Cardiovascular-renal axis disorders: renal biomarkers in dogs affected by myxomatous mitral valve disease

Abstract

The heart and kidneys are closely related whereby acute or chronic dysfunction in one organ may lead to acute or chronic dysfunction in the other organ; cardiovascular- renal axis disorders have been described in dogs with myxomatous mitral valve disease (MMVD). Early recognition of renal involvement would allow adjustment of cardiovascular therapy, however, serum creatinine, that is currently the most widely used marker for monitoring kidney function in dogs, is a late marker and it is not able to detect early renal disfunction. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and uNGAL to urinary creatinine ratio (uNGALC) are novel promising biomarkers of renal damage, proposed in humans and dogs. In addition, urine chemistry has received growing attention to estimate the diuretic response in dogs with cardiac disease. This doctoral thesis work is aimed to study different aspects of cardiovascular-renal axis disorders in dogs affected by MMVD at different American College of Veterinary Internal Medicine (ACVIM) stages. In particular, the aims of the study are: - to evaluate renal tubular damage in dogs with stable MMVD by evaluation of uNGAL - to evaluate the association between echocardiographic indexes and uNGAL or uNGALC, in dogs with MMVD. - to evaluate the impact of the time elapsed between the oral furosemide administration and the sample collection on urine chemistry in dogs with MMVD stage ACVIM C. This is a multicentric prospective observational case-control study. Dogs with MMVD at different ACVIM stage were included and underwent physical exam, echocardiographic exam, blood and urine sample for the determination of serum and urine chemistry, including uNGAL and uNGALC. Dogs were monitored over time at established time intervals based on the ACVIM stage. The values of uNGAL and uNGALC were compared between MMVD dogs and healthy controls, and among different MMVD ACVIM stages. Moreover, echocardiographic data were correlated with uNGAL and uGALC values. The echocardiographic indexes analyzed were shortening fraction (SF), normalized left ventricular diastolic (LVIDDn) and systolic (LVIDSn) diameters, left atrium to aortic root ratio (LA/Ao), maximal (LAVMax) and minimal (LAVMin) left atrial volumes, LA stroke volume (LASV), E wave peak velocity (EVmax), E/E', aortic (VTIAo) and mitralic (VTIMit) velocity time integrals and their ratio (VTIMit/VTIAo) and tricuspid regurgitation velocity (TRVmax). For the last aim of the study, dogs with MMVD were divided, based on the time of blood and urine sampling, in two groups. The morning group (MMVD-MG) included the dogs in which the sampling was obtained between 1 to 6 h after the oral furosemide administration, and the evening group (MMVD-EG) included the dogs sampled over 6 h from oral furosemide administration. Analogously, healthy dogs sampled between 9 a.m. and 1 p.m. and between 2 and 7 p.m. were divided in a morning group (H-MG) and an evening group (H-EG), respectively. Urine chemistry, including fractional excretion of electrolytes, was evaluated and compared among groups. The MMVD dogs had significantly higher uNGAL and uNGALC (1204 pg/mL; range, 30-39 732 and 1816 pg/mg; range, 22-127 693, respectively) compared to healthy dogs (584 pg/mL; range, 56-4072 and 231 pg/mg; range, 15-2407, respectively; P=.002 and P< .0001, respectively). Both uNGAL and uNGALC increased with the increasing ACVIM stage (P=.001 and P< .001, respectively). In the univariate analysis LASV, TRVmax, LAVMax, LVIDDn and VTIMit/VTIAo were independent predictors of increased uNGAL and uNGALC, however only LASV [(OR: 3.26, 95% CI: 1.13–9.38), P= 0.03 for NGAL and (OR: 4.62, 95% CI: 1.44–14.88), P= 0.01 for NGALC] and TRVmax [(OR: 1.77, 95% CI: 1.16–2.73), P < 0.01 for NGAL and (OR: 1.52, 95% CI: 1.01–2.30), P = 0.05 for NGALC] remained statistically significant in the multivariable analysis. An higher excretion of sodium and chloride and higher urine sodium to urine potassium ratio (uNa+:uK+) were detected in MMVD-MG than MMVD-EG (P= 0.021, P= 0.038, and P= 0.016, respectively). Natriuresis, chloriuresis, and uNa+:uK+ were higher in MMVD-MG than H-MG, while no differences were found in the comparison between H-MG and H-EG and between MMVD-EG and H-EG. In conclusion, renal tubular damage is present in dogs with stable MMVD, as measured by increased uNGAL. In our population the tubular damage is subclinical, occurs in all stages of MMVD even in the absence of azotemia, and increases with the severity of MMVD. Based on our results LASV and TRVmax are associated with increased uNGAL and uNGALC. These parameters might detect patients at higher risk to develop kidney damage in course of MMVD. Reno protective approaches to manage MMVD dogs should be explored to slow the progression of renal tubular damage in these patients. Urinary electrolyte excretion is significantly increased within 6 h from furosemide administration in dogs with MMVD ACVIM stage C. Time of sampling from furosemide administration significantly affects urine chemistry in MMVD dogs and should be considered in the clinical practice and the research field.