allergic acute tubulointerstitial nephritis
Introduction
Introduction to allergic acute tubulointerstitial nephritis Allergic tubulo-interstitial nephritis (allergic tubulo-interstitial nephritis), also known as drug-induced acute tubulo-interstitial nephritis or acute allergic tubulointerstitial nephritis, is a common immune-mediated renal damage It is a non-immune-mediated acute tubulointerstitial damage caused by many widely used drugs such as antibiotics, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs). basic knowledge The proportion of illness: 0.003% Susceptible people: no specific population Mode of infection: non-infectious Complications: metabolic acidosis, acute renal failure
Cause
Causes of allergic acute tubulointerstitial nephritis
Drugs (30%):
At present, there are many kinds of drugs causing acute allergic interstitial nephritis, which account for 2/3 of antibiotics. However, usually only a few drugs are often reported to cause AIN, and methicillin is generally considered to be a common drug that causes AIN. It has been used less and is strongly associated with acute interstitial nephritis: methicillin (neopenicin I), penicillin, cefotaxime (cephalosporin I), non-steroidal anti-inflammatory drugs and citaminidine , may be related to: carbenicillin (carboxylin), cephalosporins, oxacillin (neopenicillin II), sulfonamides, rifampicin, thiazides, furosemide, interleukins, benzoquinone Diketones, weakly related are: phenytoin, tetracycline, probenecid, acetophenric acid, allopurinol, erythromycin, chloramphenicol and yidulipid (antamine), which have been reported both at home and abroad in recent years. Acute allergic interstitial nephritis caused by Chinese herbal allergies should be noted.
Immune mechanism (30%):
Including humoral immunity and cellular immunity, such acute renal failure is generally caused by allergic reactions, and has little to do with the direct toxicity of the drug. Because acute interstitial nephritis occurs only in a small number of patients who take the drug, it may be the body's action on the drug. Highly sensitive, regardless of the dose, acute allergic interstitial nephritis, in addition to II, type I hypersensitivity reaction, type III hypersensitivity may also play a role in some drugs allergic interstitial nephritis.
Evidence about the pathogenesis of this disease comes from human studies. There is no satisfactory experimental model. The serum IgE levels in some cases of this disease are increased. There are a large number of mononuclear cells including lymphocytes, monocytes and multinucleated giant cells in the renal interstitial. It was found that there were IgG and C3 deposited along the TBM line. These findings are the three basic factors that establish the hypothesis of the pathogenesis of this disease.
The first step of the pathogenesis of this disease may be the binding of the drug hapten to the renal interstitial and/or tubulosin basement membrane (TBM) structural proteins, thereby forming a stable hapten-protein complex, which should be able to initiate antibody binding. The induced response, as well as delayed allergic reactions, subsequently cause renal damage by humoral or cellular immunity.
Studies have shown that antibodies bind to tubulointerstitial antigen in situ, possibly by inducing inflammation through activation of complement, or by directing chemokines to induce inflammation, or direct toxic effects on tubular cells, or in antigen- and antibody-dependent cells. The guiding cytotoxic effect acts as a bridge.
In a few cases, humoral immune responses produce IgE antibodies, and the resulting IgE antibodies bind directly to tissue eosinophils, basophils, and mast cell specific receptors, causing these cells to degranulate, releasing proteases, histamine, PAF, and white. Trienes, prostaglandins and peroxidases directly cause local tissue damage.
Observations suggest that there is a cell-mediated immune mechanism in the pathogenesis of drug-induced ATIN. In most cases, cell infiltration with mononuclear cells is dominant, and epithelial cells and multinucleated giant cells are contained. This lesion is not associated with immunoglobulin. .
According to the results of the study, it is speculated that the mechanism of renal damage in this disease involves multiple links from the pathogenic drug along the tubule basement membrane (TBM) and/or interstitial deposition to the sensitization of lymphocytes to drugs. Lymphocyte infiltration of renal tissue leads to the release of various lymphokines and other mediators that cause tissue damage. The results suggest that drug haptens may bind to the surface of tubule cells, so they may also act as T cell-mediated cytolysis or antibody-dependent Cell-mediated cell lysis (ADCC).
Immunohistochemical studies have found that T lymphocytes dominate in infiltrating cells in some cases, and CD4+ and CD8+ T lymphocyte subsets are common in acute interstitial infiltration, especially in cases of drug-induced acute tubulointerstitial nephritis caused by antibiotics and NSAIDs. CD8+ cell infiltration is predominant, while CD4+ cell infiltration is predominant in cases of drug-induced acute tubulointerstitial nephritis caused by other drugs.
The above evidence supports the immunological basis of the pathogenesis of drug-induced ATIN, but fails to explain the specific link and whether it is mediated by humoral or cellular immunity.
Van Ypersele combines the various conclusions about the pathogenesis of this disease and the various immune disorders observed in the past, and puts forward the hypothesis that these drugs accumulated in the interstitial may be through broken TBM. Dispersion, on the one hand, may be the concentration of the drug in the capillaries around the tubules, and on the other hand may be combined with the TBM hapten.
Principles of immunology (30%):
Humoral immunity can be systemic, manifested as the formation of circulating antibodies against the corresponding drug or TBM, or localized, manifested as interstitial infiltration of monocytes, lymphocytes and plasma cells, which can synthesize immunoglobulins locally. Proteins form in situ complexes, and delayed allergic reactions can lead to interstitial infiltration of lymphocytes activated by macrophages. Therefore, an acceptable view is that the same drug can cause the same tubulointerstitial through different immune mechanisms. Damage, and the type of response is determined by the patient's innate immune response, the extent and characteristics of the immune stimulus, and the amount of the causative agent.
The pathogenesis of ATIN caused by non-steroidal anti-inflammatory drugs is different from the above-mentioned mechanisms of ATIN caused by other drugs, which are mediated by mechanisms such as inhibition of prostaglandin synthesis.
Prevention
Allergic acute tubulointerstitial nephritis prevention
It is mainly to use all kinds of related drugs that are easy to cause this disease. For those with allergic diseases, they should actively treat the disease and prevent the occurrence of interstitial nephritis.
Complication
Allergic acute tubulointerstitial nephritis complications Complications metabolic acidosis acute renal failure
Mainly complicated by metabolic acidosis, heart failure and acute renal failure.
Symptom
Allergic acute tubulointerstitial neuritis symptoms Common symptoms Systemic allergy and fever... Fever with rash hematuria proteinuria
Drug-induced acute interstitial nephritis can occur at various ages, but ATIN caused by NSAID mainly occurs in the elderly (64.6 years ± 2.1 years).
The duration of exposure to drugs before the onset of allergic ATIN varies, usually around 15 days. ATIN caused by NSAID often occurs after several months.
The clinical symptoms of the onset of the disease are often fever, rash and hematuria. About 1/3 of the drug-induced ATIN cases, rash, fever and joint pain can occur at the same time. In a few cases, there may be obvious low back pain. In this case, the ATIN caused by the NSAID Less common, 95% of patients have hematuria, 1/3 of cases have gross hematuria, about 86% of patients have more than 30% of eosinophils in leukocytosis, but only 5% of ATIN-induced ATIN patients have eosinophils Urinary; most patients generally only have mild proteinuria, 24h quantitative less than 1.5g, proteinuria in the range of nephrotic syndrome is not common, except for ATIN caused by small lesion nephritis caused by NSAID, experimental examination with or without serum IgE ( Renal biopsy confirmed that only half of the patients diagnosed with elevated serum IgE levels, so the negative results can not rule out the diagnosis of the disease), 60% to 80% of cases can have a short period of eosinophilia, the diagnosis of this disease is greater help.
Acute renal failure often occurs in this disease, and 20% to 50% of cases are oliguria or urinary. In many cases, the urine test results are similar to acute tubular necrosis (ATN), and the degree of renal failure varies. More than 30% of these patients require dialysis.
In most of the previously reported cases of drug-induced ATIN, the association between acute renal damage and the clinical manifestations of acute allergic reactions may suggest a diagnosis of this disease. A multicenter prospective study evaluated the value of rapid allergic symptoms in predicting ATIN. Among them, blood eosinophilia has the greatest significance for predicting ATIN.
Some cases may have no such allergic symptoms, and renal failure may occur alone, especially in 30% to 40% of cases are non-oliguric renal failure. In these cases, the diagnosis of this disease is still difficult, therefore, allergic interstitial Nephritis is often missed clinically, unless a renal biopsy is performed for all unexplained acute renal dysfunction.
Examine
Examination of allergic acute tubulointerstitial nephritis
1. Blood routine eosinophilia.
2. Urine routine or microscopic hematuria; leukocyte urine, such as Wright staining, mainly eosinophils; visible light, moderate proteinuria, such as glomerular damage can produce a large amount of proteinuria.
3. Blood biochemical BUN, Sc3 increased, blood immunoglobulin IgE content increased, anti-TBM antibodies were detected in the blood, and some patients showed acute elevation of serum creatinine.
1. Kidney biopsy case examination The pathological changes of this disease are diffuse lesions of bilateral kidneys, diffuse or multifocal inflammatory cell infiltration of renal interstitium, resulting in interstitial edema, renal tubules with varying degrees of degenerative changes and even necrosis; The globules are more normal, and some patients can see the deposition of immunoglobulin IgG and complement C3.
(1) Light microscopy: renal biopsy can be seen in diffuse interstitial edema involving the entire cortex, moderate to severe interstitial infiltration, mainly composed of lymphocytes, plasma cells and eosinophils, eosinophils generally at an earlier time It appears and disappears rapidly. Because the renal biopsy of this disease case is often performed late, the eosinophilia in the tissue may not be obvious. The tubule changes include leukocyte infiltration, which is characterized by a small layer closely surrounding the small tube. , lymphocytes infiltrate, and other lymphocytes located in the opposite position of the basement membrane of the tubule and tightly connected tubule epithelial cells, with or without tubule basement membrane damage, Ooi et al described this as tubulitis, The presence of granuloma with megakaryocytes is considered to be a specific manifestation of drug hypersensitivity. In some reports, renal interstitial epithelial granuloma is found in 25% to 50% of drug-induced ATIN, glomeruli and blood vessels. Generally normal, there are also reports of glomerular and vascular lesions.
(2) Immunofluorescence: IgG-like deposition was observed in some cases, and C3 deposition was observed along the basement membrane of the tubule. These manifestations were mainly found in methicillin, penicillin or phenytoin-induced ATIN, using corresponding antibodies in 3 cases. The patient detected a linear deposition of methicillin-dimethicillin along TBM, suggesting that the hapten. The vector mechanism may be related to the induction of anti-TBM antibodies in these cases, caused by a case of phenytoin sodium. Anti-TBM antibodies were detected in patients with ATIN, and phenytoin sodium deposited along TBM was also found, but in most of the reported cases, immunofluorescence showed no immunoglobulin, complement and cellulose deposition in renal tissue.
(3) Electron microscopy: There are a few reports on the drug-induced ATIN electron microscopy. Ooi et al found that the mitochondria of the tubules were swollen, the rough endoplasmic reticulum was significantly dilated, the distal tubule lesions were more severe than the proximal tubules, and the perivascular basement membrane of the cortical tubules was increased. Thick and divided into multiple layers, the reason for thickening may be the proliferation of the basement membrane material. Due to the destruction of the interstitial structure, the lesions in the interstitial region are described by Galpin et al as chaotic lesions, and the inflammatory infiltrating cells are composed of lymphocytes. Plasma cells and eosinophils, a small number of neutrophils, glomeruli are generally normal, only in the case of drug-induced ATIN complicated with nephrotic syndrome, significant foot process fusion.
(4) Pathological changes of non-steroidal anti-inflammatory drugs nephropathy: The pathological changes of ATIN caused by non-steroidal anti-inflammatory drugs are different from ATIN caused by other drugs mentioned above, often accompanied by small ball involvement, see non-steroidal anti-inflammatory drugs Kidney disease.
2. Others: B-ultrasound to check the volume of both kidneys increased.
Diagnosis
Diagnosis and diagnosis of allergic acute tubulointerstitial nephritis
Diagnostic criteria
According to clinical manifestations, medical history and laboratory tests can make a diagnosis, the main clinical features of this disease: most patients in the second week after administration of the disease, manifested as an acute increase in serum creatinine after the use of a nephrotoxic drug; Fever (75% of patients, usually after the onset of fever has been controlled or after the start of drug treatment); rash (less than 50%); joint pain (15% to 20%); elevated eosinophils (80%; but Uncommon in AIN) caused by NSAID drugs; urine analysis: mild to moderate proteinuria; red blood cells and white blood cells, white blood cell casts; blood eosinophilia (as seen in 86% of cases; AIN caused by NSAID drugs is not common) Increased eosinophils in urine is an important clue to the diagnosis of allergic interstitial nephritis, but the positive rate is often not high, urine alkalization helps to detect eosinophils, bilateral or unilateral rib waist pain Uncommon, this may be due to the diffuse enlargement of the kidney to pull the renal capsule; in the interstitial nephritis infiltrated by inflammatory cells, radioactive gallium citrate imaging is often positive, especially in the early stages of the disease, This check appears to be more meaningful because it is in the acute kidney The positive rate of necrosis is very low, which is very valuable for identification with AIN. B-ultrasound often finds that the renal pyramid is enlarged, suggesting renal interstitial edema. According to the above characteristics, the factors of pre-renal and post-renal are excluded. Basically, the clinical diagnostic criteria for acute allergic interstitial nephritis have not been unified yet. It is generally recognized that:
1. A recent history of allergic drugs.
2. Systemic allergic reaction: AIN caused by NSAID drugs is not common; elevated eosinophils in urine is an important clue for the diagnosis of allergic interstitial nephritis, but the positive rate is often not high, urine alkalization helps It was found that eosinophils, bilateral or unilateral rib lumbar pain are not common, which may be caused by diffuse enlargement of the kidney to pull the renal capsule; radioactive citrate in interstitial nephritis infiltrating inflammatory cells Gallium imaging is often positive, especially in the early stages of the disease, and this check appears to be more meaningful.
3. Abnormal urine test: Aseptic leukocyte urine (including eosinophilic urine) may be associated with leukocyte cast, microscopic hematuria or gross hematuria, mild to severe proteinuria (often mild proteinuria, but non-steroidal resistance) Inflammatory drugs cause proteinuria to be severe).
4. Progressive renal dysfunction in the short term: partial and/or distal renal tubular functional damage and glomerular dysfunction.
B-ultrasound shows that the size of the kidneys is normal or large. If all of the above 1, 2 and 3 and/or 4 are available, the clinical diagnosis can be established, but atypical cases (especially those caused by non-steroidal anti-inflammatory drugs) Often no 2, must rely on renal biopsy pathological examination to confirm the diagnosis, renal biopsy see pathological changes for bilateral renal diffuse lesions, renal interstitial diffuse or multifocal inflammatory cell infiltration, resulting in interstitial edema, renal tubules have varying degrees Degenerative changes and even necrosis; glomerular more normal, some patients can see the deposition of immunoglobulin IgG and complement C3, or anti-TBM antibodies can be measured in the blood.
Indications for renal biopsy include failure to recover spontaneously after discontinuation and/or progressive decline in renal function. Renal biopsy contributes to the identification of acute tubular necrosis, which is characterized by extensive tubular damage and lack of inflammation. In many cases, renal biopsy is necessary for ARF patients because histological diagnosis is of special significance for some treatments.
Differential diagnosis
1. Identification of acute tubular necrosis: There is no history of application of allergic drugs in acute tubular necrosis, no allergic reaction (or rash) occurs, eosinophils in urine do not increase, blood IgE is not high or normal can be Identification of the disease, if there is difficulty, can be identified by renal biopsy.
2. Identification with acute renal failure: acute glomerulonephritis, acute glomerulonephritis, primary nephrotic syndrome, lupus nephritis and acute renal failure caused by acute tubular necrosis, all with acute renal failure Performance and specific manifestations of their primary disease, but no systemic allergy and eosinophilic urinary performance, gallium scan examination in acute interstitial nephritis increased renal uptake density, and acute tubular necrosis is not ingested, can also Help differential diagnosis.
3. Identification of renal failure in the original chronic glomerular disease: When there is unexplained acute renal failure or progressive renal failure, renal function decline is difficult to explain, should be alert to the possibility of acute allergic interstitial nephritis, looking for the whole body Allergic manifestations such as rash, elevated IgE in the blood, eosinophilic urine, etc. are helpful in diagnosis, if necessary, renal biopsy to confirm the diagnosis.
4. Identification with eosinophilic urine: Eosinophilic urine can also be seen in upper and lower urinary tract infections, acute nephritis, IgA nephropathy, obstructive nephropathy, chronic renal failure, renal papillary necrosis, prostatitis, acute kidney transplantation Posterior heterosexual atherosclerotic disease should be identified by their different clinical characteristics.
