Safety and efficacy of intravenous infusion of allogeneic cryopreserved mesenchymal stem cells for treatment of chronic kidney disease in cats: results of three sequential pilot studies

Abstract

IntroductionAdministration of mesenchymal stem cells (MSCs) has been shown to improve renal function in rodent models of chronic kidney disease (CKD), in part by reducing intrarenal inflammation and suppressing fibrosis. CKD in cats is characterized by tubulointerstitial inflammation and fibrosis, and thus treatment with MSCs might improve renal function and urinary markers of inflammation in this disease. Therefore, a series of pilot studies was conducted to assess the safety and efficacy of intravenous administration of allogeneic adipose-derived MSCs (aMSCs) in cats with naturally occurring CKD.MethodsCats enrolled in these studies received an intravenous infusion of allogeneic aMSCs every 2 weeks collected from healthy, young, specific pathogen-free cats. Cats in pilot study 1 (six cats) received 2 × 106 cryopreserved aMSCs per infusion, cats in pilot study 2 (five cats) received 4 × 106 cryopreserved aMSCs per infusion, and cats in pilot study 3 (five cats) received 4 × 106 aMSCs cultured from cryopreserved adipose. Serum biochemistry, complete blood count, urinalysis, urine protein, glomerular filtration rate, and urinary cytokine concentrations were monitored during the treatment period. Changes in clinical parameters were compared statistically by means of repeated measures analysis of variance (ANOVA) followed by Bonferroni’s correction.ResultsCats in pilot study 1 had few adverse effects from the aMSC infusions and there was a statistically significant decrease in serum creatinine concentrations during the study period, however the degree of decrease seems unlikely to be clinically relevant. Adverse effects of the aMSC infusion in cats in pilot study 2 included vomiting (2/5 cats) during infusion and increased respiratory rate and effort (4/5 cats). Cats in pilot study 3 did not experience any adverse side effects. Serum creatinine concentrations and glomerular filtration rates did not change significantly in cats in pilot studies 2 and 3.ConclusionsAdministration of cryopreserved aMSCs was associated with significant adverse effects and no discernible clinically relevant improvement in renal functional parameters. Administration of aMSCs cultured from cryopreserved adipose was not associated with adverse effects, but was also not associated with improvement in renal functional parameters.

Controversial results of therapy with mesenchymal stem cells in the acute phase of canine distemper disease

“…However, in this study, no adverse effects were observed during or after MSC transplantation. Conversely, intravenous transplantation enables the activation of paracrine, anti-inflammatory, immunomodulatory, and anti-fibrotic mechanisms, which are important in stem cell-based therapies (Deak et al, 2010;Quimby et al, 2013). A high mortality rate was observed in both groups, which may be related to acute clinical and neurological symptoms and to the severity of the disease.…”

Creative technology advances tissue preservation

“…The cryoprotectant, DMSO, in VS55 cryopreservation medium is a known carcinogen that can cause serious side effects when administered intravenously at relatively low concentrations in cell suspensions (14,15). Removal can be complicated and time consuming (16).…”

<b>Avaliação sequencial do metabolismo de cálcio e fósforo com ênfase na determinação do fator de crescimento de fibroblastos 23 (FGF-23) e da excreção fracionada de fósforo urinária (uFEP) de cães com doença renal crônica submetidos a terapia com células-tronco mesenquimal</b>

“…Possíveis mecanismos KIM et al, 2007;TOGEL et al, 2007;QUIMBY et al, 2011;QUIMBY et al, 2013;DOW, 2015).…”

“…Recentemente, diversos estudos tem sugerido o uso de célula-tronco mesenquimal como uma nova opção de tratamento na doença renal crônica, encourajado a partir de estudos realizado em ratos e camundongos, bem como na espécie felina e canina (CAVAGLIERI et al, 2009;SEMEDO et al, 2009;LEE et al, 2010;QUIMBY et al, 2011;VILLANUEVA et al, 2011;QUIMBY et al, 2013;DOW, 2015;LIM et al, 2016).…”

“…Estudos prévios demonstraram que a CTM podem ser administradas por via intravenosa (IV) em humanos e roedores, porem em roedores foi relatado a ocorrência de tromboembolismo pulmonar quando administrada rapidamente por via intravenosa (DEAK et al, 2010). Outras vias para a aplicação incluem a artéria renal e a administração direta no parenquima renal ou no espaço subcapsular renal (CAVAGLIERI et al, 2009;SEMEDO et al, 2009;LEE et al, 2010;VILLANUEVA et al, 2011 Recentemente foi realizado dois estudos em gatos com DRC de curso natural com o uso de CTM, sendo que em um estudo a administração de CTM foi por via intra-renal guiado por ultrassom (QUIMBY et al, 2011) e em outro estudo por via intravenosa (QUIMBY et al, 2013), entretanto nessas referidas investigações, não foi observada melhora significante da função renal quando avaliada pela concentração sérica de creatinina, apenas uma melhora moderada quando analisada a partir da determinação da TFG (QUIMBY et al, 2011;QUIMBY et al, 2013).…”