A. Ahsan Ejaz

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.

Elevated Uric Acid Increases the Risk for Acute Kidney Injury

BACKGROUND Uric acid has been proposed to play a role in acute kidney injury. We therefore investigated the potential influence of preoperative serum uric acid (SUA) on acute kidney injury in patients undergoing cardiovascular (CV) surgery. The primary aims were to investigate the incidence of acute kidney injury, peak serum creatinine (SCr) concentrations, hospital length of stay, and days on mechanical ventilation. METHODS Retrospective study included patients who underwent CV surgery and had preoperative SUA available. Acute kidney injury was defined as an absolute increase in SCr ≥0.3 mg/dL from baseline within 48 hours after surgery. Univariate and multivariate logistic regression analysis was performed to determine the odds ratio for acute kidney injury. RESULTS There were 190 patients included for analysis. SUA were divided into deciles. The incidences of acute kidney injury were higher with higher deciles of SUA. When the incidences of acute kidney injury were plotted against all available values of SUA at increments of 0.5 mg/dL, a J-shaped curve emerged demonstrating higher incidences of acute kidney injury associated with both hypo- and hyperuricemia. In the univariate analysis, SUA ≥5.5 mg/dL was associated with a 4-fold (odds ratio [OR] 4.4; 95% confidence interval [CI], 2.4-8.2), SUA ≥6 mg/dL with a 6-fold (OR 5.9; 95% CI, 3.2-11.3), SUA ≥6.5 mg/dL with an 8-fold (OR 7.9; 95% CI, 3.9-15.8), and SUA ≥7 mg/dL with a 40-fold (OR 39.1; 95% CI, 11.6-131.8) increased risk for acute kidney injury. In the multivariate analysis, SUA ≥7 mg/dL also was associated with a 35-fold (OR 35.4; 95% CI, 9.7-128.7) increased risk for acute kidney injury. The 48-hour postoperative and hospital-stay mean peak SCr levels also were higher in the SUA ≥5.5 mg/dL group compared with the SUA <5 mg/dL group. SUA ≥7 mg/dL was associated with increased length of hospital stay (SUA <7 mg/dL, 18.5 ± 1.8 days vs SUA ≥7 mg/dL, 32.0 ± 6.8 days, P = 0.058) and a longer duration of mechanical ventilation support (SUA <7 mg/dL, 2.4 ± 0.4 days vs SUA ≥7 mg/dL, 20.4 ± 4.5 days, P = 0.001). CONCLUSION Preoperative SUA was associated with increased incidence and risk for acute kidney injury, higher postoperative SCr values, and longer hospital length of stay and duration of mechanical ventilation support in patients undergoing cardiac surgery. A J-shaped relationship appears to exist between SUA and acute kidney injury.

A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome

Tumour lysis syndrome (TLS) is a complication associated with the treatment of tumour types with high proliferative rate, large tumour burden or high sensitivity to cytotoxic therapy. The implementation of risk stratification strategies [1], appropriate prophylactic measures, vigilant monitoring of laboratory parameters and active interventions to reduce risk factors has dramatically decreased the incidence of clinically significant morbidity that results in end organ damage and mortality. Despite these advances, 5–6% of atrisk paediatric and adult patients undergoing chemotherapy develop acute kidney injury (AKI), and 40–50% of these patients will require dialysis therapies with associated allcause mortality in excess of 50% [2–4]. Similar outcomes are reported with spontaneous TLS [5]. The lack of standardized definitions and outcome measures has hampered appreciation of the extent of adverse renal outcomes in TLS. Recent adoption of a uniform definition of AKI (increase in serum creatinine of 0.3 mg/dL from baseline or a 50% increase in serum creatinine from baseline values within 48 h) [6] and the recognition that the development of in-hospital AKI have significant implications for long-term mortality [7] underscores the need to understand the mechanisms involved in AKI associated with TLS. Furthermore, the effect of chronic kidney disease (CKD) on renal outcomes in TLS requires a study, as clinical tumour lysis occurs more frequently in patients with pretreatment renal impairment [8]. One study examining risk factors for in-hospital AKI of diverse aetiologies reported that CKD increases the risk of AKI 40-fold with a 20-fold increased risk for dialysis [9]. Here, we will briefly review the current understanding of the pathogenesis of TLS-induced AKI. In particular, a recent literature suggests that AKI and nephropathy are not simply due to intrarenal crystal deposition of urate and phosphate. Mechanism of AKI associated with intrarenal deposition of uric acid crystals TLS is a group of metabolic complications that occur after the treatment of large volume, rapidly proliferating haematological cancers including not only acute leukaemia and aggressive lymphomas but also some solid tumours. Metabolic alterations that result include hyperkalaemia, hyperphosphataemia, hyperuricaemia and hyperuricosuria, hypocalcaemia and consequent AKI. Specifically, AKI associated with TLS has been considered to be exclusively a crystal-dependent process caused by the massive and abrupt release of intracellular metabolites from chemosensitive, rapidly proliferating tumour cells that undergo rapid lysis and release nucleic acid breakdown products, phosphorus and potassium. Both urate and calcium phosphate crystals may cause crystal-dependent injury of the kidney which overwhelms the normal homeostatic mechanism(s) autoregulating normal renal physiology [10]. One of the most important mediators of AKI resulting from TLS is uric acid. When dying cells release DNA and RNA, they are degraded in the liver and other sites with the rapid production of uric acid. Serum uric acid rises acutely, resulting in marked uricosuria. Such cell death and degradation also results in acid generation, often with volume depletion, resulting in acidic urine that decreases the solubility of uric acid. When levels of urinary uric acid exceed its solubility, both micro- and macrocrystal formations occur in the distal tubules and collecting ducts with obstruction of the tubular lumen. The prevention of AKI resulting from TLS includes initiating prophylactic measures prior to and during chemotherapy, including hydration, alkalinization of the urine, use of the xanthine oxidase inhibitor allopurinol, as well as the urate oxidase inhibitor, rasburicase or its derivatives.

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.

An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome

Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic disorder that occurs when tumor cells undergo rapid decomposition spontaneously or in response to cytoreductive therapy. Delayed recognition of the metabolic imbalances caused by the massive release of tumor cell contents may result in clinical complications such as acute kidney injury, seizures, and cardiac arrhythmias. Prevention, the key principle in TLS management, relies on the identification of patients at risk for developing TLS during chemotherapy or because of disease progression. TLS-related risk factors pertain to tumor type (particularly hematologic malignancies), specific tumor characteristics (e.g. bulky tumor, high cellular proliferation rate, sensitivity to cytoreductive therapy), and other host-related factors. A comprehensive grading system proposed by Cairo and Bishop classifies TLS syndromes into laboratory or clinical TLS, thus facilitating TLS prevention and management. The mainstays of TLS management include monitoring of electrolyte abnormalities, vigorous hydration, prophylactic antihyperuricemic therapy with allopurinol, and rasburicase treatment of patients at high TLS risk or with established hyperuricemia. Urine alkalinization and use of diuretics remain controversial clinical practices. In this review, we describe the incidence of, risk factors for, and diagnostic characteristics of TLS and summarize strategies for the prevention and management of TLS-associated metabolic abnormalities, particularly hyperuricemia. We specifically highlight recently published TLS management guidelines, which focus on the prevention of TLS and hyperuricemia based on a patients level of risk, and the important role of nephrologists in the prevention and treatment of one of the most serious complications of TLS, acute kidney injury.

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 blood pressure monitoring may be more useful.

Prophylactic nesiritide does not prevent dialysis or all-cause mortality in patients undergoing high-risk cardiac surgery

OBJECTIVES Natriuretic peptides have been shown to improve renal blood flow and stimulate natriuresis. In a recent retrospective trial, we documented that prophylactic use of nesiritide was associated with a 66% reduction in the odds for dialysis or in-hospital mortality at 21 days in patients undergoing high-risk cardiac surgery; therefore, we designed a prospective trial. METHODS This prospective, randomized, clinical trial included 94 patients undergoing high-risk cardiac surgery comparing a 5-day course of continuous nesiritide (at a dose of 0.01 microg x kg(-1) x min(-1) started before surgery) versus placebo. The primary end point was dialysis and/or all-cause mortality within 21 days; secondary end points were incidence of acute kidney injury, renal function, and length of stay. RESULTS Nesiritide did not reduce the primary end point of incidence of dialysis and/or all-cause mortality through day 21 (6.6% vs 6.1%; P = .914). Fewer patients receiving nesiritide had acute kidney injury (defined as an absolute increase in serum creatinine > or = 0.3 mg/dL from baseline or a percentage increase in serum creatinine > or = 50% from baseline within 48 hours) compared with controls (2.2% vs 22.4%; P = .004), and mean serum creatinine was lower in the immediate postoperative period in the nesiritide group (1.18 +/- 0.41 mg/dL vs 1.45 +/- 0.74 mg/dL; P = .028). However, no difference in length of stay was noted (nesiritide 20.73 +/- 3.05 days vs control 21.26 +/- 4.03 days; P = .917). CONCLUSIONS These results do not demonstrate a benefit for prophylactic use of nesiritide on the incidence of dialysis and/or death in patients undergoing high-risk cardiac surgery. Although nesiritide may provide some renal protection in the immediate postoperative period, no effect on length of stay was observed.

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.

Characteristics of 100 Consecutive Patients Presenting With Orthostatic Hypotension

OBJECTIVE To elucidate the demographic and clinical characteristics of a consecutive series of patients who presented for evaluation of orthostatic hypotension. PATIENTS AND METHODS From January 1, 1997, through September 30, 2001, we assessed retrospectively the demographic and clinical characteristics, antihypertensive medication use, and blood pressure variability in 100 consecutive patients with orthostatic hypotension who underwent 24-hour ambulatory blood pressure monitoring (OH group) and in a convenience sample of 100 age-matched patients who underwent 24-hour ambulatory blood pressure monitoring for evaluation of hypertension (HTN group). RESULTS The OH group had a mean +/- SD age of 71.6 +/- 9.4 years, and 42% were women. The most common symptoms were light-headedness and weakness. Comorbid conditions included neurologic diseases (38%), preexisting hypertension (36%), hyperlipidemia (31%), cardiac arrhythmias and coronary artery disease (45%), and neoplasm (28%). During ambulatory blood pressure monitoring, postprandial decreases in blood pressure were noted in 83% of the OH group, supine or sleep hypertension in 84%, and noncompensatory heart rate variability in 75%. Findings on autonomic testing were abnormal in 99% of patients, serum creatinine value was increased in 30%, proteinuria was present in 27%, and left ventricular hypertrophy was present in 20%. CONCLUSIONS Orthostatic hypotension is present in a heterogeneous group of disease states, is usually symptomatic, and is often associated with an abnormal blood pressure profile of reversal of circadian pattern, postprandial hypotension, and noncompensatory heart rate variability. Consequent target organ (kidney) damage can be as frequent as in patients who undergo 24-hour ambulatory blood pressure monitoring for evaluation of hypertension.

Post-operative serum uric acid and acute kidney injury.

BACKGROUND We hypothesized that post-operative serum uric acid (SUA) may be associated with acute kidney injury (AKI). METHODS In this prospective, observational study, the relationships between SUA, urine neutrophil gelatinase-associated lipocalin (uNGAL) and interleukin-18 (uIL-18), serum monocyte chemoattractant protein-1 (sMCP-1) and tumor necrosis factor-alpha (sTNF-alpha), and incidence of AKI were determined. SUA were divided into tertiles and their association with AKI investigated. RESULTS A total of 100 cardiac surgery patients were included for analyses. The 1st, 2nd, and 3rd SUA tertiles were associated with 15.1%, 11.7%, and 54.5% incidence of AKI, respectively. The 3rd SUA tertile, compared to the referent 1st tertile, was associated with an eightfold (OR 8.38, CI95% 2.13-33.05, p=0.002) increased risk for AKI. Patients with AKI on post-operative day 1 (n=11) were then excluded for the purpose of determining the predictive value of SUA to diagnose AKI on postoperative day 2 and during hospital stay. In comparison to the referent 1st tertile, the 3rd tertile SUA was associated with an eightfold increased risk for AKI on post-operative day 2 (adjusted OR 7.94, CI95% 1.50-42.08, P=.015) and a five-fold increased risk for AKI during hospital stay (OR 4.83, CI95% 1.21-19.20, P=.025), respectively. SUA (Area Under Curve, AUC 0.77 (CI95% 0.66-0.88, P<.001), serum creatinine (0.73, CI95% 0.62-0.84, P<.001) and sTNF-alpha (0.76, CI95% 0.65-0.87, P<.001) had the best diagnostic performance measured by the Receiver Operating Characteristics curves. CONCLUSIONS We conclude that post-operative SUA is associated with an increased risk for AKI and compares well to conventional markers of AKI.