Evaluation of albuminuria and its relationship with blood pressure in dogs with chronic kidney disease

Background: Microalbuminuria and hypertension have long been associated with a guarded prognosis in human patients with a variety of diseases. In veterinary medicine, tests for microalbuminuria have been used for detecting early kidney damage, but there is little information regarding its association with high blood pressure in dogs with chronic kidney disease (CKD). Objective: The objective of this study was to evaluate albuminuria and its association with arterial hypertension in dogs with CKD. Methods: Urinary albumin:creatinine (UAC) ratio, urinary protein:creatinine (UPC) ratio, and systolic blood pressure were determined in 39 clinically healthy dogs and 40 dogs with CKD. Results: UAC in dogs with CKD (range, 0.002–7.99; median, 0.38) was statistically different from that of control dogs (range, 0.0005–0.01; median, 0.002). Microalbuminuria (UAC 0.03–0.3) and macroalbuminuria (UAC>0.3) were detected in 32.5% and 50% of dogs with CKD, respectively. Sixty percent (24/40) of dogs with CKD had systolic pressure ≥180 mmHg; in these dogs, UAC ratio (range, 0.006–7.99; median, 1.72) was significantly higher than in dogs with CKD and systolic pressure<180 mmHg (range, 0.002–4.83; median, 0.10). Of hypertensive dogs with CKD, those with UPC>1.0 usually had macroalbuminuria, those with UPC 0.5–1.0 usually had microalbuminuria, and those with UPC<0.5 usually lacked albuminuria. Conclusions: UAC ratio was higher in hypertensive than in normotensive dogs with CKD. Tests designed to detect microalbuminuria may be useful for hypertensive dogs with CKD and a UPC≤1.0 to detect the onset and magnitude of albuminuria. Once macroalbuminuria is overt, the UPC ratio itself can be used for the same purpose.     

Absence of renal cortical anisotropic backscattering artifact in feline chronic kidney disease

Renal cortical anisotropy backscattering artifact (CABA) is a focal hyperechoic region where the tubules are parallel to the incident ultrasound beam, reflecting most of the beams to the transducer. To investigate the association between chronic kidney disease (CKD) and the absence of renal CABA in cats. Ultrasonographic renal images of 40 cats with CKD (stage II-IV) and 36 clinically healthy cats were blindly evaluated by two observers to determine the visibility of renal CABA. Inter- and intraobserver agreements were evaluated using McNemar’s test. The association between the absence of renal CABA and CKD was assessed using Fisher’s exact test. Excellent intraobserver and substantial interobserver agreements were demonstrated. A significant association (P < .0001) between absent renal CABA and CKD stage was revealed in all cats. Cats with CKD had an increased risk of the absence of renal CABA (Odds ratio, 56.0; 95% CI, 13.8–227.0) compared with the clinically healthy cats. The absence of renal CABA revealed 87.5% sensitivity and 88.9% specificity to detect CKD in all cats, and 91.7% sensitivity and 83.3% specificity in aged cats. Our study demonstrated a correlation between feline CKD and the absence of renal CABA, providing a feasible and alternative method for feline CKD evaluation.     

Comparative study of chronic kidney disease in dogs and cats: Induction of myofibroblasts

We investigated the kidneys of dogs and cats to clarify whether renal myofibroblasts induction is associated with the severity of chronic kidney disease (CKD). Immunohistochemical expression of myofibroblast markers, α-smooth muscle actin (SMA) and vimentin, were evaluated quantitatively. The degrees of glomerulosclerosis, glomerular hypertrophy, interstitial cell infiltration, and interstitial fibrosis were also evaluated quantitatively. The plasma creatinine (pCre) concentrations correlated with glomerulosclerosis, cell infiltration, and fibrosis in dogs, and only with fibrosis in cats. The α-SMA expression correlated with pCre, glomerulosclerosis, cell infiltration, and fibrosis in dogs, and with pCre and fibrosis in cats. Tubular vimentin expression correlated with fibrosis in cats, but not in dogs. Interstitial vimentin expression correlated with pCre, glomerulosclerosis, cell infiltration, and fibrosis in dogs, but only with pCre in cats. In conclusion, it was suggested that the severity of CKD in dogs and cats was mediated by different pathways associated with myofibroblasts expression.     

Shear wave elastography evaluation of cats with chronic kidney disease

Chronic kidney disease (CKD) is a major health condition in cats that can lead to poor quality of life and financial implications for therapy. Currently staging and identification of CKD is limited by diagnostic testing such as creatinine and urine-specific gravity, which do not change until late in the disease course. Other methods to evaluate CKD would be valuable in the clinical setting. Shear wave elastography is one novel ultrasound method, which has shown promise in identifying increases in tissue stiffness and identifying CKD in people. As CKD is often histologically characterized by tubulointerstitial fibrosis, shear wave elastography has the potential to identify CKD and differentiate between stages of CKD in cats. This prospective observational case-control study with 78 cats found no difference in shear wave velocities between groups (P = 0.33), a contradictory finding to one prior publication. There was no effect of weight (P = 0.65), nor the presence of mineralization (P = 0.31) or infarction (P = 0.52) on cortical shear wave velocities. There was a significant effect of age on shear wave velocity (P = 0.018) where velocities increased with age. The intraclass correlation coefficient was only moderate (0.62). Possible reasons for the difference in results between our work and that published prior, include differences in methodology and differences in instrumentation. Variability in measurements in our population may be due to the effects of respiratory motion or limitations in shear wave elastography software. As such, shear wave elastography is not currently recommended as a tool to evaluate CKD in cats and further work is necessary.     

A longitudinal study on the acceptance and effects of a therapeutic renal food in pet dogs with IRIS‐Stage 1 chronic kidney disease

Currently, nutritional management is recommended when serum creatinine (Cr) exceeds 1.4 mg/dl in dogs with IRIS‐Stage 2 chronic kidney disease (CKD) to slow progressive loss of kidney function, reduce clinical and biochemical consequences of CKD, and maintain adequate nutrition. It is unknown if dietary interventions benefit non‐azotemic dogs at earlier stages. A prospective 12‐month feeding trial was performed in client‐owned dogs with IRIS‐Stage 1 CKD (n = 36; 20 had persistently dilute urine with urine specific gravity (USG) <1.020 without identifiable non‐renal cause; six had persistent proteinuria of renal origin with urine protein creatinine (UPC) ratio >0.5; 10 had both). Ease of transition to therapeutic renal food and effects on renal biomarkers and quality of life attributes were assessed. Dogs were transitioned over 1 week from grocery‐branded foods to renal food. At 0, 3, 6, 9, and 12‐months a questionnaire to assess owner's perception of their pet's acceptance of renal food and quality of life was completed. Renal biomarkers, including serum Cr, blood urea nitrogen (BUN), and symmetric dimethylarginine (SDMA), and USG and UPC ratio were measured. Of 36 dogs initially enrolled, 35 (97%) dogs were transitioned to therapeutic renal food. Dogs moderately or extremely liked the food 88% of the time, ate most or all of the food 84% of the time, and were moderately or extremely enthusiastic while eating 76% of the time. All renal biomarkers (Cr, BUN, and SDMA) were decreased (p ≤ .05) from baseline at 3‐months, and remained decreased from baseline at 12‐months in dogs completing the study (n = 20). Proteinuria was reduced in 12 of 16 dogs (p = .045) with proteinuria. Owners reported improvement in overall health and quality of life attributes, and hair and coat quality (all p < .01). In summary, dogs with IRIS‐Stage 1 CKD readily transition to renal food. Decreasing serum biomarker concentrations and reduction in proteinuria suggest stabilized kidney function.     

Clinical findings, rhinoscopy and histological evaluation of 54 dogs with chronic nasal disease

Nasal diseases are very common in dogs and rhinoscopy is often required for a definitive diagnosis. Rhinoscopy, while superficial in nature, can guide the clinician to the final diagnosis. In this study, rhinoscopy was performed on 54 dogs with symptoms of chronic nasopharyngeal disease. The endoscopic diagnosis of neoplasia or chronic nasal inflammation was validated with histological examination of pathological samples, in order to evaluate the degree of concordance between endoscopic findings and histological diagnosis. The agreement between endoscopy and histology was tested by application of Cohen''s kappa coefficient. We conclude that correlation between endoscopic results and histological diagnosis, expressed by a Cohen''s kappa coefficient of 0.73, is only possible with a constant cooperation between the clinician and the pathologist.     

Treatment response and long term follow up in nineteen dogs diagnosed with chronic enteropathy in Australia

Chronic enteropathy (CE) in dogs is common worldwide, but little data is available from Australia. The aim of this study was to describe treatment response and long‐term outcome in a cohort of dogs with CE. Dogs were prospectively enrolled at Murdoch University and the University of Melbourne. After diagnostic investigation to rule out diseases other than CE, dogs underwent sequential therapeutic trials until achieving a clinical response (diet then antibiotics, and finally immunosuppressants). Success was defined as 75% reduction of clinical severity for a minimum of five weeks. A total of 21 dogs were enrolled, and 19 completed the study. One dog was euthanised for lack of response to treatment and one excluded for lack of owner compliance. Most dogs responded to diet (n = 10), followed by antibiotics (n = 7) and immunosuppressants (n = 2). Long‐term remission (median 21.1 months, [3.0‐44.7]) was achieved in eight out of ten dietary responders without additional treatment. In contrast, only two dogs with antibiotic response remained in long‐term remission, of which one needed on‐going antibiotic treatment. Longer term remission was achieved in the two dogs treated with immunosuppressants with on‐going low dose therapy. This study concludes that most dogs referred for CE in Australia respond to dietary treatment (even after previous dietary interventions), and remission is long‐term compared to dogs treated with an antibiotic. Furthermore, the need for long‐term antibiotics in some dogs to maintain response may lead to antibiotic resistance. This study supports adequate dietary trials for CE in dogs, and a need for alternative second‐line treatments.     

Urinary albumin and transferrin as early diagnostic markers of chronic kidney disease

Feline renal diseases are increasingly noted in veterinary practice. It is important to diagnose and identify the pathological basis of renal dysfunction accurately at an early stage, but there are only a few reports on this area in clinical veterinary medicine. We investigated the efficacy of measurement of urinary albumin (u-Alb) and urinary transferrin (u-Tf) for early diagnosis using 5-µl urine samples collected noninvasively by catheterization from normal (IRIS stage I) cats and cats with stage I chronic kidney disease (CKD). The u-Alb levels in normal and stage I CKD cats were 6.0 ± 4.5 and 11.2 ± 8.4 mg/dl, respectively, and the u-Tf levels were 0.09 ± 0.42 and 0.52 ± 0.79 mg/dl, respectively. Based on ROC curve analysis, the sensitivity and specificity of u-Alb and u-Tf were higher than those of the currently used biomarker, the plasma creatinine level. The sensitivity of u-Alb was higher than that of u-Tf, whereas the specificity of u-Tf was higher than that of u-Alb. The validity of the threshold albumin level (20 mg/dl) was confirmed by measurements using SDS-PAGE. Since leakage of u-Tf in urine precedes leakage of u-Alb, inclusion of u-Tf in biochemistry tests may be appropriate for IRIS staging as a diagnostic marker of early diagnosis of renal disorder in cats.     

Serum cystatin C concentration can be used to evaluate glomerular filtration rate in small dogs

Serum cystatin C levels (CysC) are used in human medicine to document progressive kidney failure. Although CysC are not thought to be useful for the diagnosis of kidney dysfunction in dogs, there has been no specific consideration of body weight as a confounding issue. The aim of this study was to assess that the utility of CysC for the diagnosis of decreased glomerular filtration rate (GFR) in smaller vs. larger dogs. In clinically healthy dogs, serum creatinine (Cre) and CysC correlate directly with body weight; we found that dogs weighing <20 kg had significantly lower CysC than those weighing ≥20 kg (0.27 ± 0.07 vs. 0.34 ± 0.05 mg/l, respectively, P<0.001). In dogs weighing <20 kg, CysC had superior diagnostic accuracy for the detection of mildly decreased plasma iohexol clearance (PCio) (<1.8 ml/min/kg) compared with Cre (sensitivity 100% vs. 80.9% and specificity 100% vs. 85.7%); this was not true for dogs weighing ≥20 kg. Additionally, using a cut-off PCio of <1.8 ml/min/kg, the area under receiver-operating characteristics curve (AUC) of CysC was significantly higher than that of Cre in dogs weighing <20 kg (P<0.05); this was not true for dogs weighing ≥20 kg (P=0.695). In conclusion, CysC is a useful marker for the detection of a mild decreasing GFR compared with Cre in dogs weighing <20 kg.     

Predictive model for the detection of pulmonary hypertension in dogs with myxomatous mitral valve disease

Pulmonary hypertension (PH) often occurs due to a left heart disease, such as myxomatous mitral valve disease (MMVD), in dogs and is diagnosed using Doppler echocardiography and estimated pulmonary arterial pressure. Diagnosis of PH in dogs requires expertise in echocardiography: however, the examination for PH is difficult to perform in a clinical setting. Thus, simple and reliable methods are required for the diagnosis of PH in dogs. The purpose of this study was to develop models using multiple logistic regression analysis to detect PH due to left heart disease in dogs with MMVD without echocardiography. The medical records of dogs with MMVD were retrospectively reviewed, and 81 dogs were included in this study and classified into PH and non-PH groups. Bivariate analysis was performed to compare all parameters between the groups, and variables with P values of <0.25 in bivariate analysis were included in multiple logistic regression analysis to develop models for the detection of PH. In multiple logistic regression analysis, the model included a vertebral heart scale short axis of >5.2 v, and a length of sternal contact of >3.3 v was considered suitable for the detection of PH. The predictive accuracy of this model (85.9%) was judged statistically adequate, and therefore, this model may be useful to screen for PH due to left heart disease in dogs with MMVD without echocardiography.     

Relationship of glomerular filtration rate based on serum iodixanol clearance to IRIS staging in cats with chronic kidney disease

We examined the correlation between the glomerular filtration rate (GFR) estimated from an equation based on the serum iodixanol clearance technique and International Renal Interest Society (IRIS) stages of chronic kidney disease (CKD) in cats. The equation included the injection dose, sampling time, serum concentration and estimated volume of distribution (Vd) of the isotonic, nonionic, contrast medium iodixanol as a test tracer. The percent changes in the median basal GFR values calculated from the equation in CKD cats resembled those of IRIS stages 1–3. These data validate the association between the GFR derived from the simplified equation and IRIS stages based on the serum creatinine concentration in cats with CKD. They describe the GFR ranges determined using single-sample iodixanol clearance for healthy cats and cats with various IRIS stages of CKD.     

Cardiovascular and renal effects of constant rate infusions of remifentanil, dexmedetomidine and their combination in dogs anesthetized with sevoflurane

We evaluated changes in cardiovascular and renal functions as well as arginine vasopressin (AVP) secretion, with remifentanil and dexmedetomidine administration alone or in combination in sevoflurane-anesthetized dogs. Six healthy adult Beagle dogs received one of the following four treatments in a randomized crossover study: saline (C), remifentanil alone at successively increasing doses (R; 0.15, 0.60, and 2.40 µg/kg/min), dexmedetomidine alone (D; 0.5 µg/kg intravenously for initial 10 min followed by a constant rate infusion at 0.5 µg/kg/hr), and a combination of remifentanil and dexmedetomidine at the above-mentioned doses (RD). Sevoflurane doses were adjusted to 1.5 times of minimum alveolar concentration (MAC) equivalent according to MAC-sparing effects with remifentanil and dexmedetomidine as previously reported. Cardiovascular measurements, renal function data, and plasma AVP concentrations were determined before and every 60 min until 180 min after drug administration as per each treatment. In the R, D and RD, heart rate significantly decreased and mean arterial pressure significantly increased from baseline or with C. Cardiac index significantly decreased and systemic vascular resistance index increased with D and RD. Oxygen extraction ratio, renal blood flow, and glomerular filtration rate were not affected. The plasma AVP concentrations significantly decreased in D and RD, but increased in R. Only in D, the natriuresis was elicited. The combination of remifentanil and dexmedetomidine in sevoflurane-anesthetized dogs was acceptable in terms of the hemodynamics, oxygenation, and renal function. Remifentanil may interfere with dexmedetomidine-induced diuresis and inhibition of AVP secretion.     

Evaluation of the degree and distribution of lymphangiectasia in full-thickness canine small intestinal specimens diagnosed with lymphoplasmacytic enteritis and granulomatous lymphangitis

Intestinal lymphangiectasia (IL) is often observed in dogs with chronic small intestinal diseases. Hypoplasia of the lymphatic vessel due to decreased lymphangiogenesis, which has been suggested in human idiopathic IL, may contribute to the pathogenesis of canine IL. This study aimed to evaluate the diameter and number of lymphatic vessels in full-thickness small intestinal specimens of dogs with IL. Immunohistochemical labeling of lymphatic endothelial cell markers was performed on retrospectively retrieved full-thickness small intestinal specimens. Sixteen dogs with histologically confirmed IL were included, of which 10 had lymphoplasmacytic enteritis (LPE), and six had granulomatous lymphangitis (GL). Nine dogs that died from non-gastrointestinal disorders and with little or no abnormalities in the small intestine were used as controls. Lymphatic vessel diameters in dogs with IL were significantly increased in all layers of the small intestine, including the villus lacteal, lamina propria, submucosa, muscularis, and mesentery, compared with controls (all P<0.01). There was no significant difference in the lymphatic vessel diameters between dogs with LPE and GL (all P>0.05). There was no significant difference in the number of lymphatic vessels between dogs with IL and the controls in all layers of the small intestine (all P>0.05). This study demonstrated that IL was observed in all layers of the small intestine, including the submucosa, muscularis, and mesentery, independent of the underlying disease. Factors other than reduced lymphatic vessels would contribute to the pathogenesis of IL in dogs.     

Aldosterone and the mineralocorticoid receptor in renal injury: A potential therapeutic target in feline chronic kidney disease

There is a growing body of experimental and clinical evidence supporting mineralocorticoid receptor (MR) activation as a powerful mediator of renal damage in laboratory animals and humans. Multiple pathophysiological mechanisms are proposed, with the strongest evidence supporting aldosterone-induced vasculopathy, exacerbation of oxidative stress and inflammation, and increased growth factor signalling promoting fibroblast proliferation and deranged extracellular matrix homeostasis. Further involvement of the MR is supported by extensive animal model experiments where MR antagonists (such as spironolactone and eplerenone) abrogate renal injury, including ischaemia-induced damage. Additionally, clinical trials have shown MR antagonists to be beneficial in human chronic kidney disease (CKD) in terms of reducing proteinuria and cardiovascular events, though current studies have not evaluated primary end points which allow conclusions to made about whether MR antagonists reduce mortality or slow CKD progression. Although differences between human and feline CKD exist, feline CKD shares many characteristics with human disease including tubulointerstitial fibrosis. This review evaluates the evidence for the role of the MR in renal injury and summarizes the literature concerning aldosterone in feline CKD. MR antagonists may represent a promising therapeutic strategy in feline CKD.