Renal Failure

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 (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 (E_PAH), however, may vary with injury and sepsis; true E_PAH requires renal vein sampling to accurately measure TRPF (TRPF = ERPF/E_PAH).^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 (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 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 (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 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 (C_Na), osmoles (C_Osm), and free water (UV − C_Osm).⁴ With normal water and solute intake, both 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, 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 C_Na and C_Osm 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 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 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, C_Na, and C_Osm. 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. 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 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, C_Na, C_Osm, 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.^21,28 Patients randomized to receive 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). 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.²⁹ Unfortunately, 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

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