Acute Renal Failure
Objectives
By the end of this session you should be able to:
* List the three major etiologic categories of acute renal failure.
* List the major causes of each of the three major categories of acute renal failure.
* Be aware of the basic findings in the urine that suggests the etiology of a patient's renal compromise. * Be aware of the information provided by urine electrolytes and urine osmolality.
* Be able to calculate FENa and understand what the results of this calculation indicate.
* Cite the value, if any, of radiographic procedures such as intravenous pyelograms, ultrasound, and CT scans.
* Cite the major causes of post-ischemic and nephrotoxic acute renal failure and be aware of the ways in which it differs from pre-renal and post-renal causes of acute renal failure.
* Delineate the basic approach to managing patients with acute renal failure.
* Cite the most common complications that may need to be addressed in patients with acute renal failure. * Diagnose the cause of a patient's renal failure and treat it appropriately depending on that etiology. * List some of the more common medications that cause nephrotoxic acute renal failure.
Outline
I. Introduction
II. Etiology of Acute Renal Failure III. Pathophysiology of Acute Renal Failure
Pre-renal Acute Renal Failure Intra-renal Acute Renal Failure
Glomerular Disease
Post-ischemic and Nephrotoxic Acute Renal Failure
Interstitial Disease
Post-renal Acute Renal Failure IV. Diagnosis of Acute Renal Failure
History and Physical Findings Laboratory Testing
Examination of the Urine
Dipstick findings
Microscopic findings
Serum and Urine Chemical Analysis Creatinine and urea nitrogen
Urine osmolality
Urine sodium concentration
Other indicies
Radiographic Procedures
V. Specific Diseases Causing Acute Renal Failure Pre-renal disease
Pre-renal azotemia caused by volume depletion Pre-renal azotemia caused by advanced liver disease Pre-renal azotemia caused by congestive heart failure Post-ischemic and Nephrotoxic Acute Renal Failure
Initial phase
Maintenance phase
Recovery phase
Post-renal disease
VI. Complications of Acute Renal Failure Cardiovascular system Pulmonary system Gastrointestinal system Neurologic system Infectious complications Endocrine system Electrolyte metabolism VII. Treatment of Acute Renal Failure
Diuretics Diet Dialysis
I. INTRODUCTION
Acute renal failure (ARF) is the generic term used to define an abrupt decrease in renal function sufficient to result in retention of nitrogenous waste (urea nitrogen and creatinine) in the body. The hallmark of ARF is progressive azotemia caused by the accumulation of the nitrogenous end-products of metabolism. This accumulation is accompanied by a wide range of other disturbances depending on the severity and duration of the renal dysfunction. These include metabolic derangements such as metabolic acidosis and hyperkalemia, disturbances of body fluid balance, and effects on many other organ systems.
Table 1
ARF - Incidence
• Community acquired – 1% of hospital admissions
• pre-renal ARF (70%), intra-renal (11%), post-renal (17%). Overall mortality 15%
• Hospital acquired
– 5% of hospitalized patients; 30% in ICU • decreased renal perfusion, postoperative renal
insufficiency (60%), nephrotoxic agents (20%). Overall mortality 45%; Mortality due to ARF 27%
ARF is commonly encountered in the practice of medicine, and 5% of hospital admissions to a general medical/surgical ward will go on to develop ARF. This disorder is less common in children than adults. Abrupt renal decline and failure is a final common pathway for a number of disease processes and is associated with significant morbidity and mortality (Table 1).
II. ETIOLOGY OF ACUTE RENAL FAILURE
Table 2 ARF - Etiology • Pre-renal ARF: ↓renal blood flow
– Absolute volume depletion – Functional volume depletion
• Intra-renal ARF: renal parenchymal disease – Glomerular disease
– Tubulo -interstitial disease • Post-renal ARF: Urinary obstruction
The various causes of ARF can be grouped into three major categories (Table 2):
• those that decrease renal blood flow (pre-renal)
• those that produce a renal parenchymal insult (intra-renal)
• those that obstruct urine flow (post-renal or obstructive).
Identification of either a pre-renal or post-renal cause of ARF makes the initiation of a specific therapy possible. If, however, these two categories can be ruled out, then an intra-renal cause can be implicated. The renal parenchymal causes of ARF are usually subdivided into those primarily affecting the glomeruli or the renal interstitium. The term acute tubular necrosis denotes another broad category of intrinsic renal failure characterized by renal tubular injury that cannot be attributed to glomerular, vascular, or interstitial causes. The complete list of the most common causes of acute renal failure is noted in Table 3.
Table 3
Causes of Acute Renal Failure
Pre-renal Acute Renal Failure Absolute volume depletion Functional volume depletion Advanced liver disease Congestive heart failure Pharmacologic agents
Angiotensin converting agents
Non-steroidal anti-inflammatory agents Diseases of the Renal Vasculature Renal Artery Occlusion
Thromboemboli Thrombosis
Dissecting aortic aneurysm Renal artery stenosis Renal vein thrombosis Dehydration (infants) Diseases of the Renal Cortex Bilateral Cortical Necrosis Obstetrical accidents Abruptio placentas Placentas previa Gram-negative septicemia Ischemia
Hyperacute renal allograft rejection
Diseases of the Renal Medulla Bilateral Papillary Necrosis Analgesic abuse
Sickle cell disease Diabetes mellitus
Acute Tubulointerstitial Diseases Acute pyelonephritis
Acute allergic interstitial nephritis Hypokalemic nephropathy Hypercalcemia
Acute uric acid nephropathy Multiple myeloma
Acute Glomerular Diseases Acute Glomerulonephritis Postinfectious glomerulonephritis Bacterial endocarditis
Henoch-Schonlein Purpura Hypersensitivity angiitis
Rapidly Progressive Glomerulonephritis Systemic lupus erythematosis
Wegener’s Granulomatosis Goodpasture’s syndrome Thrombotic Microangiopathy Hemolytic-uremic Syndrome
Thrombotic Thrombocytopenic Purpura Scleroderma
Malignant Hypertension
Postischemic Acute Renal Failure Nephrotoxic Acute Renal Failure Urinary Obstruction
Intrarenal abnormalities Ureteral obstruction
III. PATHOPHYSIOLOGY OF ACUTE RENAL FAILURE
Pathophysiology of Pre-renal ARF:
Pre-renal acute renal failure results from a decrease in renal blood flow. As a result, the glomerular filtration rate (GFR) is reduced and the kidney retains water and salt, causing oliguria (a reduction in urine flow to less than 500 ml/day), production of a concentrated urine, and a progressive inability to excrete nitrogenous wastes (Table 4).
Pathophysiology of Intra-renal ARF:
a) Glomerular Disease: Most of the
glomerular diseases producing ARF are felt to be immunologically mediated and result in disrupted glomerular filtration. Progression of the inflammatory process leads to destruction of glomerulus and a decrease in the GFR.
Table 4 Pre-Renal ARF • Decrease in renal blood flow • Glomerular filtration rate reduced
– Inability to excrete nitrogenous waste • Kidney retains water and sodium
– Concentrated urine (500 mOsm/L) – Oliguria (<500 mL/day)
– Low UNa(<20 mEq/L) and low FENa(<1%)
b) Post-ischemic and nephrotoxic acute
renal failure (Table 5): Injury to tubular epithelial cells due to hypoxia or ischemia (Post-ischemic ARF) or as a result of exposure to nephrotoxic agents (Nephrotoxic ARF) is a prominent cause of a decline in renal function.
Table 5
Pathophysiology of Tubular Injury
• Acute tubular necrosis (ATN) inappropriate although commonly used term
• Injury to tubular epithelial cells does occur but may be sublethal
– Due to hypoxia or ischemia (post-ischemic) – Exposure to nephrotoxic agents (nephrotoxic) • A number of biochemical events are involved in
promoting tubular injury
Table 6 lists some of the biochemical events that have been implicated in promoting tubular epithelial cell injury. In addition, there are significant changes in renal blood flow and renal vascular resistance. The use of the terms “Acute Tubular Necrosis” or “Vasomotor Nephropathy” should be discouraged since neither term accurately reflects the pathophysiologic events leading to acute renal failure. It is best to describe the condition in terms of the proximate cause as either post-ischemic or nephrotoxic. The term acute tubular necrosis is also an inaccurate histopathologic term, since necrosis is rarely seen on biopsy specimens of patients with this syndrome.
Table 6
Pathophysiologic Abnormalities in Phases of Renal Failure
Clinical Phase Pathophysiologic Correlates Initial phase Tubular epithelial cell injury
Vasoconstriction Maintenance phase Tubular obstruction
Passive backflow of filtrate Secondary vasoconstriction Medullary congestion
Recovery phase Restoration of tubular cell integrity Vasodilation
Figure 1 Figure 1
Figure 1 shows the typical changes including dilated tubules and interstitial edema.
Table 7 ARF: Interstitial Disease
• An inflammatory process is initiated in the renal interstitium • Etiology – Drugs – Toxic – Infectious – Infiltrative
c) Interstitial Disease (Table 7):
Interstitial nephritis is a complex collection of disease processes with a poorly understood pathophysiology. An inflammatory process is initiated in the renal interstitium in response to a wide variety of stimuli (toxic, metabolic, infectious, immune, infiltrative), although drugs are probably the most common causes.
Figure 2 Urinary Tract Obstruction
Intratubular pressure
Glomerular capillary pressure
Renal Vascular resistance
Glomerular filtration rate
3 Hours 24 Hours
Pathophysiology of Post-renal Acute Renal Failure: Obstruction of the urinary tract leads to an acute rise in intratubular pressure. As a result, there is stimulation of the renin-angiotensin II system that results in marked renal vasoconstriction. The vasoconstriction then leads to a fall in the glomerular filtration rate and acute renal failure (Figure 2).
Figure 3
Differential Diagnosis of Acute Renal Failure Acute Renal Failure
Acute Renal Failure
Pre-Renal ARF Pre-Renal ARF Post-Ischemic ARF (50% of cases) Post-Ischemic ARF (50% of cases) Acute Glomerulonephritis (5% of cases) Acute Glomerulonephritis
(5% of cases) Acute Tubular NecrosisAcute Tubular NecrosisAcute Interstitial Nephritis (10% of cases)
Acute Interstitial Nephritis (10% of cases)
Intrinsic ARF
Intrinsic ARF Post-Renal ARFPost-Renal ARF
Nephrotoxic ARF (35% of cases)
Nephrotoxic ARF (35% of cases)
IV. DIAGNOSIS OF ACUTE RENAL FAILURE
Obviously, there is a large range of medical conditions that can result in ARF (Figure 3). Given this broad range of conditions and their differing therapeutic implications, it is important to rapidly establish an accurate diagnosis.
A. History and physical exam
Evaluation of the medical history, physical exam findings, and the results of a few radiographic studies are often necessary to determine the cause of acute renal failure. The initial history should include a review of the patient’s outpatient record, or in the case of an inpatient, a review of the inpatient record. History taking should always include certain questions or considerations:
• has nausea, vomiting, and/or diarrhea been present?
• has bleeding occurred?
• does the patient have a history of heart failure or recent symptoms of dyspnea?
• does the patient have a history of chronic liver disease, hepatitis, or jaundice?
• does the patient have a history of previous renal insufficiency?
• has edema, high blood pressure, or a change in urine color occurred?
• has the patient had any unusual rashes develop recently?
• what medications has the patient been placed on, in particular, are there any new medications?
• has the patient been ill enough to have prolonged episodes of hypotension?
• has the patient received any contrast dyes?
• does the patient have a history of renal stone disease or evidence or lower urinary tract obstruction? Often, the history alone can suggest the cause as being pre-renal, renal, or post-renal. Physical exam is usually most helpful in assessing the volume status of a patient. Both the total volume and the effective circulating volume must be considered. Clues for the presence of a systemic disease (ex. vasculitis, CHF, liver disease) should be sought. Despite a careful history and physical exam, the etiology of ARF often remains unclear and additional tests must be done.
B. Laboratory testing to help with diagnosis
1. Examination of the Urine: Urinalysis is one of the first, and easiest, tests that can be done on the patient with acute renal failure. It can provide both diagnostic information as well as prognostic information about the patient. Hou et al. found that about one-half of 97 patients with ARF had an abnormal microscopic urinalysis. This abnormal microscopic exam was associated with a "renal" cause of ARF and a 35% mortality, while those with a normal urinalysis had a 15% mortality.
a. Dipstick Findings: A dipstick positive for protein (3+, 4+) suggests intrinsic renal disease with glomerular damage. Pre-renal azotemia, obstruction, and acute tubular necrosis tend to be associated with less proteinuria (trace-2+) than a glomerular lesion. If there is proteinuria present it should be quantified using a 24-hour urine collection. If there is greater than 3 gm of protein, a glomerular, rather than a tubular or interstitial, process is more likely. A dipstick positive for blood indicates the presence of RBC's (> 5/HPF). If no RBC's are present, then there may be either myoglobin or hemoglobin present in the urine.
b. Microscopic Examination Findings: In most cases the most significant amount of information is obtained from the urinalysis comes from the examination of the sediment of a centrifuged urine sample. This is prepared by placing 10 cc of urine in a conical tube and spinning at 2000 rpm for 5 minutes. The supernatant is discarded. The sediment is then resuspended in the residual urine, and a drop is placed on a slide and covered with a cover slip. The periphery of the slide, where casts tend to be concentrated, is scanned using low power. The slide is then scanned under high power for red blood cells, white cells, renal tubular epithelial cells, oval fat bodies, bacteria, and crystals.
Casts are formed from urinary Tamm-Horsfall protein, which is a product of the tubular epithelial cells. This protein tends to gel in conditions of high concentration and when mixed with red cells, tubular cells, or cellular debris. Thus, the composition of this cast reflects the contents of the tubule.
Hyaline casts (http://medstat.med.utah.edu/WebPath/jpeg2/URIN069.jpg) are those that are devoid of contents, and are seen with dehydration, or after exercise.
Red cell casts (http://www.hsc.virginia.edu/med-ed/cell/resources/images/UrinaryFig7.jpg) indicate glomerular hematuria, as seen with glomerulonephritis.
White cell casts (http://medlib.med.utah.edu/WebPath/jpeg2/URINE071.jpg)
Granular casts are composed of cellular remnants and debris, and are generally a non-specific indicator of renal parenchymal injury. Granular casts that are deeply pigmented, often referred to as
“muddy brown casts,” (http://www.udel.edu/medtech/mclane/ua11a.jpg), however, are a
fairly specific finding in acute tubular injury (nephrotoxic or ischemic “ATN”). .
Fatty casts (http://www.lhsc.on.ca/lab/renal/images/slide10.jpg) are usually
associated with heavy proteinuria and the nephrotic syndrome (though they can be present in other nonglomerular disease).
In patients with pre-renal azotemia, the sediment usually lacks cells, casts, and cellular debris. Similarly, postrenal causes of ARF tend to be associated with a benign sediment. The presence of dysmorphic RBC's and red cell casts is characteristic of a glomerular lesion. WBC's and white cell casts are seen in acute interstitial nephritis. The finding of eosinophils in a Hansel’s-stained urine sediment has been suggested as indicating a drug-induced acute interstitial nephritis (this is not a specific finding as eosinophils can be present in other disease states).
2. Serum and Urine Chemical Analysis:
a. Creatinine and BUN: Creatinine is formed from the breakdown of muscle creatinine and is proportional to the muscle mass. It should be stable from day to day. The creatinine concentration is a function of the amount of creatinine entering the blood from muscle, its volume of distribution, and its rate of excretion. Since the first two are usually constant, and changes in the serum creatinine level would usually be a result of a change in the GFR. Abrupt cessation of glomerular filtration causes the serum creatinine to rise by 1-2 mg/dL daily. The BUN also rises with renal dysfunction but is influenced by extrarenal factors as well. Increased protein intake, catabolism, GI bleeding, and many other factor will effect BUN.
The two important points to remember about elevations of serum creatinine and BUN are: First, they are late signs of renal dysfunction because the GFR may need to be reduced by as much as 75% before the BUN and creatinine rise to abnormal levels. Second, many non-renal variables affect both these levels. Generally, a serum BUN to creatinine ratio of greater than 20 suggests pre-renal azotemia rather than ATN, which is associated with a ratio of 10 to 1.
b. Urine Osmolality: Normally, the kidney can concentrate urine to levels of approximately 1,200 mOsm/kg. The ability to do this depends on an intact tubular system. Urine osmolality levels greater than 500 mOsm/kg suggest pre-renal azotemia (Table 8). By comparison, extensive tubular damage, such as that seen in ATN, impairs the ability of the kidney to generate a concentrated urine. Typically, the urine osmolality in ATN approximates that of the serum (300-350 mOsm/kg).
Table 8
Tests useful in the diagnosis of acute renal failure due to pre-renal
causes
Urine sodium less than 20 mEq/L
Urine osmolality greater than plasma osmolality BUN-to-serum creatinine ratio greater than 20 Urine osmolality greater than 500 mOsm/kg Fractional sodium excretion less than 1% Diagnostic ultrasound shows normal sized kidneys
c. Urine Sodium Concentration: Urine sodium excretion reflects how well the nephron retains the filtered sodium load. With renal hypo-perfusion due to either volume depletion or ineffective circulating blood volume, the kidney will avidly retain sodium as a result of increased proximal and distal reabsorption. If the kidney is responding appropriately to a decreased effective intravascular volume, the urine sodium concentration will usually be low (less than 20 mEq/L) and the fractional excretion of sodium (FENa) will be < 1%. The average FENa has been
reported to be > 4.0% in patients with postischemic or nephrotoxic ARF (Table 9).
Table 9
ATN versus Pre-renal Azotemia
Indices Prerenal ATN
UNa < 20 mEq/L > 40 mEq/L
FeNA < 1% > 4%
U/PCreat > 40 < 20
Uosm > 500 mOsm/kg 300-350 mOsm/kg
d. Other Indices: There are multiple other indices than can be measured when trying to evaluate renal failure. These include Urine/Serum Creatinine Ratio, Renal Failure Index, Urine/Serum Urea Ratio, creatinine clearance, and Free Water Clearance. None of these tests have advantages in diagnosis over the FENa.
Table 10
Urinary Findings in Intra-renal ARF
Uosm > 500 mOsm/kg FENa+ < 1 % RBC casts Moderate to heavy Glomerulo-nephritis Uosm 300-350 mOsm/kg FENa+ > 4% WBC casts Eosinophiluria Mild to moderate Interstitial Nephritis Uosm 300-350 mOsm/kg FENa+ > 4% “Muddy brown” granular casts Mild to moderate Ischemic and Nephrotoxic Tubular Injury Urine Chemistries Urine sediment Protein
The urinary and serum indices help to distinguish pre-renal from intrinsic causes of ARF (Tables 10 &11). However, several points should be remembered. In diseases that affect the renal glomerulus primarily, such as acute glomerulonephritis, the urinary and serum indices will more closely resemble those of pre-renal azotemia rather than intrinsic renal disease. Post renal causes of ARF can also be associated with indices similar to those of pre-renal azotemia early in the course of obstruction. With continued obstruction, tubular function becomes impaired and the indices mimic those of intrinsic disease.
Table 11
Urinary Findings in Pre-renal and Post-renal ARF
Variable Crystals, red or
white cell casts None to trace Post-renal Uosm > 500 mOsm/kg FENa+ < 1% Normal or hyaline casts None to trace Pre-renal Urine Chemistries Urine Sediment Protein
3. Radiographic Procedures
a. Intravenous Pyelogram: IVP provides an anatomic picture of the kidney but does not help evaluate kidney function. It also subjects the patient to a dye load. This can potentially be harmful to kidneys that may have already had previous insult. At this time there is little indication for IVP in the patient with acute renal failure.
b. Ultrasonography: Renal ultrasound is the most valuable diagnostic technique for the assessment of the patient with ARF. It can be performed easily in the patient with impaired renal function and has no associated morbidity. It is a sensitive test for obstruction (93-98%) and provides information about kidney size (the kidney size can be helpful in judging the chronicity of the kidney disease).
c. Computed tomography (CT): This can be helpful in some patients. Hydronephrosis can be recognized without contrast. The cause of obstruction (Ex. lymphoma, retroperitoneal fibrosis, etc) can often be delineated. CT is the technique of choice for visualizing ureteral obstruction at the level of the bony pelvis.
d. Other Tests: Radionuclide scans can be used if there is a concern about vascular perfusion of the kidneys. percutaneous nephrostomy combined with antegrade pyelography can be employed to diagnose the precise level of obstruction in the urinary tract. Ultimately, if the diagnosis is still unclear, the patient may need a renal biopsy.
So How do I Make the Diagnosis (Table 12)? Start with the history and physical exam as already discussed. The general strategy is to rule out both pre-renal and postrenal causes before considering the many intrinsic reasons. First, sources of volume loss and causes of decreased cardiac output should be sought in the history. The patient should be questioned for bleeding sources, GI losses, evidence of CHF, or history of liver disease. In males, a history should be taken searching for evidence of prostatic disease. A documented history of anuria could imply high-grade obstruction, but this can accompany severe volume depletion, severe acute glomerulonephritis, cortical necrosis, or bilateral vascular occlusion. Intermittent anuria is more suggestive of obstructive disease.
Table 12
Diagnostic Evaluation of Renal Failure • Assess volume status
• Exclude urinary tract obstruction • Ascertain nephrotoxic exposures • Examine the urine sediment • Check urinary indices
The patient should further be questioned about the use of all medications as well as recent exposure to contrast dyes. A history of recent pharyngitis, hypertension, rash, fever, or dark colored urine may suggest glomerulonephritis associated with a multisystem process.
The physical exam should focus on signs of volume depletion or overload. An attempt to percuss the bladder should be made. If the dome of the bladder is felt, this implies that there is 500cc of urine present. Prostate exam in males and a pelvic exam in females are essential. The skin should be assessed for the presence of a rash.
Laboratory evaluation should start with a dipstick of the urine and then microscopic analysis. An attempt at quantification of urine output should be made. BUN, creatinine, urine electrolytes, and then FENa levels should be determined. Next, a CBC, serum electrolytes, calcium, phosphorus, magnesium should be done. A serum creatinine kinase should be obtained to evaluate for rhabdomyolysis when suspected, such as following multiple trauma or crush injuries. An ECG and chest x-ray may aid in the evaluation.
Pre-renal azotemia should be suspected in the setting of volume loss, volume redistribution, or decreased effective renal perfusion. It is typically associated with a normal urinalysis, high BUN/Creat ratio, increased urine osmolarity, urine sodium levels less than 20 mEq/L, and a FENa less than 1%.
Urethral or bladder neck obstruction is documented by the finding of significant amounts of residual urine in the bladder on catheterization after the patient attempts to void spontaneously. Urine indices in obstruction may not be helpful, although the BUN/creat ratio may be elevated. Since obstruction is a reversible cause of renal failure, an ultrasound should always be obtained early in the evaluation.
Finally, the presence of a renal parenchymal disorder can often be diagnosed by its manifestations on microscopic urinalysis, by associated extrarenal manifestations, or by the clinical setting of recent exposure to a new medication. In the absence of these clues, the failure to find evidence of pre-renal or postrenal disease may be taken as presumptive evidence of an intrarenal parenchymal process. The possibility of a vascular insult should always be kept in mind since timely intervention is critical to preserving renal function.
V. SPECIFIC DISEASES CAUSING ACUTE RENAL FAILURE 1. Pre-renal Disease
A reduction in renal blood flow is the most common cause of acute renal failure. This can occur from true volume depletion or from selective renal ischemia (as in bilateral renal artery stenosis or sepsis). The usual causes of pre-renal azotemia are true volume depletion, or a decrease in the effective circulating blood volume as occurs in sepsis, advanced liver disease, and congestive heart failure.
a. Pre-renal Azotemia Caused by True Volume Depletion: The cause of volume depletion is usually evident from the history and exam. In severe cases the patient may be in hypovolemic shock. Oliguria is present in most individuals and this is an appropriate response given the clinical situation. Normal or increased urine output indicates that an osmotic agent or other diuretic agent is acting, or that there is tubular dysfunction such as ATN.
b. Pre-renal Azotemia Caused by Sepsis: The mechanisms by which sepsis leads to decreased renal perfusion are incompletely understood. Decreased renal blood flow independent from the effects of systemic hypotension has been demonstrated. Factors that may contribute to such include altered autonomic regulation of renal blood flow as well as cytokine-induced renal vasoconstriction.
c. Pre-renal Azotemia Caused by Advanced Liver Disease: Liver disease is associated with two major changes in renal function: sodium retention, initially manifested as ascites, and a progressive decline in GFR. Both humoral and hemodynamic factors play a primary role in the development of these problems. The progressive decline in renal function that occurs in hepatic cirrhosis is thought to be hemodynamically mediated because tubular function is intact (as evidenced by low urine sodium concentration and a normal urinalysis) and the kidneys are histologically intact.
d. Pre-renal Azotemia Caused by Congestive Heart Failure: CHF is associated with two major alterations in renal function: sodium retention early in the course of the disease and a decline in GFR as cardiac function worsens. Neurohumoral factors and certain therapies may contribute to these problems.
2. Acute Tubular Necrosis:
The characteristic tubular injury in this disorder represents a nonspecific response that can be seen with a variety of renal insults, including renal ischemia and exposure to exogenous or endogenous nephrotoxins (see table 13). The net effect is a rapid decline in renal function that may require a period of dialysis before spontaneous resolution occurs. There are two major histologic changes that take place in ATN: (1) tubular necrosis with sloughing of the epithelial cells; and (2) occlusion of the tubular lumina by casts and by cellular debris. These changes may be patchy and seem mild compared to the degree of the renal failure. In addition of the tubular obstruction, two other factors appear to contribute to the development of renal failure in ATN: backleak of filtrate across the damaged tubular epithelia and a primary reduction in glomerular filtration. The decrease in glomerular filtration results both from arteriolar vasoconstriction and from mesangial contraction. The decline in renal function in ATN has a variable onset. It typically begins abruptly following a hypotensive episode, rhabdomyolysis, or the administration of a radiocontrast media. In comparison, when aminoglycosides are the cause, the onset is more insidious, with the first rise in creatinine being at seven or more days.
Table 13
Major Causes of Nephrotoxic Acute Renal Failure
Antibacterial Agents
• Aminoglycosides
• Beta Lactam Antibiotics
• Vancomycin • Sulfonamides Antiviral Agents • Acyclovir • Indinavir • Foscarnet Antifungal Agents • Amphotericin Antiprotozoal Agents • Pentamidine Chemotherapeutic Agents Alkylating Agents • Cisplatinum Antimetabolites • Methotrexate Antitumor Antibiotics • Mitomycin Immunotherapeutic Agents • Interleukin-2 • Interferon Immunosuppressive Agents • Cyclosporine • Tacrolimus
Nonsteroidal Anti-inflammatory Drugs Radiocontrast agents
Environmental and Occupational Agents
• Organic Solvents
• Ethylene Glycol
• Heavy Metals
• Mercury
• Pesticides, Insecticides, Herbicides and Fungicides • Chlordane, Paraquat Biologicals • Mycotoxins • Ochratoxin A • Venoms • Mushrooms Osmotic Agents • Sucrose • Mannitol Heme Pigments • Hemoglobin • Myoglobin Uric Acid
VI. COMPLICATIONS OF RENAL FAILURE 1. Cardiovascular System:
Complications of the cardiovascular system are common in ARF. In a study with 462 patients with ATN, cardiovascular complications (congestive heart failure, myocardial infarction, and cardiac arrest) occurred in 35% of cases. In the oliguric patient with ARF, volume overload with hypertension, edema, and pulmonary congestion is an ever-present threat. Pericarditis may rarely complicate the course of ARF, and may lead to pericardial tamponade and life-threatening cardiovascular compromise.
2. Pulmonary System Complications:
Pulmonary infiltrates due to edema from volume overload and/or infection are encountered frequently in ARF. Remember that there are several disease processes that can cause simultaneous pulmonary and renal involvement. These include glomerulonephritis, Goodpasture’s, SLE, Wegener's, polyarteritis, sarcoidosis, renal vein thrombosis with pulmonary embolism, and several others. The development of pulmonary complications in ARF is an adverse prognostic factor.
3. Gastrointestinal System Complications:
The most common GI manifestations of ARF are severe nausea, vomiting, and anorexia. Upper GI bleeding is another significant complication. Stress ulcers and gastritis are common.
4. Neurologic System Complications:
CNS disorders are frequent accompaniments of ARF. Initially, lethargy, somnolence, lassitude, and fatigue are present. These symptoms may progress to irritability, confusion, disorientation, decreased memory, twitching, asterixis, and myoclonus. In advanced cases, generalized seizures may occur with somnolence and coma. The encephalopathy of ARF has not yet been firmly identified as a complication of a single specific identifiable toxin. Thus, the pathophysiology of neurologic complications of ARF remains unclear. One thing to consider is whether the CNS disturbance may in fact be coming from the medications the patient is on in the face of ARF.
5. Infectious Complications:
ARF and infections are commonly associated. Not only is septicemia frequently associated with the onset of ARF, but also infections often complicate the course of ARF. Common foci include pulmonary, urinary, and central venous catheter related bacteremia. These infectious complications can be a leading source of morbidity and mortality.
6. Endocrine System Complications:
Several hormonal abnormalities have been described in ARF. For, example, ATN is often associated with disturbances in divalent ion metabolism (hypocalcemia, hyperphosphatemia, and hypermagnesemia). Altered PTH action and vitamin D metabolism may play a pathogenic role in the hypocalcemia and hyperphosphatemia. Several studies have demonstrated high PTH levels in ATN, which may occur in response to the low calcium levels. Thyroid function tests may show decreased levels of Total T4 and T3, but the patients are usually euthyroid. High plasma renin activity and angiotensin II levels often occur in the setting of ARF. Whether these factors contribute to the hypertension has yet to be determined.
7. Disorders of Electrolyte Metabolism:
Hyperkalemia, hyponatremia, metabolic acidosis, and hypocalcemia often occur in ARF. These abnormalities should be expected and searched for so that the appropriate treatment can be initiated. Certain other disease entities being present can significantly worsen these levels (such as rhabdomyolysis). Hyperphosphatemia can also be expected, because of the decreased renal excretion of phosphate. In cases of coexisting tissue damage this could be worse.
VII. TREATMENT OF ACUTE RENAL FAILURE
The patient with acute renal failure may present extremely ill and sometimes moribund. There is almost no margin for error and the differential diagnosis can be extremely difficult. In spite of this, it is necessary to take a strict logical approach to the patient. First, resuscitate, next search for the correct diagnosis and treat accordingly, and finally prevent complications through the use of supportive measures and dialysis (Table 14).
Resuscitation: The two most common causes of death early in the resuscitative phase are hyperkalemia and pulmonary edema. Over hydration with resultant pulmonary edema is usually iatrogenic as a result of futile attempts to restore urine output before the etiology of the renal failure has been established.
Post-renal Failure: In those with postrenal failure, a passage for the drainage of urine must be created. The exact method that is used will depend entirely on the level of the obstruction and may be as simple as a urinary catheter, or as complex as a percutaneous nephrostomy tube.
Pre-renal Failure: Treatment for True Volume Depletion: Therapy for this type of ARF is aimed at restoration of the normal circulating blood volume. The major question that needs to be addressed is the rate at which the fluid should be given. This usually depends on the clinical status of the patient. Initially fluid boluses may be needed, and if indicated blood transfusion may be required. The patient must be constantly reassessed to insure that the patient is not getting overhydrated. The adequacy of fluid repletion can be assessed from physical exam and by monitoring renal function and urine output.
Pre-renal Failure: Treatment for ARF due to Advanced Liver Disease: Dietary sodium restriction and periods of bed rest are the mainstays of nonmedical therapy in this disease entity. Medical therapies are as follows. Diuretics therapy is often indicated and the preferred agent is spironolactone. Normally this is a fairly weak diuretic, however in cases of liver failure it is very effective. Spironolactone is the only diuretic that does not require secretion into the lumen of the kidney. Rather, it enters the collecting tubule cells from the blood side and competes for the aldosterone receptor. The rate of diuresis needs to be slow and steady. Paracentesis may be helpful in those patients with tense ascites. Albumin may be given at the same time to help prevent the worsening of intravascular depletion. A peritoneovenous shunt, which drains into the internal jugular vein and translocates the ascitic fluid into the vascular space may be helpful in cases of severe portal hypertension and ascites, but is often complicated by worsening hepatic encephalopathy. Pre-renal Failure: Treatment of ARF Caused by Congestive Heart Failure: The use of diuretics may be of some help as this will increase the renal output and relieve pulmonary congestion. Another option is a trial of inotropic agents to help increase cardiac output and thus increase renal perfusion. ACE inhibitors may also be helpful to improve cardiac output, but must be used with caution in patients with acute renal failure as they may cause a fall in GFR, particularly in patients with renal vascular disease.
Renal Causes of ARF: When pre-renal and renal causes of ARF have been ruled out, the challenge becomes to identify the cause of the intrinsic renal failure, keeping in mind the multitude of known possible causes.
Most commonly, the cause of the intrinsic renal failure will be from ATN. Therapy in established ATN, other than correction of the underlying problem, is largely supportive. In particular, attention must be paid to maintenance of the fluid and electrolyte balance and to proper nutrition. Despite management, some patients will require dialysis. Indications for dialysis include:
• marked fluid overload
• severe hyperkalemia
• presence of uremic signs or symptoms (pericarditis, nausea and vomiting, confusion, bleeding with coagulopathy present)
• severe metabolic acidosis (controversial)
• BUN levels greater than 100
Table 14
Summary of Therapy and Goals in the Initial Phase of Acute Renal Failure
Therapy Goal
Volume expansion/hydration Prevention of injury
Diuretics Management of volume overload
Vasoactive agents Restoration of renal perfusion
Dopamine
Atrial natriuretic peptide
Cytoprotective agents Preservation of cell integrity
Free radical scavengers Xathine oxidase inhibitors Calcium channel blockers Prostaglandins
The use of diuretics may be able to convert oliguric ATN into nonoliguric ATN. While nonoliguric ATN has a better prognosis than oliguric ATN this is only the case when it occurs spontaneously. Conversion of oliguric ARF to nonoliguric ARF by the use of diuretics does not improve the prognosis. Lasix is often used in high doses either by rapid infusion or by a continuous drip to help manage volume overload. Finally, dopamine may be an effective agent along with lasix in an effort to increase urine output but with no documented improvement in outcome.
