NSAID-induced nephropathy
Introduction
Introduction to non-steroidal anti-inflammatory drug-induced nephropathy There are several ways in which NSAIDs can cause kidney damage, including acute renal failure due to changes in renal hemodynamics, causing tubulointerstitial nephritis and direct nephrotoxicity, such as proteinuria and hypertension syndrome. basic knowledge The proportion of sickness: 5-9% Susceptible people: no special people Mode of infection: non-infectious Complications: Hypertension Hyperkalemia
Cause
Non-steroidal anti-inflammatory drug-induced nephropathy
(1) Causes of the disease
1. The effect of traditional NSAIDs on the kidney The multiple effects of NSAIDs on the kidney are related to the inhibition of cyclooxygenase (COX) and the blocking of prostaglandins (PG) synthesis. PG is a derivative of arachidonic acid. The latter is an arachidonic acid produced by the acetylation of membrane phospholipids. The types of PG produced by the kidney are diverse. The main species include prostacyclin (PGI2) and thromboxane (thromboxane). , TXA2) and PGE2, PG will exert its physiological effects in situ after synthesis. PGE2 and PGF2 are synthesized by renal interstitial cells, while PGI2 is synthesized by cortical arteries and glomeruli. PGE2 and TXA2 can also be composed of kidney. Cortical glomerular synthesis.
2. The impact of PG on renal hemodynamics can include the following:
(1) In the case of normal body fluid volume, the synthesis rate of PG is very low, so it is difficult to confirm the role of PG in the maintenance of renal function.
(2) When PG synthesis is stimulated to increase, usually the system cycle is out of balance. At this time, PG usually plays a neutral or buffering role to antagonize the effects of factors that cause its synthesis on the kidney, for example, angiotensin II. And norepinephrine (which causes vasoconstriction) is a potential stimulator of PGI2 and PGE2 synthesis, while PGI2 and PGE2 are renal vasodilators that reduce the vasoconstrictor effect caused by angiotensin II, renal vasoconstrictor and This interaction between dilators is dynamic, and the release of PG (especially prostacyclin and PGE2) in basic glomerular disease, renal insufficiency, hypercalcemia and vasoconstrictors such as angiotensin II Increased release upon action with norepinephrine and, in addition, increased release in the absence of effective blood volume, such as heart failure, cirrhosis, and volume depletion due to loss of salt and water in the gastrointestinal tract or kidney, under the above conditions The vasodilator PG can protect renal blood flow by reducing vascular tone before glomeruli and maintain glomerular filtration rate (GFR), which is insufficient in effective blood volume. Important, and when NSAIDs are used, compensated vasodilation is blocked, vasoconstriction predominates, leading to decreased renal blood flow and renal insufficiency, while in glomerular disease, when glomerular capillaries When the vascular permeability is significantly decreased, the increase in PG production maintains GFR.
PG can also directly or indirectly affect sodium excretion. Many studies have shown that PG has a beneficial effect on sodium and urine. NSAIDs can partially attenuate the diuretic effect of certain diuretics through its regulation of renal vasomotor tone, and PG also weakens. The ability of the kidney to maximize urine concentration, the antidiuretic effect is regulated by the antagonism of vasopressin and PGE2 on the epithelial cells of the collecting duct, and the application of NSAIDs may impair the water excretion of the kidney, leading to water retention and hyponatremia. PGE2 and PGI2 may play an antagonistic role in increasing the cAMP of paracellular cells, and the role of renin. In addition, PG may play an important role in maintaining the normal function of arterial baroreceptors and dense plaques that control renin release, resulting from the clinical application of NSAIDs. Low renin, low aldosteronism can lead to potassium retention and hyperkalemia. Therefore, PG plays a very important role in renal blood circulation, including renal vasodilation, renin secretion and sodium excretion, with non-steroidal resistance. Inflammatory drugs potently block PG synthesis will cause increased vascular tone, anti-urinary excretion effects, anti-renin effects, and anti-diuretic effects .
Acute interstitial nephritis and nephrotic syndrome are most common in fenoprofen, but can also occur in other NSAIDs. The mechanism of occurrence is unclear. The delayed allergic reaction to NSAIDs seems to be a reasonable one. Hypothesis, but why no glomerular damage can cause nephrotic syndrome is unclear, another possible reason is that the COX pathway is inhibited by NSAIDs, causing the arachidonic acid metabolite to be diverted to the lipoxygenase bypass and produced Leukotrienes, which regulate inflammation and increase vascular permeability, chemotactic T lymphocytes and eosinophils, activate T cells, release toxic lymphokines, and cause nephrotic syndrome caused by microscopic lesions.
Long-term use of NSAIDs can cause urinary tumors, the reason is not clear, some people believe that the accumulation of N-hydroxylated phenacetin metabolites in the kidney has potential alkylation, leading to malignant tumors, due to the concentration of urine, these Metabolites in the kidney medulla, ureter, bladder reach the highest concentration, may be the cause of tumors in these areas.
The mechanism by which patients with analgesic nephropathy are more likely to develop atherosclerotic vascular disease remains unclear.
3. The effect of specific COX-2 inhibitors on the kidney In recent years, COX has two isoenzymes, COX-1 and COX-2, in order to specifically block the synthesis of PG under pathological conditions and reduce severe gastrointestinal In the side-reaction, a specific COX-2 inhibitor has been developed. Previous studies have suggested that the production of physiological PG in the kidney is mainly regulated by COX-1 isoenzyme; however, the new results show that both COX-1 and COX-2 are present. Involved in the synthesis of PG in the kidney, COX-1 is mainly expressed in the blood vessels of the kidney, mesangial cells, cortical and medullary collecting ducts, although the expression of COX-2 is less than that of COX-1, but its expression In areas important for maintaining renal function, such as rodent COX-2 is mainly expressed in dense plaques and cortical ascending segments and medullary stromal cells, indicating its regulation of renal vascular tone and renin The release of the small tube plays an important role in regulating the absorption and regulation of medullary blood flow. In the human kidney cortex, COX-2 has a low level of expression in dense plaques, mainly expressed in podocytes in the glomerulus, so COX-2 Role may also include regulation of glomerular blood flow through contraction of podocytes Learning changes, it is unclear whether these data from animal models can be applied to humans, with reduced sodium absorption, volume depletion, renal artery stenosis, active lupus nephritis, partial nephrectomy and the use of angiotensin-converting enzyme inhibitors or In the treatment of angiotensin receptor inhibitors, the expression of COX-2 in the renal cortex, but not COX-1, is up-regulated. In addition, the expression of COX-2 in the kidney decreases with the failure of sodium in the body, and increases with the high sodium diet. .
The expression of COX-2 in the kidney indicates that this isoenzyme plays an important role in maintaining water and electrolyte balance in a wide range of physiological and pathological conditions. Conversely, COX-1 is mainly involved in renal blood flow due to its mainly expressed in the vascular endothelium. Kinetic regulation plays an important role. It should be noted that under normal physiological conditions, the functions of the two COX isozymes overlap each other; as mentioned above, in some renal functions, physiological conditions that are more dependent on PG Under the influence of COX-2 expression in the kidney and its role, specific COX-2 inhibitors inhibit the synthesis of intrarenal PG can also cause kidney side effects, so the renal side effects of specific COX-2 inhibitors may also be compared with traditional The NSAID is the same, but for healthy adults, the hemodynamics of the kidneys regulated by COX-1 are not affected. There are no reports of acute interstitial nephritis and nephrotic syndrome caused by COX-2 inhibitors.
(two) pathogenesis
The kidneys respond to any life-threatening ischemic injury by promoting prostaglandin secretion, resulting in improved vasoconstriction and reduced glomerular blood flow. When using NSAIDs to inhibit prostaglandin synthesis, they can block themselves. The adjusted compensation mechanism, which is characterized by acute renal failure caused by NSAIDs, is rapid (sometimes within 24 hours of administration), and once the drug is stopped, the kidney function rapidly returns to the basal level.
Because prostaglandins are important biologically active substances in the body, some adverse reactions will occur in the reduction of their synthesis. The medulla and interstitial cells mainly synthesize PGE2, antagonizing the permeability of vasopressin to water and maintaining local blood flow. Reduced effective blood volume and hyponatremia, due to the renin-angiotensin-aldosterone (RAA) system, renal sympathetic activation and increased release of vasopressin, the body's prostaglandin with vasodilator Dependence increases. At this time, if NSAIDs are used, this local regulation mechanism of the kidney is impaired due to inhibition of prostaglandin synthesis, renal perfusion cannot be maintained, and water and sodium retention, hyperkalemia and other water electrolytes may occur. Disorders, even acute renal insufficiency, interstitial nephritis and renal papillary necrosis, therefore, hemodynamics depends on prostaglandin regulation in certain pathological conditions or in combination with other renal risk factors, NSAIDs It is possible that it will have an adverse effect on the above-mentioned adverse reactions, including:
1. Congestive heart failure, cirrhosis, low sodium, low blood volume or reduced blood volume caused by renal hypoperfusion pressure.
2. Age is greater than 60 years old.
3. Significant arteriosclerosis or decreased renal function.
4. Those who use diuretics at the same time.
Prevention
Non-steroidal anti-inflammatory drug-induced nephropathy prevention
Due to the widespread use of NSAIDs, how to prevent premature pain drug nephropathy has attracted people's attention. Most experts agree that changes in renal function should be closely observed when using NSAIDs. In addition, avoid using multi-components when using painkillers for a long time. Analgesic drugs, but with hormones or cytotoxic drugs (such as cyclophosphamide) can reduce kidney damage. Considering the abuse of current prescription and over-the-counter painkillers, all patients who use NSAIDs should be carefully asked if they have basic kidneys. History of the disease, such as the original kidney disease, especially nephrotic syndrome with renal insufficiency is banned, in addition, the use of NSAIDs should fully understand its mechanism of action and related adverse reactions, especially adverse reactions to the kidney, the dose should be individualized It is not advisable to overdosage. The endogenous creatinine clearance rate (Ccr) can be used to monitor renal function. If Ccr is found, the drug is stopped immediately. For high-risk patients, especially those over 60 years old, hypertension, diabetes, arteriosclerosis, Heart failure, dehydration, severe infection or sepsis, hyperkalemia when using aminoglycosides or analgesics, Caution or not sodium and other NSAIDs.
Complication
Non-steroidal anti-inflammatory drug nephropathy complications Complications Hypertension hyperkalemia
Concurrent renal papillary necrosis, malignant hypertension, hyperkalemia, acute renal failure.
Symptom
Non-steroidal anti-inflammatory drug nephropathy symptoms Common symptoms Atherosclerosis Chronic renal insufficiency Chronic kidney damage Septicemia Proteinuria Hypotension Back pain
Non-steroidal anti-inflammatory drugs (NSAIDs) can cause two different types of acute renal failure, namely hemodynamically regulated renal failure and acute interstitial nephritis (often accompanied by nephrotic syndrome), both with NSAIDs The synthesis of induced PG is reduced directly.
1. Acute renal failure Some patients have greater likelihood of developing renal dysfunction after using NSAIDs, including those with congestive heart failure, older patients (age > 65 years), hypovolemia or shock, sepsis, high Blood pressure, also treated with diuretics, patients with underlying kidney disease, usually most patients with urinary changes in the absence of acute renal function deterioration, in addition, some patients with such renal failure can have low urinary sodium excretion (<1 %), elevated plasma creatinine levels are usually seen 3 to 7 days after the start of treatment, at which time NSAIDs achieve stable blood levels in the body and block the synthesis of PG to the greatest extent, such as early diagnosis, such renal failure Discontinuation of NSAIDs is reversible. In addition, the incidence of hyperkalemia is 75%, which is also the most significant clinical manifestation. Their common precursor status is high renin and high angiotensin status.
With regard to acute renal failure caused by NSAIDs, it is important to note that different NSAIDs may have different nephrotoxicity, low doses of aspirin, low-dose over-the-counter ibuprofen and sulindac. (sulindac) may be safer because they have less effect on the synthesis of kidney PG. Ketorolate is a non-gastrointestinally administered analgesic that was previously considered to be more toxic. Recent studies have shown the use of ketones. The risk of renal failure caused by acidity of less than 5 days was not different from that of the control group.
The second form of acute renal failure induced by NSAIDs, patients with acute interstitial nephritis and nephrotic syndrome caused by minimal lesions, the most common drug to induce such kidney damage is fenoprofen, but Other painkillers can also cause this type of damage. These syndromes are characterized by a large change in the time to progression to severe kidney damage, averaging 5.4 months; only 19% of patients have fever, rash, eosinophilia 83% of patients have manifestations of nephrotic syndrome, often with hematuria, pyuria, leukocyte cast, large amounts of proteinuria and acute serum creatinine, although all NSAIDs-induced nephrotic syndrome has been reported, confirmed by biopsy It is a small lesion, but recent studies have shown that it can also be membranous nephropathy. Many patients with membranous nephropathy have been treated with diclofenac, but other NSAIDs can also be caused. Recent studies have suggested that NSAIDs induce membranous nephropathy. It used to be common.
2. Chronic kidney damage In addition to the acute kidney damage mentioned above, it has been suggested that the use of NSAIDs for more than one year per day may increase the risk of chronic kidney damage, possibly due to necrosis of the kidney, a recent statistic indicates Long-term use of NSAIDs (alone or in combination with other drugs) will cause renal papillary necrosis, which is higher in men than in women (1.9:1) compared with traditional analgesic kidney disease.
3. Water-electrolyte balance disorder and increased blood pressure Sodium retention is a common complication of the use of NSAIDs, which occurs in about 25% of patients. This positive sodium balance is generally very short-lived and often not clinically significant, but significant sodium retention can also occur. For patients prone to pulmonary edema should be closely observed, the use of NSAIDs can cause diuretic drug resistance, especially in intensive care patients, the role of large doses of parenteral diuretics is often weakened by the common use of NSAIDs, also, use NSAIDs can cause hyperkalemia, which can occur in patients with normal and abnormal renal function; patients with high levels of potassium and who must use NSAIDs should be monitored for serum potassium levels.
In addition, NSAIDs can also cause an increase in blood pressure. Theoretically, because NSAIDs can lower the levels of renin and aldosterone, they should lower blood pressure, and NSAIDs also have the effect of reducing water and sodium excretion, which can lead to an increase in extracellular fluid volume and Hypertension; NSAIDs can eliminate the vasodilator PG may play a role in vascular tone.
4. Patients with atherosclerotic disease analgesic nephropathy are more likely to develop atherosclerotic vascular disease, such as myocardial infarction and sudden thrombosis, such as women aged 30 to 49 taking phenacetin for a long time, 20 After the year, the risk of myocardial infarction is increased by a factor of two, and the risk of developing cardiovascular disease is increased by a factor of three.
5. Malignant tumors use painkillers for a long time, and can also cause urinary malignant tumors. At this time, the incidence of transitional cell carcinoma and renal cell carcinoma of the renal pelvis, ureter and bladder (which may be multiple and bilateral) increases, 50 years old. The following women, the abuse of painkillers is the most common cause of bladder cancer, but for young women this disease is not common, the abuse of painkillers for 15 to 25 years, the incidence of urinary tumors increased significantly, and often occurred in clinical confirmation In patients with painful kidney disease, the main manifestations of pain-relieving nephropathy-related urological malignancies are microscopic hematuria and gross hematuria. Therefore, long-term monitoring of patients with analgesic nephropathy is necessary. For example, new hematuria must be carried out in urine cells. Analysis and, if necessary, cystoscopy and retrograde pyelography can be performed. It is prudent to perform cytological examinations on patients who have stopped taking the drug for several years and continue to take drugs. Patients with pain-relieving nephropathy undergo bladder transplantation after renal transplantation. The incidence rate is similar to that of patients with end-stage renal failure caused by painkiller nephropathy, up to 10%, so there is It is recommended to remove the original kidney before kidney transplantation, but the effectiveness of this program has not been confirmed.
Acute renal insufficiency caused by NSAIDs is characterized by blood urea nitrogen, a significant increase in creatinine, severe sodium retention, and hyperkalemia, which may not be parallel with acute renal failure, mostly reversible, usually without dialysis; long-term use of NSAIDs (4 to 5 years or more) chronic renal insufficiency can occur, resulting in permanent kidney damage, severe low back pain and hematuria can be independent of the dose and course of NSAIDs used, and sometimes these symptoms can occur with a single use of NSAIDs.
Examine
Non-steroidal anti-inflammatory drug nephropathy
1. Blood test for eosinophilia, hyperkalemia, acute renal insufficiency manifested as blood urea nitrogen, a significant increase in creatinine.
2. Urine examination urine analysis can be normal or aseptic pyuria and (or) mild proteinuria (<1.5g / d =; urine eosinophilia, individual may have more proteinuria, or even kidney disease comprehensive In the range, a large amount of proteinuria may be released by sensitive lymphocytes, synthesizing lymphokine activin, which increases the permeability of the glomerular basement membrane, while the small tube damage is not obvious; the urine sodium decreases.
3. Renal biopsy histopathological examination is usually similar to the pathological changes of acute interstitial nephritis caused by other drugs. Short-term medication is mainly caused by tubulointerstitial pathological changes, and there may be interstitial edema and diffuse inflammatory cell infiltration, generally no hobby. Acidic cells, acute interstitial nephritis with nephrotic syndrome, glomerular lesions are often mild, biopsy confirmed as a small lesion, can also be membranous nephropathy, interstitial mainly T lymphocyte infiltration, focal interstitial fibrosis, Immunofluorescence is often non-specific, but in some cases, IgG, IgA, IgM, and C3 staining are weakly positive in the stroma. Long-term use of nephrotic syndrome caused by light microscopy, immunofluorescence and electron microscopy show morphologically similar to small lesions. In glomerular lesions, the most prominent histological changes are still limited to interstitial and tubules.
4. Radiological examination mainly uses intravenous pyelography and CT scan to diagnose or exclude painkiller nephropathy. 25% to 40% of patients may have partial and complete renal papillary necrosis; most of the other patients show renal enlargement. The renal pelvis becomes dull, similar to chronic pyelonephritis. Intravenous pyelography is limited in the diagnosis of ischemic nephropathy (low sensitivity and potential nephrotoxicity in patients with impaired renal function).
5. B-ultrasound to rule out other kidney diseases.
Diagnosis
Diagnosis and identification of non-steroidal anti-inflammatory drug nephropathy
Diagnostic criteria
According to the medical history, clinical manifestations and intravenous pyelography and other examinations can make the diagnosis of this disease, the disease carefully asked about the history of chronic pain or low back pain and the use of painkillers, there are other complaints, such as fatigue or discomfort Long-term use of aspirin caused by digestive ulcer disease.
Renal manifestations of analgesic nephropathy are non-specific, with careful history, such as clinical nephrotic syndrome, acute renal failure, chronic renal failure and hypertension, anemia, low back pain or hematuria, normal urine analysis or Sterile pyuria, hematuria, proteinuria, (clinical protein can be mild proteinuria, nephrotic syndrome proteinuria, can exceed 3.5g / d); CT scan or intravenous pyelography can be seen in patients and All kidney papillary necrosis, kidney shrinkage, phlegm dullness and other similar changes with chronic pyelonephritis can be considered for the diagnosis of this disease.
Differential diagnosis
Need to pay attention to other causes of renal papillary necrosis, such as diabetes (especially acute pyelonephritis), urethral obstruction, sickle cell anemia, kidney tuberculosis, etc., patient history and appropriate laboratory tests can often help identify, differential diagnosis also includes Urethral obstruction, polycystic kidney disease (can be excluded by ultrasound), renal sclerosis and other causes of chronic interstitial disease such as hypercalcemia, sarcomatoid nephropathy, medullary cystic nephropathy, sponge kidney, Chinese herbal medicine Kidney damage, etc. In addition, myeloma nephropathy can be ruled out by simple serum protein electrophoresis. In addition, it should be differentiated from eosinophilia and other causes of nephrotic syndrome.
