Efficacy Of Umbilical Cord Mesenchymal Stem Cell Transfusion For The Treatment Of Severe AKI: A Protocol For A Randomised Controlled Trial

Follow-up 

The trial follow-up schedule is shown in Table 2. At the screening stage, the study participants will undergo assessment for the inclusion and exclusion criteria alongside a full medical history and physical examination. Follow-up visits will be conducted during hospitalization and after discharge. In the intervention period (days 0–28), data will be recorded at 1, 3, 7, 14 and 28 days. After discharge, follow-up will take place during outpatient clinic visits at 2 months and 3 months for both study groups. We will establish contact via telephone and ask whether tumors occurred after hospital discharge for 3 years.

Click to cistanche herba for kidney disease

Blood and urine sample collection

Urine and blood samples for the biomarker assay will be collected at enrolment and on days 3, 7, and 28. The samples will be frozen at −80°C immediately after processing until use. We plan to use these samples to detect kidney injury biomarkers, renal repair biomarkers, inflammatory markers, immunomodulatory factors, and fibrosis markers. 

Sample size 

Due to the exploratory nature of the study, no sample size calculation was performed. Assuming a 20% dropout rate, the final sample size is set to 50 participants in each group.

Clinical assessments and data collection

Clinical information, including age, medical history, comorbidities, Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation II score and the severity of AKI, will be documented within the clinical information system of the hospital after enrolment. The type and duration of RRT, the use of vasoactive drugs, and the number of blood products will be recorded at all interviews from the beginning of the study by the investigating physician. Vital signs, including breathing, body temperature, pulse, blood pressure, and adverse events, used for safety assessment, will be measured during human MSC infusion. Any adverse events, such as fever, itching, headache, vomiting, and weakness, will be reported to the Medical Ethics Committee of the Chinese PLA General Hospital within 15 days

Routine blood, urine test, biochemical, renal function (serum creatinine, blood urea nitrogen, and cystatin C (CysC) levels), panel-reactive antibody, cardiac markers (creatine kinase, lactate dehydrogenase, phosphocreatine kinase isoenzyme), blood coagulation, ECG, tumor marker and serological tests will be performed. These routine lab measurements were analyzed at the Central Clinical Chemistry Laboratory, Chinese PLA General Hospital.

For cases withdrawn from the study or dropped out for follow-up, the investigator should actively take measures to complete the last test as much as possible in order to analyze its efficacy and safety and take corresponding treatment measures. For all dropped cases, we will document the reason for the case drop on the CRF.

Confidentiality 

Information will be entered into a standardized electronic CRF from the clinical information system of the hospital, stored in the Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital with a password-protected hard disk. All data will be handled and processed anonymously to ensure the confidentiality of the individuals. Only the researchers will have access to the final trial dataset.

Statistical analysis 

Statistical analyses will be performed using SPSS V.21. If the disease progressed rapidly after randomization so that the patient receives only one infusion or no infusion, we will still include them for the primary analysis, as allocation to MSC treatment or placebo control arm could influence the likelihood that patients receive a transfusion. Continuous variables will be summarised as means with SD if normally distributed and medians with first and third quartiles otherwise. We will use the one-sample Kolmogorov-Smirnov test to check whether the data are normally distributed. For the effectiveness analysis, missing data will be imputed using last observation carried forward, and for patients with missing data due to death, missing data will be imputed using the worst possible value (in the dataset). For the safety analysis, it will be conducted with the raw data. Because of the small sample sizes, we considered subgroup analyses to be less suitable in the present study. We planned no subgroup analyses prespecified based on baseline characteristics. However, a posthoc subgroup analysis will only analyzed if there is no difference between the two groups, in order to provide the basis for our next research. Due to the exploratory nature of the study, a forInterventtionsmal data monitoring committee or interim analyses were not considered. However, data monitoring will be conducted by the research team regularly.

For continuous variables, such as hospital length of intensive care unit (ICU) stay and total hospital length of stay, we will use non-parametric tests to analyze the differences between groups. Continuous variables such as creatinine, GFR, CysC, urine volume, urea nitrogen, and all kinds of biomarkers are repeat-measurement data. We will develop a statistical analysis plan in consultation with a statistician, taking into account the repeated nature of the measurements. Data for categorical variables, including the survival of patients with severe AKI at 28 days and 3 months after receiving MSC, RRT dependence at 3 months, complete recovery rate, partial recovery rate, and the incidence of adverse events, will be presented as proportions and compared using a χ2 test.

Patient and public involvement 

The development of the research questions and outcome measures were not informed by patients’ priorities, experience or preferences. Patients and the public will not be involved in the design nor recruitment and conduct of the study. Results will be disseminated to all study participants after study completion. The burden of the intervention was not assessed by the patients themselves.

Safety consideration

All necessary procedures and precautions will be taken to maximize participant safety. First, patients with higher potential risks will be excluded based on the exclusion criteria. Second, an infusion time of more 30min was chosen to minimize the risk of infusion-related adverse effects. Third, during the infusion, vital signs will be continuously monitored. Fourth, once an adverse event occurs, SAEs considered to be related to the study procedure will be submitted to the principal investigator within 24hours and to the ethics committee within 15 days of the completion of treatment. Then, the ethics committee will report the event to the Food and Drug Administration and the Provincial Health and Family Planning Commission of China. The patient will be followed up until the event has stabilized. No independent auditing of trial conduct is planned.

ETHICS AND DISSEMINATION 

The study protocol and trial documents including the consent form and participant information sheet have been approved by the Ethics Committee of the Chinese PLA General Hospital. The findings of the study will be disseminated through scientific peer-reviewed journals as well as research conferences.

DISCUSSION 

Severe AKI is associated with high mortality in patients. MSC therapy has shown the most attractive results in both preclinical and clinical research. At present, there are only three clinical trials registered in clinical trials. gov of MSCs in the treatment of severe acute renal injury. Two of them have been completed, and one is recruiting subjects. Due to the opposite conclusions of the two trials and scarce evidence, more clinical trials are required to verify these inconsistent conclusions. Our study was designed to define the effects of uc-MSCs on severe AKI.

A strength of this study is that we will include only patients with AKI caused directly by renal tubular epithelial cell damage, and not those with AKI caused by glomerular or vascular disease, to ensure the homogeneity of the study sample. We will also exclude patients who are severely ill due to damage to other organs that may aggravate the patient’s condition and possibly result in a higher mortality rate, which may mask the genuine action of MSCs.

A novel aspect of this study is the two intravenous infusions of MSCs on days 0 and 7. When cells are injected into an injured environment, they face a harsh internal environment, including ROS and anoikis, which contribute to MSC apoptosis.30–32 Additionally, cell accumulation in the lung, liver and spleen leads to a small number of cells surviving to engraft injured kidneys. Due to the high risk of pulmonary embolism in bed-ridden patients, who are too ill to receive a large volume of cells that could accumulate in the lungs, a dose of 106 MSCs per 1kg will be used in this trial, which is half the number administered in other clinical trials. At the same time, considering the need for a sufficient dose of cells, an additional infusion will be conducted to increase the possibility of a good curative effect. MSCs will be administered by intravenous infusion, which is different from previous research. Compared with arterial infusion, intravenous infusion is more convenient and more easily accepted by patients.

Finally, our primary outcome measure is an objective measure of creatinine during the intervention period and follow-up periods to assess the change in renal function. The selection of these objective measures will make it possible to monitor continuous and dynamic changes in renal function and differences between the two groups. However, the main limitation of our trial should be noted. A small sample size due to the nature of exploratory clinical trials needs to be further explored in the future.

TRIAL STATUS

Patient recruitment started on 31 December 2021 and will be completed on 31 December 2022. 

Acknowledgments We thank Xiaowei Sun, Shuwei Duan, and Quan Hong for their help and advice. 

Contributors GC obtained the research funding and is the principal investigator. GC, YY and JG conceived and designed this study. YY drafted the manuscript. SW, WW, F-LZ, XW, SLia, ZF, SLin, LZ and XC all participated in the final design of the study. YY corrected this manuscript. 

Funding This work is supported by the National Key R&D Program of China (2018YFA0108803). 

Competing interests None declared. 

Patient consent for publication is Not applicable. 

Provenance and peer review Not commissioned; externally peer-reviewed. 

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

REFERENCES

1 Yang X, de Caestecker M, Otterbein LE, et al. Carbon monoxide: an emerging therapy for acute kidney injury. Med Res Rev 2020;40:1147-1177. 

2 Rewa O, Bagshaw SM. Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol 2014;10:193–207.

3 Hoste EAJ, Kellum JA, Selby NM, et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol 2018;14:607–25

4 Ishani A, Xue JL, Himmelfarb J, et al. Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol 2009;20:223–8.

5 Hoste EAJ, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015;41:1411–23. 

6 Kaddourah A, Basu RK, Bagshaw SM, et al. Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med 2017;376:11–20. 

7 Thiele RH, Isbell JM, Rosner MH. AKI associated with cardiac surgery. Clin J Am Soc Nephrol 2015;10:500–14. 

8 Rahman M, Shad F, Smith MC. Acute kidney injury: a guide to diagnosis and management. Am Fam Physician 2012;86:631–9. 

9 Chawla LS, Eggers PW, Star RA, et al. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 2014;371:58–66. 

10 Molitoris BA, Okusa MD, Palevsky PM, et al. Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected Hospital settings. Clin J Am Soc Nephrol 2012;7:856–60.

11 Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 2012;81:442–8. 12 Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 2011;121:4210–21.

Supportive Service Of Wecistanche-The largest cistanche exporter in the China:

Email:wallence.suen@wecistanche.com 

Whatsapp/Tel:+86 15292862950

Shop For More Specifications Details:

https://www.xjcistanche.com/cistanche-shop

GET NATURAL ORGANIC CISTANCHE EXTRACT WITH 25% ECHINACOSIDE AND 9% ACTEOSIDE FOR KIDNEY INFECTION