Open Veterinary Journal, (2021), Vol. 11(3): 508–516 ISSN: 2226-4485 (Print) Original Article ISSN: 2218-6050 (Online) DOI: 10.5455/OVJ.2021.v11.i3.24 Submitted: 14/07/2021 Accepted: 01/09/2021 Published: 20/09/2021 Is proteinuria a rare condition in apparently healthy and sick cats? A feline practice experience (2007–2018) Maria Cristina López1* , Valentina Aybar2, Andrea Zatelli3, Anna Vila4, Juan Jose Vega2, Eduard Hernando4, Alejandro Jiménez5 and Xavier Roura1 1 Hospital Clínic Veterinari, Universitat Autònoma de Barcelona, Bellaterra, Spain 2 Hospital Felino Madrid, Madrid, Spain 3 Department of Veterinary Medicine, University of Bari, Valenzano, Italy 4 Hospital Veterinario San Vicente Mártir, Universidad Católica de Valencia, Valencia, Spain 5 Facultat de Matemàtiques, Universitat Autònoma de Barcelona, Bellaterra, Spain Abstract Background: Proteinuria is assumed to be less frequent in cats than in dogs and is mainly associated with chronic kidney disease (CKD). Aim: The current study aimed to evaluate and compare urine protein-to-creatinine (UPC) values retrospectively in cats visited for comprehensive annual health check or for presenting systemic clinical signs related to CKD. Methods: UPC ratio was retrospectively evaluated in 112 owned cats, out of which 51 (45.5%) were apparently healthy cats according to their owners who visited for comprehensive annual health checks and 61 (54.5%) sick cats, presenting systemic clinical signs suggesting CKD, such as weight loss or polyuria/polydipsia, among others. Results: Based on UPC, the present study found that 54.5% of all cats included were borderline proteinuric or proteinuric, having increased UPC (UPC ≥ 0.2), with 35.7% included in the sick group and 18.7% in the health- check group. Increased UPC was also statistically associated with azotemia and isosthenuria (urinary-specific gravity between 1,008 and 1,035) in both sick and health-check groups of cats. Conclusion: Independent of the reason for their medical visit, it could be concluded that borderline proteinuria and proteinuria were statistically mainly related to CKD in cats. Furthermore, the measurement of UPC could be very useful in the detection and management of CKD in apparently healthy cats during a medical visit for annual health check irrespective of the age. Keywords: Annual health check, Kidney, Urine protein-to-creatinine ratio, UPC, Urinalysis. Introduction Smith et al., 2017; Prudic et al., 2018; Purswell et al., Proteinuria is defined as the presence of an excessive 2020). amount of proteins or abnormal proteins in the urine Chronic kidney disease (CKD) is one of the most (Lees et al., 2005; Harley and Langston, 2012). common diseases in adult domestic cats (Marino et al., Studies conducted in the past decade have shown that 2014; Brown et al., 2016; KuKanich et al., 2021), and proteinuria is highly related to reduced survival in both the main pathological feature of feline CKD consists azotemic and non-azotemic cats and dogs (Lees et al., of chronic tubular interstitial nephritis (Lawson et al., 2005; Syme et al., 2006; King et al., 2007; Wehner et 2015; McLeland et al., 2015; Rayhel et al., 2020). In al., 2008; Jepson et al., 2009; Littman, 2011; Bartges, this setting, proteinuria is mainly secondary to tubular 2012). damage, and its increase seems associated with CKD Proteinuria in cats is less frequent than in dogs due to progression and usually correlates with interstitial the different pathophysiology and predisposing causes fibrosis, although the exact mechanisms of injury are of kidney disease (Harley and Langston, 2012; Roura not clearly established (Syme et al., 2006; Chakrabarti et al., 2017; Rayhel et al., 2020), and in the absence et al., 2012; Brown et al., 2016; Lawson et al., 2018). of active urinary sediment, it is considered a marker of Furthermore, it seems that there is a strong association renal damage or dysfunction (Lees et al., 2005; Harley between systolic hypertension and the magnitude and Langston, 2012). Furthermore, unlike what happens of proteinuria in cats with CKD (Syme et al., 2006). to cats, many other potential causes of proteinuria have This link could be very important because proteinuria been described in dogs, such as infections, neoplasms, is strongly associated with survival in cats with CKD endocrinopathies, familial or aging (Herring et al., or hypertension, and managing systolic hypertension 2014; Lavoué et al., 2015; Marynissen et al., 2017; could reduce proteinuria (Syme et al., 2006; Jepson et al., 2007; King et al., 2007). *Corresponding Author: Maria Cristina López. Hospital Clínic Veterinari, Universitat Autònoma de Barcelona, 508 Bellaterra, Spain. Email: mariavirgolopez@hotmail.com http://www.openveterinaryjournal.com M. C. López et al. Open Veterinary Journal, (2021), Vol. 11(3): 508–516 Therefore, renal proteinuria is diagnostic and, especially, cats visiting a feline practice between April 2007 and a prognostic factor of CKD in cats proportionally related December 2018 for comprehensive annual health check to the risk of renal disease progression and mortality or for presenting systemic clinical signs suggesting (Lees et al., 2005; Syme et al., 2006; Chakrabarti et al., CKD were selected. After this first selection, for each 2012; IRIS, 2019; Giraldi et al., 2020). These findings case to be eligible for final inclusion in the study, a have led the International Renal Interest Society (IRIS) complete medical record including clinical history, to propose proteinuria as relevant in staging cats with signalment (age, sex, neuter status, body weight, and CKD to properly manage the progression of this disease breed), data of physical examination, total blood count, (IRIS, 2019). Cats with urine protein-to-creatinine ratio serum biochemistry, complete urinalysis with inactive (UPC) < 0.2 are classified as non-proteinuric, with sediment, UPC and systolic blood pressure (SBP), UPC > 0.4 as proteinuric, and with UPC between 0.2 and final diagnosis, should be available for review. and 0.4 to be borderline proteinuric (Lees et al., 2005; Moreover, if available, other additional diagnostic IRIS, 2019). The current IRIS recommendation is the investigations such as feline immunodeficiency virus treatment of either borderline and proteinuric cats to (FIV) and feline leukemia virus tests, serum thyroid reduce the progression of kidney disease (IRIS, 2019). levels, or abdomen ultrasound were also evaluated. As descendants of solitary animals, where hiding Data handling and statistical analysis illness is important for survival, our domestic cats Cats were subdivided into two groups for statistical display minimal behavioral signs of disease (Horwitz analysis to evaluate UPC: health-check group, which and Rodan, 2018). Furthermore, owners are reticent included healthy cats according to their owners visiting to bring cats to the veterinarian to avoid them getting for comprehensive annual health check; and sick group, stressed, or relate that it is unnecessary given the lack which included cats visiting for presenting one or more of evident clinical signs (Diez et al., 2015; Gates et al., of these systemic clinical signs suggesting underlying 2019). Based on the above, cats should benefit from CKD, such as weight loss, anorexia, polyuria/polydipsia annual health checks for early detection of diseases, (PU/PD), depression, lethargy, vomiting, diarrhea, or such as kidney disease, especially when they are blindness, among others. getting older and urine evaluation could be a useful test After carefully evaluating previous comprehensive to accomplish this objective (Chakrabarti et al., 2012; medical information, all cats were also divided into Piech and Wycislo, 2019; Mösch et al., 2020; Pérez- two additional groups, CKD group and non-CKD Accino et al., 2020). group, depending on the final diagnosis. IRIS CKD Although some original published studies have staging guidelines (IRIS, 2019) were followed in the evaluated the presence of proteinuria in cats (Syme et CKD group for statistical analyses. Finally, to evaluate al., 2006; King et al., 2007; Jepson et al., 2009; Paepe an age effect, all cats were also assigned to one of these et al., 2013; Rayhel et al., 2020), information about groups: 0–2 years (junior), >2–10 years (mature), and proteinuria in cats with and without CKD is mostly >10 years (geriatric) (Vogt et al., 2010). based on reviews and expert opinions (Lees et al., 2005; All cats were also classified as non-proteinuric (UPC Littman, 2011; Bartges, 2012; Harley and Langston, < 0.2), borderline proteinuric (UPC 0.2–0.4) or 2012; Sparkes et al., 2016; Roura et al., 2017; IRIS, proteinuric (UPC > 0.4); increased UPC was considered 2019; Piech and Wycislo, 2019) in contrast with the when cats had values of UPC ≥ 0.2. Finally, systemic information available in dogs (Jacob et al., 2005; hypertension was considered when SBP measurement Herring et al., 2014; Marynissen et al., 2017; Willems was 160 mmHg or higher. et al., 2017; Prudic et al., 2018; Gizzarelli et al., 2019; Statistical analysis was conducted in R (R Core Team, Purswell et al., 2020). 2014), and figures were generated using the package We hypothesized that the prevalence of proteinuria in ggplot2 (Wickham, 2009). The level of significance cats considered healthy, based on owners’ criteria at was set at p < 0.05. If not normally distributed data home evaluation, was higher than in previous studies were expressed as median (range). The relationship and mainly associated with CKD. So, the present between continuous variables has been studied by the study aimed to evaluate and compare UPC values non-parametric approach of calculating the Spearman’s retrospectively in cats visiting for comprehensive rank correlation coefficient. Pearson’s chi-squared annual health checks or for presenting systemic clinical test was used to examine the relationship between the signs related to CKD. presence of clinical signs and proteinuria classification. Wilcoxon signed-rank test was also used to test Materials and Methods associations between the presence of clinical signs and Study design UPC. This was a retrospective, observational, cross-sectional study. Results Case selection During the study period, a total of 2,391 cats visited the Clinical records, where urinalysis and UPC measured feline practice. Of those, 403 had a complete urinalysis by IDEXX Laboratories should be available, of owned and UPC identified through the clinical record database 509 http://www.openveterinaryjournal.com M. C. López et al. Open Veterinary Journal, (2021), Vol. 11(3): 508–516 search, and 112 cats finally met the eligibility criteria. as IRIS stage 2, 12/45 (26.7%) as IRIS stage 3, and Reasons for exclusion were incomplete clinical 15/45 (33.3%) as IRIS stage 4 (Fig. 1). records and active urinary sediment in 239 and 52 cats, Based on UPC values of all cats (Fig. 2), 51/112 (45.5%) respectively (Fig. 1). were non-proteinuric, 24/112 (21.4%) were borderline 51 out of 112 (45.5%) cats were included in the health- proteinuric, and 37/112 (33.1%) were proteinuric. A check group and 61/112 (54.5%) in the sick group. UPC ≥ 0.2, defined previously as increased UPC, was Furthermore, 82/112 (73.2%) cats had CKD as a final statistically associated with cats belonging to the sick diagnosis following the IRIS guidelines, 37/51 (72.5%) (p = 0.026) and CKD (p = 0.014) groups. Among the in the health-check group, and 45/61 (73.7%) in the 61/112 (54.5%) cats with increased UPC, 48/61 (78.6%) sick group. Inside the health-check group, 2/37 (5.4%) were finally diagnosed with CKD. Furthermore, all were classified as IRIS stage 1, 24/37 (64.9%) as IRIS cats diagnosed with CKD had an increased UPC (p stage 2, 11/37 (29.7%) as IRIS stage 3, and none as = 0.014). However, four cats had proteinuria without IRIS stage 4. Instead, within the sick group, 3/45 increased creatinine, although the final diagnosis was (6.7%) were classified as IRIS stage 1, 15/45 (33.3%) hyperthyroidism in two cats of the health-check group Fig. 1. Flow chart of all cats included in this study. 510 http://www.openveterinaryjournal.com M. C. López et al. Open Veterinary Journal, (2021), Vol. 11(3): 508–516 Fig. 2. Flow chart of UPC values of all cats included in this study. NP: non-proteinuric; BP: borderline proteinuric; P: proteinuric. Table 1. UPC results in proteinuric cats included in this study. Group N Median Proteinuric cats 37 0.86 (0.50–3.43) CKD 10 0.77 (0.51–3.43) Health check Non-CKD 2 0.51 (0.50–0.52) CKD 23 0.9 (0.45–2.38) Sick Non-CKD 2 2.25 (2.20–2.31) and FIV in the other two of the sick group. UPC values from the sick group presented the highest frequencies of all cats with proteinuria are described in Table 1. of all clinical signs: vomiting, lethargy, and PU/PD The signalment of the enrolled cats is summarized in compared to the NP and BP cats of the sick group Table 2. In the health-check group, neither body weight (Table 3). However, no statistical association was (p = 0.081), age (p = 0.385) and sex (p = 0.580) were found between any specific systemic clinical sign and statistically associated with proteinuria. In the sick grade of proteinuria. group, lower body weight (p = 0.049) was associated When clinicopathological alterations were evaluated in with proteinuria. No other statistical associations were the health-check group, increased UPC was associated found with age (p = 0.176) or sex (p = 0.321). Breed with higher values of creatinine (p = 0.037) and urea data were insufficient to draw conclusions. (p = 0.009) and lower values of urinary-specific Systemic clinical signs suggestive of CKD described gravity (USG) (p = 0.018) but did not show any in the sick group were vomiting (23, 37.7%), weight statistical association with packed cell volume (PCV), loss (20, 32.8%), anorexia (18, 29.5%), depression or potassium, phosphorous, albumin, or total protein (p > lethargy (13, 21.3%), PU/PD (12, 19.7%), diarrhea 0.05). Whereas in the sick group, increased UPC was (2, 3.3%), excessive vocalization (1, 1.6%), blindness associated with higher values of creatinine (p = 0.046), (1, 1.6%), and dyspnea (1, 1.6%). Proteinuric cats urea (p = 0.009), and phosphorous (p = 0.049), and with 511 http://www.openveterinaryjournal.com M. C. López et al. Open Veterinary Journal, (2021), Vol. 11(3): 508–516 Table 2. Signalment of the 112 cats included in this study. Breed Sex Group Age Female Weight Pedigree DLH DSH Male (entire) (entire) NP (51) 9 years 4 Siamese 0 41 29 (1) 22 (1) 4.5 kg (1 years–17 2 Russian blue (2.2–9.5) years) 1 Birman 1 Exotic 1 Siberian Forest 1 Norwegian Forest BP (24) 9.5 years 2 Siamese 1 19 8 (2) 16 (1) 3.4 kg (1 years–18 1 Sphynx (2.2–7.5) years) 1 Persian P (37) 8 years 7 Persian 0 27 26 (5) 11 (2) 3.3 kg (4 months–17 3 Siamese (1.2–6.6) years) Age and weight data are expressed as median (range). DLH: domestic long hair; DSH: domestic short hair; NP: non-proteinuric; BP: borderline proteinuric; P: proteinuric. Table 3. Clinical signs described in cats of sick group. Cats of sick group NP BP P Clinical signs N % N % N % N % Vomiting 23 37.7 9 39.1 5 21.7 9 39.1 Weight loss 20 32.8 4 20.0 8 40.0 8 40.0 Anorexia 18 29.5 3 16.7 7 38.9 8 44.4 Depression or lethargy 13 21.3 3 23.1 3 23.1 7 53.8 PU/PD 12 19.7 5 41.6 1 8.3 6 50.0 Diarrhea 2 3.3 0 0.0 1 50.0 1 50.0 Blindness 1 1.6 1 100.0 0 0.0 0 0.0 Excessive vocalization 1 1.6 0 0.0 0 0.0 1 100.0 Dyspnea 1 1.6 1 100.0 0 0.0 0 0.0 lower values of potassium (p = 0.008) and USG (p = Discussion 0.018), but did not show any statistical association with The present study showed a high prevalence of PCV, albumin, or total protein (p > 0.05). proteinuria in apparently healthy cats according to 15 out of 112 (13.4%) cats had hypertension (SBP ≥ their owners visited for a comprehensive annual health 160 mmHg). Cats with hypertension had increased UPC check. CKD was highly correlated with borderline compared with those without hypertension, and this proteinuria and proteinuria in cats. difference was statistically significant (p = 0.029). 13 out This increased UPC (UPC ≥ 0.2) was associated with of these 15 (86.6%) cats were finally diagnosed with CKD, CKD in 78.6% of cats included, similar to the results and the other 2 cats were diagnosed with hyperthyroidism. recently published (Fidalgo et al., 2020). Moreover, To finalize the results, ultrasound alterations were found 43.3% of the cats visited during the study period as part in 43 out of all cats (38.4%), but there was no statistical of annual health check were diagnosed with CKD and association between the presence of abnormalities and increased UPC. Finally, the majority of cats (86.7%) proteinuria (p = 0.63) (Table 4). included in the present study had proteinuria with UPC 512 http://www.openveterinaryjournal.com M. C. López et al. Open Veterinary Journal, (2021), Vol. 11(3): 508–516 Table 4. Kidney alterations revealed by abdominal ultrasound. Ultrasound kidney alterations N (43/112) % Poor corticomedullary definition 22/43 19.6 Nephrolithiasis 5/43 4.4 Irregular shape 9/43 8.0 Enlarged size 2/43 1.8 Decreased size 2/43 1.8 Pelvis dilatation 12/43 10.7 Hydronephrosis 1/43 0.9 Fluid-filled cysts 4/43 3.5 < 1.0, which is compatible with previously published instead of the increased UPC. Accordingly, lower body data, suggesting that the main disease process occurring weight has been previously associated with azotemic in the majority of these cats is chronic tubulointerstitial cats (Lamb et al., 2017). fibrosis rather than a primary glomerular disease (Lees Increased UPC was also associated with higher creatinine et al., 2005; Syme et al., 2006). All this together points values in both sick and health-check groups. This out the utility of UPC measurements in routine health association has been previously reported in cats and can be check to evaluate the presence of CKD in cats without explained by the hemodynamic consequences of declining evident clinical signs according to their owners. renal function, with afferent arteriolar vasodilation, Furthermore, the present study found that 54.5% of resulting in increased glomerular capillary pressure (Lees cats included had an increased UPC, with 35.7% et al., 2005; Syme et al., 2006; King et al., 2007; Jepson included in the sick group and 18.7% in the health- et al., 2009; Littman, 2011). As renal function declines, check group. These interesting results were similar the decreased number of functioning tubules is less able to a previous feline report where 34% of sick cats to reabsorb and degrade filtered protein, resulting in more and 18% of healthy cats were proteinuric (Al- intact protein molecules present in urine (Lees et al., 2005; Ghazlat et al., 2011). However, a more recent study Syme et al., 2006; King et al., 2007; Jepson et al., 2009; reported that 72.7% of healthy cats analyzed were Littman, 2011). Moreover, in the present study, higher urea non-proteinuric, higher than the 45.5% found in the and lower USG values were associated with increased present study (Paepe et al., 2013). This fact could UPC in both groups, which supports the relationship be explained because 27.5% of cats included in the between the reduction in renal function with an increased healthy group, according to their owners, visited UPC. In the sick group, increased UPC was also associated for comprehensive annual health check were finally with higher phosphorous and lower potassium values that diagnosed with CKD. The results presented here could also be related to more advanced CKD IRIS stages. point out the importance of the urinalysis with The present study found that hypertension was also UPC measurement in annual health check for the associated with increased UPC, similarly to previously evaluation of chronic diseases, such as kidney disease published data (Syme et al., 2006; Chakrabarti et al., (Chakrabarti et al., 2012; Piech and Wycislo, 2019). 2013). However, this study just found that 15.8% of This could be important in cats due to the limitation cats with CKD had hypertension, although several of owners to detect subtle or even evident signs of studies previously reported a very variable but higher illness in cats (Diez et al., 2015; Horwitz and Rodan, prevalence of hypertension in cats with CKD, ranging 2018; Gates et al., 2019). Furthermore, this could from 19% to 61% (Kobayashi et al., 1990; Syme et be especially determinant due to mild clinical signs al., 2002; Bijsmans et al., 2015). The lack of uniform displayed by cats with early stages of CKD such as measurement techniques, variable inclusion criteria, IRIS stages 1, 2, and early 3 that were the majority in and inconsistent thresholds for establishing a diagnosis the health-check group (IRIS, 2019). of hypertension in veterinary medicine could have Proteinuria in cats has been associated with aging, made prevalence data difficult to interpret. However, suggesting its monitoring in geriatric cats (Paepe et al., in the present study, most of the cats were CKD IRIS 2013). However, the present study did not show this stages 1 and 2, so it could explain this low prevalence association in accordance with other previous studies of hypertension. It was previously described that the (Syme et al., 2006). Moreover, lower weight was frequency of hypertension increased with an increase associated with increased UPC in the sick group, but in the CKD IRIS stage (Hori et al., 2018). this was not found in the health-check group. Thus, Kidney ultrasound alterations such as perinephric weight loss could probably be associated with the fluid, small kidneys, hyperechoic renal cortex, loss illness found in these cats, the majority with CKD, of corticomedullary differentiation, renal calculi, and 513 http://www.openveterinaryjournal.com M. C. López et al. Open Veterinary Journal, (2021), Vol. 11(3): 508–516 dilated renal pelvis have been statistically associated Bartges, J.W. 2012. Chronic kidney disease in dogs and with azotemia in cats similar to previously published cats. Vet. Clin. North Am. Small Anim. Pract. 42, study (Lamb et al., 2017). Furthermore, loss of 669–692. corticomedullary differentiation (19.6%) and dilated Bijsmans, E.S., Jepson, R.E., Chang, Y.M., Syme, renal pelvis (10.7%) were the most common ultrasound H.M. and Elliott, J. 2015. Changes in systolic blood findings in the present study. However, no significant pressure over time in healthy cats and cats with association was found between increased UPC and chronic kidney disease. J. Vet. Intern. Med. 29, ultrasound alterations. A possible explanation could 855–861. be that ultrasonography was recommended for the Brown, C.A., Elliott, J., Schmiedt, C.W. and Brown, investigation of individual cats with CKD but was S.A. 2016. Chronic kidney disease in aged cats: not recommended as a screening test for proteinuria clinical features, morphology, and proposed or azotemia, probably because renal ultrasound pathogeneses. Vet. Pathol. 53, 309–326. alterations have low sensitivity and specificity for an Chakrabarti, S., Syme, H.M., Brown, C.A. and Elliott, early diagnosis of kidney disease (Sparkes et al., 2016; J. 2013. Histomorphometry of feline chronic Lamb et al., 2017). kidney disease and correlation with markers of This study has several limitations that could produce renal dysfunction. Vet. Pathol. 50, 147–155. information and selection biases. First, data were Chakrabarti, S., Syme, H.M. and Elliott, J. 2012. collected retrospectively, as a consequence, the authors Clinicopathological variables predicting were reliant upon the history taken at the time of progression of azotemia in cats with chronic kidney presentation. Second, lack of homogeneous population disease. J. Vet. Intern. Med. 26, 275–281. and missing data for treatment applied or cause of Diez, M., Picavet, P., Ricci, R., Dequenne, M., Renard, death was also present. Finally, serum symmetric M., Bongartz, A. and Farnir, F. 2015. Health dimethylarginine was not carried out in all the cats screening to identify opportunities to improve included in this study, so it is possible that some cats preventive medicine in cats and dogs. J. Small had already CKD even without other markers of CKD Anim. Pract. 56, 463–469. such as an increased creatinine or lower USG. Fidalgo, M.A., Leal, R.O. and Correia, J.H.D. 2020. Significant feline proteinuria: a retrospective study Conclusion of its aetiology in 61 cats from Lisbon research. In The present study pointed out that proteinuria was Communications of the 29th ECVIM-CA Congress. a frequent condition in cats considered healthy and J. Vet. Intern. Med. 34, 339–445. without overt clinical signs suggestive of CKD. Gates, M.C., Walker, J., Zito, S. and Dale, A. 2019. Furthermore, UPC ≥ 0.2 was mainly only related to Cross-sectional survey of pet ownership, veterinary CKD in cats. Nevertheless, the results of this study were service utilisation, and pet-related expenditures in suggestive that urinalysis and UPC measurement could New Zealand. N. Z. Vet. J. 67, 306–314. be warranted in the early detection and management of Giraldi, M., Paltrinieri, S. and Scarpa, P. 2020. CKD in apparently healthy cats, irrespective of their Electrophoretic patterns of proteinuria in feline age, during the medical visits for annual health check. spontaneous chronic kidney disease. J. Feline Med. Conflict of interest Surg. 22, 114–121. The authors declared no potential conflicts of interest Gizzarelli, M., Roura, X., Scarpa, P., D’Ippolito, with respect to the research, authorship, and/or P., Foglia Manzillo, V., Oliva, G., Tarducci, A., publication of this article. Borrelli, A., Melis, G., Quintavalla, F., Uva, A., Authors’ contributions Guarraci, A. and Zatelli, A. 2019. Prevalence of All authors contributed to making the completion of proteinuria in owned dogs from Italy: a multicentric this manuscript possible. Valentina Aybar and Juanjo study. Vet. Med. Int. 2019, 5. Vega obtained all data and review inclusion criteria Harley, L. and Langston, C. 2012. Proteinuria in dogs for analyses and review the paper; Alejandro Jiménez and cats. Can. Vet. J. 53, 631–638. analyzed the data; Eduard Hernando and Anna Vila Herring, I.P., Panciera, D.L. and Werre, S.R. 2014. analyzed the data and review the paper; María C. López Longitudinal prevalence of hypertension, wrote the paper and analyzed the data; Xavier Roura proteinuria, and retinopathy in dogs with and Andrea Zatelli designed the study, supervised the spontaneous diabetes mellitus. J. Vet. Intern. Med. data, and reviewed the paper. 28, 488–495. 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