Prevention of postoperative acute renal failure.VG Reddy
Department of Anaesthesia and Critical Care, College of Medicine, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman. , Oman
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 12082335
Source of Support: None, Conflict of Interest: None
Postoperative acute renal failure (PO-ARF) is a serious complication resulting in a prolonged stay and high mortality. Patients may be at risk for this problem because of an underlying medical illness, nature of surgery, nephrotoxin exposure, or combinations of these factors. An increase in the intra abdominal pressure above 20-mm Hg is associated with an increase in the incidence of PO-ARF. Based on many clinical studies in high-risk surgical patients and patients undergoing renal transplantation, the only proven management strategies for prevention of PO-ARF are adequate volume expansion and avoidance of hypovolaemia. Drugs known to be nephrotoxic should be avoided or used with caution. Three main pharmacological agents namely mannitol, frusemide and dopamine have been extensively tried in the prevention of PO-ARF. Mannitol has proven of value only in the presence of adequate volume expansion in attenuating renal dysfunction in transplant patients. Frusemide converts oliguric renal failure to non-oliguric renal failure. The bulk of the data, including that from prospective studies indicate dopamine is only a diuretic. Fenoldopam, a dopamine analogue, has shown early promise in reports. Calcium channel blockers have not been shown to improve the outcome in renal transplantation or help in the prevention of contrast-induced nephropathy. Atrial natriuretic peptide has not been proven to be of benefit in established renal failure and its role in prevention has not been assessed.
Keywords: Atrial Natriuretic Factor, therapeutic use,Cardiotonic Agents, therapeutic use,Diuretics, therapeutic use,Dopamine, therapeutic use,Fluid Therapy, methods,Human, Kidney Failure, Acute, etiology,physiopathology,prevention &control,Postoperative Complications, prevention &control,Risk Factors,
Postoperative acute renal failure (PO-ARF) has been recognised as a complication of major vascular, cardiac and high-risk abdominal surgery. This review focuses on pathophysiology, predisposing risk factors, nephrotoxic drugs, role of increased abdominal pressure, fluid management, limitation of biochemical markers in identifying renal insufficiency and evidence based pharmacological support in the prevention of PO-ARF.
This paper reviewed in humans the prevention of PO-ARF in randomised controlled trials and is based on a computerised MEDLINE literature search in English language journals from January 1970-October 2001. All review articles on PO-ARF and the biochemical investigations in identifying renal failure published in peer-reviewed journals from 1985–2001 were included in the literature search.
Two main reasons for the varying incidence of PO-ARF are the variable definitions of acute renal failure (ARF) and the varying nature of surgery. Depending on the definition, the preoperative renal function and the preoperative complications, the incidence of PO-ARF varies from 1.1% to 17%. , Aortic surgery, coronary artery bypass surgery, renal and liver transplantation and surgery in the presence of obstructive jaundice are known to be independent risk factors for the development of PO-ARF., 
Despite advances in perioperative care and the advent of dialysis, the mortality rate exceeds 50% and depends upon the kind of surgery. In surgery for thoracoabdominal aneurysm, the mortality is 67% in patients who developed PO-ARF compared to 8.7% in those who did not do so. Chertow reported a mortality of 63% in post cardiac surgical patients with dialysis compared to 4.3% in those with intact renal function. A rise in the serum creatinine by 20% at the time of admission to the intensive care unit carried a mortality of 67% compared to 19.4% in controls., 
Kidneys receive 25% of the cardiac output (CO) but consume only 10% of total body oxygen uptake. Because of autoregulation, the glomerular filtration rate (GFR) parallels the renal blood flow (RBF) over a wide range. Nearly 90-95% of the blood flows to the cortex while the medulla receives only 5-10%, resulting in a regional PaO2 of 10-mm Hg in the medulla compared to 50 mmHg in the cortex. As a function of the active mechanisms for solute and water reabsorption, nearly 90% of the renal oxygen extraction occurs in the medulla. This explains the ease with which medullary hypoxia can develop.
Glomerular ultrafiltration depends upon a balance between the afferent and efferent arteriolar tone, which is influenced, by a balance between vasodilators and vasoconstrictors. Catecholamines, renin, angiotensin, platelet activating factor, nitric oxide, prostaglandins and adenosine are all known to affect the vascular tone. During hypoxia the medullary blood flow is augmented by the release of prostaglandin E2 and nitric oxide. The fall in the RBF is accompanied by an increase in the sodium reabsorption, which is an active process, thus increasing the oxygen demand in the medulla. Diabetic patients have a ten fold greater risk for renal deterioration in the presence of hypovolaemia.
The pathogenesis of PO-ARF depends upon the nature of surgery, preoperative and intraoperative hemodynamics and renal conditions. All intravenous or volatile induction agents affect renal function by decreasing CO and blood pressure (BP). Extradural block up to the level of T4 reduces sympathetic tone in the kidneys, resulting in a decrease in the RBF and GFR. Mechanical ventilation with positive pressure also decreases RBF. Major surgery with extensive third space fluid loss can lead to hypovolaemia and subsequent renal hypoperfusion.
The successful prevention of PO-ARF depends on identification of patients who are at risk for developing PO-ARF;,, maintenance of adequate intravascular volume; and pharmacological prophylaxis.
Prevention of PO-ARF depends on identifying risk factors, avoiding nephrotoxic drugs and limiting increases in abdominal pressure. The incidence of PO-ARF is directly proportional to the number of risk factors as shown in [Table - 1]. In cardiopulmonary surgery the four most important independent risk factors for PO-ARF are old age, preoperative renal insufficiency, a cardiopulmonary bypass time of greater than 140 min and postoperative hypotension. Known nephrotoxic drugs which are commonly used in the perioperative and postoperative period are shown in [Table - 2].
The normal intra-abdominal pressure (IAP) has a wide range from 0-17 mm Hg with a mean of 6.5-mm Hg. The IAP can increase due to intra-abdominal bleeding, intestinal distension, peritonitis, paralytic ileus and ascites. A rise above 18 mm Hg is considered abnormal., In experimental studies an IAP of 20 mmHg resulted in a 75% reduction in GFR and that of 40 mmHg in anuria., The reduction in GFR was refractory to both volume loading and increases in cardiac output suggesting that the reduction in RBF is of lesser importance than the increase in renal vein pressures.
Although ureteric compression has been considered as a possible mechanism, studies do not support this hypothesis., Improvement in renal function occurs only after abdominal decompression. The probable mechanisms by which raised IAP causes a reduction in UO are:
1. Reduced venous return and CO causing decreased RBF.
2. Compression of the renal vein with reflex renal artery vasoconstriction, resulting in a reduction in RBF and UO.
3. Elevation of the renal tubular pressure: The filtration gradient across the glomerular capillary membrane is the difference between the glomerular pressure and the proximal renal tubular pressure. Proximal renal tubular pressure approximates IAP. Hence an increase in IAP may decrease filtration.
4. Increased renin, aldosterone and ADH production.
Sugrue et al in a prospective study in patients undergoing major abdominal surgery found that an elevation of IAP was associated with an impairment of 32.7% in renal function compared to 14.1% in those in whom the IAP was normal. According to Burch et al intra-abdominal pressures above 25 cm H20 require urgent surgical evaluation and decompression is indicated if the pressure exceeds 35 cm H2O.
It is well established that hypovolemia is a major risk factor for development of PO-ARF. Adequate volume expansion with saline may reduce this risk by assuring adequate RBF and reducing renal vasoconstriction., If necessary, intravenous hydration should be instituted the day before surgery. Hemodynamic monitoring including central venous pressure (CVP), pulmonary artery wedge pressure (PAWP), cardiac index and systemic vascular resistance is helpful in optimisation of intravascular fluid status, especially in patients at risk of developing PO-ARF. In abdominal aortic surgery, maintaining extravascular volume according to CVP or PAWP by fluids reduced the incidence of PO-ARF. In postoperative trauma patients, aggressive fluid and haemodynamic management converted oliguric to nonoliguric renal failure from 18% to 100% of patients, halved the need for dialysis and decreased mortality from 70% to 28%. In cadaveric renal transplantation aggressive fluid management reduced the incidence of postoperative ATN. , In high-risk surgical patients undergoing surgery, present evidence favours aggressive fluid therapy as a means of reducing PO-ARF. In the postoperative period, the most important distinction is between prerenal failure and acute tubular necrosis (ATN). Prerenal insufficiency is completely reversible if renal perfusion and glomerular ultrafiltration pressure are restored rapidly. Patients who are oliguric in the postoperative period should be assumed to be hypovolemic unless proved otherwise. The finding of a prerenal pattern on urine analysis [Table - 3] supports this assumption. If clinical evaluation does not suggest fluid overload it is reasonable to administer serial fluid challenges (200 mL of saline) guided by CVP or PAWP.
Mannitol is an osmotic diuretic. Mannitol increases RBF secondary to release of intrarenal vasodilating prostaglandins and ANP, decreases the production of renin and reduces endothelial cell swelling, As explained in the pathophysiology, it is imperative to know whether mannitol induced increase in RBF occurs in the cortex or in the medulla. Studies in animals or humans have failed to identify whether the medullary or cortical blood flow increases. Mannitol has been extensively used as a prophylactic agent to minimise the risk of ARF in patients with hemodynamic instability, those with radiocontrast nephropathy, an d those who have undergone biliary surgery and aortic surgery None of these studies have shown any beneficial role of mannitol in preventing PO-ARF. One small study in abdominal aortic surgery patients suggested that mannitol may reduce subclinical glomerular and renal tubular damage. Three randomised studies in renal transplantation patients confirm that mannitol in the presence of adequate volume expansion reduces the incidence of PO-ARF, underlying the importance of fluid loading.,, Mannitol has been used for long time in the prophylaxis of rhabdomyolysis induced ARF. Recent study suggest aggressive volume expansion alone is sufficient to prevent ARF.
Mannitol when given in excess of 200g/d or a cumulative dose of >400g/48h can cause ARF due to severe renal vasoconstriction. The recommended dose of mannitol in renal transplantation is 250 ml mannitol 20% along with adequate volume expansion just before removal of the arterial clamp.
Frusemide a loop diuretic is prescribed by the clinician when they are faced with low urine output, with the hope that inducing diuresis is protective against ARF. Loop diuretics decrease the metabolic demand of the renal tubular cell, reducing its oxygen requirement and there by increasing its resistance to ischemia. Frusemide combines with albumin in the renal tubules and is actively reabsorbed in the proximal tubule where it exerts its actions. Therefore, correction of severe hypoalbuminemia may help. Frusemide administered to patients at risk of developing ARF produced no change in GFR, renal plasma flow, RBF and RBF distribution. Frusemide has not been found to be effective incardiac surgery or in radiocontrast induced nephrotoxicity or in combination with dopamine. Frusemide in large doses of 1.5-6mg/kg given every 4-h intravenously produced good diuresis, but there was no difference in the number of dialysis required or in the mean duration of renal failure., Prospective studies have reported that continuous infusion of frusemide is better than a large bolus dose. However, the number of dialysis, duration of renal failure and mortality were not different in the two groups.,, Frusemide induced diuresis without maintenance of volume expansion may be detrimental. The present data do not provide convincing evidence for the routine use of frusemide as a prophylactic agent against PO-ARF and its role is limited to producing a non-oliguric state, which will allow fluid manipulation. In a patient with postoperative oliguria who has not responded to volume therapy, the present evidence suggest continuous infusion of frusemide in the range of 1 to 9 mg per hour intravenously preceded by a loading dose of 10 to 20 mg.
Commonly, the so-called “renal dose” dopamine (1-3 ?g/kg/min) has been used as renal prophylaxis or to treat oliguria. Earlier studies in normal humans demonstrated dopamine increased renal plasma flow, GFR and urinary sodium excretion. Dopamine stimulates the dopaminergic receptors DA1 and DA2. The effect of DA1 and DA2 diminishes with prolonged use. If dopamine increases GFR, increased solute presentation to the medullary thick ascending loop of Henle with resultant increase in medullary oxygen demand may actually worsen ischaemia.
Several studies demonstrated the efficacy of low-dose dopamine in the prevention of PO-ARF in high-risk clinical situations. These include radio contrast induced nephrotoxicity,,, postoperative oliguria aortic surgery, cardiac surgery, renal transplantation, liver transplantation, and postpartum pre-eclampsia. These studies were flawed with respect to their small sample size, lack of randomisation and lack of blinding.
However, most randomised studies in humans have not demonstrated prevention of acute renal failure in high-risk patients or improved outcome These studies covered radio contrast induced nephrotoxicity, liver transplantation, vascular surgery,,,, cardiac surgery,,, biliary surgery, and renal transplantation. Two large randomised placebo
controlled multicenter clinical trials failed to demonstrate the beneficial role of dopamine in the prevention or treatment of acute renal failure., A meta-analysis on the role of dopamine in acute renal failure found that dopamine did not prevent the onset of acute renal failure or the need for dialysis or the mortality. The side effects of dopamine are listed in [Table - 4].
Fenoldopam mesylate is a dopamine analogue which stimulates postsynaptic, peripheral dopamine-1 receptor and has no activity on dopamine-2 receptors or on a and b adrenergic receptors. Fenoldopam has been shown to increase RBF, urine output and natriuresis. Natriuresis and diuresis can occur without vasodilation, indicating a proximal tubule site of action for fenoldopam. Fenoldopam is six times more potent than dopamine in producing renal vasodilatation. The potential advantages of fenoldopam over dopamine include: increase in dopaminergic potency, lack of tachyarrhythmias and ability to safely infuse through a peripheral vein. Two studies reported the beneficial role of fenoldopam in the prevention of PO-ARF in patients undergoing abdominal aortic aneurysm repair and coronary artery bypass graft., Further randomised studies are required before one can advocate the use of fenoldopam in the prevention of ARF.
Calcium channel blockers
During ischemia, calcium channels open resulting in vasospasm. The calcium channel blockers exert direct vascular effect with preservation of renal autoregulation and enhanced recovery of RBF, GFR and natriuresis. Three prospective studies in renal transplantation patients confirm the benefits of calcium channel blockers.,, However, it has been suggested that there may be factors other than attenuation of ARF in the positive response to calcium antagonists, including increasing plasma cyclosporin and limiting cyclosporin induced renal vasoconstriction as well as modifying T-cell function.
Calcium channel blockers have been tried successfully in the prevention of radio contrast induced nephropathy, but others have failed to confirm this. Critically ill patients may not tolerate high doses of calcium channel antagonists which may further compromise their hemodynamic status. As of now calcium channel blockers cannot be recommended for the preservation of renal function.
Atrial natriuretic peptide
This hormone is produced in the cardiac atria in response to volume overload. The action of ANP is mediated by cyclic guanosine monophosphate (cGMP). The physiological effects of ANP include;,,
1. Decreased renin and aldosterone secretion.
2. Decreased sodium reabsorption in the tubule.
3. Decreased sodium and chloride uptake in the ascending loop of Henle.
4. Redistribution of medullary blood flow.
5. Reversal of endothelin induced vasoconstriction.
6. Increased GFR.
The synthetic ANP analogue anaritide and a renally produced natriuretic peptide ularitide have been tried in preventing or improving renal failure. A preliminary study was promising, but in a subsequent large randomised multicenter study in patients with acute tubular necrosis anaritide failed to demonstrate the beneficial effect. Anaritide failed to reduce the overall mortality and dialysis-free survival, although in a subgroup, patients who were oliguric had improved dialysis-free survival, while non-oliguric patients had worsened dialysis-free survival. This was taught to be due to the hypotensive effect of anaritide. Ularitide analog of ANP, which causes less hypotension was found to effective for the treatment of incipient oliguric ARF following surgery. However, large prospective positive studies are required to warrant clinical use of the drug.
Despite advances in the management of PO-ARF and renal replacement therapy in the intensive care unit, the mortality remains high. The most common cause of PO-ARF is hypovolemia resulting in prerenal failure. Physicians looking after patients who are at risk for ARF must understand the principles of managing a patient who develops PO-ARF. Awareness of risk factors should prompt careful perioperative management and avoidance of nephrotoxic drugs. Extreme care must be taken to apply published data from different clinical scenarios to the situation at hand. The only management strategy proven to be of value in the prevention of
PO-ARF consists in providing adequate volume expansion and avoiding hypovolemia. Relaying on forced diuresis as an indicator of adequate renal function has no scientific rationale. For prophylaxis against radiocontrast-induced ATN the only proven therapy is adequate volume expansion. Frusemide converts oliguric renal failure to non-oliguric renal failure. Frusemide has no justifiable role as a prophylactic agent in the prevention of ARF. Mannitol works better in the presence of volume expansion and excessive use could cause ARF. Mannitol likely has a role as a prophylactic agent in attenuating primary renal dysfunction in transplant patients. Both mannitol and frusemide might worsen hypovolemia by causing diuresis. As for dopamine, enough evidence has been gathered to suggest that it is not a reno-protective drug and its use has additional risks. The use of ‘renal-dose’ dopamine should be avoided. A large randomised study can address the value of fenoldopam in ARF. Anaritide and Ularitide are not available in most of the countries and they wait for a large randomised study to confirm their benefits in oliguric renal failure. Postoperative ARF should be looked at as a “preventable” rather than “treatable” clinical entity.
I would like to gratefully acknowledge Dr. Bhaskar Bamachandran, Consultant Anaesthesiologist, India, who critically reviewed the manuscript and offered invaluable suggestions.
[Table - 1], [Table - 2], [Table - 3], [Table - 4]