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Chronic kidney disease(CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis.
Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a falling glomerular filtration rate and as a result a decreased capability of the kidneys to excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis (testing of a urine sample) shows that the kidney is allowing the loss of protein or red blood cells into the urine.
To fully investigate the underlying cause of kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing a small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney malfunction.
Recent professional guidelines classify the severity of chronic kidney disease in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is also called established chronic kidney disease and is synonymous with the now outdated terms end-stage renal disease (ESRD), chronic kidney failure (CKF) or chronic renal failure (CRF).
There was no specific treatment unequivocally shown to slow the worsening of chronic kidney disease, until recently. If there is an underlying cause to CKD, such as vasculitis, this may be treated directly with treatments aimed to slow the damage. In more advanced stages, treatments may be required for anemia and bone disease. Severe CKD requires one of the forms of renal replacement therapy; this may be a form of dialysis, but ideally constitutes a kidney transplant or potentially stem cell therapy.
CKD is initially without specific symptoms and can only be detected as an increase in serum creatinine or protein in the urine.
As the kidney function decreases:
- Blood pressure is increased due to fluid overload and production of vasoactive hormones created by the kidney via the RAS (renin-angiotensin system), increasing one’s risk of developing hypertension and/or suffering from congestive heart failure.
- Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Urea is excreted by sweating and crystallizes on skin (“uremic frost”).
- Fluid volume overload – symptoms may range from mild edema to life-threatening pulmonary edema.
- Hyperphosphatemia – due to reduced phosphate excretion, associated with hypocalcemia (due to 1,25 dihydroxyvitamin D deficiency). The 1,25 dihydroxyvitamin D deficiency is due to stimulation of fibroblast growth factor-23
- Later this progresses to secondary hyperparathyroidism, renal osteodystrophy and vascular calcification that further impairs cardiac function.
People with chronic kidney disease suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population.
Patients afflicted with chronic kidney disease and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.
The most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis. Together, these cause approximately 75% of all adult cases. Certain geographic areas have a high incidence of HIV nephropathy. Historically, kidney disease has been classified according to the part of the renal anatomy that is involved:
- Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathyhemolytic-uremic syndrome and vasculitis
- Glomerular, comprising a diverse group and subclassified into
- Primary Glomerular disease such as focal segmental glomerulosclerosis and IgA nephritis
- Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis
- Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis and reflux nephropathy
- Obstructive such as with bilateral kidney stones and diseases of the prostate
- On rare cases, pin worms infecting the kidney can also cause nephropathy.
Stem Cell Therapy:
There are a number of kidney disorders that may be very amenable to treatment using an advanced form of stem cell therapy. We recently did some groundbreaking work, with a patient who has end stage SFGS, he is not a candidate for a transplant. Within 24 hours of treatment there are both objective and subjective positive changes in blood chemistries and urinary function. There will be further updates along with copies of his blood work available in the next weeks, documenting our clinical observations.
The literature presents an interesting picture of potentials particularly for those with an autoimmune component to their disorder or for inflammatory components, such as vasculitis. There remains a number of theories regarding the signaling and cellular responses to the typical disease insults. Below is a brief overview with other information in the reference section of this page.
Stem cells appear to have the following functions:
1, Repairing the damaged renal cells via cell growth factor stimulation;
2. Regenerating new renal cells and potentially replace the necrotic renal cells thereby repairing and positively influencing kidney function;
3. Enhancing your immune system function, resulting in an increased resistance to external environmental insults
4. Reestablishing better hormonal output of the kidneys, with an increase in RBC’s, and better electrolyte balance.
Many theories exist on kidney repair. However, a recent study by HSCI Affiliated Faculty member Benjamin Humphreys, MD, PhD, HSCI Executive Committee member Andrew McMahon, PhD, and Joseph Bonventre, MD, PhD, head of the HSCI Kidney Disease Program, and their team went a long way toward elucidating how the tubules repair themselves.
By tagging the mature epithelial cells that form the tubule walls with a fluorescent protein, the team was able to demonstrate that the replacement cells after injury are coming from the epithelium itself rather than from circulating stem cells that enter the kidney or from local tissue-specific stem cells in the tissue between the tubules.
Cells that derive from the bone marrow and enter the kidney after injury might not be sitting on the sidelines, however. Other evidence suggests that they may be offering some assistance in stimulating the epithelial cells to multiply.
Autologous Stem-Cell Transplant Phases : After a review of your medical records and discussions with medical staff, a protocol is designed especially for you. Specifics of your condition are addressed along with any special needs.
It may be similar to the one illustrated below:
Day 1: At the clinic you will be examined by our physicians. Information including any risks and expectations concerning your treatment, plus answers to any questions you may have will be addressed. A blood draw, to determine cell counts and other chemistries will be collected and cell expansion medication may be administered. Then you will return to your hotel for a restful day or a good nights sleep.
Day 2: At the clinic our physician/s will review the laboratory results, determine if the cell count is within range, and discuss the response to the stimulation. They may or may not provide additional cell expansion medications and may add adjunctive treatments. The levels of your response will determine if you would return to the hotel, with little restriction on your activities, or possibly go forward with harvesting and processing your cells.
Day 3: If the cell count and viability is appropriate for harvest either a bone marrow or adipose collection will be utilized. We typically use local anesthetics for adults and general anesthesia for youngsters. The entire procedure normally takes less than 30 minutes. Although some pain is felt when the needle is inserted, most patients do not find the bone marrow or adipose collection procedure particularly painful. We recently placed a number of videos on our website interviewing our patient’s who discuss the procedure and their lack of discomfort. After the collection you may return to the hotel, with some restrictions. The bone marrow or adipose collected is processed in our contract State-Of-Art laboratory by trained staff, under the supervision of the lab physician. As an alternative to the above, cord blood may be used based on the patient’s individual medical condition and options.
Day 4: At the clinic or at the hospital you will be treated by IV infusion and/or a lumbar puncture, which injects the stem cells into the cerebrospinal fluid. This route transports the cells into the spinal canal and the brain directly influencing the nervous systems, thereby eliminating the brain/blood barrier. If a lumbar puncture is performed, the patient will be required to restrict their activities and potentially spend the day in the hospital or at their hotel.
Day 5: At the clinic or hospital the patient will receive a post-treatment examination and evaluation prior to their release. Additional therapy and treatments may also be utilized to maximize the placement and activities of the procedure.
Day 6: Optionally there may be the use of additional ancillary therapies to enhance the procedure.
What makes our treatment different ? Our approach includes stimulation, prior to collection, processing and expansion of the cell along with the use of growth factors, together with an integrated medical approach. This maximizes the growth and implantation potentials yielding optimized potentials of making changes in your disease.
Our staff physicians are all board certified, in their field with years of experience. Your team includes both primary and ancillary care professionals devoted to maximizing your benefits from the procedures.
We enroll you in an open registry to track your changes independently, for up to 20 years. As our patient we also keep you abreast of the newest developments in stem cell research.
This is an ongoing relationship to maintain and enhance your health. Our promise is to provide you with travel and lodging support, access to bilingual staff members throughout the entire process and most importantly the best medical care possible.
Are therapeutic stem cells justified in bilateral multicystic kidney disease? A review of literature with insights into the embryology.
Sharma S, Gupta DK, Kumar L, Dinda AK, Bagga A, Mohanty S. Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India.
Abstract Aim was to describe the challenges faced in the management of bilateral multicystic kidney disease (MCKD). A case of antenatally detected bilateral polycystic disease was referred at 28 weeks of gestation. The patient was advised to continue pregnancy till term and be in regular follow-up. Postnatally, the male baby passed urine in normal stream and was diagnosed as bilateral multicystic kidney disease on ultrasonography. He developed symptoms of renal failure. The baby was operated with right pyeloplasty and left pyelostomy, as the left ureter was atretic. The histopathology was consistent with bilateral multicystic kidney disease. Postoperatively, the baby was stable with intermittent episodes of metabolic acidosis that were managed medically and with peritoneal dialysis. Autologous stem cells were injected at the age of 1 year into the aorta at the level of the renal arteries clamping the aorta below. Repeat biopsy at time of stem cell injection showed 5/10 glomeruli showing global sclerosis on right side and 5/15 glomeruli showing global sclerosis on left side. The only improvement seen was in decreased doses of medicines to keep the child metabolically stable. The baby kept struggling but succumbed at the age of 17 months and 15 days. Post mortem bilateral renal biopsies demonstrated presence of primitive renal tubules and blastemal cells that were not demonstrated earlier. Survival for few months in bilateral multicystic kidney disease is thus possible with adequate treatment, the novel use of stem cells in these cases may prove beneficial in future though it is too early to comment further Comment: Note the date of 2003….and keep reading below.
Published in Volume 112, Issue 12 (December 15, 2003) J Clin Invest. 2003;112(12):1776–1784. doi:10.1172/JCI20530. Copyright © 2003, American Society for Clinical Investigation 125 citations have been reported for this article.
February 2009 – Volume 14 – Issue 1 – p 72-78 doi: 10.1097/MOT.0b013e328320d2f5
Stem cell transplantation: Edited by Kenneth Brayman and Raghu Mirmira
The use of stem cells in kidney disease
Chhabra, Preeti; Brayman, Kenneth LAbstract
Purpose of review: Acute and chronic kidney disease is a leading cause of morbidity and mortality worldwide with overall mortality rates between 50 and 80%. An acute shortage of compatible organs coupled with limited adaptability of current dialysis techniques has created a sense of urgency to investigate new alternatives, and the purpose of this review is to provide a concise overview of current stem cell-based strategies in renal repair following acute kidney injury. Recent findings: Bone marrow-derived mesenchymal stem cells hold therapeutic potential in repairing tubular injury, ameliorating renal function deficits, and prolonging survival in experimental models of acute kidney injury. These renoprotective effects are mediated mainly by paracrine mechanisms that act on surviving tubular cells by stimulating dedifferentiation, proliferation, migration, and eventually redifferentiation into mature epithelial cells as well as by stimulating expansion and differentiation of resident stem/progenitor cells. Mesenchymal stem cells are capable of immunosuppression as well as inducing protection against peritubular capillary changes following acute injury making them ideal for allogeneic cell therapy. Summary: Autologous transplantation of bone marrow-derived mesenchymal stem cells as well as adult renal stem/progenitor cells that can be easily harvested and expanded may be the solution to limited donor organ availability and chronic immunosuppressive therapy.
Stem cell options for kidney disease
C Hopkins, J Li, F Rae, MH Little Article first published online: 20 OCT 2008 DOI: 10.1002/path.2477
Chronic kidney disease (CKD) is increasing at the rate of 6–8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. It also examines the remaining challenges and asks the question of whether there is one solution for all forms of renal disease.
Copyright © 2008 Pathological Society of Great Britain and Ireland.
Renal repair recapitulating development: yes or no?
Although true regeneration is not thought to occur, the kidney does maintain a significant capacity to undergo repair after acute damage. For example, even after prolonged unilateral ureteric obstruction (UUO), involving considerable inflammation, tubular necrosis and apoptosis, the renal cortex can substantially remodel 9 (see Figure 1). Such postnatal repair has been proposed to involve the re-expression of genes previously critical to the development of the normal kidney. Indeed, the re-expression of developmental genes in response to renal damage has been reported in a number of human diseases and animal models, including ischaemia–reperfusion injury and diabetes. However, the re-expression of Six2 in response to tubular injury, which might signal the reactivation of the embryonic nephron induction pathway, is not observed . This raises the question of whether renal repair does involve recapitulation of development at all. Indeed, the inappropriate activity of developmental pathways can be causative of renal disease. Niranjan et al report that over-activity of the Notch pathway in podocytes can lead to apoptosis and resultant proteinuria, while genetic or biochemical suppression of this pathway, which is known to be critical for normal proximal tubular development , prevents glomerulosclerosis and proteinuria.
Masson’s trichrome staining of sections from the contralateral kidney, unilateral ureteral obstruction (UUO) and reversal of UUO (R-UUO) kidneys; collagen, blue; muscle and cytoplasm, red; nuclei, blue to black. (A) Normal histology in the contralateral unobstructed kidney. (B) Ablation of the outer renal medulla as well as thinning of the renal cortex after 7 days of obstruction. (C) Replacement of the renal medulla region 1 week after reversal. (D) Restoration of the renal parenchyma 2 weeks after reversal If the CM population does become exhausted when nephrogenesis ceases in the mammalian kidney, then do endogenous renal stem cells generate new renal cells using a different mechanism of differentiation? As will be discussed, Vogetesder et al argue that repair involves the recruitment of fully differentiated cells into the cell cycle and does not involve a source of stem cells. Alternatively, postnatal renal progenitors may not be the same as embryonic renal progenitors, and may or may not re-use similar gene expression pathways to reach the same endpoint. If no such stem cell population exists in the kidney itself, repair may require stem cells from some other location (embryonic stem cells, mesenchymal stem cells, bone marrow-derived stem cells, reprogrammed cells). In the following sections, we discuss these possibilities further.
Understanding repair options via an understanding of renal development
Exogenous cell sources for renal repair
Bone marrow-derived cellsThe bone marrow (BM) contains at least two populations of stem cells, haematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs), which provide stromal support for HSCs. It also contains many other haematopoietic cell types involved in immune surveillance, inflammatory responses and pathogen removal. It has long been proposed that bone marrow, a known source of stem cells, might be able to contribute to the repair of other organs . Early reports noted the presence of bone marrow-derived cells in the kidney, using sex-mismatching of bone marrow donor and recipient . Additionally, it was noted by Imasawa et al that mice with a spontaneous presentation of IgA nephropathy showed disease amelioration after bone marrow transplantation from an unaffected donor. The capacity of bone marrow to home to the kidney was clearly shown to be linked to damage of renal tissue, with no evidence that this occurs to any detectable level in the absence of renal damage . While it was suggested that there was evidence of cells integrating into a variety of renal cellular compartments, the degree of engraftment and the distinction between functional transdifferentiation and fusion was slower to be examined. Lin et al and Duffield et al finally concluded that the contribution of bone marrow-derived cells to the kidney was relatively low (0.06–8%). Futhermore, Held et al have shown that a 20–50% cell fusion could be induced between bone marrow-derived cells and renal tubular cells under conditions of chronic renal damage. BM transplantation can improve renal function. Whole BM transplantation has been reported to be able to improve renal function and reduce histological damage in the collagen4α3 defective model of Alport syndrome . These authors reported that BM-derived cells transdifferentiated into podocytes and mesangial cells, accompanied by re-expression of the defective collagen chains and improved renal histology and function. Furthermore, in a rat model of glomerulonephritis, BM mononuclear cells injected into the renal artery enhanced renal regeneration and this was attributed to both incorporation of the BM-derived cell into the endothelial lining and the production of angiogenic factors. A number of studies also suggest that mobilization of stem cells from the patient’s own BM using G-CSF, m-CSF and stem cell-factor (SCF) can improve renal regeneration. ( Note: this is one of our therapeutic inputs) The majority of these studies show that it is the delivery of growth factors that lead to improvement of renal function after ischaemic or toxic injury. The authors suggest that this improvement is due to increased cell proliferation and decreased apoptosis as well as a decrease in infiltrating neutrophils. Not all results have been positive. While Li et al showed the integration of unfractionated male-derived BM cells into the proximal tubules, thick ascending limbs and distal tubules and collecting ducts of female recipients, no functional improvement was seen. They proposed that whole BM may only be useful for glomerular injury. BM may also act as a source of α-SMA-positive interstitial myofibroblasts which have been shown to participate in the production of extracellular matrix in renal fibrosis . Finally, a recent study looked at the effects of SCF and G-CSF in a model of chronic UUO found that increased mobilization did not influence renal damage, fibrosis or inflammatory cell influx . However, the consensus is that BM can afford a reparative humoral effect in certain cases of renal damage. So what cells from within the BM provide a reparative humoral effect? There is a large body of work now on the role of regulatory immune cells in autoimmune disease, malignancy and transplantation tolerance. Renal inflammation can result from a myriad of insults and is characterized by the presence of infiltrating inflammatory leukocytes within the glomerulus or tubulointerstitium. This is particularly relevant for glomerulonephritis, which is thought of as immune-mediated. Recent data have demonstrated a protective role of regulatory T lymphocytes, M2 macrophages, mast cells and dendritic cells in dampening glomerular and tubulointerstitial inflammation in various models of kidney injury . Neutrophils and T cells play important roles in mediating acute kidney injury (AKI) following ischaemia–reperfusion, but the role of macrophages is less well known. Macrophage depletion has been shown to attenuate renal damage in animal models of ischaemic acute renal failure and UUO . The beneficial effects observed after macrophage depletion include decreases in inflammation, reduced apoptosis of renal tubular epithelial cells and a reduced severity of tubular necrosis. In contrast, inhibition of nuclear factor-κB, a regulator of macrophage functional differentiation, reprogrammes macrophages so that they become profoundly anti-inflammatory in settings where they would normally be classically activated and attenuate glomerular inflammation in vivo. Furthermore, ex vivo manipulation of macrophages using specific cytokines confirmed that classically activated, M1 macrophages worsen chronic inflammatory adriamycin nephropathy, whereas alternatively activated M2 macrophages reduce histological disruption and functional injury . Of note, in the heart Camargo et al have shown, using Cre recombination, that the BM-derived cells apparently homing and contributing to cardiac tissue are the myelomonocytic cells. Aside from the monocytic fraction contributed from the bloodstream, Rae et al demonstrated that resident monocytes exist within the developing kidney from prior to the commencement of nephrogenesis and that macrophage colony-stimulating factor (CSF-1) was able to increase this population and concurrently increase the rate of renal development (see Figure 2). This resident macrophage population may also play a role in organ homeostasis and response to injury. Figure 2. Macrophage distribution in kidney explant. (A) Brightfield image of metanephric explant culture of 11.5 dpc kidney cultured for 5 days on Poretics 13 mm polycarbonate inserts (Osmonics Inc.) with a membrane pore size of 1.0 µm at 37 °C in 300 µl DMEM/Ham’s F12 medium (Invitrogen) supplemented with 50 µg/ml transferrin and 20 mm glutamine. (B) Csf1r–ECFP mice were used and the blue fluorescence shows the CFP-positive macrophages present in the culture
Mesenchymal stromal cells (MSCs) The other obvious and popular candidate for the BM cell responsible for ameliorating renal damage is the MSC. Many studies have been performed to examine whether the reparative capacity of the kidney is enhanced by MSCs . Although there has been disagreement on the mechanism, MSCs have been shown to protect against both chemical (glycerol and cisplatin) and ischaemia reperfusion (IR) damage and to accelerate the repair process in rodents (see Table 1). Although initial studies suggested the potential of a high contribution of MSCs to tubular regeneration or nephron formation in a specific whole embryo culture system , the current opinion is that only a small percentage of repaired tubular cells are BM-derived MSCs and that cell fusion may explain some results interpreted as direct replacement of epithelial cells . Indeed, a recent study shows that following co-administraion of eGFP bone marrow cells with MSCs only the marrow cells engrafted into the tubules after acute renal damage . Therefore, it has been proposed that MSCs must provide paracrine and/or endocrine factors that explain their positive effects on kidney injury . Evidence for this paracrine/endocrine process was provided by Bi et al, using a model of cisplatin-induced renal damage. This study showed that the apparent reparative function of MSCs could be achieved via an intraperitoneal injection of the MSC-conditioned medium alone. MSCs have been shown to secrete a number of growth factors . Imberti et al suggest that this humoral function results from IGF1, whereas Bi et al attributed it to a combination of HGF, IGF1 and EGF. A recent paper by Togel et alsuggests that VEGF is the critical factor in the renoprotection afforded by MSCs. It has long been known that IGF1 and HGF can play a reparative role in the kidney following acute injury . BMP7 has also been shown to protect against fibrosis . There are endogenous sources of all of these growth factors in the kidney. So why doesn’t renal repair occur spontaneously? The answer may be due to the inflammatory environment after injury. Togel et al suggested that MSCs exert their renal protection through inhibition of proinflammatory cytokines. In fact, the reparative role of MSCs may be multifactorial and include the provision of cytokines to limit apoptosis, enhance proliferation and dampen the inflammatory response.
One of the important advantages of using MSCs in renal repair is their ability to home to the injured kidney. Herrera et al found that increased expression of hyaluronic acid in the injured kidney was responsible for MSC migration, as these cells express the receptor for HA, CD44 . MSCs isolated from mice lacking CD44 were unable to localize to the injured kidneys and did not provide protection from injury. MSCs have been shown to be immune-privileged, in that they avoid allogenic rejection in humans by failing to induce a proliferative T cell response. Coupled with their immunomodulatory advantage, although potentially less effective in vivo than in vitro, this immune-privileged status raises the possibility of an ‘off-the-shelf’ cellular product appropriate to any recipient. can also be obtained from autologous sources, including renal patients , making them ideal vehicles for the delivery of others genes known to be beneficial in kidney repair. In a recent paper, Hagiwara et al delivered MSCs over-expressing human tissue kallikrein, a protein they had previously shown protected the kidney from damage. These modified MSCs exhibited advanced protection over MSCs alone. This gene delivery approach has also been used successfully to improve survival of MSCs when injected into infarcted hearts, where transduction with haem oxygenase (HO-1) leads to more efficient healing . While animal studies involving models of IR or chemically-induced AKI have shown consistent improvement after MSC delivery, their effectiveness in chronic damage models is less clear . Some studies have shown improvement after MSC delivery in a model of glomerulonephropathy and no evidence of a long-term fibrotic response 3 months after delivery of MSCs to animals with severe AKI . Other studies have suggested that the beneficial effects linked to MSC injection can be marred by a long-term partial maldifferentiation of intraglomerular MSCs into adipocytes accompanied by glomerular sclerosis in a model of chronic glomerulonephritis . Other studies have shown that in models of glomerular injury MSCs have no beneficial effect. Ninichuk et al, using the murine genetic model of Alport syndrome, delivered isolated MSCs and concluded that while MSCs did reduce interstitial fibrosis, they failed to prevent progression. Despite these concerns and variable results, the first Phase 1 trial of MSCs in AKI is scheduled to begin shortly and will involve cardiac patients at high risk of developing AKI. The diversity of pathology present in CKD may also mean that no one cellular therapy will be applicable to all conditions. Whether a cellular therapy could work for polycystic kidney disease (PKD) is questionable, as the cells introduced would need a proliferative advantage over the existing mutant cells. Neither is PKD a condition in which an endogenous stem cell population will assist, as these cells would carry the same mutation as the existing renal tissue. Perhaps the only way a disease such as PKD can be treated is by the de novo generation of a replacement organ or biodevice utilizing stem cells within a bioengineering approach. What is clear is that forward progress will continue to rely on a sound understanding of normal renal development, renal turnover, response to injury and pathology.
Comment: As this conclusion suggests we are not at the point of pin point accuracy with our therapy, however there are positive changes taking place. Our current clinical experience suggests that a mixed population of stem cells, with growth factors, does effectuate a positive response. We are basing this finding on both subjective and objective measures and look forward to an expanded patient population with equal or greater responses.
Why dialysis may be a one way street
American Journal of Kidney Diseases Volume 44, Issue 5, November 2004, Pages 840-849
Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis Kay Herbrig MD, Frank Pistrosch MD, Uta Oelschlaegel MD, Gunnar Wichmann MD, Andrea Wagner, Sarah Foerster, Susanne Richter, Peter Gross MD, Jens Passauer MD Original investigations
Nephrology, Department of Internal Medicine III, Technical University of Dresden, Dresden, Germany. Hematology, Department of Internal Medicine I, Technical University of Dresden, Dresden, Germany.
Received 7 January 2004; Accepted 12 July 2004. Available online 20 October 2004.
Background: Endothelial progenitor cells (EPCs), derived from bone marrow, contribute to vessel repair and neovascularization. Because uremia is a state of endothelial dysfunction associated with high cardiovascular mortality, as well as a state of reduced hematopoiesis, we studied the number and function of EPCs in patients on long-term hemodialysis (HD) therapy.
Methods: We counted the number of EPCs in 20 HD patients and 16 healthy volunteers. To assess EPC function, we measured migratory activity, adhesion to matrix proteins, and adhesion to endothelial cells. Furthermore, we measured blood levels of vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor, factors known to influence EPC kinetics. Circulating precursor cells (CD34+, CD34+/CD133+, CD34+/KDR+ cells) were counted by means of flow cytometric analysis.
Results: The number of EPCs in HD patients was significantly elevated compared with controls (459.7 ± 92 versus 364.8 ± 77.4 EPC/high-power field). However, migratory activity was markedly decreased in HD patients (47.5 ± 27.7 versus 84.7 ± 3.2 EPC/high-power field). EPCs of HD patients showed impaired adhesion to extracellular matrix and endothelial cells. VEGF blood levels in HD patients were 2-fold greater compared with controls. The number of circulating CD34+ and CD34+/133+ cells was reduced in HD patients. There were no differences in total numbers of CD34+/KDR+ cells.
Conclusion: This study shows an elevated number, but pronounced functional impairment, of EPCs in patients on long-term HD therapy. The latter may result in limited endothelial repair, which, in turn, may contribute to endothelial dysfunction in this particular group of patients.
Decline in renal functioning is associated with longitudinal decline in global cognitive functioning, abstract reasoning and verbal memory
- Accepted September 14, 2012.
Background Decreased estimated glomerular filtration rate (eGFR) and higher serum creatinine (sCR) levels have been associated with longitudinal decline in global mental status measures. Longitudinal data describing change in multiple domains of cognitive functioning are needed in order to determine which specific abilities are most affected in individuals with impaired renal function.
Methods We conducted a 5-year longitudinal study with 590 community-living individuals (mean age 62.1 years, 60.2% female, 93.2% white, 11.4% with diabetes mellitus, mean eGFR 78.4 mL/min/1.73 m²) free from dementia, acute stroke and end-stage renal disease. To measure longitudinal change-over-time, cognitive performance measures were regressed on eGFR adjusting for baseline eGFR and cognitive performance, comorbidity and vascular risk factors. Outcome measures were scores from 17 separate tests of cognitive abilities that were used to index 5 theoretically relevant domains: verbal episodic memory, visual-spatial organization and memory, scanning and tracking, working memory and similarities (abstract reasoning).
Results Declines in eGFR values were associated with cognitive declines, when adjusted for eGFR and cognitive function scores at baseline. Change in renal functioning over time was related to change observed in global cognitive ability [b = 0.21SD decline per unit ln(eGFR), 95% CI: 0.04–0.38,P = .018], verbal episodic memory [b = 0.28 SD decline per unit ln(eGFR), 95% CI: 0.02–0.54, P = 0.038] and abstract reasoning [b = 0.36 SD decline per unit ln(eGFR), 95% CI: 0.04–0.67, P = 0.025]. Decline in cognitive functioning in association with declining renal functioning was observed despite statistical adjustment for demographic variables and CVD risk factors and the exclusion of persons with dementia or a history of acute stroke.
Conclusions Early detection of mild to moderate kidney disease is an important public health concern with regard to cognitive decline.
Peritoneal Dialysis and Epithelial-to-Mesenchymal Transition of Mesothelial Cells
María Yáñez-Mó, Ph.D., Enrique Lara-Pezzi, Ph.D., Rafael Selgas, Ph.D., M.D., Marta Ramírez-Huesca, B.S., Carmen Domínguez-Jiménez, Ph.D., José A. Jiménez-Heffernan, M.D., Abelardo Aguilera, M.D., José A. Sánchez-Tomero, Ph.D., M.D., M. Auxiliadora Bajo, Ph.D., M.D., Vincente Álvarez, Ph.D., M.D., M. Angeles Castro, Ph.D., Gloria del Peso, Ph.D., M.D., Antonio Cirujeda, M.D., Carlos Gamallo, Ph.D., M.D., Francisco Sánchez-Madrid, Ph.D., and Manuel López-Cabrera, Ph.D.
N Engl J Med 2003; 348:403-413
January 30, 2003 DOI: 10.1056/NEJMoa020809
During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated.
Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens.
Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of α2integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells.
Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients.
Comment: Basically the use of dialysis products injure the kidney and result in substantial multi-organ insults with multiple secondary disorders.
I have grade IV osteoarthritis (severe loss of cartilage leading to bone rubbing on bone) of my right hip. I have seen 3 orthopedic doctors, all of which have said I need to have surgery for hip replacement. Additional options for treatment were limited. As a nurse, and at my age, having seen both good and bad outcomes following hip replacement, and also knowing hip replacement is not without risk, I chose to seek other options of treatment for myself.Read more
Andrew is thriving. We have seen and continue to see major improvements. He has matured beyond anything I can explain (I have had to rapidly adjust my parenting as I now have a much older & more sophisticated child), his comprehension (perhaps better to say his ability to express and act upon his comprehension) is now age appropriate.Read more
Hello, When we came from Cancun the first week we noticed an improvement in eye contact. It improved about 70%. His attention improved about 50% and he was more in our world when it comes to understand what it happening around him. He lost some of his attention for the last two weeks but it is still better than it was prior stem cells and even Janik BIs therapist say it is easier to work with Janik in ABA because his eye contact is better and his focus is also better."Read more
Well Owen is happy again, which is the biggest improvement. He is laughing and giggling again. His eye contact has improved and he is playing with toys again. All of these things had stopped. I`m so happy that he is happy. ( His Mom)Read more
Interview with Dr. Ernesto Gutierrez from the World Stem Cells Clinic by Healthcare Elsewhere show with John Cote on iTunes!:October 13th, 2014
October 11, 2014 Dr. Gutierrez is the medical director and president of the World Stem Cells Clinic in Cancun, Mexico. The clinic was established i
Educating Medical Professionals &Patients on Stem Cell Advancements with Dr. Ernesto Gutierrez:October 9th, 2014
Dr. Ernesto Gutierrez, M.D. was interviewed recently for the Healthcare Elsewhere show with John Cote on iTunes! They discussed several things from pa
Doctors Seminars – Stem Cell and Regenerative Medicine Procedures for Orthopedics, Musculoskeletal and Sports Medicine Doctors Training Seminar December 4-5-6th, 2014:October 5th, 2014
Stem Cell and Regenerative Medicine Procedures for Orthopedics,