Cardiac involvement in patients with Autosomal Dominant Polycystic Kidney Disease and normal renal function after six years of follow-up

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease with a prevalence of 1:400 to 1:1000 in Caucasians. It is caused by mutations in the PKD1 gene located on chromosome 16p13.3 [27] (in about 85% cases) as well as in the PKD2 gene on chromosome 4q13–23 [14]. These genes encode polycystin-1 (PC1) and polycystin-2 proteins (PC2) [13]. The biological function of polycystins is still under investigation [19].

The presence of kidney cysts is a characteristic feature in the ADPKD patients, necessary to establish the diagnosis [25]. But in the ADPKD patients, cardiovascular abnormalities, high blood pressure (BP), left ventricle hypertrophy (LVH), intracranial and extracranial aneurysms and cardiac valvular defects are significantly more common than in the general population [6].

It has been proven that children with ADPKD and normal BP have significantly higher LVM in comparison to age-matched controls without ADPKD [30]. Some studies in normotensive children and young adults with ADPKD and normal renal function [12, 30] showed increased left ventricle mass index (LVMI), prolonged isovolumetric relaxation time [2], impaired biventricular diastolic function, reduced coronary flow velocity, increased carotid intimamedia thickness, and endothelial dysfunction [9].

These findings suggest that cardiovascular involvement starts very early in the course of ADPKD progression and factors other than hemodynamics may be involved in this process.

In adults with ADPKD the prevalence of left ventricle hypertrophy (LVH) varies from 20% to 40% [3]. Some of the differences may relate to the imaging modality, variations in parameters used to define LVH, or demographic differences in the study populations.

Higher blood pressure (BP), male gender, higher body weight, older age [3], microalbuminuria, kidney failure and insulin resistance are the factors that may increase LVM in patients with ADPKD [15, 18]. BP is the most often analyzed factor influencing LVM in patients with ADPKD. It was shown that in normotensive young ADPKD-diagnosed individuals ambulant systolic and diastolic blood pressures (SBP, DBP) were significantly higher than in age- and gender-matched controls [5] and did not decrease at night [29]. Hypertension (HT) occurs in half of the patients with ADPKD and precedes kidney failure. [8]. Martinez-Vea et al. reported a greater prevalence of LVH in hypertensive ADPKD patients than in the general population [20]. In our earlier study, we showed LVH, using echocardiography, in 13% of ADPKD patients with normal renal function and in 19% of their hypertensive subgroup [24].

The aim of the follow-up study was to compare the changes of M-mode echocardiographic parameters in the previously studied groups of ADPKD patients and controls without renal failure after six years of observation and to explore the associations of these parameters with metabolic syndrome (MS) components and kidney function.

The initial study [24] included 47 ADPKD patients (29 females and 18 males) aged 18–61 years, and 49 gender and age-matched healthy controls. The inclusion criteria for the ADPKD group were as follows: presence of cysts in both kidneys, allowing a diagnosis of PKD according to Ravine et al. [25], normal renal function (serum creatinine concentration <1.35 mg/dL). Inclusion criteria for the control group were the following; normal renal function (serum creatinine concentration <1.35 mg/dL), negative family history of ADPKD, absence of cysts in the kidneys (Ravine criteria not fulfilled) and no prior diagnosis of diabetes. After six years of observation we performed a follow-up examination in 39 ADPKD patients: 16 males and 23 females, who gave their consent. Two men from the ADPKD group started dialysis during follow-up period. These two patients were excluded from analysis that finally included 37 patients with ADPKD not requiring renal replacement therapy.

The follow-up examination was performed in 40 subjects from the control group: 17 men and 23 women, who gave their consent. The protocol of the study was approved by the Bioethics Committee of the Pomeranian Medical University (decision BN-001/135/06). Physical examination with anthropometric measurements (body weight, height, waist and hip circumferences) was performed in each subject. The body mass index (BMI) was calculated as weight /height squared (kg/m²) and WHR as waist/hip ratio. BMI <25 kg/m² was classified as normal, 25–30 kg/m² as over-weight, and ≥30 kg/m² as obesity.

BP was measured three times at 2-min intervals in the left arm using a standard mercury sphygmomanometer, in the sitting position, after a 10-min rest with a mean value used in analyses. BP was defined as the use of a hypertensive medication or systolic/diastolic blood pressure ≥ 140/90 mmHg.

The fasting venous blood sample from each patient was tested for glucose, insulin, C-peptide, HbA1C, creatinine, urea, uric acid (UA) concentrations and lipid levels. Glucose concentrations were determined with the enzymaticamperometric method (Cobas GLUC 800: 04404483190 with a Super GL system, Diagnostic Systems, Germany).

Insulin was quantified by a microparticle enzyme immunoassay (MEIA, 2 D01-20, Axsym, Abbott) and C-peptide by electrochemiluminescent method (ECLIA, reagent kit and Cobas 6000 system from Roche). HbA1C was measured in K₃EDTA-sampled blood using the immunoturbidimetric method (Cobas, HbA1c 150: 20753521322). The measurements of serum creatinine, urea, UA and lipid levels were done with the Bio-Autoanalyzer Cobas Integra 800 (Roche).

For insulin resistance, the homeostasis model assessment-% sensitivity (HOMA%S index) [1] was used, while for beta cell function we used the homeostasis model assessment-%beta (HOMA%B index) [17]. Estimated glomerular filtration rate (e-GFR) was calculated based on a single serum creatinine measurement using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [16].

All subjects underwent standard two-dimensional and two-dimensionally guided M-mode echocardiography (General Electric Vivid 9 system, 3.5 MHz transducer) by the same sonographer blinded to the diagnostic category. Two-dimensionally guided M-mode echocardiograms were performed according to the American Society of Echocardiography and European Association of Cardiovascular Imaging Guidelines. The left ventricular end-diastolic diameter (LVEDd), interventricular septal thickness in diastole (IVSd), left ventricular posterior wall thickness in diastole (LVPWd), aortic root diameter (AO), and left atrium diameter (LA) were measured. The left ventricle ejection fraction (LVEF) was estimated by Simpson’s method. Two-dimensional studies comprised the parasternal long-axis and short-axis, apical four-chamber, apical long-axis two-chamber, and subcostal views. Estimates of LVM were based on the American Society of Echocardiography convention with the Devereux correction according to the following formula: LVM (g) = 0.8 × 1.04 ([LVEDd+IVSd+LVPWd]³ – LVEDd³) + 0.6.

LVH was diagnosed based on the left ventricle mass index (LVMI) adjusted for body surface area (LVMI-S, LVH-S) or for height (LVMI-H, LVH-H). LVH-S was diagnosed when LVMI-S (mass/BSA) was greater than or equal to 125 g/m² in males and 110 g/m² in accordance with the ESH/ESC Guidelines for the management of arterial hypertension from the year 2007 or when LVMI-S was greater than or equal to 115 g/m² in males and 95 g/m² in females in accordance with the ESH/ESC Guidelines for the management of arterial hypertension from the year 2013. LVH-H was diagnosed when LVMI-H (mass/height^2.7) was greater than or equal to 50 g/m^2.7 in males and 47 g/m^2.7 in females in accordance with the ESH/ESC Guidelines for the management of arterial hypertension from the year 2017. Delta echocardiographic data were calculated for each subject as differences between the values in the current follow-up examination and the initial examination from our previous study [24].

After a 6-year follow-up, the age, BMI and body surface area (BSA) were comparable in the group of ADPKD patients and controls. In patients with ADPKD the WHR, SBP, DBP values and the percentage of patients with BP treated with angiotensin-converting enzyme inhibitors (ACE–I) were significantly higher and the e-GFR value was significantly lower than in the control group. The prevalence of LVH-S in ADPKD patients after six years of observation according to the ESH/ESC criteria from 2007 was higher with the borderline significance in comparison to controls (16% vs. 3%, p=0.051), but a significant difference of LVH-S was observed (35% vs. 10%, p=0.012) according to the ESH/ESC criteria from 2013 and of LVH-H according to the ESH/ESC criteria from 2017 (27.0% vs 7.5%, p=0.032). The prevalence of LVH-S according to the criteria from 2007 in ADPKD patients with HT did not significantly differ from patients without HT (LVH-S: 6/30 vs 0/7, p=0.57), and according to the criteria from 2017 (LVH-H: 10/30 vs 0/7, p=0.16), but a significant difference was observed (13/30 vs 0/7, p=0.038) according to the criteria from 2013 (Table 1).

ADPKD females demonstrated a significantly higher LVPWd, IVSd, AO, LA, LVM, LVMI-S and LVMI-H than control females. IVSd was significantly higher in ADPKD males than in control males (Table 2).

In patients with ADPKD no significant changes of the echocardiographic data was observed during the 6 years between the initial examination and the follow-up examination. A significant increase in AO and LA was observed in the control group (Table 3). The delta of LVEDd value was significantly lower in patients with ADPKD than in the controls, although the change of this parameter was not statistically significant in either group. The delta of AO was significantly lower in patients with ADPKD than in the control group whereas the delta values of LVPVd, IVSd, AO, LA, LVM, LVMI-S and LVMI-H did not significantly differ between the two groups.

Table 4 presents significant correlations of the echocardiographic data from follow-up examination with anthropometric, clinical and biochemical parameters from initial examination in ADPKD patients.

In women with ADPKD there were positive correlations between AO and DBP, between IVSd and SBP or DBP, between LA and fasting insulin, fasting C-peptide, TG and between LVPWd and SBP, DBP and UA. There were a positive correlation between IVSd and SBP, DBP, between LVMIS and SBP and between LVMI-H and UA, age. In women with ADPKD, a negative correlations was found between LVEDd and HDL, between LA and HOMA%S, HDL, e-GFR and between IVSd, TG and UA.

In men with ADPKD there were positive correlations between LA and BMI, WHR, SBP, DBP, TG, age, fasting C-peptide, between LVPWd and BMI, WHR, between IVSd and SBP, DBP, between LVMI-S and WHR, and between LVMI-H and BMI, WHR, SBP and DBP. In men with ADPKD negative correlations between LA and HOMA%S as well as between LVMI-H and e-GFR was observed.

The analysis of correlations between delta echocardiographic parameters and initial anthropometric, clinical and biochemical parameters from the initial examination revealed a positive correlation between delta LVPWd and SBP, DBP in patients with ADPKD (Table 5). This means that the patients with higher initial SBP and DBP values demonstrated a significantly higher increase in LVPWd during the follow-up. There was a negative correlation between delta IVSd and initial BMI, WHR, HbA1C, TG, which means that higher values of the initial anthropometric and biochemical parameters were associated with a lower increase of IVSd.

Multivariate analysis of associations between delta LVPWd as dependent variable and parameters from the initial examination as independent variables showed that SBP and DBP (analyzed separately due to their strong correlation) remained significantly positive predictors of LVPWd increase during a follow-up in the GLM model adjusted for age and gender (β=+0.40, p=0.025 for SBP, β=+0.37, p=0.031 for DBP), but the significance was lost when e-GFR was added to this model (β=+0.34, p=0.071 for SBP, β=+0.30, p=0.11 for DBP). Similar analysis for delta IVSd as a dependent variable with age, gender, initial WHR, HbA1c and e-GFR as independent variables showed that higher WHR (β=−0.49, p=0.018) and HbA1c (β=−0.47, p=0.006) as well as female gender (β=−0.50, p=0.016) were significantly negative predictors of IVSd increase.

Our previous study concerning M-mode echocardiographic data in patients with ADPKD with normal renal function showed significantly higher LVMI-S in women with ADPKD in comparison to the female control group and a positive correlation of LVMI-S with SBP and DBP. These associations were not observed in men with ADPKD [24]. After a 6-year follow-up, LVMI-S in the female ADPKD subgroup was still significantly higher than in the female control subgroup and there was a positive correlation between LVMI-S and initial SBP and LVMI-H with UA and age. In the male ADPKD patients subgroup, LVMI-S and LVMI-H did not differ significantly in comparison to the male control group. There was a positive correlation between LVMI-S and initial WHR and between LVMI-H and BMI, WHR, SBP and DBP. A negative correlation between LVMI-H at follow-up and initial e-GFR in men suggests that even slightly impaired renal function (still in normal range) is a predictor of left ventricular hypertrophy development.

During the follow-up, no significant increase of M-mode echocardiographic data was observed. However, the follow-up showed a deterioration of renal function associated with the disease.

No previous studies concerning M-mode echocardiographic data changes in patients with ADPKD and normal renal function were found in the literature. However, there were a few studies evaluating LVH prevalence during follow-up [28].

Timio et al. analyzed the occurrence of cardiovascular abnormalities in a large group of patients with ADPKD (n=228) and compared them to the control group (n=146) [28]. The M-mode criterion for LVH in adults was LVMI >134 g/m² for men and >110 g/m² for women. The LVH was present more often in patients with ADPKD than in the control group both at the beginning of the study (24% vs. 6%, p<0.01), after 5 years of follow-up (30% vs. 9%, p<0.05) and after 10 years of follow-up (35% vs. 13% p<0.002).

LVMI was significantly higher in patients with ADPKD than in the control group both at the beginning of the study and after 5 and 10 years of follow-up. In our study a higher percentage of LVH according to the ESH/ESC criteria from 2007 was observed in patients with ADPKD than in the control group at the beginning (13% vs. 2%, p=0.050) [24] and with the borderline significance after 6 years of follow-up (16% vs. 3%, p=0.051). The LVH percentage in the cited study was generally higher than in our study, probably because of different population evaluated, e.g. with higher initial serum creatinine (1.79±0.18 mg/dL).

In the general population, LVH occurs more often in men, irrespective of age. Less frequent occurrence of LVH in women, especially in the premenopausal age is associated with the beneficial impact of estrogens and their protective action against LVH [26]. Our study showed that the prevalence of LVH was not significantly different in females and males with ADPKD at the beginning (10 vs 17%, p=0.66) [24] and after 6 years of follow-up, (13 vs. 23%, p=0.64).

Bardaji et al. [2] showed that in young, normotensive patients with ADPKD (n=46) both men and women had higher LVMI-S than controls. We examined the older group of patients with ADPKD, not excluding those with HT. Our study proved that LVMI-S was significantly higher in women with ADPKD both at the beginning of the study and after a 6-year follow-up in comparison to the female control group. At the beginning of the follow-up [24], mean LVMI-S was higher by 10.8 g/m² and after 6 years of follow-up by 16.50 g/m² in men with ADPKD in comparison to the male control group, but the difference was not significant.

Our study did not show any significant increase of LVMI during the 6-year follow-up neither in the patients with ADPKD nor in the control group. It should be noted that after the 6-year follow-up no association has been found between delta M-mode echo parameter values and the patient’s gender both in patients with ADPKD and in the control group.

We have observed that during the 6 years of follow-up in patients with ADPKD and normal renal function who received treatment consistent with hypertension treatment guidelines, the adverse changes in echocardiographic data can be avoided in spite of the deterioration of the renal function. Gender, age, BMI, WHR, SBP, DBP and e-GFR do not seem to have impact on LVH in such patients but to confirm these results further studies, on larger groups of patients, are required.