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Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study

Background: Chronic tubulointerstitial fibrosis is a common final pathway leading to end stage kidney disease in cats and has no effective treatment. The use of cell-based molecules to treat kidney fibrosis may be a promising approach. The objectives were to test the effects of intra-renal chemokine...

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Autores principales: Bennington, Julie, Lankford, Shannon, Magalhaes, Renata S., Shankle, Douglas, Fanning, Jason, Kartini, Cucu, Suparto, Irma, Kusumawardhani, Winda, Putra, M. ArRaniri, Mariya, Silmi, Badlani, Gopal, Williams, J. Koudy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969654/
https://www.ncbi.nlm.nih.gov/pubmed/33748219
http://dx.doi.org/10.3389/fvets.2021.646087
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author Bennington, Julie
Lankford, Shannon
Magalhaes, Renata S.
Shankle, Douglas
Fanning, Jason
Kartini, Cucu
Suparto, Irma
Kusumawardhani, Winda
Putra, M. ArRaniri
Mariya, Silmi
Badlani, Gopal
Williams, J. Koudy
author_facet Bennington, Julie
Lankford, Shannon
Magalhaes, Renata S.
Shankle, Douglas
Fanning, Jason
Kartini, Cucu
Suparto, Irma
Kusumawardhani, Winda
Putra, M. ArRaniri
Mariya, Silmi
Badlani, Gopal
Williams, J. Koudy
author_sort Bennington, Julie
collection PubMed
description Background: Chronic tubulointerstitial fibrosis is a common final pathway leading to end stage kidney disease in cats and has no effective treatment. The use of cell-based molecules to treat kidney fibrosis may be a promising approach. The objectives were to test the effects of intra-renal chemokine CXCL12 injection in a pre-clinical cat model of unilateral ischemia/reperfusion (I/R)-induced kidney fibrosis and then, within a clinical pilot study, test the safety/feasibility of CXCL12 injection in cats that might have early chronic kidney disease (CKD). Methods: Pre-clinical: Thirty cats received intra-renal injection of 100, 200, or 400 ng of recombinant human CXCL12, or sterile saline, into the I/R kidney 70 days post-injury, or were non-injured, non-injected controls (n = 6/group). Kidney collagen content was quantified 4 months post-treatment using Masson's Trichrome and Picrosirius Red (PSR) stained tissues. In a separate study (n = 2) exploring short-term effects of CXCL12, 200 ng CXCL12 was injected into I/R kidneys and then harvested either 30 min (n = 1) or 1 month (n = 1) post-injection. Kidney concentrations of CXCL12, matrix metalloproteinase 1 (MMP-1), and lysyl oxidase-like enzyme 2 (LOXL-2) were quantified via ELISA. Clinical Pilot: 14 client-owned cats with potential early kidney disease received a single-treatment, bilateral intra-renal injection of 200 ng CXCL12 (n = 7), or received no injection (n = 7). Blood/urine samples were collected monthly for 9 months to assess renal function and CKD staging. Results: Pre-clinical: I/R increased the affected kidney collagen content, which both mid and high doses of CXCL12 restored to normal (ps < 0.05 vs. untreated). I/R increased collagen fiber width, which both mid and high doses of CXCL12 restored to normal (p < 0.001 vs. untreated). Early changes in kidney MMP-1, associated with collagen breakdown, and subsequent decreases in LOXL-2, associated with collagen cross-linking, in response to CXCL12 treatment may contribute to these findings. Clinical Pilot: Bilateral intra-renal injection of CXCL12 using ultrasound guidance in cats with CKD was feasible and safe in a general practice clinical setting with no obvious side effects noted during the 9-month follow-up period. Conclusions: Intra-renal injection of CXCL12 may prove to be an effective treatment for kidney fibrosis in cats with CKD. Additional mechanistic and clinical evaluations are needed.
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spelling pubmed-79696542021-03-19 Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study Bennington, Julie Lankford, Shannon Magalhaes, Renata S. Shankle, Douglas Fanning, Jason Kartini, Cucu Suparto, Irma Kusumawardhani, Winda Putra, M. ArRaniri Mariya, Silmi Badlani, Gopal Williams, J. Koudy Front Vet Sci Veterinary Science Background: Chronic tubulointerstitial fibrosis is a common final pathway leading to end stage kidney disease in cats and has no effective treatment. The use of cell-based molecules to treat kidney fibrosis may be a promising approach. The objectives were to test the effects of intra-renal chemokine CXCL12 injection in a pre-clinical cat model of unilateral ischemia/reperfusion (I/R)-induced kidney fibrosis and then, within a clinical pilot study, test the safety/feasibility of CXCL12 injection in cats that might have early chronic kidney disease (CKD). Methods: Pre-clinical: Thirty cats received intra-renal injection of 100, 200, or 400 ng of recombinant human CXCL12, or sterile saline, into the I/R kidney 70 days post-injury, or were non-injured, non-injected controls (n = 6/group). Kidney collagen content was quantified 4 months post-treatment using Masson's Trichrome and Picrosirius Red (PSR) stained tissues. In a separate study (n = 2) exploring short-term effects of CXCL12, 200 ng CXCL12 was injected into I/R kidneys and then harvested either 30 min (n = 1) or 1 month (n = 1) post-injection. Kidney concentrations of CXCL12, matrix metalloproteinase 1 (MMP-1), and lysyl oxidase-like enzyme 2 (LOXL-2) were quantified via ELISA. Clinical Pilot: 14 client-owned cats with potential early kidney disease received a single-treatment, bilateral intra-renal injection of 200 ng CXCL12 (n = 7), or received no injection (n = 7). Blood/urine samples were collected monthly for 9 months to assess renal function and CKD staging. Results: Pre-clinical: I/R increased the affected kidney collagen content, which both mid and high doses of CXCL12 restored to normal (ps < 0.05 vs. untreated). I/R increased collagen fiber width, which both mid and high doses of CXCL12 restored to normal (p < 0.001 vs. untreated). Early changes in kidney MMP-1, associated with collagen breakdown, and subsequent decreases in LOXL-2, associated with collagen cross-linking, in response to CXCL12 treatment may contribute to these findings. Clinical Pilot: Bilateral intra-renal injection of CXCL12 using ultrasound guidance in cats with CKD was feasible and safe in a general practice clinical setting with no obvious side effects noted during the 9-month follow-up period. Conclusions: Intra-renal injection of CXCL12 may prove to be an effective treatment for kidney fibrosis in cats with CKD. Additional mechanistic and clinical evaluations are needed. Frontiers Media S.A. 2021-03-04 /pmc/articles/PMC7969654/ /pubmed/33748219 http://dx.doi.org/10.3389/fvets.2021.646087 Text en Copyright © 2021 Bennington, Lankford, Magalhaes, Shankle, Fanning, Kartini, Suparto, Kusumawardhani, Putra, Mariya, Badlani and Williams. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Veterinary Science
Bennington, Julie
Lankford, Shannon
Magalhaes, Renata S.
Shankle, Douglas
Fanning, Jason
Kartini, Cucu
Suparto, Irma
Kusumawardhani, Winda
Putra, M. ArRaniri
Mariya, Silmi
Badlani, Gopal
Williams, J. Koudy
Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study
title Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study
title_full Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study
title_fullStr Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study
title_full_unstemmed Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study
title_short Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study
title_sort chemokine therapy in cats with experimental renal fibrosis and in a kidney disease pilot study
topic Veterinary Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969654/
https://www.ncbi.nlm.nih.gov/pubmed/33748219
http://dx.doi.org/10.3389/fvets.2021.646087
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