Assessment of intravenous adipose-derived allogeneic mesenchymal stem cells for the treatment of feline chronic kidney disease: a randomized, placebo-controlled clinical trial in eight cats

Abstract

Objectives: Feline chronic kidney disease (CKD) is characterized by chronic tubulointerstitial nephritis, and inflammation contributes to the progression of renal fibrosis. Mesenchymal stem cells (MSCs) have demonstrated anti-inflammatory and antifibrotic effects in rodent CKD models. However, few randomized trials evaluating the effectiveness of MSC therapy for diseases in companion animals have been reported. The purpose of this study was to evaluate the effectiveness of allogeneic MSCs for the treatment of feline CKD using a randomized, placebo-controlled trial.

Methods: MSCs were isolated from the cryopreserved adipose tissues of specific pathogen-free research cats and culture expanded. CKD cats were enrolled in a randomized, placebo-controlled, blinded one-way crossover clinical study. Four CKD cats were randomized to receive 2 × 10(6) MSCs/kg intravenously at 2, 4 and 6 weeks. Four CKD cats were randomized to receive placebo, with two cats crossing over to the MSC treatment group and one cat failing to complete the trial. Complete blood counts, chemistry and urinalysis were performed at weeks 0, 2, 4, 6 and 8. Glomerular filtration rate (GFR) via nuclear scintigraphy and urine protein:creatinine ratio (UPC) were determined at weeks 0 and 8.

Results: Six cats received three doses of allogeneic MSC culture expanded from cryopreserved adipose without adverse effects. No significant change in serum creatinine, blood urea nitrogen, potassium, phosphorus, GFR by nuclear scintigraphy, UPC or packed cell volume was seen in cats treated with MSCs. Individual changes in GFR were 12%, 8%, 8%, 2%, -13% and -67% in treated cats compared with 16%, 36% and 0% in placebo-treated cats.

Conclusions and relevance: While administration of MSC culture expanded from cryopreserved adipose was not associated with adverse effects, significant improvement in renal function was not observed immediately after administration. Long-term follow-up is necessary to determine whether MSC administration affects disease progression in cats with CKD.

Figure 1

Mesenchymal stem cells (MSCs) cultured from cryopreserved adipose were capable of trilineage differentiation. (a) MSCs formed intracellular lipid vacuoles (stained pink with Oil Red O) when incubated in adipocytic differentiation media for 21 days. (b) MSCs stained positive for calcium with alizarin red following differentiation into osteocytic phenotype after 21 days of incubation in differentiation media. (c) Cryosection of pellets of cartilage matrix (stained with toluidine blue) formed by MSCs when exposed to chondrocytic differentiation media for 21 days

Figure 2

Serum creatinine values for cats that received three doses of 2 × 10⁶ mesenchymal stem cells/kg intravenously 2 weeks apart. No significant difference in creatinine was detected

Figure 3

Results of glomerular filtration rate (GFR) determined by nuclear scintigraphy at 0 and 8 weeks for cats that received 2 × 10⁶ mesenchymal stem cells/kg intravenously at weeks 2, 4 and 6