CHAPTER 88 THE MANAGEMENT OF RENAL FAILURE: RENAL REPLACEMENT THERAPY AND DIALYSIS

Joseph M. Gutmann, Christopher McFarren, Lewis M. Flint, Rodney Durham

Acute renal failure (ARF) is a common and devastating problem that contributes to morbidity and mortality in critically ill patients. ARF prolongs hospital stays and increases mortality. Although effective renal replacement therapy (RRT) is available, it is not ideal and the best therapy is prevention.

The kidneys are the primary regulators of volume and composition of the internal fluid environment and their excretion. Renal failure leads to regulatory function impairment, causing retention of nitrogenous waste products and disturbance in fluid, electrolyte, and acid-base balance. Renal injury in intensive care unit (ICU) patients is a progressive process, usually starting with a prerenal insult—which progresses to severe renal injury. Other systemic issues can worsen the renal injury.

Acute renal failure in critically ill patients is a growing clinical problem. Options for RRT in these patients use convective and diffusive clearance, which may be intermittent (as in classic hemodialysis) or continuous. RRT needs to be tailored to the needs of each patient. Current and future research studies are essential in improving outcomes.

INCIDENCE

Acute renal failure is defined as an abrupt and sustained decline in the glomerular filtration rate (GFR),¹ which leads to accumulation of nitrogenous waste products and uremic toxins. In critically ill patients, more than 90% of the episodes of ARF are due to acute tubular necrosis (ATN) and are the result of ischemic or nephrotoxic etiology (or a combination of both). ARF affects nearly 5% of all hospitalized patients and as many as 15% of critically ill patients.² Like many other medical conditions, there is no gold standard of diagnosis, no specific histopathologic confirmation, and no uniform clinical picture.

The mortality rate of an isolated episode of ARF is approximately 10% to 15%. When it occurs in association with multiple-organ dysfunction, as in the ICU setting, mortality rates are much greater and vary in published series between 40% and 90%.³

In some cases, preexisting conditions may worsen. New major complications, such as sepsis and respiratory failure, may also develop after the onset of renal failure. Although ARF that requires RRT carries a high mortality,⁴ there is emerging evidence to suggest that milder forms of ARF that do not require supportive therapy with RRT have better patient outcomes.⁵

Many aspects of surgical diseases and their care have the potential to impair renal function, either by toxic effects on the renal parenchyma or by reducing renal perfusion (or a combination of the two). The prevention of ARF in critical patients consists of minimizing toxicity and ensuring adequate blood flow. Avoidance of renal failure is preferred to any treatment. Therefore, renal function should be monitored closely so that adverse circumstances can be limited.

Given the impact of ARF on mortality, it is important to prevent or hasten the resolution of even the mildest forms of ARF. The goals of a preventive strategy for the syndrome of ARF are to preserve renal function, to prevent death, to prevent complications of ARF (volume overload, acid–base disturbances, and electrolyte abnormalities), and to prevent the need for chronic dialysis (with minimum adverse effects).

This chapter explores preventive strategies, the major challenges ARF presents, and key issues to be considered. Can the patient be managed conservatively or will RRT be needed? If RRT is required, which form of RRT is most appropriate?

MECHANISM OF INJURY/ETIOLOGY

Diagnosis

Renal failure is measured routinely and easily in the ICU: the excretion of water-soluble waste products of nitrogen metabolism, urea and creatinine, and the production of urine. To understand renal failure, we need to reflect on some important aspects of renal physiology.

Water and Fluid Homeostasis

Because body water is the primary determinant of the osmolality of the extracellular fluid (ECF), disorders of body water homeostasis can be divided into hypo- and hyperosmolar disorders depending on whether there is an excess or deficiency of body water relative to body solute. The end result of any change in circulating blood volume is a change in sodium excretion by the kidneys. This is brought about by the activation of the sympathetic nervous system, the reninangiotensin-aldosterone axis, and release/suppression of natriuretic peptides.

Assessment of Renal Function

Serum concentrations of blood urea nitrogen (BUN) and creatinine are the most commonly used markers of renal function. Urea is the end product of protein and amino acid catabolism. Under normal conditions, 80%–90% of total nitrogen excretion is by the kidneys. Creatinine is formed in muscle by the nonenzymatic degradation of creatine and phosphocreatine, and is excreted primarily by glomerular filtration. A small percentage of creatinine is actively secreted into the glomerular filtrate and tubular reabsorption of creatinine is negligible.⁵

Circulating concentrations of BUN and creatinine are determined not only by how efficiently they are excreted by the kidneys but by their rate of production. Urea formation depends on the amount of protein and amino acids catabolized. It is increased with high-protein diets, reabsorption of hematomas, and digestion of blood in the gastrointestinal (GI) tract. It is reduced in starvation. These factors may change the value of the BUN, even though renal function is adequate. Creatinine production reflects muscle mass. It is constant over the short term, and steadily diminishes if muscle mass is lost. Muscle mass diminishes with age, together with intrinsic renal function. Therefore, serum creatinine stays relatively constant over time.

Creatinine Clearance

Determination of the creatinine clearance (Ccr) provides a measure of renal function. Creatinine secretion and reabsorption in the kidneys is negligible. Clearance is defined as the volume of plasma or serum cleared by the kidneys over a period of time. It is calculated as

where Ucr is urine creatinine, Pcr is serum creatine, and V is volume.

The clearance reflects the net effect of GFR, which is the amount of fluid filtered from the plasma in a given time by the kidneys. The most commonly used method for estimating Ccr is the Cockcroft-Gault formula:

Normal GFR is 125 ± 15 ml/min/1.73 m² body surface area (BSA).

Sodium has the highest serum concentration of all cations in the ECF. Any transport of sodium necessarily involves the transport of water. Renal sodium clearance is an important mechanism for the regulation of ECF volume and tonicity. Aldosterone promotes tubular reabsorption of sodium, and it is elaborated in response to changes in hydrostatic pressure within the glomerular arterioles. If renal blood flow or pressure is reduced, tubular sodium reabsorption is increased—thus preserving ECF volume. The ratio of sodium clearance to Ccr is known as the fractional excretion of sodium (FENa):

Here, Una and Ucr are the urinary concentrations of sodium and creatinine, and Pna and Pcr are the serum levels of sodium and creatinine, respectively. If the FENa is very low (<1%), it may indicate inadequate renal arteriolar pressure—suggesting that factors other than intrinsic renal dysfunction are responsible for clinically inadequate renal function.⁶

Urine Production and Output

The end result of renal function is the production of urine. Quantitative measurements of urine are important for assessing renal function. Urine output is highly sensitive to renal blood flow, making it a key indicator of renal function and total body vascular perfusion ⁷ (Table 1).

Table 1 Adequate Urine Output

Age	Urine Output (ml/kg/min)
Infant (<10 kg)	2.0
Toddler (10–20 kg)	1.5
Child (20–50 kg)	1.0
Adult (>50 kg)	0.5

MANAGEMENT OF PATIENTS

Conservative Management

Despite many advances in medical technology, the mortality and morbidity attributed to ARF in the ICU remains high. Primary strategies to prevent ARF still include adequate hydration, maintenance of mean arterial pressure (preferably MAP >60), and minimization of exposure to potentially nephrotoxic agents. Although hydration was shown to be beneficial, the type of fluid to be used in a hydration regime remains controversial.

Considering its low cost, low toxicity, and consistent benefit, NAC (N-acetylcysteine) administration with IV hydration should be considered to decrease the prevalence of nephropathy in high-risk patients. Note that the routine use of NAC is controversial and is not well studied.

Nonpharmacologic Strategies for Acute Renal Failure Prevention

Nonpharmacologic strategies to prevent ARF include ensuring adequate hydration (limiting dehydration), maintenance of adequate mean arterial pressures, and minimizing exposure to nephrotoxic agents. Four particular strategies are worth reviewing: fluids, aminoglycoside dosing, lipid-soluble preparations of amphotericin, and nonionic contrast agents.

Fluids

Adequate hydration is the cornerstone of renal failure prevention. One randomized controlled trial (n = 1620) compared hydration using 0.9% saline infusion with 0.45% saline in dextrose for prevention of radiocontrast-induced nephropathy in patients who underwent coronary angiography.⁸ Hydration with 0.9% saline infusion significantly reduced contrast nephropathy compared with 0.45% saline in dextrose hydration (0.7% vs. 2%, respectively; p = 0.04). This effect was greater in women, diabetics, and patients who received a large volume (>250 ml) of a contrast agent. A recent single-center randomized controlled trial compared the efficacy of sodium bicarbonate with 0.9% saline hydration in preventing contrast nephropathy.⁹ In this study, 119 patients who had stable serum creatinine of at least 1.1 mg/dl were randomized to 154 mEq/l infusion of sodium chloride (n = 59) or sodium bicarbonate (n = 60) before and after contrast (iopamidol) administration. One of 59 patients (1.7%) in the group that received bicarbonate developed contrast nephropathy (defined as an increase of ≥25% in serum creatinine from baseline within 48 hours) compared with 8 of 60 patients (13.3%) in the group that received saline (p = 0.02).

Nephrotoxin Exposure

Minimizing exposure to potentially nephrotoxic agents is an important strategy to prevent ARF in the ICU setting. Aminoglycosides, other antibiotics, amphotericin, and radiocontrast are the nephrotoxins encountered most commonly in the ICU. A systematic review in patients who had neutropenic fever and received aminoglycosides, however, found no significant differences in efficacy or nephrotoxicity between once daily and three times daily dosing.¹⁰

The use of lipid formulations of amphotericin B seems to cause less nephrotoxicity compared with standard formulations, but direct comparisons of long-term safety are lacking. With regard to contrast media, one systematic review (31 randomized controlled trials, 5146 patients) compared low osmolality contrast media with standard contrast media.¹¹ The study showed that low osmolality contrast media did not influence the development of ARF or the need for dialysis.

Pharmacologic Strategies for Acute Renal Failure Prevention

Loop Diuretics

Multiple small clinical trials studied the efficacy of loop diuretics in preventing ARF and have provided conflicting results. They have been underpowered, nonrandomized, or methodologically flawed. One systematic review that compared fluids with diuretics in people who were at risk for ARF from various causes did not show any benefit from diuretics with regard to prevalence of ARF, need for dialysis, or mortality.¹²

N-Acetylcysteine

Systematic reviews found that NAC plus hydration reduced the incidence of contrast nephropathy more than hydration alone in people who had baseline renal impairment and underwent radiocontrast studies.¹³ A recent study, however, suggested that NAC could decrease serum creatinine independently without any effect on GFR (as evaluated by other surrogate outcomes, such as serum cystatin C levels).¹⁴ Hence, the current implications of reduction in serum creatinine after contrast administration with the use of NAC remain unclear and need to be explored further.

INDICATIONS FOR RENAL REPLACEMENT THERAPY IN ACUTE RENAL FAILURE

As in chronic kidney disease, overt disturbances of ECF volume and body fluid composition remain the objective indications for initiation of RRT in patients with ARF (Table 2). These include volume overload, hyperkalemia, severe metabolic acidosis, uremia, and azotemia.

Table 2 Indications for Renal Replacement Therapy

Volume Overload

Volume overload is generally recognized as an indication for RRT in ARF. All modalities of RRT are effective at diminishing intravascular volume. Subjective criteria for initiation of therapy include impairment of cardiopulmonary function by pulmonary vascular congestion or compromise of cutaneous integrity and wound healing by peripheral edema.

Mehta and colleagues ¹⁵ performed a retrospective analysis of data from 522 critically ill patients who had ARF. Fifty-nine percent of these patients had been treated with diuretics. After adjustment for relevant covariates and the propensity for diuretic use, they observed a significant increase in the risk of death or nonrecovery of renal function (odds ratio 1.77, 95% confidence interval 1.14–2.76). On the basis of this, they concluded that diuretic therapy was potentially deleterious in patients who had ARF. They noted, however, that the increased risk was borne largely by patients who were unresponsive to diuretics. This suggested that this increased risk might reflect selection for a more severe degree of renal injury.

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