Non-steroidal anti-inflammatory drugs (NSAIDs) can be classified into nine types according to their chemical structure, as shown in the following table. If classified according to the selectivity of the action on cyclooxygenase (COX), they can be further divided into.
(1) non-selective COX inhibitors. The first seven classes of traditional NSAIDs in the table belong to this category, and they have significant inhibitory effects on both COX-1 and COX-2. （Although the pharmacological mechanisms of these drugs have not been fully elucidated, their main mechanism is to inhibit prostaglandin synthesis to exert antipyretic and anti-inflammatory effects, and therefore, they are widely used in the treatment of fever, pain, and inflammatory diseases.
One of the important adverse effects of these drugs has long been recognized to be renal damage, including (1) pre-renal acute renal damage, (2) acute allergic interstitial nephritis, and (3) chronic interstitial nephritis and renal papillary necrosis.
Pre-renal acute kidney damage is mostly functional
Pre-renal acute kidney damage is functional kidney damage, if NSAID is discontinued and renal ischemia is corrected in time, renal function will be fully restored and dialysis treatment is not required.
Elderly patients with fever should be cautious with strong antipyretic drugs, such as high-dose anti-inflammatory pain suppositories, because the heavy sweating during fever reduction leads to a decrease in blood volume, coupled with the NSAID’s constricting renal vascular effect, it is easy to induce pre-renal acute kidney damage, clinicians must pay attention to.
COX catalyzes the production of prostacyclin (PGI2) and prostaglandin E2 (PGE2), which are vasodilators that antagonize the action of intrarenal vasoconstrictors (such as angiotensin II) and dilate small renal arteries to regulate renal blood flow. With NSAID, especially at high doses, COX activity is inhibited, PGI2 and PGE2 production is reduced, small renal arteries, including the small inlet arteries, are constricted, and renal blood flow and glomerular filtration rate are significantly reduced, leading to decreased urination and retention of metabolic waste in the body, resulting in pre-renal acute kidney injury. This acute renal injury is particularly likely to occur in patients with an underlying renal blood supply deficit, such as the elderly (who may have atherosclerosis and reduced renal blood supply; the elderly have a sluggish sense of thirst and often do not drink enough, and have reduced tubular concentrating function and urinate more, which can lead to hypovolemia), severe heart failure (reduced left ventricular ejection fraction and reduced effective renal blood volume), cirrhotic ascites, and nephrotic Patients with nephrotic syndrome (water retention in the third interstitial space and insufficient effective renal blood volume).
The main clinical manifestations are decreased urine output (but not oliguria, i.e., urine output of at least 400 ml/d), increased serum creatinine and urea nitrogen, often mild to moderate, and disproportionate increases in both (the increase in blood urea nitrogen is more pronounced, and when both are measured in mg/dl, the ratio of blood urea nitrogen to creatinine is often > 10). If urine osmolality and urine sodium can be measured, increased urine osmolality (> 500 mOsm/L) and decreased urine sodium (< 20 mmol/L) can also be found, which is more helpful for diagnosis.
Acute allergic interstitial nephritis has a long history of drug use before the onset of the disease
The characteristics of acute allergic interstitial nephritis caused by NSAID are: (1) a long history of drug use before the onset of the disease, even up to several months; (2) systemic allergic manifestations are less frequent; and (3) patients may present with a nephrotic syndrome. Nephrotic syndrome is caused by glomerular disease that accompanies the onset of acute allergic interstitial nephritis, and the pathological type is often microscopic lesions.
NSAID may also act as a semi-antigen binding to organismal tissue proteins (carriers), inducing a hypersensitivity reaction (cell-mediated immunity predominant), leading to acute tubulointerstitial inflammation, i.e. acute allergic interstitial nephritis, also known as acute allergic tubulointerstitial nephritis.
Drug-induced acute allergic interstitial nephritis often has the following manifestations. (1) history of drug use: often within 1 to several days after drug use; (2) systemic allergic reactions: including drug rash, drug fever and other manifestations, increased peripheral blood eosinophilic leukocytes; (3) urinalysis abnormalities: urinary routine shows aseptic leukocyturia (early eosinophilic leukocyturia may appear), hematuria (degenerative red blood cell hematuria) and mild proteinuria. (4) Acute renal impairment: increased serum creatinine, acute renal failure in severe cases, often accompanied by proximal and distal tubular dysfunction, nephrogenic glycosuria and hypoosmolar urine, etc. In addition to these typical manifestations, acute allergic interstitial nephritis caused by NSAID has some characteristics of its own.
The main pathological manifestations of acute allergic interstitial nephritis are: interstitial edema, diffuse infiltration of a large number of lymphocytes and monocytes, accompanied by a variable number of eosinophilic leukocyte infiltration, degeneration of renal tubular epithelial cells, detachment of brush border, and acute tubulitis. (2) glucocorticoid therapy: such as prednisone 40mg/d, gradually reduce the dose after the condition improves, and take a total of 2~3 months. It has been confirmed that hormones can accelerate the remission of acute allergic interstitial nephritis, and hormone therapy should be given to patients with clinical presentation of acute renal failure or (and) nephrotic syndrome. (3) Dialysis treatment: Dialysis should be performed when acute renal failure reaches the dialysis index.
After the above treatment, nearly all of the acute allergic interstitial nephritis caused by NSAID can be normalized and the nephrotic syndrome can be relieved. However, chronic renal impairment may remain in a few elderly patients with severe disease.
Chronic interstitial nephritis and acute renal papillary necrosis are associated with the type and cumulative amount of NSAID
The disease should be prevented. Since fibrotic lesions are irreversible, treatment can only focus on protecting
Since the fibrotic lesions are irreversible, treatment should focus only on protecting the remaining renal tissue and delaying the progression of renal damage.
The incidence of chronic interstitial nephritis and acute renal papillary necrosis (also collectively referred to as analgesic nephropathy) caused by NSAID is low in China. The pathogenesis of this disease is not fully understood, but may be related to the deposition of NSAID metabolites (e.g., quinoneimine, a metabolite of acetaminophen) in the renal medulla, resulting in toxic effects on the kidney; it may also be related to the inhibition of prostaglandin (e.g., PGI2 and PGE2) synthesis by NSAID, resulting in renal medullary vasoconstriction and tissue hypoxia. The metabolites of NSAID are often distributed along an osmotic gradient in the renal medulla, resulting in the highest concentrations in the renal papillae and the strongest toxic and ischemic effects described above, thus inducing renal papillary necrosis.
In the last two decades, finasteride has been banned in some European countries, but it has been observed in these countries that aspirin or acetaminophen in combination with pyrazolones, or in combination tablets between pyrazolones, can also cause the disease. The disease often develops after prolonged medication use (several years to a decade) and when the cumulative amount of medication reaches 1 to 3 kg. In the literature, the incidence of the disease is reported to be as high as 70% when the cumulative amount of drugs exceeds 2 kg.
The clinical features of chronic interstitial nephritis are insidious, with the following clinical manifestations: (1) abnormal urinalysis: a small amount of proteinuria (urine protein is often <1g/d), mild microscopic hematuria (deformed red blood cell hematuria), sterile leukocyturia and tubular urine. (2) Decreased renal function: distal tubular impairment (nocturia, decreased urine specific gravity and osmolality, and type I tubular acidosis in some patients) and decreased glomerular function (decreased creatinine clearance in the early stage, followed by increased serum creatinine), and finally chronic renal failure. Proximal tubular impairment (presenting renal glycosuria, etc.) is less common and occurs only in severely ill patients. (3) Hypertension and anemia: As renal damage progresses, patients often develop renal hypertension and anemia. The kidneys are reduced in size on ultrasonography. The main pathological manifestations of this disease are: multifocal or lamellar interstitial fibrosis and tubular atrophy, with focal lymphatic and mononuclear cell infiltration in the interstitial kidney in the early stage, and normal glomerular morphology or showing ischemic wrinkling and sclerosis.
Clinically, the development of chronic interstitial nephritis and renal papillary necrosis is often closely related to the type and cumulative amount of NSAIDs taken. In the literature, the causative agents are often finasteride and acetaminophen, and combinations of these agents are more causative than single agents, such as aspirin or Antipyrine in combination with finasteride or acetaminophen in combination tablets.
When acute renal papillary necrosis occurs, there will be significant lumbar pain and carnal hematuria with blood, clots and necrotic renal papillary tissue in the urine, and renal colic and even acute renal failure may be induced when clots and necrotic tissue are embedded in the ureter. Pathological examination confirms that the tissue excreted in the urine is a necrotic renal papilla.
In addition to these manifestations, patients with chronic interstitial nephritis due to NSAID often develop epithelial cell carcinoma of the urinary tract (renal pelvis, ureter, or bladder) and should be closely monitored. Prevention and treatment strategies for this disease should be based on prevention. Patients who take NSAID drugs regularly should be educated to avoid drug abuse. In Australia and some European countries where the incidence of this disease is high, laws and regulations have been enacted to restrict the over-the-counter sale of analgesics, which has also had a significant effect in reducing the incidence of this disease.
After the onset of chronic interstitial nephritis, the focus of treatment is on protecting the remaining renal tissue and slowing the progression of renal damage because the fibrotic lesions are irreversible. These include: discontinuation of NSAIDs; low protein diet (with compounded alpha keto acids) for patients with renal insufficiency; and ACEI or ARB to antagonize fibrosis (however, patients with renal insufficiency should be monitored closely for hyperkalemia when taking these drugs). If the patient is in end-stage renal failure, renal replacement therapy (including hemodialysis, peritoneal dialysis, and renal transplantation) should be administered to maintain life. When acute renal papillary necrosis occurs, fluid intake should be ensured so that the daily urine volume reaches more than 2000 ml to reduce the concentration of drugs in the renal medulla and to flush the detached necrotic tissue from the urinary tract. If urinary tract obstruction has developed, a urologist should be called in for appropriate management.