The Effect of Stem Cells on Kidney Disease
McCrady Andrews1, Mohammed S Inayat2 and Vincent S. Gallicchio1*
1Department of Biological Sciences, College of Science, Clemson University, Clemson, South Carolina, USA, 29636
2Department of Internal Medicine, Division of Hospital Medicine, University of Cincinnati College of Medicine 231 Albert Sabin Way, ML 0535 Cincinnati, OH 45267
*Corresponding author: Vincent S. Gallicchio, Department of Biological Sciences, College of Science, Clemson University, Clemson, South Carolina, USA, 29636
Citation: Andrews MC, Inayat MS, Gallicchio VS. (2024) Stem Cells as Potential Regenerative Treatment for Retinal Degenerative Diseases and Diabetic Retinopathy. .J Stem Cell Res. 5(1):1-26.
Received: December 8, 2023 | Published: January 5, 2024
Copyright© 2024 genesis pub by Andrews MC, et al. CC BY NC-ND 4.0 DEED. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivatives 4.0 International License., This allows others distribute, remix, tweak, and build upon the work, even commercially, as long as they credit the authors for the original creation.
DOI: https://doi.org/10.52793/JSCR.2024.5(1)-54
Abstract
Kidney-related diseases including chronic kidney disease, acute kidney injuries, and end stage kidney disease are global public health matters with mortality and incidence rates increasing in recent years. Acute kidney injury is experienced by one-fifth of all adults and one-third of all children. Approximately 13.6% of Americans are diagnosed with chronic kidney disease. The increased morbidity and poor prognosis place a large burden on health systems in the public. It is estimated that more than $49 billion is spent every year on treatment for patients with chronic kidney disease. The kidneys play an important role in the elimination of toxic metabolites. When the kidney is weakened, toxic substances assemble in the bloodstream and result in biochemically toxic effects in many tissues and organs.
This issue causes additional complications including: anemia, cardiovascular disease, and neurological disorders. End stage kidney disease occurs when chronic kidney disease reaches an advanced stage and kidneys lose their ability to filter. Patients with end stage kidney disease have a high mortality risk accounting for 53% of deaths. At this stage, renal replacement therapies including dialysis or a kidney transplant are required to increase a patient’s life expectancy. 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.
This issue causes additional complications including: anemia, cardiovascular disease, and neurological disorders. End stage kidney disease occurs when chronic kidney disease reaches an advanced stage and kidneys lose their ability to filter. Patients with end stage kidney disease have a high mortality risk accounting for 53% of deaths. At this stage, renal replacement therapies including dialysis or a kidney transplant are required to increase a patient’s life expectancy. 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.
Keywords
Kidney disease; Stem cells; Treatment
Abbreviations
ACE: anglotensin converting enzyme; ACR: albumin to creatinine ratio; ADPICD: autosomal dominant polycystic kidney disease; AE: adverse event; AKI: acute kidney injury; AMR: antibody mediated rejection; ARVD: atherosclerotic renovascular disease; AT-MSC: adipose tissue mesenchymal stem cell; BMMS: bone marrow mesenchymal stromal cell; BUN: blood urea nitrogen; CAMR: chronic active antibody-mediated rejection; CBMSC: cord blood mesenchymal stem cell; CKD: chronic kidney disease; CVD: cardiovascular disease; DM: diabetesmellitus; DN: diabeticnephropathy; ELISA: enzyme linked immunoassay; ESRD: end-stage renal disease; EV: extracellular vesicles; GFR: glomerular filtration rate; HUMUSC: human umbilical mesenchymal stem cell; IL: interleukin; KTR: kidney transplant recipients; MDR-INS: multi-drug resistant idiopathic nephrotic syndrome; MSC: human mesenchymal stem cell; MV: microvesicles; NKF-KDOQI:National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative; NSAID: non steroid anti-inflammatory drug; RNA: ribonucleic acid; UCB-MSC: umbilical cord blood mesenchymal stem cell; USC-EXO: urine derived stem cells – exosomes; VEGF: vascular endothelial growth factor.
Introduction
The renal system consists of the urethra, ureters, and kidney. Filtration is the main function of the system as it filters approximately a couple hundred liters of fluid per day from renal blood flow which allows for metabolic waste products, toxins, and excess ion to be excreted while keeping needed substances in the blood. The kidney helps with the regulation of the plasma osmolarity by regulating the amount of electrolytes, water, and solutes in the blood. It ensures long-term balance of the acidity and basicity. It also produces erythropoietin which stimulates the production of red blood cells. Renin is also created for the regulation of blood pressure and converts vitamin D to its active form [1-4].
The kidneys can play a great role in the elimination of metabolites that are toxic, such as uremic toxins. When the purpose of kidney is weakened, these toxic substances assemble in the bloodstream and result in biochemically toxic effects in many tissues and organs, which causes additional complications, including, anemia, cardiovascular disease, and disorders relating to neurology [1-4].
Kidney disease prevalence and mortality rates continue to increase despite medical advances [8-9]. Extracellular matrix that has accumulated causes decreased renal function that leads to CKD. Approximately 13.6% of Americans are diagnosed with chronic kidney disease (CKD) [8-10].
The increased morbidity and poor prognosis place a large burden on health systems in the public, and it is estimated that north of forty-nine billion dollars are spent every year for treating patients with chronic kidney disease [8-9]. AKI has many possible causes, including renal ischemia from decreased blood pressure, inflammation, crush injury, and urinary tract infection or obstruction [11-12]. It is diagnosed based on increased blood urea nitrogen (BUN) or creatinine concentrations or deceased output of urine [11-12].
Common Etiologies of Acute Kidney Injury
|
Prerenal |
Cardiac Output |
acute myocardial infarction, valve rupture, acute pericarditis, acute myocarditis, drugs exacerbate heart failure (COX inhibitors, CCB, TZD, DPP-41), drugs cause direct heart injury (rheumatologic agents, anthracyclines, tisanes, targeted therapy, anti-Parkinson) |
|
|
True Hypovolemia |
renal loss (diuretics, osmotic diuresis), extrarenal loss (diarrhea, hemorrhage, burn, third spacing) |
|
|
Effective Volume |
sepsis, neurogenic shock, anaphylaxis |
|
|
Intrarenal Vasoconstrictor |
hypercalcemia, hepatorenal syndrome, drugs, (CNIs, NSAID, vasoconstrictors) |
|
Intrinsic |
Glomerular Injury |
nephrotic (MCD, MPGN, drugs (NSAID, gold, penicillamine)), 213607 nephritic (IRGN, lupus, nephritis, AAV, anti-GBM disease, IgAN, drugs (hydralazine)) |
|
|
Tubular Injury |
severe prerenal causes, toxins, endogenous: hemolysis, rhabdomyolysis, tumor lysis syndrome) or exogenous (aminoglycoside, contrast, CNIs, acyclovir, lithium, vancomycin)) |
|
|
Interstitial Injury |
allergy (drug: cephalosporin, penicillin, PPI, NSAID, herbs), infection (bacteria, fungus, virus, leptospirosis), autoimmune (Lupus, anti-TBM disease, AAV) |
|
|
Vascular Injury |
small caliber (TMA (malignant hypertension, HUS/TTP, DIC), scleroderma renal crisis) large caliber (renal infarction, renal vein thrombosis) |
|
Postrenal |
Urinary Tract |
benign prostatic hyperplasia, neurogenic bladder, intra-ureter (stones, tumors), extraureter (retroperitoneal fibrosis, intra-abdominal tumors) lesions |
|
|
Intrarenal |
Crystals (acyclovir, indinavir), stones, tumors, paraproteins (myeloma) |
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].