Reidun Heiene

ISFM AND AAFP CONSENSUS GUIDELINES Long-term use of NSAIDs in cats

NSAIDs and cats Non-steroidal anti-inflammatory drugs (NSAIDs) are an important class of drug in feline medicine, having analgesic, anti-inflammatory and antipyretic activity. While most published data on their use in this species relate to short-term (often perioperative) therapy, there is increasing evidence of the value of these drugs in treating chronic pain in cats (for example, that associated with degenerative joint disease), and some NSAIDs have now become licensed for long-term use in cats in some geographies. Most of our knowledge of therapeutic mechanisms or adverse drug reactions associated with NSAIDs is extrapolated from work in other species, and there is a paucity of published data relating to cats. Guidelines These guidelines have been drawn together by an expert panel, which have reviewed the current literature on long-term NSAID use in cats and other species, and developed guidance on their use based on this information. The aim is to provide practical information for veterinarians to encourage appropriate NSAID therapy whenever cats will benefit from the use of these drugs.

Glomerular filtration rate estimated by 3-sample plasma clearance of iohexol in 118 healthy dogs.

BACKGROUND Glomerular filtration rate (GFR) decreases in the aging human kidney, but limited data exist in dogs. HYPOTHESIS There is an effect of age and body size on estimated GFR in healthy dogs. ANIMALS One hundred and eighteen healthy dogs of various breeds, ages, and body weights presenting to 3 referral centers. METHODS GFR was estimated in clinically healthy dogs between 1 and 14 years of age. GFR was estimated from the plasma clearance of iohexol, by a compartmental model and an empirical correction formula, normalized to body weight in kilograms or liters of extracellular fluid volume (ECFV). For data analysis, dogs were divided into body weight quartiles 1.8-12.4, 13.2-25.5, 25.7-31.6, and 32.0-70.3 kg. RESULTS In the complete data set, there was no trend toward lower estimated GFR/kg or GFR/ECFV with increasing age. GFR decreased with age in dogs in the smallest weight quartile only. A significant negative linear relationship was detected between body weight and estimated GFR/kg and GFR/ECFV. Reference ranges in different weight quartiles were 1.54-4.25, 1.29-3.50, 0.95-3.36, and 1.12-3.39 mL/min/kg, respectively. Standardization to ECFV rather than kilogram body weight did not produce substantial changes in the relationships between GFR estimates and age or weight. CONCLUSIONS AND CLINICAL IMPORTANCE Interpretation of GFR results for early diagnosis of renal failure should take into account the weight and the age of the patient for small dogs.

Estimation of glomerular filtration rate via 2- and 4-sample plasma clearance of iohexol and creatinine in clinically normal cats.

OBJECTIVE To compare 2 methods for estimation of glomerular filtration rate (GFR), study the effects of age and body size on GFR estimates, and provide a reference range for estimated GFR in clinically normal cats. ANIMALS 57 cats. PROCEDURES In each cat, GFR was estimated via plasma clearance of iohexol and creatinine. Results of a 1-compartmental model (CL1comp) were calibrated to a trapezoidal method estimate (CLtrap) by use of a correction formula applicable to dogs or humans and standardized to body weight; for iohexol clearance, data were also standardized to extracellular fluid volume (ECFV). For all 57 cats, method comparison was performed via agreement analysis. Reference ranges for GFR derived by the different methods were established by use of data from a subset of 51 cats after exclusion of 6 cats that were azotemic, Birman, or both. RESULTS In 57 cats, mean CLtrap of creatinine was 0.29 mL/min/kg (13%) higher than CLtrap of iohexol. In 51 nonazotemic cats, mean CLtrap was 2.26 mL/min/kg for iohexol (reference range, 1.02 to 3.50 mL/min/kg) and 2.55 mL/min/kg for creatinine (reference range, 1.27 to 3.83 mL/min/kg). Values of GFR/kg or GFR standardized to liters of ECFV did not decrease with increasing age. A negative linear relationship was detected between body weight and estimated GFR/kg or GFR standardized to liters of ECFV. CONCLUSIONS AND CLINICAL RELEVANCE Reference ranges for estimated GFR via plasma clearance of iohexol and creatinine should facilitate early detection of impaired renal function in cats, although body weight should be taken into account.

Evaluation of Kidney Injury in Dogs with Pyometra Based on Proteinuria, Renal Histomorphology, and Urinary Biomarkers

BACKGROUND Proteinuria is a feature of pyometra-associated renal dysfunction, but its prevalence and clinical relevance are not well characterized. OBJECTIVES To define which subset of dogs with pyometra has clinically relevant kidney injury by quantification of proteinuria; light, immunofluorescence, and electron microscopic examination of kidney biopsy specimens; and measurement of urinary biomarkers. ANIMALS Forty-seven dogs with pyometra. Ten clinically healthy intact bitches of comparable age. METHODS Prospective study. Routine clinicopathological variables including urinary protein to creatinine ratio (UPC) were analyzed. Validated assays were used to quantify urinary biomarkers for glomerular (urinary albumin, urinary immunoglobulin G, urinary C-reactive protein, urinary thromboxane B(2)) and tubular function (urinary retinol-binding protein, urinary N-acetyl-β-d-glucosaminidase). Kidney biopsy specimens from 10 dogs with pyometra and dipstick urine protein concentrations of 2+ or 3+ were collected during ovariohysterectomy. Urinalysis was repeated within 3 weeks after surgery in 9 of the 10 dogs. RESULTS UPC (median, range) was significantly higher in dogs with pyometra (0.48, 0.05-8.69) compared with healthy bitches (0.08, 0.02-0.16) (P < .01). Twenty-two of 47 dogs with pyometra had UPC>0.5, 12 had UPC>1.0, and 7 had UPC>2.0. Glomerulosclerosis and tubulointerstitial nephritis were common kidney biopsy findings in proteinuric dogs with pyometra. Dogs with glomerulosclerosis (5/10), either global or focal and segmental, had UPC>1.0 at ovariohysterectomy and afterward. Dogs with structural glomerular and tubular changes mostly had urinary biomarker to creatinine ratios above the 75th percentile. CONCLUSION Dogs with pyometra and UPC>1.0 or high ratios of urinary biomarkers appear likely to have clinically relevant renal histologic lesions and require monitoring after ovariohysterectomy. Future studies should evaluate the role of pyometra-associated pathogenic mechanisms in causing or exacerbating focal and segmental glomerulosclerosis in dogs.

Renal histomorphology in dogs with pyometra and control dogs, and long term clinical outcome with respect to signs of kidney disease

BackgroundAge-related changes in renal histomorphology are described, while the presence of glomerulonephritis in dogs with pyometra is controversial in current literature.MethodsDogs with pyometra were examined retrospectively for evidence of secondary renal damage and persisting renal disease through two retrospective studies. In Study 1, light microscopic lesions of renal tissue were graded and compared in nineteen dogs with pyometra and thirteen age-matched control bitches. In Study 2, forty-one owners of dogs with pyometra were interviewed approximately 8 years after surgery for evidence ofclinical signs of renal failure in order to document causes of death/euthanasia.ResultsInterstitial inflammation and tubular atrophy were more pronounced in dogs with pyometra than in the control animals. Glomerular lesions classified as glomerular sclerosis were present in both groups. No unequivocal light microscopic features of glomerulonephritis were observed in bitches in any of the groups.Two bitches severely proteinuric at the time of surgery had developed end stage renal disease within 3 years. In five of the bitches polyuria persisted after surgery. Most bitches did not show signs of kidney disease at the time of death/euthanasia.ConclusionTubulointerstitial inflammation was observed, but glomerular damage beyond age-related changes could not be demonstrated by light microscopy in the dogs with pyometra. However, severe proteinuria after surgery may predispose to development of renal failure.

Glomerular filtration rate estimation by use of a correction formula for slope-intercept plasma iohexol clearance in cats

OBJECTIVE To develop a formula for correcting slope-intercept plasma iohexol clearance in cats and to compare clearance of total iohexol (TIox), endo-iohexol (EnIox), and exo-iohexol (ExIox). ANIMALS 20 client-owned, healthy adult and geriatric cats. PROCEDURES Plasma clearance of TIox was determined via multisample and slope-intercept methods. A multisample method was used to determine clearance for EnIox and ExIox. A second-order polynomial correction factor was derived by performing regression analysis of the multisample data with the slope-intercept data and forcing the regression line though the origin. Clearance corrected by use of the derived formula was compared with clearance corrected by use of Brochner-Mortensen human and Heiene canine formulae. Statistical testing was applied, and Bland-Altman plots were created to assess the degree of agreement between TIox, EnIox, and ExIox clearance. RESULTS Mean ± SD iohexol clearance estimated via multisample and corrected slope-intercept methods was 2.16 ± 0.35 mL/min/kg and 2.14 ± 0.34 mL/min/kg, respectively. The derived feline correction formula was Cl(corrected) = (1.036 × Cl(uncorrected)) - (0.062 × Cl(uncorrected)(2)), in which Cl represents clearance. Results obtained by use of the 2 methods were in excellent agreement. Clearance corrected by use of the Heiene formula had a linear relationship with clearance corrected by use of the feline formula; however, the relationship of the feline formula with the Brochner-Mortensen formula was nonlinear. Agreement between TIox, EnIox, and ExIox clearance was excellent. CONCLUSIONS AND CLINICAL RELEVANCE The derived feline correction formula applied to slope-intercept plasma iohexol clearance accurately predicted multisample clearance in cats. Use of this technique offers an important advantage by reducing stress to cats associated with repeated blood sample collection and decreasing the costs of analysis.

Plasma creatinine in dogs: intra- and inter-laboratory variation in 10 European veterinary laboratories

BackgroundThere is substantial variation in reported reference intervals for canine plasma creatinine among veterinary laboratories, thereby influencing the clinical assessment of analytical results. The aims of the study was to determine the inter- and intra-laboratory variation in plasma creatinine among 10 veterinary laboratories, and to compare results from each laboratory with the upper limit of its reference interval.MethodsSamples were collected from 10 healthy dogs, 10 dogs with expected intermediate plasma creatinine concentrations, and 10 dogs with azotemia. Overlap was observed for the first two groups. The 30 samples were divided into 3 batches and shipped in random order by postal delivery for plasma creatinine determination. Statistical testing was performed in accordance with ISO standard methodology.ResultsInter- and intra-laboratory variation was clinically acceptable as plasma creatinine values for most samples were usually of the same magnitude. A few extreme outliers caused three laboratories to fail statistical testing for consistency. Laboratory sample means above or below the overall sample mean, did not unequivocally reflect high or low reference intervals in that laboratory.ConclusionsIn spite of close analytical results, further standardization among laboratories is warranted. The discrepant reference intervals seem to largely reflect different populations used in establishing the reference intervals, rather than analytical variation due to different laboratory methods.

World Small Animal Veterinary Association Renal Pathology Initiative: Classification of Glomerular Diseases in Dogs

Evaluation of canine renal biopsy tissue has generally relied on light microscopic (LM) evaluation of hematoxylin and eosin–stained sections ranging in thickness from 3 to 5 µm. Advanced modalities, such as transmission electron microscopy (TEM) and immunofluorescence (IF), have been used sporadically or retrospectively. Diagnostic algorithms of glomerular diseases have been extrapolated from the World Health Organization classification scheme for human glomerular disease. With the recent establishment of 2 veterinary nephropathology services that evaluate 3-µm sections with a panel of histochemical stains and routinely perform TEM and IF, a standardized objective species-specific approach for the diagnosis of canine glomerular disease was needed. Eight veterinary pathologists evaluated 114 parameters (lesions) in renal biopsy specimens from 89 dogs. Hierarchical cluster analysis of the data revealed 2 large categories of glomerular disease based on the presence or absence of immune complex deposition: The immune complex–mediated glomerulonephritis (ICGN) category included cases with histologic lesions of membranoproliferative or membranous patterns. The second category included control dogs and dogs with non-ICGN (glomerular amyloidosis or focal segmental glomerulosclerosis). Cluster analysis performed on only the LM parameters led to misdiagnosis of 22 of the 89 cases—that is, ICGN cases moved to the non-ICGN branch of the dendrogram or vice versa, thereby emphasizing the importance of advanced diagnostic modalities in the evaluation of canine glomerular disease. Salient LM, TEM, and IF features for each pattern of disease were identified, and a preliminary investigation of related clinicopathologic data was performed.

Consensus Recommendations for Immunosuppressive Treatment of Dogs with Glomerular Disease Based on Established Pathology

The purpose of this report was to provide consensus recommendations for the use of immunosuppressive therapy in dogs with active glomerular diseases. Recommendations were developed based on comprehensive review of relevant literature on immunosuppressive therapy of glomerular disease in dogs and humans, contemporary expert opinion, and anecdotal experience in dogs with glomerular disease treated with immunosuppression. Recommendations were subsequently validated by a formal consensus methodology. The Study Group recommends empirical application of immunosuppressive therapy for dogs with severe, persistent, or progressive glomerular disease in which there is evidence of an active immune-mediated pathogenesis on kidney biopsy and no identified contraindication to immunosuppressive therapy. The most compelling evidence supporting active immune-mediated mechanisms includes electron-dense deposits identified with transmission electron microscopic examination and unequivocal immunofluorescent staining in the glomeruli. For diseases associated with profound proteinuria, attendant hypoalbuminemia, nephrotic syndrome, or rapidly progressive azotemia, single drug or combination therapy consisting of rapidly acting immunosuppressive drugs is recommended. The Study Group recommends mycophenolate alone or in combination with prednisolone. To minimize the adverse effects, glucocorticoids should not be used as a sole treatment, and when used concurrently with mycophenolate, glucocorticoids should be tapered as quickly as possible. For stable or slowly progressive glomerular diseases, the Study Group recommends mycophenolate or chlorambucil alone or in combination with azathioprine on alternating days. Therapeutic effectiveness should be assessed serially by changes in proteinuria, renal function, and serum albumin concentration. In the absence of overt adverse effects, at least 8 weeks of the rapidly acting nonsteroidal drug therapy and 8-12 weeks of slowly acting drug therapy should be provided before altering or abandoning an immunosuppressive trial.

Quantitative determination of exo- and endo-iohexol in canine and feline samples using high performance liquid chromatography with ultraviolet detection

A sensitive and specific high performance liquid chromatography-ultraviolet detection (HPLC-UV) method for quantitative determination of exo- and endo-iohexol in cat and dog serum/plasma is presented. Sample preparation consisted of a protein precipitation step performed by adding 15 μL of trifluoroacetic acid to 100 μL of serum/plasma. Following vortexing and centrifugation, an aliquot of the supernatant was injected onto a polymeric PLRP-S column (250 mm × 4.6 mm i.d., dp: 8 μm, 100 Å), maintained at 30 °C. The mobile phase consisted of water (A) and methanol (B) and a gradient elution (flow-rate: 1.0 mL min(-1), total run-time: 21 min). The UV detector was set at a wavelength of 254 nm. Matrix-matched calibration graphs were prepared for both exo- (0.44-657 μg mL(-1)) and endo-iohexol (0.62-93.0 μg mL(-1)). Correlation and goodness-of-fit coefficients were between 0.9985-0.9999 and 4.44-9.87%, respectively. Limits of quantification and detection were 0.44 and 0.15 μg mL(-1) for exo-iohexol and 0.62 and 0.20 μg mL(-1) for endo-iohexol, respectively. Results for within-day and between-day precision and accuracy fell within the ranges specified. The reported method is simple and cost-effective. It has been successfully used for the analysis of exo- and endo-iohexol in serum/plasma samples of cats and dogs as part of pharmacokinetic studies with iohexol in order to determine plasma clearance of exo- and endo-iohexol. This indicates the usefulness of the developed method for application in the field of veterinary clinical practice and research.