Comparison of different calcium channel blockers regarding their effect on intrarenal hemodynamics in patients with arterial hypertension

Hintergrund und Ziele Kalziumantagonisten sind effektive Antihypertensiva und verzögern die Progression von Nierenerkrankungen. Nach experimentellen Ergebnissen haben individuelle Substanzen aus der dritten Generation der Kalziumantagonisten unterschiedliche Auswirkungen auf die intraglomeruläre Hämodynamik. Es wird vermutet, dass dies auf unterschiedliche Effekte auf die efferenten und afferenten Widerstandsgefäße des Glomerulums zurückzuführen ist. In dieser Arbeit wurde das etablierte Amlodipin mit Manidipin, als einem neuen Vertreter der dritten Generation, hinsichtlich der unterschiedlichen Auswirkung auf die intrarenale Hämodynamik beim Patienten mit arterieller Hypertonie verglichen. Neben dem intraglomerulären Druck als primärem Zielparameter wurde zusätzlich die Wirkung dieser beiden Kalziumantagonisten auf die Albuminurie und auf unerwünschte Nebenwirkungen, wie zum Beispiel periphere Ödeme, untersucht. Methoden Die Studie wurde prospektiv randomisiert, doppelblind und mit zwei parallelen Studienarmen durchgeführt. Insgesamt wurden 104 Patienten mit milder bis mäßiger arterieller Hypertonie eingeschlossen. Zur Ermittlung des intraglomerulären Druckes wurden die glomeruläre Filtrationsrate und der renale Plasmafluss durch die renale Clearancemethode, basierend auf einer konstanten Infusion von Inulin und Paraaminohippursäure, gemessen. Mit Hilfe der Gomez-Formeln, die auf experimentellen Modellen beruhen, lassen sich mit diesen Parametern der intraglomeruläre Druck sowie der Widerstand der afferenten und efferenten Gefäße berechnen. Ergebnisse und Beobachtungen Die Studie zeigte einen signifikanten Anstieg des intraglomerulären Druckes unter der Amlodipin-Therapie (p=0,009). Bei Patienten, die Manidipin einnahmen, ergab sich hingegen ein nahezu unveränderter intraglomerulärer Druck (p=0,951). Am Ende der Therapiephase bestand zwischen den beiden Gruppen ein signifikanter Unterschied des intraglomerulären Druckes von 1,2 mmHg (p=0,04). Hinsichtlich der Albuminurie kam es unter der Manidipin-Therapie zu einer Abnahme der Albuminurie (p=0,053). Im Gegensatz dazu zeigte sich in der Amlodipin–Gruppe eine signifikante Zunahme der Albuminurie (p=0,003). Beim Vergleich der beiden Studienarme zeigte sich ein signifikanter Unterschied in der Veränderung der Albuminurie (p<0,001). Bezüglich der unerwünschten Nebenwirkungen zeigte sich in der Manidipin–Gruppe ein signifikant geringeres Auftreten von peripheren Ödemen als in der Amlodipin–Gruppe (p=0,03). Alle drei Ergebnisse spiegeln die Unterschiede von Manidipin und Amlodipin im vaskulären Stromgebiet wider. Pathophysiologisch lässt sich der Unterschied wie folgt erklären: Sinkt der Quotient aus efferentem und afferentem Widerstand (RE/RA), führt dies zu einer Abnahme des intraglomerulären Druckes und damit des Filtrationsdruckes, sowohl in der Niere (geringere Albuminurie) als auch im systemischen Kreislauf (weniger Beinödeme). Praktische Schlussfolgerungen Entsprechend der genannten Studienergebnisse scheint Manidipin einen günstigeren Effekt auf das vaskuläre Stromgebiet, inklusive der intrarenalen Hämodynamik, als Amlodipin zu haben. Da Albuminurie als ein wichtiger kardiovaskulärer Risikofaktor etabliert ist, ist eine Verminderung der Albuminurie ein wesentliches Ziel einer antihypertensiven Therapie. Hier hat Manidipin Vorteile gegenüber Amlodipin. Da sich die Studiendauer nur auf einen Zeitraum von vier Wochen beschränkte, muss in einem nächsten Schritt die Auswirkung von Manidipin auf die renale Hämodynamik über eine längere Einnahmezeit ermittelt werden. Ziel solcher Studien wäre es, weitergehende Aussagen über den Einfluss von Manidipin, im Vergleich zu derzeit etablierten Substanzen wie Amlodipin, auf das Fortschreiten von Nierenerkrankungen treffen zu können.Background and objectives Calcium channel blockers (CCBs) are effective antihypertensive drugs and have been shown to attenuate the progression of renal diseases. According to experimental data, individual substances within the class of third generation CCBs differ regarding their effect on intraglomerular hemodynamics. This is thought to be due to differential effects on afferent and efferent resistance vessels. In this study the established drug amlodipine was compared with the novel CCB manidipine regarding their effect on intrarenal hemodynamics in patients with arterial hypertension. In addition to intraglomerular pressure we also examined the effect of both drugs on albuminuria and on adverse reactions, indluding incidence of peripheral edema. Methods The study was a prospective randomized, double–blind and parallel–group clinical trial and included 104 patients with arterial hypertension grade 1 or 2. In order to evaluate intraglomerular pressure, renal plasma flow and the glomerular filtration rate were measured by applying the constant infusion input clearance technique with para-aminohippuric acid and inulin. Subsequently, intraglomerular pressure and resistance of afferent and efferent arterioles were calculated using to the Gomez-formulas, which are based on experimental models. Results The intraglomerular pressure increased in the amlodipine group (p=0,009), while intraglomerular pressure did not change in the manidipine group (p=0,951). There was a significant difference after treatment in the two treatment regimes regarding the intraglomerular pressure. The difference amounted to 1.2 mmHg (p=0,042). Regarding albuminuria, manidipine reduced albuminuria (p=0,053), whereas amlodipine caused a significant increase of albuminuria (p=0,003). There was a significant difference after treatment in the two groups regarding albuminuria (p<0,001). Finally, patients in the manidipine group had a significantly lower incidence of peripheral edema compared to patients in the amlodipine group (p=0,03). These three findings reflect differential effects of manidipine versus amlodipine on the vasculature. The pathophysiologic explanation of these results is that a decrease in the ratio of efferent to afferent arteriolar resistance (RE/RA) leads to a lower intravascular pressure, both in the kidney (reduced albuminuria) and in the systemic vasculature (lower frequency of edema). Practical findings In summary, manidipine appears to have a superior effect on the vascular bed, including the renal circulation, compared to amlodipine. Albuminuria is a well recognized cardiovascular risk factor, and it is thus a fundamental objective to reduce albuminuria in these patients. Manidipine had superior effects on albuminuria in this study. This study was limited to a period of four weeks. A next step should be to determine the effect of manidipine versus currently established drugs such as amlodipine on intraglomerular hemodynamics, to assess its efficacy in retarding the progression of renal diseases

Change of renal function after short-term use of cardioprotective agents in patients with type 2 diabetes is not accurately assessed by the change of estimated glomerular filtration rate: an observational study

Abstract Background After initiating cardioprotective agents, a fall of estimated glomerular filtration rate (eGFR) has been reported in several studies. Our goal was to evaluate the accuracy of change of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR in patients with type 2 diabetes (T2D) after short-term pharmacological intervention with angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, gliptin or sodium-glucose cotransporter-2 inhibitor. Methods We analyzed 190 patients with T2D in the early stage of the disease, having no overt renal impairment by CKD-EPI equation. In each patient, we measured GFR (mGFR) by applying the constant infusion input clearance technique with sinistrin (Inutest; Fresenius, Linz, Austria) at baseline and after short-term (4–12 weeks) pharmacological intervention with cardioprotective agents (ramipril, telmisartan, linagliptin, metformin, empagliflozin) that potentially lead to an alteration of renal function. Simultaneously, a standardized analysis of serum creatinine was performed and eGFR was estimated by the CKD-EPI equation. Results Average mGFR was 111 ± 20 ml/min/1.73m2, whereas eGFR was lower with 93 ± 13 ml/min/1.73m2. The ratio eGFR/mGFR in relation to mGFR was almost curvilinear, showing an underestimation of renal function by eGFR in the upper normal range. At baseline only 80 patients (42%) lay within ± 10% of mGFR and the concordance correlation coefficient (CCC) was extremely low (− 0.07). After short-term pharmacological intervention changes in eGFR and mGFR correlated with each other (r = 0.286, p < 0.001). For example, for a given mGFR of 111 ml/min/1.73m2, a change of mGFR by ± 10% corresponded to ± 11 ml/min/1.73m2, but the confidence interval of eGFR was 25 ml/min/1.73m2. The CCC was low (0.22). Conclusion The agreement between eGFR by CKD-EPI and mGFR is modest and the change of renal function after short-term pharmacological intervention is not accurately and precisely reflected by the change of eGFR in patients with T2D in the early stage of their disease

Data from: Retinal capillary rarefaction in patients with type 2 diabetes mellitus

Purpose: In diabetes mellitus type 2, capillary rarefaction plays a pivotal role in the pathogenesis of end-organ damage. We investigated retinal capillary density in patients with early disease. Methods: This cross-sectional study compares retinal capillary rarefaction determined by intercapillary distance (ICD) and capillary area (CapA), measured non-invasively and in vivo by scanning laser Doppler flowmetry, in 73 patients with type 2 diabetes, 55 healthy controls and 134 individuals with hypertension stage 1 or 2. Results: In diabetic patients, ICD was greater (23.2±5.5 vs 20.2±4.2, p = 0.013) and CapA smaller (1592±595 vs 1821±652, p = 0.019) than in healthy controls after adjustment for differences in cardiovascular risk factors between the groups. Compared to hypertensive patients, diabetic individuals showed no difference in ICD (23.1±5.8, p = 0.781) and CapA (1556±649, p = 0.768). Conclusion: In the early stage of diabetes type 2, patients showed capillary rarefaction compared to healthy individuals

Retinal Capillary Rarefaction in Patients with Type 2 Diabetes Mellitus

Purpose In diabetes mellitus type 2, capillary rarefaction plays a pivotal role in the pathogenesis of end-organ damage. We investigated retinal capillary density in patients with early disease. Methods This cross-sectional study compares retinal capillary rarefaction determined by intercapillary distance (ICD) and capillary area (CapA), measured non-invasively and in vivo by scanning laser Doppler flowmetry, in 73 patients with type 2 diabetes, 55 healthy controls and 134 individuals with hypertension stage 1 or 2. Results In diabetic patients, ICD was greater (23.2±5.5 vs 20.2±4.2, p = 0.013) and CapA smaller (1592±595 vs 1821±652, p = 0.019) than in healthy controls after adjustment for differences in cardiovascular risk factors between the groups. Compared to hypertensive patients, diabetic individuals showed no difference in ICD (23.1±5.8, p = 0.781) and CapA (1556±649, p = 0.768). Conclusion In the early stage of diabetes type 2, patients showed capillary rarefaction compared to healthy individuals

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial

Abstract Background Empagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness. Methods Our analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial (http://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis. Results As previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.6 ± 12.1 vs 118.6 ± 12.9 mmHg, p < 0.001), central pulse pressure (39.1 ± 10.2 vs 41.9 ± 10.7 mmHg, p = 0.027) forward (27.1 ± 5.69 vs 28.7 ± 6.23 mmHg, p = 0.031) as well as reflected wave amplitude (18.9 ± 5.98 vs 20.3 ± 5.97 mmHg, p = 0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta = − 0.259, p = 0.054), sex (beta = 0.292, p = 0.040) and change in systolic 24-h ambulatory blood pressure (beta = 0.364, p = 0.019), the change of hsCRP (beta = 0.305, p = 0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta = 0.347, p = 0.017) on arterial stiffness parameters was found. Conclusion Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms. Trial registration http://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registere

Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine

Background!#!Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail.!##!Methods!#!Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model.!##!Results!#!Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p &amp;lt; 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both p!##!Conclusions!#!In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing R!##!Trial registration!#!The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016

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Retinal parameters.

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Measurement of intercapillary distance in perfusion image with scanning laser Doppler flowmetry and calculation of intercapillary distance using automatic full field perfusion image analyser

<p>Measurement of intercapillary distance in perfusion image with scanning laser Doppler flowmetry and calculation of intercapillary distance using automatic full field perfusion image analyser</p