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Initial report on a phase I clinical trial: Prevention and treatment of post-operative Acute Kidney Injury with allogeneic Mesenchymal Stem Cells in patients who require on-pump cardiac surgery

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Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (www.clinicaltrials.gov; NCT00733876) in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion of surgery. The MSC are dosed in an escalating fashion, the initial five patients being infused via a femoral catheter that is placed into the suprarenal aorta with a defined low dose of MSC/kg body weight. This report summarizes the clinical course of the first five patients that have been treated according to this protocol. The renal function did not deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of administration. The next group of five study subjects will receive an intermediate dose of MSC/kg body weight, and if no safety concerns arise with this dose, the final five patients will be treated with a high dose of MSC/kg body weight. Preliminary efficacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a large number of historical controls (data base at www.STS.org).
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www.ctt-journal.com 2008;1(2) 31
Citation: Cellular Therapy and Transplantation, Vol. 1, No. 2, 24 December 2008, p. 31-35
doi: 10.3205/ctt-2008-en-000028.01
© The Authors. This article is provided under the following license: Creative Commons Attribution-Noncommercial-
No Derivative Works 3.0 United States, http://creativecommons.org/licenses/by-nc-nd/3.0/us/deed.en
Submitted: 11 November 2008, accepted: 15 December 2008, published: 24 December 2008
Summary
Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an
essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic
Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (www.clinicaltrials.gov; NCT00733876)
in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In
this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are
older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive
heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion
of surgery. The MSC are dosed in an escalating fashion, the initial ve patients being infused via a femoral catheter
that is placed into the suprarenal aorta with a dened low dose of MSC/kg body weight. This report summarizes the
clinical course of the rst ve patients that have been treated according to this protocol. The renal function did not
deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed
to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator
and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of
administration. The next group of ve study subjects will receive an intermediate dose of MSC/kg body weight, and if
no safety concerns arise with this dose, the nal ve patients will be treated with a high dose of MSC/kg body weight.
Preliminary efcacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of
cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration
of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a
large number of historical controls (data base at www.STS.org).
Keywords: acute kidney injury, mesenchymal stem cells, cardiopulmonary bypass pump, open heart surgery
Initial report on a phase I clinical trial: Prevention and treatment
of post-operative Acute Kidney Injury with allogeneic Mesenchymal
Stem Cells in patients who require on-pump cardiac surgery
Anna Gooch1, John Doty2, Jean Flores2, LeAnne Swenson2,
Florian E Toegel1,3, George R Reiss4, Claudia Lange5, Axel R Zander5,
Zhuma Hu1, Scott Poole1, Ping Zhang1 and Christof Westenfelder1,6
1Division of Nephrology, Department of Medicine, University of Utah Health Sciences Center and George E. Wahlen
VA HCS, Salt Lake City, Utah, USA; 2Division of Cardiovascular Surgery, Intermountain Medical Center, Murray,
Utah, USA; 3Jacobi Hospital, Albert Einstein College of Medicine afliated Medical Center, Bronx, New York,
USA; 4Division of Cardiovascular Surgery, Department of Surgery, University of Utah Health Sciences Center, and
Research Service, George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 5Bone Marrow Transplantation Center,
University of Hamburg, Germany; 6Department of Physiology, University of Utah Health Sciences Center,
Salt Lake City, Utah, USA
Correspondence: Christof Westenfelder, MD, Section of Nephrology (111 N), George E. Wahlen VA Health Sciences
Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA, E-mail: christof.westenfelder@hsc.utah.edu
Introduction
AKI remains a common, serious, and essentially treatment resistant
syndrome of rapidly declining renal function. The mortality rates
from AKI range from 15% in the general community to 80% for
patients with multi-organ failure or for those who develop it post-
operatively [1]. Even when renal function appears to fully recover
after AKI, it is now recognized that a signicant proportion of
patients develop end stage renal disease (ESRD) as a consequence
of undiagnosed, incompletely resolved AKI, characterized by
continued inammatory and brotic processes, and microvascular
rarefaction [2]. Consequently, those patients who seemingly
recover from AKI frequently go on to develop chronic kidney
disease (CKD), eventually requiring chronic hemodialysis or a
renal transplant [2,3].
32 www.ctt-journal.com 2008;1(2)
AKI is most frequently seen in patients with shock, sepsis, trauma,
and after major surgery. Patients undergoing cardiac surgery are
at particularly high risk with up to 30% of all cardiac surgery
patients developing AKI [4]. Many studies of cardiac patients
have consistently found certain factors to be associated with
increased risk of developing AKI following surgery. These risks
include but are not limited to: the type of procedure performed
(valve procedures are found to be of particularly high risk); patient
age greater than 65; female patient gender; pre-operative serum
creatinine value above 1.2 mg/dL, or underlying renal disease;
pre-operative capillary glucose above 140 mg/dL; congestive
heart failure; combined surgeries; on-pump vs. off pump surgery;
and cardiopulmonary bypass surgery time greater than two hours
[4-6]. The treatment resistant nature of AKI, combined with high
morbidity and mortality, as well as the now recognized frequent
progression of AKI to chronic kidney disease (CKD) underscores
the urgent need for advances in treatment modalities.
Recent studies from our laboratory have led to the development
of a novel approach to AKI treatment. This treatment administers
allogeneic or syngeneic MSC to prevent further damage and to
facilitate repair of acutely injured kidneys [7-9]. We observed
that immediate (post reow) or delayed (24 hrs post reow)
treatment of I/R AKI in rats with either autologous or allogeneic
MSC signicantly protects renal function, improves survival and
hastens renal repair, mediated by complex paracrine mechanisms
(anti-apoptotic, mitogenic, anti-inammatory, vasculoprotective,
angiogenic, anti-brotic) [7-10]. The striking hypoimmunogenic
and immune modulating properties of MSC make their therapeutic
use in allogeneic protocols possible and safe, as has been
demonstrated in numerous clinical (www.clinicaltrials.gov) and
pre-clinical trials [11,12].
Compared to vehicle treated animals with I/R AKI, early allogeneic
MSC therapy has important late benets (3 months post AKI)
such as maintained creatinine clearance, decreased interstitial
brosis, and down regulation of pro-brotic gene expression
levels in the kidney (TGFβ, PAI-1, TIMP-1). In addition, MSC
therapy for AKI results in well maintained microvascular density
in the kidney, while there is signicant micorvascular rarefaction
in vehicle treated animals [7]. In AKI, administered MSC do not
engraft and disappear from the kidney and other organs within
1 to 3 days.
The aforementioned preclinical studies indicate that effective and
specic treatment of AKI with MSC is an intervention that also
prevents progressive loss of renal function, a complication that
is increasingly recognized to result in ESRD in patients in whom
AKI was not diagnosed and treated early after a renal insult [13].
Accordingly, a Phase I Clinical Trial employing this treatment
is currently underway (www.clinicaltrials.gov; NCT00733876).
This safety trial involves administration of MSC to fteen patients
divided into three cohorts of ve patients each. Each cohort
receives a dened dose of MSC, low, intermediate or high. As of
this writing, dosing of the rst cohort is complete, and we report
here the outcomes of the rst cohort of ve patients.
Study Design and Methods
The FDA and the Institutional Review Board of Intermountain
Medical Center, Murray, Utah, the site where the trial is carried
out, approved the design and conduct of this Phase I Clinical Safety
Trial. In addition, prior to initiation of the trial an independent Data
Safety and Monitoring Board (DSMB) was appointed, consisting
of a general nephrologists, a nephrologist/medical epidemiologist,
and a cardiovascular surgeon. This DSMB reviewed the trial
protocol and approved the trial, and continues to monitor the
clinical data from all enrolled and treated subjects.
The study design is a Phase 1 Safety Trial. The primary objective
is to test whether infusion of allogeneic MSC into the suprarenal
aorta of patients who have undergone on-pump cardiac surgery
(Coronary Artery Bypass Grafting and/or valve surgery) and who
are at high risk for AKI following surgery is safe. This is assessed
by monitoring patients post operatively for the occurrence of
adverse events (AEs) and serious adverse events (SAEs) that
are related to the MSC therapy. Specically, detailed, monthly
examinations for six months regarding the development of AEs
or SAEs are carried out, and the study subjects are reassessed
annually for another three years.
The major endpoint to be measured is safety, as documented by the
comparative incidence of Adverse Events, Severe Adverse Events
and complications in patients receiving cell-based therapies vs.
historical controls for this patient population. AEs will be recorded
throughout the course of the study and classied as immediate,
postoperative, or delayed. Both common, expected and unusual
AEs are listed below.
Potential immediate or early AEs related to the infusion of MSC
via a femoral catheter into the suprarenal aorta include femoral
catheter related complications such as bleeding at the catheter
insertion site, infections, cholesterol plaque dislodgement and
secondary visceral or peripheral embolic events.
Immediate AEs and SAEs occurring at the time of operation
and immediately post-op (up to 24 hours post-op) include the
following: post-operative compromise of heart function due to an
unexpected ischemic event; post-operative marked impairment
of renal function due to an unexpected ischemic coronary or
other event (bleeding, hypotension, heart failure); perioperative
complications that will require additional time in order to address
these.
Later, post-operative complications (1-30 days post-op) include
delayed deterioration in renal function post-op, requiring or not
requiring dialysis; bleeding requiring >6 units of blood transfusion;
arrhythmia requiring cardioversion; mediastinitis; cerebral
vascular accident; prolonged ventilator support (>24 hours
postoperatively); reintubation; acute myocardial infarction; wound
infection or hematoma; pericarditis; pneumonia; pulmonary
embolism; bacteremia, sepsis, shock; multiorgan failure; death.
Delayed (more than 30 days after operation) AEs and SAEs
include: dialysis dependency due to irreversible loss of kidney
function; arrhythmia requiring cardioversion; mediastinitis;
cerebral vascular accident; acute myocardial infarction; wound
infection or hematoma; pneumonia; pulmonary embolism;
malignancy; ectopic differentiation of MSC into mesodermal
cells (bone, cartilage, fat); death.
The secondary objective of this trial is preliminary efcacy of
www.ctt-journal.com 2008;1(2) 33
MSC administration for the potential prevention and treatment of
post-operative AKI. Although a priori underpowered, preliminary
efcacy in this trial is nevertheless assessed by determining the
comparative frequency and severity of post-operative AKI using
standard and novel biomarkers of AKI (serum creatinine, BUN,
urine output, creatinine clearance, electrolyte, acid-base balance,
serum cystatin C, IL-18 and NGAL levels), need for temporary or
permanent dialysis, length of hospital stay, and associated 30 day
mortality. Study data are compared to published historical data
that are collected and available for analysis from the Society of
Thoracic Surgeons (www.STS.org). Historical data from this data
base are collected and analyzed from all participating centers in
the USA, and sub-analyzed for a reporting institution, such as
IMC, and comparable institutions.
The trial is currently conducted in one center, IMC in Murray,
Utah. Allogeneic MSC, derived from healthy, screened donors,
using FDA approved protocols, are culture expanded under cGMP
conditions at the University of Utah Cell Therapy Facility, Salt
Lake City, Utah. MSC are administered in a dose escalation
protocol to a total of 15 patients who have undergone elective,
on-pump cardiac surgery (CABG and/or valve replacement). Five
patients each receive low, medium or high dose of allogeneic
MSC via a femoral catheter into the suprarenal aorta immediately
after the patient comes off pump and is hemodynamically stable.
Low, Intermediate and High Doses of allogeneic MSC are dened
per FDA approved protocol, and are infused into the suprarenal
aorta in 50 ml of normal saline via a femoral catheter.
The enrollment and exclusion criteria for the trial are summarized
in Table 1.
Results
Five eligible patients were enrolled for treatment with the lowest
MSC dose. The clinical data on these study subjects are reported
with their consent and approval of the IRB. The patients’ pre-
operative AKI risk factors and surgical procedures are listed in
Table 2. All patients underwent on-pump cardiac surgery for
CABG and/or valve repair. All patients had at least one risk factor
for post-operative development of AKI.
As stated in the introduction, several cardiac surgery associated
factors have been identied as increasing the risk of post-
operative AKI. These include the type of surgical procedure being
performed, with multiple and/or valve procedures specically
being associated with higher risk; and the length of time on the
bypass pump, with a bypass pump time of greater than 2 hours
being associated with higher risk [4-6]. Table 3 lists the intra-
operative risk factors for each of the ve subjects.
Table 1.
General Enrollment
Criteria
• age 18 or older
• able to give informed consent
• subjects with documented ischemic
coronary heart and/or valvular heart disease
who are acceptable candidates for elective
CABG and/or cardiac valve surgery
• subjects with a patent femoral artery
without abdominal aortic aneurysm
Specic Enrollment
Criteria that indicate
subject is at high risk
for post operative AK
• underlying type I or type II diabetes mellitus
• CHF, COPD
• chronic kidney disease (CKD) stages 1 – 4
• age greater than 65
• combinations of the aforementioned risk
factors
Exclusion Criteria • presence of ongoing local or systemic
infection
• age younger than 18
• participation in another clinical trial
• pregnancy
• contraindication to general anesthesia
• prisoner
• advanced CKD (stages 5 or 6)
• history of malignancy
• occluded groin arteries
• administration of nephrotoxic medications
• inadequate pre-operative time to obtain
baseline renal function data because of
urgent/emergent surgery
Table 2.
Subject # Gender Age AKI Risk Factors and Diagnoses
001 M 59 Diabetes mellitus type I (DM-I),
coronary artery disease (CAD)
002 F 79 Hypertension (HT), aortic stenosis, age
003 M 74 Mitral Valve insufciency, chronic heart
failure (CHF), CAD, CKD-2, age
004 F 66 HT, DM-II, aortic insufciency, CHF,
aneurysm of the ascending aorta, age
005 F 70 CAD, HT, chronic obstructive
pulmonary disease (COPD), age
Table 3.
Subject # Surgical procedure Time on pump
001 CABG x 3 1 h 30 min
002 Aortic valve replacement with porcine
prosthesis 1 h 28 min
003 Mitral valve repair, coronary artery
bypass x 1 2 h 03 min
004
Aortic valve replacement with porcine
bioprosthesis; replacement of the
ascending aorta
2 h 35 min
005 CABG x 4 2 h 15 min
34 www.ctt-journal.com 2008;1(2)
Serum creatinine values for each of the ve subjects, as markers
of renal function, prior to and following surgery up to the present
are shown on Figure 1.
These data demonstrate that none of the rst ve study subjects
developed signicant AKI in the immediate postoperative time in
the hospital, nor did patients 001-004 after discharge. Subject 005’s
post-discharge data are pending. Signicantly, no patient required
dialysis immediately or later after surgery, and no expected or
therapy-specic AEs or SAEs were observed. However, subject
004 died suddenly at home at 26 days after surgery and MSC
administration. Both the principal investigator and the members
of the DSMB determined that the patient’s death was not related
to the study drug or its mode of administration. This SAE was
immediately reported to the FDA, IRB and DSMB. The remaining
four subjects are doing well as of the time of this report.
Discussion
This report summarizes the clinical course of the rst ve subjects
in this rst clinical safety trial world wide in which study subjects
received allogeneic MSC after completion of on-pump cardiac
surgery. It demonstrates that up to this point after surgery and
discharge from the hospital infusion of allogeneic MSC at this low
dose is safe, as no AEs or SAEs related to this novel therapy have
been observed. Specically, renal function was well preserved
postoperatively, and none of the patients required hemodialysis.
The sudden death of patient 004 at 26 days after surgery and MSC
administration was judged by both the principal investigator and
the members of the DSMB as being unrelated to the administration
of allogeneic MSC.
Since close follow-up of each patient is continued for six months,
and annual follow-up is conducted for another three years, it is
possible that late AEs or SAEs may develop. This may include
cardiovascular and pulmonary AEs detailed above, as well as
the remote possibility of ectopic differentiation (e.g., in lungs
or kidneys) of residual MSC into bone, fat or cartilage cells or
oncogenic transformation. However, our detailed pre-clinical
studies in experimental animals as well as numerous ongoing
clinical trails with MSC (www.clinicaltrials.gov) make the latter
AEs unlikely, since we have demonstrated that administered
allogeneic MSC do not remain in the animal for more than
three days, and that they do not differentiate into target cells and
engraft in the kidney that is injured by experimental ischemia
and reperfusion, the model that most closely resembles human
ischemic AKI.
In the next groups of subjects, the acute and late safety of higher
doses of allogeneic MSC will be assessed. At this point, the
safety of the higher doses is not predictable and will have to be
investigated. However, both our animal data and all reported
clinical trials in which similar MSC doses were administered did
not result in AEs or SAEs [7,8,10];(www.clinicaltrials.gov). It will
nally be of interest to determine whether the obtained data from
all 15 study subjects will allow an assessment of the preliminary
efcacy of allogeneic MSC therapy in this cohort of high risk
patients. If demonstrated, using relevant historical controls, it
would be the basis for the conduct of a Phase II trial, in which the
efcacy of this novel cell-based therapy is tested.
Acknowledgements
We greatly appreciate the excellent work of the University of
Utah Cell Therapy facility and its director Dr. Linda Kelley. In
this facility, all allogeneic MSC that were administered were
characterized, culture expanded and release tested under cGMP
conditions. The constructive contributions of the members of
the DSMB (Drs. Carl Kablitz, Srinivasan Beddhu and David
Afeck) are greatly valued. The conduct of this trial is funded
and sponsored by AlloCure, Inc., and partially supported by the
National Kidney Foundation (UT, ID), and the Western Institute
for Biomedical Research.
References
1. Nickolas TL, O‘Rourke MJ, Yang J, Sise ME, Canetta PA, et al. Sen-
sitivity and specicity of a single emergency department measurement
of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute
kidney injury. Ann Intern Med. 2008;148(11):810-9.
2. Goldberg R, Dennen P. Long-term outcomes of acute kidney injury.
Adv Chronic Kidney Dis. 2008;15(3):297-307.
3. Girardi AC, Fukuda LE, Rossoni LV, Malnic G, Reboucas NA. Dipep-
tidyl peptidase IV inhibition downregulates Na+ - H+ exchanger NHE3
in rat renal proximal tubule. Am J Physiol Renal Physiol. 2008;294(2):
F414-22.
4. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac
surgery. Clin J Am Soc Nephrol. 2006;1(1):19-32.
5. Hsu CY, Ordonez JD, Chertow GM, Fan D, McCulloch CE, et al. The
risk of acute renal failure in patients with chronic kidney disease. Kidney
Int. 2008;74(1):101-7.
6. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney injury
prediction following elective cardiac surgery: AKICS Score. Kidney Int.
2007;72(5):624-31.
7. Togel F, Cohen A, Zhang P, Yang Y, Hu Z, et al. Autologous and al-
logeneic marrow stromal cells are safe and effective for the treatment of
acute kidney injury. Stem Cells Dev. 2008.
Figure 1.
www.ctt-journal.com 2008;1(2) 35
8. Togel F, Weiss K, Yang Y, Hu Z, Zhang P, et al. Vasculotropic, paracri-
ne actions of infused mesenchymal stem cells are important to the reco-
very from acute kidney injury. Am J Physiol Renal Physiol. 2007;292(5):
F1626-35.
9. Togel F, Westenfelder C. Adult bone marrow-derived stem cells for
organ regeneration and repair. Dev Dyn. 2007;236(12):3321-31.
10. Togel F, Hu Z, Weiss K, Isaac J, Lange C, et al. Administered mes-
enchymal stem cells protect against ischemic acute renal failure through
differentiation-independent mechanisms. Am J Physiol Renal Physiol.
2005;289(1):F31-42.
11. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, et al. Mesen-
chymal stem cells for treatment of steroid-resistant, severe, acute graft-
versus-host disease: a phase II study. Lancet. 2008;371(9624):1579-86.
12. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O.
Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultu-
res and mitogenic responses independently of the major histocompatibi-
lity complex. Scand J Immunol. 2003;57(1):11-20.
13. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, et al. Acu-
te renal failure in critically ill patients: a multinational, multicenter study.
Jama. 2005;294(7):813-8.
© The Authors. This article is provided under the following license:
Creative Commons Attribution-Noncommercial-No Derivative Works
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deed.en
Ссылка: Клеточная терапия и трансплантация, том 1, номер 2, 24 декабря 2008, c. 35
doi: 10.3205/ctt-2008-ru-000028.02
Первичный отчет о фазе I клинических испытаний: профилактика и
лечение острого послеоперационного повреждения почек
аллогенными мезенхимными стволовыми клетками у
кардиохирургических больных при операциях на открытом сердце
Гуч А., Доти Дж., Флорес Дж., Свенсон Л., Тегель Ф., Райсс Р., Ланге К.,
Цандер А.Р., Ху Дж., Пул С., Жанг П., Вестенвельдер К.
Резюме
Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП),
индуцированное ишемией/реперфузией резистентное к лечению осложнение у больных - может эффективно
лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее
время проводится одобренная FDA I фаза клинических испытаний (www.clinicaltrials.gov; NCT00733876) больных,
которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний
безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического
вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали
лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной
болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение
МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной
низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное
сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по
этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент
не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался
через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами
Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения.
Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не
возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы
тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в
этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов
у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной
зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных
исторического контроля (база данных на www.STS.org).
Ключевые слова: мезенхимные стволовые клетки, острое повреждение почек, клеточная терапия, клинические
испытания, безопасность лечения
... Based on a large body of pre-clinical evidence regarding the effectiveness of MSCs in AKI, a number of studies were proposed to test the safety and efficacy of allogeneic bmMSC infusions, in patients at high risk of developing AKI. A recently completed phase I exploratory study (NTC00733876), demonstrated the feasibility and efficacy of escalating doses of bmMSCs infused in the suprarenal aorta in 16 patients undergoing on-pump cardiac surgery [9,10]. Infusions of MSCs were safe and protected against early and late post-surgery renal function deterioration, thus decreasing hospital stays and readmission rates compared to historical case controls [9,10]. ...
... A recently completed phase I exploratory study (NTC00733876), demonstrated the feasibility and efficacy of escalating doses of bmMSCs infused in the suprarenal aorta in 16 patients undergoing on-pump cardiac surgery [9,10]. Infusions of MSCs were safe and protected against early and late post-surgery renal function deterioration, thus decreasing hospital stays and readmission rates compared to historical case controls [9,10]. These promising results were not supported by a randomised double-blind phase II study (NTC01602328) in a similar cohort of 156 patients with established AKI 48h after surgery, who received intra-aortic administration of allogeneic MSCs (AC607 2 × 10 6 cells/kg, Allocure) or placebo. ...
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The prevalence of renal diseases is emerging as a public health problem. Despite major progress in supportive therapy, mortality rates among patients remain high. In an attempt to find innovative treatments to stimulate kidney regeneration, stem cell-based technology has been proposed as a potentially promising strategy. Here, we summarise the renoprotective potential of pluripotent and adult stem cell therapy in experimental models of acute and chronic kidney injury and we explore the different mechanisms at the basis of stem cell-induced kidney regeneration. Specifically, cell engraftment, incorporation into renal structures, or paracrine activities of embryonic or induced pluripotent stem cells as well as mesenchymal stem cells and renal precursors are analysed. We also discuss the relevance of stem cell secretome-derived bioproducts, including soluble factors and extracellular vesicles, and the option of using them as cell-free therapy to induce reparative processes. The translation of the experimental results into clinical trials is also addressed, highlighting the safety and feasibility of stem cell treatments in patients with kidney injury.
... In fact, most of these secreted bioactive molecules consisted of soluble factors, exosomes and microvesicles [129]. [133] [134]. ...
... Limited attempts with contradictory results have resulted from the exploration of the safety and efficacy of MSCs in recovering renal function after post-cardiac surgery AKI. An exploratory phase I trial studied the safety and feasibility of infusing allogeneic BM-MSCs in patients with several underlying comorbidities at high risk of developing AKI after open-heart surgery (14,15). Outcomes from the first five patients showed that prevention infusion of MSCs was safe, averted postoperative decline in renal function, and decreased time of hospitalization and rates of readmission. ...
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Advanced therapy medicinal products (ATMPs) offer new prospects to improve the treatment of conditions with unmet medical needs. Kidney diseases are a current major health concern with an increasing global prevalence. Chronic renal failure appears after many years of impairment, which opens a temporary window to apply novel therapeutic approaches to delay or halt disease progression. The immunomodulatory, anti-inflammatory, and pro-regenerative properties of mesenchymal stromal cells (MSCs) have sparked interest for their use in cell-based regenerative therapies. Currently, several early-phase clinical trials have been completed and many are ongoing to explore MSC safety and efficacy in a wide range of nephropathies. However, one of the current roadblocks to the clinical translation of MSC therapies relates to the lack of standardization and harmonization of MSC manufacturing protocols, which currently hinders inter-study comparability. Studies have shown that cell culture processing variables can have significant effects on MSC phenotype and functionality, and these are highly variable across laboratories. In addition, heterogeneity within MSC populations is another obstacle. Furthermore, MSCs may be isolated from several sources which adds another variable to the comparative assessment of outcomes. There is now a growing body of literature highlighting unique and distinctive properties of MSCs according to the tissue origin, and that characteristics such as donor, age, sex and underlying medical conditions may alter the therapeutic effect of MSCs. These variables must be taken into consideration when developing a cell therapy product. Having an optimal scale-up strategy for MSC manufacturing is critical for ensuring product quality while minimizing costs and time of production, as well as avoiding potential risks. Ideally, optimal scale-up strategies must be carefully considered and identified during the early stages of development, as making changes later in the bioprocess workflow will require re-optimization and validation, which may have a significant long-term impact on the cost of the therapy. This article provides a summary of important cell culture processing variables to consider in the scale-up of MSC manufacturing as well as giving a comprehensive review of tissue of origin-specific biological characteristics of MSCs and their use in current clinical trials in a range of renal pathologies.
... An array of underlying and interconnected effects were noticed such as anti-inflammatory, immune-modulating, and mitogenic mechanisms. Patients who experienced cardiac surgeries were infused with MSCs (AC607) during phase I clinical trial through suprarenal aorta and consequently showed preservation of postoperative renal function [91]. Similar findings were reported in experimental animal researches in which MSCs improved AKI through suppressing inflammatory and oxidative pathways [92]. ...
Article
Acute kidney injury, previously known as acute renal failure (AKI), is defined as an abrupt decrease in kidney function that occurs within hours or days. This new nomenclature opens a new door for possibility of treatment of developing renal injury before progression to unresolved renal failure. AKI arises due to diverse etiologic factors that rely mainly on three categories namely, pre-renal, intrinsic renal, and post-renal factors with different clinical pictures, and confers a spectrum of injury ranging from mild to severe and sometimes leads to end-stage renal disease. Complexity of pathogenesis and other factors generate barriers to developing effective treatments despite a large number of experimental and clinical studies. In this review, recent advances in the potential of the currently used drugs for renoprotection, novel pharmacological targets, and prospective therapeutics for AKI are discussed. The information in this review was extracted from electronic resources (PubMed, Google Scholar, Wiley, Science Direct, Springer), and English scientific books by using keywords including kidney, injury, recent therapy, and pharmacological targets. The articles were carefully checked for their relevance to the current manuscript. Recent targets of cellular repair or regenerative processes involved in AKI such as autophagy, ferroptosis inhibition, and p53 antagonism seem to be effective in disease control. This may help researchers and clinicians to understand how to target the interrelated molecular and cellular mechanisms underlying the pathogenesis of AKI.
... 93,94 However, the number of trials in which evidence for the efficacy of MSC therapy in AKI can be examined is limited. As summarized in Table 1, [94][95][96][97][98] there have been 2 completed trials in this area, 2 withdrawn or terminated, 1 trial currently recruiting, and 1 not yet open for recruitment. The first phase I clinical trial (ClinicalTrials.gov ...
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A little over 10 years ago, the therapeutic potential of mesenchymal stromal cells (MSCs) for the treatment of acute kidney injury (AKI) was becoming widely recognized. Since then, there has been further intensive study of this topic with a clear translational intent. Over the past decade, many more animal model studies have strengthened the evidence that systemically or locally delivered MSC ameliorate renal injury in sterile and sepsis-associated AKI. Some of these preclinical studies have also provided a range of compelling new insights into the in vivo fate and mechanisms of action of MSC in the setting of AKI and other inflammatory conditions. Coupled with increased knowledge of the functional roles of resident and infiltrating immune cell mediators in determining the severity and outcome of AKI, the progress made in the past decade would appear to have significantly strengthened the translational pathway for MSC-based therapies. In contrast, however, the extent of the clinical experience with MSC administration in human subjects with AKI or sepsis-associated AKI has been limited to a small number of early-phase clinical trials, which appear to demonstrate safety but have not thus far delivered a strong signal of efficacy. In this review, we summarize the most significant new developments in the field of MSC-based therapies as they relate to AKI and reflect on the key gaps in knowledge and technology that remain to be addressed for the true clinical potential of MSC and, perhaps, other emerging cellular therapies to be realized.
... Although IV injection is a relatively easy and non-invasive method of administration, the main problem is the pulmonary entrapment of cells directly after injection which thereby reduces engraftment within the kidney 5 . Several studies have shown that systemic intra-arterial delivery which by-passes the lung can provide increased cell retention in kidney 6,7 . However, evidence of vascular occlusion after intra-arterial injection has been reported which raises safety concerns 8 ...
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Cell-based therapies are promising treatments for various kidney diseases. However, the major hurdle in initiating therapeutic responses is the inefficiency of injection routes to deliver cells to the kidney parenchyma. Systemic injection, such as intravenous injection only delivers a small proportion of cells to the kidney. Whereas direct delivery, such as renal artery injection require surgical procedures. A minimally invasive renal artery injection was therefore developed to enhance cell delivery to kidney. In this study, luciferase expressing human adipocyte derived stem cells (ADSC) were labelled with gold nanorods (GNR) and injected into the renal artery using ultrasound guidance. The ADSCs were tracked using bioluminescence and photoacoustic imaging serially over 7 days. Imaging confirmed that the majority of signal was within the kidney, indicative of successful injection and that signal remained stable for 3 days. Histology showed co-localization of GNRs with ADSC staining throughout the kidney with no indication of injury caused by injection. These findings demonstrate that ultrasound-guided renal artery injection is feasible in mice and can successfully deliver a large proportion of cells which are retained within the kidney for 3 days. Therefore, the techniques developed here will be useful for optimising cell therapy in kidney diseases.
... AKI can be an ideal target for cell-based therapy due to the ability of stem cells to affect different pathophysiological processes of AKI. Based on the preclinical studies of ischemic/reperfusioninduced AKI (Togel and Bonventre, 2013), a phase I study with an initial recruitment of five patients with high risk of developing severe AKI post-on-pump cardiac surgery was conducted (Gooch et al., 2008). The allogeneic MSCs were infused once through a femoral catheter into the suprarenal aorta. ...
Chapter
Kidney disease is a public health priority, due to its morbidity and mortality with limited therapeutic options. Stem cell therapies are undergoing investigation to improve the regenerative capacity of the kidney. The mechanisms underlying the reparative effects of stem cells include antiinflammatory, immunomodulatory, antiapoptotic, and pro-angiogenic properties. Stem cell clinical trials have shown efficacy in improving kidney transplantation success, whereas variable responses have been observed in acute and chronic kidney diseases, depending on various variables including disease background, cell type, route of administration, and patient population. In this article, we review the state of the stem cell therapy field in kidney disease.
... Primary results released by Gooch et al. showed that the infusion of low dose of allogenic BM-MSCs into supra-renal aorta could prevent all symptoms in 5 patients with acute kidney injury induced after cardiopulmonary bypass. It also decreased the incidence of AKI and shortened the hospitalization period (29,44). These results were consistent with the findings of Togel and Westenfelder's study that reported the reno-protective effects of intracoronary injection of allogenic BM-MSCs in patients under cardiac surgery with high risk of AKI (45). ...
Article
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Over 10 years, mesenchymal stem cells (MSCs) have been considered as valuable and suitable cells for cell-based therapy applications, particularly in clinical trials. In any case, they are as yet not utilized routinely in clinics. At first, it was believed that MSCs play their roles, especially in regenerative medicine due to their differentiation and cell replacement properties. Interestingly, it is well-known that MSCs mainly exert their therapeutic effects through their vast bioactive factors. These findings turned scientists’ consideration toward cell-free therapy concepts. From this point of view, MSCs can be considered as an arsenal of natural bioreactors in variety of therapeutic agents. MSCs inherently express various important therapeutic agents such as growth factors and cytokines that can be manufactured, handled and stored as a prepared-to-go biologic product. In this review, we provide a vision, highlight as well as discuss in order to introduce competitive natural robust bioreactor MSCs on the horizon.
Article
Introduction Accumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU). Objective This article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU. Discussion All clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies. Conclusion MSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED.
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Significant progress has been made to advance stem cell products as potential therapies for kidney diseases: various kinds of stem cells can restore renal function in preclinical models of acute and chronic kidney injury. Nonetheless this literature contains contradictory results, and for this reason, we focus this review on reasons for apparent discrepancies in the literature, because they contribute to difficulty in translating renal regenerative therapies. Differences in methodologies used to derive and culture stem cells, even those from the same source, in addition to the lack of standardized renal disease animal models (both acute and chronic), are important considerations underlying contradictory results in the literature. We propose that harmonized rigorous protocols for characterization, handling, and delivery of stem cells in vivo could significantly advance the field, and present details of some suggested approaches to foster translation in the field of renal regeneration. Our goal is to encourage coordination of methodologies (standardization) and long‐lasting collaborations to improve protocols and models to lead to reproducible, interpretable, high‐quality preclinical data. This approach will certainly increase our chance to 1 day offer stem cell therapeutic options for patients with all‐too‐common renal diseases.
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A single serum creatinine measurement cannot distinguish acute kidney injury from chronic kidney disease or prerenal azotemia. To test the sensitivity and specificity of a single measurement of urinary neutrophil gelatinase-associated lipocalin (NGAL) and other urinary proteins to detect acute kidney injury in a spectrum of patients. Prospective cohort study. Emergency department of Columbia University Medical Center, New York, New York. 635 patients admitted to the hospital with acute kidney injury, prerenal azotemia, chronic kidney disease, or normal kidney function. Diagnosis of acute kidney injury was based on the RIFLE (risk, injury, failure, loss, and end-stage) criteria and assigned by researchers who were blinded to experimental measurements. Urinary NGAL was measured by immunoblot, N-acetyl-beta-d-glucosaminidase (NAG) by enzyme measurement, alpha1-microglobulin and alpha(1)-acid glycoprotein by immunonephelometry, and serum creatinine by Jaffe kinetic reaction. Experimental measurements were not available to treating physicians. Patients with acute kidney injury had a significantly elevated mean urinary NGAL level compared with the other kidney function groups (416 microg/g creatinine [SD, 387]; P = 0.001). At a cutoff value of 130 microg/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were 0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00), respectively, and positive and negative likelihood ratios were 181.5 (CI, 58.33 to 564.71) and 0.10 (CI, 0.03 to 0.29); these values were superior to those for NAG, alpha1-microglobulin, alpha1-acid glycoprotein, fractional excretion of sodium, and serum creatinine. In multiple logistic regression, urinary NGAL level was highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit (odds ratio, 24.71 [CI, 7.69 to 79.42]). All patients came from a single center. Few kidney biopsies were performed. A single measurement of urinary NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes.
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Although acute renal failure (ARF) is believed to be common in the setting of critical illness and is associated with a high risk of death, little is known about its epidemiology and outcome or how these vary in different regions of the world. To determine the period prevalence of ARF in intensive care unit (ICU) patients in multiple countries; to characterize differences in etiology, illness severity, and clinical practice; and to determine the impact of these differences on patient outcomes. Prospective observational study of ICU patients who either were treated with renal replacement therapy (RRT) or fulfilled at least 1 of the predefined criteria for ARF from September 2000 to December 2001 at 54 hospitals in 23 countries. Occurrence of ARF, factors contributing to etiology, illness severity, treatment, need for renal support after hospital discharge, and hospital mortality. Of 29 269 critically ill patients admitted during the study period, 1738 (5.7%; 95% confidence interval [CI], 5.5%-6.0%) had ARF during their ICU stay, including 1260 who were treated with RRT. The most common contributing factor to ARF was septic shock (47.5%; 95% CI, 45.2%-49.5%). Approximately 30% of patients had preadmission renal dysfunction. Overall hospital mortality was 60.3% (95% CI, 58.0%-62.6%). Dialysis dependence at hospital discharge was 13.8% (95% CI, 11.2%-16.3%) for survivors. Independent risk factors for hospital mortality included use of vasopressors (odds ratio [OR], 1.95; 95% CI, 1.50-2.55; P<.001), mechanical ventilation (OR, 2.11; 95% CI, 1.58-2.82; P<.001), septic shock (OR, 1.36; 95% CI, 1.03-1.79; P = .03), cardiogenic shock (OR, 1.41; 95% CI, 1.05-1.90; P = .02), and hepatorenal syndrome (OR, 1.87; 95% CI, 1.07-3.28; P = .03). In this multinational study, the period prevalence of ARF requiring RRT in the ICU was between 5% and 6% and was associated with a high hospital mortality rate.
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Acute kidney injury (AKI) following cardiac surgery (AKICS) is associated with increased postoperative (post-op) morbidity and mortality. A prognostic score system for AKI would help anticipate patient (pt) treatment. To develop a predictive score (AKICS) for AKI following cardiac surgery, we used a broad definition of AKI, which included perioperative variables. Six hundred three pts undergoing cardiac surgery were prospectively evaluated for AKI defined as serum creatinine above 2.0 mg/dl or an increase of 50% above baseline value. Univariate and multivariate analyses were used to evaluate pre-, intra-, and post-op parameters associated with AKI. The AKICS scoring system was prospectively validated in a new data set of 215 pts with an incidence of AKI of 14% . Variables included in the AKICS score were age greater than 65, pre-op creatinine above 1.2 mg/dl, pre-op capillary glucose above 140 mg/dl, heart failure, combined surgeries, cardiopulmonary bypass time above 2 h, low cardiac output, and low central venous pressure. The AKICS score presented good calibration and discrimination in both the study group and validation data set. The AKICS system that we developed, which incorporates five risk categories, accurately predicts AKI following cardiac surgery.
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Acute renal failure (ARF) occurs in up to 30% of patients who undergo cardiac surgery, with dialysis being required in approximately 1% of all patients. The development of ARF is associated with substantial morbidity and mortality independent of all other factors. The pathogenesis of ARF involves multiple pathways. Hemodynamic, inflammatory, and nephrotoxic factors are involved and overlap each other in leading to kidney injury. Clinical studies have identified risk factors for ARF that can be used to determine effectively the risk for ARF in patients who undergo bypass surgery. These high-risk patients then can be targeted for renal protective strategies. Thus far, no single strategy has demonstrated conclusively its ability to prevent renal injury after bypass surgery. Several compounds such as atrial natriuretic peptide and N-acetylcysteine have shown promise, but large-scale trials are needed.
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In the microvillar microdomain of the kidney brush border, sodium hydrogen exchanger type 3 (NHE3) exists in physical complexes with the serine protease dipeptidyl peptidase IV (DPPIV). The purpose of this study was to explore the functional relationship between NHE3 and DPPIV in the intact proximal tubule in vivo. To this end, male Wistar rats were treated with an injection of the reversible DPPIV inhibitor Lys [Z(NO2)]-pyrrolidide (I40; 60 mg.kg(-1).day(-1) ip) for 7 days. Rats injected with equal amounts of the noninhibitory compound Lys[Z(NO2)]-OH served as controls. Na(+) - H(+) exchange activity in isolated microvillar membrane vesicles was 45 +/- 5% decreased in rats treated with I40. Membrane fractionation studies using isopycnic centrifugation revealed that I40 provoked redistribution of NHE3 along with a small fraction of DPPIV from the apical enriched microvillar membranes to the intermicrovillar microdomain of the brush border. I40 significantly increased urine output (67 +/- 9%; P < 0.01), fractional sodium excretion (63 +/- 7%; P < 0.01), as well as lithium clearance (81 +/- 9%; P < 0.01), an index of end-proximal tubule delivery. Although not significant, a tendency toward decreased blood pressure and plasma pH/HCO(3)(-) was noted in I40-treated rats. These findings indicate that inhibition of DPPIV catalytic activity is associated with inhibition of NHE3-mediated NaHCO3 reabsorption in rat renal proximal tubule. Inhibition of apical Na(+) - H(+) exchange is due to reduced abundance of NHE3 protein in the microvillar microdomain of the kidney brush border. Moreover, this study demonstrates a physiologically significant interaction between NHE3 and DPPIV in the intact proximal tubule in vivo.
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We aimed to study the effects of mesenchymal stem cells (MSCs) on alloreactivity and effects of T-cell activation on human peripheral blood lymphocytes (PBLs) in vitro. MSCs were expanded from the bone marrow of healthy subjects. MSCs isolated from second to third passage were positive for CD166, CD105, CD44, CD29, SH-3 and SH-4, but negative for CD34 and CD45. MSCs cultured in osteogenic, adipogenic or chondrogenic media differentiated, respectively, into osteocytes, adipocytes or chondrocytes. MSC added to PBL cultures had various effects, ranging from slight inhibition to stimulation of DNA synthesis. The stimulation index (SI = (PBL + MSC)/PBL) varied between 0.2 and 7.3. The SI was not affected by the MSC dose or by the addition of allogeneic or autologous MSCs to the lymphocytes.
Article
Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.
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Stem cells have been recognized as a potential tool for the development of innovative therapeutic strategies. There are in general two types of stem cells, embryonic and adult stem cells. While embryonic stem cell therapy has been riddled with problems of allogeneic rejection and ethical concerns, adult stem cells have long been used in the treatment of hematological malignancies. With the recognition of additional, potentially therapeutic characteristics, bone marrow-derived stem cells have become a tool in regenerative medicine. The bone marrow is an ideal source of stem cells because it is easily accessible and harbors two types of stem cells. Hematopoietic stem cells give rise to all blood cell types and have been shown to exhibit plasticity, while multipotent marrow stromal cells are the source of osteocytes, chondrocytes, and fat cells and have been shown to support and generate a large number of different cell types. This review describes the general characteristics of these stem cell populations and their current and potential future applications in regenerative medicine.
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Few studies have defined how the risk of hospital-acquired acute renal failure varies with the level of estimated glomerular filtration rate (GFR). It is also not clear whether common factors such as diabetes mellitus, hypertension and proteinuria increase the risk of nosocomial acute renal failure independent of GFR. To determine this we compared 1,746 hospitalized adult members of Kaiser Permanente Northern California who developed dialysis-requiring acute renal failure with 600,820 hospitalized members who did not. Patient GFR was estimated from the most recent outpatient serum creatinine measurement prior to admission. The adjusted odds ratios were significantly and progressively elevated from 1.95 to 40.07 for stage 3 through stage 5 patients (not yet on maintenance dialysis) compared to patients with estimated GFR in the stage 1 and 2 range. Similar associations were seen after controlling for inpatient risk factors. Pre-admission baseline diabetes mellitus, diagnosed hypertension and known proteinuria were also independent risk factors for acute kidney failure. Our study shows that the propensity to develop in-hospital acute kidney failure is another complication of chronic kidney disease whose risk markedly increases even in the upper half of stage 3 estimated GFR. Several common risk factors for chronic kidney disease also increase the peril of nosocomial acute kidney failure.
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Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation with haemopoietic stem cells. Mesenchymal stem cells modulate immune responses in vitro and in vivo. We aimed to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation. Patients with steroid-resistant, severe, acute GVHD were treated with mesenchymal stem cells, derived with the European Group for Blood and Marrow Transplantation ex-vivo expansion procedure, in a multicentre, phase II experimental study. We recorded response, transplantation-related deaths, and other adverse events for up to 60 months' follow-up from infusion of the cells. Between October, 2001, and January, 2007, 55 patients were treated. The median dose of bone-marrow derived mesenchymal stem cells was 1.4x10(6) (min-max range 0.4-9x10(6)) cells per kg bodyweight. 27 patients received one dose, 22 received two doses, and six three to five doses of cells obtained from HLA-identical sibling donors (n=5), haploidentical donors (n=18), and third-party HLA-mismatched donors (n=69). 30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (11 [37%] of 30 vs 18 [72%] of 25; p=0.002) and higher overall survival 2 years after haemopoietic-stem-cell transplantation (16 [53%] of 30 vs four [16%] of 25; p=0.018). Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD.