Severe Kidney Dysfunction Research Articles

Influence of baseline kidney dysfunction on perioperative renal outcomes after endovascular aneurysm repair with suprarenal fixation

BackgroundConflicting evidence exists regarding the comparative effects of endovascular aneurysm repair (EVAR) with and without suprarenal fixation. We compare outcomes in patients treated by EVAR with baseline normal kidney function and moderate and severe chronic kidney disease. MethodsPatients with normal kidney function (glomerular filtration rate [GFR] ≥60 mL/min/1.73 m2) or moderate (GFR = 30-59 mL/min/1.73 m2) or severe (GFR <30 mL/min/1.73 m2) kidney disease who underwent EVAR (N = 5534) were identified from the American College of Surgeons National Surgical Quality Improvement Program targeted database (2011-2015). Groups were determined by the presence (Cook Zenith [Cook Medical, Bloomington, Ind] or Medtronic Endurant [Medtronic, Minneapolis, Minn]) or absence (Gore Excluder [W. L. Gore & Associates, Flagstaff, Ariz]) of a suprarenal fixation system. Postoperative renal complications, defined as rise in creatinine concentration of >2 mg/dL without dialysis or new dialysis requirements, were analyzed within the first 30 days with results stratified by degree of kidney disease. ResultsA total of 5534 patients underwent EVAR, with 3225 (58.3%) receiving a device using a suprarenal fixation system. Suprarenal fixation systems were less commonly used for symptomatic patients (11.0% vs 13.7%; P = .002) and patients with ruptured abdominal aortic aneurysm (4.5% vs 6.3%; P = .01). There was no difference in baseline kidney function between groups. EVAR with suprarenal fixation was associated with more renal complications (1.40% vs 0.65%; P = .008). In subgroup analysis, patients with moderate kidney dysfunction (n = 1780) had more renal complications (2.2% vs 0.8%; P = .02) with suprarenal fixation systems. No differences were seen in patients with normal kidney function (0.4% vs 0.2%; P = .32; n = 3597) or severe kidney dysfunction (14.3% vs 10.2%; P = .45; n = 157). This difference was driven mostly by postoperative elevation of creatinine concentration (0.6% vs 0.2%; P = .03) without requirements for new dialysis (0.8% vs 0.4%; P = .08). After adjustments with multivariate logistic regression models, EVAR with suprarenal fixation was associated with more renal complications (odds ratio, 2.65; 95% confidence interval, 1.32-5.34). ConclusionsIn our study, EVAR with suprarenal fixation devices was associated with more perioperative renal complications in patients with moderate kidney dysfunction. Long-term evaluation of these patients undergoing EVAR should be considered.

SUN-196 Persistent Hyperkalemia After Unilateral Adrenalectomy for Aldosteronoma

IntroductionFollowing unilateral adrenalectomy, some patients experience persistent hyperkalemia. This has been attributed to hypoaldosteronism due to severe suppression of aldosterone synthesis in the contralateral adrenal gland. Additionally, excess aldosterone leads to glomerular hyperfiltration masking kidney dysfunction, which can then manifest after cure with CKD-related hyperkalemia.Case PresentationWe report a case of 51-year-old male who was diagnosed with hypertension in his late 30s. He required a beta-blocker and calcium channel blocker (CCB) for 10 years, and eventually developed hypertensive nephropathy. With worsening lower extremity edema, he was switched from a CCB to an angiotensin receptor blocker. Soon afterwards, he presented with hypertensive emergency and was discovered to have significant hypokalemia (K 2.1 mmol/L), prompting work up for primary aldosteronism.Biochemical evaluation revealed an elevated aldosterone to renin ratio of 38 [(ng/dL)/(ng/mL/hr)] and adrenal protocol CT scan revealed a 1.9 cm left adrenal nodule with benign characteristics. Adrenal vein sampling showed marked lateralization of excess aldosterone to the left adrenal gland, with proper catheter placement demonstrated in each adrenal veins (5-fold cortisol gradient bilaterally). He was started on spironolactone and 6 weeks later, underwent an uncomplicated laparoscopic left adrenalectomy. Spironolactone was discontinuedSerum K level was normal at 4.8 mmol/L immediately postoperatively. Ten hours later, his K went up to 6.6 mmol/L which was confirmed by repeat blood work, accompanied by worsened renal function (Cr 2.5 mg/dL up from a of baseline 2.0). His hyperkalemia persisted in the 5.0 – 6.0 range despite IV Calcium Gluconate, Insulin and D50. Oral potassium binders were avoided due to concerns about ileus. Upon recognition of the possibility of hypoaldosteronism, we recommended a NaHCO3 gtt, with subsequent normalization of serum K. We avoided initiating fludrocortisone in the short term, due to uncertainty about duration of hypoaldosteronism, & because he was still requiring two antihypertensive agents. Plasma aldosterone 2 wks after surgery was fully suppressed, confirming suspicion of hypoaldosteronism. He has been managed successfully with oral sodium bicarbonate tablets, remaining normokalemic at 3 weeks post-surgery.Conclusion:Here we present a case of persistent hyperkalemia following resection of a signficantly biochemically active and long-standing aldosteronoma, which was successfully managed with sodium bicarbonate. We attribute the post-operative hyperkalemia in this patient to a combination of hypoaldosteronism due to deep suppression of the mineralocorticoid production of the contralateral adrenal, as well as unmasking of more severe kidney dysfunction than was he previously thought to have once aldosterone excess was withdrawn.

Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis

Ras homolog enriched in brain (Rheb1), a small GTPase, plays a crucial role in regulating cell growth, differentiation, and survival. However, the role and mechanisms for Rheb1 in tubular cell survival and acute kidney injury (AKI) remain unexplored. Here we found that Rheb1 signaling was activated in kidney tubule of AKI patients and cisplatin-treated mice. A mouse model of tubule-specific deletion of Rheb1 (Tubule-Rheb1−/−) was generated. Compared to control littermates, Tubule-Rheb1−/− mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death including apoptosis, necroptosis and ferroptosis, mitochondrial defect and less PGC-1α expression after cisplatin injection. In primary cultured tubular cells, Rheb1 ablation exacerbated cisplatin-induced cell death and mitochondrial defect. Furthermore, haploinsufficiency for Tsc1 in tubular cells led to Rheb1 activation and mitigated cisplatin-induced cell death, mitochondrial defect and AKI. Together, this study uncovers that Rheb1 may protect against cisplatin-induced tubular cell death and AKI through maintaining mitochondrial homeostasis.

Double Filtration Plasmapheresis in the Treatment of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis with Severe Kidney Dysfunction

Background: Therapeutic plasma exchange (TPE) has been recommended by guidelines for the treatment of anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) with severe kidney dysfunction. In recent years, some researchers have proposed that double-filtration plasmapheresis (DFPP) can also be used effectively in the treatment of these patients, but the difference between the 2 modalities of plasmapheresis is not clear. Methods: In this retrospective cohort study of AAV patients with serum creatinine ≥500 μmol/L from March 2013 to July 2018 who received TPE or DFPP treatment, we compared TPE and DFPP in terms of the changes of clinical parameters before and after plasmapheresis, the rates of adverse events during plasmapheresis, and kidney and patient survival during follow-up. Results: Forty-two AAV patients with kidney injury were included in this study. Twenty patients were treated with TPE and 22 patients were treated with DFPP. All patients were followed up for a median of 22 months. In each group, there were 10 deaths, and 6 patients developed end-stage kidney disease (ESKD). There were no significant differences between TPE and DFPP in terms of the changes of renal function or other laboratory results after treatment. During the plasmapheresis treatment, there was no significant difference in the rate of adverse events (p = 0.67). During the follow-up, there was no difference between the groups regarding the level of serum creatinine for patients with kidney recovery. The hazard ratio (HR) for TPE compared to DFPP for the outcome of ESKD was 0.92 (95% CI 0.45–1.9; p = 0.79) and the HR for death was 1.11 (95% CI 0.45–2.76; p = 0.82). Conclusion: There were no differences in short-term effectiveness, safety, or long-term outcomes between the 2 modalities of plasmapheresis. Our study suggests that DFPP may be a choice of plasmapheresis for AAV patients with severe kidney injury especially in countries and regions with limited blood resources.

The Prognostic Importance of Perioperative Renal Function and Outcome of Patients Undergoing Heart Transplantation

We aimed to investigate prognosis of heart transplanted (HTx) patients who experienced RRT in perioperative period. Korean Organ Transplant Registry (KOTRY) is nationwide, organ transplant registry in Korea. We reviewed 501 HTx patients prospectively enrolled in KOTRY. Among them, 13 patients who underwent combined heart and kidney transplantation (HKTx). Remaining patients were grouped as follows; Gr 1: Patients who were free of periop RRT. Gr 2: patients who required preop RRT but not postop RRT. Gr 3: patients who were free of preop RRT but necessitated postop RRT, Gr 4: patients who needed both preop and postop RRT. Postoperative RRT was defined as the need for dialysis after HTx during postoperative management. The primary outcome was dialysis dependent end-stage renal disease (ESRD). The secondary outcome was overall mortality. Follow up duration was 22 months (9-39 month). Gr 4 pateints had significantly more ischemic heart disease, but less idiopathic DCMP. Patients who needed preop RRT (Gr 2 and 4) had higher incidence of DM. Significantly more patients who needed preop RRT (Gr 2 and Gr 4) experienced preHTx mechanical cardiac support and ventilator (p <0.001). Significantly more patients in G4 remained to be dialysis dependent ESRD (p<0.001) (Fig 1). Gr 4 patients had significantly higher mortality compared to rest of patients (Fig 2). Patients who underwent HKTx showed comparable survival rates (4 YR survival rates: 92.3%) with Gr 1. Gr 2 patients also showed comparable survival rates with Gr 1 (4 YR survival rates: 94.1%). We suggested that HF patients on HTx waiting list with severe kidney dysfunction requiring RRT still should be considered for HTx. Among patients who needed preopRRT, those who did not require postop RRT showed comparable survival rates to pateints who were free of periop RRT. Also, those with ischemic HF and DM with severe renal dysfunction requiring preoperative RRT should be considered for HKTx to improve post HTx outcome.

Kidney dysfunction is associated with risk of cardiovascular events in middle-aged and elderly population with hypertension: A5-yearcommunity-based cohort study in China .

To evaluate the association between kidney dysfunction and cardiovascular disease (CVD) events in a middle-aged and elderly population in China. In July 2009, a baseline survey of health status was performed in adults aged 55 years and older from Beijing, China. Occurrence of CVD events and mortality in subjects free of CVD at baseline was recorded in a 5-year follow-up period until December 2014. The association of mild (eGFRCKD-EPI 45 - 59 mL/min/1.73m2) and moderate to severe (eGFRCKD-EPI < 45 mL/min/1.73m2) kidney dysfunction with adverse outcomes were analyzed with Cox regression analysis. A total of 1,257 subjects were included in the final analysis. The risk of CVD events in those with mild kidney dysfunction increased by 65% (HR: 1.65, 95% CI: 1.04-2.62) as compared to those with normal kidney function. Subjects with both hypertension and CKD experienced more significantly increased risk of CVD events (adjusted HR = 1.87, 95% CI 1.17-2.97) and stroke (adjusted HR = 2.24, 95% CI 1.24-4.04). Pulse pressure (PP) ≥60 mmHg was the strongest risk factor for stroke in patients with CKD, with the adjusted HR value of 1.98 (95% CI 1.08-3.64). Moderate to severe kidney dysfunction was an independent risk predictor of CVD events. Among subjects with hypertension or poorly controlled blood pressure level, the presence of CKD significantly increased the risks of CVD events and stroke.

SWEDEHEART-1-year data show no benefit of newer generation drug-eluting stents over bare-metal stents in patients with severe kidney dysfunction following percutaneous coronary intervention.

We hypothesized that the transition from bare-metal stents (BMS) to newer generation drug-eluting stents (n-DES) in clinical practice may have reduced the risk also in patients with kidney dysfunction. Observational study in the national SWEDEHEART registry, that compared the 1-year risk of in-stent restenosis (RS) and stent thrombosis (ST) in all percutaneous coronary intervention treated patients(n = 92 994) during 2007-2013. N-DES patients were younger than BMS, but had more often diabetes, previous myocardial infarction, previous revascularization and were more often treated with potent platelet inhibition. N-DES versus BMS, was associated with lower 1-year risk of RS in patients with estimated glomerular filtration rate (eGFR) >60 with a cumulative probability of 2.1% versus 5.3%, adjusted hazard ratio 0.30, 95% CI (0.27-0.34) and with eGFR 30-60: 3.0% versus 4.9%; hazard ratio 0.46 (0.36-0.60) but not in patients with eGFR <30: 8.1% versus 6.0%; hazard ratio 1.32 (0.71-2.45) (pinteraction = 0.009) as well as lower risk of ST for eGFR >60 and eGFR 30-60: 0.5% versus 0.9%; hazard ratio 0.52 (0.40-0.68) and 0.6% versus 1.3%; hazard ratio 0.54 (0.54-0.72) but not for eGFR <30; 2.1% versus 1.1%; hazard ratio 1.49 (0.56-3.98) (pinteraction = 0.027). N-DES is associated with lower 1-year risk of in-stent restenosis and stent thrombosis in patients with normal or moderately reduced kidney function but not in patients with severe kidney dysfunction, where stenting is associated with worse outcomes regardless of stent type.

Activation of TFEB-mediated autophagy by trehalose attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury.

Aims: Cisplatin, an anticancer drug, always leads to nephrotoxicity by causing mitochondrial dysfunction. As a major mechanism for cellular self-degradation, autophagy has been proven to protect against cisplatin-induced acute kidney injury (AKI). Based on the activation of autophagy induced by trehalose, we aimed to investigate the nephroprotective effects of trehalose on cisplatin-induced AKI and its underlying mechanisms.Results: Due to the activation of autophagy, mitochondrial dysfunction (mitochondrial fragmentation, depolarization, reactive oxygen species (ROS), and reduced ATP generation) and apoptosis induced by cisplatin were markedly inhibited in trehalose-treated HK2 cells in vitro. Based on the transcriptional regulation role of transcription factor EB (TFEB) in autophagy and lysosome, we characterized trehalose-induced nuclear translocation of TFEB. Furthermore, consistent with trehalose treatment, overexpression of TFEB inhibited cell injury induced by cisplatin. However, the protective effects of trehalose were largely abrogated in tfeb-knockdown cells. In vivo, cisplatin injection resulted in severe kidney dysfunction and histological damage in mice. Trehalose administration activated TFEB-mediated autophagy, alleviated mitochondrial dysfunction and kidney injury in AKI mice.Innovation and conclusion: Our data suggest that trehalose treatment preserves mitochondria function via activation of TFEB-mediated autophagy and attenuates cisplatin-induced kidney injury.

Relationship of cutaneous manifestations with inflammatory markers in diabetic nephropathic patients on haemodialysis

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Diabetic nephropathy is a serious life threatening complication of type-2 diabetes mellitus. Apart from severe kidney dysfunction these patients are prone to various cutaneous complications including psoriasis and eczema due to accumulated nitrogenous waste products. Inflammation is the basic cause of cutaneous complications and many inflammatory markers have been shown elevated in chronic kidney dysfunction. Hence a study has been planned to assess the levels of inflammatory markers such has C-reactive protein (CRP) and interlukin-6 (IL-6) as well as to correlate these markers with creatinine levels along with existing cutaneus complications.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; The study included 50 diabetic nephropathic patients undergoing regular heamodialysis. A heparanised blood sample was collected and plasma was employed for estimation of glucose, creatinine, CRP and IL-6. A detailed dermatological examination was done to record the cutaneous complications like pruritis, xerosis, hyper pigmentation and half &amp;amp; half nails.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; The results show a significant raise in CRP and IL-6 levels in proportion to the severity of kidney dysfunction as reflected by creatinine levels. Also a positive relationship was observed between the inflammatory markers and multiplicity of cutaneous complications.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; It can be concluded from the present study that evaluation of inflammatory markers, CRP and IL-6 along with creatinine is beneficial in controlling cutanious complications in DN patients undergoing regular heamodialysis.&lt;/p&gt;

TAK1 deficiency attenuates cisplatin-induced acute kidney injury.

Cisplatin can cause acute kidney injury (AKI), but the molecular mechanisms are not well understood. The objective of the present study was to examine the role of transforming growth factor-β-activated kinase-1 (TAK1) in the pathogenesis of cisplatin-induced AKI. Wild-type mice and proximal tubule TAK1-deficient mice were treated with vehicle or cisplatin. Compared with wild-type control mice, proximal tubule TAK1-deficient mice had less severe kidney dysfunction, tubular damage, and apoptosis after cisplatin-induced AKI. Furthermore, conditional disruption of TAK1 in proximal tubular epithelial cells reduced caspase-3 activation, proinflammatory molecule expression, and JNK phosphorylation in the kidney in cisplatin-induced AKI. Taken together, cisplatin activates TAK1-JNK signaling pathway to promote tubular epithelial cell apoptosis and inflammation in cisplatin-induced AKI. Targeting TAK1 could be a novel therapeutic strategy against cisplatin-induced AKI.

A rare case of propofol related infusion syndrome in a neurosurgical patient

Background: For the last three decades propofol has been used in anaesthesia and as a sedation technique. Several reports have warned about its use in higher doses for prolonged durations as it can have severe side effects such as propofol related infusion syndrome (PRIS), which can be fatal.1,2,3 PRIS is a rare and complex clinical condition characterized by severe metabolic acidosis, rhabdomyolysis, cardiac, liver and kidney dysfunction, and lipidemia. In its advanced stage PRIS can lead to severe refractory bradycardia and asystole.4,5 Propofol and remifentanil total intravenous anaesthesia (TIVA) is a popular anaesthesia technique. The target controlled infusion (TCI) gives predicted and controlled drug concentration and has added to the increased use of TIVA. Not much literature is available about the use of propofol and remifentanil TIVA and occurrence of PRIS. We report a case of PRIS in a neurosurgical patient with history of dyslipidemia. Case presentation: A 46-year old man weighing 68 kg, with a known case of hyperlipidemia, presented with decreased hearing on the left side, headache, and perioral numbness. Computerized tomography (CT) of the head showed left cerebropontine angle cystic lesion. His home medications were oral sodium chloride 1200 mg three times daily and pravastatin 20 mg once daily. He was electively scheduled for surgery under general anaesthesia, which lasted for seven hours. He received a TCI with propofol and remifentanil. He remained hemodynamically stable throughout the procedure.Over 7 hours the patient received a total of 3332 mg of 1% propofol, remifentanil TCI 3–4 mcg/ml, ephedrine 18 mg, mannitol 20%–250 ml, pancuronium 16 mg, vecuronium 25 mg, cefazoline 2 g, dexamethasone 16 mg, neostigmine 5 mg, glycopyrolate 1 mg, and labetalol 25 mg. He received 2 liters of crystalloid and one liter of colloid during the surgery. Intra-operative blood sugar remained around 6–7 mmol/L and his central venous pressure was maintained between 8–11 mmHg.His first arterial blood gas showed increasing lactate and metabolic acidosis after two hours of anaesthesia and it continued to rise till the end of surgery. He was extubated and shifted to the surgical intensive care unit (SICU) with a Glasgow Coma Score of 15, spontaneously breathing and with stable hemodynamics. The serum lactate continued to rise in SICU for the first 12 hours and then slowly started to decline (Figure 1). A graph of the trends of carbon dioxide and serum bicarbonate levels is shown in Figure 2. The triglycerides level reached 11.46 (Figure 3), creatine kinase 1852 U/L and myoglobin 474 ng/ml which showed decline within the next 24 hours.He remained hemodynamically stable with adequate urine output. On day one we resumed atorvastatin 20 mg, labetalol prn, bicarbonate infusion. After 24 hours, his lactate levels were normalized and acidosis resolved. The patient was discharged without any complications.Conclusion: Propofol TIVA with TCI is a common anesthesia practice. In a known dyslipidemic patient it will increase the risk for PRIS. In our patient, other risk factors for development of PRIS were higher dose, neurosurgical procedure, and extended duration of propofol infusion. The authors believe it is the first case of PRIS in a dyslipidemic patient undergoing neurosurgery with TIVA.

Brain-derived neurotrophic factor is related with adverse cardiac remodeling and high NTproBNP

The brain-derived neurotrophic factor (BDNF) is a neuronal growth factor essential for normal cardiac contraction and relaxation. Alterations in BDNF signaling are related to the development of cardiovascular disease. Whether BDNF is related to subclinical cardiac remodeling is unclear. We related BDNF with echocardiographic parameters and NTproBNP in a large population-based cohort (n = 2,976, median age 48 years; 45% male). Transthoracic echocardiography was performed on all subjects and BDNF was measured by ELISA. Study participants with severe kidney dysfunction, previous myocardial infarction, and LV ejection fraction <40% were excluded. Linear regression models were adjusted for age, sex, lean mass, fat mass, current smoking, systolic blood pressure and depression. Low BDNF was associated with high NTproBNP. A 10,000 pg/ml lower BDNF was related with a 2.5 g higher (95%-confidence interval [CI]: 0.2 to 4.9; p = 0.036) LV mass, 0.01 cm posterior wall thickness (0.003 to 0.022; p = 0.007) and 0.02 E/A ratio (0.003 to 0.042, p = 0.026). Here we show that low BDNF levels are related with adverse cardiac remodeling and higher levels of NTproBNP. Further research is warranted to assess if BDNF may be used to monitor neuronal-cardiac damage during CVD progression.

P3614Impact of renal dysfunction in patients with acute myocardial infarction on early management and outcome: a first observational French study

Abstract Background Kidney dysfunction (KD) is largely associated to cardiovascular mortality. Purpose Analyse early management and outcome in real life of ST segment elevation myocardial infarction (STEMI) patients with KD compared to STEMI patients with normal renal function. Methods Using 10 years' data from OSCAR regional registry, we investigated the early management and outcome of all patients with STEMI. Kidney dysfunction (KD) has been defined by creatinine clearance (CrCl) &lt;90mL/min and was assessed using Cockcroft-Gault (CG) equation. Among them, two groups were identified: patients with normal kidney function (NKF) (CrCl ≥90mL/min) and patients with KD (CrCl &lt;90mL/min). KD patients were stratified into 3 groups: patients with mild KD (CrCl 60–90mL/min), patients with moderate KD (CrCl 30–60mL/min) and patients with severe KD (CrCl &lt;30mL/min). The comparison of the groups concerned patient characteristics, therapeutic strategy and follow-up at 1, 6 and 12 months. Results Our study included 8 003 STEMI patients from 2009 to 2018, 4 234 (52.9%) of them with KD. Among these, 2441 (57.6%) patients had mild KD, 1494 (35.3%) moderate KD and 299 (7.1%) severe KD. NKF patients were younger than KD group (54 [48–61] vs 72 [63–81]). KD patients had more cardiovascular risk factors such as diabetes, hypertension and personal history of coronary disease (p&lt;0.001), but were less smokers (p&lt;0,001). KD patients presented less often chest pain, and more dyspnea or cardiac arrest (p&lt;0,001). There was no difference in symptom-first medical contact delay (p=0.30). More than 14% of patients with KD presented with Killip≥2. In the KD group location of infarction was more often anterior and lateral. In-hospital treatment differed among the groups: KD patients received less prasugrel (11% vs 20%), ticagrelor (44% vs 49%), enoxaparin (70% vs 80%), morphine (29% vs 39%) or other analgesic (30% vs 35%), but more clopidogrel (33% vs 23%), diuretics (3% vs 0,7%) and catecholamines (5% vs 2%) (p&lt;0.001). In-hospital mortality was higher in the KD group (9% vs 1%, p&lt;0.001). One-year mortality was 14% in the KD group compared to 2% for patients with NKF (p&lt;0.001). Also, in-hospital mortality was increasing exponentially with KD severity (2%, 8% and 24% for mild, moderate and severe KD) (p&lt;0,001) as well as 1-year mortality (respectively 1%, 6% and 12% after 1 year) (p&lt;0,001). Conclusion Kidney insufficiency is an independent risk factor for death in patients after myocardial infarction and was associated with poor prognosis at short- and long-term. We observed that mortality increased with KD severity. Despite a high cardiovascular risk, KD patients presenting STEMI are less likely to receive therapy, while having more co-morbidities and extended infarction. To achieve an optimal medical care of KD patients with STEMI, we should introduce evidence-based therapies in the acute phase.

P872Activity of nonspecific systemic inflammation and biochemical markers of endothelial dysfunction as the criteria of coronary heart disease destabilization

Abstract Introduction Nonspecific systemic inflammation (NSSI) as well as endothelial dysfunction (EDF) plays an important role in the development and progression of coronary heart disease (CHD). Its exacerbation can cause the atherosclerotic plaque damage and the CHD progression with development of atherothrombotic complications. Purpose To evaluate the activity of nonspecific systemic inflammation and biochemical markers of endothelial dysfunction and their diagnostic significance in CHD patients as the criteria of disease destabilization. Methods The study included 173 CHD patients (the average age was 57.24±5.12 years). 92 patients were with stable angina (45 with 2nd and 47 with 3rd functional classes) and 81 patients were with acute coronary syndromes (ACS) (43 with unstable (progressive) angina and 38 – with acute myocardial infarction). The study excluded patients with severe chronic heart failure, liver and kidney dysfunction, acute or chronic inflammatory diseases, diabetes mellitus, severe obesity, infectious diseases. The control group included 30 healthy subjects (average age was 55.37±4.82 years). Activity of NSSI was assessed by the concentration of high sensitive C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α) and pregnancy-associated plasma protein A (PAPP-A) as a marker of endogenic destruction, which were determined by ELISA. EDF was assessed by the concentration of endothelin-1 (ET-1) and soluble vascular cell adhesion molecules (sVCAM) using ELISA method. Results CHD patients were characterized by significant increasing of hsCRP, TNF-α, PAPP-A levels regarding to control group (5.29±0.19 and 0.87±0.04 mg/L for hsCRP, respectively, p&lt;0.001; 4.28±0.18 and 1.18±0.07 ng/mL for TNF-α, respectively, p&lt;0.001; 9.81±0.16 and 3.12±0.42 mIU/L for PAPP-A, respectively, p&lt;0.01), which was the evidence of NSSI activation. Levels of both ET-1 and sVCAM-1 in CHD patients were more than twice higher than in the control group (9.89±0.28 and 4.01±0.36 ng/mL for ET-1, respectively p&lt;0.001; 1442.9±25.3 and 626.0±34.1 ng/mL for sVCAM, respectively, p&lt;0.001). Levels of biochemical markers of both NSSI and EDF increased with an increase in disease severity (p&lt;0.01) and the most severe changes were in patients with ACS, especially in patients with acute myocardial infarction. Significant relationships were between levels of both ET-1 and sVCAM with both hsCRP and TNF-α. Significant relationships were between PAPP-A level with both hsCRP and TNF-α, but were absent with both ET-1 and sVCAM levels. Therefore, we believe that the endogenic destruction of plaque is more related with activation of NSSI than with progression of EDF. Conclusion The severity of the CHD is associated with the degree of both activation of nonspecific systemic inflammation and dysfunction of vascular endothelium. Elevated production of these markers can be considered as the indicator of both atherosclerotic plaque damage and the possibility of ACS development.

Natural course of Fabry disease with the p. Arg227Ter (p.R227*) mutation in Finland: Fast study.

BackgroundFabry disease is caused by a deficient or an absent alfa‐galactosidase A activity and is an X‐linked disorder that results in organ damage and a shortened life span, especially in males. The severity of the disease depends on the type of mutation, gender, skewed X‐chromosome inactivation, and other still unknown factors.MethodsIn this article, we describe the natural course of a common classic Fabry disease mutation, p.Arg227Ter or p.R227*, in Finland.ResultsFour males and ten females belonged to two extended families. The mean age was 46 years (SD 18.4). Six patients (43%) had cardiac hypertrophy, three patients (21%) had ischemic stroke, and none had severe kidney dysfunction. Three patients had atrial fibrillation; two patients who had atrial fibrillation also had pacemakers. All males over 30 years of age had at least one of the following manifestations: cardiac hypertrophy, stroke, or proteinuria. In females, the severity of Fabry disease varied from classic multiorgan disease to a condition that mimicked the attenuated cardiac variant. No one was totally asymptomatic without any signs of Fabry disease. Cardiac magnetic resonance imaging was performed on nine of 14 patients was the most sensitive for detecting early cardiac manifestations. Five patients (55%) had late gadolinium enhancement‐positive segments.ConclusionCardiac involvement should be effectively detected in females before considering them asymptomatic mutation carriers.

S-Sulfhydration of SIRT3 by Hydrogen Sulfide Attenuates Mitochondrial Dysfunction in Cisplatin-Induced Acute Kidney Injury.

Aims: Clinical use of cisplatin (Cisp), one of the most widely used, common, and effective chemotherapeutic agents, is limited by its side effects, particularly tubular injury-associated nephrotoxicity. Previous studies suggest that hydrogen sulfide (H2S) alleviates Cisp-induced acute kidney injury (AKI). However, the underlying mechanism remains largely unclear. Results: A single intraperitoneal injection of Cisp is employed to induce AKI, and the mice exhibit severe kidney dysfunction and histological damage at day 4 after Cisp injection. Here, we reported that H2S alleviated Cisp-caused renal toxicity via SIRT3 activation and subsequent improvement of mitochondrial ATP production. Using a biotin-switch assay, we showed that H2S increased S-sulfhydration of SIRT3 and induced deacetylation of its target proteins (OPA1, ATP synthase β, and superoxide dismutase 2). These effects of H2S were associated with a reduction of mitochondrial fragmentation, an increase in ATP generation, and less oxidative injury. Notably, the S-sulfhydration of SIRT3 induced by H2S was abrogated when Cys256, Cys259, Cys280, and Cys283 residues on SIRT3 (two zinc finger domains) were mutated. Innovation and Conclusion: Our data suggest that H2S attenuates Cisp-induced AKI by preventing mitochondrial dysfunction via SIRT3 sulfhydrylation. Antioxid. Redox Signal. 31, 1302-1319.

Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction.

Several methods are available to predict unbound (free) phenytoin concentrations in patients with hypoalbuminemia; however, predictive methods have not been evaluated in patients with concurrent hypoalbuminemia and kidney dysfunction or in patients with mild to moderate (estimated glomerular filtration rate [eGFR] 30-90 ml/min/1.73 m2 ) kidney dysfunction alone. Thus the objective was to evaluate the accuracy and precision of predictive methods to estimate free phenytoin concentrations in patients with varying albumin concentrations and/or kidney dysfunction. Retrospective chart review. Large academic medical center. A total of 344 patients with free and total phenytoin, albumin, and serum creatinine concentrations obtained between November 2012 and May 2017. Free phenytoin concentrations were estimated in patients without kidney dysfunction using the Winter-Tozer, Anderson, Kane, and Cheng equations. For the analysis in patients with eGFR lower than 90ml/min/1.73m2 , free phenytoin concentrations were estimated using the Shiner-Tozer derivation with adjusted affinity coefficients (C=0.15, 0.20, 0.25, and 0.30). For both analyses, accuracy of predictive methods was evaluated by P20, the proportion of estimations within 20% of the measured free phenytoin concentration. In 158 patients with normal kidney function/normal albumin concentrations, 73 with normal kidney function/hypoalbuminemia, or 47 with mild kidney dysfunction/normal albumin concentrations, the Anderson method had the highest accuracy (86%, 82%, and 92%, respectively) and highest precision compared with the other methods. In 47 patients with normal albumin concentrations and mild kidney dysfunction or 13 with moderate kidney dysfunction, the free fraction was unchanged, and total phenytoin concentrations accurately reflected free concentrations. In 17 patients with hypoalbuminemia and mild or 17 with moderate kidney dysfunction, the Winter-Tozer (67% and 50%, respectively) and the Anderson (56% and 67%, respectively) methods had the highest accuracy compared with other methods with significantly lower accuracy compared with patients with normal kidney function. In the 14 patients with severe kidney dysfunction and hypoalbuminemia, none of the coefficients had a P20 accuracy greater than 45%. In patients with normal albumin concentrations, with or without mild or moderate kidney dysfunction and not receiving a protein-binding displacer, the free fraction of phenytoin is unchanged, and it is not necessary to measure a free phenytoin concentration. Free phenytoin concentrations should be measured directly in patients with hypoalbuminemia and kidney dysfunction.

Effect of Hepatic Organic Anion-Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver-Targeted Glucokinase Activator: A Model-Based Evaluation.

PF-04991532 ((S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato-selectivity via organic anion-transporting polypeptides (OATP)s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of OATP1B1/1B3 inhibition and renal impairment on PF-04991532 oral pharmacokinetics. Cyclosporine (600mg single dose) increased mean area under the plasma curve (AUC) of PF-04991532 by approximately threefold in healthy subjects. In a renal impairment study, PF-04991532 AUC values were ~2.3-fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically-based pharmacokinetic (PBPK) model parameterizing hepatic and renal transporter-mediated disposition based on in vitro inputs, and verified using first-in-human data, indicated the key role of OATP-mediated hepatic uptake in the systematic and target-tissue exposure of PF-04991532. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~35%) and renal organic anion transporter (OAT)3 (80-90%) function with renal impairment. This study illustrates the adequacy and utility of the PBPK approach in assessing the impact of drug interactions and kidney dysfunction on transporter-mediated disposition.

Blood urea nitrogen is independently associated with renal outcomes in Japanese patients with stage 3\u20135 chronic kidney disease: a prospective observational study

BackgroundBlood urea nitrogen (BUN) is one of the substances that affects the calculated serum osmolality (cSosm). A previous study demonstrated that BUN and cSosm were independently associated with the development of chronic kidney disease (CKD) in patients with preserved kidney function. In advanced CKD stages, there is a concomitant increase in cSosm and BUN levels. However, it remains unclear whether BUN or cSosm levels are related to renal outcomes in patients with moderate to severe kidney dysfunction. The aim of this study was to clarify whether the BUN or cSosm level is associated with kidney disease progression in patients with advanced CKD.MethodsIn this prospective study, we enrolled 459 patients with CKD (stages 3–5). The composite renal endpoint was end-stage renal disease (ESRD) or death, and ESRD alone was added as an alternative outcome. A Cox proportional hazards model was utilized to determine the risk factors for a poor renal outcome. We adjusted for covariates including estimated glomerular filtration rate (eGFR). The cSosm (mOsm/kg) was calculated using the following formula: (2 × sodium) + (BUN/2.8) + (glucose/18).ResultsDuring a median follow-up of 25.8 months, the renal endpoint was observed in 210 patients. Multivariable Cox analysis determined the hazard ratio (HR) [95% confidence interval (CI)] for the composite renal outcome in the second, third, and fourth BUN quartiles were 1.36 (0.72–2.58), 1.87 (0.95–3.66), and 2.66 (1.23–5.76) (P for trend < 0.01), respectively compared with the first BUN quartile. Conversely, by multivariable Cox analysis, the HRs (95% CIs) for poor outcomes in the second, third, and fourth cSosm quartiles, compared with the first cSosm quartile, were 1.13 (0.69–1.87), 0.95 (0.58–1.55), and 1.26 (0.78–2.03), respectively (P for trend = 0.39). In addition, with regard to the renal outcome of ESRD alone, higher BUN quartiles had a significantly increased risk for the outcome, but cSosm levels were not associated with the outcome.ConclusionsHigher BUN levels, but not cSosm levels, were associated with adverse renal outcomes independent of the eGFR, suggesting that BUN may be a useful marker for predicting kidney disease progression.

Renal Function after Ventricular Assist Device Implantation

Purpose Previous studies have shown a correlation between improved renal function and ventricular assist device implantation, resulting in improved survival rates. This study aims to strengthen this correlation and establish long term findings by increasing the size of the study cohort as well as study period. Methods We retrospectively reviewed the data of 389 patients who received ventricular assist device implantation due to terminal heart failure at our center from 12/2003 to 03/2018. Median duration of LVAD support was 307 days (range 1 to 2849 days). Renal function was assessed using the Modification of Diet in Renal Disease study-derived Glomerular Filtration Rates (MDRD-GFR; mL x min(-1) x 1.73m(-2)). According to pre-implantation measured GFR rates patients were categorized in three groups: normal renal function (GFR>90, n= 52); moderately impaired renal function (GFR 30-90; n=295) and severely impaired renal function (GFR Results Mean GFR showed a significant increase of renal function in both the moderately impaired and severely impaired kidney function groups at week 1 post-implantation (moderately: 56.0 ± 15.6 to 81.6 ± 39.0; severely: 22.7 ± 5.0 to 43.5 ± 19.0; p Conclusion Ventricular assist device implantation improves the renal function in terminal heart failure patients with moderate to severe kidney dysfunction. Normal renal function is correlated with better outcomes post LVAD implantation.