Acute kidney injury

John A Kellum; Mark L Unruh; Raghavan Murugan

. 2011 Mar 28;2011:2001.

Acute kidney injury

John A Kellum ^1,^#, Mark L Unruh ^2,^#, Raghavan Murugan ^3,^#

PMCID: PMC3217737 PMID: 21443811

Abstract

Introduction

Acute renal failure is characterised by abrupt and sustained decline in glomerular filtration rate, which leads to accumulation of urea and other chemicals in the blood. The term acute kidney injury has been introduced to encompass a wide spectrum of acute alterations in kidney function from mild to severe. Acute kidney injury is classified according to the RIFLE criteria, in which a change from baseline serum creatinine or urine output determines the level of renal dysfunction.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent acute kidney injury in people at high risk? What are the effects of treatments for critically ill people with acute kidney injury? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 82 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: albumin supplementation plus loop diuretics (intravenous), aminoglycosides, aminophylline, amphotericin B, calcium channel blockers, contrast media, dialysis membranes, dopamine, early versus late dialysis, extended daily dialysis, fenoldopam, loop diuretics, mannitol, N-acetylcysteine, natriuretic peptides, renal replacement therapy, sodium bicarbonate-based fluids, sodium chloride-based fluids, and theophylline.

Key Points

Acute renal failure (also called acute kidney injury) is characterised by abrupt and sustained decline in GFR, which leads to accumulation of urea and other chemicals in the blood.

It can be classified according to a change from baseline serum creatinine or urine output, with "Risk" being defined by either a 50% increase in serum creatinine, or a urine output of <0.5 mL/kg/hour for at least 6 hours; and "Failure" being defined by a three-fold increase in serum creatinine, or a urine output of <0.3 mL/kg/hour for 24 hours.

In people at high risk of developing acute renal failure, intravenous sodium chloride (0.9%) reduces incidences of acute renal failure compared with unrestricted oral fluids or 0.45% intravenous sodium chloride solution.

N-acetylcysteine plus intravenous fluids may reduce contrast nephropathy compared with intravenous fluids alone in people undergoing contrast nephrography, although data about prevention of renal failure are inconclusive.
Sodium bicarbonate may be as effective as sodium chloride but the evidence is conflicting so we cannot draw conclusions.
Low-osmolality contrast medium is less nephrotoxic compared with high-osmolality media, and iso-osmolar contrast media has similar nephrotoxicity to low-osmolar contrast media.
We found insufficient evidence on the effects of prophylactic renal replacement therapy.
Single-dose aminoglycosides seem as beneficial as multiple doses for treating infections, but are less nephrotoxic.
Lipid formulations of amphotericin B may cause less nephrotoxicity than standard formulations, although the evidence for this is somewhat sparse.
Mannitol, theophylline, aminophylline, fenoldopam, and calcium channel blockers do not seem useful treatments for people at high risk of acute renal failure.

We don't know whether continuous renal replacement therapy is any more effective than intermittent renal replacement therapy. High-dose continuous renal replacement therapy was ineffective in treatment of people critically ill with acute kidney injury, and is also associated with an increased risk of hypophosphataemia, hypokalaemia, and hypotension.

Synthetic dialysis membranes may be associated with improved survival compared with cellulose-based membranes for treating people with acute renal failure; however, evidence is inconclusive and of variable quality.
Loop diuretics plus fluids seem to increase the risk of developing acute renal failure compared with fluids alone, both in high-risk and critically ill people, and do not seem to improve renal function or mortality compared with placebo in people with acute renal failure, but may increase the risks of ototoxicity and volume depletion.
We found no evidence that examined whether intravenous albumin supplementation improved the effects of loop diuretics, or whether continuous infusion was any more effective than bolus injection in the treatment of people critically ill with acute renal failure.

Neither natriuretic peptides nor dopamine seem beneficial in either high-risk or critically ill people, and both are associated with significant adverse effects.

We don't know whether early versus late renal replacement therapy or extended daily dialysis improve outcomes in people critically ill with acute kidney injury.

Clinical context

About this condition

Definition

Acute renal failure is characterised by abrupt and sustained decline in glomerular filtration rate (GFR),[1] which leads to accumulation of urea and other chemicals in the blood. Most studies define it biochemically as a serum creatinine of 2 mg/dL to 3 mg/dL (200–250 micromol/L), an elevation of >0.5 mg/dL (45 micromol/L) over a baseline creatinine below 2 mg/dL, or a two-fold increase of baseline creatinine. An international interdisciplinary consensus panel has classified acute renal failure (now termed acute kidney injury) according to a change from baseline serum creatinine or urine output. The three-level classification begins with "Risk" (defined by either a 50% increase in serum creatinine or a urine output of <0.5 mL/kg/hour for at least 6 hours), and concludes with "Failure" (defined by a 3-fold increase in serum creatinine or a urine output of <0.3 mL/kg/hour for 24 hours).[2] Acute renal failure is usually additionally classified according to the location of the predominant primary pathology (prerenal, intrarenal, and postrenal failure). Critically ill people are clinically unstable and at imminent risk of death, which usually implies that they need to be in, or have been admitted to, the intensive care unit (ICU).

Incidence/ Prevalence

Two prospective observational studies (2576 people) found that established acute renal failure affected nearly 5% of people in hospital, and as many as 15% of critically ill people, depending on the definitions used.[3] [4]

Aetiology/ Risk factors

General risk factors: Risk factors for acute renal failure that are consistent across multiple causes include: age; hypovolaemia; hypotension; sepsis; pre-existing renal, hepatic, or cardiac dysfunction; diabetes mellitus; and exposure to nephrotoxins (e.g., aminoglycosides, amphotericin, immunosuppressive agents, NSAIDs, ACE inhibitors, intravenous contrast media) (see table 1 ).[4] [5] [6] [7] [8] Risk factors/aetiology in critically ill people: Isolated episodes of acute renal failure are rarely seen in critically ill people, but are usually part of multiple organ dysfunction syndromes. Acute renal failure requiring dialysis is rarely seen in isolation (<5% of people). The kidneys are often the first organs to fail.[9] In the perioperative setting, risk factors for acute renal failure include prolonged aortic clamping, emergency rather than elective surgery, and use of higher volumes (>100 mL) of intravenous contrast media. One study (3695 people) using multiple logistic regression identified the following independent risk factors: baseline creatinine clearance below 47 mL/minute (OR 1.20, 95% CI 1.12 to 1.30), diabetes (OR 5.5, 95% CI 1.4 to 21.0), and a marginal effect for doses of contrast media above 100 mL (OR 1.01, 95% CI 1.00 to 1.01). Mortality of people with acute renal failure requiring dialysis was 36% while in hospital.[5] Prerenal acute renal failure is caused by reduced blood flow to the kidney from renal artery disease, systemic hypotension, or maldistribution of blood flow. Intrarenal acute renal failure is caused by parenchymal injury (acute tubular necrosis, interstitial nephritis, embolic disease, glomerulonephritis, vasculitis, or small-vessel disease). Postrenal acute renal failure is caused by urinary tract obstruction. Observational studies (in several hundred people from Europe, North America, and West Africa with acute renal failure) found a prerenal cause in 40% to 80%, an intrarenal cause in 10% to 50%, and a postrenal cause in the remaining 10%.[7] [8] [10] [11] [12] [13] Prerenal acute renal failure is the most common type of acute renal failure in critically ill people.[7] [14] Intrarenal acute renal failure in this context is usually part of multisystem failure, most frequently caused by acute tubular necrosis due to ischaemic or nephrotoxic injury, or both.[15] [16]

Table 1.

Selected risk factors for acute kidney injury (see text).

Risk factor	Incidence of acute renal failure	Comments
Sepsis	Unknown	Sepsis seems to be a contributing factor in as many as 43% of acute renal failure cases[5]
Aortic clamping	Approaches 100% when longer than 60 minutes[6]	Refers to cross-clamping (no flow) above the renal arteries
Rhabdomyolysis	16.5%[7]	None
Aminoglycosides	8% to 26%[8]	None
Amphotericin	88% with greater than 5 g total dose[9]	60% overall incidence of nephrotoxicity

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Prognosis

One retrospective study (1347 people with acute renal failure) found that mortality was <15% in people with isolated acute renal failure.[17] One prospective study (>700 people) found that, in people with acute renal failure, overall mortality (72% in ICU v 32% in non-ICU; P = 0.001) and the need for dialysis (71% in ICU v 18% in non-ICU; P <0.001) were higher in an ICU than in a non-ICU setting, despite no significant difference between the groups in mean maximal serum creatinine (5.21 ± 2.34 mg/dL in ICU v 5.82 ± 3.26 mg/dL in non-ICU).[18] One large study (>17,000 people admitted to Austrian ICUs) found that acute renal failure was associated with a higher than 4-fold increase in mortality.[19] Even after controlling for underlying severity of illness, mortality was still significantly higher in people with acute renal failure (62.8% in people with acute renal failure v 38.5% in people with no acute renal failure), suggesting that acute renal failure is independently responsible for increased mortality, even if dialysis is used. However, the exact mechanism that leads to increased risk of death is uncertain. A systematic review including 80 articles and a total of 15,897 people with acute renal failure from 1970 to 2004 found mortality unchanged at about 50%, and exceeding 30% in most studies.[20] An observational study including 54 sites and 23 countries screened 29,269 people, and found that 1738 (6%) had severe acute renal failure warranting renal replacement therapy. Overall hospital mortality among people with severe acute renal failure was 60.3% (95% CI 58.0% to 62.6%).[21]

Aims of intervention

Prevention: To preserve renal function. Treating critically ill people: To prevent death; to prevent complications of acute renal failure (volume overload, acid–base disturbance, and electrolyte abnormalities); and to prevent the need for chronic dialysis, with minimum adverse effects.

Outcomes

Prevention: kidney injury; including rates of acute renal failure, nephrotoxicity, or both. Surrogate outcomes were limited to measurements of biochemical evidence of organ function (serum creatinine or creatinine clearance) after the intervention. Surrogate markers such as urine output or renal blood flow were not considered as evidence of effectiveness. Critically ill people: mortality; kidney injury; including rate of renal recovery; adverse effects of treatment.

Methods

Clinical Evidence search and appraisal December 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to December 2009, Embase 1980 to December 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). When editing this review we used The Cochrane Database of Systematic Reviews 2009, Issue 4. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. For early versus late renal replacement therapy and extended daily dialysis options we also searched for cohort studies with >500 participants. There was no minimum length of follow-up required to include treatment studies, but we required 48 hours follow-up for prevention. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for acute kidney injury

Important outcomes	Kidney injury, mortality, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of interventions to prevent acute kidney injury in people at high risk?
31 (5146) [22]	Kidney injury	Low-osmolality contrast media v high-osmolality contrast media	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (365)[23] [24]	Kidney injury	Intravenous sodium chloride 0.9% v oral fluids	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
1 (1620)[26]	Kidney injury	Sodium chloride 0.9% v sodium chloride 0.45%	4	0	0	0	0	High
1 (45)[27]	Kidney injury	Sodium chloride 0.45% v restricted fluids	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (36)[28]	Kidney injury	Inpatient v outpatient fluid regimens	4	−2	0	−2	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Directness points deducted for differences in amount of fluids administered and uncertainty about clinical relevance of outcome measured
28 (3570)[31] [32] [33] [34]	Kidney injury	Acetylcysteine v control in the prevention of contrast nephropathy	4	0	−1	0	0	Moderate	Consistency point deducted for heterogeneity among RCTs
10 (1193 at most)[35]	Mortality	Acetylcysteine v placebo in the prevention of perioperative acute renal failure	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
13 (1339 at most)[35] [36]	Kidney injury	Acetylcysteine v placebo in the prevention of perioperative acute renal failure	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (142)[37]	Kidney injury	Acetylcysteine v placebo in the prevention of acute renal failure after hypotension	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
29 (3270)[39] [40] [41] [42] [43]	Kidney injury	Iso-osmolar contrast media v low-osmolar contrast media	4	−1	−1	−1	0	Very low	Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for not using standardised volumes of contrast media or fluid regimens
4 (803)[45] [46]	Kidney injury	Single-dose aminoglycosides v multiple doses	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for different results for people with different disease severities
20 (26,984)[47] [48] [49] [50]	Kidney injury	Sodium bicarbonate v sodium chloride for the prevention of contrast nephropathy	4	−1	−1	−1	0	Very low	Quality point deducted for the inclusion of underpowered trials. Consistency point deducted for conflicting results. Directness point deducted for the presence of heterogeneity among trials
7 (1334)[47]	Mortality	Sodium bicarbonate v sodium chloride for the prevention of contrast nephropathy	4	−1	0	−1	0	Low	Quality point deducted for the inclusion of underpowered trials. Directness point deducted for heterogeneity among trials
1 (100)[51]	Kidney injury	Sodium bicarbonate v sodium chloride for the prevention of acute kidney injury after cardiothoracic surgery	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
3 (770)[56] [57] [58]	Kidney injury	Fenoldopam v placebo	4	0	0	0	0	High
3 (770)[56] [57] [58]	Mortality	Fenoldopam v placebo	4	0	0	0	0	High
2 (180)[59] [60]	Kidney injury	Fenoldopam v dopamine	4	−2	−1	0	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
11 (1094)[61]	Kidney injury	Fenoldopam v other treatments or control	4	−2	−1	−1	0	Very low	Quality points deducted for incomplete reporting of results and methodological weaknesses. Consistency point deducted for heterogeneity among RCTs. Directness point deducted for heterogeneous combined control
3 (168)[25] [66] [67]	Kidney injury	Mannitol with or without fluids v fluids	4	−1	0	−1	0	Low	Quality point deducted for sparse data. Directness point deducted for multiple comparisons
7 (836 at most)[68] [69]	Kidney injury	Renal replacement therapy (haemofiltration) v standard therapy	4	−2	−1	0	0	Very low	Quality points deducted for methodological weaknesses and incomplete reporting of results. Consistency point deducted for conflicting results across studies
9 (585)[72]	Kidney injury	Theophylline or aminophylline v control in radiocontrast-induced nephropathy	4	−3	0	0	0	Very low	Quality points deducted for incomplete reporting of results, uncertainty about hydration status of people receiving radiocontrast agent, and for uncertainty about heterogeneity among studies
1 (56)[73]	Kidney injury	Theophylline v sodium chloride 0.9% after CABG	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (210)[74]	Kidney injury	Calcium channel blockers v placebo in people receiving live or cadaveric kidney transplant	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
7 (349)[75]	Kidney injury	Calcium channel blockers v no calcium channel blockers in people receiving cadaveric kidney transplant	4	−2	−1	0	0	Very Low	Quality points deducted for incomplete reporting of results and for not reporting loss to follow-up or duration. Consistency point deducted for heterogeneity among RCTs
2 (132)[76] [77]	Kidney injury	Calcium channel blockers v placebo in people undergoing abdominal surgery	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
5 (284)[75]	Mortality	Calcium channel blockers v no calcium channel blockers in people receiving cadaveric kidney transplant	4	−2	−1	0	0	Very Low	Quality points deducted for incomplete reporting of results and for not reporting loss to follow-up or treatment duration. Consistency point deducted for heterogeneity among RCTs
at least 10 RCTs (at least 618 people) [78] [79] [80]	Kidney injury	Dopamine v placebo	4	0	0	0	0	High
12 (832)[78] [80]	Mortality	Dopamine v placebo	4	0	0	0	0	High
4 (297)[83] [84]	Kidney injury	Loop diuretics v fluids alone	4	0	0	−1	0	Moderate	Directness point deducted for differences in treatment protocols
2 (202)[83]	Mortality	Loop diuretics v fluids alone	4	0	0	−1	0	Moderate	Directness point deducted for differences in treatment protocols
11 (818)[86] [87]	Kidney injury	Natriuretic peptides for the prevention of acute kidney injury v other treatments	4	0	0	0	0	High
10 (794)[86] [87]	Mortality	Natriuretic peptides for the prevention of acute kidney injury v other treatments	4	0	0	0	0	High
13 (1532)[88] [89] [90]	Kidney injury	Natriuretic peptides for the prevention of acute kidney injury after cardiothoracic surgery v other treatments	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (598)[89] [90]	Mortality	Natriuretic peptides for the prevention of acute kidney injury after cardiothroacic surgery v other treatments	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
What are the effects of treatments for critically ill people with acute kidney injury?
2 (2585)[95]	Mortality	Standard-dose continuous renal replacement therapy v high-dose continuous renal replacement therapy	4	0	0	0	0	High
10 (1403 max)[97] [98]	Kidney injury	Continuous renal replacement therapy v intermittent renal replacement therapy	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
10 (1403 max)[97] [98] [99]	Mortality	Continuous renal replacement therapy v intermittent renal replacement therapy	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (360)[118]	Mortality	Renal replacement therapy (intermittent haemodialysis) v continuous veno-venous haemodiafiltration	4	0	0	−1	0	Moderate	Directness point deducted for uncertainty about applicability to usual practice
18 studies at most (1967)[108] [107]	Mortality	Dialysis membranes (synthetic) v cellulose-based	4	−3	−1	0	0	Very low	Quality points deducted for incomplete reporting of results, methodological weaknesses, and for including non-randomised trials and observational studies. Consistency point deducted for conflicting results
at least 2 RCTs (at least 422 people)[83] [110]	Kidney injury	Loop diuretics v control	4	−3	0	0	0	Very low	Quality points deducted for poor reporting and methodological weaknesses
5 (at least 574 people)[83] [110]	Mortality	Loop diuretics v control	4	−3	0	0	0	Very low	Quality points deducted for poor reporting and methodological weaknesses
10 (618)[78]	Kidney injury	Dopamine v placebo	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of observational studies
1 RCT + 11 trials (832)[78] [80]	Mortality	Dopamine v placebo	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of observational studies
8 (1043)[86]	Kidney injury	Natriuretic peptides v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
8 (354)[97] [115]	Kidney injury	Early v late renal replacement therapy	4	−1	−1	0	0	Low	Quality point deducted for inclusion of observational studies. Consistency point deducted for conflicting results
26 (3715)[97] [115] [116]	Mortality	Early v late renal replacement therapy	4	−2	−2	0	0	Very low	Quality points deducted for inclusion of observational studies and heterogeneity among pooled trials. Consistency points deducted for conflicting results and different results when sensitivity analyses were performed
1 (64)[97]	Kidney injury	Extended daily dialysis v continuous renal replacement therapy	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (64) [97]	Mortality	Extended daily dialysis v continuous renal replacement therapy	4	−1	0	0	0	Moderate	Quality point deducted for sparse data

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Type of evidence: 4 = RCT; 2 = Observational. Consistency: similarity of results across studies.Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.

Glossary

Biocompatible: Artificial materials can induce an inflammatory response. This response can be humoral (including complement) or cellular. Synthetic dialysis membranes seem to produce less of an inflammatory response in vitro and are classified as more "biocompatible". By contrast, cellulose-based membranes seem to be less biocompatible (cause more inflammation). When cellulose-based membranes are rendered semi-synthetic by modifications or substitution of materials like acetate, they may be become more biocompatible. We found no standards by which this comparison can be made.
Cellulose-based: Dialysis membranes may be made from cellulose. "Unsubstituted" cellulose has not undergone modification to attempt to improve biocompatibility. Synthetic membranes do not use cellulose.
Continuous renal replacement therapy: Any extracorporeal blood purification treatment intended to substitute for impaired renal function over an extended period of time and applied, or aimed at being applied, for 24 hours a day.
Contrast nephropathy: Intravenous radiocontrast increases serum creatinine in some people, particularly those with underlying kidney disease. Most studies define contrast nephropathy as a small change in serum creatinine (e.g., greater than 25% increase). It is not known whether agents that reduce the risk of contrast nephropathy also reduce the risk of acute renal failure.
Early allograft dysfunction: Renal dysfunction that occurs after renal transplantation, and which is usually secondary to ischaemic injury.
Early renal dysfunction: An acute derangement in renal function that is still evolving.
Glomerular filtration rate: The rate of elaboration of protein-free plasma filtrate (ultrafiltration) across the walls of the glomerular capillaries.
High-osmolality contrast media: Contrast media with osmolality greater than 800 mOsm/L. Until recently, it was considered the standard formulation for radiological assays.
High-quality evidence: Further research is very unlikely to change our confidence in the estimate of effect.
Lipid formulations of amphotericin B: Complexes of amphotericin B and phospholipids or sterols. This reduces the toxicity of amphotericin B while preserving its antifungal activity.
Low-osmolality contrast media: Contrast media with osmolality of 600 mOsm/L to 800 mOsm/L.
Low-quality evidence: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Multiple organ dysfunction syndrome: A syndrome of progressive organ failure, affecting one organ after another and believed to be the result of persistent or recurrent infection or inflammation.
Nephrotoxic agents: Any agent that has the potential to produce nephrotoxicity.
Nephrotoxicity: Renal parenchymal damage manifested by a decline in glomerular filtration rate, tubular dysfunction, or both.
Oliguria: Urine output of less than 5 mL/kg daily.
Renal replacement therapy: General terminology that refers to the modalities for assisting or replacing kidney function — that is, continuous and intermittent forms of haemodialysis, peritoneal dialysis, and kidney transplantation.[117]
Very low-quality evidence: Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

John A Kellum, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA.

Mark L Unruh, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, USA.

Raghavan Murugan, Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA.

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BMJ Clin Evid. 2011 Mar 28;2011:2001.

Contrast media (low-osmolality)

Summary

KIDNEY INJURY Compared with high-osmolality contrast media: Low-osmolality contrast media are more effective at reducing nephrotoxicity, particularly in people with underlying renal failure, but are no more effective at reducing the development of acute renal failure or the need for dialysis ( moderate-quality evidence ).

Benefits

Low-osmolality contrast media versus high-osmolality contrast media:

We found one systematic review (search date 1991, 31 RCTs, 5146 people receiving intravascularly administered iodinated contrast material) comparing low-osmolality contrast media with high-osmolality contrast media.[22] The review found no significant difference between low-osmolality and high-osmolality contrast media in the development of acute renal failure or need for dialysis (these are rare events), but there was less nephrotoxicity with low-osmolality contrast media, measured by serum creatinine. Subgroup analysis found that low-osmolality contrast media significantly reduced the proportion of people with a rise in serum creatinine of 44 micrograms/L or more compared with high-osmolality contrast media in people with underlying renal failure. It found no significant difference between treatments for people without prior renal failure (prior underlying renal impairment: 8 RCTs, 1418 people; OR 0.50, 95% CI 0.36 to 0.68; no underlying renal impairment: 20 RCTs, 2865 people; OR 0.75, 95% CI 0.52 to 1.10).

Low-osmolality contrast media versus iso-osmolar contrast media:

See benefits of iso-osmolar contrast media.

Harms

Low-osmolality contrast media versus high-osmolality contrast media:

The review did not report any adverse effects.[22]

Low-osmolality contrast media versus iso-osmolar contrast media:

See harms of iso-osmolar contrast media.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Sodium chloride-based fluids

Summary

KIDNEY INJURY Intravenous sodium chloride 0.9% compared with oral fluids: Intravenous sodium chloride seems more effective at reducing acute renal failure 48 hours after catheterisation in people having elective cardiac catheterisation, but not in people with chronic renal failure undergoing various radiological procedures ( moderate-quality evidence ). Sodium chloride 0.9% compared with sodium chloride 0.45%: Sodium chloride 0.9% infusion is more effective at reducing contrast nephropathy, particularly in women, in people with diabetes, and in people receiving >250 mL of contrast ( high-quality evidence ). Sodium chloride 0.45% compared with restricted fluids: Preoperative intravenous sodium chloride may be more effective at reducing kidney injury in people with moderate to severe renal insufficiency undergoing cardiac surgery. Hydration may also be more effective at reducing the proportion of people requiring postoperative dialysis ( low-quality evidence ). Inpatient compared with outpatient fluid regimens: We don't know whether inpatient intravenous fluid regimens are more effective at reducing serum creatinine levels in people with renal dysfunction having cardiac cathetherisation ( very low-quality evidence ).

Benefits

Intravenous sodium chloride 0.9% versus oral fluids:

We found one RCT (53 people having elective cardiac catheterisation with a contrast agent containing iodine), which compared intravenous sodium chloride (sodium chloride 0.9% for 24 hours at a rate of 1 mL/kg/hour begun 12 hours before catheterisation) versus unrestricted oral fluids.[23] It found that sodium chloride hydration significantly reduced acute renal failure compared with unrestricted oral fluids within 48 hours (acute renal failure defined as increase in serum creatinine by at least 44.2 micromol/L [about 0.5 mg/dL]: 1/27 [4%] with intravenous sodium chloride v 9/26 [35%] with unrestricted oral fluids; RR 0.11, 95% CI 0.015 to 0.79).

A second RCT (312 people with chronic renal failure [serum creatinine 201 ± 81 micromol/L] undergoing various radiological procedures with a non-ionic, low-osmolality contrast agent) compared 4 groups: oral sodium chloride 0.1 g/kg of body weight per day for 2 days before the procedure (the oral saline hydration group); intravenous 0.9% sodium chloride 15 mL/kg for 6 hours before the procedure; intravenous 0.9% sodium chloride plus theophylline 5 mg/kg orally 1 hour before the procedure; intravenous 0.9% sodium chloride plus furosemide 3 mg/kg intravenously just after the procedure.[24] Contrast nephropathy was defined as an increase in serum creatinine of 44 micromol/L (0.5 mg/dL), and occurred in 27/312 people (9%) overall. The RCT found no significant difference in contrast nephropathy among groups (5/76 [7%] with oral sodium chloride v 4/77 [5%] with intravenous sodium chloride v 6/80 [7%] with oral sodium chloride plus theophylline v 12/79 [15%] with intravenous sodium chloride plus furosemide; P >0.05).[24]

Older RCTs compared combinations of fluids (especially sodium chloride 0.45% infusion) versus other active treatments. Comparisons between outcomes in these trials and historical untreated controls are difficult to evaluate, but suggest benefit from fluids.[25] In certain settings, such as traumatic rhabdomyolysis, early and aggressive fluid resuscitation has had dramatic benefits compared with historical controls.[6]

Sodium chloride 0.9% versus sodium chloride 0.45%:

We found one RCT (1620 people who had coronary angiography), which compared the effects of sodium chloride 0.9% infusion versus sodium chloride 0.45% in dextrose infusion on contrast nephropathy.[26] Infusion solution was given on the morning of the procedure for people having elective surgery, or immediately before surgery in the case of emergency surgery. Contrast nephropathy was defined as an increase in serum creatinine of >45 micromol/L (0.5 mg/dL) within 48 hours. The RCT found that sodium chloride 0.9% infusion significantly reduced contrast nephropathy compared with sodium chloride 0.45% in dextrose infusion (0.7% with sodium chloride 0.9% infusion v 2.0% with sodium chloride 0.45% infusion; P = 0.04). Three predefined subsets of people (women, people with diabetes, and people receiving >250 mL of contrast) benefited the most from sodium chloride 0.9% infusion (reduction in contrast-mediated associated nephropathy; women: reduction from 5.1% to 0.6%; P = 0.01; people with diabetes: reduction from 9.8% to 5.5%; P = 0.01; people receiving >250 mL of contrast: reduction from 3.0% to 0%; P = 0.01).

Sodium chloride 0.45% versus restricted fluids:

We found one RCT (45 people with chronic kidney disease undergoing cardiac surgery), which compared intravenous 0.45% sodium chloride before surgery versus restricted fluids.[27] People admitted for elective open heart surgery with a quantified GFR of <45 mL/minute were assigned using a 2:1 randomisation process, to either an intravenous infusion of 0.45% sodium chloride (1 mL/kg/hour) for 12 hours before the operation (hydration group, 30 people) or to fluid restriction (control group, 15 people). The RCT found that kidney injury (defined as at least 25% increase in serum creatinine from baseline) developed in 9/30 (30%) people with hydration compared with 8/15 (53%) people with control (statistical analysis between groups not reported). The RCT found that hydration significantly reduced the proportion of people requiring postoperative dialysis compared with control (0/30 [0%] with hydration v 4/15 [27%] with control; P <0.01).[27]

Inpatient versus outpatient fluid regimens:

We found one RCT (36 people with renal dysfunction having cardiac catheterisation), which compared an inpatient intravenous fluid regimen (sodium chloride 0.45% at 75 mL/hour iv for 12 hours before and after cardiac catheterisation) with an outpatient oral fluid regimen (1 L of clear liquids over 10 hours followed by 6 hours of iv fluids starting just before contrast exposure) for the prevention of radiocontrast-induced renal dysfunction.[28] The predefined primary end point was the maximal change in creatinine up to 48 hours after cardiac catheterisation. The RCT found no significant differences between groups in the maximal changes in serum creatinine (0.21 ± 0.38 mg/dL [18 ± 33 micromol/L] for inpatients v 0.12 ± 0.23 mg/dL [11 ± 20 micromol/L] for outpatients; P >0.05; no additional data reported). However, this study may have been underpowered to rule out clinically important differences. The outpatient group also received more fluid volume.

Sodium chloride versus sodium bicarbonate:

See benefits of sodium bicarbonate-based fluids.

Harms

The volumes of fluids recommended (e.g., 1 L) and the rates of infusion (generally <500 mL/hour) have little potential for harm in most people.

Intravenous sodium chloride 0.9% versus oral fluids:

The RCT (53 people having non-emergency cardiac catheterisation) comparing sodium chloride versus unrestricted oral fluids found no adverse effects with sodium chloride.[23] The second RCT reported that one person had vomiting with oral sodium chloride alone, and no other adverse effects in the other three arms.[24]

Sodium chloride 0.9% versus sodium chloride 0.45%:

The RCT found no significant differences in cardiac or peripheral vascular complications between sodium chloride 0.9% and sodium chloride 0.45% plus dextrose (cardiac complications: 5.3% with sodium chloride 0.9% v 6.4% with sodium chloride 0.45% plus dextrose; P = 0.59; peripheral vascular complications: 1.6% with sodium chloride 0.9% v 1.5% with sodium chloride 0.45% plus dextrose; P = 0.93).[26]

Sodium chloride 0.45% versus restricted fluids:

The RCT did not report on harms.[27]

Inpatient versus outpatient fluid regimens:

The RCT comparing inpatient versus outpatient fluid regimen gave no information on adverse effects.[28]

Sodium chloride versus sodium bicarbonate:

See harms of sodium bicarbonate-based fluids.

Comment

Clinical guide:

Hypovolaemia is a significant risk factor for acute renal failure. The provision of adequate maintenance fluids is considered important in preventing acute renal failure. Additional fluid loading may be useful because it ensures adequate intravascular volume. It also stimulates urine output, theoretically limiting renal exposure time to higher concentrations of nephrotoxins.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Amphotericin B (lipid formulations)

Summary

We found no direct information from RCTs about the effects of amphotericin B in people with acute kidney injury. NOTE Lipid formulations of amphotericin B seem to cause less nephrotoxicity compared with standard formulations, but direct comparisons of long-term safety are lacking.

Benefits

We found no systematic review or RCTs.

Harms

We found no evidence of increased adverse effects from lipid formulations of amphotericin B. However, these formulations are still nephrotoxic and should be used with care.

Comment

A phase II trial of lipid formulations of amphotericin B (556 people) found an incidence of renal toxicity (defined by any increase in serum creatinine) of 24% (v 60–80% with standard formulation of amphotericin B). People with baseline serum creatinine in excess of 2.5 mg/dL (221 micromol/L) on standard amphotericin B showed a significant decrease in serum creatinine when transferred to the lipid formulation (P <0.001).[29] One trial found that simply infusing amphotericin B in a lipid solution designed for parenteral nutrition did not result in any benefit, and may be associated with pulmonary adverse effects.[30]

Clinical guide:

Fluid loading can be useful in reducing the risk of acute renal failure from all nephrotoxins. Considerable variability may exist between individual lipid formulations of amphotericin B, in terms of efficacy and safety, hence the current consensus is that lipid formulations of amphotericin B are less nephrotoxic than standard formulations. It is prudent not to use any form of amphotericin B in people with or at high risk of acute renal failure, if an alternative drug treatment is available.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

N-Acetylcysteine

Summary

KIDNEY INJURY Compared with control in the prevention of contrast nephropathy: N-acetylcysteine seems more effective at reducing contrast nephropathy ( moderate-quality evidence ). Compared with placebo in the prevention of perioperative acute renal failure: N-acetylcysteine seems no more effective at reducing the incidence of acute renal failure in people undergoing major surgery but without any contrast exposure or in people undergoing cardiothoracic surgery (moderate-quality evidence). Compared with placebo in the prevention of acute renal failure after hypotension: N-acetylcysteine is no more effective at reducing the incidence of acute renal failure in people with new-onset (within 12 hours) hypotension or vasopressor requirement of at least 30 minutes' duration, or both (moderate-quality evidence). MORTALITY Compared with placebo in the prevention of perioperative acute renal failure: N-acetylcysteine is no more effective at reducing mortality in people undergoing major surgery but without any contrast exposure (moderate-quality evidence).

Benefits

N-Acetylcysteine versus control in the prevention of contrast nephropathy:

We found two systematic reviews[31] [32] and two subsequent RCTs [33] [34] that reported on the use of N-acetylcysteine in people at high risk.

The first review (search date 2006, 26 RCTs) assessed the effectiveness of either low-dose or high-dose N-acetylcysteine compared with control (saline solution) in people with chronic renal impairment undergoing radiographic procedures.[31] The primary outcome was the development of contrast-induced nephropathy, defined as an absolute increase in baseline serum creatinine >44.2 micromol/L (>0.5 mg/dL) or a relative increase greater than 25% at 48 hours after contrast injection. The review found that N-acetylcysteine significantly reduced the incidence of contrast nephropathy compared with control (26 RCTs; 147/1751 [8%] with N-acetylcysteine v 229/1642 [14%] with control; RR 0.62, 95% CI 0.44 to 0.88; P = 0.0). However, the review reported significant heterogeneity across studies (P = 0.001; see comment).[31]

The second review (search date 2008, 16 RCTs, 9 of which are also included in the first review; 1667 people) compared the use of high-dose N-acetylcysteine (iv or oral >1200 mg/day) with hydration alone.[32] The average population age was 68 years, and 39% had a history of diabetes, with a mean baseline creatinine of 1.58 mg/dL.[32] The review found significantly lower incidence of contrast nephropathy with high-dose N-acetylcysteine compared with hydration alone (OR 0.52, 95% CI 0.34 to 0.78; absolute numbers not reported). The review reported no significant heterogeneity among studies (P = 0.09). However, the study found a wide variation in the reported doses of N-acetylcysteine used, route of administration, and quality of studies. Furthermore, the review did not report on clinically relevant patient-centred outcomes such as requirement of renal replacement therapy, hospital resource use, or mortality in patients with contrast nephropathy.[32]

The first subsequent RCT (87 high-risk people who underwent contrast-enhanced CT scan) compared intravenous N-acetylcysteine with hydration.[33] People in the N-acetylcysteine group received a 900-mg injection of N-acetylcysteine 1 hour before and another immediately after injection of contrast medium. People in the control group received hydration only. Serum levels of creatinine and cystatin C, a more sensitive marker of GFR, were measured at admission and on days 2 and 4 after the CT scan. The RCT found that N-acetylcysteine significantly reduced the proportion of people with a 25% or greater increase in serum creatinine compared with hydration (5% with N-acetylcysteine v 21% with hydration; P = 0.02; absolute numbers not reported), but found no significant difference between groups in the proportion of people with a 25% or greater increase in serum cystatin C concentration (17% with N-acetylcysteine v 22% with hydration; P = 0.59). The RCT found that administration of N-acetylcysteine seemed protective against the nephrotoxicity of contrast medium only when creatinine was used as an outcome. No effect was found when serum cystatin C concentration was used to assess renal function, suggesting that the true effect of N-acetylcysteine on serum creatinine level remains unclear and may not be related to a renoprotective action.[33]

A second subsequent RCT (90 people with either diabetes or chronic kidney disease undergoing coronary angiography) compared oral N-acetylcysteine (600 mg twice daily, starting 24 hours before the procedure) with placebo, in adjunct to hydration.[34] The RCT found no significant difference in the incidence of contrast nephropathy between N-acetylcysteine and placebo (11% with N-acetylcysteine v 14% with placebo; P = 0.65; absolute numbers not reported).[34]

N-Acetylcysteine versus placebo in the prevention of perioperative acute kidney injury:

We found two systematic reviews that evaluated the use of perioperative N-acetylcysteine compared with placebo in people undergoing major surgery.[35] [36]

The first review (search date 2008, 10 RCTs; 1193 adults undergoing major surgery but without any contrast exposure) compared perioperative N-acetylcysteine versus placebo. The review found no significant difference in mortality (OR 1.05, 95% CI 0.58 to 1.92; absolute data not reported), acute renal failure requiring dialysis (OR 1.04, 95% CI 0.45 to 2.37; absolute data not reported), incremental increase in serum creatinine concentration >25% above baseline (OR 0.84, 95% CI 0.64 to 1.11; absolute data not reported), or length of ICU stay (WMD in days, 0.46, 95% CI 0.43 to 1.36; absolute data not reported) between groups. However, most people had normal preoperative renal function and underwent cardiac surgery.[35]

The second review (search date 2008, 13 RCTs; 7 of which are also included in the first review, 1338 people undergoing cardiothoracic surgery) compared postoperative N-acetylcysteine versus placebo. The review found no significant difference between groups in the incidence of postoperative acute kidney injury (OR 0.99, 95% CI 0.50 to 1.94; absolute data not reported) or renal replacement therapy (OR 0.73, 95% CI 0.34 to 1.57; absolute data not reported).[36]

N-Acetylcysteine versus placebo in the prevention of acute kidney injury after hypotension:

One RCT (142 people) evaluated whether oral N-acetylcysteine reduced the incidence of acute renal failure in people with new-onset (within 12 hours) hypotension of at least 30 minutes' duration or vasopressor requirement, or both, compared with placebo.[37] People (on medical, cardiac, surgical, trauma/neurosurgical ICUs) were randomised to receive either N-acetylcysteine or placebo for 7 days in addition to standard supportive therapy. The RCT found no significant difference in the incidence of acute kidney injury (defined as at least 0.5 mg/dL increase in creatinine) between groups (11/71 [15%] with N-acetylcysteine plus standard care v 12/71 [17%] with placebo plus standard care; P = 0.82).[37]

Harms

N-Acetylcysteine versus control in the prevention of contrast nephropathy:

Neither of the systematic reviews gave any information on adverse effects of N-acetylcysteine.[31] [32]

N-Acetylcysteine versus placebo in the prevention of perioperative acute renal failure:

Neither of the systematic reviews gave any information on adverse effects of N-acetylcysteine.[35] [36] However, N-acetylcysteine has been widely used to treat people with paracetamol (acetaminophen) overdose, and has virtually no toxicity at therapeutic levels (see harms of N-acetylcysteine in review on paracetamol [acetaminophen] poisoning).

N-Acetylcysteine versus placebo in the prevention of acute renal failure after hypotension:

The RCT reported that two people taking N-acetylcysteine developed rashes (both possibly due to broad-spectrum antibiotics), and three people taking N-acetylcysteine had adverse effects attributable to treatment (2 people with nausea, 1 person with intolerance to taste and odour).[37]

Comment

We found one further review (search date 2004, 22 RCTs, 17 of which are also included in the first review[31]), which also found evidence of heterogeneity across studies (P = 0.04).[38] Further analysis of changes in serum creatinine levels from baseline to different reported nephrotoxicity rates in different trials followed by model-based, unsupervised clustering analysis resolved trials into two distinct and significantly different populations. Cluster 1 studies showed no benefit (RR 0.87, 95% CI 0.68 to 1.12; P = 0.28), while cluster 2 studies indicated that N-acetylcysteine was highly beneficial (RR 0.15, 95% CI 0.07 to 0.33; P <0.0001). Cluster 2 studies were relatively early, small, and of lower quality compared with cluster 1 studies.[38]

The primary outcome assessed in the RCTs included in the systematic reviews was radiocontrast-induced nephropathy at 48 hours (defined as an increase in serum creatinine of at least 0.5 mg/dL [45 micromol/L] or >25% from baseline after 48 hours).[32] [34] The timing and dose of administration of N-acetylcysteine differed widely among included RCTs. Despite the reported association of contrast-induced nephropathy with adverse outcomes, very few studies have examined clinically relevant end points, such as dialysis dependency, or in-hospital morbidity and mortality. The largest systematic review so far revealed significant heterogeneity among studies, suggesting differences in patient populations or study methodology.[31] Hence, these results should be interpreted with caution. Therefore, the role of N-acetylcysteine to prevent acute renal failure remains unclear. The use of N-acetylcysteine in the prevention of perioperative acute kidney injury after major surgery and cardiothoracic surgery is not supported by evidence.

Substantive changes

N-Acetylcysteine New evidence added.[31] [32] [33] [34] [35] [36] [38] Categorisation of N-acetylcysteine changed from Likely to be beneficial to Unknown effectiveness as the reviews pooled heterogenous trials.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Contrast media (iso-osmolar)

Summary

KIDNEY INJURY Compared with low-osmolar contrast media: We don't know whether non-ionic iso-osmolar contrast media is more effective at reducing the risk of contrast media-induced nephropathy ( very low-quality evidence ).

Benefits

We found one systematic review,[39] one additional RCT,[40] and three subsequent RCTs.[41] [42] [43]

The systematic review (search date 2007, 25 RCTs, 3270 people) compared the effects of non-ionic, iso-osmolar contrast media (iodixanol) versus low-osmolar contrast media on the incidence of contrast nephropathy.[39] Contrast nephropathy was defined as an increase in serum creatinine of 25% or >0.5 mg/dL increase within 24 to 48 hours. The review found no significant difference between iodixanol compared with low-osmolar contrast media in contrast nephropathy overall (RR 0.80, 95% CI 0.61 to 1.04; absolute data not reported), or in the subgroup with pre-existing renal insufficiency (RR 1.07, 95% CI 0.56 to 2.02; absolute data not reported), or after intra-arterial administration (RR 0.68, 95% CI 0.46 to 1.01; absolute data not reported).[39] However, among the subgroup of people with combined intra-arterial administration and renal insufficiency, the review found that iodixanol significantly reduced the risk of contrast medium-induced nephropathy compared with low-osmolar contrast media (iohexol) (RR 0.38, 95% CI 0.21, 0.68; absolute data not reported).[39]

In the additional RCT (300 people with creatinine clearance 60 mL/minute or less), iodixanol (a non-ionic iso-osmolar contrast media) or ioxaglate (a low-osmolar contrast media) were used in people having coronary angiography with or without a percutaneous coronary intervention.[40] Contrast nephropathy was defined as an increase in serum creatinine of at least 25% (or at least 0.5 mg/dL [44.2 micromol/L]). The RCT found that the incidence of contrast nephropathy was significantly lower with iodixanol compared with ioxaglate (11/140 [8%] with iodixanol v 23/135 [17%] with ioxaglate; OR 0.42, 95% CI 0.19 to 0.89; P = 0.02). In subgroup analysis, it found that the incidence of contrast nephropathy was also significantly lower with iodixanol in people with severe renal impairment, in people with concomitant diabetes, or in people given at least 140 mL of contrast media (severe renal impairment: 31 people; P = 0.02; diabetes: 97 people; P = 0.04; contrast media at least 140 mL: 171 people; P = 0.04).[40]

The first subsequent RCT (146 people with chronic renal insufficiency undergoing coronary angiography) compared non-ionic iso-osmolar contrast media (iodixanol) versus ionic low-osmolar contrast media (ioxaglate).[41] The primary end point of the study was median peak increase of serum creatinine from day 0 through to day 3 after angiography. The RCT found no significant difference between iodixanol and ioxaglate for the primary end point (0.09 mg/dL, interquartile range 0 mg/dL to 0.30 mg/dL with iodixanol v 0.15 mg/dL, interquartile range 0 mg/dL to 0.40 mg/dL with ioxaglate; P = 0.07). The RCT also found no significant difference between groups in the proportion of people with a peak increase of serum creatinine of 0.5 mg/dL or more (16% with iodixanol v 18% with ioxaglate; P = 0.82), 1.0 mg/dL or more (1% with iodixanol v 5% with ioxaglate; P = 0.36), and 25% or more (16% with iodixanol v 24% with ioxaglate; P = 0.28). The RCT found no significant difference between groups in the incidence of in-hospital acute renal failure (11% with iodixanol v 18% with ioxaglate; RR 0.63, 95% CI 0.28 to 1.43; P = 0.35).[41]

The second subsequent RCT (108 people with chronic kidney disease undergoing coronary interventions) compared iso-osmolar iodixanol versus low-osmolar iopromide.[42] People with chronic kidney disease (creatinine clearance 60 mL/minute or less) were randomised to iodixanol (106 people) or iopromide (102 people). The primary end point was incidence of contrast-induced nephropathy, defined as an increase in serum creatinine of at least 25% or 0.5 mg/dL within 72 hours of contrast exposure. The RCT found that iodixanol significantly reduced the incidence of contrast nephropathy compared with iopromide (6% with iodixanol v 17% iopromide; P = 0.011; absolute data not reported).[42]

The third subsequent RCT (191 high-risk people undergoing coronary angiography) compared iso-osmolar contrast media (iodixanol) versus low-osmolar contrast media (iopromide).[42] Both arms of the study received pre-procedural hydration and oral N-acetylcysteine. The RCT found no significant difference in the incidence of contrast nephropathy at 48 hours (15% with iodixanol v 12% with iopromide; P = 0.56) or at 1 week (23% with iodixanol v 27% with iopromide; P = 0.48).[42]

Harms

The systematic review found that the risk of contrast nephropathy with low-osmolar contrast media iohexol was higher compared with iodixanol in people with intra-arterial administration pre-existing renal insufficiency.[39]

The additional RCT found no difference between groups in a composite safety end point (death, MI, revascularisation, cerebral infarction, dialysis after contrast procedure: 3/140 [2.1%] with iodixanol v 3/135 [2.2%] with ioxaglate; statistical analysis between groups not reported).[40]

Comment

One systematic review suggests that the risk of contrast nephropathy is similar between non-ionic, iso-osmolar contrast media and low-osmolar contrast media in high-risk patients.[44] It is therefore possible that factors other than osmolality may be important in determining renal toxicity. However, in many of the studies reported in the systematic review, neither the volume of contrast media nor the fluid regimens were standardised.[44] Therefore, the results of the systematic review can only be considered as hypothesis generating.

Substantive changes

Contrast media (iso-osmolar) New evidence added.[39] [41] [42] [43] Categorisation changed from Likely to be beneficial to Unknown effectiveness as all studies assessed only incidence of contrast media-induced nephropathy.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Aminoglycosides (single dose)

Summary

KIDNEY INJURY Single-dose aminoglycosides compared with multiple doses: Single-dose aminoglycosides seem more effective at reducing nephrotoxicity in people with fever, but not in people with fever and neutropenia ( low-quality evidence ).

Benefits

We found one systematic review[45] and one additional RCT.[46]

The systematic review (search date 1995, 4 RCTs, 803 people with fever and neutropenia, not limited to people in ICUs) found no significant difference between single and multiple doses of aminoglycosides in antimicrobial efficacy, clinical cure rates, and nephrotoxicity (antimicrobial efficacy: 2 RCTs, 57 people; RR 1.00, 95% CI 0.86 to 1.16; clinical cure rates: 4 RCTs, 961 episodes; RR 0.97, 95% CI 0.91 to 1.05; nephrotoxicity, defined as increase in serum creatinine by >35–45 micromol/L [about 0.5 mg/dL]: 3 RCTs, 718 episodes; RR 0.78, 95% CI 0.31 to 1.94; see comment below).[45]

The additional RCT (85 people with fever) compared a once-daily dose of gentamicin versus three-times-daily doses of gentamicin.[46] It found that single dosing significantly reduced nephrotoxicity compared with multiple dosing (defined as an increase in serum creatinine of at least 0.5 mg/dL [45 micromol/L]: 2/40 [5%] with single dosing v 11/45 [24%] with multiple dosing; RR 0.21, 95% CI 0.05 to 0.87; NNT 5, 95% CI 2 to 24).[46]

Harms

The review found no evidence of greater harm from once-daily aminoglycoside dosing (see RR of nephrotoxicity in benefits section above).[45]

Comment

The systematic review defined clinical cure according to the definitions used by investigators in the primary studies, which may have varied among studies.[45] The risk from aminoglycosides is highest in people with: volume depletion; underlying renal, cardiac, or hepatic disease; or when combined with diuretics or other nephrotoxic agents. Two studies included in the systematic review randomised episodes of infection, allowing for people to be included in more than one option in the study.[22]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Sodium bicarbonate-based fluids

Summary

KIDNEY INJURY Compared with sodium chloride for the prevention of contrast nephropathy: Sodium bicarbonate may be as effective at reducing the rate of contrast-induced nephropathy, but not acute renal failure requiring dialysis ( very low-quality evidence ). Compared with sodium chloride for the prevention of acute kidney injury after cardiothoracic surgery: Sodium bicarbonate may be as effective at reducing the rate of renal dysfunction (>25% increase in plasma creatinine concentration) at 5 days after surgery ( low-quality evidence ). MORTALITY Compared with sodium chloride for the prevention of contrast nephropathy: Sodium bicarbonate seems as effective at reducing mortality ( moderate-quality evidence ).

Benefits

Sodium bicarbonate versus sodium chloride for prevention of contrast nephropathy:

We found two systematic reviews[47] [48] and two subsequent RCTs,[49] [50] which compared the use of intravenous isotonic sodium bicarbonate solution versus isotonic sodium chloride solution for prevention of contrast nephropathy.

The first review (search date 2008, 17 RCTs, 26,433 people) compared pre-procedural hydration with sodium bicarbonate versus sodium chloride.[47] The review found that pre-procedural hydration with sodium bicarbonate significantly decreased the rate of contrast-induced nephropathy compared with sodium chloride (17 RCTs; OR 0.52, 95% CI 0.34 to 0.80; P = 0.003, NNT 16, 95% CI 10 to 34; absolute data not reported).[47] However, the RCT found no significant difference in the incidence of acute kidney failure in need of post-procedure haemodialysis or mortality between groups (post-procedure haemodialysis: 12 RCTs, 2011 people; 6/934 [0.6%] with sodium bicarbonate v 12/927 [1.3%] with sodium chloride; OR 0.53, 95% CI 0.20 to 1.41; P = 0.20; mortality between groups: 7 RCTs, 1334 people; 8/886 [1%] with sodium bicarbonate v 12/666 [2%] with sodium chloride; OR 0.74, 95% CI 0.29 to 1.9; P = 0.53). The RCT reported that there was a moderate heterogeneity across trials regarding participant characteristics and treatment protocols (P = 0.015) and close evaluation of the review suggests that the benefit of sodium bicarbonate was seen only from earlier smaller studies but not in later larger trials (see comment).

The second review (search date 2008, 4 RCTs, 3 of which are also included in the first review, 573 people undergoing radiocontract procedures) compared isotonic sodium bicarbonate versus placebo or normal saline.[48] The review also found that isotonic sodium bicarbonate significantly reduced the risk of an incremental rise in serum creatinine concentration 25% above baseline (4 RCTs; 9/286 [3%] with sodium bicarbonate v 41/287 [14%] with saline; RR 0.22, 95% CI 0.11 to 0.44; P <0.0001) and had a significant protective effect on the absolute change in serum creatinine concentration (WMD −9.4 micromol/L, 95% CI −17.2 micromol/L to −1.7 micromol/L; P = 0.02) and creatinine clearance (WMD 3.7 mL/minute, 95% CI 0.55 micromol/L to 6.80 micromol/L; P = 0.02) after radiocontrast compared with placebo or sodium chloride.[48] However, the review found no significant difference in the incidence of acute renal failure requiring dialysis with isotonic sodium bicarbonate compared with placebo or normal saline (RR 0.59, 95% CI 0.15 to 2.42; P = 0.47).[48]

The first subsequent three-armed RCT (286 people undergoing coronary angiography or percutaneous coronary intervention) compared sodium bicarbonate, normal saline alone, or normal saline plus acetazolamide.[49] Only the sodium bicarbonate versus normal saline results will be reported here. The RCT found that sodium bicarbonate significantly reduced the risk of acute kidney injury after contrast exposure compared with normal saline (4/96 [4%] with sodium bicarbonate v 12/96 [13%] with normal saline; P <0.04).[49] However, this study did not report volume status and other concurrent interventions in the three arms of the study.[49]

The second subsequent RCT (265 high-risk people undergoing coronary angiography) compared isotonic sodium bicarbonate plus isotonic saline versus isotonic saline alone.[50] The RCT found no significant difference in the proportion of people who developed contrast-induced nephropathy between groups (9/135 [7%] with sodium bicarbonate plus isotonic salinev 7/130 [5%] with saline alone; OR 1.26, 95% CI 0.45 to 3.50; P = 0.6).[50]

Sodium bicarbonate versus sodium chloride for prevention of acute kidney injury after cardiothoracic surgery:

We found one RCT (100 people undergoing cardiopulmonary bypass) that evaluated whether perioperative sodium bicarbonate infusion (4 mmol/kg) can attenuate postoperative increases in serum creatinine compared with sodium chloride (4 mmol/kg).[51] The primary outcome measure was the proportion of people who developed acute renal dysfunction defined as a postoperative increase in plasma creatinine concentration >25% of baseline within the first 5 postoperative days.[51] The RCT found that sodium bicarbonate significantly reduced the proportion of people who developed acute renal dysfunction compared with sodium chloride (16/50 [32%] with sodium bicarbonate v 26/50 [52%] with sodium chloride; OR 0.43, 95% CI 0.19 to 0.98; P = 0.043).[51]

Harms

Sodium bicarbonate versus sodium chloride for prevention of contrast nephropathy:

The reviews[47] [48] and subsequent RCTs[49] [50] gave no information on adverse effects.

Sodium bicarbonate versus sodium chloride for prevention of acute kidney injury after cardiothoracic surgery:

The RCT gave no information on adverse effects.[51]

Comment

The largest systematic review to date reported moderate heterogeneity across studies regarding participant characteristics and treatment protocols. [47]Moreover, careful evaluation of the review suggests that the benefit of sodium bicarbonate was seen only from earlier smaller studies but not in later larger studies. Nevertheless, this review did not report analysis that compared earlier versus later trials on sodium bicarbonate. A larger adequately powered RCT is required with careful control of co-interventions to assess the benefit of sodium bicarbonate in people exposed to radiocontrast, as well as in the cardiothoracic surgery population.

While no trials have reported harms associated with sodium bicarbonate, there are no commercially available isotonic bicarbonate solutions on the market. Therefore, the risk of compounding errors with bedside preparation of these solutions exists and caution is advised.

Substantive changes

Sodium bicarbonate-based fluids New evidence added.[47] [48] [49] [50] [51] Categorisation unchanged (Unknown effectiveness) as the RCTs identified had weak methods and there was some suggestion from a systematic review that that the benefit of sodium bicarbonate was seen only from earlier smaller studies but not in later larger trials.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Fenoldopam

Summary

KIDNEY INJURY Compared with placebo: Fenoldopam is no more effective at preventing acute renal failure, or at reducing the need for dialysis in people having invasive cardiovascular procedures, in people with sepsis, or in critically ill people with early acute tubular necrosis ( high-quality evidence ). Compared with dopamine: We don't know whether fenoldopam is more effective at reducing the incidence of acute renal failure ( very low-quality evidence ). Compared with other treatments or control: We don't know whether fenoldopam is more effective at reducing the risk of acute kidney injury or the need for renal replacement therapy in people in ICUs, or in people having major surgery (very low-quality evidence). MORTALITY Compared with placebo: Fenoldopam is no more effective at reducing mortality in people having invasive cardiovascular procedures, in people with sepsis, or in critically ill people with early acute tubular necrosis (high-quality evidence). Compared with other treatments or control: We don't know whether fenoldopam is more effective at reducing in-hospital death in people in ICUs, or in people having major surgery (very low-quality evidence). NOTE Fenoldopam may cause hypotension.

Benefits

Fenoldopam versus placebo:

We found 7 RCTs.[52] [53] [54] [55] [56] [57] [58]

Four of the RCTs found some improvement in renal perfusion and creatinine clearance, but had weak methods;[52] [53] [54] [55] either they were underpowered, had differences between groups at baseline, did not compare interventions between groups directly, or did not assess valid clinical outcomes.

The fifth and largest RCT (double-blind, multicentre, 315 people with creatinine clearance below 60 mL/minute having invasive cardiovascular procedures) compared intravenous fenoldopam mesylate (0.05 micrograms/kg/minute titrated to 0.10 micrograms/kg/minute) versus placebo.[56] All people were hydrated, and treatment started 1 hour before angiography and continued for 12 hours. Contrast nephropathy was defined as an increase of 25% or more in serum creatinine level within 96 hours after the procedure. The RCT found no significant difference between fenoldopam and placebo in contrast nephropathy, 30-day mortality, dialysis, or readmission to hospital (contrast nephropathy: 34% with fenoldopam v 30% with placebo; RR 1.11, 95% CI 0.79 to 1.57; P = 0.61; 30-day mortality: 2.0% with fenoldopam v 3.8% with placebo; P = 0.50; dialysis: 2.6% with fenoldopam v 1.9% with placebo; P = 0.72; readmission to hospital: 17.6% with fenoldopam v 19.9% with placebo; P = 0.66).[56]

The sixth RCT,[57] 300 people with sepsis and baseline serum creatinine concentrations <150 micromol/L (about 1.7 mg/dL) were randomised to continuous infusion of either fenoldopam (150 people; 0.09 micrograms/kg/minute) or placebo (150 people). The primary outcome measure was the incidence of acute renal failure (defined as a serum creatinine concentration increase to >150 micromol/L [approximately below 1.7 mg/dL]) during drug infusion. Although the incidence of acute renal failure was significantly lower in the fenoldopam group compared with the control group (29 people with fenoldopam v 51 people with control; P = 0.006), there were no differences between the groups in the incidence of severe acute renal failure or need for dialysis, or in mean survival time (creatinine >300 micromol/L [about 3.3 mg/dL]: 10 with fenoldopam v 21 with control; P = 0.056; mean survival time: 47 ± 2 days with fenoldopam v 42.1 ± 2.2 days with control; P = 0.068).

The seventh RCT randomised 155 people with early acute tubular necrosis (serum creatinine level increased to 50% greater than admission levels within 24 hours and mean arterial pressure >70 mm Hg) to fenoldopam (80 people; 0.05 micrograms/kg/minute titrated to 0.2 micrograms/kg/minute) or placebo (75 people) for 72 hours.[58] There was no significant difference between the groups in the incidence of dialysis or 21-day mortality (dialysis: 16% with fenoldopam v 25% with placebo; P = 0.163; 21-day mortality: 14% with fenoldopam v 25% with placebo; P = 0.068).

Fenoldopam versus dopamine:

Two RCTs compared fenoldopam versus low-dose dopamine in the prevention of acute renal failure.[59] [60]

The first RCT randomised 100 critically ill adults with early renal dysfunction (ICU stay <1 week; haemodynamic stability; and urine output 0.5 mL/kg or less over a 6-hour period, or serum creatinine concentration 1.5–3.5 mg/dL [135–315 micromol/L], or both) to dopamine (2 micrograms/kg/minute) or fenoldopam mesylate (0.1 micrograms/kg/minute) continuous infusion for 4 days.[59] Systemic haemodynamic and renal function variables were recorded daily. The RCT found no differences between groups in heart rate, or in systolic, diastolic, or mean arterial pressure. Fenoldopam produced a more significant reduction in creatinine concentration compared with dopamine after 2, 3, and 4 days of infusion (change from baseline; at day 2: –0.32 mg/dL [–29 micromol/L] with fenoldopam v –0.03 mg/dL [–3 micromol/L] with dopamine; P = 0.047; at day 3: –0.45 mg/dL [–41 micromol/L] with fenoldopam v –0.09 mg/dL [–8 micromol/L] with dopamine; P = 0.047; at day 4: –0.041 mg/dL [–4 micromol/L] with fenoldopam v –0.09 mg/dL [–8 micromol/L] with dopamine; P = 0.02). The RCT did not evaluate clinically relevant end points such as need for dialysis, survival, or renal recovery.

In the second RCT, 80 high-risk people having cardiac surgery were randomised to either fenoldopam (0.05 micrograms/kg/minute) or dopamine (2.5 micrograms/kg/minute) for a 24-hour period after the induction of anaesthesia.[60] The RCT found no significant difference in incidence of acute renal failure between groups (17/40 [42%] with fenoldopam v 16/40 [40%] with dopamine; P = 0.9).

Fenoldopam versus other treatments or control:

One systematic review (search date 2005, 16 RCTs, 1290 people) pooled results of RCTs evaluating fenoldopam compared with placebo or other active treatments in people in ICUs or in people undergoing major surgery.[61] It included RCTs comparing fenoldopam versus a control treatment in people in surgical or intensive care, but excluded RCTs in which people were administered radiocontrast dye. Of the 16 included RCTs, 4 had been reported only as abstracts. Five RCTs were performed in cardiac surgery, three RCTs in vascular surgery, two RCTs in liver transplantation, one RCT in renal transplantation, and 5 RCTs were performed in the ICU. It reported that fenoldopam dosage varied across studies, and that there was no standardisation of indications for renal replacement therapy and biochemical definitions for acute kidney injury.[61] The pooled analysis included RCTs comparing fenoldopam versus placebo (10 RCTs), versus dopamine (4 RCTs), versus dopamine or dobutamine after loop diuretics (1 RCT) or versus a control that was not reported (1 RCT). Many included RCTs had weak methods. The review did not report a separate analysis of fenoldopam versus placebo alone or versus dopamine alone. It found that, compared with the combined control, fenoldopam significantly reduced the risk for acute kidney injury, the need for renal replacement therapy, and in-hospital death (acute kidney injury: 11 RCTs, 1094 people; OR 0.43, 95% CI 0.32 to 0.59; P <0.001; need for renal replacement therapy: 11 RCTs, 1094 people; OR 0.54, 95% CI 0.34 to 0.84; P = 0.007; in-hospital death: 11 RCTs, 1028 people; OR 0.64, 95% CI 0.45 to 0.91; P = 0.01). These benefits were associated with a significantly shorter intensive care stay compared with the combined control (11 RCTs, 840 people; WMD −0.61 days; 95% CI, −0.99 days to −0.23 days; P = 0.002).[61] However, the results are difficult to interpret given the heterogeneous combined control (including placebo, dopamine, and other unspecified treatment) and diversity between included RCTs. Given the limitations of the studies analysed (most were small, diverse, some had weak methods including inadequate or unclear allocation concealment, high risk of bias, and incomplete reporting of methods, and many were not placebo controlled), the review recommends that a large placebo-controlled trial is needed.[61]

Harms

Fenoldopam versus placebo:

Only two of the 7 RCTs reported data on potential adverse effects of fenoldopam.[54] [56] One RCT (45 people) found that fenoldopam significantly lowered the mean arterial pressure within 30 minutes of the infusion, and for the entire 4-hour infusion after angiography compared with sodium chloride.[54] The largest RCT found that fenoldopam significantly decreased blood pressure (P = 0.001), and increased heart rate (P = 0.01) compared with placebo (results presented graphically).[56] It found that fenoldopam treatment had to be stopped more often than placebo, most commonly for mild hypotension or tachycardia. It found no significant difference for the combined adverse-effects outcome of death, dialysis, MI, or readmission to hospital (23.4% with fenoldopam v 23.1% with placebo; P >0.99).

Fenoldopam versus dopamine:

In the RCT comparing fenoldopam versus low-dose dopamine, fenoldopam did not cause any clinically significant haemodynamic impairment compared with low-dose dopamine.[59]

Fenoldopam versus other treatments or control:

The systematic review found that fenoldopam was associated with a non-significant trend towards a greater rate of hypotensive episodes or use of vasopressors compared with the combined control (118/498 [24%] people with fenoldopam v 103/544 [19%] people with the combined control; OR 1.31, 95% CI 0.93 to 1.83; P = 0.12).[61]

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Mannitol

Summary

KIDNEY INJURY Mannitol with or without fluids compared with fluids: Mannitol with or without fluids may be no more effective at reducing the incidence of acute renal failure in people having cardiac surgery ( low-quality evidence ).

Benefits

Mannitol with or without fluids versus fluids:

We found no systematic review. Several small RCTs found no reduction in the incidence of acute renal failure with mannitol plus intravenous fluids compared with intravenous fluids alone in a variety of conditions, including: CABG,[62] traumatic rhabdomyolysis,[63] and vascular[64] and biliary tract surgery.[65] One RCT comparing sodium chloride 0.45% alone, furosemide plus sodium chloride 0.45%, and mannitol plus sodium chloride 0.45% (78 people with chronic renal insufficiency who had a cardiac angiography, mean serum creatinine 2.1 ± 0.6 mg/dL [186 ± 53 micromol/L]) found that mannitol plus sodium chloride 0.45% increased acute renal failure (defined as an increase in serum creatinine of at least 0.5 mg/dL [45 micromol/L] at 48 hours) compared with sodium chloride 0.45% alone, although the difference was not significant (AR: 7/25 [28%] with mannitol v 3/28 [11%] with sodium chloride 0.45%; RR 2.61, 95% CI 0.76 to 9.03).[25]

Two small RCTs evaluated the role of mannitol in people with normal preoperative renal function (40 people having bypass surgery, preoperative plasma creatinine <130 micromol/L) [66]and in those with pre-existing renal dysfunction (50 people having bypass surgery, serum creatinine between 130 micromol/L and 250 micromol/L)[67]undergoing cardiopulmonary bypass. The RCTs compared mannitol (0.05 g/kg) versus the equivalent volume of Hartmann's solution (sodium chloride). The RCTs found no significant difference between the groups in plasma creatinine or change in creatinine from baseline, urine output, or fluid balance over the first three postoperative days (all measures reported as not significant, data presented graphically).[66] [67]

Harms

The RCTs gave no information on adverse effects.[25] [66] [67]

Comment

Mannitol is an intravascular volume expander and may function as a free-radical scavenger as well as an osmotic diuretic. The RCT addressing the effect of mannitol on renal function provided a three-way comparison showing significant differences among the three groups (P <0.05).[25] Although the same control group seems to have been used to compare both interventions, no adjustment was made for multiple comparisons.

Substantive changes

Mannitol New evidence added.[66] [67] Categorisation unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Renal replacement therapy (prophylactic haemofiltration/dialysis)

Summary

KIDNEY INJURY Compared with standard therapy: We don't know whether peri- or post-procedural haemodialysis reduces the risk of contrast nephropathy ( very low-quality evidence ). NOTE Haemofiltration is invasive, expensive, and can lead to important clinical complications such as hypotension.

Benefits

We found one systematic review[68] and one subsequent RCT.[69]

The review (search date 2006, 8 trials [6 RCTs, 2 non-randomised trials], 412 people) evaluated whether peri-procedural extracorporeal blood purification prevented contrast nephropathy compared with standard medical treatment.[68] Six trials assessed haemodialysis, whereas one trial assessed continuous veno-venous haemofiltration and continuous veno-venous haemodiafiltration. The review performed a subgroup analysis that included only RCT evidence, which we report here. The review found no significant difference in the incidence of contrast nephropathy between haemofiltration and standard treatment (6 RCTs; RR 0.95, 95% CI 0.34 to 2.60; no absolute numbers reported). However, there was high heterogeneity among RCTs (P <0.0001).[68]

The subsequent three-armed large single-centre RCT (424 consecutive people with serum creatinine concentrations between 1.3 mg/dL and 3.5 mg/dL who underwent elective coronary angiography) also evaluated the incidence of contrast nephropathy.[69] The participants were randomised to one of three treatment strategies with everyone receiving pre- and post-procedural hydration; the first group received no additional treatment, the second group received haemodialysis once after contrast exposure, and the third group received oral N-acetylcysteine. We only report the haemodialysis and hydration arms here. The RCT found that haemodialysis after contrast media significantly increased the incidence of contrast nephropathy (defined as an increase in serum creatinine of 0.5 mg/dL or more) compared with pre- and post-procedural hydration at 72 hours after catheterisation (18/113 [16%] with haemodialysis v 7/115 [6%] with hydration alone; P = 0.008). The RCT found no significant difference between groups in increased (0.5 mg/dL or more) serum creatinine concentration after 30 to 60 days (6/118 [5.1%] with haemodialysis v 6/125 [4.8%] with hydration only; P = 0.700), and similar long-term survival rates at 3 years (P = 0.50).[69]

Harms

The review and subsequent RCT gave no information on harms.[68] [69]

Comment

Haemofiltration is expensive, invasive, and can lead to important clinical complications, such as hypotension. Notably, studies of prophylactic haemodialysis to remove contrast dye have shown that, although these techniques can remove the contrast from the circulation, there is no reduction in the risk of contrast nephropathy.[70] One study considered cost-effectiveness of haemofiltration to prevent contrast nephropathy in an economic evaluation using decision analysis.[71] Prophylactic haemofiltration was compared with intravenous saline in people at risk for developing contrast nephropathy having angiography in a tertiary- or quaternary-care hospital. It found that prophylactic haemofiltration could be potentially cost-effective only in a small fraction of people (those with baseline serum creatinine >265 micromol/L [about 2.9 mg/dL]), and remains materially less attractive than other strategies.[71]

Substantive changes

Renal replacement therapy (prophylactic haemofiltration/dialysis) New evidence added.[68] [69] Categorisation unchanged (Unknown effectiveness) as all studies we found primarily addressed only surrogate outcomes.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Theophylline or aminophylline

Summary

KIDNEY INJURY Compared with control in radiocontrast-induced nephropathy: Theophylline or aminophylline may be no more effective at preventing radiocontrast-induced nephropathy in people receiving radiocontrast media ( very low-quality evidence ). Compared with sodium chloride 0.9% after CABG: Theophylline is no more effective at preventing renal impairment after elective CABG ( moderate-quality evidence ).

Benefits

Theophylline or aminophylline versus control in radiocontrast-induced nephropathy:

We found one systematic review (search date 2003, 9 RCTs, 585 people in hospital receiving radiocontrast media) comparing theophylline or aminophylline versus control.[72]The treatment protocols and the definition of contrast nephropathy varied across trials. The review found no significant difference between groups in the incidence of contrast nephropathy (9 RCTs; OR 0.40, 95% CI 0.14 to 1.16; P =0.09; absolute data not reported). However, the review reported that in many of the RCTs included in the review, the hydration status of people receiving the radiocontrast agent was unclear and there was evidence of heterogeneity between trials (P = 0.08).[72]

Theophylline versus sodium chloride 0.9% after CABG:

We found one RCT (56 people with normal renal function), which compared theophylline (a bolus of 4 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/hour for up to 96 hours) versus sodium chloride 0.9% for prevention of renal impairment after elective CABG.[73] It found no significant difference between theophylline and sodium chloride in rates of renal impairment, but the RCT may have been underpowered to detect clinically important differences (renal impairment, defined as an increase in serum creatinine of at least 0.4 mg/dL [35 micromol/L] from baseline at day 5 after surgery: 5/28 [18%] with theophylline v 4/28 [14%] with sodium chloride; P >0.05).

Harms

Theophylline or aminophylline versus control in radiocontrast-induced nephropathy:

Theophylline has a narrow therapeutic index and known adverse effects (see harms of theophyllines in review on COPD). One RCT included in the review (100 people) reported transient tachycardia with 200 mg of intravenous theophylline.[72] No other adverse events were reported by the review.

Theophylline versus sodium chloride 0.9% after CABG:

The RCT found no difference between the placebo and theophylline groups in the number of people whose study medication was stopped owing to presumed adverse effects. Heart rate and systolic and diastolic blood pressures were similar between the groups.[73]

Comment

None.

Clinical guide:

Use of theophylline in select populations may be limited by relative contraindications, particularly in patients with active coronary ischaemia, arrhythmias, or pre-existing seizure disorders.

Substantive changes

Theophylline or aminophylline New evidence added.[72] Categorisation unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Calcium channel blockers

Summary

KIDNEY INJURY Compared with placebo in people receiving live or cadaveric kidney transplant: The calcium channel blocker isradipine is more effective at improving median serum creatinine levels at 3 to 12 months, but is no more effective at preventing early allograft dysfunction ( moderate-quality evidence ). Compared with no calcium channel blockers in people receiving cadaveric kidney transplant: Calcium channel blockers given in the perioperative period may be more effective at reducing post-transplant acute tubular necrosis, but not graft loss ( very low-quality evidence ). Compared with placebo in people undergoing abdominal surgery: Nicardipine may reduce the risk of renal insufficiency and abnormal serum creatinine, and diltiazem may improve creatinine clearance during pneumoperitonemum in people undergoing abdominal surgery ( low-quality evidence ). MORTALITY Compared with no calcium channel blockers in people receiving cadaveric kidney transplant: Calcium channel blockers given in the perioperative period may be no more effective at reducing mortality (very low-quality evidence). NOTE Calcium channel blockers are associated with hypotension and bradycardia.

Benefits

Calcium channel blockers versus placebo in people receiving live or cadaveric kidney transplant:

We found one RCT, which compared isradipine versus placebo after living and cadaveric renal transplants.[74] The RCT (210 people) found that isradipine significantly improved median serum creatinine levels at 3 and 12 months compared with placebo (3 months: 185 micromol/L [2.0 mg/dL] with isradipine v 220 micromol/L [2.4 mg/dL] with placebo; P = 0.002; 12 months: 141 micromol/L [1.4 mg/dL] with isradipine v 158 micromol/L [1.6 mg/dL] with placebo; P = 0.021). However, it found no significant difference in the incidence or duration of early allograft dysfunction (incidence: 34/98 [35%] with isradipine v 44/112 [39%] with placebo; RR 1.13, 95% CI 0.79 to 1.62; duration: 9.1 days with isradipine v 9.3 days with placebo; P value not reported).

Calcium channel blockers versus no calcium channel blockers in people receiving cadaveric kidney transplant:

We found one systematic review (search date 2005, 10 RCTs, 575 people), which compared calcium channel blockers versus no calcium channel blocker after cadaveric kidney transplantation.[75] It included heterogeneous RCTs, in which any calcium channel blocker was given by any route before or immediately after transplant, to recipient or donor, or added to the perfusate (see comments below).[75] Duration of follow-up, where stated, ranged from 4 weeks to 4 years. None of the included studies mentioned losses to follow-up. The review found that calcium channel blockers in the peri-transplant period significantly decreased acute tubular necrosis (7 RCTs, 349 people; RR 0.57, 95% CI 0.40 to 0.82). However, it found no significant difference between treatments for graft loss, mortality, or requirement for haemodialysis postoperatively (graft loss: 6 RCTs, 347 people; RR 0.93, 95% CI 0.44 to 1.97; mortality: 5 RCTs, 284 people; RR 0.86, 95% CI 0.16 to 4.66; postoperative haemodialysis: 4 RCTs: quantitative results not reported).

Calcium channel blockers versus placebo in people undergoing abdominal surgery:

We found no systematic review, but found two small RCTs that assessed the role of calcium channel blockers in people undergoing laparoscopic surgery.[76] [77]

The first RCT (100 people undergoing robot-assisted radical laparoscopic prostatectomy) compared continuous infusion of nicardipine (0.5 micrograms/kg/minute, 50 people) versus normal saline (50 people).[76] The RCT found that nicardipine significantly lowered serum creatinine (P = 0.004) and significantly increased estimated GFR (eGFR; P = 0.006) compared with control at postoperative day 1. The RCT also found that nicardipine significantly reduced the number of people with renal insufficiency (eGFR <60 mL/minute/1.73 m²; 1/50 [2%] with nicardipine v 9/50 [18%] with control; P = 0.016) and abnormal serum creatinine level (>1.4 mg/dL; 0/50 [0%] with nicardipine v 3/50 [6%] with control; P = 0.05) compared with control at postoperative day 1.[76]

The second small single-centre RCT (32 people with pneumoperitoneum undergoing laparoscopic surgery) compared intravenous diltiazem (2 micrograms/kg/minute) versus normal saline.[77] Urinary flow, urinary sodium excretion, creatinine clearance, and haemodynamic variables were determined during pneumoperitoneum and at 2 hours after surgery. Creatinine clearance using the Cockcroft–Gault equation was calculated before surgery (baseline), and at postoperative days 1 and 2. The study found that diltiazem significantly increased creatinine clearance during pneumoperitoneum compared with control (90.8 mL/minute/1.73 m² with diltiazem v 54.2 mL/minute/1.73 m² with control; P = 0.026). However, the RCT found no significant difference in creatinine clearance between groups at postoperative days 1 and 2 (reported as not significant, data presented graphically).[77]

Harms

Calcium channel blockers versus placebo in people receiving live or cadaveric kidney transplant:

The RCT gave no information on adverse effects.[74]

Calcium channel blockers versus no calcium channel blockers in people receiving cadaveric kidney transplant:

The systematic review found insufficient information to comment on adverse effects.[75] However, as a class, calcium channel blockers are associated with hypotension and bradycardia, as well as several less-serious adverse effects. The incidence and nature of adverse effects varies between individual drugs.

Calcium channel blockers versus placebo in people undergoing abdominal surgery:

A further large RCT evaluating calcium channel blockers in patients undergoing abdominal surgery is required.

Comment

The systematic review[75] did not include the RCT[74] that looked at the effect of isradipine on renal function after renal transplantation, because it included living donors. This RCT is the largest multicentre RCT to date. Moreover, the implications of the conclusion of this systematic review are unclear because the studies pooled were heterogeneous. The studies differed in terms of drugs used (diltiazem, nifedipine, and gallopamil), dose, route, timing, recipient (transplant recipient or donor), and immunosuppression used after the transplant.

Substantive changes

Calcium channel blockers New evidence added.[76] [77] Categorisation unchanged (Likely to be ineffective or harmful).

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Dopamine

Summary

KIDNEY INJURY Compared with placebo: Dopamine (including low doses) is no more effective at preventing the development of acute renal failure, or the need for dialysis, in people with or at risk of acute renal insufficiency, or in critically ill people with signs of sepsis ( high-quality evidence ). MORTALITY Compared with placebo: Dopamine is no more effective at reducing mortality (high-quality evidence). NOTE Dopamine is associated with serious adverse effects, such as extravasation necrosis, gangrene, and conduction abnormalities.

Benefits

We found two systematic reviews[78] [79] and one subsequent large RCT.[80]

The first systematic review (search date 1999, 17 RCTs, 854 people) examined the effects of any dose of dopamine.[78] It was adequately powered and found no significant difference between dopamine and placebo in mortality, onset of acute renal failure, or need for dialysis (mortality: 11 RCTs, 508 people; 4.7% with dopamine v 5.6% with placebo; RR 0.83, 95% CI 0.39 to 1.77; onset of acute renal failure: 11 RCTs, 511 people; 15.3% with dopamine v 19.5% with placebo; RR 0.79, 95% CI 0.54 to 1.13; dialysis: 10 RCTs, 618 people; 13.9% with dopamine v 16.5% with placebo; RR 0.89, 95% CI 0.66 to 1.21).

The second systematic review (search date 2000, 15 RCTs, 970 adults either with or at risk of acute renal insufficiency; see comments below) assessed the effects of low-dose dopamine.[79] It was also adequately powered and found no significant difference between low-dose dopamine (2–5 micrograms/kg/minute) and placebo in acute deterioration in renal function (defined as an increase in serum creatinine of >25% from baseline; AR: 31% with low-dose dopamine v 33% with placebo; RR 1.01, 95% CI 0.79 to 1.28).

The subsequent RCT (328 critically ill people with signs of sepsis) evaluated dopamine in early renal dysfunction.[80] It found no significant difference between dopamine and placebo in the development of acute renal failure, requirement for dialysis, ICU length of stay, hospital length of stay, or mortality (development of acute renal failure: peak serum creatinine concentration during treatment: 2.7 ± 1.6 mg/dL [245 ± 144 micromol/L] with dopamine v 2.8 ± 1.6 mg/dL [249 ± 147 micromol/L] with placebo; P = 0.93; requirement for dialysis: 35/161 [22%] with dopamine v 40/163 [25%] with placebo; RR 0.89, 95% CI 0.58 to 1.30; ICU stay: 13 ± 14 days with dopamine v 14 ± 15 days with placebo; P = 0.67; hospital stay: 29 ± 27 days with dopamine v 33 ± 39 days with placebo; P = 0.29; mortality: 69/161 [43%] with dopamine v 66/163 [40%] with placebo; RR 1.06, 95% CI 0.8 to 1.33).

Harms

The systematic reviews[78] [79] and the subsequent RCT in people with sepsis[80] gave no information on adverse effects. Dopamine has known adverse effects, including extravasation necrosis, gangrene, tachycardia, headache, and conduction abnormalities.

Comment

Most of the studies examining the effects of dopamine included people with early indications of renal dysfunction. The distinction between the effects of dopamine for prevention and for treatment is, therefore, blurred. We have used the same studies to infer preventive and treatment effects. One RCT (60 people having CABG) compared 4 interventions: dopamine, diltiazem, dopamine plus diltiazem, and control (not specified). Drug administration (iv infusion rates diltiazem 2 micrograms/kg/minute and dopamine 2 micrograms/kg/minute) was initiated 24 hours before surgery and continued for 72 hours after surgery.[81] Creatinine clearance (primary end point) was significantly higher in the diltiazem-plus-dopamine group compared with the dopamine-only, diltiazem-only, and control groups 24 hours after surgery. However, this study was underpowered, and the hydration status of the people was not controlled. The increase in urine output associated with dopamine is often thought to be caused exclusively by the increase in renal blood flow and, therefore, it may be confused with evidence of benefit. However, dopamine also has a significant diuretic effect. The review comparing low-dose dopamine versus placebo included: people with normal renal function having elective vascular surgery, cardiac surgery, and liver transplantation; people with obstructive jaundice; people with diabetes; people receiving nephrotoxic drugs or having radiocontrast investigations; and people with renal insufficiency having cardiac surgery or receiving radiocontrast agents.[79]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Loop diuretics

Summary

KIDNEY INJURY Compared with fluids alone: Adding loop diuretics to fluids is no more effective at reducing renal dysfunction, the need for renal replacement therapy, or dialysis in people at high risk of acute renal failure ( moderate-quality evidence ). MORTALITY Compared with fluids alone: Adding loop diuretics to fluids is no more effective at reducing in-hospital mortality in people at high risk of acute renal failure (moderate-quality evidence).

Benefits

We found two systematic reviews (search dates 1997[82] and 2006[83]), and one subsequent RCT, [84] which compared fluids alone versus diuretics plus fluids in people at risk of acute renal failure from various causes.

The largest review[83] compared furosemide versus control, and pooled data. However, the overall analysis included studies in which furosemide was used to prevent acute renal failure (3 RCTs, 325 people) and also to treat acute renal failure (6 RCTs, 623 people). In the overall analysis, the review found no significant difference between furosemide and control in in-hospital mortality, the risk for requiring renal replacement therapy or dialysis, the number of dialysis sessions required, or the proportion of people with persistent oliguria (in-hospital mortality: 7 RCTs [2 RCTs in preventing acute renal failure], 776 people; RR 1.11, 95% CI 0.92 to 1.33; requiring renal replacement therapy or dialysis; 7 RCTs [3 RCTs in preventing acute renal failure], 459 people; RR 0.99, 95% CI 0.80 to 1.22; number of dialysis sessions required: 5 RCTs [no RCTs in preventing acute renal failure], 516 people, WMD –0.48 sessions, 95% CI –1.45 sessions to +0.50 sessions; proportion of people with persistent oliguria: urine output <500 mL/day: 3 RCTs [no RCTs in preventing acute renal failure], 183 people; RR 0.54, 95% CI 0.18 to 1.61). There was significant heterogeneity in the results for need for renal replacement therapy or dialysis, and for people who remained oliguric.[83] In an analysis restricted to the three RCTs in which furosemide was solely used to prevent acute renal failure (to prevent acute deterioration in renal function), the review found no significant difference between furosemide and placebo in in-hospital mortality or in the requirement for renal replacement therapy or dialysis (in-hospital mortality: 2 RCTs; 10/103 [10%] with furosemide v 4/99 [4%] with placebo; RR 2.33, 95% CI 0.75 to 7.25; P = 0.15; requirement for renal replacement therapy or dialysis: 3 RCTs; 3/128 [2%] with furosemide v 0/127 [0%] with placebo; RR 4.08, 95% CI 0.46 to 35.96; P = 0.21). The three preventive studies included people who had cardiac surgery, cardiac angiography, and major general or vascular surgery, and the review noted that treatment protocols with furosemide varied between the studies. The methodological quality of the 9 included RCTs was variable (Jadad score: RCTs in preventing acute renal failure, scores 2, 4, and 5; RCTs in treating acute renal failure, scores 1, 1, 1, 1, 3, and 5).[83] The other, older review (7 RCTs) found no evidence of improved survival, of decreased incidence of acute renal failure, or of need for dialysis associated with diuretics.[82]

The small subsequent RCT (42 high-risk people undergoing cardiothoracic surgery) compared furosemide infusion (4 mg/hour; 21 people) versus saline (2 mL/hour; 21 people).[84] The RCT included people with preoperative serum creatinine >130 micromol/L (1.4 mg/dL), left-ventricular ejection fraction <50%, congestive heart failure, diabetes, or procedures involving prolonged cardiopulmonary bypass. Infusion began after the induction of anaesthesia and continued for 12 hours postoperatively. Renal dysfunction was defined as >50% increase in serum creatinine postoperatively, or >130 micromol/L (1.4 mg/dL), or requirement for haemodialysis, or all of these. In people with preoperative serum creatinine >130 micromol/L, >50% increase over preoperative levels was used to define postoperative renal dysfunction. The RCT found that following cardiac surgery, furosemide significantly increased peak serum creatinine (98 ± 33 micromol/L to 177 ± 123 micromol/L with furosemide v 96 ± 20 micromol/L to 143 ± 87 micromol/L with placebo; P <0.001), and significantly decreased peak creatinine clearance (64.3 ± 29.4 mL/minute to 39.1 ± 16.6 mL/minute with furosemide v 65.5 ± 38.6 mL/minute to 41.8 ± 17.8 mL/minute with placebo; P <0.001), implying significant renal injury at 12 hours following cardiac surgery.[84] However, the RCT found no significant difference between groups in peak creatinine levels (177 ± 123 micromol/L with furosemide v 143 ± 87 micromol/L with placebo; P = 0.35) and peak creatinine clearance (39.1 ± 16.6 mL/minute with furosemide v 41.8 ± 17.8 mL/minute with placebo; P = 0.61) beyond the first 12 hours post surgery. The RCT also found no significant difference in the incidence of renal dysfunction between furosemide compared with control (9/21 [43%] with furosemide v 8/21 [38%] with control; RR 1.1, 95% CI 0.6 to 2.2; P = 0.99).[84]

Harms

One review found an increased risk of temporary deafness and tinnitus in people treated with high doses of furosemide compared with control, which was of borderline significance (4 RCTs [all RCTs in treatment of acute renal failure], 514 people; RR 3.97, 95% CI 1.00 to 15.78; P = 0.05).[83] One RCT included in this review (81 people after cardiac surgery) in the prevention of acute renal failure found that furosemide plus fluids significantly increased acute renal failure compared with sodium chloride 0.9% alone (6/41 [15%] with furosemide v 0/40 [0%] with sodium chloride; NNH 6, 95% CI 3 to 34).[85] The other review did not report on adverse effects.[82]

Comment

None.

Substantive changes

Loop diuretics (under question to prevent acute kidney injury in people at high risk) New evidence added.[84] Categorisation unchanged (Likely to be ineffective or harmful).

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Natriuretic peptides

Summary

KIDNEY INJURY Compared with other treatment for the prevention of acute kidney injury: Natriuretic peptides are more effective at preventing acute renal failure induced by contrast media ( high-quality evidence ). Compared with other treatment for the prevention of acute kidney injury after cardiothoracic surgery: Natriuretic peptides are more effective at preventing acute renal failure induced by contrast media. Prolonged infusion of low-dose human recombinant atrial natriuretic peptide may be more effective at reducing the proportion of people requiring dialysis after major surgery and following high-risk cardiothoracic surgery ( moderate-quality evidence ). MORTALITY Compared with other treatment for the prevention of acute kidney injury: Low-dose natriuretic peptides are as effective at reducing mortality (high-quality evidence). Compared with other treatment for the prevention of acute kidney injury after cardiothoracic surgery: Natriuretic peptides are as effective at reducing mortality in people after cardiovascular surgery (moderate-quality evidence)

Benefits

Atrial natriuretic peptide versus other treatment for prevention of acute kidney injury:

We found two systematic reviews[86] [87] published by the same authors, which compared use of either high-dose or low-dose atrial natriuretic peptide (ANP) for prevention of acute kidney injury in a heterogeneous population. Two reviews reported the same RCTs, and the same outcomes. Therefore, only the second review will be reported in detail here.[87]

The review (search date 2009, 11 prevention RCTs, 8 treatment RCTs, 1861 hospitalised adults) found that low-dose ANP significantly reduced the risk of renal replacement therapy compared with control (11 RCTs; 5/462 [1%] with low-dose ANP v 21/332 [6%] with control; RR 0.32, 95% CI 0.14 to 0.71; P = 0.005), but the risk of renal replacement therapy was not significantly different between high-dose ANP compared with control (1 RCT; 6/12 [50%] with high-dose ANP v 6/12 [50%] with control; RR 1.00, 95% CI 0.45 to 2.23; P = 1.0).[87] Overall, the review found that ANP (low or high dose) significantly reduced the risk of renal replacement therapy compared with control (11 RCTs; 11/474 [2%] with ANP v 27/344 [8%] with control; RR 0.56, 95% CI 0.32 to 0.99; P = 0.048). The review also found no significant difference in mortality between low-dose ANP compared with control (10 RCTs; 4/462 [0.9%] with low-dose ANP v 6/332 [1.8%] with control; RR 0.69, 95% CI 0.21 to 2.23; P = 0.53).[87] The review reported that the one RCT included that compared high-dose ANP versus control reported no deaths in either group.[87]

Atrial natriuretic peptide versus other treatment for prevention of acute kidney injury after cardiothoracic surgery:

We found one systematic review[88] and two subsequent RCTs.[89] [90]

The review (search date 2008, 13 RCTs, 934 adults undergoing cardiovascular surgery) compared ANP versus placebo administration after surgery in the management of cardiovascular surgery-associated renal dysfunction.[88] The review found that ANP significantly reduced the proportion of people with acute renal failure requiring dialysis compared with control (11 RCTs; 13/300 [4%] with ANP v 32/296 [11%] with control; OR 0.32, 95% CI 0.15 to 0.66; P = 0.02) and there was a statistically non-significant trend towards a reduction in 30-day or in-hospital mortality (12 RCTs; 18/432 [4%] with ANP v 26/423 [6%] with control; OR 0.59, 95% CI 0.31 to 1.12; P = 0.11).[88] The review also found that ANP significantly reduced post-surgery peak serum creatinine levels compared with control (5 RCTs, 294 people; OR −0.27, 95% CI −0.38 to −0.16; P <0.002). Most of the RCTs included in the review were small and lacked adequate power to reach statistical significance on their own. There were no uniform indications for dialysis in most of the included trials, and the decision to initiate dialysis was left to the participating physicians. The incidence of dialysis varied widely in different studies.[88]

The first subsequent RCT (504 people who underwent CABG) compared low-dose (0.02 micrograms/kg/minute) human recombinant ANP (hANP) versus placebo in people with normal renal function.[89] The RCT found no significant difference between groups in mortality or dialysis compared with placebo (mortality: 4/251 [2%] with hANP v 6/253 [2%] with placebo; P = 0.53; dialysis: 0/251 [0%] with hANP v 4/253 [2%] with placebo; P = 0.123). The RCT found that hANP significantly lowered serum creatinine (P <0.0001) and significantly increased creatinine clearance (P <0.0001) compared with placebo between postoperative day 1 to week 1. The maximum postoperative creatinine level and percentage increase of creatinine were significantly lower with hANP compared with placebo (P <0.0001).[89]

The second subsequent RCT (94 people undergoing high-risk cardiac surgery) compared continuous nesiritide (at a dose of 0.01 mg/kg/minute started before surgery) versus placebo for 5 days.[90] The primary end point was dialysis and/or all-cause mortality within 21 days; secondary end points were incidence of acute kidney injury, and renal function. The RCT found no significant difference between nesiritide and placebo for the primary end point (3/45 [7%] with nesiritide v 3/49 [6%] with placebo; P = 0.914). The RCT also found that, compared with placebo, nesiritide significantly reduced the proportion of people who had acute kidney injury (defined as an absolute increase in serum creatinine of 0.3 mg/dL or more from baseline or a percentage increase in serum creatinine >50% from baseline within 48 hours; 1/45 [2%] with nesiritide v 11/49 [22%] with placebo; P = 0.004), and significantly reduced the mean serum creatinine in the immediate postoperative period (1.18 ± 0.41 mg/dL with nesiritide v 1.45 ± 0.74 mg/dL with placebo; P = 0.028).[90]

Harms

Atrial natriuretic peptide versus other treatment for prevention of acute kidney injury:

The systematic review reported hypotension and cardiac arrhythmias with high-dose ANP. No adverse events were reported with low-dose ANP.[87]

Atrial natriuretic peptide versus other treatment for prevention of acute kidney injury after cardiothoracic surgery:

The review gave no information on adverse effects.[88] The first subsequent RCT reported that postoperative complications were significantly less frequent with hANP compared with placebo (8/251 [3%] with hANPv 20/253 [8%] with placebo; P = 0.0208).[89]

See also harms of natriuretic peptides in critically ill people.

Comment

Natriuretic peptides (atrial natriuretic peptide and urodilatin) have also been evaluated in the treatment of acute renal failure (see benefits of natriuretic peptides in critically ill people). The small positive RCT that found benefit with human recombinant atrial natriuretic peptide infusion in postoperative cardiothoracic surgery differed from the previous larger, negative RCTs.[89] The dose used was much smaller (0.02 micrograms/kg/minute) and the duration of treatment was longer. Further, larger RCTs in this specific population at similar doses and duration are needed to better evaluate the potential effectiveness of this agent on clinically relevant end points such as requirement for renal replacement therapy, dialysis-free survival, or mortality.

Clinical guide:

Natriuretic peptides are potentially dangerous drugs without a regulatory approval for use in preventing acute kidney injury.

Substantive changes

Natriuretic peptides New evidence added.[86] [87] [88] [89] [90]Categorisation unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Continuous high-dose renal replacement therapy versus continuous low-dose renal replacement therapy

Summary

MORTALITY Compared with standard-dose continuous renal replacement therapy (haemofiltration): High-dose continuous renal replacement therapy is no more effective at reducing mortality at 60 and 90 days ( high-quality evidence ). NOTE: Continuous high-dose renal replacement therapy has been associated with an increased risk of hypophosphataemia, hypokalaemia, and hypotension.

Benefits

We found no systematic review but found two large multicentre RCTs examining the dose of continuous renal replacement therapy.[91] [92]

The first large multicentre RCT (1124 people) assessed the effectiveness of intensive dialysis (high-dose continuous renal replacement therapy [35 mL/kg/hour] or haemodialysis 6 times a week) versus standard therapy (continuous renal replacement [20 mL/kg/hour] or haemodialysis 3 times a week) on 60-day mortality.[91] The RCT found no significant difference between groups in mortality at 60 days (289/561 [52%] with standard dialysis v 302/563 [54%] with intensive dialysis; OR 1.09, 95% CI 0.86 to 1.40; P = 0.47) or dialysis dependence among survivors at day 60 (403/555 [73%] with standard dialysis v 419/553 [76%] with intensive dialysis; P = 0.24). The RCT found no significant difference in rates of mortality between intensive and standard renal replacement therapy in any of the prespecified subgroups (sepsis: OR 1.19, 95% CI 0.88 to 1.62; oliguria: RR 1.04, 95% CI 0.79 to 1.37; Sequential Organ Failure Assessment [SOFA] cardiovascular score of 3 or 4: RR 0.93, 95% CI 0.66 to 1.29; male sex: RR 1.19, 95% CI 0.89 to 1.60).[91]

The second large multicentre RCT (1461 people) compared the effect of high-dose continuous renal replacement therapy (40 mL/kg/hour) versus standard-dose therapy (25 mL/kg/hour) on 90-day mortality.[92] The RCT found no significant difference between groups in survival to 90 days (332/743 [44.6%] with standard dose v 322/721 [44.7%] with high dose; OR 1.0, 95% CI 0.81 to 1.23; P = 0.99) or dialysis dependence among survivors at day 90 (18/411 [4%] with standard dose v 27/399 [7%] with high dose; OR 1.59, 95% CI 0.86 to 2.92; P = 0.14). The RCT found no significant difference in rates of mortality between intensive and standard renal replacement therapy in any of the prespecified subgroups: sepsis (OR 0.84, 95% CI 0.62 to 1.12), at least one non-renal organ failure (OR 1.02, 95% CI 0.82 to 1.27), a SOFA cardiovascular score of 3 or 4 (OR 1.08, 95% CI 0.85 to 1.37), or patients with an estimated GFR <60 mL/minute (OR 0.93, 95% CI 0.65 to 1.34).[92]

Harms

The first RCT found that intensive dialysis significantly increased the rate of hypophosphataemia, hypokalaemia, and hypotension requiring vasopressor support compared with standard therapy (hypophosphataemia: 11% with standard dose v 18% with intensive dose; P <0.001; hypokalaemia: 5% with standard dose v 8% with intensive dose; P <0.03; hypotension requiring vasopressor support: 10% with standard dose v 14% with intensive dose; P <0.02).[91] The RCT found no significant differences between groups in the prevalence of any serious event (50% with standard dose v 51% with high dose; P = 0.72).[91]

The second RCT reported that high-dose continuous renal replacement therapy increased the rate of hypophosphataemia compared with standard therapy (54% with standard dose v 65% with high dose; P <0.0001).[92] The RCT found no significant differences between groups in the prevalence of hypokalaemia, arrhythmia, or disequilibrium (hypokalaemia: 24% with standard dose v 23% with high dose; P = 0.93; arrhythmia: 46% with standard dose v 42% with high dose; P = 0.18; disequilibrium: 0% with standard dose v 5% with high dose; P <0.08).[92]

Comment

Numerous studies have documented a large discrepancy between prescribed and delivered dose of therapy either with intermittent haemodialysis[93] or with continuous renal replacement therapy (CRRT).[94] Because the two RCTs were rigorous clinical trials, steps were taken to minimise this discrepancy — in other words, the therapy delivered adhered more closely to the ideal than in what has been described in practice.[95] For example, in the less-intensive arm of the first study,[91] the prescribed CRRT dose was practically identical to that delivered, while only 68% has been observed for routine clinical practice.[94] These RCTs show that survival rates can be just as good when the delivery of CRRT is 19 mL/kg/hour to 22 mL/kg/hour as when higher doses are delivered. However, clinicians must prescribe 25 mL/kg/hour to 30 mL/kg/hour in order to achieve this delivery. The aim of CRRT intensity should not be 19 mL/kg/hour to 22 mL/kg/hour because this approach will certainly result in under-dialysis, and under-dialysis is potentially harmful.[95]

Substantive changes

Continuous high-dose versus low-dose renal replacement therapy New evidence added.[91] [92]Categorisation changed from Likely to be beneficial to Likely to be ineffective or harmful.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Loop diuretics (continuous infusion)

Summary

We found no clinically important results about continuous infusion compared with bolus injection of loop diuretics in critically ill people with acute kidney injury.

Benefits

We found no systematic review or RCTs comparing continuous infusion versus bolus injection of loop diuretics in critically ill people with acute kidney injury.

Harms

One small crossover RCT (8 people with acute deterioration of chronic renal failure, mean creatinine clearance 0.28 mL/second [16.8 mL/minute]) found that fewer people experienced myalgia when treated with continuous infusion than with a bolus dose of bumetanide (3/8 [38%] people with bolus dose v 0/8 [0%] people with continuous infusion).[96]

Comment

The small crossover trial found that continuous infusion resulted in a net increase in sodium excretion over 24 hours (mean increase in sodium excretion 48 mmol/day, 95% CI 16 mmol/day to 60 mmol/day; P = 0.01).[96]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Continuous renal replacement therapy (CRRT) versus intermittent renal replacement therapy (IRRT)

Summary

KIDNEY INJURY Continuous compared with intermittent renal replacement therapy: Continuous renal replacement therapy may be no more effective at reducing the need for dialysis or increasing the rate of renal recovery in people with acute kidney injury ( moderate-quality evidence ). MORTALITY Continuous compared with intermittent renal replacement therapy: Continuous renal replacement therapy may be no more effective at reducing mortality in critically ill adults with acute renal failure (moderate-quality evidence). NOTE Observational data support the choice that continuous renal replacement therapy as initial therapy is associated with better renal recovery.

Benefits

Continuous renal replacement therapy (CRRT) versus intermittent renal replacement therapy (IRRT):

We found three systematic reviews comparing CRRT with IRRT.[97] [98] [99]

The first systematic review (search date 2007, 8 RCTs, 918 critically ill adults with acute kidney injury) compared dialytic therapies in acute kidney injury.[97] The review found no significant differences between CRRT versus IRRT in mortality, renal recovery, or a composite outcome of chronic dialysis or mortality (mortality: 7 RCTs, 918 people; RR 1.10, 95% CI 0.99 to 1.23; dialysis dependence: 5 RCTs, 308 people; RR 0.91, 95% CI 0.56 to 1.49; dialysis dependence or death: 4 RCTs, 425 people; RR 1.11, 95% CI 0.87 to 1.42).[97]

The second review (search date 2006, 9 RCTs, 6 of which were identified by the first review, 1403 critically ill adults with acute kidney injury) compared the effect of CRRT versus IRRT on mortality.[98] The review found no significant differences between CRRT and IRRT in mortality (OR 0.99, 95% CI 0.78 to 1.26; P = 0.93), renal recovery (OR 0.76, 95% CI 0.28 to 2.07; P = 0.59), or a composite outcome of chronic dialysis or mortality (OR 1.23, 95% CI 0.86 to 1.76; P = 0.25).[98]

The third review (search date 2006, 7 RCTs, 6 of which were identified by the second review, 1245 critically ill adults with acute kidney injury) compared the effect of CRRT versus IRRT on mortality.[99] The review found no significant difference between groups in mortality (413/648 [64%] with CRRT v 376/597 [63%] with IRRT; RR 1.01, 95% CI 0.92 to 1.12; P = 0.83).[99] The pooled data included one study that had an unclear randomisation scheme for the first 32 study participants.

Harms

The systematic reviews gave no information on adverse effects.[97] [98] [99]

Heparin is often used with IRRT and CRRT, and may have adverse effects (see review on thromboembolism).[100] The continuous exposure to the extracorporeal circuit may also lead to depletion of nutrients and subtherapeutic levels of antimicrobial agents. Hypotension is common with intermittent haemodialysis, whereas haemodynamic stability is better preserved with CRRT.[101]

Comment

Another meta-analysis performed a subgroup analysis by timing of the study (search date 2007, 9 RCTs, 1635 critically ill adults with acute kidney injury) for CRRT versus IRRT for mortality. [102]After stratifying the studies by whether they were done before 2000, the review found no significant difference between CRRT compared with IRRT if the study was done before 2000 (mortality: RR 1.06, 95% CI 0.67 to 1.68); however, the review found that in studies done after 2000, CRRT improved survival compared with IRRT (mortality: RR 0.61, 95% CI 0.50 to 0.74). [102]

We found one earlier systematic review (search date 1998, 13 studies, including 3 RCTs, 1400 critically ill people with acute renal failure),[103]which performed subgroup analysis, adjusting by baseline severity of illness, that found a survival benefit with CRRT (mortality: RR 0.48, 95% CI 0.34 to 0.69). A secondary analysis in the review, including all studies and adjusting for study quality, found that continuous modalities significantly reduced mortality (RR 0.72, 95% CI 0.60 to 0.87).[103] In a large international prospective cohort of 1218 people treated with CRRT or IRRT for acute renal failure, unadjusted dialysis independence at hospital discharge was higher after CRRT than after IRRT (85.5% with CRRT v 66.2% with IRRT; P <0.0001).[104] Multivariate logistic regression showed that choice of CRRT was not an independent predictor of survival, but was a predictor of dialysis independence at hospital discharge among survivors (OR 3.33, 95% CI 1.85 to 6.02; P <0.0001).[104] In a retrospective cohort study between 1995 and 2004 including 2642 people from 32 ICUs in Scandinavia, CRRT was associated with better renal recovery compared with IRRT (91.7% with CRRT v 83.5% with IRRT; OR 2.19, 95% CI 1.35 to 3.53), but mortality did not differ significantly between the groups.[105]

Substantive changes

Continuous renal replacement therapy (CRRT) versus intermittent renal replacement therapy (IRRT) New evidence added.[97] [98] [99] Categorisation unchanged (Unknown effectiveness) as results across reviews are conflicting.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Albumin supplementation plus loop diuretics (intravenous)

Summary

We found no direct information from RCTs about the effects of intravenous albumin supplementation plus loop diuretics in critically ill people with acute kidney injury.

Benefits

We found no systematic review or RCTs evaluating clinical outcomes of intravenous albumin supplementation plus loop diuretics in critically ill people with acute kidney injury.

Harms

We found no RCTs.

Comment

One crossover RCT (9 people with nephrotic syndrome) compared three interventions: furosemide alone, furosemide plus albumin, and albumin alone.[106] It found that furosemide was superior to albumin alone, and furosemide plus albumin resulted in the greatest urine and sodium excretion. The clinical significance of this finding is unclear.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Dialysis membranes (synthetic)

Summary

MORTALITY Synthetic membranes compared with cellulose-based membranes: We don't know whether synthetic dialysis membranes are more effective at reducing mortality in critically ill people with acute renal failure requiring in-centre haemodialysis ( very low-quality evidence ).

Benefits

We found two systematic reviews comparing synthetic versus cellulose-based dialysis membranes in critically ill people with all-cause acute renal failure.[107] [108]

The first review (search date 2007, 10 RCTs and controlled clinical trials, 1100 people) compared biocompatible versus bioincompatible haemodialysis membranes.[107] The review found no significant difference between synthetic membranes and cellulose-based membranes in mortality among people with acute renal failure requiring in-centre haemodialysis (RR 0.93, 95% CI 0.81 to 1.07, absolute data not reported).[107] The review also found no significant difference in the recovery of renal function between the synthetic and cellulose-based membranes (RR 1.3, 95% CI 0.83 to 2.02, absolute data not reported).[107]

The second systematic review (search date 2000, 8 prospective trials providing survival data, data on recovery of renal function, or both, 867 people) found that synthetic membranes significantly increased survival rates compared with cellulose-based membranes (OR 1.37, 95% CI 1.02 to 1.83; P = 0.03) and showed a non-significant trend towards improved renal recovery (OR 1.23, 95% CI 0.90 to 1.68; P = 0.18).[108] A sensitivity analysis performed by stratifying studies according to the type of membrane used in the control group found that the mortality reduction observed with synthetic membranes was evident when compared with unsubstituted cellulose, but not when compared with modified cellulose.

Harms

Severe anaphylactoid reactions in people taking ACE inhibitors have been reported occasionally with certain synthetic biocompatible membranes (exact frequency unknown).[109]

Comment

Many of the RCTs included in both systematic reviews had methodological limitations, and all studies were underpowered. Differences in effect on outcomes seem most easily demonstrable when synthetic membranes are compared with unsubstituted cellulose. Whether synthetic membranes are superior to modified cellulose (e.g., cellulose triacetate) remains controversial. However, no study has shown an advantage with any cellulose-based membrane over synthetic membranes, except that cellulose-based membranes are generally less expensive.

Substantive changes

Dialysis membranes (synthetic) New evidence added.[107] Categorisation unchanged (Unknown effectiveness) as results with different systematic reviews conflict.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Loop diuretics

Summary

KIDNEY INJURY Compared with control: Loop diuretics may be no more effective at improving renal recovery or at reducing the requirement for renal replacement therapy ( very low-quality evidence ). MORTALITY Compared with control: Loop diuretics may be no more effective at reducing mortality (very low-quality evidence). NOTE Loop diuretics have been associated with ototoxicity and may lead to volume depletion.

Benefits

We found two systematic reviews.[110] [83]

The first systematic review (search date 2006, 5 RCTs, 555 people) compared loop diuretics versus control in people with acute renal failure, and pooled data.[110] It included RCTs in adults with established acute renal failure, and which reported at least one of the following: need for renal replacement therapy, death, or renal recovery. Two of the 5 RCTs (330 people, 92 people) enrolled critically ill people; but the proportion admitted to an ICU was not specified. The review reported that oliguria was variously defined and was present in 258/443 (58%) people in three RCTs; the remaining three RCTs did not report figures for people with oliguria. The review reported that the overall methodological quality and reporting of the RCTs was poor, with only one RCT reporting adequate allocation concealment, while two RCTs did not report loss to follow-up, and one RCT had significant differences between groups at baseline.[110] The review found no significant difference between loop diuretics (mainly furosemide, one RCT with torasemide) and control in mortality or renal recovery (mortality: 4 RCTs; 129/295 [44%] with loop diuretics v 84/240 [35%] with control; OR 1.28, 95% CI 0.89 to 1.84; P = 0.18; renal recovery: 2 RCTs; 96/228 [42%] with loop diuretics v 94/194 [48%] with control; OR 0.88, 95% CI 0.59 to 1.31; P = 0.5).

The second systematic review included furosemide used both in prevention and treatment of acute renal failure.[83] See benefits of loop diuretics to prevent acute renal failure in people at high risk. However, it reported a subgroup analysis for 6 RCTs used to treat renal failure. Of these 6 RCTs, 5 were included in the first review, and it also included one additional small RCT (56 people). The review found no significant difference between furosemide and placebo in in-hospital mortality, or in requirement for renal replacement therapy (in-hospital mortality: 5 RCTs, 574 people; RR 1.09, 95% CI 0.90 to 1.31; requirement for renal replacement therapy or dialysis: 4 RCTs, 204 people; RR 0.94, 95% CI 0.71 to 1.26).[83]

Harms

See harms of loop diuretics to prevent acute renal failure in people at high risk. The first review noted that reporting of harms was inconsistent, and valid estimates of occurrence could not be determined.[110] Ototoxicity can occur with high doses of loop diuretics. No adverse effects were reported in one included RCT.[111] Deafness occurred in two people randomised to furosemide in another RCT included in the second review.[112] In one of these people, hearing loss was permanent.[112] The largest RCT included in the reviews reported no significant differences between groups in adverse effects.[113] Diuretics may reduce renal perfusion and add a prerenal component to the renal failure, but the frequency of this event is uncertain.[114]

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Dopamine

Summary

KIDNEY INJURY Compared with placebo: Dopamine is no more effective at reducing the need for dialysis ( moderate-quality evidence ). MORTALITY Compared with placebo: Dopamine is no more effective at reducing mortality (moderate-quality evidence). NOTE Dopamine has been associated with important adverse effects, including extravasation necrosis, gangrene, and conduction abnormalities.

Benefits

We found one systematic review[78] and one additional RCT.[80] The systematic review (search date 1999, 58 trials, of which 17 were RCTs, 2149 people) found no significant difference between dopamine and placebo in mortality or need for dialysis (mortality: 11 trials, 508 people; 4.7% with dopamine v 5.6% with placebo; RR 0.83, 95% CI 0.39 to 1.77; need for dialysis: 10 trials, 618 people; 13.9% with dopamine v 16.5% with placebo; RR 0.89, 95% CI 0.66 to 1.21).[78] The additional RCT (multicentre, double-blind, placebo-controlled, 328 people with early renal dysfunction defined as oliguria or increase in serum creatinine) found no significant difference in mortality at discharge between low-dose dopamine and placebo (69/161 [43%] with dopamine v 66/163 [41%] with placebo; RR 1.06, 95% CI 0.82 to 1.37).[80]

Harms

Dopamine has recognised adverse effects, including extravasation necrosis, gangrene, tachycardia, headache, and conduction abnormalities. The systematic review[78] and RCT[80] gave no information on adverse effects.

Comment

Studies evaluating dopamine to prevent renal failure or to ameliorate its progression have found no benefit. Studies evaluating the effectiveness of dopamine for the treatment of acute renal failure have focused on early renal dysfunction, and have often included people with normal renal function who were at risk of acute renal failure. The distinction between the effects of dopamine for prevention and treatment is, therefore, blurred, and we have used the same studies to infer preventive and treatment effects.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Natriuretic peptides

Summary

KIDNEY INJURY Compared with placebo: Low-dose, but not high-dose, atrial natriuretic peptide seems more effective at reducing the need for renal replacement therapy in adults with acute kidney injury ( moderate-quality evidence ).

Benefits

We found one systematic review (search date 2007, 8 treatment RCTs, 1043 adults with acute kidney injury), which compared atrial natriuretic peptide (ANP) versus control.[86] The review found no significant difference between groups in renal replacement therapy (RR 0.59, 95% CI 0.32 to 1.08; P = 0.12, absolute data not reported). There was moderate statistical heterogeneity found among the studies (P = 0.006). To investigate the heterogeneity between studies, the review performed subgroup analysis for low-dose or high-dose APN compared with control. The review found that low-dose ANP significantly reduced the rate of renal replacement therapy (RR 0.34, 95% CI 0.12 to 0.96; P = 0.04), but found no significant difference in renal replacement therapy between high-dose ANP and control (RR 0.87, 95% CI 0.52 to 1.46; P = 0.60). The review also found no significant difference between groups in rates of mortality (RR 1.01, 95% CI 0.72 to 1.43). There was no evidence of heterogeneity with this outcome.

Harms

The review gave no information on adverse effects. [86]

Comment

We found no evidence of significant improvement of acute renal failure with atrial natriuretic peptide.

Substantive changes

Natriuretic peptides New evidence added.[86] Categorisation unchanged (Likely to be ineffective or harmful).

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Early versus late renal replacement therapy

Summary

KIDNEY INJURY Early compared with late renal replacement therapy: We don't know whether early renal replacement therapy is more effective at increasing renal recovery in people with acute renal failure ( low-quality evidence ). MORTALITY Early compared with late renal replacement therapy: We don't know whether early renal replacement therapy is more effective at reducing mortality in people with acute renal failure ( very low-quality evidence ).

Benefits

We found two systematic reviews[115] [97] and one subsequent observational study[116] examining whether early initiation of dialysis benefited survival or renal recovery.

The first review (search date 2006, 23 studies, 5 randomised or quasi-randomised clinical trials, 18 observational studies, 2378 people) compared early versus late renal replacement therapy.[115] The review found that early renal replacement therapy significantly reduced mortality compared with late renal replacement therapy (23 studies; 473/1050 [45%] with early renal replacement v 642/1058 [61%] with late renal replacement; RR 0.72, 95% CI 0.64 to 0.82).[115] However, the review reported that there was significant heterogeneity among studies when RCTs and cohort studies were pooled (P = 0.005). Therefore, the review performed an additional sensitivity analysis of RCTs only, and found no significant difference between groups in mortality (4 RCTs; 31/125 [25%] with early renal replacement v 59/145 [41%] with late renal replacement; RR 0.69, 95% CI 0.37 to 1.26). The review also found no significant difference between early and late renal replacement in renal recovery in people with acute kidney failure (7 studies; 89/169 [53%] with early renal replacement v 100/146 [68%] with late renal replacement; RR 0.76, 95% CI 0.55 to 1.05; P value for heterogeneity 0.06).[115]

The second review (search date 2007, 38 studies, 30 RCTs, 8 prospective studies, 2 of which were also reported in the first review[115]) compared early versus late initiation of continuous renal replacement therapy in people with acute renal failure.[97] The review found that early renal replacement significantly reduced mortality compared with late renal replacement therapy (2 studies, 99 people; 25/49 [51%] with early renal replacement v 32/50 [64%] with late renal replacement; RR 0.48, 95% CI 0.06 to 3.97), but found no significant difference between groups in renal recovery (1 study, 39 people; 1/17 [6%] with early renal replacement v 0/22 [0%] with late renal replacement; RR 3.83, 95% CI 0.17 to 88.62).[97]

The large subsequent multicentre cohort study (1238 people at 54 ICUs) stratified people into early and late dialysis by using the median urea nitrogen and creatinine at the time of dialysis initiations.[116] The study found no significant difference in covariate-adjusted mortality between early and late renal replacement when initiation of treatment was assessed using urea (OR 1.25, 95% CI 0.91 to 1.70). However, the RCT found that when initiation of treatment was assessed using creatinine, early renal replacement therapy significantly reduced covariate-adjusted mortality (OR 0.51, 95% CI 0.36 to 0.58).[116]

Harms

The systematic review gave no information on adverse effects.[115]

Dialysis may be harmful because of vascular-access-related complications and treatment-related complications such as hypotension.

Comment

Randomised studies examining early initiation of dialysis have been limited in size and several were performed before 2000. There are also very few randomised studies of early initiations of continuous renal replacement therapy.

Substantive changes

Early versus late renal replacement therapy New option added with two systematic reviews[97] [115] and one observational study.[116] Categorised as Unknown effectiveness as results from systematic reviews conflict.

BMJ Clin Evid. 2011 Mar 28;2011:2001.

Extended daily dialysis

Summary

KIDNEY INJURY Compared with continuous renal replacement: Extended daily dialysis seems as effective at reducing the rate of chronic dialysis dependence in people with acute renal failure ( moderate-quality evidence ). MORTALITY Compared with continuous renal replacement: Extended daily dialysis seems as effective at reducing mortality in people with acute renal failure (moderate-quality evidence).

Benefits

Extended daily dialysis versus continuous renal replacement therapy:

We found one systematic review (search date 2007, 38 studies, 30 RCTs, 8 prospective studies) assessing renal replacement therapy in people with acute kidney injury.[97] The review included only one RCT comparing extended dialysis versus continuous renal replacement therapy (CRRT). The review found no significant difference in mortality or chronic dialysis dependence between extended dialysis and CRRT (1 RCT; mortality: 20/28 [71%] with extended dialysis v 14/26 [54%] with CRRT; RR 1.33, 95% CI 0.87 to 2.03; chronic dialysis: 2/28 [7%] with extended daily dialysis v 2/26 [8%] with CRRT; RR 1.25, 95% CI 0.22 to 7.02).[97]

Extended daily dialysis versus intermittent renal replacement therapy:

We found no RCTs.

Harms

Extended daily dialysis versus continuous renal replacement therapy:

The systematic review gave no information on adverse effects.[97]

Extended daily dialysis versus intermittent renal replacement therapy:

We found no RCTs.

Comment

Randomised studies examining extended dialysis have been underpowered. There are no RCTs examining standard haemodialysis compared with extended dialysis.

Substantive changes

Extended daily dialysis New option added with one systematic review.[97] Categorised as Unknown effectiveness as there remains insufficient evidence to judge this intervention.

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PERMALINK

Acute kidney injury

John A Kellum

Mark L Unruh

Raghavan Murugan, MD, MS, MRCP

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

Clinical context

About this condition

Definition

Incidence/ Prevalence

Aetiology/ Risk factors

Table 1.

Prognosis

Aims of intervention

Outcomes

Methods

Table 1.

Glossary

Disclaimer

Contributor Information

References

Contrast media (low-osmolality)

Summary

Benefits

Low-osmolality contrast media versus high-osmolality contrast media:

Low-osmolality contrast media versus iso-osmolar contrast media:

Harms

Low-osmolality contrast media versus high-osmolality contrast media:

Low-osmolality contrast media versus iso-osmolar contrast media:

Comment

Substantive changes

Sodium chloride-based fluids

Summary

Benefits

Intravenous sodium chloride 0.9% versus oral fluids:

Sodium chloride 0.9% versus sodium chloride 0.45%:

Sodium chloride 0.45% versus restricted fluids:

Inpatient versus outpatient fluid regimens:

Sodium chloride versus sodium bicarbonate:

Harms

Intravenous sodium chloride 0.9% versus oral fluids:

Sodium chloride 0.9% versus sodium chloride 0.45%:

Sodium chloride 0.45% versus restricted fluids:

Inpatient versus outpatient fluid regimens:

Sodium chloride versus sodium bicarbonate:

Comment

Clinical guide:

Substantive changes

Amphotericin B (lipid formulations)

Summary

Benefits

Harms

Comment

Clinical guide:

Substantive changes

N-Acetylcysteine

Summary

Benefits

N-Acetylcysteine versus control in the prevention of contrast nephropathy:

N-Acetylcysteine versus placebo in the prevention of perioperative acute kidney injury:

N-Acetylcysteine versus placebo in the prevention of acute kidney injury after hypotension:

Harms

N-Acetylcysteine versus control in the prevention of contrast nephropathy:

N-Acetylcysteine versus placebo in the prevention of perioperative acute renal failure:

N-Acetylcysteine versus placebo in the prevention of acute renal failure after hypotension:

Comment

Substantive changes

Contrast media (iso-osmolar)

Summary

Benefits

Harms

Comment

Substantive changes

Aminoglycosides (single dose)