Effects of Serum Uric Acid on Estimated GFR in Cardiac Surgery Patients: A Pilot Study.

BACKGROUND: The aim of the study was to investigate the effects of serum uric acid (SUA) on acute kidney injury (AKI) in patients undergoing cardiac surgery. METHODS: Prospectively collected data from a previous study were analyzed to investigate the relationship between SUA and AKI as assessed by neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine (SCr) and kinetic estimated glomerular filtration rate (KeGFR). RESULTS: Patients undergoing cardiovascular surgery (n = 37) were included. SUA was measured at postoperative 1 h. Statistically significant correlations were present between SUA and NGAL measured at postoperative 1 h (r = 0.39, p = 0.008), 6 h (r = 0.31, p = 0.029) and 24 h (r = 0.31, p < 0.001), respectively. Significant correlations were also noted between SUA and SCr measured on postoperative day 1 (r = 0.41, p = 0.006), day 2 (r = 0.29, p = 0.042) and day 3 (r = 0.42, p = 0.009). Negative correlations were demonstrated between SUA and day 1 (r = -0.44, p = 0.007), day 2 (r = -0.43, p = 0.007), day 3 (r = -0.44, p = 0.006 and day 4 KeGFR (r = -0.35, p = 0.035). The inverse relationship of SUA and KeGFR was also demonstrated with a different method (Jelliffe) of measurement. CONCLUSIONS: A reduction in glomerular filtration rate (GFR) can lead to a rise in SUA. However, in this study, we are able to show that SUA at 1 h (maximal dilution time) effectively predicts subsequent changes in urinary NGAL, SCr, KeGFR, and the development of AKI. Thus, these findings suggest that uric acid precedes and predicts acute changes in renal function and cannot be ascribed to a simple relationship in which a reduced GFR raises SUA.

Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy.

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

Fructokinase activity mediates dehydration-induced renal injury.

The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

Are diuretics harmful in the management of acute kidney injury?

PURPOSE OF REVIEW: To assess the role of diuretics in acute kidney injury (AKI) and their effectiveness in preventing AKI, achieving fluid balance, and decreasing progression to chronic kidney disease (CKD). RECENT FINDINGS: Diuretics are associated with increased risk for AKI. The theoretical advantage of diuretic-induced preservation of renal medullary oxygenation to prevent AKI has not been proven. A higher cumulative diuretic dose during the dialysis period can cause hypotension and increase mortality in a dose-dependent manner. Data on the use of forced euvolemic diuresis to prevent AKI remains controversial. Positive fluid balance has emerged as an independent predictor of adverse outcomes. Post-AKI furosemide dose had a favorable effect on mortality due in part to the reduction of positive fluid balance. There are exciting experimental data suggesting that spironolactone may prevent AKI once an ischemic insult has occurred and thus prevent the progression to CKD. SUMMARY: Diuretics are ineffective and even detrimental in the prevention and treatment of AKI, and neither shorten the duration of AKI, nor reduce the need for renal replacement therapy. Diuretics have an important role in volume management in AKI, but they are not recommended for the prevention of AKI. There is increased emphasis on the prevention of progression of AKI to CKD.

Renal support in acute kidney injury.

Acute kidney injury requiring renal replacement therapy (RRT) is associated with an unacceptably high mortality rate. Despite the identification of the modality, timing and intensity of dialysis, membrane biocompatibility, hollow fiber and catheter properties as potential modifying factors, there is little convincing evidence for the superiority of one over the other. However, the available data suggest that the early initiation of RRT may be beneficial. A focused review of clinical trials and meta-analysis of clinical trials of RRT is provided.

Perioperative fluid balance and acute kidney injury.

BACKGROUND: Positive fluid balance (FB) has been linked to adverse clinical outcomes. We performed this study to explore the relationship between perioperative fluid balance and acute kidney injury (AKI). METHODS: The relationships between FB and AKI were explored using a prospective, observational design. Patients were divided into quartiles based on FB status in the first 24 h from initiation of surgery in order to further explore this relationship. RESULTS: One hundred adult patients undergoing cardiovascular surgery were included in the analysis. The major finding of the study was that positive FB occurred early in the intraoperative period and progressed into the postoperative period and that fluid administration was not clearly associated with any identifiable volume-sensitive event. The evolution of positive FB preceded the rise in serum creatinine. Progressive severity of positive FB was associated with increased incidence of AKI. The highest quartile FB group had a five-fold increased risk for AKI (adjusted odds ratio 4.98, 95 % confidence interval 1.38-24.10, p = 0.046) compared to the lowest quartile group, higher postoperative peak serum creatinine values (p < 0.001), surgery-related complications (p < 0.001) and intensive care unit (p < 0.001) and hospital length of stay (p = 0.048). CONCLUSIONS: Positive FB was associated with increased incidence of AKI.

Early blood biomarkers predict organ injury and resource utilization following complex cardiac surgery.

BACKGROUND: Patients undergoing complex cardiac surgery (thoracic aorta and valve) are at risk for organ failure and increased resource utilization. Neutrophil gelatinase-associated lipocalin (NGAL) has been found to be an early biomarker for renal injury. Multiplex cytokine immunoassays allow the evaluation of the early inflammatory response. We examined the relationship between early biomarker appearance (NGAL and multiplex cytokines) and organ injury and resource utilization. MATERIALS AND METHODS: NGAL and multiplex cytokine immunoassays were performed at baseline, 1, 6, and 24 h following surgery on 38 patients undergoing thoracic aorta and valve operations. The mean age was 65 y with 26 males and 12 females. Acute kidney injury (AKIN definition), pulmonary failure (>24 h ventilation), and intensive care unit and hospital stays were examined. RESULTS: One hour following complex cardiac surgery, the quartile of patients with the greatest IL-6 response had higher serum NGAL levels compared with the lowest quartile (347 versus 145 ng/mL, P=0.002), and 70% of these patients progressed to clinical kidney injury. Six hours following surgery, the quartile of patients with the greatest IL-10 response had higher serum NGAL compared with the lowest quartile (271 versus 160, P =0.04), more pulmonary failure (60% versus 10%, P =0.01), and longer ICU and hospital stays (P =0.001). CONCLUSIONS: Patients with early elevated biomarkers of inflammation exhibited higher NGAL, more pulmonary failure, and greater resource utilization. Earlier identification of patients at risk for organ injury may allow for earlier intervention and reduce resource utilization.

Anaerobic clavicular osteomyelitis following colonoscopy in a hemodialysis patient.

Patients on dialysis are immunocompromised and are therefore susceptible to both common and unusual infectious complications. These infections are often related to their dialysis access but even routine diagnostic tests unrelated to dialysis can also lead to rare adverse events. We present an unusual case of clavicular osteomyelitis from Bacteroides fragilis in a patient on maintenance hemodialysis following colonoscopy. The risk factors for this unusual site of infection, the incidence and guidelines for prophylactic antibiotic administration are discussed here.

Brain natriuretic peptide is not reno-protective during renal ischemia-reperfusion injury in the rat.

BACKGROUND: Acute kidney injury (AKI) occurs in 30% of patients undergoing complex cardiovascular surgery, and renal ischemia-reperfusion (I/R) injury is often a contributing factor. A recent meta-analysis observed that perioperative natriuretic peptide administration was associated with a reduction in AKI requiring dialysis in cardiovascular surgery patients. This study was designed to further clarify the potential reno-protective effect of brain natriuretic peptide (BNP) using an established rat model of renal I/R injury. METHODS: The study comprised three groups (n = 10 kidneys each): (1) control (no injury); (2) I/R injury (45 min of bilateral renal ischemia followed by 3 h of reperfusion); and (3) BNP (I/R injury plus rat-BNP pretreatment at 0.01 µg/kg/min). Glomerular filtration rate (GFR) and a biomarker of AKI, urinary neutrophil gelatinase-associated lipocalin (uNGAL), were measured at baseline and at 30 minute intervals post-ischemia. Groups were compared using two-way repeated measures analysis of variance (mean ± SD, significance P < 0.05). RESULTS: Baseline GFR measurements for control, I/R, and BNP groups were 1.07 ± 0.55, 0.88 ± 0.51, and 1.03 ± 0.59 mL/min (P = 0.90), respectively. Post-ischemia, GFR was significantly lower in I/R and BNP compared with controls at 30 min, 1.29 ± 0.97, 0.08 ± 0.04, and 0.06 ± 0.05 mL/min (P < 0.01), and remained lower through 3 h, 1.79 ± 0.44, 0.30 ± 0.17, and 0.32 ± 0.12 mL/min (P < 0.01). Comparing I/R to BNP groups, GFR did not differ significantly at any time point. There was no significant difference in uNGAL levels at 1 h (552 ± 358 versus 516 ± 259 ng/mL, P = 0.87) or 2 h (1073 ± 589 versus 989 ± 218 ng/mL, P = 0.79) between I/R and BNP. CONCLUSIONS: BNP does not reduce the renal injury biomarker, urinary NGAL, or preserve GFR in acute renal ischemia-reperfusion injury.

Natriuretic peptides in acute kidney injury - A sojourn on parallel tracks?

OBJECTIVE: The focus of this review was to elicit the mechanistic logic of the experimental and clinical study designs of natriuretic peptides (NP) in acute kidney injury (AKI) and to understand their respective outcomes. METHODS: Online search of PubMed and manual review of articles. Randomized trials, observational and physiologic studies of NPs and AKI were extracted. Rationale, design and study outcomes were analyzed. RESULTS: In experimental models of AKI, infusion of NP prevented post-ischemic fall in renal blood flow (RBF) or improvement in RBF, GFR, diuresis and natriuresis and demonstrated anti-inflammatory properties. NPs were most effective in the early stages of AKI, also in established phase of AKI but their effectiveness were limited to the time of infusion. Hypotension was a major side-effect. Based on these observations, preliminary clinical studies were performed which demonstrated improved urine output, RBF and GFR and reduced need for dialysis. However, randomized, controlled trials failed to demonstrate improvement in dialysis-free survival in different cohorts and study designs. Although NPs reduced the incidence of AKI in the postoperative period in cardiac surgery, it was not associated with improved long-term survival. In contrast to randomized trials, meta-analysis reported favorable results. CONCLUSIONS: Reasons for the divergence of experimental and clinical outcomes of NPs in AKI are discussed in this review article.

Uric acid: a novel risk factor for acute kidney injury in high-risk cardiac surgery patients?

BACKGROUND: Uric acid has been reported to be a risk factor for the development of chronic kidney disease; however, no study has examined whether uric acid may confer a risk for acute kidney injury. METHODS: We investigated the relation between serum uric acid and the incidence of postoperative acute kidney injury in patients undergoing high-risk cardiovascular surgery (cardiac valve and aneurysm surgery). RESULTS: Following cardiovascular surgery, 18 of 58 patients (31%) developed acute kidney injury, with 11 of 24 (45.8%) in the elevated uric acid group (defined as >6 mg/dl) and 7 of 34 (20.5%) in the normal uric acid group (p = 0.05). After controlling for baseline renal function, left ventricular ejection fraction, use of nesiritide, type of surgery, and history of previous surgery, an elevated preoperative uric acid conferred a 4-fold risk for acute kidney injury (OR: 3.98, CI: 1.10-14.33, p = 0.035) and longer hospital stay (36.35 vs. 24.66 days, p = 0.009). CONCLUSION: This preliminary study suggests that uric acid may be a novel risk factor for acute kidney injury in patients undergoing high-risk cardiovascular surgery.

The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD.

Hyperuricaemia is common among patients with chronic kidney disease (CKD), and increases in severity with the deterioration of kidney function. Although existing guidelines for CKD management do not recommend testing for or treatment of hyperuricaemia in the absence of a diagnosis of gout or urate nephrolithiasis, an emerging body of evidence supports a direct causal relationship between serum urate levels and the development of CKD. Here, we review randomized clinical trials that have evaluated the effect of urate-lowering therapy (ULT) on the rate of CKD progression. Among trials in which individuals in the control arm experienced progressive deterioration of kidney function (which we define as ≥4 ml/min/1.73 m² over the course of the study - typically 6 months to 2 years), treatment with ULT conferred consistent clinical benefits. In contrast, among trials where clinical progression was not observed in the control arm, treatment with ULT was ineffective, but this finding should not be used as an argument against the use of uric acid-lowering therapy. Although additional studies are needed to identify threshold values of serum urate for treatment initiation and to confirm optimal target levels, we believe that sufficient evidence exists to recommend routine measurement of serum urate levels in patients with CKD and consider initiation of ULT among those who are hyperuricaemic with evidence of deteriorating renal function, unless specific contraindications exist.

Shortened hemofilter survival time due to lipid infusion in continuous renal replacement therapy.

BACKGROUND: Continuous renal replacement therapy is widely used for the treatment of critically ill patients with acute renal failure in critical care units. The survival time of the extracorporeal circuit is an important factor in providing renal replacement therapy. Despite rigorous efforts to maintain hemofilter patency, clinicians are occasionally faced with an unexplained short circuit survival time. METHODS: We present a critically ill patient undergoing continuous venovenous hemofiltration with regional citrate anticoagulation for management of acute renal failure in the context of sepsis. Once the patient was started on lipid infusion as part of total parenteral nutrition, we observed a shortened circuit survival due to premature hemofilter failure necessitating frequent changes of the hemofilter. The known potential causes for this phenomenon were ruled out. RESULTS: Evaluation revealed grossly lipemic serum associated with severe hypertriglyceridemia. Discontinuation of the lipid infusion was followed by a rapid return of circuit survival time to its baseline. Evaluation of the hemofilter by electron microscopy revealed that the rapid blockage of the hollow fibers was caused by lipid microparticles and fibrin deposits. CONCLUSION: Since total parenteral nutrition is commonly administered to malnourished and hypercatabolic critically ill patients on continuous renal replacement therapy, we suggest that intravenous lipid therapy might be a previously unreported and unappreciated remediable cause of premature hemofilter failure.

Nesiritide following maze and mitral valve surgery.

BACKGROUND: Fluid retention following "maze" and mitral valve surgery has been associated with diminished levels of atrial natriuretic peptide (ANP). We hypothesized prophylactic administration of nesiritide (human recombinant brain natriuretic peptide, NES, Natrecor, Scios, Fremont, CA, USA), which has similar physiologic properties to ANP and would promote diuresis in maze and mitral patients postoperatively. METHODS: Randomized, blinded, prospective pilot study comparing patients undergoing maze and mitral surgery including excision of the left atrial appendage. Three hours after cardiopulmonary bypass, patients received either a 72-hour infusion of NES at 0.01 mcg/kg/min (n = 9) or placebo (n = 10). Diuresis, diuretics, time to extubation, oxygenation, ANP, and serum Endothelin-1 levels were measured. Nonparametric analysis with Mann-Whitney test was performed with SPSS (SPSS Inc., Chicago, IL, USA). RESULTS: In both groups, postoperative ANP levels fell from baseline (NES 330 to 280 ng/mL and control 220 to 150 ng/mL). There were no significant differences in patients receiving NES compared to controls in diuresis (1.33 mL/kg/hour urine output NES vs. 1.68 mL/kg/hour controls, p = 0.14); furosemide dosage (0.04 mg/kg/hour NES vs. 0.04 mg/kg/hour controls, p = 0.08); time to extubation (17.5 hours NES vs. 19.5 control, p = 0.42) or PaO2/FiO2 ratio at 48 hours (NES 200 vs. 273 control, p > 0.05). Endothelin-1 levels were higher at baseline with NES but not at 1 and 72 hours after cardiopulmonary bypass (NES 3.1, 3.8, 2.9 pg/mL vs. control 1.85, 4.05, 2.75 pg/mL; p = 0.01, 0.77, 0.47). CONCLUSIONS: This pilot study did not demonstrate additional diuresis with nesiritide in postoperative mitral/maze patients already following a loop diuretic protocol.

The rise and fall of natriuretic peptides in acute kidney injury: a misunderstood relationship?

The vasodilatory, natriuretic, and diuretic properties of natriuretic peptides (NPs) make them attractive agents in the treatment of acute kidney injury (AKI). However, there is conflicting evidence of their beneficial effects. This article examines the reasons for the differences, and provides insight that the reported outcomes may be related to the unique physiologic effects and mechanisms of action of NPs, the designs and cohorts of the trials, and the characteristic renal hemodynamics associated with AKI. NPs are effective in the prevention of AKI when applied prophylactically, in lower doses, for prolonged duration, in patients with mild to moderate impairment in renal function, and in predictable clinical settings with clearly defined outcome measurements.

24-hour blood pressure monitoring in the evaluation of supine hypertension and orthostatic hypotension.

The presence of orthostatic hypotension has been shown to be a significant, independent predictor of all-cause mortality. Systolic and diastolic orthostatic hypotension, reversal of the circadian pattern, and postprandial hypotension are some of the hemodynamic factors that may contribute to the increased mortality seen in patients with orthostatic hypotension. The high variability of blood pressure in orthostatic hypotension cannot usually be adequately assessed by a one-time measurement. In this group of patients, 24-hour ambulatory.