Depressed Cardiac Autonomic Modulation in Patients With Chronic Kidney Disease Diagnosed by Spectral Analysis
Condition: Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Study type: Observational

Summary: 
      Background/Aims: To evaluate the sympathovagal balance in patients with chronic kidney
      disease (CKD) on conservative treatment. Methods: In a cross-sectional study, patients with
      CKD stages 3, 4 and 5 not yet on dialysis (CKD group) and age-matched healthy subjects (CON
      group) underwent continuous heart rate recording during two twenty-minute periods in the
      supine position (pre-inclined), followed by passive postural inclination at 70° (inclined
      period). Power spectral analysis of the heart rate variability was used to assess the
      normalized low frequency (LFnu), indicative of sympathetic activity, and the normalized high
      frequency (HFnu), indicative of parasympathetic activity. The LFnu/HFnu ratio represented
      sympathovagal balance.
    

Detailed description: 
      Patients We evaluated 32 individuals (18 men and 14 women) with CKD at stages 3, 4 or 5 who
      were not yet on dialysis. The individuals were recruited at the Interdisciplinary Nucleus for
      Studies, Research and Treatment in Nephrology, Federal University of Juiz de Fora. All
      patients had been followed by a nephrologist for at least 6 months before inclusion in the
      study. Patients with severe cardiac disease, cancer, diabetes, collagen and demyelinating
      diseases, left ventricular systolic dysfunction, or a history of stroke were excluded. The
      control group consisted of 14 subjects with normal renal function who were non-diabetic,
      normotensive and free of heart disease. The study was approved by the Ethics Committee of the
      University Hospital of the Federal University of Juiz de Fora, document number 073/2007, and
      all subjects signed an informed consent before being included in the protocol.

      Study Design This was a cross-sectional study in which we evaluated ANS function in patients
      with CKD under conservative treatment and compared the results to a control group. Power
      spectral analysis of the HRV at rest and during a passive orthostatic stress was performed in
      both groups.

      Cardiovascular Evaluation The medical evaluation was performed by a cardiologist and
      consisted of an interview and clinical examination. Blood pressure was measured at each 2
      minutes intervals using a conventional sphygmomanometer. A conventional 12-lead
      electrocardiogram (ECG) was performed with an electrocardiograph (model Apex 1000, TEB,
      Brazil). To detect LVH, we used the Cornell criterion [9]. Ventricular geometry and function
      were analyzed using a two-dimensional Doppler echocardiogram generated using a Philips
      EnVisor C Ultrasound System (Philips Medical Systems-Ultrasound, MA, USA). Measurements and
      indices of left ventricular function at rest were obtained through the two-dimensional and M
      modes, using a 3.5 MHz linear transducer placed over the third or fourth intercostal space.
      The diagnosis of LVH was based on the left ventricular mass index (LVMI), values for which
      were considered normal up to 115 g/m2 for men and up to 95 g/m2 for women [10]. The data were
      interpreted according to criteria established by the American Society of Echocardiography
      [11].

      Laboratory Evaluation The results of the following tests were obtained from the patients'
      charts: glomerular filtration rate (eGFR; estimated from creatinine using the Modification of
      Diet in Renal Disease equation) [12], urea, potassium, calcium, phosphorus, hemoglobin, uric
      acid, parathyroid hormone (PTH), total cholesterol, HDL cholesterol, LDL cholesterol,
      triglycerides, glucose and urinalysis. The diagnosis of CKD was based on the Kidney Disease
      Outcomes Quality Initiative of the National Kidney Foundation (KDOQI/NKF) [13]: eGFR <60
      ml/min/1.73 m2 and/or at least one marker of renal parenchymal damage (e.g., proteinuria),
      present for a period of ≥3 months.

      Analysis of Heart Rate Variability The HRV was measured at rest in the supine position and
      during orthostatic stress. All subjects were instructed to fast for six hours and not to
      smoke or drink caffeine for 12 hours prior to the test. All medications that could
      potentially interfere with the cardiovascular response such as non-dihydropyridine calcium
      channel blockers, beta-blockers, central sympatholytic, tricyclic antidepressants as well as
      anti-arrhythmic drugs were withdrawn for at least five drug half-lives before the study. The
      evaluation was conducted in the morning in a calm environment with low light on a tilting
      table with seat belts and a platform for a footrest. The subjects underwent continuous HR
      recording using a Holter system (Cardio Light, Brazil) during two 20 minute periods in the
      supine position (pre-inclined), followed by passive postural inclination at 70° (inclined
      period) [14,15]. To evaluate the spectral analysis of HRV, a fast Fourier transform was used
      [16], obtained by means of Holter-specific software (Cardio Smart 550, Brazil), that allows
      periodic signals, an average of 500 sequential R-R intervals, to be divided into various
      bands of frequency response: ultra-low frequency (ULF: <0.0033 Hz), very low frequency (VLF:
      0.0033 to 0.04 Hz), low frequency (LF: 0.04 to 0.15 Hz), and high frequency (HF: 0.15 to 0.4
      Hz). The LF and HF components were used as markers of sympathetic and parasympathetic
      activities, respectively, and the LF/HF ratio was used as a measure of the sympathovagal
      balance. To minimize the effects of changes in ULF and VLF bands, the data were normalized
      and the results expressed as normalized units (nu). The normalization was done by dividing
      the power of a given component (LF or HF) by the total power spectrum; from this result, the
      VLF component was subtracted, and this number was then multiplied by 100. Thus, the variables
      used for the HRV analysis were LFnu, HFnu and the LFnu/HFnu ratio. The data were interpreted
      following previously published guidelines [17]. The HRV was analyzed using the highest total
      power expressed in msec², which was obtained after 10 minutes in the supine position and
      during the first 5 minutes after tilting the table.

      Statistical Analysis The variables are described as mean, standard deviation, percentage or
      median. The descriptive statistics and normality of the data were tested by the Kolmogorov
      Smirnov test. The laboratory data of the control and CKD groups at baseline were compared
      using an independent sample T test, Chi-square test or Mann Whitney test depending on the
      characteristics of the variable. Spectral analysis of heart rate variability was assessed
      within groups in the pre-inclined and inclined periods by Kruskal Wallis or ANOVA (with post
      Hoc test) for both the control group and for the CKD group divided into disease stages three,
      four and five. The LFnu / HFnu ratio for the control and CKD groups was compared by the Mann
      Whitney Test. To assess the correlation between CKD stages and biochemical variables with the
      LFnu/HFnu ratio, Spearman's linear correlation coefficient was used. A p value less than or
      equal to 0.05 was considered statistically significant. All analyses were performed using
      SPSS 13.0 for Windows (SPSS Inc., Chicago, USA).
    

Observational model: Case-Crossover
Sampling method: Non-Probability Sample
Study population: 
        patients with CKD stages 3, 4 and 5 not yet on dialysis (CKD group) and age-matched healthy
        subjects (CON group)
      
Keywords: Chronic Kidney Disease; Autonomic Dysfunction