Charles E. Lucas, Michael T. White, and Anna M. Ledgerwood
The human body is a complex organism composed, primarily, of water and its contained solutes. A 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) of 11 L. The cardiac output (CO) in the 70-kg person is 5 L/min with 20% of this flow going to kidneys; the kidneys, with a combined weight of about 600 g, have a renal blood flow (RBF) of 1,250 mL/min or more than 2 mL/(min g) of renal parenchymal. This unusually large ratio of RBF reflects their vital 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. This chapter reviews normal renal physiology, the renal response to shock and sepsis, guidelines for prevention of acute renal failure (ARF), and treatment of ARF.
NORMAL RENAL FUNCTION
Renal function is affected by general anesthesia, intraoperative manipulation of organs, general stress, hemorrhage, hypovolemia from trauma, postoperative fluid shifts, and sepsis. The 1,250 mL/min of RBF exits 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 (CPAH) 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 TRPF (TRPF = ERPF/EPAH).2–5 TRBP may be calculated by correcting the TRPF for hematocrit: TRBF = TRPF/(1 − Hct).
FIGURE 59-1 The kidney is divided into three components. The outer cortex (CI) contains 85% of the glomeruli. The inner cortex/outer medulla (CII) contains the remaining juxtamedullary glomeruli whose peritubular vessels extend to the vasa recta in the inner medulla (CIII) that establishes the hyperosmolality within the loops of Henle.
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 (juxtamedullary, 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 venous system adjacent to the same glomerulus.2,3
The normal glomerular filtration rate (GFR) averages 125 mL/min (180 L per day) and is measured by the renal clearance (urine concentration × volume/plasma concentration) of exogenous inulin (CIn) or endogenous creatinine (CCr), both of which are completely filtered; the CIn is slightly higher than the CCr 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 isosmolar state. The nonfiltered blood, now protein-rich, perfuses the efferent arterioles and the peritubular vessels, which augment 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. 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 (36 L per day) 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 (CH2O) by the CH2O + sodium clearance (CNa) in patients with a positive CH2O. 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 and mediated by distal tubular sodium concentration, afferent arteriole pressure, afferent arteriole pulse pressure, and others.3,7–9
After passing through the distal convoluted tubules, the remaining hypotonic filtrate (15 mL/min or 31 L per day) 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 isosmolar to 1,400 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 14 mL/min or 30 L per day with the remaining 1 mL/min (1,440 mL per day) being excreted as urine.
The renal handling of sodium, osmoles, and water is expressed as the clearances of sodium (CNa), osmoles (COsm), and free water (UV − COsm).4 With normal water and solute intake, both the CNa and COsmaverage 1–3% of the GFR; CH2O is usually negative, reflecting the excretion of concentrated urine. A decrease in RBF or PV causes CNa and COsm to fall, reflecting sodium preservation.3 Likewise, a breakdown in the countercurrent mechanism brought about by a selective insult to the juxtamedullary nephrons and their loops of Henle causes increased CNa and COsm from impaired tubular concentration of sodium.3,4
RENAL RESPONSE TO INJURY AND HEMORRHAGIC SHOCK
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 5,000 to 8,000 dyne s/cm5 with a concomitant decrease in RBF from 1,250 to 800 mL/min while maintaining a normal GFR (Fig. 59-2). Excretion of metabolites is thus maintained, while 400 mL of blood/min is redirected to core areas. This phenomenon of maintained GFR despite a reduction in RBF is known as autoregulation (Fig. 59-2). 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, in turn, 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 injury and potential ARF.
TABLE 59-1 Graded Renal Response to Acute Hypovolemia
FIGURE 59-2 Mild to moderate hemorrhage causes efferent arteriolar vasoconstriction resulting in reduced RBF (520 mL/min) while maintaining GFR (125 mL/min). This is known as autoregulation that redirects blood flow to the systemic circuit without compromising filtration and excretion.
During hypoperfusion, the kidney conserves salt and water. This results from decreased GFR, increased ADH, and renin release with aldosterone generation leading to sodium, water, and osmole reabsorption.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 systemic status 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 in the excellent studies performed 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, 16 Other studies, however, showed 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.18
Interoperative protection of the kidney in a hypovolemic, hypotensive patient must be directed toward improving the cardiovascular status by PV expansion with fluid, blood, and blood products. Inotropic support should be added when PV expansion causes an elevated control pressure despite persistent hypotension and oliguria. Experimental and clinical studies show that a temporary delay in reestablishing urine flow after arterial pressure (MAP) is restored may result from a persistent rise in RVR after hypovolemia is corrected.7,10 Renal vasodilation, experimentally, can reverse this lagging anuria, but such therapy is difficult and hazardous in humans.10 Based on clinical observations, some 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 persistent perfusion by catecholamines in stable patients; measurements of renin and arginine vasopressin (AVP) at this time in stable patients 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 and IFS deficit may exceed 1,500 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 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.16–18
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 (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 CNa exceeds 3%. Therapy for this syndrome should be by maintenance of effective PV as judged by vital signs until the polyuric phase subsides, usually within 5 hours of operation.19
FIGURE 59-3 Following restoration of PV during and shortly following operation, a renal concentrating defect may exist whereby a patient may have a low-normal MAP (84 torr) with a markedly reduced GFR (35 mL/min) while excreting a large urine volume (8.2 mL/min; 500 mL/h). This concentrating defect is likely due to inner medullary washout of osmoles, thus impairing reabsorption of sodium and water in response to aldosterone and AVH. This phenomenon seldom lasts more than 5 hours following conclusion of operation.
TABLE 59-2 Impaired Concentration During and Shortly After Operation
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 minimal 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 (500–1,000 mg/100 mL) and hyperosmolemia (310–320 mOs/L) have occurred in patients resuscitated with only crystalloid solutions containing 5% dextrose. This hazard is circumvented by limiting the amount of 5% dextrose in crystalloid solution to 2,000 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).
FIGURE 59-4 Following an operation requiring 23 RBC units and 9 L crystalloid solution, this patient became oliguric (1 hour) and was treated with low-dose furosemide causing prompt diuresis and hypotension. Fluid bolus restored pressure (2 hours) and inotropes were added for rising central pressures (steroid use was part of a prospective randomized trial). Low-dose dopamine was added at 7 hours and this improved perfusion pressure. Furosemide at hour 9 reproduced prompt diuresis and hypotension treated with additional fluid bolus through hour 10. Clearly, loop diuresis during the fluid update phase is hazardous. The patient made a full recovery.
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. This typically occurs during the initial 12 hours after operation and causes decreased ERPF, GFR, UO, CNa, and COsm. During the 36 hours of obligatory IFS expansion, the patient may need 10 L balanced electrolyte solution to maintain kidney function. Inotropes and ventilator support are often needed during this fluid uptake phase.20 Restoring PV, hemoglobin level, and normal MAP enables the kidney to maintain GFR and urine output even though RBF may be reduced. CNa and COsm 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; CH2O is negative at this time.11 When a therapeutic decision is made to restrict fluids because of high central pressures, the resultant PV depletion and reduction in RBF often leads to ARF which, in the fluid sequestration phase, usually results in death.2,21 The advocates of fluid restriction ascribe such a death to multiple organ failure not related to ARF since renal function may be maintained by hemodialysis (HD); more likely, multiple organ failure reflects the initial deficiency in circulating volume that led to ARF as part of the multiple organ failure syndrome.2,21, 22
The technique used to provide ventilatory support during the fluid uptake phase may also affect kidney function.23,24 When the lungs that are supported by continuous positive pressure breathing with high tidal volumes (above 10 mL/kg body weight), the arterial gases show better saturation but there is a fall in MAP and CO resulting in reduced ERPF, GFR, and urine flow.23 Likewise, the addition of positive end-expiratory pressure (PEEP) above 10 cm H2O causes improved arterial oxygenation but reduction in MAP, CO, ERPF, CNa, COsm, and urine output.24 This response appears to be mediated through sinoaortic baroreceptors, renal innervation, and renal vein pressure changes.25 The reduced ERPF associated with PEEP may also cause renal renin release that causes increased sodium reabsorption.25, 26 The SICU team must adjust ventilatory settings with renal function in mind.
THE RENAL EFFECTS OF COLLOID RESUSCITATION
The type of fluid therapy during the sequestration phase will also affect renal function. Early administration of human serum albumin (HSA) has been recommended to prevent weight gain and IFS expansion during the obligatory fluid uptake phase.27 This recommendation is based on the belief that colloid, such as HSA, will remain within the PV and, by its oncotic effect, cause fluid to return to the PV. Unfortunately, HSA leaves the PV at an increased rate after intravenous administration and causes a prolonged sequestration phase, larger fluids needs, a greater weight gain, and altered renal dynamics.21,28Patients randomized to receive HSA during the sequestration phase exhibit an increase in PV and RBF but, paradoxically, a reduction in GFR, CNa, COsm, 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). This hyperoncotic filtrate extracts water and, with it, 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 aldosterone and ADH. Both aldosterone and ADH facilitate the reabsorption of sodium and water in direct response to the inner medullary oncotic and osmotic gradients (Table 59-3).2,3, 21 Furthermore, almost half of the patients receiving HSA supplementation required loop diuresis compared with only 20% of the non-albumin-supplemented patients.21 Finally, 13 of the 46 albumin-supplemented patients developed some type of renal failure compared with 1 of the 48 nonalbumin patients.21,28 This phenomenon has been duplicated in a canine model of isolated renal perfusion and had the same effect (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).21
TABLE 59-3 Renal Effects of Randomized Albumin-Supplemented Resuscitation
Vasopressor Therapy and Renal Function
Besides inotropic support, 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 that decreases the release of ADH promotes increased urine output. This increase in urine volume can be duplicated initially with all vasopressor agents when administered at a low dosage.29Unfortunately, when tachyphylaxis to the vasopressor agent occurs, increased doses must be administered; this leads to excessive vasoconstriction including the renal circulatory bed resulting in a subsequent oliguria that often progresses to ARF.
One of the 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 not shown renal benefits (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).30 Prior studies have demonstrated that low-dose dopamine in critically ill trauma and septic patients almost uniformly produces an increase in urine output (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data). These low-dose infusions, however, increased MAP and CO so that the resultant increase in urine output is mediated through baroreceptor responses to the pituitary that blocks ADH release (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data). Similar results have been seen with other vasopressor agents such as norepinephrine and Aramine (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).
More recently, there has been a relook at AVP as a means of restoring peripheral pressure in hypotensive patients and, at the same time, protecting the kidney. AVP exerts its effects at three different receptors. The AVP receptor two (V2R), within the renal collecting tubular cells, responds to minute doses of AVP and facilitates the reabsorption of water from the renal tubule in accordance with the inner medullary (CIII) osmolar gradient.31 V1A acts on the myocardium and will exert an inotropic effect; this increases the MAP and, through the same mechanism as the other low-dose vasopressor agents, stimulates a reduction in ADH release through the baroreceptor stimulation of the pituitary. 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 an average of 36 hours of IFS sequestration, patients who receive an average of 15 RBC transfusions segue into a fluid mobilization phase. This process is the result of 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 and averages 5.6 days.28
This rate of IFS fluid relocation into the PV may exceed 10 L in 24 hours causing acute hypervolemia associated with impaired renal excretion.20,28 This intravascular flux should be anticipated and treated aggressively with fluid restriction and loop diuresis.20,28 The renal function studies during the first 48 hours of mobilization reflect the increase in MAP and PV so that GFR, CNa, COsm, and urine output increase; RVR, however, continues to be elevated, primarily at the postglomerular level (Table 59-4). Once reverse movement ensues, an increase in MAP follows and hypertension (BP >150/100 torr) often ensues.20 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.20,28 When loop diuretics do not reverse the acute hypertension, low-dose vasodilators are indicated.
TABLE 59-4 The Renal Factor and Postresuscitative Hypertension (PRH)
THE RENAL FACTOR IN POSTRESUSCITATIVE HYPERTENSION
The mechanism that leads to the PRH syndrome during the fluid mobilization phase is not fully understood but is related to altered renal function. When comparing patients who develop PRH with comparably injured patients without PRH, there is impaired mobilization from the IFS (Table 59-5). The IFS sequestration phase in the PRH patients averages 7 days compared with 5.3 days in comparably injured patients without PRH.33 Despite comparable GFR levels 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). Consequently, there was a marked increase in RVR which averaged 15,808 dyne s/cm5 in the PRH patients compared with 8,039 dyne s/cm5 in non-PRH patients (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).33 Renal oxygen consumption was also reduced in PRH patients (Table 59-4). The rise in RVR occurs primarily at the postglomerular level since GFR was maintained. 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 (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).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.33,35The cause of reduced IFS compliance and hypervolemia with the PRH remains obscure but is likely consequent to a renal tubular ischemic insult.34 The marked increase in RVR was associated with a reduction in the renal perfusion index (RBF/CO). Measurements of renin activity and aldosterone-like effect in the two groups of patients showed no differences (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data). Delays in recovery of renal perfusion following hemorrhagic shock have been demonstrated in both humans and animals.11,36 The mechanisms leading to this delayed restoration of perfusion, however, have never been fully explained. The increase in the IFS in non-PRH patients suggests some mechanism, whereby the kidneys may be responsible for maintenance of the PV/IFS ratio following severe hemorrhagic shock (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).33
TABLE 59-5 Relationship of Serum Creatinine to Renal Hemodynamic Studies in Injured and Septic Patients
The renal response to loop diuresis was also evaluated in PRH and non-PRH patients.35 Patients without PRH had a much greater increase in CNa, COsm, and urine output in comparison to the non-PRH patients. 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 tolerated the loop diuresis with marked increases in urine output and maintained 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 can only be caused by an 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. Possibly the renal hypoperfusion causes ischemic injury to the arteriolar walls leading to transmural migration of sodium on to intramural collagen, thus making these vessels in both the periphery and the kidney more sensitive to a normal level of circulating catecholamines.34,36 Following recovery, renal function studies in both groups of patients are normal.
THE RENAL RESPONSE TO SEPSIS
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. Those factors that have created the most controversy regarding this response, therefore, are an extension of the controversy regarding the cardiovascular response to sepsis.37 Historically, sepsis has been characterized as a hypodynamic state with increased TPR and decreased CO; the kidneys, traditionally, shared in this response with increased RVR and decreased RBF, especially outer cortical (CI) flow.38 These traditional concepts, however, reflect endotoxin studies in animals and a poor understanding of fluid shifts in septic patients.
The empirical recognition that septic patients respond better to a fluid challenge questioned these traditional views.39 Clinical studies in 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”. The kidney often shares in this hyperdynamic state.39
Polyuria exceeding 2 L per day is seen in many severely septic patients if resuscitation is initiated early enough to prevent renal ischemia and shutdown.39,40 Furthermore, polyuria may be inappropriate and persist despite fluid restriction that causes hypovolemia and hypotension.40 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.40 The physiology and danger of this phenomenon are illustrated in the following example (Fig. 59-5).
FIGURE 59-5 This young woman had reoperation for massive peritonitis. Inappropriate polyuria through the first 28 hours after operation persisted despite normal vital signs. Fluid restriction to protect the cardiovascular status led to hypotension, tachycardia, and renal failure within 4 hours resulting in her later demise on day 3.
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; fluids containing vasopressors were administered. Vital signs responded to 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 (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.40 Past experiences indicate that fluid restriction leading to ARF in comparable septic patients almost always is fatal despite the availability of HD. Since pulmonary function generally shows little improvement with fluid restriction during the initial 24 hours of a massive septic insult, the pulmonary insufficiency appears to result from the sepsis, perse, rather than a PV overload. Patients with this 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.39,40
Mechanism of Inappropriate Polyuria of Sepsis
The polyuria of sepsis was initially observed by Ladd during the Korean conflict; he postulated osmotic diuresis as the etiology.12 Hyperosmolemia (between 290 and 330 mOs/L; normal is 270–278 mOs/L) has been confirmed in septic patients; furthermore, 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).39,40 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.39 This 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, COsm in septic patients averages about 3 mL/min, which is the upper limit of normal.39 The positive correlations between the OsmDiff and polyuria are probably spurious in that both factors are indices of the severity of sepsis. Hyperosmolemia, per se, however, may contribute to the polyuria by a mechanism not related to diuresis. It is a potent vasodilator in many vascular beds, including the kidney, and may facilitate diuresis by renal vasodilatation and its described effects.39,41
The polyuria of sepsis might be due, partially, to 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. This reduces the inner medullary interstitial (CIII) osmotic pressure, thereby temporarily “paralyzing” the countercurrent mechanism. This explanation would explain polyuria that occurs during the early postresuscitation interval when the inner medullary osmolar gradient becomes reestablished. Two factors have negated this postulate. First, the period of increased RBF and decreased RVR in septic patients is transient, usually lasting 48–96 hours; in contrast, the polyuria may last beyond that time in patients subjected to a second septic insult that is not associated with hypotension. Second, RBF distribution measurements by 133Xe disappearance during the period of inappropriate polyuria, but 72 hours after the initial insult when the TPR was normal, did not support this conclusion.40 Each patient had normal intrarenal distribution to all three renal components (Fig. 59-6).40
FIGURE 59-6 This patient with extensive peritonitis had inappropriate polyuria (6 mL/min; 360 mL/h) despite marginal blood pressure and normal RPF (1,200 mL/min), GFR (95 mL/min), and RBF distribution to CI, CII, and CIII. This inappropriate polyuria subsided after 36 hours and he recovered.
Experimental studies on the effects of sepsis on renal hemodynamics show a decrease in RVR and an increase in RBF.41,42 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.41 Ravikant and Lucas monitored renal circulation with this hind limb sepsis model, using radioactive microspheres; they showed a hyperdynamic state with increased CO and RBF despite a lower MAP and CVP when compared with control animals.42 Ravikant and Lucas also showed a decrease in EPAH indicating that some blood entering the kidney was shunted into the renal vein without actively engaging in renal metabolism.42 The reduced EPAH in septic animals led to clinical studies in which renal vein sampling was used to measure EPAH in septic patients.40 These measurements showed a significant reduction in EPAH, calculated RBF using measured EPAH, and documented decreased RVR and increased RBF early in the course of septic patients who were fully resuscitated and had normal vital signs.40 Decreased EPAH in septic animals and patients parallels similar findings in human volunteers receiving pyrogens intravenously.43 Both septic patients and volunteers receiving pyrogens have a comparable increase in RBF, urine output, and CNa; the same is seen in animals and humans after vasodilation with phenoxybenzamine administration.43
Hermreck et al. implicated a diabetes insipidus—like syndrome.41 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.40 This syndrome has also been attributed to a distal tubular blockade of aldosterone receptor sites; calculated aldosterone-like effect on the renal tubules (CH2O/(CH2O + CNa) in septic patients with positive free water clearance, however, shows no such impairment. Indeed, most septic patients can reabsorb sodium with great efficiency right up to the development of AORF, and few have a positive CH2O (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).39
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.39 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.39
Renal Response to Hypodynamic Sepsis
Not all septic patients develop the hyperdynamic state.37,39 Indeed, up to 35% of patients with sepsis develop 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 CNa, COsm, 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 3,200 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 (CH2O) represents the difference between urine output and osmolar clearance (COsm). The addition of CH2O measurements provides more insight into renal concentrating capacity.44Concentrating 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.45 Excess CH2O (CH2O > −0.25 mL/min) in critically ill patients is associated with a reduction in PV, GFR, and ERPF.45 This subgroup of patients has the highest incidence of subsequent renal failure (21%). When the CH2O 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.44 Patients with a rising CH2O, without evidence of PV expansion, need to be watched carefully for toxic renal insult, particularly from associated medicines such as renal toxic antimicrobials (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data). The effect of the random addition of albumin (HSA) to a resuscitation regimen also affects CH2O.45 The significant decrease in CNa associated with HSA-supplemented resuscitation causes a rise in CH2O. This is due to both increased peritubular oncotic pressure and decreased filtered sodium load. These changes are mediated through distal nephron sodium–potassium exchange.45
SIGNIFICANCE OF A SERUM CREATININE VALUE
The GFR provides the best single study assessment of renal function. Ideally, this is a 24-hour GFR to filter out subtle renal changes during the day. The 24-hour GFR, however, is seldom measured as one relies on 2-hour samplings of GFR using CCr. When a 2-hour GFR is not performed, one has only a static serum creatinine value to estimate the current renal function.46,47
Based on detailed studies of injured and septic patients, one can estimate that approximately 1 million or 50% of the 2 million nephrons are functioning when the serum creatinine is 1.5 mg/dL (Table 59-5).47Likewise, the ERPF has decreased to about 400 mL/min and the calculated RBF has fallen to less than 700 mL/min. When the serum creatinine level reaches 2.5 mg/dL, the number of functioning nephrons has decreased to about 250,000 with a GFR of about 30 mL/min (Table 59-1; Fig. 59-1). This, in turn, is associated with an ERPF and RBF of 148/min and 269/min, respectively. This represents severe renal insufficiency and progression to ARF is threatened.47 When the serum creatinine exceeds 3.1 mg/dL, the GFR has fallen to less than 10 mL/min, which is defined as ARF. When this occurs, all nephrotoxic agents should be discontinued to try to prevent progression to oliguric ARF.47
RIFLE CRITERIA FOR RENAL FAILURE
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. The RIFLE criteria focus on changes in GFR, serum creatinine, and urine output.48 Renal risk of ARF is defined 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 injuryis defined as an increase in serum creatinine by two times, a fall in GFR by more than 50%, or a fall in U/O to less than 0.5 mL/(kg h) for more than 12 hours. Renal failure is defined as an increase in serum creatinine by three times, a decrease in GFR by 75%, a U/O less than 0.3 mL/(kg h) for 24 hours, or anuria for 12 hours. Renal loss is defined as failure that lasts more than 4 weeks. End-stage renal 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.47
The Acute Kidney Injury Network (AKIN) developed a similar system for defining ARF that they referred to as acute kidney injury (AKI).49 The AKIN, like the RIFLE classification, defines three separate levels of AKI with these three levels based on the clinical parameters of urine output and changes in serum creatinine levels. When the AKIN system is compared with the RIFLE system, there appears to be no significant change in sensitivity between the two systems in defining ARF or in the ability of either system to predict the outcome of critically ill patients.49 Advocates for the AKIN or RIFLE system in defining severity stages for ARF point out that creatinine clearance may not be an accurate monitor for renal function in patients with low GFR because the creatinine is both filtered at the glomerulus and secreted by the renal tubules. Comparisons between GFR measured by CCr and CIn that is not secreted by the tubules show that the increase in CCr over CIn is predictable at all ranges of GFR (Fig. 59-7).47,48Thus, renal function with one test would be the CCr corrected for the known relationship between CCr and CIn (Table 59-5; Fig. 59-7).47
FIGURE 59-7 Correlation between SCr and GFR. Measurements made on 289 severely injured patients and 34 septic patients show that, at each level of serum creatinine (SCr), the creatinine clearance (dashed line) is greater than the inulin clearance (solid line). This occurs because creatinine is both filtered and secreted, whereas inulin is only filtered.
Effects of Renal Trauma on Renal Function
Injury to the kidney, per se, affects renal function.50 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 failure.50 Likewise, when renal hemostasis is achieved by means of suture repair, the postoperative renal function is not different from matched controls.50 When nephrectomy is needed, there is a significant reduction in RBF and GFR.50 Furthermore, the incidence of ARF rises when partial or total nephrectomy is required for hemostasis in comparison to comparably injured patients without renal injury. 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.50Consequently, one must emphasize the importance of successful repair of renal injuries without nephrectomy when following a policy for exploration of intermediate severity renal injuries.50, 51
CONTRAST-INDUCED RENAL INJURY
Most seriously injured patients undergo computed tomography (CT), usually in conjunction with an iodinated intravenous contrast media injection. A major complication is contrast-induced nephropathy. This complication is the third leading cause of hospital-acquired ARF that, in turn, is associated with significant mortality rates.52,53 This complication occurs even though less toxic, nonionic, iso-osmolar contrast agents have replaced hyperosmolar ionic contrast agents that were associated with red cell crenation and small vascular occlusion.53 Careful restoration of PV and correction of electrolyte abnormalities, particularly hyperchloremia, are important preventative steps.53Contrast-induced ARF occurs in all age groups.54 The likelihood for contrast-induced ARF increases precipitously when the creatinine is greater than 1.5 mg/dL prior to study; furthermore, the patient with nonoliguric ARF is likely to progress to renal shutdown when the prestudy creatinine exceeds 3.0 mg/dL.53 A rise in the serum creatinine or a fall in urine output prior to study would meet the risk portion of the RIFLE criteria as being another warning for contrast-induced nephrotoxicity.54 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, 56 PV expansion is preventative; the addition of osmotic or loop diuresis does not appear to be helpful and may, in selective circumstances, cause nephrotoxicity.53 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.55
Crush Injury and the Kidney
The association between ARF and crush injury was made many years ago. This occurred in 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 which led to their demise. The mechanism for crush-induced ARF is thought to be a combination of reduced PV due to fluid sequestration in the crushed limb, lowered RBF and GFR, and tubular insult due to the by-products of rhabdomyolysis.56 The myoglobin that is released from the injured muscle may attach to haptoglobin that lowers GFR. Furthermore, 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.56 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.57, 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 likely will contain dark brown granular casts.55Treatment 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. 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.57
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 catheters, correlates directly with a reduction in CNa, COsm, and urine output (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).9 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). The most severe form of abdominal hypertension occurs in patients with the abdominal compartment syndrome (ACS), who have had 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 while correcting the intra-abdominal hypertension. Renal function is typically promptly restored with abdominal decompression as long as the renal insult was not excessively prolonged (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).9
Similar changes in tubular function were shown in a canine model in which super renal IVC hypertension was created by different stages of venous constriction (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data). When extreme hypertension was created by materializing the left renal vein, all renal perfusion ceased on the left experimental side while the normal kidney continued to function (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).
Differential Diagnosis of Oliguria
Oliguria, refractory to initial PV expansion, 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 CNa 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 with 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.
TABLE 59-6 Differential Diagnosis of Oliguria
Nephrotoxic Agents and ARF
Many medicines, particularly antimicrobials, used in the critically ill patient cause nephrotoxicity. These agents are best avoided when the serum creatinine exceeds 1.5 mg/dL.59 For example, such patients with yeast infections are best treated with fluconazole and not amphotericin which has significant nephrotoxicity. The aminoglycosides are also 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.59 Adherence to these recommendations, however, has not prevented ARF.47,59 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 aminoglycoside into the IFS where it has direct contact with the tubular cells. There are no studies on renal dosing of antimicrobials that take into account IFS concentration of antimicrobials (C. E. Lucas and I. K. Rosenberg, Surgical renal study unit, unpublished data).47 Consequently, nephrotoxic agents should be avoided when the serum creatinine is greater than 1.5 mg/dL.
Acute Renal Failure
ARF 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 for ARF following injury include advanced age, high injury severity score, shock, multiple fractures, rhabdomyolysis, major head injury, and lung injury requiring mechanical ventilation. All definitions include anuria (renal shutdown) and oliguria (less than 200 mL per day) as 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 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
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.60 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.60,61 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.60,61HD is also associated with decreased CO and increased intestinal oxygen consumption producing mucosal acidosis.62Likewise, there may be a fall in urine output in patients with nonoliguric ARF following HD.61 Indeed, increased mortality rates have been described in a randomized controlled trial in patients who have more frequent HD in comparison to the subgroup with less frequent HD.61 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 who have higher GFR.62 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. 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 d. Continuous RRT also helps correct problems with acidosis due to impaired renal tubular function.63 Future advances for making earlier diagnosis of renal injury, such as measurements of neutrophil gelatinase-associated lipocalin and in the development of renal-assisted devices that have a standard hemofiltration cartridge seeded with renal tubular cells await more clinical trials.64, 65 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.
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3. Smith HW. Principles of Renal Physiology. New York: Oxford University Press; 1956.
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5. Birtch AG, Zakheim RM, Jones LG, et al. Redistribution of renal blood flow produced by furosemide and ethacrynic acid. Circ Res. 1967;21:869.
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11. Hayes DF, Werner MH, Rosenberg IK, et al. Effects of traumatic hypovolemic shock on renal function. J Surg Res. 1974;16:490–497.
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24. Lucas CE, Ledgerwood AM, Liebold WC, et al. Effect of end-expiratory pressure on total oxygen dynamics. Surgery. 1983;94(4):643–649.
25. Mullins RJ, Dawe EJ, Lucas CE, et al. Mechanisms of impaired renal function with PEEP. J Surg Res. 1984;37:189–196.
26. Fewell JE, Bond GC. Renal denervation eliminates the renal response to continuous positive-pressure ventilation. Proc Soc Exp Biol Med. 1979;161:574–578.
27. The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350: 2247–2256.
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29. Denton M, Chertow G, Brady H. “Renal-dose” dopamine for the treatment of acute renal failure: scientific rationale experimental studies and clinical trials. Kidney Int. 1996;49:4–14.
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34. Lucas J, Floyer MA. Changes in body fluid distribution and interstitial space compliance during the development or reversal of experimental renal hypotension in the rat. Clin Sci. 1974;47:1.
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36. Conger J, Falk S, Robinette J. Cytosolic smooth muscle calcium: kinetics in the 48-hour post-ischemic renal vasculature. J Am Soc Nephrol. 1994;6:895.
37. Wilson RF, Thal AP, Kindling PH, et al. Hemodynamic measurements in septic shock. Arch Surg. 1965;91:121–129.
38. Reddin JL, Starzecki B, Spink WW. Comparative hemodynamic and humeral responses of puppies and adult dogs to endotoxin. Am J Physiol. 1966;210:540–544.
39. Lucas CE, Rector FE, Werner M, et al. Altered renal homeostasis with acute sepsis. Arch Surg. 1973;106:444–449.
40. Cortez A, Zito J, Lucas CE, et al. Mechanism of inappropriate polyuria in septic patients. Arch Surg. 1977;112:471–476.
41. Hermreck AS, Berg RA, Ruhlen JR, et al. The polyuria of sepsis. Surg Forum. 1972;23:53–54.
42. Ravikant T, Lucas CE. Renal blood flow distribution in septic hyperdynamic pigs. J Surg Res. 1977;22(3):294–298.
43. Lathem W. The urinary excretion of sodium and potassium during the pyrogenic reaction in man. J Clin Invest. 1956;35:947–953.
44. Kosinski JP, Lucas CE, Ledgerwood AM. Meaning and value of free water clearance in injured patients. J Surg Res. 1983;33:184–188.
45. Moon MR, Lucas CE, Ledgerwood AM, et al. Free water clearance after supplemental albumin resuscitation for shock. Circ Shock. 1989;28:1–8.
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48. Venkataraman R, Kellum JA. Defining acute renal failure: the RIFLE criteria. J Intensive Care Med. 2007;22(4):187–193.
49. Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of Akin and Rifle criteria. Shock. 2010;33:247–252.
50. McGonnigal MD, Lucas CE, Ledgerwood AM. The effects of renal trauma on renal function. J Trauma. 1987;27(5):471–476.
51. McAninch JW, Carroll PR. Renal trauma: kidney preservation through improved vascular control—a refined approach. J Trauma. 1982;22: 285–290.
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