After almost a decade of stagnation in clinical research for HF treatment, five large randomized trials recently published have supported the use of four new classes of drugs, namely: angiotensin receptor/neprilysin inhibitor, sodium–glucose co-transporters 2 inhibitors, soluble guanylate cyclase modulators, and myosin activators. Each treatment has proved to be beneficial for both long-term outcomes and quality of life. Beside their clinical relevance, all these novel treatments have a different mechanism of action beyond the usual neuro-hormonal blockage. These different pathways, together with the unquestionable clinical evidence, advocate a re-thinking of HF treatment and of the appropriate drug to integrate with the existing standard therapy, according to different characteristics of HFrEF patients. This study aimed to offer a synthetic overview of the mechanisms of action of the new drugs and to propose a more personalized approach, considering patients’ characteristics and safety profiles. To this end, we have identified seven profiles for patients with chronic heart failure with reduced ejection fraction and two for pre-discharge patients. A New Era” has emerged for medical treatment of heart failure with reduced ejection fraction (HFrEF). After the 1970s, when heart failure (HF) was empirically treated with diuretics, digitalis, and bed rest, a revolution started based on the understanding that, for the failing heart, long-lasting neuroendocrine activation is deleterious rather than beneficial [RCTs) exploring new treatments provided, at best, neutral results. In 2014, the scientific community started to be resigned and to believe that the limit of HF knowledge was reached.In the last six years, “neficial . Then, aARNI), sodium–glucose transporter 2 inhibitors (SGLT2i), sodium guanylate cyclase (SGC) modulators, and myosin activators, have shown to further increase survival and/or hospitalization for patients with HFrEF and are, or soon will be, available for HFrEF treatment. In anticipation of the new guidelines, several suggestions on how to integrate these treatments have been proposed [Since 2014, five landmark randomized clinical trials (RCTs) have reported unexpected favorable results in HFrEF from four new classes of drugs acting beyond the classical neuro-hormonal blockage. These new drugs, namely, angiotensin receptor/neprilysin inhibitors  to the inhibition (by sacubitril) of a new target, neprilysin, a ubiquitarian enzyme that degrades several peptides, including endogenous natriuretic peptides (ANP). As a result, the deleterious vasoconstriction and water retention induced by angiotensin II are counteracted, whilst the beneficial vasodilatation and diuretic action of natriuretic peptides are emphasized [CV) death and a 21% reduction in hospitalizations for HF (HHF) compared to enalapril in symptomatic HFrEF patients with left ventricular ejection fraction (LVEF) ≤40% (subsequently amended to ≤35%) and high BNP/NT-proBNP. Clinical benefit was rapid as shown by the Kaplan–Mayer curves for primary outcome, which start to diverge already after the first month. This was, in part at least, attributable to reverse cardiac remodeling, with improvement in left ventricular function concomitant to early reduction in NT-proBNP levels [ARNI represents a change of paradigm in HFrEF treatment. This class of drugs combines RAAS inhibition through angiotensin II receptor blockage  requirements for new antidiabetic drugs, since 2008 three major cardiovascular (CV) outcome trials were performed with SGLT2i to rule out CV harm, while improving glucose control. Unexpectedly, all these trials showed positive outcomes in terms of CV death, representing a real case of serendipity [SGLT2i are a new class of drugs originally created and approved as antidiabetic agents for the treatment of type 2 diabetes mellitus. SGLT2i promote urinary glucose excretion by inhibition of glucose and sodium reabsorption from the renal proximal tubules where SGLT2 located . To fulfendipity . These oendipity .CV death and HHF) in treated patients [The DAPA-HF trial showed a 26% reduction in the primary endpoint of CV mortality and HHF or urgent HF visits in patients with LVEF ≤ 40% and high BNP/NT-proBNP, regardless of the diabetic status. As a result, in 2020, the FDA approved the SGLT2i dapagliflozin for the treatment of patients with HFrEF . One yeapatients . The pripatients .ARNI, BB, MRA, and SGLT2i) vs. conventional  therapy [In both studies, benefits occurred early, after receiving the active drugs regardless of background evidence-based therapy but with no more than 20% of patients on ARNI. The data confirmed significantly better results for both SGLT2i in all the predefined groups with clear amelioration of kidney functions and outcome and excellent tolerability. A cross-sectional analysis demonstrated a 1.4 to 6.3 years gain of life expectancy with comprehensive  which, in turn, is synthesized by three nitric oxide synthases (NOS) from L-arginine. In endothelial cells, NO is produced by eNOS. being a gas, NO rapidly reaches the smooth muscle cells and binds to SGC, its target enzyme. The binding activates SGC which, in turn, is responsible for the release of the second messenger cGMP. cGMP causes dilatation through three intracellular pathways, such as cGMP-dependent protein kinases, cGMP regulated ion channels, and phosphodiesterases. All the three transduction pathways exert different effects including dilatation by smooth muscle relaxation, inhibition of smooth muscle proliferation, anti-inflammatory effects, and anti-fibrotic action [The nitric-oxide-guanylate cyclase (SGC)-CGMP is a complex signal transduction mechanism exerting a key role in the regulation of the CV system. Central to these pathways is latelets . SGC hasc action . HF is cc action . Riocigui.e., LVEF ≤ 45%) patients [9.1% vs. 7.9%), syncope (4% vs. 3.5%), and anemia (7.6% vs. 5.7%), which were more frequent in the treated than in placebo arm [The phase III VICTORIA trial, following the mixed results of the phase II SOCRATES-reduced trial, was a gamble worth taking. The VICTORIA results show that vericiguat lowered the incidence of the composite of CV death and HHF in symptomatic HFrEF (patients . The pricebo arm . The enrPi) from myosin. The resulting myosin–ADP complex binds tightly to actin and strongly pulls myosin against actin, generating a strong interaction. The complex myosin–ADP–actin dissociates when a new ATP molecule binds again to the myosin head and a new cycle starts. This happens 60 times in a minute for all our life! Of note, during a systole, only 10–30% of the myosin heads interact with actin filaments, leaving ample room for improvement [148. The subsequent conformational changes increase the speed of the ATP hydrolysis, thus promoting Pi release and the transition from a weak to a strong bond. In so doing, more myosin heads are bound to actin filaments and remain attached for a longer period, thus boosting force production. From a functional point of view, this translates to prolongation of systole duration and increased cardiac contractility. Differently from the other positive inotropes, the mechanism of action of omecamtiv mecarbil is independent from the levels of intracellular calcium and peripheral resistance, without a chronotropic rebound and, importantly, without an increase in myocardial oxygen consumption [Omecamtiv mecarbil is the first-in-class of selective cardiac myosin activators. It was developed from the knowledge that, physiologically, the binding of myosin to actin filaments is weak until the generation of energy from hydrolysis of ATP to ADP occurs . This isrovement . Omecamtsumption . In the sumption ,35.i.e., LVEF ≤ 35%), both in hospitalized or recently dismissed HF patients [In the GALACTIC-HF trial, omecamtiv mecarbil caused a modest but significant lowering of the combined endpoint of CV death and HF events in patients with symptomatic HFrEF  in both trials, the efficacy was proved in just a single randomized study; (2) the risk reduction was modest: 10% in the VICTORIA trial and 8% in the GALACTIC-HF trial; (3) the main drivers of the primary outcome were HHF and urgent unplanned outpatient visits for worsening HF. No difference was observed in CV mortality. Nevertheless, the high exposure to HF hospitalizations resulted in an absolute risk reduction similar to those observed in the PARADIGM-HF and DAPA-HF, and a prolongation of the trials likely would have resulted in a reduction in CV mortality ,38.i.e., HR for beta-blockers or ANP levels for ACEi) instead of target doses should be used. Physicians are authorized to add further anti-hormonal drugs, such as MRA, only when the clinical condition does not improve. After these steps, ARNi, ivabradine, or devices should be considered, according to patients’ characteristics [enemy” to combat: the excess of neuroendocrine response. Today, the situation is different. Other known or unknown effects, independent from of the neuroendocrine activation, do matter and it would be no longer ethical to deprive HFrEF patients from the benefit produced by the new treatments [fantastic four”  to be used, unless contraindication, in combination from the beginning of the treatment and at the maximum tolerated dose, without uptitration [The scenario produced by these RCTs advocates a reconsideration of the therapeutical approach of HFrEF ,4,5,6,7.eristics ,4,5,6,7.eatments . FurtherBesides the fantastic quartet, it is important to consider also the other two first-in-class treatments: vericiguat and omecamtiv mecarbil. Thus far, these drugs have not received the same attention of ARNI and SGLT2i as the evidence of their effects comes from one RCT and not from two or more. In addition, the benefit in outcome seems to be less robust than that offered by sacubitril/valsartan and SGLT2i as total or CV mortality was not significantly reduced. However, the studies on vericiguat and omecamtiv mecarbil recruited patients with more advanced HF than those enrolled in the ARNI and SGLT2i trials, and if the studies had been prolonged, a significant reduction in mortality probably would have been achieved ,39. ThesOur proposal is reported, in a schematic form, in  The tables show that the patients enrolled and the criteria used in the various studies were not homogeneous. The most frequent differences related to %EF, renal function, serum K+, NT-proBNP, and blood pressure. Data on associations between the new drugs were not available and caution should be taken at this regard.a) HFrEF and reduced blood pressure (systolic BP < 100 mmHg): there is not a unanimous definition of the meaning of low blood pressure in HF. A systolic blood pressure <90 mmHg is often taken as a limit. Even this assumption might vary, i.e., in patients with proven or underlying CAD, a systolic blood pressure >120 mmHg is suggested. For these reasons, we arbitrarily considered a systolic blood pressure <100 mmHg. In this case, ARNI and vericiguat were not suggested, as a BP <100 was an exclusion criterion in the respective trials. In PARAGON-HF, the effects of sacubitril/valsartan on blood pressure reduction were superior than that of enalapril. The occurrence of symptomatic hypotension (<90 mmHg systolic BP) was present in 2.7% of the randomized population vs. 1.4% in the enalapril arm. Equally, hypotension was a side effect of vericiguat. BB, ACEi/ARBs, and gliflozins could also reduce blood pressure but to less extent than ARNI and vericiguat and were normally utilized in asymptomatic patients with BP as low as 95–100 mmHg in view of the offered relevant improvement of outcome. MRA was known to reduce blood pressure in hypertensive patients, but not in those with HF. In RALES, low blood pressure was not an exclusion criterion and in EMPHASIS, patients with blood pressure <85 mmHg were excluded. Therefore, MRA could be safely used. The only two other drugs that had no effect on blood pressure were omecamtiv mecarbil and ivabradine. In both GALACTIC-HF and SHIFT, only patients with a systolic blood pressure <85 mmHg were excluded. (b) HFrEF and hyperkalemia (serum potassium > 5–5.3 mmol/L): under this condition, both ARNI and ACEi were not suggested. In the PARAGON-HF trial, 16% and 17.4% of patients receiving sacubitril/valsartan and enalapril (respectively) showed a serum potassium >5.5 mmol/L. It should also be underlined that in PARADIGM-HF, patients with a value of serum potassium >5.2 mmol at screening and of > 5.4 mmol at randomization were excluded. The same was true for MRA, as in EMPHASIS and in RALES serum potassium >5 mmol/L was an exclusion criterion [ HFrEF and chronic kidney disease (CKD): CKD with glomerular (eGFR < 60 mL/min/1.73 m2) is common in HF patients and is a negative prognostic indicator as it carries a double risk for all-cause mortality. As a result, in absolute terms, patients with CKD might benefit the most from treatment with neuroendocrine blockers and/or from the new drugs. It should be considered that eGFR declines with age and more so in patients with HF and may change during the course of HF. Despite this, most RCTs have excluded patients with severe CKD (eGFR < 30 mL/mm/1.73 m2), whilst registries show that patients with HF and CKD are undertreated, most likely for fear of worsening CKD. This is wrong because, for example, a sub analysis of the RALES trial showed that spironolactone caused a 30% relative risk reduction for mortality, independently from baseline eGFR, with most benefit in patients with the lowest eGFR. Nevertheless, RALES patients with a creatinine level >2.5 mg/dL were excluded, whilst in EMPHASIS those with an eGFR < 30 mL/min/i.73 m2 were not admitted. These are most likely the limits for use of MRA provided that there is no sudden increase in creatinine and serum potassium. The same limitation applied to ivabradine in SHIFT. It is common practice to use ACEi with caution in patients with reduced eGFR and in SOLVD, patients with serum creatinine higher than 2 mg/dL were not randomized. However, it is advised not to stop ACEi/ARRS, but just to reduce the dose in the case that creatinine increases to >3.5 mg/dL or eGFR is reduced to <20 mL/min/1.73 m2. Theoretically, caution should be necessary also for gliflozins and ARNI. In the DAPA-HF trial, patients with eGFR < 30 mL/min/1.73 m2 and 20 mL/min/1.73 m2 in EMPEROR-Reduced were excluded. However, both in CREDENCE and DAPA CKD and also in EMPEROR-Reduced, gliflozins reduced the risk of progression of both CKD and HF, consistent with the benefit on kidney function observed in trials of SGLT2i in diabetic patients who largely did not have HF [2 was also an exclusion criterion for both sacubitril/valsartan and enalapril but, in the long treatment, sacubitril/valsartan actually improved kidney function [2. The same applied to vericiguat as, in the VICTORIA trial, it was given to patients with eGFR < 30 mL/min/1.73 m2. BB can also be safely used down to eGFR < 30 mL/min/1.73 m2.  HFrEF with increased arrhythmic burden (non-sustained ventricular tachycardia -NSVT or repetitive extra systoles at Holter monitoring): this is not a contraindication for the majority of drugs prescribed in HF. It is an election criterion for BB. CIBIS III showed that early treatment with bisoprolol reduced runs of TVNS and arrhythmic death better than ACEi [BRV were not included. Caution should be applied when using omecamtiv mecarbil which, theoretically, could increase arrythmias as a consequence of the positive inotropism. It is, however, fair to report that in the GALACTIC trials, ventricular arrhythmias were not increased in the treated arms. For gliflozins or vericiguat, there were no data.(han ACEi . Sudden HR) and/or atrial fibrillation (AF). a) > 70 beats/min).HFrEF in sinus rhythm with elevated HR  HFrEF with atrial fibrillation (AF) and HR > and < 100 beats/min. There was no clear indication on the optimal HR in patients with HF and AF. It is common practice to try to maintain HR between 60 and 70 beats/min [especially if blood pressure is low) for rate control [ or dry.(1)Post-acute HF wet: often, during hospitalization, patients may be stabilized but remain congestive. In this condition, BBs were not suggested despite some positive data in the severely compromised patients enrolled in COPERNICUS [PERNICUS . These, (2)Post-acute HF dry: gliflozins, and ivabradine also had no data to support or exclude their use. The other “classical” drugs, such as BB, ACEi, MRA, and ARNI can be used, depending on the circumstances. Vericiguat and omecamtiv mecarbil also had no data in the post-acute phase independently from being hypervolemic or not. However, the two respective trials enrolled more severely hospitalized patients than in those for the other classes of drugs and their respective effects, so vasodilatation and increased inotropism might be important.sort of guideline” or a “consensus” on how to treat HFrEF. These have been recently made available [New Era” for treatment of HF, to show the limited evidence available for the most common phenotype of patients, and to stimulate physicians to make their own decision on the best therapy for each patient without fixed algorithms as guidelines tend to do. Equally, no attempt is made to suggest the ideal drug combinations which, in absence of clear evidence, should be considered on the basis of the mechanism of action of each treatment. We have considered the most utilized drugs in HF. We have not commented on diuretics, digoxin, anticoagulant, and ferric carboxymatose. In addition, we have limited our discussion to patients with chronic and just post-acute HF but not on advanced HF. This later HF population has totally different clinical profiles and therapeutic goals needing more intensive treatment than just drug therapy. Equally, we have not commented on the emerging role of imaging and especially MRI in HF patients.Our study had several limitations, which, basically, were due to scarce availability of data. This article is not at all intended to be a “vailable . On the The scientific community is fortunate to have four new classes of drugs to treat HFrEF, each acting with an individual mechanism of action. The European guidelines have recently provided information on how to use them . Accordi


Polycystic liver disease (PLD) is a condition that most often occurs in patients with autosomal dominant polycystic kidney disease (ADPKD) and less commonly as isolated liver disease. The presence of both conditions has proven to be a therapeutic challenge. Patients with ADPKD can suffer from significant renal and extra-renal complications and symptoms as a result of space-occupying cysts from polycystic kidney and liver enlargement. We present a case of ADPKD in a 56-year-old Caucasian female who developed pelvic organ prolapse, a rare complication, while also dealing with multiple other complications of ADPKD. Despite the high prevalence of ADPKD, complications such as pelvic organ prolapse have seldom been reported and discussed in the literature. The care team should do a prompt gynecological examination when they realize the burden of cysts becomes so large. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited disease of kidneys due to mutations in the PKD1 gene located on chromosome 16p13.3, encoding polycystin-1, which is a large integral membrane protein that plays a role in adhesion and extracellular matrix regulation. ADPKD type I accounts for 85% to 90% of ADPKD cases [Polycystic liver disease (PLD) is a common extra-renal manifestation in patients with ADPKD. The prevalence of PLD in patients with ADPKD ranges from 20% to 75%. The pathogenesis of PLD associated with ADPKD involves cell adhesion disruption as the primary defect. The majority of patients that present with isolated PLD are usually asymptomatic. However, patients with liver cysts associated with ADPKD are more prone to symptoms related to renal failure and liver cysts account for up to 10% mortality in ADPKD patients on hemodialysis [A 56-year-old Caucasian nulliparous female presented to our outpatient clinic with left lower quadrant abdominal discomfort. The discomfort was described as a fluid wave that radiates from the left lower quadrant to the umbilicus, which was worse after eating. For the past 6 years, she had suffered from a 4/10 chronic flank pain. She has a history of ADPKD, multiple liver cysts along with other complications of ADPKD including stage 3 CKD, nephrolithiasis, constipation, mitral valve prolapse, pelvic organ prolapse. Ten years ago she had a total hysterectomy with bilateral salpingo-oophorectomy. Six months ago, she underwent robotic-assisted laparoscopic sacral colpopexy, paravaginal defect repair with cystocele repair, rectocele repair with perineorrhaphy using mesh. She has no children. Family history is significant with a father with polycystic kidney disease, hypertension, aneurysm, and heart disease, a mother with ovarian cancer. Her vital signs were unremarkable with weight 116 lb (52.6 kg), pulse 68 BPM, temperature 98.8℉ (37.1 ℃), blood pressure 108/62 mmHG, BMI of 20.34 (18.5-24.9) and hyposthenia body habitus. On the physical exam, she had a +3 systolic murmur with a mid-systolic click at the apex; the abdomen was diffusely distended with two-third of the abdomen filled with palpable masses from the liver and kidney cysts and tenderness to palpation.Labs showed elevated blood urea nitrogen (BUN) of 51 mg/dl (7-18 mg/dL), creatinine of 2.14 mg/dL (0.6-1.2 mg/dL), decreased eGFR of 24ml/min (120−130 mL/min), and low sodium of 133 mEq/L (136-146 mEq/L). Complete blood count shows low RBCs of 3.94*10^6/µL (4.10-5.10*10^6/µL), and hemoglobin of 11.9 g/dL (12-16 g/dL). Renal ultrasound showed enumerable simple and complex cysts in bilateral kidneys, with kidneys measuring 13.7 x 7.6 x 7.2 cm on the left and 12.2 x 6.1 x 6.3 on the right. Abdominal ultrasound shows liver size measuring 20.4 in the cranial-caudal direction, with innumerable simple cysts seen throughout the liver. An echocardiogram showed mildly dilated left atrium with impaired diastolic dysfunction. Moderate to severe mitral valve prolapse and mitral regurgitation is also appreciated. Non-contrast Computed tomography (CT) scan of the abdomen and pelvis showed extensive cysts with coarse calcifications in bilateral kidneys Figures , 1B and ADPKD is the most common inherited cause of kidney disease which accounts for 4.7% of end-stage renal disease in the United States .We hypothesize space-occupying lesions are the main cause of cystocele and rectocele complications in patients with ADPKD. Space occupying lesions displace the surrounding organs to the periphery causing an increase in intra-abdominal pressure. Moreover, another cause of increased intra-abdominal pressure can be constipation, which is also caused by opioids that our patient was on for chronic pain. In a study by Kim et al., the pressure burden of space-occupying cysts caused complications such as leg edema 20.4%), ascites (16.6%), and hernia (3.6%) were common, the risk of such complications increased by sixfolds in patients with moderate to severe PLD [%, asciteAdding to the burden of space-occupying lesions, hysterectomy increases the risk of pelvic floor prolapse as it disturbs the uterine ligamentous support . The aboMost of the patients are diagnosed with ADPKD through abdominal ultrasound either incidentally or as a part of family history. Routine gynecological examination is recommended in any woman with ADPKD especially with a sudden drop in eGFR to determine the risk of pelvic organ prolapse and to provide early intervention . The droControl of blood pressure with antihypertensive agents especially by angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) has shown improved LVH and mortality in ADPKD patients. Chronic pain in these patients should not be treated with opioids as they can aggravate constipation, hence leading to increased abdominal pressure. Somatostatin analogs such as octreotide or lanreotide are shown to be beneficial for patients with PLD as they can help in both symptom relief and liver volume reduction . Cyst feCompression of surrounding organs is a well-known complication in patients with ADPKD and PLD. Pelvic organ prolapse is a rare complication in a nulliparous woman while underlying ADPKD could be the probable etiology. Despite the high prevalence of ADPKD, there are still a lot of unknown pathophysiology mechanisms and associations of many extra-renal manifestations. Nevertheless, nephrologists and physicians should be aware of the possibility of such rare complications and manage accordingly in a timely manner to prevent morbidity and mortality.


Leptin is an adipokine that regulates appetite and body mass and has many other pleiotropic functions, including regulating kidney function. Increased evidence shows that chronic kidney disease (CKD) is associated with hyperleptinemia, but the reasons for this phenomenon are not fully understood. In this review, we focused on potential causes of hyperleptinemia in patients with CKD and the effects of elevated serum leptin levels on patient kidney function and cardiovascular risk. The available data indicate that the increased concentration of leptin in the blood of CKD patients may result from both decreased leptin elimination from the circulation by the kidneys  and increased leptin production by the adipose tissue. The overproduction of leptin by the adipose tissue could result from: (a) hyperinsulinemia; (b) chronic inflammation; and (c) significant lipid disturbances in CKD patients. Elevated leptin in CKD patients may further deteriorate kidney function and lead to increased cardiovascular risk. Chronic kidney disease (CKD) is a major clinical and public health problem. CKD can lead to end-stage renal disease (ESRD) and is a strong risk factor for cardiovascular morbidity and mortality . The preAdipose tissue is responsible for the secretion of many signaling molecules, including adipokines, hormones, cytokines and growth factors, such as leptin, adiponectin, resistin, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-β (TGF-β), and angiotensin II ,5,6. ManLeptin is a 167 amino acid protein adipokine with a molecular mass of approximately 16 kDa that is encoded by the LEP gene . The sitLeptin is a pleiotropic adipokine. The main physiological role of leptin is to transmit information to the hypothalamus about the amount of stored energy, such as the mass of adipose tissue, and to influence energy expenditure by reducing appetite ,31. Howeob/ob  and db/db  mice exhibit morphological and functional kidney abnormalities similar to those of human diabetic nephropathy, it has been suggested that leptin plays a functional role in the kidney and that the kidneys are not only responsible for removing leptin from the circulation but are also sites of action of this adipokine [Due to its relatively small size, leptin freely passes through the glomerular filter of the kidneys and is then reabsorbed in the proximal part of the convoluted tubules. The basic mechanism of leptin reabsorption is receptor-mediated endocytosis . The muldipokine . In the dipokine ,45,46,47dipokine .The inability of the kidney to remove leptin from the circulation is probably not the only mechanism responsible for the development of abnormal levels of this adipokine. It is very likely that the increased leptin levels in the blood of CKD patients result from leptin overproduction in the adipose tissue due to hyperinsulinemia and chronic inflammation  ,27. MoreLEP and CKD are poorly studied. To the authors’ best knowledge, only two papers discuss the potential link between CKD and LEP. SNP 2548G/A was proposed as a risk marker of CKD progression to ESRD. However, the study was conducted only on the Egyptian population [Additionally, the fact that the leptin gene polymorphism is associated with the risk of CKD ,53 suggepulation . Anotherpulation ,58,59,60LEP gene in subcutaneous adipose tissue from CKD patients compared to the controls. Moreover, the adipose tissue level of leptin mRNA positively correlated with serum leptin concentration [Aminzadeh et al. and Kalbacher et al. demonstrated that incubating murine 3T3-L1 adipocytes in a medium containing plasma from hemodialysis patients or patients with ESRD could induce the release of significantly more leptin by adipocytes than medium containing plasma from healthy subjects ,61. Thusntration . This fiLEP gene in adipose tissue [Significant lipid disturbances are observed in patients with CKD ,63. The e tissue .These results suggest that in CKD patients, (a) an increase in leptin synthesis takes place in the adipose tissue, which contributes to hyperleptinemia, and (b) chronic inflammation, hyperinsulinemia and alterations in the FA profile could be important factors that stimulate leptin synthesis in the adipose tissue .Overall, the results presented so far suggest that in CKD patients: (a) the rate of leptin elimination from the circulation by the kidneys and (b) the stimulation of leptin biosynthesis in the adipose tissue both determine serum leptin level .2D3) and enzymes . In healthy kidneys, only a small proportion of proteins  passes through the glomerular filtration barrier, and even this load is reabsorbed in the proximal convoluted tubule, resulting in only trace amounts of albumin in urine. Leptin plays a role in disturbing this homeostasis.The main functions of the kidneys are the excretion of waste products, the regulation of water homeostasis and blood pressure, and the secretion of hormones Hyperleptinemia in CKD may promote pathophysiological changes in the kidney, leading to disease progression and comorbidity . These pCKD is characterized by increased oxidative stress and inflammation. Leptin can activate NADPH oxidase and generate reactive oxygen species (ROS), which affect the structure and function of the kidneys . ROS-indThe results discussed in this section suggest that the harmful effect of hyperleptinemia on CKD patients could be associated with (a) an increase in protein leakage into the filtrate; (b) the accumulation of ECM, glomerular fibrosis and glomerulosclerosis; and (c) an increase in oxidative stress and inflammation .Numerous studies have shown that a decrease in eGFR is associated with increased frequency and severity of cardiovascular disease (CVD) . CKD, toLeptin may contribute to the development of cardiovascular dysfunction by inducing inflammation, oxidative stress and endothelial dysfunction ,76. It iVascular endothelial dysfunction is an essential factor that precedes and facilitates the development of atherosclerosis. These disorders are common in the course of CKD . AccumulThe aforementioned oxidative stress caused by leptin may also contribute to the dysfunction of blood vessels and promote the development of atherosclerosis by modifying lipid components, lipoproteins, and proteins. ROS affect the progression of atherosclerosis by reducing the availability of nitric oxide (NO), which is necessary to maintain proper vessel functions. Altered NO metabolism in CKD can be an important element linking oxidative stress with atherosclerosis ,76,77. TMany lines of evidence suggest an association between leptin and CKD. It seems that leptin is involved in both disease development and the development of CKD comorbidities. The molecular mechanism (a) leads to elevations in serum leptin concentrations in CKD patients, and (b) harmful effects of hyperleptinemia on kidney function and associated diseases seem to be complex and need to be further explained. Future studies are needed to determine whether patients with CKD would benefit from therapeutic modulation of circulating leptin levels.


PTGER1-4) and study associations with nephrosclerosis risk and clinical outcomes. We identified 96 tag-SNPs capturing global variability in PTGER1-4 and screened 1209 nephrosclerosis patients and controls. The effect of these variants was evaluated by multivariate regression analyses. Two PTGER3 SNPs, rs11209730 and rs10399704, remained significant in a backward elimination regression model with other non-genetic variables (OR = 1.45 (1.07–1.95), p = 0.016 and OR = 0.71 (0.51–0.99), p = 0.041, respectively). In the nephrosclerosis patients, a proximal region of PTGER3 was tagged as relevant for eGFR . Two consecutive PTGER3 SNPs, rs2284362 and rs2284363, significantly decreased systolic (p = 0.005 and p = 0.0005), diastolic (p = 0.039 and p = 0.005), and pulse pressure values (p = 0.038 and 0.014). Patients were followed for a median of 47 months (7–54) to evaluate cardiovascular (CV) risk. Cox regression analysis showed that carriers of the PTGER1rs2241360 T variant had better CV event-free survival than wild-type individuals (p = 0.029). In addition, PTGER3rs7533733 GG carriers had lower event-free survival than AA/AG patients (p = 0.011). Our results indicate that genetic variability in PGE2 receptors, particularly EP3, may be clinically relevant for nephrosclerosis and its associated CV risk.Prostaglandin E2 (PGE2) is a major actor mediating renal injury. We aimed to determine genetic variability in the genes coding for its receptors ( Chronic kidney disease (CKD), whose prevalence has increased by an alarming 30% in the last 30 years , is now Chronic reduction of prostaglandins in the kidney, such as that caused by non-steroidal anti-inflammatory drugs (NSAIDs), may result in hypertension . In addiPTGER1-4), given the aforementioned role of this PG, may favor the onset of nephrosclerosis and/or affect clinical outcomes. Despite the existence of a few reports linking some of these single nucleotide polymorphisms (SNPs) to hypertension [The susceptibility to CKD is significantly influenced by genetics ,14; therrtension ,16 and artension , their eClinical and demographic characteristics of the population are shown in PTGER2 and six in PTGER3 were not in Hardy–Weinberg equilibrium and hence they were ruled out from subsequent analyses.The overall call rate and reproducibility percentages of the genotyping analysis were 97.8 and 99.71, respectively. One SNP in PTGER3 gene, were significantly associated with the risk of the disease  in favor of the combined genetics/classic model, the difference was not statistically significant (p = 0.016 and OR = 0.71 (0.51–0.99), p = 0.041, respectively, Next, we included these 10 SNPs together in an adjusted multiple regression model with backward elimination controlling for the aforementioned covariates. Four SNPs remained in the final model, two of which, rs11209730 and rs10399704, still showed a statistically significant association with the risk of nephrosclerosis (OR = 1.45 (1.07–1.95), PTGER3, mainly located in the proximal region of the gene, showed a significant association with eGFR, with p values ranging from 0.0003 to 0.038  and diastolic blood pressure (DBP) and pulse pressure—were located in PTGER3, mostly in a distal area of the gene , DBP (p = 0.039 and p = 0.005), and pulse pressure values . Among the CKD patients, those with CV events were significantly older and predominantly males. These and other characteristics of the patients experiencing or not CV events are summarized in Participants were followed for a median of 47 months (range 7–54), in which a total of 50 CV events were reported, nine in the control group (1.3%), and 41 (8.3%) in the nephrosclerosis patients (OR = 7.13 (3.4–14.8), p value (OR = 2.65 (1.28–5.46), p = 0.01, PTGER1 rs2241360 T variant allele had better CV event-free survival than homozygous wild-type carriers did (log-rank p = 0.014), whilst patients homozygous for the PTGER3 rs7533733 G variant allele experienced more events than AA/AG carriers .In order to narrow down the number of SNPs to be analyzed in the survival study, we carried out a previous analysis of the crude association of the 89 variants with the risk of experiencing a CV event under the selected genetic model. Five SNPs resulted in significant associations, with the rs7533733 GG genotype displaying the highest OR and the lowest The evolution of kidney damage in nephrosclerosis is usually slower than in diabetic nephropathy. However, the high prevalence of the disease and the great interindividual variability in its progression result in a significant proportion of cases experiencing a vicious cycle: kidney damage worsens CV risk, which, in turn, increases disease progression to ESRD ,19. TherPTGER3 gene locus, and rs2268062, also in PTGER3, which was included in the study for being reportedly linked to hypertension [PTGER3 gene locus has not been extensively studied, and consequently there is no data regarding the functional impact of polymorphisms. We do know, however, that the administration of EP3 antagonists in vivo increases COX-2-mediated PGE2 expression in the kidney, whilst the receptor activation decreases PGE2 levels [PTGER3 is very scarce. To our knowledge, there is only one report mentioning an association of rs2268062 with hypertension in the general population, although the observation could not be replicated in a validation sample [Our findings showed that nine tag-SNPs, each representing a haplotype block in the rtension , were si2 levels . This is2 levels . Therefo2 levels , regulat2 levels , or main2 levels . Finallyn sample . In our PTGER3 gene associated with significant changes in renal parameters and blood pressure traits. In particular, the effect on eGFR was especially noticeable, with several SNPs tagging a proximal region of the gene (from genomic position 1:70854192 to 1:70905737) highly linked to altered filtration. Again, we can only speculate on the consequences of genetic variants in this area, but given that one of the main EP3 roles is to reduce hyperfiltration by constricting the afferent arteriole [The study of the nephrosclerosis cohort identified several variants in the rteriole ,26, it iPTGER3 that were relevant for blood pressure. This is in line with previous in vitro data and animal studies. Thus, rodent models have shown that the administration of selective EP3 agonists results in an acute and significant rise in arterial pressure [PTGER3 were relevant for blood pressure. Accordingly, it has been reported that the expression levels of EP3 in both renal resistance vessels and the aorta are much higher than those of other EP receptors, and that its vasopressor effects are far superior to EP2 and EP4 vasodilator properties [PTGER3 SNPs identified in this study, and therefore that of the tagged regions, is that some of these variants were repeatedly pinpointed in both the risk analysis and the cohort study. Most notably, out of the 89 polymorphisms studied, rs11209708 was observed to increase the risk of nephrosclerosis as well as affecting eGFR and pulse pressure values. In any case, it should be mentioned that the overall effects of PGE2 that are mediated by EP receptors are particularly complex and depend on many factors aside from genetics—e.g., EP1–4 relative expression levels—additional hormonal signaling  or the individual clinical status [The study also tagged regions in pressure  and thatpressure . Furtheroperties . Finally2+ via phospholipase C, in opposition to EP2 or EP4, which have no effect on Ca2+. Voltage-dependent Ca2+ channels are widely distributed throughout the body and play a critical role in the maintenance of vascular tone. Indeed, substantial research has demonstrated the association between cardiovascular disease and the dysregulation of intracellular calcium [CV mortality in nephrosclerosis is up to 20 times more frequent than in the general population , and eve calcium ,30,31. M calcium ,33. Inde calcium  and athe calcium . This baPTGER3 gene was far more polymorphic than PTGER1, 2, and 4 and therefore many more SNPs were needed to tag the entire gene locus. This could have resulted in more relevant results obtained. Finally, one limitation was inherent to the study design. We analyzed representative SNPs in a region of the genome with high linkage disequilibrium—i.e., their determination makes it possible to infer total genetic variability and identify phenotypic associations without genotyping the rest of SNPs in that area. However, there is a drawback, tag-SNPs are intronic variants and therefore we cannot speculate on their functional consequences as we could in the case, for instance, of a nonsynonymous polymorphism.This work has a number of limitations. First, a validation cohort was lacking; paradoxically, however, this was a consequence of one of the strengths of the study: the requirement of a specific nephrosclerosis diagnosis, which improved the homogeneity of the cohort by excluding patients with diabetic kidney disease. Another limitation is that the PTGER1 and PTGER3 that were solidly linked to the occurrence of CV events, including death. These findings strengthen the aforementioned hypothesis that PGE2 receptors may constitute valuable therapeutic targets in nephrosclerosis and point to certain areas in the genes loci that may be of interest in this regard. Notwithstanding, more data from independent cohorts, and especially in vitro studies that can characterize the functional consequences of SNPs in PTGER1-4, are warranted to confirm our findings.In a seminal review, Nasrallah et al. propose targeting PGE2 receptors as a potential new pharmacological mechanism to prevent kidney damage and dysfunction in CKD , althougThe study was designed as an observational, retrospective study on 493 patients diagnosed with nephrosclerosis and 716 controls. Patients’ samples were obtained from two sources: (i) the NEFRONA repository, which archives biological samples that were collected in a former multicenter study of cardiovascular morbidity and mortality in Spanish subjects with CKD stage 3 or higher (see explanation below), including patients in dialysis ; and  is a global nonprofit organization developing and implementing evidence-based clinical practice guidelines in kidney disease. According to its guidelines, CKD is defined as abnormalities of kidney structure or function, present for more than three months, with implications for health. CKD is divided into five stages based on levels of kidney function assessed by the glomerular filtration rate, which was estimated using the Modification of Diet in Renal Disease (MDRD) equation. These stages are Stage 1: Mild kidney damage, eGFR 90 mL/min/1.73 m2 or higher; Stage 2: Mild loss of kidney function, eGFR 60–89 mL/min/1.73 m2; Stage 3a and 3b: Mild to severe loss of kidney function, eGFR 30–59 mL/min/1.73 m2; Stage 4: Severe loss of kidney function, eG FR 15–29; and Stage 5: Kidney failure or close to failure, eGFR less than 15 mL/min/1.73 m2. Therefore, our patients (stage 3 and higher) had all an eGFR lower than 60 mL/min/1.73 m2.KDIGO . CV risk was defined as the likelihood of experiencing a fatal or non-fatal CV event in the four-year follow-up (54 months). CV events included acute myocardial infarction, acute coronary syndrome, coronary catheterization requiring angioplasty, coronary bypass, typical angina with positive stress tests, sudden death, cerebrovascular accident, peripheral arterial disease, aortic aneurysm, and lower limb ischemia.Nephrosclerosis patients over 18 years of age were selected according to current diagnostic guidelines, i.e., those with biopsy alterations typical of vascular nephropathy or that met clinical criteria. These criteria were based on the absence of signs of other kidney diseases and the presence of data suggestive of the pathology . Patients with proteinuria higher than 1 g were biopsied to confirm the diagnosis. Proteinuria was defined as a value greater than 500 mg or albuminuria higher than 300 mg in 24 h urine. Diagnostic and prognostic stratification of patients were carried out using the KDIGO classification, the KDIGO table of risk of progression and the CONSORTIUM-CKD equation  Badajoz University Hospital; (ii) Primary Care centers throughout the country in the case of samples from the NEFRONA repository; and (iii) the DNA repository of the Instituto de Salud Carlos III . Exclusion criteria included previous history of any CV event, transplantation of any organ, carotid artery surgery, active infection, pregnancy or life expectancy below one year. All subjects gave written consent for their participation in the study, which had been approved by the Ethics Committee of the participating institutions, and that was carried out in accordance with the Declaration of Helsinki and its subsequent revisions.Control subjects matched by sex and age with eGFR > 60 mL/min/1.73 mPTGER1 , PTGER2 , PTGER3 , and PTGER4  genes, coding for EP1–4 receptors, and identified tag-SNPs (polymorphisms that represent genetic variability in a certain area) with Haploview 4.2 . In order to capture common variations, we chose a pair-wise tagging with a minimum r2 of 0.80 and a threshold for minor allele frequency of 10%. In addition to the tag-SNPs identified, we included two variants, rs17197 and rs2268062, with a reported impact on BP [PTGER1, 8 SNPs in PTGER2, 73 SNPs in PTGER3, and 9 SNPs in PTGER4 were analyzed. The list of all evaluated SNPs is shown in We retrieved the coding sequence and adjacent 3′ and 5′ UTR regions of the Whole blood samples (10 mL) were drawn from the participants recruited at the Badajoz University Hospital and stored at −80 °C until DNA purification, which was conducted with a standard phenol-chloroform extraction and ethanol precipitation. DNA samples were then stored at 4 °C in sterile plastic vials. In the case of participants recruited in the NEFRONA study, genetic material was obtained from biological samples stored at the REDinREN biobank  using QI® OpenArray Genotyping  with a customized panel on a QuantStudio™ 12K Flex Real-Time PCR System  in the Centro Nacional de Genotipado-Instituto de Salud Carlos III . A trio of samples from the Coriell Institute biorepository, with known genotypes, were included in each chip as quality control.Genotyping was performed by allelic discrimination using TaqMant/Mann–Whitney or ANOVA/Kruskal–Wallis tests, depending on the normality of the data and the number of groups compared. Categorical variables were compared with the Chi-square test. Logistic regression modeling was used to examine the influence of the SNPs on vascular CKD risk, adjusting for demographics and classic risk factors, namely age, sex, ethnicity, diabetes and hypertension, as formerly described [Differences between quantitative variables were assessed by the Student’s escribed . After tescribed ,40, becaThe incidence of CV events and its association with the presence of SNPs was assessed by Kaplan–Meier curves, which were compared with the log-rank test. Cox regression modeling was carried out in order to evaluate the effect of additional covariates. Patients were followed up until the earliest of CV event, death, or end of study.SNPassoc, pROC, and survival packages in the R environment and the IBM SPSS statistical software .Statistical analyses were carried out with the The determination of genetic variability of PGE2 receptors, and particularly that of EP3, may be useful to identify patients at risk of nephrosclerosis and/or the detection of patients with this disease that have a higher likelihood of experiencing CV events.


Introduction: At present, we are witnessing an increase in preeclampsia, especially the most severe forms, which are associated with an increased risk of maternal-perinatal morbidity and mortality. As a severity criterion, acute kidney injury (AKI) has been associated with a worse prognosis, and for this reason, the maternal and perinatal variables associated with AKI in patients with severe preeclampsia (SP) were analysed in this study. Methods: An observational, retrospective, single-centre study of patients with SP treated at a tertiary hospital between January 2007 and December 2018 was conducted. The case criteria based on the criteria established by the ACOG Practice Guidelines for Gestational Hypertension and Preeclampsia. AKI is considered when serum creatinine exceeds 1.1 mg/dL in a pregnant woman with previously normal renal function. In patients with existing chronic kidney disease (CKD), it is referred to as AKI if the baseline serum creatinine increases by 1.5 fold. Pregestational, gestational and postpartum variables were analysed up to 12 weeks postpartum using univariate and multivariate logistic regression analysis. Results: During the study period, 76,828 births were attended, and 303 pregnant women were diagnosed with SP. The annual incidence of SP increased gradually throughout the study period, reaching 1.79/100 births/year in 2018. Acute kidney injury (AKI) occurred in 24.8% of the patients. The multivariate analysis revealed an increased association with a history of previous CKD, the use of assisted reproductive techniques and caesarean section. Uric acid and thrombotic microangiopathy (TMA) had a high correlation with AKI. Indications for caesarean section are associated with AKI in SP. Regarding perinatal outcomes in cases of AKI, there was a higher percentage of neonates who required foetal lung maturation with steroids and an increased need for NICU admission. No case of maternal death was recorded; however, an increase in neonatal mortality was found among patients who did not develop AKI. After 12 weeks postpartum, 72 patients were referred to the nephrology consultation for persistent hypertension, proteinuria or renal failure. Conclusions: In preeclampsia, AKI is a common complication, especially among patients with a history of CKD, those who became pregnant using assisted reproduction techniques and those who delivered via caesarean section. The perinatal impact of AKI is mainly centred on a higher rate of NICU admission and a lower mortality rate. Among biochemical and haematological markers, the uric acid level prior to renal failure has a direct and significant correlation with the risk of AKI, as does the development of TMA in patients with preeclampsia. Therefore, the monitoring of renal function in cases of preeclampsia should be strict, and referral for a nephrology consultation may be necessary in some cases. Preeclampsia (PE) is a syndrome characterised by the de novo appearance in a woman more than 20 weeks pregnant of hypertension (HT) associated with proteinuria and/or other manifestations of organ dysfunction. It is included within the category of hypertensive disorders of pregnancy (HDP), a term that refers to a set of entities whose link is the presence of arterial HT in a pregnant woman ,2.There are clinical and analytical conditions that confer severity upon preeclampsia and further increase the risk of maternal-perinatal morbidity and mortality ,4. Among2 It is classically defined as a rare complication within the maternal clinical manifestations of PE. When it occurs in this context, it is associated with a worse maternal and perinatal prognosis [At present, we are witnessing an increase in the incidence of preeclampsia and SP; it is a frequently encountered obstetric complication and one of the main causes of maternal-perinatal morbidity and mortality ,9,10,11.rognosis . In factrognosis ,4.The objective of this study is to compare the maternal and perinatal clinical and analytical variables in patients with SP who develop AKI vs. those who do not develop this condition.3), disseminated intravascular coagulation (DIC) or haemolysis; placental involvement with foetal manifestations including intrauterine growth restriction (IGR), abnormal umbilical artery Doppler results and foetal death [Design and patients: An observational study was conducted with a retrospective, hospital-based cohort of patients with SP treated at a tertiary centre between January 2007 and December 2018 to compare maternal-perinatal variables between patients who develop AKI and those who do not. SP was diagnosed according to the criteria of the American College of Obstetricians and Gynecologists Practice Guidelines for Gestational Hypertension and Preeclampsia  in patieal death . In thisal death . This cuIn patients with pre-existing CKD, AKI was considered when the baseline serum creatinine level was 1.5 times higher than the baseline level. Oliguria was considered at a diuresis rate of less than 500 mL in 24 h or less than 0.5 mL/kg/h for 2 consecutive hours . If AKI The study protocol was approved by the centres Ethics Committee for Medical Research, and patient follow-up was performed from the point at which the women were diagnosed with SP during either pregnancy, childbirth or postpartum, mainly until the normalisation of blood pressure (without the need for antihypertensive medication) and proteinuria; the maximum postpartum follow-up duration was 12 weeks in cases of specialised postpartum consultation for at-risk patients.The study variables were collected at the following time points: pre-gestational; gestational; at the time of the preeclampsia diagnosis; peripartum; perinatal; upon discharge from the hospital; and at the 12-weeks postpartum consultation.p-value equal to or less than 0.20 were included in the multivariate logistic regression analysis. Results with p less than 0.05 were accepted as significant.The study data were stored in a database created for this purpose until the statistical analysis. The variables were analysed using the statistical package IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. are presented as means and SDs for quantitative variables and as number and percentages for qualitative variables. For the comparison of the variables between the study groups, we conducted a univariate analysis by logistic regression to determine the probability ratio, odds ratio (OR) and 95% confidence interval (CI). After univariate analysis, variables with clinical relevance or a During the study period, 76,828 births took place at the centre; of these, 303 were to women diagnosed with SP. The annual incidence increased gradually over the study period, reaching 1.79% births/year in 2018. During the study period, no cases of maternal death were recorded among patients with SP. AKI occurred in 75 patients (24.8%), of whom 34.66% had oliguria, with a mean serum creatinine of 1.53 ± 0.73 mg/dL and a mean urea of 58.39 ± 25.83 mg/dL. In 32% of cases, AKI was caused by CKD, and in 5.33% (4 patients), it was caused by CRF. In the AKI group, 25.33% (19 patients) developed AKI in the context of HELLP syndrome, and in 3 developed AKI in the context of haemolytic uraemic syndrome secondary to pregnancy. Twenty-one patients who developed AKI (28%) required the transfusion of packed red blood cells; 12 of these patients also had HELLP syndrome, and 3 also had haemolytic uraemic syndrome secondary to pregnancy. Only 1 patient required temporary dialysis to recover renal function.n = 303), those who developed AKI (n = 75) and those who did not develop AKI (n = 228). As Regarding the variables measured at the time of SP diagnosis, presented in Regarding variables measured intrapartum and immediately postpartum, shown in A perinatal mortality rate of 5.1% was found for all 351 neonates. A total of 64% were premature (<37 weeks of gestation), and 5.3% were extremely premature at less than 28 weeks of gestation at birth. The mean gestational age at delivery was 34 weeks. Regarding the variables measures at the time of hospital discharge, shown in After hospital discharge, 9.2% of the participants were lost to follow-up. At discharge from the postpartum risk consultation, as shown in After a maximum follow-up of 12 weeks postpartum, 25 patients (9%) without a previous history of chronic HT remained hypertensive. Similarly, 19 patients (7%) without pregestational proteinuria showed persistent postpartum proteinuria (protein/creatinine index greater than 0.3 mg/mg), and 7 patients (2.3%) had persistent AKI, including 2 who had previous CRF. After 12 weeks postpartum, 72 patients were referred to the nephrology consultation for persistent HT, proteinuria or renal failure.In the multivariate logistic regression analysis , previouOur results describe a high frequency of AKI in our series of pregnant women with SP stands out: it affects 25% of these patients and 9.76/10,000 births in our hospital-based population. In SP cases, AKI occur in the third trimester and in the immediate postpartum period, and HDP, mainly preeclampsia and HELLP syndrome, are the main causes ,20,21. OComparing to the literature, in a series of pregnancy-associated AKI in India, the researchers observed that 17% of patients with preeclampsia and 60% of patients with HELLP syndrome developed AKI . In any Seventy-five percent of cases of AKI occur in the third trimester and in the immediate postpartum period, and HDP, mainly preeclampsia and HELLP syndrome, are the main causes ,20,21. Pp = 0.02, for CRF. This result is supported by the findings of other authors [In the general population, one of the main risk factors for AKI is a history of CRF and, above all, its severity . The res authors ,28.Regarding pregnancy-related variables, a higher frequency of assisted reproductive techniques and IVF use was found among the SP patients who developed AKI than in those without AKI (32 vs. 17.1%). The risk of developing AKI was 2.28 times higher among patients with SP who underwent IVF. To date, we have not found any studies that that relate AKI to the use of assisted reproductive techniques in patients with SP, although there are studies that describe the relationship between AKI and assisted reproduction techniques in pregnant women in general ,30. Whatp < 0.001. This result is explained by the fact that uric acid is eliminated mainly by the kidneys and therefore, when SP develops and the GFR and tubular secretion decrease, uric acid levels increase [When analysing the association between the development of AKI and variables measured at the time of SP diagnosis, it was found that the mean uric acid value was significantly higher in the group with SP and AKI than in the group without AKI, 8.87 ± 1.74 vs. 6.88 ± 1.45 mg/dL, increase . Hyperurincrease ,40,41,42p < 0.01. In contrast, the aforementioned authors considered that AKI determines the risk of developing HELLP syndrome [In our series, HELLP syndrome, a form of TMA associated with pregnancy ,43,44, osyndrome . AlthougRegarding the measurement of variables at the time of delivery, we observed a statistically significant association between the development of AKI and gestational age at the time of delivery, with a higher percentage of preterm births (<37 weeks of gestation) to patients with AKI. In the meta-analysis of Liu Y et al.  mentionep < 0.01). This value is higher than that reported in the meta-analysis of Liu Y et al. [The risk of caesarean section was 3.35 times higher in the SP group with AKI than in the group without AKI . Peripartum haemorrhage is a frequent cause of AKI associated with pregnancy and is even more common than preeclampsia in some developing countries ,53,54. Sp < 0.05). The higher need for treatments for foetal lung maturation is probably linked to the greater number of newborns with a gestational age between 28 and 37 weeks in the AKI group. In our study, there was a higher percentage of SGA infants in the SP group without AKI (23.9% vs. 10.8% in the AKI group). However, no significant differences were found in the percentage of IGR. These somewhat contradictory results are reflected in the literature: the meta-analysis of Liu Y et al. [p 0.002); however, perinatal mortality in the group of pregnant women with SP and AKI was 2.7%, significantly lower than that of the group with SP without AKI (7%). This result is in disagreement with the report of Liu Y et al. [Regarding the perinatal variables, it should first be noted that the need for steroids for foetal lung maturation was 1.89 times more frequent in the SP with AKI group OR 1.89 . Uric acid, as a marker of renal risk, was maintained as a predictor of AKI, but the average haemoglobin, platelet and LDH values were not. The relationship of these analytical variables with TMA, defined as microangiopathic haemolytic anaemia and thrombocytopenia, probably justifies the loss of their statistical association with AKI, . Finally, caesarean section maintained its statistical significance, but the need for transfusion did not. The association of transfusion with TMA and postpartum haemorrhage, which is more common with caesarean delivery, may explain this result. Liu Y et al. [In the multivariate analysis performed to predict the risk of AKI, only a history of CKD, IVF, TMA (including HELLP syndrome), uric acid level and caesarean section were independently associated with the development of AKI in pregnant women with SP. CRF and pregestational proteinuria, which had a high magnitude of effect in the univariate analysis, lost their statistical significance in the multivariate analysis because both are related to CKD. When HELLP syndrome was considered in isolation outside of TMA, it also lost the ability to predict AKI, despite its important association with AKI in the univariate analysis. A likely explanation is the small sample size (Y et al.  conducteY et al. . DespiteAt the same time, they found a significantly higher risk of perinatal mortality, prematurity and SGA. Regarding the renal prognosis, they observed a 2.4% incidence of the evolution to terminal renal failure with the need for renal replacement therapy.The prognosis of AKI associated with preeclampsia is relatively good as long as there are no other associated complications, such as sepsis, DIC or severe bleeding, and most patients resume normal renal function postpartum ,50. PersThe study has limitations that are important to take into consideration when interpreting the data including a lack of other variables that were not the focus of this study, and that could provide additional information, such as ethnicity, body mass index or weight gain during pregnancy. In addition, we must clarify that since some study variables, such as the c-section, can occur before or after the appearance of AKI, as well as before or after the appearance of SP, the established causal associations must be analyzed with caution due to the fact that the temporality of the cause and effect is not fulfilled in all cases. In relation to the strengths of the study, although our results are not novel and support those obtained previously by the various studies already described in the discussion, with a large number of SP patients. All these patients were attended in a tertiary hospital in Madrid, one of the reference hospitals for obstetrics in Spain with more than 70,000 deliveries, attended over more than 11 years. Furthermore, our study analyses and compared the maternal and perinatal variables between AKI and No AKI groups.Severe preeclampsia is constantly increasing in developing countries and in those patients, AKI is a common complication, especially among those with a history of CKD, those who became pregnant using assisted reproduction techniques and in cases of caesarean section. Among biochemical and haematological markers, the uric acid level prior to the development of AKI has a direct and significant correlation with the risk of AKI in patients with preeclampsia, as does the development of TMA. Therefore, the need for strict monitoring of renal function in cases of preeclampsia should be noted.


In Group B, 18 patients underwent nominal flows CPB. Tapered CPB allowed for a mean reduction of flows of 34%. No difference in terms of blood-gas analysis, spectroscopy trend, laboratory analyses, and hospital outcome were recorded. In patients developing AKI (20%), renal damage was correlated with demographic characteristics and with renal NIRS during the first 6 h in the ICU. A safe individualized strategy for conduction of CPB, which allows significant flow reduction while maintaining normal hemodynamic and metabolic parameters, does not impact on renal function and hospital outcomes.During cardiopulmonary bypass (CPB), high flows can allow an adequate perfusion to kidneys, but, on the other hand, they could cause emboli production, increased vascular pressure, and a more intense inflammatory response, which are in turn causes of renal damage. Along with demographic variables, other intra-operative management and post-operative events, this might lead to Acute kidney injury (AKI) in infants undergoing cardiac surgery. The aim of our study was to investigate if a CPB strategy with flow requirements based on monitoring of continuous metabolic and hemodynamic parameters could have an impact on outcomes, with a focus on renal damage. Thirty-four consecutive infants and young children undergoing surgery requiring CPB, comparable as for demographic and patho-physiological profile, were included. In Group A, 16 patients underwent, for a variable period of 20 min, CPB aiming for the minimal flow that could maintain values of MVO Acute kidney injury (AKI) is one of the most common complication after congenital cardiac surgery, occurring in 6 to 50% patients, with an associated mortality ranging from 20 to 61%, based on the different diagnostic criteria adopted and the characteristics of the population studied [Historically, cardiopulmonary bypass (CPB) flows during cardiac surgery have been calculated solely on patient weight. However, as a result, CPB flows employed for pediatric patients undergoing surgery for congenital cardiac diseases are often arguably overestimated. Higher CPB flows are related to increased risk of morbidity , and a more conspicuous volume of warm venous blood returning to the operating field, which in turn can hinder both surgeon’s vision and myocardial protection). Nonetheless, decreasing flows could lead to inadequate perfusion, possibly resulting in organ damage  with prolonged and more complicated post-operative length of stay.We hypothesized that a different strategy of CPB management with tapered flows, tailored on patient’s metabolic needs measured by means of near-infrared spectroscopy (NIRS) and continuous in-line blood-gas monitoring, could help reducing detrimentally high flows safely, while monitoring end-organs necessities in real time during surgery.The aim of this work is to assess an approach, previously investigated , in termApproval for this study was granted by the institutional review board, while the families of patients qualifying for the study were asked for consent.Between May 2016 and October 2017, families of all consecutive infants and young children undergoing elective surgical repair using CPB were offered to participate in the study. A total of 34 patients’ families consented . In group B, CPB was conducted according to conventional flow parameters.In group A, CPB was managed indexing flows to the minimum value to maintain SvOBlood-gas data from CDI and CPB parameters were collected. NIRS  were registered before the operation, throughout surgery, and for a minimum of 24 h in the Intensive care unit (ICU). The pediatric-sized sensor to measure renal oximetry on the right flank overlying the right kidney were placed on arrival in the operating room, along with two frontal sensors. Demographic  and laboratory  data were collected. Risk adjustment for congenital heart surgery RACHS-1) classification  was used classifiChoice of oxygenator was based on flow requirements: Capiox® FX05  if nominal flow was lower than 1500 mL/min, with perfusion tubing system Terumo x-Coating ®  with integrated arterial filter or Dideco® Kids D101  if nominal flow was greater than 1500 mL/min, with perfusion tubing system Phisio and arterial filter D131 . Tubing prime was composed by ringer-acetate, bicarbonate, and albumin; mannitol was added if necessary. Blood was added only after Hb concentration and patient weight evaluation (blood was added in patients weighing less than 10 kg). During CPB, threshold level to add packed red blood cells to prime was hemoglobin lower than 8.5 g/dL. Vacuum assisted (up to − 25 mmHg) venous drainage use and position of the oxygenator support closest to the operative table thereby reducing tubing length, were also instrumental to further reduce prime volume. Under normothermic conditions , flow was maintained between 120 and 150 ml/kg/min. Cardioplegic arrest was induced by anterograde Buckberg cardioplegia, administering type A solution at induction (15 ml/kg/min), B1 maintenance solution every 20 min, at a temperature between 4 °C and 10 °C, and normothermic blood as a reperfusion solution before clamp release. Modified ultrafiltration was routinely applied before removal of arterial and venous cannulae.Terumo CDI 500®  was used for continuous in-line blood-gas monitoring. This system updates data every 5 s. Those data were collected into an electronic chart every 30 s, from bypass start to end. CDI was calibrated by analysing venous blood samples at bypass start and rechecked every 20 min during CPB. The assessment of cerebral metabolism was conducted by continuous rSO2 measurement from both cerebral hemispheres and renal region using NIRS technology  throughout the entire operation, recording data electronically every 5 min. We focused the analysis of our data on five distinct time frames . Patients in Group B did not undergo the 20 min period of metabolic CPB management, therefore no T2 and T3 period was considered.P-value of ≤ 0.05 was deemed statistically significant. Descriptive statistics illustrate post-operative morbidity.Continuous variables are presented as mean value ± standard deviation (SD) and categorical variables as a number or a percentage. Normal distribution of all collected data was ensured before analysis. Statistical analysis was performed using the software SPSS for Windows version 22 . Continuous variables with normal distribution were compared using a Student t-test, for variables without normal distribution, a Mann–Whithney U-test was employed; for categorical values Fischer’s Exact Test was employed. A multivariate logistic regression analysis was conducted to identify a potential independent predictor for AKI among the pre-operative and intra-operative variables. Moreover, a linear regression analysis was performed to investigate for post-operative period trends for NIRS values and laboratory parameters. For all the tests, a The proposed metabolic management of CPB allowed an overall average tapering of flows of 34%. As expected, reduction was greater in the hypothermic population (47%) and slightly less among normothermic participants (30%) Table .Table 2FWhen pre-operative characteristics were compared between the two groups Table , no sign2 to be significantly higher at the end of the 20 min period. No other parameter, including lactates, was significantly modified by the test  in patients that would develop AKI. No other NIRS value was significantly altered at any of the time points of our study. Moreover, aside from the expected significant increase in creatinine values, no other laboratory parameter measured was different between patients affected by AKI and unaffected ones.Seven cases of AKI were identified . Only the KDIGO criteria for serum creatinine change were used (at least 1.5 times baseline or at least 26.5 µmol/l increase), since liberal use of diuretics could have otherwise biased our analysis. Comparison between patients presenting AKI with the unaffected ones allowed to identify some significant differences regarding, mostly, demographic parameters . When the parameters that performed better  were included in a multiple regression model, the model returned an AIC of 25.88 and consequently a p value of 0.001.In a logistic regression, among the pre-operative characteristics, NIRS measurements and perfusion parameters, only renal NIRS 6 h after surgery were a significant independent predictor for developing renal injury  required a pharmacological inotropic support higher than 0.05 mcg/Kg/min longer than 24 h, two patients needed mechanical life support , eight patients needed prolonged (greater than 96 h) mechanical respiratory support , seven manifested organ infection , requiring prolonged (14 days) antibiotic therapy, two patients presented recurrent pleural effusions (group B), three patients required dialysis , and no patient needed re-exploration for bleeding  are being considered for the early detection of renal injury. Nonetheless, it has been shown how renal NIRS recorded intraoperatively may perform better than said biomarker in detecting AKI . Our resThe efficacy of near-infrared spectroscopy is nowadays widely appreciated in everyday practice in adult cardiac surgery, since the first reporting of this methodology by Jobsis  in 1977 2), therefore offering a higher prognostic value [2 can evaluate these data in the whole body. Moreover, ScvO2 allows to overcome some intrinsic limitations of NIRS monitoring, such as inter- and intra- individual variability, falsely low values secondary to agitation or to regional anomalies  and the absence of threshold for normative data.In the presented experience, frontal NIRS and renal NIRS measurements were combined. In fact, as Gil Anton and colleagues showed combined NIRS correlate better with hemodynamic measurement  period plays a major role in the genesis of renal injury, at least on par with the operative period, since no significant difference in blood-gas analysis and spectroscopy data between the two groups despite the different CPB management strategy could be identified. The role of renal spectroscopy in the timely diagnosis of AKI is particularly promising, as supported by similar studies , in whicLimitations to our work comes from the small sample considered and the intrinsic heterogeneity of conditions in our population; however, we believe that tighter exclusion criteria would have been detrimental to the analysis of outcomes by hindering the comparison with the ordinary population treated in our Unit.No urinary biomarker was employed in our investigations; nonetheless these are not yet considered in KDIGO guidelines and, once again, our aim was to perform an analysis that could be close to the clinical routine of laboratory exams.Further multicenter studies considering a higher number of patients would be highly beneficial to assess outcomes and would prove useful to cost–benefit analysis concerning NIRS employ, a matter as of today, yet to be investigated.


Pulse transit time and pulse wave velocity (PWV) are related to blood pressure (BP), and there were continuous attempts to use these to predict BP through wearable devices. However, previous studies were conducted on a small scale and could not confirm the relative importance of each variable in predicting BP.This study aims to predict systolic blood pressure and diastolic blood pressure based on PWV and to evaluate the relative importance of each clinical variable used in BP prediction models.This study was conducted on 1362 healthy men older than 18 years who visited the Samsung Medical Center. The systolic blood pressure and diastolic blood pressure were estimated using the multiple linear regression method. Models were divided into two groups based on age: younger than 60 years and 60 years or older; 200 seeds were repeated in consideration of partition bias. Mean of error, absolute error, and root mean square error were used as performance metrics.The model divided into two age groups (younger than 60 years and 60 years and older) performed better than the model without division. The performance difference between the model using only three variables  and the model using 17 variables was not significant. Our final model using PWV, BMI, and age met the criteria presented by the American Association for the Advancement of Medical Instrumentation. The prediction errors were within the range of about 9 to 12 mmHg that can occur with a gold standard mercury sphygmomanometer.Dividing age based on the age of 60 years showed better BP prediction performance, and it could show good performance even if only PWV, BMI, and age variables were included. Our final model with the minimal number of variables  would be efficient and feasible for predicting BP. High blood pressure (BP) is the leading cause of cardiovascular disease (CVD) such as coronary artery disease, stroke, heart failure, peripheral artery disease, and many kinds of microvascular disease. Furthermore, hypertension accounts for more CVD deaths than any other modifiable CVD risk factors. Most countries have published their own definition of hypertension and treatment guidelines. Those guidelines emphasize controlling BP in patients with hypertension because it can prevent CVD and reduce mortality according to a large amount of evidence -3. For dWe can measure BP with many kinds of devices in an office setting and an out-of-office setting. However, BP varies with many factors such as cuff size and patient’s position. Ambulatory BP monitoring with automated and programmable inflating cuff for 24 hours is considered as the reference standard BP since this method can rule out whitecoat hypertension or masked hypertension and measure nocturnal BP -10. AlthThe aim of this study is to develop BP prediction models with PWV in a large sample size of 1362 patients and to evaluate the relative importance of each clinical variable used in BP prediction models.2) squared. Venous blood samples for high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, glucose, hemoglobin A1c (HbA1c), creatinine, and C-reactive protein (CRP) were collected after 12-hour overnight fasting. Diabetes mellitus was defined as treated with diabetes medication, HbA1c≥6.5%, or fasting glucose ≥126 mg/dL.This study was conducted on men older than 18 years who had a health medical examination at the Samsung Medical Center from January 2014 to December 2015 and conducted a test of the brachial-ankle PWV calculated by PTT. Among them, 1362 patients who were not taking antihypertensive medications or alpha-blockers for treating benign prostate hypertrophy were recruited for data analysis since these medications can affect PWV. Data was extracted from the Clinical Data Warehouse Darwin-C of Samsung Medical Center for this study. This study was approved by the Institutional Review Board (IRB) of the Samsung Medical Center (IRB number 2016-02-142). Each participant prepared a self-assessment questionnaire that included a past medical history, medication history, and smoking status. Smoking status was divided into three groups: nonsmokers, ex-smokers, and current smokers. Anthropometric measurements including body weight and height were performed with light clothing, and the BMI was calculated as weight (kg) divided by height  in the supine position with cuffs placed on both arms and ankles. They measure bilateral brachial and posterior tibial artery pressure waveform using an oscillometric method. PWV was calculated automatically with the distance from the heart to the ankle and the distance from the heart to the upper arm (L) divided by the pulse wave propagation time (PTT).BP was obtained simultaneously with PWV measurement. Systolic BP (SBP) and diastolic BP (DBP) were defined as the average of pressures in both arms. Normotension was defined as SBP<140 mmHg and DBP<90 mmHg. Hypertension was defined as SBP≥140 mmHg or DBP≥90 mmHg.t test, and categorical variables were compared frequencies through chi-square tests.Continuous variables were presented as means and SDs, and categorical variables were reported as percentages. Continuous variables were compared means between two groups using the Student A total of 1362 participants were recruited in the model development cohort, and they were split up into the train and validation sets in a ratio of 7:3. The model development cohort repeated 200 different random seeds considering the effect of partition bias. The validation cohort was chosen randomly by selecting 100 patients each from the age group younger than 60 years and 60 years and older by stratifying age and BMI. Since BP and prostate medications can affect PWV, these patients were excluded. After Spearman correlation was conducted for 33 variables, including PWV, age, questionnaires, physical information, and chemistry electrolyte tests, 17 variables with absolute values of correlation numbers of 0.5 or less were selected to exclude multicollinearity. The BP prediction model used multilinear regression analysis, and this study compared the performance of the model based on the total age  and the model made by dividing it into two age groups based on the age of 60 years , smoke status, white blood cell count (WBC), hemoglobin, uric acid, sodium, potassium, LDL, HDL, triglyceride, testosterone, creatinine, CRP, and diabetes into model 2. Two sample analysis . For theanalysis ,15. All Based on the data of 1362 adult males older than 18 years in this study, the baseline clinical characteristics of study participants are shown in P<.001, one-sample t test). When estimating DBP with algorithm 1, underestimation occurred in the younger than 60 years group, and overestimation was only performed on model 1 for those 60 years and older. In algorithm 1, model 1 had the worst performance. The average of the mean of error was significantly smaller when algorithm 2 was applied in SBP forecasts compared to algorithm 1. In the case of DBP prediction, the average of the mean of error was significantly lower when algorithm 2 was applied in comparison to algorithm 1 in the younger than 60 years age group.From the view of RMSE, the performance of model 2 with the condition of age <60 years was better in algorithm 2 than in algorithm 1. The performance of model 2 with the condition of age ≥60 years was not significantly different between algorithms 1 and 2 . When coAfter considering all the aforementioned, we selected model 2 based on algorithm 2 as the best prediction model. To evaluate the performance of the final prediction model, criteria provided by the AAMI and the BHS were applied. All of AAMI’s criteria were satisfied, and BHS’s criteria were only met by the 60 years or older DBP with class A. Although our prediction model did not meet the BHS criteria, it is still within acceptable range for clinical use according to AAMI’s protocol .About 30% of the world’s deaths are caused by CVD . Among tMost people measure BP in the office, but the office BP is relatively inaccurate compared to other measurement methods due to many factors such as cuff size, patient’s position, and emotional state. Therefore, recent guidelines recommend other methods of BP measurement such as ambulatory or home BP monitoring ,20. HoweRecently, continuous BP monitoring with PTT and PWV was developed to compensate for the weaknesses of conventional BP measurement methods. Many attempts have been made using wearable devices attached to chest, ear, or wrist for continuous monitoring. However, previous studies were small in a sample size of less than 500 patients, and there was no study to evaluate the relative importance of clinical variables in predicting BP. We made BP predicting models using PWV and clinical data based on a large-scale population of over a thousand and evaluated the relative importance of the clinical variables.After creating various types of BP predicting models, we concluded that the performance of the models was better in age-based stratification since the cardiovascular system changes as the age increases. The prevalence of hypertension is 30% to 45% in adults, and hypertension becomes progressively more common with age. Over 60% of people aged older than 60 years are diagnosed with hypertension . MoreoveAlthough the exact etiology of primary hypertension remains unclear, a number of risk factors are strongly and independently associated with its development, including not only age but also race, family history, obesity, diet, and physical activity ,25. In aOur final model, model 2 in algorithm 2, satisfied the criteria of the AAMI by the mean of error, although it did not meet the criteria of the BHS in absolute pressure difference. The prediction errors were within the range of about 9 to 12 mmHg that can occur with a gold standard mercury sphygmomanometer. According to a previous validation survey by O’Brian et al , only a In conclusion, stratification of age is important in developing a BP prediction model with better accuracy. In addition, BP is influenced predominantly by PWV, BMI, and age out of other clinical factors. Our final model with minimal number of variables would be efficient and feasible for predicting BP.This analysis was conducted among healthy male participants. The study population included patients that were hypotensive and hypertensive but excluded those taking antihypertensive drugs. Further studies should be warranted on a diverse population, including patients on antihypertensive medications and female participants, and on the performance of PWV in wider range of BPs.The Health Promotion Center at Samsung Medical Center does not request detailed medication information except for hypertensive medication on the personal questionnaire for health checkup. Receiving additional information on medication is impossible, as this is a retrospective study. Accordingly, there is some limitation in analyzing the effects of different types of medication such as alpha-blockers or calcium channel blockers. Further studies are needed including drug information.Our prediction model was internally validated; however, this model should be validated externally.