Natalie Finch

The role of phosphorus in the pathophysiology of chronic kidney disease.

OBJECTIVE To review the human and veterinary literature on the role of phosphorus in the pathophysiology of chronic kidney disease (CKD) and to explore why control of plasma phosphorus concentration is an important goal in the management of patients with this disease. DATA SOURCES Human and veterinary studies, reviews, clinical reports, textbooks, and recent research findings focused on phosphate homeostasis and CKD patient management. HUMAN DATA SYNTHESIS Recent studies using rodent models and human patients with CKD have focused on trying to elucidate the role of the phosphatonins, predominantly fibroblast growth factor-23, in phosphate homeostasis and the pathophysiology of secondary renal hyperparathyroidism (SRHP). Fibroblast growth factor-23 is now considered to be a key regulator of plasma phosphorus concentration in people but has only recently been investigated in companion animal species. VETERINARY DATA SYNTHESIS Cross-sectional studies of naturally occurring CKD in dogs and cats have shown hyperphosphatemia and SRHP to be highly prevalent and associated with increased morbidity and mortality in these patients. Experimental studies of surgically induced renal impairment in the dog and cat, and cases of naturally occurring CKD have emphasized the ability of renal care diets to modify plasma phosphorus and parathyroid hormone concentrations. Evidence from these studies indicates that maintaining plasma phosphorus concentrations to within the International Renal Interest Society targets for CKD patients improves survival time and reduces clinical manifestations of hyperphosphatemia and SRHP. CONCLUSIONS The maintenance of plasma phosphorus concentrations in to within the International Renal Interest Society targets is recommended in management of CKD patients. The discovery of the phosphatonins has improved understanding of the mechanisms involved in phosphorus homeostasis and SRHP and may lead to improved ability to monitor and manage these patients.

Parathyroid hormone concentration in geriatric cats with various degrees of renal function

OBJECTIVE To determine whether cats in the nonazotemic stages of chronic kidney disease have increased plasma parathyroid hormone (PTH) concentrations as a compensatory physiologic mechanism to maintain plasma phosphate concentration within the reference interval. DESIGN Prospective longitudinal study. ANIMALS 118 client-owned geriatric cats with various degrees of renal function. PROCEDURES For each cat, a blood sample was obtained for plasma biochemical analysis and determination of plasma PTH concentration, and a urine sample was obtained for determination of urine specific gravity at study entry (baseline) and after 12 months. For a subset of 30 cats, plasma calcitriol concentration was determined at baseline. Cats were categorized into 1 of 3 groups on the basis of kidney function at the end of 12 months. At baseline and after 12 months, plasma concentrations of variables associated with calcium homeostasis were compared between the 3 groups and also within groups over time. Multivariable linear regression was used to identify variables associated with plasma PTH concentration. RESULTS Plasma PTH concentration was significantly increased in cats that developed azotemia, compared with PTH concentration in cats that remained nonazotemic, and PTH concentration increased before changes in plasma calcium and phosphate concentrations were detected. A moderate positive association between plasma calcitriol and PTH concentrations was identified. Plasma PTH concentration was associated with age and plasma urea, creatinine, and total calcium concentrations in the final multivariable model. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that renal secondary hyperparathyroidism can develop prior to azotemia in cats, even in the absence of hyperphosphatemia and hypocalcemia.

ISFM Consensus Guidelines on the Diagnosis and Management of Feline Chronic Kidney Disease

Practical relevance: Chronic kidney disease (CKD) is one of the most commonly diagnosed diseases in older cats. In most cats, CKD is also a progressive disease and can be accompanied by a wide range of clinical and clinicopathological changes. These ISFM Consensus Guidelines have been developed by an independent panel of clinicians and academics to provide practical advice on the diagnosis and management of this complex disease. Clinical challenges: Although CKD is a common clinical problem in cats, the manifestations of disease vary between individuals. Thus there is a need for careful and repeat evaluation of cats with CKD and adjustment of therapy according to individual needs. In addition to addressing problems arising from CKD and improving quality of life (QoL) for the patient, therapy may also target slowing the underlying progression of disease and hence prolonging life. While maintaining QoL is of paramount importance in our patients, this can be challenging when multiple therapies are indicated. In some cases it is necessary to prioritise therapy, given an understanding of what is likely to most benefit the individual patient. Evidence base: In preparing these Guidelines, the Panel has carefully reviewed the existing published literature, and has also graded the quality of evidence for different interventions to help to provide practical recommendations on the therapeutic options for feline CKD. This is a field of veterinary medicine that has benefited from some excellent published clinical research and further research findings will undoubtedly modify the recommendations contained in these Guidelines in the future.

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.

Association of urinary cadmium excretion with feline hypertension

Fifty client-owned senior cats (32 normotensive and 18 hypertensive) with renal function ranging from normal to moderately reduced were recruited into a prospective cross-sectional study exploring the association of urinary cadmium excretion and hypertension in cats. Heparinised plasma samples were collected and analysed for routine biochemical parameters. Urine samples were collected via cystocentesis and were analysed for cadmium concentrations using inductively coupled plasma mass spectrometry (ICP-MS). Blood pressure was measured using the Doppler method. Urinary cadmium concentrations were indexed to urinary creatinineconcentration. Comparison of urinary cadmium excretion was made between hypertensive and normotensive cats.The median (range) urinary cadmium concentration standardised to urinary creatinine concentration (UCdCr) in the normotensive and hypertensive cats was 0.08 (0.02 to 0.37) and 0.12 (0.02 to 1.38) nmol/mmol creatinine. The UCdCr was significantly higher in hypertensive compared with normotensive cats (P=0.016). UCdCr and plasma creatinine concentration remained independent predictors of hypertensive status in a logistic regression model. UCdCr and plasma creatinine concentration were not correlated (r=−0.01, P=0.956). These data suggest cadmium exposure and accumulation in cats may play a role in the development of feline hypertension.

A Single Sample Method for Estimating Glomerular Filtration Rate in Cats

BACKGROUND Validated methods of estimating glomerular filtration rate (GFR) in cats requiring only a limited number of samples are desirable. HYPOTHESIS/OBJECTIVES To test a single sample method of determining GFR in cats. ANIMALS The validation population (group 1) consisted of 89 client-owned cats (73 nonazotemic and 16 azotemic). A separate population of 18 healthy nonazotemic cats (group 2) was used to test the methods. METHODS Glomerular filtration rate was determined in group 1 using corrected slope-intercept iohexol clearance. Single sample clearance was determined using the Jacobsson and modified Jacobsson methods and validated against slope-intercept clearance. Extracellular fluid volume (ECFV) was determined from slope-intercept clearance with correction for the 1 compartment assumption and by deriving a prediction formula for ECFV (ECFV Predicted ) based on the body weight. The optimal single sample method was tested in group 2. RESULTS A blood sample at 180 minutes and ECFV Predicted were optimal for single sample clearance. Mean ± SD GFR in group 1 determined using the Jacobsson and modified Jacobsson formulae was 1.78 ± 0.70 and 1.65 ± 0.60 mL/min/kg, respectively. When tested in group 2, the Jacobsson method overestimated multisample clearance. The modified Jacobsson method (mean ± SD 2.22 ± 0.34 mL/min/kg) was in agreement with multisample clearance (mean ± SD 2.19 ± 0.34 mL/min/kg). CONCLUSIONS AND CLINICAL IMPORTANCE The modified Jacobsson method provides accurate estimation of iohexol clearance in cats, from a single sample collected at 180 minutes postinjection and using a formula based on the body weight to predict ECFV. Further validation of the formula in patients with very high or very low GFR is required.

Risk Factors for Development of Chronic Kidney Disease in Cats

Background Identification of risk factors for development of chronic kidney disease (CKD) in cats may aid in its earlier detection. Hypothesis/objectives Evaluation of clinical and questionnaire data will identify risk factors for development of azotemic CKD in cats. Animals One hundred and forty‐eight client‐owned geriatric (>9 years) cats. Methods Cats were recruited into the study and followed longitudinally for a variable time. Owners were asked to complete a questionnaire regarding their pet at enrollment. Additional data regarding dental disease were obtained when available by development of a dental categorization system. Variables were explored in univariable and multivariable Cox regression models. Results In the final multivariable Cox regression model, annual/frequent vaccination (P value, .003; hazard ratio, 5.68; 95% confidence interval, 1.83–17.64), moderate dental disease (P value, .008; hazard ratio, 13.83; 95% confidence interval, 2.01–94.99), and severe dental disease (P value, .001; hazard ratio, 35.35; 95% confidence interval, 4.31–289.73) predicted development of azotemic CKD. Conclusion Our study suggests independent associations between both vaccination frequency and severity of dental disease and development of CKD. Further studies to explore the pathophysiological mechanism of renal injury for these risk factors are warranted.

Hypercalcaemia in cats The complexities of calcium regulation and associated clinical challenges

Practical relevance: Calcium is essential for many normal physiological processes within the body. Aberrations in calcium homeostasis leading to hypercalcaemia can result in clinical signs such as polyuriav and polydipsia, lethargy and weakness due to depressed excitability of muscle and nervous tissue, and gastrointestinal (GI) signs due to effects on GI smooth muscle. Hypercalcaemia in cats is mostly idiopathic, with chronic kidney disease and neoplasia also being common causes. Clinical challenges: Hypercalcaemia can be a diagnostic challenge and a good understanding of the regulation of calcium homeostasis can aid in interpreting results of diagnostic tests. Furthermore, the management approach may depend on the underlying cause of hypercalcaemia, and also its severity and chronicity. Audience: This review offers a comprehensive discussion of the regulation of calcium homeostasis, with a focus on the normal response to hypercalcaemia. It also discusses the diagnostic approach to, and management of, hypercalcaemia in cats, as well as specific aetiologies. This is relevant to all clinicians working with feline patients. Evidence base: The review draws evidence from peer-reviewed publications and also the author’s own clinical experience.

Measurement of glomerular filtration rate in cats Methods and advantages over routine markers of renal function

Practical relevance: Routinely used markers of renal function in clinical practice include urea and creatinine. However, these are insensitive markers, particularly in the early stages of kidney disease. Measurement of glomerular filtration rate (GFR) is regarded as the most sensitive index of functioning renal mass. It may be useful for feline patients in varying clinical scenarios; for example, where a more accurate measurement of renal function may aid diagnosis, to enable response to therapeutic interventions to be more closely monitored, or to evaluate renal function prior to the use of nephrotoxic or renally cleared drugs. Clinical challenges: Traditional methods of measuring GFR, such as renal clearance or multisample plasma clearance techniques, are generally impractical for clinical use. Limited sampling and single sample plasma clearance methods using the filtration marker iohexol have been validated in cats. These have the advantages of reduced stress to cats associated with repeated sampling and reduced costs of analysis, and therefore offer greater clinical utility. Attempts to develop an estimated GFR (eGFR) formula similar to that used in human patients have been made in cats, although currently an accurate and reliable formula is not available. Audience: This review presents the basis for the theoretical understanding and practical measurement of GFR for any veterinary practitioner wishing to obtain a more accurate and sensitive assessment of renal function than routinely used markers provide. Evidence base: The review draws evidence from peer-reviewed publications, the author’s PhD thesis and also clinical experience.

Determination of Extracellular Fluid Volume in Healthy and Azotemic Cats

Background Methods for determining extracellular fluid volume (ECFV) are important clinically for cats. Bromide dilution has been studied in cats to estimate ECFV. Markers of GFR also distribute in ECFV and can be used for its measurement. Hypothesis/Objectives The primary objective was to develop a method of determining ECFV from iohexol clearance in cats and evaluate agreement with that determined using bromide dilution. Additional objectives were to compare ECFV between azotemic and nonazotemic cats and evaluate appropriate methods of standardizing ECFV. Animals Client‐owned cats with varying renal function. Methods Validation of ECFV determined from slope‐intercept iohexol clearance was performed in 18 healthy nonazotemic cats. ECFV was then determined using the validated method and bromide dilution and agreement assessed. Appropriateness of standardization to body weight (BW) and body surface area (BSA) was evaluated. Results Extracellular fluid volume determined from slope‐intercept iohexol clearance and bromide dilution was 0.84 ± 0.32 L and 0.85 ± 0.19 L (mean ± SD), respectively. There were wide limits of agreement between the methods (−0.58 to 0.54 L) and therefore, agreement was considered to be poor. ECFV did not differ significantly between azotemic and nonazotemic cats (P = .177). BSA was found to be the best method for standardizing ECFV measurement in cats. Conclusions and Clinical Importance This study developed a method for determining ECFV from slope‐intercept iohexol clearance which provides simultaneous assessment of renal function and an estimate of ECFV. ECFV does not differ between azotemic and nonazotemic cats, which suggests fluid volume loss or overload is not an important clinical feature in cats with mild chronic kidney disease.