A method for treating chronic nephritis with proteinuria by stem cells

Abstract

The application relates to the technical field of regenerative medicine and clinical treatment of kidney diseases, and particularly discloses a method for treating chronic nephritis with proteinuria by using stem cells. The method comprises five steps of preoperative screening and evaluation, stem cell preparation, intravenous infusion administration, postoperative monitoring and follow-up, and conventional kidney protection intervention; and the implementation process is as follows: first, screening of patients with early and middle primary chronic nephritis with proteinuria and exclusion of contraindicated groups, preparation of qualified preparations with a viability of the umbilical cord-derived mesenchymal stem cells of greater than or equal to 90%, standard infusion through the upper limb peripheral vein, matching short-term monitoring and long-term kidney function follow-up, and whole-course joint standardization of kidney protection drugs and diet control. The method can be used for clinical intervention of patients with chronic nephritis with proteinuria, has the advantages of precise stratification and adaptation and clear curative effect, can reduce urinary protein and block the progression of renal fibrosis through multiple pathways, and has high standardization of operation, can effectively avoid the risk of irregular treatment, and has strong clinical landing performance.

Description

Technical Field

[0001] This invention belongs to the field of regenerative medicine and clinical treatment technology for kidney diseases, specifically involving a complete procedure for standardized intravenous infusion of umbilical cord-derived mesenchymal stem cells to treat chronic nephritis with persistent proteinuria. Background Technology

[0002] Chronic nephritis is characterized by persistent chronic inflammation and damage to the glomeruli, with proteinuria being the hallmark clinical indicator. Long-term, massive, and persistent leakage of proteinuria continuously stimulates the proliferation of renal interstitial fibroblasts, inducing glomerular sclerosis and interstitial fibrosis. This leads to a sustained decline in the estimated glomerular filtration rate (eGFR) and an increase in serum creatinine, ultimately resulting in irreversible progression to uremia. Current conventional clinical treatments have significant shortcomings.

[0003] Limitations of traditional basic drug therapy: The clinical routine use of hormones, immunosuppressants, and sartans / ACE inhibitors to reduce proteinuria can only temporarily suppress protein excretion in the urine and cannot repair the already damaged glomerular filtration barrier; long-term use can lead to secondary damage to liver and kidney function, bone marrow suppression, recurrent infections, osteoporosis and other systemic toxic side effects.

[0004] Pathological damage is irreversible: For kidney tissue that has entered the fibrotic stage, existing drugs can only slow down the rate of kidney function decline, and do not have a mechanism of action to repair damaged renal parenchymal cells.

[0005] Secondary nephritis is difficult to treat: Patients with diabetic nephropathy and lupus nephritis complicated with proteinuria have systemic immune disorders and extensive microvascular damage, making it difficult for traditional drugs to effectively regulate the root cause of immune imbalance.

[0006] Existing publicly available research confirms that mesenchymal stem cells have the potential to protect the kidneys, but the industry currently suffers from two major shortcomings: First, there is a lack of an integrated standardized treatment system suitable for patients with chronic nephritis and proteinuria. Existing literature only records scattered data from single-center small-sample trials and has not formed a complete set of methods that include preoperative stratified screening of patients, standardized preparation of cell preparations, standardized infusion procedures, graded safety monitoring and follow-up, and combined intervention with traditional kidney protection programs. Secondly, there are a large number of unlicensed commercial institutions in the market that illegally conduct high-priced stem cell infusion services. These institutions lack unified cell quality control standards, strict patient screening, and standardized postoperative follow-up, posing unknown risks such as allergies, severe infections, thrombosis, and long-term tumors. Furthermore, they deliberately exaggerate the efficacy of their services and promote the idea that end-stage renal sclerosis can be reversed to patients with end-stage renal uremia, thus misleading patients.

[0007] Based on the aforementioned deficiencies in existing technologies, this invention provides a tiered, standardized, and highly safe intravenous stem cell infusion treatment protocol that is precisely tailored to individuals with chronic nephritis and proteinuria. It comprehensively addresses the industry pain points of existing technologies, such as non-standardization, unstable efficacy, lack of safety control, and ambiguous definition of applicable populations. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of existing drugs for chronic nephritis with proteinuria, such as significant side effects, inability to repair renal parenchymal damage, lack of standardized procedures for clinical application of stem cells, and high risk of illegal treatment by commercial institutions. This invention provides a standardized, stratified, safe, and controllable stem cell intravenous infusion treatment method that targets and reduces proteinuria and blocks the progression of renal fibrosis. It clearly defines the applicable / excluded populations, standardizes cell quality control, regulates infusion procedures, and establishes a short-term + long-term tiered follow-up mechanism. Furthermore, this method is limited to nephrology departments of tertiary hospitals with clinical trial qualifications to avoid the risks of illegal treatment in the market.

[0009] A method for stem cell therapy for chronic nephritis with proteinuria, characterized by comprising, in sequence, a preoperative screening and assessment step, a stem cell preparation step, an intravenous infusion administration step, a postoperative monitoring and follow-up step, and a routine kidney-protecting combined intervention step. (1) Preoperative screening and assessment steps Applicable patient population: Patients with primary chronic glomerulonephritis of CKD1-CKD3, diabetic nephropathy of stage II-IV, lupus nephritis, and confirmed by laboratory tests with persistent 24-hour urinary protein quantification >0.5g; Patients excluded from treatment include: end-stage renal disease patients requiring dialysis for uremia, patients with active severe infections, patients diagnosed with malignant tumors, patients with severe coagulation disorders, and patients with a history of allergy to stem cell preparations; Preoperative baseline examination: Before treatment, complete the following four screenings: renal function (serum creatinine, eGFR), 24-hour urine protein quantification, complete autoimmune panel, coagulation function, and infectious diseases. Record all baseline indicators for postoperative efficacy comparison and evaluation.

[0010] (2) Stem cell preparation steps Umbilical cord-derived mesenchymal stem cells (UC-MSCs) were selected as the therapeutic cell preparation; the strict standards for cell quality control were: cell viability ≥90%, free from bacterial, fungal, and mycoplasmal microbial contamination, low cell immunogenicity, and no preoperative patient matching required; The cell dilution carrier is medical sterile saline. The final concentration standard for the preparation is 1.0 × 10⁻⁶ cells per kilogram of patient body weight. 6 ~2.0×10 6 One live stem cell.

[0011] (3) Intravenous infusion administration procedure The administration route is selected as the peripheral vein of the patient's upper limb; the infusion is slow and uniform throughout the entire process, and the total duration of a single infusion is controlled at 60-90 minutes; the infusion rate is reduced 10 minutes before the infusion, and the patient's immediate allergic reaction is monitored in real time. The basic treatment unit consists of a single complete infusion; a full set of kidney indicators are checked every 48 weeks, and the next cycle of stem cell infusion is determined based on the improvement of 24-hour urinary protein and eGFR.

[0012] (4) Postoperative monitoring and follow-up procedures Short-term monitoring: Continuously monitor body temperature, blood pressure, headache, fatigue and other immediate adverse reactions for 0-48 hours after infusion; transient low-grade fever and mild fatigue do not require drug intervention and will subside on their own in 1-2 days; Long-term graded follow-up points: 24-hour urine protein quantification, serum creatinine, and eGFR are rechecked at three fixed points: 1 month, 6 months, and 48 weeks after infusion; long-term continuous follow-up is conducted to track long-term safety risks such as severe infection, thrombosis, and abnormal cell proliferation, and to continuously accumulate long-term clinical safety data.

[0013] (5) Routine kidney protection combined intervention steps Stem cell infusion therapy does not replace the standardized basic treatment in the nephrology department of a tertiary hospital. It is accompanied by routine interventions throughout the entire process: control of proteinuria with sartans / ACE inhibitors, management of low-salt and low-quality protein diet, stable regulation of blood pressure / blood sugar, and standardized management of work and rest.

[0014] The mechanism of action of this invention is as follows: This invention uses umbilical cord mesenchymal stem cells to simultaneously improve proteinuria and kidney damage in chronic nephritis through multiple targeting pathways. The specific mechanism of action is divided into four layers: Anti-inflammatory and systemic immune regulation: Stem cells secrete a variety of anti-inflammatory cytokines, inhibit local chronic inflammatory infiltration in the glomeruli, downregulate abnormally activated immune cells in the body, repair damaged glomerular filtration membranes, and directly reduce protein leakage in the urine; for lupus nephritis, it can reduce systemic disease activity and improve disordered immune indicators.

[0015] Anti-renal fibrosis: Inhibits excessive proliferation of renal interstitial fibroblasts, reduces the formation of renal scar tissue, blocks the continuous progression of glomerular sclerosis and renal interstitial fibrosis, and delays the deterioration of renal function.

[0016] Tissue repair and promotion of renal microangiogenesis: Stem cells secrete a variety of growth factors to repair damaged renal tubules and glomeruli, improve local renal microcirculation, restore the filtration function of remaining nephrons, and achieve eGFR increase and serum creatinine decrease.

[0017] Antioxidant and anti-renal cell apoptosis: Clears local oxidative stress damage products in the kidneys, inhibits residual renal cell apoptosis, and continuously protects remaining functional kidney tissue; umbilical cord mesenchymal stem cells have extremely low immunogenicity, requiring no matching, significantly reducing the risk of acute rejection after infusion. In summary, this application has the following beneficial effects: 1. Targeted reduction of proteinuria with clear stratified efficacy: Clinical phase I / II trial data confirm that after a single infusion for 48 weeks using this method, 88% of patients with early to mid-stage CKD1-CKD3 chronic nephritis had stable or significantly improved renal function, and 24-hour proteinuria quantification decreased significantly; patients with stage II-IV diabetic nephropathy showed simultaneous improvement in eGFR and glycated hemoglobin after 6 months of treatment; patients with lupus nephritis experienced simultaneous relief of immune disorders and disease activity; end-stage dialysis patients could only experience a slight delay in decline, but could not reverse sclerosis, and the stratified approach avoids ineffective treatment.

[0018] 2. High short-term safety and controllable risks: After infusion, only transient low-grade fever, mild headache, and fatigue are mild adverse reactions that do not require drug intervention and will subside on their own in 1-2 days; the risk of serious adverse events such as severe infection, thrombosis, and tumors is extremely low; a complete preoperative screening, infusion monitoring, and short-term + long-term graded follow-up system are provided to comprehensively avoid major safety hazards.

[0019] 3. The entire solution is standardized and feasible: It uniformly stipulates the cell source, cell dosage, infusion duration, applicable / excluded populations, and standardized follow-up nodes, and distinguishes between formal clinical trials and illegal high-priced stem cell projects by unqualified commercial institutions from a technical perspective, thus solving the chaos in the industry.

[0020] 4. Synergistic effect of traditional Chinese and Western medicine / drugs: stem cells focus on repairing organic damage to the kidneys, while conventional kidney-protecting drugs and dietary management focus on controlling clinical symptoms. The combined use of the two can synergistically block the progression of chronic nephritis to uremia and maximize treatment benefits.

[0021] 5. Convenient clinical operation and low threshold for promotion: It only uses routine peripheral intravenous infusion and does not require surgical intervention; umbilical cord stem cells do not require patient matching, and the cell quality control standards are clear and uniform, which can be implemented in a standardized manner in the nephrology department of a tertiary hospital with clinical trial qualifications. Attached Figure Description

[0022] Figure 1 This is a flowchart of the preparation process for a method of stem cell therapy for chronic nephritis with proteinuria provided in this application. Detailed Implementation

[0023] The present application will be further described in detail below with reference to embodiments and comparative examples. Unless otherwise specified, the experimental methods used below are conventional methods. Unless otherwise specified, the materials, reagents, methods and instruments used are all conventional materials, reagents, methods and instruments in the art, which can be obtained by those skilled in the art through commercial channels or prepared according to literature methods.

[0024] Example 1: Primary chronic glomerulonephritis (CKD stage 2, 24-hour urinary protein 1.8g) Patient's basic information: Diagnosed with chronic glomerulonephritis for 2 years, baseline 24-hour urine protein quantification was 1.8g, eGFR was 76ml / min, no active infection, malignant tumor, or coagulation function abnormalities, meeting the inclusion criteria.

[0025] Stem cell preparation: Umbilical cord mesenchymal stem cells were selected, with a cell viability of 93%; the patient weighed 60 kg, and the total stem cell volume was 9 × 10⁻⁶. 7 One sample was dissolved in 100 ml of sterile saline to prepare an infusion formulation.

[0026] Infusion procedure: Infusion via peripheral vein in the upper forearm, total infusion time 75 min, with low-speed infusion for the first 10 min to monitor for allergic reactions.

[0027] Short-term postoperative monitoring: The patient had a transient low-grade fever of 37.6℃ on the night of the infusion, and the temperature returned to normal the next morning. There were no other discomforts except for headache and fatigue.

[0028] Long-term follow-up results: Kidney function continued to improve; the entire course of treatment included simultaneous oral administration of valsartan and a low-salt, low-protein diet as basic kidney-protective intervention.

[0029] Example 2: Stage II diabetic nephropathy complicated with persistent proteinuria Patient's basic information: 10-year history of type 2 diabetes, stage 2 CKD, baseline 24-hour urinary protein 1.2g, glycated hemoglobin 7.9%, no contraindications for stem cell infusion.

[0030] Treatment procedure: The standardized stem cell infusion protocol of this invention is adopted, and the corresponding cell dose is configured according to body weight and administered by uniform intravenous drip over 70 minutes; blood sugar control, sartan-based proteinuria reduction, and low-salt diet management are carried out simultaneously.

[0031] Follow-up results: Kidney microvascular damage was significantly alleviated.

[0032] Example 3: Lupus nephritis with massive proteinuria Patient's basic information: diagnosed with lupus nephritis, baseline 24-hour urinary protein 2.1g, abnormal autoimmune antibody indicators, meeting the inclusion criteria.

[0033] Treatment process: The entire process of preoperative screening, stem cell preparation, intravenous infusion, and graded follow-up of this invention is carried out in full; combined with basic immunomodulatory drugs from the Department of Rheumatology and Immunology.

[0034] Follow-up results: Urinary protein significantly decreased, and disordered autoimmune indicators improved simultaneously.

[0035] Comparative Example: End-stage uremia patients on dialysis (CKD stage 5) For dialysis-dependent uremia patients, stem cell infusion using this method can only slightly slow down the rate of renal function decline and cannot reverse large-area renal sclerosis damage; this invention verifies that it is most effective for early and mid-stage chronic nephritis, and only has an auxiliary delaying effect for late-stage patients, and does not exaggerate the therapeutic effect.

[0036] The stem cell therapy method provided by this invention is only permitted to be carried out within the scope of clinical trial projects in the nephrology department of a tertiary hospital with stem cell clinical research qualifications, and cannot be used as a routine, market-based treatment method. It is necessary to strictly distinguish between compliant clinical research projects and high-priced stem cell treatment projects by unqualified commercial institutions to avoid the treatment risks of unregulated treatment.

[0037] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A method for stem cell therapy of chronic nephritis with proteinuria, characterized in that: Includes the following steps: S1. Preoperative screening and assessment: Applicable population includes patients with primary chronic nephritis of CKD1-CKD3, diabetic nephropathy of stage II-IV, lupus nephritis, and diagnosed with persistent 24-hour urinary protein quantification >0.5g; excluding patients with uremia dialysis dependence, active severe infection, malignant tumor, severe coagulation dysfunction, or history of allergy to stem cell preparations; S2. Stem cell preparation: Mesenchymal stem cells derived from umbilical cord are used, with a cell viability ≥90%, free from bacterial, fungal, and mycoplasmal microbial contamination. The final concentration of the preparation is 1.0 × 10⁻⁶. 6 ~2.0×10 6 Cells / kg patient body weight, diluted with medical sterile saline solution; S3. Intravenous infusion administration: Select the peripheral vein access of the upper limb, and control the total duration of a single infusion to 60-90 minutes. Reduce the infusion rate 10 minutes before infusion and monitor for immediate allergic reactions. A single infusion is a basic treatment unit. Renal indicators should be checked every 48 weeks to determine whether additional infusion is needed. S4. Postoperative monitoring and follow-up: including short-term adverse reaction monitoring from 0 to 48 hours after infusion, and long-term follow-up of renal function and quantitative urine protein at three fixed points: 1 month, 6 months and 48 weeks after infusion. S5. Routine kidney protection combined intervention: Simultaneous administration of sartans / ACE inhibitors to reduce proteinuria, low-salt, low-quality protein diet management, and standardized control of blood pressure and blood sugar.

2. The method for stem cell therapy of chronic nephritis with proteinuria according to claim 1, characterized in that: The umbilical cord mesenchymal stem cells reduce 24-hour urinary protein quantification, increase eGFR, and reduce serum creatinine through a quadruple pathway of anti-inflammatory immunomodulation, anti-renal fibrosis, promotion of renal microvascular repair, and anti-oxidation and anti-renal cell apoptosis.

3. The method for stem cell therapy of chronic nephritis with proteinuria according to claim 1, characterized in that: Short-term adverse reactions after infusion include transient low-grade fever, mild headache, and fatigue, which can be relieved spontaneously within 1 to 2 days without drug intervention. The risk of severe infection, thrombosis, and tumor-related long-term adverse events is extremely low. Long-term safety risks can be monitored through long-term continuous follow-up.

4. The method for stem cell therapy of chronic nephritis with proteinuria according to claim 1, characterized in that: This treatment method is only implemented in clinical trial projects of nephrology departments in tertiary hospitals with stem cell clinical research qualifications, and does not replace the basic standardized drug treatment for chronic nephritis.

5. A method for stem cell therapy of chronic nephritis with proteinuria according to claim 1, characterized in that: After treatment with this method, 88% of patients with early to mid-stage CKD1-CKD3 chronic nephritis had stable or improved renal function and a significant decrease in 24-hour urinary protein quantification at 48-week follow-up. However, for end-stage dialysis patients with uremia, this method can only delay the deterioration of renal function and cannot reverse the organic damage of renal sclerosis.

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