Acute Renal Failure

Chapter 3 Acute Renal Failure

Introduction

A. Acute renal failure (ARF) is a clinical syndrome characterized by an abrupt increase in serum creatinine and blood urea nitrogen (BUN) concentrations to above normal (azotemia).
1. ARF also may be associated with abnormal regulation of electrolytes, acid-base, and fluid balances.
2. ARF may be catastrophic for renal function or patient survival if resolution does not occur within a reasonable time period.
B. Acute renal failure can be prerenal, intrinsic (primary), or postrenal in origin.

image Acute renal failure is characterized by an abrupt increase in serum creatinine and blood urea nitrogen concentrations.

1. The term acute renal failure is commonly used to refer to acute intrinsic renal failure (AIRF), but prerenal and postrenal causes also should be considered
2. Prerenal azotemia is the most important differential diagnosis to consider along with intrinsic causes of azotemia.
3. Postrenal causes of ARF usually are easily excluded from consideration after complete physical examination and appropriate diagnostic imaging.
C. Early recognition of AIRF is crucial because it can be reversed in patients with enough surviving nephrons when treatment is instituted early on in the course of the disease.
D. AIRF probably occurs more frequently than appreciated and may go undiagnosed or be confused with chronic renal failure. Although AIRF can sometimes be successfully treated, many affected patients do not survive. Recognizing situations in which AIRF is likely to develop and taking appropriate preventive measures are preferable to treating established AIRF.
E. The frequency of underlying conditions associated with AIRF varies with the location and nature of veterinary practice.
1. Nephrotoxicity is the most common cause of AIRF at The Ohio State University Veterinary Hospital, followed by nephritis (e.g., leptospirosis) and ischemia.
2. The aggressive use of potentially nephrotoxic antibiotics, especially aminoglycosides, contributes to the frequency of nephrotoxic AIRF.
3. Indiscriminate use of or accidental exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and exposure of veterinary patients to extensive surgical procedures and aggressive posttraumatic resuscitative maneuvers also may contribute to an increased frequency of ischemic AIRF.

Pathogenesis and Pathophysiology of Acute Renal Failure (Figure 3-1)

Prerenal Acute Renal Failure

1. Reduced perfusion of the kidneys results in retention of nitrogenous wastes. A substantial decrease in hydrostatic pressure in the glomeruli results in decreased glomerular filtration rate (GFR) and solute retention.
2. Early in the process of volume depletion, renal autoregulation preserves excretory function and continued excretion of waste products. Autoregulation eventually is overcome and azotemia develops.
3. The most common causes of reduced renal perfusion are dehydration, hypotension, shock, and reduced cardiac output.
4. Early prerenal ARF is associated with physiologic oliguria (assuming normal kidneys initially), which is a normal response to decreased renal perfusion.
5. Decreased renal perfusion is detected in the kidney and by peripheral baroreceptors, and results in increased reabsorption of salt and water from the glomerular filtrate.
6. Severe and prolonged hypoperfusion of the kidneys can produce primary lesions in the kidneys (ischemic nephrosis or ischemic acute tubular necrosis).
7. Prerenal azotemia readily resolves after correction of decreased cardiac output and circulating blood volume.
8. A component of prerenal azotemia often contributes to the total magnitude of azotemia in patients with primary renal or postrenal disease.
image

FIGURE 3-1 Classification of acute renal failure: Prerenal, intrinsic renal, and postrenal causes must be considered.

Postrenal Acute Renal Failure (See Chapters 11, Urinary Tract Obstruction, and 12, Urinary Tract Trauma and Uroabdomen)

Causes

a. Bilateral renal obstruction.
(1) Urolithiasis.
(2) Bilateral ureteral or urethral obstruction.
(3) Urethral plugs in cats.
b. Uroabdomen (rupture of urinary tract with accumulation of urine).

Pathogenesis

a. Obstruction results in failure to filter waste products due to back pressure in the nephron.
b. Uroabdomen results in recycling of waste products across the peritoneum.

Acute Intrinsic Renal Failure (primary ARF)

Causes of Acute Intrinsic Renal Failure (see Chapter 4, Specific Syndromes Causing Acute Intrinsic Renal Failure)

Nephrotoxicity

(1) Ethylene glycol (EG).
(2) Antimicrobials.
(a) Aminoglycosides.
(b) Amphotericin-B.
(c) Sulfonamides administered to a dehydrated patient.
(d) Tetracyclines administered IV.
(e) Nafcillin administered intraoperatively.
(3) Easter lily (cats).
(4) Grape or raisin toxicity (dogs).
(5) Hypercalcemia and hypercalciuria.
(a) Cholecalciferol rodenticide (Quintox, Rampage).
(b) Calcipotriene (Dovonex).
(6) Anticancer drugs.
(a) Cisplatin.
(b) High dose doxorubicin (Adriamycin).
(7) Radiocontrast agents administered IV.
(8) Heavy metals (e.g., zinc, arsenic, lead).
(9) Hydrocarbons.
(10) Fluorinated inhalation anesthetics.
(11) Calcium ethylenediaminetetraacetic acid (EDTA).
(12) Mycotoxins (e.g., ochratoxin, citrinin).
(13) Tainted food (melamine and cyanuric acid).

Renal Ischemia

(1) Dehydration.
(2) Trauma.
(3) Anesthesia.
(4) Sepsis.
(5) Heat stroke.
(6) Pigment nephropathy.
(a) Hemolysis.
(i) Immune-mediated hemolytic anemia.
(ii) Envenomation.
(•) Coral snake.
(•) Hymenoptera (bee sting).
(b) Myoglobinuria.
(7) Angiotensin-converting enzyme (ACE) inhibitors.
(8) Shock.
(9) Hemorrhage.
(10) Surgery.
(11) Burns.
(12) Hypothermia.
(13) NSAIDs.
(14) Acute papillary necrosis (e.g., medullary renal amyloidosis, Fanconi syndrome).

Nephritis

(1) Leptospirosis — acute tubulointerstitial nephritis.
(2) Borrelia — rapidly progressive glomerulonephritis.
(3) Acute bacterial pyelonephritis.
(4) Embolic nephritis.
(5) Allergic interstitial nephritis.

Acute Hyperphosphatemia

(1) Tumor lysis syndrome.
(2) Phosphate enema.
(3) Phosphate acidifier.
(4) Massive soft tissue trauma.

Pathophysiology of Acute Intrinsic Renal Failure Due to Nephrosis

a. Exposure to nephrotoxins or ischemia causes tubular injury along a spectrum from degeneration to necrosis and is referred to as nephrosis or acute tubular necrosis (ATN) (Figure 3-2). Some patients have minimal to no light microscopic lesions but experience severe renal excretory failure.
(1) Early lesions may be distributed preferentially in tubules of the outer medulla, an area that is not easily biopsied.
(2) Renal tubular lesions may be subtle in nature and patchy in distribution making them easy to overlook on routine microscopy.
(3) Subtle tubular lesions can cause decreased sodium reabsorption proximally which can promote sustained vasoconstriction in parent glomeruli as sensed at the macula densa (so-called vasomotor nephropathy).
b. Factors that contribute to azotemia and oliguria during AIRF (Figure 3-3 A-E).
(1) Tubular backleak (across or between damaged tubules).
(2) Intraluminal tubular obstruction by casts, debris, or tubular swelling.
(3) Extraluminal tubular obstruction by interstitial edema or cellular infiltrates.
(a) Increased pressure inside tubular lumen.
(b) Decreased interstitial blood supply (i.e., as a consequence of edema).
(4) Primary filtration failure.
(a) Vasomotor nephropathy.
(i) Afferent arteriolar vasoconstriction.
(ii) Efferent arteriolar vasodilatation.
(b) Decrease in glomerular permeability.
(i) Decreased size or number of endothelial pores.
(ii) Decreased surface area of glomerular membranes.
c. The mechanism(s) that initiates AIRF may not be the same one(s) that maintains AIRF. A combination of mechanisms likely is operative in clinical patients.
d. Renal ischemia consists of a spectrum from prerenal azotemia to acute tubular necrosis and in its most devastating form, bilateral cortical necrosis.
(1) The renal cortex is richly supplied with adrenergic innervation, which results in vasoconstriction during renal ischemia. Due to a large reserve of blood supply, temporary or mild reductions in renal blood flow do not result in tubular necrosis.
(2) Deprivation of blood supply, if severe and prolonged, results in loss of cellular energy production and loss of cell integrity. Tubules with high metabolic activity are at greatest risk of injury during reduced oxygen supply.
(a) It is not necessary for systemic hypotension to occur for the kidneys to experience intrarenal hypotension.
image

FIGURE 3-2 Photomicrograph of acute tubular necrosis (hematoxylin and eosin stain, ×200). A, Normal glomerulus with areas of tubular necrosis. Note some tubules with loss of tubular epithelium, some with flattened epithelium (suggesting restitution), and tubular lumens filled with necrotic debris. B, Note relatively normal tubules in upper left field (focal areas of attenuation exist here). Just below the normal tubules are several tubules with complete loss of epithelium and abundant intraluminal detritus

(Courtesy of Dr. Steve Weisbrode, Columbus, Ohio.)

image image

FIGURE 3-3 General mechanisms contributing to decreased GFR and oliguria in AIRF. The illustration represents all nephrons in the kidneys. The mechanism or mechanisms that initiate the injury may differ from those that cause ongoing injury and maintain the state of AIRF. Multiple mechanisms may be operative simultaneously. It is almost never clinically possible to identify the specific operative mechanism in an individual patient. A, Normal nephron. Normally, about 30% of the blood entering the glomerulus is filtered into the Bowman’s space. Glomerular filtration pressure normally is not impeded to any appreciable extent by the normally low intratubular pressure. The healthy renal tubular epithelium prevents tubular fluid from leaking between or across tubular cells. No obstructing material is present within the tubular lumen, and the lumen is completely patent. B, Afferent arteriolar constriction (vasomotor nephropathy). Glomerular filtration is severely decreased by constriction of the afferent arteriole. Decreased intraglomerular pressure can result in azotemia and decreased urine production. Sympathetically mediated vasoconstriction may result from systemic hypotension, pain, tissue handling during surgery, and anesthesia. Damaged afferent arteriolar myocytes perpetuate vasoconstriction as calcium enters the cells and results in contraction. Sustained vasoconstriction not only decreases GFR but also impairs oxygen delivery to the tubular cells via the post glomerular vessels, which can result in acute tubular necrosis. C, Obstruction, increased intratubular pressure. Increased intratubular pressure occurs proximal to the obstructed segment of the nephron. The obstruction can be intraluminal or extraluminal, and the resultant increase in pressure opposes glomerular filtration. The obstructing material can be cellular debris (e.g., sloughed brush border cell membranes, regurgitated organelles), precipitated proteins, or, occasionally, crystalline precipitates. Interstitial edema or cellular infiltrates can cause extraluminal obstruction and decrease renal blood flow by compressing interstitial blood vessels. Tubular swelling can also contribute to increased intraluminal pressure. D, Tubular backleak. In this situation, the filtration pressure may be normal, but filtered fluid leaks back across the damaged tubular epithelium into the interstitium. Some fluid also may accumulate within the damaged tubule. Tubular backleak occurs in patients with more severe tubular injury. Backleak is increased by any concurrent increase in tubular pressure. E, Decreased glomerular permeability. In this example, the disease process has decreased the surface area available for glomerular filtration. Decreased glomerular permeability can arise as a consequence of mesangial cell contraction and decreases in the number or diameter of the glomerular fenestrae. (Drawn by Tim Vojt.)

image NSAIDs do not directly damage the kidney. Acute renal injury only occurs if mediators of vasoconstriction have been activated by the body’s perception of volume depletion.

(b) The outer medullary region of the kidney is the most metabolically active and is supplied with the lowest amount of oxygen. The last part of the proximal tubule (pars recta, P3) and the medullary thick ascending limb of the loop of Henle are located here and these areas are at increased risk for early injury during hypoxia. The medulla already is an area of low blood supply that is at increased risk when blood flow is further reduced.
e. NSAIDs block renal production of vasodilatory prostaglandins that maintain renal blood flow during dehydration resulting in renal ischemia (Figure 3-4).
f. True nephrotoxins exert their deleterious effects directly on the kidney after binding to tubular cell membranes. Reduced energy production and cell death follow. Some nephrotoxins also cause renal vasoconstriction, but the major effect is direct cell injury rather than ischemia.
g. The term nephrotoxicant refers to a chemical or drug that can result in renal injury regardless of whether it is by direct nephrotoxic injury (e.g., aminoglycosides) or by renal ischemia (e.g., NSAIDs, myoglobin).
h. Patients with underlying renal disease develop episodes of AIRF more readily than patients that had normal kidneys before the insult.
(1) The ability of diseased kidneys to autoregulate blood flow and GFR is decreased, placing them at greater risk for renal ischemia. They cannot undergo compensatory vasodilatation to compensate for systemic hypotension.
(2) The ability to synthesize renal vasodilatory prostaglandins is reduced, placing them at risk for renal ischemia.
image

FIGURE 3-4 Renal blood flow during times of hemodynamic insult. Normal renal vascular resistance and renal blood flow are relatively well maintained during times of vasoconstriction if synthesis of renal vasodilator substances is normal. Renal vasoconstriction, however, proceeds unopposed if the synthesis of renal vasodilatory prostaglandins has been blocked by NSAID administration. Progression to AIRF may occur.

image Animals with pre-existing renal disease develop AIRF more readily than do normal animals.

(3) The increased tubular metabolic rate of remnant nephrons places them at risk due to their increased workload. They are more readily injured during ischemia and exposure to toxins.
(4) Increased single nephron GFR in remnant nephrons provides an increased filtered load of potential toxins per remaining nephron.
(5) Hypertrophy of tubular membranes in remnant nephrons provides increased surfaces for exposure to potential nephrotoxins.
i. Dehydration magnifies the propensity for and severity of AIRF after exposure to renal ischemia or nephrotoxins.

image Simultaneous exposure to nephrotoxins and renal ischemia dramatically increases the risk of renal injury.

(1) Dehydration promotes maximal water and solute reabsorption along the nephron. Toxins that are filtered across the glomeruli progressively increase in concentration along the course of the proximal tubule as water and sodium are iso-osmotically reabsorbed.
(2) The slow tubular flow rate associated with dehydration favors formation of obstructing casts after renal ischemia or exposure to a nephrotoxin.
(3) Dehydration already has activated vasoconstrictor signals to the kidneys, which facilitates additional ischemic damage to the kidneys.
j. Loss of integrity of the cytoskeleton of the renal tubular cell and actin dysregulation are pivotal early events in nephrosis. Loss of microvilli occurs with loss of the cytoskeleton. Cell adhesion is impaired at tight junctions (loss of occludin) and along basolateral membranes (loss or redistribution of integrin). These events facilitate detachment of tubular cells from one another and from the tubular basement membrane. Relocation of Na+-K+ adenosine triphosphatase (ATPase) from the basolateral to luminal cellular membranes impairs sodium reabsorption and results in activation of the renin-angiotensin-aldosterone system and afferent arteriolar vasoconstriction (i.e., vasomotor nephropathy). Depletion of intracellular adenosine triphosphate (ATP) triggers a cascade of events that alters cell membrane permeability, increases calcium influx, and impairs cell function ultimately causing in cell death. The balance between nitric oxide and endothelin, which maintains normal renal blood flow, is altered (decreased nitric oxide and increased endothelin) favoring renal vasoconstriction. Damaged myocytes of afferent arterioles allow calcium influx which potentiates vasoconstriction. Growth factors (e.g., epidermal growth factor, hepatocyte growth factor, insulin-like growth factor, transforming growth factor) and heat shock proteins appear to be important in recovery from AIRF.
k. Phases for AIRF (Figure 3-5).
(1) The latent phase represents the time after exposure to a nephrotoxin or renal ischemia but before the onset of azotemia. It is associated with increasing number and severity of renal tubular lesions over time if the renal insult is not stopped.
(a) Lethal and sublethal renal tubular injury occurs.
(b) The latent phase usually is not detected because clinical signs are absent or minimal.
(c) Early removal of the inciting cause of injury will result in rapid return to normal renal function.
(d) The latent phase is most likely to be detected in closely monitored hospitalized patients with critical illness.
image

FIGURE 3-5 Phases of AIRF. The progression from the latent to the fixed renal failure of the maintenance phase can be halted if the ischemic or toxic injury is corrected before azotemia has developed. Oliguria occurs in patients with more severe acute renal injury. Many patients do not survive without dialysis due to the metabolic effects of uremia. Recovery is possible, however, but often with substantial reduction in functional renal mass. Some patients survive and go on to develop chronic renal failure. Recovery is facilitated by the onset of diuresis in patients that initially were oligoanuric.

image It’s not the quantity of urine, but rather the quality of urine produced that matters most.

(e) Older definitions of AIRF required that oliguria be documented during the clinical course, but this is no longer a requirement. Oliguria, normal urine production, or polyuria all may occur depending on the specific cause and severity of renal injury and the phase of AIRF.
(f) Physiological oliguria is common during the latent phase and early maintenance phase.
(2) The maintenance phase of AIRF is characterized by a persistently increased serum creatinine concentration despite correction of all prerenal factors (i.e., restoration of extracellular fluid volume and cardiac output).
(a) Oligo-anuria occurs in patients with the most severe intrarenal injury (e.g., those with EG or lily toxicity).
(b) Nonoliguria is typical of AIRF caused by exposure to aminoglycosides.
(c) Entry into the maintenance phase signifies that a critical amount of lethal injury has occurred in the renal tubules and a course of 1 to 3 weeks of AIRF is expected before restoration of renal function can occur.
(d) Removal of the inciting cause will not result in the immediate return of normal renal function.
(e) Renal injury may be so severe that it may not be possible for the patient to ever leave the maintenance phase.

image Preservation of some RBF allows for potential recovery of damaged renal tissue. Otherwise, complete necrosis of renal tissue would occur.

(f) Severe reduction in RBF and even further reduction in GFR characterize AIRF. RBF may be restored early or even may exceed normal in some patients when treated by volume expansion, but GFR remains very low during the maintenance phase in animals with well-established AIRF.
(3) During the recovery phase, BUN and serum creatinine concentration return to normal as GRF and RBF recover in animals capable of surviving the maintenance phase. Functional renal mass, however, has been reduced.
(a) Diuresis ensues during the recovery phase in patients that were previously anuric or oliguric.
(b) Complete return of BUN and serum creatinine concentrations to normal may not be possible for patients that have sustained the greatest renal injury. They may, however, show partial improvement that will allow a reasonable quality of life as a chronic renal failure patient.
(c) Nephron dropout and subsequent renal fibrosis occur, resulting in chronic renal failure (CRF).
(d) Remaining renal tissue is not completely normal even when BUN and serum creatinine concentrations have returned to normal. Some nephrons invariably have been lost and replaced with fibrous tissue. Renal hypertrophy and hyperplasia have enabled the kidney to restore some RBF and GFR with fewer remaining surviving nephrons.
(e) Maximal urinary concentrating ability and urinary acidification do not return entirely to normal, but these limitations are not usually of clinical consequence.

History and Clinical Signs

Prerenal Acute Renal Failure

1. Oliguria is the most common sign of prerenal acute renal failure.
2. Patients with prerenal ARF usually have supporting historical or physical findings of dehydration, shock, hypotension, or reduced cardiac output.

Postrenal Acute Renal Failure (see Chapter 11, Urinary Tract Obstruction, and Chapter 12, Urinary Tract Trauma and Uroabdomen)

1. Patients with postrenal ARF usually have obvious supporting historical, physical, and diagnostic imaging findings.
2. Urinary outflow obstruction or urine accumulation in the peritoneum must be promptly ruled out as potential causes of ARF.

Acute Intrinsic Renal Failure

1. Clinical signs are those of uremia, including anorexia, lethargy, vomiting, and diarrhea. These signs are not specific for AIRF.
2. Signs will be of recent onset, and a longstanding history of polyuria or polydipsia should not be present.
3. Based on clinical studies, approximately 18% of affected patients are expected to have anuria, 43% to have oliguria (urine output of 0.1-1 mL/kg/hr), 25% to have normal urine output (1-2 mL/kg/hr), and 14% to have polyuria (urine output >2 mL/kg/hr).
4. Lack of urinations may be noted in animals with oliguric AIRF or polyuria may be noticed in those with nonoliguric ARF.
5. Recent trauma, shock, surgery, or anesthetic procedures suggests the possibility of ischemic nephropathy.
6. Recent administration of known nephrotoxins (e.g., aminoglycosides) should lead to a suspicion of nephrotoxic AIRF.
7. Recent administration or accidental ingestion of NSAIDs should lead to a suspicion of ischemic AIRF.
8. Access to EG or actual observation of EG consumption indicates nephrotoxic AIRF, but often a positive history cannot be obtained.
9. Postural changes (e.g., hunching of the back) or reluctance to move may be indicative of renal pain.
10. Lack of food and water intake associated with systemic illness arouses suspicion of ischemic nephropathy or nephritis (e.g., leptospirosis).

Physical Examination

Prerenal Acute Renal Failure

1. Dehydration often is detected by assessment of skin turgor and observation of dryness of the mucous membranes.
2. Poor quality femoral pulses may be detected.
3. Kidneys are normal-sized and nonpainful.
4. The lower urinary tract is normal.

Postrenal Acute Renal Failure (see Chapter 11, Urinary Tract Obstruction, and Chapter 12, Urinary Tract Trauma and Uroabdomen)

Acute Intrinsic Renal Failure

a. Signs of uremia tend to be more severe than those observed with prerenal azotemia, and include uremic breath and oral ulceration.
b. Mucous membrane pallor should not be observed (as may be the case with CRF).
c. Fever may be present in animals with intra renal ARF due to nephritis (e.g., leptospirosis).
d. Hypothermia is commonly encountered in animals with ARF due to nephrosis, but hypothermia can be encountered in any animal near death, regardless of the cause of azotemia.
e. Dehydration frequently is present in animals with primary AIRF due to fluid losses from vomiting, diarrhea, and lack of food and water intake. Dehydration may be exacerbated by excessive urinary loss of fluid in animals with nonoliguric or polyuric AIRF.

image Dehydration is frequently present in animals with primary AIRF due to fluid losses from vomiting, diarrhea, and lack of food and water intake.

Related posts:

  1. Familial Renal Diseases of Dogs and Cats
  2. Diseases of the Glomerulus
  3. Disorders of Micturition and Urinary Incontinence
  4. Urinalysis

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Jul 10, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Acute Renal Failure

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