Publications by authors named "Charles J Ferro"

123 Publications

Hyperkalemia in Chronic Kidney Disease in the New Era of Kidney Protection Therapies.

Drugs 2021 Sep 27;81(13):1467-1489. Epub 2021 Jul 27.

School of Medicine, IIS-Fundacion Jimenez Diaz, University Autonoma of Madrid, FRIAT and REDINREN, Madrid, Spain.

Despite recent therapeutic advances, chronic kidney disease (CKD) is one of the fastest growing global causes of death. This illustrates limitations of current therapeutic approaches and, potentially, unidentified knowledge gaps. For decades, renin-angiotensin-aldosterone system (RAAS) blockers have been the mainstay of therapy for CKD. However, they favor the development of hyperkalemia, which is already common in CKD patients due to the CKD-associated decrease in urinary potassium (K) excretion and metabolic acidosis. Hyperkalemia may itself be life-threatening as it may trigger potentially lethal arrhythmia, and additionally may limit the prescription of RAAS blockers and lead to low-K diets associated to low dietary fiber intake. Indeed, hyperkalemia is associated with adverse kidney, cardiovascular, and survival outcomes. Recently, novel kidney protective therapies, ranging from sodium/glucose cotransporter 2 (SGLT2) inhibitors to new mineralocorticoid receptor antagonists have shown efficacy in clinical trials. Herein, we review K pathophysiology and the clinical impact and management of hyperkalemia considering these developments and the availability of the novel K binders patiromer and sodium zirconium cyclosilicate, recent results from clinical trials targeting metabolic acidosis (sodium bicarbonate, veverimer), and an increasing understanding of the role of the gut microbiota in health and disease.
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http://dx.doi.org/10.1007/s40265-021-01555-5DOI Listing
September 2021

Intravenous iron therapy and the cardiovascular system: risks and benefits.

Clin Kidney J 2021 Apr 26;14(4):1067-1076. Epub 2020 Nov 26.

CNR-IFC Clinical Epidemiology of Renal Diseases and Hypertension, Reggio Calabria, Italy.

Anaemia is a common complication of chronic kidney disease (CKD). In this setting, iron deficiency is frequent because of the combination of increased iron needs to sustain erythropoiesis with increased iron losses. Over the years, evidence has accumulated on the involvement of iron in influencing pulmonary vascular resistance, endothelial function, atherosclerosis progression and infection risk. For decades, iron therapy has been the mainstay of therapy for renal anaemia together with erythropoiesis-stimulating agents (ESAs). Despite its long-standing use, grey areas still surround the use of iron therapy in CKD. In particular, the right balance between either iron repletion with adequate therapy and the avoidance of iron overload and its possible negative effects is still a matter of debate. This is particularly true in patients having functional iron deficiency. The recent Proactive IV Iron Therapy in Haemodialysis Patients trial supports the use of intravenous (IV) iron therapy until a ferritin upper limit of 700 ng/mL is reached in haemodialysis patients on ESA therapy, with short dialysis vintage and minimal signs of inflammation. IV iron therapy has also been proven to be effective in the setting of heart failure (HF), where it improves exercise capacity and quality of life and possibly reduces the risk of HF hospitalizations and cardiovascular deaths. In this review we discuss the risks of functional iron deficiency and the possible benefits and risks of iron therapy for the cardiovascular system in the light of old and new evidence.
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http://dx.doi.org/10.1093/ckj/sfaa212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223589PMC
April 2021

Ambulatory blood pressure changes with lung ultrasound-guided dry-weight reduction in hypertensive hemodialysis patients: 12-month results of a randomized controlled trial.

J Hypertens 2021 Jul;39(7):1444-1452

CNR-IFC Clinical Epidemiology of Renal Diseases and Hypertension, Reggio Calabria, Italy.

Objectives: Hypertension is highly prevalent and independently associated with adverse outcomes in patients undergoing hemodialysis. Volume overload is the main mechanism of increased blood pressure (BP) in these individuals. This study examines the long-term effects of dry-weight reduction with a standardized lung-ultrasound (US)-guided strategy on ambulatory BP in hypertensive hemodialysis patients.

Methods: This is the report of the 12-month follow-up of a randomized controlled trial in 71 clinically euvolemic, hemodialysis patients with hypertension. Patients were randomized to dry-weight reduction guided by prehemodialysis lung ultrasound and to standard care. A 48-h ambulatory BP monitoring (ABPM) was performed in all study participants at baseline and after 12 months.

Results: During follow-up, a greater proportion of patients in the active group underwent dry-weight reduction compared with the control group (71.4% vs. 22.2%; P < 0.001). The number of lung US-B lines (a metric of lung water) reduced in the active (-4.83 ± 13.73) and increased in the control arm (+5.53 ± 16.01; P = 0.005) paralleling dry-weight changes (-1.68 ± 2.38 vs. 0.54 ± 2.32 kg; P < 0.001). At 12 months, 48-h systolic BP (136.19 ± 14.78 vs. 130.31 ± 13.57 mmHg; P = 0.034) and diastolic BP (80.72 ± 9.83 vs. 76.82 ± 8.97 mmHg; P = 0.008) were lower compared to baseline in the active but similar in the control group. Changes in 48-h systolic BP (-7.78 ± 13.29 vs. -0.10 ± 14.75 mmHg; P = 0.021) were significantly greater in the active compared to the control group. The proportion of patients experiencing ≥1 episode of intradialytic hypotension was nominally lower in the active group (71.4% vs. 88.9%, P = 0.065).

Conclusions: Lung-US-guided dry-weight reduction can effectively and safely decrease ambulatory BP levels in the long-term.
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http://dx.doi.org/10.1097/HJH.0000000000002818DOI Listing
July 2021

Changes in left ventricular structure and function associated with renal transplantation: a systematic review and meta-analysis.

ESC Heart Fail 2021 06 15;8(3):2045-2057. Epub 2021 Mar 15.

Birmingham Cardio-Renal Group, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.

Aims: This study aimed to examine if the cardiac changes associated with uraemic cardiomyopathy are reversed by renal transplantation.

Methods And Results: MEDLINE, Embase, OpenGrey, and the Cochrane Library databases were searched from 1950 to March 2020. The primary outcome measure was left ventricular mass index. Secondary outcome measures included left ventricular dimensions and measures of diastolic and systolic function. Studies were included if they used any imaging modality both before and after successful renal transplantation. Data were analysed through meta-analysis approaches. Weight of evidence was assessed through the Grading of Recommendations Assessment, Development and Evaluation system. Twenty-three studies used echocardiography, and three used cardiac magnetic resonance imaging as their imaging modality. The methodological quality of the evidence was generally poor. Four studies followed up control groups, two using cardiac magnetic resonance imaging and two using echocardiography. Meta-analysis of these studies indicated that there was no difference in left ventricular mass index between groups following transplantation {standardized mean difference -0.07 [95% confidence interval (CI) -0.41 to 0.26]; P = 0.67}. There was also no difference observed in left ventricular ejection fraction [mean difference 0.39% (95% CI -4.09% to 4.87%); P = 0.86] or left ventricular end-diastolic volume [standardized mean difference -0.24 (95% CI -0.94 to 0.45); P = 0.49]. Inconsistent reporting of changes in diastolic dysfunction did not allow for any meaningful analysis or interpretation.

Conclusions: The evidence does not support the notion that uraemic cardiomyopathy is reversible by renal transplantation. However, the evidence is limited by methodological weaknesses, which should be considered when interpreting these findings.
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http://dx.doi.org/10.1002/ehf2.13283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120418PMC
June 2021

Role of hypertension in kidney transplant recipients.

J Hum Hypertens 2021 May 4. Epub 2021 May 4.

Department of Renal Medicine, University Hospitals Birmingham, Birmingham, UK.

Cardiovascular events are one of the leading causes of mortality in kidney transplant recipients. Hypertension is the most common comorbidity accompanying chronic kidney disease, with prevalence remaining as high as 90% even after kidney transplantation. It is often poorly controlled. Abnormal blood pressure profiles, such as masked or white-coat hypertension, are also extremely common in these patients. The pathophysiology of blood pressure elevation in kidney transplant recipients is complex and includes transplantation-specific risk factors, which are added to the traditional or chronic kidney disease-related factors. Despite these observations, hypertension management has been an under-researched area in kidney transplantation. Thus, relevant evidence derives either from studies in the general population or from small trials in kidney transplant recipients. Based on the relevant guidelines in the general population, lifestyle modifications should probably be applied as the first step of hypertension management in kidney transplant recipients. The optimal pharmacological management of hypertension in kidney transplant recipients is also not clear. Dihydropyridine calcium channel blockers are commonly used as first line agents because of their lack of adverse effects on the kidney, while other antihypertensive drug classes are under-utilised due to fear of the possible haemodynamic consequences on renal function. This review summarizes the existing data on the pathophysiology, diagnosis, prognostic significance and management of hypertension in kidney transplantation.
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http://dx.doi.org/10.1038/s41371-021-00540-5DOI Listing
May 2021

Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease.

Nephrol Dial Transplant 2021 May 4. Epub 2021 May 4.

Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Diabetic kidney disease develops in about 40% of patients with diabetes and is the commonest cause of chronic kidney disease worldwide. Patients with chronic kidney disease, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular death. The use of renin-angiotensin system blockers to reduce the incidence of kidney failure in patients with diabetic kidney disease dates back to studies that are now 20 or more years old. During the last few years sodium-glucose co-transporter-2 inhibitors have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with renin-angiotensin system blockers and sodium-glucose co-transporter-2 inhibitors, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of cardiovascular death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists reduce albuminuria and surrogate markers of cardiovascular disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In The FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) study comparing the actions of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo, finerenone reduced the progression of diabetic kidney disease and the incidence of cardiovascular events with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of mineralocorticoid receptor antagonists, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic chronic kidney disease.
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http://dx.doi.org/10.1093/ndt/gfab167DOI Listing
May 2021

Coronary microvascular dysfunction is associated with degree of anaemia in end-stage renal disease.

BMC Cardiovasc Disord 2021 04 26;21(1):211. Epub 2021 Apr 26.

Birmingham Cardio-Renal Group, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.

Background: Coronary microvascular dysfunction (CMD) is common in end-stage renal disease (ESRD) and is an adverse prognostic marker. Coronary flow velocity reserve (CFVR) is a measure of coronary microvascular function and can be assessed using Doppler echocardiography. Reduced CFVR in ESRD has been attributed to factors such as diabetes, hypertension and left ventricular hypertrophy. The contributory role of other mediators important in the development of cardiovascular disease in ESRD has not been studied. The aim of this study was to examine the prevalence of CMD in a cohort of kidney transplant candidates and to look for associations of CMD with markers of anaemia, bone mineral metabolism and chronic inflammation.

Methods: Twenty-two kidney transplant candidates with ESRD were studied with myocardial contrast echocardiography, Doppler CFVR assessment and serum multiplex immunoassay analysis. Individuals with diabetes, uncontrolled hypertension or ischaemic heart disease were excluded.

Results: 7/22 subjects had CMD (defined as CFVR < 2). Demographic, laboratory and echocardiographic parameters and serum biomarkers were similar between subjects with and without CMD. Subjects with CMD had significantly lower haemoglobin than subjects without CMD (102 g/L ± 12 vs. 117 g/L ± 11, p = 0.008). There was a positive correlation between haemoglobin and CFVR (r = 0.7, p = 0.001). Similar results were seen for haematocrit. In regression analyses, haemoglobin was an independent predictor of CFVR (β = 0.041 95% confidence interval 0.012-0.071, p = 0.009) and of CFVR < 2 (odds ratio 0.85 95% confidence interval 0.74-0.98, p = 0.022).

Conclusions: Among kidney transplant candidates with ESRD, there is a high prevalence of CMD, despite the absence of traditional risk factors. Anaemia may be a potential driver of microvascular dysfunction in this population and requires further investigation.
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http://dx.doi.org/10.1186/s12872-021-02025-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074270PMC
April 2021

The Role of Uric Acid in the Acute Myocardial Infarction: A Narrative Review.

Angiology 2021 Apr 27:33197211012546. Epub 2021 Apr 27.

Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey.

Increased serum uric acid (SUA) levels have been associated with various pathologic processes such as increased oxidative stress, inflammation, and endothelial dysfunction. Thus, it is not surprising that increased SUA is associated with various adverse outcomes including cardiovascular (CV) diseases. Recent epidemiological evidence suggests that increased SUA may be related to acute myocardial infarction (AMI). Accumulating data also showed that elevated UA has pathophysiological role in the development of AMI. However, there are also studies showing that SUA is not related to the risk of AMI. In this narrative review, we summarized the recent literature data regarding SUA and AMI after providing some background information for the association between UA and coronary artery disease. Future studies will show whether decreasing SUA levels is beneficial for outcomes related to AMI and the optimum SUA levels for best outcomes in CV diseases.
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http://dx.doi.org/10.1177/00033197211012546DOI Listing
April 2021

Accuracy of Peridialytic, Intradialytic, and Scheduled Interdialytic Recordings in Detecting Elevated Ambulatory Blood Pressure in Hemodialysis Patients.

Am J Kidney Dis 2021 Apr 20. Epub 2021 Apr 20.

Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Rationale & Objective: Current recommendations suggest the use of ambulatory blood pressure monitoring (ABPM) as the gold standard for hypertension diagnosis and management in hemodialysis patients. This study assesses the accuracy of peridialytic, intradialytic, and scheduled interdialytic recordings in detecting abnormally elevated 44-hour interdialytic blood pressure (BP).

Study Design: Diagnostic test study.

Settings & Participants: 242 Greek hemodialysis patients who successfully underwent ABPM.

Tests Compared: Ambulatory BP was used as the reference method to evaluate the accuracy of the following BP metrics: predialysis and postdialysis BP, intradialytic BP, intradialytic plus pre/postdialysis BP, and scheduled interdialytic BP (on an off-dialysis day at 8:00 am, 8:00 pm, and their average).

Outcome: 44-hour ambulatory systolic BP/diastolic BP (SBP/DBP) ≥ 130/80 mm Hg.

Results: The 44-hour SBP/DBP levels differed significantly from predialysis and postdialysis BP but showed no or minor differences compared with the other BP metrics. Bland-Altman plots showed an absence of systematic bias for all metrics but large between-method difference and wider 95% limits of agreement for predialysis and postdialysis BP compared with intradialytic, intradialytic plus pre/postdialysis, and averaged scheduled interdialytic BP. The sensitivity/specificity and κ-statistic for diagnosing 44-hour SBP ≥ 130 mm Hg were low for predialysis (86.5%/38.6%, κ-statistic = 0.27) and postdialysis BP (63.1%/73.3%, κ-statistic = 0.35), but better for intradialytic BP (77.3%/76.2%, κ-statistic = 0.53), intradialytic plus pre/postdialysis BP (76.6%/72.3%, κ-statistic = 0.49), and scheduled interdialytic BP (87.9%/77.2%, κ-statistic = 0.66). In receiver operating characteristic (ROC) analyses, the areas under the curve (AUC) of predialysis SBP (AUC = 0.723) and postdialysis SBP (AUC = 0.746) were significantly lower than that of intradialytic SBP (AUC = 0.850), intradialytic plus pre/postdialysis SBP (AUC = 0.850), and scheduled interdialytic SBP (AUC = 0.917) (z test, P < 0.001 for all pairwise comparisons). Similar observations were made for DBP.

Limitations: Typical home BP data were not obtained, and no assessment was obtained of the reproducibility of the examined metrics over time.

Conclusions: Intradialytic, intradialytic plus pre/postdialysis, and scheduled interdialytic BP measurements were more accurate in detecting elevated 44-hour BP than predialysis and postdialysis BP. Averaged intradialytic BP recordings or scheduled readings at the off-dialysis day appear to be promising approaches to the diagnosis of elevated BP in hemodialysis.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.022DOI Listing
April 2021

Acute kidney injury is more common in men than women after accounting for socioeconomic status, ethnicity, alcohol intake and smoking history.

Biol Sex Differ 2021 04 8;12(1):30. Epub 2021 Apr 8.

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2GW, UK.

Background: The association of several comorbidities, including diabetes mellitus, hypertension, cardiovascular disease, heart failure and chronic kidney or liver disease, with acute kidney injury (AKI) is well established. Evidence on the effect of sex and socioeconomic factors are scarce. This study was designed to examine the association of sex and socioeconomic factors with AKI and AKI-related mortality and further to evaluate the additional relationship with other possible risk factors for AKI occurrence.

Methods: We included 3534 patients (1878 males with mean age 61.1 ± 17.7 and 1656 females 1656 with mean age 60.3 ± 20.0 years) admitted to Queen Elizabeth or Heartlands Hospitals, Birmingham, between October 2013 and January 2016. Patients were prospectively followed-up for a median 47.70 [IQR, 18.20] months. Study-endpoints were incidence of AKI, based on KDIGO-AKI Guidelines, and all-cause mortality. Data acquisition was automated, and information on mortality was collected from the Hospital Episode Statistics and Office of National Statistics. Socioeconomic status was evaluated with the Index of Multiple Deprivation (IMD).

Results: Incidence of AKI was higher in men compared to women (11.3% vs 7.1%; P < 0.001). Model regression analysis revealed significant association of male sex with higher AKI risk (OR, 1.659; 95% CI, 1.311-2.099; P < 0.001); this association remained significant after adjustment for age, eGFR, IMD, smoking, alcohol consumption, ethnicity, existing comorbidities and treatment (OR, 1.599; 95% CI, 1.215-2.103; P = 0.001). All-cause mortality was higher in patients with compared to those without AKI. Males with AKI had higher mortality rates in the first 6-month and 1-year periods after the index AKI event. The association of male sex with mortality was independent of socioeconomic factors but was not statistically significant after adjustment for existing comorbidities.

Conclusions: Men are at higher risk of AKI and this association is independent from existing risk factors for AKI. The association between male sex and AKI-related mortality was not independent from existing comorbidities. A better understanding of factors associated with AKI may help accurately identify high-risk patients.
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http://dx.doi.org/10.1186/s13293-021-00373-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034098PMC
April 2021

Blood pressure monitoring in kidney transplantation: a systematic review on hypertension and target organ damage.

Nephrol Dial Transplant 2021 Mar 25. Epub 2021 Mar 25.

CNR-Institute of Clinical Physiology; Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy.

Background: Sparse studies show that ambulatory blood pressure monitoring (ABPM) is superior to office BP (oBP) measurements to predict target organ damage and cardiovascular (CV) events in kidney transplant recipients (KTRs). We performed a systematic review aimed at determining the potential associations between BP recordings by different methods and renal and CV outcomes in this population.

Methods: Major medical databases were searched for studies enrolling adult KTRs undergoing 24h ABPM compared to office or home BP measurements. Main outcomes were: associations between different BP recordings and renal and CV outcomes. Additionally, any association between the circadian BP pattern (dipping/non-dipping status) and outcomes was assessed.

Results: Twenty-two studies (2078 participants) were reviewed. Amongst 12 studies collecting data on renal endpoints, ten studies found that BP assessed by ABPM was a stronger predictor of renal function decline, assessed by serum creatinine (SCr) and/or creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), than traditional office measurements. Twelve studies analyzed the relation between different BP recordings and CV target organ damages and reported robust correlations between echocardiographic abnormalities [i.e. left ventricular mass index (LVM/LVMI)] and 24h ABPM, but not with office BPs. Furthermore, 24h ABPM correlated better than oBP with markers of vascular damage, such as carotid intima-media thickness (IMT), diffuse thickening, and endothelial dysfunction. Additionally, abnormal circadian BP pattern (non-dippers and reverse dippers) identified a group of kidney recipients at risk for kidney function loss and CV abnormalities.

Conclusions: In our systematic review, ABPM reflected target organ damage more closely than oBP in KTRs. Furthermore, altered circadian BP profile associated with renal and CV target organ damages.
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http://dx.doi.org/10.1093/ndt/gfab076DOI Listing
March 2021

Early renal function trajectories, cytomegalovirus serostatus and long-term graft outcomes in kidney transplant recipients.

BMC Nephrol 2021 03 20;22(1):102. Epub 2021 Mar 20.

Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, Edgbaston, Birmingham, B15 2TT, UK.

Background: Improved recognition of factors influencing graft survival has led to better short-term kidney transplant outcomes. However, efforts to prevent long-term graft decline and improve graft survival have seen more modest improvements. The adoption of electronic health records has enabled better recording and identification of donor-recipient factors through the use of modern statistical techniques. We have previously shown in a prevalent renal transplant population that episodes of rapid deterioration are associated with graft loss.

Methods: Estimated glomerular filtration rates (eGFR) between 3 and 27 months after transplantation were collected from 310 kidney transplant recipients. We utilised a Bayesian approach to estimate the most likely eGFR trajectory as a smooth curve from an average of 10,000 Monte Carlo samples. The probability of having an episode of rapid deterioration (decline greater than 5 ml/min/1.73 m per year in any 1-month period) was calculated. Graft loss and mortality data was collected over a median follow-up period of 8 years. Factors associated with having an episode of rapid deterioration and associations with long-term graft loss were explored.

Results: In multivariable Cox Proportional Hazard analysis, a probability greater than 0.8 of rapid deterioration was associated with long-term death-censored graft loss (Hazard ratio 2.17; 95% Confidence intervals [CI] 1.04-4.55). In separate multivariable logistic regression models, cytomegalovirus (CMV) serostatus donor positive to recipient positive (Odds ratio [OR] 3.82; 95%CI 1.63-8.97), CMV donor positive (OR 2.06; 95%CI 1.15-3.68), and CMV recipient positive (OR 2.03; 95%CI 1.14-3.60) were associated with having a greater than 0.8 probability of an episode of rapid deterioration.

Conclusions: Early episodes of rapid deterioration are associated with long-term death-censored graft loss and are associated with cytomegalovirus seropositivity. Further study is required to better manage these potentially modifiable risks factors and improve long-term graft survival.
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http://dx.doi.org/10.1186/s12882-021-02285-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981965PMC
March 2021

Finerenone and Chronic Kidney Disease Outcomes in Type 2 Diabetes.

N Engl J Med 2021 03;384(11):e42

Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.

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http://dx.doi.org/10.1056/NEJMc2036175DOI Listing
March 2021

Renin-angiotensin system blockade in patients with chronic kidney disease: benefits, problems in everyday clinical use, and open questions for advanced renal dysfunction.

J Hum Hypertens 2021 Jun 2;35(6):499-509. Epub 2021 Mar 2.

Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Management of hypertension and albuminuria are considered among the primary goals of treatment to slow the progression of chronic kidney disease (CKD). Renin-angiotensin system (RAS) blockers, i.e., angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are the main drugs to achieve these goals. Seminal studies have showed that RAS blockers present significant renoprotective effects in CKD patients with very high albuminuria. In post hoc analyses of such trials, these renoprotective effects appeared more robust in patients with more advanced CKD. However, randomized trials specifically addressing whether RAS blockers should be initiated or maintained in patients with advanced CKD are scarce and do not include subjects with normoalbuminuria, thus, many clinicians are unconvinced for the beneficial effects of RAS blockade in these patients. Further, the fear of hyperkalemia or acute renal decline is another factor due to which RAS blockers are usually underprescribed and are easily discontinued in patients with more advanced CKD; i.e., those in Stages 4 and 5. This review summarizes evidence from the literature regarding the use of RAS blockers in patients with advanced CKD.
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http://dx.doi.org/10.1038/s41371-021-00504-9DOI Listing
June 2021

Cardiovascular Effects of Unilateral Nephrectomy in Living Kidney Donors at 5 Years.

Hypertension 2021 04 8;77(4):1273-1284. Epub 2021 Feb 8.

From the Institute of Cardiovascular Sciences (A.M.P., V.M.S., R.V., M.K.H., B.L., S.B., L.C.P., A.R., J.P.L., R.P.S., N.C.E., C.J.F., J.N.T.), College of Medical and Dental Sciences, University of Birmingham, United Kingdom.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968960PMC
April 2021

Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: A validation study.

PLoS Med 2021 02 3;18(2):e1003405. Epub 2021 Feb 3.

Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.

Background: Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays.

Methods And Findings: For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation.

Conclusions: Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF.

Trial Registration: Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom.
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http://dx.doi.org/10.1371/journal.pmed.1003405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857735PMC
February 2021

The effect of admission and pre-admission serum creatinine as baseline to assess incidence and outcomes of acute kidney injury in acute medical admissions.

Nephrol Dial Transplant 2021 Jan 17. Epub 2021 Jan 17.

Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, Birmingham, UK.

Background: Acute kidney injury (AKI) in hospital-admitted patients is a common complication associated with increased mortality. The diagnosis of AKI relies on the ascertainment of peak increase in serum creatinine (SCr). This study evaluated the incidence of AKI using the increase from mean 7-365 days pre-admission (AKIpre) and admission (AKIadm) SCr levels, and examined the associations of AKI and changes in SCr levels with all-cause mortality.

Methods: A total of 2436 patients admitted to a tertiary hospital were recruited and followed-up for a median of 47.70 (interquartile range 18.20) months. AKI incidence and severity were defined according to the Kidney Disease: Improving Global Outcomes-AKI Guidelines. Follow-up data were collected from the Hospital Episode Statistics and Office of National Statistics. Mortality was evaluated during a short- (30 days), mid- (1 year) and long-term (4 years) period.

Results: No difference in the AKI rates using AKIpre and AKIadm (12.5% versus 12.2%; P = 0.695) or in the AKI severity (P = 0.261) was evident. Agreement between the two definitions was modest (Kappa-statistic = 0.596, P < 0.001). Patients with AKIpre or AKIadm had increased all-cause mortality compared with those without AKI during all follow-up periods. In fully adjusted regression analysis, AKIpre [hazard ratio (HR) = 2.226, 95% confidence interval (CI) 1.140-4.347; P = 0.027] and AKIadm (HR = 2.105, 95% CI 1.090-4.064; P = 0.027) remained associated with 30-day mortality. Results for the 1- and 4-year periods were similar. Increases of >4.00 μmol/L and >6.06% from pre-admission or >6.00 μmol/L and >17.24% from admission SCr levels presented increased mortality risk during follow-up.

Conclusions: Use of admission or pre-admission SCr provides similar incidence rates, but they diagnose different sets of patients. Even minor increases in SCr, below those required for the classification of AKI, were associated with increased mortality. These findings can help the clinicians to identify patients at higher risk for adverse outcomes.
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http://dx.doi.org/10.1093/ndt/gfaa333DOI Listing
January 2021

Sodium--glucose co-transporter-2 inhibitors for patients with diabetic and nondiabetic chronic kidney disease: a new era has already begun.

J Hypertens 2021 Jun;39(6):1090-1097

Division of Nephrology, Wuerzburg University Clinic, Würzburg, Germany.

Chronic kidney disease (CKD) is a major issue of public health. Hypertension control and use of renin--angiotensin system (RAS) blockers are the cornerstones of treatment for CKD of any cause. However, even under optimal RAS blockade, many individuals will progress towards more advanced CKD. Within the past few years, evidence from cardiovascular outcome trials with sodium--glucose co-transporter-2 (SGLT-2) inhibitors clearly suggested that these agents substantially delay CKD progression in patients with diabetes mellitus on top of standard-of-care treatment. The Canagliflozin-and-Renal-Events-in-Diabetes-with-Established-Nephropathy-Clinical-Evaluation (CREDENCE) study, showed that canagliflozin substantially reduced the risk of doubling of SCr, end-stage kidney disease (ESKD), or death from renal or cardiovascular causes in 4401 patients with diabetic CKD compared with placebo (hazard ratio 0.70; 95% CI 0.59-0.82). Recently, the Study-to-Evaluate-the-Effect-of-Dapagliflozin-on-Renal-Outcomes-and-Cardiovascular-Mortality-in-Patients-With-Chronic-Kidney-Disease (DAPA-CKD), including 2510 patients with diabetic and 1803 with nondiabetic CKD, also showed an impressive reduction in the risk of ≥50% decline in eGFR, ESKD, or death from renal or cardiovascular causes (HR 0.61; 95% CI 0.51-0.72). The benefit was similar for patients with diabetic and nondiabetic CKD, including patients with glomerulonephritides. Following this conclusive evidence, relevant guidelines should accommodate their recommendations to implement treatment with SGLT-2 inhibitors for patients with diabetic and nondiabetic CKD.
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http://dx.doi.org/10.1097/HJH.0000000000002776DOI Listing
June 2021

Oxidative stress links periodontal inflammation and renal function.

J Clin Periodontol 2021 03 28;48(3):357-367. Epub 2021 Jan 28.

Periodontal Research Group, School of Dentistry, University of Birmingham and Birmingham Community Healthcare Trust, Birmingham, UK.

Aims: Patients with chronic kidney disease (CKD) are also susceptible to periodontitis. The causal link between periodontitis and CKD may be mediated via systemic inflammation/oxidative stress. Using structural equation modelling (SEM), this cross-sectional study aimed to explore the causal relationship between periodontal inflammation (PI) and renal function.

Materials And Methods: Baseline data on 770 patients with stage 3-5 (pre-dialysis) CKD from an ongoing cohort study were used. Detailed, bioclinical data on PI and renal function, as well as potential confounders and mediators of the relationship between the two, were collected. SEMs of increasing complexity were created to test the causal assumption that PI affects renal function and vice versa.

Results: Structural equation modelling confirmed the assumption that PI and renal function are causally linked, mediated by systemic oxidative stress. The magnitude of this effect was such that a 10% increase in PI resulted in a 3.0% decrease in renal function and a 10% decrease in renal function resulted in a 25% increase in PI.

Conclusions: Periodontal inflammation represents an occult source of oxidative stress in patients with CKD. Further clinical studies are needed to confirm whether periodontal therapy, as a non-pharmacological approach to reducing systemic inflammatory/oxidative stress burden, can improve outcomes in CKD.
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http://dx.doi.org/10.1111/jcpe.13414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986430PMC
March 2021

Serum Copeptin, NLPR3, and suPAR Levels among Patients with Autosomal-Dominant Polycystic Kidney Disease with and without Impaired Renal Function.

Cardiorenal Med 2020 17;10(6):440-451. Epub 2020 Nov 17.

Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece,

Background: The pathophysiology of renal disease progression in autosomal-dominant polycystic kidney disease (ADPKD) involves not only cystogenesis but also endothelial dysfunction, leading to the activation of inflammatory and fibrotic pathways. This study evaluated the levels of biomarkers related to osmoregulation, immune system activation, and tubular injury in ADPKD patients with impaired or preserved renal function.

Methods: This study included 26 ADPKD patients with modestly impaired renal function (estimated glomerular filtration rate [eGFR] 45-70 mL/min/1.73 m2; Group A), 26 age- and sex-matched ADPKD patients with relatively preserved renal function (eGFR >70 mL/min/1.73 m2; Group B), and 26 age- and sex-matched controls (Group C). Serum levels of copeptin, the inflammasome nucleotide-binding and oligomerization domain-like receptors pyrin domain-containing protein 3 (NLRP3), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured with ELISA techniques.

Results: Patients in Group A had higher levels of copeptin (median [interquartile range]: 50.44 [334.85] pg/mL), NLRP3 (5.86 [3.89] ng/mL), and suPAR (390.05 [476.53] pg/mL) compared to patients in Group B (32.38 [58.33], p = 0.042; 2.42 [1.96], p < 0.001; and 313.78 [178.85], p = 0.035, respectively) and Group C (6.75 [6.43]; 1.09 [0.56]; and 198.30 [28.53], respectively; p < 0.001 for all comparisons). Levels of all studied markers were also significantly higher in Group B patients compared to controls (p < 0.001), despite having similar eGFR. In patients with ADPKD, all studied biomarkers were correlated positively with asymmetric-dimethylarginine (ADMA) and endocan levels, and negatively with eGFR. ADMA and endocan levels were the only parameters independently associated with increased copeptin levels.

Conclusions: This study showed that ADPKD patients with impaired and preserved renal function had higher copeptin, NLRP3, and suPAR levels than controls. Such findings support that cystogenesis and inflammation are associated with endothelial dysfunction, even in the early stages of ADKPD.
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http://dx.doi.org/10.1159/000510834DOI Listing
August 2021

Volume overload in hemodialysis: diagnosis, cardiovascular consequences, and management.

Nephrol Dial Transplant 2020 Nov 13. Epub 2020 Nov 13.

CNR-IFC Clinical Epidemiology of Renal Diseases and Hypertension, Reggio Calabria, Italy.

Volume overload in haemodialysis (HD) patients associates with hypertension and cardiac dysfunction and is a major risk factor for all-cause and cardiovascular mortality in this population. The diagnosis of volume excess and estimation of dry weight is based largely on clinical criteria and has a notoriously poor diagnostic accuracy. The search for accurate and objective methods to evaluate dry weight and to diagnose subclinical volume overload has been intensively pursued over the last 3 decades. Most methods have not been tested in appropriate clinical trials and their usefulness in clinical practice remains uncertain, except for bioimpedance spectroscopy and lung ultrasound (US). Bioimpedance spectroscopy is possibly the most widely used method to subjectively quantify fluid distributions over body compartments and produces reliable and reproducible results. Lung US provides reliable estimates of extravascular water in the lung, a critical parameter of the central circulation that in large part reflects the left ventricular end-diastolic pressure. To maximize cardiovascular tolerance, fluid removal in volume-expanded HD patients should be gradual and distributed over a sufficiently long time window. This review summarizes current knowledge about the diagnosis, prognosis and treatment of volume overload in HD patients.
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http://dx.doi.org/10.1093/ndt/gfaa182DOI Listing
November 2020

Routine serum biomarkers, but not dual-energy X-ray absorptiometry, correlate with cortical bone mineral density in children and young adults with chronic kidney disease.

Nephrol Dial Transplant 2020 Oct 23. Epub 2020 Oct 23.

Great Ormond St Hospital for Children NHS Foundation Trust, University College London Institute of Child Health, London, UK.

Background: Biomarkers and dual-energy X-ray absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The Kidney Disease: Improving Global Outcomes guidelines suggest using DXA if the results will affect patient management, but this has not been studied in children or young adults in whom bone mineral accretion continues to 30 years of age. We studied the clinical utility of DXA and serum biomarkers against tibial cortical BMD (CortBMD) measured by peripheral quantitative computed tomography, expressed as Z-score CortBMD, which predicts fracture risk.

Methods: This was a cross-sectional multicentre study in 26 patients with CKD4 and 5 and 77 on dialysis.

Results: Significant bone pain that hindered activities of daily living was present in 58%, and 10% had at least one low-trauma fracture. CortBMD and cortical mineral content Z-scores were lower in dialysis compared with CKD patients (P = 0.004 and P = 0.02). DXA BMD hip and lumbar spine Z-scores did not correlate with CortBMD or biomarkers. CortBMD was negatively associated with parathyroid hormone (PTH; r = -0.44, P < 0.0001) and alkaline phosphatase (ALP; r = -0.22, P = 0.03) and positively with calcium (Ca; r = 0.33, P = 0.001). At PTH <3 times upper limit of normal, none of the patients had a CortBMD below -2 SD (odds ratio 95% confidence interval 7.331 to infinity). On multivariable linear regression PTH (β = -0.43 , P < 0.0001), ALP (β = -0.36, P < 0.0001) and Ca (β = 0.21, P = 0.005) together predicted 57% of variability in CortBMD. DXA measures did not improve this model.

Conclusions: Taken together, routinely used biomarkers, PTH, ALP and Ca, but not DXA, are moderate predictors of cortical BMD. DXA is not clinically useful and should not be routinely performed in children and young adults with CKD 4-5D.
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http://dx.doi.org/10.1093/ndt/gfaa199DOI Listing
October 2020

Hypertension Management in Patients With Autosomal Dominant Polycystic Kidney Disease: Time for a Paradigm Shift?

Am J Kidney Dis 2020 11 18;76(5):743. Epub 2020 Sep 18.

Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

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http://dx.doi.org/10.1053/j.ajkd.2020.06.011DOI Listing
November 2020

Changes in Blood Pressure and Arterial Hemodynamics following Living Kidney Donation.

Clin J Am Soc Nephrol 2020 09 25;15(9):1330-1339. Epub 2020 Aug 25.

Birmingham Cardio-Renal Group, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.

Background And Objectives: The Effect of a Reduction in GFR after Nephrectomy on Arterial Stiffness and Central Hemodynamics (EARNEST) study was a multicenter, prospective, controlled study designed to investigate the associations of an isolated reduction in kidney function on BP and arterial hemodynamics.

Design, Setting, Participants, & Measurements: Prospective living kidney donors and healthy controls who fulfilled criteria for donation were recruited from centers with expertise in vascular research. Participants underwent office and ambulatory BP measurement, assessment of arterial stiffness, and biochemical tests at baseline and 12 months.

Results: A total of 469 participants were recruited, and 306 (168 donors and 138 controls) were followed up at 12 months. In the donor group, mean eGFR was 27 ml/min per 1.73 m lower than baseline at 12 months. Compared with baseline, at 12 months the mean within-group difference in ambulatory day systolic BP in donors was 0.1 mm Hg (95% confidence interval, -1.7 to 1.9) and 0.6 mm Hg (95% confidence interval, -0.7 to 2.0) in controls. The between-group difference was -0.5 mm Hg (95% confidence interval, -2.8 to 1.7; =0.62). The mean within-group difference in pulse wave velocity in donors was 0.3 m/s (95% confidence interval, 0.1 to 0.4) and 0.2 m/s (95% confidence interval, -0.0 to 0.4) in controls. The between-group difference was 0.1 m/s (95% confidence interval, -0.2 to 0.3; =0.49).

Conclusions: Changes in ambulatory peripheral BP and pulse wave velocity in kidney donors at 12 months after nephrectomy were small and not different from controls.

Clinical Trial Registry Name And Registration Number: NCT01769924 (https://clinicaltrials.gov/ct2/show/NCT01769924).
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http://dx.doi.org/10.2215/CJN.15651219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480552PMC
September 2020

Coronary flow velocity reserve and inflammatory markers in living kidney donors.

Int J Cardiol 2020 Dec 14;320:141-147. Epub 2020 Aug 14.

Birmingham Cardio-Renal Group, Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; Department of Cardiology, Queen Elizabeth Hospital, Birmingham, United Kingdom.

Background: Coronary microvascular dysfunction is prevalent in chronic kidney disease (CKD), and may contribute to the development of myocardial dysfunction in CKD. Coronary flow velocity reserve (CFVR) is a marker of coronary microvascular function and falls with increasing CKD stage. Living kidney donors have renal function consistent with early stage CKD and concern has been raised about their cardiovascular risk. No studies to date have investigated the presence of coronary microvascular dysfunction in living kidney donors.

Methods: 25 healthy controls and 23 living kidney donors were recruited and underwent assessment with transthoracic echocardiography, Doppler CFVR, myocardial contrast echocardiography and serum multiplex immunoassay panels.

Results: Doppler CFVR was significantly reduced in living kidney donors compared to controls (mean CFVR 3.4 ± 0.7 vs 3.8 ± 0.6, mean difference 0.4 95% confidence interval 0.03-0.8, p =.036). Quantitative myocardial contrast echocardiography showed a trend towards reduced coronary flow reserve in living kidney donors. Compared to controls, living kidney donors had higher serum high sensitivity C reactive peptide (hsCRP) and lower levels of uromodulin.

Conclusions: This is the first study of CFVR in living kidney donors. We have shown that the modest drop in estimated glomerular filtration rate in living kidney donors is associated with lower values of Doppler CFVR compared to controls, suggesting that isolated reductions in renal function may lead to altered microvascular function. The increase in hsCRP and reduction in uromodulin suggests that chronic subclinical inflammation may contribute to altered microvascular function in this population.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584109PMC
December 2020

Defining Myocardial Abnormalities Across the Stages of Chronic Kidney Disease: A Cardiac Magnetic Resonance Imaging Study.

JACC Cardiovasc Imaging 2020 11 15;13(11):2357-2367. Epub 2020 Jul 15.

Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom; Green Lane Cardiovascular Service, Auckland, New Zealand. Electronic address:

Objectives: A proof of concept cross-sectional study investigating changes in myocardial abnormalities across stages of chronic kidney disease (CKD). Characterizing noninvasive markers of myocardial fibrosis on cardiac magnetic resonance, echocardiography, and correlating with biomarkers of fibrosis, myocardial injury, and functional correlates including exercise tolerance.

Background: CKD is associated with an increased risk of cardiovascular death. Much of the excess mortality is attributed to uremic cardiomyopathy, defined by increased left ventricular hypertrophy, myocardial dysfunction, and fibrosis. The prevalence of these abnormalities across stages of CKD and their impact on cardiovascular performance is unknown.

Methods: A total of 134 nondiabetic, pre-dialysis subjects with CKD stages 2 to 5 without myocardial ischemia underwent cardiac magnetic resonance (1.5-T) including; T mapping (biomarker of diffuse fibrosis), T mapping (edema), late gadolinium enhancement, and assessment of aortic distensibility. Serum biomarkers including collagen turnover (P1NP, P3NP), troponin T, and N-terminal pro-B-type natriuretic peptide were measured. Cardiovascular performance was quantified by bicycle cardiopulmonary exercise testing and echocardiography.

Results: Native myocardial T times increased incrementally from stage 2 to 5 (966 ± 21 ms vs. 994 ± 33 ms; p < 0.001), independent of hypertension and aortic distensibility. Left atrial volume, E/e', N-terminal pro-B-type natriuretic peptide, P1NP, and P3NP increased with CKD stage (p < 0.05), while effort tolerance (% predicted VOPeak, %VOVT) decreased (p < 0.001). In multivariable linear regression models, estimated glomerular filtration rate was the strongest predictor of native myocardial T time (p < 0.001). Native myocardial T time, left atrial dilatation, and high-sensitivity troponin T were independent predictors of % predicted VOPeak (p < 0.001).

Conclusions: Imaging and serum biomarkers of myocardial fibrosis increase with advancing CKD independent of effects of left ventricular afterload and might be a key intermediary in the development of uremic cardiomyopathy. Further studies are needed to determine whether these changes lead to the increased rates of heart failure and death in CKD. (Left Ventricular Fibrosis in Chronic Kidney Disease [FibroCKD]; NCT03176862).
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http://dx.doi.org/10.1016/j.jcmg.2020.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607516PMC
November 2020

SGLT-2 Inhibitors to Treat Hyponatremia Associated with SIADH: A Novel Indication?

Am J Nephrol 2020 9;51(7):553-555. Epub 2020 Jul 9.

IIS-Fundacion Jimenez Diaz, School of Medicine, University Autonoma of Madrid, FRIAT and REDINREN, Madrid, Spain.

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http://dx.doi.org/10.1159/000509082DOI Listing
July 2021

Relevance of physicochemical properties and functional pharmacology data to predict the clinical safety profile of direct oral anticoagulants.

Pharmacol Res Perspect 2020 06;8(3):e00603

School of Pharmacy, University of Birmingham, Birmingham, UK.

Direct oral anticoagulants (DOACs) have rapidly become the drug class of choice for anticoagulation therapy in secondary care. It is known that gastrointestinal hemorrhage are potential side effects of the DOAC drug class. In this study we have investigated the relevance of molecular structure and on/off-target pharmacology as a predictor of adverse drug reactions (ADRs) for the DOAC drug class. Use of the Reaxys MedChem module allowed for data mining of all possible reported off-target effects of the DOAC class members. For the first time, the MHRA Yellow card database in combination with prescribing rates in the United Kingdom (data for n = 30 566 936 DOAC R (up to 2017) and ADR data n = 22 275 (up to 2018)) were used for our data comparison of DOACs. From the underlying reported data, we were able to rank the DOACs in terms of the likely adverse events we would expect to observe. We identified potential risks of ADRs based on the DOACs pharmacology including the expected GI hemorrhage, but also the unexpected risk of stroke, pulmonary embolism and kidney injury. Statistically significant (P < .001) differences were found between all DOACs and their total number of ADRs. Although the risks are small, strong statistical correlation between observed pharmacology and national ADR data is observed in three out of the five areas of concern.
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http://dx.doi.org/10.1002/prp2.603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272392PMC
June 2020

Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.

N Engl J Med 2020 05;382(21):e65

Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain

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http://dx.doi.org/10.1056/NEJMc2004861DOI Listing
May 2020

Clinical Potential of Targeting Fibroblast Growth Factor-23 and αKlotho in the Treatment of Uremic Cardiomyopathy.

J Am Heart Assoc 2020 04 26;9(7):e016041. Epub 2020 Mar 26.

Birmingham Cardio-Renal Group University Hospitals Birmingham University of Birmingham United Kingdom.

Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor-23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor-23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end-stage renal disease.
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http://dx.doi.org/10.1161/JAHA.120.016041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428638PMC
April 2020
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