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Keywords:

  • Azotemia;
  • Canine;
  • Heart failure;
  • Kidney;
  • Ultrasonography

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Background

Azotemia occurs frequently in dogs with degenerative mitral valve disease (DMVD). It could indicate changes in renal hemodynamics.

Hypothesis/Objectives

To assess the renal resistive index (RI) in dogs with DMVD, and the statistical link between heart failure class, azotemia, echo-Doppler parameters, several plasma variables, and RI.

Animals

Fifty-five dogs with naturally occurring DVMD were used (ISACHC class 1 [n = 28], 2 [n = 19], and 3 [n = 8]).

Methods

Observational, blinded study, performed under standardized conditions. Physical examination, renal ultrasonography, and echo-Doppler examinations were performed in awake dogs. The RI of the renal, interlobar, and arcuate arteries were measured. Plasma creatinine, urea, and N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP) were determined. Statistical links between variables and RI were tested by means of a general linear model.

Results

Although the RI of renal and arcuate arteries were unaffected by ISACHC class, the left interlobar RI increased (P < .001) from 0.62 ± 0.05 (mean ± SD) in class 1 to 0.76 ± 0.08 in class 3. It was also higher (P < .001) in azotemic (0.74 ± 0.08) than in non-azotemic (0.62 ± 0.05) dogs. Similar findings were observed for right interlobar RI. Univariate analysis showed a positive statistical link between NT-proBNP (P = .002), urea (P < .001), creatinine (P = .002), urea-to-creatinine ratio (P < .001), left atrium-to-aorta ratio (P < .001), regurgitation fraction (P < .001), systolic pulmonary arterial pressure (P < .001), shortening fraction (P = .035), and RI.

Conclusion and Clinical Importance

In dogs with DMVD, interlobar RI increases with heart failure severity and azotemia but a cause and effect relationship remains to be established.

Abbreviations
ACEI

angiotensin converting enzyme inhibitor

Ao

aorta

ARJ

maximum area of the regurgitant jet signal

DMVD

degenerative mitral valve disease

EDV

left ventricular end-diastolic volume

EDVI

left ventricular end-diastolic volume index

EF

ejection fraction

EMITRAL

early diastolic transmitral flow velocity

EROA

effective regurgitant orifice area

ESV

left ventricular end-systolic volume

ESVI

left ventricular end-systolic volume index

GFR

glomerular filtration rate

HF

heart failure

ISACHC

International Small Animal Cardiac Health Council

IVSD

interventricular septal thickness in diastole

IVSS

interventricular septal thickness in systole

LA

left atrium

LAA

left atrium area

LV

left ventricle

LVd

left ventricular end-diastolic diameter

LVs

left ventricular end-systolic diameter

LVFWd

left ventricular free-wall in diastole

LVFWs

left ventricular free-wall in systole

NT-proBNP

N-terminal pro-B-type natriuretic peptide plasma concentration

NYHA

New York Heart Association

PUCR

plasma urea-to-creatinine ratio

PISA method

proximal isovelocity surface area method

RF

regurgitation fraction

RI

resistive index

RVd

right ventricular end-diastolic diameter

RVWs

right ventricular wall thickness in systole

SAP

systolic arterial pressure

SF

shortening fraction

SPAP

systolic pulmonary arterial pressure

TR

tricuspid regurgitation

Glomerular filtration rate (GFR) is decreased in advanced, as compared to mild, degenerative mitral valve disease (DMVD) in dogs.[1] This decrease in GFR is associated with azotemia, which increases in prevalence with heart failure (HF) class (up to 71% in New York Heart Association [NYHA] class IV).[1] The most frequent cause of azotemia is abnormally high urea and not creatinine concentrations.[1] Because reabsorption of urea increases when tubular flow decreases, the more pronounced increase in plasma urea concentration could result from hemodynamic changes (ie, a prerenal cause) induced by decreased cardiac output, activation of neuroendocrine systems, or both.[1]

The renal resistive index (RI) allows noninvasive assessment of renal vascular resistance.[2] Alterations in renal RI have been identified in dogs with hepatic disorders,[3] hyperadrenocorticism,[4] diabetes mellitus,[4] renal diseases,[5] hypoadrenocorticism,[6] and experimentally induced anemia.[7] Interestingly, RI is increased in human cardiac patients,[8] but links between cardiac disease and RI have never been documented in dogs.

The purpose of this study therefore was to measure RI in dogs with naturally occurring DMVD, and to determine the links between HF class, azotemia, echo-Doppler parameters, several plasma variables (urea, creatinine, N-terminal pro-B-type natriuretic peptide plasma concentration [NT-proBNP] and plasma urea-to-creatinine ratio [PUCR]) and RI.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Study Design

The study was observational, blinded, and performed under standardized conditions. Overnight-fasted dogs underwent physical examination, blood pressure measurement, ECG, echocardiography, renal ultrasonography, and blood collection, successively on the same day.

Dogs

Dogs were prospectively recruited. Client-owned dogs with DMVD and body weight ≤20 kg were enrolled. The body weight criterion was based on the fact that dogs with DMVD weighing >20 kg have been shown to have a 5.8 higher chance of developing decreased shortening fraction (SF), increased end-diastolic volume index, atrial fibrillation, and ventricular arrhythmias than dogs with body weight ≤20 kg.[9, 10] Plasma creatinine concentration also can be affected by body size in dogs.1 Exclusion criteria were other cardiac diseases, neoplasia, acute renal failure, and treatment with potentially nephrotoxic drugs. Diagnosis of DMVD was performed, as previously described.[11] Dogs were included only if the color-flow jet of systolic mitral insufficiency was adequate for assessment of mitral regurgitation by the proximal isovelocity surface area (PISA) method.[12] Dogs with DMVD were categorized according to the International Small Animal Cardiac Health Council[13] (ISACHC) classification. Current treatment for each dog was recorded.

Echocardiographic and Doppler Examination

Conventional echo-Doppler examinations2 were performed in awake dogs, as previously validated.[14] Operators were trained and blinded to other results.

Left ventricular end-diastolic and end-systolic diameters (LVDd, LVDs), left ventricular free-wall and interventricular septal thickness in diastole and systole (LVFWd, LVFWs, IVSd, IVSs, respectively) were measured by 2-dimensional (2D) guided M-mode echocardiography.[15] The SF then was calculated. The aorta (Ao) and the left atrial (LA) dimensions were measured by a 2D-echocardiographic method.[14]

Left ventricular end-systolic and end-diastolic volumes (ESV and EDV, respectively) were assessed by applying the Simpson's derived planimetric method by the left apical 4-chamber view, as previously validated.3,[11] These volumes were used to calculate the LV ejection fraction (EF). They also were indexed to body surface area (ESVI and EDVI, respectively).[16]

Mitral regurgitation was assessed by the color Doppler mapping and PISA methods, as previously described and validated.[12] The maximum area of the regurgitant jet signal (ARJ)/LA area (LAA) ratio, the regurgitation fraction (RF, corresponding to the percentage of stroke volume ejected into the LA during systole), and the effective regurgitant orifice area (EROA) were calculated.[12]

When tricuspid regurgitation (TR) was identified, peak-systolic TR velocity was used to calculate systolic pulmonary arterial pressure (SPAP).[17] The transmitral-peak-velocity of early and late diastolic flows (EMITRAL and late diastolic transmitral flow velocity waves, respectively) also were measured.

Renal Ultrasonography

Renal ultrasonography of the 2 kidneys was performed by validated operators (see below) by an ultrasound unit4 with a 7.5 MHz linear phase-array transducer. Operators were blinded to other results. Unsedated dogs were gently restrained in lateral recumbency. A morphometric examination was performed. Renal length and height were measured on the longitudinal axis, and renal width and height were measured on the transverse axis. Arterial and venous flows were visualized by color Doppler examination. Once visualized, a pulsed-wave recording was performed on the renal artery (near its aortic origin), the interlobar artery (which crosses the medulla from renal sinus to cortico-medullary junction), and the arcuate artery (at the cortico-medullary junction). The RI was calculated by measuring peak-systolic and end-diastolic flow velocities according to the following formula:

RI = (peak-systolic flow velocity − end-diastolic flow velocity)/peak-systolic flow velocity.

Morphometric and Doppler measurements were repeated 3 times. The mean of the 3 measurements was used for statistical analysis.

To determine within-day variability for the 2 investigators and the above renal ultrasonographic variables, 3 examinations were performed on 4 healthy adult Beagle dogs at 3 nonconsecutive times on the same day. Each variable was measured 3 times during each ultrasonographic examination, by the same frame, and mean values were used to calculate variability.

Blood Pressure Measurement

Systolic arterial blood pressure (SAP) was measured in awake dogs gently restrained in lateral recumbency, by the Doppler method5 with the inflatable cuff placed on the tail. As recommended,[18] several measurements were taken over 5–10 minutes to obtain the average of 5 values from a stable set of readings and the mean was used for the statistical analyses.

Blood Sample Collection and Assays

Blood samples (5 mL in a lithium-heparinized tube and 2 mL in an EDTA tube) were obtained and centrifuged (3000 × g for 10 minutes at 4°C). Heparinized and EDTA plasma were stored at −20°C and −70°C, respectively. Plasma concentrations of the following analytes: glucose, urea (urea [mg/dL] = blood urea nitrogen [mg/dL] × 2.14), creatinine, potassium, chloride, calcium, total proteins, phosphate, triglycerides, cholesterol, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and creatinine kinase were assayed, by the same analyzer.6 The plasma urea-to-creatinine ratio then was calculated by dividing the plasma urea concentration expressed in mg/dL by the plasma creatinine expressed in mg/dL. Dogs were considered azotemic if either plasma creatinine or urea was above or equal to the upper limit of the reference interval (i.e, 133 μmol/L [1.5 mg/dL] for creatinine and 10.9 mmol/L [66 mg/dL] for urea).

NT-proBNP concentration was measured by means of EDTA-potassium samples7 and a commercially available canine-specific assay,8 as previously published.[19],9

The operators performing the assays were blinded to the patient's information.

Statistical Analysis

All statistical analyses were performed by means of a computer software.10 Data are expressed as mean ± SD.

The following general linear model was used to assess the measurement variability of each renal echographic variable for each investigator[14]:

  • display math

where Yijk was the ith value measured for dog k at time j, μ was the general mean, Dogk was the effect of dog k, (Time * Dog)jk the interaction term between time and dog effects, and εijkl was the model error.

The SD of the within-day variability was determined from the square root of the mean square of the time effect. The corresponding coefficient of variation (CV) was determined by dividing the SD value by the overall mean. A Chi-squared test was performed to compare sex, breed, and treatment between groups. Left and right interlobar RI values were compared in each class by a paired t-test. The normality of residuals was tested with a Kolmogorov-Smirnov test.

The statistical link between ISACHC class, azotemia, and all of the tested variables was assessed by an analysis of variance. Assessment between groups was performed by multiple comparisons with Tukey adjustment. The statistical link between each co-variable statistically affected by ISACHC class and RI was tested by means of the following general linear model:

  • display math

where μ is the mean, a is the regression coefficient for the variable, and ε is the model error.

P < .05 was considered significant. Adjusted R² values were used to compare the different statistically significant models. Stepwise regression analysis with a P-value of .20 to enter and a P-value of .10 to remove was performed for the left and right interlobar RI.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Study Population

Fifty-five dogs (28 [50.9%] in ISACHC class 1, 19 [34.5%] in class 2, and 8 [14.5%] in class 3) were included in the study (Table 1). Dogs from class 1 were younger than those from classes 2 and 3. Body weight, heart rate, and SAP were not statistically different among ISACHC classes. No chronic kidney disease was diagnosed in any dog. No dog had any other concomitant diagnosed disease at the time of the study, except 1 dog in class 2 for which hypothyroidism had been diagnosed. Nevertheless, this dog was under treatment with levothyroxine at the time of the study.

Table 1. Characteristics of the 55 dogs with degenerative mitral valve disease according to ISACHC classes.
CharacteristicsPopulation (n = 55)ISACHC Class
1 (n = 28)2 (n = 19)3 (n = 8)P-value
  1. ACEI, angiotensin converting enzyme inhibitors; bpm, beats per minute; CKC, Cavalier King Charles Spaniel; ISACHC, International Small Animal Cardiac Health Council; PUCR, plasma urea-to-creatinine ratio (mg/dL)/(mg/dL); NT-proBNP, N-terminal pro-B-type natriuretic peptide plasma concentration; SAP, systolic arterial pressure.

  2. a, b, c: when the superscripts are different, the difference between groups is statistically significant (P < .05).

Sex
Male39 (70.9%)21 (75%)14 (73.7%)4 (50%).369
Female16 (29.1%)7 (25%)5 (26.3%)4 (50%)
Age (years) (mean ± SD, [range])10.9 ± 3.7 [2.2–17]9.4 ± 3.6a [2.2–14]11.9 ± 3.6b [8–17]13.8 ± 1.0b [12.5–15].003
Body weight (kg) (mean ± SD, [range])9.7 ± 4.3 [1.4–20]10.9 ± 5.0 [1.4–20]8.6 ± 2.6 [3.6–15]8.2 ± 4.2 [3–16].101
Breed
Poodle9 (16.4%) 3 (10.7%)4 (21.1%)2 (25%).782
CKC Spaniel15 (27.3%) 9 (32.1%)6 (31.6%)0
Yorkshire Terrier 4 (7.3%) 1 (3.6%)2 (10.5%)  1 (12.5%)
Bichon 3 (5.5%) 1 (3.6%)1 (5.3%)  1 (12.5%)
Cross breed9 (16.4%) 4 (14.3%)3 (15.8%)2 (25%)
O ther breeds 15 (27.3%)10 (35.7%)3 (15.8%)2 (25%)
Treatments
ACEI 36 (65%)14 (50%)15 (79%)7 (88%).011
Spironolactone 18 (33%) 2 (7%)9 (47%)7 (88%)
Furosemide 15 (27%) 1 (4%)6 (32%)  8 (100%)
Pimobendan 1 (2%)01 (5%)0
Theophylline 5 (9%) 1 (4%)3 (16%)1 (13%)
Others 8 (15%) 1 (4%)4 (21%)3 (16%)
Heart rate (bpm) (mean ± SD, [range])129 ± 29 [70–210]120 ± 18 [80–165]138 ± 33 [90–210]139 ± 40 [70–190].060
SAP (mmHg) (mean± SD, [range])145 ± 18 [100–185]150 ± 16 [110–185]140 ± 17 [100–160]137 ± 19 [110–170].056
NT-proBNP (pmol/L)1043 ± 1260 [174–4890]309 ± 127a [174–700]921 ± 571b [349–2273]3561 ± 1291c [1871–4890]<.001
Urea (mmol/L)8.9 ± 9.0 [1.3–47.7]5.4 ± 2.7a [2.5–16.7]8.8 ± 6.8a [1.3–31.9]21.7 ± 15.4b [9.3–47.7]<.001
Creatinine (μmol/L)89 ± 44 [53–327]76 ± 21a [53–137]84 ± 23a [55–128]144 ± 88b [83–327]<.001
PUCR51 ± 34 [12–214]39 ± 19a [19–111]55 ± 43a,b [12–214]82 ± 35b [51–156].004

Thirty-eight of the 55 dogs (69.1%) received at least 1 treatment at the time of diagnosis. Dogs in class 3 received higher doses (P < .001) of furosemide (3.0 ± 2.3 mg/kg/day) than the only dog in class 1 (1 mg/kg/day) or those in class 2 (0.8 ± 1.6 mg/kg/day).

Validation of Renal Ultrasonography

Within-day CVs for the renal ultrasonographic and Doppler measurements are presented in Table 2. Maximal values for renal, interlobar, and arcuate RI were 14.7%, 17.2%, and 25.4%, respectively.

Table 2. Coefficients of variation (%) for within-day renal morphometric and Doppler ultrasonography values measured by the 2 investigators in 6 healthy Beagles.
 Investigator 1Investigator 2
  1. Long, longitudinal axis; trans, transversal axis; RI, resistive index.

Left Kidney
Length-long4.67.6
Height-long8.55.6
Width-trans5.115.7
Height-trans4.95.4
RI renal4.514.7
RI interlobar13.016.7
RI arcuate18.39.9
Right Kidney
Length-long1.817.5
Height-long1.817.3
Width-trans18.94.8
Height-trans9.912.9
RI renal4.29.3
RI interlobar7.317.2
RI arcuate25.415.8

Links between ISACHC Class and Tested Variables

No departure of normality was observed for any of the tested variables. The LA/Ao ratio increased significantly with HF class as well as SF, EMITRAL, ARJ/LAA, EROA, RF, SPAP, and EDVI (Table 3).

Table 3. Cardiovascular variables in 55 dogs with degenerative mitral valve disease according to ISACHC classes.
VariableUnitTotalISACHC ClassP
1 (n = 28)2 (n = 19)3 (n = 8)
  1. ARJ/LAA, maximum area of the regurgitant jet signal/left atrium area ratio; EMITRAL, early diastolic transmitral flow velocity; EROA, effective regurgitant orifice area; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; IVSd, interventricular septum in diastole; IVSs, interventricular septum in systole; LA/Ao, left atrium-to-aorta ratio; LVFWd, left ventricular free-wall in diastole; LVFWs, left ventricular free-wall in systole; SPAP, systolic pulmonary arterial pressure; LVd, left ventricular end-diastolic diameter; LVs, left ventricular end-systolic diameter.

  2. a, b, c: when the superscripts are different, the difference between groups is statistically significant (P < .05).

LA/Ao1.48 ± 0.651.07 ± 0.28a1.76 ± 0.69b2.27 ± 0.29c<.001
IVSdmm7.0 ± 1.57.2 ± 1.76.8 ± 1.26.9 ± 1.4.633
LVdmm34.7 ± 6.833.3 ± 6.535.4 ± 6.937.8 ± 7.1.229
LVFWdmm7.2 ± 1.57.5 ± 1.87.0 ± 1.26.5 ± 1.0.251
IVSsmm11.7 ± 2.111.5 ± 2.111.5 ± 1.913.2 ± 2.0.110
LVsmm19.1 ± 4.719.4 ± 4.419.1 ± 4.418.2 ± 6.7.816
LVFWsmm11.9 ± 2.412.1 ± 2.911.4 ± 1.812.3 ± 2.0.569
Shortening fraction%44.9 ± 8.541.9 ± 7.6a46.0 ± 7.5ab52.6 ± 9.7b.004
EMITRALm/s1.15 ± 0.460.95 ± 0.36a1.3 ± 0.47b1.6 ± 0.36b<.001
ARJ/LAA0.81 ± 0.230.71 ± 0.26a0.89 ± 0.15b0.94 ± 0.11b.005
EROAcm²0.09 ± 0.070.06 ± 0.04a0.11 ± 0.08b0.15 ± 0.09b.003
Regurgitation fraction%35.3 ± 16.127.3 ± 12.3a41.4 ± 16.1b49.1 ± 13.4b<.001
SPAPmmHg49.4 ± 28.939.5 ± 18.6a51.3 ± 32.3ab77.0 ± 31.9b.004
ESVIcm3/m²18.7 ± 8.918.4 ± 8.517.0 ± 9.523.8 ± 7.9.190
EDVIcm3/m²65.3 ± 21.358.1 ± 18.5a65.8 ± 20.7a89.5 ± 14.7b.001
EF (Simpson's method)%71.1 ± 9.868.4 ± 9.674.0 ± 9.973.3 ± 8.9.122

Right and left interlobar RI measurements were missing for 9 and 3/55 dogs, respectively, because the dogs were not cooperative during imaging. Interlobar RI was the only renal ultrasonographic variable significantly affected by ISACHC class (Table 4). Right and left interlobar RI were significantly increased in class 3.

Table 4. Renal ultrasonographic and Doppler variables in 55 dogs with degenerative mitral valve disease, according to ISACHC classes.
KidneyVariableTotalISACHC ClassP
1 (n = 28)2 (n = 19)3 (n = 8)
  1. LS, longitudinal section; RI, resistive index; TS, transversal section.

  2. a, b, c: when the superscripts are different, the difference between groups is statistically significant (P < .05).

RightLength (mm)32.2 ± 22.829.6 ± 22.930.2 ± 24.548.2 ± 11.5.248
Height (LS) (mm)17.9 ± 12.916.1 ± 12.617.3 ± 14.026.9 ± 8.4.245
Height (TS) (mm)17.2 ± 12.915.0 ± 12.517.7 ± 14.325.7 ± 9.0.329
Width (mm)19.2 ± 15.415.6 ± 14.620.9 ± 17.030.4 ± 10.2.203
Renal RI0.68 ± 0.080.71 ± 0.090.64 ± 0.050.69 ± 0.07.054
Interlobar RI0.67 ± 0.070.64 ± 0.05a0.68 ± 0.08ab0.77 ± 0.06b.004
Arcuate RI0.64 ± 0.080.64 ± 0.080.63 ± 0.080.65 ± 0.14.803
LeftLength (mm)33.5 ± 22.335.4 ± 22.129.1 ± 24.037.9 ± 19.6.573
Height (LS) (mm)20.0 ± 13.020.5 ± 13.018.3 ± 13.922.6 ± 11.2.750
Height (TS) (mm)18.8 ± 12.819.0 ± 13.018.3 ± 13.819.8 ± 10.3.967
Width (mm)21.5 ± 14.622.1 ± 15.120.4 ± 15.622.5 ± 11.1.921
Renal RI0.69 ± 0.080.68 ± 0.080.71 ± 0.080.68 ± 0.08.500
Interlobar RI0.65 ± 0.080.62 ± 0.05a0.67 ± 0.08b0.76 ± 0.08c<.001
Arcuate RI0.65 ± 0.080.65 ± 0.100.65 ± 0.070.64 ± 0.07.909

Plasma urea and creatinine concentrations were significantly higher in dogs from class 3 than in those from classes 1 and 2. The plasma urea-to-creatinine-ratio also was higher in dogs from class 3 than in those from class 1. Plasma NT-proBNP also increased with ISACHC class (Table 1). Other plasma variables were unaffected by HF class.

Azotemia and Other Tested Variables

Sixteen of 55 dogs (29%) were azotemic because of an abnormally high concentration of plasma urea (n = 12), creatinine (n = 1), or both (n = 3). Azotemic dogs were older and were receiving higher doses of furosemide. Left atrium-to-aorta ratio, EMITRAL, EROA, RF, SPAP, interlobar RI, plasma NT-proBNP, PUCR, and triglycerides also were higher in azotemic dogs compared to nonazotemic dogs (Table 5).

Table 5. Effect of azotemic status on covariables in 55 dogs with degenerative mitral valve disease. Only statistically significant results are presented.
VariableUnitNonazotemic Dogs (n = 39)Azotemic Dogs (n = 16)P
  1. EMITRAL, early diastolic transmitral flow velocity; EROA, effective regurgitant orifice area; LA/Ao, left atrium-to-aorta ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide plasma concentration; PUCR, plasma urea-to-creatinine ratio; RI, resistive index; SPAP, systolic pulmonary arterial pressure.

AgeYear10.0 ± 3.713.3 ± 2.4.002
Furosemide dosemg/kg/day0.28 ± 1.02.0 ± 2.2<.001
LA/Ao1.28 ± 0.572.00 ± 0.54<.001
EMITRALm/s1.1 ± 0.421.4 ± 0.47.015
EROAcm²0.08 ± 0.060.12 ± 0.08.043
Regurgitation fraction%31.2 ± 15.146.4 ± 13.7.001
SPAPmmHg43.0 ± 25.165.6 ± 32.1.009
Right interlobar RI0.65 ± 0.060.75 ± 0.06<.001
Left interlobar RI0.62 ± 0.050.74 ± 0.08<.001
NT-proBNPpmol/L610 ± 5632648 ± 1825<.001
Ureammol/L5.3 ± 2.218.6 ± 12.6<.001
Creatinineμmol/L75.6 ± 19.1123.4 ± 68.2<.001
PUCR(mg/dL)/(mg/dL)37.1 ± 13.983.1 ± 46.7<.001
Triglyceridesmmol/L0.52 ± 0.330.85 ± 0.76.031

Covariables Affecting Interlobar RI

Left and right interlobar RI were not statistically different within each ISACHC class. Right and left interlobar RI increased with age, furosemide dose, LA/Ao, SF, RF, SPAP, plasma NT-proBNP, plasma urea, plasma creatinine, and PUCR. Left interlobar RI also increased with ARJ/LAA, EROA, and EDVI (Table 6). The highest R² value was observed for urea.

Table 6. Statistically significant models including 1 variable and affecting the right and left interlobar resistive RI tested by a general linear model (RI = μ + a × variable + ε) in a population of 55 dogs with degenerative mitral valve disease.
VariableUnitaμP
  1. ARJ/LAA, maximum area of the regurgitant jet signal/left atrium area ratio EDVI, end-diastolic volume index; EROA, effective regurgitant orifice area; LA/Ao, left atrium-to-aorta ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide plasma concentration; PUCR, plasma urea-to-creatinine ratio; RI, resistive index; SPAP, systolic pulmonary arterial pressure; μ, mean; a, regression coefficient of the variable; ε, the residual corresponding to the model error.

Right interlobar artery
AgeYear0.0070.597.0400.093
Furosemide dosemg/kg/day0.0260.654<.0010.395
LA/Ao0.0720.568<.0010.316
Shortening fraction%0.0030.528.0280.109
Regurgitation fraction%0.0020.607.0110.153
SPAPmmHg0.0010.635.0340.106
NT-proBNPpmol/L0.031 .10−30.636.0020.288
Ureammol/L0.0070.617<.0010.450
Creatinineμmol/L0.0010.572.0020.237
PUCRmg.dL−1/ mg.dL−10.0020.593<.0010.390
Left interlobar artery
AgeYear0.0100.540<.0010.222
Furosemide dosemg/kg/day0.0300.631<.0010.390
LA/Ao0.0710.548<.0010.335
Shortening fraction%0.0030.532.0350.067
ARJ/LAA0.1020.571.0280.075
EROAcm²0.5110.607.0010.191
Regurgitation fraction%0.0030.558<.0010.309
SPAPmmHg0.0010.590<.0010.236
EDVIcm3/m²0.0010.575.0240.080
NT-proBNPpmol/L0.034 .10−30.613<.0010.386
Ureammol/L0.0060.601<.0010.473
Creatinineμmol/L0.0010.559<.0010.358
PUCRmg.dL−1/ mg.dL−10.0010.600<.0010.209

The stepwise regression analysis provided the following 2 models:

Left interlobar RI = −0.001 × Heart rate (bpm) + 0.031 × LA/Ao + 0.001 × SPAP (mmHg) + 0.004 × Urea (mmol/L) + 2.2.10−4 × Creatine Kinase (U/L), R² = 0.643

Right interlobar RI = −0.001 × Heart rate (bpm) + 0.013 × Urea (mmol/L) + 0.014 × Sodium (mmol/L) − 0.004 × Chloride (mmol/L), R² = 0.676

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This present study indicates that interlobar RI increases with HF severity and with azotemia. The studied population was representative of dogs with DMVD.[20] As previously described, age, plasma urea, creatinine, NT-proBNP, and PUCR increased with ISACHC class.[1, 11, 12, 17]

Only interlobar RI was affected by HF severity. No difference was observed between left and right interlobar RI within each ISACHC class, as previously reported.[4, 5] Interlobar RI values in class 1 dogs were consistent with those reported in normal dogs.[5, 7, 21, 22] Conversely, dogs in class 3 had similar interlobar RI to those of dogs with renal dysplasia (0.73 ± 0.006) or acute kidney injury (0.72 ± 0.08).[5] The right interlobar RI increased significantly by 22% only between classes 1 and 3. A significant increase in left interlobar RI was observed between classes (ie, 20% between classes 1 and 3, 6% between classes 1 and 2, and 13% between classes 2 and 3). Within-day variability for left interlobar RI measurement for the 2 investigators, however, was 13.0% and 16.7%. Consequently, a clinical interpretation of the increase in left interlobar RI was only possible between classes 1 and 3. The intrinsic measurement variability was higher than that described in humans (CV = 4.8–7.1%),[23, 24] probably attributable to the difficulty of obtaining such measurements in awake dogs. The potential factors of variation explaining such variability could be the handling and position of the animal, probe application, and direct measurement of peak-systolic and end-diastolic velocities by the investigator. Surprisingly, only interlobar RI showed statistically significant differences according to the ISACHC class, whereas renal and arcuate RI values remained unchanged. Our data do not allow such discrepancies to be explained. In humans, the most frequently measured RI is interlobar RI based on 1 report,[24] which indicated that interlobar RI was the parameter with the most consistent results and should be preferred in clinical situations. In our study, within-day CV for measurement of renal RI was better than that of interlobar RI. Therefore, the lack of difference observed cannot be explained by the intrinsic variability of the measurement per se. On the other hand, this latter finding could provide a potential explanation for arcuate RI.

Such differences also could mean that hemodynamic alterations differ according to the level of renal vasculature. In humans, discrepancies also have been observed according to the site of measurement of RI in different clinical settings.[25-27] Interpretation of an increase in interlobar RI may be misleading, because RI indeed is dependent on vascular compliance, resistance, and cross-sectional area of the distal vascular bed.[2, 28] In humans, vascular compliance may be altered with age, medication, and renal diseases. Nevertheless, in the present study, interlobar RI appeared to be affected by markers of DMVD severity and prognosis (LA/Ao, NT-proBNP),[29, 30] and by functional markers of renal function (urea, creatinine, and PUCR). Moreover, based on R² value, urea alone explained almost 50% of the variability of the left and right interlobar RI. The R² values were only very slightly increased by models with 2 variables. A potential confounding factor could be treatment differences among ISACHC classes. Most (>79%) of the dogs in ISACHC classes 2 and 3 received an angiotensin converting enzyme inhibitor (ACEI). In class 1, only 50% of the dogs were treated with ACEI. Although ACEI have a limited effect on renal function in dogs with cardiac disease,[31, 32] they may affect intrarenal hemodynamics. In dogs with experimental chronic kidney disease, enalapril preferentially induced vasodilatation of the efferent arteriole.[33] Moreover, infusion of angiotensin II increases renal vascular resistance in rats.[34] Thus, a decrease and not an increase in interlobar RI would have been expected as a consequence of ACEI treatment.

Furosemide was given to 4%, 32%, and 100% of the dogs in classes 1, 2, and 3, respectively. This class-dependent difference in furosemide treatment could explain in part the changes in renal function and interlobar RI. Azotemia caused by increased plasma urea concentration has been described in dogs with cardiac disease treated with both furosemide and enalapril.[35] Treatment with furosemide also decreases GFR in healthy dogs.[36] Moreover, tubuloglomerular feedback, which is a major renal blood flow autoregulating system, is blocked by furosemide.[37, 38] In humans, furosemide has no effect on normal kidney RI but increases RI in kidneys with ureteral obstruction.[39] In dogs, furosemide has no effect on RI in kidneys with ureteral obstruction.[40] However, the effects of long-term furosemide administration on kidney function in dogs with cardiac disease have never been investigated. In our study, furosemide-induced changes in interlobar RI cannot be excluded because the administered dose was associated (P < .001, R² = 0.39–0.40) with an increase in interlobar RI.

The final model obtained with stepwise regression for left and right interlobar RI had R² values of 0.64 and 0.68, respectively, indicating that the variables tested in this study do not explain the total variability observed for RI. Urea was a statistically significant variable in the models indicating again that RI and changes in plasma urea concentration occur in parallel. Interestingly, when heart rate increased, RI decreased. This result appears paradoxical because it has been reported that heart rate >140 bpm is an indicator of more severe cardiac disease.[41] However, a similar relationship, as identified here, between RI and heart rate has been reported in humans.[42, 43] The other variables included in the models differ according to the side (left versus right) and their clinical relevance is more difficult to explain here, although LA/Ao[41] and SPAP[11, 44] have been reported as prognostic indicators in DMVD.

In conclusion, canine DMVD is associated with increased interlobar RI according to HF class. Further investigations are now required to document the underlying pathophysiologic mechanisms responsible for such class-dependent RI changes and to determine their impact on prognosis and medical management in dogs with DMVD.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The authors gratefully acknowledge funding from Eurotransbio (Biomarks) and Dr Hawa (Biomedica Gruppe, Divischgasse 4, A-1210 Vienna, Austria) for the NT-proBNP assays.

Footnotes
  1. 1

    Craig AJ, Seguela J, Queau Y, et al. Redefining the reference interval for plasma creatinine in dogs: effect of age, gender, body weight, and breed. J Vet Intern Med 2006;20:740 (abstract)

  2. 2

    Vivid 7, General Electric Medical System, Waukesha, WI

  3. 3

    Echopac Dimension, General Medical System, Waukesha, WI

  4. 4

    Logic 5 Expert – Scill Healthcare, General Electric Medical System, Fairfield, CT

  5. 5

    811-BL, Parks Medical Electronics, Inc, Aloha, OR

  6. 6

    Vitros 250 chemistry system, Ortho-Clinical Diagnostics, Johnson & Johnson, Illkirch Graffenstaden, France

  7. 7

    Biomedica Gruppe, Divischgasse 4, A-1210 Vienne, Austria

  8. 8

    Vetsign Canine CardioScreen NT-proBNP, Guildhay, Ltd, Surrey, UK

  9. 9

    Zieba M, Beardow A, Carpenter C, et al. Analytical validation of a commercially available canine N-terminal prohormone Brain Natriuretic Peptide elisa. J Vet Intern Med 2008;22:717 (abstract)

  10. 10

    Systat, version 12.00.08, SPSS Inc, Chicago, IL

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References