The kidney is a paired organ located in the abdominal cavity and is responsible for cleaning the blood from metabolic products and regulating the water-salt balance in the body. During normal operation, the kidneys filter up to 150 liters of blood every day and excrete up to two liters of urine. Some common symptoms that may indicate that the kidneys are not working properly: swelling of different parts of the body (legs, ankles, feet, lower abdomen), high blood pressure, foamy urine, hematuria (blood in the urine or its color change to very dark), tiredness, loss of appetite and weight gain due to retaining too much fluid.Urine and blood tests can determine the functional state of the kidneys. 1
Urine albumin-to-creatinine ratio (UACR) test estimates both albumin (important blood protein) and creatinine (a waste product of normal muscle breakdown) levels in a single urine sample. If this test detects more than 30 mg of albumin to 1gr of creatinine it could be a sign of kidney disease. When the kidneys are damaged, increased amounts of albumin leak into the urine. This condition is called albuminuria. For many people, albuminuria is the earliest sign of kidney diseases. 24-hour urine collection test shows volume of secreted urine and dynamic change of main indicators. The kidneys do not work properly if the volume of collected urine is more than 2 liters or less than one liter. Blood test includes measuring whole protein, albumin, glomerular filtration rate (GFR), total cholesterol and other lipids, total glucose and many others indicators that may reveal kidney dysfunction and related disorders.
Reduced GFR value (less than 60) usually means inefficient filtering of wastes from the blood due to kidney disease. A GFR of 15 or less indicates kidney failure and need for dialysis. Imaging techniques such as ultrasound, CT, MRI and Kidney biopsy tests are used for confirmation and clarification of the state of the kidneys.
All pathological conditions of the kidneys fall into two categories: chronic kidney diseases (CKD) and acute kidney injuries (AKI). AKI could transform to CDK (or vice versa) due to various accompanied diseases and side effects of their treatment. If kidney lose 85 percent or more of its function this means that acute or chronic kidney disease progress to End-stage renal disease (ESRD) that is treated by dialysis or kidney transplantation.
Underlying causes of AKI and CKD could be very different:
Treatments for the renal disorders depend on its causes, but most commonly aims to relief symptoms and support kidney state to delay progression of ESRD. A diet to reduce the amount of fat, cholesterol, limit intake of sodium (salt) and fluids to help control swelling could be developed. Blood glucose levels will be thoroughly controlled in case of diabetic nephropathy. An angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) could reduce protein loss and lower blood pressure, which is often high in people with nephrotic syndrome. A diuretic drug reduces swelling by helping the kidneys remove fluid from the blood could be prescribed. In some cases medicines that suppress patient's immune system would be prescribed as well. Dialysis for the elimination of metabolic products may be needed.
It is well known that mesenchymal stem cells (MSC) have immunomodulatory, anti-inflammatory, and tissue repair activities that could be used for additional therapy of some kinds of AKI and CKD when these MSC properties could play a sufficient role.2
Clinical trials evidenced the safety and tolerability of MSC administration to most of the patients. MSCs are shown to inhibit T and B cell activation and proliferation, contribute to transformation of monocytes and macrophages from a proinflammatory to an anti-inflammatory phenotype, increase level of regulatory T cells (Tregs) thus providing immunomodulatory, anti-inflammatory therapeutic effects of stem cell administration. At the local tissue level, MSCs decrease tubular cell apoptosis, reduce oxidative stress, induce angiogenesis and demonstrate antifibrosis actions through paracrine mechanisms thus providing regenerative effects on the kidney. Moreover MSCs could manage the mitochondrial recovery in an injured cells.3
AKI is difficult to treat, because disease-specific therapies are lacking, and supportive care is the main option for the patients. MSCs appeared to protect early and late postsurgery kidney function against AKI development. Renal ischemia/reperfusion injury (IRI) occurs as a result of a sudden blockage of blood flow to the kidney. Compared with standardized medical treatment, the infusion of MSCs result in a significant increase in cortical perfusion and renal blood flow, a reduction of tissue hypoxia, and stabilization of measured GFR at 3-month follow-up. MSCs may lower vascular insufficiency and inflammatory injury through proangiogenic and immunomodulatory effects thus improving AKI state of kidney.
Diabetes mellitus usually progresses to CKD, named diabetic kidney disease (DKD) or diabetic nephropathy (DN). High levels of free glucose in blood cause kidney damage. There are some data provided evidence that MSC-based therapy may decrease fasting blood glucose (FBG) and glycated haemoglobin (HbA1c).4
Improvement in glycemic control was observed after MSC therapy when eGFR was higher than 30. Therefore it is important to start MSC therapy in an early phase of DKD before the structural integrity of the kidney cells and their parts are irreversibly destroyed.
Experience with MSC in kidney transplantation indicates that this cell therapy may be used safely in combination with an adequate immunosuppressive regimen and is capable to diminish immune responses thus prolonging solid organ graft survival.
MSC administration could be performed via renal artery or in standard (intravenous) way at a high dose of 2-6×10^6 cells per kilogram and is well tolerated by patients. However the effectiveness of cell therapy has not always been observed in clinical trials. The lack of positive effects from cell therapy may be due to the fact that not all types of renal diseases can be alleviated with the help of MSCs, as well as the harmful environment into which cells enter when administered to a patient with renal disorders, because the blood of such patients contains toxins and unfiltered metabolic products (for example p-cresol). The problem of cytotoxicity can be solved in two ways: by preconditioning MSCs with various substances or by therapy using MSC-derived extracellular vesicles (EVs).5
Extracellular vesicles (EVs) are tiny bubble-like structures secreted by MSCs and contain cytokines, proteins, mRNAs, miRNA. EVs are able to regulate cell signaling in recipient's cells and have similar activities to MSC although they cannot maintain their presence in the body for long-term action. The preconditioning or priming of MSCs protects them from the harmful environment, improves their survival rate and therapeutic functions. This method employ incubation of MSCs in cultural media with cytokines, natural or chemically synthesized compounds. Before administration of primed MSC into the patient's body these cells are washed to remove these compounds and therefore are safe for therapy. Kintaro could provide an optional priming of Bone marrow derived mesenchymal stem cells with melatonin to improve beneficial effects from therapy of kidney disorders by MSC. In some cases blood dialysis procedure before MSC administration could also improve results as the level of toxic compounds will be lower. However due to very different underlying causes of kidney disease, comprehensive blood and urine tests along with consultation with a physician are needed before starting the therapy with Kintaro cells.