The Effect of Stem Cells on Kidney Disease

Table 1: Outlines common etiologies of acute kidney injury [12].

The mortality rate in AKI patients is about fifty percent. The majority of surviving patients recover full renal function. However, some patients develop CKD, requiring further treatment, such as renal transplantation and dialysis [13]. CKD is characterized by a progressive loss of the purpose of the kidney, leading to end-stage renal disease (ESRD) and collage accumulation, due to inflammation, leading to fibrosis [14]. At the ending stage of CKD, irreversible renal function loss is treated with transplantation of the kidney or dialysis. AKI can also result in ESRD, leading to a rise in the risk of CKD or aggravated CKD symptoms [7-15]. CKD is a progressive disease as well, leading to significant morbidity and mortality. Although surgical or pharmaceutical therapies may improve the overall function of the kidney, they cannot improve the regeneration and functional recovery of the tissues near the affected kidney damage. Therefore, there is a need to develop more effective strategies for treating injury to the kidney [11-12].

There is a high variability in CKD that are estimated in glomerular filtration rate (GFR) trajectories. This occurrence can insinuate that there are a large array of heterogenous risk factors potentially contributing to the overall development of CKD. If we wish to attain renoprotection, then these risk factors may end up becoming certain targets of therapy. Certain lifestyle factors such as one’s diet, loss of sleep and exercise, and smoking as well as socioeconomic factors are well-known factors of risk related to the development of CKD. Systemic and metabolic disorders, including hypertension, diabetes mellitus (DM), cardiovascular diseases, and gout can cause the increase of CKD and aggravation of the decline of GFR. Atrial fibrillation has recently been demonstrated to be a contributor to a quick decline in GFR as well as the CHA2DS2-VASc score (a stroke-risk stratification representation for patients who have atrial fibulation) has the ability to infer renal progression [12-15].

Many factors can lead to increased risk of CKD including: race, education, income and access to food. Pacific Islanders and African Americans typically have increased rates of diabetes, hypertension, and obesity that can lead to increased risk for developing ESKD. Gene encoding apolipoprotein L1 (APOL1) may be another contributing factor. Individuals with 2 APOL1 risk alleles are twice as likely to develop CKD. Sickle cell trait has been associated with increased kidney disease [16-18].

Risk Factors and Management Strategies of CKD Development and Progression

Figure 1: Outlines risk factors and management strategies of CKD development and progression [12].

Anatomy and Physiological Function

Kidneys are located in retroperitoneal space on both sides of the spine. The liver being on the right side of the abdominal cavity has led to the left kidney being located a little higher up than the right [19-21]. During the embryologic development, there are three sets of kidneys that are developed: mesonephros, metanephros, and pronephros. Beginning to form around the fourth week, the pronephros will not form into a functioning kidney. The metanephric kidney can excrete urine into the amniotic fluid in the third week of fetal development [1].

Each kidney typically weighs between 125 to 175 grams for males and 115 to 155 grams for females and measures approximately 11 to 14 centimeters in length, 6 centimeters in width and 4 centimeters thick. Approximately one third of all blood leaving the heart passes into the kidneys for filtration and is then pumped into the cells and tissues of the body [19-21]. Fat, muscles, and ribs protect the kidneys. Renal fat pat, also called perirenal fat, protects the kidneys from damage caused by external force. The renal hilum is a medial dimple that serves as the entry and exit point for nerves, ureters, vessels and lymphatics to help supply or drain the kidneys [19-21].

Anatomy of the Kidney

Blood is supplied to the kidney by the renal arteries. Specialized capillary beds called glomeruli are formed by these renal arteries that create a network of afferent arterioles that is highly specialized. Each of the glomerulus will create one part of a nephron and in order to create the efferent arterioles, capillaries will merge again. Forming a peritubular network, the efferent arterioles will twist around the tubules in the outer cortex. In the inner third of the cortex and medulla, straight long branches also known as the vasa recta will replace the peritubular network [19-20].

Figure 2: Outlines anatomy of the kidney [22].

There are 1.3 million nephrons per kidney that make up its primary functional unit. The tubules and corpuscles are the two key components of the kidney. The glomeruli are found in the corpuscles. The regulation of the passage of various chemicals into and out of the blood is done by the tubules, small tubes traveling through the inner part of the kidney. They are composed of three parts: loop of Henle, convoluted tubule, and distal convoluted tubule [1,19-20].

 The outer renal tissue if found under the renal capsule and the cortex will be lighter in color. The proximal and distal convoluted tubules as well as the renal corpuscles are also found here. The cortex will reach into the inner renal tissue or medulla and will divide into renal pyramids. The loops of Henle of the renal tubes as well as the collecting ducts can be found in the renal pyramids [1-19-20].

Collecting through the minor calyx, the urine is formed inside the pyramids. Several minor calices combined together will end up forming the major calyx. The urine will move toward the renal pelvis through the major calices. The renal pelvis is a funnel-shaped structure that will be formed at the connection of all major calices [1-19-20].

Kidney Disease Staging

The disease progression helps classify kidney diseases: acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage kidney disease (ESKD) [23]. Presenting a serious clinical problem, AKI can be explained as an abrupt decline in kidney function. There is a slightly larger percentage of children (34%) compared to adults (22%) across the world who will be diagnosed with AKI during hospitalization. Intensive care unit patients have the potential to have mortality rates that exceed 50%. Environmental pollutants, ischemia, and nephrotoxic medications, which have the potential to lead to apoptosis, cell damage, inflammation, vascular dysfunction, and oxidative stress can cause damage to cells within the nephron [24]. Acute kidney injury can lead to the potential recovery and regeneration of tissue that is injured or to CKD. This is known as the AKI-to-CKD transition [25]. Several patients who were able to survive the acute phase of AKI will not recover the normal function of their kidneys. This can lead to the development of ESKD and CKD. There is a complicated correlation between CKD and AKI: CKD increases the risk of AKI and AKI has the potential to lead to CKD [26-27-40].

The impact of CKD on patients is substantial as it has a 10% rate of occurrence in adults all across the world, and a rise in the rate found with the population that are aging [28]. CKD is found to exist in higher rates in countries with low and middle income. Hypertension, infection, glomerulonephritis, and environmental exposures in countries that are still developing is likely attributed to CKD. The risk of CKD has also been linked to a variety of genetic factors. Common in people with African ancestry, the 2 APOL1 risk alleles and sickle cell trait has been seen to double the risk of CKD [16]. CKD can be classified into stages 1-5 according to the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-KDOQI). In stages 1 and 2 of CKD, the function of the kidney will experience mild changes in the glomerular filtration rate (GFR) and proteinuria. As the kidney will start to climb into stages 3 and 4, there will be about 50% of a normal kidney function. Stage 5 experiences a requirement for maintenance dialysis as the GFR is less than 15 mL/min/ 1.73 m2 [29-30].

Stages of Chronic Kidney Disease and Recommended Action Plan

Table 2: Outlines Stages of Chronic Kidney Disease and Recommended Action Plan [33].

When CKD reaches an advanced stage and the kidney begins to lose its ability to filter (GFR < 15 mL/min/1.73 m²), ESKD is known to occur. There is a high mortality risk in patients with ESKD as it accounts for 53% of deaths [31]. Kidney transplants or renal replacement therapies such as hemodialysis and peritoneal dialysis are required during this stage to increase the patient’s life expectancy [23]. An injured kidney that is classified as AKI will usually not have the ability to repair itself fully in the same capacity as other regenerative organs such as the liver or heart [8-9].

A kidney may undergo extracellular matrix deposition and fibroblast activation. This can potentially lead to nephron loss, a cycle of fibrogenesis, and induced development of CKD [8-9-32]. There is a 13 times increased risk of developing CKD sometime in their life in patients with AKI who can survive the acute phase [8-9]. The development of CKD can be caused by a kidney injury that has led to metabolic disorder and mitochondrial injury, epigenetic alterations, profibrogenic signal production, and capillary rarefaction [8-9].

Diagnostic Procedures

An important part of the management of patients with kidney disease is the assessment of renal function. Renal function tests can help assist with the identification of the presence of renal diseases, determining the progression of these diseases, and monitoring the overall response treatment [20]. Several clinical laboratory tests have been utilized in the investigation and evaluation of kidney function. The primary tests conducted for evaluating renal function are checking proteinuria and measuring the glomerular filtration rate (GFR) [20].

Equations for Estimating Glomerular Filtration Rate

Table 3: Outlines equations for estimating glomerular filtration rate [33].

The glomerular filtration rate (GFR) has been demonstrated to be the most effective indicator for looking at glomerular function. The GFR is the rate in millimeters per minute that which different substances found in the plasma can be filtered through the glomerulus. The clearance of substances from the blood is indicated through this.

The most commonly used endogenous marker for the assessment of glomerular function is creatine. An indicator of GFR is the calculated clearance of creatine involving a 24-hour urine collection. The creatine clearance can be calculated utilizing the formula: C= (U x V)/P. C is the clearance, V is the urinary flow rate, P is the plasma concentration, and U is the urinary concentration [16-34].

Screening can be vital to the early detection of kidney disease as the majority of patients with CKD are asymptomatic. Serum creatine measurement is used as a kidney profile test created by the National Kidney Foundation to help estimate GFR in urine (albumin to creatinine ratio) ACR. People with a history of diabetes/hypertension or those older than 60 years are recommended to partake in a risk-based approach to screening. Screening should also be considered in those with other risk factors such as obesity, kidney stones, autoimmune disease, reduced kidney mass, recurrent urinary tract infections, exposure to certain medications such as lithium or non-steroid anti-inflammatory drugs (NSAID), or weight loss [16,34]. Certain clinicians should inquire about more symptoms that might lead to the belief of a systemic cause (hearing loss, neuropathy, rash, hemoptysis) or obstruction in the urinary pathway (frequent/incomplete bladder emptying, urinary hesitancy, rash). Other risk factors such as prior exposure to nephrotoxins (herbal remedies, phosphate-based bowel preparations), presence of comorbidities (autoimmune disease, hypertension, chronic infections), genetic risk factors (sickle cell trait), family history of chronic kidney disease, and history of nephrolithiasis/ recurrent urinary tract infections [16].

Additional clues regarding the underlying reason for CKD can be provided through a detailed physical examination. It should also include the patient’s urine volume status. Depletion of volume could cause poor oral intake, diarrhea, and vomiting. Volume overload could be due to liver failure, nephrotic syndrome, and decompensated heart failure. A patient with enlarged kidneys or flank pain should be evaluated for polycystic kidney disease, obstructive uropathy, nephrolithiasis, and pyelonephritis. Following the examination of the skin one may find palpable purpura (vasculitis, cryobulinemia, Henoch-Schonlein purpura), extensive sclerosis (scleroderma), rash (systemic lupus erythematosus, acute interstitial nephritis), and telangiectasias (Fabry disease, scleroderma). Patients that are experiencing an advanced form of CKD may exhibit skin excoriations, asterixis, muscle wasting, altered mental status, and pericardial rub [16].

Kidney Disease Diagnosis and Staging

Figure 3: Outlines kidney disease diagnosis and staging [16].

Medical and Surgical Interventions for Kidney Disease

To discuss the possibility of kidney replacement therapy and transplant evaluation, patients with advanced kidney disease should be referred to a specialist known as a nephrologist. Clinical symptoms and GFR level are two criteria that should be considered in the decision for kidney replacement therapy. Pericarditis, pleuritis due to severe uremia, and encephalopathy are urgent symptoms that should be considered. Nausea, vomiting, pericardial rub or effusion, metallic taste, altered mental status, or volume overload including pulmonary or lower extremity edema are all symptoms indicating the initiation of dialysis [16].

The diffusion or movement of solute particles across a semipermeable membrane describes the process of dialysis. Creatinine, urea, and other metabolic waste products will diffuse down the concentration gradient from the circulation into the dialysate (sodium chloride (NaCl), sodium bicarbonate (NaHCO3), deionized water, acid concentrate). The particles size will determine the rate of diffusion across the membrane during the diffusion of dialysate. Larger solute particles will typically diffuse more slowly across the membrane. The arteriovenous shunt is formed as arteries carrying oxygenated blood from the heart are connected to a vein. This strengthens the vein by forming certain muscles around the vein [35-36].

Dialysis Process

Figure 4: Outlines kidney dialysis process [36].

Hypotension, muscle cramps, cardiovascular disease (CVD) complications, and anaphylactic reactions are all side effects of dialysis. The main reason for the diseased kidney is ongoing inflammation. It typically does not respond to medications. Chronic inflammation leads to the accumulation of metabolic wastes in the body as well as affects the normal functioning of the kidneys. The kidney may slowly regain its function as the process of dialysis can help remove certain toxins from the body. The effectiveness of the dialysis treatment can depend on the patient’s health condition and age [35-36].

Kidney Transplant

The optimal therapy for ESKD is considered to be kidney transplantation. The best outcomes have been demonstrated when the living donor kidney transplantations are performed before or shortly following dialysis. Home hemodialysis, peritoneal dialysis, in-center hemodialysis, or conservative care without dialysis are all alternative therapies for ESKD. Poor candidates for peritoneal dialysis include those with unstable housing options or patients with multiple surgeries in the abdominal area with resultant peritoneal scarring present. Immediately following the transplant, patient mortality risk is higher. However, it becomes much lower within a few months than patients on dialysis. The survivability of the patient varies depending on the patient's health and the quality of the transplant organ. Younger patients with diabetes have demonstrated the greatest transplant benefit through extending their years of life. After dialysis, patients who are 20-39 years of age live an average of 8 years vs 25 years after a transplant [16-37-40].

Patients with renal failure have seen survival and long-term improvements following a kidney transplant. The infectious disease risk and patient cardiovascular risk should be assessed before undergoing a renal transplant procedure. In order to maintain a successful kidney transplant, potential immune suppression treatment is required. Following the transplant, patients should be monitored for immunosuppressant side effects, recurrent disease, and opportunistic infections [37].

Kidney Transplant

Figure 5: Shows the anatomy of a transplanted kidney [37].

The surgeon connects the transplanted kidney to the blood vessel and balder during the kidney transplant procedure. Blood will flow through an artery and into the transplanted kidney and a vein will take the filtered blood out. The urine will then flow through the transplanted ureter and into the bladder [37].

There have been some recent improvements when it comes to renal transplants. Infection awareness and prevention increase as well as stronger immunotherapy have all been utilized. Long-term toxicity can be reduced due to the increased emphasis on induction therapy and decrease of maintenance therapy. The decrease in complications can be related to the screening for donor-specific antibodies at the time of the transplant [37-41].

Smoking is one example of multiple contraindications to a solitary kidney transplant. Quitting smoking is required by most transplant centers at least 1 year prior to the transplant. There is a doubled rate of malignancy as well as a doubled risk of a cardiac event for long-standing smokers. Active human immunodeficiency virus infection, other active infections, acute malignancy, poor financial or psychosocial situation threatening adequate care following a transplant, chronic illness with short life expectancy, acute substance abuse, lung or liver disease, active coronary artery disease, advanced age, morbid obesity, habitual noncompliance, active peptic ulcer or inflammatory bowel disease, etc. are all additional contraindications for kidney transplant [37-38-41].

There has been an increase in the number of patient candidates on the kidney waiting list over the past few decades. However, the number of transplants that are performed each year has remained consistent. Only 19,000 of the 100,000 of the patients on the list were able to receive a transplant. Three to five years is the typical wait time for a kidney transplant and rose to 6 years for decreased-donor kidney organs [37-41].

The glomerular filtration rate (GFR) is estimated to be 20mL/min/1.73 m2 or less for a patient to be placed on the waiting list for a deceased-donor kidney transplant, although referral to the list can be made earlier. Typically, 10% of transplant recipients had no dialysis before transplant. This is known as a preemptive transplant. These are the patients who will typically show the most promising outcomes and are usually living donor organ recipients. When the GFR is less than 15 mL/min/1.73m is when most patients will receive a kidney transplant [37].

Discussion

Stem cells have been tested in preclinical models and clinical trials as well as shown potential in the treatment of different diseases. The isolation of human mesenchymal stem cells (MSC) has collected from various tissues: adipose tissue, umbilical cord, and bone marrow [7, 42-47]. MSCs have the qualities of multipotent cells with self-renewal, proliferative potential, and multi-lineage differentiation [48-54]. Forming a network throughout the microvasculature, MSCs are originally from renal pericytes. The regulation of immunity, promotion of damaged tissue recovery, enhancement of potential expansion, and differentiation of host cells can all be regulated through the different cytokines and growth factors that MSCs can secrete [46,48-50,55]. MSCs also possess several intrinsic properties: anti-inflammation, immunomodulation, and anti-oxidation. These are beneficial for the limitation of acute injury and for reversing chronic depression [8,9,56,57]. The modulation of renal blood flow, endothelial survivability, immunological responses, and capillary permeability are affected by MSCs [52-54,58,59]. The recovery of sites that were damaged as well as the treatment for a variety of pathological conditions (renal injury and renal failure) are helped through the use of cells from MSCs. These characteristics support MSCs as the most promising therapeutic strategy for regenerative kidney therapy [7,51,55,60].

There are existing therapies for kidney disease that will target a variety of pathogenic mechanisms. However, these therapies do not support a cure, but they rather slow down the progression of the disease. MSCs have the benefit of presenting many regenerative effects for the protection of the kidney organ while pharmacologic interventions will only target a single aspect of AKI-CKD transition process [8-9,61,62].

In preclinical studies, MSCs have demonstrated beneficial effects. In addition, extracellular vesicles (EVs) that were released by MSCs therapy became an option in various preclinical models of kidney disease due to the immune modulatory, regenerative, and anti-inflammatory properties that were potent-cell free [23,58-59,61,63,64].

Stem Cell Trials in Animals for Kidney Disease

[65] evaluated the possible role of exosome derived from MSC for their effect on diabetic nephropathy (DN) and the enhancement of autophagy activity. There were five different groups of rats that were used in this study: DN treated with exosomes; DN treated with 3-methyladenine and chloroquine (autophagy inhibitors); DN treated with 3-methlyaldeine (3-MA), chloroquine and exosome groups; DN; and the control. The renal morphology, function, and fibrosis were all evaluated. Histological restoration of renal tissues and exosomes improved renal function were seen in this study. This research demonstrated that the attenuation of DN in a rat model of streptozotocin-induced diabetes mellitus could be linked to autophagy induction by exosomes [65].

[66] investigated a canine model of acute kidney injury (AKI) to examine the improvement of renal function as well as the utilization of mesenchymal stem cells originating from the blood of the umbilical cord. The canine AKI model was developed in 14 male beagle dogs through the utilization of an IV injection of cisplatin and gentamycin. After AKI induction, the cUCB-MSCs were administered into the renal corticomedullary junction. There was then an analysis of the clinical signs, survival time, histological parameters, and blood. In this study decreased blood creatinine and nitrogen level was shown in the group treated with AKI plus cUCB-MSCS demonstrated improved histological manifestations and an extended life-span. Overall, this study suggests that an alternative therapeutic agent for canine AKI could be cUCB-MSCs [66].

[67] tested whether extracellular vesicles can attenuate renal inflammation through the utilization of the porcine model of metabolic syndrome and renal artery stenosis as well as if their cargo of anti-inflammatory cytokine interleukin (IL) could mediate this capacity. Following 16 weeks of untreated renal artery stenosis or treated four weeks earlier with one single intrarenal delivery of extracellular vesicle gathered from tissue derived from adipose autologous MSCs, ten pigs were studied. Five more pigs displaying renal artery stenosis and metabolic syndrome each received extracellular vesicles containing pre-silenced IL10 (IL10 knock-down). They decided to study glomerular filtration rate, oxygenation, and single-kidney renal blood flow in vivo and looked at renal injury pathways ex vivo. Improvement in medullary oxygenation and fibrosis as well as the attenuation of renal inflammation were due to the extracellular vesicle delivery. Compared to metabolic syndrome, glomerular filtration rate and renal blood flow fell in metabolic syndrome and renal artery stenosis. In pigs that were treated with IL10- depleted extracellular vesicles, these renoprotective effects were blunted. This study revealed that patients with renal artery stenosis and metabolic syndrome might find extracellular vesicle-based regenerative strategies to be useful [67-69].

[70] 2017 studied 2K1C rats for the therapeutic possibility of renal subcapsular mesenchymal stem cells (MSC). The functional and morphological changes of the kidney were analyzed: renin angiotensin-converting enzyme (ACE), expression of angiotensin-II type 1 (AT1R) and type 2 (AT2R) receptors, Na+ & K+ ATPase expression and activity. There were 3 effects observed. MSC therapy reduced systolic blood pressure, ACE, renin, and AT1R; it had and upregulation in podocin and AT2R; it helped restore renal Na+ & K+ ATPase expression and activity. In addition, it also decreased proteinuria, restored plasma levels in proteins, enhanced renal morphology, and decreased fibrosis and TGF-β expression in the clipped kidney. This study showed that MSC provides a good candidate for cell therapy as well as an efficient route is transplantation into a renal subcapsule [70].

[71] 2016 investigated whether at an early age diabetic nephropathy in vivo and in vitro could be prevented by exosomes retrieved from urine stem cells. There was an isolation of exosomes coming from a conditioned medium of urine-derived stem cells (USCs-Exo). In order to look at the protective effect of USCs-Exo on podocyte apoptosis, podocytes treated with USCs-Exo in vitro were cultured in high-glucose medium. This study revealed that USCs-Exo can possibly prevent podocyte apoptosis and encourage vascular regeneration and cell survival preventing injury to the kidneys from diabetes [71].

[72] When associated with injured kidneys, researched the effect of pro-angiogenesis as well as tested the factors relating to angiogenesis that would further shine light on the most likely mechanisms. There was the isolation of EVs from the medium of the human MSCs derived from the human umbilical cord. These huMSCs were later inserted intravenously into rats after unilateral kidney ischemia. The results showed that the EVs could decrease cell apoptosis while enhancing the proliferation 24 hours following one’s kidney injury. The renal function was enhanced and there was a mitigation of the histological lesion. This study demonstrated that human MSC-EVs had the ability to protect one against reperfusion/ischemic injury through pro-angiogenesis effects in HIF-1 1α independent manner. Both ribonucleic acid (RNA) and the delivery of pro-angiogenesis-related vascular endothelial growth factor (VEGF) were involved in this process [72-73].

[74] looked at the administration effects of mesenchymal stem cells (MSCs) on diabetic nephropathy (DN) progression in severe diabetes mellitus relating to animal mode. Following diabetes induction, one group received a single dose of MSCs (DM + MSCs) while the other group received the vehicle (DM). Compared to the untreated mice, there was substantial improvement in the DM + MSCs mice group in functional parameters of the kidney. There was a decrease in renal apoptotic index and the restoration of anti-inflammatory cytokine levels/progenerative factors and an increased renal proliferation index in the DM + MSC mice. This study that was conducted showed that the administration of MSC will trigger a proregenerative microenvironment within the DN kidney. This will allow for the preservation of kidney function even if the diabetes was not corrected [74-75].

[76] investigated the repair mechanisms and biological effects of MVs. Microvesicles were gathered from MSC supernatants. Treated with a transforming growth factor known as TGF-β1, the proximal tubular epithelial cells (HK-2) were obtained in vitro. In vitro the mice were separated into four different groups. The first group was the unilateral obstruction (UUO). The second and third groups were the UUO+ MSC and UUO+MV group. The final group was the control. MVs and MSCs were then injected after surgery. The results demonstrated MV was able to help reverse the morphological changes induced by the transforming growth factor- β1 (TGF-β1). It also reduced the secretion of HK2 cells and α-SMA as well as firmed the expression of E-cadherin. This study showed that Micro-vesicles (MVs) will protect the kidneys both in vitro as well as in vivo. It also demonstrated that MVs are superior to MSCs in certain areas suggesting that MVs can be a possible treatment in the cure of kidney-related diseases [76].

[77] utilized rats to research mesenchymal stem cells (MSC) and its overall effects on diabetic nephropathy as well as the potential paracrine signals that could mediate their overall action. The rats were divided into three different groups. The first two groups were the DN rats and DN rats receiving MSCs. The final group consisted of the controls. A dose of MSCs was given to 106 cells by intravenous injection. The results demonstrated that MSC therapy could substantially enhance 24-hour urinary albumin, increase angiogenic growth factor VEGF, creatinine and serum urea concentrations, and anti-apoptotic protein bc12 while reducing pro-inflammatory TNF- α, pro-apoptotic Bax, and fibro genic growth factor TGF β. The histopathology examination demonstrated the degeneration in renal tubules as well as patchy areas of minimal necrosis [77]. This study demonstrated MSCs have the ability to enhance the function of the kidney as well as the regeneration of its tissues in DN rats. This is most probable through their paracrine action via varying growth factors: TNFα,VEGF, & TGFβ. This can also be accomplished through antiapoptotic action via Bax and bc12 genes [77].

[73] examined the effect of MVs administered following ischemic AKI on kidney injury in both the chronic and acute stages. Following the isolation of MVs from a conditioned medium inserted intravenously in rats, the ischemia of the left kidney was examined for 60 minutes. The results demonstrated that there was a mitigation of renal cell apoptosis as well as enhanced proliferation following the administration of hWJMSC-MVs in acute kidney injury (AKI) rats. Following this administration inflammation was also seen to be alleviated in the first 48 hours. This study revealed that immediately following ischemic AKI, the administration of MVs could ameliorate injury to the kidney in both the chronic and acute stages. Through the suppression of CX3CL1, the anti-inflammatory property of MVs could be the mechanism. This finding establishes a significant framework for future treatment and research [72-73].

Kidney Stem Cells in Animals Research

 

Research Team	Results
Ebrahim et al (2018)	Exosomes improved renal function and demonstrated histological restoration of renal tissues. Autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus
Lee et al (2017)	AKI plus cUCB-MSCs had decreased blood urea nitrogen and creatinine levels, showed extended life-span and improved histological manifestations. MSCs were detected around the tubules of these kidneys at the histological level. cUCB-MSCs could be an alternative therapeutic agent for canine AKI
Eirinet al (2017)	Extracellular vesicle delivery attenuated renal inflammation and improved medullary oxygenation and fibrosis. Extracellular vesicle-based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis
Lira et al (2017)	MSC improved renal morphology, reduced fibrosis and TGF-β expression in the clipped kidney, decreased proteinuria and restored protein plasma levels. Transplantation into a renal subcapsule is an efficient route and MSC is a good candidate for cell therapy
Jiang et al (2016)	In vitro, podocytes cultured in high-glucose medium were treated with USCs-Exo to test the protective effect of USCs-Exo on podocytic apoptosis. USCs-Exo may have the potential to prevent kidney injury from diabetes by inhibiting podocyte apoptosis and promoting vascular regeneration and cell survival
Zou et al (2016)	EVs could reduce cell apoptosis and enhances proliferation 24 hours after kidney injury. Renal function was improved and the histological lesion was mitigated. Human MSC-EVs could protect against ischemic/reperfusion injury induced kidney injury through pro-angiogenesis effects in HIF-1α independent manner, and both the delivery of pro-angiogenesis related VEGF and RNAs were involved in this process
Ezqueret al (2015)	DM + MSC mice presented increased renal proliferation index, decreased renal apoptotic index and the restoration of proregenerative factors, and anti-inflammatory cytokines levels. MSC administration triggers a proregenerative microenvironment in DN kidney, which allows the preservation of the renal function even if diabetes was uncorrected
He et al (2015)	In vitro, MV reversed transforming growth factor-β1 (TGF-β1)-induced morphological changes, and firmed the expression of E-cadherin and reduced the secretion of α-SMA in HK2 cells. Micro-vesicles (MVs) protect kidneys both in vivo and vitro, and MVs are superior to MSCs in some respects and further suggested that MVs can be a potential therapy in treatment of kidney diseases
Abdel Aziz et al (2014)	MSC therapy significantly improved 24 hour urinary albumin, serum urea and creatinine concentrations, increased angiogenic growth factor VEGF, and anti-apoptotic protein bcl2 while decreased the pro-inflammatory TNF-α, fibrogenic growth factor TGF β, and pro-apoptotic protein Bax. MSCs are capable of improving the kidney function and regenerating kidney tissues in DN rats most probably through their paracrine action via different growth factors such as VEGF, TGFβ & TNFα and antiapoptotic action via bcl2 &Bax genes
Zou et al (2014)	After administration of hWJMSC-MVs in acute kidney injury (AKI) rats, renal cell apoptosis was mitigated and proliferation was enhanced, inflammation was alleviated in the first 48 hours. Single administration of MVs immediately after ischemic AKI could ameliorate renal injury in both the acute and chronic stage, and the anti-inflammatory property of MVs through suppression of CX3CL1 may be a potential mechanism.