Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017 : Expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine.

BACKGROUND: Acute kidney injury (AKI) in the intensive care unit is associated with significant mortality and morbidity. OBJECTIVES: To determine and update previous recommendations for the prevention of AKI, specifically the role of fluids, diuretics, inotropes, vasopressors/vasodilators, hormonal and nutritional interventions, sedatives, statins, remote ischaemic preconditioning and care bundles. METHOD: A systematic search of the literature was performed for studies published between 1966 and March 2017 using these potential protective strategies in adult patients at risk of AKI. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, exposure to potentially nephrotoxic drugs and radiocontrast. Clinical endpoints included incidence or grade of AKI, the need for renal replacement therapy and mortality. Studies were graded according to the international GRADE system. RESULTS: We formulated 12 recommendations, 13 suggestions and seven best practice statements. The few strong recommendations with high-level evidence are mostly against the intervention in question (starches, low-dose dopamine, statins in cardiac surgery). Strong recommendations with lower-level evidence include controlled fluid resuscitation with crystalloids, avoiding fluid overload, titration of norepinephrine to a target MAP of 65-70 mmHg (unless chronic hypertension) and not using diuretics or levosimendan for kidney protection solely. CONCLUSION: The results of recent randomised controlled trials have allowed the formulation of new recommendations and/or increase the strength of previous recommendations. On the other hand, in many domains the available evidence remains insufficient, resulting from the limited quality of the clinical trials and the poor reporting of kidney outcomes.

Renal recovery after acute kidney injury.

Acute kidney injury (AKI) is a frequent complication of critical illness and carries a significant risk of short- and long-term mortality, chronic kidney disease (CKD) and cardiovascular events. The degree of renal recovery from AKI may substantially affect these long-term endpoints. Therefore maximising recovery of renal function should be the goal of any AKI prevention and treatment strategy. Defining renal recovery is far from straightforward due in part to the limitations of the tests available to assess renal function. Here, we discuss common pitfalls in the evaluation of renal recovery and provide suggestions for improved assessment in the future. We review the epidemiology of renal recovery and of the association between AKI and the development of CKD. Finally, we stress the importance of post-discharge follow-up of AKI patients and make suggestions for its incorporation into clinical practice. Summary key points are that risk factors for non-recovery of AKI are age, CKD, comorbidity, higher severity of AKI and acute disease scores. Second, AKI and CKD are mutually related and seem to have a common denominator. Third, despite its limitations full recovery of AKI may best be defined as the absence of AKI criteria, and partial recovery as a fall in AKI stage. Fourth, after an episode of AKI, serial follow-up measurements of serum creatinine and proteinuria are warranted to diagnose renal impairment and prevent further progression. Measures to promote recovery are similar to those preventing renal harm. Specific interventions promoting repair are still experimental.

Recovery from AKI in the critically ill: potential confounders in the evaluation.

PURPOSE: Studies on recovery from acute kidney injury (AKI) in ICU patients yield variable results. We assessed the impact of different recovery definitions, of different exclusion criteria, and of imputing missing baseline creatinine on AKI recovery in a heterogeneous ICU population. METHODS: Secondary analysis of the EPaNIC database. Recovery of kidney function in patients who developed AKI in ICU was assessed at hospital discharge. We studied recovery rates of different AKI stages with different definitions of recovery after inclusion or exclusion of non-survivors and in patients with or without chronic kidney disease (CKD). In addition, the impact of imputing missing baseline creatinine was investigated. RESULTS: A total of 1310 AKI patients were studied of which 977 were discharged alive from hospital. Rate of complete recovery (absence of KDIGO criteria) was markedly higher in survivors than in all AKI patients (79.5 vs 67.0%), especially for more severe forms of AKI. For patients with CKD, only the need for renal replacement therapy worsened kidney outcome as compared with no-CKD patients. Using stricter definitions of complete recovery significantly reduced its occurrence. New or worsening CKD occurred in 30% of AKI survivors. In no-CKD patients with available baseline creatinine, using an imputed baseline did not affect recovery. Patients with unavailable baseline creatinine were different from those with known baseline and revealed different recovery patterns. CONCLUSION: These results indicate the need for rigorous description of AKI severity, the included population, definitions, and baseline creatinine handling in reports on AKI recovery.

The impact of using estimated GFR versus creatinine clearance on the evaluation of recovery from acute kidney injury in the ICU.

PURPOSE: To quantify the error in evaluating recovery from acute kidney injury (AKI) with estimated GFR (eGFR) in relation to ICU stay. METHODS: Secondary analysis performed on the database of the EPaNIC trial. In a cohort of patients who developed AKI during ICU stay we compared eGFR with measured creatinine clearance (Clcr) at ICU discharge. Recovery of kidney function was assessed by comparison with baseline eGFR and the accuracy of eGFR to detect "potential CKD status" defined by Clcr was quantified. The same analysis was performed in subgroups with different ICU stay. Multivariate regression was performed to determine independent predictors of the eGFR-Clcr difference. RESULTS: A total of 757 patients were included. The bias (limits of agreement (LOA)) between eGFR and Clcr at ICU discharge related to ICU stay, increasing from +1.3 (-37.4/+40) ml/min/1.73 m(2) in patients with short stay to +34.7 (-54.4/+123.8) ml/min/1.73 m(2) in patients with ICU stay of more than 14 days. This resulted in a significantly different incidence of complete recovery with the two evaluation methods and reduced sensitivity to detect "potential CKD status" with eGFR in patients with prolonged ICU stay. Independent predictors of the bias included creatinine excretion on the last day in ICU, baseline eGFR, ICU stay, gender, and age. CONCLUSION: Compared to Clcr, discharge eGFR results in overestimation of renal recovery in patients with prolonged ICU stay and in reduced accuracy of "CKD staging". Since age, gender and race do not change during ICU stay the same conclusion can be drawn with regard to plasma creatinine.

Prevention of cardiac surgery-associated acute kidney injury.

Numerous strategies have been evaluated to prevent early CSA-AKI. Although correction of hemodynamic problems is paramount, there are no clinical studies that compare different hemodynamic management or monitoring strategies with regard to their effect on kidney function. Pharmacologic strategies including diuretics, different classes of vasodilators and drugs with anti-inflammatory effects such as N-acetyl-cysteine, do not appear to be effective. Most of the studies are underpowered and use physiological rather than clinical endpoints. Further trials are warranted with fenoldopam and nesiritide (rhBNP). Observational and underpowered randomized studies show beneficial renal effects of off-pump technique and avoidance of aortic manipulation. There is very limited evidence for preoperative fluid loading and preemptive RRT. Potentially nephrotoxic agents should be used with caution in patients at risk of CSA-AKI. Tranexamic acid or aminocaproic acid should be preferred over aprotinin. No pharmacologic intervention has been adequately tested in the prevention of late CSA-AKI. A singlecenter study, including a predominance of patients after cardiac surgery, showed a decrease of kidney injury with tight glycemic control.

The kidney in the critically ill.

Acute kidney injury (AKI) is a common and serious complication in the intensive care setting. It seldom occurs in isolation, but is mostly part of a multiple organ dysfunction syndrome. The pathogenesis is frequently multifactorial, with sepsis contributing to 50% of the cases.The development of AKI in critically-ill patients is "bad news": patients with AKI have a high morbidity and mortality. In addition, AKI, even in its mildest from, is not only a marker of illness severity but appears to be independently associated with mortality. Prevention of AKI is therefore a major goal to improve outcome of critically-ill patients. Treatment of established AKI is largely supportive. The optimal modality for renal replacement therapy in critically-ill patients still remains a matter of debate). The majority of survivors recover renal function.

Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury.

Using a large, international cohort, we sought to determine the effect of initial technique of renal replacement therapy (RRT) on the outcome of acute renal failure (ARF) in the intensive care unit (ICU). We enrolled 1218 patients treated with continuous RRT (CRRT) or intermittent RRT (IRRT) for ARF in 54 ICUs in 23 countries. We obtained demographic, biochemical and clinical data and followed patients to either death or hospital discharge. Information was analyzed to assess the independent impact of treatment choice on survival and renal recovery. Patients treated first with CRRT (N=1006, 82.6%) required vasopressor drugs and mechanical ventilation more frequently compared to those receiving IRRT (N=212, 17.4%), (p<0.0001). Unadjusted hospital survival was lower (35.8% vs. 51.9%, p<0.0001). However, unadjusted dialysis-independence at hospital discharge was higher after CRRT (85.5% vs. 66.2%, p<0.0001). Multivariable logistic regression showed that choice of CRRT was not an independent predictor of hospital survival or dialysis-free hospital survival. However, the choice of CRRT was a predictor of dialysis independence at hospital discharge among survivors (OR: 3.333, 95% CI: 1.845 - 6.024, p<0.0001). Further adjustment using a propensity score did not significantly change these results. We conclude that worldwide, the choice of CRRT as initial therapy is not a predictor of hospital survival or dialysis-free hospital survival but is an independent predictor of renal recovery among survivors.

Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based?

OBJECTIVES: Critical illness increases the tendency to both coagulation and bleeding, complicating anticoagulation for continuous renal replacement therapy (CRRT). We analyzed strategies for anticoagulation in CRRT concerning implementation, efficacy and safety to provide evidence-based recommendations for clinical practice. METHODS: We carried out a systematic review of the literature published before June 2005. Studies were rated at five levels to create recommendation grades from A to E, A being the highest. Grades are labeled with minus if the study design was limited by size or comparability of groups. Data extracted were those on implementation, efficacy (circuit survival), safety (bleeding) and monitoring of anticoagulation. RESULTS: Due to the quality of the studies recommendation grades are low. If bleeding risk is not increased, unfractionated heparin (activated partial thromboplastin time, APTT, 1-1.4 times normal) or low molecular weight heparin (anti-Xa 0.25-0.35 IU/l) are recommended (grade E). If facilities are adequate, regional anticoagulation with citrate may be preferred (grade C). If bleeding risk is increased, anticoagulation with citrate is recommended (grade D(-)). CRRT without anticoagulation can be considered when coagulopathy is present (grade D(-)). If clotting tendency is increased predilution or the addition of prostaglandins to heparin may be helpful (grade C(-)). CONCLUSION: Anticoagulation for CRRT must be tailored to patient characteristics and local facilities. The implementation of regional anticoagulation with citrate is worthwhile to reduce bleeding risk. Future trials should be randomized and should have sufficient power and well defined endpoints to compensate for the complexity of critical illness-related pro- and anticoagulant forces. An international consensus to define clinical endpoints is advocated.

Do we have reliable biochemical markers to predict the outcome of critical illness?

Current outcome prediction in critically ill patients relies on the art of clinical judgement and/or the science of prognostication using illness severity scores. The biochemical processes underlying critical illness have increasingly been unravelled. Several biochemical markers reflecting the process of inflammation, immune dysfunction, impaired tissue oxygenation and endocrine alterations have been evaluated for their predictive power in small subpopulations of critically ill patients. However, none of these parameters has been validated in large populations of unselected ICU patients as has been done for the illness severity and organ failure scores. A simple biochemical predictor of ICU mortality will probably remain elusive because the processes underlying critical illness are very complex and heterogeneous. Future prognostic models will need to be far more sophisticated.

Anticoagulation for continuous renal replacement therapy.

Anticoagulation during continuous renal replacement therapy should aim for an optimal filter performance allowing the delivery of an adequate dose of renal replacement therapy. On the other hand, the patient's safety should not be endangered. Although numerous options have been proposed, none of them appears to be ideal. Unfractionated heparin is still the most widely used anticoagulant. Reported experience with low-molecular-weight heparin is limited and does not confirm the anticipated increased safety. Regional citrate anticoagulation has been shown to reduce bleeding complications during continuous haemodialysis. A recent report demonstrates the feasibility and safety of citrate anticoagulation during continuous predilution haemofiltration. However, its use is labour intensive and the prevention of side-effects requires meticulous monitoring. Hirudin, a selective thrombin inhibitor, appears to be a suitable, although not completely safe, alternative in patients with heparin-induced thrombocytopenia. Continuous renal replacement therapy without anticoagulation may result in acceptable filter lives in patients with reduced coagulatory potential or an increased risk of bleeding. Although receiving little attention in the literature, the adequate selection of treatment characteristics may also contribute to an improved filter performance.

Intensive insulin therapy in critically ill patients.

BACKGROUND: Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. METHODS: We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]). RESULTS: At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care. CONCLUSIONS: Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.

Non-renal indications for continuous renal replacement therapy.

While there is clear support for the use of continuous renal replacement therapy (CRRT) in critically ill acute renal failure patients, there are other illnesses without renal involvement where CRRT might be of value. These include sepsis and other inflammatory syndromes such as acute respiratory distress syndrome (ARDS) and cardiopulmonary bypass where removal of inflammatory mediators by hemofiltration is hypothesized to improve outcome. Adsorption appears to be the predominant mechanism of mediator elimination. However, the observed hemodynamic improvement can, at least partially, be attributed to a reduction of body temperature or to fluid removal, and the evidence for a clinically important removal of proinflammatory cytokines remains limited. Continuous and therefore smooth fluid removal may improve organ function in ARDS, after surgery with cardiopulmonary bypass, and in patients with refractory congestive heart failure. Continuous removal of endogenous toxins, eventually combined with intermittent hemodialysis, is probably beneficial in inborn errors of metabolism, severe lactic acidosis, or tumor lysis syndrome.

Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues.

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.