Feline chronic kidney disease: novel approaches to etiology, specific therapy and supportive care
Date
2012
Authors
Quimby, Jessica M., author
Dow, Steve, advisor
Lappin, Michael, advisor
Lunn, Katharine, committee member
Olver, Christine, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Chronic kidney disease is one of the leading causes of morbidity and mortality in geriatric cats, affecting conservatively 30% of the population; an estimated 24 million cats nationwide in the United States. Despite the common nature of the disease, its etiology is yet unknown, and there is no definitive cure short of renal transplantation. The goals of the research described in this dissertation were to explore possible etiologies of chronic kidney disease and to develop novel treatment strategies to help cats afflicted with this disease. The first part of this project investigated a possible etiology for CKD; renal aging as manifested by telomere shortening and cellular senescence. In these studies telomere length and cellular senescence were assessed in cats with CKD in comparison to young healthy and geriatric healthy controls. Using a TELI-FISH assay to measure telomere length in specific renal cell populations, significantly shorter telomeres were found in the renal proximal and distal tubular cell population of CKD cats compared to young normal or geriatric normal cats. There was no difference between CKD cats and normal cats when liver or skin telomere length was measured. Additionally, β-galactosidase assay revealed increased cellular senescence in the kidneys of CKD cats in comparison to young normal. CKD cats tended to have increased β-galactosidase staining in comparison to normal geriatric cats, but this did not reach statistical significance. Neither telomere length nor cellular senescence were correlated with age, but the normal geriatric population available for assessment was small. It was concluded that telomere shortening and cellular senescence are present in feline CKD; future studies will be necessary to determine cause and effect aspects of this relationship. Demonstration of an association between telomere shortening, cellular senescence and feline CKD could be the foundation of new treatment strategies. Cats with CKD frequently have poor appetites and nutritional management of these patients is important. Mirtazapine is an appetite stimulant and anti-nausea medication that has recently gained popularity in veterinary medicine and anecdotally appears to be helpful for the management of appetite. However, no pharmacokinetic or pharmacodynamic information exists on the drug in cats. The aims of the second part of these studies were a) the assessment of the pharmacokinetics and pharmacodynamics of commonly prescribed doses of mirtazapine in normal cats, elderly cats and cats with CKD, and b) a placebo-controlled blinded crossover clinical trial to assess the efficacy of mirtazapine in CKD cats. These studies demonstrated that there are differences in the metabolism of mirtazapine between young normal cats, geriatric normal cats and CKD cats. Based on the pharmacokinetic studies, young cats could receive daily mirtazapine at a low dose without significant likelihood of drug accumulation whereas CKD cats should receive the drug every other day due to delayed clearance. In a subsequent clinical trial, mirtazapine significantly increased appetite, activity and weight in CKD cats when administered at a low dose every other day for three weeks. Additionally, a significant decrease in vomiting was noted. This demonstrated that mirtazapine does have significant appetite stimulating and anti-nausea effects in CKD cats. The information gathered in this body of work will help clinicians prescribe mirtazapine more effectively with a decreased incidence of unwanted drug side effects. Most importantly, it will help improve the quality of life and potentially prognosis of cats suffering from CKD. Most treatments for CKD are palliative in nature and do not directly address the underlying pathology. CKD is characterized by tubulointerstitial inflammation, fibrosis and progressive loss of renal function. Mesenchymal stem cell (MSC) therapy is thought to be anti-inflammatory, and has the potential to improve or stabilize renal function in animals with renal failure, based on evidence from rodent model studies of induced renal disease. At present, there is little published work regarding the use of MSC for treatment of naturally occurring CKD. The last section of this body of work focuses on the evaluation of MSC therapy as a novel treatment strategy for cats with CKD. A series of pilot studies was performed; a pilot study of intrarenal injection of autologous stem cells and two pilot studies of intravenously injected allogeneic cryopreserved MSC. Urinary cytokines were measured to assess intra-renal inflammation, fibrosis and vascular health and the possible effects of MSC injection on these factors. We determined that MSC could be successfully harvested and cultured from bone marrow and adipose sources, but the latter was preferred for ease of collection, expansion and superior yield. Intrarenal injection did not induce immediate or longer-term adverse effects. Two CKD cats that received intrarenal adipose-derived MSC experienced modest improvement in GFR and a mild decrease in serum creatinine concentration. In the allogeneic cryopreserved intravenous study, six cats received 2 x 106 MSC per injection and experienced a significant decrease in serum creatinine with negligible side effects. Five cats received 4 x 106 MSC per injection and side effects included vomiting during infusion and increased respiratory rate. Variable decreases in serum creatinine, increases in GFR by iohexol clearance and changes in urinary cytokines were seen. Despite the mild improvement in creatinine seen in some of the cats, none had improvement to the extent described in rodent models. While MSC therapy potentially holds promise for palliation of CKD, additional work is necessary to determine if this therapy can be manipulated to increase its efficacy. The work described in this dissertation has increased our knowledge of the biology of renal aging and its relationship to CKD. In addition it has assessed the effect of two novel treatment strategies on cats with CKD. This information will directly improve the lives of cats with CKD as well as providing a strong foundation for further research in this area.
Description
Rights Access
Subject
feline
kidney
mesenchymal stem cells
mirtazapine
telomeres