As one of the important organs of the human body, the kidneys are responsible for the discharge of metabolic waste products from the body, while regulating the electrolyte and acid-base balance in the body to maintain the stability of the internal environment. When the human kidney function is abnormal, the metabolic waste in the human body cannot be discharged and accumulates in large quantities, which will bring damage to various organs, cause kidney disease, and eventually lead to uremia.
This process is a slow pathological process of chronic kidney disease, which is defined as chronic renal structural and functional disorders (history of kidney damage greater than 3 months) caused by various causes, including pathological damage to normal and abnormal renal GFR, abnormal blood or urine composition, and abnormal imaging tests, or unexplained GFR decline (<60 ml/min · 1.73 m2) for more than 3 months, that is, CKD.
Causes of chronic kidney disease include a variety of primary and secondary glomerulonephritis, tubular damage, and renal vascular lesions. Generally, chronic kidney disease is divided into 5 stages, early detection and early intervention can significantly reduce the complications of CKD patients, significantly improve survival rate, for the treatment of CKD, including the treatment of primary disease, the treatment of various risk factors and the progression of slow renal insufficiency, when CKD patients progress to stage 5, renal replacement therapy should be carried out in time.
At present, the number of patients with chronic kidney disease in China exceeds 120 million, accompanied by high morbidity, high mortality and high medical consumption, as well as low public awareness.
The existing treatment methods for kidney disease have obvious drawbacks
As an almost completely irreversible damage, chronic renal failure refers to chronic, progressive renal parenchymal damage caused by complex pathogenesis and mechanisms, resulting in significant renal atrophy and difficulty in maintaining its basic function.
Dialysis remains the most common means
Clinically, the main clinical syndrome is metabolite retention, water, electrolyte and acid-base imbalance, and systemic involvement; therefore, its most important clinical manifestations are metabolic disorders and symptoms of various different systems, and the manifestations are relatively diverse.
Most patients with kidney disease need to rely on and receive long-term drug treatment to control and delay the disease, and end-stage kidney disease consumes a lot of medical resources in China. For patients in the stages of exhaustion and uremia, current treatment is mainly renal replacement therapy, including dialysis and kidney transplantation.
Limitations of dialysis:
Dialysis has higher requirements for medical conditions, while the treatment process of patients is relatively painful, dialysis can replace part of the kidney function, but it is difficult to replace the endocrine and metabolic functions of the kidneys, resulting in high clinical mortality.
Limitations of kidney transplantation:
Kidney transplantation is an effective treatment for uremia patients, but the number of donors is relatively limited, and there are high matching requirements and risk of immune rejection, and the incidence of postoperative complications is high; high medical costs are also a major reason why transplantation is difficult to implement and promote.
Mechanisms of mesenchymal stem cells in the treatment of nephropathy
The therapeutic potential of stem cells is mediated by a variety of mechanisms, such as differentiation into various types of renal parenchymal cells; regulation of the activation of immune cells; secretion of cytokines such as various signaling factors, nutritional factors and anti-inflammatory factors; anti-renal apoptosis, anti-fibrosis and anti-stress oxidation response to play a role in kidney tissue repair.
With the progress of basic research, in vivo experiments have gradually increased, and in vivo experiments have proved that stem cells can improve kidney function while reducing kidney damage. It has not only shown an effective role in the treatment of acute kidney injury models, but also played a role in the treatment of chronic kidney disease.
Zhang et al. transplanted mesenchymal stem cells (MSCs) into CKD model rats, and found that the serum creatinine and urea nitrogen levels of rats treated by stem cells were significantly improved, the degree of interstitial fibrosis was lower than that of the model group, and the kidney function was significantly improved. Dong et al. injected MSCs into rats with doxorubicin chronic kidney disease, and found that the rats had decreased urine protein, elevated blood albumin, and decreased blood cholesterol.
1. Mechanism of exogenous MSCs inducing renoprotective action
Studies have shown that after injecting IN VITro amplified MSCs, it can have a protective effect on acute kidney injury and accelerate the recovery of kidney function.
In addition, exogenous MSCs are also effective in the treatment of chronic kidney disease. MSCs have a property that they preferentially homing to areas of tissue injury or sites of inflammation. Studies have shown that intravenous MSCs are able to migrate to glomerulus, renal interstitium, peria tubular vessels, and tubules in model animals with acute and chronic kidney injury.
2. Exogenous MSCs guide the mechanism of kidney recovery
(1) MSCs migrate and differentiate into host tissues or organs;
(2) Therapeutic fusion with existing host cells;
(3) Release of autocrine/paracrine signals from MSCs;
(4) Stimulate endogenous repair by regenerating the patient's own inherent stem cells.
After transplanted stem cells enter the human body, stem cells will reach the damaged kidney through the induction of "migration" and "homing", these transplanted stem cells can differentiate into newborn kidney functional cells according to the surrounding microenvironment on the one hand; on the other hand, they can also "awaken" their own kidney cells to "regenerate", so that kidney cells can be repaired and regenerated to the greatest extent, and finally the patient's kidney function is gradually restored.
Stem cells for kidney disease – a clinical case
Case 1: Cantaluppi et al. summarized the Phase I/II clinical trial of Clinical Trials.gov stem cells for various kidney diseases, most of which were explored to determine the safety and efficacy of stem cell therapy.
For 61 cases of CDK patients using systemic and local infusion method stem cell transplantation, after two weeks the patient's urea nitrogen, creatinine, uric acid and other indicators decreased significantly, excretion and other indicators also changed significantly, the patient's kidney function improved, stem cells on CDK treatment is very effective!
Case 2: The researchers injected MSCs intravenously into 6 patients with CKD at a dose of 1×106/kg. The results showed that no adverse reactions were detected in 6 patients, there was no significant decrease in GFR and a significant improvement in urine protein excretion during the 1 year of stem cell transplantation. Researchers believe that stem cells can improve kidney function, reduce histological damage, and reduce kidney tissue fibrosis.
Case 3: A clinical trial of stem cell transplantation and control in 30 patients with CKD found that the serum creatinine clearance in the stem cell group increased significantly at the first, third and sixth months after transplantation, and the proteinuria in 2 subjects disappeared.
Case 4: Packham DK et al. conducted a Phase I clinical trial in which 30 patients with diabetic nephropathy were given a single intravenous injection in the stem cell group and followed up for 60 weeks. The results showed that stem cell infusion was safe and well tolerated, and the renal indicators of patients receiving stem cell therapy improved.
Case 5: A 62-year-old Indonesian woman diagnosed with chest paraplegia, chronic renal failure, diabetes mellitus, long-term renal involvement, and chronic renal failure for 2 years. Treatment was given with a human cord mesenchymal stem cell transplant regimen. 1.6×107 mesenchymal stem cells were injected intrathecally, 1.6 × 107 mesenchymal stem cells were injected intravenously. The results showed that the patient could move his toes and his kidney function was significantly improved.
prospect
Compared with traditional treatment methods, stem cells have irreplaceable advantages, good therapeutic effect, and good repair and reconstruction effect on kidney function. At the same time, when dealing with diseased kidney cells, dialysis can be selected as an adjunct, the dialysis interval can be appropriately extended, and the therapeutic effect of getting rid of dialysis can even be achieved, complications can be improved, the process of kidney failure can be delayed, and the quality of life can be improved.
With the continuous deepening of stem cell research, the clinical application of stem cell therapy for CKD will develop rapidly, so that more patients with chronic kidney disease can obtain clinical benefits.