte function, and the concentration of zinc ions is related to thymosin synthesis.

　　5. Local factors. The rupture of the skin caused by pleural effusion, ascites, and severe edema of the skin, as well as the dilution of local body fluids and weakened defense function, are all susceptible factors for patients with nephrotic syndrome. Before the advent of antibiotics, bacterial infection was one of the main causes of death in patients with nephrotic syndrome. Severe infections mainly occur in children and the elderly, while they are less common in adults. Common clinical infections include: primary peritonitis, cellulitis, respiratory tract infections, and urinary tract infections. Once an infection is diagnosed, it should be treated immediately.

　　II. Hypercoagulability and venous thrombosis

　　Nephrotic syndrome exists in a hypercoagulable state, mainly due to changes in blood coagulation factors. This includes a decrease in factors IX and XI, and an increase in factors V, VIII, X, fibrinogen, β-thromboglobulin, and platelet levels. The adhesion and aggregation ability of platelets is enhanced. Antithrombin III and antifibrinolytic enzyme activity is reduced. Therefore, the increase in procoagulant and procoagulation factors, the decrease in anticoagulant and anticoagulation factors, and the damage to the fibrinolysis mechanism are the reasons for the hypercoagulable state in nephrotic syndrome. The application of antibiotics, hormones, and diuretics is a加重 factor for venous thrombosis. Hormones act through coagulation proteins, while diuretics increase blood viscosity by concentrating blood.

　　In nephrotic syndrome, when plasma albumin is less than 2.0g/dl, the risk of renal vein thrombosis increases. Most believe that thrombosis first forms in small veins, then extends, and finally involves the renal veins. Renal vein thrombosis can be as high as 50% in patients with membranous nephropathy, and in other pathological types, the incidence rate is 5% to 16%. Acute type patients with renal vein thrombosis may present with sudden onset of flank pain, hematuria, leukocyteuria, increased proteinuria, and renal function impairment. Chronic type patients may have no symptoms, but renal congestion after thrombosis often worsens proteinuria or poor response to treatment. Due to thrombus detachment, renal embolism symptoms are common, and pulmonary embolism can occur. It may also be accompanied by tubular dysfunction, such as glycosuria, aminoaciduria, and tubular acidosis. Definite diagnosis requires renal venography. Non-invasive examinations such as Doppler ultrasound, CT, and IMR are also helpful for diagnosis. Increased plasma beta-thromboprotein levels suggest potential thrombosis, and increased blood alpha2-antifibrinogen levels are also considered as markers of renal vein thrombosis. The incidence rate of peripheral deep vein thrombosis is about 6%, commonly occurring in the deep veins of the lower legs, with only 12% having clinical symptoms, and 25% detectable by Doppler ultrasound. The incidence rate of pulmonary embolism is 7%, and still 12% have no clinical symptoms. Other venous involvement is rare. Arterial thrombosis is even less common, but in children, although the incidence of thrombosis is relatively low, arterial involvement is as common as venous involvement.

　　Three, Acute renal failure

　　Acute renal failure is the most serious complication of nephrotic syndrome and often requires dialysis treatment. Common causes include:

　　1. Hemodynamic changes: Nephrotic syndrome often has hypoalbuminemia and vascular lesions, especially in elderly patients who often have renal arteriolar sclerosis. They are very sensitive to decreases in blood volume and blood pressure. Therefore, after acute hemorrhage, vomiting, diarrhea, fluid loss due to surgery, ascites, excessive diuresis, and the use of antihypertensive drugs, blood pressure can further decrease, leading to a sudden decrease in renal perfusion, and subsequently reducing glomerular filtration rate. This can also lead to acute renal failure due to edema,变性, and necrosis of tubular epithelial cells after acute ischemia.

　　2. Interstitial edema: Hypoalbuminemia can cause peripheral tissue edema, which can also lead to interstitial edema. Interstitial edema compresses the renal tubules, increasing the hydrostatic pressure in the Bowman's capsule of the proximal tubules, and reducing GFR.

　　3. Acute interstitial nephritis caused by medication.

　　4. Bilateral renal vein thrombosis.

　　5. Vascular constriction: Some nephrotic syndrome patients show increased renin concentration during hypoalbuminemia, which causes renal arterioles to constrict and reduce GFR. This condition is more common in elderly individuals with vascular lesions.

　　6. Concentrated protein casts blocking the distal renal tubules: may be one of the mechanisms involved in the acute renal failure of nephrotic syndrome.

　　7. In nephrotic syndrome, there is often a widespread fusion of glomerular epithelial foot processes, disappearance of slit pores, which significantly reduces the effective filtration area.

　　8. Rapid progressive glomerulonephritis.

　　9. Ureteral obstruction.

　　4. Renal tubular dysfunction

　　Renal tubular dysfunction in nephrotic syndrome, more common in children. The mechanism is considered to be the massive reabsorption of filtered proteins, which damages the tubular epithelial cells. It is often manifested as glycosuria, aminoaciduria, hyperphosphaturia, tubular potassium loss, and hyperchloric acidosis. The presence of multiple tubular dysfunction defects often suggests a poor prognosis.

　　1. Acute lithium poisoning can cause mental and neuromuscular symptoms, including apathy, delayed response, tremors, rigidity, and ataxia, and may lead to disturbance of consciousness and coma.

　　2. Acute lithium poisoning can lead to acute renal failure and various kidney lesions, including chronic tubulointerstitial disease, nephrogenic diabetes insipidus and concentration dysfunction, incomplete distal tubular acidosis, progressive tubulointerstitial disease, formation of microcysts in distal tubules, acute renal failure, ADH-resistant urine concentration dysfunction, but it is reversible, and it is more common in more than 50% of patients who have been receiving long-term lithium treatment. About 20% of cases have polyuria, 85% of long-term lithium treatment recipients have normal GFR, 15% have mild GFR damage, and significant GFR decline is only seen in patients who have been receiving lithium treatment for more than 10 to 15 years.

　　It is mainly cautious to use lithium preparations and related drugs that are prone to cause this disease during the treatment of mental illness. For patients with obvious symptoms of lithium poisoning, symptomatic treatment should be actively carried out to prevent the occurrence of more serious interstitial nephritis and renal damage.

　　1. Urine examination

　　Mild proteinuria, 24-hour urine protein quantification

　　2. Renal tubular function examination

　　The function of urine concentration and dilution test is poor, the concentration of amino acids and bicarbonate in urine increases, the acidification of urine cannot reach pH 5.4, urine pH is greater than 6, the titratable acid in urine decreases, and the concentration of N-acetyl-β-D-glucosaminidase (NAG) in urine increases. Acute renal failure patients may have increased blood urea nitrogen and creatinine.

　　3. Renal biopsy

　　Acute renal failure associated with acute lithium poisoning and lithium treatment patients without acute toxic symptoms show interstitial leukocyte infiltration, tubular dilation and degeneration, and other pathological changes related to acute toxicity in renal biopsies. In patients who have been receiving long-term lithium treatment, interstitial fibrosis and focal tubular atrophy can be observed. Renal biopsies in humans show characteristic pathological changes in the distal renal tubules and collecting ducts. Under light microscopy, cell swelling and vacuolation related to PAS-positive glycogen accumulation can be seen. This lesion exists in all lithium treatment patients who undergo renal biopsy, appearing a few days after the start of lithium treatment and disappearing after the treatment is stopped. This characteristic lesion can also be seen in the rabbit kidneys with lithium poisoning, but there is no aforementioned characteristic acute glycogen accumulation phenomenon in the renal tubular cells of rats that do not contain glycogen.

　　4. Imaging Examination

　　Early manifestations of urinary tract X-ray examination are not obvious, and typical manifestations of renal papillary necrosis appear in the late stage. Abdominal flat film shows changes in the shape and size of the kidney.

1. Diet

　　What kind of food is good for lithium nephropathy: Dietary recommendations for kidney disease include chicken, peach, scallion, soybean, pork, chestnut, huoxiang, kidney, bitter almond, oyster yellow, deer breast, deer fetus, deer tail, deer penis, deer horn glue, sea dog kidney, cow kidney, sheep kidney, bull penis, black bean, prepared rehmannia, salt, Wuling Shen, chicken kidney, duck kidney, quail, eared pheasant, chicken kidney grass, deer mouth grass.

　　The above information is for reference only, please consult a doctor for details

　　1. Treatment

　　The main treatment for this disease is symptomatic treatment. Polyuria and thirst caused by renal diabetes insipidus, as well as other acute manifestations of kidney damage caused by lithium, often disappear quickly after the discontinuation of lithium preparations. When treating mental illness with lithium preparations, both effective control of mental illness and avoidance of side effects should be considered. Polyuria can be used as an indicator of the side effects of lithium preparations. It should be noted that the serum lithium concentration should be monitored, as kidney damage is more likely to occur when the lithium concentration is persistently high or lithium toxicity recurs. The treatment principles for lithium nephropathy patients are the same as those for other toxic nephropathy, including timely discontinuation of medication, symptomatic supportive treatment, and treatment of severe renal insufficiency according to renal failure treatment.

　　2. Prognosis

　　Most acute lithium poisoning kidney diseases are reversible if diagnosed in time and the drug is discontinued quickly. Generally, the prognosis is good. If diagnosis is delayed or the drug is misused again, kidney disease may worsen, and the prognosis is poor when severe acute renal failure occurs. Poor prognosis is associated with interstitial fibrosis and focal tubular atrophy on renal biopsy pathology.