Pediatric tubulointerstitial nephritis

　　Etiology:

　　1. Infections include bacterial infections (such as Streptococcus, Staphylococcus, Corynebacterium diphtheriae, Salmonella typhi, etc.), legionella, leptospirosis, toxoplasma, and viral infections. Kidney or systemic infections caused by the above pathogens can induce TIN, but it is not the pathogens that directly invade the kidneys, but the immune response mechanism.

　　2. Drug reactions are common in antibiotics (such as aminoglycosides, penicillins, cephalosporins, amphotericin, tetracyclines, sulfonamides, doxorubicin, antituberculosis drugs, etc.), non-hormonal anti-inflammatory drugs (such as indomethacin, ibuprofen, aspirin, etc.), long-term exposure to heavy metal salts (such as lead, mercury, etc.), antiepileptic drugs, anesthetics, central stimulants, immunosuppressants, diuretics, and others.

　　3. Urinary tract obstruction or vesicoureteral reflux leading to tubulointerstitial injury.

　　4. Immune glomerular lesions include anti-glomerular basement membrane antibodies, immune complex deposition, and others.

　　5. Vascular diseases such as renal artery硬化, renal artery thrombosis, or renal vein thrombosis.

　　Pediatric tubulointerstitial nephritis patients may have complications such as hypertension, anemia, acute renal failure, and can coexist with kidney stones, severely affecting patients' health, so timely treatment is essential.

　　First, typical clinical

　　Present with fever, rash, joint pain, which constitute the triad of AIN. Children may have varying degrees of edema, nocturia, polyuria, vomiting, diarrhea, anorexia, abdominal pain. Children may have microscopic hematuria, pyuria, and in severe cases, renal failure may occur, most of which are non-oliguric.

　　Second, various and diverse clinical manifestations

　　1. Acute TIN:Most are caused by infection, drug hypersensitivity, vascular lesions, or drug nephrotoxicity, a few are idiopathic. The characteristics of ATIN are an acute onset, often accompanied by fever, rash, and bladder irritation symptoms, allergic to various drugs, and severe cases may present with acute renal failure. Pathologically, it is mainly characterized by变质渗出, with significant edema in the interstitium, infiltrating inflammatory cells vary according to the cause and pathogenesis. CTIN patients may experience flank pain due to renal edema, renal capsule traction, and physical examination may show renal area tenderness. The common clinical manifestation is that patients may have varying degrees of acute renal failure, and additional manifestations may appear according to different causes:

　　①Caused by infection: There are often symptoms of chills, high fever, general malaise, decreased appetite, and other toxic symptoms. Neutrophils in the blood increase, and antimicrobial therapy is effective.

　　②Caused by drug hypersensitivity: There is a history of medication use, and allergic symptoms such as rash, fever, joint pain, and lymphadenopathy may appear during or shortly after medication, with increased eosinophils and IgE levels in the blood. Urinalysis in one-third of patients can find eosinophils.

　　③Caused by drug nephrotoxicity: Most patients have a clear history of medication use, and renal tubular epithelial cells may appear in the urine.

　　2. Chronic TIN:②The main manifestation is renal tubular dysfunction, such as proximal tubule involvement leading to type II renal tubular acidosis and Fanconi syndrome, and severe distal tubule involvement may manifest as type I or IV renal tubular acidosis.

　　①The clinical characteristics of CTIN: The clinical manifestations are not as obvious as ATIN, patients may have no自觉 symptoms, and various renal tubular function abnormalities can be found upon careful examination. Blood pressure may be normal or elevated, and mild proteinuria is often present. When large amounts of proteinuria occur, it suggests concurrent glomerular disease. Some CTINs coexist with kidney stones. Urothelial malignancies can occur in Balkan nephritis or patients with analgesic abuse. Renal papillary necrosis can occur concurrently with analgesic abuse, CTIN caused by sickle cell disease or chronic urinary tract obstruction presents with fever, hematuria, and renal colic, occasionally with necrotic tissue excreted in the urine. Anemia and azotemia are not proportional to the degree of illness, commonly seen in medullary cystic disease, analgesic abuse, and multiple myeloma. Increased nocturia is an important diagnostic clue for many CTINs.

　　②The characteristic pathological manifestations of CTIN are interstitial fibrosis, tubular atrophy, and mononuclear cell infiltration. In the late stage, the kidneys become smaller and irregular in shape (which is a manifestation of scar formation), with single or multiple calyces dilated. Due to fibrosis, the tubules deform, the tubular basement membrane thickens, and secondary glomerular changes and renal vascular lesions can occur in the later stage. Because there is more interstitial tissue in the medulla, the medulla and papilla are severely affected. Since each segment of the renal tubules has the function of reabsorbing sodium ions, any segmental renal tubular epithelial cell injury caused by primary CTIN reaching a certain degree can lead to inappropriate loss of sodium ions. It is very worthy of clinical attention that primary CTIN generally does not cause sodium retention, while CTIN caused by secondary CTIN and vascular lesions often accompanies sodium retention, manifested as edema and hypertension. Detailed inquiry into the medical history can find the cause or trigger of TIN. Typical clinical manifestations include fever, rash, and joint pain triad; or unexplained renal failure, allergic systemic symptoms; laboratory tests show increased serum IgE, increased count of peripheral blood eosinophils, increased urine β2-microglobulin, hypokalemia; urine contains red blood cells, white blood cells, and white blood cell casts; renal function impairment, renal biopsy may be necessary for diagnosis.

　　There is no effective preventive measure. For drug-induced cases, attention should be paid to medication safety. Low-salt diet, low-protein diet, avoid greasy food, have regular meals, avoid over-fatigue, and maintain a regular lifestyle.

　　I. Routine urine examination

　　1. Urinary sediment examination:The changes in urinary sediment vary with the primary disease. Generally, moderate amounts of red blood cells, white blood cells, renal tubular epithelial cells, and casts can be seen in the urinary sediment. Renal tubular epithelial cells and casts are of great importance for the diagnosis of TIN. Renal tubular epithelial cells are not easily seen in the urinary sediment of normal individuals, and their presence is a direct evidence of tubular damage. Normal individuals can only see a small amount of hyaline casts in concentrated acidic urine. The presence of cellular casts or granular casts in the urine, or hyaline casts in non-concentrated acidic urine, or a large amount of hyaline casts in concentrated acidic urine, all suggest damage to the renal parenchyma. Those caused by infection have a higher number of white blood cells in the urine, and the middle urine culture can be positive. Those caused by drug allergy have eosinophils in 1/3 of patients' urinary sediment, and the number of eosinophils in the blood can also increase.

　　2. Urine protein analysis:In the case of simple TIN, the daily urine protein amount is usually less than 1.5g, and it is a renal tubular small molecular proteinuria, which can be subject to small molecular protein quantification examination or urine protein disc electrophoresis.

　　Secondly, during the renal function test of ATIN:

　　Renal function impairment is mostly transient; while in CTIN, renal function impairment is persistent. The impairment of tubulointerstitial function is particularly significant. The form and degree of functional injury are related to the location and degree of injury to the renal tubulointerstitium by the pathogenic factor.

　　1. Decreased active secretion function of renal tubules:Some substances (organic anions) are actively secreted by the proximal tubule while being filtered by the glomerulus during renal excretion. After the active secretion function of the renal tubule decreases, blood uric acid concentration can increase, and the renal excretion rate of certain anionic drugs can also slow down. The clearance rate of phenol red excretion test decreases during clinical phenol red excretion test. Currently, the phenol red excretion test is widely used in clinical practice, and it is generally believed that an abnormal result of the test indicates a decrease in the excretion function of proximal tubular epithelial cells. In the actual clinical application process, the phenol red excretion test has the following defects:

　　(1) Affected by the effective renal plasma flow.

　　(2) Affected by the number of surviving renal units [or glomerular filtration rate (GFR)]. Total phenol red excretion rate = Single renal unit phenol red excretion rate × Total number of renal units. Total phenol red excretion rate = Single renal unit phenol red excretion rate × Total number of renal units.

　　(3) Limited by the accuracy of urine collection methods.

　　2. Decreased function of renal tubular reabsorption:Under normal circumstances, small molecular useful substances filtered by the glomerulus, such as amino acids, glucose, and small molecular globulins, are almost all reabsorbed in the proximal tubule and rarely lost. After the damage of the proximal tubule, the reabsorption function decreases, which can lead to the appearance of small molecular proteinuria, aminoaciduria, or glucosuria. In severe cases, the reabsorption function of the proximal tubule is completely collapsed, manifested as Fanconi syndrome (with simultaneous impairment of glucose, amino acid, and carbonate reabsorption). Currently, the methods commonly used in clinical practice to check the function of renal tubular reabsorption include:

　　(1) Uric acid β2 microglobulin excretion rate: An increased urine excretion of β2 microglobulin, with normal serum β2 microglobulin concentration, suggests a decrease in the function of proximal tubular reabsorption of small molecular proteins. The clinical significance of urine lysozyme examination is similar to that of β2 microglobulin. However, in cases of mild to moderate chronic renal failure, the decrease in the number of renal units can sometimes offset the impact of decreased function of proximal tubular reabsorption of small molecular proteins: Total β2 microglobulin excretion rate = Single renal unit β2 microglobulin excretion rate × Total number of renal units. Total β2 microglobulin excretion rate = Single renal unit β2 microglobulin excretion rate↑ × Total number of renal units. Total β2 microglobulin excretion rate = Single renal unit β2 microglobulin excretion rate × Total number of renal units↓. Total β2 microglobulin excretion rate = Single renal unit β2 microglobulin excretion rate × Total number of renal units.

　　(2) Urine protein disc electrophoresis: When the concentration of small molecular proteins in plasma is not abnormally increased, urine protein disc electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) shows proteinuria mainly composed of small molecular proteins, which also indicates that the reabsorption function of small molecular proteins in the proximal renal tubules is decreased.

　　(3) Maximum glucose reabsorption test: There is a reabsorption function of glucose from the proximal tubule to the distal tubule, but it is mainly in the proximal tubule. Therefore, when the renal tubules are damaged, it is easy to cause renal glycosuria. Similar to the principle of β2-microglobulin excretion rate, the maximum glucose reabsorption function is affected by both the total number of renal units and the function of each single tubule. Therefore, the clinical significance of abnormal or normal results of the maximum glucose reabsorption test needs to be analyzed in specific situations.

　　(4) Urine amino acid test: After the renal tubular reabsorption function of amino acids decreases, the excretion of amino acids in urine significantly increases.

　　Pay attention to eating vegetables rich in potassium, calcium, and vitamins in the diet. The specific foods high in potassium are mainly underground tubers, such as potatoes, sweet potatoes, and yams, and fruits such as oranges and bananas. If the renal function is still normal, calcium supplementation is also very important. In terms of correcting acidosis, it is sodium bicarbonate, calcium carbonate, and the like, and the dietary principles of kidney disease.
　　1. General dietary principles: Eat light, avoid drinking alcohol and spicy foods, and eat less greasy and rich in animal protein foods (such as fatty meat, shrimp, crabs, etc.). Different kidney diseases have different diets.
　　2. The amount of salt intake for normal adults is about 5-6 grams per day. Salt is sodium chloride, alkali is sodium carbonate, and baking soda is sodium bicarbonate. Excessive intake of sodium and alkali in food is easy to cause water retention in the human body and induce edema. Therefore, for patients with renal edema, the intake of salt and alkali should be controlled, and 2-3 grams of salt per person is considered low-salt diet. A salt-free diet is also not scientific, and it is easy to cause fatigue and dizziness over time.
　　3. The normal urine volume of a person is generally 1500-2000ml per day. For patients with acute nephritis, acute renal failure with oliguria, nephrotic syndrome, and chronic renal failure with oliguria and edema, it is necessary to control the intake of water (including drinking water, water content in food, and the volume of liquid in intravenous medication). Because the water intake cannot be excreted, it accumulates in the human body and aggravates edema, and is also prone to increase hypertension. At this time, the water intake should be 500ml more than the urine output. After the urine output increases, the water intake can be relaxed. While patients with normal urine output can drink normally. In addition, for patients with urinary system infections such as acute pyelonephritis, urethritis, cystitis, etc., in addition to seeking medical attention and taking medication in a timely manner, drinking plenty of water and urinating frequently is very beneficial to the recovery of the disease.
　　4. For kidney patients, high-quality protein diet, 0.7-1.0 grams per kilogram of body weight per day, should be guided by the amount of urine protein and renal function for individualization.
　　5. Some kidney patients have a long course of disease and slow recovery, often discussing and exchanging information and experiences with each other. It should be noted that everyone has their own characteristics and should not imitate each other.
　　6. During the treatment, if symptoms such as cold, fever, infection, etc. occur, emergency contact with a specialist doctor should be made to facilitate timely treatment and avoid the exacerbation of complications.
　　7. Do not overeat and do not eat unclean food. Maintain smooth defecation, which is conducive to the excretion of waste products and the reduction of the absorption of toxins. Develop a regular defecation habit, eat more vegetables and fruits, and use a softener if necessary.

　　One, treatment

　　1. The treatment measures are as follows:

　　(1) Finding the cause and removing it in a timely manner such as removing urinary tract obstruction or eliminating infection foci.

　　(2) Treatment for the underlying disease such as anti-infection.

　　(3) The use of desensitizing drugs such as diphenhydramine.

　　(4) Symptomatic and supportive treatment.

　　(5) Patients with concurrent renal failure need to follow the treatment principles of renal failure and dialysis therapy may be necessary if needed.

　　2. There is controversy about the use of hormones and/or immunosuppressants. Most scholars believe that hormones can improve clinical symptoms, help in the recovery of renal function, and reduce dialysis or the development of CTIN. After the etiology of TIN is removed, the lesion generally stops developing, and early cases can be completely recovered. For those related to infection, active anti-infection should be carried out; for those with urinary tract obstruction, the obstructive factors should be removed; for those caused by drugs or nephrotoxic substances, the use of drugs and toxins should be discontinued promptly, and corresponding treatment should be given. For those caused by metabolic disorders, efforts should be made to correct metabolic disorders. For water, electrolyte and acid-base imbalance, hypertension, anemia, edema, and other symptoms caused by TIN, symptomatic treatment should be given. If acute or chronic renal failure occurs, treatment should be carried out according to renal failure. The possibility of complete remission of acute interstitial nephritis is inversely proportional to the duration of renal failure. Studies have reported that in cases where the duration of acute renal failure is less than 2 weeks, the serum creatinine concentration can be maintained at a normal level after recovery, while in cases where the duration of acute renal failure is more than 3 weeks, the serum creatinine concentration after recovery is often above 250 umol/L. Persistent active tubulointerstitial damage is often accompanied by irreversible interstitial fibrosis.

　　3. Another factor affecting the prognosis is the degree of infiltration of mononuclear cells in the renal interstitium. Sporadic infiltration is easy to recover. It is noteworthy that if the underlying cause is not removed, patients are prone to develop end-stage renal failure. In patients with acute idiopathic TIN, although they can be naturally relieved, more than 50% of the patients have residual renal insufficiency. The positivity of anti-tubular basement membrane antibody often has a predictive role in the occurrence of renal insufficiency, especially in patients with severe renal damage. In cases where there is a lack of ideal responsiveness to etiological treatment and infection is excluded, adrenal corticosteroids can be used.

　　4. Generally, 1mg/kg prednisone is used daily, and other adrenal cortical steroids can be flexibly selected based on this. Most patients show significant improvement in renal function within 1 to 2 weeks after starting treatment, at which time the duration of use of adrenal cortical steroids is 4 to 6 weeks. For patients whose renal function does not improve after 2 weeks of hormone use, immunosuppressants such as cyclophosphamide 2mg/kg per day can be considered. Some believe that if effective, the drug can be used continuously for up to one year. Of course, close attention should be paid to the changes in blood leukocyte count during the medication process. If there is no improvement in the condition after 6 weeks of using cyclophosphamide, it is recommended to stop using the aforementioned two drugs. For patients with明显fibrosis shown by renal biopsy, consideration should be given to the diagnosis of CTIN, and these patients are not suitable for chemotherapy. More than one-third of drug-induced ATIN patients require hemodialysis treatment. Plasma exchange is reasonable for patients with positive anti-renin basement membrane antibodies and ATIN caused by systemic lupus erythematosus.

　　II. Prognosis

　　Children with the disease have a better prognosis. The course of ATIN is generally 2 weeks to 2 months. There are reports that about 7% develop chronic renal insufficiency one year after follow-up. Approximately 3% die due to renal failure or secondary infection. Factors affecting prognosis include etiology and primary disease, and poor prognosis is associated with severe renal function damage. Those with a course longer than 2 months are more likely to develop into CTIN. Poor prognosis is associated with diffuse and severe renal biopsy lesions. The occurrence and development of TIN are not only influenced by the primary disease or primary etiological factors but also by some factors that exacerbate the development of TIN. For example, the use of high-dose aminoglycoside antibiotics can cause tubular damage, and the addition of diuretics or failure to correct dehydration in patients can exacerbate TIN. Different etiological factors or primary diseases cause TIN to have different exacerbating factors.