Renal medicine in the intensive care unit: a narrative review.

Kidney disease, both acute and chronic, is commonly encountered on the intensive care unit. Due to the role the kidneys play in whole body homeostasis, it follows that their dysfunction has wide-ranging implications and can affect prescribing and therapeutic management. This narrative review discusses the pathophysiology of acute kidney injury and chronic kidney disease, and how this relates to critically unwell patients. We cover several aspects of the management of renal dysfunction on the critical care unit, exploring some of the recurrent themes within the literature, including type and timing of kidney replacement therapy, management of acute kidney injury, as well as discussing how novel biomarkers for acute kidney injury may help to identify patients suffering from acute kidney injury as well as risk stratifying these patients. We discuss how early involvement of specialist nephrology services can improve outcomes in patients with kidney disease as well as offer valuable diagnostic and specialist management advice, particularly for patients with established end stage kidney disease and patients who are already known to nephrology services. We also explore some of the ongoing research questions that need to be answered within this arena.

Renal complications of anaesthesia.

Peri-operative acute kidney injury is common, accounting for 30-40% of all in-hospital cases of acute kidney injury. It is associated with clinically significant morbidity and mortality even with what was hitherto regarded as relatively trivial increases in serum creatinine, and carries over a 12-fold relative risk of death following major abdominal surgery. Comorbid conditions such as diabetes, hypertension, liver disease and particularly pre-existing chronic kidney disease, as well as the type and urgency of surgery, are major risk factors for the development of postoperative acute kidney injury. As yet, there are no specific treatment options for the injured kidney, although there are several modifiable risk factors of which the anaesthetist should be aware. As well as the avoidance of potential nephrotoxins and appropriate volume balance, optimal anaesthetic management should aim to reduce the risk of postoperative renal complications. This may include careful ventilatory management and blood pressure control, as well as appropriate analgesic strategies. The choice of anaesthetic agent may also influence renal outcomes. Rather than concentrate on the classical management of acute kidney injury, this review focuses on the potential development of acute kidney injury peri-operatively, and the means by which this may be ameliorated.

Peri-operative renal dysfunction: prevention and management.

Postoperative increases in serum creatinine concentration, by amounts historically viewed as trivial, are associated with increased morbidity and mortality. Acute kidney injury is common, affecting one in five patients admitted with acute medical disease and up to four in five patients admitted to intensive care, of whom one in two have had operations. This review is focused principally on the identification of patients at risk of acute kidney injury and the prevention of injury. In the main, there are no interventions that directly treat the damaged kidney. The management of acute kidney injury is based on correction of dehydration, hypotension, and urinary tract obstruction, stopping nephrotoxic drugs, giving antibiotics for bacterial infection, and commencing renal replacement therapy if necessary.

Introduction of an electronic physiological early warning system: effects on mortality and length of stay.

BACKGROUND: The Worthing physiological scoring system (PSS) was first validated in 2005 as a tool to predict hospital mortality on admission and was subsequently introduced into clinical practice at Worthing Hospital, UK. Five years on, this study was conducted to determine the effects on mortality and length of stay (LOS) after the introduction of electronic alerting software using the PSS. In addition, we investigated whether the Worthing PSS predictive ability could be improved by addition of further variables. METHODS: Prospective observational study conducted in the acute medical unit, Worthing Hospital, UK. Patient physiological data on admission and discharge/transfer were collected between February and July 2010 from the electronic alerting software VitalPAC™. Patient characteristics, co-morbidity, outcomes, and biochemistry data were taken from the hospital administration and pathology systems. RESULTS: The observed mortality reduction from 8.3% to 5.2% over 5 yr was not statistically significant after adjustment for admission Worthing PSS score. Median LOS was reduced from 4 to 2 days, but this reflected an increase in short stay admissions. Worthing PSS was not significantly improved with the addition of biochemical variables or patient co-morbidity. A score taken before admission to a medical ward showed an improved predictive ability when compared with the initial admission score, but further analysis found no additional clinical benefit. CONCLUSIONS: The introduction of an electronic alerting PSS did not lead to a reduction in mortality when adjusted for severity of illness defined by physiological variables. Predictive performance was not enhanced by the addition of biochemical variables and co-morbidities.

Withdrawal of active treatments in terminally ill heart failure patients.

INTRODUCTION: Heart failure (HF) constitutes a growing public health problem in aging societies: when pharmacological therapies fail, HF can be sustained intensively if patients are eligible for either orthotopic heart transplantation (OHT) or mechanical ventricular assistance, otherwise additional treatments could be inappropriate. In December 2017 Italian Legislator brought in the provisions regarding the end-of-life choices, including indications for withdrawing and withholding life-sustaining therapies. The aim of our study was to provide an overview of the daily practice of our center with regard to terminally ill HF patients. METHODS AND RESULTS: In April 2019 the 7 intensivist cardiologists and 21 nurses of a tertiary ICCU were asked in, to complete a questionnaire relating to a hypothetical terminally ill HF patient for whom the decision to withdraw active treatment had been made. To assess current practice, we also identified patients who died in the previous 12 months. Out of 29 deceased patients, 18 were identified as terminally ill HF, with no indications for therapy upgrading. We observed a striking disparity between belief and practice. CONCLUSIONS: Our survey showed that the care of terminally ill HF patients in our ICCU was characterized by aggressive use of medical therapy and invasive technology. The wide disparity between belief and practice could be in part a consequence of lack of professional training, with regard to law, ethics and communication techniques.

Shared antigenic determinants by mitogen receptors and antibody molecules to the same thymus-independent antigen.

The antibody response to dextran B1355 is thymus independent, and in high responder mice, over 90% of the antibodies carry the idiotype of an alpha-1,3 binding myeloma protein (J558). The present experiments demonstrate: (a) dextran B1355 is a B-cell mitogen both in a strain which carries the J558 idiotype on antibodies and in a low-responder strain which does not express that idiotype on antibodies to dextran; (b) anti-idiotypic antibodies to J558 recognize a dextran-specific surface receptor on 10--15% of all splenic B cells in those two strains as well as in all strains so far tested; (c) as shown by inhibition experiments such surface receptors cross-react with J558, and (d) anti-idiotypic antibodies are mitogenic for spleen cells of both strains resulting in B-cell proliferation and maturation to polyclonal antibody secretion.

Immunoglobulin spots on the surface of rabbit lymphocytes.

Small and medium lymphocytes from the peripheral blood and lymphoid tissues of the rabbit react in suspension with antibodies directed against different immunoglobulin determinants. Through immunofluorescence, it was possible to show that numerous discrete spots on the surface of the positive lymphocytes carry immunoglobulin molecules. The positive lymphocytes are about one-half of all lymphocytes in the different preparations; thymus lymphocytes are all negative. With antisera specific for rabbit IgM as well as with antisera directed against allotypic determinants specific for IgM or IgG, it was possible to show that about nine-tenths of the immunoglobulin-positive lymphocytes carry IgM molecules on their surface. With antisera directed against a- and b-locus determinants, it was also possible to demonstrate that both heavy and light chains were present in the surface immunoglobulins. Furthermore, in animals which were heterozygous at the a or the b locus, it was found that each lymphocyte had immunoglobulins synthesized under the influence of only one of two alleles. A very small proportion of lymphocytes could be shown to have a specific surface reaction with one antigen (horse ferritin); the proportion of these cells increased very much after immunization.

Blocking and redistribution ("capping") of antigen receptors on T and B lymphocytes by anti-immunoglobulin antibody.

Antigen-binding T and B lymphocytes were studied by combined autoradiography and immunofluorescence; mouse spleen lymphocytes binding the antigens, [(125)I]MSH or [(125)I]TIGAL, were incubated with rhodamine-labeled anti-Ig reagents or with a rhodamine-labeled IgG fraction of anti-theta serum. B cells were identified as Ig+ or theta-, T cells as Ig- or theta+. It was found that: (a) 20% (1-2 mo after priming) to 30% (3.5-4 mo after priming) of the antigen-binding cells were T cells. (b) The range of antigen molecules bound by B and T cells was similar. (c) Binding of antigen to B and T cells was inhibited by polyvalent anti-Ig, anti-micro, or anti-L reagents. Binding to T cells was more readily inhibited than to B cells. Normal rabbit serum, antimouse lymphocyte serum, or anti-theta did not inhibit antigen binding. (d) When Ig at the surface of B cells was induced, by noninhibiting concentrations of anti-Ig reagents, to redistribute into polar caps and the cells subsequently exposed to [(125)I)antigen under noncapping conditions, the [(125)I]antigen silver grains were distributed in caps superimposed on the Ig fluorescent cap. Of crucial importance, antigen was found in cap in the same proportion of T cells as B cells. Significant capping of antigen receptors was not induced in B or T cells with normal rabbit serum or by anti-Ig reagents absorbed with mouse Ig. The main conclusions of this series of experiments using direct visualization of antigen-binding B and T lymphocytes is that T cells have antigen-specific receptors, probably of IgM nature, and that the number of these receptors appears to range in the order of thousands.

Immunoglobulin D as a lymphocyte receptor.

A large proportion of the human peripheral blood lymphocytes of adults and newborns having IgD were found also to have IgM on their membranes and vice versa. A few lymphocytes had one of these classes only. IgD and IgM could be capped independently on the same cell. The possibility that IgD was acquired by a cytophilic process was excluded by the finding that IgD-bearing cells were of one light chain type only, and by the direct demonstration of reappearance of IgD on the lymphocyte membrane during incubation in an IgD-free culture medium. On the basis of these findings, it is proposed that IgD functions as a lymphocyte antigen receptor.

IgM-producing tumors in the BALB-c mouse: a model for B-cell maturation.

Five adjuvant induced BALB/c tumors producing IgM-McPc 1748, W 3469, TEPC 183, McPc 774, and Y 5781-were characterized morphologically by electron microscopy, analysis of the distribution of surface-bound and intracytoplasmic IgM using immunofluorescence, and by biochemical study of IgM synthesis, turnover, and secretion. The cells of different tumors appear to represent different stages in B-cell maturation when compared to normal, lipopolysaccharide-stimulated B cells. Thus, McPc 1748 tumor cells resemble 10-25-h stimulated normal B cells, 3469 cells resemble 20-35-h stimulated B cells, TEPC 183 cells resemble 45-65-h stimulated B cells, Y 5781 cells resemble 80-110-h stimulated B cells, and McPc 774 cells resemble 100-130-h stimulated B cells.

Switch in immunoglobulin class production observed in single clones of committed lymphocytes.

Mouse spleen cells, after stimulation with lipopolysaccharide, were cloned in culture. After 4 to 5 days, the daughter cells were stained and examined for immunoglobulin class with double immunofluorescent reagents. A switch of the stained color of these cells was observed, implying a switch from imunoglobulin M to immunoglobulin G production in the progeny of a single B cell.

Report of the first AKI Round Table meeting: an initiative of the ESICM AKI Section.

PURPOSE: Critical Care Nephrology is an emerging sub-specialty of Critical Care. Despite increasing awareness about the serious impact of acute kidney injury (AKI) and renal replacement therapy (RRT), important knowledge gaps persist. This report represents a summary of a 1-day meeting of the AKI section of the European Society of Intensive Care Medicine (ESICM) identifying priorities for future AKI research. METHODS: International Members of the AKI section of the ESICM were selected and allocated to one of three subgroups: "AKI diagnosis and evaluation", "Medical management of AKI" and "Renal Replacement Therapy for AKI." Using a modified Delphi methodology, each group identified knowledge gaps and developed potential proposals for future collaborative research. RESULTS: The following key research projects were developed: Systematic reviews: (a) epidemiology of AKI with stratification by patient cohorts and diagnostic criteria; (b) role of higher blood pressure targets in patients with hypertension admitted to the Intensive Care Unit, and (c) specific clearance characteristics of different modalities of continuous renal replacement therapy (CRRT). Observational studies: (a) epidemiology of critically ill patients according to AKI duration, and (b) current clinical practice of CRRT. Intervention studies:( a) Comparison of different blood pressure targets in critically ill patients with hypertension, and (b) comparison of clearance of solutes with various molecular weights between different CRRT modalities. CONCLUSION: Consensus was reached on a future research agenda for the AKI section of the ESICM.

Predicting AKI in emergency admissions: an external validation study of the acute kidney injury prediction score (APS).

OBJECTIVES: Hospital-acquired acute kidney injury (HA-AKI) is associated with a high risk of mortality. Prediction models or rules may identify those most at risk of HA-AKI. This study externally validated one of the few clinical prediction rules (CPRs) derived in a general medicine cohort using clinical information and data from an acute hospitals electronic system on admission: the acute kidney injury prediction score (APS). DESIGN, SETTING AND PARTICIPANTS: External validation in a single UK non-specialist acute hospital (2013-2015, 12 554 episodes); four cohorts: adult medical and general surgical populations, with and without a known preadmission baseline serum creatinine (SCr). METHODS: Performance assessed by discrimination using area under the receiver operating characteristic curves (AUCROC) and calibration. RESULTS: HA-AKI incidence within 7 days (kidney disease: improving global outcomes (KDIGO) change in SCr) was 8.1% (n=409) of medical patients with known baseline SCr, 6.6% (n=141) in those without a baseline, 4.9% (n=204) in surgical patients with baseline and 4% (n=49) in those without. Across the four cohorts AUCROC were: medical with known baseline 0.65 (95% CIs 0.62 to 0.67) and no baseline 0.71 (0.67 to 0.75), surgical with baseline 0.66 (0.62 to 0.70) and no baseline 0.68 (0.58 to 0.75). For calibration, in medicine and surgical cohorts with baseline SCr, Hosmer-Lemeshow p values were non-significant, suggesting acceptable calibration. In the medical cohort, at a cut-off of five points on the APS to predict HA-AKI, positive predictive value was 16% (13-18%) and negative predictive value 94% (93-94%). Of medical patients with HA-AKI, those with an APS ≥5 had a significantly increased risk of death (28% vs 18%, OR 1.8 (95% CI 1.1 to 2.9), p=0.015). CONCLUSIONS: On external validation the APS on admission shows moderate discrimination and acceptable calibration to predict HA-AKI and may be useful as a severity marker when HA-AKI occurs. Harnessing linked data from primary care may be one way to achieve more accurate risk prediction.

Acute kidney injury associated with endurance events-is it a cause for concern? A systematic review.

INTRODUCTION: A growing body of evidence suggests even small rises in serum creatinine (SCr) are of considerable clinical relevance. Given that participants in endurance events are exposed to potential (repeated) renal insults, a systematic review was undertaken to collate current evidence for acute kidney injury (AKI), complicating such events. METHODS: A systematic review of studies and case reports meeting inclusion criteria on Medline and EMBASE (inception to October 2015). Included: studies with markers of renal function before and after endurance or ultraendurance events; case reports of severe AKI. Two reviewers assessed risk of bias using the Newcastle-Ottawa scale. RESULTS: Eleven case report publications (n=27 individuals) of severe AKI, were retrieved, with risk factors including systemic illness or nephrotoxic medications usually identified. From 30 studies of endurance and ultraendurance events, mean rise in SCr was 29 (±12.3) µmol/L after marathon or ultramarathon (17 studies, n=568 participants) events. Where follow-up tests were conducted, SCr returned to baseline within 48 hours. Rises in biomarkers suggest potential parenchymal insult, rather than simply muscle breakdown. However, evidence of long-term deleterious effects is lacking. CONCLUSIONS: Raised levels of SCr are reported immediately after endurance events. It is not clear whether this is either clinically significant, or if repeated participation predisposes to long-term sequelae. The aetiology of severe exercise-associated AKI is usually multifactorial, with risk factors generally identified in the rare cases reported. On-site biochemistry, urine analysis and biomarkers of AKI may help identify collapsed runners who are at significant short-term risk and allow suitable follow-up.

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.

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.

An investigation of the novel anti-inflammatory agents ONO-3144 and MK-447. Studies on their potential antioxidant activity.

Oxygen-derived free radicals have been implicated as contributors to inflammatory disorders and it has been suggested that certain anti-inflammatory drugs act by scavenging free radicals. In this paper we have studied the free radical scavenging activity of two such experimental anti-inflammatory drugs MK-447 and ONO-3144. Using the technique of pulse radiolysis we have been able to obtain rate constants for the reactions of these compounds with specific free radicals including OH and O2-. We have also investigated the antioxidant capacity of these compounds using rat liver microsomal lipid peroxidation systems. It is suggested that this approach yielding quantitative data concerning defined free radical species will lead to a better understanding of the role of radical scavenging in anti-inflammatory activity.

The enhancement of antibody response by IgM antibodies is dependent on antigen-specific T helper cells.

The enhancement of antibody responses by IgM antibodies administered with low doses of antigen has been studied in a T-dependent (SRBC) and an T-independent (alpha 1,6 dextran) system. It has been found that IgM anti-SRBC antibodies do not enhance a SRBC response in nude mice. The T-cell dependency was also directly demonstrated by showing the effect of IgM on T-cell priming in transfer experiments. The simultaneous injection of antigen and IgM antibody also induced a polyclonal increase of IgM, PFC, which was not due to a non-specific "adjuvant" effect of IgM, as we could not detect a similar effect on an ongoing response to HRBC in mice simultaneously given SRBC and IgM anti-SRBC antibodies. The specificity of the helper cell for either the antibody or the antigen was investigated in a response to alpha 1, 6 dextran, in which we could demonstrate antibody-specific helper T cells, but no antigen-specific help. We have found that IgM anti-dextran antibodies do not enhance and rather suppress the response of normal, high-responder mice, to dextran, suggesting that the T cells mediating the "19S enhancement" are antigen-specific. The magnitude of the enhancement response, as compared to the responses induced by either antigen or antibody alone, implies a synergistic mechanism, possibly involving antigen-specific and antibody(idiotype)-specific T helper cells.