Hypertensive Chronic Kidney Disease Research Articles

Telemonitoring and Case Management for Hypertensive and Remote-Dwelling Patients With Chronic Kidney Disease-The Telemonitoring for Improved Kidney Outcomes Study (TIKO): A Clinical Research Protocol.

Background:Hypertension, together with poorly controlled blood pressure (BP) are known risk factors for kidney disease and progression to kidney failure as well as increased cardiovascular (CV) morbidity and mortality. Several studies in patients without kidney disease have demonstrated the efficacy of home BP telemonitoring (HBPT) for BP control.Objective:The primary aim of this study is to assess the mean difference in systolic BP (SBP) at 12 months, from baseline in remote dwelling patients with hypertension and chronic kidney disease (CKD) in Northern Alberta, Canada, comparing HBPT + usual care versus HBPT + a case manager. Other secondary objectives, including cost-effectiveness and acceptability of HBPT as well as occurrence of adverse events will also be assessed.MethodsDesign:This study is designed as a pragmatic randomized controlled trial (RCT) of HBPT plus clinical case management compared to HBPT with usual care.Setting:Peace River region in Northern Alberta Region, Canada.Patients:Primary care patients with CKD and hypertension.Measurements:Eligible patients will be randomized 1:1 to HBPT + BP case management versus HBPT + usual care. In the intervention arm, BP will be measured 4 times daily for 1 week, with medications titrated up or down by the study case manager until guideline targets (systolic BP [SBP]: <130 mmHg) are achieved. Once BP is controlled, (ie, to guideline-concordant targets), this 1-week protocol will be repeated every 3 months for 1 year. Patients in the control arm will also follow the same BP measurement protocol; however, there will be no interactions with the case manager; they will share their BP readings with their primary care physicians or nurse practitioners at scheduled visits.Limitations:Potential limitations of this study include the relatively short duration of follow-up, possible technological pitfalls, and need for patients to own a smartphone and have access to the internet to participate.Conclusions:As this study will focus on a high-risk population that has been characterized by a large care gap, it will generate important evidence that would allow targeted and effective population-level strategies to be implemented to improve health outcomes for high-risk hypertensive CKD patients in Canada’s remote communities.Trial Registration:www.clinicaltrials.gov (NCT number: NCT04098354)

New Aspects in the Management of Hypertension in Patients with Chronic Kidney Disease not on Renal Replacement Therapy.

With chronic kidney disease (CKD) being a global arising health problem, strategies for delaying kidney disease progression and reducing the high cardiovascular risk inherent to CKD, are the main objectives of the actual management of patients with kidney diseases. In these patients, the control of arterial hypertension is essential, as high blood pressure (BP) is a strong determinant of worst cardiovascular and renal outcomes. Achieving target blood pressures recommended by international guidelines is mandatory and often demands a multiple levels management, including several pharmacological and lifestyle measures. Even in the presence of adequate BP control, the residual cardiovascular risk remains high. In this respect, the recent demonstration that novel agents such as sodium glucose transporter 2 (SGLT2) inhibitors or the new non-steroidal mineralocorticoid antagonist finerenone can retard the progression of kidney diseases and reduce cardiovascular mortality on top of standard of care treatment with renin-angiotensin system inhibitors represent enormous progresses. These studies also demonstrate that cardiovascular and renal protection can be obtained beyond blood pressure control. Other promising novelties are still to come such as renal denervation and endothelin receptor antagonists in the setting of diabetic and non-diabetic kidney diseases. In the present review, we shall discuss the classic and the new aspects for the management of hypertension in CKD, integrating the new data from recent clinical studies.

Renin-angiotensin system blockers during the COVID-19 pandemic: an update for patients with hypertension and chronic kidney disease.

ABSTRACTHypertension and chronic kidney disease (CKD) are among the most common comorbidities associated with coronavirus disease 2019 (COVID-19) severity and mortality risk. Renin–angiotensin system (RAS) blockers are cornerstones in the treatment of both hypertension and proteinuric CKD. In the early months of the COVID-19 pandemic, a hypothesis emerged suggesting that the use of RAS blockers may increase susceptibility for COVID-19 infection and disease severity in these populations. This hypothesis was based on the fact that angiotensin-converting enzyme 2 (ACE2), a counter regulatory component of the RAS, acts as the receptor for severe acute respiratory syndrome coronavirus 2 cell entry. Extrapolations from preliminary animal studies led to speculation that upregulation of ACE2 by RAS blockers may increase the risk of COVID-19-related adverse outcomes. However, these hypotheses were not supported by emerging evidence from observational and randomized clinical trials in humans, suggesting no such association. Herein we describe the physiological role of ACE2 as part of the RAS, discuss its central role in COVID-19 infection and present original and updated evidence from human studies on the association between RAS blockade and COVID-19 infection or related outcomes, with a particular focus on hypertension and CKD.

The roles of sodium and volume overload on hypertension in chronic kidney disease.

Chronic kidney disease (CKD) is associated with increased risk of cardiovascular (CV) events, and the disease burden is rising rapidly. An important contributor to CV events and CKD progression is high blood pressure (BP). The main mechanisms of hypertension in early and advanced CKD are renin-angiotensin system activation and volume overload, respectively. Sodium retention is well known as a factor for high BP in CKD. However, a BP increase in response to total body sodium or volume overload can be limited by neurohormonal modulation. Recent clinical trial data favoring intensive BP lowering in CKD imply that the balance between volume and neurohormonal control could be revisited with respect to the safety and efficacy of strict volume control when using antihypertensive medications. In hemodialysis patients, the role of more liberal use of antihypertensive medications with the concept of functional dry weight for intensive BP control must be studied.

Is the KDIGO Systolic Blood Pressure Target

Meticulous management of hypertension is important in chronic kidney disease (CKD) to reduce the risk of cardiovascular disease, mortality, and progression of CKD. The recently published Kidney Disease Improving Global Outcomes (KDIGO) guideline on blood pressure (BP) management in CKD stresses the importance of standardized BP measurement and strict control of BP. This is a useful document that will help to improve the management of hypertension in CKD globally. However, the recommendation of systolic BP target of <120 mm Hg by KDIGO is controversial. It is based on weak evidence derived mainly from a single randomized controlled trial and its CKD subgroup analysis. Here, we review the current evidence surrounding BP target in CKD. We argue that the target recommended by KDIGO is not generalizable to the majority of people with CKD. Standardized BP measurements are challenging to implement outside specialist hypertension and research clinics, and the target of <120 mm Hg BP systolic cannot be extrapolated to routine clinic BP measurements. If applied to routine BP measurement, this target will expose the multimorbid and frail CKD patients to the risk of adverse events including falls and fractures. Furthermore, it will not be achievable in the majority of CKD patients. The target recommended by KDIGO is an outlier among contemporary major international hypertension guidelines and is likely to perplex clinicians. We believe the KDIGO-recommended target systolic BP <120 mm Hg for CKD is inappropriate in the majority of CKD patients and it may even be harmful for patients managed in routine clinical practice.

Renal Denervation in Combination With Angiotensin Receptor Blockade Prolongs Blood Pressure Trough During Hemorrhage.

Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6-8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.

Managing diabetes and hypertension in chronic kidney disease.

Since 2020, several guidelines have been published to help health practitioners better manage hypertension and diabetes in patients with chronic kidney disease. Scrutiny on the inclusion of race in determining the estimated glomerular filtration rate (eGFR) as well as breakthrough research regarding the drug dapagliflozin for the treatment of patients with chronic kidney disease are discussed.

A renaissance in the treatment of diabetic kidney disease, hypertension in chronic kidney disease, and beyond.

Chronic kidney disease (CKD) affects approximately 15% of the US population and is associated with significant cardiovascular morbidity and mortality. The two leading causes of end stage kidney disease are hypertension and diabetes mellitus, both of which are modifiable risk factors. The cornerstones of CKD care include early detection, management of associated risk factors, modification of cardiovascular disease risk, slowing progression of disease, and management of complications including anemia, acid base disturbance, and mineral and bone disorders. For the last 20 years, renin-angiotensin system inhibitors were the mainstay treatment for proteinuric diabetic and nondiabetic kidney disease. Recently, new therapies such as sodium-glucose linked transporter 2 inhibitors, have emerged as powerful tools in the treatment of CKD with indications in both diabetic and nondiabetic kidney disease. In this article, we define CKD staging, review new hypertension and diabetic guidelines for CKD patients, and discuss major trials for new potential therapies in CKD, particularly diabetic kidney disease. We will provide practical guidance for primary care physicians to diagnose CKD and implement these agents early in the disease course to prevent the progression of disease and reduce the morbidity and mortality of this vulnerable population.

Modified CHA2DS2-VASc can predict mortality in COVID-19 patients admitted to the emergency department

IntroductionCHA2DS2-VASc score is used to determine the thromboembolic risk, but its prognostic value has been demonstrated in several cardiovascular (CV) diseases. Except for female gender, many CV risk factors comprising this score are recognized as risk factors for mortality in COVID-19. Cetinak G. et al demonstrated the ability of modified CHA2DS2-VASc (M-CHA2DS2-VASc) to predict mortality in COVID-19, which is based on changing gender criteria from female to male.PurposeTo evaluate the prognostic value of a M-CHA2DS2-VASc score to predict pulmonary embolism (PE) and mortality in pts with COVID-19 admitted at the emergency department (ED).MethodsRetrospective study of pts admitted to the ED between June 2020-January 2021, who underwent computed tomography pulmonary angiography (CTPA) due to PE suspicion. Pts were stratified into 3 M-CHA2DS2-VASc risk groups: lower (0–1), intermediate (2–3) and high risk (≥4). Kruskal-Wallis and X-square test were used to compare score risk groups. Logistic regression was used to determine predictors of PE and mortality. ROC curve was performed to evaluate the discriminative power of the score.ResultsWe included 300 pts: median age 71 years, 59% male. Hypertension (59%) chronic kidney disease (CKD, 33%), dyslipidemia (32%) and diabetes (28%) were the most common comorbidities. PE was diagnosed in 46 pts (15%). We found no difference in PE incidence according to M-CHA2DS2-VASc groups (p=0.531) and it showed no predictive value for PE (OR: 1.050, p=0.596). The AUC of M-CHA2DS2-VASc was 0.52, suggesting no discriminative power to predict PE.Regarding mortality, M-CHA2DS2-VASc score was higher in non-survivors COVID-19 pts than in survivors [4 (IQR 3–5) vs 2 (1–4), respectively, p<0.001]. A multivariate logistic regression analysis was performed for mortality based on M-CHA2DS2-VASC, troponin, CKD and smoking history, and only M-CHA2DS2-VASc was identified as an independent predictor of mortality (OR: 1.406, p=0.007). Kaplan-Meier showed that M-CHA2DS2-VASc score was associated with mortality: the survival rate was 92%, 80% and 63% in the lower, intermediate and higher M-CHA2DS2VASc score risk group (logrank test p<0.001; Fig. A).Most of the pts in the cohort were hospitalized (83%), but 21 pts (17%) discharged from the ED. Among these pts, 33% (n=17) had low risk, 37% (n=19) intermediate risk and 29% (n=15) high risk for mortality according to the M-CHA2DS2VASc score. The Kaplan-Meier individual survival analysis for hospitalized patients (Fig. B) and for those discharged from the ED (Fig. C) showed that M-CHA2DS2-VASc score had a good discriminative ability to predict short-term mortality for both groups (logrank test p<0.001 and p=0.007, respectively).ConclusionConsidering the lack of validated scores to predict mortality in COVID-19 pts, the M-CHA2DS2-VASc might be a simple tool to predict short-term mortality in these pts, irrespectively of the need for hospitalization or not.Funding AcknowledgementType of funding sources: None.

Assessments of left ventricular systolic and diastolic functions with tissue Doppler imaging and myocardial performance index in children with chronic kidney disease.

This study aimed to document early left ventricular (LV) dysfunction in chronic kidney disease (CKD) using methods such as tissue Doppler imaging and the myocardial performance index (MPI). A total of 40 patients diagnosed with CKD (mean age, 10.1 ± 4.1 years) and 40 sex- and age-matched healthy controls (mean age, 9.6 ± 4.3 years) were examined. In the patient group, 20 patients had early stage (Stage 2-3) CKD and 20 patients had late-stage (stage 4-5) CKD, and 18 patients had hypertension. The pulmonary artery systolic pressure (PAPs) and LV mass index (LVMI) were significantly higher in the patient group (P < 0.05). The LV septal and lateral margins of the mitral annulus E'/A' ratio, E/E' ratio and MPI results were significantly different between the groups (P < 0.05). The MPI scores were higher in late-stage CKD than in early stage CKD (P < 0.05). The E'/A' ratio was lower and the MPI was higher in the hypertensive CKD group compared with the normotensive CKD group (P < 0.05). The E/E' ratio was correlated positively with the LVMI, and the PAPs, and negatively with glomerular filtration rate, S' value, E'/A' ratio. The MPI was correlated positively with blood pressure, LVMI, PAPs, and the S value, and negatively with the E'/A' ratio. The E'/A' ratio, the E/E' ratio, and the isovolumetric relaxation time measured by tissue Doppler imaging is highly accurate and easily applicable for detecting diastolic LV function, and the MPI is suitable for detecting both systolic and diastolic LV dysfunction. Their routine use may be useful in evaluating LV functions in children with CKD.

Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice

Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, serelaxin (RLX), enhanced BM-MSC-induced renoprotection in preclinical CKD models. Given the increased interest and manufacturing advantages to using stem cell-derived exosomes (EXO) as therapeutics, this study determined whether RLX could enhance the therapeutic efficacy of BM-MSC-EXO, and compared the renoprotective effects of RLX and BM-MSC-EXO versus RLX and BM-MSCs in mice with hypertensive CKD. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and given saline to drink (1K/DOCA/salt) for 21 days. Control mice were uninephrectomised and given normal drinking water for the same time-period. Subgroups of 1K/DOCA/salt-hypertensive mice were then treated with either RLX (0.5 mg/kg/day) or BM-MSC-EXO (25 μg/mouse; equivalent to 1–2 × 106 BM-MSCs/mouse) alone; combinations of RLX and BM-MSC-EXO or BM-MSCs (1 × 106/mouse); or the mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day), from days 14–21. 1K/DOCA/salt-hypertensive mice developed kidney tubular damage, inflammation and fibrosis, and impaired kidney function 21 days post-injury. Whilst RLX alone attenuated the 1K/DOCA/salt-induced fibrosis, BM-MSC-EXO alone only diminished measures of tissue inflammation post-treatment. Comparatively, the combined effects of RLX and BM-MSC-EXO or BM-MSCs demonstrated similar anti-fibrotic efficacy, but RLX and BM-MSCs offered broader renoprotection over RLX and/or BM-MSC-EXO, and comparable effects to spironolactone. Only RLX and BM-MSCs, but not RLX and/or BM-MSC-EXO, also attenuated the 1K/DOCA/salt-induced hypertension. Hence, although RLX improved the renoprotective effects of BM-MSC-EXO, combining RLX with BM-MSCs provided a better therapeutic option for hypertensive CKD.

Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling.

Chronic kidney disease (CKD) is characterized by the progressive functional loss of nephrons and hypertension (HTN). Some antihypertensive regimens attenuate the progression of CKD (blockers of the renin-angiotensin system). Although studies have suggested that calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, there are few long-term clinical studies that have determined the impact of CCBs in patients with hypertensive CKD. Dihydropyridine (DHP) or L-type CCBs preferentially vasodilate the afferent arteriole and have been associated with glomerular HTN and increases in proteinuria in animal models with low renal function. Small clinical studies in vulnerable populations with renal disease such as African Americans, children, and diabetics have also suggested that DHP CCBs exacerbate glomerular injury, which questions the renoprotective effect of this class of antihypertensive drug. We used an established integrative mathematical model of human physiology, HumMod, to test the hypothesis that DHP CCB therapy exacerbates pressure-induced glomerular injury in hypertensive CKD. Over a simulation of 3 yr, CCB therapy reduced mean blood pressure by 14-16 mmHg in HTN both with and without CKD. Both impaired tubuloglomerular feedback and low baseline renal function exacerbated glomerular pressure, glomerulosclerosis, and the decline in renal function during L-type CCB treatment. However, simulating CCB therapy that inhibited both L- and T-type calcium channels increased efferent arteriolar vasodilation and alleviated glomerular damage. These simulations support the evidence that DHP (L-type) CCBs potentiate glomerular HTN during CKD and suggest that T/L-type CCBs are valuable in proteinuric renal disease treatment.NEW & NOTEWORTHY Our physiological model replicates clinical trial results and provides unique insights into possible mechanisms that play a role in glomerular injury and hypertensive kidney disease progression during chronic CCB therapy. Specifically, these simulations predict the temporal changes in renal function with CCB treatment and demonstrate important roles for tubuloglomerular feedback and efferent arteriolar conductance in the control of chronic kidney disease progression.

Thromboxane A2 is involved in the development of hypertension in chronic kidney disease rats

Hypertension is one of the most common complications of chronic kidney disease (CKD). Some research has indicated that changes in large artery function especially caused by thromboxane A2 (TXA2) may be a novel factor acting to induce hypertension in CKD. We studied the 5/6 nephrectomy rat model and measured serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), TXA2-stable metabolites (thromboxane B2, TXB2), and caudal artery pressure after nephrectomy. The tension variations in thoracic aortas were measured after stimulating by vasoconstrictor/vasodilator using the cumulative concentration administration method and then tested the expression of TXA2 receptors in the thoracic aortas through western blots. The CKD rats developed uremia, electrolyte imbalances，and hypertension. They also exhibited a significant increase in TXB2 concentration. The aortic rings of CKD rats showed an increased contraction response to U46619 (a TXA2 analogue) and the expression of TXA2 receptors also enhanced. In the meanwhile, the diastolic function decreased in the CKD group. Our results demonstrate that the impairment of artery contractile function caused by the increase of TXA2 receptors on the wall of aortic rings may be involved in hypertension in CKD rats.

Pulmonary Hypertension in Chronic Kidney Disease.

There is a high prevalence of pulmonary hypertension in chronic kidney disease (CKD), with rates increasing as glomerular filtration rate declines. Pulmonary hypertension is associated with a higher risk of cardiovascular events and mortality in non-dialysis-dependent CKD stages 3 to 5, dialysis-dependent CKD, as well as kidney transplant recipients. The pathophysiology of pulmonary hypertension in CKD is multifactorial and includes higher pulmonary capillary wedge pressure caused by ischemic heart disease and cardiomyopathy, higher cardiac output caused by anemia and arteriovenous access used for hemodialysis, as well as potentially higher pulmonary vascular resistance. Treatment should focus on the underlying cause.

Effects of enhanced versus reduced vasodilating treatment on brachial and central blood pressure in patients with chronic kidney disease: a randomized controlled trial.

Blood pressure (BP) control is important in chronic kidney disease (CKD), but a reduction in brachial BP may not mirror changes in central aortic BP (cBP) during antihypertensive medication. We hypothesize that a fall in cBP is better reflected during enhanced vasodilation treatment (EVT) compared with reduced vasodilation treatment (RVT) because of different hemodynamic actions of these interventions. Eighty-one hypertensive CKD stage 3-4 patients (mean measured glomerular filtration rate 36 ml/min per 1.73 m2) were randomized to either EVT based on renin--angiotensin blockade and/or amlodipine or RVT based on nonvasodilating β-blockade (metoprolol). Before randomization and following 18 months of treatment, we performed 24-h ambulatory BP measurements (ABPM) and radial artery pulse wave analysis for estimation of cBP and augmentation index (AIx). Forearm resistance (Rrest) was determined by venous occlusion plethysmography and arterial stiffness by carotid--femoral pulse wave velocity (PWV). Matched healthy controls were studied once for comparison. Compared with controls, CKD patients had elevated ABPM, cBP and PWV. Although ABPM remained unchanged from baseline to follow-up in both treatment groups, cBP decreased 4.7/2.9 mmHg (systolic/diastolic) during EVT and increased 5.1/1.5 mmHg during RVT (Δ=9.8/4.4 mmHg, P=0.02 for SBP, P = 0.05 for DBP). At follow-up, the difference between systolic cBP and 24-h ABPM (ΔBPsyst) was negatively associated with heart rate and positively associated with AIx and Rrest (all P < 0.01) but not PWV (P = 0.32). In CKD patients, EVT and RVT have opposite effects on cBP and the difference between cBP and ambulatory BP is larger for EVT than RVT.

Blunted natriuretic response to saline loading in sheep with hypertensive kidney disease following radiofrequency catheter-based renal denervation

Renal sympathetic nerves contribute to renal excretory function during volume expansion. We hypothesized that intact renal innervation is required for excretion of a fluid/electrolyte load in hypertensive chronic kidney disease (CKD) and normotensive healthy settings. Blood pressure, kidney hemodynamic and excretory response to 180 min of isotonic saline loading (0.13 ml/kg/min) were examined in female normotensive (control) and hypertensive CKD sheep at 2 and 11 months after sham (control-intact, CKD-intact) or radiofrequency catheter-based RDN (control-RDN, CKD-RDN) procedure. Basal blood pressure was ~ 7 to 9 mmHg lower at 2, and 11 months in CKD-RDN compared with CKD-intact sheep. Saline loading did not alter glomerular filtration rate in any group. At 2 months, in response to saline loading, total urine and sodium excretion were ~ 40 to 50% less, in control-RDN and CKD-RDN than intact groups. At 11 months, the natriuretic and diuretic response to saline loading were similar between control-intact, control-RDN and CKD-intact groups but sodium excretion was ~ 42% less in CKD-RDN compared with CKD-intact at this time-point. These findings indicate that chronic withdrawal of basal renal sympathetic activity impairs fluid/electrolyte excretion during volume expansion. Clinically, a reduced ability to excrete a saline load following RDN may contribute to disturbances in body fluid balance in hypertensive CKD.

658-P: Sustained Glucagon Effect on Cardiovascular Renal and Metabolic Disorders Mediated by a Long-Acting Glucagon Analog, HM15136, in Animal Disease Models

Obesity is an increasing health problem worldwide, implicated with various metabolic disorders such as cardiovascular disease and chronic kidney disease (CKD). Previously, we showed that chronic treatment of HM15136, a long-acting GCG analog, led to robust body weight loss (BWL) in rodent obese models. Moreover, recent studies unveiled a novel role of GCG in vasodilation and inflammation. So, we hypothesized that HM15136 improve chronic metabolic disorders via direct action in addition to secondary effect to BWL. Here, we investigated potential therapeutic effect of HM15136 in animal models of cardiovascular renal and metabolic diseases. In DIO mice, BW, liver triglyceride (TG), and blood cholesterol (CHO) were measured, and all measurements were significantly reduced by HM15136 treatment (-37.5, -72.7, -78.4% vs. vehicle for BW, liver TG, blood CHO at day 17). Next, to explore therapeutic effect of HM15136 on cardiovascular renal diseases, spontaneously hypertensive rats, known model for hypertensive CKD, were used. Interestingly, abnormal elevation in blood pressure and renal function markers such as urine albumin/creatinine ratio (-23.6% vs. SHR vehicle at day 46) was meaningfully reduced by HM15136 treatment. In unilateral ureteral obstruction mice, known as acute kidney injury model, similar results were observed (-17.6%, -48.2% vs. vehicle for serum creatinine, kidney pro-collagen1α1 at day 12). Consistently, increase of vasodilation markers in rat aorta and inhibition of human primary podocyte apoptosis were confirmed, explaining underlying mechanism for these beneficial effects. Therefore, HM15136 could mitigate obesity and related complications especially hypertension and CKD. Hence, mechanistic study results highlight the essential role of direct GCG engagement in improvement of cardiovascular renal and metabolic diseases. Further studies are needed to assess a clinical relevance of these findings. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None. I. Choi: Employee; Self; Hanmi Pharmaceutical.

MO489GESTATIONAL DIABETES AND THE LONG-TERM RISK OF MATERNAL KIDNEY DISEASE: A SWEDISH NATIONAL COHORT STUDY

Abstract Background and Aims Gestational diabetes (GDM) is increasingly common worldwide. GDM is associated with increased risk of type 2 diabetes (T2DM) and cardiovascular disease in women. It is uncertain whether GDM is independently associated with long-term risk of maternal kidney disease. We aimed to examine the association between GDM and maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD) and to determine whether this depends on progression to overt T2DM. Method A nationwide retrospective cohort study was designed using data from the Swedish national registers. Women were included if their first delivery occurred between 1 January 1987 and 31 December 2012. Previous GDM was the main exposure variable, and this was stratified according to whether women developed T2DM after pregnancy. We estimated the risk of CKD, ESKD and different CKD subtypes (tubulointerstitial, glomerular, hypertensive, diabetic, other/non-specific). Cox-proportional hazard regression models were used with time-dependent covariates. We adjusted for a wide range of confounders including maternal age, country of origin, maternal education, parity, antenatal BMI, gestational weight gain, smoking during pregnancy and preeclampsia. Results There were 1,121,633 women included, of whom 15,595 (1.4%) had a diagnosis of GDM. Overall, GDM-diagnosed women were at increased risk of CKD (aHR 1.81, 95% CI 1.54-2.14) and ESKD (aHR 4.52, 95% CI 2.75-7.44). Associations were strongest for diabetic CKD (aHR 8.81, 95% CI 6.36-12.19), hypertensive CKD (aHR 2.46, 95% CI 1.06-5.69), and glomerular CKD (aHR 1.86, 95% CI 1.37-2.51). However, these associations were largely explained by progression to post-pregnancy T2DM. Among women who had GDM + subsequent T2DM, strong associations were observed with CKD (aHR 21.70, 95% CI 17.17-27.42) and ESKD (aHR 112.37, 95% CI 61.22-206.38). By contrast, women who only experienced GDM (and no future T2DM) were not at significantly higher risk of CKD (aHR 1.11, 95% CI 0.89-1.38) or ESKD (aHR 1.58, 95% CI 0.70-3.60). Conclusion Women who experience GDM are at increased risk of CKD and ESKD if they develop T2DM. However, GDM-diagnosed women who do not develop overt T2DM in later life have a similar risk of CKD/ESKD to those with uncomplicated pregnancies.

Renin‐Angiotensin System Blockade is Associated with Exercise Capacity, Sympathetic Activity and Endothelial Function in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) patients have exercise intolerance that is associated with cardiovascular mortality. CKD patients have exaggerated increases in blood pressure (BP) reactivity and impaired ability to maintain skeletal muscle perfusion during exercise mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. Activation of the renin-angiotensin system (RAS) increases central SNS activation and reduces NO synthesis, and prior studies have suggested that RAS blockade may modulate physical function declines. The aim of this study was to investigate whether use of RAS inhibitors (RASi) is associated with greater exercise capacity in CKD, and whether greater exercise capacity with RASi is linked to lower SNS activity and increased NO-dependent endothelial function. 35 hypertensive CKD patients (56.7 ± 7.0 yr) and 20 age-matched controls without CKD (CON, 52.5 ± 8.2 yr) were recruited. Exercise capacity was measured via VO2 peak from a maximal treadmill test, muscle sympathetic nervous activity (MSNA) was measured via microneurography, and vascular endothelial function was measured by flow-mediated dilation (FMD). Participants with CKD were further grouped by current usage of RASi including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) for group difference analyses. There were no baseline differences in demographics or hemodynamics between CKD patients with and without RASi. VO2 peak was greater in CKD patients with RASi compared to CKD patients not on RASi and lower compared to CON (23.3 ± 5.8 vs.16.4 ± 2.9, p=0.007; vs.30.0 ± 7.7, p=0.005 ml/min/kg respectively). MSNA in CKD patients with RASi was lower compared to CKD patients not on RASi but similar with CON (43.9 ± 7.1 vs. 53.8 ± 8.2; p=0.009, vs.38.0 ± 20.3; p=0.103 bursts/min respectively). FMD in CKD patients with RASi was greater compared to CKD patients not on RASi and lower compared to CON (3.2 ± 2.6 vs. 1.3 ± 1.6; p=0.007, vs. 5.0 ± 3.0; p=0.045 % respectively). VO2 peak was positively associated with FMD (r=0.417, p=0.038) and was predicted by the combination of FMD and RASi status (r2 =0.344, p=0.01) and MSNA and RASi status (r2 =0.575, p=0.040) in CKD patients. In summary, hypertensive CKD patients on RASi have better exercise capacity compared to those not on RASi. Furthermore, greater exercise capacity in RASi-treated group was associated with lower resting SNS activity and better NO-dependent vascular endothelial function. Long-term randomized trials examining the effects of RASi on physical function and underlying autonomic and vascular mechanisms are needed to determine its causal effect and its responsible mechanisms in CKD.

Prevalence of Periapical Abscesses in Patients with Hypertension: A Cross-sectional Study of a Large Hospital Population

IntroductionHypertension is a common major systemic disease and 1 of the most significant causes of mortality worldwide. Persistent hypertension is 1 of the risk factors for stroke, heart attack, heart failure, and arterial aneurysm and is a leading cause of chronic kidney failure. Common medications used to treat hypertension include beta blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers. The purpose of this study was to assess the prevalence of periapical abscesses in patients with different types of hypertension conditions and to evaluate the effect of commonly used antihypertensive medications on the prevalence of periapical abscesses. MethodsThe integrated data of hospital patients were used. Data from the corresponding diagnosis codes for hypertensive conditions and periapical abscess were retrieved by searching the appropriate query in the database. The odds ratio (OR) of periapical abscesses, its association with hypertensive conditions, and the intake of 4 antihypertensive medications were calculated and analyzed statistically. ResultsThe prevalence of periapical abscesses in patients with hypertensive conditions was 1.2% compared with 0.558% in the general patient population of the hospital. The OR for the prevalence of periapical lesions in patients with hypertension was 2.32. For primary hypertension, the OR was 2.02; for hypertensive heart disease, the OR was 2.68; for hypertensive chronic kidney disease, the OR was 2.1; for hypertensive heart and chronic kidney diseases, the OR was 4.16; for secondary hypertension, the OR was 4.16; and for hypertension crisis, the OR was 5.64. For patients treated with beta blockers, the OR was 2.58; for patients treated with angiotensin-converting enzyme inhibitors, the OR was 2.73; for patients treated with angiotensin II receptor blockers, the OR was 1.93; and for patients treated with calcium channel blockers, the OR was 2.79. The differences were statistically significant (P < .0001). The OR for the prevalence of periapical abscesses in patients treated with angiotensin II receptor blockers was significantly lower than that of patients treated with either beta blockers or calcium channel blockers (P < .00001). ConclusionsUnder the conditions of this study, it appears that the prevalence of perapical abscesses is significantly higher in hypertensive patients. The prevalence of periapical abscesses is higher in patients with secondary hypertension than in those with primary hypertension. Angiotensin II receptor blockers may significantly lower the prevalence of periapical abscesses in hypertensive patients.