StemCell&CKD: SVF (Adipose Tissue Derived MSC) Based Therapy for CKD.
Study Details
Study Description
Brief Summary
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To assess the safety of stromal vascular fraction (Autologous Non Expanded ADSC) injection to patients with Chronic Kidney Disease.
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To assess the efficacy of stromal vascular fraction (Autologous Non Expanded ADSC) injection to patients with Chronic Kidney Disease.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 1/Phase 2 |
Detailed Description
Introduction:
Chronic kidney disease (CKD) is a disease of alarmingly increasing prevalence (8 - 16%) associated with mortality [1]. CKD can progress towards end-stage renal disease (ESRD), requiring renal replacement therapy. ESRD currently accounts for 6.3% of the Medicare spending in the United States, and is projected to increase by 85% by 2015 [2]. In a study conducted among rural population in Bangladesh overall CKD prevalence was found about 19% [3]. Furthermore, ESRD has a major impact on quality of life and life expectancy [4]. Therefore, it is very important to develop therapeutic interventions to prevent, alleviate, or decelerate progression of renal failure.
Diabetes mellitus and hypertension represent major causes of CKD and initiation of dialysis [5]. In addition, glomerular diseases, malnutrition, infectious diseases, and acute kidney injury may lead to ESRD, contributing to the increased global burden of death [6]. Current treatment modalities often fail to target the major underlying contributors for progression of renal disease [7]. Management of CKD at present mostly aims at control of the predisposing factors and supplementation of kidneys homeostatic functions but not at the treatment of the diseased kidney itself. Again due to lack of adequate facilities or financial constraints people of a developing country like Bangladesh are unable to continue long term or lifelong dialysis. Chronic glomerular and tubule-interstitial fibrosis is a common pathway to ESRD, often associated with apoptosis, oxidative damage, fibrosis and microvascular rarefaction. Unfortunately, the regenerative potential of kidney is limited under chronic conditions and inefficient to prevent progressive glomerulosclerosis and tubule-interstitial fibrosis [8]. Treatment strategies that boost cellular regeneration might therefore offer good alternatives for patients with CKD.
Stromal vascular fraction (SVF):
SVF of adipose tissue is a rich source of pre-adipocytes, mesenchymal stem cells (MSC), endothelial progenitor cell, T cells, B cells, mast cells as well as adipose tissue macrophages [9,10]. SVF is a component of the lipo-aspirate obtained from liposuction of subcutaneous tissue. Lipo-aspirate contains a large population of stem cells called adipose derived stem cells (ADSCs), which share a number of similarities with bone marrow stem cells, including the capacity for multilineage differentiation .
Stem Cells:
A stem cell is a generic term referring to any unspecialized cell that is capable of long-term self-renewal through cell division but that can be induced to differentiate into a specialized, functional cell. Stem cells are generally two types, embryonic stem cells and adult stem cells. Adult stem cells can be obtained from many differentiated tissues including bone marrow, bone, fat, and muscle etc. Obtaining adult stem cells also does not raise any ethical concerns [11]. For most studies, the adult stem cell in question is actually a mesenchymal stem cell (MSC) or mesenchymal stromal cell. They are multipotent but not pluripotent, which means they can differentiate into some, or "multiple," but not all tissue types [11]. Stem cells that are harvested from the patient with the intention of administering them back to the same patient are termed autologous MSCs. MSC can also be isolated from the bone marrow (bmMSC), peripheral blood, connective tissue, skeletal muscle, dental pulp (dpMSC), umbilical cord wall (ucMSC), umbilical cord blood (cbMSC), amniotic fluid (afMSC) and all have been used in experimental settings to treat various types of renal diseases. An important feature of MSCs is their capacity to induce proliferation of renal glomerular and tubular cells, increasing cellular survival [12].
Advantages of adipose tissue-derived stem cells (ADSCs):
ADSCs are somatic stem cell population contained in fat tissue and have been shown to possess stem cell properties such as trans-differentiation and self-renewal [13]. Similar to other types of MSCs, ADSCs express multiple CD marker antigens (CD73+CD90+CD105+ CD34+/- CD11b- CD104b- CD19- CD31- CD45- SMA-) [14,15]. Additionally, utilizing ADSCs is advantageous in that large quantities of stem cells are easily isolated using minimally invasive surgical procedures [16].
ADSCs are vascular precursor cells. Many studies have shown that SVF contains progenitor cells that are able to differentiate into endothelial cells and participate in blood vessel formation [17]. Additionally, a recent study demonstrated that SVF cells expressing both pericyte and mesenchymal markers reside in a peri-endothelial location and stabilize endothelial networks [17] Another study showed that ADSCs transplanted into an ischemic renal cortex preferentially migrate toward micro vessels where they differentiate into vascular smooth muscle cells [18]. Some trials on kidney transplant recipients as well as the one on FSGS and 2 on CKD patients include in their protocol the utilization of adMSC. Adipose tissue is an important source of MSC, with a frequency 100 to 1000 times higher than bmMSC. They also seem to possess a higher potential for angiogenesis or vasculogenesis [19].
Kidney disease and mesenchymal stem cells:
A number of different types of cells from the bone marrow have been tested in animals and in clinical studies for potential use in kidney disease. Amongst all the cells under investigation, MSCs have shown the most promising results to date as they help kidney cells to grow, inhibit cell death and encouraging the kidney's own stem cells to repair kidney damage [20].
Few clinical trials have tested safety and efficacy of MSCs for renal disease. Reinders and colleagues studied safety and feasibility in six kidney allograft recipients who received two intravenous infusions of expanded autologous bone marrow-derived MSCs [21]. Importantly, delivery of autologous MSCs was not associated with adverse events, nor did it compromise graft survival. Several clinical trials are currently underway to evaluate the therapeutic potential of autologous and allogeneic MSCs for treatment of renal diseases [22] Administration of both bmMSC and adMSC has demonstrated significant reno-protective effects including reduction of intrarenal inflammatory infiltrate, decreased fibrosis, and glomerulosclerosis [12] MSCs possess unique immunomodulatory properties that ameliorate inflammation and immune responses, constituting a promising tool to facilitate renal repair. In recent years, experimental studies have uncovered the potential of MSCs to improve renal function in several models of CKD, and several clinical studies have indicated their safety and efficacy in CKD [22].
ADSCs could be incorporated into damaged tissues or organs which could give rise to new functional components and also exert potent anti-inflammatory, anti-fibrotic, or immunomodulation effects through paracrine or autocrine routes (via vascular endothelial growth factor, granulocyte/macrophage colony stimulating factor, stromal-derived factor-1alpha and hepatocyte growth factor) [23,24]. Interestingly, it is proposed that even apoptotic or dying ADSCs exhibit distinctive immunosuppressive properties [25]. ADSCs have been shown to possess stronger anti-inflammatory and immuno-modulating functions than bone marrow derived MSCs [26].
Villanueva et al. explored the effect of ADSCs on CKD by a single intravenous infusion of ADSCs on a nephrectomy induced CKD model of rats [27]. ADSC treatment was associated with reduced plasma creatinine, higher levels of epitheliogenic and angiogenic proteins, and improved renal function. Work by Hyun et al [28] illustrated the beneficial effects of ADSCs on improving renal function on a IgAN mouse model. Zhang et al. [30] found that repeated systemic administration of ADSCs attenuated proteinuria, glomerulus hypertrophy, and tubular interstitial injury in a DN rat model [29].
Currently, several Clinical trials have been uploaded in the NIH database, all aim to test mainly the safety of using MSC and their efficacy in treating CKD. Two of them propose the use of autologous bmMSC and two adMSC. A study conducted in Tehran, Islamic Republic of Iran, which was designed to provide confirmation of Mesenchymal stem cell therapy in CKD. There 18 months safety and efficacy of autologous MSC as a therapy for CKD total of 10 patients were conducted with I/V injection of high dose of 2x106/kg of autologous MSC. Assessments were performed at 1,3,6,12 and 18 months after cell injections [30].
Another study conducted in Birmingham, Alabama, Rochester, Minnesota, Jackson, Mississippi, USA where stem cell product called "Mesenchymal stem cell" grown from person's own fat tissue infused back in to the patient's own kidney and primary outcome measured after 3 months where renal tissue oxygenation increased and decrease in kidney inflammation was seen as secondary outcome [31].
Route of delivery:
Various routes for delivery of ADSCs, ADSC-induced cells, or ADSCs combined with compound materials have been developed for the treatment of different diseases or damaged tissue. These routes can be classified into two categories: systemic delivery through blood vessels (intravenous injection or intra-arterial injection) or local delivery directly into injured tissues or organs [32] The route of MSC delivery may influence the cells' capacity to home and engraft the damaged tissue, and thereby their efficacy for renal repair. Commonly used experimental methods to deliver MSCs include systemic intravenous, intra-arterial, or intra-parenchymal delivery. In nonhuman primates the cells distribute broadly into the kidneys, skin, lung, thymus, and liver with estimated levels of engraftment ranging from 0.1 to 2.7% [33].
The route of MSC delivery, intravenous, intra-arterial, or intra-parenchymal, may affect their efficiency for kidney repair. When labeled MSC intravenously infused into baboons were observed for 9-21 months, estimated levels of engraftment in the kidney, lung, liver, thymus, and skin ranged from 0.1-2.7% [34] Indeed, the intravenous route lags in delivery efficiency, because MSC may initially be trapped in the lungs. Intra-arterial infusion of MSC was the most effective route to achieve immunomodulation in rat kidney transplantation, possibly by avoiding lodging in the pulmonary circulation, allowing MSC to home to the injured kidney [35].
An important feature of MSCs is their capacity to induce proliferation of renal glomerular and tubular cells, increasing cellular survival. By secreting proangiogenic and trophic factors, injected MSCs not only can enhance proliferation, but also can decrease apoptosis of tubular cells [36]. Several routes of administration (intra-parenchymal, sub-capsular, intravenous) have been explored and all seem to be effective. Multiple, repeated injections of MSCs appear to be even more effective than single injections [37,38].
Methodology:
A Prospective study from April 2019 onwards (Approximately Five years or till completion of sample requirements with minimum one year of follow up) will be conducted in Bangladesh LASER & Cell Surgery Institute & Hospital , Dhaka. 31 Patients of CKD who fulfill the selection criteria and admitted at the selected health care facility for treatment will be included in the study. SVF (stromal vascular fraction) will be collected from the abdominal subcutaneous adipose tissue. Subsequent processing ( Incubation, centrifugation, mixing, washing & neutralization ) will produce final viable & active SVF (ADSCs) cell which will be transfused intravenously. Considering the possibility of further damage of the already damaging or damaged kidney during angiography and placement of catheter into the renal artery, the investigators opt for intra-venous transfusion of the SVF. Before transfusion sample will be collected & cell counting will be done using automated fluorescent cell counter.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group A Participants having a harvested total "Adipose Derived Stem Cell (ADSC)" count (in 5 ml SVF solution) more than 1 x 10^6. Genetic: SVF containing Autologous Non Expanded ADSC. |
Biological: SVF Containg Autologous Non Expanded ADSC
5 ml of SVF containing Autologous Non Expanded ADSC will be injected intravenously and outcome will be observed over the period of 1(one) year.
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Outcome Measures
Primary Outcome Measures
- Incidence of minor adverse events (MAEs) , serious adverse events (SAEs) which may be immediate, early or late - for Phase I [Week 48]
Minor adverse events (MAEs): Pain from lipo-suction > 7 days (Early) Fever > 7 days (Early) Subcutaneous hematoma / abscess formation (Early) Allergic reaction (Immediate) Serious adverse events (SAEs) Anaphylaxis (Immediate) Pulmonary embolism or infarction (Immediate) Outset of any neoplastic change (Late) Outset of new Cardiovascular events (Late) Outset of new Cerebrovascular or neurological events (Late) Reactivation of treated tuberculosis (Late)
- Change from baseline to 24 week visit in glomerular filtration rate (GFR) and split renal function in all patients - for Phase II [Weeks 0, 24]
GFR with split renal function will be evaluated using DTPA Renogram.
- Change from baseline to 24 week visit in estimated glomerular filtration rate (eGFR) with serum creatinine level in patients with CKD 4 and below - for Phase II [Weeks 0, 2, 4, 12, 24]
eGFR will be calculated by Serum Creatinine level using MRDR formula during all visits.
- Change from baseline to 24 week visit in need for dialysis in patients with CKD 5 - for phase II [Weeks 0, 2, 4, 12, 24]
Need for dialysis is described as No dialysis needed - Score 0 Randomly (more than 6 days interval) - Score 1 At 6 (six) days interval / Once weekly - Score 2 At 5 (five) days interval - Score 3 At 4 (four) days interval - Score 4 At 3 (three) days interval / 2 times a week - Score 5 At 2 (two) days interval - Score 6 At 1 (one) day interval / every alternate day./ 3 times a week - Score 7
Secondary Outcome Measures
- Change from baseline to all post-treatment visits in body weight [Weeks 0, 2, 4, 12, 24, 36, 48]
Weight in Kg will be recorded for each patient during each follow up
- Change from baseline to all post-treatment visits in Blood-pressure [Weeks 0, 2, 4, 12, 24, 36, 48]
Blood pressure will be measured in each patient during each follow up
- Change from baseline to all post-treatment visits in S.creatinine [Weeks 0, 2, 4, 12, 24, 36, 48]
S. Creatinine level will be measured during each follow up. In case of patients having dialysis Pre and Post dialysis S. Creatinine levels will be measured at or near follow up dates.
- Change from baseline to all post-treatment visits in blood urea. [Weeks 0, 2, 4, 12, 24, 36, 48]
Blood Urea will be measured in all patients during each follow up.
- Change from baseline to all post-treatment visits in Hemoglobin level [Weeks 0, 2, 4, 12, 24, 36, 48]
Hemoglobin level will be measured in gm/dl and percentage Need for blood transfusion will be recorded Need for erythropoietin will be recorded
- Change from baseline to all post-treatment visits in urine microalbumin-to-creatinine ratio (UMCR) [Weeks 0, 2, 4, 12, 24, 36, 48]
Urinary Microalbumin and creatinine will be measured in each patient during each follow up
- Change from baseline to all post-treatment visits in hemoglobin A1c [Weeks 0, 2, 4, 12, 24, 36, 48]
HbA1C will be measured in each patient during each follow up
- Change from baseline to all post-treatment visits in random blood sugar (RBS) [Weeks 0, 2, 4, 12, 24, 36, 48]
RBS will be measured in each patient during each follow up
- Change from baseline to all post-treatment visits in Anti-Hypertensive medication if there is any. [Weeks 0, 2, 4, 12, 24, 36, 48]
All anti hypertensive medicines with their doses will be recorded including any changes in each patient during each follow up
- Change from baseline to all post-treatment visits in Hypoglycemic agent if there is any. [Weeks 0, 2, 4, 12, 24, 36, 48]
All hypoglycemic agents including their doses with any changes will be recorded for all diabetic patients during each follow up
- Change from baseline to post-treatment visits in urine total protein-creatinine ratio (UPCR) [Weeks 0, 24, 48]
Urinary total protein and Creatinine ratio will be done in each patient during each follow up
- Change from baseline to all post-treatment visits in urinary Protein-to-creatinine ratio PCR) [Weeks 0, 2, 4, 12, 24, 36, 48]
Urinary Protein and creatinine will be measured in each patient during each follow up
- Change from baseline to post-treatment level of serum Alpha Feto Protein [Weeks 0, 24, 48]
Serum Alpha Feto protein will be measured as a tumour marker for Hepato-cellular carcinoma and also Tumour of Testis and Ovary.
- Change from baseline to post-treatment level of serum CEA level [Weeks 0, 24, 48]
Serum CEA level will be measured as a tumour marker for Colo-rectal Carcinoma and also for Cancer of Stomach, pancreas, breast, lungs, thyroid and ovary.
- Change from baseline to post-treatment level of serum CA 19.9 level [Weeks 0, 24, 48]
Serum C.A 19.9 level will be measured as a tumour marker for Pancreatic Carcinoma
- Change from baseline to post-treatment level LDH level [Weeks 0, 24, 48]
Serum LDH level will be measured as tumour marker for Lymphoma
- Change from baseline to post-treatment level of Beta 2 Microglobulin level [Weeks 0, 24,48]
Serum Beta 2 Microglobulin level will be measured as a prognostic tool, as CKD patients invariably has a raised serum level.
- Change from baseline to post-treatment level of serum CA 125 level (in case of female patients) [Weeks 0, 24, 48]
Serum C.A 125 level will be measured as a tumour marker for Ovarian Cancer
- Change from baseline to post-treatment level of PSA level (in case of male patients) [Weeks 0, 24,48]
Serum PSA level will be measured as a tumour marker for Prostatic Cancer
Eligibility Criteria
Criteria
Inclusion Criteria:
- A patient is eligible for the study if all of the followings apply:
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Aged 18-80 years (inclusive)
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With chronic kidney disease (CKD)stage 3 to 5 (eGFR 60 to 0 mL/min/1.73m2 (inclusive)) Note : eGFR = estimated glomerular filtration rate
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Having provided informed written consent.
Exclusion Criteria:
Any patient meeting any of the exclusion criteria will be excluded from study participation.
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Known hypersensitivity to any component used in the study.
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With inadequate hematologic function with: absolute neutrophil count (ANC) <1,500/μL OR platelets < 100,000/μL OR Hemoglobin < 8 g/dL
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With impaired hepatic function with: serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase (AKP), prothrombin time above and normal reference and serum albumin below normal reference range.
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With hemoglobin A1c (HbA1c) > 8.0%
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With serious prior or ongoing medical conditions (e.g. concomitant illness such as cardiovascular (e.g. New York Heart Association grade III or IV), hepatic e.g. Child-Pugh Class C), psychiatric condition, alcoholism, drug abuse), medical history, physical findings, ECG findings, or laboratory abnormality that in the investigators' opinion could interfere with the results of the trial or adversely effect the safety of the patient
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Pregnant or lactating women or premenopausal with childbearing potential but not taking reliable contraceptive method(s) during the study period
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With known history of human immunodeficiency virus (HIV) infection or any type of hepatitis
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Judged to be not applicable to this study by investigator such as difficulty of follow-up observation
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With any other serious diseases/medical history considered by the investigator not in the condition to enter the trial
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Known or suspected abuse of alcohol or narcotics
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With known history of cancer within past 5 years
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With any autoimmune disease
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With congenital kidney disease
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With precancerous condition or with raised tumour markers like Alpha feto protein, Carcino embryonic antigen (CEA), C.A 19.9, C.A 125, Serum PSA above normal reference range.
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Parcipants having a harvested total "Adipose Derived Stem Cell (ADSC)" count (in 5 ml SVF solution) less than 1 x 10^6 will be excluded from the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Bangladesh Laser And Cell Surgery Institute And Hospital | Dhaka | Bangladesh | 1212 |
Sponsors and Collaborators
- Bangladesh Laser & Cell Surgery Institute & Hospital
Investigators
- Principal Investigator: Prof. Dr. Md. Firoj Khan, MBBS,FRCP,MD, Bangladesh Laser and Cell Surgery Institute and Hospital, Dhaka, Bangladesh.
- Study Chair: Dr. Mohammed Yakub Ali MBBS, MPhil, MSc, PhD, Bangladesh Laser and Cell Surgery Institute and Hospital, Dhaka, Bangladesh.
- Study Director: Dr. Jahangir Md. Sarwar, MBBS, FCPS, Bangladesh Laser and Cell Surgery Institute and Hospital, Dhaka, Bangladesh.
Study Documents (Full-Text)
More Information
Publications
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- BangladeshLCS001