Monica Bonello

North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS-AKI): Targeting the Problem with the RIFLE Criteria

Acute kidney injury (AKI) in the intensive care unit (ICU) is associated with an enhanced mortality. The Acute Dialysis Quality Initiative group has proposed the RIFLE (Risk-Injury-Failure-Loss-ESRD) classification to standardize the approach to AKI. This study was performed to estimate the AKI incidence in ICU patients in northeastern Italy and describe clinical characteristics and outcomes of patients with AKI on the basis of their RIFLE class. A prospective multicenter observational study was performed of patients who fulfilled AKI criteria in 19 ICU in northeastern Italy. Data were analyzed using multivariate logistic regression and survival curve analysis. Of 2164 ICU patients who were admitted during the study period, 234 (10.8%; 95% confidence interval 9.5 to 12.1%) developed AKI; 19% were classified as risk (R), 35% as injury (I), and 46% as failure (F). Preexisting kidney disease was present in 36.8%. The most common causes of AKI were prerenal causes (38.9%) and sepsis (25.6%). At diagnosis of AKI, median serum creatinine and urine output were 2.0 mg/dl and 1100 ml/d, respectively. ICU mortality was 49.5% in class F, 29.3% in I, and 20% in R. Independent risk factors for mortality included RIFLE class, sepsis, and need for renal replacement therapy, whereas a postsurgical cause of AKI, exposure to nephrotoxins, higher serum creatinine, and urine output were associated with lower mortality risk. In this study, AKI incidence in the ICU was between 9 and 12%, with 3.3% of ICU patients requiring renal replacement therapy. Sepsis was a significant contributing factor. Overall mortality was between 30 and 42%, and was highest among those in RIFLE class F.

Extracorporeal Therapies in Non-Renal Disease: Treatment of Sepsis and the Peak Concentration Hypothesis

In the setting of intensive care, patients with acute renal failure often present a clinical picture of the systemic inflammatory response syndrome (SIRS). SIRS can be caused by bacterial stimuli or by non-microbiological stimuli that induce a significant inflammatory response. When this response is exaggerated, the patient experiences multiple organ system failure and a condition of sepsis also defined as a systemic malignant inflammation. This is mostly characterized by an invasion of cytokines and other pro-inflammatory mediators into the systemic circulation where major biological effects take place, including vasopermeabilization, hypotension and shock. At the same time, the monocyte of the septic patient seems to be hyporesponsive to inflammatory stimuli to a certain extent. In this condition, the patient faces a situation of hyperinflammation but at the same time of immunodepression expressing a clinical entity defined as counter anti-inflammatory response syndrome. The general picture of the clinical disorder is therefore better characterized by an immunodysregulation than by a simple pro- or anti-inflammatory disorder. Due to the short half-life of cytokines and other mediators spilled over into the circulation, it is extremely difficult to approach the problem at the right moment with the right pharmacological agent. For these reasons, the peak concentration hypothesis suggests that continuous renal replacement therapies, due to their continuity and unspecific capacity of removal, might be beneficial in cutting the peaks of the concentrations of both pro- and anti-inflammatory mediators, restoring a situation of immunohomeostasis. Thus the patient may benefit from a lesser degree of immunodysregulation and he/she may restore a close-to-normal capacity of response to exogenous stimuli.

Phosphate Kinetics during Different Dialysis Modalities

Background: An abnormal serum phosphate concentration is common in acute renal failure patients, with a reported incidence of 65–80%. Phosphate removal and kinetics during intermittent hemodialysis (IHD) have been investigated, but there is no information on its kinetics during slow low-efficiency dialysis (SLED) and continuous renal replacement therapy (CRRT). Methods: Eight IHD, 8 SLED, and 10 continuous venovenous hemofiltration (CVVH) patients with a residual renal clearance of <4.0 ml/min were studied during a single treatment to evaluate phosphate removal and kinetics. CVVH was studied the first 24 h after initiation. Dialysis/replacement fluid contained no phosphate. Kt/V, clearance of urea (Ku), inorganic phosphate (Kp) and solute removal was determined by direct dialysate quantification (DDQ). Results: Kp recorded with the three techniques were: IHD, 126.9 ± 18.4 ml/min; SLED, 58.0 ± 15.8 ml/min, and CVVH, 31.5 ± 6.0 ml/min. However, in shorter dialysis treatment the total removal of phosphate was significantly lower than in longer dialysis (IHD, 29.9 ± 7.7 mmol; SLED, 37.6 ± 9.6 mmol; CVVH, 66.7 ± 18.9 mmol, p = 0.001). The duration of treatment is the only factor determining phosphate removal (r = 0.7, p < 0.0001 by linear correlation model). Like IHD, phosphate kinetics during SLED could not be explained by the two-pool kinetic model, and the rebound of phosphate extended beyond 1 h after dialysis. Rebound, however, is less marked than in short dialysis. Conclusion: These results are reliable evidence about amount of phosphate removal and behavior of intradialytic phosphate kinetics in renal failure patients undergoing different dialysis modalities. These data will help clinicians plan phosphate supplementation and treatment intensity.

Reviews: Uremic Toxins: A New Focus on an Old Subject

The uremic syndrome is characterized by an accumulation of uremic toxins due to inadequate kidney function. The European Uremic Toxin (EUTox) Work Group has listed 90 compounds considered to be uremic toxins. Sixty‐eight have a molecular weight less than 500 Da, 12 exceed 12,000 Da, and 10 have a molecular weight between 500 and 12,000 Da. Twenty‐five solutes (28%) are protein bound. The kinetics of urea removal is not representative of other molecules such as protein‐bound solutes or the middle molecules, making Kt/V misleading. Clearances of urea, even in well‐dialyzed patients, amount to only one‐sixth of physiological clearance. In contrast to native kidney function, the removal of uremic toxins in dialysis is achieved by a one‐step membrane‐based process and is intermittent. The resulting sawtooth plasma concentrations of uremic toxins contrast with the continuous function of native kidneys, which provides constant solute clearances and mass removal rates. Our increasing knowledge of uremic toxins will help guide future treatment strategies to remove them.

Pulse High-Volume Hemofiltration in Critically Ill Patients: A New Approach for Patients with Septic Shock

Mortality rates in septic shock remain unacceptably high despite advances in our understanding of the syndrome and its treatment. Humoral factors are increasingly recognized to participate in the pathogenesis of septic shockgiving a biological rationale to therapies that might remove varied and potentially dangerous humoral mediators. While plasma water exchange in the form of hemofiltration can remove circulating cytokines in septic patientsthe procedureas routinely performeddoes not have a substantial impact on their plasma levels. More intensive plasma water exchangeas high‐volume hemofiltration (HVHF)can reduce levels of these mediators and potentially improve clinical outcomes. Howeverthere are concerns about the feasibility and costs of HVHF as a continuous modality—very high volumes are difficult to maintain over 24 hours and solute kinetics are not optimized by this regimen. We propose pulse HVHF (PHVHF)—HVHF of 85 ml/kg/hr for 6–8 hours followed by continuous venovenous hemofiltration (CVVH) of 35 ml/kg/hr for 16–18 hours—as a new method to combine the advantages of HVHFimprove solute kineticsand minimize logistic problems. We treated 15 critically ill patients with severe sepsis and septic shock using daily PHVHF in order to evaluate the feasibility of the techniqueits effects on hemodynamicsand the impact of the treatment on pathologic apoptosis in sepsis. Hemodynamic improvements were obtained after 6 hours of PHVHF and were maintained subsequently by standard CVVHas demonstrated by the reduction in norepinephrine dose. PHVHFbut not CVVHsignificantly reduces apoptotic plasma activity within 1 hour and the pattern was maintained in the following hours. PHVHF appears to be a feasible modality that may provide the same or greater benefits as HVHFwhile reducing the workload and cost.

Oxidant and Carbonyl Stress-Related Apoptosis in End-Stage Kidney Disease: Impact of Membrane Flux

Apoptosis is a highly regulated process which mostly affects cell-mediated immunity. In this open-label, randomized, prospective clinical study, we determined the impact in 10 hemodialysis patients treated with high-, medium-, and low-flux membranes on spontaneous or plasma-induced apoptosis, on monocytes, as well as on oxidant and carbonyl stress. High- and medium-flux membranes significantly reduced patients’ plasma-dependent proapoptotic activity on U937 monocytic cell lines. Patients who had the highest levels of plasma-induced proapoptotic activity exhibited the highest plasma levels of advanced oxidation protein products (AOPPs) and carbonyls. Plasma carbonyl residues but not AOPPs were significantly lowered. Finally, a significant correlation could be drawn between the extent of plasma-induced proapoptotic activity and both plasma carbonyl and AOPP levels.

Rasburicase therapy in acute hyperuricemia and renal dysfunction.

Neoplastic disorders may be complicated by acute renal failure (ARF). Different tumors may cause ARF: solid tumors involving the kidney, solid tumors not of hematological origin and not primarily involving the kidney or, more frequently, rapidly developing hematological tumors. The pathogenesis of ARF is different depending on the type of cancer, but the most frequent clinical feature is the acute tumor lysis syndrome, characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and acute, frequently oliguric, ARF. The presence of a neoplastic disorder and associated acute illness may sometimes lead to the presence of immunodysfunction, septic complications and multiple organ dysfunction. In these settings patients develop systemic inflammation and diffuse endothelial damage, related to different mediators. Among these substances, in cancer patients, high circulating levels of uric acid are a common finding. Hyperuricemia is caused by the increase of purine metabolism, which is result of the increased cellular turnover or the aggressive cancer chemotherapy regimens that worsen cell lysis and release of purine metabolites. Even if hyperuricemia is not the first insult to the kidney, its development might represent a concomitant factor aggravating other previous or simultaneous insults. The most efficient therapy for lowering uric acid is rasburicase, a recombinant form of urate oxidase, a nonhuman proteolytic enzyme that oxidizes uric acid to allantoin. It is efficacious in reducing serum uric acid levels with associated diuresis more effectively and much faster than allopurinol, and to correct renal dysfunction more rapidly than allopurinol.

Continuous Renal Replacement Technology: From Adaptive Technology and Early Dedicated Machines towards Flexible Multipurpose Machine Platforms

Since the initial description of continuous arteriovenous hemofiltration (CAVH) in 1977 by Peter Kramer [1], continuous renal replacement therapies (CRRT) have progressively evolved from a last-chance therapy for acute renal failure (ARF) to a standardized, widely used, fully independent form of artificial kidney support. This happened since the shortcomings of intermittent hemodialysis are becoming more evident, especially when treating critically ill septic patients with multiple organ failure [2]. Moreover, the technology supporting the application of CRRT has greatly improved both as far as the hardware and the software are concerned. The trend of this evolution and the potential of CRRT is today growing to a point in which multiple organ support therapy (MOST) is envisaged as a possible therapeutic approach in the critical care setting [3].

Protective Effect of Urate Oxidase on Uric Acid Induced-Monocyte Apoptosis

Uremic patients have a higher risk of infection and malignancy than normal subjects. Previous studies have deomonstrated that monocytes isolated from uremic patients display an increased apoptosis rate compared to normal subjects; furthermore uremic plasma can increase apoptosis rates on U937, a human monocytic cell line. In several pathological conditions, precipitation of uric acid crystals can lead to renal insufficiency or acute renal failure by different mechanisms. In recent studies uric acid has been shown to induce inflammatory response from monocytes and it has been suggested to be involved in cell dysfunction. Rasburicase is a new recombinant urate oxidase developed to prevent and treat hyperuricaemia in patients with cancer or renal failure; it degrades uric acid to allantoin, a less toxic and more soluble product. In the present study, we aimed at determining whether uric acid may be a factor affecting U937 apoptosis, and whether urate oxidase may reduces or even prevent uric acid induced cell apoptosis. Hoechst staining and internucleosome ledder fragmentation of DNA showed that uric acid increased the percentage of apoptotic cells comparing to the control and that when the U937 cells were incubated with uric acid and urate oxidase the percentage of apoptosis significantly decreased (from 43+/-7% to 19+/- 3%, p<0.05). Also, the activity of caspase-8 and caspase-3 showed the same trend (caspase 3: from 2.7+/-0.53 to 1.6+/-0.42; caspase-8: from 2.2+/-0.43 to 1.3+/-0.57). A reduction of intracellular reduced glutathione (GSH) concentration was found in uric acid treated cells while the addition of urate oxidase in the uric acid incubated cells decreased the GSH extrusion. The concentration of TNF-alpha was increased in the sample incubated with uric acid comparing to the control. Uric acid is an inducer of apoptosis on U937 cell line, and therefore it may be a component of the mosaic of uremic toxins both in acute and chronic renal disease. We can hypothesize that uric acid might be directly involved in the apoptotic process trough the activation of both death receptor and mitochondrial-mediated pathways. We have, also, demonstrated that urate oxidase is able to prevent at least in part, the effect of uric acid on U937 apoptosis. This effect might be a result of different mechanisms of action.

Cadmium Exposure and Kidney Stone Formation in the General Population—An Analysis of the National Health and Nutrition Examination Survey III Data

BACKGROUND AND PURPOSE Cadmium exposure has been associated with a greater risk of kidney stone formation in occupational exposure studies, but data on such an association in the general population are scarce. SUBJECTS AND METHODS We assessed the National Health and Nutrition Examination Survey data from 1988 to 1994 in terms of the risk of stone formation. Persons reporting a history of kidney stones were defined as stone formers (n=749), and the association between a positive history of kidney stones and high environmental cadmium exposure levels (defined as urinary cadmium >1 μg/g) was analyzed by logistic regression analysis, stratifying by sex and adjusting for age, race/ethnicity, body mass index, smoking habits, region of residence, and daily intake of calcium and sodium. RESULTS The odds ratio of lithiasis associated with urinary cadmium >1 μg/g was 1.40 (95% confidence interval 1.06, 1.86) in females (P = 0.019). The association between urinary cadmium and kidney stones was not significant in males. CONCLUSIONS These findings suggest that moderately high levels of urinary cadmium are associated with a greater propensity for kidney stone formation in females in the general population.