Elevated Serum Uric Acid And Utilization Of RAS Inhibitors:the Relationship Between This Two Non-traditional Risk Factors And Acute Kidney Injury In Cardiovascular Inpatients

BackgroundAcute kidney injury (AKI)is defined by an abrupt decrease in kidney function, which is one of a number of conditions that affect kidney structure and function. Currently, hospital-acquired acute kidney injury is one of the hot and difficult topics. The commonly causes of AKI include sepsis、cardiac surgery、contrast induced nephrology, and cardiorenal symptom type Ⅰ,which is defined as AKI secondary to acute cardiac insufficiency and has been an increasingly important focus of doctors. Epidemiological evidence supports the notion that even mild, reversible AKI has important clinical consequences, including increased early and long-term patient morbidity and mortality, as well as the subsequent development of chronic kidney disease (CKD). We advocate that efforts focused on preventing AKI be coupled with early detection and treatment and adequate follow up.Cardiovascular diseases is an important cause of hospital-acquired AKI, So our AKI Research Group has foucused on cardiovascular inpatients for a long time. Elevated serum uric acid is common in patients with cadiovacular diseases. Uric acid has long been linked to acute kidney injury associated with tumor lysis syndrome via crystal-dependent mechanisms. However, there is increasing epidemiological, experimental, and clinical evidence that uric acid, in concentrations that do not cause intratubular crystal precipitation, may play a role in the pathogenesis of acute kidney injury. Serum uric acid influences many of the proposed mechanisms of acute kidney injury, that is, it induces renal vasoconstriction, impairs autoregulation, has proinflammatory and anti-angiogenic properties. Some studies have reported that uric acid can increase the morbility of Contrast Induced Nephrology. Our aim is to investigate the effect of pre-operative uric acid on acute kidney injury (AKI) after cardiac surgery in elderly patients.Renin Angiotensin System inhibitors, including Angiotensin Conversing Enzyme Inhibitor (ACEI) and Angiotensin Ⅱ Receptor Blocker (ARB),are commonly used to treat coronary heart diseases、heart falure and renal diseases. They have been proved that can improve mortality. However, in circumstances in which maintenance of glomerular filtration requires efferent arteriolar constriction, ACEI or ARB may cause acute kidney injury. A study has reported that preoperative use of RAS inhibitors was associated with increased odds of postoperative AKI in patients undergoing cardiovascular surgery. Whether ACEI or ARB will increase the morbility of Cardiorenal Syndrome(CRS) Type Ⅰ and Contrast Induced Nepgrology is unclear.Chaper One Effect of pre-operative serum uric acid on acute kidney injury after cardiac surgery in elderly patientsObjectiveAcute Kidney Injury(AKI) occurs in as many as 30% of patients undergoing cardiac surgery, with about 1% of all patients needing dialysis. AKI can increase mortality, extend the length of hospitalization time, and increase the risk of developing chronic kidney disease. Uric acid has long been linked to acute kidney injury associated with tumor lysis syndrome via crystal-dependent mechanisms. However, there is increasing epidemiological, experimental, and clinical evidence that uric acid, in concentrations that do not cause intratubular crystal precipitation, may play a role in the pathogenesis of acute kidney injury. Serum uric acid (SUA) influences many of the proposed mechanisms of acute kidney injury, that is, it induces renal vasoconstriction, impairs autoregulation, has proinflammatory and anti-angiogenic properties. Some studies have reported that uric acid can increase the morbility of contrast induced nephrology. Our aim is to investigate the effect of pre-operative uric acid on acute kidney injury (AKI) after cardiac surgery in elderly patients.MethodsClinical data was collected from 936 cases elderly patients (age≥60 years) undergoing cardiac surgery with cardiopulmonary bypass in our Hospital between January 2005 and May 2011 to analyse retrospectively. The baseline serum creatinine was defined as the latest serum creatinine before surgery, and the diagnosis of AKI was according to RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) criteria. The patients were divided into three groups according to the sex-specific cutoff points of serum uric acid tertiles,and A group was≤384.65μmol/L in men, and≤354.00μmol/L in women, B group was 384.66-476.99μmol/L in men and 354.01-437.96μmol/L in women, C group was>477.00μmol/L in men and≥437.97 μmol/L in women. Multivariate Logistic regression analysis was used to analyse the independent risk factors for AKI.ResultsAmong 936 elderly patients,576 cases (61.5%) developed AKI. Mean uric acid concentration was higher in AKI patients than Non-AKI patients((436.6±119.1) μmol/L vs (398.0±107.2)μmol/L,P<0.001). The incidence of AKI was56.1%(175/312) in A group,56.3%(175/311) in B group,72.2%(226/313) in C group(P<0.001). Multiple logistic regression analysis showed that,after adjusted for age, gender, co-morbidities(hypertension, diabetes mellitus, cerebrovascular disease, chronic obstructive pulmonary disease), previous cardiac surgery, eGFR<60 ml/min/1.73 m2, heart function grade of NYHA≥3, positive urine protein,combination of coronary artery bypass grafting and valvular surgery, cardiopulmonary bypass time, aortic cross-clamping time, exposuring to angiotensin converting enzyme inhibitor or angiotensin Ⅱ receptor blocker and lipid-lowering drugs pre-operative, early postoperative variables (use of angiotensin converting enzyme inhibitor or angiotensin Ⅱ receptor blockers, diuretics and digoxin, central venous pressure),compared with A group, C group had higher risk of AKI (OR 1.897,95%C7 1.270-2.833, P=0.002)Conclusion:Pre-operative elevated uric acid can increase the risk of AKI after cardiac surgery in elderly patients. Attention should be paid to this non-traditional risk factor.Chaper Two The effect of RAS inhibitors on AKI of cardiovascular inpatients2.1 The relationship between RAS inbitors and Contrast Induced NephrologyObjectiveContrast-induced nephropathy (CIN) is the third leading cause of in-hospital acute renal failure. CIN is commonly defined as an increase in serum creatinine ≥0.5mg/dl or 25% above baseline and is typically recongnized 48-72 hours after contrast exposure. CIN has been shown to increase the length of hospitalization, the likelihood of chronic kidney disease, and mortality. Risk factors that have been cited as increasing the risk of developing CIN include preexisting renal impairment, diabetes, heart failure, advanced age, aniemia, high volume of contrast media used, and reduced intravascular volume. The prevention strategies of CIN to date include volume expansion, decreasing volume of contrast media, avoidance of high oumolar agents and other nephrotoxic agents. Renin Angiotensin System (RAS) inhibitors, including Angiotensin Conversing Enzyme Inhibitor (ACEI) and Angiotensin Ⅱ Receptor Blocker (ARB), are commonly used to treat hypertension、heart falure and diabetic nephropathy. However, the role of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker(ARB) in CIN is controversial. Some studies pointed out that it was effective in the prevention of CIN, while some concluded that it was a risk for the development of CIN. Our aim is to conduct a meta-analysis of these trials to assess the relationship between ACEI or ARB and CIN.MethodsWe performed a literature search of PubMed, Cochrane library, Scopus, Web of Science using the keywords about Renin Angiotensin System inhibitors, including the name of drugs, and contrast induced nephropathy. The primary end point is CIN. The literature was selected and reviewed by two researchers independently according to inclusion criteria. They carried out data on author, publishing year, patients characteristics, definition of CIN, complications (hypertension, diabetes, coronary heart diseases, et al), type and volume of contrast media, prevention strategies. Heterogeneity across trials was analyzed by means of I2 statistics, with an I2 value>50% indicating at least moderate statistical heterogeneity. Where no significant statistical heterogeneity was identified, the fixed-effects estimate was used preferentially, otherwise the random-effects model was chosed. All statistical analyses were performed using Review Manager version 5.2.ResultsA total of 18 trials were pooled.10 studies treated patients with ACEI,2studies with ARB, and 6 studies with ACEI or ARB. Two studies included patients with diabetes, and six studies included patients with chronic kidney diseases.7 studies included ACEIor ARB naive subjecs,5 studies included subjects on ACEI or ARB therapy over one month.4 studies did not specify if subjects had pior ACEI or ARB. The meta-analysis of 9 randomized controlled trials found ACEI or ARB to be useful for the prevention of contrast-induced nephropathy(OR 0.54,95% CI 0.36～0.82, P=0.004,I2=12%). However, the meta-analysis of 9 observational studies (including 7 retrospective studies and 2 prospective cohort studies) showed that ACEI or ARB can increase the risk of CIN (OR 1.82,95% CI 1.22-2.71, P=0.004,I2=77%)..ConclusionThe role of RAS inhibitors in CIN is paradoxical. The pooled analysis of randomized controlled trials found ACEI or ARB to be useful for the prevention of contrast-induced nephropathy. However, the pooled analyss of observational studies showed that ACEI or ARB can increase the risk of CIN. For the reason that most of observation studies are retrospective studies, with significant heterogeneity between studies, the pooled result of randomed rudies may relative relaiable. RAS inhibitors may offter protection against development of CIN. Under the condition that it is widely used in clinical practices before CM administration, larger randomized controlled trials are urgently required to furtherly and deeply investigate the role of RAS inhibitor in the development of CIN,as well as the hard endpoint such as death.2.2 The effect of RAS inhibitors on cardiorenal syndrome type ⅠObjectiveRenin Angiotensin System (RAS) inhibitors, including Angiotensin Conversing Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB), are commonly used to treat cardiovascular disease. A great many of studies have demonstrated that ACEI and ARB play an integral role in the treatment of patients with renal and heart diseases. However, in circumstances in which maintenance of glomerular filtration requires efferent arteriolar constriction, ACEI or ARB may cause acute kidney injury (AKI). A meta analysis has reported that preoperative use of RAS inhibitors was associated with increased odds of postoperative AKI in patients undergoing cardiovascular surgery. Whether ACEI or ARB will increase the morbility of cardiorenal syndrome(CRS) type I is unclear.MethodsClinical datas were collected from 1058 acute heart failure(AHF) patients in our Hospital and the First Affiliated Hosipital of Sun Yat Xian Hospital between July 2005 and July 2012. AKI was diagnosed according to KDIGO criteria.Baseline SCr was estimated from either the admission value (if this was within the normal range) or if available, from another value within 3 months, whichever was lowest. Logistic regression analysis was used to determine whether ACEI or ARB is an independent risk factor for the occurrence of CRS type I and in-hospital mortality or not.ResultsAmong 1058 patients,559 cases (52.8%) developed AKI and 142 patients died. The use of ACEI or ARB in AKI group was significantly lower than non-AKI group(63.9% VS 71.3%, P=0.01). Multiple logistic regression analysis showed that, after adjusted for diabetes mellitus, eGFR<60 ml/min/1.73 m2, uric acid, hemoglobin<110g/l, albumin<30g/l, proteinuria, diuretics and vasoactive agents use, ACEI or ARB was a protective factor for the development of CRS type I, but not significantly.(OR 0.763, P=0.076). The use of ACEI or ARB in dead group was significantly different from the non-dead group(52.8% VS 69.7%, P<0.001). Datas were adjusted for age, diabetes mellitus, cerebrovascular disease, AKI, hemoglobin<110g/l, uric acid, proteinuria, β blockers and vasoactive agents use. ACEI or ARB could also decrease the in-hospital motality(OR 0.564,95%CI 0.383-0.830). ACEI or ARB do not increase the incidence of AKI in patients with eGFR<60ml/min/1.73m2(ORO0.881,P=0.540), and also protect them from death(OR 0.525,95%CI 0.326-0.846).ConclusionACEI or ARB do not increase the risk of AKI and may protect the AHF patients from death, which is different from the effect of ACEI or ARB on postoperative AKI.