(1)
Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
Keywords
Acute kidney injuryRenal failureUreaCreatinineContrast agentsRhabdomyolysisHemodialysisContinuous renal replacement therapy (CRRT)FurosemideFluid resuscitationAcute kidney injury (formally known as acute renal failure) is a common problem in the ICU. AKI is a syndrome characterized by the rapid loss of the kidney’s excretory function and is typically diagnosed by the accumulation of the end products of nitrogen metabolism (urea and creatinine) or decreased urine output or both [1, 2]. Although serum creatinine (Scr) is not a perfect marker of GFR, it is frequently used as a surrogate to estimate GFR. Currently, additional biomarkers are undergoing investigation as more sensitive indicators of AKI (cystatin C, IL-18, neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, etc.) [2, 3]. AKI is defined as a twofold or greater increase in Scr, a GFR decrease of >50 % or urine output of 0.5 ml/kg/h for 12 h [2]. AKI represents a spectrum from risk to kidney injury to kidney failure to complete loss of kidney function. The RIFLE criteria have been used to define and classify AKI (see Table 41.1) [4]. In critically ill patients AKI is usually the result of extrarenal insults, most commonly sepsis, trauma, hypovolemic “shock”, and rhabdomyolysis. The pathophysiology of AKI in patients with sepsis is complex and poorly understood; however decreased renal blood flow does not appear to play a role [2]. AKI occurs in up to two-thirds of ICU patients and increasing severity of AKI is associated with increasing mortality [5]. Even modest degrees of AKI not resulting in dialysis treatment increase the risk of death approximately fivefold [6]. Coca and colleagues demonstrated that elevations of the Scr less than used in the RIFLE classification are associated with a twofold risk of short-term death [7]. In this study patients with a 10–24 % increase in Scr had a relative risk of death of 1.8 (95 % CI, 1.3–2.5). The mortality of patients who require dialysis has remained in excess of 50 % despite improvements in renal-replacement therapy and aggressive supportive care [8]. It is therefore essential that all efforts be made to avoid this complication; i.e. appropriate fluid resuscitation and avoidance of potentially nephrotoxic drugs. The therapeutic intervention of choice in patients with intravascular volume depletion and oliguria is fluid resuscitation and not furosemide/Lasix™. However, as discussed in Chap. 9, excessive volume resuscitation with a high central venous pressure will “paradoxically” impair renal function (see Chap. 8). A rational evidence-based approach to fluid resuscitation is therefore essential to reduce the risk of renal dysfunction in critically ill patients.
Serum creatinine criteria | Urine output criteria | |
---|---|---|
Risk | Inc 1.5–2 × baseline | <0.5 mL/hg/h for 6 h |
Injury | Inc 2–3 × baseline | <0.5 mL/kg/h for 12 h |
Failure | Inc > 3 baseline or Scr > 4 mg/dl | <0.3 mL/kg/h for 24 h or anuria for 12 h |
Loss | Persistent renal failure > 4 weeks | |
End–stage renal disease | Persistent renal failure > 3 months |
While low-dose dopamine increases renal blood flow and urine output in patients with normal renal function, dopamine does not improve renal function, reduce the need for dialysis or alter the course of AKI in critically ill patients [9]. In addition, studies have demonstrated that furosemide is of no value in modifying azotemia, reducing the need for dialysis, altering the time to recovery of renal function, reducing hospital stay or impacting survival in established AKI [10–12]. Indeed, diuretics have been reported to be associated with a significant increase in the risk of death and non-recovery of renal function [13]. A meta-analysis concluded that furosemide was not associated with any significant clinical benefit and perhaps an increased risk of harm [14]. Diuretics in any form (bolus, continuous infusion, topical) have no role in the management/prevention of acute renal failure (the only exceptions are patients with hypercalcemia/tumor lysis as part of a forced diuresis protocol). Optimization of intravascular volume, cardiac output and mean arterial pressure remains the cornerstone of both the prevention and treatment of AKI. No pharmacologic intervention has yet to be demonstrated to (positively) alter the clinical course of patients with renal dysfunction. In patients who remain oliguric/anuric after adequate fluid resuscitation it is important to exclude urinary tract obstruction (and urinary catheter obstruction), as this as an immediately reversible cause of acute renal failure. In patients with compromised renal function nephrotoxic drugs (particularly aminoglycosides and contract agents) should be avoided.
Pre-Renal Azotemia
While some experts have suggested that the term pre-renal azotemia is biologically flawed [2], others contend that the concept of pre-renal azotemia has clinical utility. Pre-renal azotemia refers to the syndrome of oliguria and an increased BUN/creatinine ratio in the setting of volume depletion, which resolves in 2–3 days with fluid administration. Patients with pre-renal azotemia have a urinary Na < 40 meq/l and an increased serum BUN/Creatinine ratio. The fractional excretion of sodium (FENa) has been used to distinguish pre-renal azotemia form AKI. Prerenal azotemia is indicated by a FENa less than 1 % whereas FENa greater than 1 suggests AKI. However, FENa may be spuriously low in patients with severe sepsis as well as in patients with severe heart failure (cardio-renal syndrome) and cirrhosis (hepato-renal syndrome). The FENa may be falsely elevated in patients on diuretics, with glucosuria or with preexisting renal insufficiency.
FENa = (urine Na × Scr)/(serum Na × urine creatinine) × 100
Patients with pre-renal azotemia should be managed by targeted fluid resuscitation. Glomerular filtration is highly dependent on renal blood flow and renal perfusion pressure (MAP). When renal blood flow and/or renal perfusion pressure falls, the GFR and urine output fall sharply. Patients with pre-renal azotemia should be adequately fluid resuscitated to achieve an adequate MAP (>65 mmHg) and cardiac output (CI > 2.5 L/minM2). In the elderly and in patients with diseases affecting the integrity of the afferent arterioles, lesser degrees of hypotension may cause a decline in renal function and oliguria. In these patients a higher MAP (70–75 mmHg) may be preferable.
Contrast Agents and the Kidney
Contrast-induced nephropathy, defined as an increase in serum creatinine greater than 25 % (or >0.5 mg/dL) within 3 days of intravascular contrast administration in the absence of an alternative cause, is a common cause of AKI in hospitalized patients [15, 16]. Contrast induced nephropathy develops in up to 10 % of patients with normal renal function. However the incidence may be as high as 25 % in high risk patients, namely those with:
preexisting renal dysfunction, esp. diabetic nephropathy
Congestive heart failure
Dehydration
Multiple myeloma
Concomitant drugs
angiotensin-converting-enzyme inhibitors
nonsteroidal antiinflammatory drugs
All attempts should be made to avoid iodinated contrast agents in patients with pre-renal azotemia and in patients with acute renal insults. In all patients receiving intravenous contrast agents vigorous pre-hydration is required. There is evidence that low-osmolality contrast agents lowers the risk of nephrotoxicity in patients with elevated serum creatinine concentrations (>1.5 mg/dL) [17].
Prevention of Contrast Induced AKI
Acetylcysteine and vigorous pre-hydration (? with NaHCO3) should be considered in all patients at high risk of contrast induced nephrotoxicity [1]. Acetylcysteine should be given as 600 or 1,200 mg by mouth (or IV) twice daily the day before and the day of the procedure [19, 20]. Since ascorbic acid has a very favorable side-effect profile the addition of this agent (2 g BID, PO) should also be considered [27]. It is likely, though not proven, that a combination of agents may have a greater reno-protective effect than anyone agent alone [1]. In patients with acute renal failure in whom the use of contrast agents is essential, dialysis immediately after the contrast procedure may limit additional renal compromise (contrast agents are dialyzable). However, post procedure dialysis is not required in patients on chronic hemodialysis who receive an intravenous contrast agent unless the patient becomes volume overloaded.
Extreme caution should be exercised when using contrast agents in patients with cirrhosis. These patients have a diminished intravascular volume which is frequently exacerbated by the use of diuretics. Contrast induced renal failure is a devastating complication in these patients. Should contrast be required all cirrhotic patients should be vigorously volume resuscitated (5 % albumin) and given acetylcysteine.
“Common” Nephrotoxic Agents
Interstitial nephritis
Beta-lactams (esp. ampicillin)
Quinolones
NSAID
rifampicin
sulphonamides
acyclovir
vancomycin
cisplatin
cimetidine
allopurinol
omeprazole and lansoprazole
Tubular cell toxicity
aminoglycosides
amphotericin B
antiretrovirals
cisplatin
Crystal nephropathy
foscarnet
ganciclovir
Altered intraglomerular hemodynamics
cyclosporine
tacrolimus
NSAID
ACE
Management of Established Acute Renal Failure
Acute renal failure is a reversible process in the majority of cases and often requires only careful fluid and electrolyte management and an adjustment of drug dosage according to the level of the glomerular filtration rate. Multiple pharmacologic agents including dopamine, fenoldopam, loop diuretics, atrial natriuretic peptide, insulin growth factor-1 and thyroxine are effective for the treatment of AKI in animal models. However, similar success has not been observed in human studies [28]. Indeed, once the patient is in established acute renal failure no intervention or therapy has been demonstrated to hasten recovery of renal function. However, further kidney insults should be rigorously avoided as this will delay renal recovery.
The kidney is pretty much a stupid organ. Once it decides to stop working there is not much you can do about it!
When to Initiate Renal Replacement Therapy (RRT)
The “classic” criteria for initiating renal replacement therapy include:
hyperkalemia (K > 6.5 mmol/L)
progressive acidosis with pH < 7.20
fluid overload with pulmonary edema
pericardial effusion
uremic symptoms, i.e. nausea, vomiting, altered mental status, asterixis
increase of serum creatinine >2 mg/dL/day
These recommendations were formulated for patients with chronic renal failure. However, most intensivists (and critical care nephrologists) contend that there is no reason to wait for significant physiological derangements (hyperkalemia, severe acidosis, fluid overload, uremic complication) to develop in the already physiologically fragile, critically ill patient before initiating RRT. The early initiation of RRT facilitates early nutritional support, simplifies fluid management and may prevent complications. However, there is no solid data to support this strategy and a review of the literature does not allow recommendations regarding the optimal timing of renal replacement therapy [29].
Mode of Renal Replacement Therapy
Continuous renal replacement therapies (CRRT) have been developed to enable the critically ill patient with acute renal failure to be treated more effectively. Acute renal failure in the critically ill patient almost always develops in the setting of shock, sepsis, major surgery and/or major trauma, and is invariably associated with multi-organ dysfunction and/or failure. In addition these patients usually have hemodynamic and respiratory abnormalities that make conventional intermittent hemodialysis both technically difficult and fraught with many complications. The patients’ fluid, electrolyte and acid-base status fluctuate widely within a 24 period; intermittent dialysis is not suited to these changing circumstances. Continuous renal replacement therapies were developed with the aim of providing a more physiological method of renal replacement therapy; i.e., to function more like a normal kidney. Over the last two decades CRRT has undergone a remarkable revolution, the major aspects of which include the introduction of countercurrent dialysate flow, the use of double lumen venous access and development of modular, portable CVVHD machines
Advantages of CRRT Therapy Include
hemodynamically well tolerated
minimal change in plasma osmolarity
better control of azotemia and electrolytes and acid-base balance
very effective in removing fluid
technically simple
membrane capable of removing cytokines in septic patients
better membrane biocompatibility
From a conceptual standpoint, it seems logical that the use of CRRT with its gradual fluid and solute removal would be superior to the rapid volume and solute flux associated with IHD in the critically ill patient with hemodynamic instability. However, clinical trials have not demonstrated outcome benefits associated with CRRT [29–32]. Based on current data, IHD and CRRT appear to lead to similar clinical outcomes for patients with AKI.
Dosing of RRT
Until recently, the optimal dosing of IHD and CRRT in the ICU was unclear with data suggesting that more aggressive RRT (daily IHD or CVVHD at an ultrafiltration rate of at least 35 mL/kg/h) was associated with improved renal recovery [29, 33]. The VA/NIH Acute Renal Failure Trial Network randomized 1,124 patients with AKI to receive intensive or less intensive RRT [8]. Hemodynamically stable patients underwent intermittent HD (6 vs. 3 times per week) and hemodynamically unstable patients underwent CVVHD (35 vs. 20 mL/kg/h). There was no difference in clinical outcomes between the two groups of patients. The RENAL Replacement Therapy Study Investigators randomized 1,508 patients with AKI to continuous venovenous hemodiafiltration with a flow of either 40 mL/kg/h (higher intensity) or 25 mL/kg/h (lower intensity) [34]. In this study there was no difference in the primary end point (mortality at 90 days) between the two groups.
Summary of Recommendations for RRT in Patients with AKI [35]
RRT should be initiated in patients with life threatening changes in fluid, electrolyte and acid-base balance
Continuous RRT (CRRT) rather than intermittent hemodialysis (IHD) should be used in patients with hemodynamic instability
An uncuffed, non-tunneled dialysis catheter should be used at the initiation of CRRT. The right internal jugular vein is the preferred choice for insertion of a catheter. The second choice is the femoral vein and the last choice is the subclavian. This catheter should be replaced by a tunneled catheter in patients who require RRT for longer than 7 days [35].
In patients undergoing CRRT who are not already receiving systemic anticoagulation regional citrate anticoagulation is recommended.
An effluent flow rate of 20–25 mL/kg/h is recommended for CRRT
Rhabdomyolysis
Rhabdomyolysis is characterized by muscle breakdown and necrosis resulting in the leakage of the intracellular muscle constituents into the circulation and extracellular fluid. Rhabdomyolysis ranges from an asymptomatic illness with elevation in the creatine kinase (CK) to a life-threatening condition associated with extreme elevations in CK, electrolyte imbalances, AKI, and disseminated intravascular coagulation (DIC) [36, 37]. The cause of rhabdomyolysis is usually easily identified; however, in some instances the etiology is elusive. Muscular trauma is the most common cause of rhabdomyolysis. Less common causes include muscle enzyme deficiencies, electrolyte abnormalities, infectious causes, drugs, toxins and endocrinopathies. Rhabdomyolysis is commonly associated with myoglobinuria, and if this is sufficiently severe, it can result in AKI. Weakness, myalgia and tea-colored urine are the main clinical manifestations. The most sensitive laboratory finding of muscle injury is the CPK; a level greater than 5,000 U/L indicates serious muscle injury in the absence of myocardial or brain infarction. The management of patients with rhabdomyolysis includes vigorous hydration and dialysis in patients with established AKI. The use of alkalizing agents and osmotic diuretics, while commonly used, remains of unproven benefit [36, 37].