Dissertation committee:
Δημήτριος Τούσουλης, Ομότιμος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Βλαχάκος, Ομότιμος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Τσιούφης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνα Αγγέλη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ελευθέριος Τσιάμης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Σμαραγδή Μαρινάκη, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Σοφία Λιονάκη, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Objective: Renal Functional Reserve (RFR) has been considered as a promising tool for the diagnosis of early nephron loss and functional renal mass. A reduced RFR has been demonstrated by some studies in early stages of arterial hypertension, attributed mainly to impaired vasodilator responsiveness and with the overactivity of the sympathetic nervous system (SNS) considered as one of the candidates involved mechanisms. In the present study we aimed to assess 1) whether RFR plays a prognostic role in the progression of eGFR in healthy and hypertensive patients with preserved renal function and 2) any associations of RFR with the hemodynamic load, inotropic capacity of the heart and asymptomatic end-organ damage in hypertensives with eGFR≥60 ml/min/1.73m2.
Design and Methods: In a 24-month prospective and interventional study, 51 newly diagnosed essential hypertensives (age 53.2±12.1 years, 54% men) and 20 healthy normotensives (age 54.3±10.0 years, 45% men) with eGFR≥60 ml/min/1.73m2 who met the study’s entry criteria were followed. Participants initially underwent laboratory and paraclinical testing to rule out secondary hypertension as well as office blood pressure (BP) and 24h ambulatory BP measurements (ABPM). Hypertensives were additionally screened for asymptomatic target organ damage with echocardiographic study to assess left ventricular mass index (LVMI) and with measurements of pulse wave velocity (PWV). In addition, they underwent a treadmill test to control the inotropic response. In all participants, RFR was determined by endogenous creatinine clearance and by using cooked meal as protein load (1.2gr/kg). Normal RFR was defined as RFR≥30ml/min. Afterwards, antihypertensive treatment with valsartan was started and the doses were titrared according to office BP at subsequent visits. To calculate the annual and two-year change in eGFR, serum creatinine (Scr) was determined in all participants at months 12 and 24 respectively.
Results: Demographic characteristics and markers of renal function (Scr, eGFR, urine albumin-creatinine ratio) were similar for both hypertensives and normotensives. No significant differences were found for RFR between these two groups (25.1±18.7 vs 27.7±15.7ml/min, p=0.6). Despite the apparently normal renal function based on eGFR, 32 hypertensive patients exhibited reduced RFR. In the hypertensive population, eGFR at 24 months was found to be significantly lower than eGFR at baseline (98.2±13.6 vs 98.8±13.6 ml/min/1.73m2, p=0.02). In the normotensive poplulation, eGFR at 12 and 24 months were significantly lower than baseline eGFR (96.4±15.6 vs 97.1±15.1 ml/min/1.73m2, p=0.001 and 96.0±15.4 vs 97.1±15.1, p <0.001 respectively). However, no significant difference was observed in the annual (Delta(12-0)m) and two-year (Delta(24-0)m) change in eGFR between hypertensive patients and normotensive controls (0.04±1.8 vs -0.75±0.9 ml/min/1.73m2, p=0.06 and -0.70±2.3 vs -1.1±1.1 ml/min/1.73m2, p=0.46 respectively).
When analyzing the data separately based on the RFR level, eGFR at 12 months was not significantly different from the baseline eGFR in the hypertensives with RFR<30ml/min. The same finding was confirmed for the hypertensives with RFR≥30ml/min. In contrast, eGFR at 24 months was significantly lower than the baseline eGFR in the subgroup of hypertensives with RFR<30ml/min only (96.5±12.1 vs 97.9±12.4 ml/min/1.73m2, p<0.001). Furthermore, when comparing the annual and two-year change in eGFR between the hypertensives with RFR≥30ml/min and the hypertensives with RFR<30ml/min, the Delta(24-0)m change differed significantly between them (0.5±2.6 vs -1.4± 1.7 ml/min/1.73m2, p=0.002), indicating that hypertensives with RFR≥30ml/min are showing a less pronounced change.
eGFR at 12 months was significantly lower than the baseline eGFR (88.7±16.8 vs 89.8±16.1 ml/min/1.73m2, p<0.01) in the normotensive controls with RFR<30ml/min. The same finding was confirmed for the normotensive controls with RFR≥30ml/min (104±10.1 vs 104.4±10.2 ml/min/1.73m2, p=0.02). eGFR at 24 months was significantly lower than baseline eGFR only in the normotensive controls with RFR<30ml/min (88.2±16.1 vs 89.8±16.1 ml/min/1.73m2, p<0.001). Furthermore, when comparing the annual and two-year change in eGFR between the normotensives with RFR≥30ml/min and the normotensives with RFR<30ml/min, the Delta(24-0)m change differed significantly between them (-0.6±1.3 vs -1.6±0.7 ml/min/1.73m2, p=0.02), indicating that normotensive controls with RFR≥30ml/min are showing a less pronounced change.
When analyzing the data of hemodynamic load, hypertensive patients with normal RFR found to be more frequently dippers for systolic BP than hypertensive patients with low RFR (64.4 vs 34.4 %, p=0.02). According to the data of the inotropic response to treadmill test, a significantly higher maximum systolic BP and maximum heart rate (HR) were found in hypertensive patients with RFR ≥30ml/min compared to hypertensive patients with RFR<30ml/min (190.4±22.8 vs 175.5±23.6 mmHg, p=0.01 and 168.8±9.3 vs 157.8±16.5 bpm, p=0.005 respectively). In addition, a positive correlation was found between RFR and the maximal systolic BP (r= 0.31, sig 0.03) as well as with the maximal HR (r= 0.29, sig 0.04) during the treadmill test. Age and gender did not have any effect on these correlations. Finally, no differences were observed in the markers of the asymptomatic target organ damage (LVMI and PWV) based on the RFR level.
Conclusions: RFR did not differ between hypertensive and normotensive subjects with preserved renal function. Furthermore, RFR seems to play a partial role in the mid-term change in glomerular filtration rate at 2 years, with the normotensives exhibiting RFR≥30ml/min and the hypertensive patients exhibiting RFR≥30ml/min showing a less pronounced change in GFR than the normotensive patients with RFR<30ml/min and the hypertensive patients with RFR<30ml/min respectively. In hypertensive patients with preserved renal function, a reduced RFR is more often associated with a non-dipping pattern for systolic BP as well as with a reduced HR response to exercise, suggesting that SNS overactivity may be a common pathway.
Given that the loss of RFR is a risk factor for acute or chronic kidney injury, hypertensive patients with reduced RFR may require more individualized treatment, more strict modification of cardiovascular risk factors and a closer nephrological monitoring. Moreover, in patients at increased risk for rapid decline in renal function (e.g, patients with recurrent episodes of acute kidney injury, chronic kidney disease with severe proteinuria, uncontrolled hypertension and diabetes), a regular assessement of RFR level might be proved in the future helpful for providing prognostic information and tailor-guided interventions (e.g endothelin antagonists, renal denervation, 3rd generation mineralocorticoid antagonists, SGLT2 inhibitors, GLP-1 agonists etc).
