Renal damage caused by Human Immunodeficiency Virus (HIV) infection

　　一、发病原因

　　1983年法国Montanier从患者分离出的病原体，命名为LAV，美国Gallo于1983年发现而于1984年报告的AIDS病原体命名为HTIV-Ⅲ，研究证明这两种病毒是同一种病毒，至1986年国际艾滋病病毒命名委员会建议命名为人免疫缺陷病毒(humanimmunodeficiencyvirus；HIV)统一了病原体的命名。

　　HIV为RNA反转录病毒，多为圆形或椭圆形，具有9213个核苷酸结构和9749个碱基对。HIV抗原性较强，侵入人体后可迅速占有游离免疫球蛋白。感染后可刺激机体产生抗体，分为抗病毒抗体和中和抗体两种，个体的血清抗体效价差异很大，严重的AIDS病例效价反较轻症病例为低。在疾病初期，病毒可引起淋巴细胞增殖，以后辅助T淋巴细胞(CD4细胞)被杀死，失去辅助B细胞的功能，使抗体产生功能减弱。故HIV对CD4细胞的破坏是AIDS致病的中心环节。

　　二、发病机制

　　HIV是一种嗜T淋巴细胞病毒，感染后选择性攻击CD4细胞。HIV侵入CD4淋巴细胞后病毒与组织膜上HIV受体结合而进入胞内，并脱去包膜。在胞内，病毒RNA反转录成DNA，然后整合至宿主细胞染色体上。当受感染细胞被激活时，此整合的前病毒DNA即转录RNA，合成蛋白质，最后组成完整的HIV颗粒，以芽生形式从细胞表面释入血循环，再感染新的CD4细胞。致使患者CD4细胞大量破坏导致免疫缺陷。同时，失去对B淋巴细胞的辅助作用引起体液免疫紊乱，失去正常免疫功能。CD4细胞的减少可引起相对的CD4/CD8(抑制T淋巴细胞)的倒置。

　　AIDS is prone to various infections due to the suppression of cellular immune function, especially opportunistic infections; due to the loss of immune surveillance function and self-stabilization function, malignant tumors often occur. Both are major causes of death.

　　The pathogenesis of HIVAN has not yet been elucidated. Most scholars believe that it is the direct invasion of HIV into the kidneys, causing the entire renal parenchymal cells to be involved, resulting in various renal pathological morphological changes. Cohen et al. found that the renal glomeruli and tubular epithelium of patients with focal segmental glomerulosclerosis and tubulointerstitial lesions associated with HIV-positive serum could bind to HIV nucleic acid and p24 antigen probes. Recently, DNA in situ hybridization technology has confirmed the presence of HIV genome in renal biopsy and autopsy specimens of HIVAN patients, strongly suggesting the viral invasion theory of HIVAN. The mechanism also includes immune injury, infection, tumor, drug toxicity, long-term intravenous injection of drugs, and changes in renal hemodynamics, which may be direct and/or indirect causes of HIVAN.

　　1. AIDS patients

　　The most common opportunistic infections are Pneumocystis carinii pneumonia, cytomegalovirus (CMV), Mycobacterium avium infection, candidal infection of the oral or esophageal mucosa, herpesvirus, cryptococcal meningitis, toxoplasmosis, Giardia lamblia infection, and others. According to literature reports, CMV can often be detected in immune complex nephritis, proving that CMV infection can also cause nephritis, and it can be accompanied by severe tubulointerstitial lesions. Some have found that CMV can spread through renal transplantation, and in vitro culture shows that CMV can infect glomerular mesangial cells and replicate. There have also been reports of HBsAg and HBeAg found in glomeruli.

　　2. Drugs

　　The nephropathy caused by intravenous injection of diacetylmorphine has been reported in literature for a long time, and about 50% of AIDS patients have a history of drug addiction, in addition to the fact that the pathological morphological changes of HIVAN and HAN are very similar, making it difficult to distinguish and compare the pathological changes of these two nephropathies. The main differences are shown in Table 1.

　　Early in HIVAN, there are glomerular lesions such as segmental glomerulosclerosis, capillary collapse, and intermittent expansion of the glomerular capsule, and severe tubular lesions, including microcystic expansion, plasma protein casts, and in the ultrastructure, inclusions of the cytoplasm and nuclear changes, as well as typical tubular reticular structures. Chander believes that there is no tubular reticular structure in HAN.

　　In addition, the size of the kidneys in HIVAN is larger than normal in both early and late stages, while the kidneys in HAN are significantly smaller in the late stage; the time to reach end-stage renal failure is usually 3 to 4 months in the former, and 2 to 4 years in the latter; and hypertension is generally not present in the former, while it is common in the latter; there is also a significant difference in prognosis, with HIVAN having a short course and a high mortality rate, while HAN has relatively stable conditions and life can be prolonged through dialysis treatment.

　　3. Tumors

　　In the post-mortem examination of 36 AIDS patients, Pardo et al. found renal glomerular pathological changes in 17 cases, including 10 cases with Kaposi's sarcoma. Bennett et al. found pathological changes of FSGS in 25 of 170 AIDS patients, including 2 cases with Kaposi's sarcoma. In addition, cases of lymphoma and renal cell carcinoma were also found.

　　4. Nephrotoxic drugs

　　Nephrotoxic drugs can cause renal damage in AIDS patients, therefore, caution should be exercised when using nephrotoxic drugs in AIDS patients, especially aminoglycoside antibiotics, amphotericin B, cyclosporine, and chemotherapeutic drugs. In addition to the direct toxic effect on the kidneys, nephrotoxic drugs can also cause allergic interstitial nephritis.

　　5. Hemodynamic changes

　　The loss or abnormal distribution of body fluids, sepsis, shock, and other conditions can cause renal damage in AIDS patients, therefore, the etiologies that can cause changes in blood volume should be paid attention to.

　　6. Abnormal immune function

　　The immune function abnormality in AIDS patients has been proven. The onset of nephrotic syndrome may be related to the function of T lymphocytes; the lymphotoxin produced by lymphocytes can increase vascular permeability and has a direct toxic effect on the glomerular basement membrane; regarding the role of humoral immunity in HIVAN, some people believe that it is unrelated to the pathogenesis related to immune complexes, but in a few cases, granular immunoglobulin and complement deposits can often be detected in the glomerular capillaries or mesangium.

　　Among the above pathogenic factors, some are relatively clear, such as nephrotoxicity, but some factors are complex. In view of the fact that AIDS is a disease affected by multiple factors, the damage to the kidneys is necessarily caused by multiple factors.

　　The main complications of AIDS include severe infections, progressive renal insufficiency, and multi-system, multi-organ dysfunction. Various primary and secondary malignant tumors can also occur.

      Common complications mainly include:

　　1. Pneumocystis carinii pneumonia is shown on X-ray chest films as patchy shadows around both hilum, presenting as interstitial pneumonia.

　　2. Enteritis can cause diarrhea symptoms.

　　3. Tuberculosis, mainly pulmonary tuberculosis, and tuberculous pericarditis are common.

　　4. Skin and mucosal damage.

　　5. Fungal infections can be seen in patients with white thick membranes on the tongue, buccal mucosa, soft palate, and posterior pharyngeal wall.

　　6. Concurrent renal damage can cause interstitial nephritis and tubular necrosis, leading to proteinuria, oliguria, severe edema, azotemia, and renal failure.

　　7. Damage to the endocrine system can lead to adrenal insufficiency and hyporeninemia, hypotension, persistent hyponatremia and hyperkalemia, hypothyroidism, diabetes, and adrenal crisis, etc.

　　I. Clinical manifestations of AIDS

　　Extremely complex, due to irreversible immune deficiency, AIDS not only has obvious systemic symptoms, often complicated by opportunistic infections and malignant tumors, but also, due to the absence of effective treatment, the final outcome is death.

　　The period from HIV infection to the production of HIV antibodies is generally 2 months. About 10% to 15% of HIV-positive serum patients can develop into AIDS patients. Before the onset of clinical symptoms, it is in the latent period, most of which is 1-3 years, the shortest being 6 months, and the longest up to 4-8 years. The general clinical stage is:

　　1. Latent period

　　Also known as the subclinical infection period, individuals with HIV infection but without clinical symptoms are in the latent period, but HIV antibodies or HIV virus and CD4 cell count decrease can be detected in laboratory tests. During this period, there are three possibilities: first, a long-term latent state; second, after a relatively long latent period, onset occurs; third, entering the AIDS-related complex after a latency period of 1-3 years.

　　2. AIDS-related complex (AIDS-related complex, ARC)

　　The patient may have irregular fever, night sweats, anorexia, fatigue, diarrhea, and other symptoms, and may have generalized lymphadenopathy. Biopsy shows lymphocyte proliferation, follicular degeneration, increased plasma cells. Later, the lymphatic tissue atrophies, the immune system changes, and CD4/CD8 inversion, thrombocytopenia, and other conditions may occur.

　　3. Clinical AIDS stage

　　Also known as the AIDS onset period, the patient has undergone a significant destruction of CD4 cells, forming a severe and irreversible immune deficiency, with more obvious systemic symptoms such as fever, excessive sweating, generalized weakness, weight loss, cachexia, etc. At this time, it is prone to various pathogenic infections and opportunistic infections (such as Pneumocystis carinii pneumonia PCP), as well as various primary and secondary malignant tumors, including Kaposi's sarcoma, non-Hodgkin's lymphoma, brain tumors, mediastinal lymphosarcoma, prostate cancer, and so on.

　　2. Clinical manifestations of HIVAN

　　About 10% of HIVAN patients are characterized by nephrotic syndrome, with most patients showing large amounts of proteinuria (>3g/d), hypoalbuminemia (95%) at the onset (compensatory period) with normal blood pressure, and blood pressure still normal when renal function deteriorates progressively. Ultrasound examination of the kidneys and post-mortem examination all prove that the kidneys are enlarged, and the echo of the renal parenchyma is enhanced. The typical clinical course of HIVAN is a rapid decrease in glomerular filtration rate (GFR), often developing into end-stage renal failure within 8-16 weeks. Although dialysis support therapy is available, the survival time is often less than 1 year, and there are some reports that the survival time of patients with end-stage renal failure due to HIVAN can be prolonged by maintenance dialysis or kidney transplantation.

　　Prevention of AIDS has attracted the attention of countries worldwide, and each country has established corresponding prevention and control research institutions and taken a series of preventive measures.

　　1. Management Measures

　　1. Establish management and prevention institutions. Currently, the WHO has established a special committee, and China also established a prevention and control group for AIDS in 1986.

　　2. Limit behaviors such as homosexuality.

　　3. Ban drugs and strictly prohibit drug use.

　　4. Manage the patients and carriers, and implement sexual isolation for patients and carriers. Pregnant AIDS patients or carriers should terminate their pregnancy.

　　Good publicity work, publicize AIDS knowledge, protect oneself consciously, and resist homosexual and drug-taking behaviors.

　　Two. Technical Measures

　　1. Prohibition of import and use of imported blood and blood products.

　　2. Vaccine research and development: AIDS vaccines are currently being developed using genetic engineering, and preliminary results have been obtained.

　　3. Good customs quarantine work and AIDS detection work, timely discovery of patients and carriers.

　　4. Good disinfection work in patients' homes and hospitals. Experimental evidence shows that HIV is very sensitive to disinfectants. Necessary disinfection should be done in patients' homes, hospitals, and places contaminated by patients. For example, 70% ethanol, 3% hydrogen peroxide, 1% glutaraldehyde, 0.2% to 0.5% sodium hypochlorite, 0.9% formaldehyde, 0.08% quaternary ammonium chloride, calcium hypochlorite, etc., all have the effect of killing HIV.

　　In summary, actively implementing the above preventive measures to control HIV infection and early treatment of HIV patients can effectively reduce the risk of kidney disease occurrence and development.

　　One. Blood Routine Examination

　　1. White blood cell count: AIDS patients have a reduced white blood cell count, usually below 4×10^9/L.

　　2. Lymphocyte count: usually below 1×10^9/L (normal people are higher than 1.5×10^9/L).

　　3. Platelet count: usually below 0.1×10^12/L.

　　4. Increased eosinophil count.

　　Two. Immunological Examination

　　1. The CD4/CD8 ratio decreases, often less than 1, and in severe cases, it may drop to 0.02, mainly due to a decrease in CD4 cells.

　　2. Lymphocytes show reduced or absent response to mitogens such as PHA, ConA, PWM, and to antigens such as tuberculin.

　　3. The production of interferon decreases, weakening the ability to kill the virus.

　　4. NK cell count is normal, but activity is reduced.

　　5. Delayed hypersensitivity of the skin diminishes or disappears.

　　6. Positive for anti-lymphocyte antibodies, anti-nuclear antibodies, and anti-sperm antibodies.

　　Three. Pathogen Examination

　　1. HIV examination:Electron microscopic examination of blood or tissue biopsy samples can detect HIV.

　　2. Pneumocystis carinii examination:Sputum smear, lung biopsy.

　　3. Candida albicans examination:Direct microscopic examination and culture of the lesion site and secretions.

　　4. Examination of pathogens of other infections.

　　Four. Serological Examination

　　Serological examination for AIDS can determine the presence of HIV antibodies, which is the main tool for detecting AIDS and an important basis for the diagnosis of AIDS as well as an important means for epidemiological investigation. The currently applied detection methods include the following:

　　1. Enzyme-linked Immunosorbent Assay (ELISA):It is one of the most widely used methods, with simple operation and strong sensitivity.

　　2. Immunofluorescence Assay (IFA):After HIV infection, the virus antigen is often expressed on the cell membrane, and the immune fluorescence method can detect the antibody to this antigen. The method is simple and can be used for blood bank screening of blood donors.

　　3. Protein Blotting (Western blot, WB):This method has high sensitivity and specificity, but the operation is more complicated, and it can generally be used as a method to verify other serological tests.

　　4. Radioimmunoprecipitation Test (RIP):Including solid-phase radioimmunoassay and competitive radioimmunoassay, this method has high sensitivity and specificity and is of great value for the diagnosis of AIDS.

　　5. Gel Particle Agglutination Test (GPAT):This method is rapid and simple, with high sensitivity, but false positives may occur.

　　6. Polymerase Chain Reaction (PCR)：Ex vivo amplification of HIV DNA sequences, DNA molecular hybridization, this technique is the most specific and sensitive detection method, and is being rapidly promoted.

　　V. Other auxiliary examinations

　　1. Pathological changes of HIVAN

　　It is found that in renal biopsies and autopsies of AIDS patients, renal glomerular pathological changes account for 30% to 50%, mainly manifested as focal segmental glomerulosclerosis (FSGS) accounting for 83%, mesangial proliferative glomerulonephritis accounting for 6%, minimal change accounting for 3%, and other glomerular lesions (including diabetic glomerulosclerosis, post-infection glomerulonephritis, membranous or proliferative glomerulonephritis) accounting for 6%.

　　2. Renal biopsy

　　The pathological changes of FSGS in HIV nephropathy were found.

　　(1) Light microscopy: visible swelling and proliferation of glomerular visceral epithelial cells, accompanied by the formation of large vacuoles in the cytoplasm or protein reabsorption droplets. There is extensive collapse of the capillary wall and it often presents as globular atrophy. The atrophic vascular丛 is covered by a layer of hypertrophic visceral epithelial cells 'crowned'. Foam cells are visible in the still open lumens. Mesangial matrix proliferation, with a large number of infiltrative lesions, the renal capsule is often dilated and filled with protein. In addition, there are obvious renal tubular lesions, such as the disappearance of the brush border of the proximal tubule, cell flattening, and microcystic dilation of the tubules. Tubular epithelial cells contain a large number of protein reabsorption droplets, accompanied by various degeneration, necrosis, and regeneration. This type of dilated tubule is seen throughout the cortex and medulla, especially at the corticomedullary junction, where the lumen is filled with large casts, but some tubular atrophy is still visible. Interstitial diffuse edema, on the contrary, there is no fibrosis, and infiltration of lymphocytes and monocytes is rare, and there is a lack of hypertensive arteriopathy.

　　(2) Immunofluorescence: shows IgM, C3, and C1q in the segments of glomerulosclerosis and mesangial area, indicating granular segmental deposition. IgG or IgA, and C3 circulating immune complexes can also be detected. These immunological features are similar to those of type I membranoproliferative glomerulonephritis.

　　(3) Electron microscopy: visible fusion of podocytes in the glomerular visceral epithelial cells, separation of epithelial cells from the basement membrane, especially in the segments of glomerulosclerosis. There are various complex inclusions in the nuclei and cytoplasm of multiple cells, abundant tubular reticular structures (TRS) are present in endothelial cells and mesenchymal cells. These inclusions are numerous, large, and fused together. The presence of such inclusions in renal biopsies of FSGS without symptoms of HIV infection can be considered as a strong evidence of HIV carrier status. Parallel stacking and columnar pitting changes (CCC) are also seen in the cytoplasm of renal tubular epithelial cells and other cells, which are also known as test tube and ring-like changes.

　　The above pathological features of FSGS in HIV nephropathy can help distinguish it from other kidney diseases that cause FSGS, but they are still not specific, especially similar to heroin-associated nephropathy (HAN), so they should be carefully differentiated.

　　Pay attention to a light diet, eat more vegetables and fruits rich in vitamins and fiber, avoid spicy and stimulating foods. You can eat more tomatoes, carrots, Chinese cabbage, winter melon, and so on. At the same time, you can appropriately strengthen nutrition, eat more soy milk, fish, and so on, but pay attention not to consume too much sugar and fat. Do a good job of disinfection and isolation in the patient's family and hospital, and experiments have confirmed that HIV is very sensitive to disinfectants.

　　First, treatment

　　To date, there is no effective drug for AIDS. The main direction of AIDS treatment at present is to kill HIV virus and enhance the body's immune function.

　　1. General therapy

　　(1) Isolation of the source of infection to prevent the continuous increase of AIDS. In addition, the protection of medical staff, doing a good job of disinfection and isolation, is very important.

　　(2) For patients with AIDS in the active stage who have concurrent various infections and malignant tumors, adequate rest, high-sugar, high-protein diet, and sufficient caloric intake should be ensured.

　　(3) Symptomatic treatment, antipyretics and physical cooling can be used during high fever. Patients often suffer from fear of AIDS, anxiety, tension, and a desire for life, and patients with brain space-occupying lesions may develop mental disorders, which should be appropriately treated with sedatives.

　　2. Anti-HIV treatment

　　The treatment of HIV is an important measure for the treatment of AIDS, but there is still no effective drug to date.

　　(1) Suramin: It is a reverse transcriptase inhibitor that can also protect CD4 cells from the cytotoxic effects of HIV. However, it should be taken early as it has high toxicity, often causing kidney damage, nausea, vomiting, fainting, and even sudden death and other toxic and side effects.

　　(2) Zidovudine (Zidovudine, AZT): It is an inhibitor of the second-generation reverse transcriptase, which can interfere with HIV and prevent the synthesis of viral core proteins. This drug can pass through the blood-cerebrospinal fluid barrier and has good curative effects on brain lesions. The side effects are relatively small.

　　(3) Ribavirin: It has the function of resisting RNA viruses and also has the effect of inhibiting HIV. It has low toxicity but cannot pass through the blood-cerebrospinal fluid barrier.

　　(4) Others: Such as HPA-23, trimethaphosphate (Forcarnet), inosine pranobex (Imunovir) and so on, have certain inhibitory effects on HIV and regulatory effects on the immune system.

　　All of the above anti-HIV drugs have certain limitations and shortcomings, hence still remain an unresolved treatment challenge.

　　3. Immune enhancement therapy

　　HIV infection mainly causes immune suppression, therefore, enhancing and restoring the body's immune function is an important link in the treatment of AIDS, but there are not many effective methods for AIDS.

　　(1) Bone marrow transplantation: It can only achieve temporary improvement in immune status and extend life in the short term, but cannot fundamentally improve the state of immune suppression.

　　(2) Recombinant human interferon X-A (rIFNX-A): It can inhibit HIV replication and may be valuable for early treatment and prevention of AIDS when used in combination with antiviral drugs.

　　(3) Aldesleukin (Interleukin-2): In vitro studies have shown that it can increase the proliferation response of AIDS patients' lymphocytes to PHA, ConA, and mixed lymphocyte reactions. It must be used in conjunction with antiviral drugs when aldesleukin (IL-2) is used.

　　(4) Granulocyte-macrophage colony-stimulating factor (GMCSF) has immune-enhancing and antiviral effects.

　　(5) Others: Human blood gamma globulin can help enhance the patient's resistance, and Lentinan can increase interferon production, but neither can change the body's immune status.

　　4. Treatment of complications

　　(1) Antimicrobial treatment: Patients with infectious pathogens and opportunistic infections should choose sensitive antimicrobial drugs to control the infection focus and prevent the spread and formation of sepsis.

　　(2) Antifungal treatment: The appropriate antifungal drugs should be selected according to the type and location of the fungal infection.

　　(3) Antiprotozoal treatment:

　　① Pneumocystis carinii pneumonia: The combination of pyrimethamine and sulfadiazine, or pentamidine (Pentamidine) or sulfamethoxazole (SMZ) plus trimethoprim (TMP) can be used. It can only temporarily control the condition and is prone to recurrence after discontinuation of medication. Recently, the use of Eflornithine, an antiprotozoal drug, has achieved success.

　　② Toxoplasmosis: The combination of pyrimethamine and sulfadiazine should be used for treatment, both of which can act on the brain through the blood-brain barrier, but the drugs can only kill the trophozoites and cannot eliminate the cysts.

　　(4) Antiviral treatment:

　　① Herpes simplex: Acyclovir, ganciclovir, morpholine guanidine, interferon, and other drugs can be used.

　　② Herpes zoster: In addition to the aforementioned antiviral treatment, vitamin B1 and analgesics should be added.

　　(5) Antitumor treatment: AIDS often complicates Kaposi sarcoma, non-Hodgkin's lymphoma, and brain lymphoma. The commonly used drugs are vinblastine, vincristine, and other antitumor drugs, which have only recent efficacy and are prone to recurrence. Moreover, opportunistic infections often occur during the treatment process.

　　5. Treatment of kidney complications

　　Patients with Acquired Immune Deficiency Syndrome (AIDS) often have kidney complications.

　　HIVAN currently lacks effective treatment measures, FSGS causes nephrotic syndrome or other types of kidney disease, and corticosteroids are ineffective. Some propose to try Azithromycin for the treatment of HIVAN, which can prevent or reduce the progression of FSGS in HIVAN patients, but it should be used before there is only a small amount of proteinuria and the renal function has not significantly deteriorated.

　　6. Treatment of Acute Renal Failure

      The incidence of acute renal failure in AIDS patients with renal damage is about 55%. Acute renal tubular necrosis-induced acute renal failure is caused by renal ischemia (often due to fluid or blood loss, sepsis leading to shock) or renal toxicity (often caused by drug toxicity such as gentamicin, amphotericin B, pentamidine, etc.).

　　In addition, large amounts of proteinuria and severe hypoproteinemia can cause renal edema, and hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), as well as multiple myeloma, can also cause acute renal failure. Pre-existing kidney disease is also a risk factor for acute renal failure, with dehydration being the most common cause.

　　Most acute renal failure patients can be reversed after correcting dehydration, antishock treatment, adjusting medication, and, if necessary, dialysis therapy. Dialysis therapy can reverse the renal function of acute renal failure, thereby extending the patient's life. However, for chronic renal failure hemodialysis, it can only extend the survival for a few months and cannot enable the patient to recover. In summary, hemodialysis is not ideal for the treatment of HIVAN renal failure. Regarding the issue of kidney transplantation in HIVAN, due to the small number of cases, its efficacy cannot be definitely confirmed, and there have been some successful reports. However, the incidence of opportunistic infections in kidney transplant patients is very high, affecting the prognosis.

　　II. Prognosis

　　So far, due to the lack of effective treatment for AIDS, the mortality rate is extremely high. Some people have compared the prognosis of AIDS patients with and without kidney disease, and the results are significantly different. In a group of 13 AIDS patients with concurrent kidney disease, 4 required dialysis treatment, and 11 had died before the end of this study; while in another group of 19 cases without kidney complications, none required dialysis treatment, and 5 had died before the end of this study. It can be seen that there is a significant difference in the outcomes of the two groups. In summary, patients with concurrent HIVAN have a rapid progression of the disease, and severe renal failure occurs within 8-16 weeks, and they often die within a year. In addition, the incidence of fungal infections in HIVAN is also high, and the prognosis is poor.