Abstract
Acute kidney injury (AKI) is common in critically ill patients and associated with grim short- and long-term outcome. Although in the vast majority of cases AKI is multifactorial, with sepsis, shock and nephrotoxicity accounting for most episodes, specific causes of AKI are not uncommon. Despite remaining uncertainties regarding their prevalence in the ICU, prompt recognition of specific aetiologies of AKI is likely to ensure timely management, limit worsening of renal dysfunction, and ultimately limit renal and systemic consequences of AKI. The ability to recognize conditions that may be associated with specific aetiologies and the appropriate use of clinical imaging, biological and immunological tests, along with optimal assessment of the need for renal biopsies, should be part of routine ICU care. In this review, we summarize uncertainties, current knowledge and recent advances regarding specific types of AKI. We describe the most common specific causes as well as rare aetiologies requiring urgent management, and outline available tools that may be used during the diagnostic work-up along with their limitations.
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Introduction
Acute kidney injury (AKI) can portend an incremental risk for short- and long-term complications including fatal outcome [1], nephron loss along with risk of chronic kidney disease (CKD) or end-stage kidney disease (ESKD) [2]. In intensive care unit (ICU) settings, up to 60% of patients develop AKI and up to 12% of patients require renal replacement therapy (RRT) [1]. Although the vast majority of AKI is multifactorial, with sepsis, shock and nephrotoxicity accounting for most episodes [1, 3], it is important to remember that critically ill patients may also present with specific types of AKI requiring targeted diagnostic work-up and treatment.
In this review, we will summarize uncertainties, current knowledge and recent advances regarding specific types of AKI, and outline available tools that may be used during the diagnostic work-up.
Diagnosis of AKI and Input of biomarkers
The Kidney Disease Improving Global Outcomes (KDIGO) guideline defines AKI as an abrupt decrease of kidney function over a period of 7 days or less based on a rise in serum creatinine or an episode of oliguria [4]. For patients whose renal function returns to baseline within 48 h, the Acute Disease Quality Initiative (ADQI) 16 conference proposed to use the term “rapid reversal” of AKI, while “persistent AKI” is characterized by a duration beyond 48 h [5]. In patients with persistent AKI, it is essential to determine its underlying aetiology. In addition, it is recommended to evaluate the haemodynamic and volume status, and to identify complications that may indicate the need for RRT. A period of renal dysfunction that persists for >7 days is categorized as Acute Kidney Disease (AKD) [4, 5], and the term Chronic Kidney Disease (CKD) is used for patients with kidney disease persistent after 90 days [4, 5].
The KDIGO definition for AKI is based on creatinine and oliguria, two imperfect markers. Other biomarkers may indicate kidney damage earlier than conventional biomarkers. At present, two kidney damage biomarkers are available for clinical use: neutrophil gelatinase-associated lipocalin (NGAL) can be measured in urine and blood, and the combination of urinary insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases 2 (TIMP-2) can be measured using the NephroCheck® point of care device. Although the use of these biomarkers might allow earlier AKI detection [6,7,8], their performance is limited and their impact on relevant patient or kidney outcomes is uncertain, as is their usefulness for other endpoints such as use of RRT and long-term kidney outcomes [9].
Although the importance of differentiating functional volume-responsive AKI from intrinsic parenchymal diseases is classically emphasized, several studies have pointed out the frequent coexistence of intrinsic and pre-renal injury in critically ill patients [10,11,12,13,14]. This translates into poor performance of urinary indices and limited performance of kidney damage markers in predicting volume-responsive AKI [10,11,12,13,14]. Urine sediment analysis remains, however, mandatory to detect proteinuria, haematuria, leukocyturia or eosinophiluria, that may suggest specific causes of AKI.
Clinical imaging
Renal imaging is a mandatory component of AKI diagnostic work-up. Depending on the technique, it enables to evaluate organ morphology and provides insights in function, perfusion and possibly aetiology.
Ultrasonography
Renal ultrasonography (US) represents the first-line imaging modality in most cases of AKI [15, 16]. It is inexpensive, non-invasive, widely available, can be performed at the bedside and may influence further investigations and management.
Conventional (B-mode) imaging
Conventional (B-mode) is the basic examination mode. It generates grey-scale images based on the property of sound waves to reflect at interfaces of media of different densities. This mode permits the evaluation of longitudinal size and parenchyma echogenicity and demonstrates (or rules out) the presence of hydronephrosis or cysts.
Kidney size is typically measured in its long axis (bipolar length). Normal values range from 9 to 12 cm according to patient size and gender. Small kidney size is suggestive of underlying CKD, while enlarged kidneys might be observed in infiltrative diseases, renal vein thrombosis or acute rejection in transplanted kidneys.
Renal echogenicity is evaluated by comparison with that of adjacent tissues (liver or spleen). Decreased echogenicity can be physiologic but might be associated with pathological processes such as oedema. Hyperechogenicity almost always indicates diffuse kidney parenchymal pathology (infiltrative diseases, inflammatory states). Chronic kidney disease is often associated with increased brightness since fibrous tissues increase echogenicity.
Urinary tract obstruction represents a relatively easily reversible cause of AKI. Although less commonly encountered in ICU patients, it should be ruled out in all patients with AKI with suggestive history or lack of clear causes of AKI. On US, the collecting system of the kidney is not normally visible unless significant hydronephrosis is present. Hypovolemia, early obstruction and retroperitoneal tumours or fibrosis may lead to false negative results. False positive findings can be observed in pregnancy and in patients with diabetes insipidus, vesico-ureteral reflux, megacystis-megaureter syndrome, full bladder and urinary tract infection.
Although unrelated to AKI, cysts are often encountered on renal US examination. Benign cysts are well delineated with a clear content, while complex cysts contain septa or wall thickening. Solid masses are usually neoplastic. Specialist referral is required when such images are encountered.
Doppler-based resistive indices (RI)
Adding Doppler technology to grey-scale images enables visualization of intra-renal vasculature and computation of dynamic parameters. The most studied of those is the intra-renal resistive index (RI). RI can be calculated based on two parameters of flow (the peak systolic shift and minimum diastolic shift) which can be measured in the arcuate or interlobar arteries in pulsed wave Doppler mode [RI = (peak systolic velocity − end diastolic velocity)/peak velocity]. Renal RI is a simple, non-invasive tool easy to use at the patient bedside (Fig. 1). It has been shown to have an excellent inter-observer reproducibility but limited precision [17]. RI is considered normal if <0.70; however, the normal RI range is age-dependent [18].
Unfortunately, the physiological and clinical significance of RI remain debated. Initially considered an indicator of renal vascular resistance and blood flow, changes in RI have been proposed to help titrate norepinephrine to better tailor mean arterial pressure in ICU patients [19]. However, in vivo and in vitro studies have suggested a correlation with vascular compliance (vascular distensibility) [18]. In addition, RI is largely influenced by extra-renal factors such as cardiac output, heart rate, PaCO2 and PaO2, and renal interstitial and intra-abdominal pressures [18]. As a result, the use of RI for AKI diagnosis is currently not recommended and further studies are required to establish its role in clinical practice [20].
Contrast-enhanced ultrasonography (CEUS)
CEUS is a newer ultrasound-based imaging modality that utilizes dedicated US contrast agents. US contrast agents are made of gas microbubbles, which act as potent ultrasound reflectors. Commercially available preparations have high stability and very small-sized microbubbles. They are injected into the peripheral vein and can be visualized in arteries and capillaries. As such, CEUS enables delicate visualization of organs’ macro- and microcirculation (Fig. 2). Cortical necrosis can be detected using CEUS. Methods have been proposed to use CEUS-derived techniques to measure organ perfusion. These methods have been validated in animal models and healthy volunteers [21]. To date, there are limited data on its possible utilization in critically ill patients. Studies have shown that CEUS was feasible and safe in such contexts [22] but with potentially conflicting results [23]. Further research is required to establish the role of CEUS in ICU.
Computerized tomography (CT)
CT is increasingly used in the ICU. Despite the potential nephrotoxicity of iodinated contrast agents, in patients with septic AKI, contrast CT may be necessary to identify the source of sepsis. Non-contrast CT remains the gold standard for the diagnosis of urolithiasis and complicated pyelonephritis. It enables detection of underlying renal or abdominal abnormalities in patients with AKI (cysts, renal carcinoma, aortic aneurysms, etc.) and detection of hydronephrosis. Finally, last generation triphasic CT (functional CT), can allow assessment of GFR and renal blood flow, but the exact role in critically ill patients needs to be determined in future studies [24].
Magnetic resonance imaging (MRI)
MRI techniques allow detailed assessment of renal anatomy, tumors and infections. Some techniques enable quantification of renal perfusion and differentiation between cortical and medullar areas. Unfortunately, these techniques require the injection of gadolinium, which has been associated with the risk of nephrogenic systemic fibrosis in patients with altered renal function [25]. Non-contrast methods such as cine-contrast MRI or BOLD MRI have been proposed and tested in critically ill patients [26]. To date, given the cost, availability and length of the protocols, MRI does not play a role in the routine diagnostic workup of AKI outside research studies.
Renal biopsy in the intensive care setting
Given that the common heterogeneity in causes of AKI, histological diagnosis is often not considered, and indeed renal biopsy, despite being an essential tool in non-critical care nephrology, is rarely performed. However, as outlined above, there are specific situations where histopathological diagnosis does deserve consideration. In spite of the improved AKI recognition and assessment of severity provided by recently developed scoring systems such as KDIGO, recent evidence demonstrates a lack of correlation between KDIGO classification and actual AKI aetiology [27]. These studies emphasize that kidney biopsy should be considered more frequently than currently employed in order to better understand AKI and avoid missing specific causes of AKI and treatment opportunities to reduce the risk of subsequent CKD.
Indications in the ICU
Although the common causes of AKI within the ICU can be diagnosed clinically without histological confirmation, the presumptive diagnosis risks ignoring treatable conditions such as acute interstitial nephritis (AIN). Occasionally, AKI may be due to a specific multi-systemic disorder or conditions fulfilling standard indications for renal biopsy such as nephritic and/or nephrotic syndrome, or rapidly progressive AKI of unclear aetiology. Although renal biopsy should probably be discussed after initial diagnostic work-up in patients with AKI without obvious aetiologies or in patients with renal parenchymal disease, clinicians must ensure that the benefits of renal biopsy outweigh the risks. Thus, renal biopsy is usually not done if the expected histological findings are assumed neither to guide a specific treatment nor to determine a change in treatment. Main indications for renal biopsy in the critically ill patient include persistent loss of kidney function, proteinuria greater than 3 g/day or a clinical picture suggestive of systemic disease [28].
Precautions and contraindications
Careful patient selection as well as the use of real-time US has minimized the risks associated with percutaneous renal biopsy, but it does carry a morbidity and mortality risk [29]. Significant complications include haemorrhage, infection and arteriovenous fistula formation occurring in 3–13% of cases and a mortality risk of up to 0.2% [30]. Although controlling blood pressure for preventing complications has not been firmly demonstrated, maintaining blood pressure under 140/90 mmHg on the day of renal biopsy is a classical objective. Haemostatic abnormalities and particularly a decreased platelet count have been reported to be associated with higher complication rates [31], but whether there is a role for routinely measuring bleeding time and administering desmopressin prior to renal biopsy remains a matter of debate. In patients with coagulation disorders or taking anticoagulants or antiplatelet treatment, we suggest managing patients according to national guidelines on perioperative management of patients at high risk of bleeding. The “classic” contraindications to renal biopsy are outlined in Table 1.
Technique
Renal biopsy can be performed at the bedside under real-time US guidance in a patient placed in the prone position. It should only be done by clinicians that are expert in performing the procedure. In patients on mechanical ventilation, a ventilator pause can be used to stop kidney movement with respiration. Non-percutaneous renal biopsy techniques may be considered where there are absolute contraindications to the percutaneous technique. These include open renal biopsy [32], laparascopic approach [33] and transjugular approach, the latter carrying the risk of inadequate tissue sampling [34]. This is relevant in that renal biopsy findings must be interpreted in the clinical context and in tandem with laboratory features, as prognostication based upon renal pathology alone is affected by the sample size and may be less accurate in biopsies with few glomeruli (i.e. ≤5).
Renal biopsy on the ICU: experience
Only two studies, both from France, have examined the impact of renal biopsy in the critically ill. Augusto et al. preformed a multicentre retrospective analysis over a 10-year period from ten ICUs [31]. Among 77 patients who underwent a renal biopsy (88% on native kidneys), 50% of non-transplanted patients had a specific diagnosis including glomerulonephritis (22%), acute vascular nephritis (10%), AIN (3%), and deposit disease (3%) [31]. The occurrence of AKI before hospital admission, the presence of clinical extra-renal signs, and the absence of classical contributory factors of acute tubular necrosis were associated with renal biopsy yielding a specific diagnosis [31]. In this study, one-fifth of the non-transplanted patients had their treatment modified and one-sixth had a specific treatment stopped. Similarly, Philipponnet et al. described a retrospective multicenter study over 10 years in five French ICUs. Of the 54 kidney biopsies preformed, acute tubular necrosis was found in 46%, glomerulonephritis in 25%, acute vascular nephritis in 20%, AIN in 10%, and deposit disease in 5% [28]. Of note, in most cases, interstitial nephritis had not been suspected prior to renal biopsy, and renal biopsy results contributed to the management in over 70% of cases [28].
Interestingly, in both studies, biopsy findings confirmed clinical suspicion, suggesting a selection bias which may have contributed to the high diagnostic and therapeutic contribution. Patient inclusion in these cohorts was highly selective with biopsies performed in less than 1% of patients with AKI on ICU, and as such no recommendations can be drawn as to who may require biopsy. It must be noted, however, that in both these studies complications related to biopsy were more frequently observed in ICU patients when compared to the reported incidences in nephrology patients, including a high risk of severe and even fatal bleeding [28, 31].
These studies demonstrate that in highly selected cases renal biopsy may carry meaningful and clinically relevant information at a cost of significant risk of severe complications. Most patients underwent a percutaneous procedure, and it remains unclear whether complications could have been prevented by using a transjugular approach. Similarly, it is also possible that the development of new biomarkers or techniques to image renal injury will reduce the need for renal biopsies [35].
Acute kidney injury in specific settings and diagnosing unexpected aetiologies
Several situations or settings deserve particular attention. In addition, some patients may present with AKI without associated manifestations or obvious predisposing factors. In these patients, a basic diagnostic work-up should be performed to avoid missing specific types of AKI (Fig. 3). This also applies to AKI in transplant recipients (Table 2). Additionally, several ICU conditions, including prolonged and complex surgery, comatose states or status epilepticus, and exposure to some drugs such as cocaine and envenomation may predispose to rhabdomyolysis [36]. To ensure prompt implementation of preventive measures, measuring creatinine kinase levels should be part of the routine testing in such high-risk patients. Last, intensivists should be aware of differential diagnosis of AKI in specific conditions such bile acid-induced cholemic nephropathy in patients with advanced liver disease and AKI unresponsive to vasopressin analog [37].
Acute glomerulonephritis—systemic diseases: vasculitis
Acute glomerulonephritis or rapidly progressive glomerulonephritis (RPGN) are rare forms of renal diseases manifesting by a sub-acute and progressive rise in serum creatinine. In the majority of cases, RPGN is encountered in the context of systemic diseases with multiple organ involvement. The pathological lesion of RPGN is extracapillary glomerular proliferation (crescents). The usual classification is based on immunofluorescence examination of the glomerulus [38]. Goodpasture’s disease is due to antibodies directed against the glomerular basement membrane (GBM). It typically presents as RPGN and intra-alveolar haemorrhage. Immunofluorescence examination shows linear deposition of IgG along the GBM.
Immune complex diseases are characterized by granular deposits of various immunoglobulins and complement fractions. Several diseases share this presentation, including systemic lupus erythematosus, Henoch–Schönlein purpura, cryoglobulinemia and post-infectious glomerulonephritis (in particular endocarditis). Lastly, pauci-immune glomerulonephritis is characterized by the absence of immune deposits on immunofluorescence and is associated with antineutrophil cytoplasmic antibodies (ANCA)-positive vasculitides.
Although RGPN is uncommon in ICU patients, its exact prevalence remains unknown. Outside the ICU setting, a study showed that acute glomerulonephritis was diagnosed in 5.6% of 748 patients admitted over a year in a nephrology unit [39]. Frequency may rise up to 31% in patients aged 65 years or older [40]. Among ICU patients undergoing a renal biopsy, RGPN was observed in 25% of cases [31]. Finally, in a recent study on 363 patients admitted to the ICU with rheumatic disease, one-third of them were admitted for disease activity and less than 10% for RGPN [41]. In this subset of patients, ANCA-associated vasculitis were the most frequent diseases [41]. Studies on ANCA-associated vasculitis in ICU patients showed a higher incidence of granulomatosis with polyangiitis than microscopic polyangiitis [42].
Patient and renal outcomes depend on rapid initiation of a specific treatment. The combination of a low incidence, an acute presentation mimicking more frequent pathologies, and the need for emergent specific treatment make RPGN diagnosis particularly challenging in ICU patients. RPGN are classically characterized by development of AKI or AKD over a period of days to a few weeks, arterial hypertension, proteinuria and haematuria. Hypertension may be absent especially in ICU patients, and proteinuria and haematuria are often non-specific. [43]. Acute respiratory failure with lung consolidation and rising serum creatinine (the so-called “pulmonary-renal syndrome”) may occasionally be due to RGPN and intra-alveolar haemorrhage associated with vasculitis [44]. Non-renal symptoms evocative of systemic diseases including weight loss, symptoms lasting over several weeks, haemoptysis with anemia, arthritis, skin involvement, sinusitis and peripheral neurologic disease are important clues that should alert the ICU physician [31, 44]. The diagnosis of RPGN relies on examination of a renal biopsy, which in this case is a medical emergency. However, alternate diagnostic approaches based on immunological blood assays may be preferred when available. An evocative clinical picture should prompt the measurement of ANCA, anti-GBM antibodies, cryoglobulins, anti-nuclear and anti-DNA antibodies and complement fractions C3, C4 and CH50. It must be noted, however,that these auto-antibodies should be interpreted cautiously since low titres can be observed in inflammatory conditions.
In ICU patients with suspected vasculitis, urgent treatment is required. In case of probable or confirmed Goodpasture disease or ANCA-associated vasculitis, treatment with steroids, cyclophosphamide and plasma exchange is often required. Although the efficacy of anti-CD20 antibodies (i.e. Rituximab) has been demonstrated, its clinical usefulness in ICU patients remains uncertain [45, 46].
Acute interstitial nephritis
Acute interstitial nephritis (AIN) accounts for 10–25% of biopsy-proven AKI and should be considered one of the frequently missed AKI diagnoses in the ICU [28, 47, 48]. It is a histological diagnosis characterized by infiltration of inflammatory cells within the renal interstitium with sparing of the glomeruli and blood vessels. AIN can evolve to interstitial fibrosis within 7–10 days [28, 47, 48]. The most frequent causes of AIN are drugs, primary renal infections such as acute bacterial pyelonephritis, inflammatory disorders such as systemic lupus, Sjögren’s syndrome and sarcoidosis, or neoplastic diseases. Any drug can cause AIN, but antibiotics, non-steroidal anti-inflammatory drugs and proton-pump inhibitors are the most common medications associated with AIN. Drug-induced AIN can manifest at any stage after starting the medication and is not usually dose-related [49].
In critically ill patients with AIN, classical symptoms are usually absent. The presence of a rash, eosinophilia or eosinophiluria in a patient with AKI may be suggestive of AIN, and although insufficient to confirm diagnosis, should raise ICU physician awareness. Renal biopsy is the only definitive method of establishing the diagnosis. New diagnostic tests are urgently needed to improve AIN diagnosis, especially in critically ill patients [47].
Management of AIN consists of withdrawal of offending medications and treatment of an underlying inflammatory disease. Although the use of corticosteroids remains controversial, delayed initiation of steroids has been associated with incomplete renal recovery. Therefore, it is reasonable to use corticosteroids when there is no improvement within 3–7 days after discontinuation of the offending drug [47, 48].
AKI in haematological patients
Critically ill cancer patients seem at higher risk of developing AKI [50, 51]. Although most of the AKI episodes are multifactorial, specific causes may deserve urgent therapies. Thus, cancer patients may develop obstructive diseases and are more prone to nephron loss due to nephrectomy, nephrotoxic agents or previous AKI episodes [52].
Tumor lysis syndrome (TLS) may arise as result of rapid destruction of malignant cells leading to the release of intracellular ions, proteins, and metabolites into the extra-cellular space [53]. Although TLS usually occurs in patients with extensive, rapidly growing, chemosensitive malignancies, TLS has also been described in patients with low-grade malignancy treated with targeted therapies. The diagnostic criteria of TLS have been recently standardized (Table S1) [54]. Accordingly, a constellation of metabolic disturbances (hyperkalaemia, hyperphosphataemia, hypocalcaemia, and hyperuricaemia) defines laboratory TLS in high-risk patients, while clinical manifestations (cardiac, renal or neurological manifestations of TLS) in patients with laboratory TLS defines clinical TLS [54]. TLS may occur rapidly. Frequent (up to every 6 h) and routine search for metabolic disturbances, along with preventative measures, including hydration and treatment with urate oxidase, are mandatory [54].
In patients with myeloma, cast nephropathy remains the most common cause of renal injury, and reversibility may be achieved in up to 60% of these patients with immediate initiation of appropriate therapy [55, 56]. Cast nephropathy is caused by the precipitation of monoclonal light chains which bind Tamm Horsfall protein causing tubular obstruction. High amounts of Bence Jones proteinuria, extreme κ/λ light chain ratios or high serum levels of free light chains are suggestive of cast nephropathy [57, 58]. In some patients, renal biopsy may be avoided since cast nephropathy is the most common pathology, especially if urine albumin excretion is low (<25%) [59]. Early detection of cast nephropathy, combined with urgent chemotherapy, may improve the chances of renal recovery [55]. Bortezomib-based combinations are considered the most effective therapy for patients with AKI due to cast nephropathy, and should start as soon as possible [55]. The role of plasmapheresis is not established, and renal replacement therapy with high cut-off membranes (with cut-off around 50 kDa) might decrease free light chain concentrations [60]. Two prospective studies have recently shown conflicting results on the potential benefits of such an approach in patients with cast nephropathy [61, 62], and further analysis is required to identify which patients may get the maximum benefit from this demanding approach.
In patients with haemolytic anemia and thrombocytopenia, thrombotic microangiopathy (TMA) should be ruled out. Although rare, the combination of microangiopathic anaemia [non-immune haemolytic anaemia due to mechanical damage of red blood cells and resulting in high plasma lactate dehydrogenase (LDH) levels] with peripheral thrombocytopenia suggests this syndrome [63, 64]. The presence of damaged red blood cells (schistocytes) on peripheral blood smears confirms the microangiopathy. Differential diagnoses include auto-immune cytopenia and infectious causes of microangiopathic anaemia (malaria, babesiosis). Various organ dysfunctions may occur related to small vessel obstruction [63, 64]. Although overlap may occur, renal injury is more frequent in patients with haemolytic uremic syndrome (HUS), while neurological dysfunction is more common in patients with thrombotic thrombocytopenic purpura (TTP, also known as Moschowitz syndrome) [63, 64]. Three main syndromes should be searched for, including diarrhoea-associated HUS, usually associated with Shiga toxin-producing E. coli [63, 64], atypical HUS (aHUS) which is usually complement-mediated and associated with congenital abnormalities of the alternative complement pathway regulation [63,64,65] and TTP which is related to congenital or acquired ADAMTS13 deficiency [62, 63]. In patients suspected of either aHUS and TTP, looking for congenital complement abnormalities, measuring ADAMTS13 activity and looking for anti-ADAMTS13 antibodies should be the rule [62, 63].
AKI in the obstetric setting
In the developed world, the incidence of AKI during pregnancy, currently estimated around 1/20,000 pregnancies, has substantially decreased due to better prenatal care and reduction of illegal abortion. The diagnosis of obstetric AKI may be masked by the physiological increase of GFR (up to 40%). Obstruction by the gravid uterus may cause obstructive AKI, the diagnosis of which is complicated by physiological hydronephrosis and hydroureter. AKI during pregnancy is often multifactorial with both pregnancy-related and other potential causes. Timing may help in the differential diagnosis (Figure S1) [65]. In the early phase, sepsis (pyelonephritis, septic abortion) and hypovolemia (hyperemesis gravidarum, haemorrhage) are the most common causes, whereas in the later phase haemorrhage (abruptio placentae, postpartum haemorrhage), sepsis and typical pregnancy-related complications predominate. Preeclampsia, a poorly understood systemic disorder due to dysregulation of angiogenic factors, characterized by hypertension and proteinuria, or its variant Hemolysis with Elevated Liver tests and Low Platelets (HELLP), typically develop during the third trimester. The TMA include aHUS, that more commonly begins peri- and post-partum, and TTP, which develops in the second and third trimester. Pregnancy predisposes to TTP due to a decrease of ADAMTS-13 activity and increase of von Willebrand factor concentrations, but may also be a triggering factor for aHUS (due to dysregulation of the alternative complement pathway). Acute fatty liver of pregnancy (AFLP), caused by foetal and maternal congenital defects in beta-oxidation of fatty acids, is a rare but life-threatening cause of pregnancy-related AKI that mostly occurs close to term. Other potential causes of peripartum AKI include amniotic fluid embolism or cardiomyopathy.
Differentiating HUS/TTP from HELLP and AFLP is challenging but vital because of the therapeutic consequences [66,67,68]. An adequate differential diagnosis requires careful history including timing of onset, clinical examination, drug review, dipstick and microscopic urine examination, proteinuria, haemoglobin level, platelet counts, peripheral blood smears, LDH, coagulation tests, bilirubin, transaminases, blood glucose levels, ADAMTS-13 activity, complement factors and ultrasound (Table S2).
Acute kidney injury in low and middle income countries
In low and middle income countries (LMIC), early preventive and therapeutic measures are the key way to decrease morbidity, mortality and cost (Table 3). Early detection of AKI is impaired by limited diagnostic assets and poor understanding of the condition [69]. Such limited understanding—to a large extent determined by inadequate reporting and education—limits awareness and early recognition and delays the implementation of adequate management [70]. In LMIC, the common lack of access to specialized nephrology care requires that AKI be understood and recognized at all levels of the healthcare system [71]. A practical and easily accessible educational strategy focused on providers at the forefront of healthcare delivery (including primary physicians, nurses and community healthcare providers) is indispensable to achieve this goal [72].
In the community, in areas where infectious diseases such as severe malaria, leptospirosis or dengue are endemic and associated with high rates of AKI, a febrile patient should elicit concern for renal injury [73]. Similarly, in patients with severe volume depletion due to gastrointestinal loss, volume resuscitation is central to care and to prevent renal injury—preferably before the onset of persistent oliguria [72]. In some areas of the world, exposure to snake venom represents a frequent cause of AKI. Administration of herbs by traditional healers has been associated with nephrotoxicity and must be considered when confronted with AKI of unclear aetiology [74]. Increased availability and use of over-the-counter medications such as NSAIDs significantly contribute to a rising incidence of AKI.
The development of AKI as a maternal and neonatal complication is especially important in the LMIC environment [74], where failure to recognize renal injury frequently leads to significant consequences for mother and child. In this area, successful efforts to improve early recognition have clearly demonstrated benefit—especially by reducing some of the more dreaded consequences such as cortical necrosis [75].
Conversely, in the LMIC hospital and ICU settings, AKI recognition faces challenges akin to those seen in the developed world; among hospitalized patients, AKI related to exposure to nephrotoxic medications, antibiotics, intravascular administration of iodinated radiocontrast and surgical procedures is very common. Especially in the LMIC setting, additional testing and urinary microscopy are necessary to identify the underlying etiology. The performance of basic urine microscopy focusing on the presence of erythrocytes, leukocytes, eosinophils and casts in the sediment is invaluable to assess the initial presentation of the patient with AKI [76]. Training in microscopic urine examination and availability of basic examination equipment for such testing should be promoted as a key, low-resource test for detection of AKI in LMIC. Point of care testing (POCT) for creatinine measurements can be performed by non-laboratory-trained individuals, thus eliminating delays in testing and reporting of results [77]. However, it requires the implementation of a quality assurance program that ensures accurate and reliable results. Last, kidney biopsies in patients with AKI are more common in LMIC than in HIC and, thus, there is a greater appreciation of the relative incidence of multiple aetiologies and the value of a renal biopsy to guide management [69].
Conclusion and future directions
Identifying and diagnosing specific causes of AKI in critically ill patients remains challenging. A high degree of suspicion must be the rule and a systematic diagnostic work-up should be undertaken in every AKI presenting without an obvious predisposing factor or following an unusual course. Although data regarding specific causes of AKI remain limited, increased recognition of the nephrotoxic contribution to AKI [78], and of the infrequent finding of true “acute tubular necrosis” in critically ill patients, will result in improved AKI management [79,80,81].
It may be time to search more closely for specific causes, assess more carefully the prevalence of aetiologies even when typical symptoms are misleadingly absent—such as acute post-infectious glomerulonephritis or AIN—and, ultimately, reshape an old-fashioned and probably outdated AKI diagnostic paradigm.
Abbreviations
- ADAMTS-13:
-
A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13
- ADQI:
-
Acute Disease Quality Initiative
- AFLP:
-
Acute fatty liver of pregnancy
- aHUS:
-
Atypical hemolytic uremic syndrome
- AIDS:
-
Acquired immunodeficiency syndrome
- AKD:
-
Acute kidney disease
- AKI:
-
Acute kidney injury
- AIN:
-
Acute interstitial nephritis
- ANCA:
-
Anti-neutrophil cytoplasmic antibodies
- CEUS:
-
Contrast-enhanced ultrasonography
- CKD:
-
Chronic kidney disease
- CT:
-
Computerized tomography
- DIC:
-
Disseminated intravascular coagulation
- ESKD:
-
End-stage kidney disease
- GBM:
-
Glomerular basal membrane
- GFR:
-
Glomerular filtration rate
- HELLP:
-
Haemolysis with elevated liver tests and low platelets
- HIC:
-
High-income country
- HIV:
-
Human immunodeficiency virus
- ICU:
-
Intensive care unit
- IGFBP7:
-
Insulin-like growth factor-binding protein 7
- KDIGO:
-
Kidney Disease: Improving Global Outcomes
- LDH:
-
Lactate dehydrogenase
- LMIC:
-
Low- and middle-income countries
- MRI:
-
Magnetic resonance imaging
- NGAL:
-
Neutrophil gelatinase-associated lipocalin
- NOACs:
-
New oral anticoagulants
- RI:
-
Resistive index
- RPGN:
-
Rapidly progressive glomerulonephritis
- RRT:
-
Renal replacement therapy
- TIMP-2:
-
Tissue inhibitor of metalloproteinase 2
- TLS:
-
Tumor lysis syndrome
- TTP:
-
Thrombotic thrombocytopenic purpura
- US:
-
Renal ultrasonography
References
Hoste EAJ, Bagshaw SM, Bellomo R et al (2015) Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 41:1411–1423. doi:10.1007/s00134-015-3934-7
Chawla LS, Eggers PW, Star RA, Kimmel PL (2014) Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371:58–66. doi:10.1056/NEJMra1214243
Nisula S, Kaukonen K-M, Vaara ST et al (2013) Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med 39:420–428. doi:10.1007/s00134-012-2796-5
Kidney Disease: Improving Global, Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int 2:1–138
Chawla LS, Bellomo R, Bihorac A et al (2017) Expert consensus document Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol (in press)
Haase-Fielitz A, Haase M, Devarajan P (2014) Neutrophil gelatinase-associated lipocalin as a biomarker of acute kidney injury: a critical evaluation of current status. Ann Clin Biochem 51:335–351. doi:10.1177/0004563214521795
Kashani K, Al-Khafaji A, Ardiles T et al (2013) Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 17:1
Vandenberghe W, De Loor J, Hoste EAJ (2017) Diagnosis of cardiac surgery-associated acute kidney injury from functional to damage biomarkers. Curr Opin Anaesthesiol 30:66–75. doi:10.1097/ACO.0000000000000419
Koyner JL, Shaw AD, Chawla LS et al (2015) Tissue inhibitor metalloproteinase-2 (TIMP-2) IGF-binding protein-7 (IGFBP7) levels are associated with adverse long-term outcomes in patients with AKI. J Am Soc Nephrol JASN 26:1747–1754. doi:10.1681/ASN.2014060556
Schneider AG, Bellomo R (2013) Urinalysis and pre-renal acute kidney injury: time to move on. Crit Care Lond Engl 17:141. doi:10.1186/cc12676
Darmon M, Vincent F, Dellamonica J et al (2011) Diagnostic performance of fractional excretion of urea in the evaluation of critically ill patients with acute kidney injury: a multicenter cohort study. Crit Care Lond Engl 15:R178. doi:10.1186/cc10327
Pons B, Lautrette A, Oziel J et al (2013) Diagnostic accuracy of early urinary index changes in differentiating transient from persistent acute kidney injury in critically ill patients: multicenter cohort study. Crit Care Lond Engl 17:R56. doi:10.1186/cc12582
Nejat M, Pickering JW, Devarajan P et al (2012) Some biomarkers of acute kidney injury are increased in pre-renal acute injury. Kidney Int. doi:10.1038/ki.2012.23
Vanmassenhove J, Glorieux G, Hoste E et al (2013) Urinary output and fractional excretion of sodium and urea as indicators of transient versus intrinsic acute kidney injury during early sepsis. Crit Care Lond Engl 17:R234. doi:10.1186/cc13057
Faubel S, Patel NU, Lockhart ME, Cadnapaphornchai MA (2014) Renal relevant radiology: use of ultrasonography in patients with AKI. Clin J Am Soc Nephrol 9:382–394. doi:10.2215/CJN.04840513
Barozzi L, Valentino M, Santoro A et al (2007) Renal ultrasonography in critically ill patients. Crit Care Med 35:S198–S205. doi:10.1097/01.CCM.0000260631.62219.B9
Schnell D, Reynaud M, Venot M, et al (2014) Resistive index or color-Doppler semi-quantitative evaluation of renal perfusion by inexperienced physicians: results of a pilot study. Miner Anestesiol 80:1273–1281
Schnell D, Darmon M (2012) Renal Doppler to assess renal perfusion in the critically ill: a reappraisal. Intensive Care Med 38:1751–1760. doi:10.1007/s00134-012-2692-z
Deruddre S, Cheisson G, Mazoit J-X et al (2007) Renal arterial resistance in septic shock: effects of increasing mean arterial pressure with norepinephrine on the renal resistive index assessed with Doppler ultrasonography. Intensive Care Med 33:1557–1562. doi:10.1007/s00134-007-0665-4
Ichai C, Vinsonneau C, Souweine B et al (2016) Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies). Ann Intensive Care 6:48. doi:10.1186/s13613-016-0145-5
Schneider AG, Hofmann L, Wuerzner G et al (2012) Renal perfusion evaluation with contrast-enhanced ultrasonography. Nephrol Dial Transplant 27:674–681. doi:10.1093/ndt/gfr345
Schneider AG, Goodwin MD, Schelleman A et al (2013) Contrast-enhanced ultrasound to evaluate changes in renal cortical perfusion around cardiac surgery: a pilot study. Crit Care Lond Engl 17:R138. doi:10.1186/cc12817
Schneider AG, Goodwin MD, Schelleman A et al (2014) Contrast-enhanced ultrasonography to evaluate changes in renal cortical microcirculation induced by noradrenaline: a pilot study. Crit Care Lond Engl 18:653. doi:10.1186/s13054-014-0653-3
Martinez-Suarez HJ, Durso T, Kadlec AO et al (2015) Three-dimensional renal parenchymal volume as a surrogate for renal function estimation in obstructed kidneys undergoing surgical repair. J Endourol 29:630–633. doi:10.1089/end.2014.0232
Kaewlai R, Abujudeh H (2012) Nephrogenic systemic fibrosis. Am J Roentgenol 199:W17–W23. doi:10.2214/AJR.11.8144
Prowle JR, Molan MP, Hornsey E, Bellomo R (2012) Measurement of renal blood flow by phase-contrast magnetic resonance imaging during septic acute kidney injury: a pilot investigation. Crit Care Med 40:1768–1776. doi:10.1097/CCM.0b013e318246bd85
Chu R, Li C, Wang S et al (2014) Assessment of KDIGO definitions in patients with histopathologic evidence of acute renal disease. Clin J Am Soc Nephrol 9:1175–1182. doi:10.2215/CJN.06150613
Philipponnet C, Guérin C, Canet E et al (2013) Kidney biopsy in the critically ill patient, results of a multicentre retrospective case series. Miner Anestesiol 79:53–61
Brachemi S, Bollée G (2014) Renal biopsy practice: what is the gold standard? World J Nephrol 3:287–294. doi:10.5527/wjn.v3.i4.287
Stratta P, Canavese C, Marengo M et al (2007) Risk management of renal biopsy: 1387 cases over 30 years in a single centre. Eur J Clin Invest 37:954–963. doi:10.1111/j.1365-2362.2007.01885.x
Augusto J-F, Lassalle V, Fillatre P et al (2012) Safety and diagnostic yield of renal biopsy in the intensive care unit. Intensive Care Med 38:1826–1833. doi:10.1007/s00134-012-2634-9
Chodak GW, Gill WB, Wald V, Spargo B (1983) Diagnosis of renal parenchymal diseases by a modified open kidney biopsy technique. Kidney Int 24:804–806
Shetye KR, Kavoussi LR, Ramakumar S et al (2003) Laparoscopic renal biopsy: a 9-year experience. BJU Int 91:817–820
Thompson BC, Kingdon E, Johnston M et al (2004) Transjugular kidney biopsy. Am J Kidney Dis 43:651–662
Mischak H (2015) Pro: urine proteomics as a liquid kidney biopsy: no more kidney punctures! Nephrol Dial Transplant 30:532–537. doi:10.1093/ndt/gfv046
Chavez LO, Leon M, Einav S, Varon J (2016) Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice. Crit Care Lond Engl 20:135. doi:10.1186/s13054-016-1314-5
Jennette JC, Falk RJ, Bacon PA et al (2013) 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 65:1–11. doi:10.1002/art.37715
Liaño F, Pascual J (1996) Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int 50:811–818
Uezono S, Hara S, Sato Y et al (2006) Renal biopsy in elderly patients: a clinicopathological analysis. Renal Fail 28:549–555. doi:10.1080/08860220600840165
Dumas G, Géri G, Montlahuc C et al (2015) Outcomes in critically ill patients with systemic rheumatic disease: a multicenter study. Chest 148:927–935. doi:10.1378/chest.14-3098
Kimmoun A, Baux E, Das V et al (2016) Outcomes of patients admitted to intensive care units for acute manifestation of small-vessel vasculitis: a multicenter, retrospective study. Crit Care Lond Engl 20:27. doi:10.1186/s13054-016-1189-5
Lerolle N, Nochy D, Guérot E et al (2010) Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration. Intensive Care Med 36:471–478. doi:10.1007/s00134-009-1723-x
de Prost N, Parrot A, Cuquemelle E et al (2012) Diffuse alveolar hemorrhage in immunocompetent patients: etiologies and prognosis revisited. Respir Med 106:1021–1032. doi:10.1016/j.rmed.2012.03.015
Stone JH, Merkel PA, Spiera R et al (2010) Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 363:221–232. doi:10.1056/NEJMoa0909905
Specks U, Merkel PA, Seo P et al (2013) Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 369:417–427. doi:10.1056/NEJMoa1213277
Praga M, Sevillano A, Auñón P, González E (2015) Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrol Dial Transplant 30:1472–1479. doi:10.1093/ndt/gfu326
Raghavan R, Eknoyan G (2014) Acute interstitial nephritis—a reappraisal and update. Clin Nephrol 82:149–162
Krishnan N, Perazella MA (2015) Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment. Iran J Kidney Dis 9:3–13
Bagshaw SM, Laupland KB, Doig CJ et al (2005) Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care Lond Engl 9:R700–R709. doi:10.1186/cc3879
Darmon M, Vincent F, Canet E et al (2015) Acute kidney injury in critically ill patients with haematological malignancies: results of a multicentre cohort study from the Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologie. Nephrol Dial Transplant 30:2006–2013. doi:10.1093/ndt/gfv372
Soares M, Salluh JIF, Carvalho MS et al (2006) Prognosis of critically ill patients with cancer and acute renal dysfunction. J Clin Oncol 24:4003–4010. doi:10.1200/JCO.2006.05.7869
Darmon M, Vincent F, Camous L et al (2013) Tumour lysis syndrome and acute kidney injury in high-risk haematology patients in the rasburicase era. A prospective multicentre study from the Groupe de Recherche en Réanimation Respiratoire et Onco-Hématologique. Br J Haematol 162:489–497. doi:10.1111/bjh.12415
Coiffier B, Altman A, Pui C-H et al (2008) Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26:2767–2778. doi:10.1200/JCO.2007.15.0177
Dimopoulos MA, Terpos E, Chanan-Khan A et al (2010) Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 28:4976–4984. doi:10.1200/JCO.2010.30.8791
Dimopoulos MA, Roussou M, Gavriatopoulou M et al (2016) Bortezomib-based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis. Am J Hematol 91:499–502. doi:10.1002/ajh.24335
Hutchison CA, Batuman V, Behrens J et al (2011) The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol 8:43–51. doi:10.1038/nrneph.2011.168
Gerth J, Sachse A, Busch M et al (2012) Screening and differential diagnosis of renal light chain-associated diseases. Kidney Blood Press Res 35:120–128. doi:10.1159/000330715
Leung N, Gertz M, Kyle RA et al (2012) Urinary albumin excretion patterns of patients with cast nephropathy and other monoclonal gammopathy-related kidney diseases. Clin J Am Soc Nephrol 7:1964–1968. doi:10.2215/CJN.11161111
Hutchison CA, Bradwell AR, Cook M et al (2009) Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 4:745–754. doi:10.2215/CJN.04590908
Bridoux F, Pegourie B, Augel-Meunier K, et al (2016) Treatment of myeloma cast nephropathy (MCN): a randomized trial comparing intensive haemodialysis (HD) with high cut-off (HCO) or standard high-flux dialyzer in patients receiving a Bortezomib-based regimen (the MYRE Study, by the Intergroupe Francophone du Myélome (IFM) and the French Society of Nephrology (SFNDT). Blood 978
Cook M, Hutchison CA, Fifer L, et al (2016) High cut-off haemodialysis(HCO-HD) does not improve outcomes in myeloma cast nephropathy: results of European trial of Free Light Chain removal extended haemodialysis in cast nephropathy(EULITE). EHA P270
Mannucci PM (2015) Understanding organ dysfunction in thrombotic thrombocytopenic purpura. Intensive Care Med 41:715–718. doi:10.1007/s00134-014-3630-z
George JN, Nester CM (2014) Syndromes of thrombotic microangiopathy. N Engl J Med 371:654–666. doi:10.1056/NEJMra1312353
Fremeaux-Bacchi V, Fakhouri F, Garnier A et al (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8:554–562. doi:10.2215/CJN.04760512
Fakhouri F, Vercel C, Frémeaux-Bacchi V (2012) Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy. Clin J Am Soc Nephrol 7:2100–2106. doi:10.2215/CJN.13121211
Stella CL, Dacus J, Guzman E et al (2009) The diagnostic dilemma of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the obstetric triage and emergency department: lessons from 4 tertiary hospitals. Am J Obstet Gynecol 200:381.e1–381.e6. doi:10.1016/j.ajog.2008.10.037
Pourrat O, Coudroy R, Pierre F (2015) Differentiation between severe HELLP syndrome and thrombotic microangiopathy, thrombotic thrombocytopenic purpura and other imitators. Eur J Obstet Gynecol Reprod Biol 189:68–72. doi:10.1016/j.ejogrb.2015.03.017
Thomas MR, Robinson S, Scully MA (2016) How we manage thrombotic microangiopathies in pregnancy. Br J Haematol 173:821–830. doi:10.1111/bjh.14045
Mehta RL, Cerdá J, Burdmann EA et al (2015) International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet 385:2616–2643. doi:10.1016/S0140-6736(15)60126-X
Swanepoel CR, Wearne N, Okpechi IG (2013) Nephrology in Africa—not yet uhuru. Nat Rev Nephrol 9:610–622. doi:10.1038/nrneph.2013.168
Lewington AJP, Cerdá J, Mehta RL (2013) Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int 84:457–467. doi:10.1038/ki.2013.153
Mehta RL, Burdmann EA, Cerdá J et al (2016) Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study. Lancet Lond Engl 387:2017–2025. doi:10.1016/S0140-6736(16)30240-9
Basu G, Chrispal A, Boorugu H et al (2011) Acute kidney injury in tropical acute febrile illness in a tertiary care centre—RIFLE criteria validation. Nephrol Dial Transplant 26:524–531. doi:10.1093/ndt/gfq477
Cerdá J, Bagga A, Kher V, Chakravarthi RM (2008) The contrasting characteristics of acute kidney injury in developed and developing countries. Nat Clin Pract Nephrol 4:138–153. doi:10.1038/ncpneph0722
Prakash J, Pant P, Singh AK et al (2015) Renal cortical necrosis is a disappearing entity in obstetric acute kidney injury in developing countries: our three decade of experience from India. Ren Fail 37:1185–1189. doi:10.3109/0886022X.2015.1062340
Perazella MA (2015) The urine sediment as a biomarker of kidney disease. Am J Kidney Dis 66:748–755. doi:10.1053/j.ajkd.2015.02.342
Shephard MD (2011) Point-of-care testing and creatinine measurement. Clin Biochem Rev 32:109–114
McDonald RJ, McDonald JS, Bida JP et al (2013) Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology 267:106–118. doi:10.1148/radiol.12121823
Takasu O, Gaut JP, Watanabe E et al (2013) Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 187:509–517. doi:10.1164/rccm.201211-1983OC
Langenberg C, Gobe G, Hood S et al (2014) Renal histopathology during experimental septic acute kidney injury and recovery. Crit Care Med 42:e58–e67. doi:10.1097/CCM.0b013e3182a639da
Langenberg C, Bagshaw SM, May CN, Bellomo R (2008) The histopathology of septic acute kidney injury: a systematic review. Crit Care Lond Engl 12:R38. doi:10.1186/cc6823
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Dr. Darmon reports having received speaker fees from Astellas, MSD and Bristol Myers-Squibb, research support from Astute Medical, research grant from MSD, and funds in organizing educational meetings from MSD, Astellas and Jazz Pharmaceutical. Dr. Ostermann received speaker honoraria and research funding from Fresenius Medical Care and Baxter Gambro. Dr. Cerdá has received adviser and speaker honoraria from Baxter. Dr. Dimopoulos declares having no conflict of interest related to this manuscript. Dr. Forni declares having no conflict of interest related to this manuscript. Dr. Hoste reports having received fees for speaking from Alexion and Astute Medical and Research Grant support from Bellco. Dr. Legrand reports consulting fees from Astellas, Sphingotec, research grant from Baxter and speaker fees from Gilead. Dr. Lerolle declares having received speaking fees from Baxter. Dr. Rondeau reports having received fees for speaking for Alexion and Fresenius. Dr. Schneider has received consulting and speaking support from B. Braun, Fresenius Medical Care and Baxter. Dr. Souweine declares having no conflict of interest related to this manuscript. Dr. Schetz declares having no conflict of interest related to this manuscript.
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Darmon, M., Ostermann, M., Cerda, J. et al. Diagnostic work-up and specific causes of acute kidney injury. Intensive Care Med 43, 829–840 (2017). https://doi.org/10.1007/s00134-017-4799-8
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DOI: https://doi.org/10.1007/s00134-017-4799-8