Prerenal Kidney Failure

Etiology

An essential function of the kidneys is the excretion and filtration of nitrogenous toxins from the body. To accomplish this, the kidneys typically receive twenty-five percent of the cardiac output. In acute kidney injury, there is a rapid decrease in the glomerular filtration rate (GFR), which leads to the build-up of nitrogenous wastes such as creatinine and blood urea nitrogen. However, it is important to remember that these markers serve as an imperfect proxy of GFR.[2] Therefore, it is through the serial measurements of these markers, by which we make the diagnosis of AKI. This topic will focus on prerenal AKI, but to understand the overarching concept, a brief explanation will be provided on the other causes as well. The causes of AKI can be separated into three major categories that are prerenal, intrinsic, and post-renal/obstructive.

Prerenal renal failure occurs due to poor perfusion of nephrons, which in turn leads to a decrease in the GFR. Fundamentally, it is related to an imbalance in the delivery of nutrition and oxygen to the nephrons during periods of increased energy demand. Therefore, any process that affects the systemic circulation or decreases renal perfusion can compromise the GFR. In a healthy individual, autoregulatory functions are in place, which helps to uphold the GFR. However, in patients with a history of chronic kidney disease (CKD), these autoregulatory mechanisms may be inadequate to bolster the GFR. A few of the causes of prerenal AKI include but are not limited to; intravascular volume depletion,  hypotension, sepsis, shock, over diuresis, heart failure, cirrhosis, bilateral renal artery stenosis/solitary functioning kidney which is worsened by angiotensin-converting enzyme (ACE) inhibitors, and also by other drugs (i.e., non-steroidal anti-inflammatory drugs (NSAIDs), calcineurin inhibitors, diuretics, etc.).

Intrinsic causes of AKI can be further subdivided into vascular, interstitial, glomerular, and tubular. Of these causes, acute tubular necrosis (ATN) is the most common. A nephrotoxic insult or prolonged ischemia usually causes ATN. Unlike prerenal etiologies of AKI, ATN is not improved by volume repletion. Both causes of ATN eventually do improve over time, but depending on the degree of the impairment, renal replacement therapy can be warranted. Glomerular causes of intrinsic AKI are related to underlying systemic illnesses or rheumatological diseases (i.e., lupus, Wegner, and Goodpasture syndrome). This occurs secondary to inflammation of the renal vasculature, and glomeruli, and can be best identified by renal biopsy. The treatment usually consists of immunomodulators or cytotoxic agents. Acute interstitial nephritis (AIN), is typically associated with medication use, but can also be related to other conditions. Although not pathognomic, eosinophiluria is generally seen in AIN. Post-renal AKI is usually provoked by obstructive causes, such as diseases that obstruct urinary flow (enlarged prostate). Post-renal AKI usually improves once the obstruction is relieved.[3]

Epidemiology

The prevalence of prerenal kidney failure has increased significantly in the last decade. This rise is secondary to the increased incidence of acute critical illnesses, septicemia, shock, and respiratory failure. It is reported that about 30% of acutely critically sick patients have AKI preadmission.[4] The prevalence of AKI is 53.2% in septic patients, 20.9% in stroke patients, and 12.9% in acute (ST-elevation myocardial infarction) STEMI patients.[5] 

In a retrospective single-center study published in 2006 using the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria, it was reported that AKI was present in 9% of the patients in the hospital, and about 50% in the ICU setting. The majority of the hospital causes of AKI are secondary to prerenal disease and acute tubular necrosis (ATN). Combined, these two entities account for about three-quarters of the cases of AKI. Prerenal AKI represented about 21% of AKI in hospitalized patients.[6]

Pathophysiology

The pathophysiology of the prerenal disease is multifold. To understand the causes, it is crucial to know the concept that renal perfusion and GFR have a direct correlation. Whenever there is hypotension or poor systemic perfusion, baroreceptors in arteries and receptors in the heart recognize these changes. In response, they increase the sympathetic tone. The decreased perfusion sensed by the afferent arterioles leads to an increase in renin secretion and antidiuretic hormone secretion. The afferent arteriole can maintain adequate perfusion until the systolic blood pressure drops below 80 mmHg.[7]

Renin is a protein enzyme released by the juxtaglomerular cells that are present in the afferent arteriolar wall, which works by converting angiotensin 1 to angiotensin 2. Angiotensin 2 then increases aldosterone synthesis, causes vasoconstriction, and sympathetic nervous system stimulation. Additionally, when there is a mild to moderate decrease in cardiac output, angiotensin 2 works on the efferent arteriole to maintain the filtration fraction. If under these circumstances, the intravascular volume or cardiac output decreases further, then an additional increase in angiotensin 2 will cause constriction of the afferent arteriole and a subsequent decrease in GFR.[8]

The combined effect of these processes preserves blood flow to the heart and brain, but in turn, it leads to vasoconstriction of the renal, splanchnic, and mucocutaneous circulations. The renal vasoconstriction, as mentioned earlier, leads to a decrease in GFR. In contrast, if these compensatory mechanisms are ineffective in certain patients, the persistent decline in cardiac output, or arterial pressures will also lead to a decrease in GFR. Renal perfusion can also be compromised in conditions that lead to edema/anasarca. In this case, renal perfusion decreases as splanchnic and cardiac dysfunction lead to venous pooling of blood.[9]

History and Physical

Although the history and physical exam are not the primary sources for the diagnosis of prerenal kidney failure, they do aid in identifying the underlying cause of prerenal AKI. An intricate history may divulge a cause for volume loss such as sepsis, dehydration, vomiting, diarrhea, or bleeding. Also, reviewing medications can help in identifying a reason for AKI. For hospitalized patients, reviewing flowsheets for vitals, intra-operative reports, use of contrast in imaging, and monitoring for sepsis can all assist in finding potentially reversible cause for AKI. Reversible insults can also be identified in hospitalized patients by investigating the day at which the rise in creatinine occurred and looking for suspected causes. It is also important to remember that conditions which cause low flow/edematous states such as heart failure and cirrhosis, should also be investigated as potential culprits for AKI.[10]

Evaluation

As a clinician, it is essential to understand how prerenal kidney failure differs from other causes of AKI. To make this distinction, many tests must be obtained. Some of these tests include a urinalysis, urine sodium/fractional excretion of sodium (FENa)/fractional excretion of urea (FEUrea), and the gold standard is the response of the AKI to volume resuscitation (however this does not apply to prerenal AKI secondary to hepatorenal/cardiorenal syndromes).

It is important to remember that in prerenal AKI, the urine analysis (UA) should be normal or near normal. The only exception for this rule is if there is an underlying or superimposed renal disease. Occasionally, it is normal to see hyaline or granular casts. In contrast, patients who have ATN have muddy brown casts, epithelial casts, or renal epithelial cells. In a 2008 study by Perazella et al. [11], which was a prospective study of 267 patients, that examined the diagnostic value of UA in distinguishing the causes of AKI in hospitalized patients, important conclusions were drawn. Notably, in patients with a high pretest probability for ATN, the UA had a high positive predictive value and low negative predictive value. Whereas, in patients with a low pretest probability, UA had a high negative predictive value. However, UA also has its shortcomings. In the early stages of ATN, cast formation, and cell sloughing might be absent, or not as prevalent so the UA may seem normal. Also, in patients with severe hyperbilirubinemia, the UA will reveal granular or epithelial casts (pathophysiology of this is not well understood).

The next most important diagnostic tool in distinguishing the types of AKI is the urine sodium and the fractional excretion of sodium (FENa). The premise behind the concept of FeNa is that in a hypovolemic state, the urine sodium should be less than 20 mEq/L, and this, in turn, preserves serum sodium concentration. The exception to this concept is during states in which the patient has a sodium wasting predisposition. Therefore in prerenal AKI, the urine sodium should be less than 20 mEq/L. However, the problem with urine sodium is that it is affected by the volume of urine, and is not a good predictor of the total body sodium excretion. Fractional excretion of sodium (FENa) is, therefore, a better predictor for urine sodium excretion as it is not affected by urine output and measures only the percent of sodium excreted. FENa is usually less than one percent in prerenal AKI and greater than two percent in ATN.

FENa is also not without its limitations. For example, in patients with superimposed heart failure, or cirrhosis, FENa may remain low. FENa of less than one percent is also seen in vasculitis, contrast-induced nephropathy, and acute glomerulonephritis. In these conditions, the GFR decreases, but the tubular function of the kidney is maintained. Finally, in the patient who is on diuretics, the FENa will be falsely elevated, as the diuretics increase the urine sodium load. In these situations, the fractional excretion of urea provides a better diagnostic tool. The excretion of urea occurs in the proximal tubules. In prerenal AKI, the FEUrea is less than 35 %, whereas, in intrinsic AKI, it is greater than 50%.

The reported gold standard in differentiating prerenal from other causes of AKI is responsiveness to fluid administration. When a sufficient amount of fluid is given to correct for volume depletion, then the serum creatinine should trend down to baseline within 24 to 72 hours. Intravascular depletions should be managed with isotonic saline. The rate of saline repletion is dependent on the degree of volume loss. It is also important to factor in the patient's overall volume status, as prerenal AKI can be present in situations such as heart failure, and cirrhosis.

Other tests that are commonly used include the rate of increase in serum creatinine levels. In ATN, the serum creatinine will rise at a rate of 0.3 to 0.5 mg/dl per day. In prerenal disease, the rate of increase will occur at a much slower pace. Also, the measurement of the BUN to creatinine ratio is essential as well. Typically, this ratio is 10, in ATN, it is about 15:1, and in prerenal disease, it is higher than 20:1. This occurs secondary to the passive reabsorption of urea in the proximal tubules, which follows the proximal tubule reabsorption of sodium and water that occurs in prerenal disease. Urine osmolality can also be used to identify prerenal from ATN.

In prerenal conditions, the body still retains the ability to concentrate the urine so that the urine osmolality will be higher than 500 mosm/kg. However, in ATN, the urine concentration abilities are compromised so that the urine osmolality will be below 450 msom/kg. Lastly, it is important to remember that pre-existing renal disease may skew the usefulness of many of the tests mentioned above. In underlying renal disease, sodium conservation and urine concentration ability are undermined.[12]

Treatment / Management

The management of prerenal kidney failure is dependent on the stage of AKI, underlying etiology, and the setting where it is identified.

In an outpatient setting, patients who stage as 2 or 3 by the KDIGO criteria with AKI should be sent to the emergency department (ED) for further evaluation. Similarly, patients from resource-limited clinics should be sent to the ED for further evaluation.

In the emergency department or the hospital setting, the mainstay of treatment of prerenal AKI is isotonic fluid administration. It is both therapeutic and diagnostic. A downtrend in creatinine after administration of isotonic fluids is the gold standard in diagnosis. The degree of volume resuscitation depends on the degree of volume depletion caused by the underlying condition.

The approach to the management of AKI is two-pronged:

(1) Treat any life-threatening features:

Hypotension and shock should be immediately evident when assessing the patient and require urgent treatment. Unless there are ECG (electrocardiogram) changes or changes in cardiac monitoring, hyperkalemia is unlikely to be immediately apparent. It will only be detected when the chemistry is available.

(2) Identify and treat the cause of AKI:

A thorough history and physical exam should be coupled with investigations to find out the cause of AKI, and the management should be directed towards that cause.[10]

Since AKI is due to hypoperfusion of the kidneys, fluid resuscitation is at the forefront of its management. The optimal resuscitation fluid for this purpose is still debated. Normal saline and 4% albumin have similar outcomes, shown in the recent SAFE study done in the ICUs in Australia and New Zealand, and which negates previous studies suggesting that the use of albumin may be associated with higher mortality.[13][14] Once the euvolemic state is achieved (when the patient has become normotensive with no postural drop, and jugular venous pressure and/or central venous pressure is normal), special care should be taken to prevent fluid overload. A maintenance regimen should be started, which takes account of renal and also insensible losses. The aim is the achieve a positive balance of 500 ml/day. This requires careful observation and recording by nursing staff and regular assessment by the clinician to avoid fluid overload, which may result in pulmonary edema.[15](A1)

Due to the risk of life-threatening cardiac arrhythmias, severe hyperkalemia (plasma potassium of more than 6.5 mmol/l) is considered a medical emergency. If the serum potassium is more than 6.5 mmol/l or if any ECG changes (tall peaked T waves, shortened QT interval, prolonged PR interval, wide QRS complex) are present, the treatment of hyperkalemia should be promptly started. By stabilizing the myocardium within a few minutes of infusion, calcium counters the effects of hyperkalemia and produces a more normal ECG trace without affecting serum potassium. If P wave or QRS changes are present, its administration should not be delayed. 10 to 20 ml of 10% calcium gluconate or calcium chloride is given in bolus form intravenously over two to five minutes.[16] Insulin increases intracellular potassium uptake. To prevent hypoglycemia, glucose is added to insulin bolus. Ten units of fast-acting soluble insulin are added to 50 ml of 50% dextrose and given in infusion form intravenously over 10 to 20 minutes. A reduction in potassium level is seen after 20 to 30 minutes.[17] 

Albuterol binds to β2 receptors and activates the Na+/K+ATPase, thus enhancing intracellular potassium uptake. Combination therapy with insulin and dextrose plus albuterol may produce better results than either treatment alone.[17] While the above interventions act to redistribute potassium from the extracellular compartment to the intracellular compartment, the total amount of potassium retained by the patient will still be excessive. In prerenal failure, if the patient responds to resuscitation, then increased renal potassium excretion will lead to normal whole-body levels of potassium. Additional measures to increase potassium loss are often needed in those whose renal function fails to improve. Ion exchange resins bind potassium in the gastrointestinal tract, in exchange for calcium or sodium, and result in increased excretion of potassium in the stool.

Resonium A (sodium polystyrene sulfate) and calcium resonium (calcium polystyrene sulphonate) are the most frequently used resins. Hypercalcemia and water/salt overload (with calcium and sodium-containing resins, respectively) are common side effects. Hemodialysis is indicated in severe hyperkalemia that is refractory to other treatments. This is the definitive way by which potassium can be removed from the body.[10]

Nephrotoxic drugs should be avoided or dosed according to plasma concentrations to prevent further renal insults. The most commonly used nephrotoxic drugs include NSAIDs, ACE inhibitors, Angiotensin 2 receptor blockers (ARBs), and aminoglycoside antibiotics. Iodinated contrast should be used with extreme caution.[10]

Low dose dopamine has been used in renal failure due to its ability to increase renal perfusion, but recent studies have shown that it does not achieve its preset goals and may even worsen renal function.[18](B3)

Dietary modifications are important in patients with any cause of AKI. There are protein catabolism and negative nitrogen balance due to complex reasons. These patients should increase their daily consumption of protein/amino acids from 1 g/kg/day to 1.2 to 1.5 g/kg/day. Glucose intake should not exceed 5 g/kg/day. Lipids consumption should be 0.5 to 1.0 g/kg/day. Water-soluble vitamins should be supplemented, especially in patients requiring any kind of replacement therapy. The preferred route of administration of nutrition is enteral. However, it is not always possible to achieve nutritional goals through the enteral route alone, and the parenteral route becomes necessary.[19]

Renal replacement therapy (RRT) has a vital role in the management of AKI. Indications for RRT are given below:[20]

1.Severe refractory hyperkalemia2. Fluid overload with pulmonary edema (less likely in prerenal kidney failure)3. Uremia (blood urea >30 to 50 mmol/l)4. Severe acidosis (pH <7.1)5. Drug overdose with a dialysable toxin6. Complications due to severe uremia: pericarditis,  encephalopathy, neuropathy/myopathyRRT can be intermittent or continuous. Intermittent therapy is given as intermittent hemodialysis (IHD). Continuous renal replacement therapy (CRRT) is given in several ways that are classified based on the method of accessing the circulation and also depends on how solute removal is achieved.[21] Techniques that are based on venous access alone are mostly used. There is no absolute evidence that there is a difference in the outcomes with continuous or intermittent therapy. Each modality has its advantages and disadvantages that must be weighed by the clinician depending on the individual patient.[22]

Differential Diagnosis

Prerenal kidney failure can present in a wide variety of ways that is why its differential diagnoses are diverse. Following are some important differentials that should be considered while making the diagnosis of prerenal kidney failure:[23]

• Acute tubular necrosis
• Allergic interstitial nephritis
• Contrast-induced nephropathy
• Acute glomerulonephritis
• Goodpasture syndrome
• Renal vasculitis
• Post-obstructive AKI
• Gastrointestinal bleeding
• Cardiorenal syndrome type 1
• Hepatorenal syndrome type 1
• Sepsis

Staging

Staging is discussed in terms of undifferentiated prerenal kidney failure. The currently used staging criteria is the KDIGO staging criteria[24]

Stage 1:

• Elevation in creatinine 1.5 to 1.9 times baseline
• Rise in serum creatinine by ≥0.3 mg/dL (≥26.5 μmol/L)
• Decline in urine output to <0.5 mL/kg/hour for 6 to 12 hours

Stage 2:

• Rise in serum creatinine to 2.0 to 2.9 times baseline
• A decline in urine output to <0.5 mL/kg/hour for ≥12 hours

Stage 3:

• Rise in serum creatinine to 3.0 times baseline
• Rise in serum creatinine to ≥4.0 mg/dL
• Decrease in urine output to <0.3 mL/kg/hour for ≥24 hours
• Anuria for ≥12 hours
• Need for renal replacement therapy
• Pediatric patients <18 years, decline in estimated glomerular filtration rate (eGFR) to <35 mL/min/1.73 m

Prognosis

Prognosis also depends on the duration of disease and the underlying cause. In otherwise healthy individuals with cases of hypovolemia, the prognosis is pretty good. However, it is essential to note that patients with prerenal kidney failure do have a higher risk of developing chronic kidney disease, and then the end-stage renal disease. There are certain factors, which do put individuals at increased risk for mortality.

Factors that lead to increased risk of morbidity and mortality include:[25]

• Male sex
• Race (lower mortality in black patients compared to white patients)[26]
• Increased age (odds ratio increases 1.13 every decade)
• Sepsis
• Presence of underlying liver failure
• Thrombocytopenia
• Acute respiratory distress syndrome
• Poor nutritional status[27]

In patients who are recovering from an AKI, the risk for an irreversible decline in renal function is also associated with certain risk factors. Examples of risk factors that can lead to this decline are; age higher than 65 yrs, low albumin state, low baseline GFR, and co-morbidities, including heart failure, and hypertension. Also, the more elevated the serum creatinine is at discharge, and the severity of AKI, the greater is the risk for progression to CKD. Studies have also shown that severe in-hospital AKI has been associated with cardiovascular mortality. This increased cardiovascular disease is thought to be secondary to an increase in hypertension and a rise in the development of CKD. Similarly, patients who have AKI are also at increased risk for hypertension.

Complications

Complications are related to the duration of Prerenal kidney failure and progression to ischemic changes. These include but are not limited to:[5]

• Progression to chronic kidney disease
• Development of end-stage renal disease
• Cardiovascular disease
• Hyperkalemia
• Hypocalcemia
• Hypermagnesemia, and hypomagnesemia
• Hyperphosphatemia
• Metabolic acidosis
• Metabolic alkalosis
• Volume overload
• Uremia
• Uremic pericarditis