Non-steroidal anti-inflammatory drug-induced nephropathy

　　First, the cause of the disease

　　1. The effects of traditional NSAIDs on the kidneys:The various effects of NSAIDs on the kidneys are related to their inhibition of cyclooxygenase (cyclooxygenase, COX) and the blocking of prostaglandin (prostaglandins, PG) synthesis within the kidneys. PGs are derivatives of arachidonic acid, which is a twenty-carbon four-烯ic acid produced by acetylation of membrane phospholipids. The types of PGs produced by the kidneys are diverse, mainly including prostacyclin (prostacyclin, PGI2), thromboxane (thromboxane, TXA2), and PGE2. After being synthesized at a certain location, PGs exert their physiological effects at that location. PGE2 and PGF2 are initially synthesized by interstitial cells of the kidney, while PGI2 is synthesized by cortical arteries and glomeruli. PGE2 and TXA2 can also be synthesized by renal cortical glomeruli.

　　2. The effects of PGs on renal hemodynamics can include the following aspects:

　　(1) Under normal fluid volume, the synthesis rate of PGs is very low, making it difficult to confirm the role of PGs in maintaining renal function.

　　(2) When the synthesis of prostaglandins (PGs) is stimulated, the system cycle is usually unbalanced at this point. At this time, PGs usually act as a neutralizing or buffering agent to counteract the effects of factors that cause their synthesis on the kidneys. For example, angiotensin II and norepinephrine (both causing vasoconstriction) are potential stimulatory factors for the synthesis of PGI2 and PGE2, while PGI2 and PGE2 are substances that dilate renal blood vessels, which can alleviate the vasoconstrictive effect caused by angiotensin II. This interaction between renal vasoconstrictors and vasodilators is dynamically present. The release of PGs (especially prostacyclin and PGE2) increases in basic glomerular diseases, renal insufficiency, hypercalcemia, and the action of vasoconstrictors such as angiotensin II and norepinephrine. In addition, its release increases in situations of insufficient effective blood volume, such as heart failure, liver cirrhosis, and the loss of salt and water through the gastrointestinal tract or kidneys, leading to volume depletion. Under these conditions, the vasodilator PGs can protect renal blood flow by reducing preglomerular vascular tension and maintain glomerular filtration rate (glomerular filtration rate, GFR), which is very important in cases of insufficient effective blood volume. When NSAIDs are used, the compensatory vasodilatory effect is blocked, and vasoconstrictive effects become dominant, leading to decreased renal blood flow and renal insufficiency. In glomerular diseases, when the permeability of glomerular capillaries is significantly reduced, the increased production of PGs can maintain GFR.

　　PG can also directly or indirectly affect sodium excretion, and many studies have shown that PG has a natriuretic effect. NSAIDs can partially weaken the natriuretic effect of some diuretics by regulating their effect on renal vascular tone. PG also weakens the kidney's ability to concentrate urine to the maximum extent, and the antidiuretic effect is regulated by the antagonistic action of antidiuretic hormone and PGE2 on the collecting duct epithelial cells. The use of NSAIDs may damage the kidney's water excretion, leading to water retention and hyponatremia. PGE2 and PGI2 may exert an antagonistic effect on the renin's action by increasing the cAMP of juxtaglomerular cells. In addition, PG may play an important role in maintaining the normal function of the arterial pressure receptors and macula densa that control renin release. The low-renin, low-albunogenemia state caused by clinical application of NSAIDs can lead to potassium retention and hyperkalemia. Therefore, PG plays an important role in renal circulation, including renal vasodilation, renin secretion, and sodium and water excretion. Strongly blocking PG synthesis by non-steroidal anti-inflammatory drugs will cause increased vasoconstrictive tension, antinatriuretic effect, antirenin effect, and antidiuretic effect.

　　Acute interstitial nephritis and nephrotic syndrome are most commonly associated with fenoprofen (fenoprofen), but they can also occur with other NSAIDs, and the pathogenesis is not clear. A delayed hypersensitivity reaction to NSAIDs seems to be a reasonable hypothesis. However, it is not clear why renal glomerular damage can cause nephrotic syndrome without renal小球 damage. Another possible cause is that the COX pathway is inhibited by NSAIDs, leading to the shunting of arachidonic acid metabolites to the lipoxygenase pathway and the production of leukotrienes, which can regulate inflammation and increase vascular permeability, chemoattract T lymphocytes and eosinophils, activate T cells, and cause the release of toxic lymphokines, leading to nephrotic syndrome caused by minimal change.

　　Long-term use of NSAIDs can cause urinary tract tumors, and the reason is not yet clear. Some believe that the accumulation of N-hydroxylated phenacetin metabolites within the kidney has potential alkylating effects, leading to the occurrence of malignant tumors. Due to the concentration of urine, these metabolites reach the highest concentration in the renal medulla, ureter, and bladder, which may be the cause of tumors in these areas.

　　The mechanism by which patients with analgesic nephropathy are more prone to atherosclerotic vascular disease is not yet clear.

　　3. The impact of specific COX-2 inhibitors on the kidneys:Recent research has found that COX has two isozymes, namely COX-1 and COX-2. To specifically block the synthesis of PG under pathological conditions and reduce severe gastrointestinal side effects, specific COX-2 inhibitors have been developed. Previous studies believed that the production of physiological PG in the kidneys is mainly regulated by the COX-1 isozyme; however, new research results show that both COX-1 and COX-2 are involved in the synthesis of renal PG, with COX-1 mainly expressed in the renal blood vessels, glomerular mesangial cells, and the collecting tubules of the cortex and medulla. Although the expression of COX-2 is less than that of COX-1, its expression location is very important for maintaining renal function. For example, in rodents, COX-2 is mainly expressed in the macula densa and the thick ascending limb and interstitial cells of the medulla, indicating that it plays an important role in regulating renal vascular tension, the release of renin, regulating tubular absorption, and regulating medullary blood flow. In the cortex of humans, COX-2 is expressed at a low level in the macula densa and mainly expressed in podocytes within the glomerulus, so the function of COX-2 may also include regulating the hemodynamic changes of the glomerulus through the contraction of podocytes. It is currently unclear whether these data from animal models can be applied to humans. Under conditions such as reduced sodium absorption, volume depletion, renal artery stenosis, active lupus nephritis, partial nephrectomy, and treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor inhibitors, the expression of renal cortex COX-2, rather than COX-1, is upregulated. In addition, the expression of COX-2 in the kidneys decreases with the exhaustion of sodium in the body and increases with a high-sodium diet.

　　The expression of COX-2 in the kidneys indicates that this isozyme plays an important role in maintaining the balance of water and electrolytes in the body under a wide range of physiological and pathological conditions. In contrast, due to its main expression in vascular endothelium, COX-1 mainly plays an important role in regulating renal hemodynamics. It should be noted that under normal physiological conditions, the functions of the two COX isozymes are overlapping; as mentioned earlier, under certain physiological conditions where renal function is more dependent on PG, the expression and function of COX-2 in the kidneys also increase, and the inhibition of renal PG synthesis by specific COX-2 inhibitors can also lead to renal side effects. Therefore, the renal side effects of specific COX-2 inhibitors may also be similar to those of traditional NSAIDs. However, in healthy adults, the renal hemodynamics regulated by COX-1 is not affected. There are no reports of COX-2 inhibitors causing acute interstitial nephritis and nephrotic syndrome at present.

　　2. Pathogenesis

　　The basic response of the kidneys to any life-threatening ischemic injury is to promote the secretion of prostaglandins, thus improving vascular contraction and restoring the reduced glomerular blood flow. When NSAIDs such as those that inhibit prostaglandin synthesis are used, the compensatory mechanism of self-regulation can be blocked. The acute renal failure caused by NSAIDs is characterized by rapid onset (sometimes within 24 hours of taking the medication), and the renal function returns quickly to the baseline level once the medication is stopped.

　　Since prostaglandins are important biologically active substances in the body, a decrease in their synthesis will inevitably lead to some adverse reactions. The medullary and interstitial cells mainly synthesize PGE2, which antagonizes the permeability effect of antidiuretic hormone on water and maintains local blood flow. When there is a decrease in effective blood volume and low blood sodium, due to the activation of the renin-angiotensin-aldosterone (RAA) system, renal sympathetic nervous system, and increased release of antidiuretic hormone, the body's dependence on vasodilatory prostaglandins increases. At this time, if NSAIDs are used, due to their inhibition of prostaglandin synthesis, the local regulatory mechanism of the kidney is damaged, kidney perfusion cannot be maintained, and water and sodium retention, hyperkalemia, and other electrolyte and water disorders may occur, even leading to acute renal insufficiency, interstitial nephritis, and renal papillary necrosis. Therefore, NSAIDs may have adverse effects on the kidney only under certain pathological conditions or when combined with other kidney risk factors, where renal hemodynamics depends on the regulation of prostaglandins, and adverse reactions such as those mentioned above may occur. These conditions include:

　　1, renal hypoperfusion caused by conditions such as congestive heart failure, liver cirrhosis, hyponatremia, hypovolemia, or reduced effective blood volume.

　　2, those over the age of 60.

　　3, those with obvious atherosclerosis or those with decreased renal function.

　　4, those who are concurrently using diuretics.

　　Complications include renal papillary necrosis, malignant hypertension, hyperkalemia, and acute renal failure.

　　The clinical manifestations of renal papillary necrosis depend on the type of underlying pathogenic factor, which can be the manifestation of chronic renal function damage (which can be diagnosed by intravenous pyelography) or the manifestation of acute fulminant sepsis. The chronic stationary phase usually has no obvious symptoms, only showing renal function damage, decreased renal concentrating function, pyuria, and proteinuria. Acute renal papillary necrosis usually manifests as acute fulminant Gram-negative bacterial sepsis, which may be complicated with acute renal failure.

　　In the absence of antihypertensive drugs, hypertension is divided into stages 1, 2, and 3 according to blood pressure levels: systolic blood pressure ≥ 139 mmHg and/or diastolic blood pressure ≥ 89 mmHg.

　　Serum potassium levels above 5.5 mmol/L are referred to as hyperkalemia, and above 7.0 mmol/L as severe hyperkalemia.

　　Acute renal failure, abbreviated as ARF, is a clinical critical illness. This disease is an acute renal damage caused by various etiologies, which can cause a sharp decrease in the regulatory function of renal units within a few hours to several days, leading to the inability to maintain fluid and electrolyte balance and excrete metabolic products, resulting in hyperkalemia, metabolic acidosis, and acute uremic syndrome. This syndrome is clinically known as acute renal failure.

　　Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause two different types of acute renal failure, namely, hemodynamic-regulated renal failure and acute interstitial nephritis (often accompanied by nephrotic syndrome), both of which are directly related to the reduction in the synthesis of prostaglandins induced by NSAIDs.

　　1. Acute renal failure:Some patients are more likely to develop renal dysfunction after taking NSAIDs than others. These patients include those with congestive heart failure, elderly patients (age >65 years), hypovolemia or shock, sepsis, hypertension, those taking diuretics for treatment, and patients with underlying kidney disease. Most patients do not show significant changes in urine when acute renal deterioration occurs. In addition, some patients with this type of renal failure may have very low urinary sodium excretion (

　　Regarding the acute renal failure caused by NSAIDs, it is also important to note that the nephrotoxicity of different NSAIDs may vary. Low-dose aspirin, low-dose over-the-counter ibuprofen, and sulindac may be safer because they have less impact on the synthesis of renal prostaglandins. Ketorolac tromethamine is a non-gastrointestinal analgesic that was previously considered to have a higher nephrotoxicity, but recent studies show that the risk of renal failure from using ketorolac for less than 5 days is no different from that of the control group.

　　The second form of acute renal failure induced by NSAIDs, in which patients can present with nephrotic syndrome caused by acute interstitial nephritis and minimal change, is the most common form of kidney damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Fenoprofen is the most common drug to induce this type of damage, but other analgesics can also cause it. The characteristic of this syndrome is that the time to develop severe kidney damage varies greatly, with an average of 5.4 months; only 19% of patients have fever, rash, and increased eosinophils, and 83% of patients have symptoms of nephrotic syndrome. Patients often present with hematuria, pyuria, leukocyte casts, large amounts of proteinuria, and acute elevation of serum creatinine. Although all NSAIDs-induced nephrotic syndromes have been confirmed to be minimal change by biopsy, recent research indicates that they can also be membranous nephropathy. Many patients with membranous nephropathy have used diclofenac sodium (diclofenac) for treatment, but other NSAIDs can also cause it. Recent research suggests that NSAIDs-induced membranous nephropathy is more common than before.

　　2. Chronic kidney damage:In addition to the acute kidney damage effects mentioned above, some propose that using NSAIDs daily for more than 1 year can increase the risk of chronic kidney damage, possibly due to renal papillary necrosis. Recent statistical data indicate that long-term use of NSAIDs (either alone or in combination with other medications) can lead to renal papillary necrosis, and the incidence of this complication is higher in males than in females (1.9:1) compared to traditional analgesic nephropathy.

　　3. Disturbance of water and electrolyte balance and increased blood pressure:Sodium retention is a common complication of NSAIDs, occurring in about 25% of patients. This positive sodium balance is usually very short and often has no clinical significance, but significant sodium retention can also occur. For patients prone to pulmonary edema, close observation is required. NSAIDs can cause diuretic resistance, especially in critically ill patients, the effect of large doses of non-enteral diuretics is often weakened due to the concomitant use of NSAIDs. Similarly, NSAIDs can cause hyperkalemia, which can occur in patients with normal and abnormal renal function; patients with high blood potassium levels who must use NSAIDs should monitor their blood potassium levels.

　　In addition, NSAIDs can also cause increased blood pressure. In theory, since NSAIDs can reduce renin and aldosterone levels, they should lower blood pressure. However, NSAIDs also have the effect of reducing water and sodium excretion, which can lead to increased extracellular fluid volume and hypertension. NSAIDs can eliminate the vasodilator effect of prostaglandin (PG), which may play a certain role in blood vessel tension.

　　4. Atherosclerotic diseases:Patients with analgesic nephropathy are more prone to atherosclerotic vascular diseases, such as myocardial infarction and sudden thrombosis. For women aged 30-49 who have been taking phenacetin for a long time, the risk of myocardial infarction increases twofold after 20 years, and the risk of cardiovascular disease increases threefold.

　　5. Malignant tumors:Long-term use of analgesics can also lead to malignant tumors of the urinary system. At this time, the incidence of transitional cell carcinoma and renal cell carcinoma of the renal pelvis, ureter, and bladder (which can be multifocal and bilateral) increases. For women under 50 years old, the abuse of analgesics is the most common cause of bladder cancer. This disease is not common in young women. The incidence of urinary system tumors increases significantly after 15-25 years of analgesic abuse, and they often occur in patients with analgesic nephropathy confirmed by clinical evidence. The main manifestations of urinary system malignant tumors related to analgesic nephropathy are microscopic hematuria and gross hematuria. Therefore, long-term monitoring of patients with analgesic nephropathy is necessary. If new hematuria appears, urine cytological analysis must be performed, and bladderoscopy and retrograde pyelography may be performed if necessary. It is more cautious to perform cytological examination annually for patients who have stopped taking medication for several years and for those who continue to take medication, as the incidence of bladder epithelial cancer in patients with analgesic nephropathy after kidney transplantation is similar to that in patients with end-stage renal failure caused by analgesic nephropathy, reaching 10%. Therefore, some people suggest resecting the original kidney before kidney transplantation, but the effectiveness of this plan has not been proven.

　　Acute renal insufficiency caused by NSAIDs is manifested by significant elevation of blood urea nitrogen and creatinine, severe water and sodium retention, and hyperkalemia may not be parallel with acute renal failure, it is mostly reversible and usually does not require dialysis; long-term use of NSAIDs (4-5 years or more) can lead to chronic renal insufficiency, causing permanent kidney damage. Severe lumbar pain and hematuria can be unrelated to the dose and duration of the NSAIDs used, and sometimes these symptoms can appear with a single use of NSAIDs.

　　Due to the widespread use of NSAIDs, how to prevent analgesic nephropathy has attracted people's attention. Most experts advocate close observation of renal function changes when using NSAIDs. In addition, it is advisable to avoid using multiple-component analgesics in the long-term use of analgesics, but the use of corticosteroids or cytotoxic drugs (such as cyclophosphamide, etc.) can reduce renal damage. Considering the current abuse of prescription and over-the-counter analgesics, careful inquiry should be made regarding a history of underlying kidney disease for all patients using NSAIDs, such as pre-existing kidney disease, especially in patients with nephrotic syndrome and renal insufficiency. In addition, a thorough understanding of the mechanism of action and adverse reactions, especially renal adverse reactions, should be gained when using NSAIDs. The dose should be individualized, not too high, and renal function can be monitored during medication with creatinine clearance rate (Ccr). If Ccr decreases, medication should be discontinued immediately. Caution should be exercised or NSAIDs should not be used in high-risk patients, especially those over 60 years old, with hypertension, diabetes, arteriosclerosis, heart failure, dehydration, severe infection, or sepsis, when using aminoglycoside drugs or analgesics, with hyperkalemia, hypernatremia, etc.

　　1. Blood tests:Increased blood eosinophils, hyperkalemia, and acute renal insufficiency are manifested by significant increases in blood urea nitrogen and creatinine.

　　2. Urinalysis:Urine analysis may be normal or show sterile pyuria and/or mild proteinuria (

　　3. Renal biopsy tissue pathological examination:The pathological changes are usually similar to those caused by other drugs in acute interstitial nephritis. Short-term use mainly involves tubulointerstitial pathological changes, which may include interstitial edema and diffuse infiltration of inflammatory cells. Generally, there are no eosinophils. In patients with acute interstitial nephritis and nephrotic syndrome, the glomerular lesions are often mild, confirmed by biopsy as minimal change disease, which can also be membranous nephropathy. The main infiltrate in the interstitium is T lymphocytes, with focal interstitial fibrosis. Immunofluorescence examination is usually non-specific, but in some cases, IgG, IgA, IgM, and C3 staining may be weakly positive in the interstitium. Long-term use leading to nephrotic syndrome shows morphological similarities to minimal change glomerular lesions under light microscopy, immunofluorescence, and electron microscopy, with the most prominent histological changes still limited to the interstitium and tubules.

　　4. Radiological examination:The diagnosis or exclusion of analgesic nephropathy mainly involves venous pyelography and CT scans; 25% to 40% of patients may experience partial or complete renal papillary necrosis; the majority of the remaining patients exhibit kidney shrinkage, blunted renal calyces, similar to chronic pyelonephritis. Venous pyelography has certain limitations in the diagnosis of ischemic nephropathy (low sensitivity and potential nephrotoxicity for patients with impaired renal function).

　　5. Ultrasound examination:To exclude other kidney diseases.

　　1. Dietetic therapy for non-steroidal anti-inflammatory drug-induced nephritis

　　1. Winter melon pork kidney soup

　　Main ingredients: winter melon 250 grams, pork kidney one pair, Job's tears 9 grams, Astragalus 9 grams, Job's tears 9 grams, mushrooms 5 pieces, chicken broth, scallions, ginger slices, monosodium glutamate as required

　　Method of preparation: peel and de-seed the winter melon, cut into pieces, remove the membrane from the pork kidney, cut into slices and wash, blanch with boiling water; pour chicken broth into the pot and bring to a boil, add scallions, ginger slices, Job's tears, Astragalus, and winter melon, cook over medium heat; after 40 minutes, add pork kidney, mushrooms, and Job's tears, reduce to low heat; after boiling, add monosodium glutamate and mix well before removing from heat.

　　Method of consumption: as a meal, once a day.

　　2. Adzuki beans stewed with duck meat

　　Main ingredients: duck meat 1200 grams, adzuki beans 90 grams, euryale seeds 60 grams, salt, scallions, ginger slices, yellow wine, monosodium glutamate as required

　　Method of preparation: cut the old hen into pieces, heat the oil to seven成热, add it to the pot, stir-fry for 3 minutes, add yellow wine, add an appropriate amount of water and boil; add scallions, ginger slices, and a little salt, simmer over low heat for about two hours, then add adzuki beans and euryale seeds and continue to simmer for one hour. When the duck meat is tender, add monosodium glutamate and remove from heat.

　　Method of consumption: accompany meals, eat within two to three days.

　　3. Astragalus and American ginseng soup

　　Astragalus 100 grams, American ginseng 30 grams, glutinous rice flour 50 grams, an appropriate amount of sugar, 1000 milliliters of water. Cut the Astragalus into slices and wrap it loosely with gauze. Slice the American ginseng and add water to simmer over low heat until about 500 milliliters, remove the Astragalus dregs, and then add glutinous rice flour, sugar, and cook for a moment.

　　4. Other

　　Astragalus 60 grams, Codonopsis 30 grams, 10 dates, 100 grams of glutinous rice. Astragalus and Codonopsis are cooked together to remove the dregs and take the juice. Glutinous rice and dates are added to the pot and cooked into porridge, then the medicinal juice is added and cooked for a moment. Add an appropriate amount of sugar.

　　2. What is good for the body for patients with non-steroidal anti-inflammatory drug-induced nephritis

　　1. It is recommended to eat fresh vegetables and fruits rich in vitamins.

　　2. It is advisable to eat light and easy-to-digest foods.

　　3. What is not good for the body for patients with non-steroidal anti-inflammatory drug-induced nephritis

　　1. Avoid caffeine, tobacco, alcohol, drugs, and other substances.

　　2. Avoid cold and cool foods.

　　1. Treatment

　　1. Symptomatic treatment:Firstly, the use of these drugs should be stopped, including the discontinuation of local use. The course of renal disease caused by analgesics depends on the severity of kidney damage at the time of clinical manifestation and whether drug treatment continues. If drug treatment is continued, renal function deterioration can progress continuously. For example, aspirin, which is often non-toxic when used alone, can also worsen renal damage if continued use. After stopping the use of analgesics, renal function can stabilize or slightly improve. It is reported that acute interstitial nephritis can spontaneously remit after several weeks to several months of treatment cessation. However, if kidney disease has progressed, there may also be progression after stopping medication, which may be due to secondary hemodynamic changes and metabolic changes associated with the loss of renal units. In addition, symptomatic treatment includes antihypertensive therapy, correction of electrolyte and acid-base imbalances, etc.

　　2. Corticosteroid Treatment:Once it is confirmed that the kidney damage is caused by NSAIDs, medication should be discontinued immediately and corticosteroids should be used for treatment, with 30-60mg of prednisone given orally per day for about 3 months. There is no clear evidence to confirm that corticosteroid treatment can benefit. However, for patients with renal failure lasting 1-2 weeks after discontinuing NSAIDs, a course of prednisone (Prednisone) treatment should be considered. Whether the use of corticosteroids can alleviate the condition caused by minimal change and nephrotic syndrome induced by NSAIDs is not yet clear, but there are non-controlled studies that confirm the effectiveness of hormone treatment.

　　3. Angiotensin-converting Enzyme Inhibitor Treatment:Use angiotensin-converting enzyme inhibitors (ACEIs) such as enalapril 2.5-5mg/d, oral, most patients have a rapid decrease in urinary protein after discontinuation of medication; but there are also reports that the combination of ACEIs with NSAIDs may worsen the nephrotoxicity of NSAIDs. The reason is that NSAIDs inhibit the vasodilatory effect of prostaglandins, causing the afferent and efferent arterioles of the glomerulus to constrict. After the use of ACEIs, the contraction effect of the efferent arterioles is inhibited, resulting in further decrease in GFR.

　　4. Hemodialysis or Peritoneal Dialysis:If renal insufficiency occurs, substitute treatment such as hemodialysis or peritoneal dialysis should be carried out immediately.

　　II. Prognosis

　　NSAIDs are prone to cause analgesic nephropathy, and high-risk patients with poor prognosis such as liver cirrhosis and heart failure; existing kidney diseases, especially nephrotic syndrome and renal insufficiency; any factor that activates RAA such as emergency state, severe infection, anesthesia, etc.; high renin state and malignant hypertension; the application of diuretics, analgesics, aminoglycoside antibiotics, etc.; the elderly, hypernatremia, hyperkalemia, etc., NSAIDs should be used with caution, and it is best not to use NSAIDs for these high-risk patients.