Dual soluble epoxide hydrolase inhibitor - farnesoid X receptor agonist interventional treatment attenuates renal inflammation and fibrosis.

Introduction: Renal fibrosis associated with inflammation is a critical pathophysiological event in chronic kidney disease (CKD). We have developed DM509 which acts concurrently as a farnesoid X receptor agonist and a soluble epoxide hydrolase inhibitor and investigated DM509 efficacy as an interventional treatment using the unilateral ureteral obstruction (UUO) mouse model. Methods: Male mice went through either UUO or sham surgery. Interventional DM509 treatment (10mg/kg/d) was started three days after UUO induction and continued for 7 days. Plasma and kidney tissue were collected at the end of the experimental protocol. Results: UUO mice demonstrated marked renal fibrosis with higher kidney hydroxyproline content and collagen positive area. Interventional DM509 treatment reduced hydroxyproline content by 41% and collagen positive area by 65%. Renal inflammation was evident in UUO mice with elevated MCP-1, CD45-positive immune cell positive infiltration, and profibrotic inflammatory gene expression. DM509 treatment reduced renal inflammation in UUO mice. Renal fibrosis in UUO was associated with epithelial-to-mesenchymal transition (EMT) and DM509 treatment reduced EMT. UUO mice also had tubular epithelial barrier injury with increased renal KIM-1, NGAL expression. DM509 reduced tubular injury markers by 25-50% and maintained tubular epithelial integrity in UUO mice. Vascular inflammation was evident in UUO mice with 9 to 20-fold higher ICAM and VCAM gene expression which was reduced by 40-50% with DM509 treatment. Peritubular vascular density was reduced by 35% in UUO mice and DM509 prevented vascular loss. Discussion: Interventional treatment with DM509 reduced renal fibrosis and inflammation in UUO mice demonstrating that DM509 is a promising drug that combats renal epithelial and vascular pathological events associated with progression of CKD.

Successful management of acute bilirubin encephalopathy in a dog with immune-mediated hemolytic anemia using therapeutic plasma exchange.

OBJECTIVE: To describe the successful management of acute bilirubin encephalopathy in a dog with immune-mediated hemolytic anemia (IMHA) treated with therapeutic plasma exchange (TPE) in conjunction with conventional medical management. CASE SUMMARY: A 6-year-old neutered male Australian Cattle Dog diagnosed with IMHA developed severe hyperbilirubinemia and stupor within the first 48 hours of implementing immunosuppressive therapy consisting of corticosteroids and mycophenolate. The patient received 4 blood transfusions during this period, but remained severely anemic PCV (18%) and experienced a subsequent increase in total bilirubin from 78 µmol/L (4.6 mg/dL) to a peak value of 1,563 µmol/L (91.4 mg/dL). The patient's neurological status rapidly deteriorated, resulting in lateral recumbency, vertical nystagmus, extensor rigidity, and stuporous mentation. Over the next 3 days, TPE was provided once every 24 hours, decreasing serum bilirubin, immunoglobulin G (IgG), and immunoglobulin M (IgM). The patient's red blood cell (RBC) transfusion requirements decreased immediately, requiring only 1 transfusion over the next 7 days that was required due to procedure-associated blood loss. Gradual neurological improvement was noted as serum bilirubin decreased. A brain magnetic resonance imaging (MRI) did not reveal any structural abnormalities and the patient was discharged after 11 days of hospitalization. Following discharge, the patient had complete remission of IMHA without any residual neurological deficits. Therapeutic plasma exchange played an integral role in case management and was successful in reducing bilirubin, IgG, and IgM. NEW OR UNIQUE INFORMATION PROVIDED: Bilirubin encephalopathy has been rarely reported in small animal medicine and cases have been limited to postmortem documentation. This is the first suspected case of acute bilirubin encephalopathy in a dog that survived and describes the clinical course of disease. The kinetics of serum bilirubin, IgG, and IgM concentrations before and after TPE and throughout the hospitalization period are also described.

Feline acute kidney injury: 1. Pathophysiology, etiology and etiology-specific management considerations.

PRACTICAL RELEVANCE: Acute kidney injury (AKI) is a frequently recognized disease process in cats that requires immediate and aggressive intervention. A thorough understanding of the pathophysiologic processes underlying AKI and familiarity with the most common etiologies are essential for providing the most effective and timely therapy. Possessing this knowledge will also allow a more accurate prognosis to be given, and afford the best chance of a favorable outcome. CLINICAL CHALLENGES: Feline patients often present with vague signs of AKI, which may delay treatment and adversely affect the prognosis. Their response to injury and treatment is often different to that of other species. AUDIENCE: This two-part review article is directed at small animal practitioners as well as specialists. Part 1 reviews mechanisms underlying AKI in the cat, as well as etiologies and treatments related to some specific causes of AKI. EVIDENCE BASE: The veterinary literature is limited with regards to the pathophysiology of AKI unique to the cat. However, there are numerous feline studies evaluating causes of AKI.

Feline acute kidney injury: 2. Approach to diagnosis, treatment and prognosis.

PRACTICAL RELEVANCE: Feline acute kidney injury (AKI) is a commonly recognized problem in small animal practice that requires prompt diagnosis and directed therapy. There are many treatment methods with which practitioners should be familiar, including medical options, surgical interventions and renal replacement therapy (dialysis). It is important to know which option is most appropriate for each cause and stage of AKI to deliver the most effective therapy. CLINICAL CHALLENGES: AKI can cause vague clinical signs, but a vast array of life-threatening sequelae. Rapid recognition of potential complications and knowledge of treatment options is imperative for successful management. Feline patients also require an understanding of their unique physiology as it relates to the therapeutic plan. AUDIENCE: This two-part review article is directed at small animal practitioners as well as specialists. Part 2 discusses the diagnosis of AKI in cats using physical examination findings, clinicopathologic results and imaging modalities. The treatment of AKI and its sequelae is also reviewed, with information on recent advances in this area. EVIDENCE BASE: While there is very limited data comparing the outcomes of various treatment options, there is literature addressing the use of several medications, as well as renal replacement therapy, in cats.

Estimation of glomerular filtration rate in dogs by plasma clearance of gadolinium diethylenetriamine pentaacetic acid as measured by use of an ELISA.

OBJECTIVE-To evaluate use of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) to estimate glomerular filtration rate (GFR) by plasma clearance and use of an ELISA as the method of Gd-DTPA quantification. ANIMALS-16 dogs of various sexes and breeds (12 dogs were clinically normal, and 4 dogs were polyuric and polydipsic with no other clinical or biochemical abnormalities). PROCEDURES-GFR was estimated by measuring the plasma clearance of Gd-DTPA and iohexol by use of an ELISA and high-performance liquid chromatography (HPLC), respectively. The GFR was determined by use of a 1-compartment model for both methods. The GFRs obtained by Gd-DTPA plasma clearance were compared with those obtained by iohexol plasma clearance by use of correlation analysis, paired t tests, and limits of agreement analysis. A paired t test was used to evaluate differences between the 2 plasma clearance methods. RESULTS-A strong linear correlation (r(2) = 0.90) was found between GFRs derived from the plasma clearance of Gd-DTPA and those derived from the plasma clearance of iohexol. By use of limits of agreement analysis, almost all (13/14) dogs had Gd-DTPA GFRs that were within 12% of iohexol GFRs. The remaining dog had a Gd-DTPA GFR that was 45% higher than the iohexol GFR. There was no significant difference between Gd-DTPA GFRs and those obtained with iohexol. CONCLUSIONS AND CLINICAL RELEVANCE-This study revealed that plasma clearance of Gd-DTPA measured by use of an ELISA is an effective method to estimate GFR in dogs because it compared favorably with results for the iohexol-HPLC method.