Immunosuppressive and anticancer drug toxic nephropathy
Introduction
Introduction to immunosuppressive drugs and anticancer drugs for toxic nephropathy Immunosuppressive drugs and anticancer drug nephropathy (nephropathyduetopoisoningofimmunosuppressivedrugandanticancerdrug) refers to glomerular, tubular and interstitial lesions and bladder damage caused by the application of immunosuppressants and anticancer drugs. The kidney is the main organ for drug, toxic metabolism and excretion in the body. During its metabolism and excretion, it can cause toxic effects on the kidney in various ways, causing kidney damage and toxic kidney disease. In recent years, due to the widespread use or abuse of various drugs in clinical practice, the incidence of acute and chronic renal failure caused by drugs is increasing, especially in the elderly and patients with existing kidney diseases. basic knowledge Sickness ratio: 0.0001% Susceptible people: no special people Mode of infection: non-infectious Complications: alopecia, acute renal failure, hemolytic uremic syndrome, acute tubular necrosis
Cause
Immunosuppressive drugs and anticancer drugs
Hypoproteinemia and renal insufficiency (25%):
In patients with kidney disease or liver disease, the combination of drugs and plasma proteins is reduced due to hypoproteinemia, and the free part of the drug is increased. Therefore, the excretion of drugs from the kidneys increases, and the chance of kidney damage increases. When renal insufficiency occurs, some The drug can not be discharged normally through the kidney, the half-life is prolonged, and the accumulation of the drug in the body for a long time causes an increase in nephrotoxicity.
Age factor (20%):
In elderly patients, renal reserve capacity is reduced, and there are often potential renal lesions (such as hypertensive arteriosclerosis, diabetic microangiopathy, etc.) and the body's immunity is reduced, which may lead to infection. If the medication is inadvertent, it is prone to renal toxicity, such as cyclophosphorus. Kidney damage caused by amide (CTX) and ifosfamide (IFO) is a common cause of aggravating bladder hemorrhage. The dose is too large, and pelvic radiotherapy, with other bladder lesions or oliguria, combined with phenylpropionate mustard.
Direct toxic effects on the kidneys (15%):
Normal human kidney blood flow accounts for 25% of the whole body, and the weight of the kidney is only 0.4% to 0.5% of the body weight. Therefore, the kidney is the most abundant organ in the body, and a large amount of drugs and their metabolites flow to the kidney with blood. It has a direct toxic effect on the kidneys.
Drugs with extensive contact with glomeruli and renal tubules have an increased chance of toxic damage through extensive exposure to the surface of glomerular capillary endothelial cells and renal tubular epithelial cells.
Kidney oxygen demand Kidney tissue has high metabolic activity, requires adequate blood flow and oxygen supply, and consumes a large amount of oxygen. When ischemia and hypoxia occur, the sensitivity of the kidney to drugs increases, which is apt to produce toxic effects.
The countercurrent multiplication mechanism of the renal tubules (convection concentrating) due to the reabsorption of water by the renal tubules, the drug is concentrated in the renal tubules, the drug concentration in the small lumen is increased, and the drug accumulates to cause toxic nephropathy, especially It is a tubular lesion.
Pathogenesis
There may be the following aspects: direct action on renal blood vessels, reducing renal blood flow; preventing or inhibiting the production and release of prostacyclin stimulating factor, facilitating platelet aggregation and deposition, causing vascular endothelial damage; directly injuring renal tubules, and Other drug-induced toxic tubular lesions are similar; activation of calcium channels leads to increased calcium-dependent nephrotoxicity.
Prevention
Immunosuppressive drugs and anticancer drugs for toxic kidney disease prevention
1. Strictly grasp the indications for medication, medication dose and course of treatment should pay attention to closely monitor urine routine, urine enzymes, kidney function, in order to early detection of nephrotoxicity and timely withdrawal.
2. Prevention and treatment of CsA nephrotoxicity Strictly control the indications, dosage and course of treatment, the general dose is 4 ~ 6mg / (kg · d), pay attention to monitor the blood concentration of CsA when using the drug, blood concentration greater than 250ng / ml may produce nephrotoxicity, When it is more than 400 ng/ml, the nephrotoxicity is obvious, and the combination with the calcium ion antagonist can reduce the nephrotoxicity.
3. For the prevention and treatment of cyclophosphamide (CTX) and ifosfamide (IFO) nephrotoxicity, pay attention to rehydration, maintain urine volume in 2 ~ 3L / 24h, and alkalinize urine, generally do not use diuretics; The drug can be injected into physiological saline. In recent years, calcium channel blockers and conversion enzyme inhibitors have been reported to reduce nephrotoxicity. For patients with hemorrhagic cystitis, cystoscopy should be performed promptly, and telangiectasia should be detected immediately. Stop the drug to prevent the lesion from developing into bladder fibrosis and contracture.
Complication
Immunosuppressive drugs and anticancer drugs toxic nephropathy complications Complications, acute renal failure, hemolytic uremic syndrome, acute tubular necrosis
Extrarenal complications include myelosuppression, alopecia, liver damage, gonadal inhibition, gastrointestinal reactions, secondary infections and secondary tumors; intrarenal complications include acute renal failure, hemolytic uremic syndrome and acute Renal tubular necrosis.
Symptom
Immunosuppressive drugs and anticancer drugs toxic nephropathy symptoms common symptoms anuria hemolytic anemia oliguria alopecia hydronephrosis thrombocytopenia renal damage bladder fibrosis hypertension hypokalemia
The main clinical manifestations of kidney damage caused by immunosuppressive drugs and anticancer drugs vary with different drugs. The main clinical manifestations are hairy, gingival hyperplasia, elevated blood pressure, liver damage, etc.; renal lesions are mild, moderate proteinuria, cast Urine, oliguria, renal tubular acidosis, azotemia, electrolyte imbalance, hyperkalemia, hypertension and acute and chronic renal failure, the following are the manifestations of kidney damage caused by several common drugs.
1. Cyclosporine causes kidney damage
(1) Acute tubular necrosis: Acute tubular necrosis caused by cyclosporine occurs mostly in the early post-transplantation. It is reported that cyclosporine has a high incidence of anuria after transplantation, oliguria-anuria, and receives cyclosporine. Acute tubular necrosis occurred in patients with allogeneic renal transplantation, and the morphological changes are not specific. In cases with prolonged oliguria-anuria, mild diffuse interstitial fibrosis can be seen. After renal function recovery, some cases Interstitial fibrosis can be completely abolished, and a few cases can persist with focal or diffuse interstitial fibrosis. With long-term impaired renal function, it is still controversial whether to discontinue cyclosporine in patients with prolonged anuria.
(2) Small tube toxicity: The small tube toxicity of cyclosporine refers to the small tube damage caused by short-term cyclosporine treatment, which is different from the long-term application of cyclosporine-induced chronic nephropathy. It is treated with cyclosporine. In the same kidney transplant patients, conventional or fine needle biopsy can see several morphological changes of tubule cells, including large mitochondria, small cell vacuolation and microcalcification, but these lesions are non-cyclosporin toxicity. Specifically, the clinical manifestations of cyclosporine tubule toxicity are similar to functional nephrotoxicity, but the decrease in glomerular filtration rate is more pronounced. It is strange that there is no manifestation of proximal tubule dysfunction, urinary lysosome, N-acetylglucoside Enzyme excretion is in the normal range, no Fanconi syndrome reported, the appearance of tubule toxicity is a manifestation of the overall toxicity of cyclosporine, so it can guide clinicians to adjust the dose of cyclosporine, or stop the simultaneous application of cyclosporine Other nephrotoxic drugs.
In clinical practice, it is very important to identify acute cyclosporine toxicity and acute rejection early, but sometimes it is difficult. Clinically, acute rejection often has reduced urine output, fever, and ultrasound examination shows renal edema and acute In patients with rejection, the increase in serum creatinine is more toxic than cyclosporine. The decrease in urinary sodium excretion and the increase in urinary protein excretion are rare in acute rejection, but highly suggestive of rejection. Renal biopsy shows diffuse cell infiltration in acute rejection. Cyclosporine toxicity is sometimes associated with small arterial disease, but in patients with no rejection, inflammatory infiltration is not uncommon in patients treated with cyclosporine. On the other hand, large mitochondria, small cell vacuolation and microcalcification can also be used. Found in patients with rejection.
(3) CsA-associated chronic nephropathy: The most difficult complication of long-term cyclosporine treatment is chronic progressive decline of renal function. This renal damage of cyclosporine is called cyclosporine chronic kidney disease. The cause is chronic tubulo-interstitial toxicity of cyclosporine, whose pathological and clinical manifestations are difficult to distinguish from chronic rejection. The most characteristic pathological change of cyclosporine chronic kidney disease is small arteries ( Arteriole) lesions and interstitial fibrosis, and the three major pathological changes in chronic rejection are intimal thickening of the greater arteries of the kidney, interstitial infiltration and fibrosis, glomerular sclerosis, cyclosporine chronic kidney disease Vascular lesions mainly occur in arteriole, including interlobular arteries and arcuate arteries. Recently, cyclosporine chronic kidney disease has been reported to involve the aorta. Cyclosporine-induced arteriolopathy occurs in two forms. One is the deposition of circulating proteins on the wall of small arteries, resulting in stenosis or obstruction of the vascular lumen. The second is thickening of the intima, causing stenosis of the vascular lumen. These lesions further cause scarring. , Secondary to vasoconstriction and ischemia resulting in a small tube collapse and interstitial fibrosis, visible between irregular or spotty ribbon fibrosis and tubular atrophy lesions in the renal cortex.
The clinical features of cyclosporine chronic kidney disease are progressive renal dysfunction and arterial hypertension. Proteinuria may be mild or no proteinuria, although the clinical and pathological changes of cyclosporine chronic kidney disease and chronic rejection are very similar, but chronic Rejection vasculopathy is dominated by larger arteries (Artery), arteriole lesions often correspond to larger arterial lesions, and cyclosporine chronic nephropathy vasculopathy is mainly small arteries, which can be used for cyclosporine Chronic kidney disease and chronic rejection are identified.
The natural course of cyclosporine chronic kidney disease is unclear. In the last 2 years, the glomerular filtration rate remained stable. The heart transplant recipients treated with cyclosporine, Myers et al found severe renal tissue lesions and suggested patients. Progressive irreversible renal dysfunction will occur, and similar histological changes may also be seen in patients with autoimmune uveitis who have been treated with cyclosporine and have normal renal function. These reports suggest that long-term cyclosporine treatment can cause irreversible Renal failure, clinically, most patients with cyclosporine chronic kidney disease can maintain stable renal function after cyclosporine reduction, but in a few cases, renal function is not improved after reducing cyclosporine dose, for cyclosporine There is no consensus on whether patients with chronic kidney disease have changed cyclosporine to azathioprine. It has been reported that after 5 years of follow-up observation, patients who took cyclosporine and patients who switched to azathioprine were all Seeing a slight increase in serum creatinine levels, on the other hand, patients who switched to azathioprine were at risk of acute rejection, but because cyclosporine could not be reduced The incidence of chronic rejection, both in patients with cyclosporine and in patients with azathioprine, is at risk of chronic organ rejection leading to graft failure.
2. Renal damage caused by cyclophosphamide (CTX) and ifosfamide (IFO) Both CTX and IFO are metabolized by the kidney into an active cytotoxic form, which produces acrolein and chloroacetic acid, which can cause cystitis, which is characterized by acute bladder. Bleeding and chronic fibrosis, acute hemorrhagic cystitis is more common in children, manifested as bladder mucosal congestion and ulcers, clinically different hematuria, 40% of cases of severe bleeding, occasionally bleeding more than death, the lesion is reversible Most of them recover within 2 to 3 weeks after stopping the drug. The chronic lesions are bladder fibrosis. Some patients have bladder contracture. In severe cases, they may cause urinary tract obstruction and slow progressive hydronephrosis. It is more common in late chemotherapy or after chemotherapy stops. IFO has greater bladder toxicity than CTX. CTX can induce bladder cancer and renal pelvis cancer. IFO can cause mild tubular disease, transient proteinuria and elevated urinary enzymes, and even Fanconi syndrome can occur. Hypokalemia and renal insufficiency, renal tubular function can be restored after withdrawal, extra-renal manifestations of myelosuppression, alopecia, liver damage, gonadal inhibition, gastrointestinal reactions, secondary infections and secondary tumors.
3. Streptozotocin The kidney is the main excretion pathway of the chain. After administration, 73% of the drugs and their metabolites are excreted in the urine. The pathological changes of nephrotoxicity are mainly the involvement of proximal convoluted tubules, tubule atrophy, and inflammatory cell infiltration. , clinical manifestations vary, tubule dysfunction with phosphorus loss or manifested as Fanconi syndrome with glomerular insufficiency and develop into renal insufficiency, once the symptoms of nephrotoxicity should be discontinued immediately, the above changes can be reversed, otherwise the condition can be Progress, irreversible kidney damage can occur if medication is continued.
4. Fluorouracil (5-Fu) The clinical manifestations of renal damage are two syndromes, hemolytic uremic syndrome and acute renal failure with microangiopathic hemolytic anemia and thrombocytopenia. Histology shows renal arterioles There are fibrosis, interstitial fibrosis, tubule atrophy and glomerular sclerosis, the above syndrome can be fatal, the former usually 3 to 4 weeks, the latter 3 to 8 months.
5.5-Azacytidine is a second-line drug for the treatment of non-lymphocytic leukemia. It can cause defects in tubule transport function when used in combination with other anti-tumor drugs, such as glucose, bicarbonate, phosphate or sodium. Translocation defects, defects in tubule transport function can be reversed after stopping treatment, but nephrotoxicity is minimal when applied alone.
6. Thioguanine (6-FG) analog, mild, reversible azotemia only at high doses, no nephrotoxic effects at standard oral doses.
7. Anti-tumor antibiotics
(1) Mitomycin C (Mitomycin C): nephrotoxicity manifested as proteinuria, hematuria, azotemia, with or without microangiopathic hemolytic anemia and thrombocytopenia, nephrotoxicity often After several treatments, it is dose-related, the cumulative dose is less than 50mg/m2 or the interval is 10-15mg/m2 per week, and it can be tolerated for 6-8 weeks.
(2) Mithramycin: nephrotoxicity is characterized by decreased proteinuria and creatinine clearance, renal biopsy showing swelling of proximal convoluted tubules, necrotic tubule necrosis, and occasionally hemolytic uremic syndrome.
(3) Doxorubicin: nephrotoxicity is characterized by pre-renal azotemia and acute renal failure, which occurs 1 to 6 months after administration, usually occurs within 2 months, and the drug dose is preferably low. At 20mg/m2 per week.
8. Biological preparations
(1) Interferon: The nephrotoxicity caused by -interferon is mainly characterized by reversible acute renal insufficiency and nephrotic syndrome, clinical and histological manifestations of acute interstitial nephritis and minimal pathological nephropathy, electron microscopy Shows tubulointerstitial changes, glomerular epithelium with diffuse foot process fusion, glomerular basement membrane without electron dense deposits, nephrotic proteinuria but negative circulating immune complex, suggesting that immune complexes are not the cause of kidney damage mechanism.
It has been reported that patients with nephrotic syndrome who have been treated with -interferon for 1 year are membrane proliferative glomerulonephritis, and clinical proteinuria is 1g/d to 2g/d, and proteinuria disappears 10 days after withdrawal.
(2) Interleukin-2 (IL-2): nephrotoxicity is characterized by prerenal acute renal failure, which is caused by capillary leakage syndrome caused by the application of IL-2. Lead to decreased renal perfusion, clinical hypotension, oliguria or urinary filtration fraction decreased significantly and blood urea nitrogen, creatinine increased, clinical observation found that with IL-2, although the supplemental fluid maintains stable blood volume and lung Capillary wedge pressure, but the incidence of acute renal failure is still high after 5 days, some patients with acute tubular necrosis, nephrotoxicity, if the serum creatinine base value is lower than 132.6mol / L (1.5 mg / Dl), usually the kidney function can be restored in the first week after stopping the drug, otherwise it takes a long time to recover.
Examine
Examination of immunosuppressive drugs and anticancer drugs for toxic nephropathy
Routine inspection
1. Acute renal failure caused by drug poisoning, mostly manifested as non-oliguric type, generally daily urine volume is more than 600ml for isotonic urine, blood creatinine, urea nitrogen can suddenly and rapidly rise, but lighter than normal oliguria The urine sodium content is also lower, the endogenous creatinine clearance rate decreases, the urine osmotic pressure and urine specific gravity decrease, a few severe cases, complex conditions and elderly patients can gradually develop to chronic renal insufficiency with severe hypokalemia or hyperkalemia, urine The enzyme is elevated, and even clinical changes in Fanconi syndrome can occur.
2. Drug-induced acute interstitial nephritis laboratory showed a small amount of proteinuria, microscopic hematuria, aseptic leukocyte urine, urinary sediment see eosinophils accounted for more than 1/3, may have renal function involvement, manifested as blood Urea nitrogen, elevated creatinine, decreased endogenous creatinine clearance, occasionally elevated blood IgE, elevated blood eosinophil count.
3. Clinically, patients with nephritic syndrome or nephrotic syndrome may have proteinuria and hematuria. A small number of patients have nephrotic syndrome due to massive proteinuria, hypoalbuminemia and hyperlipidemia. There is renal dysfunction, blood urea nitrogen, creatinine increased significantly.
4. Acute obstructive nephropathy examination showed hematuria, blood urea nitrogen, creatinine increased significantly.
1. Renal biopsy pathological examination
(1) Circulsin chronic renal disease vascular lesions mainly occur in arteriole, including interlobular arteries and arcuate arteries. Recently, cyclosporine chronic kidney disease has been reported to involve aorta, cyclosporine-induced arterioleopathy (arteriolopathy) ) occurs in two forms, one of which is the deposition of circulating proteins in the wall of the small arteries, resulting in stenosis or obstruction of the vascular lumen, and the second is thickening of the intima, causing stenosis of the vascular lumen, which further causes scarring, secondary vasoconstriction and Ischemia leads to tubule collapse and interstitial fibrosis, and irregular focal or banded interstitial fibrosis and tubule atrophy lesions are seen in the renal cortex.
(2) Nephrotoxicity induced by -interferon mainly manifested as reversible acute renal insufficiency and nephrotic syndrome, histology showed fibrous infarction of renal arterioles, interstitial fibrosis, tubule atrophy and glomerular sclerosis, clinical and Histological manifestations of acute interstitial nephritis and minimally pathological nephropathy, electron microscopy showed tubulointerstitial changes, glomerular epithelial diffuse foot process fusion, glomerular basement membrane without electron dense sedimentation, ie nephrotic circulating immune complex Negative.
(3) In the clinical stage of acute tubular necrosis, the proximal renal tubular epithelial cells degeneration, necrosis, basement membrane rupture and interstitial edema, and the distal renal tubules are also involved, even involving glomeruli.
(4) Patients with acute interstitial nephritis, light microscopy showed high edema of renal interstitial, interstitial with a large number of eosinophils, lymphocytes and mononuclear cells infiltration, mild diffuse interstitial fibrosis, a few cases can be sustainable There is focal or diffuse interstitial fibrosis, and renal tubular epithelial cell degeneration and necrosis can be seen. Immunofluorescence shows IgG deposition along the renal tubule basement membrane with C3 deposition.
2. Other inspections
Radionuclide kidney obstruction pattern; B-ultrasound hydronephrosis; cystoscopy for patients with hemorrhagic cystitis, can be found to expand into bladder fibrosis and contracture when telangiectasia or exacerbation.
Diagnosis
Diagnostic and differential diagnosis of immunosuppressive drugs and anticancer drugs for toxic nephropathy
According to the history of the original disease and medication, combined with clinical manifestations and laboratory tests can make a diagnosis of various types of toxic nephropathy.
Mainly the differential diagnosis of kidney damage caused by various drugs or with chronic rejection, such as clinical and pathological changes of cyclosporine chronic kidney disease and chronic rejection, but chronic rejection of vascular lesions with larger arteries ( Artery) is dominant, arteriole lesions often correspond to larger arterial lesions, and cyclosporine chronic nephropathy vasculopathy is mainly small arteries, which can identify cyclosporine chronic kidney disease and chronic rejection. It should be differentiated from chronic kidney disease caused by other causes.
