StemCell Therapy

Abstract Introduction

Administration 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.

Cats 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 Bonferronis correction.

Cats 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.

Administration 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.

Chronic kidney disease (CKD) is a common condition in elderly cats and is characterized by tubulointerstitial inflammation, tubular atrophy and interstitial fibrosis with subsequent progressive loss of renal function [1,2]. Currently there is no definitive therapy short of renal transplant to improve kidney function in cats with CKD. Therefore, novel and effective therapeutic options are highly desired for treating this disease in cats.

Recently, a number of studies have suggested the use of mesenchymal stem cells (MSCs) as a novel treatment option for management of CKD, based on encouraging data from rodent studies [3-7]. There have been several rationales advanced for the use of MSCs for treatment of CKD. Rodent studies have suggested that MSCs may incorporate into the renal parenchyma and give rise to new renal tubular cells, though the process appears to be relatively inefficient [8-17]. MSCs also exert potent anti-inflammatory and antifibrotic effects and may therefore indirectly improve renal function by reducing disease-associated inflammation and fibrosis through paracrine effects [3-7]. For example, MSCs have been shown to inhibit lymphocyte proliferation and cytokine production, suppress dendritic cell function, and suppress interferon (IFN) production by natural killer (NK) cells [18].

Since inflammation appears to be present at all stages of CKD in cats, the immunomodulatory actions of MSCs are appealing as an alternative means of suppressing intrarenal inflammation long term and with fewer side effects than with conventional anti-inflammatory drugs. In the majority of experimentally-induced CKD models investigated, MSC administration resulted in improved renal function, decreased intrarenal inflammation, and reduction of renal fibrosis [3-7]. Thus, MSC therapy may be an effective new approach to slow the progression of CKD and improve renal function.

Previous studies have demonstrated that cultured MSCs can be administered intravenously to rodents as well as to humans. However, in rodent models there is a significant risk of pulmonary thrombosis when high numbers of MSCs are rapidly administered intravenously [19]. Alternative routes of delivery have included injection via the renal artery, injection directly into the renal parenchyma, and injection into the renal subcapsular space [3-7]. One potential advantage of intravenous delivery compared to other routes may be the induction of renotropic paracrine effects following intravenous administration of MSCs [20].

Based on compelling results from rodent studies, we conducted a series of pilot studies to investigate the safety and potential efficacy of adipose-derived MSC (aMSC) therapy as a treatment for cats with naturally occurring CKD. These studies were designed to test the hypothesis that allogeneic cryopreserved aMSCs could be safely administered to cats with CKD and would result in improvement in kidney function. For this study, aMSCs were derived from allogeneic, healthy, specific pathogen-free (SPF) donor cats and cryopreserved, either as cells or adipose tissue, prior to intravenous administration to study cats. One primary study endpoint was to determine safety and potential adverse effects of repeated intravenous administration of cryopreserved aMSCs. The second major endpoint was to determine whether repeated MSC administrations were associated with improvement in renal function or urinary markers of intrarenal inflammation. These studies produced evidence of modest, but unlikely to be clinically significant, improvement in renal function but also showed evidence of significant adverse effects associated with intravenous administration of higher doses of cryopreserved aMSCs.

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