Chapter 59: Renal Failure

The average 70-kg person has 42 L of water divided into the intracellular space (ICF) of 28 L and the extracellular space (ECF) of 14 L. The ICF is subdivided into the red blood cell (RBC) mass of 2 L and the visceral mass of 26 L; the ECF is subdivided into a plasma volume (PV) of 3 L and an interstitial fluid space (IFS) volume of 11 L. The cardiac output (CO) in this 70-kg person is 5 L/min with 20% of this flow going to kidneys; thus the kidneys, with a combined weight of about 600 g, have a renal blood flow (RBF) of 1250 mL/min or more than 2 mL/min/g of renal parenchymal. This unusually large RBF reflects the vital renal role in regulating the ICF and ECF, controlling fluid and electrolyte balance, modulating acid-base balance, and excreting undesirable catabolyes.^1,2 Protection of renal function is essential for recovery after a shock or septic insult. This chapter reviews normal renal physiology, the renal response to shock and sepsis, guidelines for prevention and treatment of acute renal failure (ARF).

The 1250 mL/min of RBF passes through the renal artery into the interlobar, the arcuate, and, finally, the intralobar arteries; 85% of the RBF perfuses the outer cortical glomeruli; the remaining 15% of RBF perfuses the juxtamedullary glomeruli (Fig. 59-1). The glomeruli (Bowman’s capsules) are like capillaries except that proteins, normally, are not filtered.^2,3 While passing through the glomeruli, 20% of the plasma is filtered as a cell-free, protein-free filtrate. The effective renal plasma flow (ERPF) through these tubular vessels is determined by the clearance of para-aminohippurate (C_PAH) that is filtered and secreted but not reabsorbed by the renal tubules. Ninety-one percent of PAH is cleared in one passage; 9% remains bound to the plasma protein. Renal oxygen consumption parallels ERPF which averages 650 mL/min. True renal plasma flow (TRPF) is calculated by dividing ERPF by 0.91 and averages 710 mL/min. The extraction ratio of PAH (EPAH), however, may vary with injury and sepsis; true EPAH requires renal vein sampling to accurately measure true renal plasma flow (TRPF) (TRPF = ERPF/EPAH).^2,3,4,5 TRBP may be calculated by correcting the TRPF for hematocrit: TRBF = TRPF/(1-Hct).

The distribution of RBF can be measured by isotopic disappearance of radioactive xenon-133 (¹³³Xe) or krypton-85 that can be graphically portrayed as a cumulative slope composed of four separate subslopes reflecting parallel flow in mL/min per 100 g to components CI (outer cortex), CII (inner cortex and outer medulla), CIII (inner medulla), and CIV (renal pelvis and fat) (Fig. 59-1).^2,5,6 Blood leaving the juxtamedullary component II glomeruli perfuses the peritubular vessels to the long straight vasa recta in the inner medulla prior to returning to the small veins adjacent to the same glomerulus.^2,3

The normal glomerular filtration rate (GFR) averages 125 mL/min (180 L/d) and is measured by the renal clearance (urine concentration × volume/plasma concentration) of exogenous inulin (C_in) or endogenous creatinine (C_cr), both of which are completely filtered; the C_in is slightly higher than the C_cr since creatinine in humans is partially reabsorbed by the renal tubules.^3,7 The work of GFR is performed by the heart. The protein-free filtrate passes through the proximal convoluting tubules where approximately 80% of the sodium and water are reabsorbed by active sodium transport and the passive movement of water, thereby, maintaining an isomolar state. The nonfiltered blood, now protein-rich, perfuses the efferent arterioles and the peritubular vessels, and augments tubular reabsorption and secretion.⁸

The juxtaglomerular (CII) nephrons that receive 15% of the RBF are unique; each has a loop of Henle with descending and ascending straight segments that pass into the inner medulla.^2,3 These segments actively reabsorb sodium against a gradient and, thereby, create a hypertonic medullary interstitium (CIII) that facilitates the subsequent concentration of glomerular filtrate and the preservation of salt and water in response to antidiuretic hormone and aldosterone. Glucose and electrolytes, namely, chloride, phosphate, and potassium, are likewise absorbed at this site. This hypertonic medullary interstitium is further regulated by the peritubular vessels and vasa recta passing close to the loop of Henle (Fig. 59-1). Rapid blood flow through these vessels may cause a “washout” of sodium ions and osmoles resulting in transient “paralysis” of the renal concentrating mechanism; inadequate blood flow with ischemia injury to these tubular cells impedes sodium reabsorption against a gradient, thus preventing medullary hypertonicity and normal filtrate preservation.^2,3 This is discussed later.

Twenty percent (ie, 36 L/d) of protein-free filtrate and sodium enters the distal convoluting tubules where additional sodium is reabsorbed by active transport as chloride follows passively.^3,8 This process is facilitated by aldosterone. The distal tubular aldosterone effect is estimated by dividing the free water clearance (C_H2O) by the C_H2O + sodium clearance (C_Na) in patients with a positive C_H2O. When the product is greater than 0.73, the “aldosterone” effect has been blocked. The distal tubule also exchanges sodium for either potassium or hydrogen depending on pH and potassium load. Each distal tubule returns to its own glomerulus at the afferent arteriole where the macula densa and Polkissen body, known as the juxtaglomerular apparatus (JGA), are located. The JGA serves as a “feedback” loop for each nephron affecting sodium and water balance which are mediated by distal tubular sodium concentration, afferent arteriole pressure, afferent arteriole pulse pressure, and others.^3,7,8,9

After passing through the distal convoluted tubules, the remaining hypotonic filtrate (18 mL/min or 36 L/d) enters the collecting ducts where water reabsorption occurs; this is facilitated by antidiuretic hormone (ADH) as the filtrate passes through the hypertonic inner medullary (CIII) interstitium to the renal pelvis.³ The final concentration and urine volume, therefore, vary with PV, serum osmolality, ADH release, and other factors; urine concentration may range from isomolar to 1400 mOs/L. Alteration of this highly integrated system occurs with hemorrhagic shock so that the renal concentrating ability may be restricted to 600 mOs/L.⁴ The collecting ducts normally reabsorb approximately 17 mL/min or 34 L/d with the remaining 1 mL/min (1440 mL/d) being excreted as urine.

The renal handling of sodium, osmoles, and water is expressed as the clearances of sodium (C_Na), osmoles (C_osm), and free water (UV – C_osm).⁴ With normal water and solute intake, the C_Na and C_osm average 1–3% of the GFR; C_H2O is usually negative, reflecting the excretion of concentrated urine. A decrease in RBF or PV causes C_Na and C_osm to fall due to sodium preservation.³ Likewise, a breakdown in the counter current mechanism brought about by a selective insult to the juxtamedullary nephrons and their loops of Henle causes increased C_Na and C_osm from impaired tubular concentration of sodium.^3,4

The very high ratio of RBF to kidney weight allows the kidney to efficiently preserve PV after injury and hemorrhage (Table 59-1).^3,10 Renal vasoconstriction at the efferent arteriole permits a rise in renal vascular resistance (RVR) from a normal 5000–8000 dyne s/cm⁵ with a concomitant decrease in RBF from 1250 to 800 mL/min while maintaining a normal GFR (Fig. 59-2). This phenomenon of maintained GFR despite a reduction in RBF is known as autoregulation (Fig. 59-2). Excretion of metabolites is thus maintained, while 400 mL of blood/min is redirected to core areas. Both experimental and clinical studies show that autoregulation allows GFR to be maintained while RBF is decreased to 70% of normal.^2,3,11 The filtration fraction (GFR/ERPF) under such circumstances increases from a normal of 20% to as high as 40%.^3,11 More severe hypovolemia causes vasoconstriction at both the afferent and efferent arterioles, thus leading to a reduction in GFR (Table 59-1). The mechanism for the rise in RVR is multifactorial due primarily to the renal perfusion of peripherally generated catecholamines that, in turn, activates the JGA to stimulate intrarenal renin release. This stimulates the renin-angiotensin-aldosterone system (RAAS) which not only promotes sodium reabsorption but may also increase RVR.^7,12,13 When the RVR increases above 14,000 dyne s/cm⁵, the RBF falls below 500 mL/min, thereby allowing over 700 mL/min to be redirected to core organs. When hypovolemia causes hypotension below 70 mm Hg, GFR ceases and essentially all RBF is redirected to the systemic circuit (Table 59-1). This causes renal ischemia and potentiates ARF.

During hypoperfusion, the kidney conserves salt and water due to decreased GFR, increased ADH, and increased renin release with aldosterone generation.^3,13 When PV and CO are restored, the renal vasoconstriction subsides—first at the preglomerular afferent arteriole and later at the postglomerular efferent arteriole. The increase in RVR, however, may persist for many hours and even days in patients with a severe hemorrhagic shock.^3,13,19

The Kidney During Operation After Injury

During operation, the kidney exerts the same autoregulatory response to a PV deficit as described above. The major difference reflects the altered humoral response brought about by general anesthesia, especially in the marginally volemic patient in whom systemic vasoconstriction was maintaining a blood pressure prior to induction. This was first described by Ladd during the Korean conflict.¹² Civilian studies have shown the same phenomenon.^2,3 The sudden reduction in protective vasoconstriction plus continued bleeding from injured organs precipitates a marked reduction in PV and CO causing hypotension, increased RVR, and decreased RBF with an abrupt reduction in CI flow; the consequent fall in GFR causes oliguria or anuria, which may persist as ARF after operation.^2,12

The prime objective during operation is to correct the depleted PV and ineffective CO while hemostasis is obtained. When hemostasis has been achieved and the blood pressure has been restored, oliguria often persists. Osmotic or loop diuretics, such as mannitol or furosemide, have been advocated in this setting on the assumption that induced diuresis increases RBF, GFR, and urine output, and prevents ARF.^2,14 Most studies, however, show that diuresis in this setting provides no renal protection.^16,17 Loop diuresis in combination with low-dose dopamine, likewise, affords no renal protection during major surgery.¹⁷ Induced diuresis causes a further decrease in effective PV, thus making the likelihood of ARF greater.¹⁸ Furthermore, induced diuresis interferes with one of the crucial monitors of effective postoperative PV replacement, namely, uninduced urine output rates.

Intraoperative protection of the kidney in a hypovolemic, hypotensive patient must be directed toward obtaining hemostasis and improving the cardiovascular status by PV expansion with crystalloid solution, blood, and blood products. Inotropic support should be added when PV expansion causes an elevated central pressure despite persistent hypotension and oliguria. Resuscitation in his setting is best accomplished by a balanced electrolyte solution rather than 0.9% saline which may contribute to ARF by the resultant hyperchloremia and acidosis.¹⁸ Experimental and clinical studies show that a temporary delay in reestablishing urine flow after mean arterial pressure (MAP) is restored results from a prolonged rise in RVR after hypovolemia is corrected.^7,10 Renal vasodilation, experimentally, can reverse this lagging oliguria, but such therapy is difficult and hazardous in humans.¹⁰ Based on clinical observations, many patients in whom the MAP has been restored are still PV and IFS depleted, resulting in a marked increase in both total peripheral resistance (TPR) and RVR. The persistent elevation in RVR is likely due to the prior ischemic insult and not perfusion by catecholamines in stable patients; measurements of renin and arginine vasopressin (AVP) at this time have been normal (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data). Thus, pharmacologic intervention with angiotensin-converting enzyme blockade or nitrous oxide would likely be ineffective.¹³ Since both peripheral and renal vasoconstriction can lead to a doubling of total resistance, the CO may be reduced by 50% of normal despite a normal MAP. Thus, the PV may be only 1500 mL after the MAP rises to normal. Assuming that concomitant oliguria reflects this vasoconstriction and PV depletion, the rapid infusion of 1 or 2 L of balanced electrolyte solution plus whole blood, if indicated, will restore RBF, GFR, and urine output. This approach protects renal function in the early postoperative period. The few patients who are unresponsive to this regimen may be treated by a loop diuretic, such as furosemide (40 mg), which typically produces a dramatic diuresis. Such patients, however, must be monitored closely since even small dosages of a loop diuretic may induce excessive diuresis, leading to subsequent hypovolemia and hypotension.^16,17

Early Postoperative Juxtamedullary Washout and Polyuria

An interesting, but potentially hazardous, renal response to shock in injured patients is a transient period of polyuria during or immediately after operation (Fig. 59-3).¹⁹ This polyuria is not excessive, seldom exceeding 250 mL/30 min, and usually abates by 5 hours following operation (Table 59-2). This phenomenon tends to occur in patients who have had a major hemorrhagic shock insult requiring more than 15 blood transfusions prior to successful hemostasis.¹⁹ On arrival to the SICU, the blood pressure and pulse normalize while the urine output exceeds 3 mL/min (ie, 180 mL/h) at the expense of effective PV. The urine sodium concentration exceeds 40 mEq/L and the fractional excretion of sodium (FENa) or C_Na exceeds 3%. Therapy for this syndrome should be by maintenance of effective PV as judged by vital signs until the polyuric phase subsides, usually by 2–5 hours after operation.¹⁹

The mechanism for early postoperative polyuria is unclear but likely is due to an inner medullary (CIII) washout of osmoles. During shock, the primary reduction in RBF occurs in the outer cortex (CI) with less reduction in juxtamedullary (CII) flow; this is referred to as cortical to medullary shunting.^2,3 Since the juxtamedullary nephrons have loops of Henle that affect interstitial medullary (CIII) tonicity, a relative increase in RBF to these nephrons may cause a “washout” of osmoles. This disrupts the countercurrent regulatory system and precludes effective sodium and water reabsorption from the collecting ducts when outer cortical flow is first reestablished.¹⁹

Increased osmotic diuresis with polyuria may also be due to the overutilization of solutions containing 5% dextrose. Marked hyperglycemia (500–1000 mg/100 mL) and hyperosmolemia (310–320 mOs/L) have occurred in patients resuscitated exclusively with crystalloid solutions containing 5% dextrose. This hazard is circumvented by limiting the amount of 5% dextrose in crystalloid solution to 2000 mL after which a nonglucose balanced electrolyte solution is infused along with whole blood and blood products as needed.^2,19

Postoperative Oliguria During Extravascular Fluid Sequestration Phase

Following operative control of bleeding after severe hemorrhagic shock, there are major shifts in sodium, water, and protein from the plasma into the IFS. This causes reduced PV, MAP, CO, RBF, GFR, and urine output. This phase of extravascular fluid sequestration lasts about 36 hours in patients who have received an average of 15 RBC transfusions prior to operative control of bleeding.²⁰ Part of the IFS expansion includes intrapulmonary sequestration resulting in respiratory insufficiency.²⁰ Successful therapy mandates a careful balance to maintain perfusion and protect the kidney while not overloading the pulmonary circulation (Fig. 59-4).

When the intravenous infusion rate is decreased because of increased weight gain and IFS sequestration, the MAP falls, causing a fall in RBF and potential ARF. Mesenteric leukotrienes which colocalize with 5-lipoxygenase activating protein and may contribute to ARF after hemorrhagic shock; mesenteric lymph diversion of the 5-lipoxygenase ameliorates the subsequent kidney insult in a rodent hemorrhagic shock model.²¹ This typically occurs during the initial 12 hours after operation and causes decreased ERPF, GFR, UO, C_Na, and C_Osm. During this period of obligatory IFS expansion, the patient may need many liters of balanced electrolyte solution to maintain kidney perfusion. Inotropes and ventilator support are often needed.²¹ Restoring PV, hemoglobin level, coagulation status, and normal MAP enables the kidney to maintain GFR and urine output even though RBF may be reduced. C_Na and C_Osm during this period reflect the underlying renal circulatory status and are decreased when RBF is lowered but return to normal when the effective circulatory volume is restored; C_H2O is negative at this time.¹¹ Excess crystalloid resuscitation, especially, during the latter portion of the fluid uptake phase is detrimental causing acute lung injury, cardiac compromise, and, even, the abdominal compartment syndrome. Restricting crystalloids, however, will not prevent IFS expansion but will lead to PV depletion with reduced perfusion with the need for inotropic support and vasopressors. This sequence promotes ARF which, in the fluid sequestration phase, usually results in death.^2,20,22 A therapeutic balance is required.

The technique used to provide ventilatory support during the fluid uptake phase may also affect kidney function.^23,24 High tidal volumes (>10 mL/kg body weight), with or without high positive end-expiratory pressure (PEEP > 10 cm H₂O) may improve oxygen tension by reducing atelectasis but compromise oxygen delivery reducing CO.²³ This reduces MAP, CO, ERPF, C_Na, C_Osm, and urine output.²⁴ The renal response is mediated through sinoaortic baroreceptors and renal vein pressure.^25,26 The SICU team must adjust ventilatory settings with renal function in mind.

Colloid supplementation during the sequestration phase also affects renal function.²⁷ Human serum albumin (HSA) therapy given to prevent weight gain and IFS expansion during the fluid uptake phase, ignores the fact that 7% of serum albumin exits the PV into the IFS each hour and increases when supplemental HSA is administered; this causes a prolonged fluid uptake phase, greater crystalloid needs, greater weight gain, and compromised renal dynamics.^27,28 Patients receiving HSA during the sequestration phase exhibit an increase in PV and RBF but, paradoxically, a reduction in GFR, C_Na, C_osm, and urine output.²⁸ The reduction in GFR is caused by the HSA oncotic properties within the glomerular tufts where Bowman’s capsule acts like a modified capillary except that it is impervious to protein transmigration. The hyperoncotic blood leaving the glomerular tufts perfuses the vasa recta in the inner medulla (CIII) and extracts excess water and sodium from the interstices of the inner medulla. The resultant hyperosmolar CIII interstices facilitate the reabsorption of sodium and water from the distal nephrons under the influence of these facultative hormones (Table 59-3).^2,3,21 Patients receiving HSA supplementation require more frequent loop diuresis and are more likely to develop ARF compared with patients not receiving supplemented HSA.^21,28 This phenomenon has been duplicated in a canine model of isolated renal perfusion (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).²¹

Vasopressor Therapy and Renal Function

The hypotension associated with IFS expansion after operation often stimulates therapy with vasopressor agents to restore MAP by precapillary vasoconstriction. The resultant rise in MAP may stimulate the baroreceptor response so that the pituitary reduces the release of ADH, thereby, promoting increased urine output. This increase in urine volume can be duplicated initially with all vasopressor agents when administered at a low dosage.²⁹ Unfortunately, when tachyphylaxis to the vasopressor agent occurs, increased vasopressor doses must be administered; the resultant vasoconstriction affects the renal circulation and potentiates ARF.

A popular vasopressor agents, dopamine, has been described as having a beneficial effect on the renal circulation when given at low doses (<5 μg/kg/min).²⁹ This salutary effect has been attributed to a dopaminergic-induced reduction in RVR resulting in increased RBF, GFR, and urine output. Clinical studies, however, have shown no change in RBF or RVR with low dose dopamine infusion. The increased urine in this setting is secondary to increased MAP and CO which, through baroreceptor responses, blocks ADH release (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).

More recently, arginine vasopressin (AVP) has been used to restore peripheral pressure in hypotensive patients and, simultaneously, protect the kidney. AVP exerts its effects at three different receptors. The AVP receptor two (V2R), within the renal tubular cells, responds to minute doses of AVP and facilitates the water reabsorption in accordance with the inner medullary (CIII) osmolar gradient.³¹ AVP is also an inotrop and increases the MAP and, thereby, stimulates a reduction in ADH release. AVP may be beneficial in patients with hypotension that is refractory to the standard vasopressor agents such as norepinephrine.³² It does not increase renal perfusion so that the temporary improvement in urine output will be followed by oliguria as tachyphylaxis occurs unless the underlying clinical problem is corrected.^31,32

Fluid Mobilization and Renal Changes

After the period of IFS sequestration, patients will segue into a fluid mobilization phase. This process is due to contraction of the IFS matrix that forces large quantities of salt and water into the adjacent lymphatics for remote delivery into the PV.^21,28 The duration of this mobilization phase is documented by determining the time from maximal weight gain during the fluid sequestration phase until maximal weight loss.²⁸

This rate of IFS fluid relocation into the PV may exceed 10 L in 24 hours causing acute hypervolemia.^21,28 This intravascular flux should be anticipated and treated aggressively with fluid restriction and loop diuresis.^21,28 Renal function studies during the first 48 hours of mobilization reflect the increase in MAP and PV so that GFR, C_Na, C_Osm, and urine output increase; RVR, however, continues to be elevated.²¹ Lack of appreciation of the “new plateau” of MAP in the fluid mobilization phase leads to the “postresuscitative hypertension (PRH) syndrome” with associated respiratory failure, cardiac compromise, confusion, and hematuria (Table 59-4).^21,28 When loop diuretics do not reverse the acute hypertension, low-dose vasodilators are indicated.

The mechanism that leads to the PRH syndrome during the fluid mobilization phase is not fully understood but is associated with altered renal function (Table 59-4). When comparing patients who develop PRH with comparably injured patients without PRH, there is impaired mobilization from the IFS (Table 59-5). The IFS mobilization phase in the PRH patients averages 7 days compared with 5.3 days in comparably injured patients without PRH.³³ Despite similar GFR between the two groups of patients (98 mL/min vs 112 mL/min), the patients with PRH had a marked reduction in TRPF and RBF that averaged 397 and 602 mL/min, respectively, compared with the non-PRH patients in whom the TRPF and RBF averaged 659 and 990 mL/min (Table 59-1). Thus the RVR averaged 15,808 dyne s/cm⁵ in the PRH patients compared with 8039 dyne s/cm⁵ in non-PRH patients.³³ PRH is a problem of fluid maldistribution rather than simple total body fluid overload. The patients with PRH had a higher PV and MAP in comparison to the non-PRH patients but had a lower IFS volume. Thus, the PV/IFS ratio was markedly increased in the PRH patients compared with those without PRH.³³ This combination of increased PV with reduced IFS implies a reduction in the interstitial space compliance.³⁴ Likewise, the PRH patients had a reduction in the total ECF which averaged 25% of total body weight compared with 30% of total body weight in the non-PRH patients.^33,35 The cause of reduced IFS compliance and hypervolemia with the PRH remains obscure but is likely consequent to a renal tubular ischemic insult.³⁴ Measurements of renin activity and aldosterone-like effect in the two groups of patients showed no differences.

Another interesting difference between the two groups of patients reflects the changes in blood pressure following the therapeutic administration of loop diuresis.³⁵ The PRH patients often went from hypertension to hypotension within 2 hours after completion of the loop diuresis, whereas the non-PRH patients excreted a large urine output without change in perfusion pressure suggesting rapid restoration of the PV by the IFS.³⁵ The inability of the expanded IFS to rapidly replenish a depleted PV after loop diuresis in the PRH patients can only be caused by altered IFS compliance.^33,34 A reduction in IFS volume due to reduced compliance, as was seen in the PRH patients, would explain the postdiuresis hypotensive response since the IFS is not available for reentry into the PV.^33,34 PRH with increased PV has been reproduced in a rodent model of renal insufficiency; these animals have reduced IFS volume and compliance.³⁴ The factor responsible for these changes can be cross-perfused into normal control rats, thus indicating that this is a humeral factor.³⁴ The excessive response to loop diuresis must be carefully monitored to be certain that PRH patients do not rapidly go from hypertension to hypotension. Following recovery, renal function studies in both groups of patients are normal.^34,36

Patients with severe multiple injuries often develop sepsis. The renal response to sepsis is, for the most part, a renal adaptation to an altered systemic circulatory status. Clinical studies in many severely septic patients showed an expanded PV, increased CO, decreased TPR, increased IFS volume, and increased urine volume.^37,39 This hemodynamic response has been called the “hyperdynamic state of sepsis.” Polyuria exceeding 2 L/d is seen in many severely septic patients if resuscitation is initiated early enough to prevent renal ischemia and shutdown.^37,38 This polyuria may be inappropriate and persist despite fluid restriction that causes hypovolemia and hypotension.³⁸ Since a vital renal function is regulation of PV by both diuresis and water conservation, this “inappropriate polyuria” soon after a septic insult is an unusual paradox.³⁸ The physiology and danger of this phenomenon are illustrated in the following example (Fig. 59-5).

This 27-year-old woman presented with a 3-day history of lower abdominal pain, distention, fever, tenderness, leukocytosis, and a lower quadrant mass. Shortly thereafter, she became hypotensive and agitated; vital signs and a high urine flow (>4 mL/min) occurred after large-volume intravenous replacement. Laparotomy revealed massive peritoneal spillage from a ruptured viscus. Postoperatively, she exhibited marked fluid sequestration, weight gain, increased CVP (22–25 cm H₂O), and polyuria (>300 mL/h); she received large volumes of intravenous fluid to prevent hypotension and was given inotropes. Her urine sodium concentration was 47 mEq/L. Despite objections from the surgical team, a fluid restriction regimen was instituted to “protect” the lungs (Fig. 59-5). Within 4 hours, the blood pressure fell to 90/70 mm Hg and the pulse rose to 125/min as the urine volume decreased from 300 to 50 mL/h. The pooled 4-hour urine specimen, which averaged 140 mL/h, contained 12 mEq sodium. By hour 28, hypotension (80/60 mm Hg) and tachycardia (155/min) worsened and she became anuric; the CVP fell to 21 cm H₂O. The urine sodium just prior to ARF was 5 mEq/L. She remained anuric and died of respiratory failure 2 days later (see Fig. 59-5).

This brief summary shows how the polyuric state of sepsis persists after the initiation of fluid restriction and contributes to hypotension; thus, it is inappropriate polyuria. Studies on patients with inappropriate polyuria of sepsis show an elevated CO, normal GFR, and normal TRPF associated with normal RBF distribution to the outer cortex, inner medulla–outer cortex, and inner medulla.³⁸ Past experiences indicate that fluid restriction leading to ARF in comparable septic patients almost always is fatal despite the availability of hemodialysis. Since pulmonary function generally shows little improvement with fluid restriction during the initial 24 hours of a massive septic insult, the respiratory failure appears to result from the sepsis, per se, rather than a PV overload. Patients with the inappropriate polyuric syndrome must be monitored closely. When the urine sodium level falls below 10 mEq/L or the FENA is less than 1, expansion of PV to enhance renal perfusion is indicated.^37,38

Mechanism of Inappropriate Polyuria of Sepsis

The polyuria of sepsis was initially observed by Ladd during the Korean conflict; he postulated osmotic diuresis as due to hyperosmolemia (between 290 and 330 mOs/L with a normal being 270–278 mOs/L).¹² This hyperosmolemia cannot be explained by the combined osmolar effects of serum sodium, blood urea nitrogen (BUN), and serum glucose concentrations that are used to measure calculated serum osmolality (Calc Osm) by the following formula: Calc Osm = serum sodium × 1.86 + BUN (mg/dL)/2.5 + serum glucose (mg/dL)/18. The Calc Osm in septic patients, typically, is normal (250–265 mOs/L).^37,38 The osmolar difference (OsmDiff) equals the actual serum osmolarity minus the Calc Osm and is usually increased in severely septic patients, averaging 47 mOs/L compared with a normal of 15 mOs/L.³⁷ The increased OsmDiff reflects the severity of sepsis and correlates closely with mortality rates and the degree of polyuria. Contrary to Ladd’s theory that the polyuria is due to osmotic diuresis, however, C_Osm in septic patients averages about 3 mL/min, which is the upper limit of normal.³⁷ The positive correlations between the OsmDiff and polyuria are probably spurious in that both factors are indices of the severity of sepsis.³⁷

The polyuria of sepsis likely, is not caused by a juxtamedullary “washout” secondary to selective decrease of RBF to the outer cortex (CI) with maintained flow to the juxtamedullary nephrons (CII) prior to volume replacement. Measurements of RBF distribution by ¹³³Xe disappearance during the period of inappropriate polyuria, shows that intrarenal distribution to all three renal components are not altered (Fig. 59-6).⁴⁰

Experimental studies on the effects of sepsis on renal hemodynamics show a decrease in RVR and an increase in RBF.^39,40 Hermreck et al demonstrated that dogs made septic by the introduction of enteric flora into the muscles of the hind limb developed increased RBF as measured by an electromagnetic flow meter.³⁹ Ravikant and Lucas monitored renal circulation with this hind limb sepsis model, using radioactive microspheres and showed a hyperdynamic state with increased CO and RBF despite a lower MAP and CVP when compared with control animals.⁴⁰ Ravikant and Lucas also showed a decrease in E_PAH indicating that some blood entering the kidney was shunted into the renal vein without actively engaging in renal metabolism.⁴⁰ The reduced E_PAH in septic animals led to clinical studies in which renal vein sampling was used to measure E_PAH in septic patients.⁴⁰ These measurements showed a significant reduction in E_PAH, calculated RBF using measured E_PAH, and documented decreased RVR and increased RBF early in the course of septic patients who were fully resuscitated and had normal vital signs.³⁸ Decreased E_PAH in septic animals and patients parallels similar findings in human volunteers receiving pyrogens intravenously.⁴¹ Both septic patients and volunteers receiving pyrogens have a comparable increase in RBF, urine output, and C_Na; the same is seen in animals and humans after vasodilation with phenoxybenzamine administration.⁴¹

Hermreck et al implicated a diabetes insipidus–like syndrome.³⁹ They blocked the polyuria in dogs with infected hind limbs by the systemic administration of ADH. The ADH dosage, however, was greater than that which produces a specific renal effect independent of systemic vasoconstriction. Using renal physiologic dosages of ADH (1–2 μg/kg/h) injected into the renal arteries of septic patients with inappropriate polyuria, no effect was seen on the polyuria.³⁸ This syndrome has also been attributed to a distal tubular blockade of aldosterone receptor sites; calculated aldosterone-like effect on the renal tubules (C_H2O/(C_H2O + C_Na)) in septic patients with positive free water clearance, however, shows no such impairment.³⁷ Indeed, most septic patients can reabsorb sodium with great efficiency right up to the development of AORF, and few have a positive C_H2O (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).³⁷

The therapeutic implications of this syndrome are apparent. Clinicians must recognize that “a good urine output” of 35–50 mL/h in the early septic period may not be adequate and may reflect PV deficiency. Likewise, a large urine output exceeding 200 mL/h need not reflect overload.³⁷ Polyuria, together with large insensible losses, IFS expansion, and increased gastric losses over a period of days, may lead to an incipient hypovolemia that goes unrecognized prior to a “sudden” vascular collapse. Careful monitoring of intake and output provides clues of impending collapse; blood pressure, pulse, pulse pressure, and urine sodium concentration must be monitored closely.³⁷

Renal Response to Hypodynamic Sepsis

Not all septic patients develop the hyperdynamic state.^35,37 Indeed, up to 35% of patients with sepsis have a low CO and a high TPR. The renal response to “hypodynamic” sepsis consists of increased RVR, decreased RBF, and decreased GFR reflecting, primarily, a decrease in outer cortical (CI) flow. This leads to a low C_Na, C_Osm, and urine output. Therapy for the oliguria must be directed toward supporting the myocardium and maintaining PV. Persistent oliguria in fully resuscitated patients requires induced diuresis with mannitol or a loop diuretic.³⁵ When oliguric ARF is developing, a loop diuretic, such as furosemide, beginning at 40 mg and doubling this dose every 30–60 minutes to a total of 3200 mg, may prevent renal shutdown. If a renal response does occur with this regimen, it usually occurs by the time the furosemide dosage has reached 160 mg.³⁵ When there is no response, the end result is oliguric ARF.

Significance of Free Water Clearance

Free water clearance (C_H2O) represents the difference between urine output and osmolar clearance (C_Osm). The addition of C_H2O measurements provides more insight into renal concentrating capacity.⁴² Concentrating impairment, as reflected by the excretion of a dilute urine, is due to an intrinsic renal dysfunction. This defect may proceed azotemia and oliguria by 24–72 hours.⁴³ Excess C_H2O (C_H2O > –0.25 mL/min) in critically ill patients is associated with a reduction in PV, GFR, and ERPF.⁴³ This subgroup of patients has the highest incidence of subsequent renal failure (21%). When the C_H2O approaches unity (±0.25 mL/min), careful monitoring will help determine whether this is a normal response to increased PV or to an intrinsic tubular defect predicting subsequent ARF.⁴² Patients with a rising C_H2O, without evidence of PV expansion, need to be watched carefully for toxic renal insult, particularly from associated renal toxic antimicrobials colloid supplemented resuscitation regimen also causes a rise in C_H2O due to distal nephron sodium–potassium exchange.⁴³

The GFR provides the best single assessment of renal function. Ideally, this is a 24-hour GFR to filter out subtle renal changes during the day but 2-hour samplings of GFR are more practical.⁴⁴ Aburahma found that the actual GFR measurement was more sensitive for predicting a bad result following carotid endarectomy. When a 2-hour GFR is not performed, one can use a static serum creatinine value to estimate renal function.^43,44 Based on detailed studies of injured and septic patients, one can estimate that approximately one million (50%) nephrons are functioning when the serum creatinine is 1.5 mg/dL (Table 59-5).⁴⁶ The simultaneous ERPF will be about 400 mL/min and the calculated RBF will be less than 700 mL/min. When the serum creatinine level reaches 2.3 mg/dL, the number of functioning nephrons has decreased to about 250,000 with a GFR of about 30 mL/min; the associated ERPF and RBF will be 148/min and 269/min, respectively (see Table 59-1; Fig. 59-1).⁴⁶ This represents severe renal insufficiency with threatened progression to ARF.⁴⁶ A serum creatinine above 3.1 mg/dL, reflects a GFR less than 10 mL/min, which is defined as nonoliguric ARF.⁴⁶ When this occurs, all nephrotoxic agents should be discontinued to try to prevent progression to oliguric ARF.

Whereas the serum creatinine provides a static image of renal function, the risk, injury, failure, loss, and ESKD (RIFLE) criteria emphasize change in function during treatment. Biteker and coworkers demonstrated that the RIFLE provides the best prediction of cardiovascular complications and death in patients undergoing noncardiac surgical procedures.⁴⁷ The RIFLE criteria focus on changes in GFR, serum creatinine, and urine output.⁴⁸ Renal risk of ARF is present when the serum creatinine increases by 1.5 times, the GFR decreases by 35%, or the U/O is less than 0.5 mL/kg/h (<35 mL/h/70 kg) for more than 6 hours. Renal injury is present when the serum creatinine doubles, the fall in GFR exceeds 50%, or the U/O is less than 0.5 mL/kg/h for more than 12 hours. Renal failure is defined when the serum creatinine triples, the GFR falls by 75%, the U/O is less than 0.3 mL/(kg h) for 24 hours, or anuria ensues for 12 hours. Renal loss is defined as failure that lasts more than 4 weeks. End-stage kidney disease (ESKD) is defined as failure that lasts more than 3 months.⁴⁸ Recovery from ARF is defined as partial or complete depending on how far the patient reverses the above process of RIFLE. When there is no baseline creatinine or GFR with which ongoing values can be compared, an age-, gender-, and race-based nomogram is used to define what the initial serum creatinine should have been.⁴⁸ Just as a low serum creatinine will estimate the number of functioning nephrons, so will the RIFLE criteria identify when renal function is worsening so that all nephrotoxic agents can be discontinued.⁴⁶

The Acute Kidney Injury Network (AKIN) developed a similar system for defining ARF that is called acute kidney injury (AKI).⁴⁹ The AKI criteria are also good predictors of survival which is worse in older patients who have “impaired autoregulation.”⁴⁹ The AKIN, like the RIFLE classification, defines three separate levels of AKI which are based on the clinical parameters of urine output and serum creatinine levels. The AKIN and RIFLE systems for defining ARF have similar statistical sensitivity.⁵⁰ Advocates for the AKIN or RIFLE system in defining severity stages for ARF emphasize that creatinine clearance may not be accurate in patients with low GFR since creatinine is both filtered and secreted in the nephron. Comparisons between GFR measured by C_cr and C_in which is not secreted by the tubules show that the slight increase in C_Cr over C_in is predictable at all ranges of GFR (Fig. 59-7).^46,48

Effects of Renal Trauma on Renal Function

Renal injury, per se, affects renal function.⁴⁹ When the renal injury does not require retroperitoneal exploration for hemostasis or correction of a urine leak, the postoperative renal function is comparable to those patients who had similar hemorrhagic shock insult requiring a comparable number of RBC transfusions during operation but did not have renal injury.⁵¹ Likewise, when renal hemostasis is achieved by means of suture repair, the postoperative renal function is not different from matched controls without renal injury.⁵¹ When nephrectomy is needed, there is a significant reduction in RBF and GFR.⁵¹ The incidence of ARF rises when partial or total nephrectomy is required for hemostasis.⁵¹ Finally, nephrectomy is associated with an increased mortality due to the underlying trauma/shock insult in comparison to comparably injured patients who receive the same number of RBC transfusions during operation but do not require nephrectomy.⁵¹ Consequently, one must emphasize the importance of successful repair of renal injuries without nephrectomy when following a policy for exploration of intermediate-severity renal injuries.^51,52

Most seriously injured patients undergo computed tomography (CT), usually, with an iodinated intravenous contrast media injection. Contrast-induced nephropathy which is the third leading cause of hospital-acquired ARF and is associated with significant mortality rates.^53,54 This complication occurs even though less toxic, nonionic, iso-osmolar contrast agents have replaced hyperosmolar ionic contrast agents that were associated with red cell creation and small vascular occlusion.⁵⁴ Although Matsushima and coworkers report that low osmolar contrast agents do not increase the renal insult in patients with significant injury, the authors would recommend that unnecessary contrast studies be avoided because of contrast-induced ARF. Careful restoration of PV and correction of electrolyte abnormalities, particularly hyperchloremia, are important preventative steps.⁵⁴ The likelihood increases precipitously when the creatinine is greater than 1.5 mg/dL prior to study. Repeat CT studies magnify the risk. The mechanism for contrast-induced ARF is due to reduced RBF and oxygen consumption leading to direct tubular insult.⁵⁵ PV expansion is preventative; the addition of osmotic or loop diuresis does not appear to be helpful and may, in selective circumstances, cause nephrotoxicity.⁵⁴ The value of adding sodium bicarbonate to the hydration fluid is controversial; Merten and colleagues suggested that the incidence of ARF is lowered in comparison to prestudy resuscitation with sodium chloride.⁵⁶

Crush Injury and the Kidney

The association between ARF and crush injury was made many years ago during World War II when citizens of London were trapped in falling buildings during the Nazi blitz. Patients who were safely extracted after limb crush, shortly thereafter, developed ARF due to reduced PV from fluid sequestration in the crushed limb, lowered RBF and GFR, and tubular insult due to the by-products of rhabdomyolysis.⁵⁶ The crush injury leads to multiple organ dysfunction because of the myeloperoxidase injury to capillaries affecting not only the kidney but the lungs and muscles.⁵⁷ Free myoglobin that is filtered may precipitate in the tubule causing obstruction from cast formation; tubular obstruction is aggravated by uric acid cast formation. Both are accelerated by a low pH of the tubular filtrate due to the systemic hypoperfusion.⁵⁷ Other causes of extensive muscle ischemia causing myoglobin-induced ARF include limb ischemia, cocaine administration, excessive amphetamine exposure, bacterial myonecrosis, and, occasionally, extensive hemolysis from transfusion reactions.⁵⁸

The diagnosis is made from the classical history, an elevated creatinine phosphokinase (CPK), hyperkalemia, and myoglobin in the urine; the urine typically has a deep orange color and may contain dark brown granular casts.⁵⁶ Treatment includes prompt PV expansion, correction of the acidosis, and both osmotic and loop diuresis to unplug the obstructed tubules. An induced urine output of 200 mL/h until the serum creatinine and CPK values have returned toward normal is recommended; this may take 4 or 5 days.⁵⁸ Early institution of this regimen helps prevent the progression to ARF. When this therapeutic regimen is delayed and ARF ensues, HD is required. In contrast to patients with ARF due to severe hemorrhagic shock or massive sepsis, the patients with ARF from an isolated crush syndrome will survive.⁵⁸

Intraperitoneal Pressure and the Kidney

Increases in the intraperitoneal pressure affect renal function first at the tubular level and subsequently at the glomerulus.⁹ Patients with abdominal hypertension due to ascites from liver cirrhosis or stage IV malignancies have increased abdominal pressure; the extent of intra-abdominal venous hypertension, as monitored through indwelling inferior vena caval (IVC) catheters, correlates directly with a reduction in C_Na, C_Osm, and urine output; when the IVC pressure rises above 20 torr, there is a reduction in ERPF and GFR (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).⁹ The worst form of abdominal hypertension occurs in patients with the abdominal compartment syndrome (ACS), after massive injury or sepsis requiring large-volume fluid and blood product replacement. Intra-abdominal hypertension above 35 torr is associated with renal shutdown; such patients must be rapidly decompressed with some type of abdominal wall pack used to maintain the viscera within the peritoneal cavity. Renal function typically is promptly restored with abdominal decompression as long as the renal insult was not excessively prolonged. Similar renal changes were shown in a canine model in which super renal IVC hypertension was created by different degrees of venous constriction; when extreme hypertension was created by arterializing the left renal vein, all left renal perfusion ceased while the right normal kidney continued to function (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).

Differential Diagnosis of Oliguria

Oliguria may be prerenal, intrinsic renal, or postrenal.² Postrenal oliguria may be due to a plugged, kinked, or malpositioned indwelling catheter, urethral disruption, or unrecognized retroperitoneal bladder injury. Once diagnosed, the mechanical problem can be corrected. Distinguishing between a prerenal and an intrinsic oliguria requires an analysis of the urine (Table 59-6). Prerenal oliguria is due to reduced CO, RBF, and GFR resulting in a urine with a high specific gravity, high osmolality, low sodium concentration, low C_Na and FENA, and an elevated urine/plasma osmolar ratio and urea ratio. The oliguria due to intrinsic renal failure will be dilute with a low specific gravity, osmolality, and urine/plasma osmolar ratio and a urine sodium concentration greater than 40 mEq/L (Table 59-6). When the differential between prerenal and intrinsic oliguria is unclear, a rapid infusion of 500 mL of balanced electrolyte solution over 20 minutes while monitoring central pressures and peripheral pressures should yield a prompt diagnosis that will guide therapy.

Nephrotoxic Agents and ARF

Many medicines, particularly antimicrobials, cause nephrotoxicity. These agents are best avoided when the serum creatinine exceeds 1.5 mg/dL.⁶⁰ For example, renal compromised patients with yeast infections are best treated with fluconazole and not amphotericin which has significant nephrotoxicity. The aminoglycosides are notorious for nephrotoxicity, particularly in the patient with marginal renal function. Reduced dosage and single daily dosage based on peak and trough measurements have been purported to circumvent this toxicity.⁶⁰ Adherence to these recommendations, however, has not prevented ARF.^46,60 Peak and trough dosing recommendations are based on serum levels that have been associated with nephrotoxicity. Critically ill patients, however, have expansion of the IFS with free movement of an aminoglycoside into the IFS where it has direct contact with the tubular cells. There are no published studies on renal dosing of antimicrobials that take into account IFS concentration of antimicrobials. When a stable septic patient has a gradual daily rise in serum creatinine during therapy with a so-called non-nephrotoxic antimicrobial, it should be stopped; the serum creatinine will continue to rise for one more day, plateau for two days, and gradually fall to normal levels. In this setting the second or third best antimicrobial, based on sensitivity studies, should be used. Postoperative pain medicine may also adversely affect renal function; the authors have seen renal toxicity after tromethamine therapy given at the end of operation.⁵⁹ Exposure to 3,4-methylenedioxymethamphetamine (“ecstasy”) is sometimes used at nightclubs or “rave parties” in patients who are injured. Ecstasy causes serotonin release and stimulates ADH with resultant thirst. Polydipsia, water retention, hyponatremia, and death.⁶¹ It also causes liver toxicity, vasculitis with rhabdomyolysis, acidosis seizures, and strokes.⁶¹

The kidneys are not immune to the ravages of aging. The best data documenting this process come from the Baltimore Longitudinal Study of Aging (BLSA) which has monitored, in a longitudinal assessment, the effects of aging on renal function for 50 years.⁶² The BLSA study shows a progressive annual fall in C_Cr of 0.26 mL/min in healthy patients between the ages of 20 and 40; this increases to 1.51 mL/min after age 80. This study was limited to men and had few elderly patients. The BLSA also reported that patients with C_cr less than 60 mL/min were more likely die during the followup period compared to patients with C_cr greater than 90 mL/min.⁶²

The main controversy regarding these observed changes focuses on whether they result from intrinsic renal dysfunction or result from comorbidities which secondarily affect kidney function. Weinstein and Anderson showed that this phenomenon is associated with comorbidities such as hypertension, smoking, dyslipidemia, atherosclerotic disease, and others.⁶³ All these comorbidities cause reductions in renal blood flow and elevations in renal vascular resistance. These perfusion changes may give rise to progressive glomerulosclerosis with increased basement membrane permeability, albuminuria, and impaired sodium and water metabolism. The renin-angiotensin system is likely involved in these changes which increase renal vasoconstriction, thus, affecting glomerular filtration and renal excretory function. Endogenous nitric oxide, which provides renal protection by vasodilation, may be less available in aged patients thus favoring excess vasoconstriction. The association between progressive renal dysfunction and the above comorbidities suggest that the kidney is sharing in the so-called “metabolic response” to the detrimental effects of obesity, hypertension, diabetes-mellitus, smoking, and hyperlipidemia.^63,64

Regardless of whether these detrimental renal changes with aging are inherent within the kidneys, or secondary to comorbidities, the response to treatment remains the same. All of the adverse renal changes that occur with injury are more threatening to renal function and patient survival when the preinjury renal function is compromised. Thus, rapid restoration of renal perfusion during resuscitation, avoidance of hypotension, careful monitoring of contrast dye exposure, and treatment with various potentially renal toxic antibiotics becomes more critical in the elderly patient. Furthermore, the subsequent hazard of renal failure and death is even greater in the elderly compromised patient in comparison to younger patients with better renal reserve.

Acute Renal Failure

Acute renal failure may be defined as an abrupt and sustained decline in renal function that leads to the accumulation of nitrogenous waste products and uremic toxins. Many definitions of ARF have been proposed. Risk factors following injury include advanced age, high injury severity score, shock, multiple fractures, rhabdomyolysis, major head injury, and lung injury requiring mechanical ventilation. Oliguria (<200 mL/d) is ARF. Nonoliguric ARF implies the maintenance of some filtration; when the GFR is less than 10 mL/min the patient has nonoliguric ARF, whereas, when the GFR is greater than 10 mL/min but less than 30 mL/min the patient has acute renal insufficiency.^7,47 Although this definition does not get into the many subtleties of tubular dysfunction, reduction in GFR is the prime component for the development of ARF in the critically injured patient. Such patients with increased mortality and length of stay result in exorbitant hospital cost.^7,47

Renal Replacement Therapy

The standard renal replacement therapy (RRT) for ARF in the critically ill patient is intermittent HD. Questions exist, however, about the timing and frequency.⁶⁵ There is a general consensus that HD is mandated in patients with increased PV, electrolyte abnormalities, particularly hyperkalemia, symptomatic azotemia such as confusion, circulating toxins, and metabolic acidosis not corrected by hyperventilation.^65,66 Retrospective studies suggest that when intermittent HD is begun early in a patient’s course, there is marked increase in survival, whereas other studies show that HD is not benign and is associated with increased need for vasopressor therapy, bleeding, and infections.^65,66 HD is also associated with decreased CO and increased intestinal oxygen consumption producing mucosal acidosis.⁶⁷ Likewise, there may be a fall in urine output in patients with nonoliguric ARF following HD.⁶⁰ Indeed, increased mortality rates have been described in a randomized controlled trial of patients who have more frequent HD in comparison to the subgroup with less frequent HD.⁶³ Technical improvements in HD are developing, particularly, with the use of biocompatible membranes that are associated with less inflammatory reaction than the traditional cellulose-based membranes.

A number of techniques for continuous RRT have been described. The most popular is continuous venovenous hemofiltration (CVVH), which is safer for unstable patients who are not candidates for HD; CVVH has better results in those patients with a higher GFR.⁶⁷ Other forms of continuous RRT include the continuous arterial venous hemofiltration and continuous arterial venous HD that use the patient’s MAP to provide the flow through the membranes.⁶⁷ These types of continuous RRT will help remove circulating toxins of low-molecular-weight substances including antimicrobials, such as gentamycin, with molecules less than 500 days. Continuous RRT also helps correct problems with acidosis due to impaired renal tubular function.⁶⁸ Future advances for making an earlier diagnosis of renal injury, such as measurements of neutrophil gelatinase-associated lipocalin and the development of renal-assisted devices that have a standard hemofiltration cartridge seeded with renal tubular cells await more clinical trials.⁶⁹ Regardless of technique employed, there must be a close working relationship between the RRT team and the primary care team. Injured and septic patients often have IFS expansion that is due to cellular insult and not PV overload or heart failure. Attempts to remove excess fluid in this setting will compromise PV and renal perfusion, thus aggravating the renal insult. For this reason, the authors prefer to limit RRT for the classical indications of PV overload, electrolyte abnormality (mainly hyperkalemia), toxemia, and symptomatic azotemia in patients with altered mental status. Finally, patients who progress from oliguric ARF to nonoliguric ARF may have impaired tubular function and need close monitoring to identify and correct PV deficiency and hypokalemia.